This chapter discusses a group of nonviral conditions that result in chronic inflammation of the liver, ultimately leading to fibrosis, cirrhosis, and liver failure. The epidemiology, pathogenesis, and management of autoimmune liver disease, Wilson disease, and α₁-antitrypsin deficiency are described.

General Considerations

Autoimmune hepatitis (AIH) is a heterogeneous group of chronic inflammatory hepatic disorders identified by the presence of circulating antinuclear antibody (ANA), antismooth muscle antibody (ASMA), or anti–liver kidney microsomal antibody (ALKM), and elevated serum γ-globulins. The pathogenesis of the disease is unclear, although it is believed that genetic predisposition in susceptible individuals ultimately leads to an immunologic process directed against hepatocytes. Among the many suspected inciting factors in those genetically predisposed are toxins, medications, and infectious agents. The inflammatory disorder can result in hepatocellular necrosis and collapse or in fibrosis and cirrhosis. The disease is present in all racial groups and all age groups but is more common in women than in men, with a frequency of 3.6:1. It is responsible for approximately 2–3% of pediatric liver transplantation and 4–6% of adult liver transplantation in Europe and the United States.

Pathogenesis

The mechanism of hepatic injury in AIH is not well characterized. There appear to be both genetic and environmental influences.

AIH is classified into two distinct subtypes based on the presence of autoantibodies. The clinical relevance of this classification system is unclear as it is not certain that autoantibodies play a role in disease pathogenesis. Type 1 or “classic” autoimmune hepatitis is present in patients who test positive for ANA or ASMA, or both. ASMA is thought to be reflective of the more specific antiactin antibody (AAA) particularly when the ASMA titer is >1:320. This is the most common form and has been linked to HLA DRB 10301 (DR3) and DRB 10401 (DR4). Type 2 disease is present in patients who are positive for ALKM-1 antibody and/or antibodies directed against liver cytosol antigen (ALC-1). This form is common in Europe and is often present in younger women in the second and third decades of life. The linkage is to HLA DRB 10701. ALKM-2 antibodies are seen in patient with ticrynafen hepatitis and ALKM-3 antibodies are seen in patients with chronic hepatitis D virus (HDV). A third variant (type 3 autoimmune hepatitis) characterized by the presence of antibody to the soluble liver antigen (ASLA) has been abandoned because the ASLA is also present in 10–30% patients with type 1 or 2 AIH. Currently, ASLA is touted as a possible prognostic marker for identifying patients who may relapse after cessation of corticosteroid therapy.

It is worth noting that in some patients, autoimmune hepatitis may be part of a larger syndromic manifestation of autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED). This is disorder, caused by a mutation in the gene for the autoimmune regulator protein (AIRE), is inherited in an autosomal-recessive fashion.

In “classic” (nonsyndromic) AIH, genetic predisposition is inferred by associations with HLA alleles as discussed earlier. However, inheritance of AIH is not Mendelian in nature but polygenic. Therefore genetic screening of affected individuals and their kin for classic nonsyndromic AIH is of limited clinical importance.

The frequency with which autoantibodies occur varies in the general population. For example, a positive ANA result is found in 67% of patients with AIH. It is present alone in 13% of patients but is accompanied by the ASMA in an additional 54%. It can be present in patients who have primary biliary cirrhosis, PSC, viral hepatitis, drug-induced hepatitis, and nonalcoholic steatohepatitis (NASH). ASMA is present in 87% of patients with AIH. It is seen alone in 33% of patients and in combination with ANA in 54% of patients. The target antigen is thought to be actin and nonactin components of the smooth muscle. In fact, a serologic test for a component of actin (F-Actin) is now used in place of the ASMA assay by many laboratories in screening for AIH. The ALKM-1 antibody is seen in 4% of patients and is often seen in the absence of ANA and ASMA. The target is thought to be the enzyme CYP2D6, which shares homology to hepatitis C. As a result, the ALKM-1 antibody can be falsely positive in patients who are chronically infected with the hepatitis C virus. It is important to realize, however, that the presence of autoantibody by itself is not diagnostic (see later discussion of diagnostic criteria, and Table 41–1).

Drug-induced liver injury (DILI) with features of autoimmune hepatitis is an important and increasingly recognized cause of chronic hepatitis. Medications classically associated with AI-DILI include minocycline, nitrofurantoin, HMG-CoA reductase inhibitors (statins), α-methyl DOPA, hydralazine and more recently anti–TNF-α agents. Circulating autoantibodies, elevated γ-globulin are frequently seen and liver biopsy shows features similar to that seen with classic autoimmune hepatitis with a lymphoplasmacytic portal infiltrate with interface hepatitis. Resolution after decussation of the medication can occur, however, some patients need treatment with prednisone.

Clinical Findings

Autoimmune hepatitis is most common in females in the fourth and fifth decade of life but can affect all ethnic groups of any age. Clinical presentation can be variable from asymptomatic presentation to that of end-stage liver disease or fulminant liver failure. Initial clinical evaluation should establish the diagnosis of AIH while eliminating processes that may mimic AIH (see Table 41–1). Thus, several other causes of hepatitis need to be excluded (see “Differential Diagnosis,” later).

Historic information helps elucidate potential toxin or medication-induced causes of hepatitis. Serologic evaluations help eliminate viral hepatitis and inherited liver diseases (eg, Wilson disease, hemochromatosis, α₁-antitrypsin deficiency). Additionally, PSC and primary biliary cirrhosis (PBC) need to be excluded. Personal and family history of AIH should be sought.

A. Symptoms and Signs

The most common presenting symptoms are fatigue (seen in 87% of patients), dark urine and light-colored stools (77%), right upper quadrant pain (48%), and anorexia (30%). Physical examination findings include hepatomegaly (seen in 78% of patients), spider angiomata (58%), palpable spleen (40%), scleral icterus (46%), ascites (20%), and encephalopathy (14%).

AIH is associated with several other autoimmune disorders. Among the most common are autoimmune thyroiditis, rheumatoid arthritis, hemolytic anemia, immune thrombocytopenia and ulcerative colitis. Additional conditions, although rare, include insulin-dependent diabetes mellitus, Sjögren syndrome, Graves disease, dermatitis herpetiformis, vitiligo, myasthenia gravis, pernicious anemia, and celiac sprue.

B. Laboratory Findings

The presentation of AIH is variable. Severe AIH characterized by marked elevation in transaminases (>10 times the upper limit of normal [ULN]) is the presentation in around 40% of patients. Approximately 3% of these patients have liver failure on presentation. Around 40% of those with untreated severe AIH disease die within 6 months; 40% of the survivors are cirrhotic at presentation, and 54% have varices within 2 years. The 5-year mortality is approximately 58%. In patients who have an alanine aminotransferase (ALT) level more than 10 times the ULN or serum γ-globulins three times the ULN or who have bridging necrosis on histology, 82% are cirrhotic within 5 years, and mortality is 45% during this period of time.

C. Histologic Findings

Liver biopsy should be performed, and the resulting histologic evaluation should be consistent with findings known to be present in AIH. Findings consistent with interface hepatitis, and presence of a lymphoplasmacytic infiltrate in the portal area, are reliable clues and helpful histologic findings. Histologic changes suggestive of biliary tract disease (eg, granulomas), as seen in patients with primary biliary cirrhosis should not be present in the canonical form of AIH.

D. Diagnostic Criteria

Among patients whose diagnosis is not straightforward, response to corticosteroids can aid in determining if AIH is likely. As a result of discrepancies and difficulties in diagnosis, a scoring system for AIH has been designed. An original scoring system developed by Alvarez et al has been felt by many to be too cumbersome. A revised and simplified version of this scoring system is shown in Table 41–1. Prior to treatment with corticosteroids, a score of ≥7 implies a definite diagnosis with an 81% sensitivity and a 99% specificity; a score of >6 implies a probable diagnosis with a 88% sensitivity and 97% specificity.

Differential Diagnosis

The differential diagnosis of AIH includes various forms of acute and chronic hepatitis. These include toxin-induced hepatitis, hepatotropic (hepatitis A–E viruses) and nonhepatotropic viral hepatitis (cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and varicella virus) infections, metabolic liver disorders such as NASH, and inherited liver disorders such as hemochromatosis, Wilson disease, and α₁-antitrypsin deficiency.

Treatment

Treatment is indicated in patients with elevations in serum aminotransferases greater than10 times the ULN; serum aminotransferase levels greater than five times ULN and serum γ-globulin greater than two times ULN; bridging necrosis or multiacinar necrosis on liver biopsy examination; and incapacitating symptoms. Relative indications for treatment include symptoms (jaundice, fatigue, arthralgias); serum aminotransferase and/or γ-globulin levels less than stated in absolute indication; interface hepatitis. Treatment is not indicated in asymptomatic patients with normal or near-normal aminotransferases and γ-globulin levels or in patients with inactive cirrhosis or minimal inflammation on liver biopsy. The cornerstone of treatment is the use of immunosuppressive agents (Table 41–2). Induction of remission should include corticosteroids. Noncorticosteroid immunomodulatory agents such as azathioprine and mycophenolate mofetil may be used for maintenance.

In three distinct randomized clinical trials on adults with severe AIH, those who received prednisone as part of the initial therapy had clinical and histologic improvement in addition to lower mortality when compared with those who did not receive the drug. (Table 41–3) summarizes clinical outcomes of two published trials. Improvement in clinical indices occurs, as well, in patients who are already cirrhotic at the time of diagnosis. As a result, corticosteroids remain the standard therapy for AIH, either given alone or in combination with azathioprine.