Hepatitis, Autoimmune

Essentials of Diagnosis

• Chronic hepatitis with high serum globulins and characteristic liver histology

• Antinuclear antibody (ANA) and/or smooth muscle antibody positive

• Usually occurs in young to middle-aged women

• Responds to corticosteroids

General Considerations

• The onset is usually insidious

• About 20% of cases present with acute hepatitis (and occasionally acute liver failure)

• Some cases follow

  • A viral illness, such as

    • Hepatitis A

    • Epstein-Barr infection

    • Measles

  • Exposure to a drug or toxin, such as

    • Nitrofurantoin

    • Minocycline

    • Hydralazine

    • Methyldopa

    • Infliximab

• 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)

• The risk of autoimmune hepatitis is increased in first-degree relatives of affected patients

• Simplified diagnostic criteria are based on

  • Detection of autoantibodies (1 or 2 points depending on titers)

  • Elevated IgG levels (1 or 2 points depending on levels)

  • Characteristic histologic features (1 or 2 points depending on how typical the features are)

  • Exclusion of viral hepatitis (2 points)

• Score of 6 indicates probable and a score of 7 indicates definite autoimmune hepatitis

• Diagnostic criteria for an overlap of autoimmune hepatitis and primary biliary cholangitis ("Paris criteria") have been proposed

Demographics

• Though usually a disease of young women, autoimmune hepatitis can occur in either sex at any age

• Disease appears to be more aggressive in black than in white patients

• Affected younger persons are often positive for HLA-B8 and -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

Symptoms and Signs

• Typically, a healthy-appearing young woman with multiple spider telangiectasias, cutaneous striae, acne, hirsutism, and hepatomegaly

• Amenorrhea may be a presenting feature

• Frequency of depression appears to be increased

• Extrahepatic features

  • Arthritis

  • Sjögren syndrome

  • Thyroiditis

  • Nephritis

  • Ulcerative colitis

  • Coombs-positive hemolytic anemia

Differential Diagnosis

• Chronic viral hepatitis

• Primary biliary cholangitis

• Primary sclerosing cholangitis

• Wilson disease

• Hemochromatosis

• Drug-induced liver disease

• α₁-Antiprotease (antitrypsin) deficiency

Laboratory Tests

• The serum bilirubin is usually increased, but 20% are anicteric

• Serum aminotransferase levels may be > 1000 units/L

• 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 this setting, the enzyme immunoassay for antibody to hepatitis C virus may be falsely positive

    • Other antibodies, including antineutrophil cytoplasmic antibodies (ANCA), may be found

• Type II

  • Seen more often in Europe in girls under age 14

  • Characterized by circulating antibodies to liver–kidney microsome type 1 (anti-LKM1)— directed against cytochrome P450 2D6 — or anti-liver cytosol type 1 —directed against formiminotransferase — without anti-smooth muscle antibodies or ANA

  • Can be seen in patients with autoimmune polyglandular syndrome type 1

Medications

• Prednisone

  • With or without azathioprine improves symptoms and reduces hepatic inflammation; azathioprine often started 2 weeks after prednisone

  • Indicated for symptomatic patients with at least a tenfold elevation of aminotransferases (or fivefold if the serum globulins are elevated at least twofold)

  • Asymptomatic patients with modest enzyme elevations may also be treated, but most asymptomatic patients have mild disease histologically and do not require immunosuppressive therapy

  • Initially, give prednisone, 30 mg/day orally with azathioprine, 50 mg/day orally

    • Taper prednisone after 1 week to 20 mg/day and again after 2 or 3 weeks to 15 mg/day

    • Ultimately, a maintenance dose of 10 mg/day is the goal

  • For acute severe autoimmune hepatitis, intravenous corticosteroid or prednisone, 60 mg orally daily, is recommended

• Budesonide, 3 mg orally two or three times daily

  • May be at least as effective as prednisone in noncirrhotic autoimmune hepatitis

  • Associated with fewer side effects

Surgery

• Liver transplantation

  • May be required for treatment failures and patients with severe acute presentation

  • As immunosuppression is reduced, the disease has been recognized to recur in up to 70% of transplanted livers at 5 years (and rarely to develop de novo)

  • Sirolimus can be effective in such cases

  • Predictors for liver transplantation (or liver-related death) include

    • Age ≤ 20 years or > 60 years at presentation

    • Low serum albumin level at diagnosis

    • Cirrhosis at diagnosis

    • Presence of anti-soluble liver antigen (anti-SLA)

    • Incomplete normalization of the serum ALT level after 6 months of treatment

Follow-Up

• Monitor complete blood counts weekly for the first 2 months of azathioprine therapy and monthly thereafter because of the small risk of bone marrow suppression

• Once complete remission is achieved (usually after at least 18 months of treatment), therapy may be withdrawn

  • Subsequent relapse rate is 90% by 3 years

  • Relapses may again be treated in the same manner as the initial episode, with the same remission rate

• After successful treatment of a relapse

  • Treat with azathioprine up to 2 mg/kg or the lowest dose of prednisone with or without azathioprine 50 mg/day needed to maintain serum aminotransferase levels as close to normal as possible

  • Another attempt at withdrawing therapy may be considered in patients remaining in remission long term (eg, ≥ 4 years)

• Nonresponders to corticosteroids and azathioprine may be considered for a trial of cyclosporine, tacrolimus, sirolimus, everolimus, methotrexate, rituximab, or infliximab

• Mycophenolate mofetil, 1 g twice daily, is an effective alternative to azathioprine in patients who respond but cannot tolerate it, but is less effective in nonresponders to azathioprine

• Occasionally, 6-mercaptopurine may be tolerated in patients who do not tolerate azathioprine

Complications

• Concurrent primary biliary cholangitis or primary sclerosing cholangitis

  • Occurs in 7–13% and 6–11% of patients, respectively

  • Liver biopsy is indicated for diagnosis and to determine the need for treatment

• Progression to cirrhosis and liver failure is an indication for liver transplantation

Prognosis

• With immunosuppressive therapy, there is prompt symptomatic improvement but biochemical improvement is more gradual, with normalization of serum aminotransferase levels after several months in many cases

• Histologic resolution of inflammation lags behind biochemical remission by 3–8 months, and repeat liver biopsy is recommended after 18 months of treatment

• Fibrosis may reverse after apparent biochemical and histologic remission

• The overall response rate is at least 80%

• Failure of aminotransferase levels to normalize invariably predicts lack of histologic resolution

• Overall long-term mortality appears to be twofold higher than that of the general population despite response to immunosuppressive therapy

Prevention

• Monitor bone density, particularly with corticosteroid use, for osteoporosis

When to Refer

• For liver biopsy

• For immunosuppressive therapy

When to Admit

• Hepatic encephalopathy

• INR > 1.6