refers to mild disease in which the inflammation is confined to the portal tracts. Serum transaminases may be near normal or moderately elevated.

refers to symptomatic CH in which the liver tests and histology are compatible with active inflammation, necrosis, and fibrosis, which may lead to cirrhosis. On histology, there is active inflammation spilling out of the portal tracts into the parenchyma with piecemeal necrosis and fibrosis.

refers to lobular inflammation with spotty necrosis.

The histologic classification emphasizes the importance of liver biopsy in the diagnosis, management, and prognosis of the disease. Any of the causes described in section B can take any of these forms in histologic appearance; hence histology alone is not sufficient for diagnosis and proper management of these patients.

is a progressive inflammatory liver disease of unknown cause in which immune reactions against host antigens are believed to be the major pathogenic mechanism. Exclusion of other liver diseases that have similar features are very important before diagnosis of AH is made. These include Wilson’s disease, chronic viral hepatitis, alpha-1-antitrypsin deficiency, hemochromatosis, alcoholic and nonalcoholic steatohepatitis, drug-induced liver disease, primary biliary cirrhosis, and primary sclerosing cholangitis.

i. Type I (or Lupoid) AH is the most common type in the United States and affects all ages. The majority (78%) of patients are women of northern European descent. Most patients also may have concurrent extrahepatic autoimmune diseases including autoimmune thyroiditis, Graves disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, pernicious anemia, progressive systemic sclerosis, systemic lupus erythematosus, Coombs positive hemolytic anemia, idiopathic thrombocytopenic purpura, leukoclastic vasculitis, nephritis, erythema nodosum, and fibrosing alveolitis. HLA-DR₃ and DR₄ are independence risk factors of susceptibility.

Most patients (40%) present with an acute onset, and a subset of patients present with fulminant hepatitis. Others (25%) may present with cirrhosis indicating an indolent progressive subclinical disease.

a) Prevalence in Europe and the United States is approximately 17 per 100,0000. AH accounts for 11% to 23% of chronic hepatitis in the United States.

1) Clinical features. Most common symptoms are malaise and easy fatigability. Hepatomegaly and jaundice are usually present.

2) Laboratory findings. Serum transaminases are usually elevated up to 10 times normal. Hyperbilirubinemia is usually below 3 times normal. Serum alkaline phosphatase level is frequently increased, but usually below 2 times normal. Patients also have hypergammaglobulinemia in the range of 50 to 100 g/L with a predominance of IgG fraction. Autoantibodies necessary for diagnosis included ANA, SMA, and anti-LKMI, but other antibodies may also be present. These include antiactin, SLA/LP, ASGPR, liver cytosol type I. Cryoglobulinemia may occur. The autoantibody and gamma globulin profiles are discussed in Table 54-2.

3) On pathologic examination of the liver biopsies there is moderate to severe interface hepatitis and no biliary lesions, granulomas, or prominent changes suggestive of another liver disease. Plasma cells and rosettes may be seen.

ii. Type II: anti-KLM (kidney-liver-microsomal) antibody-positive. Type II is less prevalent than type I and has been described most often in Continental Europe. It tends to present predominantly in the pediatric age group (ages 2-14); however, it may also occur in adults and is more often associated with other autoimmune diseases, such as insulin-dependent diabetes mellitus, autoimmune thyroid disease, and vitiligo. The presentation is often acute, even fulminant, and has a propensity to progress rapidly to cirrhosis.

iii. Type III: Anti-SLE-LP (soluble liver antigen). These patients constitute a small group of AH patients who are, in general, negative for antinuclear antibody (ANA) and KLM antibodies. Type III AH may be a variant of Type I AH rather than a separate entity.

However, up to 30% of these patients may have smooth muscle antibody (SMA) and liver membrane antibody (LMA), rheumatoid factor, antithyroid antibodies, or antimitochondrial antibody (AMA). Nevertheless, there is no evidence that these patients differ in any significant respect from those with type I AH.

b. Other findings. Anti-liver specific protein (anti-LSP) and anti-asialoglycoprotein receptor (anti-ASGP-R) are found in virtually all AH patients with positive ANA or SMA and KLM-I. Anti-LSP is found in a number of chronic liver disorders, primarily those with an underlying immunopathology and in which periportal inflammation is a feature. Titers of anti-LSP and anti-ASGP-R correlate with histologically assessed disease severity and fluctuate in response to immunosuppressive therapy.

The distinction between AH and primary biliary cirrhosis is not always clearcut; histologic, clinical, and immunologic overlaps have been well described. In some young patients, AH may progress to sclerosing cholangitis.

Viral hepatitis (A, B, C, D, and E) should be excluded initially. The frequent finding of false-positive anti-HCV in patients with AH should be confirmed with HCV viral titer determination by the polymerase chain reaction (PCR).

AH runs a slow course in most patients. In some cases, however, a dramatic acute episode may develop, which may result in sudden death.

c. Treatment. In the past, patients with AH were diagnosed with histologic features showing advanced liver disease, and the disease was noted to be progressive and fatal within 4 to 5 years. In current practice, most patients come to medical attention in the earlier stages of the disease before the development of cirrhosis; thus, the life expectancy is improved. The mortality figures in the placebo groups of the major controlled trials all showed that more than half of the untreated patients died within 3 to 5 years. There is considerable evidence that immunosuppressive therapy that includes corticosteroids leads to a decrease in mortality. The goals of therapy are to diminish hepatic inflammation and fibrosis and prevent the progression of the chronic hepatitis to cirrhosis.

Following assessment of alternative causes of chronic hepatitis and of the extent of liver injury by liver biopsy, a therapeutic trial should be initiated. A response should occur within 3 months or will not occur at all. Soon after initiation of corticosteroid therapy, patients with AH feel better with abatement of fatigue, malaise, anorexia, and fever. Serum AST, ALT, and bilirubin levels fall, and there is a reduction in serum gamma globulin levels.

i. Corticosteroids. There is general agreement that the treatment of ACH should begin with a corticosteroid. Prednisone and prednisolone are equally effective. An acceptable regimen is prednisone or prednisolone 30 to 40 mg per day for 2 to 4 weeks. If the patient has a good response, the dose of the corticosteroid is reduced every 2 weeks according to serum ALT and AST levels. Once remission is obtained, some patients do remarkably well at low doses (2.5-7.5 mg per day) only to relapse if the drug is discontinued. In most (about 75%) of the patients, lifelong
treatment is required. When a patient is in remission, a trial of drug withdrawal may be reasonable. If relapse occurs, however, treatment should be instituted promptly and continued indefinitely.

Patients who receive long-term corticosteroid therapy are at risk for progressive osteoporosis and vertebral compression fractures. Regular exercise, calcium 1.0 to 1.5 g daily and vitamin D 400 U daily and a bisphosphonate are indicated and recommended.

Corticosteroids have well-established, predictable dose-related side effects including hypertension, cataracts, diabetes mellitus, osteoporosis, and a predisposition to a variety of infections and weight gain. Most of these side effects are manageable if the dose is kept at less than 10 to 15 mg per day.

ii. Azathioprine and 6-Mercaptopurine (6-MP). The use of azathioprine has been of considerable value in permitting a lower dose of corticosteroids to be used to achieve remission.

It is recommended that azathioprine be started along with the corticosteroid at 2 mg/kg dose. Although azathioprine alone has not been effective in achieving remission, in some patients its use alone has been sufficient in maintaining remission. The dose is decreased to 75 to 50 mg when patients reach remission.

6-MP is an active metabolite of azathioprine, but the drugs are not equivalent in the treatment of AH. In small clinical trials, it was noted that 6-MP initially at 50 mg daily and increased to 1.5 mg/kg daily can salvage patients who have failed therapy with azathioprine.

Homozygous deficiency of thiopurine methyl transferase (TPMT) (an enzyme in the metabolic pathway of azathioprine and 6-MP) occurs in 0.3% of the population and heterozygous (intermediate deficiency) in 11% of the population. These deficiencies increase the potency of a given dose and enhance toxicity such as neutropenia, bone marrow suppression. Thus, TPMT enzyme genetics should be determined prior to onset of therapy with azathioprine and 6-MP.

Side effects of this therapy include nausea, vomiting, rash, pancreatitis, and cytopenia in less than 10% of patients. Side effects are reversible with dose reduction or termination of therapy. Risk of extrahepatic malignancy is about 1.4-fold in age- and sex-matched normal population.

iii. Alternative therapeutic approaches. Cyclosporine 5 to 6 mg/kg has been reported to be effective in treating patients with ACH in whom there has been no response to corticosteroids and in whom drug sensitivity prevents the use of azathioprine.

Other drugs including tacrolimus (4 mg twice daily), mycophenolate mofetil (1 g twice daily), 6-thioguanine (0.3 mg daily), sirolimus (1-3 mg daily), and budesonide (9 mg daily) have been tried in small numbers patients with variable results.

iv. Treatment results. Remission is accomplished in 65% of patients within 18 months and 80% of patients within 3 years. Histologic resolution lags behind clinical resolution by 3 to 8 months.

Drug withdrawal may be tried in patients who satisfy remission criteria; however, it is achievable in about 21% of patients. Relapse after drug withdrawal occurs in 50% within 6 months and 70% to 86% within 3 years. Reinstitution of original therapy usually induces another remission, but relapse commonly occurs if therapy is stopped. Thus maintenance therapy either with low-dose prednisolone or azathioprine is recommended.

Treatment failure occurs in about 10% of patients. Higher doses of prednisone (60 mg daily) or prednisolone (30 mg daily) in conjunction with azathioprine (150 mg daily) results in improvement in 70% of these patients. Therapy needs to be continued indefinitely. Dose decrease of the drugs may be tried after remission is attained.

Ten-year life expectancy for treated patients is about 90%. Histologic cirrhosis does not alter treatment response and these patients should be treated similarly as those without cirrhosis.

Hepatocellular carcinoma (HCC) occurs in 0.5% of patients with AH, but only in patients with cirrhosis. Yearly abdominal ultrasound may be used for surveillance.

v. Liver transplantation may be offered to patients who have advanced liver disease and have failed medical therapy It is recommended that patients with AH be considered for liver transplantation at early stages of disease, before severe complications of cirrhosis develop. Survival ranges from 83% to 92% and 10-year survival is 75%. Recurrent disease may be seen mainly in recipients who are inadequately immunosuppressed. De Novo AH occurs in 3% to 5% of recipients transplanted for nonautoimmune disease, especially children receiving cyclosporin.