A. Introduction [3]

1. Generally progressive chronic hepatitis
2. Autoimmune in nature, with autoantibodies
3. Disease occurs in adults and children
   1. Environmental triggers have been suggested but not confirmed
   2. Associated with specific major histocompatibility complex (MHC) genes
4. Associated with other diseases
   1. May have overlapping syndromes with other (gastrointestinal) inflammatory diseases
   2. Presence of hypergammaglobulinemia (>1.5X normal) is almost universal
   3. Antinuclear antibodies (ANA) are very common
5. Generally good prognosis with glucocorticoids ± immunosuppressive agents
6. Frank hepatic fibrosis from autoimmune hepatitis may be reversible with therapy [4]

B. Classification and Diagnosis

1. Type 1
   1. Previously "lupoid" or "autoimmune chronic active" hepatitis
   2. Most common form of autoimmune hepatitis in USA
   3. Female to male 10:1
   4. Majority of cases are ANA+
   5. Anti-smooth muscle Ab (anti-F-actin) in ~70% of cases
   6. Anti-SLA/LP (soluble liver antigen / liver-pancreas) in ~20% (very specific marker)
   7. >90% of severe cases of Type 1 disease are perinuclear ANCA+ (atypical pANCA+)
   8. HLA-A1, B8, DR3, DR4 common in this disease;
   9. Concurrent autoimmune disorders in ~17% of patients
   10. Includes thyroiditis, ulcerative colitis, type 1 diabetes, rheumatoid arthritis, celiac disease
   11. Apparently due to autoantibody mediated Killer (K-) cell cytotoxicity
   12. Cytotoxic T lymphocytes do not appear to be major effector cell type
2. Type 2a
   1. Anti-LKM1 (liver-kidney microsome) Ab positive without evidence of viral infection
   2. Most patients are age 2-14, mainly females, often with low IgA levels
   3. Associated with arthritis, thyroiditis and ulcerative colitis (overall ~40%)
   4. Includes ~30% of patients with anti-parietal cell antibodies
   5. More progressive disease than type 1 and 3 with potential progression to cirrhosis
   6. Good response to glucocorticoids ± cytotoxic agents in most patients
   7. Autoantigen appears to be P450 IID6 (recognized by anti-LKM1 Ab)
3. Type 2b
   1. Mainly in adults >40 years old, and is associated with HCV infection
   2. Comprises ~4% of chronic hepatitis cases
   3. May represent an immune response to an abnormal HCV strain
   4. Viral induction of CTL responses and hepatocyte apoptosis may be responsible []
   5. Unclear responses to glucocorticoids
   6. Interferon alpha may be helpful for HCV, but can exacerbate autoimmune disease
4. HCV Overlap [3]
   1. About 5% of patients with autoimmune hepatitis have HCV antibodies
   2. 11% of patients with chronic HCV infection have anti-smooth muscle Abs
   3. 28% of patients with chronic HCV infection have anti-nuclear Abs (ANA)
   4. In patients with predominantly autoimmune disease, glucocorticoids are recommended
   5. Patients with mainly viral pathology on biopsy may be treated with interferon alpha
   6. Combination therapy (glucocorticoids and interferon) may be considered
5. Non-classical Autoimmune Hepatitis
   1. Antibodies to asialoglycoprotein receptor (ASGR) may be found
   2. Absence of viral infection and other autoantibodies
   3. ASGR may be a true initiating autoantigen in chronic autoimmune hepatitis [6]
   4. Overlap syndrome with primary biliary cirrhosis (anti-mitochondrial antibodies)
   5. Overlap syndrome with autoimmune sclerosing cholangitis (usually pANCA+)
6. Granulomatous Hepatitis
   1. Rare disease of unknown cause
   2. Recurrent fevers with conspicuous granulomas in the liver
   3. Associations: sarcoidosis, lymphoma, drug allergies, fungal/mycobacterial infections
   4. Idiopathic variety is quite responsive to glucocorticoids

C. Diagnosis [1]

1. Diagnosis based on histologic abnormalities, clinical symptoms, biochemical abnormalities
2. Autoantibodies are found in >90% of cases
3. Serum immune globulin levels are 1.5-3X normal
4. Liver Function Tests
   1. Most patients have chronic transaminase elevations
   2. Minimal increases in bilirubin or cholestatic enzymes
5. Diagnosis requires that other causes of hepatitis are ruled out
   1. Absence of viral markers and of excess alcohol consumption are required
   2. Medications causing hepatitis are common and should be reviewed
   3. A subset of patients with chronic hepatitis C virus (HCV) infection have autoantibodies
6. Histology of Typical Autoimmune Hepatitis
   1. Mononuclear cell infiltrate invading limiting plate
   2. Limiting plate is is the hepatocyte boundary that surrounds portal triad
   3. This periportal infiltrate also called piecemeal necrosis or interface hepatitis
   4. May progress to lobular hepatitis
   5. May be abundance of plasma cells
   6. Eosinophils are frequently present
   7. In advanced disease, fibrosis is extensive, with regenerative nodules (cirrhosis)

D. Treatment [1]

1. Standard Therapy
   1. Should be given to all patients with interface hepatitis on biopsy, with or without cirrhosis
   2. Autoantibody or serum immune globulin levels to not predict treatment response
   3. Most patients respond to initial therapy
   4. Standard therapy includes oral prednisone or prednisolone ± azathioprine
2. Glucocorticoids
   1. Prednisone or prednisolone used alone or in combination
   2. Prednisone 20-60mg/day for adults, 1-2mg/kg per day for children as monotherapy
   3. If combined with azathioprine, initiate prednisone at half of the monotherapy dose
   4. Taper over time when used with azathioprine (or 6-mercaptopurine, 6-MP)
3. Azathioprine
   1. Initial is 50-100mg/day in adults, 1.5-2.0mg/kg/day in children
   2. May be used as single agent maintenance therapy (same dose)
   3. 6-MP may be used instead of azathioprine (25-100mg/day adults, 0.75-1.0mg/kg children)
4. Other Agents
   1. Cyclosporine - monotherapy in adults or children
   2. Tacrolimus - unclear role
   3. Mycophenolate mofetil - good for patients with adverse reactions to azathioprine or 6-MP
   4. Ursodiol - may be used with other agents, may improve cholestatic picture
5. Prognosis
   1. Ten year survival (without transplant) >90%
   2. 20 year survival ~75% without cirrhosis
   3. In patients with cirrhosis at presentation, 20 year survival ~40%

References

1. Krawitt EL. 2006. NEJM. 354(1):54
2. Galperin C and Gershwin ME. 1997. JAMA. 278(22):1946
3. Arribas JR, Storch GA, Clifford DB, Tselis AC. 1996. Ann Intern Med. 125(7):577
4. Dufour JF, DeLellis R, Kaplan MM. 1997. Ann Intern Med. 127(11):981
5. Rust C and Gores GJ. 2000. Am J Med. 108(7):567
6. McFarlane IG. 2000. Lancet. 355(9214):1475