Clinically this is defined as any hepatitis lasting 6 months or longer. The classification is usually based on histological grounds. There are three forms:
1 Chronic persistent hepatitis (CPH)
2 Chronic lobular hepatitis (CLH)
3 Chronic active hepatitis (CAH)
This simple histological classification has limitations as more becomes known about the aetiological factors. Morphological changes can be inaccurate due to sampling errors and also may show similar features at different clinical stages of the disease.
CHRONIC PERSISTENT HEPATITIS. There is marked expansion of the portal tracts with infiltration by mononuclear cells. The liver architecture is undisturbed and the limiting plate between hepatocytes is intact. This is often seen in HCV virus.
CHRONIC LOBULAR HEPATITIS. This histologically resembles acute viral hepatitis with predominant intraacinar inflammation and necrosis. It is uncommon and presents with a hepatitic picture. The course is prolonged (greater than 3 months) with remissions and excerbations. It can follow HBV and HCV hepatitis often with coexistent CPH. Alternatively serum autoantibodies may be present and this often responds to steroids. It usually does not progress to cirrhosis.
CHRONIC ACTIVE HEPATITIS. The hallmark of CAH is piecemeal necrosis. There is the destruction of liver cells at an interface between parenchyma and connective tissue leading to the erosion of the limiting plates of hepatocytes around portal tracts (zone 1). An inflammatory infiltrate, predominantly of lymphocytes and plasma cells, expands the portal area and infiltrates into the liver. The zone 1 hepatocytes with inflammatory infiltrates form rosettes with severe CAH; bridging necrosis (where fibrous septa extend between portal-central or portal-portal areas) is also seen. Milder forms may only show slight erosion of the limiting plate and some piecemeal necrosis.
CLINICAL FEATURES AND PRESENTATION
Patients may present in a variety of ways. Clinically, symptoms may range from none to mild fatigue or patients may present with the complications of cirrhosis.There may be no signs, but jaundice or signs of chronic liver disease may be present. Alternatively a patient may have been identified by abnormal liver biochemical tests, e.g. a raised serum bilirubin, transaminase or AP. Always check the medication that a patient may be taking as many drugs, e.g. isoniazid, antithyroid drugs, nitrofurantoin, dantrolene, can cause abnormal liver biochemistry. The ethnic origin of the patient, homosexuality, intravenous drug abuse or blood transfusions may suggest HBV or HCV infection.
Test for viral markers-HBsAg and anti-HCV. If these are negative, check the autoantibodies and exclude Wilson’s disease, iron overload and aI-antitrypsin deficiency. Liver biopsy should be carried out to assess activity and the presence or absence of cirrhosis.
Chronic hepatitis B infection
This group makes up approximately 50% of all cases of CAH in some countries, e.g. Greece. It is much less common in the UK where only 3% of patients who have an acute HBV infection progress to CAH. Patients with a poor cell-mediated response to the virus develop chronic hepatitis: if the response is very poor, they become healthy carriers; if the response is slightly better there is continuing hepatocellular damage. Cytotoxic T cells recognize the viral antigen via HLA class I molecules on the infected hepatocyte; this mechanism may be defective in these patients. HBV infection goes through a replicative and an integrated phase. In the former there is active viral replication with hepatic inflammation and the patient is highly infectious with HBeAg and HBV DNA positivity. At some stage the viral genome becomes integrated into the host DNA and the viral genes are transcribed along with those of the host. This can cause malignant transformation to hepatocellular carcinoma. There is no association with autoimmune disease or any particular genetic markers.
Chronic hepatitis occurs mainly in men and it is often not preceded by an acute attack. The condition may be asymptomatic or may present as a mild, slowly progressive hepatitis; 50% present with established chronic liver disease.
Investigations show a moderately raised serum bilirubin and AST and a slightly raised AP. HBsAg is positive and HBeAg is usually present. Histologically there may be a full spectrum of changes from near normal to CAH and cirrhosis. HBsAg may be seen as a ‘ground-glass’ appearance in the cytoplasm on haematoxylin and eosin staining and this can be confirmed on orcein staining or more specifically with immunohistochemical staining. HBcAg can also be demonstrated in hepatocytes by appropriate immunohistochemical staining.
Untreated patients seroconvert, i.e. converting from HBeAg to anti-HBe, at a rate of 15% per year; this varies with the age and ethnic origin of the patient. The aim of the treatment is to inhibit HBV replication. It is, however, difficult to achieve the eradication of HBsAg once it has been integrated into the host genome and most patients will have a biochemical and histological remission once HBeAg antigen, viral DNA and DNA polymerase have disappeared from the sera with seroconversion to anti- HBe. .
Ideally, patients with CAH and asymptomatic carriers who have HBeAg and HBV DNA in the serum should be treated with antiviral agents. All patients with progressive liver disease should also be treated but decompensated cirrhosis is a contraindication.
Many antiviral agents have been tried but currently interferon seems to be the most successful. The dosage regimen is 5-9 MU three times per week. The response rate varies between 14 and 75% depending on the age of onset of infection, sexual preference and type of liver disease. HBsAg usually persists. During therapy patients often have a clinical relapse of their liver disease, suggesting an immunomodulatory effect of interferon. Side-effects of interferon treatment include a ‘flu’ -like illness with headaches, myalgia and non-specific malaise, diarrhoea, nausea, reversible hair loss and depression. The patient’s blood and platelet counts should be monitored at frequent intervals. Drug trials are still being performed.
The progression is slow and remission may occur. Established cirrhosis is associated with a poor prognosis. Primary liver cell carcinoma is a frequent association and is one of the commonest carcinomas in HBV endemic areas uch as the Far East.
Chronic hepatitis C infection
Most patients are asymptomatic. Even with cirrhosis, the stigmata of chronic liver disease are few. The course is slow with persistently raised (mild-to-moderate) serum aminotransferases which fluctuate markedly over years. Serum albumin, bilirubin and PT are usually normal. Liver histology shows features of CPH with only minimal piecemeal necrosis although it can progress to cirrhosis. Interferon-a therapy (3 MU three times weekly i.m. for 3-12 months) shows a 50-60% response rate but over 50% relapse. Indications for therapy are still being discussed but patients who have anti-HCV or HCV RNA, abnormal liver biochemistry and abnormal liver histology without cirrhosis should probably be given treatment. Side effects are few on this low dose. Preliminary studies suggest that type I responds poorly to treatment.
Chronic autoimmune hepatitis
This condition occurs more frequently in young (10-20 years) and middle-aged women. There is an association with other autoimmune diseases, e.g. pernicious anaemia, thyroiditis and Coombs’ -positive haemolytic anaemia, and 60% are associated with HLA-B8, DR3, Dw3. The cause is unknown, but many immunological abnormalities are seen. There is a defect of suppressor (regulatory) T cells, which may be primary or secondary,
resulting in the production of autoantibodies against hepatocyte surface antigens. Humoral disturbances are associated with a hypergammaglobulinaemia (mainly IgG) and nuclear, smooth muscle (actin), liver/kidney microsomal (LKM1) antibodies are found in the serum. The association with other diseases suggests immune complex formation and deposition. The condition was called ‘lupoid hepatitis’ as a positive lupus erythematosus (LE) cell test was found in 15%. CAH produced by some drugs (see below) may also be associated with the production of autoantibodies. HCV and HBV markers are negative in this condition.
The onset may be insidious but 25% present as acute hepatitis. Alternatively, patients can be asymptomatic for years and the signs of chronic liver disease are discovered on a routine examination. Amenorrhoea is common. Examination shows the signs of chronic liver disease, hepatosplenomegaly, cutaneous striae, acne, hirsuties and bruises. Jaundice may be present. In advanced cases the complications of cirrhosis occur. An ill patient can also have features of an autoimmune disease with a fever, migratory polyarthritis, glomerulonephritis, pleurisy, pulmonary infiltration or fibrosing alveolitis. The ‘sicca’ syndrome can occur.
The hallmark of this condition is positive antibodies against nuclei, smooth muscle (actin) and occasionally mitochondria. LKM1 antibodies are found in some patients who tend to be younger and have more aggressive disease. Additional antibodies to a soluble liver antigen and the measles virus are seen, possibly due to hyperfunction of the immune system. Serum bilirubin, globulins and aminotransferases are very high. A mild normochromic normocytic anaemia with thrombocytopenia and leucopenia is present even before portal hypertension and splenomegaly. Histology of the liver biopsy shows the changes of CAH with piecemeal necrosis.
Prednisolone 30 mg is given daily for 2 weeks followed by a maintenance dose of 10-15 mg daily along with azathioprine 1-2 mg kg-l daily.
Remissions and exacerbations occur, and 50% of patients will die of liver failure within 5 years if no treatment is given. The prognosis can be considerably improved with steroid and azathioprine therapy (90% 5-year survival), underlining the importance of establishing this diagnosis by liver histology and immune markers. Most patients, nevertheless, develop cirrhosis. In a severe case with failure of medical treatment, orthotopic liver transplantation should be considered.
Drug-induced chronic hepatitis
Many drugs can cause a CAH which clinically bears many similarities to autoimmune hepatitis. Patients are often female, present with jaundice and hepatomegaly have raised serum transaminases and globulin levels and LE cells and anti-LKMI antibodies may be detected. Improvement follows drug withdrawal but exacerbations can occur with drug reintroduction.