Approach

The presenting clinical picture of autoimmune hepatitis (AIH) may look similar to many other liver diseases. Characteristic features of AIH include the presence of other autoimmune diseases, elevated aminotransferase levels, the presence of specific autoantibodies, and interface hepatitis on liver biopsy.[1][20]

Medical history

Clinical manifestations are variable, ranging from an asymptomatic condition to fulminant hepatic failure. Common symptoms include:[1]

  • fatigue

  • malaise

  • lethargy

  • anorexia

  • nausea

  • abdominal discomfort

  • mild pruritus

  • arthralgia involving small joints.

Rarely, patients may present with fever, oligomenorrhea, encephalopathy, and gastrointestinal bleeding associated with portal hypertension.[1][21][22]

A history of other autoimmune diseases may be present such as thyroiditis, type 1 diabetes, celiac disease, and ulcerative colitis.[1][3]​​​​

Physical exam

Physical signs are usually absent in patients with AIH.

Signs of advanced chronic liver disease (e.g., spider nevi, caput medusa, splenomegaly, ascites, palmar erythema) or manifestations of extrahepatic autoimmune disease may be seen (e.g., vitiligo, inflammatory bowel disease).[1]

Laboratory evaluation

Liver function tests (LFTs) are performed on all patients who present with the described symptoms and signs. In patients with AIH, they will be abnormal at presentation.

Aminotransferase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels are more strikingly elevated than those of bilirubin and alkaline phosphatase (ALP), with values averaging 200 to 300 international units/L, although values of several thousands are sometimes found in patients with an acute (fulminant) course.[23]

Bilirubin and ALP levels are mildly to moderately increased in most patients. However, AIH can sometimes present with a cholestatic picture marked by high levels of conjugated bilirubin and ALP.[14]​​

Elevated serum gamma globulins, particularly immunoglobulin (Ig) G, is another characteristic laboratory feature.[1] Serum albumin levels may be reduced and prothrombin time prolonged.[24][25]​​​

Patients whose LFTs are abnormal are then tested for serum autoantibodies to further determine whether they have AIH and, if so, what type. Patients of all ages are usually routinely tested for all the autoantibodies available.[1]

Serologic categorization of AIH

Type 1 AIH

Characterized by the detection of antinuclear antibodies (ANAs) and/or smooth muscle antibodies (SMAs)/anti-actin antibodies.[1]

ANAs are found in 43% of patients with type 1 AIH and are the traditional markers of the disease, although they are not disease-specific.[26] They are directed against diverse nuclear antigens, including centromeres, ribonucleoproteins, and ribonucleoprotein complexes.[2] Patients with ANA-positive type 1 AIH may also have antibodies directed against single-stranded DNA (anti-ssDNA) and double-stranded DNA (anti-dsDNA).[27]​ SMAs are directed against actin and nonactin components, including tubulin, vimentin, desmin, and skeletin, and are also standard markers of AIH.[2] Anti-actin antibodies are found in 41% of patients with type 1 AIH.[26]

Type 2 AIH

Type 2 AIH is characterized by antibodies to liver kidney microsome type 1 (anti-LKM-1), usually in the absence of ANA and SMA.[1]

Antibodies to liver cytosol type 1 (anti-LC1) are present in 32% of patients with anti-LKM-1, occurring mainly in children with severe disease.​[1] Neither anti-LKM-1 nor anti-LC1 are disease specific, as they have also been identified in a small proportion (5% to 10%) of adult and pediatric patients with chronic hepatitis C infection.[3]​​​

Anti-LKM-3 antibodies are present in 17% of patients with type 2 AIH, and may be useful in assessing otherwise seronegative patients.[1]

Antibodies against soluble liver antigen/liver pancreas (anti-SLA/LP) are found in approximately 10% to 30% of all patients with AIH.[28][29]​ Anti-SLA/LP is the only disease-specific autoantibody and therefore has high diagnostic value. This has led to the development of reliable commercial assays for anti-SLA/LP detection (enzyme-linked immunosorbent assay [ELISA] and dot-blot).[26]​​

Patients seronegative for ANA/SMA or anti-SLA/LP

In patients who are seronegative for ANA/SMA or anti-SLA/LP, it is useful to test for atypical perinuclear antineutrophil cytoplasmic autoantibodies (pANCA) and antibodies against the asialoglycoprotein receptor (anti-ASGP-R) to determine if they have AIH.[1]

The prevalence of pANCA, traditionally associated with primary sclerosing cholangitis and inflammatory bowel disease, is 40% to 95% among patients with type 1 AIH.[2][3]​ Anti-ASGP-R are targeted against a transmembrane glycoprotein on the hepatocyte surface (ASGP-R) and seem to correlate with histologic activity.[2]

Patients with primary biliary cirrhosis

Patients with primary biliary cirrhosis will test positive for antimitochondrial antibodies (AMA), but it is worth remembering that they can be seen in AIH as well (overlap syndrome).[1]

Other tests to exclude differential diagnoses

The differential diagnosis includes alcoholic hepatitis, viral hepatitides, drug induced liver injury, Wilson disease, alpha-1 antitrypsin deficiency, and metabolic dysfunction-associated steatohepatitis (formerly known as nonalcoholic steatohepatitis). The following tests are ordered to help exclude some of these differential diagnoses:[1]

  • IgM antibodies to hepatitis A virus (IgM anti-HAV)

  • hepatitis B surface antigen (HBsAg)

  • antibodies to hepatitis B core antigen (anti-HBc)

  • hepatitis C antibody and hepatitis C viral RNA (viral hepatitis)

  • plasma ceruloplasmin (Wilson disease)

  • alpha-1 antitrypsin level (alpha-1 antitrypsin deficiency)

  • serum iron and total iron-binding capacity (genetic hemochromatosis).

Diagnostic scoring systems

The diagnostic scoring system of the International Autoimmune Hepatitis Group (IAIHG) was created in 1993, revised in 1999, and simplified in 2008 (see Criteria).[1] The revised scoring system may be helpful for those patients who do not present with features characteristic of AIH.[1] Validation of the revised original and simplified scoring systems in prospective studies is required.

Once the diagnosis has been determined, and before treatment, it is recommended that patients are tested for thiopurine methyltransferase (TPMT) activity. In patients with TPMT deficiency, azathioprine is contraindicated.[1]

Imaging studies

Most patients who have elevated liver enzymes will have an abdominal ultrasound. There are no characteristic imaging features for AIH; however, ultrasound can evaluate for extrahepatic biliary obstruction, abnormalities in liver morphology, and changes associated with portal hypertension such as splenomegaly.[30][31]

Liver histology

Unless contraindicated, a liver biopsy should be performed to determine the diagnosis and evaluate the liver status prior to treatment, as therapy can alter the histologic findings.[1][26]​ The percutaneous route is generally not considered safe if the international normalized ratio (INR) is more than 1.5 or the platelet count is less than 50,000/mm³. The transjugular route is preferred in patients with coagulopathy, severe thrombocytopenia, or ascites​.[32] Possible complications include bleeding, bowel perforation, and pneumothorax. Risk of mortality is very low (0.01%).[33]​​

AIH is characterized by a periportal lesion or interface hepatitis (a portal mononuclear and plasma cell infiltrate). The diagnosis is dependent on the presence of abundant plasma cells. Some degree of fibrosis is almost invariably present. Other histologic features include panacinar (lobular) hepatitis and centrilobular (Rappaport zone 3) necrosis, which are thought to be early histologic manifestations of AIH.

Fibrosis may be absent in the mildest forms of the disease and extensive in advanced disease, connecting portal and central areas (bridging) and leading to architectural distortion of lobules, appearance of regenerating nodules, and cirrhosis.

Bile duct changes may be present in approximately 25% of patients, but are usually mild. Prominent biliary changes are suggestive of an alternate disease process and should raise suspicion of primary sclerosing cholangitis or overlap syndromes.

A plasma cell infiltrate, rosettes of hepatocytes, and multinucleated giant cells may be seen.[1][34]​​

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