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MD Consult: Books: Goldman: Cecil Medicine: Chapter 152 – CHRONIC HEPATITIS

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 152 – CHRONIC HEPATITIS

Jay H. Hoofnagle

Definition

Chronic hepatitis comprises several diseases that are marked by chronic necro-inflammatory injury to the liver. The disease is defined as chronic if there is evidence of ongoing injury for 6 months or longer. The various forms of chronic hepatitis have similar clinical manifestations and outcomes, and each can lead to cirrhosis and end-stage liver disease ( Table 152-1 ). The most common forms are chronic hepatitis B and C and autoimmune hepatitis. Drug-induced ( Chapter 153 ) or metabolic ( Chapter 154 ) liver diseases, alcoholic steatohepatitis ( Chapter 156 ), and nonalcoholic steatohepatitis ( Chapter 156 ) can also cause chronic necro-inflammatory lesions of the liver. Despite extensive testing, some cases cannot be attributed to any known cause.


TABLE 152-1   — 
MAJOR CAUSES OF CHRONIC HEPATITIS

Chronic hepatitis B
Chronic hepatitis D
Chronic hepatitis C
Autoimmune hepatitis
Drug-induced chronic hepatitis
Wilson’s disease
Cryptogenic hepatitis (non-A–E hepatitis)
Epidemiology

The incidence and prevalence of chronic hepatitis in the general U.S. population have not been well defined. In population-based surveys, 2.3% of Americans have elevations in serum alanine aminotransferase (ALT) levels, 0.2% are seropositive for hepatitis B surface antigen (HBsAg), and 1.6% are reactive for antibody to hepatitis C virus (anti-HCV). Not all ALT elevations are due to chronic hepatitis, however, and not all HBsAg-positive or anti-HCV–positive individuals have active liver disease. A fair estimate is that chronic hepatitis affects 2% of the population, but these diseases tend to occur mostly in high-risk groups rather than the general population. For hepatitis B, high-risk groups include recent immigrants from endemic areas of the world (Africa, eastern Europe, Southeast Asia), persons with multiple sexual partners, men who have sex with men, injection drug users, recipients of blood or blood products before 1987, hemophiliacs, oncology and renal dialysis patients, and health care workers. For hepatitis C, high-risk groups include recipients of blood or blood products before 1992, hemophiliacs who received blood products before 1986, injection drug users, renal dialysis patients, health care workers, and persons with multiple sexual partners. Chronic hepatitis B and C probably cause 10,000 to 12,000 deaths yearly, and about another 2000 patients with these diseases undergo liver transplantation annually for end-stage liver failure.

Clinical Manifestations

The clinical symptoms of chronic hepatitis are typically nonspecific, intermittent, and mild; a large proportion of patients have no symptoms of liver disease. The most common symptom is fatigue, which may be intermittent. Some patients have sleep disorders or difficulty concentrating. Right upper quadrant pain, if present, is usually mild, intermittent, and aching in character. In many cases, the diagnosis of chronic hepatitis is made in a person without any symptoms after liver test abnormalities are identified when blood is drawn for a routine health evaluation, during assessment for an unrelated health problem, or at the time of voluntary blood donation ( Chapter 150 ). Symptoms of advanced disease or an acute exacerbation include nausea, poor appetite, weight loss, muscle weakness, itching, dark urine, and jaundice. When cirrhosis is present, weakness, weight loss, abdominal swelling, edema, ready bruisability, gastrointestinal bleeding, and hepatic encephalopathy with mental confusion may arise.

The clinical signs of liver disease in patients with chronic hepatitis are also usually minimal. The most common finding is liver tenderness. In patients with severe or advanced disease, other findings may include a firm liver or enlargement of the spleen, spider angiomas (see Fig. 134-4 ), and palmar erythema (see Fig. 149-5 ). When cirrhosis is present, signs may include muscle wasting, ascites (see Fig. 149-3 ), edema, skin excoriations (see Fig. 149-2 ) or bruises, and hepatic fetor.

Diagnosis

Although symptoms and signs are not particularly useful in identifying chronic hepatitis, biochemical and hematologic blood test results are reliable. Most typical are elevations in ALT and aspartate aminotransferase (AST) levels with little or no elevation in the alkaline phosphatase level. The elevations are usually in the range of one to five times the upper limit of normal, and the ALT level is generally higher than the AST level, unless cirrhosis is present. Serum aminotransferase levels can be normal when the disease is mild or inactive but can also be markedly elevated in the range typical of acute hepatitis (10 to 25 times the upper limit of normal) during acute exacerbations. Although there may be major discrepancies between the height of the liver enzyme elevations and histologic estimates of activity as shown by liver biopsy, monitoring of these values over time generally provides a reasonable estimate of the severity of disease and likelihood of progression.

In general, alkaline phosphatase and γ-glutamyl transpeptidase elevations are minimal in chronic hepatitis, unless cirrhosis is present. Creatine kinase and lactate dehydrogenase levels are normal. Serum bilirubin and albumin levels and the prothrombin time are normal in patients with chronic hepatitis, unless the disease is severe or advanced. Any elevation in serum direct bilirubin or decrease in albumin should be considered evidence of serious disease activity or injury. Serum immunoglobulin levels are mildly elevated or normal in chronic viral hepatitis but may be strikingly elevated in chronic autoimmune hepatitis. Blood counts are normal in chronic hepatitis, unless cirrhosis or portal hypertension is present with associated decreases in the white blood cell and platelet counts. Serial determinations of platelet counts may provide the earliest clinical evidence of progression of chronic hepatitis to advanced fibrosis and cirrhosis. Blood tests results that suggest the presence of advanced fibrosis are low platelet counts (below 160,000), AST levels higher than ALT levels, elevations in serum bilirubin, decreases in serum albumin, prolongation of the prothrombin time, elevations in α-fetoprotein levels, and the presence of rheumatoid factor or high globulin levels.

Imaging

Imaging with ultrasound can be performed to define hepatic texture and size, determine the presence of hepatic masses, assess the gallbladder and intrahepatic bile ducts, define the size of the spleen, and determine the presence of collateral vessels and portal venous flow. Computed tomography and magnetic resonance imaging of the liver are less helpful unless a mass or other abnormality is found by ultrasound. More recently, hepatic elastography has been used to assess hepatic stiffness as a marker for liver fibrosis. Though still experimental, preliminary results suggest that elastography may be a reliable, noninvasive means of detecting worsening of hepatic fibrosis and cirrhosis.

Histologic Analysis

Hepatic histologic characteristics include spotty hepatocellular necrosis, chronic inflammatory cell infiltration in the portal areas, and variable degrees of fibrosis. The hepatocellular necrosis is typically eosinophilic degeneration or ballooning degeneration. The necrosis is spotty throughout the parenchyma, but activity is usually greater in the periportal area; the pattern is termed piecemeal necrosis or interface hepatitis. The hepatocellular necrosis seems to be mediated largely by apoptosis in association with cytotoxic lymphocytes. Chronic inflammatory cells (CD4+ and CD8+ lymphocytes and plasma cells, histiocytes, and macrophages) are found in the areas of necrosis and in sinusoids but most prominently in the portal areas. Fibrosis occurs insidiously during the course of chronic hepatitis and typically begins in the periportal regions. Ultimately, bands of fibrosis can link up adjacent portal areas or portal and central areas (bridging fibrosis), distort the hepatic architecture, and lead to cirrhosis and portal hypertension.

Hepatic histologic analysis is useful for grading the severity of necro-inflammation and for staging the degree of fibrosis in chronic hepatitis and is generally obtained to confirm the diagnosis made through the patient’s history, physical examination, and blood test results. Hepatic histologic evaluation may help confirm the diagnosis of autoimmune hepatitis and clarify the role of α1-antitrypsin deficiency or Wilson’s disease. Most importantly, liver histologic analysis can exclude other diagnoses that can mimic chronic hepatitis clinically or cause similar patterns of elevated liver enzyme levels, including fatty liver, alcoholic liver disease, steatohepatitis ( Chapter 156 ), drug-induced liver disease ( Chapter 153 ), sclerosing cholangitis ( Chapter 159 ), iron overload ( Chapter 231 ), and veno-occlusive disease.

The grade of chronic hepatitis refers to the activity of the disease in terms of necrosis and inflammation; the grade of disease fluctuates and is reversible. The stage of disease refers to how advanced the fibrosis process is and whether cirrhosis is present; stages of disease have previously been considered irreversible, but it is now clear that successful treatment of chronic hepatitis caused by hepatitis B, hepatitis C, or autoimmune processes can result in reversal of hepatic fibrosis. The most commonly used system of grading and staging is the histology activity index, in which the combined scores for periportal necrosis and inflammation (0 to 10), lobular necrosis and inflammation (0 to 4), and portal inflammation (0 to 4) define the grade or activity of disease. Disease stage is defined by scores between 0 and 4 for fibrosis, with 4 indicating cirrhosis. A modification of the histology activity index system scores fibrosis from 0 to 6 (Ishak score), with stages 3 and 4 indicating bridging hepatic fibrosis and stages 5 and 6 representing incomplete and established cirrhosis. The Metavir system, which is used widely in Europe, grades activity on a 4-point scale (A0, A1, A2, A3) and fibrosis (F0, F1, F2, F3, F4) on a 5-point scale.

Differential Diagnosis

Chronic hepatitis can be caused by several diseases that are similar clinically but respond differently to therapy and must be managed individually. Patients with suspected chronic hepatitis should be evaluated carefully for fatty liver, alcohol- ( Chapter 156 ) or drug-induced ( Chapter 153 ) liver disease, and metabolic liver diseases ( Chapter 154 ), not only because these conditions mimic disorders that cause chronic hepatitis but also because they can coexist with the disorders that cause chronic hepatitis. After taking a history designed to elucidate risk factors for viral hepatitis, specific and appropriate serologic tests ( Table 152-2 ) can be used to make the diagnosis. Liver biopsy with special stains can be performed to confirm the diagnosis, assess the activity and severity of injury, and stage the disease.


TABLE 152-2   — 
DIFFERENTIAL DIAGNOSIS OF CHRONIC HEPATITIS

Diagnosis Screening Tests Confirmatory Tests (Serum or Liver) Comments
Chronic hepatitis B HBsAg HBV DNA, HBeAg, or HBcAg in liver  
Chronic hepatitis C Anti-HCV HCV RNA (using PCR) Immunoblot for anti-HCV can be used to confirm antibody reactivity
Chronic hepatitis D Anti-HDV HDV RNA or HDV antigen in the liver  
Autoimmune hepatitis ANA (anti-LKM1) Exclusion of other causes and patterns of clinical disease Suggested by raised IgG levels and by response to corticosteroid therapy
Drug-induced liver disease History Rechallenge, if necessary, is considered safe Medications most suspected include isoniazid, NSAIDs, methyldopa, nitrofurantoin
Wilson’s disease Ceruloplasmin Urine and hepatic copper concentration Suggested by hemolysis or severe chronic hepatitis in a child or adolescent
Cryptogenic Exclusion of other causes   Major differential is with autoimmune hepatitis and drug-induced liver disease

ANA = antinuclear antibody; anti-LKM1 = liver-kidney microsomal 1 antibody; HBcAg = hepatitis B core antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; IgG = immunoglobulin G; NSAIDs = nonsteroidal anti-inflammatory drugs.

Treatment

A treatment strategy should arise from careful consideration of the diagnosis and the grade and stage of disease (see later). With advances currently being made in antiviral and immunomodulatory therapeutics, it is anticipated that the considerable progress made in treating these diseases will continue in the future.

   CHRONIC HEPATITIS B

Pathobiology

Chronic hepatitis B is caused by infection with the hepatitis B virus (HBV), a DNA virus belonging to the family Hepadnaviridae ( Chapter 151 ). The diagnosis of chronic hepatitis B is generally suspected on the basis of HBsAg in the serum of a patient with chronic hepatitis and confirmed by the finding of HBV DNA in serum or hepatitis B core antigen (HBcAg) in the liver. Most patients with chronic hepatitis B also have hepatitis B e antigen (HBeAg) in serum as a result of high levels of viral replication. Some patients have active liver disease with HBsAg and high levels of HBV DNA but no HBeAg in serum. These patients usually harbor a mutant HBV that replicates efficiently and is pathogenic but does not produce HBeAg.

Liver injury and the pathogenesis of chronic hepatitis B are believed to be immunologically mediated, so the severity and course of disease do not correlate well with the level of virus in serum or with antigen expression in the liver. Antigen-specific cytotoxic T cells are believed to mediate the cellular injury in hepatitis B and account for ultimate viral clearance. Specific cytokines produced by cytotoxic and other T cells also have antiviral effects on hepatocytes that contribute to viral clearance without cell death. The progression of acute to chronic hepatitis B is attributed to lack of a vigorous cytotoxic T-cell response to hepatitis B antigens. Similarly, spontaneous seroconversion from HBeAg to anti-HBe during chronic hepatitis B may be immunologically mediated, as suggested from the transient flare of disease that often immediately precedes clearance of HBeAg. Some HBV strains may be more pathogenic and more likely to lead to chronic infection because they are less immunogenic or more resistant to T-cell attack. Seroconversion may be due to spontaneous mutations in the predominant HBV species to forms that produce HBsAg without HBeAg (e-negative mutant) and that are less efficient in replication and less pathogenic.

Epidemiology

There are at least six different genotypes of HBV, the most common being A, B, C, and D. The genotypes of HBV have distinct geographic variation in frequency and, in the United States, vary in prevalence by risk group. Genotype A is found largely in Western countries and is the most common genotype identified in men who have sex with men. Genotype D is most frequent in Mediterranean and eastern European countries and is common in injection drug users in the United States. Genotypes B and C are the major genotypes of China and Southeast Asia. Genotyping tests using line probe hybridization assays are available and generally accurate. There may be minor differences in the natural history of hepatitis B related to genotypes, with genotype C being associated with a greater likelihood of cirrhosis and hepatocellular carcinoma. More importantly, there may be genotypic differences in response to interferon-based therapy.

Clinical Manifestations

In the typical course of hepatitis B, HBsAg, HBeAg, and HBV DNA become detectable in serum during the incubation period and gradually rise in titer ( Fig. 152-1 ). Symptoms appear 30 to 152 days after exposure (mean incubation period, 75 days), usually at the time of peak viral levels. Symptoms are mild and nonspecific, and jaundice is rare. The appearance of jaundice during the course of acute infection is highly predictive of eventual recovery.

FIGURE 152-1  Typical serologic course of chronic hepatitis B. ALT = alanine aminotransferase; HBc = hepatitis B core antigen; HBeAg, HBe = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; PCR = polymerase chain reaction.

In chronic hepatitis, serum ALT levels decrease after the acute phase of infection but persist at levels between 1 and 10 times the upper limit of normal. HBsAg, HBeAg, and HBV DNA persist, generally at high levels; the finding of HBeAg more than 2 months after the onset of symptoms indicates evolution to chronicity. Levels of HBV DNA are generally in the range of 107 to 1011 genome copies/mL.

The subsequent course of chronic hepatitis B is highly variable. Some patients continue to have active viral replication with high levels of HBV DNA and HBeAg in serum and progressive liver injury; cirrhosis and end-stage liver disease may soon develop. In other patients, the disease is more indolent and insidiously leads to cirrhosis in decades. In a large proportion of patients, however, the outcome is more benign; the disease eventually goes into remission spontaneously, symptoms (if present) resolve, serum aminotransferase levels decrease to the normal range, and liver histologic characteristics improve. Remission is often preceded by a transient flare of disease and can be precipitous; it coincides with a major decrease in the level of HBV DNA and seroconversion from HBeAg to anti-HBe. HBsAg persists in serum at levels lower than before this seroconversion, and HBV DNA can be detected at low levels (generally <105 genome copies/mL) if sensitive techniques such as polymerase chain reaction (PCR) are used.

With the decrease in viral levels and loss of HBeAg, the disease seems to go into remission, thus suggesting that there has been a transition from chronic hepatitis B to an “inactive” carrier state with no symptoms, normal serum aminotransferase levels, and inactive liver disease indicated by biopsy findings. Loss of HBeAg is not always followed by permanent resolution of disease, however. In some patients, reactivation occurs with reappearance of HBeAg; in others, an HBV mutant develops and replicates efficiently but cannot produce HBeAg. These patients with HBeAg-negative chronic hepatitis B can have severe disease and often experience multiple clinical relapses.

Extrahepatic manifestations of chronic hepatitis B include mucocutaneous vasculitis, glomerulonephritis, and polyarteritis nodosa. The glomerulonephritis of hepatitis B occurs more commonly in children than adults and is usually characterized by nephrotic syndrome with little decrease in renal function. Polyarteritis nodosa ( Chapter 291 ) occurs primarily in adults and is marked by a sudden, severe onset of hypertension, renal disease, and systemic vasculitis with arteritis in vessels of the kidney, gallbladder, intestine, or brain.

Diagnosis

There are two general forms of chronic hepatitis B: typical, HBeAg-positive chronic hepatitis B, in which there is HBsAg, HBeAg, and high levels of HBV DNA in serum, and the less common HBeAg-negative form, in which there is HBsAg and anti-HBe without HBeAg in serum. Patients with HBeAg-negative chronic hepatitis B often have moderate or fluctuating levels of HBV DNA in serum. These forms of chronic hepatitis B should be distinguished from the inactive (which has been inappropriately referred to as healthy) HBsAg carrier state, in which HBsAg persists in serum without active liver disease and minimal or no detectable viral replication ( Table 152-3 ); in the inactive carrier state, HBV DNA is not detectable in serum with conventional hybridization assays sensitive to levels of 106 viral copies/mL. Testing for HBV DNA by the more sensitive PCR assays generally shows low levels of viral genome (almost always <104 viral copies/mL) in the serum of patients with the inactive carrier state.


TABLE 152-3   — 
THREE FORMS OF CHRONIC HEPATITIS B VIRUS INFECTION

Pattern HBsAg HBeAg HBV DNA[*] (Titer) HBcAg in Liver Chronic Hepatitis
Typical chronic hepatitis B Positive Positive Positive, 107–1011 Positive (nuclear) Active
HBeAg-negative chronic hepatitis B Positive Negative Positive, 105–109 Positive (cytoplasmic) Active (relapsing)
Inactive HBsAg carrier state Positive Negative Positive, 101–105 Negative Inactive

HBcAg = hepatitis B core antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus.

* Positive or negative result by hybridization techniques (sensitive to a titer of 106 genome-equivalents/mL). Titers less than 106 genome-equivalents/mL generally require polymerase chain reaction assays for detection.

Treatment

Nonspecific recommendations for the management of chronic hepatitis B include vaccination of all household and sexual contacts. Patients should be counseled on the modes of transmission of hepatitis B and means of prevention of spread. Vaccination against hepatitis A is also recommended. Patients with hepatitis B should be advised to abstain from alcohol and to avoid all but the most necessary use of immunosuppressive medications. Severe flares of hepatitis B and even deaths have followed short courses of corticosteroids or cancer chemotherapy. If corticosteroids or chemotherapy is required for other conditions, prophylaxis against reactivation should be given (see later).

Medical Therapy

The conventional treatment of chronic hepatitis B is a course of standard or pegylated interferon alfa (peginterferon). Because of its ease of administration and better efficacy, peginterferon has largely replaced standard interferon. Peginterferon is given by subcutaneous injection in doses of 180 μg (peginterferon alfa-2a) or 1.5 μg/kg body weight (alfa-2b) weekly for 24 to 48 weeks, a regimen that results in clearance of HBeAg in about a third and clearance of HBsAg in up to 5% of patients ( Table 152-4 ). The combination of other antiviral agents with peginterferon does not appear to increase the sustained response rate.

Therapy with peginterferon is indicated for patients who have chronic hepatitis B with HBsAg, HBeAg, and HBV DNA in serum and elevations in serum aminotransferase levels. Therapy with peginterferon is contraindicated in patients with advanced cirrhosis, in solid organ transplant recipients, in immunosuppressed patients, and in patients with other serious major illnesses. Peginterferon therapy is not recommended for patients with normal or near-normal serum aminotransferase levels (even if high levels of HBV DNA are present), largely because it is usually ineffective in this situation. The major factors associated with a higher likelihood of response to peginterferon are initial high levels of serum aminotransferase (elevated more than five-fold), lower levels of HBV DNA (less than 107 genome copies/mL), HBV genotypes A and B (vs. C and D), and absence of immunosuppression. The potential benefits and risks of interferon therapy should be discussed thoroughly before treatment. The major side effects of interferon include fatigue, muscle aches, fever, depression, and irritability; uncommon severe side effects include suicide, psychosis, renal and cardiac failure, bacterial infections, and induction of autoimmune disorders (see the discussion of treatment of chronic hepatitis C).

With initiation of treatment, levels of HBV DNA usually decrease. In patients with a beneficial response (as defined by loss of HBeAg with treatment), the disease may flare transiently with elevations in serum ALT to levels two to three times baseline after 2 to 3 months of therapy, coinciding with a precipitous fall in HBV DNA levels and loss of HBeAg. Serum aminotransferase levels decrease to normal, and a proportion of patients lose HBsAg, often many months to several years after loss of HBeAg. Reactivation of disease with rises in aminotransferase levels and reappearance of HBeAg and high levels of HBV DNA occurs rarely. Nonresponders to peginterferon therapy, who remain HBeAg positive, may have improvements in serum aminotransferase levels and disease activity, but over time these improvements are generally lost. Such patients should be considered for maintenance therapy with oral antiviral agents.

Several oral nucleoside and nucleotide analogues, including lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate, entecavir, clevudine (L-FMAU), emtricitabine (FTC), and telbivudine (l-thymidine), have been shown to have potent effects against HBV in vitro and in vivo. Four of these agents (lamivudine, telbivudine, adefovir, and entecavir) are currently approved for use in the United States (see Table 152-4 ), and several others are likely to be approved in the near future.

Lamivudine is a negative enantiomer of a 3′ sulfated cytidine analogue and has major activity against HBV and human immunodeficiency virus (HIV). Lamivudine is recommended at a dose of 100 mg/day for 1 year. Initiation of therapy is followed rapidly by marked falls in HBV DNA by 4 to 6 log10 units to levels less than 105 viral copies/mL within the first 3 to 6 months of starting therapy. Prolonged therapy (≥1 year) is associated with loss of HBeAg in up to a third of patients. With loss of HBeAg and the development of anti-HBe, lamivudine therapy can be stopped; relapses are uncommon when seroconversion occurs. Most patients remain HBeAg positive, however, despite improvements in HBV DNA and aminotransferase levels. In patients with HBeAg-negative chronic hepatitis B, lamivudine is associated with a higher rate of response, with improvements in ALT levels and liver histology in two thirds of patients. However, relapse is almost invariable in HBeAg-negative chronic hepatitis B once lamivudine therapy is discontinued. Lamivudine is well tolerated; in randomized trials, side effects were no more common with lamivudine than with placebo. The lack of side effects with lamivudine and the improvements in HBV DNA and serum aminotransferase levels that occur with therapy support the use of lamivudine as maintenance, long-term therapy for hepatitis B with the goal of long-term suppression of HBV replication.[1]

Instances of long-term biochemical and histologic improvement have been reported in chronic hepatitis B with continuous lamivudine therapy. However, long-term therapy is associated with development of viral resistance in a high proportion of patients. Lamivudine resistance is marked by a rise in HBV DNA toward baseline levels, followed by elevations in serum aminotransferase levels. Most patients with viral resistance harbor an HBV mutant with amino acid changes in the conserved region of the polymerase gene (YMDD mutates to either YIDD or YVDD). Typically, patients with YMDD mutations have lower levels of HBV DNA and serum aminotransferase levels than were present before therapy, thus suggesting that the mutant HBV is less efficient in replication and less pathogenic than the wild-type virus. Lamivudine resistance develops in 20 to 25% of patients in each year of therapy, so after 4 to 5 years of treatment, more than two thirds of patients have HBV mutants.

Telbivudine, the L-enantiomer of deoxythymidine, is a potent and specific inhibitor of HBV replication in vitro and in vivo. In preliminary studies in patients with HBeAg-positive chronic hepatitis B, a 1-year course of telbivudine resulted in a 106 log10 decrease in HBV DNA levels and loss of HBeAg in 28% of patients. Adefovir dipivoxil is a nucleotide analogue (bis-POM-PMEA) that acts as a prodrug of adefovir with enhanced oral availability. Adefovir has activity in vitro and in vivo against both wild-type and lamivudine-resistant HBV strains. Monotherapy with adefovir dipivoxil (given in a dose of 10 mg daily) leads to marked decreases in HBV DNA levels (by 3 to 4 log10 units) and subsequent improvements in serum aminotransferase levels and hepatic histology in approximately half of patients (see Table 152-4 ). Even higher rates of response are reported in HBeAg-negative chronic hepatitis B. However, discontinuation of therapy is usually followed by relapse and return of disease activity, particularly in HBeAg-negative patients. Long-term trials of adefovir dipivoxil therapy are now under way; studies of treatment for up to 4 years show that clinical and genetic evidence of viral resistance occurs slowly (0% at 1, 3% at 2, 11% at 3, and 18% at 4 years). [2] [3] The safety of 10 mg of adefovir daily has been shown in randomized trials in which side effects were no more common with adefovir than with placebo. Higher doses of adefovir are associated with the development of renal toxicity (renal tubular acidosis) after 6 to 12 months of treatment. For these reasons, the dose of adefovir should be kept to 10 mg daily or less, and patients should be monitored for increases in serum creatinine; any elevation of greater than 0.5 mg/dL above baseline levels should lead to an immediate modification of the dose or temporary withholding of therapy. The safety of adefovir dipivoxil in patients with preexisting renal disease has not been shown. Thus, adefovir dipivoxil monotherapy is a practical approach to long-term therapy for both HBeAg-positive and HBeAg-negative disease and can be used in cases of lamivudine resistance.

Entecavir, a recently approved oral nucleoside analogue therapy for chronic hepatitis B, appears to be the most potent. Entecavir is a guanosine analogue with activity against wild-type HBV in cell culture, but somewhat less activity against lamivudine-resistant strains. Studies in humans at doses of 0.5 mg daily show that therapy is followed by a rapid decrease in HBV DNA levels averaging 105 to 107 log10 declines within 6 to 12 months. Entecavir is well tolerated and associated with a high rate of response as assessed by loss of detectable HBV DNA, normalization of aminotransferase levels, and improvement in liver histology (see Table 152-4 ). Unfortunately, entecavir, like lamivudine and adefovir, leads to loss of HBeAg in only 20 to 25% of patients, and relapse is frequent once treatment with the drug is stopped.[4] Thus, long-term therapy is required for continued suppression of HBV and improvement in liver disease. Importantly, entecavir has been associated with a very low rate of antiviral resistance: in preliminary reports, no resistance was detected after 1 to 2 years of treatment except in patients with preexisting lamivudine resistance. Although entecavir is effective against lamivudine-resistant HBV strains, higher doses (1 mg daily) are recommended and response rates are lower than in patients without resistance. These findings lend support to the recommendation to avoid the use of long-term lamivudine monotherapy in HBeAg-positive chronic hepatitis B. The safety and continued efficacy of long-term entecavir therapy are still under evaluation.

There are no clear guidelines for the use of antiviral therapy for hepatitis B. Peginterferon is effective in approximately a third of patients with HBeAg-positive chronic hepatitis B, but it is expensive and poorly tolerated. Lamivudine, telbivudine, adefovir, and entecavir are easy to administer and have minimal side effects, but they are less likely to lead to sustained loss of HBeAg or HBsAg (see Table 152-4 ). Furthermore, the decision of whether to stop or continue therapy after 1 to 2 years is often difficult. Withdrawal of therapy with nucleoside or nucleotide analogues usually results in a rapid return of HBV DNA levels toward baseline, and this return of viral replication can be associated with a transient exacerbation of disease, which in some instances can be severe or even fatal and ultimately reverse any benefit of years of treatment. Management of lamivudine resistance is particularly challenging; it is often appropriate to stop therapy when resistance develops.

At present, monotherapy with nucleoside or nucleotide analogues should be limited to patients who have moderate to severe chronic hepatitis B as shown by liver biopsy histology or by clinical features. Selected patients with HBeAg-positive chronic hepatitis B should be treated first with peginterferon, with the oral antiviral agents reserved for those who fail to respond to or cannot tolerate a course of peginterferon. When using nucleoside or nucleotide therapy for hepatitis B, the need for long-term treatment should be expected. The benefits of long-term therapy with the oral antiviral agents in patients with advanced fibrosis and cirrhosis have been shown dramatically in studies of lamivudine therapy in which it was demonstrated that long-term suppression of viral replication can decrease the rate of hepatic decompensation and hepatocellular carcinoma and improve survival. The benefits of long-term therapy in patients with less-advanced stages of chronic hepatitis B have not been proved, although marked improvements in biochemical test results and liver histology have been shown in selected patients. The choice of oral antiviral agent should be based on the response rate and likelihood of resistance. Patients with lamivudine resistance should be reevaluated for the necessity of therapy and perhaps are best switched to adefovir dipivoxil therapy (discontinuing lamivudine). Combinations of antiviral agents have been proposed as being effective in preventing antiviral resistance, but the added benefit of combination therapy over monotherapy for hepatitis B has yet to be demonstrated in clinical trials.[5]

The oral antiviral agents should not be used in patients with mild or minimal disease despite the presence of HBeAg or high levels of HBV DNA (or both). An exception to this caution is a patient with chronic hepatitis B or an inactive carrier state who requires therapy with a pulse or short course of immunosuppression or corticosteroids, as with cyclic cancer chemotherapy or bone marrow transplantation. The use of lamivudine in this situation is directed at preventing reactivation of hepatitis, which can be severe and even life-threatening. These patients should be treated for the duration of immunosuppressive therapy. Recommendations regarding indications and regimens and the duration of therapy will change as more effective combination antiviral therapies are developed.


TABLE 152-4   — 
RESPONSE RATES TO 48 WEEKS OF THERAPY FOR CHRONIC HEPATITIS B[*]

Antiviral Agent Loss of HBsAg Loss of HBeAg Loss of HBV DNA (by PCR) Normal ALT Levels Improved Histology
HBeAg-POSITIVE CHRONIC HEPATITIS B
Peginterferon[] 3.0% 34% 14% 41% 38%
Lamivudine 1.1% 20% 36% 60% 62%
Adefovir <1% 24% 21% 48% 53%
Entecavir 1.7% 22% 67% 68% 72%
Placebo <1% 11% <1% 16% 25%
HBeAg-NEGATIVE CHRONIC HEPATITIS B
Peginterferon[] 4.0% NA 19% 59% 48%
Lamivudine <1% NA 72% 71% 61%
Adefovir <1% NA 51% 72% 64%
Entecavir <1% NA 90% 78% 70%
Placebo <1% NA <1% 29% 33%

ALT = alanine aminotransferase; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; NA = not applicable; PCR = polymerase chain reaction.

* Summarized from six recent randomized controlled trials.
Results were measured at the end of 48 weeks of therapy and while still on treatment, with the exception of results for peginterferon, which were measured 24 weeks after stopping treatment.

   CHRONIC HEPATITIS D

Epidemiology and Pathobiology

Hepatitis D is caused by combined infection with hepatitis B and the hepatitis D virus (HDV), a defective RNA virus that replicates and spreads efficiently only in the presence of HBsAg ( Chapter 151 ). Hepatitis D is the least common form of chronic viral hepatitis but is also the most severe. On average, cirrhosis develops in 70% of patients with chronic hepatitis D, generally at a younger age than in patients with hepatitis B alone.

Diagnosis

The diagnosis of chronic hepatitis D is usually made on the basis of finding antibody to HDV (anti-HDV) in a patient with chronic hepatitis and HBsAg in serum. The diagnosis can be confirmed by identification of HDV antigen in liver or by detection of HDV RNA in serum, a research test not generally available. Most patients with chronic hepatitis D have HBsAg without serologic markers of active viral replication (i.e., they have a negative result for HBeAg and either low levels [<105 viral copies/mL] or no detectable HBV DNA). Delta hepatitis should be considered in all patients with HBsAg in serum and active liver disease, particularly those who have low levels or no detectable HBV DNA in serum. Replication of HDV seems to suppress replication of HBV.

Treatment

Therapy for hepatitis D is difficult. A prolonged course of high doses of interferon alfa (5 to 10 million U/day or three times weekly) results in improvements in serum aminotransferase levels and liver histology in approximately a third of patients. With the exception of patients who become HBsAg negative during treatment, however, most patients have a relapse when therapy is stopped. Trials of long-term therapy with peginterferon are currently under way. Neither corticosteroids nor lamivudine or adefovir is helpful. General management recommendations for hepatitis D are the same as for hepatitis B.

   CHRONIC HEPATITIS C

Epidemiology

Hepatitis C is spread largely by the parenteral route, most commonly as a result of injection drug use or receipt of blood transfusions before the introduction of routine screening of blood for anti-HCV (in 1992) or receipt of plasma products before the introduction of inactivation procedures (in 1986). Hepatitis C also occurs after accidental needlesticks and is an occupational hazard for health care workers. In 10 to 30% of patients, a parenteral source of infection cannot be identified, even after careful questioning. These sporadic cases of hepatitis C are probably related to sexual contact or “inapparent” parenteral spread. Sexual spread of hepatitis C can occur, but the risk is low, and sexual transmission has been described primarily in individuals with multiple partners and in patients after exposure to acute rather than chronic hepatitis C. Maternal-infant spread of HCV occurs in approximately 5% of infants of mothers with chronic hepatitis C. Neither breast-feeding nor the type of delivery correlates with transmission, but transmission is more frequent in newborns of women with prolonged labor, early rupture of membranes, and invasive fetal monitoring. Coinfection with HIV in the mother may also increase the risk for transmission of HCV.

Pathobiology

Chronic hepatitis C is caused by infection with HCV, an RNA virus classified in the genus Hepacivirus, family Flaviviridae ( Chapter 151 ). HCV has marked genetic heterogeneity, with nucleotide variability between different isolates ranging from 1 to 50%. Phylogenetic analysis indicates that there are at least six different genotypes of HCV (differing by 30 to 50% in sequence) and more than 90 subtypes (differing by 15 to 30%). Different isolates of a single genotype can vary by 5 to 15%, and virions isolated from a single individual often differ by 1 to 5%, a phenomenon that is termed quasispecies diversity and that may account for the propensity of this virus to lead to chronic infection. The most common genotypes in the United States are 1a and 1b (approximately 75%), 2a and 2b (approximately 15%), and 3a (approximately 7%). Genotype 4 typically occurs in Africa and the Middle East and is uncommon in the United States. Genotype 5 is rare outside South Africa, and genotype 6 is rare outside Southeast Asia. Infections with different genotypes do not differ in clinical expression or disease severity, but responses to interferon-based therapies depend on the genotype of the infection.

The pathogenesis of viral persistence and the cause of hepatic injury in chronic HCV infection are unknown, but cytotoxic T-lymphocyte–mediated responses are probably important. In general, the degree of liver injury does not correlate with the level or genotype of virus but tends to increase with the duration of infection. Nevertheless, some individuals remain infected with HCV for decades yet have minimal changes on liver biopsy. Alcohol ingestion and other causes of liver injury (e.g., iron overload, nonalcoholic steatohepatitis, or concurrent hepatitis virus infection) may augment the liver injury in chronic HCV infection.

Clinical Manifestations

In the typical course of chronic hepatitis C ( Fig. 152-2 ), HCV RNA becomes detectable soon after exposure and remains present throughout the course of the acute illness and thereafter. Approximately a third of patients experience symptoms during the acute episode, and a similar percentage are jaundiced. Aminotransferase levels vary widely but after the acute episode are usually less than 10 times the upper limit of normal. In about a third of infected individuals, serum aminotransferase levels decrease and remain in the normal range despite persistence of HCV RNA. These individuals nevertheless have chronic hepatitis on liver biopsy. Anti-HCV rises after the onset of ALT elevations and symptoms, and it generally persists at high titer. Anti-HCV may not become detectable in patients who have renal failure, are immunosuppressed, or have hypogammaglobulinemia or agammaglobulinemia.

FIGURE 152-2  Typical serologic course of chronic hepatitis C. ALT = alanine aminotransferase; HCV = hepatitis C virus; PCR = polymerase chain reaction.

Natural History

The natural history of hepatitis C is highly variable. A small proportion of patients have severe and progressive disease, and cirrhosis and end-stage liver disease develop within a few years; other patients have a benign outcome. In patients monitored from the time of acute infection (e.g., after blood transfusion or receipt of contaminated blood products), chronic infection arises in approximately 55 to 85%, but cirrhosis develops in only 5 to 20% within the first 20 years. In these patients there is little or no increase in hepatitis C–related mortality during the first 2 decades of infection. When patients with established chronic hepatitis C are monitored prospectively, cirrhosis develops in 30 to 50% and morbidity and mortality rates are substantial, with the development of end-stage liver disease or hepatocellular carcinoma, particularly in patients with cirrhosis or severe fibrosis indicated on initial liver biopsy. At the time of diagnosis, the average patient probably has had the infection for 15 to 25 years (dating the onset from the time of presumed exposure).

Factors associated with a risk for development of cirrhosis in patients with chronic hepatitis C include age, male sex, alcohol use, and coinfection with other hepatitis viruses or HIV. Factors associated with an increased rate of development of hepatocellular carcinoma are cirrhosis or advanced fibrosis on liver biopsy, age, male sex, and alcohol abuse. In some retrospective studies, treatment with interferon alfa, even without a sustained virologic response, has been associated with a lower rate of development of liver cancer. Obesity, diabetes, and steatosis on liver biopsy have been associated with more advanced disease in some studies, but it remains unclear whether these factors are the result rather than the cause of the worse disease. Viral genotype and high virus levels have not been linked to an increased rate of cirrhosis or liver cancer.

Extrahepatic manifestations of chronic hepatitis C include cryoglobulinemia ( Chapter 198 ), glomerulonephritis ( Chapter 122 ), mucocutaneous vasculitis ( Chapter 291 ), sicca syndrome ( Chapter 289 ), non-Hodgkin’s B-cell lymphoma ( Chapter 196 ), porphyria cutanea tarda ( Chapter 229 ), lichen planus ( Chapter 464 ), and perhaps fibromyalgia ( Chapter 295 ). Cryoglobulinemia, which is the most common and well-defined complication of hepatitis C, occurs in approximately 1% of adults with this infection. Typical manifestations are fatigue, myalgias, arthralgias, rash (purpura, hives, and leukocytoclastic vasculitis), neuropathy, and renal disease (glomerulonephritis). Laboratory testing reveals high levels of rheumatoid factor and cryoglobulins containing anti-HCV and HCV RNA, with low levels of complement. Cryoglobulinemia can be severe and lead to end-stage renal disease or severe neuropathies. Long-term cryoglobulinemia has been linked to B-cell lymphomas.

Diagnosis

The diagnosis of chronic hepatitis C is usually based on detection of anti-HCV in a patient with serum aminotransferase elevations or a risk factor for hepatitis C ( Table 152-5 ). The typical test for anti-HCV is an enzyme immunoassay, which can occasionally yield a false-positive result. A recombinant immunoblot assay can be used to confirm anti-HCV reactivity. The diagnosis of hepatitis C is confirmed more aptly, however, by a qualitative, sensitive assay for HCV RNA in serum, such as reverse transcriptase PCR. If anti-HCV is present without HCV RNA, recovery from hepatitis C rather than persistent infection has probably occurred. Several commercial assays are available to quantify HCV RNA levels in serum, but these tests have been difficult to standardize. Most patients with chronic hepatitis C have 105 to 107 IU of HCV RNA in serum, and levels are usually stable over time. HCV RNA levels should be measured before and during therapy, but otherwise there is little clinical value in monitoring levels of HCV RNA.


TABLE 152-5   — 
INTERPRETATION OF SEROLOGIC MARKERS FOR HEPATITIS C

Anti-HCV (EIA) Anti-HCV (RIBA) HCV RNA (PCR) ALT Interpretation
Positive Positive Positive Elevated Acute or chronic hepatitis C
Positive Positive Positive Normal Chronic hepatitis C
Positive Positive Negative Normal Resolved hepatitis C
Positive Negative Negative Normal False-positive EIA assay result

ALT = alanine aminotransferase; Anti-HCV = antibody to hepatitis C virus; EIA = enzyme immunoassay; HCV RNA = hepatitis C viral RNA; PCR = polymerase chain reaction; RIBA = recombinant immunoblot assay.

Treatment

Management of patients with chronic hepatitis C should include counseling to abstain from alcohol and evaluation for hepatitis A and B vaccination. Therapy for hepatitis C is rapidly evolving, and the development of pegylated interferons has improved response rates to a 48-week course of the combination of peginterferon and ribavirin to 54 to 56%.[6]

Combination Therapy

With combination therapy, HCV RNA levels typically decrease rapidly on starting treatment and, in responders, become undetectable within 1 to 3 months ( Fig. 152-3 ). Serum aminotransferase levels become normal in most patients with a virologic response. In patients who relapse, HCV RNA and elevations in serum ALT levels reappear soon after therapy is stopped. In nonresponders, ALT levels may decrease and become normal, but HCV RNA remains detectable. The presence or absence of HCV RNA during therapy is the most accurate means of assessing response, and the most accurate end point in defining a beneficial response to treatment is absence of detectable HCV RNA (by a reliable and sensitive PCR technique) for at least 6 months after stopping therapy. A 6-month, post-treatment sustained virologic response is highly predictive of long-term remission and resolution of the liver disease and probably indicates eradication of the infection and cure of the disease.

The major pretreatment factor associated with a beneficial response to combination therapy is the viral genotype, which determines the optimal recommendations for dose and duration of therapy. In patients with genotypes 2 and 3, sustained response rates are 70 to 80%, and these rates can be achieved by a 24-week course of therapy with a lower dose of ribavirin (800 mg daily). In contrast, in patients with genotype 1, sustained response rates are higher with a 48-week course of therapy (40 to 45%) than with a 24-week course, and optimal response rates require a full dose of ribavirin (1000 to 1200 mg daily). In patients with genotype 1 infection, other pretreatment factors that are associated with a higher likelihood of response are low levels of HCV RNA (below 800,000 IU/mL), lack of severe hepatic fibrosis or cirrhosis, young age, female sex, and non–African American race. These factors have minimal effects on response rates in patients with HCV genotypes 2 and 3.

Response rates to combination therapy are lower in African American patients (25 to 30%) than in white patients (45 to 55%) with HCV genotype 1 infection for reasons that are unclear. Response rates are also lower in patients with cirrhosis. However, these negative predictive factors should not be used to deny or exclude patients from treatment; indeed, patients with advanced fibrosis and cirrhosis are the most likely to benefit from a sustained virologic response. Patients with genotype 1 infection can be assessed for the likelihood of response during therapy to allow for early discontinuation in those who are unlikely to have a sustained response. The conventional approach is to test for HCV RNA after 24 weeks of combination therapy and discontinue treatment in patients who are still reactive. An alternative approach is to measure HCV RNA levels at the start of therapy and again after 12 weeks. Patients who fail to have a 2-log10 decrease in HCV RNA levels (or to become negative) are unlikely to have a sustained virologic response (<2% likelihood). This early stopping rule can be helpful in limiting the expense and side effects of treatment in patients who are unlikely to have a sustained response to a full 48-week course of treatment. This approach is not necessary in patients with genotypes 2 or 3.

At present, therapy is recommended for patients with chronic hepatitis C and HCV RNA in serum, raised serum aminotransferase levels, chronic hepatitis of at least moderate severity on a liver biopsy specimen (presence of fibrosis or moderate degrees of inflammation and necrosis), and no contraindications to treatment. Contraindications to combination therapy with peginterferon and ribavirin are decompensated liver disease, renal failure, severe immunosuppression, solid organ transplantation, cytopenia, severe psychiatric disease, and active substance abuse. Ribavirin therapy is contraindicated in patients with hemolysis, anemia, significant coronary or cerebrovascular disease, or renal insufficiency. Because ribavirin is teratogenic, it is essential that adequate contraception be practiced during therapy in men and women and for at least 6 months thereafter. Patients with genotype 1 should receive a 48-week course of peginterferon (1.5 μg/kg of alfa-2b or 180 μg of alfa-2a) weekly in combination with ribavirin at a dose of 1000 mg if body weight is less than 75 kg and 1200 mg if body weight is greater than 75 kg. Patients with genotype 2 or 3 should receive a 24-week course of peginterferon (at the same dose as for genotype 1 patients) and ribavirin at a dose of 800 mg/day. The side effects of interferon and ribavirin must be reviewed carefully before starting therapy. Interferon induces an influenza-like syndrome with the first several doses. Thereafter, the major side effects are fatigue, malaise, depression, difficulty concentrating, bone marrow suppression, and in rare instances, bacterial infections or induction of autoimmune disease. Side effects of ribavirin include a dose-related hemolysis that usually results in a 5 to 15% decrease in hemoglobin level, mild itching, and nasal congestion. Dose modification is frequently required during therapy. Ribavirin should be decreased in 200-mg increments for side effects of anemia and hemolysis. In the event of interferon side effects, peginterferon should be decreased stepwise, from 180 to 135 to 90 μg/wk for peginterferon alfa-2a and from 1.5 to 1.0 to 0.5 μg/kg/wk for peginterferon alfa-2b.

Even with combination therapy, the overall sustained virologic response rate to interferon treatment in hepatitis C is only 50%, and many patients find the therapy difficult to tolerate. At present there are no satisfactory therapies for patients who have contraindications to therapy or who are nonresponders. For patients with decompensated liver disease secondary to hepatitis C, liver transplantation ( Chapter 158 ) is indicated. The use of long-term peginterferon with and without ribavirin in nonresponder patients with the goal of suppression rather than eradication of HCV is undergoing evaluation in randomized controlled trials and cannot be recommended at present. Patients who relapse after a conventional course of peginterferon and ribavirin may achieve a sustained response with retreatment for a longer duration or with higher doses of either drug, but the overall efficacy and safety of this approach have not been proved. Several HCV protease, helicase, and polymerase inhibitors are in early clinical trials for chronic hepatitis C.

FIGURE 152-3  Virologic responses to treatment of chronic hepatitis C for 48 weeks. HCV = hepatitis C virus; SVR = sustained virologic response.

   AUTOIMMUNE HEPATITIS

Definition

Autoimmune hepatitis is a chronic inflammatory disorder of the liver of unknown cause. It is characterized by presence of autoantibodies, high levels of serum immunoglobulins, and frequent association with other autoimmune diseases.

Epidemiology

The disease is more common in women than men and typically has its onset either in childhood and young adulthood (between the ages of 15 and 25) or around the time of menopause (between the ages of 45 and 60). Two types of autoimmune hepatitis have been described: type 1 (or classic) and type 2. Both forms have similar clinical and serum biochemical features. Type 2 autoimmune hepatitis is found largely in Europe and typically affects young women or girls.

Autoimmune hepatitis is one of the three major autoimmune liver diseases, along with primary biliary cirrhosis and primary sclerosing cholangitis ( Chapters 157 and 159 ). Also within this group of autoimmune liver diseases are variant forms of autoimmune hepatitis, which have been termed overlap syndromes because they share features of autoimmune hepatitis and another type of chronic liver disease, and outlier syndromes, which have features of autoimmune hepatitis but do not meet the criteria established by the International Autoimmune Hepatitis Group.

Pathobiology

The pathogenesis of autoimmune hepatitis is not known, but it is believed to be caused by autoimmune reactions against normal hepatocytes. The disease seems to occur in genetically predisposed individuals on exposure to as yet unidentified noxious environmental agents that trigger an autoimmune process directed at liver antigens. In patients with autoimmune hepatitis, primary associations are seen with the human leukocyte antigen (HLA) class I B8 and class II DR3 and DR52a loci. In Asians, autoimmune hepatitis is associated with HLA-DR4, an association that is less common in Western patients.

Clinical Manifestations

Autoimmune hepatitis is a heterogeneous disease with a wide spectrum of clinical features. It tends to be more severe and florid in onset than chronic hepatitis B or C. Autoimmune hepatitis is usually progressive and leads to end-stage liver disease if not treated with immunosuppression. In some patients it is detected before the onset of symptoms and jaundice if elevated serum aminotransferase levels are found on a routine health evaluation. More typically, patients are first seen because of jaundice and fatigue. Abnormalities in routine liver test results are also similar to the abnormalities found in other forms of chronic hepatitis with elevations in serum aminotransferase levels. Elevations in bilirubin or alkaline phosphatase indicate more severe or advanced disease. Perhaps most characteristic of autoimmune hepatitis are striking elevations in serum gamma globulin and, specifically, immunoglobulin G (IgG), accompanied by autoantibodies directed at non–organ-specific cellular constituents.

Diagnosis

The presence of serum autoantibodies is the basis for diagnosis of the two types of autoimmune hepatitis: type 1 (classic) autoimmune hepatitis is characterized by the detection of antinuclear (ANA), anti–smooth muscle (SMA), antiactin, and antiasialoglycoprotein receptor antibodies. Type 2 autoimmune hepatitis is characterized by the detection of anti–liver-kidney microsomal 1 antibodies (anti-LKM1) and anti–liver cytosol 1 antibodies and the absence of ANA or SMA. To meet criteria for the diagnosis of autoimmune hepatitis, these antibodies should be present in titers of at least 1:80 in adults and 1:20 in children.

Liver biopsy specimens in patients with autoimmune hepatitis show features characteristic of chronic hepatitis (as described earlier). Plasma cell infiltrates, which are rare in other forms of chronic hepatitis, are characteristic of autoimmune hepatitis.

Treatment

Most typical of autoimmune hepatitis is a rapid clinical response to corticosteroid therapy in terms of resolution of clinical symptoms and improvement in serum aminotransferase and serum bilirubin elevations. In typical cases, prednisone should be initiated at a dose of 20 to 30 mg/day. Higher doses of prednisone may be needed in patients with more severe disease. A biochemical response with a decrease in serum aminotransferase levels to the normal or near-normal range should occur within 1 to 3 months. A lack of biochemical or clinical response should lead to reevaluation of the diagnosis. To prevent the side effects of long-term prednisone therapy, azathioprine, 50 to 100 mg, can be combined with prednisone starting at the same time or added later. In the typical patient, prednisone can be tapered slowly to a maintenance regimen of 5 to 10 mg/day combined with azathioprine, 50 to 150 mg/day. In some patients, azathioprine alone, at a dose of 2 mg/kg body weight per day, can be used instead of prednisone as maintenance therapy. The long-term side effects of azathioprine (immune suppression, bone marrow suppression, and risk of cancer) need to be considered. Corticosteroid or immunosuppressive therapy is usually continued indefinitely. In patients with long-term remission (3 years or more), attempts can be made to withdraw therapy, but these patients should be monitored carefully thereafter because severe and even fatal flares of disease can occur weeks to months after stopping prednisone.

Prognosis

The prognosis in this disease is generally related to the histologic stage of disease at the time of diagnosis and initiation of therapy, but patients whose disease responds to immunosuppressive therapy can do well for many years. Patients with autoimmune hepatitis that progresses to end-stage liver disease have excellent survival rates after liver transplantation ( Chapter 158 ).

   CRYPTOGENIC CHRONIC LIVER DISEASE

The term cryptogenic chronic liver disease is normally reserved for patients with chronic hepatitis or cirrhosis of unknown cause. Cryptogenic hepatitis is a diagnosis of exclusion and should be made only after hepatitis B, C, and D, autoimmune hepatitis, and other causes of a chronic hepatitis–like syndrome are excluded (see Table 152-1 ). It is most important to exclude drug-induced ( Chapter 153 ) and inherited metabolic liver diseases ( Chapter 154 ) such as Wilson’s disease (by serum ceruloplasmin and, if necessary, urine and liver copper concentrations) and α1-antitrypsin deficiency (by serum levels of α1-antitrypsin and phenotyping). Diseases that can resemble chronic hepatitis on blood tests but are readily excluded by liver biopsy histologic findings include alcoholic liver disease, fatty liver, nonalcoholic steatohepatitis ( Chapter 156 ), hemochromatosis ( Chapter 231 ), primary biliary cirrhosis ( Chapter 159 ), and sclerosing cholangitis ( Chapter 159 ). Cryptogenic cirrhosis may represent the end stage of any of these diseases, but particularly nonalcoholic steatohepatitis, which in its later stages may be associated with little or no fat and loss of the other usual characteristics of the disease.

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