William D. Carey, MD

In Reply: We thank Dr. Homler for bringing hepatitis D as a potential cause of acute liver failure to our attention.

Hepatitis D virus, first described in the 1970s, requires the hepatitis B surface antigen (HBsAg) capsid to enter the hepatocyte and, thus, can only cause liver injury when the patient is also infected simultaneously with hepatitis B virus.¹ Hepatitis D virus can cause either coinfection (presence of immunoglobulin M anti-HB core antibody with or without HBsAg) or superinfection (presence of HBsAg without immunoglobulin M anti-HB core antibody) with hepatitis B virus. In India, coinfection has been reported to be the cause of acute liver failure in about 4% of all patients, and superinfection in 4.5%.²

While simultaneous treatment for hepatitis D and B viruses with pegylated interferon and any of the agents used for treatment of hepatitis B has been successful in treating chronic hepatitis, it has not been proven useful in patients with acute liver failure, and liver transplant remains the only treatment option.³

In Reply: We thank Dr. Homler for bringing hepatitis D as a potential cause of acute liver failure to our attention.

Hepatitis D virus, first described in the 1970s, requires the hepatitis B surface antigen (HBsAg) capsid to enter the hepatocyte and, thus, can only cause liver injury when the patient is also infected simultaneously with hepatitis B virus.¹ Hepatitis D virus can cause either coinfection (presence of immunoglobulin M anti-HB core antibody with or without HBsAg) or superinfection (presence of HBsAg without immunoglobulin M anti-HB core antibody) with hepatitis B virus. In India, coinfection has been reported to be the cause of acute liver failure in about 4% of all patients, and superinfection in 4.5%.²

While simultaneous treatment for hepatitis D and B viruses with pegylated interferon and any of the agents used for treatment of hepatitis B has been successful in treating chronic hepatitis, it has not been proven useful in patients with acute liver failure, and liver transplant remains the only treatment option.³

In Reply: We thank Dr. Homler for bringing hepatitis D as a potential cause of acute liver failure to our attention.

Hepatitis D virus, first described in the 1970s, requires the hepatitis B surface antigen (HBsAg) capsid to enter the hepatocyte and, thus, can only cause liver injury when the patient is also infected simultaneously with hepatitis B virus.¹ Hepatitis D virus can cause either coinfection (presence of immunoglobulin M anti-HB core antibody with or without HBsAg) or superinfection (presence of HBsAg without immunoglobulin M anti-HB core antibody) with hepatitis B virus. In India, coinfection has been reported to be the cause of acute liver failure in about 4% of all patients, and superinfection in 4.5%.²

While simultaneous treatment for hepatitis D and B viruses with pegylated interferon and any of the agents used for treatment of hepatitis B has been successful in treating chronic hepatitis, it has not been proven useful in patients with acute liver failure, and liver transplant remains the only treatment option.³

When the liver fails, it usually fails gradually. The sudden (acute) onset of liver failure, while less common, demands prompt management, with transfer to an intensive care unit, specific treatment depending on the cause, and consideration of liver transplant, without which the mortality rate is high.

This article reviews the definition, epidemiology, etiology, and management of acute liver failure.

DEFINITIONS

Acute liver failure is defined as a syndrome of acute hepatitis with evidence of abnormal coagulation (eg, an international normalized ratio > 1.5) complicated by the development of mental alteration (encephalopathy) within 26 weeks of the onset of illness in a patient without a history of liver disease.¹ In general, patients have no evidence of underlying chronic liver disease, but there are exceptions; patients with Wilson disease, vertically acquired hepatitis B virus infection, or autoimmune hepatitis can present with acute liver failure superimposed on chronic liver disease or even cirrhosis.

The term acute liver failure has replaced older terms such as fulminant hepatic failure, hyperacute liver failure, and subacute liver failure, which were used for prognostic purposes. Patients with hyperacute liver failure (defined as development of encephalopathy within 7 days of onset of illness) generally have a good prognosis with medical management, whereas those with subacute liver failure (defined as development of encephalopathy within 5 to 26 weeks of onset of illness) have a poor prognosis without liver transplant.^2,3

NEARLY 2,000 CASES A YEAR

There are nearly 2,000 cases of acute liver failure each year in the United States, and it accounts for 6% of all deaths due to liver disease.⁴ It is more common in women than in men, and more common in white people than in other races. The peak incidence is at a fairly young age, ie, 35 to 45 years.

CAUSES

The most common cause of acute liver failure in the United States and other Western countries is acetaminophen toxicity, followed by viral hepatitis. In contrast, viral hepatitis is the most common cause in developing countries.⁵

Acetaminophen toxicity

Patients with acetaminophen-induced liver failure tend to be younger than other patients with acute liver failure.¹ Nearly half of them present after intentionally taking a single large dose, while the rest present with unintentional toxicity while taking acetaminophen for pain relief on a long-term basis and ingesting more than the recommended dose.⁶

After ingestion, 52% to 57% of acetaminophen is converted to glucuronide conjugates, and 30% to 44% is converted to sulfate conjugates. These compounds are nontoxic, water-soluble, and rapidly excreted in the urine.

However, about 5% to 10% of ingested acetaminophen is shunted to the cytochrome P450 system. P450 2E1 is the main isoenzyme involved in acetaminophen metabolism, but 1A2, 3A4, and 2A6 also contribute.^7,8 P450 2E1 is the same isoenzyme responsible for ethanol metabolism and is inducible. Thus, regular alcohol consumption can increase P450 2E1 activity, setting the stage under certain circumstances for increased acetaminophen metabolism through this pathway.

Reprinted from Schilling A, Corey R, Leonard M, Eghtesad B. Acetaminophen: old drug, new warnings. Cleve Clin J Med 2010; 77:19–27.

Metabolism of acetaminophen through the cytochrome P450 pathway results in production of N-acetyl-p-benzoquinone imine (NAPQI), the compound that damages the liver. NAPQI is rendered nontoxic by binding to glutathione, forming NAPQI-glutathione adducts. Glutathione capacity is limited, however. With too much acetaminophen, glutathione becomes depleted and NAPQI accumulates, binds with proteins to form adducts, and leads to necrosis of hepatocytes (Figure 1).^9,10

Acetylcysteine, used in treating acetaminophen toxicity, is a substrate for glutathione synthesis and ultimately increases the amount of glutathione available to bind NAPQI and prevent damage to hepatocytes.¹¹

Acetaminophen is a dose-related toxin. Most ingestions leading to acute liver failure exceed 10 g/day (> 150 mg/kg/day). Moderate chronic ingestion, eg, 4 g/day, usually leads to transient mild elevation of liver enzymes in healthy individuals¹² but can in rare cases cause acute liver failure.¹³

Whitcomb and Block¹⁴ retrospectively identified 49 patients who presented with acetaminophen-induced hepatotoxicity in 1987 through 1993; 21 (43%) had been taking acetaminophen for therapeutic purposes. All 49 patients took more than the recommended limit of 4 g/day, many of them while fasting and some while using alcohol. Acute liver failure was seen with ingestion of more than 12 g/day—or more than 10 g/day in alcohol users. The authors attributed the increased risk to activation of cytochrome P450 2E1 by alcohol and depletion of glutathione stores by starvation or alcohol abuse. 

Advice to patients taking acetaminophen is given in Table 1.

Other drugs and supplements

A number of other drugs and herbal supplements can also cause acute liver failure (Table 2), the most common being antimicrobial and antiepileptic drugs.¹⁵ Of the antimicrobials, antitubercular drugs (especially isoniazid) are believed to be the most common causes, followed by trimethoprim-sulfamethoxazole. Phenytoin is the antiepileptic drug most often implicated in acute liver failure.

Statins can also cause acute liver failure, especially when combined with other hepatotoxic agents.¹⁶

The herbal supplements and weight-loss agents Hydroxycut and Herbalife have both been reported to cause acute liver failure, with patients presenting with either the hepatocellular or the cholestatic pattern of liver injury.¹⁷ The exact chemical in these supplements that causes liver injury has not yet been determined.

The National Institutes of Health maintains a database of cases of liver failure due to medications and supplements at livertox.nih.gov. The database includes the pattern of hepatic injury, mechanism of injury, management, and outcomes.

Viral hepatitis

Hepatitis B virus is the most common viral cause of acute liver failure and is responsible for about 8% of cases.¹⁸

Patients with chronic hepatitis B virus infection—as evidenced by positive hepatitis B surface antigen—can develop acute liver failure if the infection is reactivated by the use of immunosuppressive drugs for solid-organ or bone-marrow transplant or medications such as anti-tumor necrosis agents, rituximab, or chemotherapy. These patients should be treated prophylactically with a nucleoside analogue, which should be continued for 6 months after immunosuppressive therapy is completed.

Hepatitis A virus is responsible for about 4% of cases.¹⁸

Hepatitis C virus rarely causes acute liver failure, especially in the absence of hepatitis A and hepatitis B.^3,19

Hepatitis E virus, which is endemic in areas of Asia and Africa, can cause liver disease in pregnant women and in young adults who have concomitant liver disease from another cause. It tends to cause acute liver failure more frequently in pregnant women than in the rest of the population and carries a mortality rate of more than 20% in this subgroup.

TT (transfusion-transmitted) virus was reported in the 1990s to cause acute liver failure in about 27% of patients in whom no other cause could be found.²⁰

Other rare viral causes of acute liver failure include Epstein-Barr virus, cytomegalovirus, and herpes simplex virus types 1, 2, and 6.

Other causes

Other causes of acute liver failure include ischemic hepatitis, autoimmune hepatitis, Wilson disease, Budd-Chiari syndrome, and HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome.

MANY PATIENTS NEED LIVER TRANSPLANT

Many patients with acute liver failure ultimately require orthotopic liver transplant,²¹ especially if they present with severe encephalopathy. Other aspects of treatment vary according to the cause of liver failure (Table 3).

SPECIFIC MANAGEMENT

Management of acetaminophen toxicity

If the time of ingestion is known, checking the acetaminophen level can help determine the cause of acute liver failure and also predict the risk of hepatotoxicity, based on the work of Rumack and Matthew.²² Calculators are available, eg, http://reference.medscape.com/calculator/acetaminophen-toxicity.

If a patient presents with acute liver failure several days after ingesting acetaminophen, the level can be in the nontoxic range, however. In this scenario, measuring acetaminophen-protein adducts can help establish acetaminophen toxicity as the cause, as the adducts last longer in the serum and provide 100% sensitivity and specificity.²³ While most laboratories can rapidly measure acetaminophen levels, only a few can measure acetaminophen-protein adducts, and thus this test is not used clinically.

Acetylcysteine is the main drug used for acetaminophen toxicity. Ideally, it should be given within 8 hours of acetaminophen ingestion, but giving it later is also useful.¹

Acetylcysteine is available in oral and intravenous forms, the latter for patients who have encephalopathy or cannot tolerate oral intake due to repeated episodes of vomiting.^24,25 The oral form is much less costly and is thus preferred over intravenous acetylcysteine in patients who can tolerate oral intake. Intravenous acetylcysteine should be given in a loading dose of 150 mg/kg in 5% dextrose over 15 minutes, followed by a maintenance dose of 50 mg/kg over 4 hours and then 100 mg/kg given over 16 hours.¹ No dose adjustment is needed in patients who have renal toxicity (acetaminophen can also be toxic to the kidneys).

Most patients with acetaminophen-induced liver failure survive with medical management alone and do not need a liver transplant.^3,26 Cirrhosis does not occur in these patients.

Management of viral acute liver failure

When patients present with acute liver failure, it is necessary to look for a viral cause by serologic testing, including hepatitis A virus IgM antibody, hepatitis B surface antigen, and hepatitis B core IgM antibody.

Hepatitis B can become reactivated in immunocompromised patients, and therefore the hepatitis B virus DNA level should be checked. Detection of hepatitis B virus DNA in a patient previously known to have undetectable hepatitis B virus DNA confirms hepatitis B reactivation.

Patients with hepatitis B-induced acute liver failure should be treated with entecavir or tenofovir. Although this treatment may not change the course of acute liver failure or accelerate the recovery, it can prevent reinfection in the transplanted liver if liver transplant becomes indicated.^27–29

Herpes simplex virus should be suspected in patients presenting with anicteric hepatitis with fever. Polymerase chain reaction testing for herpes simplex virus should be done,³⁰ and if positive, patients should be given intravenous acyclovir.³¹ Despite treatment, herpes simplex virus disease is associated with a very poor prognosis without liver transplant.

Autoimmune hepatitis

The autoantibodies usually seen in autoimmune hepatitis are antinuclear antibody, antismooth muscle antibody, and anti-liver-kidney microsomal antibody, and patients need to be tested for them.

The diagnosis of autoimmune hepatitis can be challenging, as these autoimmune markers can be negative in 5% of patients. Liver biopsy becomes essential to establish the diagnosis in that setting.³²

Guidelines advise starting prednisone 40 to 60 mg/day and placing the patient on the liver transplant list.¹

Wilson disease

Although it is an uncommon cause of liver failure, Wilson disease needs special attention because it has a poor prognosis. The mortality rate in acute liver failure from Wilson disease reaches 100% without liver transplant.

Wilson disease is caused by a genetic defect that allows copper to accumulate in the liver and other organs. However, diagnosing Wilson disease as the cause of acute liver failure can be challenging because elevated serum and urine copper levels are not specific to Wilson disease and can be seen in patients with acute liver failure from any cause. In addition, the ceruloplasmin level is usually normal or high because it is an acute-phase reactant. Accumulation of copper in the liver parenchyma is usually patchy; therefore, qualitative copper staining on random liver biopsy samples provides low diagnostic yield. Quantitative copper on liver biopsy is the gold standard test to establish the diagnosis, but the test is time-consuming. Kayser-Fleischer rings around the iris are considered pathognomic for Wilson disease when seen with acute liver failure, but they are seen in only about 50% of patients.³³

A unique feature of acute Wilson disease is that most patients have very high bilirubin levels and low alkaline phosphatase levels. An alkaline phosphatase-to-bilirubin ratio less than 2 in patients with acute liver failure is highly suggestive of Wilson disease.³⁴

Another clue to the diagnosis is that patients with Wilson disease tend to develop Coombs-negative hemolytic anemia, which leads to a disproportionate elevation in aminotransferase levels, with aspartate aminotransferase being higher than alanine aminotransferase.

Once Wilson disease is suspected, the patient should be listed for liver transplant because death is almost certain without it. For patients awaiting liver transplant, the American Association for the Study of Liver Diseases guidelines recommend certain measures to lower the serum copper level such as albumin dialysis, continuous hemofiltration, plasmapheresis, and plasma exchange,¹ but the evidence supporting their use is limited.

NONSPECIFIC MANAGEMENT

Acute liver failure can affect a number of organs and systems in addition to the liver (Figure 2).

General considerations

Because their condition can rapidly deteriorate, patients with acute liver failure are best managed in intensive care.

Patients who present to a center that does not have the facilities for liver transplant should be transferred to a transplant center as soon as possible, preferably by air. If the patient may not be able to protect the airway, endotracheal intubation should be performed before transfer.

The major causes of death in patients with acute liver failure are cerebral edema and infection. Gastrointestinal bleeding was a major cause of death in the past, but with prophylactic use of histamine H₂ receptor blockers and proton pump inhibitors, the incidence of gastrointestinal bleeding has been significantly reduced.

Although initially used only in patients with acetaminophen-induced liver failure, acetylcysteine has also shown benefit in patients with acute liver failure from other causes. In patients with grade 1 or 2 encephalopathy on a scale of 0 (minimal) to 4 (comatose), the transplant-free survival rate is higher when acetylcysteine is given compared with placebo, but this benefit does not extend to patients with a higher grade of encephalopathy.³⁵

Cerebral edema and intracranial hypertension

Cerebral edema is the leading cause of death in patients with acute liver failure, and it develops in nearly 40% of patients.³⁶

The mechanism by which cerebral edema develops is not well understood. Some have proposed that ammonia is converted to glutamine, which causes cerebral edema either directly by its osmotic effect^37,38 or indirectly by decreasing other osmolytes, thereby promoting water retention.³⁹

Cerebral edema leads to intracranial hypertension, which can ultimately cause cerebral herniation and death. Because of the high mortality rate associated with cerebral edema, invasive devices were extensively used in the past to monitor intracranial pressure. However, in light of known complications of these devices, including bleeding,⁴⁰ and lack of evidence of long-term benefit in terms of mortality rates, their use has come under debate.

Treatments. Many treatments are available for cerebral edema and intracranial hypertension. The first step is to elevate the head of the bed about 30 degrees. In addition, hyponatremia should be corrected, as it can worsen cerebral edema.⁴¹ If patients are intubated, maintaining a hypercapneic state is advisable to decrease the intracranial pressure.

Of the two pharmacologic options, mannitol is more often used.⁴² It is given as a bolus dose of 0.5 to 1 g/kg intravenously if the serum osmolality is less than 320 mOsm/L.¹ Given the risk of fluid overload with mannitol, caution must be exercised in patients with renal dysfunction. The other pharmacologic option is 3% hypertonic saline.

Therapeutic hypothermia is a newer treatment for cerebral edema. Lowering the body temperature to 32 to 33°C (89.6 to 91.4°F) using cooling blankets decreases intracranial pressure and cerebral blood flow and improves the cerebral perfusion pressure.⁴³ With this treatment, patients should be closely monitored for side effects of infection, coagulopathy, and cardiac arrythmias.¹

l-ornithine l-aspartate was successfully used to prevent brain edema in rats, but in humans, no benefit was seen compared with placebo.^44,45 The underlying basis for this experimental treatment is that supplemental ornithine and aspartate should increase glutamate synthesis, which should increase the activity of enzyme glutamine synthetase in skeletal muscles. With the increase in enzyme activity, conversion of ammonia to glutamine should increase, thereby decreasing ammonia circulation and thus decreasing cerebral edema.

Patients with cerebral edema have a high incidence of seizures, but prophylactic antiseizure medications such as phenytoin have not been proven to be beneficial.⁴⁶

Infection

Nearly 80% of patients with acute liver failure develop an infectious complication, which can be attributed to a state of immunodeficiency.⁴⁷

The respiratory and urinary tracts are the most common sources of infection.⁴⁸ In patients with bacteremia, Enterococcus species and coagulase-negative Staphylococcus species⁴⁹ are the commonly isolated organisms. Also, in patients with acute liver failure, fungal infections account for 30% of all infections.⁵⁰

Infected patients often develop worsening of their encephalopathy⁵¹ without fever or elevated white blood cell count.^49,52 Thus, in any patient in whom encephalopathy is worsening, an evaluation must be done to rule out infection. In these patients, systemic inflammatory response syndrome is an independent risk factor for death.⁵³

Despite the high mortality rate with infection, whether using antibiotics prophylactically in acute liver failure is beneficial is controversial.^54,55

Gastrointestinal bleeding

The current prevalence of upper gastrointestinal bleeding in acute liver failure patients is about 1.5%.⁵⁶ Coagulopathy and endotracheal intubation are the main risk factors for upper gastrointestinal bleeding in these patients.⁵⁷ The most common source of bleeding is stress ulcers in the stomach. The ulcers develop from a combination of factors, including decreased blood flow to the mucosa causing ischemia and hypoperfusion-reperfusion injury.

Pharmacologic inhibition of gastric acid secretion has been shown to reduce upper gastrointestinal bleeding in acute liver failure. A histamine H₂ receptor blocker or proton pump inhibitor should be given to prevent gastrointestinal bleeding in patients with acute liver failure.^1,58

EXPERIMENTAL TREATMENTS

Artificial liver support systems

Membranes and dialysate solutions have been developed to remove toxic substances that are normally metabolized by the liver. Two of these—the molecular adsorbent recycling system (MARS) and the extracorporeal liver assist device (ELAD)—were developed in the late 1990s. MARS consisted of a highly permeable hollow fiber membrane mixed with albumin, and ELAD consisted of porcine hepatocytes attached to microcarriers in the extracapillary space of the hollow fiber membrane. Both systems allowed for transfer of water-soluble and protein-bound toxins in the blood across the membrane and into the dialysate.⁵⁹ The clinical benefit offered by these devices is controversial,^60–62 thus limiting their use to experimental purposes only.

Hepatocyte transplant

Use of hepatocyte transplant as a bridge to liver transplant was tested in 1970s, first in rats and later in humans.⁶³ By reducing the blood ammonia level and improving cerebral perfusion pressure and cardiac function, replacement of 1% to 2% of the total liver cell mass by transplanted hepatocytes acts as a bridge to orthotopic liver transplant.^64,65

PROGNOSIS

Different criteria have been used to identify patients with poor prognosis who may eventually need to undergo liver transplant.

The King’s College criteria system is the most commonly used for prognosis (Table 4).^37,66–69 Its main drawback is that it is applicable only in patients with encephalopathy, and when patients reach this stage, their condition often deteriorates rapidly, and they die while awaiting liver transplant.^37,66,67

The Model for End-Stage Liver Disease (MELD) score is an alternative to the King’s College criteria. A high MELD score on admission signifies advanced disease, and patients with a high MELD score tend to have a worse prognosis than those with a low score.⁶⁸

The Acute Physiology and Chronic Health Evaluation (APACHE) II score can also be used, as it is more sensitive than the King’s College criteria.⁶

The Clichy criteria^66,69 can also be used.

Liver biopsy. In addition to helping establish the cause of acute liver failure, liver biopsy can also be used as a prognostic tool. Hepatocellular necrosis greater than 70% on the biopsy predicts death with a specificity of 90% and a sensitivity of 56%.⁷⁰

Hypophosphatemia has been reported to indicate recovering liver function in patients with acute liver failure.⁷¹ As the liver regenerates, its energy requirement increases. To supply the energy, adenosine triphosphate production increases, and phosphorus shifts from the extracellular to the intracellular compartment to meet the need for extra phosphorus during this process. A serum phosphorus level of 2.9 mg/dL or higher appears to indicate a poor prognosis in patients with acute liver failure, as it signifies that adequate hepatocyte regeneration is not occurring.

When the liver fails, it usually fails gradually. The sudden (acute) onset of liver failure, while less common, demands prompt management, with transfer to an intensive care unit, specific treatment depending on the cause, and consideration of liver transplant, without which the mortality rate is high.

This article reviews the definition, epidemiology, etiology, and management of acute liver failure.

DEFINITIONS

Acute liver failure is defined as a syndrome of acute hepatitis with evidence of abnormal coagulation (eg, an international normalized ratio > 1.5) complicated by the development of mental alteration (encephalopathy) within 26 weeks of the onset of illness in a patient without a history of liver disease.¹ In general, patients have no evidence of underlying chronic liver disease, but there are exceptions; patients with Wilson disease, vertically acquired hepatitis B virus infection, or autoimmune hepatitis can present with acute liver failure superimposed on chronic liver disease or even cirrhosis.

The term acute liver failure has replaced older terms such as fulminant hepatic failure, hyperacute liver failure, and subacute liver failure, which were used for prognostic purposes. Patients with hyperacute liver failure (defined as development of encephalopathy within 7 days of onset of illness) generally have a good prognosis with medical management, whereas those with subacute liver failure (defined as development of encephalopathy within 5 to 26 weeks of onset of illness) have a poor prognosis without liver transplant.^2,3

NEARLY 2,000 CASES A YEAR

There are nearly 2,000 cases of acute liver failure each year in the United States, and it accounts for 6% of all deaths due to liver disease.⁴ It is more common in women than in men, and more common in white people than in other races. The peak incidence is at a fairly young age, ie, 35 to 45 years.

CAUSES

The most common cause of acute liver failure in the United States and other Western countries is acetaminophen toxicity, followed by viral hepatitis. In contrast, viral hepatitis is the most common cause in developing countries.⁵

Acetaminophen toxicity

Patients with acetaminophen-induced liver failure tend to be younger than other patients with acute liver failure.¹ Nearly half of them present after intentionally taking a single large dose, while the rest present with unintentional toxicity while taking acetaminophen for pain relief on a long-term basis and ingesting more than the recommended dose.⁶

After ingestion, 52% to 57% of acetaminophen is converted to glucuronide conjugates, and 30% to 44% is converted to sulfate conjugates. These compounds are nontoxic, water-soluble, and rapidly excreted in the urine.

However, about 5% to 10% of ingested acetaminophen is shunted to the cytochrome P450 system. P450 2E1 is the main isoenzyme involved in acetaminophen metabolism, but 1A2, 3A4, and 2A6 also contribute.^7,8 P450 2E1 is the same isoenzyme responsible for ethanol metabolism and is inducible. Thus, regular alcohol consumption can increase P450 2E1 activity, setting the stage under certain circumstances for increased acetaminophen metabolism through this pathway.

Reprinted from Schilling A, Corey R, Leonard M, Eghtesad B. Acetaminophen: old drug, new warnings. Cleve Clin J Med 2010; 77:19–27.

Metabolism of acetaminophen through the cytochrome P450 pathway results in production of N-acetyl-p-benzoquinone imine (NAPQI), the compound that damages the liver. NAPQI is rendered nontoxic by binding to glutathione, forming NAPQI-glutathione adducts. Glutathione capacity is limited, however. With too much acetaminophen, glutathione becomes depleted and NAPQI accumulates, binds with proteins to form adducts, and leads to necrosis of hepatocytes (Figure 1).^9,10

Acetylcysteine, used in treating acetaminophen toxicity, is a substrate for glutathione synthesis and ultimately increases the amount of glutathione available to bind NAPQI and prevent damage to hepatocytes.¹¹

Acetaminophen is a dose-related toxin. Most ingestions leading to acute liver failure exceed 10 g/day (> 150 mg/kg/day). Moderate chronic ingestion, eg, 4 g/day, usually leads to transient mild elevation of liver enzymes in healthy individuals¹² but can in rare cases cause acute liver failure.¹³

Whitcomb and Block¹⁴ retrospectively identified 49 patients who presented with acetaminophen-induced hepatotoxicity in 1987 through 1993; 21 (43%) had been taking acetaminophen for therapeutic purposes. All 49 patients took more than the recommended limit of 4 g/day, many of them while fasting and some while using alcohol. Acute liver failure was seen with ingestion of more than 12 g/day—or more than 10 g/day in alcohol users. The authors attributed the increased risk to activation of cytochrome P450 2E1 by alcohol and depletion of glutathione stores by starvation or alcohol abuse. 

Advice to patients taking acetaminophen is given in Table 1.

Other drugs and supplements

A number of other drugs and herbal supplements can also cause acute liver failure (Table 2), the most common being antimicrobial and antiepileptic drugs.¹⁵ Of the antimicrobials, antitubercular drugs (especially isoniazid) are believed to be the most common causes, followed by trimethoprim-sulfamethoxazole. Phenytoin is the antiepileptic drug most often implicated in acute liver failure.

Statins can also cause acute liver failure, especially when combined with other hepatotoxic agents.¹⁶

The herbal supplements and weight-loss agents Hydroxycut and Herbalife have both been reported to cause acute liver failure, with patients presenting with either the hepatocellular or the cholestatic pattern of liver injury.¹⁷ The exact chemical in these supplements that causes liver injury has not yet been determined.

The National Institutes of Health maintains a database of cases of liver failure due to medications and supplements at livertox.nih.gov. The database includes the pattern of hepatic injury, mechanism of injury, management, and outcomes.

Viral hepatitis

Hepatitis B virus is the most common viral cause of acute liver failure and is responsible for about 8% of cases.¹⁸

Patients with chronic hepatitis B virus infection—as evidenced by positive hepatitis B surface antigen—can develop acute liver failure if the infection is reactivated by the use of immunosuppressive drugs for solid-organ or bone-marrow transplant or medications such as anti-tumor necrosis agents, rituximab, or chemotherapy. These patients should be treated prophylactically with a nucleoside analogue, which should be continued for 6 months after immunosuppressive therapy is completed.

Hepatitis A virus is responsible for about 4% of cases.¹⁸

Hepatitis C virus rarely causes acute liver failure, especially in the absence of hepatitis A and hepatitis B.^3,19

Hepatitis E virus, which is endemic in areas of Asia and Africa, can cause liver disease in pregnant women and in young adults who have concomitant liver disease from another cause. It tends to cause acute liver failure more frequently in pregnant women than in the rest of the population and carries a mortality rate of more than 20% in this subgroup.

TT (transfusion-transmitted) virus was reported in the 1990s to cause acute liver failure in about 27% of patients in whom no other cause could be found.²⁰

Other rare viral causes of acute liver failure include Epstein-Barr virus, cytomegalovirus, and herpes simplex virus types 1, 2, and 6.

Other causes

Other causes of acute liver failure include ischemic hepatitis, autoimmune hepatitis, Wilson disease, Budd-Chiari syndrome, and HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome.

MANY PATIENTS NEED LIVER TRANSPLANT

Many patients with acute liver failure ultimately require orthotopic liver transplant,²¹ especially if they present with severe encephalopathy. Other aspects of treatment vary according to the cause of liver failure (Table 3).

SPECIFIC MANAGEMENT

Management of acetaminophen toxicity

If the time of ingestion is known, checking the acetaminophen level can help determine the cause of acute liver failure and also predict the risk of hepatotoxicity, based on the work of Rumack and Matthew.²² Calculators are available, eg, http://reference.medscape.com/calculator/acetaminophen-toxicity.

If a patient presents with acute liver failure several days after ingesting acetaminophen, the level can be in the nontoxic range, however. In this scenario, measuring acetaminophen-protein adducts can help establish acetaminophen toxicity as the cause, as the adducts last longer in the serum and provide 100% sensitivity and specificity.²³ While most laboratories can rapidly measure acetaminophen levels, only a few can measure acetaminophen-protein adducts, and thus this test is not used clinically.

Acetylcysteine is the main drug used for acetaminophen toxicity. Ideally, it should be given within 8 hours of acetaminophen ingestion, but giving it later is also useful.¹

Acetylcysteine is available in oral and intravenous forms, the latter for patients who have encephalopathy or cannot tolerate oral intake due to repeated episodes of vomiting.^24,25 The oral form is much less costly and is thus preferred over intravenous acetylcysteine in patients who can tolerate oral intake. Intravenous acetylcysteine should be given in a loading dose of 150 mg/kg in 5% dextrose over 15 minutes, followed by a maintenance dose of 50 mg/kg over 4 hours and then 100 mg/kg given over 16 hours.¹ No dose adjustment is needed in patients who have renal toxicity (acetaminophen can also be toxic to the kidneys).

Most patients with acetaminophen-induced liver failure survive with medical management alone and do not need a liver transplant.^3,26 Cirrhosis does not occur in these patients.

Management of viral acute liver failure

When patients present with acute liver failure, it is necessary to look for a viral cause by serologic testing, including hepatitis A virus IgM antibody, hepatitis B surface antigen, and hepatitis B core IgM antibody.

Hepatitis B can become reactivated in immunocompromised patients, and therefore the hepatitis B virus DNA level should be checked. Detection of hepatitis B virus DNA in a patient previously known to have undetectable hepatitis B virus DNA confirms hepatitis B reactivation.

Patients with hepatitis B-induced acute liver failure should be treated with entecavir or tenofovir. Although this treatment may not change the course of acute liver failure or accelerate the recovery, it can prevent reinfection in the transplanted liver if liver transplant becomes indicated.^27–29

Herpes simplex virus should be suspected in patients presenting with anicteric hepatitis with fever. Polymerase chain reaction testing for herpes simplex virus should be done,³⁰ and if positive, patients should be given intravenous acyclovir.³¹ Despite treatment, herpes simplex virus disease is associated with a very poor prognosis without liver transplant.

Autoimmune hepatitis

The autoantibodies usually seen in autoimmune hepatitis are antinuclear antibody, antismooth muscle antibody, and anti-liver-kidney microsomal antibody, and patients need to be tested for them.

The diagnosis of autoimmune hepatitis can be challenging, as these autoimmune markers can be negative in 5% of patients. Liver biopsy becomes essential to establish the diagnosis in that setting.³²

Guidelines advise starting prednisone 40 to 60 mg/day and placing the patient on the liver transplant list.¹

Wilson disease

Although it is an uncommon cause of liver failure, Wilson disease needs special attention because it has a poor prognosis. The mortality rate in acute liver failure from Wilson disease reaches 100% without liver transplant.

Wilson disease is caused by a genetic defect that allows copper to accumulate in the liver and other organs. However, diagnosing Wilson disease as the cause of acute liver failure can be challenging because elevated serum and urine copper levels are not specific to Wilson disease and can be seen in patients with acute liver failure from any cause. In addition, the ceruloplasmin level is usually normal or high because it is an acute-phase reactant. Accumulation of copper in the liver parenchyma is usually patchy; therefore, qualitative copper staining on random liver biopsy samples provides low diagnostic yield. Quantitative copper on liver biopsy is the gold standard test to establish the diagnosis, but the test is time-consuming. Kayser-Fleischer rings around the iris are considered pathognomic for Wilson disease when seen with acute liver failure, but they are seen in only about 50% of patients.³³

A unique feature of acute Wilson disease is that most patients have very high bilirubin levels and low alkaline phosphatase levels. An alkaline phosphatase-to-bilirubin ratio less than 2 in patients with acute liver failure is highly suggestive of Wilson disease.³⁴

Another clue to the diagnosis is that patients with Wilson disease tend to develop Coombs-negative hemolytic anemia, which leads to a disproportionate elevation in aminotransferase levels, with aspartate aminotransferase being higher than alanine aminotransferase.

Once Wilson disease is suspected, the patient should be listed for liver transplant because death is almost certain without it. For patients awaiting liver transplant, the American Association for the Study of Liver Diseases guidelines recommend certain measures to lower the serum copper level such as albumin dialysis, continuous hemofiltration, plasmapheresis, and plasma exchange,¹ but the evidence supporting their use is limited.

NONSPECIFIC MANAGEMENT

Acute liver failure can affect a number of organs and systems in addition to the liver (Figure 2).

General considerations

Because their condition can rapidly deteriorate, patients with acute liver failure are best managed in intensive care.

Patients who present to a center that does not have the facilities for liver transplant should be transferred to a transplant center as soon as possible, preferably by air. If the patient may not be able to protect the airway, endotracheal intubation should be performed before transfer.

The major causes of death in patients with acute liver failure are cerebral edema and infection. Gastrointestinal bleeding was a major cause of death in the past, but with prophylactic use of histamine H₂ receptor blockers and proton pump inhibitors, the incidence of gastrointestinal bleeding has been significantly reduced.

Although initially used only in patients with acetaminophen-induced liver failure, acetylcysteine has also shown benefit in patients with acute liver failure from other causes. In patients with grade 1 or 2 encephalopathy on a scale of 0 (minimal) to 4 (comatose), the transplant-free survival rate is higher when acetylcysteine is given compared with placebo, but this benefit does not extend to patients with a higher grade of encephalopathy.³⁵

Cerebral edema and intracranial hypertension

Cerebral edema is the leading cause of death in patients with acute liver failure, and it develops in nearly 40% of patients.³⁶

The mechanism by which cerebral edema develops is not well understood. Some have proposed that ammonia is converted to glutamine, which causes cerebral edema either directly by its osmotic effect^37,38 or indirectly by decreasing other osmolytes, thereby promoting water retention.³⁹

Cerebral edema leads to intracranial hypertension, which can ultimately cause cerebral herniation and death. Because of the high mortality rate associated with cerebral edema, invasive devices were extensively used in the past to monitor intracranial pressure. However, in light of known complications of these devices, including bleeding,⁴⁰ and lack of evidence of long-term benefit in terms of mortality rates, their use has come under debate.

Treatments. Many treatments are available for cerebral edema and intracranial hypertension. The first step is to elevate the head of the bed about 30 degrees. In addition, hyponatremia should be corrected, as it can worsen cerebral edema.⁴¹ If patients are intubated, maintaining a hypercapneic state is advisable to decrease the intracranial pressure.

Of the two pharmacologic options, mannitol is more often used.⁴² It is given as a bolus dose of 0.5 to 1 g/kg intravenously if the serum osmolality is less than 320 mOsm/L.¹ Given the risk of fluid overload with mannitol, caution must be exercised in patients with renal dysfunction. The other pharmacologic option is 3% hypertonic saline.

Therapeutic hypothermia is a newer treatment for cerebral edema. Lowering the body temperature to 32 to 33°C (89.6 to 91.4°F) using cooling blankets decreases intracranial pressure and cerebral blood flow and improves the cerebral perfusion pressure.⁴³ With this treatment, patients should be closely monitored for side effects of infection, coagulopathy, and cardiac arrythmias.¹

l-ornithine l-aspartate was successfully used to prevent brain edema in rats, but in humans, no benefit was seen compared with placebo.^44,45 The underlying basis for this experimental treatment is that supplemental ornithine and aspartate should increase glutamate synthesis, which should increase the activity of enzyme glutamine synthetase in skeletal muscles. With the increase in enzyme activity, conversion of ammonia to glutamine should increase, thereby decreasing ammonia circulation and thus decreasing cerebral edema.

Patients with cerebral edema have a high incidence of seizures, but prophylactic antiseizure medications such as phenytoin have not been proven to be beneficial.⁴⁶

Infection

Nearly 80% of patients with acute liver failure develop an infectious complication, which can be attributed to a state of immunodeficiency.⁴⁷

The respiratory and urinary tracts are the most common sources of infection.⁴⁸ In patients with bacteremia, Enterococcus species and coagulase-negative Staphylococcus species⁴⁹ are the commonly isolated organisms. Also, in patients with acute liver failure, fungal infections account for 30% of all infections.⁵⁰

Infected patients often develop worsening of their encephalopathy⁵¹ without fever or elevated white blood cell count.^49,52 Thus, in any patient in whom encephalopathy is worsening, an evaluation must be done to rule out infection. In these patients, systemic inflammatory response syndrome is an independent risk factor for death.⁵³

Despite the high mortality rate with infection, whether using antibiotics prophylactically in acute liver failure is beneficial is controversial.^54,55

Gastrointestinal bleeding

The current prevalence of upper gastrointestinal bleeding in acute liver failure patients is about 1.5%.⁵⁶ Coagulopathy and endotracheal intubation are the main risk factors for upper gastrointestinal bleeding in these patients.⁵⁷ The most common source of bleeding is stress ulcers in the stomach. The ulcers develop from a combination of factors, including decreased blood flow to the mucosa causing ischemia and hypoperfusion-reperfusion injury.

Pharmacologic inhibition of gastric acid secretion has been shown to reduce upper gastrointestinal bleeding in acute liver failure. A histamine H₂ receptor blocker or proton pump inhibitor should be given to prevent gastrointestinal bleeding in patients with acute liver failure.^1,58

EXPERIMENTAL TREATMENTS

Artificial liver support systems

Membranes and dialysate solutions have been developed to remove toxic substances that are normally metabolized by the liver. Two of these—the molecular adsorbent recycling system (MARS) and the extracorporeal liver assist device (ELAD)—were developed in the late 1990s. MARS consisted of a highly permeable hollow fiber membrane mixed with albumin, and ELAD consisted of porcine hepatocytes attached to microcarriers in the extracapillary space of the hollow fiber membrane. Both systems allowed for transfer of water-soluble and protein-bound toxins in the blood across the membrane and into the dialysate.⁵⁹ The clinical benefit offered by these devices is controversial,^60–62 thus limiting their use to experimental purposes only.

Hepatocyte transplant

Use of hepatocyte transplant as a bridge to liver transplant was tested in 1970s, first in rats and later in humans.⁶³ By reducing the blood ammonia level and improving cerebral perfusion pressure and cardiac function, replacement of 1% to 2% of the total liver cell mass by transplanted hepatocytes acts as a bridge to orthotopic liver transplant.^64,65

PROGNOSIS

Different criteria have been used to identify patients with poor prognosis who may eventually need to undergo liver transplant.

The King’s College criteria system is the most commonly used for prognosis (Table 4).^37,66–69 Its main drawback is that it is applicable only in patients with encephalopathy, and when patients reach this stage, their condition often deteriorates rapidly, and they die while awaiting liver transplant.^37,66,67

The Model for End-Stage Liver Disease (MELD) score is an alternative to the King’s College criteria. A high MELD score on admission signifies advanced disease, and patients with a high MELD score tend to have a worse prognosis than those with a low score.⁶⁸

The Acute Physiology and Chronic Health Evaluation (APACHE) II score can also be used, as it is more sensitive than the King’s College criteria.⁶

The Clichy criteria^66,69 can also be used.

Liver biopsy. In addition to helping establish the cause of acute liver failure, liver biopsy can also be used as a prognostic tool. Hepatocellular necrosis greater than 70% on the biopsy predicts death with a specificity of 90% and a sensitivity of 56%.⁷⁰

Hypophosphatemia has been reported to indicate recovering liver function in patients with acute liver failure.⁷¹ As the liver regenerates, its energy requirement increases. To supply the energy, adenosine triphosphate production increases, and phosphorus shifts from the extracellular to the intracellular compartment to meet the need for extra phosphorus during this process. A serum phosphorus level of 2.9 mg/dL or higher appears to indicate a poor prognosis in patients with acute liver failure, as it signifies that adequate hepatocyte regeneration is not occurring.

When the liver fails, it usually fails gradually. The sudden (acute) onset of liver failure, while less common, demands prompt management, with transfer to an intensive care unit, specific treatment depending on the cause, and consideration of liver transplant, without which the mortality rate is high.

This article reviews the definition, epidemiology, etiology, and management of acute liver failure.

DEFINITIONS

Acute liver failure is defined as a syndrome of acute hepatitis with evidence of abnormal coagulation (eg, an international normalized ratio > 1.5) complicated by the development of mental alteration (encephalopathy) within 26 weeks of the onset of illness in a patient without a history of liver disease.¹ In general, patients have no evidence of underlying chronic liver disease, but there are exceptions; patients with Wilson disease, vertically acquired hepatitis B virus infection, or autoimmune hepatitis can present with acute liver failure superimposed on chronic liver disease or even cirrhosis.

The term acute liver failure has replaced older terms such as fulminant hepatic failure, hyperacute liver failure, and subacute liver failure, which were used for prognostic purposes. Patients with hyperacute liver failure (defined as development of encephalopathy within 7 days of onset of illness) generally have a good prognosis with medical management, whereas those with subacute liver failure (defined as development of encephalopathy within 5 to 26 weeks of onset of illness) have a poor prognosis without liver transplant.^2,3

NEARLY 2,000 CASES A YEAR

There are nearly 2,000 cases of acute liver failure each year in the United States, and it accounts for 6% of all deaths due to liver disease.⁴ It is more common in women than in men, and more common in white people than in other races. The peak incidence is at a fairly young age, ie, 35 to 45 years.

CAUSES

The most common cause of acute liver failure in the United States and other Western countries is acetaminophen toxicity, followed by viral hepatitis. In contrast, viral hepatitis is the most common cause in developing countries.⁵

Acetaminophen toxicity

Patients with acetaminophen-induced liver failure tend to be younger than other patients with acute liver failure.¹ Nearly half of them present after intentionally taking a single large dose, while the rest present with unintentional toxicity while taking acetaminophen for pain relief on a long-term basis and ingesting more than the recommended dose.⁶

After ingestion, 52% to 57% of acetaminophen is converted to glucuronide conjugates, and 30% to 44% is converted to sulfate conjugates. These compounds are nontoxic, water-soluble, and rapidly excreted in the urine.

However, about 5% to 10% of ingested acetaminophen is shunted to the cytochrome P450 system. P450 2E1 is the main isoenzyme involved in acetaminophen metabolism, but 1A2, 3A4, and 2A6 also contribute.^7,8 P450 2E1 is the same isoenzyme responsible for ethanol metabolism and is inducible. Thus, regular alcohol consumption can increase P450 2E1 activity, setting the stage under certain circumstances for increased acetaminophen metabolism through this pathway.

Reprinted from Schilling A, Corey R, Leonard M, Eghtesad B. Acetaminophen: old drug, new warnings. Cleve Clin J Med 2010; 77:19–27.

Metabolism of acetaminophen through the cytochrome P450 pathway results in production of N-acetyl-p-benzoquinone imine (NAPQI), the compound that damages the liver. NAPQI is rendered nontoxic by binding to glutathione, forming NAPQI-glutathione adducts. Glutathione capacity is limited, however. With too much acetaminophen, glutathione becomes depleted and NAPQI accumulates, binds with proteins to form adducts, and leads to necrosis of hepatocytes (Figure 1).^9,10

Acetylcysteine, used in treating acetaminophen toxicity, is a substrate for glutathione synthesis and ultimately increases the amount of glutathione available to bind NAPQI and prevent damage to hepatocytes.¹¹

Acetaminophen is a dose-related toxin. Most ingestions leading to acute liver failure exceed 10 g/day (> 150 mg/kg/day). Moderate chronic ingestion, eg, 4 g/day, usually leads to transient mild elevation of liver enzymes in healthy individuals¹² but can in rare cases cause acute liver failure.¹³

Whitcomb and Block¹⁴ retrospectively identified 49 patients who presented with acetaminophen-induced hepatotoxicity in 1987 through 1993; 21 (43%) had been taking acetaminophen for therapeutic purposes. All 49 patients took more than the recommended limit of 4 g/day, many of them while fasting and some while using alcohol. Acute liver failure was seen with ingestion of more than 12 g/day—or more than 10 g/day in alcohol users. The authors attributed the increased risk to activation of cytochrome P450 2E1 by alcohol and depletion of glutathione stores by starvation or alcohol abuse. 

Advice to patients taking acetaminophen is given in Table 1.

Other drugs and supplements

A number of other drugs and herbal supplements can also cause acute liver failure (Table 2), the most common being antimicrobial and antiepileptic drugs.¹⁵ Of the antimicrobials, antitubercular drugs (especially isoniazid) are believed to be the most common causes, followed by trimethoprim-sulfamethoxazole. Phenytoin is the antiepileptic drug most often implicated in acute liver failure.

Statins can also cause acute liver failure, especially when combined with other hepatotoxic agents.¹⁶

The herbal supplements and weight-loss agents Hydroxycut and Herbalife have both been reported to cause acute liver failure, with patients presenting with either the hepatocellular or the cholestatic pattern of liver injury.¹⁷ The exact chemical in these supplements that causes liver injury has not yet been determined.

The National Institutes of Health maintains a database of cases of liver failure due to medications and supplements at livertox.nih.gov. The database includes the pattern of hepatic injury, mechanism of injury, management, and outcomes.

Viral hepatitis

Hepatitis B virus is the most common viral cause of acute liver failure and is responsible for about 8% of cases.¹⁸

Patients with chronic hepatitis B virus infection—as evidenced by positive hepatitis B surface antigen—can develop acute liver failure if the infection is reactivated by the use of immunosuppressive drugs for solid-organ or bone-marrow transplant or medications such as anti-tumor necrosis agents, rituximab, or chemotherapy. These patients should be treated prophylactically with a nucleoside analogue, which should be continued for 6 months after immunosuppressive therapy is completed.

Hepatitis A virus is responsible for about 4% of cases.¹⁸

Hepatitis C virus rarely causes acute liver failure, especially in the absence of hepatitis A and hepatitis B.^3,19

Hepatitis E virus, which is endemic in areas of Asia and Africa, can cause liver disease in pregnant women and in young adults who have concomitant liver disease from another cause. It tends to cause acute liver failure more frequently in pregnant women than in the rest of the population and carries a mortality rate of more than 20% in this subgroup.

TT (transfusion-transmitted) virus was reported in the 1990s to cause acute liver failure in about 27% of patients in whom no other cause could be found.²⁰

Other rare viral causes of acute liver failure include Epstein-Barr virus, cytomegalovirus, and herpes simplex virus types 1, 2, and 6.

Other causes

Other causes of acute liver failure include ischemic hepatitis, autoimmune hepatitis, Wilson disease, Budd-Chiari syndrome, and HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome.

MANY PATIENTS NEED LIVER TRANSPLANT

Many patients with acute liver failure ultimately require orthotopic liver transplant,²¹ especially if they present with severe encephalopathy. Other aspects of treatment vary according to the cause of liver failure (Table 3).

SPECIFIC MANAGEMENT

Management of acetaminophen toxicity

If the time of ingestion is known, checking the acetaminophen level can help determine the cause of acute liver failure and also predict the risk of hepatotoxicity, based on the work of Rumack and Matthew.²² Calculators are available, eg, http://reference.medscape.com/calculator/acetaminophen-toxicity.

If a patient presents with acute liver failure several days after ingesting acetaminophen, the level can be in the nontoxic range, however. In this scenario, measuring acetaminophen-protein adducts can help establish acetaminophen toxicity as the cause, as the adducts last longer in the serum and provide 100% sensitivity and specificity.²³ While most laboratories can rapidly measure acetaminophen levels, only a few can measure acetaminophen-protein adducts, and thus this test is not used clinically.

Acetylcysteine is the main drug used for acetaminophen toxicity. Ideally, it should be given within 8 hours of acetaminophen ingestion, but giving it later is also useful.¹

Acetylcysteine is available in oral and intravenous forms, the latter for patients who have encephalopathy or cannot tolerate oral intake due to repeated episodes of vomiting.^24,25 The oral form is much less costly and is thus preferred over intravenous acetylcysteine in patients who can tolerate oral intake. Intravenous acetylcysteine should be given in a loading dose of 150 mg/kg in 5% dextrose over 15 minutes, followed by a maintenance dose of 50 mg/kg over 4 hours and then 100 mg/kg given over 16 hours.¹ No dose adjustment is needed in patients who have renal toxicity (acetaminophen can also be toxic to the kidneys).

Most patients with acetaminophen-induced liver failure survive with medical management alone and do not need a liver transplant.^3,26 Cirrhosis does not occur in these patients.

Management of viral acute liver failure

When patients present with acute liver failure, it is necessary to look for a viral cause by serologic testing, including hepatitis A virus IgM antibody, hepatitis B surface antigen, and hepatitis B core IgM antibody.

Hepatitis B can become reactivated in immunocompromised patients, and therefore the hepatitis B virus DNA level should be checked. Detection of hepatitis B virus DNA in a patient previously known to have undetectable hepatitis B virus DNA confirms hepatitis B reactivation.

Patients with hepatitis B-induced acute liver failure should be treated with entecavir or tenofovir. Although this treatment may not change the course of acute liver failure or accelerate the recovery, it can prevent reinfection in the transplanted liver if liver transplant becomes indicated.^27–29

Herpes simplex virus should be suspected in patients presenting with anicteric hepatitis with fever. Polymerase chain reaction testing for herpes simplex virus should be done,³⁰ and if positive, patients should be given intravenous acyclovir.³¹ Despite treatment, herpes simplex virus disease is associated with a very poor prognosis without liver transplant.

Autoimmune hepatitis

The autoantibodies usually seen in autoimmune hepatitis are antinuclear antibody, antismooth muscle antibody, and anti-liver-kidney microsomal antibody, and patients need to be tested for them.

The diagnosis of autoimmune hepatitis can be challenging, as these autoimmune markers can be negative in 5% of patients. Liver biopsy becomes essential to establish the diagnosis in that setting.³²

Guidelines advise starting prednisone 40 to 60 mg/day and placing the patient on the liver transplant list.¹

Wilson disease

Although it is an uncommon cause of liver failure, Wilson disease needs special attention because it has a poor prognosis. The mortality rate in acute liver failure from Wilson disease reaches 100% without liver transplant.

Wilson disease is caused by a genetic defect that allows copper to accumulate in the liver and other organs. However, diagnosing Wilson disease as the cause of acute liver failure can be challenging because elevated serum and urine copper levels are not specific to Wilson disease and can be seen in patients with acute liver failure from any cause. In addition, the ceruloplasmin level is usually normal or high because it is an acute-phase reactant. Accumulation of copper in the liver parenchyma is usually patchy; therefore, qualitative copper staining on random liver biopsy samples provides low diagnostic yield. Quantitative copper on liver biopsy is the gold standard test to establish the diagnosis, but the test is time-consuming. Kayser-Fleischer rings around the iris are considered pathognomic for Wilson disease when seen with acute liver failure, but they are seen in only about 50% of patients.³³

A unique feature of acute Wilson disease is that most patients have very high bilirubin levels and low alkaline phosphatase levels. An alkaline phosphatase-to-bilirubin ratio less than 2 in patients with acute liver failure is highly suggestive of Wilson disease.³⁴

Another clue to the diagnosis is that patients with Wilson disease tend to develop Coombs-negative hemolytic anemia, which leads to a disproportionate elevation in aminotransferase levels, with aspartate aminotransferase being higher than alanine aminotransferase.

Once Wilson disease is suspected, the patient should be listed for liver transplant because death is almost certain without it. For patients awaiting liver transplant, the American Association for the Study of Liver Diseases guidelines recommend certain measures to lower the serum copper level such as albumin dialysis, continuous hemofiltration, plasmapheresis, and plasma exchange,¹ but the evidence supporting their use is limited.

NONSPECIFIC MANAGEMENT

Acute liver failure can affect a number of organs and systems in addition to the liver (Figure 2).

General considerations

Because their condition can rapidly deteriorate, patients with acute liver failure are best managed in intensive care.

Patients who present to a center that does not have the facilities for liver transplant should be transferred to a transplant center as soon as possible, preferably by air. If the patient may not be able to protect the airway, endotracheal intubation should be performed before transfer.

The major causes of death in patients with acute liver failure are cerebral edema and infection. Gastrointestinal bleeding was a major cause of death in the past, but with prophylactic use of histamine H₂ receptor blockers and proton pump inhibitors, the incidence of gastrointestinal bleeding has been significantly reduced.

Although initially used only in patients with acetaminophen-induced liver failure, acetylcysteine has also shown benefit in patients with acute liver failure from other causes. In patients with grade 1 or 2 encephalopathy on a scale of 0 (minimal) to 4 (comatose), the transplant-free survival rate is higher when acetylcysteine is given compared with placebo, but this benefit does not extend to patients with a higher grade of encephalopathy.³⁵

Cerebral edema and intracranial hypertension

Cerebral edema is the leading cause of death in patients with acute liver failure, and it develops in nearly 40% of patients.³⁶

The mechanism by which cerebral edema develops is not well understood. Some have proposed that ammonia is converted to glutamine, which causes cerebral edema either directly by its osmotic effect^37,38 or indirectly by decreasing other osmolytes, thereby promoting water retention.³⁹

Cerebral edema leads to intracranial hypertension, which can ultimately cause cerebral herniation and death. Because of the high mortality rate associated with cerebral edema, invasive devices were extensively used in the past to monitor intracranial pressure. However, in light of known complications of these devices, including bleeding,⁴⁰ and lack of evidence of long-term benefit in terms of mortality rates, their use has come under debate.

Treatments. Many treatments are available for cerebral edema and intracranial hypertension. The first step is to elevate the head of the bed about 30 degrees. In addition, hyponatremia should be corrected, as it can worsen cerebral edema.⁴¹ If patients are intubated, maintaining a hypercapneic state is advisable to decrease the intracranial pressure.

Of the two pharmacologic options, mannitol is more often used.⁴² It is given as a bolus dose of 0.5 to 1 g/kg intravenously if the serum osmolality is less than 320 mOsm/L.¹ Given the risk of fluid overload with mannitol, caution must be exercised in patients with renal dysfunction. The other pharmacologic option is 3% hypertonic saline.

Therapeutic hypothermia is a newer treatment for cerebral edema. Lowering the body temperature to 32 to 33°C (89.6 to 91.4°F) using cooling blankets decreases intracranial pressure and cerebral blood flow and improves the cerebral perfusion pressure.⁴³ With this treatment, patients should be closely monitored for side effects of infection, coagulopathy, and cardiac arrythmias.¹

l-ornithine l-aspartate was successfully used to prevent brain edema in rats, but in humans, no benefit was seen compared with placebo.^44,45 The underlying basis for this experimental treatment is that supplemental ornithine and aspartate should increase glutamate synthesis, which should increase the activity of enzyme glutamine synthetase in skeletal muscles. With the increase in enzyme activity, conversion of ammonia to glutamine should increase, thereby decreasing ammonia circulation and thus decreasing cerebral edema.

Patients with cerebral edema have a high incidence of seizures, but prophylactic antiseizure medications such as phenytoin have not been proven to be beneficial.⁴⁶

Infection

Nearly 80% of patients with acute liver failure develop an infectious complication, which can be attributed to a state of immunodeficiency.⁴⁷

The respiratory and urinary tracts are the most common sources of infection.⁴⁸ In patients with bacteremia, Enterococcus species and coagulase-negative Staphylococcus species⁴⁹ are the commonly isolated organisms. Also, in patients with acute liver failure, fungal infections account for 30% of all infections.⁵⁰

Infected patients often develop worsening of their encephalopathy⁵¹ without fever or elevated white blood cell count.^49,52 Thus, in any patient in whom encephalopathy is worsening, an evaluation must be done to rule out infection. In these patients, systemic inflammatory response syndrome is an independent risk factor for death.⁵³

Despite the high mortality rate with infection, whether using antibiotics prophylactically in acute liver failure is beneficial is controversial.^54,55

Gastrointestinal bleeding

The current prevalence of upper gastrointestinal bleeding in acute liver failure patients is about 1.5%.⁵⁶ Coagulopathy and endotracheal intubation are the main risk factors for upper gastrointestinal bleeding in these patients.⁵⁷ The most common source of bleeding is stress ulcers in the stomach. The ulcers develop from a combination of factors, including decreased blood flow to the mucosa causing ischemia and hypoperfusion-reperfusion injury.

Pharmacologic inhibition of gastric acid secretion has been shown to reduce upper gastrointestinal bleeding in acute liver failure. A histamine H₂ receptor blocker or proton pump inhibitor should be given to prevent gastrointestinal bleeding in patients with acute liver failure.^1,58

EXPERIMENTAL TREATMENTS

Artificial liver support systems

Membranes and dialysate solutions have been developed to remove toxic substances that are normally metabolized by the liver. Two of these—the molecular adsorbent recycling system (MARS) and the extracorporeal liver assist device (ELAD)—were developed in the late 1990s. MARS consisted of a highly permeable hollow fiber membrane mixed with albumin, and ELAD consisted of porcine hepatocytes attached to microcarriers in the extracapillary space of the hollow fiber membrane. Both systems allowed for transfer of water-soluble and protein-bound toxins in the blood across the membrane and into the dialysate.⁵⁹ The clinical benefit offered by these devices is controversial,^60–62 thus limiting their use to experimental purposes only.

Hepatocyte transplant

Use of hepatocyte transplant as a bridge to liver transplant was tested in 1970s, first in rats and later in humans.⁶³ By reducing the blood ammonia level and improving cerebral perfusion pressure and cardiac function, replacement of 1% to 2% of the total liver cell mass by transplanted hepatocytes acts as a bridge to orthotopic liver transplant.^64,65

PROGNOSIS

Different criteria have been used to identify patients with poor prognosis who may eventually need to undergo liver transplant.

The King’s College criteria system is the most commonly used for prognosis (Table 4).^37,66–69 Its main drawback is that it is applicable only in patients with encephalopathy, and when patients reach this stage, their condition often deteriorates rapidly, and they die while awaiting liver transplant.^37,66,67

The Model for End-Stage Liver Disease (MELD) score is an alternative to the King’s College criteria. A high MELD score on admission signifies advanced disease, and patients with a high MELD score tend to have a worse prognosis than those with a low score.⁶⁸

The Acute Physiology and Chronic Health Evaluation (APACHE) II score can also be used, as it is more sensitive than the King’s College criteria.⁶

The Clichy criteria^66,69 can also be used.

Liver biopsy. In addition to helping establish the cause of acute liver failure, liver biopsy can also be used as a prognostic tool. Hepatocellular necrosis greater than 70% on the biopsy predicts death with a specificity of 90% and a sensitivity of 56%.⁷⁰

Hypophosphatemia has been reported to indicate recovering liver function in patients with acute liver failure.⁷¹ As the liver regenerates, its energy requirement increases. To supply the energy, adenosine triphosphate production increases, and phosphorus shifts from the extracellular to the intracellular compartment to meet the need for extra phosphorus during this process. A serum phosphorus level of 2.9 mg/dL or higher appears to indicate a poor prognosis in patients with acute liver failure, as it signifies that adequate hepatocyte regeneration is not occurring.

Primary care physicians and specialists alike often encounter patients with chronic liver disease. Fortunately, these days we need to resort to liver biopsy less often than in the past.

The purpose of this review is to provide a critical assessment of the growing number of noninvasive tests available for diagnosing liver disease and assessing hepatic fibrosis, and to discuss the implications of these advances related to the indications for needle liver biopsy.

WHEN IS LIVER BIOPSY USEFUL?

In diagnosis

Needle liver biopsy for diagnosis remains important in cases of:

Diagnostic uncertainty (eg, in patients with atypical features)

Coexisting disorders (eg, human immunodeficiency virus [HIV] and hepatitis C virus infection, or alcoholic liver disease and hepatitis C)

An overlapping syndrome (eg, primary biliary cirrhosis with autoimmune hepatitis).

Fatty liver. Needle liver biopsy can distinguish between benign steatosis and progressive steatohepatitis in a patient with a fatty liver found on imaging, subject to the limitations of sampling error.

Because fatty liver disease is common and proven treatments are few, no consensus has emerged about which patients with suspected fatty liver disease should undergo needle biopsy. Many specialists eschew needle biopsy and treat the underlying risk factors of metabolic syndrome, reserving biopsy for patients with findings that raise the concern of cirrhosis.

Hereditary disorders, eg, hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson disease.

In management

Periodic needle biopsy is also valuable in the management of a few diseases.

In autoimmune hepatitis, monitoring the plasma cell score on liver biopsy may help predict relapse when a physician is considering reducing or discontinuing immunosuppressive therapy.¹

After liver transplantation, a liver biopsy is highly valuable to assess for rejection and the presence and intensity of disease recurrence.

PROBLEMS WITH LIVER BIOPSY

Liver biopsy is invasive and can cause significant complications. Nearly 30% of patients report having substantial pain after liver biopsy, and some experience serious complications such as pneumothorax, bleeding, or puncture of the biliary tree. In rare cases, patients die of bleeding.²

Furthermore, hepatic pathology, particularly fibrosis, is not always uniformly distributed. Surgical wedge biopsy provides adequate tissue volume to overcome this problem. Needle biopsy, on the other hand, provides a much smaller volume of tissue (1/50,000 of the total mass of the liver).³

As examples of the resulting sampling errors that can occur, consider the two most common chronic liver diseases: hepatitis C and fatty liver disease.

Regev et al⁴ performed laparoscopically guided biopsy of the right and left hepatic lobes in a series of 124 patients with chronic hepatitis C. Biopsy samples from the right and left lobes differed in the intensity of inflammation in 24.2% of cases, and in the intensity of fibrosis in 33.1%. Differences of more than one grade of inflammation or stage of fibrosis were uncommon. However, in 14.5%, cirrhosis was diagnosed in one lobe but not the other.

In a study in patients with nonalcoholic fatty liver disease, Ratziu et al⁵ found that none of the features characteristic of nonalcoholic steatohepatitis were highly concordant in paired liver biopsies. Clearly, needle liver biopsy is far from an ideal test.

Increasingly, liver diseases can be diagnosed precisely with laboratory tests, imaging studies, or both. Thus, needle liver biopsy is playing a lesser role in diagnosis.

ADVANCES IN NONINVASIVE DIAGNOSIS OF LIVER DISEASE

Over the past 30 years, substantial strides have been made in our ability to make certain diagnoses through noninvasive means.

Blood tests can be used to diagnose viral hepatitis A, B, and C and many cases of hemochromatosis and primary biliary cirrhosis. For a detailed discussion of how blood tests are used in diagnosing liver diseases, see www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/guide-to-common-liver-tests/.

Imaging studies. Primary sclerosing cholangitis can be diagnosed with an imaging study, ie, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). The value of needle biopsy in these patients is limited to assessing the degree of fibrosis to help with management of the disease and, less often, to discovering other liver pathologies.⁶

Most benign space-occupying liver lesions, both cystic and solid, can be fully characterized by imaging, especially in patients who have no underlying chronic liver disease, and no biopsy is needed. Whether biopsy should be performed to investigate liver lesions depends on the clinical scenario; the topic is beyond the scope of this paper but has been reviewed in detail by Rockey et al.²

CAN NONINVASIVE TESTS DETECT HEPATIC FIBROSIS?

Based on information in Batts KP, Ludwig J. Chronic hepatitis: an update on terminology and reporting. Am J Surg Pathol 1995; 19:1409–1417.

Cirrhosis (stage 4 fibrosis) results in nodular transformation of the liver and impedance of portal blood flow, setting the stage for portal hypertension and its sequelae. Knowing whether cirrhosis is present is important in subsequent management.

In advanced cases, cirrhosis is associated with typical clinical manifestations and laboratory and radiographic findings. In such cases, needle biopsy will add little. However, in most cases, particularly early in the course, clinical, laboratory, and radiologic correlates of cirrhosis are absent. In one study of patients with hepatitis C, 27% had cirrhosis, but in only a small number would cirrhosis have been apparent from clinical signs and laboratory and imaging studies.⁶

Since a major contemporary role for liver biopsy is in assessing the degree of fibrosis, it is reasonable to ask if newer noninvasive means are available to estimate hepatic fibrosis. The remainder of this review focuses on assessing our increasing ability to stage the degree of fibrosis (including the presence or absence of cirrhosis) by noninvasive means.

Clinical features point to cirrhosis, but not earlier fibrosis

Clinical manifestations help point to the diagnosis of cirrhosis but not to earlier stages of fibrosis.

For example, if a patient is known to have liver disease, the findings of ascites, splenomegaly, or asterixis mean that cirrhosis is highly probable. Similarly, hypersplenism (splenomegaly with a decrease in circulating blood cells but a normal to hyperactive bone marrow) in a patient with liver test abnormalities almost always represents portal hypertension due to cirrhosis, although other, nonhepatic causes are possible, such as congestive heart failure and constrictive pericarditis.

These features generally emerge late in the course of cirrhosis. The absence of such stigmata certainly does not preclude the presence of cirrhosis. Thus, these clinical signs have a high positive predictive value but a low negative predictive value, making them insufficient by themselves to diagnose or stage liver disease.

Laboratory tests are of limited value in assessing the degree of fibrosis

Standard liver tests are of limited value in assessing the degree of fibrosis.

Usual laboratory tests. At one end of the spectrum, anemia, thrombocytopenia, and leukopenia in the presence of liver disease correlate with cirrhosis. At the other end, a serum ferritin concentration of less than 1,000 mg/mL in a patient with hemochromatosis and no confounding features such as hepatitis C, HIV infection, or heavy alcohol use strongly predicts that the patient does not have significant hepatic fibrosis.⁸

Bilirubin elevation is a late finding in cirrhosis, but in cholestatic diseases bilirubin may be elevated before cirrhosis occurs.

Albumin is made exclusively in the liver, and its concentration falls as liver function worsens with progressive cirrhosis.

The prothrombin time increases as the liver loses its ability to synthesize clotting factors in cirrhosis. Coagulopathy correlates with the degree of liver disease.

Hyponatremia due to impaired ability to excrete free water is seen in patients with cirrhosis and ascites.

In summary, the usual laboratory tests related to liver disease are imprecise and, when abnormal, often indicate not just the presence of cirrhosis, but impending or actual decompensation.

Newer serologic markers, alone or in combination, have been proposed as aids in determining the degree of fibrosis or cirrhosis in the liver. Direct markers of fibrosis measure the turnover or metabolism of extracellular matrix. Indirect markers of fibrosis reflect alterations in hepatic function (see below).

Parkes et al⁹ reviewed 10 different panels of serum markers of hepatic fibrosis in chronic hepatitis C. Only 35% of patients had fibrosis adequately ruled in or ruled out by these panels, and the stage of fibrosis could not be adequately determined.

These serologic markers have not been validated in other chronic liver diseases or in liver disease due to multiple causes. Thus, although they show promise for use by the general internist, they need to be validated in patients with disease and in normal reference populations before they are ready for “prime time.”

Direct serologic markers of fibrosis

Direct serologic markers of fibrosis include those associated with matrix deposition—eg, procollagen type III amino-terminal peptide (P3NP), type I and IV collagens, laminin, hyaluronic acid, and chondrex.

P3NP is the most widely studied marker of hepatic fibrosis. It is elevated in both acute and chronic liver diseases; serum levels reflect the histologic stage of hepatic fibrosis in various chronic liver diseases, including alcoholic, viral, and primary biliary cirrhosis.^10–12 Successful treatment of autoimmune hepatitis has been shown to lead to reductions of P3NP levels.¹³

Other direct markers of fibrosis are those associated with matrix degradation, ie, matrix metalloproteinases 2 and 3 (MMP-2, MMP-3) and tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2). Levels of MMP-2 proenzymes and active enzymes are increased in liver disease, but studies are inconsistent in correlating serum levels of MMP-2 to the degree of hepatic fibrosis.^14,15 These tests are not commercially available, and the components are not readily available in most clinical laboratories.

Some indirect markers are readily available:

The AST:ALT ratio. The normal ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is approximately 0.8. A ratio greater than 1.0 provides evidence of cirrhosis. However, findings have been inconsistent.

The AST:platelet ratio index (APRI), a commonly used index, is calculated by the following formula:

In studies of hepatitis C and hepatitis C-HIV, the APRI has shown a sensitivity of 37% to 80% and a specificity of 45% to 98%, depending on the cutoff value and whether a diagnosis of severe fibrosis or cirrhosis was being tested.^16–19 These sensitivities and specificities are disappointing and do not provide information equal to that provided by needle liver biopsy in most patients with chronic liver disease.

The combination of prothrombin, gamma glutamyl, and apolipoprotein AI levels (PGA index) has been validated in patients with many types of chronic liver disease, and its accuracy for detecting cirrhosis is highest (66%–72%) in patients with alcoholic liver disease.^20,21

FibroIndex uses the platelet count, AST level, and gamma globulin level to detect significant fibrosis in chronic hepatitis C, but its accuracy has yet to be validated.²²

The FIB-4 index is based on four independent predictors of fibrosis, ie, age, the platelet count, AST level, and ALT level. It has shown good accuracy for detecting advanced fibrosis in two studies in patients with hepatitis C.^23,24

Fibrometer (based on the platelet count; the prothrombin index; the levels of AST, alfa-2 macroglobulin, hyaluronate, and blood urea nitrogen; and age) predicted fibrosis well in chronic viral hepatitis.^25,26

Fibrotest and Fibrosure are proprietary commercial tests available in many laboratories. They employ a mathematical formula to predict fibrosis (characterized as mild, significant, or indeterminate) using the levels of alpha-2 macroglobulin, alpha-2 globulin, gamma globulin, apolipoprotein A1, gamma glutamyl transferase, and total bilirubin. For detecting significant fibrosis, these tests are reported to have a sensitivity of about 75% and a specificity of 85%.^27–29

ActiTest incorporates the ALT level into the Fibrotest to reflect liver fibrosis and necro-inflammatory activity.

A meta-analysis showed that Fibrotest and ActiTest could be reliable alternatives to liver biopsy in patients with chronic hepatitis C.³⁰ The area under the receiver operator characteristic curve for the diagnosis of significant fibrosis ranged from 0.73 to 0.87; for the diagnosis of significant histologic activity it ranged from 0.75 to 0.86. Fibrotest had a negative predictive value for excluding significant fibrosis of 91% with a cutoff of 0.31. ActiTest’s negative predictive value for excluding significant necrosis was 85% with a cutoff of 0.36. None of these serum tests have become part of standard of practice for diagnosing fibrosis or cirrhosis.

The Sequential Algorithm for Fibrosis Evaluation (SAFE) combines the APRI and Fibrotest-Fibrosure tests in a sequential fashion to test for fibrosis and cirrhosis. In a large multicenter study³¹ validating this algorithm to detect significant fibrosis (stage F2 or greater by the F0–F4 METAVIR scoring system³²), its accuracy was 90.1%, the area under the receiver operating characteristic curve was 0.89 (95% CI 0.87–0.90), and it reduced the number of liver biopsies needed by 46.5%. When the algorithm was used to detect cirrhosis, its accuracy was 92.5%, the area under the curve was 0.92 (95% CI 0.89–0.94), and it reduced the number of liver biopsies needed by 81.5%.

Another algorithm was developed to simultaneously detect significant fibrosis and cirrhosis. It had a 97.4% accuracy, but 64% of patients still required a liver biopsy.³¹

SAFE algorithms have the potential to reduce the number of needle biopsies needed to assess the degree of hepatic fibrosis.

CONVENTIONAL IMAGING STUDIES ARE NOT SENSITIVE FOR FIBROSIS

Standard imaging studies often show findings of cirrhosis but are not particularly sensitive, with a low negative predictive value.

Ultrasonography can show a small, nodular liver in advanced cirrhosis, but surface nodularity or increased echogenicity can be seen in hepatic steatosis as well as in cirrhosis. In one study,³³ ultrasonography identified diffuse parenchymal disease but could not reliably distinguish fat from fibrosis or diagnose cirrhosis.

Often, in cirrhosis, the right lobe of the liver is atrophied and the caudate or left lobes are hypertrophied. Efforts to use the ratio of the widths of the lobes to diagnose cirrhosis have shown varying performance characterstics.^34,35

One study of the splenic artery pulsatility index has shown this to be an accurate predictor of cirrhosis.³⁶

Computed tomography provides information similar to that of ultrasonography, and it can identify complications of cirrhosis, including portal hypertension and ascites. On the other hand, it costs more and it exposes the patient to radiation and contrast media.

ELASTOGRAPHY, A PROMISING TEST

Hepatic elastography, a method for estimating liver stiffness, is an exciting recent development in the noninvasive measurement of hepatic fibrosis. Currently, elastography can be accomplished by ultrasound or magnetic resonance.

Ultrasound elastography

The FibroScan device (EchoSens, Paris, France) uses a mild-amplitude, low-frequency (50-Hz) vibration transmitted through the liver.³⁷ It induces an elastic shear wave that is detected by pulse-echo ultrasonography as the wave propagates through the organ.

The velocity of the wave correlates with tissue stiffness: the wave travels faster through denser, fibrotic tissue.^38,39

Ultrasound elastography (also called transient elastography) can sample a much larger area than liver biopsy can, providing a better understanding of the entire hepatic parenchyma. ⁴⁰ Moreover, it can be repeated often without risk. This device is in widespread use in many parts of the world, but it is not yet approved in the United States.

A meta-analysis of 50 studies assessed the overall performance of ultrasound elastography for diagnosing liver fibrosis.⁴¹ The areas under the receiver operating characteristic curve were as follows:

• For significant fibrosis: 0.84 (95% CI 0.82–0.86)
• For severe fibrosis: 0.89 (95% CI 0.88–0.91)
• For cirrhosis: 0.94 (95% CI 0.93–0.95).

The type of underlying liver disease influenced the diagnosis of significant fibrosis, which was diagnosed most consistently in patients with hepatitis C. The authors concluded that ultrasound elastography had excellent diagnostic accuracy for diagnosing cirrhosis irrespective of the underlying liver disease, while the diagnosis of significant fibrosis had higher variation, which was dependent on the underlying liver disease.

A meta-analysis of nine studies42 showed ultrasound elastography to have a sensitivity of 87% (95% CI 84%–90%) and a specificity of 91% (95% CI 89%–92%) for the diagnosis of cirrhosis. In seven of the nine studies, it diagnosed stage II to IV fibrosis with 70% sensitivity (95% CI 67%–73%) and 84% specificity (95% CI 80%–88%).

Limitations. Ultrasound elastography is less effective in obese patients, as the adipose tissue attenuates the elastic wave, and it has not been reliable in patients with acute viral hepatitis.⁴³ Male sex, body mass index greater than 30, and metabolic syndrome seem to increase liver stiffness, thus limiting the use of this test.⁴⁴

Until more data are available, the ultimate value of ultrasound elastography in reducing the number of liver biopsies needed remains unknown. However, this test shows potential as a reliable and noninvasive way to assess the degree of fibrosis in patients with liver disease.

Magnetic resonance elastography

From Talawalkar JA. Elastography for detecting hepatic fibrosis: options and considerations. Gastroenterology 2008; 135:299–302; used with permission from the American Gastroenterological Society.

Studies have shown a magnetic resonance scoring system that distinguishes Child-Pugh grade A cirrhosis from other grades to be 93% sensitive and 82% specific.⁴⁵

Reprinted from Huwart L, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008; 135:32–40; used with permission from the American Gastroenterological Society.

Cost may limit the use of magnetic resonance elastography, and some patients may be unable to tolerate the procedure because of claustrophobia. It seems clear, though, that this test currently has the most promise in reducing the need for liver biopsy for grading the severity of hepatic fibrosis.

WHERE ARE WE NOW?

The importance of liver biopsy in arriving at a diagnosis of diffuse parenchymal liver disease is being diminished by accurate blood testing strategies for chronic viral hepatitis, autoimmune hepatitis, and primary biliary cirrhosis. Further, imaging tests are superior to liver biopsy in the diagnosis of primary sclerosing cholangitis.

However, many cases remain in which diagnostic confusion exists even after suitable laboratory testing and imaging studies. Diagnosing infiltrative disease (eg, amyloidosis, sarcoidosis), separating benign fatty liver disease from steatohepatitis, and evaluating liver parenchyma after liver transplantation are best accomplished by liver biopsy.

While needle biopsy is still the mainstay in diagnosing hepatic fibrosis, its days of dominance seem limited as technology improves. When physical examination or standard laboratory tests reveal clear-cut signs of portal hypertension, liver biopsy will seldom add useful information. Similarly, when imaging studies provide compelling evidence of cirrhosis and portal hypertension, needle biopsy is not warranted.

The SAFE algorithms warrant further evaluation in all chronic liver diseases, as they may help decrease the number of liver biopsies required. And we believe elastography will play an ever-increasing role in the assessment of hepatic fibrosis and will significantly reduce the need for biopsy in patients with liver disease.

Primary care physicians and specialists alike often encounter patients with chronic liver disease. Fortunately, these days we need to resort to liver biopsy less often than in the past.

The purpose of this review is to provide a critical assessment of the growing number of noninvasive tests available for diagnosing liver disease and assessing hepatic fibrosis, and to discuss the implications of these advances related to the indications for needle liver biopsy.

WHEN IS LIVER BIOPSY USEFUL?

In diagnosis

Needle liver biopsy for diagnosis remains important in cases of:

Diagnostic uncertainty (eg, in patients with atypical features)

Coexisting disorders (eg, human immunodeficiency virus [HIV] and hepatitis C virus infection, or alcoholic liver disease and hepatitis C)

An overlapping syndrome (eg, primary biliary cirrhosis with autoimmune hepatitis).

Fatty liver. Needle liver biopsy can distinguish between benign steatosis and progressive steatohepatitis in a patient with a fatty liver found on imaging, subject to the limitations of sampling error.

Because fatty liver disease is common and proven treatments are few, no consensus has emerged about which patients with suspected fatty liver disease should undergo needle biopsy. Many specialists eschew needle biopsy and treat the underlying risk factors of metabolic syndrome, reserving biopsy for patients with findings that raise the concern of cirrhosis.

Hereditary disorders, eg, hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson disease.

In management

Periodic needle biopsy is also valuable in the management of a few diseases.

In autoimmune hepatitis, monitoring the plasma cell score on liver biopsy may help predict relapse when a physician is considering reducing or discontinuing immunosuppressive therapy.¹

After liver transplantation, a liver biopsy is highly valuable to assess for rejection and the presence and intensity of disease recurrence.

PROBLEMS WITH LIVER BIOPSY

Liver biopsy is invasive and can cause significant complications. Nearly 30% of patients report having substantial pain after liver biopsy, and some experience serious complications such as pneumothorax, bleeding, or puncture of the biliary tree. In rare cases, patients die of bleeding.²

Furthermore, hepatic pathology, particularly fibrosis, is not always uniformly distributed. Surgical wedge biopsy provides adequate tissue volume to overcome this problem. Needle biopsy, on the other hand, provides a much smaller volume of tissue (1/50,000 of the total mass of the liver).³

As examples of the resulting sampling errors that can occur, consider the two most common chronic liver diseases: hepatitis C and fatty liver disease.

Regev et al⁴ performed laparoscopically guided biopsy of the right and left hepatic lobes in a series of 124 patients with chronic hepatitis C. Biopsy samples from the right and left lobes differed in the intensity of inflammation in 24.2% of cases, and in the intensity of fibrosis in 33.1%. Differences of more than one grade of inflammation or stage of fibrosis were uncommon. However, in 14.5%, cirrhosis was diagnosed in one lobe but not the other.

In a study in patients with nonalcoholic fatty liver disease, Ratziu et al⁵ found that none of the features characteristic of nonalcoholic steatohepatitis were highly concordant in paired liver biopsies. Clearly, needle liver biopsy is far from an ideal test.

Increasingly, liver diseases can be diagnosed precisely with laboratory tests, imaging studies, or both. Thus, needle liver biopsy is playing a lesser role in diagnosis.

ADVANCES IN NONINVASIVE DIAGNOSIS OF LIVER DISEASE

Over the past 30 years, substantial strides have been made in our ability to make certain diagnoses through noninvasive means.

Blood tests can be used to diagnose viral hepatitis A, B, and C and many cases of hemochromatosis and primary biliary cirrhosis. For a detailed discussion of how blood tests are used in diagnosing liver diseases, see www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/guide-to-common-liver-tests/.

Imaging studies. Primary sclerosing cholangitis can be diagnosed with an imaging study, ie, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). The value of needle biopsy in these patients is limited to assessing the degree of fibrosis to help with management of the disease and, less often, to discovering other liver pathologies.⁶

Most benign space-occupying liver lesions, both cystic and solid, can be fully characterized by imaging, especially in patients who have no underlying chronic liver disease, and no biopsy is needed. Whether biopsy should be performed to investigate liver lesions depends on the clinical scenario; the topic is beyond the scope of this paper but has been reviewed in detail by Rockey et al.²

CAN NONINVASIVE TESTS DETECT HEPATIC FIBROSIS?

Based on information in Batts KP, Ludwig J. Chronic hepatitis: an update on terminology and reporting. Am J Surg Pathol 1995; 19:1409–1417.

Cirrhosis (stage 4 fibrosis) results in nodular transformation of the liver and impedance of portal blood flow, setting the stage for portal hypertension and its sequelae. Knowing whether cirrhosis is present is important in subsequent management.

In advanced cases, cirrhosis is associated with typical clinical manifestations and laboratory and radiographic findings. In such cases, needle biopsy will add little. However, in most cases, particularly early in the course, clinical, laboratory, and radiologic correlates of cirrhosis are absent. In one study of patients with hepatitis C, 27% had cirrhosis, but in only a small number would cirrhosis have been apparent from clinical signs and laboratory and imaging studies.⁶

Since a major contemporary role for liver biopsy is in assessing the degree of fibrosis, it is reasonable to ask if newer noninvasive means are available to estimate hepatic fibrosis. The remainder of this review focuses on assessing our increasing ability to stage the degree of fibrosis (including the presence or absence of cirrhosis) by noninvasive means.

Clinical features point to cirrhosis, but not earlier fibrosis

Clinical manifestations help point to the diagnosis of cirrhosis but not to earlier stages of fibrosis.

For example, if a patient is known to have liver disease, the findings of ascites, splenomegaly, or asterixis mean that cirrhosis is highly probable. Similarly, hypersplenism (splenomegaly with a decrease in circulating blood cells but a normal to hyperactive bone marrow) in a patient with liver test abnormalities almost always represents portal hypertension due to cirrhosis, although other, nonhepatic causes are possible, such as congestive heart failure and constrictive pericarditis.

These features generally emerge late in the course of cirrhosis. The absence of such stigmata certainly does not preclude the presence of cirrhosis. Thus, these clinical signs have a high positive predictive value but a low negative predictive value, making them insufficient by themselves to diagnose or stage liver disease.

Laboratory tests are of limited value in assessing the degree of fibrosis

Standard liver tests are of limited value in assessing the degree of fibrosis.

Usual laboratory tests. At one end of the spectrum, anemia, thrombocytopenia, and leukopenia in the presence of liver disease correlate with cirrhosis. At the other end, a serum ferritin concentration of less than 1,000 mg/mL in a patient with hemochromatosis and no confounding features such as hepatitis C, HIV infection, or heavy alcohol use strongly predicts that the patient does not have significant hepatic fibrosis.⁸

Bilirubin elevation is a late finding in cirrhosis, but in cholestatic diseases bilirubin may be elevated before cirrhosis occurs.

Albumin is made exclusively in the liver, and its concentration falls as liver function worsens with progressive cirrhosis.

The prothrombin time increases as the liver loses its ability to synthesize clotting factors in cirrhosis. Coagulopathy correlates with the degree of liver disease.

Hyponatremia due to impaired ability to excrete free water is seen in patients with cirrhosis and ascites.

In summary, the usual laboratory tests related to liver disease are imprecise and, when abnormal, often indicate not just the presence of cirrhosis, but impending or actual decompensation.

Newer serologic markers, alone or in combination, have been proposed as aids in determining the degree of fibrosis or cirrhosis in the liver. Direct markers of fibrosis measure the turnover or metabolism of extracellular matrix. Indirect markers of fibrosis reflect alterations in hepatic function (see below).

Parkes et al⁹ reviewed 10 different panels of serum markers of hepatic fibrosis in chronic hepatitis C. Only 35% of patients had fibrosis adequately ruled in or ruled out by these panels, and the stage of fibrosis could not be adequately determined.

These serologic markers have not been validated in other chronic liver diseases or in liver disease due to multiple causes. Thus, although they show promise for use by the general internist, they need to be validated in patients with disease and in normal reference populations before they are ready for “prime time.”

Direct serologic markers of fibrosis

Direct serologic markers of fibrosis include those associated with matrix deposition—eg, procollagen type III amino-terminal peptide (P3NP), type I and IV collagens, laminin, hyaluronic acid, and chondrex.

P3NP is the most widely studied marker of hepatic fibrosis. It is elevated in both acute and chronic liver diseases; serum levels reflect the histologic stage of hepatic fibrosis in various chronic liver diseases, including alcoholic, viral, and primary biliary cirrhosis.^10–12 Successful treatment of autoimmune hepatitis has been shown to lead to reductions of P3NP levels.¹³

Other direct markers of fibrosis are those associated with matrix degradation, ie, matrix metalloproteinases 2 and 3 (MMP-2, MMP-3) and tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2). Levels of MMP-2 proenzymes and active enzymes are increased in liver disease, but studies are inconsistent in correlating serum levels of MMP-2 to the degree of hepatic fibrosis.^14,15 These tests are not commercially available, and the components are not readily available in most clinical laboratories.

Some indirect markers are readily available:

The AST:ALT ratio. The normal ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is approximately 0.8. A ratio greater than 1.0 provides evidence of cirrhosis. However, findings have been inconsistent.

The AST:platelet ratio index (APRI), a commonly used index, is calculated by the following formula:

In studies of hepatitis C and hepatitis C-HIV, the APRI has shown a sensitivity of 37% to 80% and a specificity of 45% to 98%, depending on the cutoff value and whether a diagnosis of severe fibrosis or cirrhosis was being tested.^16–19 These sensitivities and specificities are disappointing and do not provide information equal to that provided by needle liver biopsy in most patients with chronic liver disease.

The combination of prothrombin, gamma glutamyl, and apolipoprotein AI levels (PGA index) has been validated in patients with many types of chronic liver disease, and its accuracy for detecting cirrhosis is highest (66%–72%) in patients with alcoholic liver disease.^20,21

FibroIndex uses the platelet count, AST level, and gamma globulin level to detect significant fibrosis in chronic hepatitis C, but its accuracy has yet to be validated.²²

The FIB-4 index is based on four independent predictors of fibrosis, ie, age, the platelet count, AST level, and ALT level. It has shown good accuracy for detecting advanced fibrosis in two studies in patients with hepatitis C.^23,24

Fibrometer (based on the platelet count; the prothrombin index; the levels of AST, alfa-2 macroglobulin, hyaluronate, and blood urea nitrogen; and age) predicted fibrosis well in chronic viral hepatitis.^25,26

Fibrotest and Fibrosure are proprietary commercial tests available in many laboratories. They employ a mathematical formula to predict fibrosis (characterized as mild, significant, or indeterminate) using the levels of alpha-2 macroglobulin, alpha-2 globulin, gamma globulin, apolipoprotein A1, gamma glutamyl transferase, and total bilirubin. For detecting significant fibrosis, these tests are reported to have a sensitivity of about 75% and a specificity of 85%.^27–29

ActiTest incorporates the ALT level into the Fibrotest to reflect liver fibrosis and necro-inflammatory activity.

A meta-analysis showed that Fibrotest and ActiTest could be reliable alternatives to liver biopsy in patients with chronic hepatitis C.³⁰ The area under the receiver operator characteristic curve for the diagnosis of significant fibrosis ranged from 0.73 to 0.87; for the diagnosis of significant histologic activity it ranged from 0.75 to 0.86. Fibrotest had a negative predictive value for excluding significant fibrosis of 91% with a cutoff of 0.31. ActiTest’s negative predictive value for excluding significant necrosis was 85% with a cutoff of 0.36. None of these serum tests have become part of standard of practice for diagnosing fibrosis or cirrhosis.

The Sequential Algorithm for Fibrosis Evaluation (SAFE) combines the APRI and Fibrotest-Fibrosure tests in a sequential fashion to test for fibrosis and cirrhosis. In a large multicenter study³¹ validating this algorithm to detect significant fibrosis (stage F2 or greater by the F0–F4 METAVIR scoring system³²), its accuracy was 90.1%, the area under the receiver operating characteristic curve was 0.89 (95% CI 0.87–0.90), and it reduced the number of liver biopsies needed by 46.5%. When the algorithm was used to detect cirrhosis, its accuracy was 92.5%, the area under the curve was 0.92 (95% CI 0.89–0.94), and it reduced the number of liver biopsies needed by 81.5%.

Another algorithm was developed to simultaneously detect significant fibrosis and cirrhosis. It had a 97.4% accuracy, but 64% of patients still required a liver biopsy.³¹

SAFE algorithms have the potential to reduce the number of needle biopsies needed to assess the degree of hepatic fibrosis.

CONVENTIONAL IMAGING STUDIES ARE NOT SENSITIVE FOR FIBROSIS

Standard imaging studies often show findings of cirrhosis but are not particularly sensitive, with a low negative predictive value.

Ultrasonography can show a small, nodular liver in advanced cirrhosis, but surface nodularity or increased echogenicity can be seen in hepatic steatosis as well as in cirrhosis. In one study,³³ ultrasonography identified diffuse parenchymal disease but could not reliably distinguish fat from fibrosis or diagnose cirrhosis.

Often, in cirrhosis, the right lobe of the liver is atrophied and the caudate or left lobes are hypertrophied. Efforts to use the ratio of the widths of the lobes to diagnose cirrhosis have shown varying performance characterstics.^34,35

One study of the splenic artery pulsatility index has shown this to be an accurate predictor of cirrhosis.³⁶

Computed tomography provides information similar to that of ultrasonography, and it can identify complications of cirrhosis, including portal hypertension and ascites. On the other hand, it costs more and it exposes the patient to radiation and contrast media.

ELASTOGRAPHY, A PROMISING TEST

Hepatic elastography, a method for estimating liver stiffness, is an exciting recent development in the noninvasive measurement of hepatic fibrosis. Currently, elastography can be accomplished by ultrasound or magnetic resonance.

Ultrasound elastography

The FibroScan device (EchoSens, Paris, France) uses a mild-amplitude, low-frequency (50-Hz) vibration transmitted through the liver.³⁷ It induces an elastic shear wave that is detected by pulse-echo ultrasonography as the wave propagates through the organ.

The velocity of the wave correlates with tissue stiffness: the wave travels faster through denser, fibrotic tissue.^38,39

Ultrasound elastography (also called transient elastography) can sample a much larger area than liver biopsy can, providing a better understanding of the entire hepatic parenchyma. ⁴⁰ Moreover, it can be repeated often without risk. This device is in widespread use in many parts of the world, but it is not yet approved in the United States.

A meta-analysis of 50 studies assessed the overall performance of ultrasound elastography for diagnosing liver fibrosis.⁴¹ The areas under the receiver operating characteristic curve were as follows:

• For significant fibrosis: 0.84 (95% CI 0.82–0.86)
• For severe fibrosis: 0.89 (95% CI 0.88–0.91)
• For cirrhosis: 0.94 (95% CI 0.93–0.95).

The type of underlying liver disease influenced the diagnosis of significant fibrosis, which was diagnosed most consistently in patients with hepatitis C. The authors concluded that ultrasound elastography had excellent diagnostic accuracy for diagnosing cirrhosis irrespective of the underlying liver disease, while the diagnosis of significant fibrosis had higher variation, which was dependent on the underlying liver disease.

A meta-analysis of nine studies42 showed ultrasound elastography to have a sensitivity of 87% (95% CI 84%–90%) and a specificity of 91% (95% CI 89%–92%) for the diagnosis of cirrhosis. In seven of the nine studies, it diagnosed stage II to IV fibrosis with 70% sensitivity (95% CI 67%–73%) and 84% specificity (95% CI 80%–88%).

Limitations. Ultrasound elastography is less effective in obese patients, as the adipose tissue attenuates the elastic wave, and it has not been reliable in patients with acute viral hepatitis.⁴³ Male sex, body mass index greater than 30, and metabolic syndrome seem to increase liver stiffness, thus limiting the use of this test.⁴⁴

Until more data are available, the ultimate value of ultrasound elastography in reducing the number of liver biopsies needed remains unknown. However, this test shows potential as a reliable and noninvasive way to assess the degree of fibrosis in patients with liver disease.

Magnetic resonance elastography

From Talawalkar JA. Elastography for detecting hepatic fibrosis: options and considerations. Gastroenterology 2008; 135:299–302; used with permission from the American Gastroenterological Society.

Studies have shown a magnetic resonance scoring system that distinguishes Child-Pugh grade A cirrhosis from other grades to be 93% sensitive and 82% specific.⁴⁵

Reprinted from Huwart L, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008; 135:32–40; used with permission from the American Gastroenterological Society.

Cost may limit the use of magnetic resonance elastography, and some patients may be unable to tolerate the procedure because of claustrophobia. It seems clear, though, that this test currently has the most promise in reducing the need for liver biopsy for grading the severity of hepatic fibrosis.

WHERE ARE WE NOW?

The importance of liver biopsy in arriving at a diagnosis of diffuse parenchymal liver disease is being diminished by accurate blood testing strategies for chronic viral hepatitis, autoimmune hepatitis, and primary biliary cirrhosis. Further, imaging tests are superior to liver biopsy in the diagnosis of primary sclerosing cholangitis.

However, many cases remain in which diagnostic confusion exists even after suitable laboratory testing and imaging studies. Diagnosing infiltrative disease (eg, amyloidosis, sarcoidosis), separating benign fatty liver disease from steatohepatitis, and evaluating liver parenchyma after liver transplantation are best accomplished by liver biopsy.

While needle biopsy is still the mainstay in diagnosing hepatic fibrosis, its days of dominance seem limited as technology improves. When physical examination or standard laboratory tests reveal clear-cut signs of portal hypertension, liver biopsy will seldom add useful information. Similarly, when imaging studies provide compelling evidence of cirrhosis and portal hypertension, needle biopsy is not warranted.

The SAFE algorithms warrant further evaluation in all chronic liver diseases, as they may help decrease the number of liver biopsies required. And we believe elastography will play an ever-increasing role in the assessment of hepatic fibrosis and will significantly reduce the need for biopsy in patients with liver disease.

Primary care physicians and specialists alike often encounter patients with chronic liver disease. Fortunately, these days we need to resort to liver biopsy less often than in the past.

The purpose of this review is to provide a critical assessment of the growing number of noninvasive tests available for diagnosing liver disease and assessing hepatic fibrosis, and to discuss the implications of these advances related to the indications for needle liver biopsy.

WHEN IS LIVER BIOPSY USEFUL?

In diagnosis

Needle liver biopsy for diagnosis remains important in cases of:

Diagnostic uncertainty (eg, in patients with atypical features)

Coexisting disorders (eg, human immunodeficiency virus [HIV] and hepatitis C virus infection, or alcoholic liver disease and hepatitis C)

An overlapping syndrome (eg, primary biliary cirrhosis with autoimmune hepatitis).

Fatty liver. Needle liver biopsy can distinguish between benign steatosis and progressive steatohepatitis in a patient with a fatty liver found on imaging, subject to the limitations of sampling error.

Because fatty liver disease is common and proven treatments are few, no consensus has emerged about which patients with suspected fatty liver disease should undergo needle biopsy. Many specialists eschew needle biopsy and treat the underlying risk factors of metabolic syndrome, reserving biopsy for patients with findings that raise the concern of cirrhosis.

Hereditary disorders, eg, hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson disease.

In management

Periodic needle biopsy is also valuable in the management of a few diseases.

In autoimmune hepatitis, monitoring the plasma cell score on liver biopsy may help predict relapse when a physician is considering reducing or discontinuing immunosuppressive therapy.¹

After liver transplantation, a liver biopsy is highly valuable to assess for rejection and the presence and intensity of disease recurrence.

PROBLEMS WITH LIVER BIOPSY

Liver biopsy is invasive and can cause significant complications. Nearly 30% of patients report having substantial pain after liver biopsy, and some experience serious complications such as pneumothorax, bleeding, or puncture of the biliary tree. In rare cases, patients die of bleeding.²

Furthermore, hepatic pathology, particularly fibrosis, is not always uniformly distributed. Surgical wedge biopsy provides adequate tissue volume to overcome this problem. Needle biopsy, on the other hand, provides a much smaller volume of tissue (1/50,000 of the total mass of the liver).³

As examples of the resulting sampling errors that can occur, consider the two most common chronic liver diseases: hepatitis C and fatty liver disease.

Regev et al⁴ performed laparoscopically guided biopsy of the right and left hepatic lobes in a series of 124 patients with chronic hepatitis C. Biopsy samples from the right and left lobes differed in the intensity of inflammation in 24.2% of cases, and in the intensity of fibrosis in 33.1%. Differences of more than one grade of inflammation or stage of fibrosis were uncommon. However, in 14.5%, cirrhosis was diagnosed in one lobe but not the other.

In a study in patients with nonalcoholic fatty liver disease, Ratziu et al⁵ found that none of the features characteristic of nonalcoholic steatohepatitis were highly concordant in paired liver biopsies. Clearly, needle liver biopsy is far from an ideal test.

Increasingly, liver diseases can be diagnosed precisely with laboratory tests, imaging studies, or both. Thus, needle liver biopsy is playing a lesser role in diagnosis.

ADVANCES IN NONINVASIVE DIAGNOSIS OF LIVER DISEASE

Over the past 30 years, substantial strides have been made in our ability to make certain diagnoses through noninvasive means.

Blood tests can be used to diagnose viral hepatitis A, B, and C and many cases of hemochromatosis and primary biliary cirrhosis. For a detailed discussion of how blood tests are used in diagnosing liver diseases, see www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/guide-to-common-liver-tests/.

Imaging studies. Primary sclerosing cholangitis can be diagnosed with an imaging study, ie, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). The value of needle biopsy in these patients is limited to assessing the degree of fibrosis to help with management of the disease and, less often, to discovering other liver pathologies.⁶

Most benign space-occupying liver lesions, both cystic and solid, can be fully characterized by imaging, especially in patients who have no underlying chronic liver disease, and no biopsy is needed. Whether biopsy should be performed to investigate liver lesions depends on the clinical scenario; the topic is beyond the scope of this paper but has been reviewed in detail by Rockey et al.²

CAN NONINVASIVE TESTS DETECT HEPATIC FIBROSIS?

Based on information in Batts KP, Ludwig J. Chronic hepatitis: an update on terminology and reporting. Am J Surg Pathol 1995; 19:1409–1417.

Cirrhosis (stage 4 fibrosis) results in nodular transformation of the liver and impedance of portal blood flow, setting the stage for portal hypertension and its sequelae. Knowing whether cirrhosis is present is important in subsequent management.

In advanced cases, cirrhosis is associated with typical clinical manifestations and laboratory and radiographic findings. In such cases, needle biopsy will add little. However, in most cases, particularly early in the course, clinical, laboratory, and radiologic correlates of cirrhosis are absent. In one study of patients with hepatitis C, 27% had cirrhosis, but in only a small number would cirrhosis have been apparent from clinical signs and laboratory and imaging studies.⁶

Since a major contemporary role for liver biopsy is in assessing the degree of fibrosis, it is reasonable to ask if newer noninvasive means are available to estimate hepatic fibrosis. The remainder of this review focuses on assessing our increasing ability to stage the degree of fibrosis (including the presence or absence of cirrhosis) by noninvasive means.

Clinical features point to cirrhosis, but not earlier fibrosis

Clinical manifestations help point to the diagnosis of cirrhosis but not to earlier stages of fibrosis.

For example, if a patient is known to have liver disease, the findings of ascites, splenomegaly, or asterixis mean that cirrhosis is highly probable. Similarly, hypersplenism (splenomegaly with a decrease in circulating blood cells but a normal to hyperactive bone marrow) in a patient with liver test abnormalities almost always represents portal hypertension due to cirrhosis, although other, nonhepatic causes are possible, such as congestive heart failure and constrictive pericarditis.

These features generally emerge late in the course of cirrhosis. The absence of such stigmata certainly does not preclude the presence of cirrhosis. Thus, these clinical signs have a high positive predictive value but a low negative predictive value, making them insufficient by themselves to diagnose or stage liver disease.

Laboratory tests are of limited value in assessing the degree of fibrosis

Standard liver tests are of limited value in assessing the degree of fibrosis.

Usual laboratory tests. At one end of the spectrum, anemia, thrombocytopenia, and leukopenia in the presence of liver disease correlate with cirrhosis. At the other end, a serum ferritin concentration of less than 1,000 mg/mL in a patient with hemochromatosis and no confounding features such as hepatitis C, HIV infection, or heavy alcohol use strongly predicts that the patient does not have significant hepatic fibrosis.⁸

Bilirubin elevation is a late finding in cirrhosis, but in cholestatic diseases bilirubin may be elevated before cirrhosis occurs.

Albumin is made exclusively in the liver, and its concentration falls as liver function worsens with progressive cirrhosis.

The prothrombin time increases as the liver loses its ability to synthesize clotting factors in cirrhosis. Coagulopathy correlates with the degree of liver disease.

Hyponatremia due to impaired ability to excrete free water is seen in patients with cirrhosis and ascites.

In summary, the usual laboratory tests related to liver disease are imprecise and, when abnormal, often indicate not just the presence of cirrhosis, but impending or actual decompensation.

Newer serologic markers, alone or in combination, have been proposed as aids in determining the degree of fibrosis or cirrhosis in the liver. Direct markers of fibrosis measure the turnover or metabolism of extracellular matrix. Indirect markers of fibrosis reflect alterations in hepatic function (see below).

Parkes et al⁹ reviewed 10 different panels of serum markers of hepatic fibrosis in chronic hepatitis C. Only 35% of patients had fibrosis adequately ruled in or ruled out by these panels, and the stage of fibrosis could not be adequately determined.

These serologic markers have not been validated in other chronic liver diseases or in liver disease due to multiple causes. Thus, although they show promise for use by the general internist, they need to be validated in patients with disease and in normal reference populations before they are ready for “prime time.”

Direct serologic markers of fibrosis

Direct serologic markers of fibrosis include those associated with matrix deposition—eg, procollagen type III amino-terminal peptide (P3NP), type I and IV collagens, laminin, hyaluronic acid, and chondrex.

P3NP is the most widely studied marker of hepatic fibrosis. It is elevated in both acute and chronic liver diseases; serum levels reflect the histologic stage of hepatic fibrosis in various chronic liver diseases, including alcoholic, viral, and primary biliary cirrhosis.^10–12 Successful treatment of autoimmune hepatitis has been shown to lead to reductions of P3NP levels.¹³

Other direct markers of fibrosis are those associated with matrix degradation, ie, matrix metalloproteinases 2 and 3 (MMP-2, MMP-3) and tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2). Levels of MMP-2 proenzymes and active enzymes are increased in liver disease, but studies are inconsistent in correlating serum levels of MMP-2 to the degree of hepatic fibrosis.^14,15 These tests are not commercially available, and the components are not readily available in most clinical laboratories.

Some indirect markers are readily available:

The AST:ALT ratio. The normal ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is approximately 0.8. A ratio greater than 1.0 provides evidence of cirrhosis. However, findings have been inconsistent.

The AST:platelet ratio index (APRI), a commonly used index, is calculated by the following formula:

In studies of hepatitis C and hepatitis C-HIV, the APRI has shown a sensitivity of 37% to 80% and a specificity of 45% to 98%, depending on the cutoff value and whether a diagnosis of severe fibrosis or cirrhosis was being tested.^16–19 These sensitivities and specificities are disappointing and do not provide information equal to that provided by needle liver biopsy in most patients with chronic liver disease.

The combination of prothrombin, gamma glutamyl, and apolipoprotein AI levels (PGA index) has been validated in patients with many types of chronic liver disease, and its accuracy for detecting cirrhosis is highest (66%–72%) in patients with alcoholic liver disease.^20,21

FibroIndex uses the platelet count, AST level, and gamma globulin level to detect significant fibrosis in chronic hepatitis C, but its accuracy has yet to be validated.²²

The FIB-4 index is based on four independent predictors of fibrosis, ie, age, the platelet count, AST level, and ALT level. It has shown good accuracy for detecting advanced fibrosis in two studies in patients with hepatitis C.^23,24

Fibrometer (based on the platelet count; the prothrombin index; the levels of AST, alfa-2 macroglobulin, hyaluronate, and blood urea nitrogen; and age) predicted fibrosis well in chronic viral hepatitis.^25,26

Fibrotest and Fibrosure are proprietary commercial tests available in many laboratories. They employ a mathematical formula to predict fibrosis (characterized as mild, significant, or indeterminate) using the levels of alpha-2 macroglobulin, alpha-2 globulin, gamma globulin, apolipoprotein A1, gamma glutamyl transferase, and total bilirubin. For detecting significant fibrosis, these tests are reported to have a sensitivity of about 75% and a specificity of 85%.^27–29

ActiTest incorporates the ALT level into the Fibrotest to reflect liver fibrosis and necro-inflammatory activity.

A meta-analysis showed that Fibrotest and ActiTest could be reliable alternatives to liver biopsy in patients with chronic hepatitis C.³⁰ The area under the receiver operator characteristic curve for the diagnosis of significant fibrosis ranged from 0.73 to 0.87; for the diagnosis of significant histologic activity it ranged from 0.75 to 0.86. Fibrotest had a negative predictive value for excluding significant fibrosis of 91% with a cutoff of 0.31. ActiTest’s negative predictive value for excluding significant necrosis was 85% with a cutoff of 0.36. None of these serum tests have become part of standard of practice for diagnosing fibrosis or cirrhosis.

The Sequential Algorithm for Fibrosis Evaluation (SAFE) combines the APRI and Fibrotest-Fibrosure tests in a sequential fashion to test for fibrosis and cirrhosis. In a large multicenter study³¹ validating this algorithm to detect significant fibrosis (stage F2 or greater by the F0–F4 METAVIR scoring system³²), its accuracy was 90.1%, the area under the receiver operating characteristic curve was 0.89 (95% CI 0.87–0.90), and it reduced the number of liver biopsies needed by 46.5%. When the algorithm was used to detect cirrhosis, its accuracy was 92.5%, the area under the curve was 0.92 (95% CI 0.89–0.94), and it reduced the number of liver biopsies needed by 81.5%.

Another algorithm was developed to simultaneously detect significant fibrosis and cirrhosis. It had a 97.4% accuracy, but 64% of patients still required a liver biopsy.³¹

SAFE algorithms have the potential to reduce the number of needle biopsies needed to assess the degree of hepatic fibrosis.

CONVENTIONAL IMAGING STUDIES ARE NOT SENSITIVE FOR FIBROSIS

Standard imaging studies often show findings of cirrhosis but are not particularly sensitive, with a low negative predictive value.

Ultrasonography can show a small, nodular liver in advanced cirrhosis, but surface nodularity or increased echogenicity can be seen in hepatic steatosis as well as in cirrhosis. In one study,³³ ultrasonography identified diffuse parenchymal disease but could not reliably distinguish fat from fibrosis or diagnose cirrhosis.

Often, in cirrhosis, the right lobe of the liver is atrophied and the caudate or left lobes are hypertrophied. Efforts to use the ratio of the widths of the lobes to diagnose cirrhosis have shown varying performance characterstics.^34,35

One study of the splenic artery pulsatility index has shown this to be an accurate predictor of cirrhosis.³⁶

Computed tomography provides information similar to that of ultrasonography, and it can identify complications of cirrhosis, including portal hypertension and ascites. On the other hand, it costs more and it exposes the patient to radiation and contrast media.

ELASTOGRAPHY, A PROMISING TEST

Hepatic elastography, a method for estimating liver stiffness, is an exciting recent development in the noninvasive measurement of hepatic fibrosis. Currently, elastography can be accomplished by ultrasound or magnetic resonance.

Ultrasound elastography

The FibroScan device (EchoSens, Paris, France) uses a mild-amplitude, low-frequency (50-Hz) vibration transmitted through the liver.³⁷ It induces an elastic shear wave that is detected by pulse-echo ultrasonography as the wave propagates through the organ.

The velocity of the wave correlates with tissue stiffness: the wave travels faster through denser, fibrotic tissue.^38,39

Ultrasound elastography (also called transient elastography) can sample a much larger area than liver biopsy can, providing a better understanding of the entire hepatic parenchyma. ⁴⁰ Moreover, it can be repeated often without risk. This device is in widespread use in many parts of the world, but it is not yet approved in the United States.

A meta-analysis of 50 studies assessed the overall performance of ultrasound elastography for diagnosing liver fibrosis.⁴¹ The areas under the receiver operating characteristic curve were as follows:

• For significant fibrosis: 0.84 (95% CI 0.82–0.86)
• For severe fibrosis: 0.89 (95% CI 0.88–0.91)
• For cirrhosis: 0.94 (95% CI 0.93–0.95).

The type of underlying liver disease influenced the diagnosis of significant fibrosis, which was diagnosed most consistently in patients with hepatitis C. The authors concluded that ultrasound elastography had excellent diagnostic accuracy for diagnosing cirrhosis irrespective of the underlying liver disease, while the diagnosis of significant fibrosis had higher variation, which was dependent on the underlying liver disease.

A meta-analysis of nine studies42 showed ultrasound elastography to have a sensitivity of 87% (95% CI 84%–90%) and a specificity of 91% (95% CI 89%–92%) for the diagnosis of cirrhosis. In seven of the nine studies, it diagnosed stage II to IV fibrosis with 70% sensitivity (95% CI 67%–73%) and 84% specificity (95% CI 80%–88%).

Limitations. Ultrasound elastography is less effective in obese patients, as the adipose tissue attenuates the elastic wave, and it has not been reliable in patients with acute viral hepatitis.⁴³ Male sex, body mass index greater than 30, and metabolic syndrome seem to increase liver stiffness, thus limiting the use of this test.⁴⁴

Until more data are available, the ultimate value of ultrasound elastography in reducing the number of liver biopsies needed remains unknown. However, this test shows potential as a reliable and noninvasive way to assess the degree of fibrosis in patients with liver disease.

Magnetic resonance elastography

From Talawalkar JA. Elastography for detecting hepatic fibrosis: options and considerations. Gastroenterology 2008; 135:299–302; used with permission from the American Gastroenterological Society.

Studies have shown a magnetic resonance scoring system that distinguishes Child-Pugh grade A cirrhosis from other grades to be 93% sensitive and 82% specific.⁴⁵

Reprinted from Huwart L, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008; 135:32–40; used with permission from the American Gastroenterological Society.

Cost may limit the use of magnetic resonance elastography, and some patients may be unable to tolerate the procedure because of claustrophobia. It seems clear, though, that this test currently has the most promise in reducing the need for liver biopsy for grading the severity of hepatic fibrosis.

WHERE ARE WE NOW?

The importance of liver biopsy in arriving at a diagnosis of diffuse parenchymal liver disease is being diminished by accurate blood testing strategies for chronic viral hepatitis, autoimmune hepatitis, and primary biliary cirrhosis. Further, imaging tests are superior to liver biopsy in the diagnosis of primary sclerosing cholangitis.

However, many cases remain in which diagnostic confusion exists even after suitable laboratory testing and imaging studies. Diagnosing infiltrative disease (eg, amyloidosis, sarcoidosis), separating benign fatty liver disease from steatohepatitis, and evaluating liver parenchyma after liver transplantation are best accomplished by liver biopsy.

While needle biopsy is still the mainstay in diagnosing hepatic fibrosis, its days of dominance seem limited as technology improves. When physical examination or standard laboratory tests reveal clear-cut signs of portal hypertension, liver biopsy will seldom add useful information. Similarly, when imaging studies provide compelling evidence of cirrhosis and portal hypertension, needle biopsy is not warranted.

The SAFE algorithms warrant further evaluation in all chronic liver diseases, as they may help decrease the number of liver biopsies required. And we believe elastography will play an ever-increasing role in the assessment of hepatic fibrosis and will significantly reduce the need for biopsy in patients with liver disease.

Hepatitis B virus (HBV) infection is highly prevalent worldwide and is a major cause of morbidity and death. Two billion people globally have been infected with HBV, 350 to 400 million are chronic carriers, and tens of millions of new cases occur annually. Of those infected, 15% to 40% develop HBV complications, namely cirrhosis or hepatocellular carcinoma (HCC).^1–3

The high prevalence of HBV infection represents an enormous failure of public health, considering that HBV immunization has been available for an entire generation, and where it has been employed it has been highly effective at reducing the incidence of HBV infection. Immunization, however, has been underused.

This supplement to the Cleveland Clinic Journal of Medicine, derived from a live symposium, aims to enhance awareness of the natural history of HBV infection and clarify its management recommendations with illustrative case histories. The supplement starts with a brief review of HBV terminology, natural history, and epidemiology.

CHRONIC HBV INFECTION TERMINOLOGY

Familiarity with the terms commonly used to describe chronic HBV infection will help clinicians in the management of the disease⁴:

• Chronic HBV infection is defined as presence of hepatitis B surface antigen (HBsAg) for more than 6 months. Those with infection may also express another antigen, HB e antigen (HBeAg), a marker of heightened infectivity. At the same time, those who are HBeAg positive are better responders to antiviral therapy compared with those who are HBeAg negative.
• An inactive HBsAg carrier is an individual who is HBsAg positive with a very low level of circulating virus, liver enzyme levels within normal limits, and a low likelihood of having chronic progressive disease.
• Resolved HBV infection is defined as previous HBV infection with no remaining evidence of active disease. Such individuals test negative for HBsAg and positive for antibody to HBsAg (anti-HBs) and to HB core antigen (anti-HBc). They also have no detectable viral load, or HBV DNA, in their blood. In most instances, they are protected from reinfection.
• Reactivation is the reappearance of HBV infection in someone who is known to be an inactive HBsAg carrier or whose previous HBV infection had resolved (see “Case: Recurrence despite anti-HBs and HBsAg negativity”).
• HBeAg seroconversion is the transition from HBeAg-positive to HBeAg-negative status and development of antibody to HBeAg (anti-HBe), usually accompanied by less active liver disease and lower viral loads.
• HBeAg clearance is disappearance of HBeAg without the development of anti-HBe; reactivation or reversion to HBeAg-positive status can occur.

GEOGRAPHIC DISTRIBUTION OF CHRONIC HBV INFECTION

The global prevalence of HBV varies widely. Regions are divided into areas of low, intermediate, and high prevalence, defined as follows⁴:

• High prevalence implies that at least 8% of the population is currently infected, with a lifetime likelihood of active or resolved infection greater than 60%. About 45% of the world’s population lives in regions of high prevalence. Among this group, early childhood infections are common, with the virus usually transmitted from mother to infant during the perinatal period.
• Intermediate prevalence is defined as 2% to 7%, with a lifetime risk of infection of 20% to 60%. These regions represent about 43% of the global population. In intermediate-prevalence areas, infections occur in all age groups.
• Low prevalence is defined as less than 2% and represents only 12% of the global population. In these regions, the lifetime risk of infection is less than 20%.

North America is a low-prevalence area except for the northern rim, where Inuit and Yupik Eskimos have a high prevalence, and communities that have a substantial immigrant population from high-prevalence areas, such as sub-Saharan Africa and many parts of Asia.

Chronic HBV infection in the United States

Approximately 1.25 million individuals in the United States are HBsAg carriers.^2,4 In Asian Americans and Alaskan natives, the prevalence of HBsAg positivity, or chronic disease, is 5% to 15%.^5,6 Similarly, US health statistics sources estimate that among those who are chronically infected, approximately half are Asian American.⁷ As the Asian American population continues to increase (1.5 million to 7 million from 1970 to 1990^5,8; 11.9 million in the 2000 US Census⁸), the total prevalence of chronic HBV infection will increase as well.

Adapted, with permission, from Cleveland Clinic Journal of Medicine (Elgouhari HM, et al. Hepatitis B virus infection: understanding its epidemiology, course, and diagnosis. Cleve Clin J Med 2008; 75:881–889).

Chronic HBV usually causes microinflammatory changes that evoke a fibrotic response in the liver, and many infected individuals will eventually develop cirrhosis and are at risk for the development of HCC. Inactive HBsAg carriers often bypass the development of cirrhosis but remain at risk for HCC if their viral load is very high. This is particularly true when infection is acquired in infancy.

The age at acquisition of HBV has a large impact on the likelihood of the disease becoming chronic. The chance of chronic infection is 90% or greater among neonates who become infected with HBV through perinatal transmission. Exposure during adolescence or young adulthood is associated with a 95% or greater likelihood that the disease will be self-limiting.

The typical North American patient with HBV acquires the infection as an adolescent or young adult and is not at risk of HCC unless cirrhosis develops. In most patients who acquire the disease in adolescence or adulthood, the infection resolves after weeks or a few months and they are not at risk of either cirrhosis or HCC. However, an individual such as the one described in the accompanying case, who becomes immunocompromised, is at risk of reactivation of HBV infection (see “Case revisited”).

HBV MODES OF TRANSMISSION

In low-prevalence areas, such as most of North America, most cases of HBV infection are acquired during adolescence to midadulthood, a period during which behaviors that increase the risk of HBV infection (ie, intravenous drug abuse or unprotected sexual activity) are most likely.^9,10 Sex workers and homosexuals are at particular risk of sexual transmission of HBV. Intravenous drug abusers and health workers are at risk of parenteral transmission.

In high-prevalence areas, HBV is mostly transmitted during the perinatal period from mother to infant, conferring a high likelihood of chronicity.^9,10 Mothers who are HBsAg positive, particularly those who are also HBeAg positive, are much more likely than others to transmit HBV to their offspring.

FACTORS THAT INFLUENCE THE COURSE OF HBV INFECTION

Viral load has emerged as the most significant factor implicated in the development of cirrhosis or HCC. Iloeje et al¹¹ found that viral load predicted progression to cirrhosis among a cohort of nearly 4,000 Taiwanese. Other factors that can influence the course of HBV infection include age at onset, male sex, and comorbidities (ie, alcohol use, human immunodeficiency virus infection, hepatitis C virus infection). Core promoter and precore mutants may affect the likelihood of developing HCC. A genetic signature that predisposes liver cells to proliferate, termed field effects, may also lead to the development of HCC. The influence of smoking and diabetes on the development of HCC in HBV-infected individuals is not well documented.

Reduction or elimination of measurable virus is the current holy grail of treatment; available antiviral therapies are potent tools that lower viral load with the hope of reducing the likelihood of either cirrhosis or HCC.

HBV genotypes may be implicated in the progression of liver disease or the risk of development of HCC. HBV genotypes differ by region and may correlate with ethnicity and disease progression. In a study of 694 US patients with chronic HBV, Chu et al¹² found that genotypes A and C were associated with a higher prevalence of HBsAg positivity than other genotypes. Genotypes B and C were the most common among Asian American patients, while genotype A was the most common among Caucasian and African American patients. The authors suggested that HBV genotypes may explain the heterogeneity in the manifestation of the disease.

Hepatitis B virus (HBV) infection is highly prevalent worldwide and is a major cause of morbidity and death. Two billion people globally have been infected with HBV, 350 to 400 million are chronic carriers, and tens of millions of new cases occur annually. Of those infected, 15% to 40% develop HBV complications, namely cirrhosis or hepatocellular carcinoma (HCC).^1–3

The high prevalence of HBV infection represents an enormous failure of public health, considering that HBV immunization has been available for an entire generation, and where it has been employed it has been highly effective at reducing the incidence of HBV infection. Immunization, however, has been underused.

This supplement to the Cleveland Clinic Journal of Medicine, derived from a live symposium, aims to enhance awareness of the natural history of HBV infection and clarify its management recommendations with illustrative case histories. The supplement starts with a brief review of HBV terminology, natural history, and epidemiology.

CHRONIC HBV INFECTION TERMINOLOGY

Familiarity with the terms commonly used to describe chronic HBV infection will help clinicians in the management of the disease⁴:

• Chronic HBV infection is defined as presence of hepatitis B surface antigen (HBsAg) for more than 6 months. Those with infection may also express another antigen, HB e antigen (HBeAg), a marker of heightened infectivity. At the same time, those who are HBeAg positive are better responders to antiviral therapy compared with those who are HBeAg negative.
• An inactive HBsAg carrier is an individual who is HBsAg positive with a very low level of circulating virus, liver enzyme levels within normal limits, and a low likelihood of having chronic progressive disease.
• Resolved HBV infection is defined as previous HBV infection with no remaining evidence of active disease. Such individuals test negative for HBsAg and positive for antibody to HBsAg (anti-HBs) and to HB core antigen (anti-HBc). They also have no detectable viral load, or HBV DNA, in their blood. In most instances, they are protected from reinfection.
• Reactivation is the reappearance of HBV infection in someone who is known to be an inactive HBsAg carrier or whose previous HBV infection had resolved (see “Case: Recurrence despite anti-HBs and HBsAg negativity”).
• HBeAg seroconversion is the transition from HBeAg-positive to HBeAg-negative status and development of antibody to HBeAg (anti-HBe), usually accompanied by less active liver disease and lower viral loads.
• HBeAg clearance is disappearance of HBeAg without the development of anti-HBe; reactivation or reversion to HBeAg-positive status can occur.

GEOGRAPHIC DISTRIBUTION OF CHRONIC HBV INFECTION

The global prevalence of HBV varies widely. Regions are divided into areas of low, intermediate, and high prevalence, defined as follows⁴:

• High prevalence implies that at least 8% of the population is currently infected, with a lifetime likelihood of active or resolved infection greater than 60%. About 45% of the world’s population lives in regions of high prevalence. Among this group, early childhood infections are common, with the virus usually transmitted from mother to infant during the perinatal period.
• Intermediate prevalence is defined as 2% to 7%, with a lifetime risk of infection of 20% to 60%. These regions represent about 43% of the global population. In intermediate-prevalence areas, infections occur in all age groups.
• Low prevalence is defined as less than 2% and represents only 12% of the global population. In these regions, the lifetime risk of infection is less than 20%.

North America is a low-prevalence area except for the northern rim, where Inuit and Yupik Eskimos have a high prevalence, and communities that have a substantial immigrant population from high-prevalence areas, such as sub-Saharan Africa and many parts of Asia.

Chronic HBV infection in the United States

Approximately 1.25 million individuals in the United States are HBsAg carriers.^2,4 In Asian Americans and Alaskan natives, the prevalence of HBsAg positivity, or chronic disease, is 5% to 15%.^5,6 Similarly, US health statistics sources estimate that among those who are chronically infected, approximately half are Asian American.⁷ As the Asian American population continues to increase (1.5 million to 7 million from 1970 to 1990^5,8; 11.9 million in the 2000 US Census⁸), the total prevalence of chronic HBV infection will increase as well.

Adapted, with permission, from Cleveland Clinic Journal of Medicine (Elgouhari HM, et al. Hepatitis B virus infection: understanding its epidemiology, course, and diagnosis. Cleve Clin J Med 2008; 75:881–889).

Chronic HBV usually causes microinflammatory changes that evoke a fibrotic response in the liver, and many infected individuals will eventually develop cirrhosis and are at risk for the development of HCC. Inactive HBsAg carriers often bypass the development of cirrhosis but remain at risk for HCC if their viral load is very high. This is particularly true when infection is acquired in infancy.

The age at acquisition of HBV has a large impact on the likelihood of the disease becoming chronic. The chance of chronic infection is 90% or greater among neonates who become infected with HBV through perinatal transmission. Exposure during adolescence or young adulthood is associated with a 95% or greater likelihood that the disease will be self-limiting.

The typical North American patient with HBV acquires the infection as an adolescent or young adult and is not at risk of HCC unless cirrhosis develops. In most patients who acquire the disease in adolescence or adulthood, the infection resolves after weeks or a few months and they are not at risk of either cirrhosis or HCC. However, an individual such as the one described in the accompanying case, who becomes immunocompromised, is at risk of reactivation of HBV infection (see “Case revisited”).

HBV MODES OF TRANSMISSION

In low-prevalence areas, such as most of North America, most cases of HBV infection are acquired during adolescence to midadulthood, a period during which behaviors that increase the risk of HBV infection (ie, intravenous drug abuse or unprotected sexual activity) are most likely.^9,10 Sex workers and homosexuals are at particular risk of sexual transmission of HBV. Intravenous drug abusers and health workers are at risk of parenteral transmission.

In high-prevalence areas, HBV is mostly transmitted during the perinatal period from mother to infant, conferring a high likelihood of chronicity.^9,10 Mothers who are HBsAg positive, particularly those who are also HBeAg positive, are much more likely than others to transmit HBV to their offspring.

FACTORS THAT INFLUENCE THE COURSE OF HBV INFECTION

Viral load has emerged as the most significant factor implicated in the development of cirrhosis or HCC. Iloeje et al¹¹ found that viral load predicted progression to cirrhosis among a cohort of nearly 4,000 Taiwanese. Other factors that can influence the course of HBV infection include age at onset, male sex, and comorbidities (ie, alcohol use, human immunodeficiency virus infection, hepatitis C virus infection). Core promoter and precore mutants may affect the likelihood of developing HCC. A genetic signature that predisposes liver cells to proliferate, termed field effects, may also lead to the development of HCC. The influence of smoking and diabetes on the development of HCC in HBV-infected individuals is not well documented.

Reduction or elimination of measurable virus is the current holy grail of treatment; available antiviral therapies are potent tools that lower viral load with the hope of reducing the likelihood of either cirrhosis or HCC.

HBV genotypes may be implicated in the progression of liver disease or the risk of development of HCC. HBV genotypes differ by region and may correlate with ethnicity and disease progression. In a study of 694 US patients with chronic HBV, Chu et al¹² found that genotypes A and C were associated with a higher prevalence of HBsAg positivity than other genotypes. Genotypes B and C were the most common among Asian American patients, while genotype A was the most common among Caucasian and African American patients. The authors suggested that HBV genotypes may explain the heterogeneity in the manifestation of the disease.

Hepatitis B virus (HBV) infection is highly prevalent worldwide and is a major cause of morbidity and death. Two billion people globally have been infected with HBV, 350 to 400 million are chronic carriers, and tens of millions of new cases occur annually. Of those infected, 15% to 40% develop HBV complications, namely cirrhosis or hepatocellular carcinoma (HCC).^1–3

The high prevalence of HBV infection represents an enormous failure of public health, considering that HBV immunization has been available for an entire generation, and where it has been employed it has been highly effective at reducing the incidence of HBV infection. Immunization, however, has been underused.

This supplement to the Cleveland Clinic Journal of Medicine, derived from a live symposium, aims to enhance awareness of the natural history of HBV infection and clarify its management recommendations with illustrative case histories. The supplement starts with a brief review of HBV terminology, natural history, and epidemiology.

CHRONIC HBV INFECTION TERMINOLOGY

Familiarity with the terms commonly used to describe chronic HBV infection will help clinicians in the management of the disease⁴:

• Chronic HBV infection is defined as presence of hepatitis B surface antigen (HBsAg) for more than 6 months. Those with infection may also express another antigen, HB e antigen (HBeAg), a marker of heightened infectivity. At the same time, those who are HBeAg positive are better responders to antiviral therapy compared with those who are HBeAg negative.
• An inactive HBsAg carrier is an individual who is HBsAg positive with a very low level of circulating virus, liver enzyme levels within normal limits, and a low likelihood of having chronic progressive disease.
• Resolved HBV infection is defined as previous HBV infection with no remaining evidence of active disease. Such individuals test negative for HBsAg and positive for antibody to HBsAg (anti-HBs) and to HB core antigen (anti-HBc). They also have no detectable viral load, or HBV DNA, in their blood. In most instances, they are protected from reinfection.
• Reactivation is the reappearance of HBV infection in someone who is known to be an inactive HBsAg carrier or whose previous HBV infection had resolved (see “Case: Recurrence despite anti-HBs and HBsAg negativity”).
• HBeAg seroconversion is the transition from HBeAg-positive to HBeAg-negative status and development of antibody to HBeAg (anti-HBe), usually accompanied by less active liver disease and lower viral loads.
• HBeAg clearance is disappearance of HBeAg without the development of anti-HBe; reactivation or reversion to HBeAg-positive status can occur.