In Focus

Introduction

Despite a global decline in the incidence of gastric cancer over the past 3 decades, it remains the fifth most commonly diagnosed cancer and the third most common cause of cancer deaths worldwide.¹ In the United States it is the fourth most commonly diagnosed GI malignancy, after colorectal, pancreas, and liver cancer. The prevalence remains high in Latin America and Asia, which has implications in the United States because of growing Hispanic and Asian populations.^2,3 In recent years, a change in the trend of gastric cancer among non-Hispanic whites has been observed, particularly in women younger than 50 years old.⁴ Gastric intestinal metaplasia has been recognized worldwide as a premalignant precursor to gastric cancer, but currently, there are limited U.S. guidelines, leading to controversy over management of this condition.⁵

Etiology

Gastric adenocarcinomas are classified into two subcategories based on location (cardia and noncardia) and histology (intestinal and diffuse types).^6,7 Atrophic gastritis and gastric intestinal metaplasia (GIM) are considered precursors of intestinal-type noncardia gastric adenocarcinoma. The Correa cascade is a commonly accepted precancer sequence for noncardia gastric adenocarcinoma that describes mucosal changes from inflammation to atrophy to metaplasia to intraepithelial neoplasia and culminating in carcinoma.^8,9 It has been observed that GIM may be the histologic change prior to the development of dysplasia and over 50% of patients with high-grade dysplasia will progress to adenocarcinoma.^10-12 In the United States, GIM has the highest prevalence in African Americans, Hispanics, and East Asians, with the overall GIM prevalence regardless of ethnicity reported from 3.05% to 19.2%.^5,13

Risk factors and subclassification

Replacement of the foveolar and/or glandular epithelium in the oxyntic and antral mucosa by intestinal epithelium results in GIM. It can be focal when limited to one region of the stomach or extensive when two or more regions are involved.¹⁴ The main risk factors for GIM development are Helicobacter pylori infection, tobacco, alcohol consumption, high salt intake, and chronic bile reflux.^15,16 Additional risks for developing gastric cancer include older age, certain ethnicities, and male sex.¹⁷

CagA strains of H. pylori can promote carcinogenesis by inducing a mitogenic cellular response and downregulating cell adhesion.^18,19 Less carcinogenic risk is associated with H. pylori Cag-A negative strains; however, they also have oncogenic potential mediated by expression of babA2 and vacA genes.²⁰ Hence, the combination of multiple virulent factors encoded in babA2, CagA, and vacA genes has been associated with increased risk of GIM, inflammation, and development of gastric cancer.¹⁵ The clinical usefulness of genotyping H. pylori strains specifically to survey precancerous gastric lesions remains to be seen because of a lack of sufficient clinical studies. In addition, genotyping H. pylori is not commonly performed as part of clinical practice.

The loss of parietal cells seen in atrophic gastritis due to chronic H. pylori infection has been linked to the development of metaplasia due to possible loss of differentiation-promoting factors. As a result, metaplastic cells emerge that express spasmolytic polypeptide (SP or TFF2); hence, this type of metaplasia is referred to as spasmolytic polypeptide–expressing metaplasia (SPEM). The cellular mechanism that may explain a precursor role of SPEM in the development of GIM remains unknown.¹⁴ A second competing theory for the development of GIM is the clonal expansion of stem cells in the gastric isthmus that can lead to dysplasia and cancer development.¹⁴

On the basis of histological similarities with small intestinal or colonic epithelium, GIM can be further classified into complete or incomplete intestinal metaplasia.²¹ Complete intestinal metaplasia most closely resembles small intestinal epithelium with a brush border and goblet cells. Incomplete intestinal metaplasia resembles the colonic epithelium and lacks a brush border. A second classification further classifies GIM into three subtypes: Type I contains nonsecretory absorptive cells and sialomucin secreting goblet cells; type II has few absorptive cells, columnar cells secreting sialomucin, goblet cells secreting mainly sialomucin but some sulphomucin, and presence of Paneth cells; and type III consists of columnar cells secreting predominantly sulphomucin, goblet cells secreting sialomucin or sulphomucin, and absence of Paneth cells.^15,22 In this subclassification, type I GIM is known as complete GIM and types II and III as incomplete GIM.^23-25

Multiple studies performed outside of the United States have shown a higher progression risk to gastric adenocarcinoma in incomplete intestinal metaplasia, or type III intestinal metaplasia.^26-32 Also, the risk of gastric cancer has been demonstrated to be higher among patients with a greater area of metaplasia and extensive intestinal metaplasia, defined as GIM in both the antrum and corpus.^33,34 Hence, the extent of the metaplasia determined with mapping biopsies, regardless of the subtype, should also be incorporated into the risk assessment of the patient. Currently, a major limitation in the United States is a standardized method of pathologic reporting including subclassification of incomplete versus complete intestinal metaplasia.
 

Which patients to screen

Understanding this sequence of carcinogenesis offers a potential window for screening and surveillance. Subsequently, early detection of precancerous mucosal changes would be more amenable for endoscopic submucosal dissection (ESD).^35,36 Currently, U.S. society guidelines do not specifically address the management of GIM. The American Society for Gastrointestinal Endoscopy (ASGE) guidelines for management of premalignant and malignant conditions of the stomach recommend surveillance in individuals with a family history of gastric cancer or of high-risk ethnic background but with no specific optimal surveillance interval.³⁷ Also, H. pylori treatment is recommended if identified, but empiric treatment in GIM was felt to be controversial. The AGA recently sought comments on a proposed new guideline for the management of GIM. This guideline should be released after the comment period and help address management of GIM in the United States. In April of 2019, the European Society of Gastrointestinal Endoscopy (ESGE) updated the management of epithelial precancerous conditions and lesions in the stomach (MAPS II) guideline.³⁸ The MAPS II guideline identifies atrophic gastritis and intestinal metaplasia as precancerous lesions. In patients with moderate to marked atrophy or GIM affecting both antral and body mucosa, ESGE recommends endoscopic surveillance with high-definition chromoendoscopy, mapping, and guided biopsies or at least two biopsies taken separately at the lesser and greater curvature of the antrum and body. H. pylori eradication was recommended if the patient tested positive.

Furthermore, MAPS II proposed replacing atrophic gastritis (AG) in the Operative Link on Gastritis Assessment (OLGA) staging by GIM (OLGIM) as it is considered a more reliable predictor of an individual’s gastric neoplasia risk, based on the interobserver agreement kappa value 0.6 for AG versus 0.9 for GIM.³⁹ Five biopsies (two from the antrum, two from the corpus, and one from the incisura angularis) are needed for the OLGA/OLGIM score system to be considered an accurate predictor of this risk.³⁹ This is supported by the early findings of gastric atrophy and GIM in the incisura angularis.²³ In addition, for patients with GIM only in either the antrum or the body, a family history of gastric cancer, incomplete GIM, autoimmune gastritis, or persistent H. pylori infection was felt to increase the risk to warrant surveillance every 3 years. In those patients with atrophy or GIM in both the antrum and body with a first-degree relative with gastric cancer, surveillance was recommended every 1-2 years. Patients with any dysplasia and a visible lesion should have staging and resection. With no visible lesion, a follow-up endoscopy should be performed in 6 months with high-grade dysplasia and with low-grade dysplasia a repeat in 12 months. Patients with mild to moderate atrophy in the antrum and no intestinal metaplasia were not felt to warrant any further surveillance. (See Figure 1.)

How to screen

Previous studies have found a poor correlation between the endoscopic determination of gastric atrophy and the histologic diagnosis.⁴² Several studies also found that gastric cancer was missed on initial endoscopic examinations. Sensitivity of endoscopy to detect gastric cancer has ranged from 77% to 93%.^43,44 In the United States, there is a lack of standardized quality indicators for upper endoscopy exams. The ESGE has suggested several performance measures to ensure a quality endoscopy exam, including accurate photo documentation, sufficient procedure time of at least 7 minutes, adherence to biopsy protocols, and low complication rates.⁴⁵ In Asia, a systematic screening protocol is used for photo documentation, and simple techniques such as adequate air insufflation and irrigation to remove mucus are routinely used to improve the endoscopy exam.^46,47 The mean time of an endoscopy exam has also been found to increase the detection of neoplastic lesions, as slow endoscopists – with a mean exam duration of 8.6 ± 4.2 min during upper endoscopy – detected threefold more neoplastic lesions than did fast endoscopists.⁴⁸

A standardized biopsy approach is also important when screening patients. The updated Sydney protocol has been suggested for mapping the stomach to screen for atrophy and GIM. This protocol recommends two biopsies from the antrum (at the lesser and greater curvature), two from the body (at the lesser and greater curvature), and one from the incisura.²³ This biopsy protocol was also suggested in the recent MAPS II update, with the biopsy of the incisura felt to be an additional biopsy left to the discretion of the endoscopist. Notably, abnormal appearing mucosal areas should be biopsied separately from the mapping biopsies.

High-definition endoscopy with virtual chromoendoscopy is felt to be better than white-light endoscopy alone at detecting precancerous gastric lesions.³⁸ (See Figure 2.)

Courtesy Diana Curras-Martin, MD, and Susana Gonzalez, MD

In particular, narrow-band imaging (NBI) has been studied and found to increase the diagnostic yield of GIM and dysplasia compared with white light alone.⁴⁹ Several studies have shown an increased accuracy for the detection of GIM with magnification NBI.^50-52 An unfortunate limitation is the geographic availability of magnification NBI: It is not available in the United States. A multicenter study in Portugal developed a new classification system for the appearance of precancerous lesions with NBI and tested its accuracy in endoscopists with a wide range of NBI experience. An abnormal mucosal pattern that showed light blue crests/regular ridge or a tubulovillous appearance and a regular mucosal pattern was found with GIM. An irregular vascular pattern with a white opaque substance and an absent or irregular mucosal pattern was most often found with dysplasia. Furthermore, the reproducibility of these patterns was high between endoscopists.⁵³ Multiple studies have been performed on additional imaging technologies to enhance the detection of gastric neoplasia; however, these technologies are still investigational and currently not recommended for screening.^54-57

Serum pepsinogens have been studied in Europe and Asia as noninvasive indicators of gastric atrophy to determine who should be screened with endoscopy.⁵⁸ A low serum pepsinogen I level below 70 ng/mL and pepsinogen I/II ratio below 3 has generally been used to detect atrophic gastritis and at-risk populations. However, the studies performed in Europe and Asia used different methods for quantifying pepsinogen levels. Therefore, cutoff values cannot be generalized for all assays and should be validated for the specific tests used.³⁸
 

Summary

Gastric atrophy and gastric intestinal metaplasia are considered precancerous lesions with an increased risk of development of gastric cancer. H. pylori is a major risk factor for the development of GIM. The extent of GIM as well as the presence of incomplete intestinal metaplasia, or type III intestinal metaplasia has been found to have the highest gastric cancer risk. Currently, in the United States, specific guidelines on endoscopic screening and surveillance for noncardia gastric adenocarcinoma based on histological subtype of GIM, location, and extension are lacking. The ESGE recently updated guidelines that recommend surveillance of patients with extensive atrophy and intestinal metaplasia or with a significant family history. Location and extension of intestinal metaplasia plays a role in increased risk. Screening should include a standardized upper endoscopy approach with high-definition white- light endoscopy and NBI, at least a 7-minute examination, adequate insufflation and cleaning, adequate photo documentation, and a standardized biopsy protocol. Further studies are needed to determine an appropriate surveillance interval and standardized pathology reporting approach as well.

Diana Curras-Martin MD, is an internal medicine resident at Hackensack Meridian Jersey Shore University Medical Center. Susana Gonzalez, MD, is assistant professor of medicine in the division of gastroenterology and hepatology (@WCM_GI), Weill Cornell Medicine, New York Presbyterian Hospital–Cornell. 

References

1. Bray F et al. CA Cancer J Clin. 2018;68(6):394-424.

2. Global Burden of Disease Cancer Collaboration et al. JAMA Oncol. 2018;4(11):1553-68.

3. Balakrishnan M et al. Curr Gastroenterol Rep. 2017;19(8):36.

4. Anderson WF et al. J Natl Cancer Inst. 2018;110(6):608-15.

5. Trieu JA et al. Dig Dis Sci. 2019;64(5):1079-88.

6. Lauren P. Acta Pathol Microbiol Scand. 1965;64:31-49.

7. Correa P, Schneider BG. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1865-8.

8. Correa P. Cancer Res. 1992;52(24):6735-40.

9. Correa P, Piazuelo MB. J Dig Dis. 2012;13(1):2-9.

10. Correa P et al. J Natl Cancer Inst. 1970;44(2):297-306.

11. Correa P. Semin Oncol. 1985;12(1):2-10.

12. Rugge M et al. Hum Pathol. 1991;22(10):1002-8.

13. Simko V et al. Bratisl Lek Listy. 2015;116(1):3-8.

14. Giroux V, Rustgi AK. Nat Rev Cancer. 2017;17(10):594-604.

15. Jencks DS et al. Gastroenterol Hepatol (N Y). 2018;14(2):92-101.

16. Amieva M, Peek RM Jr. Gastroenterology. 2016;150(1):64-78.

17. Karimi P et al. Cancer Epidemiol Biomarkers Prev. 2014;23(5):700-13.

18. Hatakeyama M. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(4):196-219.

19. Tsutsumi R et al. Mol Cell Biol. 2006;26(1):261-76.

20. Kikuchi S et al. Am J Gastroenterol. 1999;94(12):3455-9.

21. Jass JR, Filipe MI. Histopathology. 1980;4(3):271-9.

22. Jass JR, Filipe MI. Histochem J. 1981;13(6):931-9.

23. Dixon MF et al. Am J Surg Pathol. 1996;20(10):1161-81.

24. Kang KP et al. J Gastroenterol Hepatol. 2009;24(1):140-8.

25. Gonzalez CA et al. Int J Cancer. 2010;127(11):2654-60.

26. Filipe MI et al. Gut. 1985;26(12):1319-26.

27. Filipe MI et al. Int J Cancer. 1994;57(3):324-9.

28. Gonzalez CA et al. J Gastroenterol Hepatol. 2016;31(5):953-8.

29. Cassaro M et al. Am J Gastroenterol. 2000;95(6):1431-8.

30. Shao L et al. Int J Cancer. Apr 29. 2018.

31. Stemmermann GN. Cancer. 1994;74(2):556-64.

32. Gonzalez CA et al. Int J Cancer. 2013;133(5):1023-32.

33. Reddy KM et al. Clin Gastroenterol Hepatol. 2016;14(10):1420-5.

34. Tava F et al. Hum Pathol. 2006;37(11):1489-97.

35. Fernandez-Esparrach G et al. Rev Esp Enferm Dig. 2014;106(2):120-32.

36. Ono H et al. Dig Endosc. 2016;28(1):3-15.

37. Evans JA, DeWitt JM. Gastrointest Endosc. 2016;83(1):274.

38. Pimentel-Nunes P et al. Endoscopy. 2019;51(4):365-88.

39. Capelle LG et al. Gastrointest Endosc. 2010;71(7):1150-8.

40. Saumoy M et al. Gastroenterology. 2018;155(3):648-60.

41. Gupta N et al. Gastrointest Endosc. 2011;74(3):610-24 e612.

42. Eshmuratov A et al. Dig Dis Sci. 2010;55(5):1364-75.

43. Nam JH et al. Cancer. 2012;118(20):4953-60.

44. Amin A et al. J R Coll Surg Edinb. 2002;47(5):681-4.

45. Bisschops R et al. United European Gastroenterol J. 2016;4(5):629-56.

46. Uedo N et al. Gastroenterol Clin North Am. 2013;42(2):317-35.

47. Yao K. Ann Gastroenterol. 2013;26(1):11-22.

48. Teh JL et al. Clin Gastroenterol Hepatol. 2015;13(3):480-7 e482.

49. Capelle LG et al. Dig Dis Sci. 2010;55(12):3442-8.

50. Bansal A et al. Gastrointest Endosc. 2008;67(2):210-6.

51. Tahara T et al. Gastrointest Endosc. 2009;70(2):246-53.

52. Uedo N et al. Endoscopy. 2006;38(8):819-24.

53. Pimentel-Nunes P et al. Endoscopy. 2012;44(3):236-46.

54. Kato M et al. Gastrointest Endosc. 2009;70(5):899-906.

55. Nishimura J et al. Gastroenterol Res Pract. 2014;2014:819395.

56. Dohi O et al. Gastrointest Endosc. 2019;89(1):47-57.

57. Osawa H et al. World J Gastrointest Endosc. 2012;4(8):356-61.

58. Pasechnikov V et al. World J Gastroenterol. 2014;20(38):13842-62.

Introduction

Despite a global decline in the incidence of gastric cancer over the past 3 decades, it remains the fifth most commonly diagnosed cancer and the third most common cause of cancer deaths worldwide.¹ In the United States it is the fourth most commonly diagnosed GI malignancy, after colorectal, pancreas, and liver cancer. The prevalence remains high in Latin America and Asia, which has implications in the United States because of growing Hispanic and Asian populations.^2,3 In recent years, a change in the trend of gastric cancer among non-Hispanic whites has been observed, particularly in women younger than 50 years old.⁴ Gastric intestinal metaplasia has been recognized worldwide as a premalignant precursor to gastric cancer, but currently, there are limited U.S. guidelines, leading to controversy over management of this condition.⁵

Etiology

Gastric adenocarcinomas are classified into two subcategories based on location (cardia and noncardia) and histology (intestinal and diffuse types).^6,7 Atrophic gastritis and gastric intestinal metaplasia (GIM) are considered precursors of intestinal-type noncardia gastric adenocarcinoma. The Correa cascade is a commonly accepted precancer sequence for noncardia gastric adenocarcinoma that describes mucosal changes from inflammation to atrophy to metaplasia to intraepithelial neoplasia and culminating in carcinoma.^8,9 It has been observed that GIM may be the histologic change prior to the development of dysplasia and over 50% of patients with high-grade dysplasia will progress to adenocarcinoma.^10-12 In the United States, GIM has the highest prevalence in African Americans, Hispanics, and East Asians, with the overall GIM prevalence regardless of ethnicity reported from 3.05% to 19.2%.^5,13

Risk factors and subclassification

Replacement of the foveolar and/or glandular epithelium in the oxyntic and antral mucosa by intestinal epithelium results in GIM. It can be focal when limited to one region of the stomach or extensive when two or more regions are involved.¹⁴ The main risk factors for GIM development are Helicobacter pylori infection, tobacco, alcohol consumption, high salt intake, and chronic bile reflux.^15,16 Additional risks for developing gastric cancer include older age, certain ethnicities, and male sex.¹⁷

CagA strains of H. pylori can promote carcinogenesis by inducing a mitogenic cellular response and downregulating cell adhesion.^18,19 Less carcinogenic risk is associated with H. pylori Cag-A negative strains; however, they also have oncogenic potential mediated by expression of babA2 and vacA genes.²⁰ Hence, the combination of multiple virulent factors encoded in babA2, CagA, and vacA genes has been associated with increased risk of GIM, inflammation, and development of gastric cancer.¹⁵ The clinical usefulness of genotyping H. pylori strains specifically to survey precancerous gastric lesions remains to be seen because of a lack of sufficient clinical studies. In addition, genotyping H. pylori is not commonly performed as part of clinical practice.

The loss of parietal cells seen in atrophic gastritis due to chronic H. pylori infection has been linked to the development of metaplasia due to possible loss of differentiation-promoting factors. As a result, metaplastic cells emerge that express spasmolytic polypeptide (SP or TFF2); hence, this type of metaplasia is referred to as spasmolytic polypeptide–expressing metaplasia (SPEM). The cellular mechanism that may explain a precursor role of SPEM in the development of GIM remains unknown.¹⁴ A second competing theory for the development of GIM is the clonal expansion of stem cells in the gastric isthmus that can lead to dysplasia and cancer development.¹⁴

On the basis of histological similarities with small intestinal or colonic epithelium, GIM can be further classified into complete or incomplete intestinal metaplasia.²¹ Complete intestinal metaplasia most closely resembles small intestinal epithelium with a brush border and goblet cells. Incomplete intestinal metaplasia resembles the colonic epithelium and lacks a brush border. A second classification further classifies GIM into three subtypes: Type I contains nonsecretory absorptive cells and sialomucin secreting goblet cells; type II has few absorptive cells, columnar cells secreting sialomucin, goblet cells secreting mainly sialomucin but some sulphomucin, and presence of Paneth cells; and type III consists of columnar cells secreting predominantly sulphomucin, goblet cells secreting sialomucin or sulphomucin, and absence of Paneth cells.^15,22 In this subclassification, type I GIM is known as complete GIM and types II and III as incomplete GIM.^23-25

Multiple studies performed outside of the United States have shown a higher progression risk to gastric adenocarcinoma in incomplete intestinal metaplasia, or type III intestinal metaplasia.^26-32 Also, the risk of gastric cancer has been demonstrated to be higher among patients with a greater area of metaplasia and extensive intestinal metaplasia, defined as GIM in both the antrum and corpus.^33,34 Hence, the extent of the metaplasia determined with mapping biopsies, regardless of the subtype, should also be incorporated into the risk assessment of the patient. Currently, a major limitation in the United States is a standardized method of pathologic reporting including subclassification of incomplete versus complete intestinal metaplasia.
 

Which patients to screen

Understanding this sequence of carcinogenesis offers a potential window for screening and surveillance. Subsequently, early detection of precancerous mucosal changes would be more amenable for endoscopic submucosal dissection (ESD).^35,36 Currently, U.S. society guidelines do not specifically address the management of GIM. The American Society for Gastrointestinal Endoscopy (ASGE) guidelines for management of premalignant and malignant conditions of the stomach recommend surveillance in individuals with a family history of gastric cancer or of high-risk ethnic background but with no specific optimal surveillance interval.³⁷ Also, H. pylori treatment is recommended if identified, but empiric treatment in GIM was felt to be controversial. The AGA recently sought comments on a proposed new guideline for the management of GIM. This guideline should be released after the comment period and help address management of GIM in the United States. In April of 2019, the European Society of Gastrointestinal Endoscopy (ESGE) updated the management of epithelial precancerous conditions and lesions in the stomach (MAPS II) guideline.³⁸ The MAPS II guideline identifies atrophic gastritis and intestinal metaplasia as precancerous lesions. In patients with moderate to marked atrophy or GIM affecting both antral and body mucosa, ESGE recommends endoscopic surveillance with high-definition chromoendoscopy, mapping, and guided biopsies or at least two biopsies taken separately at the lesser and greater curvature of the antrum and body. H. pylori eradication was recommended if the patient tested positive.

Furthermore, MAPS II proposed replacing atrophic gastritis (AG) in the Operative Link on Gastritis Assessment (OLGA) staging by GIM (OLGIM) as it is considered a more reliable predictor of an individual’s gastric neoplasia risk, based on the interobserver agreement kappa value 0.6 for AG versus 0.9 for GIM.³⁹ Five biopsies (two from the antrum, two from the corpus, and one from the incisura angularis) are needed for the OLGA/OLGIM score system to be considered an accurate predictor of this risk.³⁹ This is supported by the early findings of gastric atrophy and GIM in the incisura angularis.²³ In addition, for patients with GIM only in either the antrum or the body, a family history of gastric cancer, incomplete GIM, autoimmune gastritis, or persistent H. pylori infection was felt to increase the risk to warrant surveillance every 3 years. In those patients with atrophy or GIM in both the antrum and body with a first-degree relative with gastric cancer, surveillance was recommended every 1-2 years. Patients with any dysplasia and a visible lesion should have staging and resection. With no visible lesion, a follow-up endoscopy should be performed in 6 months with high-grade dysplasia and with low-grade dysplasia a repeat in 12 months. Patients with mild to moderate atrophy in the antrum and no intestinal metaplasia were not felt to warrant any further surveillance. (See Figure 1.)

How to screen

Previous studies have found a poor correlation between the endoscopic determination of gastric atrophy and the histologic diagnosis.⁴² Several studies also found that gastric cancer was missed on initial endoscopic examinations. Sensitivity of endoscopy to detect gastric cancer has ranged from 77% to 93%.^43,44 In the United States, there is a lack of standardized quality indicators for upper endoscopy exams. The ESGE has suggested several performance measures to ensure a quality endoscopy exam, including accurate photo documentation, sufficient procedure time of at least 7 minutes, adherence to biopsy protocols, and low complication rates.⁴⁵ In Asia, a systematic screening protocol is used for photo documentation, and simple techniques such as adequate air insufflation and irrigation to remove mucus are routinely used to improve the endoscopy exam.^46,47 The mean time of an endoscopy exam has also been found to increase the detection of neoplastic lesions, as slow endoscopists – with a mean exam duration of 8.6 ± 4.2 min during upper endoscopy – detected threefold more neoplastic lesions than did fast endoscopists.⁴⁸

A standardized biopsy approach is also important when screening patients. The updated Sydney protocol has been suggested for mapping the stomach to screen for atrophy and GIM. This protocol recommends two biopsies from the antrum (at the lesser and greater curvature), two from the body (at the lesser and greater curvature), and one from the incisura.²³ This biopsy protocol was also suggested in the recent MAPS II update, with the biopsy of the incisura felt to be an additional biopsy left to the discretion of the endoscopist. Notably, abnormal appearing mucosal areas should be biopsied separately from the mapping biopsies.

High-definition endoscopy with virtual chromoendoscopy is felt to be better than white-light endoscopy alone at detecting precancerous gastric lesions.³⁸ (See Figure 2.)

Courtesy Diana Curras-Martin, MD, and Susana Gonzalez, MD

In particular, narrow-band imaging (NBI) has been studied and found to increase the diagnostic yield of GIM and dysplasia compared with white light alone.⁴⁹ Several studies have shown an increased accuracy for the detection of GIM with magnification NBI.^50-52 An unfortunate limitation is the geographic availability of magnification NBI: It is not available in the United States. A multicenter study in Portugal developed a new classification system for the appearance of precancerous lesions with NBI and tested its accuracy in endoscopists with a wide range of NBI experience. An abnormal mucosal pattern that showed light blue crests/regular ridge or a tubulovillous appearance and a regular mucosal pattern was found with GIM. An irregular vascular pattern with a white opaque substance and an absent or irregular mucosal pattern was most often found with dysplasia. Furthermore, the reproducibility of these patterns was high between endoscopists.⁵³ Multiple studies have been performed on additional imaging technologies to enhance the detection of gastric neoplasia; however, these technologies are still investigational and currently not recommended for screening.^54-57

Serum pepsinogens have been studied in Europe and Asia as noninvasive indicators of gastric atrophy to determine who should be screened with endoscopy.⁵⁸ A low serum pepsinogen I level below 70 ng/mL and pepsinogen I/II ratio below 3 has generally been used to detect atrophic gastritis and at-risk populations. However, the studies performed in Europe and Asia used different methods for quantifying pepsinogen levels. Therefore, cutoff values cannot be generalized for all assays and should be validated for the specific tests used.³⁸
 

Summary

Gastric atrophy and gastric intestinal metaplasia are considered precancerous lesions with an increased risk of development of gastric cancer. H. pylori is a major risk factor for the development of GIM. The extent of GIM as well as the presence of incomplete intestinal metaplasia, or type III intestinal metaplasia has been found to have the highest gastric cancer risk. Currently, in the United States, specific guidelines on endoscopic screening and surveillance for noncardia gastric adenocarcinoma based on histological subtype of GIM, location, and extension are lacking. The ESGE recently updated guidelines that recommend surveillance of patients with extensive atrophy and intestinal metaplasia or with a significant family history. Location and extension of intestinal metaplasia plays a role in increased risk. Screening should include a standardized upper endoscopy approach with high-definition white- light endoscopy and NBI, at least a 7-minute examination, adequate insufflation and cleaning, adequate photo documentation, and a standardized biopsy protocol. Further studies are needed to determine an appropriate surveillance interval and standardized pathology reporting approach as well.

Diana Curras-Martin MD, is an internal medicine resident at Hackensack Meridian Jersey Shore University Medical Center. Susana Gonzalez, MD, is assistant professor of medicine in the division of gastroenterology and hepatology (@WCM_GI), Weill Cornell Medicine, New York Presbyterian Hospital–Cornell. 

References

1. Bray F et al. CA Cancer J Clin. 2018;68(6):394-424.

2. Global Burden of Disease Cancer Collaboration et al. JAMA Oncol. 2018;4(11):1553-68.

3. Balakrishnan M et al. Curr Gastroenterol Rep. 2017;19(8):36.

4. Anderson WF et al. J Natl Cancer Inst. 2018;110(6):608-15.

5. Trieu JA et al. Dig Dis Sci. 2019;64(5):1079-88.

6. Lauren P. Acta Pathol Microbiol Scand. 1965;64:31-49.

7. Correa P, Schneider BG. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1865-8.

8. Correa P. Cancer Res. 1992;52(24):6735-40.

9. Correa P, Piazuelo MB. J Dig Dis. 2012;13(1):2-9.

10. Correa P et al. J Natl Cancer Inst. 1970;44(2):297-306.

11. Correa P. Semin Oncol. 1985;12(1):2-10.

12. Rugge M et al. Hum Pathol. 1991;22(10):1002-8.

13. Simko V et al. Bratisl Lek Listy. 2015;116(1):3-8.

14. Giroux V, Rustgi AK. Nat Rev Cancer. 2017;17(10):594-604.

15. Jencks DS et al. Gastroenterol Hepatol (N Y). 2018;14(2):92-101.

16. Amieva M, Peek RM Jr. Gastroenterology. 2016;150(1):64-78.

17. Karimi P et al. Cancer Epidemiol Biomarkers Prev. 2014;23(5):700-13.

18. Hatakeyama M. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(4):196-219.

19. Tsutsumi R et al. Mol Cell Biol. 2006;26(1):261-76.

20. Kikuchi S et al. Am J Gastroenterol. 1999;94(12):3455-9.

21. Jass JR, Filipe MI. Histopathology. 1980;4(3):271-9.

22. Jass JR, Filipe MI. Histochem J. 1981;13(6):931-9.

23. Dixon MF et al. Am J Surg Pathol. 1996;20(10):1161-81.

24. Kang KP et al. J Gastroenterol Hepatol. 2009;24(1):140-8.

25. Gonzalez CA et al. Int J Cancer. 2010;127(11):2654-60.

26. Filipe MI et al. Gut. 1985;26(12):1319-26.

27. Filipe MI et al. Int J Cancer. 1994;57(3):324-9.

28. Gonzalez CA et al. J Gastroenterol Hepatol. 2016;31(5):953-8.

29. Cassaro M et al. Am J Gastroenterol. 2000;95(6):1431-8.

30. Shao L et al. Int J Cancer. Apr 29. 2018.

31. Stemmermann GN. Cancer. 1994;74(2):556-64.

32. Gonzalez CA et al. Int J Cancer. 2013;133(5):1023-32.

33. Reddy KM et al. Clin Gastroenterol Hepatol. 2016;14(10):1420-5.

34. Tava F et al. Hum Pathol. 2006;37(11):1489-97.

35. Fernandez-Esparrach G et al. Rev Esp Enferm Dig. 2014;106(2):120-32.

36. Ono H et al. Dig Endosc. 2016;28(1):3-15.

37. Evans JA, DeWitt JM. Gastrointest Endosc. 2016;83(1):274.

38. Pimentel-Nunes P et al. Endoscopy. 2019;51(4):365-88.

39. Capelle LG et al. Gastrointest Endosc. 2010;71(7):1150-8.

40. Saumoy M et al. Gastroenterology. 2018;155(3):648-60.

41. Gupta N et al. Gastrointest Endosc. 2011;74(3):610-24 e612.

42. Eshmuratov A et al. Dig Dis Sci. 2010;55(5):1364-75.

43. Nam JH et al. Cancer. 2012;118(20):4953-60.

44. Amin A et al. J R Coll Surg Edinb. 2002;47(5):681-4.

45. Bisschops R et al. United European Gastroenterol J. 2016;4(5):629-56.

46. Uedo N et al. Gastroenterol Clin North Am. 2013;42(2):317-35.

47. Yao K. Ann Gastroenterol. 2013;26(1):11-22.

48. Teh JL et al. Clin Gastroenterol Hepatol. 2015;13(3):480-7 e482.

49. Capelle LG et al. Dig Dis Sci. 2010;55(12):3442-8.

50. Bansal A et al. Gastrointest Endosc. 2008;67(2):210-6.

51. Tahara T et al. Gastrointest Endosc. 2009;70(2):246-53.

52. Uedo N et al. Endoscopy. 2006;38(8):819-24.

53. Pimentel-Nunes P et al. Endoscopy. 2012;44(3):236-46.

54. Kato M et al. Gastrointest Endosc. 2009;70(5):899-906.

55. Nishimura J et al. Gastroenterol Res Pract. 2014;2014:819395.

56. Dohi O et al. Gastrointest Endosc. 2019;89(1):47-57.

57. Osawa H et al. World J Gastrointest Endosc. 2012;4(8):356-61.

58. Pasechnikov V et al. World J Gastroenterol. 2014;20(38):13842-62.

Introduction

Despite a global decline in the incidence of gastric cancer over the past 3 decades, it remains the fifth most commonly diagnosed cancer and the third most common cause of cancer deaths worldwide.¹ In the United States it is the fourth most commonly diagnosed GI malignancy, after colorectal, pancreas, and liver cancer. The prevalence remains high in Latin America and Asia, which has implications in the United States because of growing Hispanic and Asian populations.^2,3 In recent years, a change in the trend of gastric cancer among non-Hispanic whites has been observed, particularly in women younger than 50 years old.⁴ Gastric intestinal metaplasia has been recognized worldwide as a premalignant precursor to gastric cancer, but currently, there are limited U.S. guidelines, leading to controversy over management of this condition.⁵

Etiology

Gastric adenocarcinomas are classified into two subcategories based on location (cardia and noncardia) and histology (intestinal and diffuse types).^6,7 Atrophic gastritis and gastric intestinal metaplasia (GIM) are considered precursors of intestinal-type noncardia gastric adenocarcinoma. The Correa cascade is a commonly accepted precancer sequence for noncardia gastric adenocarcinoma that describes mucosal changes from inflammation to atrophy to metaplasia to intraepithelial neoplasia and culminating in carcinoma.^8,9 It has been observed that GIM may be the histologic change prior to the development of dysplasia and over 50% of patients with high-grade dysplasia will progress to adenocarcinoma.^10-12 In the United States, GIM has the highest prevalence in African Americans, Hispanics, and East Asians, with the overall GIM prevalence regardless of ethnicity reported from 3.05% to 19.2%.^5,13

Risk factors and subclassification

Replacement of the foveolar and/or glandular epithelium in the oxyntic and antral mucosa by intestinal epithelium results in GIM. It can be focal when limited to one region of the stomach or extensive when two or more regions are involved.¹⁴ The main risk factors for GIM development are Helicobacter pylori infection, tobacco, alcohol consumption, high salt intake, and chronic bile reflux.^15,16 Additional risks for developing gastric cancer include older age, certain ethnicities, and male sex.¹⁷

CagA strains of H. pylori can promote carcinogenesis by inducing a mitogenic cellular response and downregulating cell adhesion.^18,19 Less carcinogenic risk is associated with H. pylori Cag-A negative strains; however, they also have oncogenic potential mediated by expression of babA2 and vacA genes.²⁰ Hence, the combination of multiple virulent factors encoded in babA2, CagA, and vacA genes has been associated with increased risk of GIM, inflammation, and development of gastric cancer.¹⁵ The clinical usefulness of genotyping H. pylori strains specifically to survey precancerous gastric lesions remains to be seen because of a lack of sufficient clinical studies. In addition, genotyping H. pylori is not commonly performed as part of clinical practice.

The loss of parietal cells seen in atrophic gastritis due to chronic H. pylori infection has been linked to the development of metaplasia due to possible loss of differentiation-promoting factors. As a result, metaplastic cells emerge that express spasmolytic polypeptide (SP or TFF2); hence, this type of metaplasia is referred to as spasmolytic polypeptide–expressing metaplasia (SPEM). The cellular mechanism that may explain a precursor role of SPEM in the development of GIM remains unknown.¹⁴ A second competing theory for the development of GIM is the clonal expansion of stem cells in the gastric isthmus that can lead to dysplasia and cancer development.¹⁴

On the basis of histological similarities with small intestinal or colonic epithelium, GIM can be further classified into complete or incomplete intestinal metaplasia.²¹ Complete intestinal metaplasia most closely resembles small intestinal epithelium with a brush border and goblet cells. Incomplete intestinal metaplasia resembles the colonic epithelium and lacks a brush border. A second classification further classifies GIM into three subtypes: Type I contains nonsecretory absorptive cells and sialomucin secreting goblet cells; type II has few absorptive cells, columnar cells secreting sialomucin, goblet cells secreting mainly sialomucin but some sulphomucin, and presence of Paneth cells; and type III consists of columnar cells secreting predominantly sulphomucin, goblet cells secreting sialomucin or sulphomucin, and absence of Paneth cells.^15,22 In this subclassification, type I GIM is known as complete GIM and types II and III as incomplete GIM.^23-25

Multiple studies performed outside of the United States have shown a higher progression risk to gastric adenocarcinoma in incomplete intestinal metaplasia, or type III intestinal metaplasia.^26-32 Also, the risk of gastric cancer has been demonstrated to be higher among patients with a greater area of metaplasia and extensive intestinal metaplasia, defined as GIM in both the antrum and corpus.^33,34 Hence, the extent of the metaplasia determined with mapping biopsies, regardless of the subtype, should also be incorporated into the risk assessment of the patient. Currently, a major limitation in the United States is a standardized method of pathologic reporting including subclassification of incomplete versus complete intestinal metaplasia.
 

Which patients to screen

Understanding this sequence of carcinogenesis offers a potential window for screening and surveillance. Subsequently, early detection of precancerous mucosal changes would be more amenable for endoscopic submucosal dissection (ESD).^35,36 Currently, U.S. society guidelines do not specifically address the management of GIM. The American Society for Gastrointestinal Endoscopy (ASGE) guidelines for management of premalignant and malignant conditions of the stomach recommend surveillance in individuals with a family history of gastric cancer or of high-risk ethnic background but with no specific optimal surveillance interval.³⁷ Also, H. pylori treatment is recommended if identified, but empiric treatment in GIM was felt to be controversial. The AGA recently sought comments on a proposed new guideline for the management of GIM. This guideline should be released after the comment period and help address management of GIM in the United States. In April of 2019, the European Society of Gastrointestinal Endoscopy (ESGE) updated the management of epithelial precancerous conditions and lesions in the stomach (MAPS II) guideline.³⁸ The MAPS II guideline identifies atrophic gastritis and intestinal metaplasia as precancerous lesions. In patients with moderate to marked atrophy or GIM affecting both antral and body mucosa, ESGE recommends endoscopic surveillance with high-definition chromoendoscopy, mapping, and guided biopsies or at least two biopsies taken separately at the lesser and greater curvature of the antrum and body. H. pylori eradication was recommended if the patient tested positive.

Furthermore, MAPS II proposed replacing atrophic gastritis (AG) in the Operative Link on Gastritis Assessment (OLGA) staging by GIM (OLGIM) as it is considered a more reliable predictor of an individual’s gastric neoplasia risk, based on the interobserver agreement kappa value 0.6 for AG versus 0.9 for GIM.³⁹ Five biopsies (two from the antrum, two from the corpus, and one from the incisura angularis) are needed for the OLGA/OLGIM score system to be considered an accurate predictor of this risk.³⁹ This is supported by the early findings of gastric atrophy and GIM in the incisura angularis.²³ In addition, for patients with GIM only in either the antrum or the body, a family history of gastric cancer, incomplete GIM, autoimmune gastritis, or persistent H. pylori infection was felt to increase the risk to warrant surveillance every 3 years. In those patients with atrophy or GIM in both the antrum and body with a first-degree relative with gastric cancer, surveillance was recommended every 1-2 years. Patients with any dysplasia and a visible lesion should have staging and resection. With no visible lesion, a follow-up endoscopy should be performed in 6 months with high-grade dysplasia and with low-grade dysplasia a repeat in 12 months. Patients with mild to moderate atrophy in the antrum and no intestinal metaplasia were not felt to warrant any further surveillance. (See Figure 1.)

How to screen

Previous studies have found a poor correlation between the endoscopic determination of gastric atrophy and the histologic diagnosis.⁴² Several studies also found that gastric cancer was missed on initial endoscopic examinations. Sensitivity of endoscopy to detect gastric cancer has ranged from 77% to 93%.^43,44 In the United States, there is a lack of standardized quality indicators for upper endoscopy exams. The ESGE has suggested several performance measures to ensure a quality endoscopy exam, including accurate photo documentation, sufficient procedure time of at least 7 minutes, adherence to biopsy protocols, and low complication rates.⁴⁵ In Asia, a systematic screening protocol is used for photo documentation, and simple techniques such as adequate air insufflation and irrigation to remove mucus are routinely used to improve the endoscopy exam.^46,47 The mean time of an endoscopy exam has also been found to increase the detection of neoplastic lesions, as slow endoscopists – with a mean exam duration of 8.6 ± 4.2 min during upper endoscopy – detected threefold more neoplastic lesions than did fast endoscopists.⁴⁸

A standardized biopsy approach is also important when screening patients. The updated Sydney protocol has been suggested for mapping the stomach to screen for atrophy and GIM. This protocol recommends two biopsies from the antrum (at the lesser and greater curvature), two from the body (at the lesser and greater curvature), and one from the incisura.²³ This biopsy protocol was also suggested in the recent MAPS II update, with the biopsy of the incisura felt to be an additional biopsy left to the discretion of the endoscopist. Notably, abnormal appearing mucosal areas should be biopsied separately from the mapping biopsies.

High-definition endoscopy with virtual chromoendoscopy is felt to be better than white-light endoscopy alone at detecting precancerous gastric lesions.³⁸ (See Figure 2.)

Courtesy Diana Curras-Martin, MD, and Susana Gonzalez, MD

In particular, narrow-band imaging (NBI) has been studied and found to increase the diagnostic yield of GIM and dysplasia compared with white light alone.⁴⁹ Several studies have shown an increased accuracy for the detection of GIM with magnification NBI.^50-52 An unfortunate limitation is the geographic availability of magnification NBI: It is not available in the United States. A multicenter study in Portugal developed a new classification system for the appearance of precancerous lesions with NBI and tested its accuracy in endoscopists with a wide range of NBI experience. An abnormal mucosal pattern that showed light blue crests/regular ridge or a tubulovillous appearance and a regular mucosal pattern was found with GIM. An irregular vascular pattern with a white opaque substance and an absent or irregular mucosal pattern was most often found with dysplasia. Furthermore, the reproducibility of these patterns was high between endoscopists.⁵³ Multiple studies have been performed on additional imaging technologies to enhance the detection of gastric neoplasia; however, these technologies are still investigational and currently not recommended for screening.^54-57

Serum pepsinogens have been studied in Europe and Asia as noninvasive indicators of gastric atrophy to determine who should be screened with endoscopy.⁵⁸ A low serum pepsinogen I level below 70 ng/mL and pepsinogen I/II ratio below 3 has generally been used to detect atrophic gastritis and at-risk populations. However, the studies performed in Europe and Asia used different methods for quantifying pepsinogen levels. Therefore, cutoff values cannot be generalized for all assays and should be validated for the specific tests used.³⁸
 

Summary

Gastric atrophy and gastric intestinal metaplasia are considered precancerous lesions with an increased risk of development of gastric cancer. H. pylori is a major risk factor for the development of GIM. The extent of GIM as well as the presence of incomplete intestinal metaplasia, or type III intestinal metaplasia has been found to have the highest gastric cancer risk. Currently, in the United States, specific guidelines on endoscopic screening and surveillance for noncardia gastric adenocarcinoma based on histological subtype of GIM, location, and extension are lacking. The ESGE recently updated guidelines that recommend surveillance of patients with extensive atrophy and intestinal metaplasia or with a significant family history. Location and extension of intestinal metaplasia plays a role in increased risk. Screening should include a standardized upper endoscopy approach with high-definition white- light endoscopy and NBI, at least a 7-minute examination, adequate insufflation and cleaning, adequate photo documentation, and a standardized biopsy protocol. Further studies are needed to determine an appropriate surveillance interval and standardized pathology reporting approach as well.

Diana Curras-Martin MD, is an internal medicine resident at Hackensack Meridian Jersey Shore University Medical Center. Susana Gonzalez, MD, is assistant professor of medicine in the division of gastroenterology and hepatology (@WCM_GI), Weill Cornell Medicine, New York Presbyterian Hospital–Cornell. 

References

1. Bray F et al. CA Cancer J Clin. 2018;68(6):394-424.

2. Global Burden of Disease Cancer Collaboration et al. JAMA Oncol. 2018;4(11):1553-68.

3. Balakrishnan M et al. Curr Gastroenterol Rep. 2017;19(8):36.

4. Anderson WF et al. J Natl Cancer Inst. 2018;110(6):608-15.

5. Trieu JA et al. Dig Dis Sci. 2019;64(5):1079-88.

6. Lauren P. Acta Pathol Microbiol Scand. 1965;64:31-49.

7. Correa P, Schneider BG. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1865-8.

8. Correa P. Cancer Res. 1992;52(24):6735-40.

9. Correa P, Piazuelo MB. J Dig Dis. 2012;13(1):2-9.

10. Correa P et al. J Natl Cancer Inst. 1970;44(2):297-306.

11. Correa P. Semin Oncol. 1985;12(1):2-10.

12. Rugge M et al. Hum Pathol. 1991;22(10):1002-8.

13. Simko V et al. Bratisl Lek Listy. 2015;116(1):3-8.

14. Giroux V, Rustgi AK. Nat Rev Cancer. 2017;17(10):594-604.

15. Jencks DS et al. Gastroenterol Hepatol (N Y). 2018;14(2):92-101.

16. Amieva M, Peek RM Jr. Gastroenterology. 2016;150(1):64-78.

17. Karimi P et al. Cancer Epidemiol Biomarkers Prev. 2014;23(5):700-13.

18. Hatakeyama M. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(4):196-219.

19. Tsutsumi R et al. Mol Cell Biol. 2006;26(1):261-76.

20. Kikuchi S et al. Am J Gastroenterol. 1999;94(12):3455-9.

21. Jass JR, Filipe MI. Histopathology. 1980;4(3):271-9.

22. Jass JR, Filipe MI. Histochem J. 1981;13(6):931-9.

23. Dixon MF et al. Am J Surg Pathol. 1996;20(10):1161-81.

24. Kang KP et al. J Gastroenterol Hepatol. 2009;24(1):140-8.

25. Gonzalez CA et al. Int J Cancer. 2010;127(11):2654-60.

26. Filipe MI et al. Gut. 1985;26(12):1319-26.

27. Filipe MI et al. Int J Cancer. 1994;57(3):324-9.

28. Gonzalez CA et al. J Gastroenterol Hepatol. 2016;31(5):953-8.

29. Cassaro M et al. Am J Gastroenterol. 2000;95(6):1431-8.

30. Shao L et al. Int J Cancer. Apr 29. 2018.

31. Stemmermann GN. Cancer. 1994;74(2):556-64.

32. Gonzalez CA et al. Int J Cancer. 2013;133(5):1023-32.

33. Reddy KM et al. Clin Gastroenterol Hepatol. 2016;14(10):1420-5.

34. Tava F et al. Hum Pathol. 2006;37(11):1489-97.

35. Fernandez-Esparrach G et al. Rev Esp Enferm Dig. 2014;106(2):120-32.

36. Ono H et al. Dig Endosc. 2016;28(1):3-15.

37. Evans JA, DeWitt JM. Gastrointest Endosc. 2016;83(1):274.

38. Pimentel-Nunes P et al. Endoscopy. 2019;51(4):365-88.

39. Capelle LG et al. Gastrointest Endosc. 2010;71(7):1150-8.

40. Saumoy M et al. Gastroenterology. 2018;155(3):648-60.

41. Gupta N et al. Gastrointest Endosc. 2011;74(3):610-24 e612.

42. Eshmuratov A et al. Dig Dis Sci. 2010;55(5):1364-75.

43. Nam JH et al. Cancer. 2012;118(20):4953-60.

44. Amin A et al. J R Coll Surg Edinb. 2002;47(5):681-4.

45. Bisschops R et al. United European Gastroenterol J. 2016;4(5):629-56.

46. Uedo N et al. Gastroenterol Clin North Am. 2013;42(2):317-35.

47. Yao K. Ann Gastroenterol. 2013;26(1):11-22.

48. Teh JL et al. Clin Gastroenterol Hepatol. 2015;13(3):480-7 e482.

49. Capelle LG et al. Dig Dis Sci. 2010;55(12):3442-8.

50. Bansal A et al. Gastrointest Endosc. 2008;67(2):210-6.

51. Tahara T et al. Gastrointest Endosc. 2009;70(2):246-53.

52. Uedo N et al. Endoscopy. 2006;38(8):819-24.

53. Pimentel-Nunes P et al. Endoscopy. 2012;44(3):236-46.

54. Kato M et al. Gastrointest Endosc. 2009;70(5):899-906.

55. Nishimura J et al. Gastroenterol Res Pract. 2014;2014:819395.

56. Dohi O et al. Gastrointest Endosc. 2019;89(1):47-57.

57. Osawa H et al. World J Gastrointest Endosc. 2012;4(8):356-61.

58. Pasechnikov V et al. World J Gastroenterol. 2014;20(38):13842-62.

Introduction

Abdominal pain is a complex phenomenon that involves unpleasant sensory and emotional experiences caused by actual or potential visceral tissue damage. As pain becomes chronic, there is a functional reorganization of the brain involved in emotional and cognitive processing leading to amplification of pain perception and associated pain suffering.^1,2 With the rising recognition of the complexity of pain management in the 1960s, the treatment of pain became a recognized field of study, leading to the formation of interdisciplinary teams to treat pain. However, although efficacious, this model lacked adequate reimbursement structures and eventually subsided as opioids (which at the time were widely believed to be nonaddictive) become more prevalent.³ Not only is there a lack of empirical evidence for opioids in the management of chronic abdominal pain, there is a growing list of adverse consequences of prolonged opioid use for both the brain and gastrointestinal tract.⁴

Recently, there has been more clinical focus on behavioral interventions that can modulate gut pain signals and associated behaviors by reversing maladaptive emotional and cognitive brain processes.⁵ One such psychological process that has received little attention is the traumatizing nature of chronic abdominal pain. Chronic pain, particularly when it feels uncontrollable to patients, activates the brain’s fear circuitry and drives hyperarousal, emotional numbing, and consolidation of painful somatic memories, which become habitual and further amplify negative visceral signals.^6,7 These processes are identical to the symptom manifestations of posttraumatic stress disorder (PTSD) such as intrusiveness, avoidance, negative mood and cognitions, and hyperarousal from life events. In fact, individuals with a history of other traumatizing exposures have an even higher risk of developing chronic pain disorders.⁸ This review has two objectives: to provide a theoretical framework for understanding chronic pain as a traumatizing experience with posttraumatic manifestations and to discuss behavioral interventions and adjunctive nonopioid pharmacotherapy embedded in multidisciplinary care models essential to reversing this negative brain-gut cycle and reducing pain-related suffering.
 

Trauma and chronic abdominal pain

Trauma is defined as an individual’s response to a threat to safety. Traumatized patients or those with PTSD are at higher risk for chronic abdominal pain.⁹ Given the strong neurobiological connection between the brain and gut that has been phylogenetically preserved, emotional (e.g., fear, terror) or physical (e.g., pain) signals represent danger, and with chronicity, there can be a kindling-related consolidation of these maladaptive neurobiological pathways leading to suffering (e.g., hopelessness, sense of failure) and disability (Figure 1).

The interrelationship between chronic pain and trauma is multifaceted and is further complicated by the traumatizing nature of chronic pain itself, when pain is interpreted as a signal that the body is sick or even dangerously ill. Patients with chronic abdominal pain may seek multiple medical opinions and often undergo extensive, unnecessary, and sometimes harmful interventions to find the cause of their pain, with fear of disability and even death driving this search for answers.

The degree to which an individual with long-lasting pain interprets their discomfort as a risk to their well-being is related to the degree of trauma they experience because of their pain.¹⁰ Indeed, many of the negative symptoms associated with posttraumatic stress are also found in those with chronic abdominal pain. Trauma impacts the fear circuitry centers of the brain, leading to altered activation of the hypothalamic-pituitary-adrenal axis and the amygdala, as well as chronic activation of the sympathetic nervous system and stress-released hormones, all of which are potential pathways that dysregulate the brain-gut relationship.^11-13 Worries for safety, which are reactivated by physiological cues (e.g., GI symptoms, pain), as well as avoidance of potential triggers of GI symptoms (e.g., food, exercise, medications, and situations such as travel or scheduled events, and fear of being trapped without bathroom access), are common. Traumatized individuals can experience a foreshortened sense of the future, which may lead to decreased investment in long-term determinants of health (e.g., balanced diet, exercise, social support) and have higher rates of functional impairment and higher health care utilization.¹⁴ Negative mood, including irritability, anxiety, depression, insomnia, and impaired concentration are common in those with trauma and chronic pain and can be accompanied by internalized blame (e.g., depression, substance abuse, suicidality) or externalized blame (e.g., negative relationships with health care providers, rejection from their support or faith system). These can be worsened by an impaired sense of trust, which impacts the patient-provider relationship and other sources of social support leading to lack of behavioral activation, anhedonia, and isolation.

Another commonality is hypervigilance, as those with chronic abdominal pain are often hyperaware of physical symptoms and always “on alert” for a signal indicative of a pain flare. Anxiety and depression frequently co-occur in populations with trauma and chronic pain; these diagnoses are associated with higher rates of catastrophizing and learned helplessness, which may be exacerbated by lack of a “cure” for functional gastrointestinal disorders (FGIDs) and chronic pain.¹⁵ These factors could potentially lead to lack of engagement with treatment or, alternatively, risky or destructive attempts to cure pain including dangerous complementary alternative treatments or substance abuse to numb sensations. Another feature of trauma in chronic pain is the sense of dissociation from and lack of control over the body, sometimes induced by negative medical experiences (e.g., unwanted physical examinations, medication side effects, traumatic procedures, or hospitalizations).^16,17

The importance of treating trauma in the management of chronic pain

Behavioral treatment is increasingly being recognized as an essential component in the management of any chronic pain syndrome.¹⁸ The most studied psychosocial interventions for chronic abdominal pain are cognitive-behavioral therapy (CBT) and gut-focused hypnosis. CBT is usually a problem-focused, short-term intervention that can be delivered individually in the office, via group therapy, or through virtual platforms. CBT is most effective when cognitive distortions and ineffective behaviors create emotional distress, and the therapy targets patient’s stress reactivity, visceral anxiety, catastrophizing, and inflexible coping styles.⁵ Gut-focused hypnosis is the second most–studied behavioral treatment for chronic abdominal pain and utilizes the trance state to make positive suggestions leading to broad and lasting physiological and psychological improvement.¹⁹ In addition to pain management, both CBT and hypnosis are efficacious treatments for PTSD.^20,21

Utilizing a multidisciplinary medical team including integrated behavioral experts, such as in a patient-centered medical home, is considered the standard of care for treatment of chronic pain. The patient-provider relationship is essential, as is consistent follow-up to ensure effective symptom management and improvements in quality of life. Additionally, patient education, including a positive (i.e., clear) diagnosis and information on the brain-gut relationship, is associated with symptom improvement. In our subspecialty medical home for inflammatory bowel disease (IBD), we found that, in our patients who were on opioids for their chronic pain, engagement with our embedded behavioral and pain specialists resulted in significant reduction in opioid use and depression as well as improved self-reported quality of life.²² Gastroenterologists and advanced-practice providers operating without embedded behavioral therapists can consider referring patients to behavioral treatment (e.g., licensed clinical social workers, licensed professional counselors, marriage and family therapists, psychologists, and psychiatrists; the latter often specialize in medication management and may not offer behavioral therapy) for trauma if patients have undergone a traumatic event (e.g., exposure to any potentially life-threatening event, serious injury, or violence) at any point in their lifetime and are experiencing intrusive symptoms (e.g., memories, dreams, or flashbacks to trauma), avoidance of trauma reminders, and negative mood or hyperarousal related to traumatic events (Table 1).²³

With the traumatization component of chronic abdominal pain, which can further drive maladaptive coping cycles, incorporation of trauma-informed treatment into gastroenterology clinics is an avenue toward more effective treatment. The core principles of trauma-informed care include safety, choice, collaboration, trustworthiness, and empowerment,²⁴ and are easily aligned with patient-centered models of care such as the interdisciplinary medical home model. Incorporation of screening techniques, interdisciplinary training of clinicians, and use of behavioral providers with experience in evidenced-based treatments of trauma enhance a clinic’s ability to effectively identify and treat individuals who have trauma because of their abdominal pain.²⁵ Additionally, the most common behavioral interventions for functional gastrointestinal disorders (FGIDs) are also efficacious in the treatment of trauma. CBT is a well-validated treatment for PTSD that utilizes exposure therapy to help individuals restructure negative beliefs shaped by their negative experience and develop relaxation skills. Hypnosis is also validated in the treatment of trauma, with the possible mechanism of action being the replacement of the negative or dissociated traumatic trance with a healthy, adaptive trance facilitated by the hypnotherapist.²¹
 

Adjunctive nonopioid medications for chronic abdominal pain

While there are few randomized controlled trials establishing efficacy of pharmacotherapy for sustained improvement of abdominal pain or related suffering, several small trials and consensus clinical expert opinion suggest partial improvement in these domains.^26,27 Central neuromodulators that can attenuate chronic visceral pain include antidepressants, antipsychotics, and other central nervous system–targeted medications.²⁶ Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, imipramine, desipramine) are often first-line treatment for FGIDs.²⁸ Serotonin noradrenergic reuptake inhibitors (e.g., duloxetine, venlafaxine, desvenlafaxine, milnacipran) are also effective in pain management. Selective serotonin reuptake inhibitors (e.g., paroxetine, fluoxetine, sertraline, citalopram, escitalopram) can be used, especially when comorbid depression, anxiety, and phobic disorders are present. Tetracyclic antidepressants (e.g., mirtazapine, mianserin, trazodone) are effective treatments for early satiety, nausea/vomiting, insomnia, and low weight. Augmenting agents are utilized when single agents do not provide maximum benefit, including quetiapine (disturbed sleep), bupropion (fatigue), aripiprazole, buspirone, and tandospirone (dyspeptic features and anxiety). Delta ligands including gabapentin and pregabalin are helpful for abdominal wall pain or fibromyalgia. Ketamine is a newer but promising pathway for treatment of pain and depression and is increasingly being utilized in outpatient settings. Additionally, partial opioid-receptor agonists including methadone and suboxone have been reported to decrease pain in addition to their efficacy in addiction recovery. Medical marijuana is another area of growing interest, and while research has yet to show a clear effect in pain management, it does appear helpful in nausea and appetite stimulation. Obtaining a therapeutic response is the first treatment goal, after which a patient should be monitored in at least 6-month intervals to ensure sustained benefits and tolerability, and if these are not met, enhancement of treatment or a slow taper is indicated. As in all treatments, a positive patient-provider relationship predicts improved treatment adherence and outcomes.²⁶ However, while these pharmacological interventions can reduce symptom severity, there is little evidence that they reduce traumatization without adjunctive psychotherapy.²⁹

Summary

Both behavioral and pharmacological treatment options are available for chronic abdominal pain and most useful if traumatic manifestations are assessed and included as treatment targets. A multidisciplinary approach to the treatment of chronic abdominal pain with increased screening and treatment of trauma is a promising pathway to improved care and management for patients with chronic pain. If trauma is left untreated, the benefits of otherwise effective treatments are likely to be significantly limited.

References
 

1. Apkarian AV et al. Prog Neurobiol. 2009 Feb;87(2):81-97.
2. Gallagher RM et al. Pain Med. 2011 Jan;12(1):1-2. 
3. Collier R et al. CMAJ. 2018 Jan 8;190(1):E26-7. doi: 10.1503/cmaj.109-5523.
4. Szigethy E et al. Nature Reviews Gastroenterology & Hepatology, 2018;15:168-80.
5. Ballou S et al. Clin Transl Gastroenterol. 2017 Jan;8(1):e214.
6. Egloff N et al. J Pain Res. 2013 Nov 5;6:765-70.
7. Fashler S et al. J Pain Res. 2016 Aug 10;9:551-61. 
8. McKernan LC et al. Clin J Pain. 2019 May;35(5):385-93.
9.  Ju T et al. J Clin  Gastroenterol. 2018 Dec 19. doi: 10.1097/MCG.0000000000001153.
10. Fishbain DA et al. Pain Med. 2017 Apr 1;18(4):711-35.
11. Martin CR et al. Cell Mol Gastroenterol Hepatol. 2018;6(2):133-48. 
12. Osadchiy V et al. Clin Gastroenterol Hepatol. 2019 Jan;17(2):322-32. 
13. Brzozowski B et al. Curr Neuropharmacol. 2016 Nov;14(8):892-900.
14. Outclat SD et al. Pain Med. 2014;15(11):1872-9.
15. Asmundson GJ et al. Can J Psychiatry. 2002;Dec;47(10):930-7. 
16. Taft TH et al. Inflamm Bowel Dis. 2019 Mar 7. doi: 10.1093/ibd/izz032.
17. Duckworth MP et al. International Journal of Rehabilitation and Health, 2000 Apr;5(2):129-39. 
18. Scascighini L et al. Rheumatology (Oxford). 2008 May;47(5):670-8.
19. Palsson O et al. European Gastroenterology & Hepatology Review. 2010;6(1):42-6. 
20. Watkins LE et al. Frontiers in Behavioral Neuroscience. 2018;12:1-9.
21. O’Toole SK et al. J Trauma Stress. 2016 Feb;29(1):97-100.
22. Goldblum Y et al. Digestive Disease Week. San Diego. 2019. Abstract in press.
23. American Psychiatric Association. Diagnostic and Statistical Manual (of Mental Disorders), Fifth Edition. Arlington, Va: American Psychiatric Publishing, 2013. 
24. United States Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. 2018. Trauma-informed approach and trauma-specific interventions. Retrieved from samhsa.gov/nctic/trauma-interventions.
25. Click BH et al. Inflamm Bowel Dis. 2017;23(5):681-94.
26. Drossman DA et al. Gastroenterology. 2018 Mar;154(4):1140-71.
27. Thorkelson G et al. Inflamm Bowel Dis. 2016 Jun 1;22(6):1509-22.
28. Törnblom H et al. Current Gastroenterology Reports. 2018;20(12):58. 
29. Watkins LE et al. Front Behav Neurosci. 2018;12:258. 
30. American Psychiatric Association. Clinical Practice Guideline for the Treatment of Posttraumatic Stress Disorder (PTSD) in Adults. 2017.
31. Bisson JI et al. Cochrane Database Syst Rev. 2013 Dec 13;(12):CD003388.
32. Department of Veterans Affairs and Department of Defense. VA/DOD clinical practice guideline for the management of posttraumatic stress disorder and acute stress disorder. 2017.
33. Karatzias T et al. Psychol Med. 2019 Mar 12:1-15. doi: 10.1017/S0033291719000436. Advance online publication.

Emily Weaver, LCSW, is a UPMC Total Care–IBD program senior social worker, Eva Szigethy, MD, PhD, is professor of psychiatry and medicine, codirector, IBD Total Care Medical Home, University of Pittsburgh Medical Center, departments of medicine and psychiatry.

Introduction

Abdominal pain is a complex phenomenon that involves unpleasant sensory and emotional experiences caused by actual or potential visceral tissue damage. As pain becomes chronic, there is a functional reorganization of the brain involved in emotional and cognitive processing leading to amplification of pain perception and associated pain suffering.^1,2 With the rising recognition of the complexity of pain management in the 1960s, the treatment of pain became a recognized field of study, leading to the formation of interdisciplinary teams to treat pain. However, although efficacious, this model lacked adequate reimbursement structures and eventually subsided as opioids (which at the time were widely believed to be nonaddictive) become more prevalent.³ Not only is there a lack of empirical evidence for opioids in the management of chronic abdominal pain, there is a growing list of adverse consequences of prolonged opioid use for both the brain and gastrointestinal tract.⁴

Recently, there has been more clinical focus on behavioral interventions that can modulate gut pain signals and associated behaviors by reversing maladaptive emotional and cognitive brain processes.⁵ One such psychological process that has received little attention is the traumatizing nature of chronic abdominal pain. Chronic pain, particularly when it feels uncontrollable to patients, activates the brain’s fear circuitry and drives hyperarousal, emotional numbing, and consolidation of painful somatic memories, which become habitual and further amplify negative visceral signals.^6,7 These processes are identical to the symptom manifestations of posttraumatic stress disorder (PTSD) such as intrusiveness, avoidance, negative mood and cognitions, and hyperarousal from life events. In fact, individuals with a history of other traumatizing exposures have an even higher risk of developing chronic pain disorders.⁸ This review has two objectives: to provide a theoretical framework for understanding chronic pain as a traumatizing experience with posttraumatic manifestations and to discuss behavioral interventions and adjunctive nonopioid pharmacotherapy embedded in multidisciplinary care models essential to reversing this negative brain-gut cycle and reducing pain-related suffering.
 

Trauma and chronic abdominal pain

Trauma is defined as an individual’s response to a threat to safety. Traumatized patients or those with PTSD are at higher risk for chronic abdominal pain.⁹ Given the strong neurobiological connection between the brain and gut that has been phylogenetically preserved, emotional (e.g., fear, terror) or physical (e.g., pain) signals represent danger, and with chronicity, there can be a kindling-related consolidation of these maladaptive neurobiological pathways leading to suffering (e.g., hopelessness, sense of failure) and disability (Figure 1).

The interrelationship between chronic pain and trauma is multifaceted and is further complicated by the traumatizing nature of chronic pain itself, when pain is interpreted as a signal that the body is sick or even dangerously ill. Patients with chronic abdominal pain may seek multiple medical opinions and often undergo extensive, unnecessary, and sometimes harmful interventions to find the cause of their pain, with fear of disability and even death driving this search for answers.

The degree to which an individual with long-lasting pain interprets their discomfort as a risk to their well-being is related to the degree of trauma they experience because of their pain.¹⁰ Indeed, many of the negative symptoms associated with posttraumatic stress are also found in those with chronic abdominal pain. Trauma impacts the fear circuitry centers of the brain, leading to altered activation of the hypothalamic-pituitary-adrenal axis and the amygdala, as well as chronic activation of the sympathetic nervous system and stress-released hormones, all of which are potential pathways that dysregulate the brain-gut relationship.^11-13 Worries for safety, which are reactivated by physiological cues (e.g., GI symptoms, pain), as well as avoidance of potential triggers of GI symptoms (e.g., food, exercise, medications, and situations such as travel or scheduled events, and fear of being trapped without bathroom access), are common. Traumatized individuals can experience a foreshortened sense of the future, which may lead to decreased investment in long-term determinants of health (e.g., balanced diet, exercise, social support) and have higher rates of functional impairment and higher health care utilization.¹⁴ Negative mood, including irritability, anxiety, depression, insomnia, and impaired concentration are common in those with trauma and chronic pain and can be accompanied by internalized blame (e.g., depression, substance abuse, suicidality) or externalized blame (e.g., negative relationships with health care providers, rejection from their support or faith system). These can be worsened by an impaired sense of trust, which impacts the patient-provider relationship and other sources of social support leading to lack of behavioral activation, anhedonia, and isolation.

Another commonality is hypervigilance, as those with chronic abdominal pain are often hyperaware of physical symptoms and always “on alert” for a signal indicative of a pain flare. Anxiety and depression frequently co-occur in populations with trauma and chronic pain; these diagnoses are associated with higher rates of catastrophizing and learned helplessness, which may be exacerbated by lack of a “cure” for functional gastrointestinal disorders (FGIDs) and chronic pain.¹⁵ These factors could potentially lead to lack of engagement with treatment or, alternatively, risky or destructive attempts to cure pain including dangerous complementary alternative treatments or substance abuse to numb sensations. Another feature of trauma in chronic pain is the sense of dissociation from and lack of control over the body, sometimes induced by negative medical experiences (e.g., unwanted physical examinations, medication side effects, traumatic procedures, or hospitalizations).^16,17

The importance of treating trauma in the management of chronic pain

Behavioral treatment is increasingly being recognized as an essential component in the management of any chronic pain syndrome.¹⁸ The most studied psychosocial interventions for chronic abdominal pain are cognitive-behavioral therapy (CBT) and gut-focused hypnosis. CBT is usually a problem-focused, short-term intervention that can be delivered individually in the office, via group therapy, or through virtual platforms. CBT is most effective when cognitive distortions and ineffective behaviors create emotional distress, and the therapy targets patient’s stress reactivity, visceral anxiety, catastrophizing, and inflexible coping styles.⁵ Gut-focused hypnosis is the second most–studied behavioral treatment for chronic abdominal pain and utilizes the trance state to make positive suggestions leading to broad and lasting physiological and psychological improvement.¹⁹ In addition to pain management, both CBT and hypnosis are efficacious treatments for PTSD.^20,21

Utilizing a multidisciplinary medical team including integrated behavioral experts, such as in a patient-centered medical home, is considered the standard of care for treatment of chronic pain. The patient-provider relationship is essential, as is consistent follow-up to ensure effective symptom management and improvements in quality of life. Additionally, patient education, including a positive (i.e., clear) diagnosis and information on the brain-gut relationship, is associated with symptom improvement. In our subspecialty medical home for inflammatory bowel disease (IBD), we found that, in our patients who were on opioids for their chronic pain, engagement with our embedded behavioral and pain specialists resulted in significant reduction in opioid use and depression as well as improved self-reported quality of life.²² Gastroenterologists and advanced-practice providers operating without embedded behavioral therapists can consider referring patients to behavioral treatment (e.g., licensed clinical social workers, licensed professional counselors, marriage and family therapists, psychologists, and psychiatrists; the latter often specialize in medication management and may not offer behavioral therapy) for trauma if patients have undergone a traumatic event (e.g., exposure to any potentially life-threatening event, serious injury, or violence) at any point in their lifetime and are experiencing intrusive symptoms (e.g., memories, dreams, or flashbacks to trauma), avoidance of trauma reminders, and negative mood or hyperarousal related to traumatic events (Table 1).²³

With the traumatization component of chronic abdominal pain, which can further drive maladaptive coping cycles, incorporation of trauma-informed treatment into gastroenterology clinics is an avenue toward more effective treatment. The core principles of trauma-informed care include safety, choice, collaboration, trustworthiness, and empowerment,²⁴ and are easily aligned with patient-centered models of care such as the interdisciplinary medical home model. Incorporation of screening techniques, interdisciplinary training of clinicians, and use of behavioral providers with experience in evidenced-based treatments of trauma enhance a clinic’s ability to effectively identify and treat individuals who have trauma because of their abdominal pain.²⁵ Additionally, the most common behavioral interventions for functional gastrointestinal disorders (FGIDs) are also efficacious in the treatment of trauma. CBT is a well-validated treatment for PTSD that utilizes exposure therapy to help individuals restructure negative beliefs shaped by their negative experience and develop relaxation skills. Hypnosis is also validated in the treatment of trauma, with the possible mechanism of action being the replacement of the negative or dissociated traumatic trance with a healthy, adaptive trance facilitated by the hypnotherapist.²¹
 

Adjunctive nonopioid medications for chronic abdominal pain

While there are few randomized controlled trials establishing efficacy of pharmacotherapy for sustained improvement of abdominal pain or related suffering, several small trials and consensus clinical expert opinion suggest partial improvement in these domains.^26,27 Central neuromodulators that can attenuate chronic visceral pain include antidepressants, antipsychotics, and other central nervous system–targeted medications.²⁶ Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, imipramine, desipramine) are often first-line treatment for FGIDs.²⁸ Serotonin noradrenergic reuptake inhibitors (e.g., duloxetine, venlafaxine, desvenlafaxine, milnacipran) are also effective in pain management. Selective serotonin reuptake inhibitors (e.g., paroxetine, fluoxetine, sertraline, citalopram, escitalopram) can be used, especially when comorbid depression, anxiety, and phobic disorders are present. Tetracyclic antidepressants (e.g., mirtazapine, mianserin, trazodone) are effective treatments for early satiety, nausea/vomiting, insomnia, and low weight. Augmenting agents are utilized when single agents do not provide maximum benefit, including quetiapine (disturbed sleep), bupropion (fatigue), aripiprazole, buspirone, and tandospirone (dyspeptic features and anxiety). Delta ligands including gabapentin and pregabalin are helpful for abdominal wall pain or fibromyalgia. Ketamine is a newer but promising pathway for treatment of pain and depression and is increasingly being utilized in outpatient settings. Additionally, partial opioid-receptor agonists including methadone and suboxone have been reported to decrease pain in addition to their efficacy in addiction recovery. Medical marijuana is another area of growing interest, and while research has yet to show a clear effect in pain management, it does appear helpful in nausea and appetite stimulation. Obtaining a therapeutic response is the first treatment goal, after which a patient should be monitored in at least 6-month intervals to ensure sustained benefits and tolerability, and if these are not met, enhancement of treatment or a slow taper is indicated. As in all treatments, a positive patient-provider relationship predicts improved treatment adherence and outcomes.²⁶ However, while these pharmacological interventions can reduce symptom severity, there is little evidence that they reduce traumatization without adjunctive psychotherapy.²⁹

Summary

Both behavioral and pharmacological treatment options are available for chronic abdominal pain and most useful if traumatic manifestations are assessed and included as treatment targets. A multidisciplinary approach to the treatment of chronic abdominal pain with increased screening and treatment of trauma is a promising pathway to improved care and management for patients with chronic pain. If trauma is left untreated, the benefits of otherwise effective treatments are likely to be significantly limited.

References
 

1. Apkarian AV et al. Prog Neurobiol. 2009 Feb;87(2):81-97.
2. Gallagher RM et al. Pain Med. 2011 Jan;12(1):1-2. 
3. Collier R et al. CMAJ. 2018 Jan 8;190(1):E26-7. doi: 10.1503/cmaj.109-5523.
4. Szigethy E et al. Nature Reviews Gastroenterology & Hepatology, 2018;15:168-80.
5. Ballou S et al. Clin Transl Gastroenterol. 2017 Jan;8(1):e214.
6. Egloff N et al. J Pain Res. 2013 Nov 5;6:765-70.
7. Fashler S et al. J Pain Res. 2016 Aug 10;9:551-61. 
8. McKernan LC et al. Clin J Pain. 2019 May;35(5):385-93.
9.  Ju T et al. J Clin  Gastroenterol. 2018 Dec 19. doi: 10.1097/MCG.0000000000001153.
10. Fishbain DA et al. Pain Med. 2017 Apr 1;18(4):711-35.
11. Martin CR et al. Cell Mol Gastroenterol Hepatol. 2018;6(2):133-48. 
12. Osadchiy V et al. Clin Gastroenterol Hepatol. 2019 Jan;17(2):322-32. 
13. Brzozowski B et al. Curr Neuropharmacol. 2016 Nov;14(8):892-900.
14. Outclat SD et al. Pain Med. 2014;15(11):1872-9.
15. Asmundson GJ et al. Can J Psychiatry. 2002;Dec;47(10):930-7. 
16. Taft TH et al. Inflamm Bowel Dis. 2019 Mar 7. doi: 10.1093/ibd/izz032.
17. Duckworth MP et al. International Journal of Rehabilitation and Health, 2000 Apr;5(2):129-39. 
18. Scascighini L et al. Rheumatology (Oxford). 2008 May;47(5):670-8.
19. Palsson O et al. European Gastroenterology & Hepatology Review. 2010;6(1):42-6. 
20. Watkins LE et al. Frontiers in Behavioral Neuroscience. 2018;12:1-9.
21. O’Toole SK et al. J Trauma Stress. 2016 Feb;29(1):97-100.
22. Goldblum Y et al. Digestive Disease Week. San Diego. 2019. Abstract in press.
23. American Psychiatric Association. Diagnostic and Statistical Manual (of Mental Disorders), Fifth Edition. Arlington, Va: American Psychiatric Publishing, 2013. 
24. United States Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. 2018. Trauma-informed approach and trauma-specific interventions. Retrieved from samhsa.gov/nctic/trauma-interventions.
25. Click BH et al. Inflamm Bowel Dis. 2017;23(5):681-94.
26. Drossman DA et al. Gastroenterology. 2018 Mar;154(4):1140-71.
27. Thorkelson G et al. Inflamm Bowel Dis. 2016 Jun 1;22(6):1509-22.
28. Törnblom H et al. Current Gastroenterology Reports. 2018;20(12):58. 
29. Watkins LE et al. Front Behav Neurosci. 2018;12:258. 
30. American Psychiatric Association. Clinical Practice Guideline for the Treatment of Posttraumatic Stress Disorder (PTSD) in Adults. 2017.
31. Bisson JI et al. Cochrane Database Syst Rev. 2013 Dec 13;(12):CD003388.
32. Department of Veterans Affairs and Department of Defense. VA/DOD clinical practice guideline for the management of posttraumatic stress disorder and acute stress disorder. 2017.
33. Karatzias T et al. Psychol Med. 2019 Mar 12:1-15. doi: 10.1017/S0033291719000436. Advance online publication.

Emily Weaver, LCSW, is a UPMC Total Care–IBD program senior social worker, Eva Szigethy, MD, PhD, is professor of psychiatry and medicine, codirector, IBD Total Care Medical Home, University of Pittsburgh Medical Center, departments of medicine and psychiatry.

Introduction

Abdominal pain is a complex phenomenon that involves unpleasant sensory and emotional experiences caused by actual or potential visceral tissue damage. As pain becomes chronic, there is a functional reorganization of the brain involved in emotional and cognitive processing leading to amplification of pain perception and associated pain suffering.^1,2 With the rising recognition of the complexity of pain management in the 1960s, the treatment of pain became a recognized field of study, leading to the formation of interdisciplinary teams to treat pain. However, although efficacious, this model lacked adequate reimbursement structures and eventually subsided as opioids (which at the time were widely believed to be nonaddictive) become more prevalent.³ Not only is there a lack of empirical evidence for opioids in the management of chronic abdominal pain, there is a growing list of adverse consequences of prolonged opioid use for both the brain and gastrointestinal tract.⁴

Recently, there has been more clinical focus on behavioral interventions that can modulate gut pain signals and associated behaviors by reversing maladaptive emotional and cognitive brain processes.⁵ One such psychological process that has received little attention is the traumatizing nature of chronic abdominal pain. Chronic pain, particularly when it feels uncontrollable to patients, activates the brain’s fear circuitry and drives hyperarousal, emotional numbing, and consolidation of painful somatic memories, which become habitual and further amplify negative visceral signals.^6,7 These processes are identical to the symptom manifestations of posttraumatic stress disorder (PTSD) such as intrusiveness, avoidance, negative mood and cognitions, and hyperarousal from life events. In fact, individuals with a history of other traumatizing exposures have an even higher risk of developing chronic pain disorders.⁸ This review has two objectives: to provide a theoretical framework for understanding chronic pain as a traumatizing experience with posttraumatic manifestations and to discuss behavioral interventions and adjunctive nonopioid pharmacotherapy embedded in multidisciplinary care models essential to reversing this negative brain-gut cycle and reducing pain-related suffering.
 

Trauma and chronic abdominal pain

Trauma is defined as an individual’s response to a threat to safety. Traumatized patients or those with PTSD are at higher risk for chronic abdominal pain.⁹ Given the strong neurobiological connection between the brain and gut that has been phylogenetically preserved, emotional (e.g., fear, terror) or physical (e.g., pain) signals represent danger, and with chronicity, there can be a kindling-related consolidation of these maladaptive neurobiological pathways leading to suffering (e.g., hopelessness, sense of failure) and disability (Figure 1).

The interrelationship between chronic pain and trauma is multifaceted and is further complicated by the traumatizing nature of chronic pain itself, when pain is interpreted as a signal that the body is sick or even dangerously ill. Patients with chronic abdominal pain may seek multiple medical opinions and often undergo extensive, unnecessary, and sometimes harmful interventions to find the cause of their pain, with fear of disability and even death driving this search for answers.

The degree to which an individual with long-lasting pain interprets their discomfort as a risk to their well-being is related to the degree of trauma they experience because of their pain.¹⁰ Indeed, many of the negative symptoms associated with posttraumatic stress are also found in those with chronic abdominal pain. Trauma impacts the fear circuitry centers of the brain, leading to altered activation of the hypothalamic-pituitary-adrenal axis and the amygdala, as well as chronic activation of the sympathetic nervous system and stress-released hormones, all of which are potential pathways that dysregulate the brain-gut relationship.^11-13 Worries for safety, which are reactivated by physiological cues (e.g., GI symptoms, pain), as well as avoidance of potential triggers of GI symptoms (e.g., food, exercise, medications, and situations such as travel or scheduled events, and fear of being trapped without bathroom access), are common. Traumatized individuals can experience a foreshortened sense of the future, which may lead to decreased investment in long-term determinants of health (e.g., balanced diet, exercise, social support) and have higher rates of functional impairment and higher health care utilization.¹⁴ Negative mood, including irritability, anxiety, depression, insomnia, and impaired concentration are common in those with trauma and chronic pain and can be accompanied by internalized blame (e.g., depression, substance abuse, suicidality) or externalized blame (e.g., negative relationships with health care providers, rejection from their support or faith system). These can be worsened by an impaired sense of trust, which impacts the patient-provider relationship and other sources of social support leading to lack of behavioral activation, anhedonia, and isolation.

Another commonality is hypervigilance, as those with chronic abdominal pain are often hyperaware of physical symptoms and always “on alert” for a signal indicative of a pain flare. Anxiety and depression frequently co-occur in populations with trauma and chronic pain; these diagnoses are associated with higher rates of catastrophizing and learned helplessness, which may be exacerbated by lack of a “cure” for functional gastrointestinal disorders (FGIDs) and chronic pain.¹⁵ These factors could potentially lead to lack of engagement with treatment or, alternatively, risky or destructive attempts to cure pain including dangerous complementary alternative treatments or substance abuse to numb sensations. Another feature of trauma in chronic pain is the sense of dissociation from and lack of control over the body, sometimes induced by negative medical experiences (e.g., unwanted physical examinations, medication side effects, traumatic procedures, or hospitalizations).^16,17

The importance of treating trauma in the management of chronic pain

Behavioral treatment is increasingly being recognized as an essential component in the management of any chronic pain syndrome.¹⁸ The most studied psychosocial interventions for chronic abdominal pain are cognitive-behavioral therapy (CBT) and gut-focused hypnosis. CBT is usually a problem-focused, short-term intervention that can be delivered individually in the office, via group therapy, or through virtual platforms. CBT is most effective when cognitive distortions and ineffective behaviors create emotional distress, and the therapy targets patient’s stress reactivity, visceral anxiety, catastrophizing, and inflexible coping styles.⁵ Gut-focused hypnosis is the second most–studied behavioral treatment for chronic abdominal pain and utilizes the trance state to make positive suggestions leading to broad and lasting physiological and psychological improvement.¹⁹ In addition to pain management, both CBT and hypnosis are efficacious treatments for PTSD.^20,21

Utilizing a multidisciplinary medical team including integrated behavioral experts, such as in a patient-centered medical home, is considered the standard of care for treatment of chronic pain. The patient-provider relationship is essential, as is consistent follow-up to ensure effective symptom management and improvements in quality of life. Additionally, patient education, including a positive (i.e., clear) diagnosis and information on the brain-gut relationship, is associated with symptom improvement. In our subspecialty medical home for inflammatory bowel disease (IBD), we found that, in our patients who were on opioids for their chronic pain, engagement with our embedded behavioral and pain specialists resulted in significant reduction in opioid use and depression as well as improved self-reported quality of life.²² Gastroenterologists and advanced-practice providers operating without embedded behavioral therapists can consider referring patients to behavioral treatment (e.g., licensed clinical social workers, licensed professional counselors, marriage and family therapists, psychologists, and psychiatrists; the latter often specialize in medication management and may not offer behavioral therapy) for trauma if patients have undergone a traumatic event (e.g., exposure to any potentially life-threatening event, serious injury, or violence) at any point in their lifetime and are experiencing intrusive symptoms (e.g., memories, dreams, or flashbacks to trauma), avoidance of trauma reminders, and negative mood or hyperarousal related to traumatic events (Table 1).²³

With the traumatization component of chronic abdominal pain, which can further drive maladaptive coping cycles, incorporation of trauma-informed treatment into gastroenterology clinics is an avenue toward more effective treatment. The core principles of trauma-informed care include safety, choice, collaboration, trustworthiness, and empowerment,²⁴ and are easily aligned with patient-centered models of care such as the interdisciplinary medical home model. Incorporation of screening techniques, interdisciplinary training of clinicians, and use of behavioral providers with experience in evidenced-based treatments of trauma enhance a clinic’s ability to effectively identify and treat individuals who have trauma because of their abdominal pain.²⁵ Additionally, the most common behavioral interventions for functional gastrointestinal disorders (FGIDs) are also efficacious in the treatment of trauma. CBT is a well-validated treatment for PTSD that utilizes exposure therapy to help individuals restructure negative beliefs shaped by their negative experience and develop relaxation skills. Hypnosis is also validated in the treatment of trauma, with the possible mechanism of action being the replacement of the negative or dissociated traumatic trance with a healthy, adaptive trance facilitated by the hypnotherapist.²¹
 

Adjunctive nonopioid medications for chronic abdominal pain

While there are few randomized controlled trials establishing efficacy of pharmacotherapy for sustained improvement of abdominal pain or related suffering, several small trials and consensus clinical expert opinion suggest partial improvement in these domains.^26,27 Central neuromodulators that can attenuate chronic visceral pain include antidepressants, antipsychotics, and other central nervous system–targeted medications.²⁶ Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, imipramine, desipramine) are often first-line treatment for FGIDs.²⁸ Serotonin noradrenergic reuptake inhibitors (e.g., duloxetine, venlafaxine, desvenlafaxine, milnacipran) are also effective in pain management. Selective serotonin reuptake inhibitors (e.g., paroxetine, fluoxetine, sertraline, citalopram, escitalopram) can be used, especially when comorbid depression, anxiety, and phobic disorders are present. Tetracyclic antidepressants (e.g., mirtazapine, mianserin, trazodone) are effective treatments for early satiety, nausea/vomiting, insomnia, and low weight. Augmenting agents are utilized when single agents do not provide maximum benefit, including quetiapine (disturbed sleep), bupropion (fatigue), aripiprazole, buspirone, and tandospirone (dyspeptic features and anxiety). Delta ligands including gabapentin and pregabalin are helpful for abdominal wall pain or fibromyalgia. Ketamine is a newer but promising pathway for treatment of pain and depression and is increasingly being utilized in outpatient settings. Additionally, partial opioid-receptor agonists including methadone and suboxone have been reported to decrease pain in addition to their efficacy in addiction recovery. Medical marijuana is another area of growing interest, and while research has yet to show a clear effect in pain management, it does appear helpful in nausea and appetite stimulation. Obtaining a therapeutic response is the first treatment goal, after which a patient should be monitored in at least 6-month intervals to ensure sustained benefits and tolerability, and if these are not met, enhancement of treatment or a slow taper is indicated. As in all treatments, a positive patient-provider relationship predicts improved treatment adherence and outcomes.²⁶ However, while these pharmacological interventions can reduce symptom severity, there is little evidence that they reduce traumatization without adjunctive psychotherapy.²⁹

Summary

Both behavioral and pharmacological treatment options are available for chronic abdominal pain and most useful if traumatic manifestations are assessed and included as treatment targets. A multidisciplinary approach to the treatment of chronic abdominal pain with increased screening and treatment of trauma is a promising pathway to improved care and management for patients with chronic pain. If trauma is left untreated, the benefits of otherwise effective treatments are likely to be significantly limited.

References
 

1. Apkarian AV et al. Prog Neurobiol. 2009 Feb;87(2):81-97.
2. Gallagher RM et al. Pain Med. 2011 Jan;12(1):1-2. 
3. Collier R et al. CMAJ. 2018 Jan 8;190(1):E26-7. doi: 10.1503/cmaj.109-5523.
4. Szigethy E et al. Nature Reviews Gastroenterology & Hepatology, 2018;15:168-80.
5. Ballou S et al. Clin Transl Gastroenterol. 2017 Jan;8(1):e214.
6. Egloff N et al. J Pain Res. 2013 Nov 5;6:765-70.
7. Fashler S et al. J Pain Res. 2016 Aug 10;9:551-61. 
8. McKernan LC et al. Clin J Pain. 2019 May;35(5):385-93.
9.  Ju T et al. J Clin  Gastroenterol. 2018 Dec 19. doi: 10.1097/MCG.0000000000001153.
10. Fishbain DA et al. Pain Med. 2017 Apr 1;18(4):711-35.
11. Martin CR et al. Cell Mol Gastroenterol Hepatol. 2018;6(2):133-48. 
12. Osadchiy V et al. Clin Gastroenterol Hepatol. 2019 Jan;17(2):322-32. 
13. Brzozowski B et al. Curr Neuropharmacol. 2016 Nov;14(8):892-900.
14. Outclat SD et al. Pain Med. 2014;15(11):1872-9.
15. Asmundson GJ et al. Can J Psychiatry. 2002;Dec;47(10):930-7. 
16. Taft TH et al. Inflamm Bowel Dis. 2019 Mar 7. doi: 10.1093/ibd/izz032.
17. Duckworth MP et al. International Journal of Rehabilitation and Health, 2000 Apr;5(2):129-39. 
18. Scascighini L et al. Rheumatology (Oxford). 2008 May;47(5):670-8.
19. Palsson O et al. European Gastroenterology & Hepatology Review. 2010;6(1):42-6. 
20. Watkins LE et al. Frontiers in Behavioral Neuroscience. 2018;12:1-9.
21. O’Toole SK et al. J Trauma Stress. 2016 Feb;29(1):97-100.
22. Goldblum Y et al. Digestive Disease Week. San Diego. 2019. Abstract in press.
23. American Psychiatric Association. Diagnostic and Statistical Manual (of Mental Disorders), Fifth Edition. Arlington, Va: American Psychiatric Publishing, 2013. 
24. United States Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. 2018. Trauma-informed approach and trauma-specific interventions. Retrieved from samhsa.gov/nctic/trauma-interventions.
25. Click BH et al. Inflamm Bowel Dis. 2017;23(5):681-94.
26. Drossman DA et al. Gastroenterology. 2018 Mar;154(4):1140-71.
27. Thorkelson G et al. Inflamm Bowel Dis. 2016 Jun 1;22(6):1509-22.
28. Törnblom H et al. Current Gastroenterology Reports. 2018;20(12):58. 
29. Watkins LE et al. Front Behav Neurosci. 2018;12:258. 
30. American Psychiatric Association. Clinical Practice Guideline for the Treatment of Posttraumatic Stress Disorder (PTSD) in Adults. 2017.
31. Bisson JI et al. Cochrane Database Syst Rev. 2013 Dec 13;(12):CD003388.
32. Department of Veterans Affairs and Department of Defense. VA/DOD clinical practice guideline for the management of posttraumatic stress disorder and acute stress disorder. 2017.
33. Karatzias T et al. Psychol Med. 2019 Mar 12:1-15. doi: 10.1017/S0033291719000436. Advance online publication.

Emily Weaver, LCSW, is a UPMC Total Care–IBD program senior social worker, Eva Szigethy, MD, PhD, is professor of psychiatry and medicine, codirector, IBD Total Care Medical Home, University of Pittsburgh Medical Center, departments of medicine and psychiatry.

Introduction

Acute pancreatitis (AP) is a major clinical and financial burden in the United States. Several major clinical guidelines provide evidence-based recommendations for the clinical management decisions in AP, including those from the American College of Gastroenterology (ACG; 2013),¹ and the International Association of Pancreatology (IAP; 2013).² More recently, the American Gastroenterological Association (AGA) released their own set of guidelines.^3,4 In this update on AP, we review these guidelines and reference recent literature focused on epidemiology, risk factors, etiology, diagnosis, risk stratification, and recent advances in the early medical management of AP. Regarding the latter, we review six treatment interventions (pain management, intravenous fluid resuscitation, feeding, prophylactic antibiotics, probiotics, and timing of endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis) and four preventive interventions (alcohol and smoking cessation, same-admission cholecystectomy for acute biliary pancreatitis, and chemoprevention and fluid administration for post-ERCP pancreatitis [PEP]). Updates on multidisciplinary management of (infected) pancreatic necrosis is beyond the scope of this review. Table 1 summarizes the concepts discussed in this article.

Recent advances in epidemiology and evaluation of AP

Epidemiology

AP is the third most common cause of gastrointestinal-related hospitalizations and fourth most common cause of readmission in 2014.⁵ Recent epidemiologic studies show conflicting trends for the incidence of AP, both increasing⁶ and decreasing,⁷ likely attributable to significant differences in study designs. Importantly, multiple studies have demonstrated that hospital length of stay, costs, and mortality have declined since 2009.^6,8-10

Persistent organ failure (POF), defined as organ failure lasting more than 48 hours, is the major cause of death in AP. POF, if only a single organ during AP, is associated with 27%-36% mortality; if it is multiorgan, it is associated with 47% mortality.^1,11 Other factors associated with increased hospital mortality include infected pancreatic necrosis,^12-14 diabetes mellitus,¹⁵ hospital-acquired infection,¹⁶ advanced age (70 years and older),¹⁷ and obesity.¹⁸ Predictive factors of 1-year mortality include readmission within 30 days, higher Charlson Comorbidity Index, and longer hospitalization.¹⁹

Risk factors

We briefly highlight recent insights into risk factors for AP (Table 1) and refer to a recent review for further discussion.²⁰ Current and former tobacco use are independent risk factors for AP.²¹ The dose-response relationship of alcohol to the risk of pancreatitis is complex,²² but five standard drinks per day for 5 years is a commonly used cut-off.^1,23 New evidence suggests that the relationship between the dose of alcohol and risk of AP differs by sex, linearly in men but nonlinearly (J-shaped) in women.²⁴ Risk of AP in women was decreased with alcohol consumption of up to 40 g/day (one standard drink contains 14 g of alcohol) and increased above this amount. Cannabis is a possible risk factor for toxin-induced AP and abstinence appears to abolish risk of recurrent attacks.²⁵

Patients with inflammatory bowel disease (IBD) have a 2.9-fold higher risk for AP versus non-IBD cohorts²⁶ with the most common etiologies are from gallstones and medications.²⁷ In patients with end-stage renal disease (ESRD), the risk of AP is higher in those who receive peritoneal dialysis, compared with hemodialysis^28-33 and who are women, older, or have cholelithiasis or liver disease.³⁴As recently reviewed,³⁵ pancreatic cancer appears to be associated with first-attack pancreatitis with few exceptions.³⁶ In this setting, the overall incidence of pancreatic cancer is low (1.5%). The risk is greatest within the first year of the attack of AP, negligible below age 40 years but steadily rising through the fifth to eighth decades.³⁷ Pancreatic cancer screening is a conditional recommendation of the ACG guidelines in patients with unexplained AP, particularly those aged 40 years or older.¹

Etiology and diagnosis

Alcohol and gallstones remain the most prevalent etiologies for AP.¹ While hypertriglyceridemia accounted for 9% of AP in a systematic review of acute pancreatitis in 15 different countries,³⁸ it is the second most common cause of acute pancreatitis in Asia (especially China).³⁹ Figure 1 provides a breakdown of the etiologies and risk factors of pancreatitis. Importantly, it remains challenging to assign several toxic-metabolic etiologies as either a cause or risk factor for AP, particularly with regards to alcohol, smoking, and cannabis to name a few.

Guidelines and recent studies of AP raise questions about the threshold above which hypertriglyceridemia causes or poses as an important cofactor for AP. American and European societies define the threshold for triglycerides at 885-1,000 mg/dL.^1,42,43 Pedersen et al. provide evidence of a graded risk of AP with hypertriglyceridemia: In multivariable analysis, adjusted hazard ratios for AP were much higher with nonfasting mild to moderately elevated plasma triglycerides (177-885 mg/dL), compared with normal values (below 89 mg/dL).⁴⁴ Moreover, the risk of severe AP (developing POF) increases in proportion to triglyceride value, independent of the underlying cause of AP.⁴⁵

Vidyard Video

Diagnosis of AP is derived from the revised Atlanta classification.⁴⁶ The recommended timing and indications for offering cross-sectional imaging are after 48-72 hours in patients with no improvement to initial care.¹ Endoscopic ultrasonography (EUS) has better diagnostic accuracy and sensitivity, compared with magnetic resonance cholangiopancreatography (MRCP) for choledocholithiasis, and has comparable specificity.^47,48 Among noninvasive imaging modalities, MRCP is more sensitive than computed tomography (CT) for diagnosing choledocholithiasis.⁴⁹ Despite guideline recommendations for more selective use of pancreatic imaging in the early assessment of AP, utilization of early CT or MRCP imaging (within the first 24 hours of care) remained high during 2014-2015, compared with 2006-2007.⁵⁰

ERCP is not recommended as a pure diagnostic tool, owing to the availability of other diagnostic tests and a complication rate of 5%-10% with risks involving PEP, cholangitis, perforation, and hemorrhage.⁵¹ A recent systematic review of EUS and ERCP in acute biliary pancreatitis concluded that EUS had lower failure rates and had no complications, and the use of EUS avoided ERCP in 71.2% of cases.⁵²

 

 

 

Risk stratification

The goals of using risk stratification tools in AP are to identify patients at risk for developing major outcomes, including POF, infected pancreatic necrosis, and death, and to ensure timely triaging of patients to an appropriate level of care. Existing prediction models have only moderate predictive value.^53,54 Examples include simple risk stratification tools such as blood urea nitrogen (BUN) and hemoconcentration,^55,56 disease-modifying patient variables (age, obesity, etc.), biomarkers (i.e., angiopoietin 2),⁵⁷ and more complex clinical scoring systems such as Acute Physiology and Chronic Health Evaluation II (APACHE II), BISAP (BUN, impaired mental status, SIRS criteria, age, pleural effusion) score, early warning system (EWS), Glasgow-Imrie score, Japanese severity score, and recently the Pancreatitis Activity Scoring System (PASS).⁵⁸ Two recent guidelines affirmed the importance of predicting the severity of AP, using one or more predictive tools.^1,2 The recent 2018 AGA technical review does not debate this commonsense approach, but does highlight that there is no published observational study or randomized, controlled trial (RCT) investigating whether prediction tools affect clinical outcomes.⁴

Recent advances in early treatment of AP

Literature review and definitions

The AP literature contains heterogeneous definitions of severe AP and of what constitutes a major outcome in AP. Based on definitions of the 2013 revised Atlanta Criteria, the 2018 AGA technical review and clinical guidelines emphasized precise definitions of primary outcomes of clinical importance in AP, including death, persistent single organ failure, or persistent multiple organ failure, each requiring a duration of more than 48 hours, and infected pancreatic or peripancreatic necrosis or both (Table 2).^3,4

 

Pain management

Management of pain in AP is complex and requires a detailed discussion beyond the scope of this review, but recent clinical and translational studies raise questions about the current practice of using opioids for pain management in AP. A provocative, multicenter, retrospective cohort study reported lower 30-day mortality among critically ill patients who received epidural analgesia versus standard care without epidural analgesia.⁵⁹ The possible mechanism of protection and the drugs administered are unclear. An interesting hypothesis is that the epidural cohort may have received lower exposure to morphine, which may increase gut permeability, the risk of infectious complications, and severity of AP, based on a translational study in mice.⁶⁰

Intravenous fluid administration

Supportive care with the use of IV fluid hydration is a mainstay of treatment for AP in the first 12-24 hours. Table 3 summarizes the guidelines in regards to IV fluid administration as delineated by the ACG and AGA guidelines on the management of pancreatitis.^1,3 Guidelines advocate for early fluid resuscitation to correct intravascular depletion in order to reduce morbidity and mortality associated with AP.^1,2,4 The 2018 AGA guidelines endorse a conditional recommendation for using goal-directed therapy for initial fluid management,³ do not recommend for or against normal saline versus lactated Ringer’s (LR), but do advise against the use of hydroxyethyl starch fluids.³ Consistent with these recommendations, two recent RCTs published subsequent to the prespecified time periods of the AGA technical review and guideline, observed no significant differences between LR and normal saline on clinically meaningful outcomes.^61,62 The AGA guidelines acknowledge that evidence was of very-low quality in support of goal-directed therapy,^3,4 which has not been shown to have a significant reduction in persistent multiple organ failure, mortality, or pancreatic necrosis, compared with usual care. As the authors noted, interpretation of the data was limited by the absence of other critical outcomes in these trials (infected pancreatic necrosis), lack of uniformity of specific outcomes and definitions of transient and POF, few trials, and risk of bias. There is a clear need for a large RCT to provide evidence to guide decision making with fluid resuscitation in AP, particularly in regard to fluid type, volume, rate, duration, endpoints, and clinical outcomes.

 

 

Feeding

More recently, the focus of nutrition in the management of AP has shifted away from patients remaining nil per os (NPO). Current guidelines advocate for early oral feeding (within 24 hours) in mild AP,^3,4 in order to protect the gut-mucosal barrier. Remaining NPO when compared with early oral feeding has a 2.5-fold higher risk for interventions for necrosis.⁴ The recently published AGA technical review identified no significant impact on outcomes of early versus delayed oral feeding, which is consistent with observations of a landmark Dutch PYTHON trial entitled “Early versus on-demand nasoenteric tube feeding in acute pancreatitis.”^4,63 There is no clear cutoff point for initiating feeding for those with severe AP. A suggested practical approach is to initiate feeding within 24-72 hours and offer enteral nutrition for those intolerant to oral feeds. In severe AP and moderately severe AP, enteral nutrition is recommended over parenteral nutrition.^3,4 Enteral nutrition significantly reduces the risk of infected peripancreatic necrosis, single organ failure, and multiorgan failure.⁴ Finally, the AGA guidelines provide a conditional recommendation for providing enteral nutrition support through either the nasogastric or nasoenteric route.³ Further studies are required to determine the optimal timing, rate, and formulation of enteral nutrition in severe AP.

 

Antibiotics and probiotics

Current guidelines do not support the use of prophylactic antibiotics to prevent infection in necrotizing AP and severe AP.^1-3 The AGA technical review reported that prophylactic antibiotics did not reduce infected pancreatic or peripancreatic necrosis, persistent single organ failure, or mortality.⁴ Guidelines advocate against the use of probiotics for severe AP, because of increased mortality risk.¹

Timing of ERCP in acute biliary pancreatitis

There is universal agreement for offering urgent ERCP (within 24 hours) in biliary AP complicated by cholangitis.^1-3,64 Figure 2 demonstrates an example of a cholangiogram completed within 24 hours of presentation of biliary AP complicated by cholangitis.

In the absence of cholangitis, the timing of ERCP for AP with persistent biliary obstruction is less clear.^1-3 In line with recent guidelines, the 2018 AGA guidelines advocate against routine use of urgent ERCP for biliary AP without cholangitis,³ a conditional recommendation with overall low quality of data.⁴ The AGA technical review found that urgent ERCP, compared with conservative management in acute biliary pancreatitis without cholangitis had no significant effect on mortality, organ failure, infected pancreatic necrosis, and total necrotizing pancreatitis, but did significantly shorten hospital length of stay.⁴ There are limited data to guide decision making of when nonurgent ERCP should be performed in hospitalized patients with biliary AP with persistent obstruction and no cholangitis.^3,64

 

 

Alcohol and smoking cessation

The AGA technical review advocates for brief alcohol intervention during hospitalization for alcohol-induced AP on the basis of one RCT that addresses the impact of alcohol counseling on recurrent bouts of AP⁴ plus evidence from a Cochrane review of alcohol-reduction strategies in primary care populations.⁶⁵ Cessation of smoking – an established independent risk factor of AP – recurrent AP and chronic pancreatitis, should also be recommended as part of the management of AP.

Cholecystectomy

Evidence supports same-admission cholecystectomy for mild gallstone AP, a strong recommendation of published AGA guidelines.³ When compared with delayed cholecystectomy, same-admission cholecystectomy significantly reduced gallstone-related complications, readmissions for recurrent pancreatitis, and pancreaticobiliary complications, without having a significant impact on mortality during a 6-month follow-up period.⁶⁶ Delaying cholecystectomy 6 weeks in patients with moderate-severe gallstone AP appears to reduce morbidity, including the development of infected collections, and mortality.⁴ An ongoing RCT, the APEC trial, aims to determine whether early ERCP with biliary sphincterotomy reduces major complications or death when compared with no intervention for biliary AP in patients at high risk of complications.⁶⁷

Chemoprevention and IV fluid management of post-ERCP pancreatitis

Accumulating data support the effectiveness of chemoprevention, pancreatic stent placement, and fluid administration to prevent post-ERCP pancreatitis. Multiple RCTs, meta-analyses, and systematic reviews indicate that rectal NSAIDs) reduce post-ERCP pancreatitis onset^68-71 and moderate-severe post-ERCP pancreatitis. Additionally, placement of a pancreatic duct stent may decrease the risk of severe post-ERCP pancreatitis in high-risk patients.³ Guidelines do not comment on fluid administrations for prevention of post-ERCP pancreatitis, but studies have shown that greater periprocedural IV fluid was an independent protective factor against moderate to severe PEP⁷² and was associated with shorter hospital length of stay.⁷³ Recent meta-analyses and RCTs support using LR prior to ERCP to prevent PEP.^74-77 Interestingly, a recent RCT shows that the combination of rectal indomethacin and LR, compared with combination placebo and normal saline reduced the risk of PEP in high-risk patients.⁷⁸

Two ongoing multicenter RCTs will clarify the role of combination therapy. The Dutch FLUYT RCT aims to determine the optimal combination of rectal NSAIDs and periprocedural infusion of IV fluids to reduce the incidence of PEP and moderate-severe PEP⁷⁹ and the Stent vs. Indomethacin (SVI) trial aims to determine the whether combination pancreatic stent placement plus rectal indomethacin is superior to monotherapy indomethacin for preventing post-ERCP pancreatitis in high-risk cases.⁸⁰

Implications for clinical practice

The diagnosis and optimal management of AP require a systematic approach with multidisciplinary decision making. Morbidity and mortality in AP are driven by early or late POF, and the latter often is triggered by infected necrosis. Risk stratification of these patients at the point of contact is a commonsense approach to enable triaging of patients to the appropriate level of care. Regardless of pancreatitis severity, recommended treatment interventions include goal-directed IV fluid resuscitation, early feeding by mouth or enteral tube when necessary, avoidance of prophylactic antibiotics, avoidance of probiotics, and urgent ERCP for patients with acute biliary pancreatitis complicated by cholangitis. Key measures for preventing hospital readmission and pancreatitis include same-admission cholecystectomy for acute biliary pancreatitis and alcohol and smoking cessation. Preventive measures for post-ERCP pancreatitis in patients undergoing ERCP include rectal indomethacin, prophylactic pancreatic duct stent placement, and periprocedural fluid resuscitation.

Dr. Mandalia is a fellow, gastroenterology, department of internal medicine, division of gastroenterology, Michigan Medicine, Ann Arbor; Dr. DiMagno is associate professor of medicine, director, comprehensive pancreas program, department of internal medicine, division of gastroenterology, University of Michigan, Ann Arbor. Dr. Mandalia reports no conflicts of interest.

 

 

References

1. Tenner S et al. Am J Gastroenterol. 2013;108:1400.

2. Besseline M et al. Pancreatology. 2013;13(4, Supplement 2):e1-15.

3. Crockett SD et al. Gastroenterology. 2018;154(4):1096-101.

4. Vege SS et al. Gastroenterology. 2018;154(4):1103-39.

5. Peery AF et al. Gastroenterology. 2019 Jan;156(1):254-72.e11.

6. Krishna SG et al. Pancreas. 2017;46(4):482-8.

7. Sellers ZM et al. Gastroenterology. 2018;155(2):469-78.e1.

8. Brown A et al. JOP. 2008;9(4):408-14.

9. Fagenholz PJ et al. Ann Epidemiol. 2007;17(7):491.e1-.e8.

10. McNabb-Baltar J et al. Pancreas. 2014;43(5):687-91.

11. Johnson CD et al. Gut. 2004;53(9):1340-4.

12. Dellinger EP et al. Ann Surg. 2012;256(6):875-80.

13. Petrov MS et al. Gastroenterology. 2010;139(3):813-20.

14. Sternby H et al. Ann Surg. Apr 18. doi: 10.1097/SLA.0000000000002766.

15. Huh JH et al. J Clin Gastroenterol. 2018;52(2):178-83.

16. Wu BU et al. Gastroenterology. 2008;135(3):816-20.

17. Gardner TB et al. Clin Gastroenterol Hepatol. 2008;6(10):1070-6.

18. Krishna SG et al. Am J Gastroenterol. 2015;110(11):1608-19.

19. Lee PJ et al. Pancreas. 2016;45(4):561-4.

20. Mandalia A et al. F1000Research. 2018 Jun 28;7.

21. Majumder S et al. Pancreas. 2015;44(4):540-6.

22. DiMagno MJ. Clin Gastroenterol Hepatol. 2011;9(11):920-2.

23. Yadav D, Whitcomb DC. Nature Rev Gastroenterol Hepatol. 2010;7(3):131-45.

24. Samokhvalov AV et al. EBioMedicine. 2015;2(12):1996-2002.

25. Barkin JA et al. Pancreas. 2017;46(8):1035-8.

26. Chen Y-T et al. J Gastroenterol Hepatol. 2016;31(4):782-7.

27. Ramos LR et al. J Crohns Colitis. 2016;10(1):95-104.

28. Avram MM. Nephron. 1977;18(1):68-71.

29. Lankisch PG et al. Nephrol Dial Transplant. 2008;23(4):1401-5.

30. Owyang C et al. Mayo Clin Proc. 1979;54(12):769-73.

31. Owyang Cet al. Gut. 1982;23(5):357-61.

32. Quraishi ER et al. Am J Gastroenterol. 2005;100:2288.

33. Vaziri ND et al. Nephron. 1987;46(4):347-9.

34. Chen HJ et al. Nephrol Dial Transplant. 2017;32(10):1731-6.

35. Kirkegard J et al. Gastroenterology. 2018;May;154(6):1729-36.

36. Karlson BM, et al. Gastroenterology. 1997;113(2):587-92.

37. Munigala S et al. Clin Gastroenterol Hepatol. 2014;12(7):1143-50.e1.

38. Carr RA et al. Pancreatology. 2016;16(4):469-76.

39. Li X et al. BMC Gastroenterol. 2018;18(1):89.

40. Ahmed AU et al. Clin Gastroenterol Hepatol. 2016;14(5):738-46.

41. Sankaran SJ et al. Gastroenterology. 2015;149(6):1490-500.e1.

42. Berglund L et al. J Clin Endocrinol Metab. 2012;97(9):2969-89.

43. Catapano AL et al. Atherosclerosis. 2011;217(1):3-46.

44. Pedersen SB et al. JAMA Intern Med. 2016;176(12):1834-42.

45. Nawaz H et al. Am J Gastroenterol. 2015;110(10):1497-503.

46. Banks PA et al. Gut. 2013;62(1):102-11.

47. Kondo S et al. Eur J Radiol. 2005;54(2):271-5.

48. Meeralam Y et al. Gastrointest Endosc. 2017;86(6):986-93.

49. Stimac D et al. Am J Gastroenterol. 2007;102(5):997-1004.

50. Jin DX et al. Dig Dis Sci. 2017;62(10):2894-9.

51. Freeman ML. Gastrointest Endosc Clin N Am. 2012;22(3):567-86.

52. De Lisi S et al. Eur J Gastroenterol Hepatol. 2011;23(5):367-74.

53. Di MY et al. Ann Int Med. 2016;165(7):482-90.

54. Mounzer R et al. Gastroenterology. 2012;142(7):1476-82; quiz e15-6.

55. Koutroumpakis E et al. Am J Gastroenterol. 2015;110(12):1707-16.

56. Wu BU et al. Gastroenterology. 2009;137(1):129-35.

57. Buddingh KT et al. J Am Coll Surg. 2014;218(1):26-32.

58. Buxbaum J et al. Am J Gastroenterol. 2018;113(5):755-64.

59. Jabaudon M et al. Crit Car Med. 2018;46(3):e198-e205.

60. Barlass U et al. Gut. 2018;67(4):600-2.

61. Buxbaum JL et al. Am J Gastroenterol. 2017;112(5):797-803.

62. de-Madaria E et al. United Eur Gastroenterol J. 2018;6(1):63-72.

63. Bakker OJ et al. N Engl J Med. 2014;371(21):1983-93.

64. Tse F et al. Cochrane Database Syst Rev. 2012(5):Cd009779.

65. Kaner EFS et al. Cochrane Database Syst Rev. 2007(2):Cd004148.

66. da Costa DW et al. Lancet. 2015;386(10000):1261-8.

67. Schepers NJ et al. Trials. 2016;17:5.

68. Vadala di Prampero SF et al. Eur J Gastroenterol Hepatol. 2016;28(12):1415-24.

69. Kubiliun NM et al. Clin Gastroenterol Hepatol. 2015;13(7):1231-9; quiz e70-1.

70. Wan J et al. BMC Gastroenterol. 2017;17(1):43.

71. Yang C et al. Pancreatology. 2017;17(5):681-8.

72. DiMagno MJ et al. Pancreas. 2014;43(4):642-7.

73. Sagi SV et al. J Gastroenterol Hepatol. 2014;29(6):1316-20.

74. Choi JH et al. Clin Gastroenterol Hepatol. 2017;15(1):86-92.e1.

75. Wu D et al. J Clin Gastroenterol. 2017;51(8):e68-e76.

76. Zhang ZF et al. J Clin Gastroenterol. 2017;51(3):e17-e26.

77. Park CH et al. Endoscopy 2018 Apr;50(4):378-85.

78. Mok SRS et al. Gastrointest Endosc. 2017;85(5):1005-13.

79. Smeets XJN et al. Trials. 2018;19(1):207.

80. Elmunzer BJ et al. Trials. 2016;17(1):120.

 

Introduction

Acute pancreatitis (AP) is a major clinical and financial burden in the United States. Several major clinical guidelines provide evidence-based recommendations for the clinical management decisions in AP, including those from the American College of Gastroenterology (ACG; 2013),¹ and the International Association of Pancreatology (IAP; 2013).² More recently, the American Gastroenterological Association (AGA) released their own set of guidelines.^3,4 In this update on AP, we review these guidelines and reference recent literature focused on epidemiology, risk factors, etiology, diagnosis, risk stratification, and recent advances in the early medical management of AP. Regarding the latter, we review six treatment interventions (pain management, intravenous fluid resuscitation, feeding, prophylactic antibiotics, probiotics, and timing of endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis) and four preventive interventions (alcohol and smoking cessation, same-admission cholecystectomy for acute biliary pancreatitis, and chemoprevention and fluid administration for post-ERCP pancreatitis [PEP]). Updates on multidisciplinary management of (infected) pancreatic necrosis is beyond the scope of this review. Table 1 summarizes the concepts discussed in this article.

Recent advances in epidemiology and evaluation of AP

Epidemiology

AP is the third most common cause of gastrointestinal-related hospitalizations and fourth most common cause of readmission in 2014.⁵ Recent epidemiologic studies show conflicting trends for the incidence of AP, both increasing⁶ and decreasing,⁷ likely attributable to significant differences in study designs. Importantly, multiple studies have demonstrated that hospital length of stay, costs, and mortality have declined since 2009.^6,8-10

Persistent organ failure (POF), defined as organ failure lasting more than 48 hours, is the major cause of death in AP. POF, if only a single organ during AP, is associated with 27%-36% mortality; if it is multiorgan, it is associated with 47% mortality.^1,11 Other factors associated with increased hospital mortality include infected pancreatic necrosis,^12-14 diabetes mellitus,¹⁵ hospital-acquired infection,¹⁶ advanced age (70 years and older),¹⁷ and obesity.¹⁸ Predictive factors of 1-year mortality include readmission within 30 days, higher Charlson Comorbidity Index, and longer hospitalization.¹⁹

Risk factors

We briefly highlight recent insights into risk factors for AP (Table 1) and refer to a recent review for further discussion.²⁰ Current and former tobacco use are independent risk factors for AP.²¹ The dose-response relationship of alcohol to the risk of pancreatitis is complex,²² but five standard drinks per day for 5 years is a commonly used cut-off.^1,23 New evidence suggests that the relationship between the dose of alcohol and risk of AP differs by sex, linearly in men but nonlinearly (J-shaped) in women.²⁴ Risk of AP in women was decreased with alcohol consumption of up to 40 g/day (one standard drink contains 14 g of alcohol) and increased above this amount. Cannabis is a possible risk factor for toxin-induced AP and abstinence appears to abolish risk of recurrent attacks.²⁵

Patients with inflammatory bowel disease (IBD) have a 2.9-fold higher risk for AP versus non-IBD cohorts²⁶ with the most common etiologies are from gallstones and medications.²⁷ In patients with end-stage renal disease (ESRD), the risk of AP is higher in those who receive peritoneal dialysis, compared with hemodialysis^28-33 and who are women, older, or have cholelithiasis or liver disease.³⁴As recently reviewed,³⁵ pancreatic cancer appears to be associated with first-attack pancreatitis with few exceptions.³⁶ In this setting, the overall incidence of pancreatic cancer is low (1.5%). The risk is greatest within the first year of the attack of AP, negligible below age 40 years but steadily rising through the fifth to eighth decades.³⁷ Pancreatic cancer screening is a conditional recommendation of the ACG guidelines in patients with unexplained AP, particularly those aged 40 years or older.¹

Etiology and diagnosis

Alcohol and gallstones remain the most prevalent etiologies for AP.¹ While hypertriglyceridemia accounted for 9% of AP in a systematic review of acute pancreatitis in 15 different countries,³⁸ it is the second most common cause of acute pancreatitis in Asia (especially China).³⁹ Figure 1 provides a breakdown of the etiologies and risk factors of pancreatitis. Importantly, it remains challenging to assign several toxic-metabolic etiologies as either a cause or risk factor for AP, particularly with regards to alcohol, smoking, and cannabis to name a few.

Guidelines and recent studies of AP raise questions about the threshold above which hypertriglyceridemia causes or poses as an important cofactor for AP. American and European societies define the threshold for triglycerides at 885-1,000 mg/dL.^1,42,43 Pedersen et al. provide evidence of a graded risk of AP with hypertriglyceridemia: In multivariable analysis, adjusted hazard ratios for AP were much higher with nonfasting mild to moderately elevated plasma triglycerides (177-885 mg/dL), compared with normal values (below 89 mg/dL).⁴⁴ Moreover, the risk of severe AP (developing POF) increases in proportion to triglyceride value, independent of the underlying cause of AP.⁴⁵

Vidyard Video

Diagnosis of AP is derived from the revised Atlanta classification.⁴⁶ The recommended timing and indications for offering cross-sectional imaging are after 48-72 hours in patients with no improvement to initial care.¹ Endoscopic ultrasonography (EUS) has better diagnostic accuracy and sensitivity, compared with magnetic resonance cholangiopancreatography (MRCP) for choledocholithiasis, and has comparable specificity.^47,48 Among noninvasive imaging modalities, MRCP is more sensitive than computed tomography (CT) for diagnosing choledocholithiasis.⁴⁹ Despite guideline recommendations for more selective use of pancreatic imaging in the early assessment of AP, utilization of early CT or MRCP imaging (within the first 24 hours of care) remained high during 2014-2015, compared with 2006-2007.⁵⁰

ERCP is not recommended as a pure diagnostic tool, owing to the availability of other diagnostic tests and a complication rate of 5%-10% with risks involving PEP, cholangitis, perforation, and hemorrhage.⁵¹ A recent systematic review of EUS and ERCP in acute biliary pancreatitis concluded that EUS had lower failure rates and had no complications, and the use of EUS avoided ERCP in 71.2% of cases.⁵²

 

 

 

Risk stratification

The goals of using risk stratification tools in AP are to identify patients at risk for developing major outcomes, including POF, infected pancreatic necrosis, and death, and to ensure timely triaging of patients to an appropriate level of care. Existing prediction models have only moderate predictive value.^53,54 Examples include simple risk stratification tools such as blood urea nitrogen (BUN) and hemoconcentration,^55,56 disease-modifying patient variables (age, obesity, etc.), biomarkers (i.e., angiopoietin 2),⁵⁷ and more complex clinical scoring systems such as Acute Physiology and Chronic Health Evaluation II (APACHE II), BISAP (BUN, impaired mental status, SIRS criteria, age, pleural effusion) score, early warning system (EWS), Glasgow-Imrie score, Japanese severity score, and recently the Pancreatitis Activity Scoring System (PASS).⁵⁸ Two recent guidelines affirmed the importance of predicting the severity of AP, using one or more predictive tools.^1,2 The recent 2018 AGA technical review does not debate this commonsense approach, but does highlight that there is no published observational study or randomized, controlled trial (RCT) investigating whether prediction tools affect clinical outcomes.⁴

Recent advances in early treatment of AP

Literature review and definitions

The AP literature contains heterogeneous definitions of severe AP and of what constitutes a major outcome in AP. Based on definitions of the 2013 revised Atlanta Criteria, the 2018 AGA technical review and clinical guidelines emphasized precise definitions of primary outcomes of clinical importance in AP, including death, persistent single organ failure, or persistent multiple organ failure, each requiring a duration of more than 48 hours, and infected pancreatic or peripancreatic necrosis or both (Table 2).^3,4

 

Pain management

Management of pain in AP is complex and requires a detailed discussion beyond the scope of this review, but recent clinical and translational studies raise questions about the current practice of using opioids for pain management in AP. A provocative, multicenter, retrospective cohort study reported lower 30-day mortality among critically ill patients who received epidural analgesia versus standard care without epidural analgesia.⁵⁹ The possible mechanism of protection and the drugs administered are unclear. An interesting hypothesis is that the epidural cohort may have received lower exposure to morphine, which may increase gut permeability, the risk of infectious complications, and severity of AP, based on a translational study in mice.⁶⁰

Intravenous fluid administration

Supportive care with the use of IV fluid hydration is a mainstay of treatment for AP in the first 12-24 hours. Table 3 summarizes the guidelines in regards to IV fluid administration as delineated by the ACG and AGA guidelines on the management of pancreatitis.^1,3 Guidelines advocate for early fluid resuscitation to correct intravascular depletion in order to reduce morbidity and mortality associated with AP.^1,2,4 The 2018 AGA guidelines endorse a conditional recommendation for using goal-directed therapy for initial fluid management,³ do not recommend for or against normal saline versus lactated Ringer’s (LR), but do advise against the use of hydroxyethyl starch fluids.³ Consistent with these recommendations, two recent RCTs published subsequent to the prespecified time periods of the AGA technical review and guideline, observed no significant differences between LR and normal saline on clinically meaningful outcomes.^61,62 The AGA guidelines acknowledge that evidence was of very-low quality in support of goal-directed therapy,^3,4 which has not been shown to have a significant reduction in persistent multiple organ failure, mortality, or pancreatic necrosis, compared with usual care. As the authors noted, interpretation of the data was limited by the absence of other critical outcomes in these trials (infected pancreatic necrosis), lack of uniformity of specific outcomes and definitions of transient and POF, few trials, and risk of bias. There is a clear need for a large RCT to provide evidence to guide decision making with fluid resuscitation in AP, particularly in regard to fluid type, volume, rate, duration, endpoints, and clinical outcomes.

 

 

Feeding

More recently, the focus of nutrition in the management of AP has shifted away from patients remaining nil per os (NPO). Current guidelines advocate for early oral feeding (within 24 hours) in mild AP,^3,4 in order to protect the gut-mucosal barrier. Remaining NPO when compared with early oral feeding has a 2.5-fold higher risk for interventions for necrosis.⁴ The recently published AGA technical review identified no significant impact on outcomes of early versus delayed oral feeding, which is consistent with observations of a landmark Dutch PYTHON trial entitled “Early versus on-demand nasoenteric tube feeding in acute pancreatitis.”^4,63 There is no clear cutoff point for initiating feeding for those with severe AP. A suggested practical approach is to initiate feeding within 24-72 hours and offer enteral nutrition for those intolerant to oral feeds. In severe AP and moderately severe AP, enteral nutrition is recommended over parenteral nutrition.^3,4 Enteral nutrition significantly reduces the risk of infected peripancreatic necrosis, single organ failure, and multiorgan failure.⁴ Finally, the AGA guidelines provide a conditional recommendation for providing enteral nutrition support through either the nasogastric or nasoenteric route.³ Further studies are required to determine the optimal timing, rate, and formulation of enteral nutrition in severe AP.

 

Antibiotics and probiotics

Current guidelines do not support the use of prophylactic antibiotics to prevent infection in necrotizing AP and severe AP.^1-3 The AGA technical review reported that prophylactic antibiotics did not reduce infected pancreatic or peripancreatic necrosis, persistent single organ failure, or mortality.⁴ Guidelines advocate against the use of probiotics for severe AP, because of increased mortality risk.¹

Timing of ERCP in acute biliary pancreatitis

There is universal agreement for offering urgent ERCP (within 24 hours) in biliary AP complicated by cholangitis.^1-3,64 Figure 2 demonstrates an example of a cholangiogram completed within 24 hours of presentation of biliary AP complicated by cholangitis.

In the absence of cholangitis, the timing of ERCP for AP with persistent biliary obstruction is less clear.^1-3 In line with recent guidelines, the 2018 AGA guidelines advocate against routine use of urgent ERCP for biliary AP without cholangitis,³ a conditional recommendation with overall low quality of data.⁴ The AGA technical review found that urgent ERCP, compared with conservative management in acute biliary pancreatitis without cholangitis had no significant effect on mortality, organ failure, infected pancreatic necrosis, and total necrotizing pancreatitis, but did significantly shorten hospital length of stay.⁴ There are limited data to guide decision making of when nonurgent ERCP should be performed in hospitalized patients with biliary AP with persistent obstruction and no cholangitis.^3,64

 

 

Alcohol and smoking cessation

The AGA technical review advocates for brief alcohol intervention during hospitalization for alcohol-induced AP on the basis of one RCT that addresses the impact of alcohol counseling on recurrent bouts of AP⁴ plus evidence from a Cochrane review of alcohol-reduction strategies in primary care populations.⁶⁵ Cessation of smoking – an established independent risk factor of AP – recurrent AP and chronic pancreatitis, should also be recommended as part of the management of AP.

Cholecystectomy

Evidence supports same-admission cholecystectomy for mild gallstone AP, a strong recommendation of published AGA guidelines.³ When compared with delayed cholecystectomy, same-admission cholecystectomy significantly reduced gallstone-related complications, readmissions for recurrent pancreatitis, and pancreaticobiliary complications, without having a significant impact on mortality during a 6-month follow-up period.⁶⁶ Delaying cholecystectomy 6 weeks in patients with moderate-severe gallstone AP appears to reduce morbidity, including the development of infected collections, and mortality.⁴ An ongoing RCT, the APEC trial, aims to determine whether early ERCP with biliary sphincterotomy reduces major complications or death when compared with no intervention for biliary AP in patients at high risk of complications.⁶⁷

Chemoprevention and IV fluid management of post-ERCP pancreatitis

Accumulating data support the effectiveness of chemoprevention, pancreatic stent placement, and fluid administration to prevent post-ERCP pancreatitis. Multiple RCTs, meta-analyses, and systematic reviews indicate that rectal NSAIDs) reduce post-ERCP pancreatitis onset^68-71 and moderate-severe post-ERCP pancreatitis. Additionally, placement of a pancreatic duct stent may decrease the risk of severe post-ERCP pancreatitis in high-risk patients.³ Guidelines do not comment on fluid administrations for prevention of post-ERCP pancreatitis, but studies have shown that greater periprocedural IV fluid was an independent protective factor against moderate to severe PEP⁷² and was associated with shorter hospital length of stay.⁷³ Recent meta-analyses and RCTs support using LR prior to ERCP to prevent PEP.^74-77 Interestingly, a recent RCT shows that the combination of rectal indomethacin and LR, compared with combination placebo and normal saline reduced the risk of PEP in high-risk patients.⁷⁸

Two ongoing multicenter RCTs will clarify the role of combination therapy. The Dutch FLUYT RCT aims to determine the optimal combination of rectal NSAIDs and periprocedural infusion of IV fluids to reduce the incidence of PEP and moderate-severe PEP⁷⁹ and the Stent vs. Indomethacin (SVI) trial aims to determine the whether combination pancreatic stent placement plus rectal indomethacin is superior to monotherapy indomethacin for preventing post-ERCP pancreatitis in high-risk cases.⁸⁰

Implications for clinical practice

The diagnosis and optimal management of AP require a systematic approach with multidisciplinary decision making. Morbidity and mortality in AP are driven by early or late POF, and the latter often is triggered by infected necrosis. Risk stratification of these patients at the point of contact is a commonsense approach to enable triaging of patients to the appropriate level of care. Regardless of pancreatitis severity, recommended treatment interventions include goal-directed IV fluid resuscitation, early feeding by mouth or enteral tube when necessary, avoidance of prophylactic antibiotics, avoidance of probiotics, and urgent ERCP for patients with acute biliary pancreatitis complicated by cholangitis. Key measures for preventing hospital readmission and pancreatitis include same-admission cholecystectomy for acute biliary pancreatitis and alcohol and smoking cessation. Preventive measures for post-ERCP pancreatitis in patients undergoing ERCP include rectal indomethacin, prophylactic pancreatic duct stent placement, and periprocedural fluid resuscitation.

Dr. Mandalia is a fellow, gastroenterology, department of internal medicine, division of gastroenterology, Michigan Medicine, Ann Arbor; Dr. DiMagno is associate professor of medicine, director, comprehensive pancreas program, department of internal medicine, division of gastroenterology, University of Michigan, Ann Arbor. Dr. Mandalia reports no conflicts of interest.

 

 

References

1. Tenner S et al. Am J Gastroenterol. 2013;108:1400.

2. Besseline M et al. Pancreatology. 2013;13(4, Supplement 2):e1-15.

3. Crockett SD et al. Gastroenterology. 2018;154(4):1096-101.

4. Vege SS et al. Gastroenterology. 2018;154(4):1103-39.

5. Peery AF et al. Gastroenterology. 2019 Jan;156(1):254-72.e11.

6. Krishna SG et al. Pancreas. 2017;46(4):482-8.

7. Sellers ZM et al. Gastroenterology. 2018;155(2):469-78.e1.

8. Brown A et al. JOP. 2008;9(4):408-14.

9. Fagenholz PJ et al. Ann Epidemiol. 2007;17(7):491.e1-.e8.

10. McNabb-Baltar J et al. Pancreas. 2014;43(5):687-91.

11. Johnson CD et al. Gut. 2004;53(9):1340-4.

12. Dellinger EP et al. Ann Surg. 2012;256(6):875-80.

13. Petrov MS et al. Gastroenterology. 2010;139(3):813-20.

14. Sternby H et al. Ann Surg. Apr 18. doi: 10.1097/SLA.0000000000002766.

15. Huh JH et al. J Clin Gastroenterol. 2018;52(2):178-83.

16. Wu BU et al. Gastroenterology. 2008;135(3):816-20.

17. Gardner TB et al. Clin Gastroenterol Hepatol. 2008;6(10):1070-6.

18. Krishna SG et al. Am J Gastroenterol. 2015;110(11):1608-19.

19. Lee PJ et al. Pancreas. 2016;45(4):561-4.

20. Mandalia A et al. F1000Research. 2018 Jun 28;7.

21. Majumder S et al. Pancreas. 2015;44(4):540-6.

22. DiMagno MJ. Clin Gastroenterol Hepatol. 2011;9(11):920-2.

23. Yadav D, Whitcomb DC. Nature Rev Gastroenterol Hepatol. 2010;7(3):131-45.

24. Samokhvalov AV et al. EBioMedicine. 2015;2(12):1996-2002.

25. Barkin JA et al. Pancreas. 2017;46(8):1035-8.

26. Chen Y-T et al. J Gastroenterol Hepatol. 2016;31(4):782-7.

27. Ramos LR et al. J Crohns Colitis. 2016;10(1):95-104.

28. Avram MM. Nephron. 1977;18(1):68-71.

29. Lankisch PG et al. Nephrol Dial Transplant. 2008;23(4):1401-5.

30. Owyang C et al. Mayo Clin Proc. 1979;54(12):769-73.

31. Owyang Cet al. Gut. 1982;23(5):357-61.

32. Quraishi ER et al. Am J Gastroenterol. 2005;100:2288.

33. Vaziri ND et al. Nephron. 1987;46(4):347-9.

34. Chen HJ et al. Nephrol Dial Transplant. 2017;32(10):1731-6.

35. Kirkegard J et al. Gastroenterology. 2018;May;154(6):1729-36.

36. Karlson BM, et al. Gastroenterology. 1997;113(2):587-92.

37. Munigala S et al. Clin Gastroenterol Hepatol. 2014;12(7):1143-50.e1.

38. Carr RA et al. Pancreatology. 2016;16(4):469-76.

39. Li X et al. BMC Gastroenterol. 2018;18(1):89.

40. Ahmed AU et al. Clin Gastroenterol Hepatol. 2016;14(5):738-46.

41. Sankaran SJ et al. Gastroenterology. 2015;149(6):1490-500.e1.

42. Berglund L et al. J Clin Endocrinol Metab. 2012;97(9):2969-89.

43. Catapano AL et al. Atherosclerosis. 2011;217(1):3-46.

44. Pedersen SB et al. JAMA Intern Med. 2016;176(12):1834-42.

45. Nawaz H et al. Am J Gastroenterol. 2015;110(10):1497-503.

46. Banks PA et al. Gut. 2013;62(1):102-11.

47. Kondo S et al. Eur J Radiol. 2005;54(2):271-5.

48. Meeralam Y et al. Gastrointest Endosc. 2017;86(6):986-93.

49. Stimac D et al. Am J Gastroenterol. 2007;102(5):997-1004.

50. Jin DX et al. Dig Dis Sci. 2017;62(10):2894-9.

51. Freeman ML. Gastrointest Endosc Clin N Am. 2012;22(3):567-86.

52. De Lisi S et al. Eur J Gastroenterol Hepatol. 2011;23(5):367-74.

53. Di MY et al. Ann Int Med. 2016;165(7):482-90.

54. Mounzer R et al. Gastroenterology. 2012;142(7):1476-82; quiz e15-6.

55. Koutroumpakis E et al. Am J Gastroenterol. 2015;110(12):1707-16.

56. Wu BU et al. Gastroenterology. 2009;137(1):129-35.

57. Buddingh KT et al. J Am Coll Surg. 2014;218(1):26-32.

58. Buxbaum J et al. Am J Gastroenterol. 2018;113(5):755-64.

59. Jabaudon M et al. Crit Car Med. 2018;46(3):e198-e205.

60. Barlass U et al. Gut. 2018;67(4):600-2.

61. Buxbaum JL et al. Am J Gastroenterol. 2017;112(5):797-803.

62. de-Madaria E et al. United Eur Gastroenterol J. 2018;6(1):63-72.

63. Bakker OJ et al. N Engl J Med. 2014;371(21):1983-93.

64. Tse F et al. Cochrane Database Syst Rev. 2012(5):Cd009779.

65. Kaner EFS et al. Cochrane Database Syst Rev. 2007(2):Cd004148.

66. da Costa DW et al. Lancet. 2015;386(10000):1261-8.

67. Schepers NJ et al. Trials. 2016;17:5.

68. Vadala di Prampero SF et al. Eur J Gastroenterol Hepatol. 2016;28(12):1415-24.

69. Kubiliun NM et al. Clin Gastroenterol Hepatol. 2015;13(7):1231-9; quiz e70-1.

70. Wan J et al. BMC Gastroenterol. 2017;17(1):43.

71. Yang C et al. Pancreatology. 2017;17(5):681-8.

72. DiMagno MJ et al. Pancreas. 2014;43(4):642-7.

73. Sagi SV et al. J Gastroenterol Hepatol. 2014;29(6):1316-20.

74. Choi JH et al. Clin Gastroenterol Hepatol. 2017;15(1):86-92.e1.

75. Wu D et al. J Clin Gastroenterol. 2017;51(8):e68-e76.

76. Zhang ZF et al. J Clin Gastroenterol. 2017;51(3):e17-e26.

77. Park CH et al. Endoscopy 2018 Apr;50(4):378-85.

78. Mok SRS et al. Gastrointest Endosc. 2017;85(5):1005-13.

79. Smeets XJN et al. Trials. 2018;19(1):207.

80. Elmunzer BJ et al. Trials. 2016;17(1):120.

 

Introduction

Acute pancreatitis (AP) is a major clinical and financial burden in the United States. Several major clinical guidelines provide evidence-based recommendations for the clinical management decisions in AP, including those from the American College of Gastroenterology (ACG; 2013),¹ and the International Association of Pancreatology (IAP; 2013).² More recently, the American Gastroenterological Association (AGA) released their own set of guidelines.^3,4 In this update on AP, we review these guidelines and reference recent literature focused on epidemiology, risk factors, etiology, diagnosis, risk stratification, and recent advances in the early medical management of AP. Regarding the latter, we review six treatment interventions (pain management, intravenous fluid resuscitation, feeding, prophylactic antibiotics, probiotics, and timing of endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis) and four preventive interventions (alcohol and smoking cessation, same-admission cholecystectomy for acute biliary pancreatitis, and chemoprevention and fluid administration for post-ERCP pancreatitis [PEP]). Updates on multidisciplinary management of (infected) pancreatic necrosis is beyond the scope of this review. Table 1 summarizes the concepts discussed in this article.

Recent advances in epidemiology and evaluation of AP

Epidemiology

AP is the third most common cause of gastrointestinal-related hospitalizations and fourth most common cause of readmission in 2014.⁵ Recent epidemiologic studies show conflicting trends for the incidence of AP, both increasing⁶ and decreasing,⁷ likely attributable to significant differences in study designs. Importantly, multiple studies have demonstrated that hospital length of stay, costs, and mortality have declined since 2009.^6,8-10

Persistent organ failure (POF), defined as organ failure lasting more than 48 hours, is the major cause of death in AP. POF, if only a single organ during AP, is associated with 27%-36% mortality; if it is multiorgan, it is associated with 47% mortality.^1,11 Other factors associated with increased hospital mortality include infected pancreatic necrosis,^12-14 diabetes mellitus,¹⁵ hospital-acquired infection,¹⁶ advanced age (70 years and older),¹⁷ and obesity.¹⁸ Predictive factors of 1-year mortality include readmission within 30 days, higher Charlson Comorbidity Index, and longer hospitalization.¹⁹

Risk factors

We briefly highlight recent insights into risk factors for AP (Table 1) and refer to a recent review for further discussion.²⁰ Current and former tobacco use are independent risk factors for AP.²¹ The dose-response relationship of alcohol to the risk of pancreatitis is complex,²² but five standard drinks per day for 5 years is a commonly used cut-off.^1,23 New evidence suggests that the relationship between the dose of alcohol and risk of AP differs by sex, linearly in men but nonlinearly (J-shaped) in women.²⁴ Risk of AP in women was decreased with alcohol consumption of up to 40 g/day (one standard drink contains 14 g of alcohol) and increased above this amount. Cannabis is a possible risk factor for toxin-induced AP and abstinence appears to abolish risk of recurrent attacks.²⁵

Patients with inflammatory bowel disease (IBD) have a 2.9-fold higher risk for AP versus non-IBD cohorts²⁶ with the most common etiologies are from gallstones and medications.²⁷ In patients with end-stage renal disease (ESRD), the risk of AP is higher in those who receive peritoneal dialysis, compared with hemodialysis^28-33 and who are women, older, or have cholelithiasis or liver disease.³⁴As recently reviewed,³⁵ pancreatic cancer appears to be associated with first-attack pancreatitis with few exceptions.³⁶ In this setting, the overall incidence of pancreatic cancer is low (1.5%). The risk is greatest within the first year of the attack of AP, negligible below age 40 years but steadily rising through the fifth to eighth decades.³⁷ Pancreatic cancer screening is a conditional recommendation of the ACG guidelines in patients with unexplained AP, particularly those aged 40 years or older.¹

Etiology and diagnosis

Alcohol and gallstones remain the most prevalent etiologies for AP.¹ While hypertriglyceridemia accounted for 9% of AP in a systematic review of acute pancreatitis in 15 different countries,³⁸ it is the second most common cause of acute pancreatitis in Asia (especially China).³⁹ Figure 1 provides a breakdown of the etiologies and risk factors of pancreatitis. Importantly, it remains challenging to assign several toxic-metabolic etiologies as either a cause or risk factor for AP, particularly with regards to alcohol, smoking, and cannabis to name a few.

Guidelines and recent studies of AP raise questions about the threshold above which hypertriglyceridemia causes or poses as an important cofactor for AP. American and European societies define the threshold for triglycerides at 885-1,000 mg/dL.^1,42,43 Pedersen et al. provide evidence of a graded risk of AP with hypertriglyceridemia: In multivariable analysis, adjusted hazard ratios for AP were much higher with nonfasting mild to moderately elevated plasma triglycerides (177-885 mg/dL), compared with normal values (below 89 mg/dL).⁴⁴ Moreover, the risk of severe AP (developing POF) increases in proportion to triglyceride value, independent of the underlying cause of AP.⁴⁵

Vidyard Video

Diagnosis of AP is derived from the revised Atlanta classification.⁴⁶ The recommended timing and indications for offering cross-sectional imaging are after 48-72 hours in patients with no improvement to initial care.¹ Endoscopic ultrasonography (EUS) has better diagnostic accuracy and sensitivity, compared with magnetic resonance cholangiopancreatography (MRCP) for choledocholithiasis, and has comparable specificity.^47,48 Among noninvasive imaging modalities, MRCP is more sensitive than computed tomography (CT) for diagnosing choledocholithiasis.⁴⁹ Despite guideline recommendations for more selective use of pancreatic imaging in the early assessment of AP, utilization of early CT or MRCP imaging (within the first 24 hours of care) remained high during 2014-2015, compared with 2006-2007.⁵⁰

ERCP is not recommended as a pure diagnostic tool, owing to the availability of other diagnostic tests and a complication rate of 5%-10% with risks involving PEP, cholangitis, perforation, and hemorrhage.⁵¹ A recent systematic review of EUS and ERCP in acute biliary pancreatitis concluded that EUS had lower failure rates and had no complications, and the use of EUS avoided ERCP in 71.2% of cases.⁵²

 

 

 

Risk stratification

The goals of using risk stratification tools in AP are to identify patients at risk for developing major outcomes, including POF, infected pancreatic necrosis, and death, and to ensure timely triaging of patients to an appropriate level of care. Existing prediction models have only moderate predictive value.^53,54 Examples include simple risk stratification tools such as blood urea nitrogen (BUN) and hemoconcentration,^55,56 disease-modifying patient variables (age, obesity, etc.), biomarkers (i.e., angiopoietin 2),⁵⁷ and more complex clinical scoring systems such as Acute Physiology and Chronic Health Evaluation II (APACHE II), BISAP (BUN, impaired mental status, SIRS criteria, age, pleural effusion) score, early warning system (EWS), Glasgow-Imrie score, Japanese severity score, and recently the Pancreatitis Activity Scoring System (PASS).⁵⁸ Two recent guidelines affirmed the importance of predicting the severity of AP, using one or more predictive tools.^1,2 The recent 2018 AGA technical review does not debate this commonsense approach, but does highlight that there is no published observational study or randomized, controlled trial (RCT) investigating whether prediction tools affect clinical outcomes.⁴

Recent advances in early treatment of AP

Literature review and definitions

The AP literature contains heterogeneous definitions of severe AP and of what constitutes a major outcome in AP. Based on definitions of the 2013 revised Atlanta Criteria, the 2018 AGA technical review and clinical guidelines emphasized precise definitions of primary outcomes of clinical importance in AP, including death, persistent single organ failure, or persistent multiple organ failure, each requiring a duration of more than 48 hours, and infected pancreatic or peripancreatic necrosis or both (Table 2).^3,4

 

Pain management

Management of pain in AP is complex and requires a detailed discussion beyond the scope of this review, but recent clinical and translational studies raise questions about the current practice of using opioids for pain management in AP. A provocative, multicenter, retrospective cohort study reported lower 30-day mortality among critically ill patients who received epidural analgesia versus standard care without epidural analgesia.⁵⁹ The possible mechanism of protection and the drugs administered are unclear. An interesting hypothesis is that the epidural cohort may have received lower exposure to morphine, which may increase gut permeability, the risk of infectious complications, and severity of AP, based on a translational study in mice.⁶⁰

Intravenous fluid administration

Supportive care with the use of IV fluid hydration is a mainstay of treatment for AP in the first 12-24 hours. Table 3 summarizes the guidelines in regards to IV fluid administration as delineated by the ACG and AGA guidelines on the management of pancreatitis.^1,3 Guidelines advocate for early fluid resuscitation to correct intravascular depletion in order to reduce morbidity and mortality associated with AP.^1,2,4 The 2018 AGA guidelines endorse a conditional recommendation for using goal-directed therapy for initial fluid management,³ do not recommend for or against normal saline versus lactated Ringer’s (LR), but do advise against the use of hydroxyethyl starch fluids.³ Consistent with these recommendations, two recent RCTs published subsequent to the prespecified time periods of the AGA technical review and guideline, observed no significant differences between LR and normal saline on clinically meaningful outcomes.^61,62 The AGA guidelines acknowledge that evidence was of very-low quality in support of goal-directed therapy,^3,4 which has not been shown to have a significant reduction in persistent multiple organ failure, mortality, or pancreatic necrosis, compared with usual care. As the authors noted, interpretation of the data was limited by the absence of other critical outcomes in these trials (infected pancreatic necrosis), lack of uniformity of specific outcomes and definitions of transient and POF, few trials, and risk of bias. There is a clear need for a large RCT to provide evidence to guide decision making with fluid resuscitation in AP, particularly in regard to fluid type, volume, rate, duration, endpoints, and clinical outcomes.

 

 

Feeding

More recently, the focus of nutrition in the management of AP has shifted away from patients remaining nil per os (NPO). Current guidelines advocate for early oral feeding (within 24 hours) in mild AP,^3,4 in order to protect the gut-mucosal barrier. Remaining NPO when compared with early oral feeding has a 2.5-fold higher risk for interventions for necrosis.⁴ The recently published AGA technical review identified no significant impact on outcomes of early versus delayed oral feeding, which is consistent with observations of a landmark Dutch PYTHON trial entitled “Early versus on-demand nasoenteric tube feeding in acute pancreatitis.”^4,63 There is no clear cutoff point for initiating feeding for those with severe AP. A suggested practical approach is to initiate feeding within 24-72 hours and offer enteral nutrition for those intolerant to oral feeds. In severe AP and moderately severe AP, enteral nutrition is recommended over parenteral nutrition.^3,4 Enteral nutrition significantly reduces the risk of infected peripancreatic necrosis, single organ failure, and multiorgan failure.⁴ Finally, the AGA guidelines provide a conditional recommendation for providing enteral nutrition support through either the nasogastric or nasoenteric route.³ Further studies are required to determine the optimal timing, rate, and formulation of enteral nutrition in severe AP.

 

Antibiotics and probiotics

Current guidelines do not support the use of prophylactic antibiotics to prevent infection in necrotizing AP and severe AP.^1-3 The AGA technical review reported that prophylactic antibiotics did not reduce infected pancreatic or peripancreatic necrosis, persistent single organ failure, or mortality.⁴ Guidelines advocate against the use of probiotics for severe AP, because of increased mortality risk.¹

Timing of ERCP in acute biliary pancreatitis

There is universal agreement for offering urgent ERCP (within 24 hours) in biliary AP complicated by cholangitis.^1-3,64 Figure 2 demonstrates an example of a cholangiogram completed within 24 hours of presentation of biliary AP complicated by cholangitis.

In the absence of cholangitis, the timing of ERCP for AP with persistent biliary obstruction is less clear.^1-3 In line with recent guidelines, the 2018 AGA guidelines advocate against routine use of urgent ERCP for biliary AP without cholangitis,³ a conditional recommendation with overall low quality of data.⁴ The AGA technical review found that urgent ERCP, compared with conservative management in acute biliary pancreatitis without cholangitis had no significant effect on mortality, organ failure, infected pancreatic necrosis, and total necrotizing pancreatitis, but did significantly shorten hospital length of stay.⁴ There are limited data to guide decision making of when nonurgent ERCP should be performed in hospitalized patients with biliary AP with persistent obstruction and no cholangitis.^3,64

 

 

Alcohol and smoking cessation

The AGA technical review advocates for brief alcohol intervention during hospitalization for alcohol-induced AP on the basis of one RCT that addresses the impact of alcohol counseling on recurrent bouts of AP⁴ plus evidence from a Cochrane review of alcohol-reduction strategies in primary care populations.⁶⁵ Cessation of smoking – an established independent risk factor of AP – recurrent AP and chronic pancreatitis, should also be recommended as part of the management of AP.

Cholecystectomy

Evidence supports same-admission cholecystectomy for mild gallstone AP, a strong recommendation of published AGA guidelines.³ When compared with delayed cholecystectomy, same-admission cholecystectomy significantly reduced gallstone-related complications, readmissions for recurrent pancreatitis, and pancreaticobiliary complications, without having a significant impact on mortality during a 6-month follow-up period.⁶⁶ Delaying cholecystectomy 6 weeks in patients with moderate-severe gallstone AP appears to reduce morbidity, including the development of infected collections, and mortality.⁴ An ongoing RCT, the APEC trial, aims to determine whether early ERCP with biliary sphincterotomy reduces major complications or death when compared with no intervention for biliary AP in patients at high risk of complications.⁶⁷

Chemoprevention and IV fluid management of post-ERCP pancreatitis

Accumulating data support the effectiveness of chemoprevention, pancreatic stent placement, and fluid administration to prevent post-ERCP pancreatitis. Multiple RCTs, meta-analyses, and systematic reviews indicate that rectal NSAIDs) reduce post-ERCP pancreatitis onset^68-71 and moderate-severe post-ERCP pancreatitis. Additionally, placement of a pancreatic duct stent may decrease the risk of severe post-ERCP pancreatitis in high-risk patients.³ Guidelines do not comment on fluid administrations for prevention of post-ERCP pancreatitis, but studies have shown that greater periprocedural IV fluid was an independent protective factor against moderate to severe PEP⁷² and was associated with shorter hospital length of stay.⁷³ Recent meta-analyses and RCTs support using LR prior to ERCP to prevent PEP.^74-77 Interestingly, a recent RCT shows that the combination of rectal indomethacin and LR, compared with combination placebo and normal saline reduced the risk of PEP in high-risk patients.⁷⁸

Two ongoing multicenter RCTs will clarify the role of combination therapy. The Dutch FLUYT RCT aims to determine the optimal combination of rectal NSAIDs and periprocedural infusion of IV fluids to reduce the incidence of PEP and moderate-severe PEP⁷⁹ and the Stent vs. Indomethacin (SVI) trial aims to determine the whether combination pancreatic stent placement plus rectal indomethacin is superior to monotherapy indomethacin for preventing post-ERCP pancreatitis in high-risk cases.⁸⁰

Implications for clinical practice

The diagnosis and optimal management of AP require a systematic approach with multidisciplinary decision making. Morbidity and mortality in AP are driven by early or late POF, and the latter often is triggered by infected necrosis. Risk stratification of these patients at the point of contact is a commonsense approach to enable triaging of patients to the appropriate level of care. Regardless of pancreatitis severity, recommended treatment interventions include goal-directed IV fluid resuscitation, early feeding by mouth or enteral tube when necessary, avoidance of prophylactic antibiotics, avoidance of probiotics, and urgent ERCP for patients with acute biliary pancreatitis complicated by cholangitis. Key measures for preventing hospital readmission and pancreatitis include same-admission cholecystectomy for acute biliary pancreatitis and alcohol and smoking cessation. Preventive measures for post-ERCP pancreatitis in patients undergoing ERCP include rectal indomethacin, prophylactic pancreatic duct stent placement, and periprocedural fluid resuscitation.

Dr. Mandalia is a fellow, gastroenterology, department of internal medicine, division of gastroenterology, Michigan Medicine, Ann Arbor; Dr. DiMagno is associate professor of medicine, director, comprehensive pancreas program, department of internal medicine, division of gastroenterology, University of Michigan, Ann Arbor. Dr. Mandalia reports no conflicts of interest.

 

 

References

1. Tenner S et al. Am J Gastroenterol. 2013;108:1400.

2. Besseline M et al. Pancreatology. 2013;13(4, Supplement 2):e1-15.

3. Crockett SD et al. Gastroenterology. 2018;154(4):1096-101.

4. Vege SS et al. Gastroenterology. 2018;154(4):1103-39.

5. Peery AF et al. Gastroenterology. 2019 Jan;156(1):254-72.e11.

6. Krishna SG et al. Pancreas. 2017;46(4):482-8.

7. Sellers ZM et al. Gastroenterology. 2018;155(2):469-78.e1.

8. Brown A et al. JOP. 2008;9(4):408-14.

9. Fagenholz PJ et al. Ann Epidemiol. 2007;17(7):491.e1-.e8.

10. McNabb-Baltar J et al. Pancreas. 2014;43(5):687-91.

11. Johnson CD et al. Gut. 2004;53(9):1340-4.

12. Dellinger EP et al. Ann Surg. 2012;256(6):875-80.

13. Petrov MS et al. Gastroenterology. 2010;139(3):813-20.

14. Sternby H et al. Ann Surg. Apr 18. doi: 10.1097/SLA.0000000000002766.

15. Huh JH et al. J Clin Gastroenterol. 2018;52(2):178-83.

16. Wu BU et al. Gastroenterology. 2008;135(3):816-20.

17. Gardner TB et al. Clin Gastroenterol Hepatol. 2008;6(10):1070-6.

18. Krishna SG et al. Am J Gastroenterol. 2015;110(11):1608-19.

19. Lee PJ et al. Pancreas. 2016;45(4):561-4.

20. Mandalia A et al. F1000Research. 2018 Jun 28;7.

21. Majumder S et al. Pancreas. 2015;44(4):540-6.

22. DiMagno MJ. Clin Gastroenterol Hepatol. 2011;9(11):920-2.

23. Yadav D, Whitcomb DC. Nature Rev Gastroenterol Hepatol. 2010;7(3):131-45.

24. Samokhvalov AV et al. EBioMedicine. 2015;2(12):1996-2002.

25. Barkin JA et al. Pancreas. 2017;46(8):1035-8.

26. Chen Y-T et al. J Gastroenterol Hepatol. 2016;31(4):782-7.

27. Ramos LR et al. J Crohns Colitis. 2016;10(1):95-104.

28. Avram MM. Nephron. 1977;18(1):68-71.

29. Lankisch PG et al. Nephrol Dial Transplant. 2008;23(4):1401-5.

30. Owyang C et al. Mayo Clin Proc. 1979;54(12):769-73.

31. Owyang Cet al. Gut. 1982;23(5):357-61.

32. Quraishi ER et al. Am J Gastroenterol. 2005;100:2288.

33. Vaziri ND et al. Nephron. 1987;46(4):347-9.

34. Chen HJ et al. Nephrol Dial Transplant. 2017;32(10):1731-6.

35. Kirkegard J et al. Gastroenterology. 2018;May;154(6):1729-36.

36. Karlson BM, et al. Gastroenterology. 1997;113(2):587-92.

37. Munigala S et al. Clin Gastroenterol Hepatol. 2014;12(7):1143-50.e1.

38. Carr RA et al. Pancreatology. 2016;16(4):469-76.

39. Li X et al. BMC Gastroenterol. 2018;18(1):89.

40. Ahmed AU et al. Clin Gastroenterol Hepatol. 2016;14(5):738-46.

41. Sankaran SJ et al. Gastroenterology. 2015;149(6):1490-500.e1.

42. Berglund L et al. J Clin Endocrinol Metab. 2012;97(9):2969-89.

43. Catapano AL et al. Atherosclerosis. 2011;217(1):3-46.

44. Pedersen SB et al. JAMA Intern Med. 2016;176(12):1834-42.

45. Nawaz H et al. Am J Gastroenterol. 2015;110(10):1497-503.

46. Banks PA et al. Gut. 2013;62(1):102-11.

47. Kondo S et al. Eur J Radiol. 2005;54(2):271-5.

48. Meeralam Y et al. Gastrointest Endosc. 2017;86(6):986-93.

49. Stimac D et al. Am J Gastroenterol. 2007;102(5):997-1004.

50. Jin DX et al. Dig Dis Sci. 2017;62(10):2894-9.

51. Freeman ML. Gastrointest Endosc Clin N Am. 2012;22(3):567-86.

52. De Lisi S et al. Eur J Gastroenterol Hepatol. 2011;23(5):367-74.

53. Di MY et al. Ann Int Med. 2016;165(7):482-90.

54. Mounzer R et al. Gastroenterology. 2012;142(7):1476-82; quiz e15-6.

55. Koutroumpakis E et al. Am J Gastroenterol. 2015;110(12):1707-16.

56. Wu BU et al. Gastroenterology. 2009;137(1):129-35.

57. Buddingh KT et al. J Am Coll Surg. 2014;218(1):26-32.

58. Buxbaum J et al. Am J Gastroenterol. 2018;113(5):755-64.

59. Jabaudon M et al. Crit Car Med. 2018;46(3):e198-e205.

60. Barlass U et al. Gut. 2018;67(4):600-2.

61. Buxbaum JL et al. Am J Gastroenterol. 2017;112(5):797-803.

62. de-Madaria E et al. United Eur Gastroenterol J. 2018;6(1):63-72.

63. Bakker OJ et al. N Engl J Med. 2014;371(21):1983-93.

64. Tse F et al. Cochrane Database Syst Rev. 2012(5):Cd009779.

65. Kaner EFS et al. Cochrane Database Syst Rev. 2007(2):Cd004148.

66. da Costa DW et al. Lancet. 2015;386(10000):1261-8.

67. Schepers NJ et al. Trials. 2016;17:5.

68. Vadala di Prampero SF et al. Eur J Gastroenterol Hepatol. 2016;28(12):1415-24.

69. Kubiliun NM et al. Clin Gastroenterol Hepatol. 2015;13(7):1231-9; quiz e70-1.

70. Wan J et al. BMC Gastroenterol. 2017;17(1):43.

71. Yang C et al. Pancreatology. 2017;17(5):681-8.

72. DiMagno MJ et al. Pancreas. 2014;43(4):642-7.

73. Sagi SV et al. J Gastroenterol Hepatol. 2014;29(6):1316-20.

74. Choi JH et al. Clin Gastroenterol Hepatol. 2017;15(1):86-92.e1.

75. Wu D et al. J Clin Gastroenterol. 2017;51(8):e68-e76.

76. Zhang ZF et al. J Clin Gastroenterol. 2017;51(3):e17-e26.

77. Park CH et al. Endoscopy 2018 Apr;50(4):378-85.

78. Mok SRS et al. Gastrointest Endosc. 2017;85(5):1005-13.

79. Smeets XJN et al. Trials. 2018;19(1):207.

80. Elmunzer BJ et al. Trials. 2016;17(1):120.

 

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.

Editor's Note: 

As quality metrics are becoming increasingly significant throughout all of medicine, our field is no exception. Recent evidence has demonstrated the importance of quality measures in colonoscopy; understanding, reporting, and improving these metrics has become a hot topic of discussion.

In this month’s In Focus article, brought to you by The New Gastroenterologist, Nabiha Shamsi, Ashish Malhotra, and Aasma Shaukat (University of Minnesota/Minneapolis VAMC) provide an outstanding overview of the evidence as well as recommended goals for important quality metrics in colonoscopy. Ultimately, improving colonoscopy quality amongst all gastroenterologists will increase colonoscopy value and lead to further decreases in the incidence and mortality of colorectal cancer.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Colonoscopy is a widely used modality to evaluate colorectal cancer because it allows for both identification of early malignancies and removal of precancerous lesions. The increased use of colonoscopy in the last 20 years has been associated with a decline in the incidence and mortality from colorectal cancer.^1,2 However, colonoscopy has its limitations. It is an invasive test with inherent risks. Additionally, studies have reported rates of post-colonoscopy cancers, also referred to as interval cancers, of 2%-7%, and miss-rates for adenomas by tandem colonoscopy of 2%-26%.^3-5

High-quality exams can maximize the value of colonoscopy, and it is important to consider the factors that contribute to high-quality colonoscopies. While there are many metrics proposed,^6,7 here we discuss the most evidence-based ones, outlined in Table 1, along with their goal values.
 

Cecal intubation rate

A high-quality colonoscopy should include a complete examination of the colon. To achieve this, it is necessary to fully intubate the cecum, passing the colonoscope past the ileocecal valve to examine the medial wall of the cecum.⁸

There are several factors that may contribute to an incomplete colonoscopy, including bowel preparation, anatomy, body habitus, and endoscopist’s skill. To calculate cecal intubation rate as a quality measure, colonoscopies that are incomplete because of poor bowel preparation, severe colitis, or known obstructing lesion are usually excluded.

The U.S. Multi-Society Task Force on Colorectal Cancer recommends a cecal intubation rate of at least 95% for screening colonoscopy and 90% for all colonoscopies.⁶ There is an expectation of photodocumentation of the ileocecal valve and appendiceal orifice to establish completion of the colonoscopy.⁶

Some methods used to assist with cecal intubation include changing patient position, applying abdominal pressure, stiffening the colonoscope, and alternating between adult or pediatric colonoscopes.
 

Adenoma detection rate

Adenoma detection rate (ADR), is defined as the proportion of patients over the age of 50 years undergoing first-time screening colonoscopies in which at least one adenomatous polyp is detected for a given endoscopist in a given time period.

Adenomas are tracked because clearing the colon of neoplasm is the goal of screening colonoscopies; adenomas are tracked instead of more advanced lesions because the higher frequency of adenomas allows for better tracking of variation between endoscopists. Tracking ADR also utilizes the assumption that, if small lesions are identified, larger ones will be as well.

ADR is the only current quality indicator reported to be significantly associated with the risk of interval cancers. In 2010, a study of 45,000 screening colonoscopies by 186 endoscopists validated the use of ADR, finding that patients who underwent colonoscopy by physicians with ADRs below 20% had hazard ratios for development of postcolonoscopy cancer greater than 10 times higher than patients of physicians with ADRs above 20%.⁹ However, this study had limited power to establish that cancer protection continues to improve when ADRs rise above 20%. Another study, which evaluated the association of ADR in 224,000 patients undergoing colonoscopies by 136 gastroenterologists, showed each 1% increase in ADR is associated with 3% decrease in the risk of interval CRC and 5% decrease in the risk of fatal interval cancers.¹⁰

Most recent guidelines propose an adequate ADR for asymptomatic individuals aged 50 years or older undergoing screening colonoscopy should be greater than 30% in men and greater than 20% in women.⁶ It remains unknown whether there is a threshold for maximum benefit of ADR, in which a very high ADR is not associated with further protective benefit. The answer to this question may depend on why a low ADR is associated with a higher rate of interval cancers and whether every missed polyp, independent of size, is a potential interval cancer or whether hasty, inadequate, or incomplete examinations of the colon are the underlying concern.

Withdrawal time

Optimizing identification of colonic lesions requires a careful and thorough exam of the colon on withdrawal. While this may seem obvious, there is often little focus on the approach to withdrawal. In four chapters on colonoscopy technique from textbooks, the number of pages describing insertion ranged from 20 to 38, while the number of pages focused on withdrawal ranged from 0.5 to 1.5.^11-14

A study examining the difference in withdrawal technique between two endoscopists who were known to differ in adenoma miss rates by tandem colonoscopy proposed the scoring system listed in Table 2 that can assess quality of examination on withdrawal. There was a statistically significant difference in quality scores for the two endoscopists, as assessed by expert review of video recordings of their colonoscopies.¹⁵

The endoscopist with the lower adenoma miss rate was also found to have an average withdrawal time of 8 minutes and 55 seconds versus 6 minutes and 41 seconds for the endoscopist with the higher adenoma miss rate. A large, community-based study with over 76,000 colonoscopies found a statistically significant correlation between interval colorectal cancer and withdrawal times shorter than 6 minutes.¹⁶ However, there was no association between ADR and colorectal cancer, suggesting that, for practices with optimal ADRs (that is, rates greater than 25%), withdrawal time may be a more sensitive marker of quality of colonoscopy than ADR is.¹⁶Intuitively, adequate examination of the colon that includes examining the proximal side of folds, washing and suctioning stool, and even repositioning the patient would likely increase withdrawal time. In a 2008 study examining 2,000 screening colonoscopies of 12 endoscopists, those with withdrawal times greater than 6 minutes had significantly higher rates of detecting adenomas and advanced neoplasia, compared with those with faster withdrawal times.¹⁷ The average ADR in this group was 28.3%, compared with 11.8% for physicians who had a withdrawal time less than 6 minutes.¹⁷ An evaluation of nearly 11,000 colonoscopies done by 43 endoscopists also identified an increase polyp yield with increased withdrawal time.¹⁸ These data drive the recommendation for a minimum withdrawal time of 6 minutes, with 2 minutes spent examining each colonic segment.

Bowel preparation

Diagnosis of colonic lesions is dependent on adequate visualization of the colon. Poor bowel preparation can limit the yield of colonoscopy and lead to missed lesions. It also leads to canceled and rescheduled procedures that reduce efficiency, increase cost, and pose an undue burden on the patient.

The quality of bowel preparation should be assessed after washing and suctioning of colonic mucosa has been completed. Adequate preparation is that which allows identification of lesions greater than 5 mm in size.¹⁹

Quality of preparation is assessed subjectively by the endoscopists and often listed as excellent, good, fair, or poor. An alternative method of reporting bowel preparation quality is the Boston Bowel Preparation Score (BBPS) (Table 3).²⁰ This scoring system allows for a more descriptive assessment of each colonic segment by assigning a score from 0 to 3 for the right, transverse, and left colon, leading to a total score between 0 and 9. The BBPS also helps standardize reporting of bowel preparation. The polyp detection rate associated with a BBPS of 5 or greater was 40%, compared with 24% associated with BBPS less than 5.¹⁹ A split-dose bowel preparation regimen with at least half of the preparation ingested on the day of the procedure is recommended to optimize quality of bowel preparation.⁶

The American Society for Gastrointestinal Endoscopy and American College of Gastroenterology task force on quality assurance in endoscopy recommends that bowel preparation should be adequate in 85% of all colonoscopy exams on a per-provider basis.⁷ One study of completed colonoscopy with inadequate preparation showed an adenoma miss rate of 48%.²¹ In the setting of inadequate bowel preparation, another study reported 42% of all adenomas detected were only found on repeat colonoscopy. When considering advanced adenomas, there was a 27% miss rate, a relatively high percentage.²²
 

When poor bowel preparation precludes the exam, colonoscopy is appropriately aborted, and the patient asked to return. However, there are situations in which the exam can be completed but the bowel preparation is still inadequate to identify polyps larger than 5 mm. In this setting, the colonoscopy should be repeated with a more aggressive bowel preparation regimen within 1 year.¹⁹ Shorter intervals are recommended if advanced neoplasm is detected within an inadequate bowel preparation.¹⁹

The appropriate surveillance interval can be unclear when bowel preparation is considered adequate to identify polyps greater than or equal to 5 mm, yet still suboptimal. “Adequate” or “fair” bowel preparation often leads to shorter-than-recommended surveillance intervals because of the concern for small missed lesions. For example, patients with normal colonoscopy results and a fair prep were recommended to undergo a screening colonoscopy in 5 years at 57.4%, while only 23.1% received a 10-year recommendation.²³ This increased frequency of colonoscopy leads to increased costs and procedural risks for the patient. Furthermore, a meta-analysis evaluating the effects of bowel preparation reported no significant difference in ADR between adequate and excellent prep.²⁴ These findings suggest that patients with adequate bowel preparation may be followed at guideline-recommended surveillance intervals without significantly affecting colonoscopy quality as measured by ADR.

Endoscopist feedback and report cards

Awareness of quality metrics among individuals and endoscopy practices is crucial to ensuring adequate performance. Several studies have shown improvement with feedback and monitoring of endoscopists.^25,26 Some strategies to improve colonoscopy technique and efficiency include having recorded or observed procedures, computer software that measures image resolution/velocity, and scorecards with quality measures. A representation of the scorecards used in our practice is shown in Table 4. Feedback measures both make endoscopists aware of how their performance compares with recommended goals for colonoscopy and help track their improvement. We recommend such feedback should be provided quarterly for most providers and more frequently for providers not meeting benchmarks.

Conclusion

Given we rely on colonoscopy to identify and clear the colon of potential malignancy, it is imperative that we provide high-value exams for our patients. The basis for a quality colonoscopy is complete intubation and careful inspection of the mucosa on withdrawal. Several quality measures are used as surrogates of a good exam such that endoscopists can assess themselves in relation to their peers. These metrics can help us in our goal of remaining mindful during each procedure we are completing and providing the best exam possible.

Dr. Shamsi is a third-year GI fellow. Dr. Malhotra is an assistant professor in the division of gastroenterology at the University of Minnesota, Minneapolis. Dr. Shaukat is a professor of medicine in the division of gastroenterology at the University of Minnesota, Minneapolis, and the GI Section Chief at the Minneapolis VA Medical Center.

References

1. Siegel R et al. CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29.

2. Edwards BK et al. Cancer. 2010 Feb 1;116(3):544-73.

3. Hosokawa O et al. Endoscopy. 2003 Jun;35(6):506-10.

4. Morris EJ et al. Gut. 2015(Aug);64(2):1248-56.

5. Bressler B et al. Gastroenterology. 2004 Aug;127(2):452-6.

6. Rex DK et al. Am J Gastroenterol. 2017 July;12(7):1016-30.

7. Rex DK et al. Gastrointest Endosc. 2015 Jan;81(1):31-53.

8. Anderson J et al. Clin Transl Gastroenterol. 2015 Feb 26;6:e77.

9. Kaminski M et al. N Engl J Med. 2010 May 13;362(19):1795-803.

10. Corley DA et al. N Engl J Med. 2014 Apr 3;370(4):1298-306.

11. Hunt RH. Colonoscopy intubation techniques without fluoroscopy. In: Colonoscopy techniques clinical practice and color atlas. Edited by Hunt RH, Waye JD. London: Chapman and Hall; 1981. p. 109-46.

12. Waye JD. Colonoscopy intubation techniques without fluoroscopy. In: Colonoscopy techniques clinical practice and color atlas. Edited by Hunt RH, Waye JD. London: Chapman and Hall; 1981. p. 147-78.

13. Williams CB et al. In: Colonoscopy principles & techniques. Edited by Raskin J, Juergen NH. New York: Igaku-Shoin Medical Publishers; 1995. p. 121-42.

14. Baillie J. Colonoscopy. In: Gastrointestinal endoscopy basic principles and practice. Oxford (UK): Butterworth-Heinemann; 1992. p. 63-92.

15. Rex DK. Gastrointest Endosc. 2000 Jan;51(1):33-6.

16. Shaukat A et al. Gastroenterol. 2015;149(4):952-7.

17. Barclay R et al. N Engl J Med. 2006 Dec 14;355(24):2533-41.

18. Simmons DT et al. Gastrointest Endosc. 2007;65(5):AB94.

19. Johnson DA et al. Gastrointest Endosc. 2014;80(4):543-62.

20. Calderwood A et al. Gastrointest Endosc. 2010 Oct;72(4):686-92.

21. Chokshi R et al. Gastrointest Endosc. 2012 Jun;75(6):1197-203.

22. Lebwohl B et al. Gastrointest Endosc. 2011 Jun;73(6):1207-14.

23. Menees SB et al. Gastrointest Endosc. 2013 Sep;78(3): 510-6.

24. Clark B et al. Am J Gastroenterol. 2014 Nov;109(11):1714-23.

25. Nielson A et al. BMJ Open Gastro. 2017 Jun. doi: 10.1136/bmjgast-2017-000142.

26. Gurudu S et al. J Gastroenterol Hepatol. 2018 Mar;33(3):645-9.

Editor's Note: 

As quality metrics are becoming increasingly significant throughout all of medicine, our field is no exception. Recent evidence has demonstrated the importance of quality measures in colonoscopy; understanding, reporting, and improving these metrics has become a hot topic of discussion.

In this month’s In Focus article, brought to you by The New Gastroenterologist, Nabiha Shamsi, Ashish Malhotra, and Aasma Shaukat (University of Minnesota/Minneapolis VAMC) provide an outstanding overview of the evidence as well as recommended goals for important quality metrics in colonoscopy. Ultimately, improving colonoscopy quality amongst all gastroenterologists will increase colonoscopy value and lead to further decreases in the incidence and mortality of colorectal cancer.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Colonoscopy is a widely used modality to evaluate colorectal cancer because it allows for both identification of early malignancies and removal of precancerous lesions. The increased use of colonoscopy in the last 20 years has been associated with a decline in the incidence and mortality from colorectal cancer.^1,2 However, colonoscopy has its limitations. It is an invasive test with inherent risks. Additionally, studies have reported rates of post-colonoscopy cancers, also referred to as interval cancers, of 2%-7%, and miss-rates for adenomas by tandem colonoscopy of 2%-26%.^3-5

High-quality exams can maximize the value of colonoscopy, and it is important to consider the factors that contribute to high-quality colonoscopies. While there are many metrics proposed,^6,7 here we discuss the most evidence-based ones, outlined in Table 1, along with their goal values.
 

Cecal intubation rate

A high-quality colonoscopy should include a complete examination of the colon. To achieve this, it is necessary to fully intubate the cecum, passing the colonoscope past the ileocecal valve to examine the medial wall of the cecum.⁸

There are several factors that may contribute to an incomplete colonoscopy, including bowel preparation, anatomy, body habitus, and endoscopist’s skill. To calculate cecal intubation rate as a quality measure, colonoscopies that are incomplete because of poor bowel preparation, severe colitis, or known obstructing lesion are usually excluded.

The U.S. Multi-Society Task Force on Colorectal Cancer recommends a cecal intubation rate of at least 95% for screening colonoscopy and 90% for all colonoscopies.⁶ There is an expectation of photodocumentation of the ileocecal valve and appendiceal orifice to establish completion of the colonoscopy.⁶

Some methods used to assist with cecal intubation include changing patient position, applying abdominal pressure, stiffening the colonoscope, and alternating between adult or pediatric colonoscopes.
 

Adenoma detection rate

Adenoma detection rate (ADR), is defined as the proportion of patients over the age of 50 years undergoing first-time screening colonoscopies in which at least one adenomatous polyp is detected for a given endoscopist in a given time period.

Adenomas are tracked because clearing the colon of neoplasm is the goal of screening colonoscopies; adenomas are tracked instead of more advanced lesions because the higher frequency of adenomas allows for better tracking of variation between endoscopists. Tracking ADR also utilizes the assumption that, if small lesions are identified, larger ones will be as well.

ADR is the only current quality indicator reported to be significantly associated with the risk of interval cancers. In 2010, a study of 45,000 screening colonoscopies by 186 endoscopists validated the use of ADR, finding that patients who underwent colonoscopy by physicians with ADRs below 20% had hazard ratios for development of postcolonoscopy cancer greater than 10 times higher than patients of physicians with ADRs above 20%.⁹ However, this study had limited power to establish that cancer protection continues to improve when ADRs rise above 20%. Another study, which evaluated the association of ADR in 224,000 patients undergoing colonoscopies by 136 gastroenterologists, showed each 1% increase in ADR is associated with 3% decrease in the risk of interval CRC and 5% decrease in the risk of fatal interval cancers.¹⁰

Most recent guidelines propose an adequate ADR for asymptomatic individuals aged 50 years or older undergoing screening colonoscopy should be greater than 30% in men and greater than 20% in women.⁶ It remains unknown whether there is a threshold for maximum benefit of ADR, in which a very high ADR is not associated with further protective benefit. The answer to this question may depend on why a low ADR is associated with a higher rate of interval cancers and whether every missed polyp, independent of size, is a potential interval cancer or whether hasty, inadequate, or incomplete examinations of the colon are the underlying concern.

Withdrawal time

Optimizing identification of colonic lesions requires a careful and thorough exam of the colon on withdrawal. While this may seem obvious, there is often little focus on the approach to withdrawal. In four chapters on colonoscopy technique from textbooks, the number of pages describing insertion ranged from 20 to 38, while the number of pages focused on withdrawal ranged from 0.5 to 1.5.^11-14

A study examining the difference in withdrawal technique between two endoscopists who were known to differ in adenoma miss rates by tandem colonoscopy proposed the scoring system listed in Table 2 that can assess quality of examination on withdrawal. There was a statistically significant difference in quality scores for the two endoscopists, as assessed by expert review of video recordings of their colonoscopies.¹⁵

The endoscopist with the lower adenoma miss rate was also found to have an average withdrawal time of 8 minutes and 55 seconds versus 6 minutes and 41 seconds for the endoscopist with the higher adenoma miss rate. A large, community-based study with over 76,000 colonoscopies found a statistically significant correlation between interval colorectal cancer and withdrawal times shorter than 6 minutes.¹⁶ However, there was no association between ADR and colorectal cancer, suggesting that, for practices with optimal ADRs (that is, rates greater than 25%), withdrawal time may be a more sensitive marker of quality of colonoscopy than ADR is.¹⁶Intuitively, adequate examination of the colon that includes examining the proximal side of folds, washing and suctioning stool, and even repositioning the patient would likely increase withdrawal time. In a 2008 study examining 2,000 screening colonoscopies of 12 endoscopists, those with withdrawal times greater than 6 minutes had significantly higher rates of detecting adenomas and advanced neoplasia, compared with those with faster withdrawal times.¹⁷ The average ADR in this group was 28.3%, compared with 11.8% for physicians who had a withdrawal time less than 6 minutes.¹⁷ An evaluation of nearly 11,000 colonoscopies done by 43 endoscopists also identified an increase polyp yield with increased withdrawal time.¹⁸ These data drive the recommendation for a minimum withdrawal time of 6 minutes, with 2 minutes spent examining each colonic segment.

Bowel preparation

Diagnosis of colonic lesions is dependent on adequate visualization of the colon. Poor bowel preparation can limit the yield of colonoscopy and lead to missed lesions. It also leads to canceled and rescheduled procedures that reduce efficiency, increase cost, and pose an undue burden on the patient.

The quality of bowel preparation should be assessed after washing and suctioning of colonic mucosa has been completed. Adequate preparation is that which allows identification of lesions greater than 5 mm in size.¹⁹

Quality of preparation is assessed subjectively by the endoscopists and often listed as excellent, good, fair, or poor. An alternative method of reporting bowel preparation quality is the Boston Bowel Preparation Score (BBPS) (Table 3).²⁰ This scoring system allows for a more descriptive assessment of each colonic segment by assigning a score from 0 to 3 for the right, transverse, and left colon, leading to a total score between 0 and 9. The BBPS also helps standardize reporting of bowel preparation. The polyp detection rate associated with a BBPS of 5 or greater was 40%, compared with 24% associated with BBPS less than 5.¹⁹ A split-dose bowel preparation regimen with at least half of the preparation ingested on the day of the procedure is recommended to optimize quality of bowel preparation.⁶

The American Society for Gastrointestinal Endoscopy and American College of Gastroenterology task force on quality assurance in endoscopy recommends that bowel preparation should be adequate in 85% of all colonoscopy exams on a per-provider basis.⁷ One study of completed colonoscopy with inadequate preparation showed an adenoma miss rate of 48%.²¹ In the setting of inadequate bowel preparation, another study reported 42% of all adenomas detected were only found on repeat colonoscopy. When considering advanced adenomas, there was a 27% miss rate, a relatively high percentage.²²
 

When poor bowel preparation precludes the exam, colonoscopy is appropriately aborted, and the patient asked to return. However, there are situations in which the exam can be completed but the bowel preparation is still inadequate to identify polyps larger than 5 mm. In this setting, the colonoscopy should be repeated with a more aggressive bowel preparation regimen within 1 year.¹⁹ Shorter intervals are recommended if advanced neoplasm is detected within an inadequate bowel preparation.¹⁹

The appropriate surveillance interval can be unclear when bowel preparation is considered adequate to identify polyps greater than or equal to 5 mm, yet still suboptimal. “Adequate” or “fair” bowel preparation often leads to shorter-than-recommended surveillance intervals because of the concern for small missed lesions. For example, patients with normal colonoscopy results and a fair prep were recommended to undergo a screening colonoscopy in 5 years at 57.4%, while only 23.1% received a 10-year recommendation.²³ This increased frequency of colonoscopy leads to increased costs and procedural risks for the patient. Furthermore, a meta-analysis evaluating the effects of bowel preparation reported no significant difference in ADR between adequate and excellent prep.²⁴ These findings suggest that patients with adequate bowel preparation may be followed at guideline-recommended surveillance intervals without significantly affecting colonoscopy quality as measured by ADR.

Endoscopist feedback and report cards

Awareness of quality metrics among individuals and endoscopy practices is crucial to ensuring adequate performance. Several studies have shown improvement with feedback and monitoring of endoscopists.^25,26 Some strategies to improve colonoscopy technique and efficiency include having recorded or observed procedures, computer software that measures image resolution/velocity, and scorecards with quality measures. A representation of the scorecards used in our practice is shown in Table 4. Feedback measures both make endoscopists aware of how their performance compares with recommended goals for colonoscopy and help track their improvement. We recommend such feedback should be provided quarterly for most providers and more frequently for providers not meeting benchmarks.

Conclusion

Given we rely on colonoscopy to identify and clear the colon of potential malignancy, it is imperative that we provide high-value exams for our patients. The basis for a quality colonoscopy is complete intubation and careful inspection of the mucosa on withdrawal. Several quality measures are used as surrogates of a good exam such that endoscopists can assess themselves in relation to their peers. These metrics can help us in our goal of remaining mindful during each procedure we are completing and providing the best exam possible.

Dr. Shamsi is a third-year GI fellow. Dr. Malhotra is an assistant professor in the division of gastroenterology at the University of Minnesota, Minneapolis. Dr. Shaukat is a professor of medicine in the division of gastroenterology at the University of Minnesota, Minneapolis, and the GI Section Chief at the Minneapolis VA Medical Center.

References

1. Siegel R et al. CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29.

2. Edwards BK et al. Cancer. 2010 Feb 1;116(3):544-73.

3. Hosokawa O et al. Endoscopy. 2003 Jun;35(6):506-10.

4. Morris EJ et al. Gut. 2015(Aug);64(2):1248-56.

5. Bressler B et al. Gastroenterology. 2004 Aug;127(2):452-6.

6. Rex DK et al. Am J Gastroenterol. 2017 July;12(7):1016-30.

7. Rex DK et al. Gastrointest Endosc. 2015 Jan;81(1):31-53.

8. Anderson J et al. Clin Transl Gastroenterol. 2015 Feb 26;6:e77.

9. Kaminski M et al. N Engl J Med. 2010 May 13;362(19):1795-803.

10. Corley DA et al. N Engl J Med. 2014 Apr 3;370(4):1298-306.

11. Hunt RH. Colonoscopy intubation techniques without fluoroscopy. In: Colonoscopy techniques clinical practice and color atlas. Edited by Hunt RH, Waye JD. London: Chapman and Hall; 1981. p. 109-46.

12. Waye JD. Colonoscopy intubation techniques without fluoroscopy. In: Colonoscopy techniques clinical practice and color atlas. Edited by Hunt RH, Waye JD. London: Chapman and Hall; 1981. p. 147-78.

13. Williams CB et al. In: Colonoscopy principles & techniques. Edited by Raskin J, Juergen NH. New York: Igaku-Shoin Medical Publishers; 1995. p. 121-42.

14. Baillie J. Colonoscopy. In: Gastrointestinal endoscopy basic principles and practice. Oxford (UK): Butterworth-Heinemann; 1992. p. 63-92.

15. Rex DK. Gastrointest Endosc. 2000 Jan;51(1):33-6.

16. Shaukat A et al. Gastroenterol. 2015;149(4):952-7.

17. Barclay R et al. N Engl J Med. 2006 Dec 14;355(24):2533-41.

18. Simmons DT et al. Gastrointest Endosc. 2007;65(5):AB94.

19. Johnson DA et al. Gastrointest Endosc. 2014;80(4):543-62.

20. Calderwood A et al. Gastrointest Endosc. 2010 Oct;72(4):686-92.

21. Chokshi R et al. Gastrointest Endosc. 2012 Jun;75(6):1197-203.

22. Lebwohl B et al. Gastrointest Endosc. 2011 Jun;73(6):1207-14.

23. Menees SB et al. Gastrointest Endosc. 2013 Sep;78(3): 510-6.

24. Clark B et al. Am J Gastroenterol. 2014 Nov;109(11):1714-23.

25. Nielson A et al. BMJ Open Gastro. 2017 Jun. doi: 10.1136/bmjgast-2017-000142.

26. Gurudu S et al. J Gastroenterol Hepatol. 2018 Mar;33(3):645-9.

Editor's Note: 

As quality metrics are becoming increasingly significant throughout all of medicine, our field is no exception. Recent evidence has demonstrated the importance of quality measures in colonoscopy; understanding, reporting, and improving these metrics has become a hot topic of discussion.

In this month’s In Focus article, brought to you by The New Gastroenterologist, Nabiha Shamsi, Ashish Malhotra, and Aasma Shaukat (University of Minnesota/Minneapolis VAMC) provide an outstanding overview of the evidence as well as recommended goals for important quality metrics in colonoscopy. Ultimately, improving colonoscopy quality amongst all gastroenterologists will increase colonoscopy value and lead to further decreases in the incidence and mortality of colorectal cancer.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Colonoscopy is a widely used modality to evaluate colorectal cancer because it allows for both identification of early malignancies and removal of precancerous lesions. The increased use of colonoscopy in the last 20 years has been associated with a decline in the incidence and mortality from colorectal cancer.^1,2 However, colonoscopy has its limitations. It is an invasive test with inherent risks. Additionally, studies have reported rates of post-colonoscopy cancers, also referred to as interval cancers, of 2%-7%, and miss-rates for adenomas by tandem colonoscopy of 2%-26%.^3-5

High-quality exams can maximize the value of colonoscopy, and it is important to consider the factors that contribute to high-quality colonoscopies. While there are many metrics proposed,^6,7 here we discuss the most evidence-based ones, outlined in Table 1, along with their goal values.
 

Cecal intubation rate

A high-quality colonoscopy should include a complete examination of the colon. To achieve this, it is necessary to fully intubate the cecum, passing the colonoscope past the ileocecal valve to examine the medial wall of the cecum.⁸

There are several factors that may contribute to an incomplete colonoscopy, including bowel preparation, anatomy, body habitus, and endoscopist’s skill. To calculate cecal intubation rate as a quality measure, colonoscopies that are incomplete because of poor bowel preparation, severe colitis, or known obstructing lesion are usually excluded.

The U.S. Multi-Society Task Force on Colorectal Cancer recommends a cecal intubation rate of at least 95% for screening colonoscopy and 90% for all colonoscopies.⁶ There is an expectation of photodocumentation of the ileocecal valve and appendiceal orifice to establish completion of the colonoscopy.⁶

Some methods used to assist with cecal intubation include changing patient position, applying abdominal pressure, stiffening the colonoscope, and alternating between adult or pediatric colonoscopes.
 

Adenoma detection rate

Adenoma detection rate (ADR), is defined as the proportion of patients over the age of 50 years undergoing first-time screening colonoscopies in which at least one adenomatous polyp is detected for a given endoscopist in a given time period.

Adenomas are tracked because clearing the colon of neoplasm is the goal of screening colonoscopies; adenomas are tracked instead of more advanced lesions because the higher frequency of adenomas allows for better tracking of variation between endoscopists. Tracking ADR also utilizes the assumption that, if small lesions are identified, larger ones will be as well.

ADR is the only current quality indicator reported to be significantly associated with the risk of interval cancers. In 2010, a study of 45,000 screening colonoscopies by 186 endoscopists validated the use of ADR, finding that patients who underwent colonoscopy by physicians with ADRs below 20% had hazard ratios for development of postcolonoscopy cancer greater than 10 times higher than patients of physicians with ADRs above 20%.⁹ However, this study had limited power to establish that cancer protection continues to improve when ADRs rise above 20%. Another study, which evaluated the association of ADR in 224,000 patients undergoing colonoscopies by 136 gastroenterologists, showed each 1% increase in ADR is associated with 3% decrease in the risk of interval CRC and 5% decrease in the risk of fatal interval cancers.¹⁰

Most recent guidelines propose an adequate ADR for asymptomatic individuals aged 50 years or older undergoing screening colonoscopy should be greater than 30% in men and greater than 20% in women.⁶ It remains unknown whether there is a threshold for maximum benefit of ADR, in which a very high ADR is not associated with further protective benefit. The answer to this question may depend on why a low ADR is associated with a higher rate of interval cancers and whether every missed polyp, independent of size, is a potential interval cancer or whether hasty, inadequate, or incomplete examinations of the colon are the underlying concern.

Withdrawal time

Optimizing identification of colonic lesions requires a careful and thorough exam of the colon on withdrawal. While this may seem obvious, there is often little focus on the approach to withdrawal. In four chapters on colonoscopy technique from textbooks, the number of pages describing insertion ranged from 20 to 38, while the number of pages focused on withdrawal ranged from 0.5 to 1.5.^11-14

A study examining the difference in withdrawal technique between two endoscopists who were known to differ in adenoma miss rates by tandem colonoscopy proposed the scoring system listed in Table 2 that can assess quality of examination on withdrawal. There was a statistically significant difference in quality scores for the two endoscopists, as assessed by expert review of video recordings of their colonoscopies.¹⁵

The endoscopist with the lower adenoma miss rate was also found to have an average withdrawal time of 8 minutes and 55 seconds versus 6 minutes and 41 seconds for the endoscopist with the higher adenoma miss rate. A large, community-based study with over 76,000 colonoscopies found a statistically significant correlation between interval colorectal cancer and withdrawal times shorter than 6 minutes.¹⁶ However, there was no association between ADR and colorectal cancer, suggesting that, for practices with optimal ADRs (that is, rates greater than 25%), withdrawal time may be a more sensitive marker of quality of colonoscopy than ADR is.¹⁶Intuitively, adequate examination of the colon that includes examining the proximal side of folds, washing and suctioning stool, and even repositioning the patient would likely increase withdrawal time. In a 2008 study examining 2,000 screening colonoscopies of 12 endoscopists, those with withdrawal times greater than 6 minutes had significantly higher rates of detecting adenomas and advanced neoplasia, compared with those with faster withdrawal times.¹⁷ The average ADR in this group was 28.3%, compared with 11.8% for physicians who had a withdrawal time less than 6 minutes.¹⁷ An evaluation of nearly 11,000 colonoscopies done by 43 endoscopists also identified an increase polyp yield with increased withdrawal time.¹⁸ These data drive the recommendation for a minimum withdrawal time of 6 minutes, with 2 minutes spent examining each colonic segment.

Bowel preparation

Diagnosis of colonic lesions is dependent on adequate visualization of the colon. Poor bowel preparation can limit the yield of colonoscopy and lead to missed lesions. It also leads to canceled and rescheduled procedures that reduce efficiency, increase cost, and pose an undue burden on the patient.

The quality of bowel preparation should be assessed after washing and suctioning of colonic mucosa has been completed. Adequate preparation is that which allows identification of lesions greater than 5 mm in size.¹⁹

Quality of preparation is assessed subjectively by the endoscopists and often listed as excellent, good, fair, or poor. An alternative method of reporting bowel preparation quality is the Boston Bowel Preparation Score (BBPS) (Table 3).²⁰ This scoring system allows for a more descriptive assessment of each colonic segment by assigning a score from 0 to 3 for the right, transverse, and left colon, leading to a total score between 0 and 9. The BBPS also helps standardize reporting of bowel preparation. The polyp detection rate associated with a BBPS of 5 or greater was 40%, compared with 24% associated with BBPS less than 5.¹⁹ A split-dose bowel preparation regimen with at least half of the preparation ingested on the day of the procedure is recommended to optimize quality of bowel preparation.⁶

The American Society for Gastrointestinal Endoscopy and American College of Gastroenterology task force on quality assurance in endoscopy recommends that bowel preparation should be adequate in 85% of all colonoscopy exams on a per-provider basis.⁷ One study of completed colonoscopy with inadequate preparation showed an adenoma miss rate of 48%.²¹ In the setting of inadequate bowel preparation, another study reported 42% of all adenomas detected were only found on repeat colonoscopy. When considering advanced adenomas, there was a 27% miss rate, a relatively high percentage.²²
 

When poor bowel preparation precludes the exam, colonoscopy is appropriately aborted, and the patient asked to return. However, there are situations in which the exam can be completed but the bowel preparation is still inadequate to identify polyps larger than 5 mm. In this setting, the colonoscopy should be repeated with a more aggressive bowel preparation regimen within 1 year.¹⁹ Shorter intervals are recommended if advanced neoplasm is detected within an inadequate bowel preparation.¹⁹

The appropriate surveillance interval can be unclear when bowel preparation is considered adequate to identify polyps greater than or equal to 5 mm, yet still suboptimal. “Adequate” or “fair” bowel preparation often leads to shorter-than-recommended surveillance intervals because of the concern for small missed lesions. For example, patients with normal colonoscopy results and a fair prep were recommended to undergo a screening colonoscopy in 5 years at 57.4%, while only 23.1% received a 10-year recommendation.²³ This increased frequency of colonoscopy leads to increased costs and procedural risks for the patient. Furthermore, a meta-analysis evaluating the effects of bowel preparation reported no significant difference in ADR between adequate and excellent prep.²⁴ These findings suggest that patients with adequate bowel preparation may be followed at guideline-recommended surveillance intervals without significantly affecting colonoscopy quality as measured by ADR.

Endoscopist feedback and report cards

Awareness of quality metrics among individuals and endoscopy practices is crucial to ensuring adequate performance. Several studies have shown improvement with feedback and monitoring of endoscopists.^25,26 Some strategies to improve colonoscopy technique and efficiency include having recorded or observed procedures, computer software that measures image resolution/velocity, and scorecards with quality measures. A representation of the scorecards used in our practice is shown in Table 4. Feedback measures both make endoscopists aware of how their performance compares with recommended goals for colonoscopy and help track their improvement. We recommend such feedback should be provided quarterly for most providers and more frequently for providers not meeting benchmarks.

Conclusion

Given we rely on colonoscopy to identify and clear the colon of potential malignancy, it is imperative that we provide high-value exams for our patients. The basis for a quality colonoscopy is complete intubation and careful inspection of the mucosa on withdrawal. Several quality measures are used as surrogates of a good exam such that endoscopists can assess themselves in relation to their peers. These metrics can help us in our goal of remaining mindful during each procedure we are completing and providing the best exam possible.

Dr. Shamsi is a third-year GI fellow. Dr. Malhotra is an assistant professor in the division of gastroenterology at the University of Minnesota, Minneapolis. Dr. Shaukat is a professor of medicine in the division of gastroenterology at the University of Minnesota, Minneapolis, and the GI Section Chief at the Minneapolis VA Medical Center.

References

1. Siegel R et al. CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29.

2. Edwards BK et al. Cancer. 2010 Feb 1;116(3):544-73.

3. Hosokawa O et al. Endoscopy. 2003 Jun;35(6):506-10.

4. Morris EJ et al. Gut. 2015(Aug);64(2):1248-56.

5. Bressler B et al. Gastroenterology. 2004 Aug;127(2):452-6.

6. Rex DK et al. Am J Gastroenterol. 2017 July;12(7):1016-30.

7. Rex DK et al. Gastrointest Endosc. 2015 Jan;81(1):31-53.

8. Anderson J et al. Clin Transl Gastroenterol. 2015 Feb 26;6:e77.

9. Kaminski M et al. N Engl J Med. 2010 May 13;362(19):1795-803.

10. Corley DA et al. N Engl J Med. 2014 Apr 3;370(4):1298-306.

11. Hunt RH. Colonoscopy intubation techniques without fluoroscopy. In: Colonoscopy techniques clinical practice and color atlas. Edited by Hunt RH, Waye JD. London: Chapman and Hall; 1981. p. 109-46.

12. Waye JD. Colonoscopy intubation techniques without fluoroscopy. In: Colonoscopy techniques clinical practice and color atlas. Edited by Hunt RH, Waye JD. London: Chapman and Hall; 1981. p. 147-78.

13. Williams CB et al. In: Colonoscopy principles & techniques. Edited by Raskin J, Juergen NH. New York: Igaku-Shoin Medical Publishers; 1995. p. 121-42.

14. Baillie J. Colonoscopy. In: Gastrointestinal endoscopy basic principles and practice. Oxford (UK): Butterworth-Heinemann; 1992. p. 63-92.

15. Rex DK. Gastrointest Endosc. 2000 Jan;51(1):33-6.

16. Shaukat A et al. Gastroenterol. 2015;149(4):952-7.

17. Barclay R et al. N Engl J Med. 2006 Dec 14;355(24):2533-41.

18. Simmons DT et al. Gastrointest Endosc. 2007;65(5):AB94.

19. Johnson DA et al. Gastrointest Endosc. 2014;80(4):543-62.

20. Calderwood A et al. Gastrointest Endosc. 2010 Oct;72(4):686-92.

21. Chokshi R et al. Gastrointest Endosc. 2012 Jun;75(6):1197-203.

22. Lebwohl B et al. Gastrointest Endosc. 2011 Jun;73(6):1207-14.

23. Menees SB et al. Gastrointest Endosc. 2013 Sep;78(3): 510-6.

24. Clark B et al. Am J Gastroenterol. 2014 Nov;109(11):1714-23.

25. Nielson A et al. BMJ Open Gastro. 2017 Jun. doi: 10.1136/bmjgast-2017-000142.

26. Gurudu S et al. J Gastroenterol Hepatol. 2018 Mar;33(3):645-9.

Editor's Note: 

As we all strive to improve the rate of colorectal cancer screening, it is important to acknowledge that barriers exist that prevent screening uptake.

Importantly, these barriers often vary between specific population subsets. In this month’s In Focus article, brought to you by The New Gastroenterologist, the members of the AGA Institute Diversity Committee provide an enlightening overview of the barriers affecting underserved populations as well as strategies that can be employed to overcome these impediments. Better understanding of patient-specific barriers will, I hope, allow us to more effectively redress them and ultimately increase colorectal cancer screening rates in all populations.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Despite the positive public health effects of colorectal cancer (CRC) screening, there remains differential uptake of CRC screening in the United States. Minority populations born in the United States and immigrant populations are among those with the lowest rates of CRC screening, and both socioeconomic status and ethnicity are strongly associated with stage of CRC at diagnosis.^1,2 Thus, recognizing the economic, social, and cultural factors that result in low rates of CRC screening in underserved populations is important in order to devise targeted interventions to increase CRC uptake and reduce morbidity and mortality in these populations.

Vidyard Video

What are the facts and figures?

The overall rate of screening colonoscopies has increased in all ethnic groups in the past 10 years but still falls below the goal of 71% established by the Healthy People project (www.healthypeople.gov) for the year 2020.³ According to the Centers for Disease Control and Prevention ethnicity-specific data for U.S.-born populations, 60% of whites, 55% of African Americans (AA), 50% of American Indian/Alaskan natives (AI/AN), 46% of Latino Americans, and 47% of Asians undergo CRC screening (Figure 1A).⁴ While CRC incidence in non-Hispanic whites age 50 years and older has dropped by 32% since 2000 because of screening, this trend has not been observed in AAs.^5,6

The incidence of CRC in AAs is estimated at 49/10,000, one of the highest amongst U.S. populations and is the second and third most common cancer in AA women and men, respectively (Figure 1B).

Similar to AAs, AI/AN patients present with more advanced CRC disease and at younger ages and have lower survival rates, compared with other racial groups, a trend that has not changed in the last decade.⁷ CRC screening data in this population vary according to sex, geographic location, and health care utilization, with as few as 4.0% of asymptomatic, average-risk AI/ANs who receive medical care in the Indian Health Services being screened for CRC.⁸

The low rate of CRC screening among Latinos also poses a significant obstacle to the Healthy People project since it is expected that by 2060 Latinos will constitute 30% of the U.S. population. Therefore, strategies to improve CRC screening in this population are needed to continue the gains made in overall CRC mortality rates.

The percentage of immigrants in the U.S. population increased from 4.7% in 1970 to 13.5% in 2015. Immigrants, regardless of their ethnicity, represent a very vulnerable population, and CRC screening data in this population are not as robust as for U.S.-born groups. In general, immigrants have substantially lower CRC screening rates, compared with U.S.-born populations (21% vs. 60%),⁹ and it is suspected that additional, significant barriers to CRC screening and care exist for undocumented immigrants.

 

 

Another often overlooked group, are individuals with physical or cognitive disabilities. In this group, screening rates range from 49% to 65%.¹⁰

Finally, while information is available for many health care conditions and disparities faced by various ethnic groups, there are few CRC screening data for the LGBTQ community. Perhaps amplifying this problem is the existence of conflicting data in this population, with some studies suggesting there is no difference in CRC risk across groups in the LGBTQ community and others suggesting an increased risk.^11,12 Notably, sexual orientation has been identified as a positive predictor of CRC screening in gay and bisexual men – CRC screening rates are higher in these groups, compared with heterosexual men.¹³ In contrast, no such difference has been found between homosexual and heterosexual women.¹⁴

What are the barriers?

Several common themes contribute to disparities in CRC screening among minority groups, including psychosocial/cultural, socioeconomic, provider-specific, and insurance-related factors. Some patient-related barriers include issues of illiteracy, having poor health literacy or English proficiency, having only grade school education,^15,16 cultural misconceptions, transportation issues, difficulties affording copayments or deductibles, and a lack of follow-up for scheduled appointments and exams.^17-20 Poor health literacy has a profound effect on exam perceptions, fear of test results, and compliance with scheduling tests and bowel preparation instructions^21-25; it also affects one’s understanding of the importance of CRC screening, the recommended screening age, and the available choice of screening tests.

Even when some apparent barriers are mitigated, disparities in CRC screening remain. For example, even among the insured and among Medicare beneficiaries, screening rates and adequate follow-up rates after abnormal findings remain lower among AAs and those of low socioeconomic status than they are among whites.^26-28 At least part of this paradox results from the presence of unmeasured cultural/belief systems that affect CRC screening uptake. Some of these factors include fear and/or denial of CRC diagnoses, mistrust of the health care system, and reluctance to undergo medical treatment and surgery.^16,29 AAs are also less likely to be aware of a family history of CRC and to discuss personal and/or family history of CRC or polyps, which can thereby hinder the identification of high-risk individuals who would benefit from early screening.^15,30

The deeply rooted sense of fatalism also plays a crucial role and has been cited for many minority and immigrant populations. Fatalism leads patients to view a diagnosis of cancer as a matter of “fate” or “God’s will,” and therefore, it is to be endured.^23,31 Similarly, in a qualitative study of 44 Somali men living in St. Paul and Minneapolis, believing cancer was more common in whites, believing they were protected from cancer by God, fearing a cancer diagnosis, and fearing ostracism from their community were reported as barriers to cancer screening.³²

Perceptions about CRC screening methods in Latino populations also have a tremendous influence and can include fear, stigma of sexual prejudice, embarrassment of being exposed during the exam, worries about humiliation in a male sense of masculinity, a lack of trust in the medical professionals, a sense of being a “guinea pig” for physicians, concerns about health care racism, and expectations of pain.^33-37 Studies have reported that immigrants are afraid to seek health care because of the increasingly hostile environment associated with immigration enforcement.³⁸ In addition, the impending dissolution of the Deferred Action for Childhood Arrivals act is likely to augment the barriers to care for Latino groups.³⁹

In addition, provider-specific barriers to care also exist. Racial and ethnic minorities are less likely than whites to receive recommendations for screening by their physician. In fact, this factor alone has been demonstrated to be the main reason for lack of screening among AAs in a Californian cohort.⁴⁰ In addition, patients from rural areas or those from AI/AN communities are at especially increased risk for lack of access to care because of a scarcity of providers along with patient perceptions regarding their primary care provider’s ability to connect them to subspecialists.^41-43 Other cited examples include misconceptions about and poor treatment of the LGBTQ population by health care providers/systems.⁴⁴

 

 

How can we intervene successfully?

Characterization of barriers is important because it promotes the development of targeted interventions. Intervention models include community engagement programs, incorporation of fecal occult testing, and patient navigator programs.^45-47 In response to the alarming disparity in CRC screening rates in Latino communities, several interventions have been set in motion in different clinical scenarios, which include patient navigation and a focus on patient education.

Patient navigators facilitate the screening process at different stages, including providing information that is easy to understand by patients, translating when patients are not proficient in English, addressing any concerns they may have about the procedure, and reminding patients about their appointments via phone calls or other means (Figure 2). Trials evaluating the effect of patient navigators in Hispanic populations have resulted in anywhere from a modest 11% to a robust 56% increase in screening.^48-50 In facilities serving a large number of Latino patients with low socioeconomic status, low-cost interventions, such as mailing information about CRC screening to all eligible patients, increased the screening rate from 12% to 28%.⁵¹ It has been shown that using bilingual and bicultural staff, language-appropriate material, and face-to-face encounters in a community setting helped recruit Chinese Americans into CRC screening trials.⁵² Similarly, an activation educational program consisting of a video and brochure that actively encouraged patients to ask their primary care physicians about CRC screening resulted in a 10% increase in screening rates.⁵³

Randomized trials have shown that outreach efforts and patient navigation increase CRC screening rates in AAs.^48,54,55 Studies evaluating the effects of print-based educational materials on improving screening showed improvement in screening rates, decreases in cancer-related fatalistic attitudes, and patients had a better understanding of the benefits of screening as compared with the cost associated with screening and the cost of advanced disease.⁵⁶ Similarly, the use of touch-screen computers that tailor informational messages to decisional stage and screening barriers increased participation in CRC screening.⁵⁷ Including patient navigators along with printed education material was even more effective at increasing the proportion of patients getting colonoscopy screening than providing printed material alone, with more-intensive navigation needed for individuals with low literacy.⁵⁸ Grubbs et al.reported the success of their patient navigation program, which included wider comprehensive screening and coverage for colonoscopy screening.⁵⁹ In AAs, they estimated an annual reduction of CRC incidence and mortality of 4,200 and 2,700 patients, respectively.

Among immigrants, there is an increased likelihood of CRC screening in those immigrants with a higher number of primary care visits.⁶⁰ The intersection of culture, race, socioeconomic status, housing enclaves, limited English proficiency, low health literacy, and immigration policy all play a role in immigrant health and access to health care.⁶¹

Courtesy Aline Charabaty

Therefore, different strategies may be needed for each immigrant group to improve CRC screening. For this group of patients, efforts aimed at mitigating the adverse effects of national immigration policies on immigrant populations may have the additional consequence of improving health care access and CRC screening for these patients.

Data gaps still exist in our understanding of patient perceptions, perspectives, and barriers that present opportunities for further study to develop long-lasting interventions that will improve health care of underserved populations. By raising awareness of the barriers, physicians can enhance their own self-awareness to keenly be attuned to these challenges as patients cross their clinic threshold for medical care.

 

 

Additional resources link: www.cdc.gov/cancer/colorectal/

References

1. Klabunde CN et al. Trends in colorectal cancer test use among vulnerable populations in the United States. Cancer Epidemiol Biomarkers Prev. 2011 Aug;20(8):1611-21.

2. Parikh-Patel A et al. Colorectal cancer stage at diagnosis by socioeconomic and urban/rural status in California, 1988-2000. Cancer. 2006 Sep;107(5 Suppl):1189-95.

3. Promotion OoDPaH. Healthy People 2020. Cancer. Volume 2017.

4. Centers for Disease Control and Prevention. Cancer screening – United States, 2010. MMWR Morb Mortal Wkly Rep. 2012 Jan 27;61(3):41-5.

5. Doubeni CA et al. Racial and ethnic trends of colorectal cancer screening among Medicare enrollees. Am J Prev Med. 2010 Feb;38(2):184-91.

6. Kupfer SS et al. Reducing colorectal cancer risk among African Americans. Gastroenterology. 2015 Nov;149(6):1302-4.

7. Espey DK et al. Annual report to the nation on the status of cancer, 1975-2004, featuring cancer in American Indians and Alaska Natives. Cancer. 2007 Nov;110(10):2119-52.

8. Day LW et al. Screening prevalence and incidence of colorectal cancer among American Indian/Alaskan natives in the Indian Health Service. Dig Dis Sci. 2011 Jul;56(7):2104-13.

9. Gupta S et al. Challenges and possible solutions to colorectal cancer screening for the underserved. J Natl Cancer Inst. 2014 Apr;106(4):dju032.

10. Steele CB et al. Colorectal cancer incidence and screening – United States, 2008 and 2010. MMWR Suppl. 2013 Nov 22;62(3):53-60.

11. Boehmer U et al. Cancer survivorship and sexual orientation. Cancer 2011 Aug 15;117(16):3796-804.

12. Austin SB, Pazaris MJ, Wei EK, et al. Application of the Rosner-Wei risk-prediction model to estimate sexual orientation patterns in colon cancer risk in a prospective cohort of US women. Cancer Causes Control. 2014 Aug;25(8):999-1006.

13. Heslin KC et al. Sexual orientation and testing for prostate and colorectal cancers among men in California. Med Care. 2008 Dec;46(12):1240-8.

14. McElroy JA et al. Advancing Health Care for Lesbian, Gay, Bisexual, and Transgender Patients in Missouri. Mo Med. 2015 Jul-Aug;112(4):262-5.

15. Greiner KA et al. Knowledge and perceptions of colorectal cancer screening among urban African Americans. J Gen Intern Med. 2005 Nov;20(11):977-83.

16. Green PM, Kelly BA. Colorectal cancer knowledge, perceptions, and behaviors in African Americans. Cancer Nurs. 2004 May-Jun;27(3):206-15; quiz 216-7.

17. Berkowitz Z et al. Beliefs, risk perceptions, and gaps in knowledge as barriers to colorectal cancer screening in older adults. J Am Geriatr Soc. 2008 Feb;56(2):307-14.

18. Dolan NC et al. Colorectal cancer screening knowledge, attitudes, and beliefs among veterans: Does literacy make a difference? J Clin Oncol. 2004 Jul;22(13):2617-22.

19. Peterson NB et al. The influence of health literacy on colorectal cancer screening knowledge, beliefs and behavior. J Natl Med Assoc. 2007 Oct;99(10):1105-12.

20. Haddock MG et al. Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients. Int J Radiat Oncol Biol Phys. 2001 Apr 1;49(5):1267-74.

21. Jones RM et al. Patient-reported barriers to colorectal cancer screening: a mixed-methods analysis. Am J Prev Med. 2010 May;38(5):508-16.

22. Basch CH et al. Screening colonoscopy bowel preparation: experience in an urban minority population. Therap Adv Gastroenterol. 2013 Nov;6(6):442-6.

23. Davis JL et al. Sociodemographic differences in fears and mistrust contributing to unwillingness to participate in cancer screenings. J Health Care Poor Underserved. 2012 Nov;23(4 Suppl):67-76.

24. Robinson CM et al. Barriers to colorectal cancer screening among publicly insured urban women: no knowledge of tests and no clinician recommendation. J Natl Med Assoc. 2011 Aug;103(8):746-53.

25. Goldman RE et al. Perspectives of colorectal cancer risk and screening among Dominicans and Puerto Ricans: Stigma and misperceptions. Qual Health Res. 2009 Nov;19(11):1559-68.

26. Laiyemo AO et al. Race and colorectal cancer disparities: Health-care utilization vs different cancer susceptibilities. J Natl Cancer Inst. 2010 Apr 21;102(8):538-46.

27. White A et al. Racial disparities and treatment trends in a large cohort of elderly African Americans and Caucasians with colorectal cancer, 1991 to 2002. Cancer. 2008 Dec 15;113(12):3400-9.

28. Doubeni CA et al. Neighborhood socioeconomic status and use of colonoscopy in an insured population – A retrospective cohort study. PLoS One. 2012;7(5):e36392.

29. Tammana VS, Laiyemo AO. Colorectal cancer disparities: Issues, controversies and solutions. World J Gastroenterol. 2014 Jan 28;20(4):869-76.

30. Carethers JM. Screening for colorectal cancer in African Americans: determinants and rationale for an earlier age to commence screening. Dig Dis Sci. 2015 Mar;60(3):711-21.

31. Miranda-Diaz C et al. Barriers for Compliance to Breast, Colorectal, and Cervical Screening Cancer Tests among Hispanic Patients. Int J Environ Res Public Health. 2015 Dec 22;13(1):ijerph13010021.

32. Sewali B et al. Understanding cancer screening service utilization by Somali men in Minnesota. J Immigr Minor Health. 2015 Jun;17(3):773-80.

 

 

33. Walsh JM et al. Barriers to colorectal cancer screening in Latino and Vietnamese Americans. Compared with non-Latino white Americans. J Gen Intern Med. 2004 Feb;19(2):156-66.

34. Perez-Stable EJ et al. Self-reported use of cancer screening tests among Latinos and Anglos in a prepaid health plan. Arch Intern Med. 1994 May 23;154(10):1073-81.

35. Shariff-Marco S et al. Racial/ethnic differences in self-reported racism and its association with cancer-related health behaviors. Am J Public Health. 2010 Feb;100(2):364-74.

36. Powe BD et al. Comparing knowledge of colorectal and prostate cancer among African American and Hispanic men. Cancer Nurs. 2009 Sep-Oct;32(5):412-7.

37. Jun J, Oh KM. Asian and Hispanic Americans’ cancer fatalism and colon cancer screening. Am J Health Behav. 2013 Mar;37(2):145-54.

38. Hacker K et al. The impact of Immigration and Customs Enforcement on immigrant health: Perceptions of immigrants in Everett, Massachusetts, USA. Soc Sci Med. 2011 Aug;73(4):586-94.

39. Firger J. Rescinding DACA could spur a public health crisis, from lost services to higher rates of depression, substance abuse. Newsweek.

40. May FP et al. Racial minorities are more likely than whites to report lack of provider recommendation for colon cancer screening. Am J Gastroenterol. 2015 Oct;110(10):1388-94.

41. Levy BT et al. Why hasn’t this patient been screened for colon cancer? An Iowa Research Network study. J Am Board Fam Med. 2007 Sep-Oct;20(5):458-68.

42. Rosenblatt RA. A view from the periphery – health care in rural America. N Engl J Med. 2004 Sep 9;351(11):1049-51.

43. Young WF et al. Predictors of colorectal screening in rural Colorado: testing to prevent colon cancer in the high plains research network. J Rural Health. 2007 Summer;23(3):238-45.

44. Kates J et al. Health and Access to Care and Coverage for Lesbian, Gay, Bisexual, and Transgender (LGBT) Individuals in the U.S. In: Foundation KF, ed. Disparities Policy Issue Brief. Volume 2017; Aug 30, 2017.

45. Katz ML et al. Improving colorectal cancer screening by using community volunteers: results of the Carolinas cancer education and screening (CARES) project. Cancer. 2007 Oct 1;110(7):1602-10.

46. Jean-Jacques M et al. Program to improve colorectal cancer screening in a low-income, racially diverse population: A randomized controlled trial. Ann Fam Med. 2012 Sep-Oct;10(5):412-7.

47. Reuland DS et al. Effect of combined patient decision aid and patient navigation vs usual care for colorectal cancer screening in a vulnerable patient population: A randomized clinical trial. JAMA Intern Med. 2017 Jul 1;177(7):967-74.

48. Percac-Lima S et al. A culturally tailored navigator program for colorectal cancer screening in a community health center: a randomized, controlled trial. J Gen Intern Med. 2009 Feb;24(2):211-7.

49. Nash D et al. Evaluation of an intervention to increase screening colonoscopy in an urban public hospital setting. J Urban Health. 2006 Mar;83(2):231-43.

50. Lebwohl B et al. Effect of a patient navigator program on the volume and quality of colonoscopy. J Clin Gastroenterol. 2011 May-Jun;45(5):e47-53.

51. Khankari K et al. Improving colorectal cancer screening among the medically underserved: A pilot study within a federally qualified health center. J Gen Intern Med. 2007 Oct;22(10):1410-4.

52. Wang JH et al. Recruiting Chinese Americans into cancer screening intervention trials: Strategies and outcomes. Clin Trials. 2014 Apr;11(2):167-77.

53. Katz ML et al. Patient activation increases colorectal cancer screening rates: a randomized trial among low-income minority patients. Cancer Epidemiol Biomarkers Prev. 2012 Jan;21(1):45-52.

54. Ford ME et al. Enhancing adherence among older African American men enrolled in a longitudinal cancer screening trial. Gerontologist. 2006 Aug;46(4):545-50.

55. Christie J et al. A randomized controlled trial using patient navigation to increase colonoscopy screening among low-income minorities. J Natl Med Assoc. 2008 Mar;100(3):278-84.

56. Philip EJ et al. Evaluating the impact of an educational intervention to increase CRC screening rates in the African American community: A preliminary study. Cancer Causes Control. 2010 Oct;21(10):1685-91.

57. Greiner KA et al. Implementation intentions and colorectal screening: A randomized trial in safety-net clinics. Am J Prev Med. 2014 Dec;47(6):703-14.

58. Horne HN et al. Effect of patient navigation on colorectal cancer screening in a community-based randomized controlled trial of urban African American adults. Cancer Causes Control. 2015 Feb;26(2):239-46.

59. Grubbs SS et al. Eliminating racial disparities in colorectal cancer in the real world: It took a village. J Clin Oncol. 2013 Jun 1;31(16):1928-30.

60. Jung MY et al. The Chinese and Korean American immigrant experience: a mixed-methods examination of facilitators and barriers of colorectal cancer screening. Ethn Health. 2017 Feb 25:1-20.

61. Viruell-Fuentes EA et al. More than culture: structural racism, intersectionality theory, and immigrant health. Soc Sci Med. 2012 Dec;75(12):2099-106.

Dr. Oduyebo is a third-year fellow at the Mayo Clinic, Rochester, Minn.; Dr. Malespin is an assistant professor in the department of medicine and the medical director of hepatology at the University of Florida Health, Jacksonville; Dr. Mendoza Ladd is an assistant professor of medicine at Texas Tech University, El Paso; Dr. Day is an associate professor of medicine at the University of California, San Francisco; Dr. Charabaty is an associate professor of medicine and the director of the IBD Center in the division of gastroenterology at Medstar-Georgetown University Center, Washington; Dr. Chen is an associate professor of medicine, the director of patient safety and quality, and the director of the small-bowel endoscopy program in division of gastroenterology at Washington University, St. Louis; Dr. Carr is an assistant professor of medicine in the division of gastroenterology at the University of Pennsylvania, Philadelphia; Dr. Quezada is an assistant dean for admissions, an assistant dean for academic and multicultural affairs, and an assistant professor of medicine in the division of gastroenterology and hepatology at the University of Maryland, Baltimore; and Dr. Lamousé-Smith is a director of translational medicine, immunology, and early development at Janssen Pharmaceuticals Research and Development, Spring House, Penn.

Editor's Note: 

As we all strive to improve the rate of colorectal cancer screening, it is important to acknowledge that barriers exist that prevent screening uptake.

Importantly, these barriers often vary between specific population subsets. In this month’s In Focus article, brought to you by The New Gastroenterologist, the members of the AGA Institute Diversity Committee provide an enlightening overview of the barriers affecting underserved populations as well as strategies that can be employed to overcome these impediments. Better understanding of patient-specific barriers will, I hope, allow us to more effectively redress them and ultimately increase colorectal cancer screening rates in all populations.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Despite the positive public health effects of colorectal cancer (CRC) screening, there remains differential uptake of CRC screening in the United States. Minority populations born in the United States and immigrant populations are among those with the lowest rates of CRC screening, and both socioeconomic status and ethnicity are strongly associated with stage of CRC at diagnosis.^1,2 Thus, recognizing the economic, social, and cultural factors that result in low rates of CRC screening in underserved populations is important in order to devise targeted interventions to increase CRC uptake and reduce morbidity and mortality in these populations.

Vidyard Video

What are the facts and figures?

The overall rate of screening colonoscopies has increased in all ethnic groups in the past 10 years but still falls below the goal of 71% established by the Healthy People project (www.healthypeople.gov) for the year 2020.³ According to the Centers for Disease Control and Prevention ethnicity-specific data for U.S.-born populations, 60% of whites, 55% of African Americans (AA), 50% of American Indian/Alaskan natives (AI/AN), 46% of Latino Americans, and 47% of Asians undergo CRC screening (Figure 1A).⁴ While CRC incidence in non-Hispanic whites age 50 years and older has dropped by 32% since 2000 because of screening, this trend has not been observed in AAs.^5,6

The incidence of CRC in AAs is estimated at 49/10,000, one of the highest amongst U.S. populations and is the second and third most common cancer in AA women and men, respectively (Figure 1B).

Similar to AAs, AI/AN patients present with more advanced CRC disease and at younger ages and have lower survival rates, compared with other racial groups, a trend that has not changed in the last decade.⁷ CRC screening data in this population vary according to sex, geographic location, and health care utilization, with as few as 4.0% of asymptomatic, average-risk AI/ANs who receive medical care in the Indian Health Services being screened for CRC.⁸

The low rate of CRC screening among Latinos also poses a significant obstacle to the Healthy People project since it is expected that by 2060 Latinos will constitute 30% of the U.S. population. Therefore, strategies to improve CRC screening in this population are needed to continue the gains made in overall CRC mortality rates.

The percentage of immigrants in the U.S. population increased from 4.7% in 1970 to 13.5% in 2015. Immigrants, regardless of their ethnicity, represent a very vulnerable population, and CRC screening data in this population are not as robust as for U.S.-born groups. In general, immigrants have substantially lower CRC screening rates, compared with U.S.-born populations (21% vs. 60%),⁹ and it is suspected that additional, significant barriers to CRC screening and care exist for undocumented immigrants.

 

 

Another often overlooked group, are individuals with physical or cognitive disabilities. In this group, screening rates range from 49% to 65%.¹⁰

Finally, while information is available for many health care conditions and disparities faced by various ethnic groups, there are few CRC screening data for the LGBTQ community. Perhaps amplifying this problem is the existence of conflicting data in this population, with some studies suggesting there is no difference in CRC risk across groups in the LGBTQ community and others suggesting an increased risk.^11,12 Notably, sexual orientation has been identified as a positive predictor of CRC screening in gay and bisexual men – CRC screening rates are higher in these groups, compared with heterosexual men.¹³ In contrast, no such difference has been found between homosexual and heterosexual women.¹⁴

What are the barriers?

Several common themes contribute to disparities in CRC screening among minority groups, including psychosocial/cultural, socioeconomic, provider-specific, and insurance-related factors. Some patient-related barriers include issues of illiteracy, having poor health literacy or English proficiency, having only grade school education,^15,16 cultural misconceptions, transportation issues, difficulties affording copayments or deductibles, and a lack of follow-up for scheduled appointments and exams.^17-20 Poor health literacy has a profound effect on exam perceptions, fear of test results, and compliance with scheduling tests and bowel preparation instructions^21-25; it also affects one’s understanding of the importance of CRC screening, the recommended screening age, and the available choice of screening tests.

Even when some apparent barriers are mitigated, disparities in CRC screening remain. For example, even among the insured and among Medicare beneficiaries, screening rates and adequate follow-up rates after abnormal findings remain lower among AAs and those of low socioeconomic status than they are among whites.^26-28 At least part of this paradox results from the presence of unmeasured cultural/belief systems that affect CRC screening uptake. Some of these factors include fear and/or denial of CRC diagnoses, mistrust of the health care system, and reluctance to undergo medical treatment and surgery.^16,29 AAs are also less likely to be aware of a family history of CRC and to discuss personal and/or family history of CRC or polyps, which can thereby hinder the identification of high-risk individuals who would benefit from early screening.^15,30

The deeply rooted sense of fatalism also plays a crucial role and has been cited for many minority and immigrant populations. Fatalism leads patients to view a diagnosis of cancer as a matter of “fate” or “God’s will,” and therefore, it is to be endured.^23,31 Similarly, in a qualitative study of 44 Somali men living in St. Paul and Minneapolis, believing cancer was more common in whites, believing they were protected from cancer by God, fearing a cancer diagnosis, and fearing ostracism from their community were reported as barriers to cancer screening.³²

Perceptions about CRC screening methods in Latino populations also have a tremendous influence and can include fear, stigma of sexual prejudice, embarrassment of being exposed during the exam, worries about humiliation in a male sense of masculinity, a lack of trust in the medical professionals, a sense of being a “guinea pig” for physicians, concerns about health care racism, and expectations of pain.^33-37 Studies have reported that immigrants are afraid to seek health care because of the increasingly hostile environment associated with immigration enforcement.³⁸ In addition, the impending dissolution of the Deferred Action for Childhood Arrivals act is likely to augment the barriers to care for Latino groups.³⁹

In addition, provider-specific barriers to care also exist. Racial and ethnic minorities are less likely than whites to receive recommendations for screening by their physician. In fact, this factor alone has been demonstrated to be the main reason for lack of screening among AAs in a Californian cohort.⁴⁰ In addition, patients from rural areas or those from AI/AN communities are at especially increased risk for lack of access to care because of a scarcity of providers along with patient perceptions regarding their primary care provider’s ability to connect them to subspecialists.^41-43 Other cited examples include misconceptions about and poor treatment of the LGBTQ population by health care providers/systems.⁴⁴

 

 

How can we intervene successfully?

Characterization of barriers is important because it promotes the development of targeted interventions. Intervention models include community engagement programs, incorporation of fecal occult testing, and patient navigator programs.^45-47 In response to the alarming disparity in CRC screening rates in Latino communities, several interventions have been set in motion in different clinical scenarios, which include patient navigation and a focus on patient education.

Patient navigators facilitate the screening process at different stages, including providing information that is easy to understand by patients, translating when patients are not proficient in English, addressing any concerns they may have about the procedure, and reminding patients about their appointments via phone calls or other means (Figure 2). Trials evaluating the effect of patient navigators in Hispanic populations have resulted in anywhere from a modest 11% to a robust 56% increase in screening.^48-50 In facilities serving a large number of Latino patients with low socioeconomic status, low-cost interventions, such as mailing information about CRC screening to all eligible patients, increased the screening rate from 12% to 28%.⁵¹ It has been shown that using bilingual and bicultural staff, language-appropriate material, and face-to-face encounters in a community setting helped recruit Chinese Americans into CRC screening trials.⁵² Similarly, an activation educational program consisting of a video and brochure that actively encouraged patients to ask their primary care physicians about CRC screening resulted in a 10% increase in screening rates.⁵³

Randomized trials have shown that outreach efforts and patient navigation increase CRC screening rates in AAs.^48,54,55 Studies evaluating the effects of print-based educational materials on improving screening showed improvement in screening rates, decreases in cancer-related fatalistic attitudes, and patients had a better understanding of the benefits of screening as compared with the cost associated with screening and the cost of advanced disease.⁵⁶ Similarly, the use of touch-screen computers that tailor informational messages to decisional stage and screening barriers increased participation in CRC screening.⁵⁷ Including patient navigators along with printed education material was even more effective at increasing the proportion of patients getting colonoscopy screening than providing printed material alone, with more-intensive navigation needed for individuals with low literacy.⁵⁸ Grubbs et al.reported the success of their patient navigation program, which included wider comprehensive screening and coverage for colonoscopy screening.⁵⁹ In AAs, they estimated an annual reduction of CRC incidence and mortality of 4,200 and 2,700 patients, respectively.

Among immigrants, there is an increased likelihood of CRC screening in those immigrants with a higher number of primary care visits.⁶⁰ The intersection of culture, race, socioeconomic status, housing enclaves, limited English proficiency, low health literacy, and immigration policy all play a role in immigrant health and access to health care.⁶¹

Courtesy Aline Charabaty

Therefore, different strategies may be needed for each immigrant group to improve CRC screening. For this group of patients, efforts aimed at mitigating the adverse effects of national immigration policies on immigrant populations may have the additional consequence of improving health care access and CRC screening for these patients.

Data gaps still exist in our understanding of patient perceptions, perspectives, and barriers that present opportunities for further study to develop long-lasting interventions that will improve health care of underserved populations. By raising awareness of the barriers, physicians can enhance their own self-awareness to keenly be attuned to these challenges as patients cross their clinic threshold for medical care.

 

 

Additional resources link: www.cdc.gov/cancer/colorectal/

References

1. Klabunde CN et al. Trends in colorectal cancer test use among vulnerable populations in the United States. Cancer Epidemiol Biomarkers Prev. 2011 Aug;20(8):1611-21.

2. Parikh-Patel A et al. Colorectal cancer stage at diagnosis by socioeconomic and urban/rural status in California, 1988-2000. Cancer. 2006 Sep;107(5 Suppl):1189-95.

3. Promotion OoDPaH. Healthy People 2020. Cancer. Volume 2017.

4. Centers for Disease Control and Prevention. Cancer screening – United States, 2010. MMWR Morb Mortal Wkly Rep. 2012 Jan 27;61(3):41-5.

5. Doubeni CA et al. Racial and ethnic trends of colorectal cancer screening among Medicare enrollees. Am J Prev Med. 2010 Feb;38(2):184-91.

6. Kupfer SS et al. Reducing colorectal cancer risk among African Americans. Gastroenterology. 2015 Nov;149(6):1302-4.

7. Espey DK et al. Annual report to the nation on the status of cancer, 1975-2004, featuring cancer in American Indians and Alaska Natives. Cancer. 2007 Nov;110(10):2119-52.

8. Day LW et al. Screening prevalence and incidence of colorectal cancer among American Indian/Alaskan natives in the Indian Health Service. Dig Dis Sci. 2011 Jul;56(7):2104-13.

9. Gupta S et al. Challenges and possible solutions to colorectal cancer screening for the underserved. J Natl Cancer Inst. 2014 Apr;106(4):dju032.

10. Steele CB et al. Colorectal cancer incidence and screening – United States, 2008 and 2010. MMWR Suppl. 2013 Nov 22;62(3):53-60.

11. Boehmer U et al. Cancer survivorship and sexual orientation. Cancer 2011 Aug 15;117(16):3796-804.

12. Austin SB, Pazaris MJ, Wei EK, et al. Application of the Rosner-Wei risk-prediction model to estimate sexual orientation patterns in colon cancer risk in a prospective cohort of US women. Cancer Causes Control. 2014 Aug;25(8):999-1006.

13. Heslin KC et al. Sexual orientation and testing for prostate and colorectal cancers among men in California. Med Care. 2008 Dec;46(12):1240-8.

14. McElroy JA et al. Advancing Health Care for Lesbian, Gay, Bisexual, and Transgender Patients in Missouri. Mo Med. 2015 Jul-Aug;112(4):262-5.

15. Greiner KA et al. Knowledge and perceptions of colorectal cancer screening among urban African Americans. J Gen Intern Med. 2005 Nov;20(11):977-83.

16. Green PM, Kelly BA. Colorectal cancer knowledge, perceptions, and behaviors in African Americans. Cancer Nurs. 2004 May-Jun;27(3):206-15; quiz 216-7.

17. Berkowitz Z et al. Beliefs, risk perceptions, and gaps in knowledge as barriers to colorectal cancer screening in older adults. J Am Geriatr Soc. 2008 Feb;56(2):307-14.

18. Dolan NC et al. Colorectal cancer screening knowledge, attitudes, and beliefs among veterans: Does literacy make a difference? J Clin Oncol. 2004 Jul;22(13):2617-22.

19. Peterson NB et al. The influence of health literacy on colorectal cancer screening knowledge, beliefs and behavior. J Natl Med Assoc. 2007 Oct;99(10):1105-12.

20. Haddock MG et al. Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients. Int J Radiat Oncol Biol Phys. 2001 Apr 1;49(5):1267-74.

21. Jones RM et al. Patient-reported barriers to colorectal cancer screening: a mixed-methods analysis. Am J Prev Med. 2010 May;38(5):508-16.

22. Basch CH et al. Screening colonoscopy bowel preparation: experience in an urban minority population. Therap Adv Gastroenterol. 2013 Nov;6(6):442-6.

23. Davis JL et al. Sociodemographic differences in fears and mistrust contributing to unwillingness to participate in cancer screenings. J Health Care Poor Underserved. 2012 Nov;23(4 Suppl):67-76.

24. Robinson CM et al. Barriers to colorectal cancer screening among publicly insured urban women: no knowledge of tests and no clinician recommendation. J Natl Med Assoc. 2011 Aug;103(8):746-53.

25. Goldman RE et al. Perspectives of colorectal cancer risk and screening among Dominicans and Puerto Ricans: Stigma and misperceptions. Qual Health Res. 2009 Nov;19(11):1559-68.

26. Laiyemo AO et al. Race and colorectal cancer disparities: Health-care utilization vs different cancer susceptibilities. J Natl Cancer Inst. 2010 Apr 21;102(8):538-46.

27. White A et al. Racial disparities and treatment trends in a large cohort of elderly African Americans and Caucasians with colorectal cancer, 1991 to 2002. Cancer. 2008 Dec 15;113(12):3400-9.

28. Doubeni CA et al. Neighborhood socioeconomic status and use of colonoscopy in an insured population – A retrospective cohort study. PLoS One. 2012;7(5):e36392.

29. Tammana VS, Laiyemo AO. Colorectal cancer disparities: Issues, controversies and solutions. World J Gastroenterol. 2014 Jan 28;20(4):869-76.

30. Carethers JM. Screening for colorectal cancer in African Americans: determinants and rationale for an earlier age to commence screening. Dig Dis Sci. 2015 Mar;60(3):711-21.

31. Miranda-Diaz C et al. Barriers for Compliance to Breast, Colorectal, and Cervical Screening Cancer Tests among Hispanic Patients. Int J Environ Res Public Health. 2015 Dec 22;13(1):ijerph13010021.

32. Sewali B et al. Understanding cancer screening service utilization by Somali men in Minnesota. J Immigr Minor Health. 2015 Jun;17(3):773-80.

 

 

33. Walsh JM et al. Barriers to colorectal cancer screening in Latino and Vietnamese Americans. Compared with non-Latino white Americans. J Gen Intern Med. 2004 Feb;19(2):156-66.

34. Perez-Stable EJ et al. Self-reported use of cancer screening tests among Latinos and Anglos in a prepaid health plan. Arch Intern Med. 1994 May 23;154(10):1073-81.

35. Shariff-Marco S et al. Racial/ethnic differences in self-reported racism and its association with cancer-related health behaviors. Am J Public Health. 2010 Feb;100(2):364-74.

36. Powe BD et al. Comparing knowledge of colorectal and prostate cancer among African American and Hispanic men. Cancer Nurs. 2009 Sep-Oct;32(5):412-7.

37. Jun J, Oh KM. Asian and Hispanic Americans’ cancer fatalism and colon cancer screening. Am J Health Behav. 2013 Mar;37(2):145-54.

38. Hacker K et al. The impact of Immigration and Customs Enforcement on immigrant health: Perceptions of immigrants in Everett, Massachusetts, USA. Soc Sci Med. 2011 Aug;73(4):586-94.

39. Firger J. Rescinding DACA could spur a public health crisis, from lost services to higher rates of depression, substance abuse. Newsweek.

40. May FP et al. Racial minorities are more likely than whites to report lack of provider recommendation for colon cancer screening. Am J Gastroenterol. 2015 Oct;110(10):1388-94.

41. Levy BT et al. Why hasn’t this patient been screened for colon cancer? An Iowa Research Network study. J Am Board Fam Med. 2007 Sep-Oct;20(5):458-68.

42. Rosenblatt RA. A view from the periphery – health care in rural America. N Engl J Med. 2004 Sep 9;351(11):1049-51.

43. Young WF et al. Predictors of colorectal screening in rural Colorado: testing to prevent colon cancer in the high plains research network. J Rural Health. 2007 Summer;23(3):238-45.

44. Kates J et al. Health and Access to Care and Coverage for Lesbian, Gay, Bisexual, and Transgender (LGBT) Individuals in the U.S. In: Foundation KF, ed. Disparities Policy Issue Brief. Volume 2017; Aug 30, 2017.

45. Katz ML et al. Improving colorectal cancer screening by using community volunteers: results of the Carolinas cancer education and screening (CARES) project. Cancer. 2007 Oct 1;110(7):1602-10.

46. Jean-Jacques M et al. Program to improve colorectal cancer screening in a low-income, racially diverse population: A randomized controlled trial. Ann Fam Med. 2012 Sep-Oct;10(5):412-7.

47. Reuland DS et al. Effect of combined patient decision aid and patient navigation vs usual care for colorectal cancer screening in a vulnerable patient population: A randomized clinical trial. JAMA Intern Med. 2017 Jul 1;177(7):967-74.

48. Percac-Lima S et al. A culturally tailored navigator program for colorectal cancer screening in a community health center: a randomized, controlled trial. J Gen Intern Med. 2009 Feb;24(2):211-7.

49. Nash D et al. Evaluation of an intervention to increase screening colonoscopy in an urban public hospital setting. J Urban Health. 2006 Mar;83(2):231-43.

50. Lebwohl B et al. Effect of a patient navigator program on the volume and quality of colonoscopy. J Clin Gastroenterol. 2011 May-Jun;45(5):e47-53.

51. Khankari K et al. Improving colorectal cancer screening among the medically underserved: A pilot study within a federally qualified health center. J Gen Intern Med. 2007 Oct;22(10):1410-4.

52. Wang JH et al. Recruiting Chinese Americans into cancer screening intervention trials: Strategies and outcomes. Clin Trials. 2014 Apr;11(2):167-77.

53. Katz ML et al. Patient activation increases colorectal cancer screening rates: a randomized trial among low-income minority patients. Cancer Epidemiol Biomarkers Prev. 2012 Jan;21(1):45-52.

54. Ford ME et al. Enhancing adherence among older African American men enrolled in a longitudinal cancer screening trial. Gerontologist. 2006 Aug;46(4):545-50.

55. Christie J et al. A randomized controlled trial using patient navigation to increase colonoscopy screening among low-income minorities. J Natl Med Assoc. 2008 Mar;100(3):278-84.

56. Philip EJ et al. Evaluating the impact of an educational intervention to increase CRC screening rates in the African American community: A preliminary study. Cancer Causes Control. 2010 Oct;21(10):1685-91.

57. Greiner KA et al. Implementation intentions and colorectal screening: A randomized trial in safety-net clinics. Am J Prev Med. 2014 Dec;47(6):703-14.

58. Horne HN et al. Effect of patient navigation on colorectal cancer screening in a community-based randomized controlled trial of urban African American adults. Cancer Causes Control. 2015 Feb;26(2):239-46.

59. Grubbs SS et al. Eliminating racial disparities in colorectal cancer in the real world: It took a village. J Clin Oncol. 2013 Jun 1;31(16):1928-30.

60. Jung MY et al. The Chinese and Korean American immigrant experience: a mixed-methods examination of facilitators and barriers of colorectal cancer screening. Ethn Health. 2017 Feb 25:1-20.

61. Viruell-Fuentes EA et al. More than culture: structural racism, intersectionality theory, and immigrant health. Soc Sci Med. 2012 Dec;75(12):2099-106.

Dr. Oduyebo is a third-year fellow at the Mayo Clinic, Rochester, Minn.; Dr. Malespin is an assistant professor in the department of medicine and the medical director of hepatology at the University of Florida Health, Jacksonville; Dr. Mendoza Ladd is an assistant professor of medicine at Texas Tech University, El Paso; Dr. Day is an associate professor of medicine at the University of California, San Francisco; Dr. Charabaty is an associate professor of medicine and the director of the IBD Center in the division of gastroenterology at Medstar-Georgetown University Center, Washington; Dr. Chen is an associate professor of medicine, the director of patient safety and quality, and the director of the small-bowel endoscopy program in division of gastroenterology at Washington University, St. Louis; Dr. Carr is an assistant professor of medicine in the division of gastroenterology at the University of Pennsylvania, Philadelphia; Dr. Quezada is an assistant dean for admissions, an assistant dean for academic and multicultural affairs, and an assistant professor of medicine in the division of gastroenterology and hepatology at the University of Maryland, Baltimore; and Dr. Lamousé-Smith is a director of translational medicine, immunology, and early development at Janssen Pharmaceuticals Research and Development, Spring House, Penn.

Editor's Note: 

As we all strive to improve the rate of colorectal cancer screening, it is important to acknowledge that barriers exist that prevent screening uptake.

Importantly, these barriers often vary between specific population subsets. In this month’s In Focus article, brought to you by The New Gastroenterologist, the members of the AGA Institute Diversity Committee provide an enlightening overview of the barriers affecting underserved populations as well as strategies that can be employed to overcome these impediments. Better understanding of patient-specific barriers will, I hope, allow us to more effectively redress them and ultimately increase colorectal cancer screening rates in all populations.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Despite the positive public health effects of colorectal cancer (CRC) screening, there remains differential uptake of CRC screening in the United States. Minority populations born in the United States and immigrant populations are among those with the lowest rates of CRC screening, and both socioeconomic status and ethnicity are strongly associated with stage of CRC at diagnosis.^1,2 Thus, recognizing the economic, social, and cultural factors that result in low rates of CRC screening in underserved populations is important in order to devise targeted interventions to increase CRC uptake and reduce morbidity and mortality in these populations.

Vidyard Video

What are the facts and figures?

The overall rate of screening colonoscopies has increased in all ethnic groups in the past 10 years but still falls below the goal of 71% established by the Healthy People project (www.healthypeople.gov) for the year 2020.³ According to the Centers for Disease Control and Prevention ethnicity-specific data for U.S.-born populations, 60% of whites, 55% of African Americans (AA), 50% of American Indian/Alaskan natives (AI/AN), 46% of Latino Americans, and 47% of Asians undergo CRC screening (Figure 1A).⁴ While CRC incidence in non-Hispanic whites age 50 years and older has dropped by 32% since 2000 because of screening, this trend has not been observed in AAs.^5,6

The incidence of CRC in AAs is estimated at 49/10,000, one of the highest amongst U.S. populations and is the second and third most common cancer in AA women and men, respectively (Figure 1B).

Similar to AAs, AI/AN patients present with more advanced CRC disease and at younger ages and have lower survival rates, compared with other racial groups, a trend that has not changed in the last decade.⁷ CRC screening data in this population vary according to sex, geographic location, and health care utilization, with as few as 4.0% of asymptomatic, average-risk AI/ANs who receive medical care in the Indian Health Services being screened for CRC.⁸

The low rate of CRC screening among Latinos also poses a significant obstacle to the Healthy People project since it is expected that by 2060 Latinos will constitute 30% of the U.S. population. Therefore, strategies to improve CRC screening in this population are needed to continue the gains made in overall CRC mortality rates.

The percentage of immigrants in the U.S. population increased from 4.7% in 1970 to 13.5% in 2015. Immigrants, regardless of their ethnicity, represent a very vulnerable population, and CRC screening data in this population are not as robust as for U.S.-born groups. In general, immigrants have substantially lower CRC screening rates, compared with U.S.-born populations (21% vs. 60%),⁹ and it is suspected that additional, significant barriers to CRC screening and care exist for undocumented immigrants.

 

 

Another often overlooked group, are individuals with physical or cognitive disabilities. In this group, screening rates range from 49% to 65%.¹⁰

Finally, while information is available for many health care conditions and disparities faced by various ethnic groups, there are few CRC screening data for the LGBTQ community. Perhaps amplifying this problem is the existence of conflicting data in this population, with some studies suggesting there is no difference in CRC risk across groups in the LGBTQ community and others suggesting an increased risk.^11,12 Notably, sexual orientation has been identified as a positive predictor of CRC screening in gay and bisexual men – CRC screening rates are higher in these groups, compared with heterosexual men.¹³ In contrast, no such difference has been found between homosexual and heterosexual women.¹⁴

What are the barriers?

Several common themes contribute to disparities in CRC screening among minority groups, including psychosocial/cultural, socioeconomic, provider-specific, and insurance-related factors. Some patient-related barriers include issues of illiteracy, having poor health literacy or English proficiency, having only grade school education,^15,16 cultural misconceptions, transportation issues, difficulties affording copayments or deductibles, and a lack of follow-up for scheduled appointments and exams.^17-20 Poor health literacy has a profound effect on exam perceptions, fear of test results, and compliance with scheduling tests and bowel preparation instructions^21-25; it also affects one’s understanding of the importance of CRC screening, the recommended screening age, and the available choice of screening tests.

Even when some apparent barriers are mitigated, disparities in CRC screening remain. For example, even among the insured and among Medicare beneficiaries, screening rates and adequate follow-up rates after abnormal findings remain lower among AAs and those of low socioeconomic status than they are among whites.^26-28 At least part of this paradox results from the presence of unmeasured cultural/belief systems that affect CRC screening uptake. Some of these factors include fear and/or denial of CRC diagnoses, mistrust of the health care system, and reluctance to undergo medical treatment and surgery.^16,29 AAs are also less likely to be aware of a family history of CRC and to discuss personal and/or family history of CRC or polyps, which can thereby hinder the identification of high-risk individuals who would benefit from early screening.^15,30

The deeply rooted sense of fatalism also plays a crucial role and has been cited for many minority and immigrant populations. Fatalism leads patients to view a diagnosis of cancer as a matter of “fate” or “God’s will,” and therefore, it is to be endured.^23,31 Similarly, in a qualitative study of 44 Somali men living in St. Paul and Minneapolis, believing cancer was more common in whites, believing they were protected from cancer by God, fearing a cancer diagnosis, and fearing ostracism from their community were reported as barriers to cancer screening.³²

Perceptions about CRC screening methods in Latino populations also have a tremendous influence and can include fear, stigma of sexual prejudice, embarrassment of being exposed during the exam, worries about humiliation in a male sense of masculinity, a lack of trust in the medical professionals, a sense of being a “guinea pig” for physicians, concerns about health care racism, and expectations of pain.^33-37 Studies have reported that immigrants are afraid to seek health care because of the increasingly hostile environment associated with immigration enforcement.³⁸ In addition, the impending dissolution of the Deferred Action for Childhood Arrivals act is likely to augment the barriers to care for Latino groups.³⁹

In addition, provider-specific barriers to care also exist. Racial and ethnic minorities are less likely than whites to receive recommendations for screening by their physician. In fact, this factor alone has been demonstrated to be the main reason for lack of screening among AAs in a Californian cohort.⁴⁰ In addition, patients from rural areas or those from AI/AN communities are at especially increased risk for lack of access to care because of a scarcity of providers along with patient perceptions regarding their primary care provider’s ability to connect them to subspecialists.^41-43 Other cited examples include misconceptions about and poor treatment of the LGBTQ population by health care providers/systems.⁴⁴

 

 

How can we intervene successfully?

Characterization of barriers is important because it promotes the development of targeted interventions. Intervention models include community engagement programs, incorporation of fecal occult testing, and patient navigator programs.^45-47 In response to the alarming disparity in CRC screening rates in Latino communities, several interventions have been set in motion in different clinical scenarios, which include patient navigation and a focus on patient education.

Patient navigators facilitate the screening process at different stages, including providing information that is easy to understand by patients, translating when patients are not proficient in English, addressing any concerns they may have about the procedure, and reminding patients about their appointments via phone calls or other means (Figure 2). Trials evaluating the effect of patient navigators in Hispanic populations have resulted in anywhere from a modest 11% to a robust 56% increase in screening.^48-50 In facilities serving a large number of Latino patients with low socioeconomic status, low-cost interventions, such as mailing information about CRC screening to all eligible patients, increased the screening rate from 12% to 28%.⁵¹ It has been shown that using bilingual and bicultural staff, language-appropriate material, and face-to-face encounters in a community setting helped recruit Chinese Americans into CRC screening trials.⁵² Similarly, an activation educational program consisting of a video and brochure that actively encouraged patients to ask their primary care physicians about CRC screening resulted in a 10% increase in screening rates.⁵³

Randomized trials have shown that outreach efforts and patient navigation increase CRC screening rates in AAs.^48,54,55 Studies evaluating the effects of print-based educational materials on improving screening showed improvement in screening rates, decreases in cancer-related fatalistic attitudes, and patients had a better understanding of the benefits of screening as compared with the cost associated with screening and the cost of advanced disease.⁵⁶ Similarly, the use of touch-screen computers that tailor informational messages to decisional stage and screening barriers increased participation in CRC screening.⁵⁷ Including patient navigators along with printed education material was even more effective at increasing the proportion of patients getting colonoscopy screening than providing printed material alone, with more-intensive navigation needed for individuals with low literacy.⁵⁸ Grubbs et al.reported the success of their patient navigation program, which included wider comprehensive screening and coverage for colonoscopy screening.⁵⁹ In AAs, they estimated an annual reduction of CRC incidence and mortality of 4,200 and 2,700 patients, respectively.

Among immigrants, there is an increased likelihood of CRC screening in those immigrants with a higher number of primary care visits.⁶⁰ The intersection of culture, race, socioeconomic status, housing enclaves, limited English proficiency, low health literacy, and immigration policy all play a role in immigrant health and access to health care.⁶¹

Courtesy Aline Charabaty

Therefore, different strategies may be needed for each immigrant group to improve CRC screening. For this group of patients, efforts aimed at mitigating the adverse effects of national immigration policies on immigrant populations may have the additional consequence of improving health care access and CRC screening for these patients.

Data gaps still exist in our understanding of patient perceptions, perspectives, and barriers that present opportunities for further study to develop long-lasting interventions that will improve health care of underserved populations. By raising awareness of the barriers, physicians can enhance their own self-awareness to keenly be attuned to these challenges as patients cross their clinic threshold for medical care.

 

 

Additional resources link: www.cdc.gov/cancer/colorectal/

References

1. Klabunde CN et al. Trends in colorectal cancer test use among vulnerable populations in the United States. Cancer Epidemiol Biomarkers Prev. 2011 Aug;20(8):1611-21.

2. Parikh-Patel A et al. Colorectal cancer stage at diagnosis by socioeconomic and urban/rural status in California, 1988-2000. Cancer. 2006 Sep;107(5 Suppl):1189-95.

3. Promotion OoDPaH. Healthy People 2020. Cancer. Volume 2017.

4. Centers for Disease Control and Prevention. Cancer screening – United States, 2010. MMWR Morb Mortal Wkly Rep. 2012 Jan 27;61(3):41-5.

5. Doubeni CA et al. Racial and ethnic trends of colorectal cancer screening among Medicare enrollees. Am J Prev Med. 2010 Feb;38(2):184-91.

6. Kupfer SS et al. Reducing colorectal cancer risk among African Americans. Gastroenterology. 2015 Nov;149(6):1302-4.

7. Espey DK et al. Annual report to the nation on the status of cancer, 1975-2004, featuring cancer in American Indians and Alaska Natives. Cancer. 2007 Nov;110(10):2119-52.

8. Day LW et al. Screening prevalence and incidence of colorectal cancer among American Indian/Alaskan natives in the Indian Health Service. Dig Dis Sci. 2011 Jul;56(7):2104-13.

9. Gupta S et al. Challenges and possible solutions to colorectal cancer screening for the underserved. J Natl Cancer Inst. 2014 Apr;106(4):dju032.

10. Steele CB et al. Colorectal cancer incidence and screening – United States, 2008 and 2010. MMWR Suppl. 2013 Nov 22;62(3):53-60.

11. Boehmer U et al. Cancer survivorship and sexual orientation. Cancer 2011 Aug 15;117(16):3796-804.

12. Austin SB, Pazaris MJ, Wei EK, et al. Application of the Rosner-Wei risk-prediction model to estimate sexual orientation patterns in colon cancer risk in a prospective cohort of US women. Cancer Causes Control. 2014 Aug;25(8):999-1006.

13. Heslin KC et al. Sexual orientation and testing for prostate and colorectal cancers among men in California. Med Care. 2008 Dec;46(12):1240-8.

14. McElroy JA et al. Advancing Health Care for Lesbian, Gay, Bisexual, and Transgender Patients in Missouri. Mo Med. 2015 Jul-Aug;112(4):262-5.

15. Greiner KA et al. Knowledge and perceptions of colorectal cancer screening among urban African Americans. J Gen Intern Med. 2005 Nov;20(11):977-83.

16. Green PM, Kelly BA. Colorectal cancer knowledge, perceptions, and behaviors in African Americans. Cancer Nurs. 2004 May-Jun;27(3):206-15; quiz 216-7.

17. Berkowitz Z et al. Beliefs, risk perceptions, and gaps in knowledge as barriers to colorectal cancer screening in older adults. J Am Geriatr Soc. 2008 Feb;56(2):307-14.

18. Dolan NC et al. Colorectal cancer screening knowledge, attitudes, and beliefs among veterans: Does literacy make a difference? J Clin Oncol. 2004 Jul;22(13):2617-22.

19. Peterson NB et al. The influence of health literacy on colorectal cancer screening knowledge, beliefs and behavior. J Natl Med Assoc. 2007 Oct;99(10):1105-12.

20. Haddock MG et al. Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients. Int J Radiat Oncol Biol Phys. 2001 Apr 1;49(5):1267-74.

21. Jones RM et al. Patient-reported barriers to colorectal cancer screening: a mixed-methods analysis. Am J Prev Med. 2010 May;38(5):508-16.

22. Basch CH et al. Screening colonoscopy bowel preparation: experience in an urban minority population. Therap Adv Gastroenterol. 2013 Nov;6(6):442-6.

23. Davis JL et al. Sociodemographic differences in fears and mistrust contributing to unwillingness to participate in cancer screenings. J Health Care Poor Underserved. 2012 Nov;23(4 Suppl):67-76.

24. Robinson CM et al. Barriers to colorectal cancer screening among publicly insured urban women: no knowledge of tests and no clinician recommendation. J Natl Med Assoc. 2011 Aug;103(8):746-53.

25. Goldman RE et al. Perspectives of colorectal cancer risk and screening among Dominicans and Puerto Ricans: Stigma and misperceptions. Qual Health Res. 2009 Nov;19(11):1559-68.

26. Laiyemo AO et al. Race and colorectal cancer disparities: Health-care utilization vs different cancer susceptibilities. J Natl Cancer Inst. 2010 Apr 21;102(8):538-46.

27. White A et al. Racial disparities and treatment trends in a large cohort of elderly African Americans and Caucasians with colorectal cancer, 1991 to 2002. Cancer. 2008 Dec 15;113(12):3400-9.

28. Doubeni CA et al. Neighborhood socioeconomic status and use of colonoscopy in an insured population – A retrospective cohort study. PLoS One. 2012;7(5):e36392.

29. Tammana VS, Laiyemo AO. Colorectal cancer disparities: Issues, controversies and solutions. World J Gastroenterol. 2014 Jan 28;20(4):869-76.

30. Carethers JM. Screening for colorectal cancer in African Americans: determinants and rationale for an earlier age to commence screening. Dig Dis Sci. 2015 Mar;60(3):711-21.

31. Miranda-Diaz C et al. Barriers for Compliance to Breast, Colorectal, and Cervical Screening Cancer Tests among Hispanic Patients. Int J Environ Res Public Health. 2015 Dec 22;13(1):ijerph13010021.

32. Sewali B et al. Understanding cancer screening service utilization by Somali men in Minnesota. J Immigr Minor Health. 2015 Jun;17(3):773-80.

 

 

33. Walsh JM et al. Barriers to colorectal cancer screening in Latino and Vietnamese Americans. Compared with non-Latino white Americans. J Gen Intern Med. 2004 Feb;19(2):156-66.

34. Perez-Stable EJ et al. Self-reported use of cancer screening tests among Latinos and Anglos in a prepaid health plan. Arch Intern Med. 1994 May 23;154(10):1073-81.

35. Shariff-Marco S et al. Racial/ethnic differences in self-reported racism and its association with cancer-related health behaviors. Am J Public Health. 2010 Feb;100(2):364-74.

36. Powe BD et al. Comparing knowledge of colorectal and prostate cancer among African American and Hispanic men. Cancer Nurs. 2009 Sep-Oct;32(5):412-7.

37. Jun J, Oh KM. Asian and Hispanic Americans’ cancer fatalism and colon cancer screening. Am J Health Behav. 2013 Mar;37(2):145-54.

38. Hacker K et al. The impact of Immigration and Customs Enforcement on immigrant health: Perceptions of immigrants in Everett, Massachusetts, USA. Soc Sci Med. 2011 Aug;73(4):586-94.

39. Firger J. Rescinding DACA could spur a public health crisis, from lost services to higher rates of depression, substance abuse. Newsweek.

40. May FP et al. Racial minorities are more likely than whites to report lack of provider recommendation for colon cancer screening. Am J Gastroenterol. 2015 Oct;110(10):1388-94.

41. Levy BT et al. Why hasn’t this patient been screened for colon cancer? An Iowa Research Network study. J Am Board Fam Med. 2007 Sep-Oct;20(5):458-68.

42. Rosenblatt RA. A view from the periphery – health care in rural America. N Engl J Med. 2004 Sep 9;351(11):1049-51.

43. Young WF et al. Predictors of colorectal screening in rural Colorado: testing to prevent colon cancer in the high plains research network. J Rural Health. 2007 Summer;23(3):238-45.

44. Kates J et al. Health and Access to Care and Coverage for Lesbian, Gay, Bisexual, and Transgender (LGBT) Individuals in the U.S. In: Foundation KF, ed. Disparities Policy Issue Brief. Volume 2017; Aug 30, 2017.

45. Katz ML et al. Improving colorectal cancer screening by using community volunteers: results of the Carolinas cancer education and screening (CARES) project. Cancer. 2007 Oct 1;110(7):1602-10.

46. Jean-Jacques M et al. Program to improve colorectal cancer screening in a low-income, racially diverse population: A randomized controlled trial. Ann Fam Med. 2012 Sep-Oct;10(5):412-7.

47. Reuland DS et al. Effect of combined patient decision aid and patient navigation vs usual care for colorectal cancer screening in a vulnerable patient population: A randomized clinical trial. JAMA Intern Med. 2017 Jul 1;177(7):967-74.

48. Percac-Lima S et al. A culturally tailored navigator program for colorectal cancer screening in a community health center: a randomized, controlled trial. J Gen Intern Med. 2009 Feb;24(2):211-7.

49. Nash D et al. Evaluation of an intervention to increase screening colonoscopy in an urban public hospital setting. J Urban Health. 2006 Mar;83(2):231-43.

50. Lebwohl B et al. Effect of a patient navigator program on the volume and quality of colonoscopy. J Clin Gastroenterol. 2011 May-Jun;45(5):e47-53.

51. Khankari K et al. Improving colorectal cancer screening among the medically underserved: A pilot study within a federally qualified health center. J Gen Intern Med. 2007 Oct;22(10):1410-4.

52. Wang JH et al. Recruiting Chinese Americans into cancer screening intervention trials: Strategies and outcomes. Clin Trials. 2014 Apr;11(2):167-77.

53. Katz ML et al. Patient activation increases colorectal cancer screening rates: a randomized trial among low-income minority patients. Cancer Epidemiol Biomarkers Prev. 2012 Jan;21(1):45-52.

54. Ford ME et al. Enhancing adherence among older African American men enrolled in a longitudinal cancer screening trial. Gerontologist. 2006 Aug;46(4):545-50.

55. Christie J et al. A randomized controlled trial using patient navigation to increase colonoscopy screening among low-income minorities. J Natl Med Assoc. 2008 Mar;100(3):278-84.

56. Philip EJ et al. Evaluating the impact of an educational intervention to increase CRC screening rates in the African American community: A preliminary study. Cancer Causes Control. 2010 Oct;21(10):1685-91.

57. Greiner KA et al. Implementation intentions and colorectal screening: A randomized trial in safety-net clinics. Am J Prev Med. 2014 Dec;47(6):703-14.

58. Horne HN et al. Effect of patient navigation on colorectal cancer screening in a community-based randomized controlled trial of urban African American adults. Cancer Causes Control. 2015 Feb;26(2):239-46.

59. Grubbs SS et al. Eliminating racial disparities in colorectal cancer in the real world: It took a village. J Clin Oncol. 2013 Jun 1;31(16):1928-30.

60. Jung MY et al. The Chinese and Korean American immigrant experience: a mixed-methods examination of facilitators and barriers of colorectal cancer screening. Ethn Health. 2017 Feb 25:1-20.

61. Viruell-Fuentes EA et al. More than culture: structural racism, intersectionality theory, and immigrant health. Soc Sci Med. 2012 Dec;75(12):2099-106.

Dr. Oduyebo is a third-year fellow at the Mayo Clinic, Rochester, Minn.; Dr. Malespin is an assistant professor in the department of medicine and the medical director of hepatology at the University of Florida Health, Jacksonville; Dr. Mendoza Ladd is an assistant professor of medicine at Texas Tech University, El Paso; Dr. Day is an associate professor of medicine at the University of California, San Francisco; Dr. Charabaty is an associate professor of medicine and the director of the IBD Center in the division of gastroenterology at Medstar-Georgetown University Center, Washington; Dr. Chen is an associate professor of medicine, the director of patient safety and quality, and the director of the small-bowel endoscopy program in division of gastroenterology at Washington University, St. Louis; Dr. Carr is an assistant professor of medicine in the division of gastroenterology at the University of Pennsylvania, Philadelphia; Dr. Quezada is an assistant dean for admissions, an assistant dean for academic and multicultural affairs, and an assistant professor of medicine in the division of gastroenterology and hepatology at the University of Maryland, Baltimore; and Dr. Lamousé-Smith is a director of translational medicine, immunology, and early development at Janssen Pharmaceuticals Research and Development, Spring House, Penn.

While constipation is one of the most common symptoms managed by practicing gastroenterologists, it can also be among the most challenging. As a presenting complaint, constipation manifests with widely varying degrees of severity and may be seen in all age groups, ethnicities, and socioeconomic backgrounds. Its implications can include chronic and serious functional impairment as well as protracted and often excessive health care utilization. A growing number of pharmacologic and nonpharmacologic interventions have become available and proven to be effective when appropriately deployed. As such, health care providers and particularly gastroenterologists should strive to develop logical and efficient strategies for addressing this common disorder.

Clinical importance

While there are a variety of etiologies for constipation (Table 1), a large proportion of chronic cases fall within the framework of functional gastrointestinal disorders, a category with a substantial burden of disease across the population. Prevalence estimates vary, but constipation likely affects between 12% and 20% of the North American population.¹ Research has demonstrated significant health care expenditures associated with chronic constipation management; U.S. estimates suggest direct costs on the order of hundreds of millions of dollars per year, roughly half of which are attributable to inpatient care.² The financial burden of constipation also includes indirect costs associated with absenteeism as well as the risks of hospitalization and invasive procedures.³

Physical and emotional complications can be likewise significant and affect all age groups, from newborns to patients in the last days of life. Hirschsprung’s disease, for example, can lead to life-threatening sequelae in infancy, such as spontaneous perforation or enterocolitis, or more prolonged functional impairments when it remains undiagnosed. Severe constipation in childhood can lead to encopresis, translating in turn into ostracism and impaired social functioning. Fecal incontinence associated with overflow diarrhea is common and debilitating, particularly in the elderly population.
 

The potential mechanical complications of constipation lead to its overlap with a variety of other gastrointestinal complaints. For example, the difficulties of passing inspissated stool can provoke lower gastrointestinal bleeding from irritated hemorrhoids, anal fissures, stercoral ulcers, or prolapsed rectal tissue. Retained stool can also lead to upper gastrointestinal symptoms such as postprandial bloating or early satiety.⁴ Delayed fecal discharge can promote an increase in fermentative microbiota, associated in turn with the production of short-chain fatty acids, methane, and other gaseous byproducts.

The initial assessment

History

Taking an appropriate history is an essential step toward achieving a successful outcome. Presenting concerns related to constipation can range from hard, infrequent, or small-volume stools; abdominal or rectal pain associated with the process of elimination; and bloating, nausea, or early satiety. A sound diagnosis requires a keen understanding of what patients mean when they indicate that they are constipated, an accurate assessment of its impact on quality of life, and a careful inventory of potentially associated complications.

It is critical to define the duration of the problem. Not infrequently, patients will focus on recent events while failing to reveal that altered bowel habits or other functional symptoms have been problematic for years. Reminding the patients to “begin at the beginning” can aid enormously in contextualizing their complaints. Individuals with longstanding symptoms and previously negative evaluations are much less likely to present with a new organic disease than are those in whom symptoms have truly arisen de novo.

Defining constipation by frequency of bowel eliminations alone has proved inaccurate at predicting actual severity. This is in part because the bowel movement frequency varies widely in healthy individuals (anywhere from thrice daily to once every 3 days) and in part because the primary indicator of effective evacuation is not frequency but volume – a much more difficult quantity for patients to gauge.⁵ The Bristol Stool Scale is a simple, standardized tool that more accurately evaluates the presence or absence of colonic dysfunction. For example, patients passing Type 1-2 (hard or lumpy) stools often have an element of constipation that needs to be addressed.⁶ However, the interpretation of stool consistency assessments is still aided by awareness of both frequency and volume. A patient passing multiple small-volume Type 6-7 (loose or watery) stools may be the most constipated, presenting with overflow or paradoxical diarrhea attributable to fecal impaction.

Physical examination

An expert physical exam is another essential aspect of the initial assessment. Alarm features can be elicited in this context as well via signs of pallor, weight loss, blood in the stool, physical abuse, or advanced psychological distress. Attention should also be paid to signs of a systemic disorder that might be associated with gastrointestinal dysmotility including previously unrecognized signs of Raynaud’s syndrome, sclerodactyly, amyloidosis, surgical scars, and joint hypermobility.^7,8 Abdominal bloating, a frequently vague symptomatic complaint, can be correlated with the presence or absence of distention as perceived by the patient and/or the examiner.⁹

Any initial evaluation of constipation should also include a detailed digital rectal exam. A complete examination should include a careful visual assessment of the perianal region for external lesions and of the degree and directional appropriateness of pelvic floor excursion (perineal elevation and descent) during squeeze and simulated defecation maneuvers, respectively. Digital examination should include palpation for the presence or absence of pain as well as stool, blood, or masses in the rectal vault, as well as an assessment of sphincter tone at baseline, with squeeze, and with simulated defecation. Rectal pressure generation with the latter maneuver can also be qualitatively assessed. Research has suggested moderate agreement between the digital rectal examination and formal manometric evaluation in diagnosing dyssynergic defecation, underscoring the former’s utility in guiding initial management decisions.¹⁰

Testing

It is reasonable to exclude metabolic, inflammatory, or other secondary etiologies of constipation in patients in whom history or examination raises suspicion. Likewise, colonoscopy should be considered in patients with alarm features or who are due for age-appropriate screening. That said, in the absence of risk factors or ancillary signs and symptoms, a detailed diagnostic work-up is often unnecessary. The AGA’s Medical Position Statement on Constipation recommends a complete blood count as the only test to be ordered on a standard basis in the work-up of constipation.¹¹

In patients new to one’s practice, the diligent retrieval of prior records is one of the most efficient ways to avoid wasting health care resources. Locating an old abdominal radiograph that demonstrates extensive retained stool can not only secure the diagnosis for vague symptomatic complaints but also obviate the need for more extensive testing. One should instead consider how symptom duration and the associated changes in objectives measures such as weight and laboratory parameters can be used to justify or refute the need for repeating costly or invasive studies.

It is important to consider the potential contribution of defecatory dyssynergy to chronic constipation early in a patient’s presentation, and to return to this possibility in the future if initial therapeutic interventions are unsuccessful. An abnormal qualitative assessment on digital rectal examination should trigger a more formal characterization of the patient’s defecatory mechanics via anorectal manometry (ARM) and balloon expulsion testing (BET). Likewise, a lack of response to initial pharmacotherapy should prompt suspicion for outlet dysfunction, which can be queried with functional testing even if a rectal examination is qualitatively unrevealing.

Initial approach to the chronically constipated patient

The aforementioned AGA Medical Position Statement provides a helpful algorithm regarding the diagnostic approach to constipation (Figure 1). In the absence of concern for secondary etiologies of constipation, an initial therapeutic trial of dietary, lifestyle, and medication-based intervention is reasonable for mild symptoms. Patients should be encouraged to strive for 25-30 grams of dietary fiber intake per day. For patients unable to reach this goal via high-fiber foods alone, psyllium husk is a popular supplement, but it should be initiated at modest doses to mitigate the risk of bloating. Fiber may be supplemented with the use of osmotic laxatives (e.g., polyethylene glycol) with instructions that the initial dose may be modified as needed to optimal effectiveness. Selective response to rectal therapies (e.g., bisacodyl or glycerin suppositories) over osmotic laxatives may also suggest utility in early queries of outlet dysfunction.

An abdominal radiograph can be helpful not only to diagnose constipation but also to assess the stool burden present at the time of beginning treatment. For patients presenting with a significant degree of fecal loading, an initial bowel cleanse with four liters of osmotically balanced polyethylene glycol can be a useful means of eliminating background fecal impactions that might have mitigated the effectiveness of initial therapies in the past or that might reduce the effectiveness of daily laxative therapy moving forward.

Patients with a diagnosis of defecatory dyssynergy made via ARM/BET should be referred to pelvic floor physical therapy with biofeedback. Recognizing that courses of therapy are highly individualized in practice, randomized controlled trials suggest symptom improvement in 70%-80% of patients, with the majority also demonstrating maintenance of response.¹² Biofeedback appears to be an essential component of this modality based on meta-analysis data and should be requested specifically by the referring provider.¹³

Pharmacologic agents

For those patients with more severe initial presentations or whose symptoms persist despite initial medical management, there are several pharmacologic agents that may be considered on a prescription basis (Table 2). Linaclotide, a minimally absorbed guanylate cyclase agonist, is approved by the Food and Drug Administration for patients with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Improvements in constipation tend to occur over a slightly shorter timeline than in abdominal pain, though both have been demonstrated in comparison to placebo.^14,15 Plecanatide, a newer agent with a similar mechanism of action, has demonstrated improvements in bowel movement frequency and was recently approved for CIC.¹⁶ Lubiprostone, a chloride channel agonist, has demonstrated benefit for IBS-C and CIC as well, though its side effect profile is more varied, including dose-related nausea in up to 30% of patients.¹⁷

For patients with opioid-induced constipation who cannot wean from the opioid medications, the peripheral acting mu-opioid receptor antagonists may be quite helpful. These include injectable as well as oral formulations (e.g., methylnaltrexone and naloxegol, respectively) with additional agents under active investigation in particular clinical subsets (e.g., naldemedine for patients with cancer-related pain).^18,19 Prucalopride, a selective serotonin receptor agonist, has also demonstrated benefit for constipation; it is available abroad but not yet approved for use in the United States.²⁰ Prucalopride shares its primary mechanism of action (selective agonism of the 5HT4 serotonin receptor) with cisapride, a previously quite popular gastrointestinal motility agent that was subsequently withdrawn from the U.S. market because of arrhythmia risk.²¹ This risk is likely attributable to cisapride’s dual binding affinity for potassium channels, a feature that prucalopride does not share; as such, cardiotoxicity is not an active concern with the latter agent.²²

Still other pharmacologic agents with novel mechanisms of action are currently under investigation. Tenapanor, an inhibitor of a particular sodium/potassium exchanger in the gut lumen, mitigates intestinal sodium absorption, which increases fluid volume and transit. A recent phase 2 study demonstrated significantly increased stool frequency relative to placebo in patients with IBS-C.²³ Elobixibat, an ileal bile acid transport inhibitor, promotes colonic retention of bile acids and, in placebo-controlled studies, has led to accelerated colonic transit and an increased number of spontaneous bowel movements in patients with CIC.²⁴

Persistent constipation

In cases of refractory constipation (in practical terms, symptoms that persist despite trials of escalating medical therapy over at least 6 weeks), it is worth revisiting the question of etiology. Querying defecatory dyssynergy via ARM/BET, if not pursued prior to trials of newer pharmacologic agents, should certainly be explored in the event that such trials fail. Inconclusive results of ARM and BET testing, or BET abnormalities that persist despite a course of physical therapy with biofeedback, may raise suspicion for pelvic organ prolapse, which may be formally evaluated with defecography. Additional testing for metabolic or structural predispositions toward constipation may also be reasonable at this juncture.

Formal colonic transit testing via radio-opaque markers, scintigraphy, or the wireless motility capsule is often inaccurate in the setting of dyssynergic defecation and should be pursued only after this entity has been excluded or successfully treated.²⁵ While there are not many practical distinctions at present in the therapeutic management of slow-transit versus normal-transit constipation, the use of novel medications with an explicitly prokinetic mechanism of action may be reasonable to consider in the setting of a document delay in colonic transit. Such delays can also help justify further specialized diagnostic testing (e.g., colonic manometry), and, in rare refractory cases, surgical intervention.

Consideration of colectomy should be reserved for highly selected patients with delayed colonic transit, normal defecatory mechanics, and the absence of potentially explanatory background conditions (e.g., connective tissue disease). Clear evidence of an underlying colonic myopathy or neuropathy may militate in favor of a more targeted surgical intervention (e.g., subtotal colectomy) or guide one’s clinical evaluation toward alternative systemic diagnoses. A diverting loop ileostomy with interval assessment of symptoms may be useful to clarify the potential benefits of colectomy while preserving the option of operative reversal. Proximal transit delays should be definitively excluded before pursuing colonic resections given evidence that multisegment transit delays portend significantly worse postoperative outcomes.²⁶

Conclusion

Constipation is a common, sometimes confusing presenting complaint and the variety of established and emergent options for diagnosis and therapy can lend themselves to haphazard application. Patients and providers both are well served by a clinical approach, rooted in a comprehensive history and examination, that begins to organize these options in thoughtful sequence.



Dr. Ahuja is assistant professor of clinical medicine, division of gastroenterology; Dr. Reynolds is professor of clinical medicine, and director of the program in neurogastroenterology and motility, division of gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

References

1. Higgins P.D., Johanson J.F. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol. 2004 Apr;99(4):750-9. PubMed PMID: 15089911.

2. Martin B.C., Barghout V., Cerulli A. Direct medical costs of constipation in the United States. Manage Care Interface. 2006 Dec;19(12):43-9. PubMed PMID: 17274481.

3. Sun S.X., Dibonaventura M., Purayidathil F.W., et al. Impact of chronic constipation on health-related quality of life, work productivity, and healthcare resource use: an analysis of the National Health and Wellness Survey. Dig Dis Sc. 2011 Sep;56(9):2688-95. PubMed PMID: 21380761.

4. Heidelbaugh J.J., Stelwagon M., Miller S.A., et al. The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden. Am J Gastroenterol. 2015 Apr;110(4):580-7.

5. Mitsuhashi S., Ballou S., Jiang Z.G., et al. Characterizing normal bowel frequency and consistency in a representative sample of adults in the United States (NHANES). Am J Gastroenterol. 2017 Aug 01. PubMed PMID: 28762379.

6. Saad R.J., Rao S.S., Koch K.L., et al. Do stool form and frequency correlate with whole-gut and colonic transit? Results from a multicenter study in constipated individuals and healthy controls. Am J Gastroenterol. 2010 Feb;105(2):403-11. PubMed PMID: 19888202.

7. Castori M., Morlino S., Pascolini G., et al. Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. American Journal of Medical Genetics Part C, Semin Med Genet. 2015 Mar;169C(1):54-75. PubMed PMID: 25821092.

8. Nagaraja V., McMahan Z.H., Getzug T., Khanna D. Management of gastrointestinal involvement in scleroderma. Curr Treatm Opt Rheumatol. 2015 Mar 01;1(1):82-105. PubMed PMID: 26005632. Pubmed Central PMCID: 4437639.

9. Malagelada J.R., Accarino A., Azpiroz F. Bloating and abdominal distension: Old misconceptions and current knowledge. Am J Gastroenterol. 2017 Aug;112(8):1221-31. PubMed PMID: 28508867.

10. Soh J.S., Lee H.J., Jung K.W., et al. The diagnostic value of a digital rectal examination compared with high-resolution anorectal manometry in patients with chronic constipation and fecal incontinence. Am J Gastroenterol. 2015 Aug;110(8):1197-204. PubMed PMID: 26032152.

11. American Gastroenterological Association, Bharucha A.E., Dorn S.D., Lembo A., Pressman A. American Gastroenterological Association medical position statement on constipation. Gastroenterology. 2013 Jan;144(1):211-7. PubMed PMID: 23261064.

12. Skardoon G.R., Khera A.J., Emmanuel A.V., Burgell R.E. Review article: dyssynergic defaecation and biofeedback therapy in the pathophysiology and management of functional constipation. Aliment Pharmacol Therapeut. 2017 Aug;46(4):410-23. PubMed PMID: 28660663.

13. Koh C.E., Young C.J., Young J.M., Solomon M.J. Systematic review of randomized controlled trials of the effectiveness of biofeedback for pelvic floor dysfunction. Br J Surg. 2008 Sep;95(9):1079-87. PubMed PMID: 18655219.

14. Rao S., Lembo A.J., Shiff S.J., et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012 Nov;107(11):1714-24; quiz p 25. PubMed PMID: 22986440. Pubmed Central PMCID: 3504311.

15. Lacy B.E., Schey R., Shiff S.J., et al. Linaclotide in chronic idiopathic constipation patients with moderate to severe abdominal bloating: A randomized, controlled trial. PloS One. 2015;10(7):e0134349. PubMed PMID: 26222318. Pubmed Central PMCID: 4519259.

16. Miner P.B., Jr., Koltun W.D., Wiener G.J., et al. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol. 2017 Apr;112(4):613-21. PubMed PMID: 28169285. Pubmed Central PMCID: 5415706.

17. Johanson J.F., Drossman D.A., Panas R., Wahle A., Ueno R. Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Therapeut. 2008 Apr;27(8):685-96. PubMed PMID: 18248656.

18. Chey W.D., Webster L., Sostek M., Lappalainen J., Barker P.N., Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014 Jun 19;370(25):2387-96. PubMed PMID: 24896818.

19. Katakami N., Oda K., Tauchi K., et al. Phase IIb, randomized, double-blind, placebo-controlled study of naldemedine for the treatment of opioid-induced constipation in patients with cancer. J Clin Oncol. 2017 Jun 10;35(17):1921-8. PubMed PMID: 28445097.

20. Sajid M.S., Hebbar M., Baig M.K., Li A., Philipose Z. Use of prucalopride for chronic constipation: A systematic review and meta-analysis of published randomized, controlled trials. J Neurogastroenterol Motil. 2016 Jul 30;22(3):412-22. PubMed PMID: 27127190. Pubmed Central PMCID: 4930296.

21. Quigley E.M. Cisapride: What can we learn from the rise and fall of a prokinetic? J Dig Dis. 2011 Jun;12(3):147-56. PubMed PMID: 21615867.

22. Conlon K., De Maeyer J.H., Bruce C., et al. Nonclinical cardiovascular studies of prucalopride, a highly selective 5-hydroxytryptamine 4 receptor agonist. J Pharmacol Exp Therapeut. 2017 Nov; doi: 10.1124/jpet.117.244079 [epub ahead of print].

23. Chey W.D., Lembo A.J., Rosenbaum D.P. Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: a phase 2, randomized, placebo-controlled efficacy and safety trial. Am J Gastroenterol. 2017;112:763-74.

24. Simren M., Bajor A., Gillberg P-G, Rudling M., Abrahamsson H. Randomised clinical trial: the ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation – a double-blind study. Aliment Pharmacol Ther. 2011 Jul;34(1):41-50.

25. Zarate N., Knowles C.H., Newell M., et al. In patients with slow transit constipation, the pattern of colonic transit delay does not differentiate between those with and without impaired rectal evacuation. Am J Gastroenterol. 2008 Feb;103(2):427-34. PubMed PMID: 18070233.

26. Redmond J.M., Smith G.W., Barofsky I., et al. Physiological tests to predict long-term outcome of total abdominal colectomy for intractable constipation. Am J Gastroenterol. 1995 May;90(5):748-53. PubMed PMID: 7733081.

While constipation is one of the most common symptoms managed by practicing gastroenterologists, it can also be among the most challenging. As a presenting complaint, constipation manifests with widely varying degrees of severity and may be seen in all age groups, ethnicities, and socioeconomic backgrounds. Its implications can include chronic and serious functional impairment as well as protracted and often excessive health care utilization. A growing number of pharmacologic and nonpharmacologic interventions have become available and proven to be effective when appropriately deployed. As such, health care providers and particularly gastroenterologists should strive to develop logical and efficient strategies for addressing this common disorder.

Clinical importance

While there are a variety of etiologies for constipation (Table 1), a large proportion of chronic cases fall within the framework of functional gastrointestinal disorders, a category with a substantial burden of disease across the population. Prevalence estimates vary, but constipation likely affects between 12% and 20% of the North American population.¹ Research has demonstrated significant health care expenditures associated with chronic constipation management; U.S. estimates suggest direct costs on the order of hundreds of millions of dollars per year, roughly half of which are attributable to inpatient care.² The financial burden of constipation also includes indirect costs associated with absenteeism as well as the risks of hospitalization and invasive procedures.³

Physical and emotional complications can be likewise significant and affect all age groups, from newborns to patients in the last days of life. Hirschsprung’s disease, for example, can lead to life-threatening sequelae in infancy, such as spontaneous perforation or enterocolitis, or more prolonged functional impairments when it remains undiagnosed. Severe constipation in childhood can lead to encopresis, translating in turn into ostracism and impaired social functioning. Fecal incontinence associated with overflow diarrhea is common and debilitating, particularly in the elderly population.
 

The potential mechanical complications of constipation lead to its overlap with a variety of other gastrointestinal complaints. For example, the difficulties of passing inspissated stool can provoke lower gastrointestinal bleeding from irritated hemorrhoids, anal fissures, stercoral ulcers, or prolapsed rectal tissue. Retained stool can also lead to upper gastrointestinal symptoms such as postprandial bloating or early satiety.⁴ Delayed fecal discharge can promote an increase in fermentative microbiota, associated in turn with the production of short-chain fatty acids, methane, and other gaseous byproducts.

The initial assessment

History

Taking an appropriate history is an essential step toward achieving a successful outcome. Presenting concerns related to constipation can range from hard, infrequent, or small-volume stools; abdominal or rectal pain associated with the process of elimination; and bloating, nausea, or early satiety. A sound diagnosis requires a keen understanding of what patients mean when they indicate that they are constipated, an accurate assessment of its impact on quality of life, and a careful inventory of potentially associated complications.

It is critical to define the duration of the problem. Not infrequently, patients will focus on recent events while failing to reveal that altered bowel habits or other functional symptoms have been problematic for years. Reminding the patients to “begin at the beginning” can aid enormously in contextualizing their complaints. Individuals with longstanding symptoms and previously negative evaluations are much less likely to present with a new organic disease than are those in whom symptoms have truly arisen de novo.

Defining constipation by frequency of bowel eliminations alone has proved inaccurate at predicting actual severity. This is in part because the bowel movement frequency varies widely in healthy individuals (anywhere from thrice daily to once every 3 days) and in part because the primary indicator of effective evacuation is not frequency but volume – a much more difficult quantity for patients to gauge.⁵ The Bristol Stool Scale is a simple, standardized tool that more accurately evaluates the presence or absence of colonic dysfunction. For example, patients passing Type 1-2 (hard or lumpy) stools often have an element of constipation that needs to be addressed.⁶ However, the interpretation of stool consistency assessments is still aided by awareness of both frequency and volume. A patient passing multiple small-volume Type 6-7 (loose or watery) stools may be the most constipated, presenting with overflow or paradoxical diarrhea attributable to fecal impaction.

Physical examination

An expert physical exam is another essential aspect of the initial assessment. Alarm features can be elicited in this context as well via signs of pallor, weight loss, blood in the stool, physical abuse, or advanced psychological distress. Attention should also be paid to signs of a systemic disorder that might be associated with gastrointestinal dysmotility including previously unrecognized signs of Raynaud’s syndrome, sclerodactyly, amyloidosis, surgical scars, and joint hypermobility.^7,8 Abdominal bloating, a frequently vague symptomatic complaint, can be correlated with the presence or absence of distention as perceived by the patient and/or the examiner.⁹

Any initial evaluation of constipation should also include a detailed digital rectal exam. A complete examination should include a careful visual assessment of the perianal region for external lesions and of the degree and directional appropriateness of pelvic floor excursion (perineal elevation and descent) during squeeze and simulated defecation maneuvers, respectively. Digital examination should include palpation for the presence or absence of pain as well as stool, blood, or masses in the rectal vault, as well as an assessment of sphincter tone at baseline, with squeeze, and with simulated defecation. Rectal pressure generation with the latter maneuver can also be qualitatively assessed. Research has suggested moderate agreement between the digital rectal examination and formal manometric evaluation in diagnosing dyssynergic defecation, underscoring the former’s utility in guiding initial management decisions.¹⁰

Testing

It is reasonable to exclude metabolic, inflammatory, or other secondary etiologies of constipation in patients in whom history or examination raises suspicion. Likewise, colonoscopy should be considered in patients with alarm features or who are due for age-appropriate screening. That said, in the absence of risk factors or ancillary signs and symptoms, a detailed diagnostic work-up is often unnecessary. The AGA’s Medical Position Statement on Constipation recommends a complete blood count as the only test to be ordered on a standard basis in the work-up of constipation.¹¹

In patients new to one’s practice, the diligent retrieval of prior records is one of the most efficient ways to avoid wasting health care resources. Locating an old abdominal radiograph that demonstrates extensive retained stool can not only secure the diagnosis for vague symptomatic complaints but also obviate the need for more extensive testing. One should instead consider how symptom duration and the associated changes in objectives measures such as weight and laboratory parameters can be used to justify or refute the need for repeating costly or invasive studies.

It is important to consider the potential contribution of defecatory dyssynergy to chronic constipation early in a patient’s presentation, and to return to this possibility in the future if initial therapeutic interventions are unsuccessful. An abnormal qualitative assessment on digital rectal examination should trigger a more formal characterization of the patient’s defecatory mechanics via anorectal manometry (ARM) and balloon expulsion testing (BET). Likewise, a lack of response to initial pharmacotherapy should prompt suspicion for outlet dysfunction, which can be queried with functional testing even if a rectal examination is qualitatively unrevealing.

Initial approach to the chronically constipated patient

The aforementioned AGA Medical Position Statement provides a helpful algorithm regarding the diagnostic approach to constipation (Figure 1). In the absence of concern for secondary etiologies of constipation, an initial therapeutic trial of dietary, lifestyle, and medication-based intervention is reasonable for mild symptoms. Patients should be encouraged to strive for 25-30 grams of dietary fiber intake per day. For patients unable to reach this goal via high-fiber foods alone, psyllium husk is a popular supplement, but it should be initiated at modest doses to mitigate the risk of bloating. Fiber may be supplemented with the use of osmotic laxatives (e.g., polyethylene glycol) with instructions that the initial dose may be modified as needed to optimal effectiveness. Selective response to rectal therapies (e.g., bisacodyl or glycerin suppositories) over osmotic laxatives may also suggest utility in early queries of outlet dysfunction.

An abdominal radiograph can be helpful not only to diagnose constipation but also to assess the stool burden present at the time of beginning treatment. For patients presenting with a significant degree of fecal loading, an initial bowel cleanse with four liters of osmotically balanced polyethylene glycol can be a useful means of eliminating background fecal impactions that might have mitigated the effectiveness of initial therapies in the past or that might reduce the effectiveness of daily laxative therapy moving forward.

Patients with a diagnosis of defecatory dyssynergy made via ARM/BET should be referred to pelvic floor physical therapy with biofeedback. Recognizing that courses of therapy are highly individualized in practice, randomized controlled trials suggest symptom improvement in 70%-80% of patients, with the majority also demonstrating maintenance of response.¹² Biofeedback appears to be an essential component of this modality based on meta-analysis data and should be requested specifically by the referring provider.¹³

Pharmacologic agents

For those patients with more severe initial presentations or whose symptoms persist despite initial medical management, there are several pharmacologic agents that may be considered on a prescription basis (Table 2). Linaclotide, a minimally absorbed guanylate cyclase agonist, is approved by the Food and Drug Administration for patients with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Improvements in constipation tend to occur over a slightly shorter timeline than in abdominal pain, though both have been demonstrated in comparison to placebo.^14,15 Plecanatide, a newer agent with a similar mechanism of action, has demonstrated improvements in bowel movement frequency and was recently approved for CIC.¹⁶ Lubiprostone, a chloride channel agonist, has demonstrated benefit for IBS-C and CIC as well, though its side effect profile is more varied, including dose-related nausea in up to 30% of patients.¹⁷

For patients with opioid-induced constipation who cannot wean from the opioid medications, the peripheral acting mu-opioid receptor antagonists may be quite helpful. These include injectable as well as oral formulations (e.g., methylnaltrexone and naloxegol, respectively) with additional agents under active investigation in particular clinical subsets (e.g., naldemedine for patients with cancer-related pain).^18,19 Prucalopride, a selective serotonin receptor agonist, has also demonstrated benefit for constipation; it is available abroad but not yet approved for use in the United States.²⁰ Prucalopride shares its primary mechanism of action (selective agonism of the 5HT4 serotonin receptor) with cisapride, a previously quite popular gastrointestinal motility agent that was subsequently withdrawn from the U.S. market because of arrhythmia risk.²¹ This risk is likely attributable to cisapride’s dual binding affinity for potassium channels, a feature that prucalopride does not share; as such, cardiotoxicity is not an active concern with the latter agent.²²

Still other pharmacologic agents with novel mechanisms of action are currently under investigation. Tenapanor, an inhibitor of a particular sodium/potassium exchanger in the gut lumen, mitigates intestinal sodium absorption, which increases fluid volume and transit. A recent phase 2 study demonstrated significantly increased stool frequency relative to placebo in patients with IBS-C.²³ Elobixibat, an ileal bile acid transport inhibitor, promotes colonic retention of bile acids and, in placebo-controlled studies, has led to accelerated colonic transit and an increased number of spontaneous bowel movements in patients with CIC.²⁴

Persistent constipation

In cases of refractory constipation (in practical terms, symptoms that persist despite trials of escalating medical therapy over at least 6 weeks), it is worth revisiting the question of etiology. Querying defecatory dyssynergy via ARM/BET, if not pursued prior to trials of newer pharmacologic agents, should certainly be explored in the event that such trials fail. Inconclusive results of ARM and BET testing, or BET abnormalities that persist despite a course of physical therapy with biofeedback, may raise suspicion for pelvic organ prolapse, which may be formally evaluated with defecography. Additional testing for metabolic or structural predispositions toward constipation may also be reasonable at this juncture.

Formal colonic transit testing via radio-opaque markers, scintigraphy, or the wireless motility capsule is often inaccurate in the setting of dyssynergic defecation and should be pursued only after this entity has been excluded or successfully treated.²⁵ While there are not many practical distinctions at present in the therapeutic management of slow-transit versus normal-transit constipation, the use of novel medications with an explicitly prokinetic mechanism of action may be reasonable to consider in the setting of a document delay in colonic transit. Such delays can also help justify further specialized diagnostic testing (e.g., colonic manometry), and, in rare refractory cases, surgical intervention.

Consideration of colectomy should be reserved for highly selected patients with delayed colonic transit, normal defecatory mechanics, and the absence of potentially explanatory background conditions (e.g., connective tissue disease). Clear evidence of an underlying colonic myopathy or neuropathy may militate in favor of a more targeted surgical intervention (e.g., subtotal colectomy) or guide one’s clinical evaluation toward alternative systemic diagnoses. A diverting loop ileostomy with interval assessment of symptoms may be useful to clarify the potential benefits of colectomy while preserving the option of operative reversal. Proximal transit delays should be definitively excluded before pursuing colonic resections given evidence that multisegment transit delays portend significantly worse postoperative outcomes.²⁶

Conclusion

Constipation is a common, sometimes confusing presenting complaint and the variety of established and emergent options for diagnosis and therapy can lend themselves to haphazard application. Patients and providers both are well served by a clinical approach, rooted in a comprehensive history and examination, that begins to organize these options in thoughtful sequence.



Dr. Ahuja is assistant professor of clinical medicine, division of gastroenterology; Dr. Reynolds is professor of clinical medicine, and director of the program in neurogastroenterology and motility, division of gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

References

1. Higgins P.D., Johanson J.F. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol. 2004 Apr;99(4):750-9. PubMed PMID: 15089911.

2. Martin B.C., Barghout V., Cerulli A. Direct medical costs of constipation in the United States. Manage Care Interface. 2006 Dec;19(12):43-9. PubMed PMID: 17274481.

3. Sun S.X., Dibonaventura M., Purayidathil F.W., et al. Impact of chronic constipation on health-related quality of life, work productivity, and healthcare resource use: an analysis of the National Health and Wellness Survey. Dig Dis Sc. 2011 Sep;56(9):2688-95. PubMed PMID: 21380761.

4. Heidelbaugh J.J., Stelwagon M., Miller S.A., et al. The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden. Am J Gastroenterol. 2015 Apr;110(4):580-7.

5. Mitsuhashi S., Ballou S., Jiang Z.G., et al. Characterizing normal bowel frequency and consistency in a representative sample of adults in the United States (NHANES). Am J Gastroenterol. 2017 Aug 01. PubMed PMID: 28762379.

6. Saad R.J., Rao S.S., Koch K.L., et al. Do stool form and frequency correlate with whole-gut and colonic transit? Results from a multicenter study in constipated individuals and healthy controls. Am J Gastroenterol. 2010 Feb;105(2):403-11. PubMed PMID: 19888202.

7. Castori M., Morlino S., Pascolini G., et al. Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. American Journal of Medical Genetics Part C, Semin Med Genet. 2015 Mar;169C(1):54-75. PubMed PMID: 25821092.

8. Nagaraja V., McMahan Z.H., Getzug T., Khanna D. Management of gastrointestinal involvement in scleroderma. Curr Treatm Opt Rheumatol. 2015 Mar 01;1(1):82-105. PubMed PMID: 26005632. Pubmed Central PMCID: 4437639.

9. Malagelada J.R., Accarino A., Azpiroz F. Bloating and abdominal distension: Old misconceptions and current knowledge. Am J Gastroenterol. 2017 Aug;112(8):1221-31. PubMed PMID: 28508867.

10. Soh J.S., Lee H.J., Jung K.W., et al. The diagnostic value of a digital rectal examination compared with high-resolution anorectal manometry in patients with chronic constipation and fecal incontinence. Am J Gastroenterol. 2015 Aug;110(8):1197-204. PubMed PMID: 26032152.

11. American Gastroenterological Association, Bharucha A.E., Dorn S.D., Lembo A., Pressman A. American Gastroenterological Association medical position statement on constipation. Gastroenterology. 2013 Jan;144(1):211-7. PubMed PMID: 23261064.

12. Skardoon G.R., Khera A.J., Emmanuel A.V., Burgell R.E. Review article: dyssynergic defaecation and biofeedback therapy in the pathophysiology and management of functional constipation. Aliment Pharmacol Therapeut. 2017 Aug;46(4):410-23. PubMed PMID: 28660663.

13. Koh C.E., Young C.J., Young J.M., Solomon M.J. Systematic review of randomized controlled trials of the effectiveness of biofeedback for pelvic floor dysfunction. Br J Surg. 2008 Sep;95(9):1079-87. PubMed PMID: 18655219.

14. Rao S., Lembo A.J., Shiff S.J., et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012 Nov;107(11):1714-24; quiz p 25. PubMed PMID: 22986440. Pubmed Central PMCID: 3504311.

15. Lacy B.E., Schey R., Shiff S.J., et al. Linaclotide in chronic idiopathic constipation patients with moderate to severe abdominal bloating: A randomized, controlled trial. PloS One. 2015;10(7):e0134349. PubMed PMID: 26222318. Pubmed Central PMCID: 4519259.

16. Miner P.B., Jr., Koltun W.D., Wiener G.J., et al. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol. 2017 Apr;112(4):613-21. PubMed PMID: 28169285. Pubmed Central PMCID: 5415706.

17. Johanson J.F., Drossman D.A., Panas R., Wahle A., Ueno R. Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Therapeut. 2008 Apr;27(8):685-96. PubMed PMID: 18248656.

18. Chey W.D., Webster L., Sostek M., Lappalainen J., Barker P.N., Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014 Jun 19;370(25):2387-96. PubMed PMID: 24896818.

19. Katakami N., Oda K., Tauchi K., et al. Phase IIb, randomized, double-blind, placebo-controlled study of naldemedine for the treatment of opioid-induced constipation in patients with cancer. J Clin Oncol. 2017 Jun 10;35(17):1921-8. PubMed PMID: 28445097.

20. Sajid M.S., Hebbar M., Baig M.K., Li A., Philipose Z. Use of prucalopride for chronic constipation: A systematic review and meta-analysis of published randomized, controlled trials. J Neurogastroenterol Motil. 2016 Jul 30;22(3):412-22. PubMed PMID: 27127190. Pubmed Central PMCID: 4930296.

21. Quigley E.M. Cisapride: What can we learn from the rise and fall of a prokinetic? J Dig Dis. 2011 Jun;12(3):147-56. PubMed PMID: 21615867.

22. Conlon K., De Maeyer J.H., Bruce C., et al. Nonclinical cardiovascular studies of prucalopride, a highly selective 5-hydroxytryptamine 4 receptor agonist. J Pharmacol Exp Therapeut. 2017 Nov; doi: 10.1124/jpet.117.244079 [epub ahead of print].

23. Chey W.D., Lembo A.J., Rosenbaum D.P. Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: a phase 2, randomized, placebo-controlled efficacy and safety trial. Am J Gastroenterol. 2017;112:763-74.

24. Simren M., Bajor A., Gillberg P-G, Rudling M., Abrahamsson H. Randomised clinical trial: the ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation – a double-blind study. Aliment Pharmacol Ther. 2011 Jul;34(1):41-50.

25. Zarate N., Knowles C.H., Newell M., et al. In patients with slow transit constipation, the pattern of colonic transit delay does not differentiate between those with and without impaired rectal evacuation. Am J Gastroenterol. 2008 Feb;103(2):427-34. PubMed PMID: 18070233.

26. Redmond J.M., Smith G.W., Barofsky I., et al. Physiological tests to predict long-term outcome of total abdominal colectomy for intractable constipation. Am J Gastroenterol. 1995 May;90(5):748-53. PubMed PMID: 7733081.

While constipation is one of the most common symptoms managed by practicing gastroenterologists, it can also be among the most challenging. As a presenting complaint, constipation manifests with widely varying degrees of severity and may be seen in all age groups, ethnicities, and socioeconomic backgrounds. Its implications can include chronic and serious functional impairment as well as protracted and often excessive health care utilization. A growing number of pharmacologic and nonpharmacologic interventions have become available and proven to be effective when appropriately deployed. As such, health care providers and particularly gastroenterologists should strive to develop logical and efficient strategies for addressing this common disorder.

Clinical importance

While there are a variety of etiologies for constipation (Table 1), a large proportion of chronic cases fall within the framework of functional gastrointestinal disorders, a category with a substantial burden of disease across the population. Prevalence estimates vary, but constipation likely affects between 12% and 20% of the North American population.¹ Research has demonstrated significant health care expenditures associated with chronic constipation management; U.S. estimates suggest direct costs on the order of hundreds of millions of dollars per year, roughly half of which are attributable to inpatient care.² The financial burden of constipation also includes indirect costs associated with absenteeism as well as the risks of hospitalization and invasive procedures.³

Physical and emotional complications can be likewise significant and affect all age groups, from newborns to patients in the last days of life. Hirschsprung’s disease, for example, can lead to life-threatening sequelae in infancy, such as spontaneous perforation or enterocolitis, or more prolonged functional impairments when it remains undiagnosed. Severe constipation in childhood can lead to encopresis, translating in turn into ostracism and impaired social functioning. Fecal incontinence associated with overflow diarrhea is common and debilitating, particularly in the elderly population.
 

The potential mechanical complications of constipation lead to its overlap with a variety of other gastrointestinal complaints. For example, the difficulties of passing inspissated stool can provoke lower gastrointestinal bleeding from irritated hemorrhoids, anal fissures, stercoral ulcers, or prolapsed rectal tissue. Retained stool can also lead to upper gastrointestinal symptoms such as postprandial bloating or early satiety.⁴ Delayed fecal discharge can promote an increase in fermentative microbiota, associated in turn with the production of short-chain fatty acids, methane, and other gaseous byproducts.

The initial assessment

History

Taking an appropriate history is an essential step toward achieving a successful outcome. Presenting concerns related to constipation can range from hard, infrequent, or small-volume stools; abdominal or rectal pain associated with the process of elimination; and bloating, nausea, or early satiety. A sound diagnosis requires a keen understanding of what patients mean when they indicate that they are constipated, an accurate assessment of its impact on quality of life, and a careful inventory of potentially associated complications.

It is critical to define the duration of the problem. Not infrequently, patients will focus on recent events while failing to reveal that altered bowel habits or other functional symptoms have been problematic for years. Reminding the patients to “begin at the beginning” can aid enormously in contextualizing their complaints. Individuals with longstanding symptoms and previously negative evaluations are much less likely to present with a new organic disease than are those in whom symptoms have truly arisen de novo.

Defining constipation by frequency of bowel eliminations alone has proved inaccurate at predicting actual severity. This is in part because the bowel movement frequency varies widely in healthy individuals (anywhere from thrice daily to once every 3 days) and in part because the primary indicator of effective evacuation is not frequency but volume – a much more difficult quantity for patients to gauge.⁵ The Bristol Stool Scale is a simple, standardized tool that more accurately evaluates the presence or absence of colonic dysfunction. For example, patients passing Type 1-2 (hard or lumpy) stools often have an element of constipation that needs to be addressed.⁶ However, the interpretation of stool consistency assessments is still aided by awareness of both frequency and volume. A patient passing multiple small-volume Type 6-7 (loose or watery) stools may be the most constipated, presenting with overflow or paradoxical diarrhea attributable to fecal impaction.

Physical examination

An expert physical exam is another essential aspect of the initial assessment. Alarm features can be elicited in this context as well via signs of pallor, weight loss, blood in the stool, physical abuse, or advanced psychological distress. Attention should also be paid to signs of a systemic disorder that might be associated with gastrointestinal dysmotility including previously unrecognized signs of Raynaud’s syndrome, sclerodactyly, amyloidosis, surgical scars, and joint hypermobility.^7,8 Abdominal bloating, a frequently vague symptomatic complaint, can be correlated with the presence or absence of distention as perceived by the patient and/or the examiner.⁹

Any initial evaluation of constipation should also include a detailed digital rectal exam. A complete examination should include a careful visual assessment of the perianal region for external lesions and of the degree and directional appropriateness of pelvic floor excursion (perineal elevation and descent) during squeeze and simulated defecation maneuvers, respectively. Digital examination should include palpation for the presence or absence of pain as well as stool, blood, or masses in the rectal vault, as well as an assessment of sphincter tone at baseline, with squeeze, and with simulated defecation. Rectal pressure generation with the latter maneuver can also be qualitatively assessed. Research has suggested moderate agreement between the digital rectal examination and formal manometric evaluation in diagnosing dyssynergic defecation, underscoring the former’s utility in guiding initial management decisions.¹⁰

Testing

It is reasonable to exclude metabolic, inflammatory, or other secondary etiologies of constipation in patients in whom history or examination raises suspicion. Likewise, colonoscopy should be considered in patients with alarm features or who are due for age-appropriate screening. That said, in the absence of risk factors or ancillary signs and symptoms, a detailed diagnostic work-up is often unnecessary. The AGA’s Medical Position Statement on Constipation recommends a complete blood count as the only test to be ordered on a standard basis in the work-up of constipation.¹¹

In patients new to one’s practice, the diligent retrieval of prior records is one of the most efficient ways to avoid wasting health care resources. Locating an old abdominal radiograph that demonstrates extensive retained stool can not only secure the diagnosis for vague symptomatic complaints but also obviate the need for more extensive testing. One should instead consider how symptom duration and the associated changes in objectives measures such as weight and laboratory parameters can be used to justify or refute the need for repeating costly or invasive studies.

It is important to consider the potential contribution of defecatory dyssynergy to chronic constipation early in a patient’s presentation, and to return to this possibility in the future if initial therapeutic interventions are unsuccessful. An abnormal qualitative assessment on digital rectal examination should trigger a more formal characterization of the patient’s defecatory mechanics via anorectal manometry (ARM) and balloon expulsion testing (BET). Likewise, a lack of response to initial pharmacotherapy should prompt suspicion for outlet dysfunction, which can be queried with functional testing even if a rectal examination is qualitatively unrevealing.

Initial approach to the chronically constipated patient

The aforementioned AGA Medical Position Statement provides a helpful algorithm regarding the diagnostic approach to constipation (Figure 1). In the absence of concern for secondary etiologies of constipation, an initial therapeutic trial of dietary, lifestyle, and medication-based intervention is reasonable for mild symptoms. Patients should be encouraged to strive for 25-30 grams of dietary fiber intake per day. For patients unable to reach this goal via high-fiber foods alone, psyllium husk is a popular supplement, but it should be initiated at modest doses to mitigate the risk of bloating. Fiber may be supplemented with the use of osmotic laxatives (e.g., polyethylene glycol) with instructions that the initial dose may be modified as needed to optimal effectiveness. Selective response to rectal therapies (e.g., bisacodyl or glycerin suppositories) over osmotic laxatives may also suggest utility in early queries of outlet dysfunction.

An abdominal radiograph can be helpful not only to diagnose constipation but also to assess the stool burden present at the time of beginning treatment. For patients presenting with a significant degree of fecal loading, an initial bowel cleanse with four liters of osmotically balanced polyethylene glycol can be a useful means of eliminating background fecal impactions that might have mitigated the effectiveness of initial therapies in the past or that might reduce the effectiveness of daily laxative therapy moving forward.

Patients with a diagnosis of defecatory dyssynergy made via ARM/BET should be referred to pelvic floor physical therapy with biofeedback. Recognizing that courses of therapy are highly individualized in practice, randomized controlled trials suggest symptom improvement in 70%-80% of patients, with the majority also demonstrating maintenance of response.¹² Biofeedback appears to be an essential component of this modality based on meta-analysis data and should be requested specifically by the referring provider.¹³

Pharmacologic agents

For those patients with more severe initial presentations or whose symptoms persist despite initial medical management, there are several pharmacologic agents that may be considered on a prescription basis (Table 2). Linaclotide, a minimally absorbed guanylate cyclase agonist, is approved by the Food and Drug Administration for patients with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Improvements in constipation tend to occur over a slightly shorter timeline than in abdominal pain, though both have been demonstrated in comparison to placebo.^14,15 Plecanatide, a newer agent with a similar mechanism of action, has demonstrated improvements in bowel movement frequency and was recently approved for CIC.¹⁶ Lubiprostone, a chloride channel agonist, has demonstrated benefit for IBS-C and CIC as well, though its side effect profile is more varied, including dose-related nausea in up to 30% of patients.¹⁷

For patients with opioid-induced constipation who cannot wean from the opioid medications, the peripheral acting mu-opioid receptor antagonists may be quite helpful. These include injectable as well as oral formulations (e.g., methylnaltrexone and naloxegol, respectively) with additional agents under active investigation in particular clinical subsets (e.g., naldemedine for patients with cancer-related pain).^18,19 Prucalopride, a selective serotonin receptor agonist, has also demonstrated benefit for constipation; it is available abroad but not yet approved for use in the United States.²⁰ Prucalopride shares its primary mechanism of action (selective agonism of the 5HT4 serotonin receptor) with cisapride, a previously quite popular gastrointestinal motility agent that was subsequently withdrawn from the U.S. market because of arrhythmia risk.²¹ This risk is likely attributable to cisapride’s dual binding affinity for potassium channels, a feature that prucalopride does not share; as such, cardiotoxicity is not an active concern with the latter agent.²²

Still other pharmacologic agents with novel mechanisms of action are currently under investigation. Tenapanor, an inhibitor of a particular sodium/potassium exchanger in the gut lumen, mitigates intestinal sodium absorption, which increases fluid volume and transit. A recent phase 2 study demonstrated significantly increased stool frequency relative to placebo in patients with IBS-C.²³ Elobixibat, an ileal bile acid transport inhibitor, promotes colonic retention of bile acids and, in placebo-controlled studies, has led to accelerated colonic transit and an increased number of spontaneous bowel movements in patients with CIC.²⁴

Persistent constipation

In cases of refractory constipation (in practical terms, symptoms that persist despite trials of escalating medical therapy over at least 6 weeks), it is worth revisiting the question of etiology. Querying defecatory dyssynergy via ARM/BET, if not pursued prior to trials of newer pharmacologic agents, should certainly be explored in the event that such trials fail. Inconclusive results of ARM and BET testing, or BET abnormalities that persist despite a course of physical therapy with biofeedback, may raise suspicion for pelvic organ prolapse, which may be formally evaluated with defecography. Additional testing for metabolic or structural predispositions toward constipation may also be reasonable at this juncture.

Formal colonic transit testing via radio-opaque markers, scintigraphy, or the wireless motility capsule is often inaccurate in the setting of dyssynergic defecation and should be pursued only after this entity has been excluded or successfully treated.²⁵ While there are not many practical distinctions at present in the therapeutic management of slow-transit versus normal-transit constipation, the use of novel medications with an explicitly prokinetic mechanism of action may be reasonable to consider in the setting of a document delay in colonic transit. Such delays can also help justify further specialized diagnostic testing (e.g., colonic manometry), and, in rare refractory cases, surgical intervention.

Consideration of colectomy should be reserved for highly selected patients with delayed colonic transit, normal defecatory mechanics, and the absence of potentially explanatory background conditions (e.g., connective tissue disease). Clear evidence of an underlying colonic myopathy or neuropathy may militate in favor of a more targeted surgical intervention (e.g., subtotal colectomy) or guide one’s clinical evaluation toward alternative systemic diagnoses. A diverting loop ileostomy with interval assessment of symptoms may be useful to clarify the potential benefits of colectomy while preserving the option of operative reversal. Proximal transit delays should be definitively excluded before pursuing colonic resections given evidence that multisegment transit delays portend significantly worse postoperative outcomes.²⁶

Conclusion

Constipation is a common, sometimes confusing presenting complaint and the variety of established and emergent options for diagnosis and therapy can lend themselves to haphazard application. Patients and providers both are well served by a clinical approach, rooted in a comprehensive history and examination, that begins to organize these options in thoughtful sequence.



Dr. Ahuja is assistant professor of clinical medicine, division of gastroenterology; Dr. Reynolds is professor of clinical medicine, and director of the program in neurogastroenterology and motility, division of gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

References

1. Higgins P.D., Johanson J.F. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol. 2004 Apr;99(4):750-9. PubMed PMID: 15089911.

2. Martin B.C., Barghout V., Cerulli A. Direct medical costs of constipation in the United States. Manage Care Interface. 2006 Dec;19(12):43-9. PubMed PMID: 17274481.

3. Sun S.X., Dibonaventura M., Purayidathil F.W., et al. Impact of chronic constipation on health-related quality of life, work productivity, and healthcare resource use: an analysis of the National Health and Wellness Survey. Dig Dis Sc. 2011 Sep;56(9):2688-95. PubMed PMID: 21380761.

4. Heidelbaugh J.J., Stelwagon M., Miller S.A., et al. The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden. Am J Gastroenterol. 2015 Apr;110(4):580-7.

5. Mitsuhashi S., Ballou S., Jiang Z.G., et al. Characterizing normal bowel frequency and consistency in a representative sample of adults in the United States (NHANES). Am J Gastroenterol. 2017 Aug 01. PubMed PMID: 28762379.

6. Saad R.J., Rao S.S., Koch K.L., et al. Do stool form and frequency correlate with whole-gut and colonic transit? Results from a multicenter study in constipated individuals and healthy controls. Am J Gastroenterol. 2010 Feb;105(2):403-11. PubMed PMID: 19888202.

7. Castori M., Morlino S., Pascolini G., et al. Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. American Journal of Medical Genetics Part C, Semin Med Genet. 2015 Mar;169C(1):54-75. PubMed PMID: 25821092.

8. Nagaraja V., McMahan Z.H., Getzug T., Khanna D. Management of gastrointestinal involvement in scleroderma. Curr Treatm Opt Rheumatol. 2015 Mar 01;1(1):82-105. PubMed PMID: 26005632. Pubmed Central PMCID: 4437639.

9. Malagelada J.R., Accarino A., Azpiroz F. Bloating and abdominal distension: Old misconceptions and current knowledge. Am J Gastroenterol. 2017 Aug;112(8):1221-31. PubMed PMID: 28508867.

10. Soh J.S., Lee H.J., Jung K.W., et al. The diagnostic value of a digital rectal examination compared with high-resolution anorectal manometry in patients with chronic constipation and fecal incontinence. Am J Gastroenterol. 2015 Aug;110(8):1197-204. PubMed PMID: 26032152.

11. American Gastroenterological Association, Bharucha A.E., Dorn S.D., Lembo A., Pressman A. American Gastroenterological Association medical position statement on constipation. Gastroenterology. 2013 Jan;144(1):211-7. PubMed PMID: 23261064.

12. Skardoon G.R., Khera A.J., Emmanuel A.V., Burgell R.E. Review article: dyssynergic defaecation and biofeedback therapy in the pathophysiology and management of functional constipation. Aliment Pharmacol Therapeut. 2017 Aug;46(4):410-23. PubMed PMID: 28660663.

13. Koh C.E., Young C.J., Young J.M., Solomon M.J. Systematic review of randomized controlled trials of the effectiveness of biofeedback for pelvic floor dysfunction. Br J Surg. 2008 Sep;95(9):1079-87. PubMed PMID: 18655219.

14. Rao S., Lembo A.J., Shiff S.J., et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012 Nov;107(11):1714-24; quiz p 25. PubMed PMID: 22986440. Pubmed Central PMCID: 3504311.

15. Lacy B.E., Schey R., Shiff S.J., et al. Linaclotide in chronic idiopathic constipation patients with moderate to severe abdominal bloating: A randomized, controlled trial. PloS One. 2015;10(7):e0134349. PubMed PMID: 26222318. Pubmed Central PMCID: 4519259.

16. Miner P.B., Jr., Koltun W.D., Wiener G.J., et al. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol. 2017 Apr;112(4):613-21. PubMed PMID: 28169285. Pubmed Central PMCID: 5415706.

17. Johanson J.F., Drossman D.A., Panas R., Wahle A., Ueno R. Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Therapeut. 2008 Apr;27(8):685-96. PubMed PMID: 18248656.

18. Chey W.D., Webster L., Sostek M., Lappalainen J., Barker P.N., Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014 Jun 19;370(25):2387-96. PubMed PMID: 24896818.

19. Katakami N., Oda K., Tauchi K., et al. Phase IIb, randomized, double-blind, placebo-controlled study of naldemedine for the treatment of opioid-induced constipation in patients with cancer. J Clin Oncol. 2017 Jun 10;35(17):1921-8. PubMed PMID: 28445097.

20. Sajid M.S., Hebbar M., Baig M.K., Li A., Philipose Z. Use of prucalopride for chronic constipation: A systematic review and meta-analysis of published randomized, controlled trials. J Neurogastroenterol Motil. 2016 Jul 30;22(3):412-22. PubMed PMID: 27127190. Pubmed Central PMCID: 4930296.

21. Quigley E.M. Cisapride: What can we learn from the rise and fall of a prokinetic? J Dig Dis. 2011 Jun;12(3):147-56. PubMed PMID: 21615867.

22. Conlon K., De Maeyer J.H., Bruce C., et al. Nonclinical cardiovascular studies of prucalopride, a highly selective 5-hydroxytryptamine 4 receptor agonist. J Pharmacol Exp Therapeut. 2017 Nov; doi: 10.1124/jpet.117.244079 [epub ahead of print].

23. Chey W.D., Lembo A.J., Rosenbaum D.P. Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: a phase 2, randomized, placebo-controlled efficacy and safety trial. Am J Gastroenterol. 2017;112:763-74.

24. Simren M., Bajor A., Gillberg P-G, Rudling M., Abrahamsson H. Randomised clinical trial: the ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation – a double-blind study. Aliment Pharmacol Ther. 2011 Jul;34(1):41-50.

25. Zarate N., Knowles C.H., Newell M., et al. In patients with slow transit constipation, the pattern of colonic transit delay does not differentiate between those with and without impaired rectal evacuation. Am J Gastroenterol. 2008 Feb;103(2):427-34. PubMed PMID: 18070233.

26. Redmond J.M., Smith G.W., Barofsky I., et al. Physiological tests to predict long-term outcome of total abdominal colectomy for intractable constipation. Am J Gastroenterol. 1995 May;90(5):748-53. PubMed PMID: 7733081.

Introduction

Direct visualization of the biliary ductal system is quickly gaining importance among gastroenterologists. Since the inception of cholangioscopy in the 1970s, the technology has progressed, allowing for ease of use, better visualization, and a growing number of indications. Conventional endoscopic retrograde cholangiopancreatography (ERCP) is successful for removal of bile duct stones (with success rates over 90%);¹ however, its use in the evaluation of potential biliary neoplasia has been somewhat disappointing. The diagnostic yield of ERCP-guided biliary brushings can range from 30% to 40%.^2-4 An alternative to ERCP-guided biliary brushings for biliary strictures is endoscopic ultrasound (EUS)-directed fine needle aspiration (FNA), but the reported sensitivity remains poor, ranging from 43% to 77% with negative predictive values of less than 30%.^5-7 These results leave much to be desired for diagnostic yield.

Clinical indications

Dr. Sonnier, Dr. Mizrahi, and Dr. Pleskow

Dr. Sonnier, Dr. Mizrahi, and Dr. Pleskow

Risks and complications

Conclusions

Direct visualization of the biliary and pancreatic ductal system with fiber-optic and now digital-based platforms have greatly expanded the diagnostic and therapeutic capabilities available to gastroenterologists in the diagnosis and management of biliary and pancreatic disorders. The digital single-operator cholangiopancreatascope system offers greater diagnostic yield of pancreaticobiliary disorders over conventional diagnostic sampling techniques. In addition, direct visualization has expanded our therapeutic ability in complex stone disease allowing laser-based therapies that are not available with traditional fluoroscopic based techniques. Cholangiopancreatoscopic techniques and indications are rapidly expanding and will continue to expand the diagnostic and therapeutic armamentarium available to gastroenterologists.

Dr. Sonnier is a general gastroenterology fellow, division of gastroenterology, University of South Alabama. Dr. Mizrahi is director of advanced endoscopy, division of gastroenterology, University of South Alabama. Dr. Pleskow, is clinical chief, department of gastroenterology, Beth Israel Deaconess Medical Center, and associate professor of medicine, Harvard Medical School, Boston. Dr. Sonnier and Dr. Mizrahi have no conflicts of interest. Dr. Pleskow serves as a consultant to Boston Scientific.

References

1. Cohen S., et al. Gastrointest Endosc. 2002;56:803–9

2. Lee J.G., et al. Am J Gastroenterol. 1995;90:722-6.

3. De Bellis M., et al. Gastrointest Endosc. 2003;58:176-82

4. Fritcher E.G., et al. Gastroenterology. 2009;136:2180-6.

5. Rosch T., et al. Gastrointest Endosc. 2004;60:390-6.

6. Byrne M.F., et al. Endoscopy. 2004;36:715-9.

7. DeWitt J., et al. Gastrointest Endosc. 2006;64:325-33.

8. Rosch W., Endoscopy. 1976;8:172-5.

9. Takekoshi T., Takagi K. Gastrointest Endosc. 1975;17:678-83.

10. Chen Y.K. Gastrointest Endosc 2007;65:303-11.

11. Navaneethan U., et al. Gastrointest Endosc 2016;84:649-55.

12. Navaneethan U., et al. Gastrointest Endosc 2015;82: 608-14.

13. Chen Y.K., Pleskow DK. Gastrointest Endosc. 2007;65:832-41.

14. Draganov P.V., et al. Gastrointest Endosc. 2011;73:971-9.

15. Ramchandani M., et al. Gastrointest Endosc. 2011;74:511-9.

16. Chen Y.K., et al. Gastrointest Endosc. 2011;74:805-14.

17. Draganov P.V., et al. Gastrointest Endosc. 2012;75:347-53.

18. Classen M., et al. Endoscopy 1988;20:21-6.

19. Parsi M.A., et al. Gastrointest Endosc 2008;67:AB102.

20. Fishman D.S., et al. World J Gastroenterol. 2009;15:1353-8.

21. Maydeo A., et al. Gastrointest Endosc. 2011;74:1308-14.

22. Yamao K., et al. Gastrointest Endosc 2003;57:205-9.

23. Hara T., et al. Gastroenterology 2002;122:34-43.

24. Rösch T., et al. Endoscopy. 2002;34:765–71.

25. Bekkali N.L., et al. Pancreas. 2017;46:528-30.

26. Adwan H., et al. Dig Endosc. 2011;23:199-200.

27. Ransibrahmanakul K., et al. Clin Gastroenterol Hepatol. 2010;8:e9.

28. Pereira P., et al. J Gastrointestin Liver Dis, June 2017;Vol. 26(No 2):165-70.

29. Kawakubo K., et al. Endoscopy 2011;43:E241-2.

Introduction

Direct visualization of the biliary ductal system is quickly gaining importance among gastroenterologists. Since the inception of cholangioscopy in the 1970s, the technology has progressed, allowing for ease of use, better visualization, and a growing number of indications. Conventional endoscopic retrograde cholangiopancreatography (ERCP) is successful for removal of bile duct stones (with success rates over 90%);¹ however, its use in the evaluation of potential biliary neoplasia has been somewhat disappointing. The diagnostic yield of ERCP-guided biliary brushings can range from 30% to 40%.^2-4 An alternative to ERCP-guided biliary brushings for biliary strictures is endoscopic ultrasound (EUS)-directed fine needle aspiration (FNA), but the reported sensitivity remains poor, ranging from 43% to 77% with negative predictive values of less than 30%.^5-7 These results leave much to be desired for diagnostic yield.

Clinical indications

Dr. Sonnier, Dr. Mizrahi, and Dr. Pleskow

Dr. Sonnier, Dr. Mizrahi, and Dr. Pleskow

Risks and complications

Conclusions

Direct visualization of the biliary and pancreatic ductal system with fiber-optic and now digital-based platforms have greatly expanded the diagnostic and therapeutic capabilities available to gastroenterologists in the diagnosis and management of biliary and pancreatic disorders. The digital single-operator cholangiopancreatascope system offers greater diagnostic yield of pancreaticobiliary disorders over conventional diagnostic sampling techniques. In addition, direct visualization has expanded our therapeutic ability in complex stone disease allowing laser-based therapies that are not available with traditional fluoroscopic based techniques. Cholangiopancreatoscopic techniques and indications are rapidly expanding and will continue to expand the diagnostic and therapeutic armamentarium available to gastroenterologists.

Dr. Sonnier is a general gastroenterology fellow, division of gastroenterology, University of South Alabama. Dr. Mizrahi is director of advanced endoscopy, division of gastroenterology, University of South Alabama. Dr. Pleskow, is clinical chief, department of gastroenterology, Beth Israel Deaconess Medical Center, and associate professor of medicine, Harvard Medical School, Boston. Dr. Sonnier and Dr. Mizrahi have no conflicts of interest. Dr. Pleskow serves as a consultant to Boston Scientific.

References

1. Cohen S., et al. Gastrointest Endosc. 2002;56:803–9

2. Lee J.G., et al. Am J Gastroenterol. 1995;90:722-6.

3. De Bellis M., et al. Gastrointest Endosc. 2003;58:176-82

4. Fritcher E.G., et al. Gastroenterology. 2009;136:2180-6.

5. Rosch T., et al. Gastrointest Endosc. 2004;60:390-6.

6. Byrne M.F., et al. Endoscopy. 2004;36:715-9.

7. DeWitt J., et al. Gastrointest Endosc. 2006;64:325-33.

8. Rosch W., Endoscopy. 1976;8:172-5.

9. Takekoshi T., Takagi K. Gastrointest Endosc. 1975;17:678-83.

10. Chen Y.K. Gastrointest Endosc 2007;65:303-11.

11. Navaneethan U., et al. Gastrointest Endosc 2016;84:649-55.

12. Navaneethan U., et al. Gastrointest Endosc 2015;82: 608-14.

13. Chen Y.K., Pleskow DK. Gastrointest Endosc. 2007;65:832-41.

14. Draganov P.V., et al. Gastrointest Endosc. 2011;73:971-9.

15. Ramchandani M., et al. Gastrointest Endosc. 2011;74:511-9.

16. Chen Y.K., et al. Gastrointest Endosc. 2011;74:805-14.

17. Draganov P.V., et al. Gastrointest Endosc. 2012;75:347-53.

18. Classen M., et al. Endoscopy 1988;20:21-6.

19. Parsi M.A., et al. Gastrointest Endosc 2008;67:AB102.

20. Fishman D.S., et al. World J Gastroenterol. 2009;15:1353-8.

21. Maydeo A., et al. Gastrointest Endosc. 2011;74:1308-14.

22. Yamao K., et al. Gastrointest Endosc 2003;57:205-9.

23. Hara T., et al. Gastroenterology 2002;122:34-43.

24. Rösch T., et al. Endoscopy. 2002;34:765–71.

25. Bekkali N.L., et al. Pancreas. 2017;46:528-30.

26. Adwan H., et al. Dig Endosc. 2011;23:199-200.

27. Ransibrahmanakul K., et al. Clin Gastroenterol Hepatol. 2010;8:e9.

28. Pereira P., et al. J Gastrointestin Liver Dis, June 2017;Vol. 26(No 2):165-70.

29. Kawakubo K., et al. Endoscopy 2011;43:E241-2.

Introduction

Direct visualization of the biliary ductal system is quickly gaining importance among gastroenterologists. Since the inception of cholangioscopy in the 1970s, the technology has progressed, allowing for ease of use, better visualization, and a growing number of indications. Conventional endoscopic retrograde cholangiopancreatography (ERCP) is successful for removal of bile duct stones (with success rates over 90%);¹ however, its use in the evaluation of potential biliary neoplasia has been somewhat disappointing. The diagnostic yield of ERCP-guided biliary brushings can range from 30% to 40%.^2-4 An alternative to ERCP-guided biliary brushings for biliary strictures is endoscopic ultrasound (EUS)-directed fine needle aspiration (FNA), but the reported sensitivity remains poor, ranging from 43% to 77% with negative predictive values of less than 30%.^5-7 These results leave much to be desired for diagnostic yield.