Transplantation for Autoimmune Hepatitis

Historical Perspective

Hyperproteinemia and idiopathic recurrent jaundice with unresolving hepatic inflammation were first described in the early 1940s, but idiopathic autoimmune hepatitis was not recognized until 1950 when Waldenström described the constellation of cirrhosis, plasma cell infiltration of the liver, and hypergammaglobulinemia in young women. In 1955 the lupus erythematous cell phenomomena and the presence of antinuclear antibodies (ANA) led Mackay et al to introduce the term lupoid hepatitis . In the 1960s subgroups of patients were distinguished by specific immunoserological findings, and Page et al demonstrated that treatment with 6-mercaptopurine (6-MP) improved clinical symptoms and decreased the level of hypergammaglobulinemia. Whittingham et al distinguished between chronic active hepatitis and systemic lupus erythematosus and introduced the term autoimmune hepatitis . In 1973 Rizzetto et al described an autoantibody reacting with the microsomal fraction of hepatocytes and renal tubular epithelium in patients with chronic active hepatitis. In 1987 the first formal proposal to subclassify AIH was introduced. The same year, Manns et al described anti–soluble liver antigen/liver pancreas (anti-SLA/LP), which occurred in about 30% of patients who presented with seronegative conventional autoantibodies, and type 3 classification for AIH was suggested. However, Ballot et al later showed that the clinical and biological features of anti-SLA/LP seropositive patients were similar to those of AIH type 1 and therefore did not warrant being distinguished as a separate subgroup.

Epidemiology

Early epidemiological studies from 1970 to 1995 in western European populations showed a mean annual incidence of AIH ranging from 1.9 to 16.9 cases per 100,000 persons. However, the incidence may have been overestimated because the condition was included within the spectrum of chronic active hepatitis. In Europe AIH accounts for 2.6% of the transplantations and in the United States, 5.9%. Type 2 AIH is most prevalent in southern Europe. Females are affected more than males (3.6:1), and all ages and ethnic groups are susceptible.

The mortality of untreated AIH is high. Up to 40% of untreated patients with decompensated liver disease die within 6 months. Cirrhosis develops in about 40% of diagnosed untreated patients. Of patients with cirrhosis, 54% develop esophageal varices within 2 years, and 20% die of variceal hemorrhage. For patients with sustained serum aminotransferase levels of more than tenfold normal or more than fivefold normal in conjunction with serum γ-globulin concentrations of at least twofold elevation, mortality without treatment is 90% at 10 years. The risk for developing cirrhosis is associated with histological findings. In patients with periportal hepatitis, cirrhosis develops in 17% within 5 years, bridging necrosis or multiacinar necrosis progresses to cirrhosis in 82% within 5 years, and mortality is 45%. Cirrhosis develops within 15 years in 49% of patients with moderate laboratory findings or serum aminotransferase levels less than tenfold normal or less than fivefold normal in conjunction with serum γ-globulin concentrations less than twofold elevation, and death from fulminant hepatic failure occurs in 10%. Hepatocellular carcinoma is relatively uncommon in patients with cirrhosis, occurring in approximately 4% of those with type 1 AIH, with a 10-year probability of developing this neoplasm at 2.9% and the risk for hepatocellular carcinoma increasing in those who have AIH cirrhosis. With immunosuppression treatment, 65% of patients achieve clinical, biochemical, and histological remission within 18 months; 80% do so within 3 years. The 20-year survival is 80% of treated patients in contrast to 10-year survival of 10% in untreated patients. Although immunosuppression remains the mainstay of therapy for AIH, 9% deteriorate on traditional regimens, 13% develop treatment-related side effects that warrant premature discontinuation of medication, 13% have an incomplete response, and of those who experience remission and discontinue therapy, 74% to 85% relapse within 3 years.

Pathophysiology

The most accepted hypothesis for the cause of AIH suggests an environmental agent triggers an autoimmune process against the liver in a genetically predisposed individual. Multiple triggering factors have been implicated, such as viruses, drugs, and toxins. Proposed viral triggers include measles virus; hepatitis A, B, and C; and the Epstein-Barr virus. Drugs that have been associated with AIH include diclofenac, methyldopa, oxyphenisatin, nitrofurantoin, and minocycline. The actual mechanisms by which these environmental agents can initiate autoimmunity and trigger AIH are unknown.

During immunological development, individuals are protected against self-reactive T and B cells by negative clonal selection and apoptosis of these cells. Many studies support the idea of epitope mimicry in which a susceptible individual is presented with an environmental agent that exhibits antigens that share homologies with host antigens. These shared homologies result in a cross-reaction and loss of self-tolerance leading to an immune response generated against the host tissue. There can potentially be a long lag time between exposure to the trigger and onset of disease, and the environmental agent may or may not be present when the autoimmune disease becomes clinically apparent.

There appears to be a clear association between HLA and AIH. The frequency of HLA markers varies between ethnic groups. HLA-DR3 and DR4 are the major risk factors for type 1 AIH in white European and North American populations. HLA-DR3 is more commonly found in the early-onset, severe form of disease (often occurring in girls and young women), whereas HLA-DR4 is more common in whites with late-onset disease and is associated with a higher incidence of extrahepatic manifestations and a better response to corticosteroids. More advanced molecular analysis reveals that there appears to be a common susceptibility determinant in the HLA-class II binding groove important to antigen recognition that is carried by the DRB1 ^∗ 0301, DRB3 ^∗ 0101, and the DRB1 ^∗ 0401 alleles in whites. Furthermore, a thorough analysis of the amino acid sequences encoded by these susceptibility alleles revealed a particular motif of Leu-Leu-Glu-Gln-Lys-Arg at positions 67 to 72 of the DR polypeptide, which is encoded by DRB1 ^∗ 0301, DRB3 ^∗ 0101, and DRB1 ^∗ 0401, with the critical amino acid in this motif likely being the Lys residue at position 71. However, how these alleles confer susceptibility to AIH is still not well understood.

Both cellular and humoral immunity are involved in the autoimmune destruction of hepatocytes. It is mediated by CD4 ⁺ helper T cells that recognize self-antigen. Cytokines such as interferon-γ, tumor necrosis factor-α, and interleukin-2 (IL-2) in the environment will lead to the differentiation of different effector cells. CD8 ⁺ cytotoxic T cells are involved in both cell-mediated and humoral autoimmunity in AIH. Antibody-dependent cytotoxic activity mainly involves antibodies against the asialoglycoprotein receptor (ASGPR), a hepatocyte membrane protein. Natural killer cells are present in the normal liver and may be involved with liver destruction, possibly through the expression of the Fas ligand and the binding of its Fc receptor with an antigen-antibody complex on the hepatocyte.

Clinical Manifestations