Clinical presentation and natural history of autoimmune hepatitis
Potential conflict of interest: Nothing to report.
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primary biliary cirrhosis
primary sclerosing cholangitis.
Autoimmune hepatitis (AIH) afflicts children and adults in all ethnic and racial groups. AIH preferentially affects women more than men by a ratio of 3.6/1.0 (Table 1). The incidence of AIH has been studied best in Scandinavia, where the prevalence is 1 to 2 cases per 100,000 persons per year with a point prevalence of 11 to 17 cases per year.[2, 3] The peak incidence occurs between the ages of 16 and 30 years. The presentation and management of AIH in children are discussed in an accompanying article.
Table 1. Epidemiology of AIH
|• Incidence: 1-2 cases per 100,000 persons per year|
|• Point prevalence: 11-17 cases per 100,000 persons per year|
|• Ratio of women to men: 3.6/1|
|• All ethnic groups|
|• All ages (peak incidence between 16 and 30 years)|
AIH has protean presentations that span the spectrum from subtle alterations in serum liver tests to severe acute liver failure or newly recognized cirrhosis (Table 2). AIH may be discovered in an otherwise asymptomatic person who is found during an employment or insurance examination to have moderately abnormal aminotransferases. The patient's sex and the presence of elevated serum immunoglobulin G (IgG) levels (sometimes shown by a disproportionately high ratio of total protein to albumin) are clues to AIH in this setting. Unexpected AIH may also be discovered when elevations of aminotransferases are detected in a patient known to have another autoimmune inflammatory disorder (Table 2). A more demonstrative hepatic presentation is a systemic illness of fatigue, malaise, and arthralgia, with further investigations revealing 10- to 50-fold elevations of serum aminotransferases and hypergammaglobulinemia (predominantly IgG). Such patients often have jaundice at presentation. In others, there may be subtle indicators of a chronic clandestine illness such as unexplained amenorrhea or weight loss. The most severe presentation is a syndrome of fulminant hepatic failure encompassing jaundice, encephalopathy, coagulopathy, and markedly elevated aminotransferase levels.
Table 2. Typical Presentations of AIH
|• Asymptomatic person|
|• Systemic illness of fatigue, malaise, and arthralgia|
|• Acute hepatitis|
|• Fulminant hepatic failure|
|• Common systemic associations (see Table 3)|
Twenty-five percent of patients with AIH have cirrhosis at the time of diagnosis.[1, 5] Up to 50% of cases of cryptogenic cirrhosis may be attributed to clandestine AIH, although the proportion appears to be decreasing as the prevalence of cases due to nonalcoholic steatohepatitis increases. The presence of autoantibodies typical for type 1 or 2 AIH and the presence of common systemic associated conditions (e.g., thyroid disease, type 1 diabetes, and vitiligo) increase the likelihood of AIH as the underlying etiology.
As shown in Table 3, AIH is often associated with other immune inflammatory disorders. The most common association is with autoimmune thyroid disease. Other associated disorders include sicca syndrome, rheumatoid arthritis, nondestructive polyarthropathy, type 1 diabetes, vitiligo, ulcerative colitis, and celiac disease. All the complications of cirrhosis and portal hypertension (ascites, varices, encephalopathy, and hepatocellular carcinoma) may arise when AIH is the underlying cause.
Table 3. Comorbid Associations With AIH
|• Autoimmune thyroid disease|
|• Sicca syndrome|
|• Rheumatoid arthritis or nondestructive polyarthropathy|
|• Type 1 diabetes|
|• Ulcerative colitis|
|• Celiac disease|
|• All complications of cirrhosis and portal hypertension (ascites, varices, encephalopathy, and hepatocellular carcinoma)|
The recognition of AIH requires a strong index of suspicion, especially when the presentation is subtle. As reviewed by Vergani and Geller in separate articles in Clinical Liver Disease, the diagnosis of AIH is based on a synthesis of clinical presentation, biochemical tests, and histology. According to the clinical guidelines of the American Association for the Study of Liver Diseases, “the diagnosis of AIH should be considered in all patients with acute or chronic hepatitis of undetermined cause, including patients with acute severe hepatitis. (Class I, Level C).” As shown in Table 4, a full diagnostic review should consider other autoimmune liver diseases, viral hepatitis, Wilson's disease, drug or toxic reactions, related autoimmune disorders that affect the liver [including primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and celiac disease], and, in certain settings, alcoholic and nonalcoholic fatty liver diseases. A particular diagnostic challenge, reviewed in accompanying articles in Clinical Liver Disease,[8, 9] arises in the patient who exhibits overlapping features of AIH and PBC, PSC or autoimmune cholangitis.[8, 9]
Table 4. Differential Diagnosis for Patients With Possible AIH
|• Other autoimmune liver diseases (PBC, PSC, and autoimmune cholangitis), including overlap syndrome|
|• Acute or chronic viral hepatitis|
|• Wilson's disease|
|• Drug or toxic reactions|
|• Celiac disease|
|• Alcoholic and nonalcoholic fatty liver disorders|
Older studies have described the rapid progression of untreated AIH to cirrhosis and death, but these observations have many limitations, such as the inclusion of patients with chronic hepatitis B and C in the study cohorts. It seems likely that AIH may persist in a nonprogressive state in some asymptomatic patients. Nevertheless, the progression of fibrosis appears to be common in untreated patients with AIH, and immunosuppressive treatment can dramatically improve clinical, biochemical, and histological parameters, even in patients with established cirrhosis.
Corticosteroids remain the first-line therapy for patients with AIH. The goal of treatment, revised in the 2010 American Association for the Study of Liver Diseases practice guideline, is to induce the remission of the necroinflammatory reaction (manifesting as a normalization of serum aminotransferase and IgG levels). Cumulative reports indicate that corticosteroids induce remission in 65% of patients within 18 months and in 80% within 3 years. However, it is important to note that remission in these reports indicated the confinement of hepatic inflammation within the portal tracts and the reduction of aminotransferase levels to 1.5 to 2 times the upper limit of normal. The frequency of remission on corticosteroids according to the criterion of alanine aminotransferase normalization remains unclear, but it is anticipated to be lower. A recent retrospective report of the longitudinal observation of a large cohort of patients with AIH in the Netherlands suggests that sustained remission is possible in very few patients. The initiation and monitoring of treatment, the place of stringent response criteria, the choice of the corticosteroid and its dose, the role of budesonide, and the use of alternative immunosuppressive therapies are discussed in detail in an accompanying article.
Long-term follow up studies of patients with treated-AIH show that both overall mortality and liver-related mortality exceed that in the general population. Patients who have cirrhosis at the time of first biopsy have a worse prognosis. Liver transplantation is the ultimate treatment for cirrhotic AIH patients who develop liver failure or hepatocellular carcinoma. AIH recurs after liver transplantation in approximately 22% of recipients; in rare cases, it will progress to end-stage graft failure, and retransplantation may be required.[14, 15]