Autoimmune Hepatitis and Overlap Syndromes

Definitions and Synonyms

Autoimmune hepatitis (AIH) is a progressive, immune-mediated inflammatory liver disease characterized by a combination of clinical and laboratory findings and histologic evidence of hepatitis. Described more than 60 years ago as a persistent hepatitis of young women, autoimmune hepatitis has since been referred to as lupoid hepatitis, autoimmune or autoimmune-type chronic active hepatitis, lupus or plasma cell hepatitis, and active juvenile cirrhosis. AIH came to represent the prototype histologic pattern of liver injury termed chronic active hepatitis based on the characteristic finding of interface activity (or so-called “piecemeal necrosis”) that distinguished it from chronic persistent hepatitis. The benefit of immunosuppressive therapy was demonstrated in multiple studies in the 1960s and 1970s, and the disease became known as autoimmune hepatitis with solidification of the concept of autoimmunity. Disease presentation is highly variable, and the diagnosis should be considered in any patient with elevated liver enzymes or other evidence of acute or chronic liver disease, or graft dysfunction. The International Autoimmune Hepatitis Group published and later revised a detailed scoring system for establishing the diagnosis primarily for research purposes, and a simplified version for clinical use was put forth in 2008. These scoring systems and the principles therein have been widely adopted for use in the diagnosis of AIH before and after treatment. Although usually not required to establish a diagnosis of AIH in routine clinical practice, they are frequently used in research studies and can be clinically helpful in difficult cases. A minority of patients with classic features of AIH also exhibit objective evidence of primary biliary cholangitis (PBC) and/or primary sclerosing cholangitis (PSC). Recurrent and de novo forms of AIH are recognized to occur after liver transplantation.

Incidence and Demographics

AIH affects patients of both genders, all ethnicities, and all ages. The disease occurs more frequently in females, with a male-to-female ratio of approximately 1:3.6. Worldwide prevalence and incidence of AIH are unknown and appear to vary regionally, being more common in North America and Northern European populations than in Asia. The reported mean annual incidence of AIH ranges from 0.08 to 3.5 per 100,000 people per year in adult populations and 0.23 to 4 per 100,000 in pediatric populations.

Clinical Manifestations

The clinical manifestations of AIH are highly variable, ranging from insidious, asymptomatic disease to features of acute or chronic liver disease with or without cirrhosis, or even fulminant hepatic failure. Although 34% to 45% of patients are entirely asymptomatic at the time of diagnosis, many patients complain of nonspecific symptoms such as fatigue and arthralgias, or flulike symptoms (lethargy, nausea, anorexia, and/or abdominal pain). Jaundice may signify advanced chronic liver disease, an acute hepatitis picture, or the presence of hemolysis or other disease. Approximately one-third of patients have cirrhosis at the time of diagnosis and may exhibit complications of cirrhosis and portal hypertension. Many patients have manifestations of extrahepatic autoimmune diseases such as arthritis, thyroid disease, inflammatory bowel disease, diabetes, vasculitis, connective tissue disease, and others.

Laboratory Findings

Laboratory testing is used to document features of AIH and exclude other potential causes of liver disease such as viral hepatitis, Wilson disease, and others. The characteristic laboratory findings in AIH include elevated transaminase (serum aspartate [AST] and alanine [ALT] aminotransferase) levels, increased serum immunoglobulin G (IgG) concentration, and detectable autoantibodies. Transaminases are consistently elevated in untreated AIH and normalize in most patients after conventional therapy. Polyclonal elevated serum globulin (particularly gamma globulin) levels are common, mainly because of elevated IgG. As nearly all patients exhibit elevated serum IgG levels at the time of diagnosis, detection of hypergammaglobulinemia can be particularly useful in patients in whom AIH is suspected but autoantibodies cannot be detected. In most patients antismooth muscle antibodies (ASMA), antinuclear antibodies (ANA), and/or antiliver/kidney microsomal 1 antibodies (anti-LKM1) or other autoantibodies can be detected. However, ASMA and ANA are neither organ nor disease specific; either autoantibody can be present in other conditions including alcoholic liver disease, nonalcoholic fatty liver disease, PBC and PSC, and even viral hepatitis C, among others. Hepatitis C antibodies can be falsely positive in this population; confirmatory ribonucleic acid (RNA) testing is recommended in individuals with positive hepatitis C antibodies. Hyperbilirubinemia and alkaline phosphatase elevations may be seen but are usually less marked than the transaminase elevations.

The mainly clinical designation of two types of AIH is based on autoantibody profiles. Type 1 AIH is more common and is characterized by the presence of serum ANA and/or ASMA. Type 2 AIH is much less common, is defined by detection of anti-LKM1 antibodies and/or antiliver cytosol type 1 autoantibodies (LC-1) and tends to present at an earlier age, occurring nearly exclusively in female children and adolescents.

Microscopic Pathology

Liver biopsy is essential in the workup and management of patients for possible AIH. Histologic evaluation is used for diagnosis, therapeutic guidance, and exclusion of concurrent forms of liver disease or alternative diagnoses, some of which can present with similar clinical and laboratory findings. There are no pathognomonic histologic features of AIH. The histologic picture is variable among patients and in a given patient depending on its presentation, treatment, and disease evolution. The characteristic histologic features of inflammation and hepatocyte injury abate after immunosuppressive therapy in most patients ( eSlide 21.1 ). Therefore, a posttreatment biopsy may not show typical AIH findings and may in fact be entirely normal.

Portal Changes and Interface Hepatitis

The characteristic histologic picture of AIH is a chronic hepatitis, a histologic pattern of injury characterized by dense portal inflammatory cell infiltrates and portal-based fibrosis ( Fig. 21.1 and eSlide 21.2, eSlide 21.3 ). The degree of inflammation and hepatocyte injury may be severe, especially in untreated patients. The portal inflammatory cell infiltrates are typically dense and composed of lymphocytes, histiocytes, and plasma cells ( Fig. 21.2 ); the latter component may be striking, with plasma cells aggregating in large clusters or sheets. However, plasma cells are not a constant nor pathognomonic feature of the disease; their absence does not exclude AIH and their presence does not exclude other diseases. In fact, moderate to severe plasma cell infiltration of portal tracts is only seen in two-thirds of patients with AIH. Interface hepatitis is often prominent in untreated patients and at presentation. Also termed interface activity, or “piecemeal necrosis,” interface hepatitis denotes the extension of portal inflammation beyond the limiting plate and into the adjacent lobule where it surrounds and injures periportal hepatocytes ( Fig. 21.3 ). This inflammation and the resultant hepatocyte injury may extend deeply into the hepatic lobules and may even extend across hepatic lobules from portal tracts to central veins as “bridging necrosis” (see later) ( eSlide 21.3 ). Posttreatment biopsies often show a marked decline in both portal inflammation and extent of interface hepatitis.

The bile ducts may show focal infiltration by lymphocytes in AIH; this feature does not exclude a diagnosis of AIH. However, definite bile duct destruction is not a feature of AIH and warrants consideration of primary biliary cholangitis, overlap syndrome, drug-induced liver injury, or other form of liver disease.