Liver, Biliary Tract, & Pancreas Disorders
``General Considerations Although autoimmune hepatitis is usually seen in young women, it can occur in either sex at any age. The incidence and prevalence are estimated to be 8.5 and 107 per million population, respectively. Affected younger persons are often positive for HLA-B8 and HLA-DR3; older patients are often positive for HLA-DR4. The principal susceptibility allele among white Americans and northern Europeans is HLA DRB1∗0301; HLA DRB1∗0401 is a secondary but independent risk factor.
``Clinical Findings A. Symptoms and Signs The onset is usually insidious, but up to 40% of cases present with an acute (occasionally fulminant) attack of hepatitis and some cases follow a viral illness (such as hepatitis A, Epstein-Barr infection, or measles) or exposure to a drug or toxin (such as nitrofurantoin, minocycline, or infliximab). Exacerbations may occur postpartum. Thirty-four percent of patients are asymptomatic. Typically, examination reveals a healthy-appearing young woman with multiple spider nevi, cutaneous striae, acne, hirsutism, and hepatomegaly. Amenorrhea may be a presenting feature. Extrahepatic features include arthritis, Sjögren syndrome, thyroiditis, nephritis, ulcerative colitis, and Coombs-positive hemolytic anemia. Patients with autoimmune hepatitis are at increased risk for cirrhosis which, in turn, increases the risk of hepatocellular carcinoma (at a rate of about 1% per year).
B. Laboratory Findings Serum aminotransferase levels may be > 1000 units/L, and the total bilirubin is usually increased. In type I (classic) autoimmune hepatitis, ANA or smooth muscle antibodies (either or both) are usually detected in serum. Serum γ-globulin levels are typically elevated (up to 5–6 g/dL [0.05–0.06 g/L]). In patients with the latter, the EIA for antibody to HCV may be falsely positive. Other antibodies, including atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) and antibodies to histones, may be found. Antibodies to soluble liver antigen (anti-SLA) characterize a variant of type I that is marked by severe disease, a high relapse rate after treatment, and absence of the usual antibodies (ANA and smooth muscle antibodies). Anti-SLA is directed against a transfer RNA complex responsible for incorporating selenocysteine into peptide chains—Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase, or SEPSECS. Type II, seen more often in girls under age 14 in Europe, is characterized by circulating antibodies to liver-kidney microsome type 1 (anti-LKM1)—directed against cytochrome P450 2D6—without anti-smooth muscle antibodies or ANA. In some cases, anti-liver cytosol type 1, directed against formiminotransferase cyclodeaminase, is detected. This type of autoimmune hepatitis can be seen in patients with autoimmune polyglandular syndrome
CMDT 2013
679
type 1. Concurrent primary biliary cirrhosis or primary sclerosing cholangitis has been recognized in 11% and 5% of patients with autoimmune hepatitis, respectively. Liver biopsy is indicated to help establish the diagnosis (interface hepatitis is the hallmark), evaluate disease severity, and determine the need for treatment. Simplified diagnostic criteria based on the detection of autoantibodies (1 or 2 points depending on titers), elevated IgG levels (1 or 2 points depending on levels), and characteristic histologic features (1 or 2 points depending on how typical the features are) and exclusion of viral hepatitis (2 points) can be useful for diagnosis; a score of 6 indicates probable and a score of 7 indicates definite autoimmune hepatitis with a high degree of specificity but moderate sensitivity.
``Treatment Prednisone with or without azathioprine improves symptoms; decreases the serum bilirubin, aminotransferase, and γ-globulin levels; and reduces hepatic inflammation. Symptomatic patients with aminotransferase levels elevated tenfold (or fivefold if the serum globulins are elevated at least twofold) are optimal candidates for therapy, and asymptomatic patients with modest enzyme elevations may be considered for therapy depending on the clinical circumstances and histologic severity; however, asymptomatic patients usually remain asymptomatic, have either mild hepatitis or inactive cirrhosis on liver biopsy specimens, and have a good long-term prognosis without therapy. Prednisone is given initially in a dose of 30 mg orally daily with azathioprine, 50 mg orally daily, which is generally well tolerated and permits the use of lower corticosteroid doses than a regimen beginning with prednisone 60 mg orally daily alone. Preliminary experience suggests that budesonide, 6–9 mg orally daily, may be at least as effective as prednisone in noncirrhotic autoimmune hepatitis and associated with fewer side effects. Whether patients should undergo testing for the genotype or level of thiopurine methyltransferase prior to treatment with azathioprine to predict toxicity is debated. Blood counts are monitored weekly for the first 2 months of therapy and monthly thereafter because of the small risk of bone marrow suppression. The dose of prednisone is lowered from 30 mg/d after 1 week to 20 mg/d and again after 2 or 3 weeks to 15 mg/d. Ultimately, a maintenance dose of 10 mg/d is achieved. While symptomatic improvement is often prompt, biochemical improvement is more gradual, with normalization of serum aminotransferase levels after several months in many cases. Histologic resolution of inflammation may require more than 12 months, and repeat liver biopsy is recommended after 18 months of treatment. Failure of aminotransferase levels to normalize invariably predicts lack of histologic resolution. The response rate to therapy with prednisone and azathioprine is 80%. Older patients and those with HLA genotype DRB1∗04 are more likely to respond than younger patients and those with HLA DRB1∗03 or hyperbilirubinemia. Fibrosis may reverse with therapy and