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154 CHRONIC HEPATITIS

154 CHRONIC HEPATITIS
Harrison’s Manual of Medicine

154

CHRONIC HEPATITIS

Overview
Chronic Hepatitis B
Chronic Hepatitis C
Autoimmune Hepatitis
Bibliography

A group of disorders characterized by a chronic inflammatory reaction in the liver for at least 6 months.
OVERVIEW
ETIOLOGY   Hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV, delta agent), drugs (methyldopa, nitrofurantoin, isoniazid, dantrolene), autoimmune hepatitis, Wilson’s disease, hemochromatosis, alpha1 antitrypsin deficiency.
HISTOLOGIC CLASSIFICATION   See Table 154-1

Table 154-1 Histologic Classification of Chronic Hepatitis

PRESENTATION   Wide clinical spectrum ranging from asymptomatic serum aminotransferase elevations to apparently acute, even fulminant, hepatitis. Common symptoms include fatigue, malaise, anorexia, low-grade fever; jaundice is frequent in severe disease. Some pts may present with complications of cirrhosis: ascites, variceal bleeding, encephalopathy, coagulopathy, and hypersplenism. In chronic hepatitis B or C and autoimmune hepatitis, extrahepatic features may predominate.
CHRONIC HEPATITIS B
Follows up to 1–2% of cases of acute hepatitis B in immunocompetent hosts; more frequent in immunocompromised hosts. Spectrum of disease: asymptomatic antigenemia, chronic hepatitis, cirrhosis hepatocellular cancer; early phase often associated with continued symptoms of hepatitis, elevated aminotransferase levels, presence in serum of HBeAg and HBV DNA, and presence in liver of replicative form of HBV; later phase in some pts may be associated with clinical and biochemical improvement, disappearance of HBeAg and HBV DNA and appearance of anti-HBe in serum, and integration of HBV DNA into host hepatocyte genome. In Mediterranean area, a frequent variant is characterized by a severe and rapidly progressive course and HBV DNA with anti-HBe in serum, due to a mutation in the pre-C region of the HBV genome that prevents HBeAg synthesis (may appear during course of chronic wild-type HBV infection as a result of immune pressure and may also account for some cases of fulminant hepatitis B). Chronic hepatitis B ultimately leads to cirrhosis in 25– 40% of cases (particularly in pts with HDV superinfection or the pre-C mutation) and hepatocellular carcinoma in many of these pts (particularly when chronic infection is acquired early in life).
EXTRAHEPATIC MANIFESTATIONS (IMMUNE-COMPLEX–MEDIATED)   Rash, urticaria, arthritis, polyarteritis, polyneuropathy, glomerulonephritis.

TREATMENT
Standard approach is interferon a 5 million units qd or 10 million units three times per week × 4 months for serum HBeAg/HBV-DNA-positive pts with symptoms, elevated aminotransferase levels, and biopsy evidence of chronic hepatitis. Results in anti-HBe seroconversion with clinical, biochemical, and histologic improvement in up to 40% of cases. Best predictors of response are serum HBV DNA level <200 ng/L and substantial elevations of aminotransferases (>100 units). Poor responders: pts positive for anti-HDV or HIV, adult carriers infected in childhood, immunocompromised pts, persons infected with HBeAg-negative “pre-core” mutant. Side effects: flulike reactions (common), bone marrow depression, precipitation of autoimmune diseases including thyroid disease, CNS symptoms, anorexia, sleep disturbance. In pts with lower aminotransferase levels (<100 U/L), efficacy of interferon may be enhanced by a priming prednisone course, 60 mg PO qd, tapering over 6 weeks, but this approach may result in fatal flare of hepatitis B and is not recommended. Avoid interferon in pts with decompensated cirrhosis (e.g., ascites, jaundice, coagulopathy, encephalopathy). The nucleoside analogue lamivudine (3TC) has recently been approved by the FDA for the treatment of chronic HBV. Treatment with lamivudine (100 mg/d) results in significant biochemical and histologic improvement in >50% of pts and anti-HBe seroconversion in 16–20%. Lamivudine is associated with minimal side effects in HBV-infected pts. Flares of HBV, which can potentially lead to decompensation of liver disease, can occur on stopping lamivudine, with development of lamivudine resistance mutations, and with seroconversion. Lamivudine should be considered as first-line therapy in pts with evidence of active hepatitis and viral replication who fall into one of the following groups: contraindications to interferon (especially decompensated cirrhosis); pts with pre- core mutations; pts with chronic immunosuppression; or pts not responsive to interferon.

CHRONIC HEPATITIS C
Follows 80% of cases of transfusion-associated and sporadic hepatitis C. Clinically mild, often waxing and waning aminotransferase elevations; mild chronic hepatitis on liver biopsy. Associated with essential mixed cryoglobulinemia, porphyria cutanea tarda, membranoproliferative glomerulonephritis, and lymphocytic sialadenitis. Diagnosis confirmed by detecting anti-HCV in serum. May lead to cirrhosis in ³20% of cases after 20 years.

TREATMENT
Therapy with interferon a 3 million units 3 times per week for 12–18 months should be considered in pts with aminotransferase elevations, biopsy evidence of moderate or severe chronic hepatitis, HCV RNA in serum; 50% achieve clinical and biochemical remission or improvement; however, at least 50% of pts relapse within 12 months of treatment and may require retreatment. Higher doses do not improve sustained response rate and cause more side effects. Sustained response is associated with loss of HCV RNA from serum. Poorer response rates are associated with cirrhosis, high serum HCV RNA levels, and HCV genotypes 1a and 1b, which are prevalent in U.S. Benefit in pts with normal or nearly normal serum aminotransferase levels or decompensated cirrhosis is doubtful. The efficacy and tolerability of a long-acting form of interferon a (PEG-Interferon) is under study.
The guanosine nucleoside analogue ribavirin is ineffective when used alone to treat chronic HCV. However, treatment with the combination of ribavirin with interferon a for 1 year yields a sustained response rate of 40% (twice as high as with interferon a alone). Response rates are even higher in pts with low viral loads and genotypes other than type 1. In pts with non-1 genotypes, 6 months of combination therapy yields sustained response rates comparable to 12 months of combination therapy. Thus, pts with low viral loads and non-1 genotypes may be treated with 6 months of combination therapy. The side effect profile of combination interferon and ribavirin therapy is similar to interferon monotherapy. Ribavirin therapy is associated with some degree of hemolysis, but the resultant modest reduction in hemoglobin is not of clinical importance in most pts.

AUTOIMMUNE HEPATITIS
CLASSIFICATION   Type I: classic autoimmune hepatitis, anti-smooth muscle and/or antinuclear antibodies. Type II: associated with anti-liver/kidney microsomal (anti-LKM) antibodies, which are directed against cytochrome P450IID6 (seen primarily in southern Europe). Type III patients lack antinuclear antibodies and anti-LKM, have antibodies reactive with hepatocyte cytokeratins; clinically similar to type I.
CLINICAL MANIFESTATIONS   Classic autoimmune hepatitis (type I): 80% women, third to fifth decades. Abrupt onset (acute hepatitis) in a third. Insidious onset in two-thirds: progressive jaundice, anorexia, hepatomegaly, abdominal pain, epistaxis, fever, fatigue, amenorrhea. Leads to cirrhosis; >50% 5-year mortality if untreated.
EXTRAHEPATIC MANIFESTATIONS   Rash, arthralgias, keratoconjunctivitis sicca, thyroiditis, hemolytic anemia, nephritis.
SEROLOGIC ABNORMALITIES   Hypergammaglobulinemia, smooth- muscle antibody (40–80%), ANA (20–50%), antimitochondrial antibody (10–20%), false-positive anti-HCV enzyme immunoassay but usually not recombinant immunoblot assay (RIBA). Type II: anti-LKM antibody.

TREATMENT
Indicated for symptomatic disease with biopsy evidence of severe chronic hepatitis (bridging necrosis), marked aminotransferase elevations (5- to 10- fold), and hypergammaglobulinemia. Prednisone or prednisolone 30–60 mg PO qd tapered to 10–15 mg qd over several weeks; often azathioprine 50 mg PO qd is also administered to permit lower glucocorticoid doses and avoid steroid side effects. Monitor LFTs monthly. Symptoms may improve rapidly, but biochemical improvement may take weeks or months and subsequent histologic improvement (to lesion of mild chronic hepatitis or normal biopsy) up to 18–24 months. Withdrawal of glucocorticoids can be attempted following clinical, biochemical, and histologic remission; relapse occurs in 50–90% of cases (re-treat). For frequent relapses, consider maintenance therapy with low-dose glucocorticoids or azathioprine 2(mg/kg)/d.
Although hepatitis A rarely causes fulminant hepatic failure, it may do so more frequently in pts with chronic liver disease—especially those with chronic hepatitis B or C. The hepatitis A vaccine is immunogenic and well tolerated in pts with chronic hepatitis. Thus, pts with chronic liver disease, especially those with chronic hepatitis B or C, should be vaccinated against hepatitis A.

Bibliography

For a more detailed discussion, see Dienstag JL, Isselbacher KJ: Chronic Hepatitis, Chap. 297, p. 1742, in HPIM-15.

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