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Chronic hepatitis
is hepatitis that lasts > 6 mo. Common causes include
hepatitis B and C viruses, autoimmune mechanisms (autoimmune hepatitis),
and drugs. Many patients have no history of acute hepatitis, and
the first indication is discovery of asymptomatic aminotransferase elevations.
Some patients present with cirrhosis or its complications (eg, portal
hypertension). Biopsy is necessary to confirm the diagnosis and to
grade and stage the disease. Treatment is directed toward complications
and the underlying condition (eg, corticosteroids for autoimmune
hepatitis, antiviral therapy for viral hepatitis). Liver transplantation
is often indicated for end-stage disease.
(See also the American Association for the Study of Liver Disease's practice
guideline and update on chronic hepatitis B.)
Etiology
and Classification
Hepatitis lasting > 6 mo is generally defined as chronic, although this duration is arbitrary. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are frequent causes of chronic hepatitis; 5 to 10% of cases of HBV infection, with or without hepatitis D virus (HDV) co-infection, and about 75% of cases of HCV infection become chronic. Hepatitis A and E viruses are not causes. Although the mechanism of chronicity is uncertain, liver injury is mostly determined by the patient's immune reaction to the infection.
Many cases are idiopathic. A high proportion of idiopathic cases have prominent features of immune-mediated hepatocellular injury (autoimmune hepatitis), including the following:
Sometimes chronic hepatitis has features of both autoimmune hepatitis and another chronic liver disorder (eg, primary biliary cirrhosis, chronic viral hepatitis). These conditions are called overlap syndromes.
Many drugs, including isoniazid , methyldopa , nitrofurantoin , and, rarely, acetaminophen , can cause chronic hepatitis. The mechanism varies with the drug and may involve altered immune responses, cytotoxic intermediate metabolites, or genetically determined metabolic defects.
Other causes of chronic hepatitis include alcoholic hepatitis and nonalcoholic steatohepatitis. Less often, chronic hepatitis results from α1‑antitrypsin deficiency or Wilson's disease.
Cases were once classified histologically as chronic persistent, chronic lobular, or chronic active hepatitis. A more useful recent classification system specifies the etiology, the intensity of histologic inflammation and necrosis (grade), and the degree of histologic fibrosis (stage). Inflammation and necrosis are potentially reversible; fibrosis generally is not.
Symptoms and Signs
Clinical features vary widely. About 1/3 of cases develop after acute hepatitis, but most develop insidiously de novo. Many patients are asymptomatic, especially in chronic HCV infection. However, malaise, anorexia, and fatigue are common, sometimes with low-grade fever and nonspecific upper abdominal discomfort. Jaundice is usually absent. Often, particularly with HCV, the first findings are signs of chronic liver disease (eg, splenomegaly, spider nevi, palmar erythema). A few patients with chronic hepatitis develop manifestations of cholestasis. In the autoimmune variant, especially in young women, manifestations may involve virtually any body system and can include acne, amenorrhea, arthralgia, ulcerative colitis, pulmonary fibrosis, thyroiditis, nephritis, and hemolytic anemia.
Chronic HCV is occasionally associated with lichen planus, mucocutaneous vasculitis, glomerulonephritis, porphyria cutanea tarda, and, perhaps, non-Hodgkin B-cell lymphoma. About 1% of patients develop symptomatic cryoglobulinemia with fatigue, myalgias, arthralgias, neuropathy, glomerulonephritis, and skin rashes (urticaria, purpura, or leukocytoclastic vasculitis); asymptomatic cryoglobulinemia is more common.
Diagnosis
(See also the American Association for the Study of Liver Disease's practice guideline Diagnosis,
Management, and Treatment of Hepatitis C and the U.S. Preventive Services Task Force's clinical guideline Screening
for Hepatitis C in Adults.) The diagnosis is suspected in patients with suggestive symptoms and signs, incidentally noted elevations in aminotransferase levels, or previously diagnosed acute hepatitis. Liver function tests are needed if not previously done and include serum ALT, AST, alkaline phosphatase, and bilirubin. Aminotransferase elevations are the most characteristic laboratory abnormalities. Although levels can vary, they are typically 100 to 500 IU/L. ALT is usually higher than AST. Aminotransferase levels can be normal during chronic hepatitis if the disease is quiescent, particularly with HCV. Alkaline phosphatase is usually normal or only slightly elevated but is occasionally markedly high. Bilirubin is usually normal unless the disease is severe or advanced. However, abnormalities in these laboratory tests are not specific and can result from other disorders, such as alcoholic liver disease, recrudescent acute viral hepatitis, and primary biliary cirrhosis.
If laboratory results are compatible with hepatitis, viral serologic tests are done to exclude HBV and HCV (see Table 4: Hepatitis: Hepatitis B Serology* , and Table 5: Hepatitis: Hepatitis C Serology). Unless these tests indicate viral etiology, further testing is required. The first tests done include autoantibodies, immunoglobulins, and α1‑antitrypsin level. Children and young adults are screened for Wilson's disease with a ceruloplasmin level. Marked elevations in serum immunoglobulins suggest chronic autoimmune hepatitis but are not conclusive. Autoimmune hepatitis is normally diagnosed based on the presence of antinuclear (ANA), anti-smooth muscle, or anti-liver/kidney microsomal type 1 (anti-LKM1) antibodies at titers of 1:80 (in adults) or 1:20 (in children). (See also the American Association for the Study of Liver Disease's practice guideline Diagnosis
and Treatment of Autoimmune Hepatitis.)
Unlike in acute hepatitis, biopsy is necessary. Mild cases may have only minor hepatocellular necrosis and inflammatory cell infiltration, usually in portal regions, with normal acinar architecture and little or no fibrosis. Such cases rarely develop into clinically important liver disease or cirrhosis. In more severe cases, biopsy typically shows periportal necrosis with mononuclear cell infiltrates (piecemeal necrosis) accompanied by variable periportal fibrosis and bile duct proliferation. The acinar architecture may be distorted by zones of collapse and fibrosis, and frank cirrhosis sometimes coexists with signs of ongoing hepatitis. Biopsy is also used to grade and stage the disease.
In most cases, the specific cause of chronic hepatitis cannot be discerned via biopsy alone, although cases caused by HBV can be distinguished by the presence of ground-glass hepatocytes and special stains for HBV components. Autoimmune cases usually have a more pronounced infiltration by lymphocytes and plasma cells. In patients with histologic but not serologic criteria for chronic autoimmune hepatitis, variant autoimmune hepatitis is diagnosed; many have overlap syndromes.
Serum albumin and PT should be measured to determine severity; hepatic insufficiency is suggested by low serum albumin or prolonged PT. If symptoms or signs of cryoglobulinemia develop during chronic hepatitis, particularly with HCV, cryoglobulin levels and rheumatoid factor should be measured; high levels of rheumatoid factor and low levels of complement suggest cryoglobulinemia.
Patients with chronic HBV infection should be screened annually for hepatocellular cancer with ultrasound and serum α‑fetoprotein measurement, although the cost-effectiveness of this practice is debated. (See also the Cochrane review abstract on alpha-fetoprotein
and/or liver ultrasonography for liver cancer screening in patients
with chronic hepatitis B.) Patients with chronic HCV infection should be similarly screened only if cirrhosis is present.
Prognosis
Prognosis is highly variable. Chronic hepatitis caused by a drug often regresses completely when the offending drug is withdrawn. Without treatment, cases caused by HBV can resolve (uncommon), progress rapidly, or progress slowly to cirrhosis over decades. Resolution often begins with a transient increase in disease severity and results in seroconversion from hepatitis B e antigen (HBeAg) to antibody to hepatitis B e antigen (anti-HBe). Co-infection with HDV causes the most severe form of chronic HBV infection; without treatment, cirrhosis develops in up to 70% of patients. Untreated chronic hepatitis due to HCV produces cirrhosis in 20 to 30% of patients, although development may take decades. Chronic autoimmune hepatitis usually responds to therapy but sometimes produces progressive fibrosis and eventual cirrhosis.
Chronic HBV infection increases the risk of hepatocellular cancer. The risk is also increased in chronic HCV infection, but only if cirrhosis has already developed (see Liver Masses and Granulomas: Hepatocellular Carcinoma).
Treatment
Treatment goals include management of complications (eg, ascites, encephalopathy) and treatment of the cause. Drugs that cause hepatitis should be stopped. Underlying disorders, such as Wilson's disease, should be treated. In chronic hepatitis due to HBV, prophylaxis for contacts of patients may be helpful (see Hepatitis: Prevention); corticosteroids and immunosuppressive drugs should be avoided because they enhance viral replication. No prophylactic measures are required for contacts of patients with HCV infection.
Autoimmune
hepatitis:
(see also the American Association for the Study of Liver Disease's practice guideline Diagnosis
and Treatment of Autoimmune Hepatitis). Corticosteroids, with or without azathioprine , prolong survival. Prednisone is usually started at 30 to 40 mg po once/day, then tapered to the lowest dose that maintains aminotransferases at normal or near-normal levels. Some experts give concomitant azathioprine 1 to 1.5 mg/kg po once/day; others add azathioprine only if low-dose prednisone fails to maintain suppression. Most patients require long-term, low-dose maintenance treatment. Liver transplantation may be required for end-stage disease.
HBV:
(see also the American Association for the Study of Liver Disease's practice guideline and update on chronic hepatitis B). Antiviral treatment is indicated for patients with elevated aminotransferase levels, clinical or biopsy evidence of progressive disease, or both. The goal is to eliminate HBV-DNA. Treatment may need to be continued indefinitely and thus may be very expensive; stopping treatment prematurely can lead to relapse, which may be severe. However, treatment may be stopped if HBeAg converts to anti-HBe or if tests for HBsAg become negative. Drug resistance is also a concern. Six antiviral drugs— entecavir , adefovir , lamivudine , interferon-α (INF-α), pegylated INF-α2a (peginterferon-α2a), and telbivudine —are available (see Table 6: Hepatitis: Comparison of Drugs Commonly Used to Treat Chronic Viral Hepatitis B*).
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Table 6
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Comparison of Drugs Commonly
Used to Treat Chronic Viral Hepatitis B*
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Effect (% of patients)
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Adefovir
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Entecavir
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Lamivudine
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Pegylated Interferon- α2a
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Serum HBV-DNA becomes undetectable
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21%
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67%
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44%
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25%
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HBsAg becomes undetectable
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†
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2%
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†
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3%
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HBeAg becomes undetectable
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24%
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22%
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32%
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30%
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ALT normalization
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48%
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68%
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41%
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39%
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Histologic improvement
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53%
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72%
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49–56%
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38%
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Resistance
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At 1 yr: 0%
At 5 yr: 15%
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At 2 yr: 0%
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At 1 yr: 14%
At 5 yr: 69%
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None
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* Telbivudine is a new drug for which sufficient data are not yet available.
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†Insufficient data.
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HBsAg = hepatitis B surface antigen; HBeAg = hepatitis B e antigen.
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Adapted from Keeffe EB et al: A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clinical Gastroenterology and Hepatology 4:1-27, 2006.
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First-line treatment is usually with an oral antiviral drug, such as entecavir (a nucleoside analogue) or adefovir (a nucleotide analogue). Combination therapy has not proved superior to monotherapy.
Entecavir appears to have higher antiviral potency than other commonly used drugs. Resistance to entecavir is uncommon, but the drug has not been in widespread clinical use for very long. Dosage is 0.5 mg po once/day; however, patients who have previously taken a nucleoside analogue should take 1 mg po once/day. Dose reduction is required in patients with renal insufficiency. Serious adverse effects appear to be uncommon so far, although the drug can induce tumors in animals.
Adefovir is also relatively potent. Dosage is 10 mg po once/day. Adefovir may cause renal dysfunction, so serum creatinine level must be measured periodically and the dose reduced if necessary.
Alternatively, lamivudine (a nucleoside analogue) 100 mg po once/day is given. It has few adverse effects, which is one of its advantages over other antiviral drugs used to treat chronic HBV infection. INF-α (usually IFN-α2b), formerly first-line treatment, can be used. Dosage is 5 million IU sc once/day or 10 million IU sc 3 times/wk for 4 mo. In about 40% of patients, this regimen eliminates HBV-DNA and causes seroconversion to anti-HBe; a successful response is usually presaged by a temporary increase in aminotransferase levels. The drug must be given by injection and is often poorly tolerated. The first 1 or 2 doses cause an influenza-like syndrome. Later, fatigue, malaise, depression, bone marrow suppression, and, rarely, bacterial infections or autoimmune disorders can occur. In patients with advanced cirrhosis, IFN-α can precipitate hepatic failure and is therefore contraindicated. Other contraindications include renal failure, immunosuppression, solid organ transplantation, cytopenia, and substance abuse. In a few patients, treatment must be stopped because of intolerable adverse effects. The drug should be given cautiously or not at all to patients with ongoing substance abuse or a major psychiatric disorder.
Pegylated IFN-α2 can also be given. Dosage is 180 μg sc once/wk. Adverse effects are similar to those of INF-α but may be less severe.
Telbivudine is a new drug that has greater efficacy than lamivudine but has high rates of resistance.
Liver transplantation should be considered for end-stage liver disease caused by HBV, but the infection aggressively attacks the graft, and prognosis is less favorable than when liver transplantation is done for other indications. Long-term posttransplantation therapy with lamivudine improves the outcome.
HCV:
(see also the American Association for the Study of Liver Disease's practice guideline Diagnosis,
Management, and Treatment of Hepatitis C and the NIH Consensus Development Conference Statement on the management
of hepatitis C). For chronic hepatitis due to HCV, treatment is indicated if aminotransferase levels are elevated and biopsy shows active inflammatory disease with evolving fibrosis. Treatment aims to permanently eliminate HCV-RNA (sustained response), which is associated with permanent normalization of aminotransferase and cessation of histologic progression.
Combination therapy with pegylated IFN‑α plus ribavirin has the best results. Pegylated IFN‑α2b, given as 1.5 μg/kg sc once/wk, and pegylated IFN‑α2a, given as 180 μg sc once/wk, have comparable results. Ribavirin 500 to 600 mg po bid is usually given, although 400 mg bid may be sufficient for viral genotypes 2 and 3.
HCV genotype and viral load are determined before treatment because results influence treatment. Genotype 1 is the most common type but is relatively resistant to treatment. Combination therapy is given for 1 yr; a sustained response rate of about 45 to 50% overall occurs. Results are more favorable in patients with early disease and less favorable in those who already have cirrhosis. HCV viral load should be measured at 3 mo and treatment stopped if RNA has not declined by at least 2 log levels compared with pretreatment values.
Less common genotypes 2 and 3 respond more favorably. Combination therapy is required for only 6 mo and gives an overall sustained response rate of about 75%. Longer treatment does not improve the results.
Adverse effects of pegylated IFN are similar to those of IFN-α but may be less severe; contraindications are also similar (see above).
Ribavirin is usually well tolerated but commonly produces anemia due to hemolysis; dosage should be decreased if hemoglobin falls to < 10 g/dL. Ribavirin is teratogenic for both men and women, necessitating contraception until 6 mo after completion of treatment. Patients who cannot tolerate ribavirin should be given pegylated IFN‑α, but results are not as good as with combination treatment. Ribavirin monotherapy is of no value.
In most adult transplantation centers, advanced cirrhosis due to HCV is now the most common indication for liver transplantation. Although HCV recurs in the graft, the course is usually indolent, and long-term survival rates are relatively high.
Last full review/revision February 2007 by Sidney Cohen, MD
Content last modified February 2007
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