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Approach to asymptomatic creatine kinase elevation
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Siamak Moghadam-Kia, MD
Chester V. Oddis, MD
Rohit Aggarwal, MD, MS

Measuring serum creatine kinase (CK) is an important part of the evaluation of patients with muscle weakness or myalgia, and of assessing patients with myopathies or rhabdomyolysis. But elevated CK sometimes is an incidental finding in a patient without muscle-related symptoms or with only minimal  nonspecific muscle symptoms (eg, cramps, spasms, fatigue) that do not significantly interfere with activities of daily living. This condition is sometimes referred to as “asymptomatic hyper-CK-emia.” Four other muscle enzymes that may also be elevated are aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and aldolase.

This review focuses on the evaluation of patients with elevated CK without significant muscle-related symptoms and proposes an algorithm for this purpose (Figure 1).

CURRENT THRESHOLDS MAY BE LOW

What appears to be an elevated CK level may in fact be normal, and it is important to determine in the initial assessment whether a CK value is truly abnormal.

Figure 1. Diagnostic workup of asymptomatic creatine kinase elevation.

Most laboratories use the central 95% of observations in white people as a reference range for serum CK, assuming that levels have a gaussian (bell-shaped) distribution, which is usually about 0 to 200 IU/L. Using these parameters, an abnormal CK level was observed in 19% of men and 5% of women in a study of nearly 1,000 healthy young people,1 leading to overdiagnosis.

The actual distribution of serum CK levels in a healthy population is markedly skewed toward higher values and is nongaussian.1–3 A 97.5% normal threshold is associated with a much lower false-positive rate and is recommended by the European Federation of Neurological Societies (now the European Academy of Neurology).4 This group also recommends pursuing further investigation only for patients whose level is at least 1.5 times the upper limit of normal; this threshold results in only a small reduction in sensitivity.

CK levels vary significantly by sex and race.5 Possible reasons include differences in muscle mass or total body mass and inherited differences in the permeability of the sarcolemma to CK.6 There is also a small reduction in CK levels as people age.2

The European Federation of Neurological Societies suggests redefining elevated CK as values 1.5 times beyond the upper limit of normal. Based on a 97.5% threshold and normal values determined by Brewster et al3 for black and white men and women, the following thresholds can be used to help decide whether to pursue further evaluation4:

  • White women—325 IU/L
  • White men—504 IU/L
  • Black women—621 IU/L
  • Black men—1,200 IU/L

PHYSICAL ACTIVITY RAISES CK

CK levels transiently rise after exercise or heavy manual labor. Serum CK levels may increase to as much as 30 times the upper limit of normal within 24 hours of strenuous physical activity, then slowly decline over the next 7 days. The degree of CK elevation depends on the type and duration of exercise, with greater elevation in those who are untrained.2,4

In assessing asymptomatic or minimally symptomatic CK elevation, the test should be repeated after 7 days without exercise. A large community study in Norway found that repeat CK levels in people with incidentally discovered elevated CK were normal after 3 days of rest in 70% of cases.2

NONNEUROMUSCULAR CAUSES
NEED TO BE INVESTIGATED

Asymptomatic or minimally symptomatic elevated CK can be due to a primary neuromuscular disease or a variety of nonneuromuscular causes.

Patients who still have elevated CK after taking into account the 97.5% threshold, repeat testing after a week of rest, and a level more than 1.5 times the upper limit of normal for sex and race should first be evaluated for the many nonneuromuscular conditions that can cause elevated CK (Table 1).7–9

Cardiac causes should be evaluated by history and physical examination, electrocardiography, and possibly testing for cardiac troponins.

Drugs commonly elevate CK

Prescription drugs and supplements are an important and common cause of CK elevation, so it is important to carefully review medications the patient is taking.

Statins can cause myalgia, muscle weakness, and rhabdomyolysis. Up to 5% of users develop CK elevation, typically 2 to 10 times the upper limit of normal.10 CK usually drops after stopping statins but may require weeks to months to normalize. Rarely, statin users develop a serious immune-mediated necrotizing myopathy.11–13

The diversity of response to statin therapy appears to have a genetic basis. The SEARCH Collaborative Group14 conducted a genome-wide association study of 300,000 markers in 85 patients with definite or incipient myopathy and in 90 controls, all of whom were taking simvastatin 80 mg daily. They identified a single-nucleotide polymorphism in the SLCO1B1 gene on chromosome 12 that was strongly associated with a higher risk of statin-induced myopathy.

Patients with statin-related myopathy seem to have a higher frequency of occult metabolic muscle disease than the general population, also suggesting genetic susceptibility, although ascertainment bias could be a factor.14

Mechanisms of CK elevation in response to statins include increased muscle membrane fragility due to decreased cholesterol content, inhibition of isoprenoid production (a necessary step in the synthesis of membrane proteins), and depletion of ubiquinone, leading to mitochondrial dysfunction.

 

 

Macro CK: An abnormal enzyme complex

About 4% of patients with asymptomatic or minimally symptomatic elevated CK have “macro CK,” an enzyme complex with an atypically high molecular mass and reduced clearance, resulting in abnormally high blood levels of CK. Macro CK type 1 is more common and is found in up to 1.2% of the general population: complexes are composed of CK and immunoglobulin and are associated with autoimmune diseases.9,15 Macro CK type 2 complexes consist of CK and an undetermined protein and are associated with malignancies.

CK electrophoresis is required to detect macro CK. Types 1 and 2 can be distinguished by protein G affinity chromatography.9,15 

Endocrine disorders

Muscle involvement in endocrine disorders often presents with muscle weakness in addition to muscle enzyme abnormalities.

Hypothyroidism often causes weakness, cramps, myalgia, and a mild to moderate serum CK elevation.16 Severe CK elevation has been reported to occur after vigorous exercise.17 Thyroid replacement usually results in normalization of serum CK levels in 1 to 2 months.18

Hyperthyroidism is typically associated with normal serum CK concentrations, but in rare cases it can cause rhabdomyolysis.19

NEUROMUSCULAR CAUSES ARE NOT ALWAYS WORTH PURSUING

Only after the nonneuromuscular causes of elevated CK have been ruled out should neuromuscular disorders be considered (Table 2). Evaluation with electromyography, nerve conduction studies, and muscle biopsy may lead to the diagnosis of a specific neuromuscular disorder: patients may be in the presymptomatic stage of disease and may or may not eventually develop muscle weakness or other symptoms.20,21

Is testing needed?

Most adult dystrophies and metabolic myopathies have no available treatment and their course is often benign, particularly if they present only with asymptomatic elevated CK. The value of a potentially extensive, expensive, and invasive evaluation for a specific neuromuscular cause should be weighed against the limited yield and treatment options. Moreover, specialized testing such as biochemical muscle enzyme analysis, sarcolemmal protein staining, and genetic testing are not available at all centers.

The European Federation of Neurological Societies guidelines recommend biopsy for  patients with asymptomatic elevated CK who also have any of the following:

  • Abnormal (myopathic) findings on electromyography
  • CK more than three times the upper limit of normal
  • Age less than 25
  • Exercise intolerance.4

Idiopathic inflammatory myopathies rarely present with asymptomatic elevated CK.22–26 In one study,27 they were found in just 5% of patients with asymptomatic elevated CK.

Hypomyopathic dermatomyositis and inclusion body myositis can present with mild CK elevations with normal muscle strength, especially early in the disease course. A myositis subset of antisynthetase syndrome can present with mildly elevated CK and interstitial lung disease.27 Many of the inflammatory myopathies respond to treatment so are worth investigating.

In view of complexities in diagnosis of these conditions, one should proceed with testing only after discussing it with patients. Referral to a rheumatology specialist is preferred.

MUSCLE BIOPSY, ELECTROMYOGRAPHY, AND NERVE CONDUCTION STUDIES

Electromyography, nerve conduction studies, or muscle biopsy, or a combination of these tests, is usually needed to investigate neuromuscular causes of elevated CK.

Muscle biopsy abnormalities are found in about two-thirds of cases of asymptomatic elevated CK, but most abnormalities include nonspecific myopathic changes that are not diagnostic. A muscle biopsy that may include special stains for sarcolemmal proteins for muscular dystrophy and biochemical muscle enzyme analysis for metabolic myopathies is diagnostic in only 20% to 25% cases of asymptomatic elevated CK on average, with a variation between different series of 0% to 79%.7,21,27–33

Electromyography and nerve conduction studies alone add little to the workup of asymp­tomatic elevated CK apart from a modest negative predictive value and as a guide for muscle biopsy. For a very few neuromuscular disorders causing an elevated CK (eg, motor neuron disease, Charcot-Marie-Tooth disease, myotonic dystrophy), electromyography and nerve conduction studies could suffice to make the diagnosis. 

Electromyography and nerve conduction studies detect abnormalities in nearly half of cases of asymptomatic CK elevation,7,21,27,28,30,31,33 but, as with biopsy, most changes are nonspecific. Although electromyography and nerve conduction studies can help distinguish primary neuropathic from myopathic disorders, the sensitivity and specificity are low for diagnosis. Normal studies do not rule out a condition, and abnormal studies are not diagnostic of a particular condition, although completely normal studies provide strong evidence against a severe neuromuscular disorder.

Combined testing

Using combined muscle biopsy, electromyography, and nerve conduction studies, the likelihood of making a diagnosis in patients with asymptomatic elevated CK is 28% on average (range of studies 4%–79%),2,7,21,26–28,30–32 and findings are nonspecific in 30% to 40% of cases. Findings are normal in about 30% to 40% of cases, which are thus diagnosed as idiopathic asymptomatic elevated CK.28–31,34

Prelle et al31 retrospectively reviewed the cases of 114 patients, ages 3 to 70, with incidentally discovered elevated CK and few or no symptoms, who underwent muscle biopsy, electromyography, and nerve conduction studies after nonneuromuscular causes were ruled out. Although muscle biopsy findings were abnormal in 39% of cases, a diagnosis was established in only 18% of cases after an extensive workup: the diagnosis was definitive in only 10% and included dystrophinopathies, metabolic myopathies, and rare noninflammatory myopathies. For the remaining 8%, the diagnosis was probable and included four cases of partial carnitine palmitoyl transferase deficiency, three cases of malignant hyperthermia, and two rare inherited disorders.

DNA testing

In women with a serum CK less than three times the upper limit of normal who have a family history of Duchenne or Becker muscular dystrophy, DNA analysis of blood lymphocytes identifies 70% of carriers.4

IDIOPATHIC ELEVATED SERUM CK

Rowland et al35 first coined the term “idiopathic hyper-CK-emia” and defined it as persistent elevation of serum CK despite a normal neurologic examination and testing, including electromyography, nerve conduction studies, and muscle biopsy.35,36 To receive this diagnosis, patients must also have no family history or clinical evidence of neuromuscular disease.

Idiopathic elevated serum CK is sometimes familial. In one study,37 elevated CK was found in family members of 13 of 28 unrelated probands. In the 13 families, 41 individuals had elevated CK. Genetic studies revealed that the condition is genetically heterogeneous and autosomal dominant in at least 60% of cases, with higher penetrance  in men.

D’Adda et al26 followed 55 people with idiopathic elevated CK for 7 years. Ten percent were eventually diagnosed with a neuromuscular disorder, 10% developed malignancy, and the remaining 80% developed no new condition. The CK level normalized or decreased in many patients, but most continued to have persistent CK elevations with minimal or no symptoms.

References
  1. Lev EI, Tur-Kaspa I, Ashkenazy I, et al. Distribution of serum creatine kinase activity in young healthy persons. Clin Chim Acta 1999; 279:107–115.
  2. Lilleng H, Abeler K, Johnsen SH, et al. Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study. Neuromuscul Disord 2011; 21:494–500.
  3. Brewster LM, Mairuhu G, Sturk A, van Montfrans GA. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J 2007; 154:655–661.
  4. Kyriakides T, Angelini C, Schaefer J, et al; European Federation of Neurological Societies. EFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia. Eur J Neurol 2010; 17:767–773.
  5. Prisant LM, Downton M, Watkins LO, et al. Efficacy and tolerability of lovastatin in 459 African-Americans with hypercholesterolemia. Am J Cardiol 1996; 78:420–444.
  6. Wong ET, Cobb C, Umehara MK, et al. Heterogeneity of serum creatine kinase activity among racial and gender groups of the population. Am J Clin Pathol 1983; 79:582–586.
  7. Brewster LM, de Visser M. Persistent hyperCKemia: fourteen patients studied in retrospect. Acta Neurol Scand 1988; 77:60–63.
  8. Weglinski MR, Wedel DJ, Engel AG. Malignant hyperthermia testing in patients with persistently increased serum creatine kinase levels. Anesth Analg 1997; 84:1038–1041.
  9. Galarraga B, Sinclair D, Fahie-Wilson MN, McCrae FC, Hull RG, Ledingham JM. A rare but important cause for a raised serum creatine kinase concentration: two case reports and a literature review. Rheumatology (Oxford) 2003; 42:186–188.
  10. Mancini GB, Tashakkor AY, Baker S, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol 2013; 29:1553–1568.
  11. Arora R, Liebo M, Maldonado F. Statin-induced myopathy: the two faces of Janus. J Cardiovasc Pharmacol Ther 2006; 11:105–112.
  12. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009; 150:858–868.
  13. Talbert RL. Safety issues with statin therapy. J Am Pharm Assoc (2003) 2006; 46:479–490.
  14. SEARCH Collaborative Group; Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 2008; 359:789–799.
  15. Wyness SP, Hunsaker JJ, La’ulu SL, Rao LV, Roberts WL. Detection of macro-creatine kinase and macroamylase by polyethylene glycol precipitation and ultrafiltration methods. Clin Chim Acta 2011; 412:2052–2057.
        
  16. Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000; 68:750–755.
  17. Riggs JE. Acute exertional rhabdomyolysis in hypothyroidism: the result of a reversible defect in glycogenolysis? Mil Med 1990; 155:171–172.
  18. Mastaglia FL, Ojeda VJ, Sarnat HB, Kakulas BA. Myopathies associated with hypothyroidism: a review based upon 13 cases. Aust N Z J Med 1988; 18:799–806.
  19. Alshanti M, Eledrisi MS, Jones E. Rhabdomyolysis associated with hyperthyroidism. Am J Emerg Med 2001; 19:317.
  20. Rosalki SB. Serum enzymes in disease of skeletal muscle. Clin Lab Med 1989; 9:767–781.
  21. Joy JL, Oh SJ. Asymptomatic hyper-CK-emia: an electrophysiologic and histopathologic study. Muscle Nerve 1989; 12:206–209.
  22. Merlini L, Sabatelli P, Columbaro M, et al. Hyper-CK-emia as the sole manifestation of myotonic dystrophy type 2. Muscle Nerve 2005; 31:764–767.
  23. Eeg-Olofsson O, Kalimo H, Eeg-Olofsson KE, et al. Duchenne muscular dystrophy and idiopathic hyperCKemia in the same family. Eur J Paediatr Neurol 2008; 12:404–407.
  24. Dwianingsih EK, Takeshima Y, Itoh K, et al. A Japanese child with asymptomatic elevation of serum creatine kinase shows PTRF-CAVIN mutation matching with congenital generalized lipodystrophy type 4. Mol Genet Metab 2010; 101:233–237.
  25. Carbone I, Bruno C, Sotgia F, et al. Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia. Neurology 2000; 54:1373–1376.
  26. D’Adda E, Sciacco M, Fruguglietti ME, et al. Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects. J Neurol 2006; 253:1399–1403.
  27. Fernandez C, de Paula AM, Figarella-Branger D, et al. Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Neurology 2006; 66:1585–1587.
  28. Simmons Z, Peterlin BL, Boyer PJ, Towfighi J. Muscle biopsy in the evaluation of patients with modestly elevated creatine kinase levels. Muscle Nerve 2003; 27:242–244.
  29. Filosto M, Tonin P, Vattemi G, et al. The role of muscle biopsy in investigating isolated muscle pain. Neurology 2007; 68:181–186.
  30. Malandrini A, Orrico A, Gaudiano C, et al. Muscle biopsy and in vitro contracture test in subjects with idiopathic hyperCKemia. Anesthesiology 2008; 109:625–628.
  31. Prelle A, Tancredi L, Sciacco M, et al. Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels. J Neurol 2002; 249:305–311.
  32. Dabby R, Sadeh M, Herman O, et al. Asymptomatic or minimally symptomatic hyperCKemia: histopathologic correlates. Isr Med Assoc J 2006; 8:110–113.
  33. Reijneveld JC, Notermans NC, Linssen WH, Wokke JH. Benign prognosis in idiopathic hyper-CK-emia. Muscle Nerve 2000; 23:575–579.
  34. Restivo DA, Pavone V, Nicotra A. Single-fiber electromyography in hyperCKemia: the value of fiber density. Neurol Sci 2012; 33:819–824.
  35. Rowland LP, Willner J, Cerri C, DiMauro S, Miranda A. Approaches to the membrane theory of Duchenne muscular dystrophy. In: Angelini C, Danielli GA, Fontanari D, editors. Muscular Dystrophy Research: Advances and New Trends, Amsterdam: Excerpta Medica; 1980:3–13.
  36. Reijneveld JC, Notermans NC, Linssen WH, Bär PR, Wokke JH. Hyper-CK-aemia revisited. Neuromuscul Disord 2001; 11:163–164.
  37. Capasso M, De Angelis MV, Di Muzio A, et al. Familial idiopathic hyper-CK-emia: an underrecognized condition. Muscle Nerve 2006; 33:760–765.
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Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine; VA Pittsburgh Healthcare System, Pittsburgh, PA

Chester V. Oddis, MD
Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA

Rohit Aggarwal, MD, MS
Associate Professor of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA

Address: Rohit Aggarwal, MD, MS, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, 3601 5th Avenue, Suite 2B, Pittsburgh, PA 15261; e-mail: aggarwalr@upmc.ed

Dr. Oddis has served on an advisory committee or review panel for Idera Pharmaceuticals and Novartis.

Dr. Aggarwal has served as a consultant for Bristol-Myers Squibb and Novartis.

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Chester V. Oddis, MD
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Chester V. Oddis, MD
Rohit Aggarwal, MD, MS
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Siamak Moghadam-Kia, MD
Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine; VA Pittsburgh Healthcare System, Pittsburgh, PA

Chester V. Oddis, MD
Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA

Rohit Aggarwal, MD, MS
Associate Professor of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA

Address: Rohit Aggarwal, MD, MS, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, 3601 5th Avenue, Suite 2B, Pittsburgh, PA 15261; e-mail: aggarwalr@upmc.ed

Dr. Oddis has served on an advisory committee or review panel for Idera Pharmaceuticals and Novartis.

Dr. Aggarwal has served as a consultant for Bristol-Myers Squibb and Novartis.

Author and Disclosure Information

Siamak Moghadam-Kia, MD
Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine; VA Pittsburgh Healthcare System, Pittsburgh, PA

Chester V. Oddis, MD
Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA

Rohit Aggarwal, MD, MS
Associate Professor of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA

Address: Rohit Aggarwal, MD, MS, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, 3601 5th Avenue, Suite 2B, Pittsburgh, PA 15261; e-mail: aggarwalr@upmc.ed

Dr. Oddis has served on an advisory committee or review panel for Idera Pharmaceuticals and Novartis.

Dr. Aggarwal has served as a consultant for Bristol-Myers Squibb and Novartis.

Article PDF
Moghadam-Kia_AsymptomaticCreatineKinaseElevation.pdf
Article PDF
Moghadam-Kia_AsymptomaticCreatineKinaseElevation.pdf

Measuring serum creatine kinase (CK) is an important part of the evaluation of patients with muscle weakness or myalgia, and of assessing patients with myopathies or rhabdomyolysis. But elevated CK sometimes is an incidental finding in a patient without muscle-related symptoms or with only minimal  nonspecific muscle symptoms (eg, cramps, spasms, fatigue) that do not significantly interfere with activities of daily living. This condition is sometimes referred to as “asymptomatic hyper-CK-emia.” Four other muscle enzymes that may also be elevated are aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and aldolase.

This review focuses on the evaluation of patients with elevated CK without significant muscle-related symptoms and proposes an algorithm for this purpose (Figure 1).

CURRENT THRESHOLDS MAY BE LOW

What appears to be an elevated CK level may in fact be normal, and it is important to determine in the initial assessment whether a CK value is truly abnormal.

Figure 1. Diagnostic workup of asymptomatic creatine kinase elevation.

Most laboratories use the central 95% of observations in white people as a reference range for serum CK, assuming that levels have a gaussian (bell-shaped) distribution, which is usually about 0 to 200 IU/L. Using these parameters, an abnormal CK level was observed in 19% of men and 5% of women in a study of nearly 1,000 healthy young people,1 leading to overdiagnosis.

The actual distribution of serum CK levels in a healthy population is markedly skewed toward higher values and is nongaussian.1–3 A 97.5% normal threshold is associated with a much lower false-positive rate and is recommended by the European Federation of Neurological Societies (now the European Academy of Neurology).4 This group also recommends pursuing further investigation only for patients whose level is at least 1.5 times the upper limit of normal; this threshold results in only a small reduction in sensitivity.

CK levels vary significantly by sex and race.5 Possible reasons include differences in muscle mass or total body mass and inherited differences in the permeability of the sarcolemma to CK.6 There is also a small reduction in CK levels as people age.2

The European Federation of Neurological Societies suggests redefining elevated CK as values 1.5 times beyond the upper limit of normal. Based on a 97.5% threshold and normal values determined by Brewster et al3 for black and white men and women, the following thresholds can be used to help decide whether to pursue further evaluation4:

  • White women—325 IU/L
  • White men—504 IU/L
  • Black women—621 IU/L
  • Black men—1,200 IU/L

PHYSICAL ACTIVITY RAISES CK

CK levels transiently rise after exercise or heavy manual labor. Serum CK levels may increase to as much as 30 times the upper limit of normal within 24 hours of strenuous physical activity, then slowly decline over the next 7 days. The degree of CK elevation depends on the type and duration of exercise, with greater elevation in those who are untrained.2,4

In assessing asymptomatic or minimally symptomatic CK elevation, the test should be repeated after 7 days without exercise. A large community study in Norway found that repeat CK levels in people with incidentally discovered elevated CK were normal after 3 days of rest in 70% of cases.2

NONNEUROMUSCULAR CAUSES
NEED TO BE INVESTIGATED

Asymptomatic or minimally symptomatic elevated CK can be due to a primary neuromuscular disease or a variety of nonneuromuscular causes.

Patients who still have elevated CK after taking into account the 97.5% threshold, repeat testing after a week of rest, and a level more than 1.5 times the upper limit of normal for sex and race should first be evaluated for the many nonneuromuscular conditions that can cause elevated CK (Table 1).7–9

Cardiac causes should be evaluated by history and physical examination, electrocardiography, and possibly testing for cardiac troponins.

Drugs commonly elevate CK

Prescription drugs and supplements are an important and common cause of CK elevation, so it is important to carefully review medications the patient is taking.

Statins can cause myalgia, muscle weakness, and rhabdomyolysis. Up to 5% of users develop CK elevation, typically 2 to 10 times the upper limit of normal.10 CK usually drops after stopping statins but may require weeks to months to normalize. Rarely, statin users develop a serious immune-mediated necrotizing myopathy.11–13

The diversity of response to statin therapy appears to have a genetic basis. The SEARCH Collaborative Group14 conducted a genome-wide association study of 300,000 markers in 85 patients with definite or incipient myopathy and in 90 controls, all of whom were taking simvastatin 80 mg daily. They identified a single-nucleotide polymorphism in the SLCO1B1 gene on chromosome 12 that was strongly associated with a higher risk of statin-induced myopathy.

Patients with statin-related myopathy seem to have a higher frequency of occult metabolic muscle disease than the general population, also suggesting genetic susceptibility, although ascertainment bias could be a factor.14

Mechanisms of CK elevation in response to statins include increased muscle membrane fragility due to decreased cholesterol content, inhibition of isoprenoid production (a necessary step in the synthesis of membrane proteins), and depletion of ubiquinone, leading to mitochondrial dysfunction.

 

 

Macro CK: An abnormal enzyme complex

About 4% of patients with asymptomatic or minimally symptomatic elevated CK have “macro CK,” an enzyme complex with an atypically high molecular mass and reduced clearance, resulting in abnormally high blood levels of CK. Macro CK type 1 is more common and is found in up to 1.2% of the general population: complexes are composed of CK and immunoglobulin and are associated with autoimmune diseases.9,15 Macro CK type 2 complexes consist of CK and an undetermined protein and are associated with malignancies.

CK electrophoresis is required to detect macro CK. Types 1 and 2 can be distinguished by protein G affinity chromatography.9,15 

Endocrine disorders

Muscle involvement in endocrine disorders often presents with muscle weakness in addition to muscle enzyme abnormalities.

Hypothyroidism often causes weakness, cramps, myalgia, and a mild to moderate serum CK elevation.16 Severe CK elevation has been reported to occur after vigorous exercise.17 Thyroid replacement usually results in normalization of serum CK levels in 1 to 2 months.18

Hyperthyroidism is typically associated with normal serum CK concentrations, but in rare cases it can cause rhabdomyolysis.19

NEUROMUSCULAR CAUSES ARE NOT ALWAYS WORTH PURSUING

Only after the nonneuromuscular causes of elevated CK have been ruled out should neuromuscular disorders be considered (Table 2). Evaluation with electromyography, nerve conduction studies, and muscle biopsy may lead to the diagnosis of a specific neuromuscular disorder: patients may be in the presymptomatic stage of disease and may or may not eventually develop muscle weakness or other symptoms.20,21

Is testing needed?

Most adult dystrophies and metabolic myopathies have no available treatment and their course is often benign, particularly if they present only with asymptomatic elevated CK. The value of a potentially extensive, expensive, and invasive evaluation for a specific neuromuscular cause should be weighed against the limited yield and treatment options. Moreover, specialized testing such as biochemical muscle enzyme analysis, sarcolemmal protein staining, and genetic testing are not available at all centers.

The European Federation of Neurological Societies guidelines recommend biopsy for  patients with asymptomatic elevated CK who also have any of the following:

  • Abnormal (myopathic) findings on electromyography
  • CK more than three times the upper limit of normal
  • Age less than 25
  • Exercise intolerance.4

Idiopathic inflammatory myopathies rarely present with asymptomatic elevated CK.22–26 In one study,27 they were found in just 5% of patients with asymptomatic elevated CK.

Hypomyopathic dermatomyositis and inclusion body myositis can present with mild CK elevations with normal muscle strength, especially early in the disease course. A myositis subset of antisynthetase syndrome can present with mildly elevated CK and interstitial lung disease.27 Many of the inflammatory myopathies respond to treatment so are worth investigating.

In view of complexities in diagnosis of these conditions, one should proceed with testing only after discussing it with patients. Referral to a rheumatology specialist is preferred.

MUSCLE BIOPSY, ELECTROMYOGRAPHY, AND NERVE CONDUCTION STUDIES

Electromyography, nerve conduction studies, or muscle biopsy, or a combination of these tests, is usually needed to investigate neuromuscular causes of elevated CK.

Muscle biopsy abnormalities are found in about two-thirds of cases of asymptomatic elevated CK, but most abnormalities include nonspecific myopathic changes that are not diagnostic. A muscle biopsy that may include special stains for sarcolemmal proteins for muscular dystrophy and biochemical muscle enzyme analysis for metabolic myopathies is diagnostic in only 20% to 25% cases of asymptomatic elevated CK on average, with a variation between different series of 0% to 79%.7,21,27–33

Electromyography and nerve conduction studies alone add little to the workup of asymp­tomatic elevated CK apart from a modest negative predictive value and as a guide for muscle biopsy. For a very few neuromuscular disorders causing an elevated CK (eg, motor neuron disease, Charcot-Marie-Tooth disease, myotonic dystrophy), electromyography and nerve conduction studies could suffice to make the diagnosis. 

Electromyography and nerve conduction studies detect abnormalities in nearly half of cases of asymptomatic CK elevation,7,21,27,28,30,31,33 but, as with biopsy, most changes are nonspecific. Although electromyography and nerve conduction studies can help distinguish primary neuropathic from myopathic disorders, the sensitivity and specificity are low for diagnosis. Normal studies do not rule out a condition, and abnormal studies are not diagnostic of a particular condition, although completely normal studies provide strong evidence against a severe neuromuscular disorder.

Combined testing

Using combined muscle biopsy, electromyography, and nerve conduction studies, the likelihood of making a diagnosis in patients with asymptomatic elevated CK is 28% on average (range of studies 4%–79%),2,7,21,26–28,30–32 and findings are nonspecific in 30% to 40% of cases. Findings are normal in about 30% to 40% of cases, which are thus diagnosed as idiopathic asymptomatic elevated CK.28–31,34

Prelle et al31 retrospectively reviewed the cases of 114 patients, ages 3 to 70, with incidentally discovered elevated CK and few or no symptoms, who underwent muscle biopsy, electromyography, and nerve conduction studies after nonneuromuscular causes were ruled out. Although muscle biopsy findings were abnormal in 39% of cases, a diagnosis was established in only 18% of cases after an extensive workup: the diagnosis was definitive in only 10% and included dystrophinopathies, metabolic myopathies, and rare noninflammatory myopathies. For the remaining 8%, the diagnosis was probable and included four cases of partial carnitine palmitoyl transferase deficiency, three cases of malignant hyperthermia, and two rare inherited disorders.

DNA testing

In women with a serum CK less than three times the upper limit of normal who have a family history of Duchenne or Becker muscular dystrophy, DNA analysis of blood lymphocytes identifies 70% of carriers.4

IDIOPATHIC ELEVATED SERUM CK

Rowland et al35 first coined the term “idiopathic hyper-CK-emia” and defined it as persistent elevation of serum CK despite a normal neurologic examination and testing, including electromyography, nerve conduction studies, and muscle biopsy.35,36 To receive this diagnosis, patients must also have no family history or clinical evidence of neuromuscular disease.

Idiopathic elevated serum CK is sometimes familial. In one study,37 elevated CK was found in family members of 13 of 28 unrelated probands. In the 13 families, 41 individuals had elevated CK. Genetic studies revealed that the condition is genetically heterogeneous and autosomal dominant in at least 60% of cases, with higher penetrance  in men.

D’Adda et al26 followed 55 people with idiopathic elevated CK for 7 years. Ten percent were eventually diagnosed with a neuromuscular disorder, 10% developed malignancy, and the remaining 80% developed no new condition. The CK level normalized or decreased in many patients, but most continued to have persistent CK elevations with minimal or no symptoms.

Measuring serum creatine kinase (CK) is an important part of the evaluation of patients with muscle weakness or myalgia, and of assessing patients with myopathies or rhabdomyolysis. But elevated CK sometimes is an incidental finding in a patient without muscle-related symptoms or with only minimal  nonspecific muscle symptoms (eg, cramps, spasms, fatigue) that do not significantly interfere with activities of daily living. This condition is sometimes referred to as “asymptomatic hyper-CK-emia.” Four other muscle enzymes that may also be elevated are aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and aldolase.

This review focuses on the evaluation of patients with elevated CK without significant muscle-related symptoms and proposes an algorithm for this purpose (Figure 1).

CURRENT THRESHOLDS MAY BE LOW

What appears to be an elevated CK level may in fact be normal, and it is important to determine in the initial assessment whether a CK value is truly abnormal.

Figure 1. Diagnostic workup of asymptomatic creatine kinase elevation.

Most laboratories use the central 95% of observations in white people as a reference range for serum CK, assuming that levels have a gaussian (bell-shaped) distribution, which is usually about 0 to 200 IU/L. Using these parameters, an abnormal CK level was observed in 19% of men and 5% of women in a study of nearly 1,000 healthy young people,1 leading to overdiagnosis.

The actual distribution of serum CK levels in a healthy population is markedly skewed toward higher values and is nongaussian.1–3 A 97.5% normal threshold is associated with a much lower false-positive rate and is recommended by the European Federation of Neurological Societies (now the European Academy of Neurology).4 This group also recommends pursuing further investigation only for patients whose level is at least 1.5 times the upper limit of normal; this threshold results in only a small reduction in sensitivity.

CK levels vary significantly by sex and race.5 Possible reasons include differences in muscle mass or total body mass and inherited differences in the permeability of the sarcolemma to CK.6 There is also a small reduction in CK levels as people age.2

The European Federation of Neurological Societies suggests redefining elevated CK as values 1.5 times beyond the upper limit of normal. Based on a 97.5% threshold and normal values determined by Brewster et al3 for black and white men and women, the following thresholds can be used to help decide whether to pursue further evaluation4:

  • White women—325 IU/L
  • White men—504 IU/L
  • Black women—621 IU/L
  • Black men—1,200 IU/L

PHYSICAL ACTIVITY RAISES CK

CK levels transiently rise after exercise or heavy manual labor. Serum CK levels may increase to as much as 30 times the upper limit of normal within 24 hours of strenuous physical activity, then slowly decline over the next 7 days. The degree of CK elevation depends on the type and duration of exercise, with greater elevation in those who are untrained.2,4

In assessing asymptomatic or minimally symptomatic CK elevation, the test should be repeated after 7 days without exercise. A large community study in Norway found that repeat CK levels in people with incidentally discovered elevated CK were normal after 3 days of rest in 70% of cases.2

NONNEUROMUSCULAR CAUSES
NEED TO BE INVESTIGATED

Asymptomatic or minimally symptomatic elevated CK can be due to a primary neuromuscular disease or a variety of nonneuromuscular causes.

Patients who still have elevated CK after taking into account the 97.5% threshold, repeat testing after a week of rest, and a level more than 1.5 times the upper limit of normal for sex and race should first be evaluated for the many nonneuromuscular conditions that can cause elevated CK (Table 1).7–9

Cardiac causes should be evaluated by history and physical examination, electrocardiography, and possibly testing for cardiac troponins.

Drugs commonly elevate CK

Prescription drugs and supplements are an important and common cause of CK elevation, so it is important to carefully review medications the patient is taking.

Statins can cause myalgia, muscle weakness, and rhabdomyolysis. Up to 5% of users develop CK elevation, typically 2 to 10 times the upper limit of normal.10 CK usually drops after stopping statins but may require weeks to months to normalize. Rarely, statin users develop a serious immune-mediated necrotizing myopathy.11–13

The diversity of response to statin therapy appears to have a genetic basis. The SEARCH Collaborative Group14 conducted a genome-wide association study of 300,000 markers in 85 patients with definite or incipient myopathy and in 90 controls, all of whom were taking simvastatin 80 mg daily. They identified a single-nucleotide polymorphism in the SLCO1B1 gene on chromosome 12 that was strongly associated with a higher risk of statin-induced myopathy.

Patients with statin-related myopathy seem to have a higher frequency of occult metabolic muscle disease than the general population, also suggesting genetic susceptibility, although ascertainment bias could be a factor.14

Mechanisms of CK elevation in response to statins include increased muscle membrane fragility due to decreased cholesterol content, inhibition of isoprenoid production (a necessary step in the synthesis of membrane proteins), and depletion of ubiquinone, leading to mitochondrial dysfunction.

 

 

Macro CK: An abnormal enzyme complex

About 4% of patients with asymptomatic or minimally symptomatic elevated CK have “macro CK,” an enzyme complex with an atypically high molecular mass and reduced clearance, resulting in abnormally high blood levels of CK. Macro CK type 1 is more common and is found in up to 1.2% of the general population: complexes are composed of CK and immunoglobulin and are associated with autoimmune diseases.9,15 Macro CK type 2 complexes consist of CK and an undetermined protein and are associated with malignancies.

CK electrophoresis is required to detect macro CK. Types 1 and 2 can be distinguished by protein G affinity chromatography.9,15 

Endocrine disorders

Muscle involvement in endocrine disorders often presents with muscle weakness in addition to muscle enzyme abnormalities.

Hypothyroidism often causes weakness, cramps, myalgia, and a mild to moderate serum CK elevation.16 Severe CK elevation has been reported to occur after vigorous exercise.17 Thyroid replacement usually results in normalization of serum CK levels in 1 to 2 months.18

Hyperthyroidism is typically associated with normal serum CK concentrations, but in rare cases it can cause rhabdomyolysis.19

NEUROMUSCULAR CAUSES ARE NOT ALWAYS WORTH PURSUING

Only after the nonneuromuscular causes of elevated CK have been ruled out should neuromuscular disorders be considered (Table 2). Evaluation with electromyography, nerve conduction studies, and muscle biopsy may lead to the diagnosis of a specific neuromuscular disorder: patients may be in the presymptomatic stage of disease and may or may not eventually develop muscle weakness or other symptoms.20,21

Is testing needed?

Most adult dystrophies and metabolic myopathies have no available treatment and their course is often benign, particularly if they present only with asymptomatic elevated CK. The value of a potentially extensive, expensive, and invasive evaluation for a specific neuromuscular cause should be weighed against the limited yield and treatment options. Moreover, specialized testing such as biochemical muscle enzyme analysis, sarcolemmal protein staining, and genetic testing are not available at all centers.

The European Federation of Neurological Societies guidelines recommend biopsy for  patients with asymptomatic elevated CK who also have any of the following:

  • Abnormal (myopathic) findings on electromyography
  • CK more than three times the upper limit of normal
  • Age less than 25
  • Exercise intolerance.4

Idiopathic inflammatory myopathies rarely present with asymptomatic elevated CK.22–26 In one study,27 they were found in just 5% of patients with asymptomatic elevated CK.

Hypomyopathic dermatomyositis and inclusion body myositis can present with mild CK elevations with normal muscle strength, especially early in the disease course. A myositis subset of antisynthetase syndrome can present with mildly elevated CK and interstitial lung disease.27 Many of the inflammatory myopathies respond to treatment so are worth investigating.

In view of complexities in diagnosis of these conditions, one should proceed with testing only after discussing it with patients. Referral to a rheumatology specialist is preferred.

MUSCLE BIOPSY, ELECTROMYOGRAPHY, AND NERVE CONDUCTION STUDIES

Electromyography, nerve conduction studies, or muscle biopsy, or a combination of these tests, is usually needed to investigate neuromuscular causes of elevated CK.

Muscle biopsy abnormalities are found in about two-thirds of cases of asymptomatic elevated CK, but most abnormalities include nonspecific myopathic changes that are not diagnostic. A muscle biopsy that may include special stains for sarcolemmal proteins for muscular dystrophy and biochemical muscle enzyme analysis for metabolic myopathies is diagnostic in only 20% to 25% cases of asymptomatic elevated CK on average, with a variation between different series of 0% to 79%.7,21,27–33

Electromyography and nerve conduction studies alone add little to the workup of asymp­tomatic elevated CK apart from a modest negative predictive value and as a guide for muscle biopsy. For a very few neuromuscular disorders causing an elevated CK (eg, motor neuron disease, Charcot-Marie-Tooth disease, myotonic dystrophy), electromyography and nerve conduction studies could suffice to make the diagnosis. 

Electromyography and nerve conduction studies detect abnormalities in nearly half of cases of asymptomatic CK elevation,7,21,27,28,30,31,33 but, as with biopsy, most changes are nonspecific. Although electromyography and nerve conduction studies can help distinguish primary neuropathic from myopathic disorders, the sensitivity and specificity are low for diagnosis. Normal studies do not rule out a condition, and abnormal studies are not diagnostic of a particular condition, although completely normal studies provide strong evidence against a severe neuromuscular disorder.

Combined testing

Using combined muscle biopsy, electromyography, and nerve conduction studies, the likelihood of making a diagnosis in patients with asymptomatic elevated CK is 28% on average (range of studies 4%–79%),2,7,21,26–28,30–32 and findings are nonspecific in 30% to 40% of cases. Findings are normal in about 30% to 40% of cases, which are thus diagnosed as idiopathic asymptomatic elevated CK.28–31,34

Prelle et al31 retrospectively reviewed the cases of 114 patients, ages 3 to 70, with incidentally discovered elevated CK and few or no symptoms, who underwent muscle biopsy, electromyography, and nerve conduction studies after nonneuromuscular causes were ruled out. Although muscle biopsy findings were abnormal in 39% of cases, a diagnosis was established in only 18% of cases after an extensive workup: the diagnosis was definitive in only 10% and included dystrophinopathies, metabolic myopathies, and rare noninflammatory myopathies. For the remaining 8%, the diagnosis was probable and included four cases of partial carnitine palmitoyl transferase deficiency, three cases of malignant hyperthermia, and two rare inherited disorders.

DNA testing

In women with a serum CK less than three times the upper limit of normal who have a family history of Duchenne or Becker muscular dystrophy, DNA analysis of blood lymphocytes identifies 70% of carriers.4

IDIOPATHIC ELEVATED SERUM CK

Rowland et al35 first coined the term “idiopathic hyper-CK-emia” and defined it as persistent elevation of serum CK despite a normal neurologic examination and testing, including electromyography, nerve conduction studies, and muscle biopsy.35,36 To receive this diagnosis, patients must also have no family history or clinical evidence of neuromuscular disease.

Idiopathic elevated serum CK is sometimes familial. In one study,37 elevated CK was found in family members of 13 of 28 unrelated probands. In the 13 families, 41 individuals had elevated CK. Genetic studies revealed that the condition is genetically heterogeneous and autosomal dominant in at least 60% of cases, with higher penetrance  in men.

D’Adda et al26 followed 55 people with idiopathic elevated CK for 7 years. Ten percent were eventually diagnosed with a neuromuscular disorder, 10% developed malignancy, and the remaining 80% developed no new condition. The CK level normalized or decreased in many patients, but most continued to have persistent CK elevations with minimal or no symptoms.

References
  1. Lev EI, Tur-Kaspa I, Ashkenazy I, et al. Distribution of serum creatine kinase activity in young healthy persons. Clin Chim Acta 1999; 279:107–115.
  2. Lilleng H, Abeler K, Johnsen SH, et al. Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study. Neuromuscul Disord 2011; 21:494–500.
  3. Brewster LM, Mairuhu G, Sturk A, van Montfrans GA. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J 2007; 154:655–661.
  4. Kyriakides T, Angelini C, Schaefer J, et al; European Federation of Neurological Societies. EFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia. Eur J Neurol 2010; 17:767–773.
  5. Prisant LM, Downton M, Watkins LO, et al. Efficacy and tolerability of lovastatin in 459 African-Americans with hypercholesterolemia. Am J Cardiol 1996; 78:420–444.
  6. Wong ET, Cobb C, Umehara MK, et al. Heterogeneity of serum creatine kinase activity among racial and gender groups of the population. Am J Clin Pathol 1983; 79:582–586.
  7. Brewster LM, de Visser M. Persistent hyperCKemia: fourteen patients studied in retrospect. Acta Neurol Scand 1988; 77:60–63.
  8. Weglinski MR, Wedel DJ, Engel AG. Malignant hyperthermia testing in patients with persistently increased serum creatine kinase levels. Anesth Analg 1997; 84:1038–1041.
  9. Galarraga B, Sinclair D, Fahie-Wilson MN, McCrae FC, Hull RG, Ledingham JM. A rare but important cause for a raised serum creatine kinase concentration: two case reports and a literature review. Rheumatology (Oxford) 2003; 42:186–188.
  10. Mancini GB, Tashakkor AY, Baker S, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol 2013; 29:1553–1568.
  11. Arora R, Liebo M, Maldonado F. Statin-induced myopathy: the two faces of Janus. J Cardiovasc Pharmacol Ther 2006; 11:105–112.
  12. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009; 150:858–868.
  13. Talbert RL. Safety issues with statin therapy. J Am Pharm Assoc (2003) 2006; 46:479–490.
  14. SEARCH Collaborative Group; Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 2008; 359:789–799.
  15. Wyness SP, Hunsaker JJ, La’ulu SL, Rao LV, Roberts WL. Detection of macro-creatine kinase and macroamylase by polyethylene glycol precipitation and ultrafiltration methods. Clin Chim Acta 2011; 412:2052–2057.
        
  16. Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000; 68:750–755.
  17. Riggs JE. Acute exertional rhabdomyolysis in hypothyroidism: the result of a reversible defect in glycogenolysis? Mil Med 1990; 155:171–172.
  18. Mastaglia FL, Ojeda VJ, Sarnat HB, Kakulas BA. Myopathies associated with hypothyroidism: a review based upon 13 cases. Aust N Z J Med 1988; 18:799–806.
  19. Alshanti M, Eledrisi MS, Jones E. Rhabdomyolysis associated with hyperthyroidism. Am J Emerg Med 2001; 19:317.
  20. Rosalki SB. Serum enzymes in disease of skeletal muscle. Clin Lab Med 1989; 9:767–781.
  21. Joy JL, Oh SJ. Asymptomatic hyper-CK-emia: an electrophysiologic and histopathologic study. Muscle Nerve 1989; 12:206–209.
  22. Merlini L, Sabatelli P, Columbaro M, et al. Hyper-CK-emia as the sole manifestation of myotonic dystrophy type 2. Muscle Nerve 2005; 31:764–767.
  23. Eeg-Olofsson O, Kalimo H, Eeg-Olofsson KE, et al. Duchenne muscular dystrophy and idiopathic hyperCKemia in the same family. Eur J Paediatr Neurol 2008; 12:404–407.
  24. Dwianingsih EK, Takeshima Y, Itoh K, et al. A Japanese child with asymptomatic elevation of serum creatine kinase shows PTRF-CAVIN mutation matching with congenital generalized lipodystrophy type 4. Mol Genet Metab 2010; 101:233–237.
  25. Carbone I, Bruno C, Sotgia F, et al. Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia. Neurology 2000; 54:1373–1376.
  26. D’Adda E, Sciacco M, Fruguglietti ME, et al. Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects. J Neurol 2006; 253:1399–1403.
  27. Fernandez C, de Paula AM, Figarella-Branger D, et al. Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Neurology 2006; 66:1585–1587.
  28. Simmons Z, Peterlin BL, Boyer PJ, Towfighi J. Muscle biopsy in the evaluation of patients with modestly elevated creatine kinase levels. Muscle Nerve 2003; 27:242–244.
  29. Filosto M, Tonin P, Vattemi G, et al. The role of muscle biopsy in investigating isolated muscle pain. Neurology 2007; 68:181–186.
  30. Malandrini A, Orrico A, Gaudiano C, et al. Muscle biopsy and in vitro contracture test in subjects with idiopathic hyperCKemia. Anesthesiology 2008; 109:625–628.
  31. Prelle A, Tancredi L, Sciacco M, et al. Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels. J Neurol 2002; 249:305–311.
  32. Dabby R, Sadeh M, Herman O, et al. Asymptomatic or minimally symptomatic hyperCKemia: histopathologic correlates. Isr Med Assoc J 2006; 8:110–113.
  33. Reijneveld JC, Notermans NC, Linssen WH, Wokke JH. Benign prognosis in idiopathic hyper-CK-emia. Muscle Nerve 2000; 23:575–579.
  34. Restivo DA, Pavone V, Nicotra A. Single-fiber electromyography in hyperCKemia: the value of fiber density. Neurol Sci 2012; 33:819–824.
  35. Rowland LP, Willner J, Cerri C, DiMauro S, Miranda A. Approaches to the membrane theory of Duchenne muscular dystrophy. In: Angelini C, Danielli GA, Fontanari D, editors. Muscular Dystrophy Research: Advances and New Trends, Amsterdam: Excerpta Medica; 1980:3–13.
  36. Reijneveld JC, Notermans NC, Linssen WH, Bär PR, Wokke JH. Hyper-CK-aemia revisited. Neuromuscul Disord 2001; 11:163–164.
  37. Capasso M, De Angelis MV, Di Muzio A, et al. Familial idiopathic hyper-CK-emia: an underrecognized condition. Muscle Nerve 2006; 33:760–765.
References
  1. Lev EI, Tur-Kaspa I, Ashkenazy I, et al. Distribution of serum creatine kinase activity in young healthy persons. Clin Chim Acta 1999; 279:107–115.
  2. Lilleng H, Abeler K, Johnsen SH, et al. Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study. Neuromuscul Disord 2011; 21:494–500.
  3. Brewster LM, Mairuhu G, Sturk A, van Montfrans GA. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J 2007; 154:655–661.
  4. Kyriakides T, Angelini C, Schaefer J, et al; European Federation of Neurological Societies. EFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia. Eur J Neurol 2010; 17:767–773.
  5. Prisant LM, Downton M, Watkins LO, et al. Efficacy and tolerability of lovastatin in 459 African-Americans with hypercholesterolemia. Am J Cardiol 1996; 78:420–444.
  6. Wong ET, Cobb C, Umehara MK, et al. Heterogeneity of serum creatine kinase activity among racial and gender groups of the population. Am J Clin Pathol 1983; 79:582–586.
  7. Brewster LM, de Visser M. Persistent hyperCKemia: fourteen patients studied in retrospect. Acta Neurol Scand 1988; 77:60–63.
  8. Weglinski MR, Wedel DJ, Engel AG. Malignant hyperthermia testing in patients with persistently increased serum creatine kinase levels. Anesth Analg 1997; 84:1038–1041.
  9. Galarraga B, Sinclair D, Fahie-Wilson MN, McCrae FC, Hull RG, Ledingham JM. A rare but important cause for a raised serum creatine kinase concentration: two case reports and a literature review. Rheumatology (Oxford) 2003; 42:186–188.
  10. Mancini GB, Tashakkor AY, Baker S, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol 2013; 29:1553–1568.
  11. Arora R, Liebo M, Maldonado F. Statin-induced myopathy: the two faces of Janus. J Cardiovasc Pharmacol Ther 2006; 11:105–112.
  12. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009; 150:858–868.
  13. Talbert RL. Safety issues with statin therapy. J Am Pharm Assoc (2003) 2006; 46:479–490.
  14. SEARCH Collaborative Group; Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 2008; 359:789–799.
  15. Wyness SP, Hunsaker JJ, La’ulu SL, Rao LV, Roberts WL. Detection of macro-creatine kinase and macroamylase by polyethylene glycol precipitation and ultrafiltration methods. Clin Chim Acta 2011; 412:2052–2057.
        
  16. Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000; 68:750–755.
  17. Riggs JE. Acute exertional rhabdomyolysis in hypothyroidism: the result of a reversible defect in glycogenolysis? Mil Med 1990; 155:171–172.
  18. Mastaglia FL, Ojeda VJ, Sarnat HB, Kakulas BA. Myopathies associated with hypothyroidism: a review based upon 13 cases. Aust N Z J Med 1988; 18:799–806.
  19. Alshanti M, Eledrisi MS, Jones E. Rhabdomyolysis associated with hyperthyroidism. Am J Emerg Med 2001; 19:317.
  20. Rosalki SB. Serum enzymes in disease of skeletal muscle. Clin Lab Med 1989; 9:767–781.
  21. Joy JL, Oh SJ. Asymptomatic hyper-CK-emia: an electrophysiologic and histopathologic study. Muscle Nerve 1989; 12:206–209.
  22. Merlini L, Sabatelli P, Columbaro M, et al. Hyper-CK-emia as the sole manifestation of myotonic dystrophy type 2. Muscle Nerve 2005; 31:764–767.
  23. Eeg-Olofsson O, Kalimo H, Eeg-Olofsson KE, et al. Duchenne muscular dystrophy and idiopathic hyperCKemia in the same family. Eur J Paediatr Neurol 2008; 12:404–407.
  24. Dwianingsih EK, Takeshima Y, Itoh K, et al. A Japanese child with asymptomatic elevation of serum creatine kinase shows PTRF-CAVIN mutation matching with congenital generalized lipodystrophy type 4. Mol Genet Metab 2010; 101:233–237.
  25. Carbone I, Bruno C, Sotgia F, et al. Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia. Neurology 2000; 54:1373–1376.
  26. D’Adda E, Sciacco M, Fruguglietti ME, et al. Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects. J Neurol 2006; 253:1399–1403.
  27. Fernandez C, de Paula AM, Figarella-Branger D, et al. Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Neurology 2006; 66:1585–1587.
  28. Simmons Z, Peterlin BL, Boyer PJ, Towfighi J. Muscle biopsy in the evaluation of patients with modestly elevated creatine kinase levels. Muscle Nerve 2003; 27:242–244.
  29. Filosto M, Tonin P, Vattemi G, et al. The role of muscle biopsy in investigating isolated muscle pain. Neurology 2007; 68:181–186.
  30. Malandrini A, Orrico A, Gaudiano C, et al. Muscle biopsy and in vitro contracture test in subjects with idiopathic hyperCKemia. Anesthesiology 2008; 109:625–628.
  31. Prelle A, Tancredi L, Sciacco M, et al. Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels. J Neurol 2002; 249:305–311.
  32. Dabby R, Sadeh M, Herman O, et al. Asymptomatic or minimally symptomatic hyperCKemia: histopathologic correlates. Isr Med Assoc J 2006; 8:110–113.
  33. Reijneveld JC, Notermans NC, Linssen WH, Wokke JH. Benign prognosis in idiopathic hyper-CK-emia. Muscle Nerve 2000; 23:575–579.
  34. Restivo DA, Pavone V, Nicotra A. Single-fiber electromyography in hyperCKemia: the value of fiber density. Neurol Sci 2012; 33:819–824.
  35. Rowland LP, Willner J, Cerri C, DiMauro S, Miranda A. Approaches to the membrane theory of Duchenne muscular dystrophy. In: Angelini C, Danielli GA, Fontanari D, editors. Muscular Dystrophy Research: Advances and New Trends, Amsterdam: Excerpta Medica; 1980:3–13.
  36. Reijneveld JC, Notermans NC, Linssen WH, Bär PR, Wokke JH. Hyper-CK-aemia revisited. Neuromuscul Disord 2001; 11:163–164.
  37. Capasso M, De Angelis MV, Di Muzio A, et al. Familial idiopathic hyper-CK-emia: an underrecognized condition. Muscle Nerve 2006; 33:760–765.
Issue
Cleveland Clinic Journal of Medicine - 83(1)
Issue
Cleveland Clinic Journal of Medicine - 83(1)
Page Number
37-42
Page Number
37-42
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Cleveland Clinic Journal of Medicine
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Cleveland Clinic Journal of Medicine
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Cardiology
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Rheumatology
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Endocrinology
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Approach to asymptomatic creatine kinase elevation
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Approach to asymptomatic creatine kinase elevation
Legacy Keywords
creatine kinase, CK, hyperCKemia, myopathy, incidental finding, Siamak Moghadam-Kia, Chester Oddis, Rohit Aggarwal
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creatine kinase, CK, hyperCKemia, myopathy, incidental finding, Siamak Moghadam-Kia, Chester Oddis, Rohit Aggarwal
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KEY POINTS

  • Standard reference ranges for serum CK levels used by most laboratories are too low and lead to overdiagnosis of abnormal values.
  • Serum CK levels are strongly affected by race, sex, and physical activity.
  • A patient with truly elevated levels should be evaluated for a variety of nonneuromuscular causes, including endocrine disorders, metabolic disturbances, drug effects, and malignancy.
  • Neuromuscular causes should be investigated only after ruling out nonneuromuscular causes and after considering whether potential benefits of a diagnosis outweigh the risks and expense of extensive testing.
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