Idiopathic Autoimmune Chronic Active Hepatitis (IACAH)
The syndrome chronic active hepatitis (CAH) is characterized histologically by periportal piecemeal necrosis and prominent plasma cell infiltration of the portal tracts and persistence of symptoms or signs for more that 6 months. However, it is unequivocally heterogenous with regard to etiology.
Infections with Hepatitis B, delta, and C are the most clearly defined etiologic agents, but CAH is also a recognized feature of other primary liver disease (Wilson’s disease and alpha one antitrypsin deficiency) and may arise as an adverse reaction to certain therapeutic drugs. The term “autoimmune” CAH has no generally accepted definition but most authorities agree that it includes those cases in which all known etiologic factors have been excluded. The definition has lead to terms such as “idiopathic”, “cryptogenic”, or “presumed” autoimmune CAH. Additionally, some authorities require the presence of immunologic features, particularly high titers (usually more than 1:40) of certain non organic specific autoantibodies and polyclonal hyperglobulinemia. In this more stringent classification, the diagnosis is established positively, rather than entirely by exclusion. The term “cryptogenic” therefore becomes reserved to those with no detectable conventional autoantibodies.
The cause of IACAH is unknown, therefore the designation idiopathic. The possibility that a viral agent may trigger the onset of autoimmune chronic active hepatitis has been extensively considered, although at present there are no strongly supported candidate agents. The apparent predisposition of individuals with HLA-B8 and DR3 haplotypes to develop IACAH suggests that genetically conditioned abnormalities may have a role in pathogenesis.
Patients with IACAH most often present with insidious onset of malaise, anorexia, fever and fatigue. Approximately 75% of these patients are female with the most frequent ages of onset between 10-40 years. However, IACAH may occur at any age and in both sexes. The most typical course for patients is to have evidence of mild to moderate disease pursuing a gradual but usually relentless deteriorating course. At the other end of the spectrum are patients with advanced disease and cirrhosis who present with ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, or bleeding form esophageal varices. Occasionally, a patient may present with an apparent acute hepatitis and jaundice. The correct diagnosis may be established only after the patient is observed to have continuing and often worsening hepatitis over several months and is found to have markedly elevated serum gamma globulin levels and autoantibodies. The apparent acute hepatitis-like onset may represent an episode of activation of an underlying chronic process that has been previously silent.
IACAH is divided into three types. Type I or classic autoimmune CAH is the most prevalent, characterized by the presence of antismooth muscle (antiactin) antibodies in 100% of patients and ANA in 33% of patients. In addition, these patients may have arthralgia, oligomenorrhea, fluctuating jaundice and cushingoid appearance with striae, hirsutism and acne. Other “autoimmune” disease such as hyperthyroidism and Coomb’s positive hemolytic anemia are seen in 10% of patients.
Type II autoimmune CAH is characterized by the presence of antiliver-kidney microsomal antibodies (anti-LKM) which are found in the absence of ANA or antiactin antibodies. It is much less prevalent than type I in all age groups but tends to present predominantly in the pediatric age group and is more often associated with “autoimmune” disorders such as insulin-dependent diabetes, autoimmune thyroid disease and vitiligo. The presentation is often acute, even fulminant, with severe histologic features and a marked propensity to progress rapidly to cirrhosis.
Type III autoimmune CAH is characterized by the presence of anti-soluble liver antigen (SLA) antibodies. This group has been less fully studied than the other two groups.
The goals of therapy in IACAH are to decrease mortality, diminish hepatic inflammation and to prevent progression to cirrhosis. Mortality figures in placebo groups of major controlled studies have showed that more than half of the untreated patients died within 3-5 years. There is considerable evidence that corticosteroids and other immunosuppressive therapy lead to decreased mortality but there is less evidence that progression to cirrhosis is slowed or prevented.
Several randomized controlled studies established that corticosteroid not only prolong life but decrease the symptoms and signs of fatigue, loss of appetite and fever. Corticosteroid therapy also lead to improvement in biochemical abnormalities (decrease bilirubin and aminotransferase level and increase albumin) as well as decrease in the inflammatory component found on liver biopsy. There is no evidence that the presence of LE cells or any other individual antibody affects the likelihood of response to therapy. There is no difference in outcome when prednisone therapy was compared to prednisone therapy.
Since therapy is immunosuppressive rather than specifically directed toward the basic cause of the disease, treatment usually needs to be continued indefinitely with gradual tapering using the level of serum aminotransferase and clinical status as guides. Azathioprine is sometimes used as an adjunctive therapy. Cyclosporine was reported to be effective in treating patients with IACAH who were refractory to therapy with corticosteroids. Alpha interferon used in viral hepatitis is known to induce exacerbation of various autoimmune disorders.
Patients with autoimmune CAH that were erroneously diagnosed as chronic Hepatitis C and received alpha interferon suffered from aggravation of liver disease. However, improvement followed discontinuation of alpha interferon and institution of corticosteroid therapy. The positive anti-HCV antibody common in patients with IACAH is caused by disease related hypergammaglobulinemia and steroid therapy usually leads to decrease in gamma globulin level and elimination of positive anti-HCV. However, the new recombinant immunoblot assay (RIBA-II) which increases the specificity of anti-HCV by testing for four separate regions of the Hepatitis C virus is less frequently positive and therefore is important for differential diagnosis especially that alpha interferon that is beneficial in viral hepatitis could be detrimental in IACAH.
Finally, liver transplantation is considered now at earlier stages of the disorder before multiple severe complication develop. However, with this new modality we will be facing the challenge of recurrence in liver graft. Therefore, an issue for the future will be to determine the likelihood for recurrence in the host or grafted liver.
Black M. Alpha-Interferon treatment of chronic Hepatitis C: Need for accurate diagnosis in selecting patients. Ann of Int Med 116: 86-88; 1992.
Chazerain P. Rheumatoid arthritis-like disease after alpha-interferon therapy. Ann of Int Med 116: 427; 1992.
Jhonson PJ. The natural cause and heterogeneity of autoimmune-type chronic active hepatitis. Seminars in Liver Dis 11: 187-196; 1991.
Maddrey W. Therapeutic concepts for the management of idiopathic autoimmune chronic hepatitis. Seminars in Liver Dis 11: 248-255; 1991.
Papo T. Autoimmune chronic hepatitis exacerbated by alpha-interferon. Ann of Int Med 116: 51-53; 1992.