US Pharm. 2022;47(6):4-6.
Autoimmune hepatitis is an inflammatory and chronic disease of the liver that is identified by elevated serum globulin levels and circulating autoantibodies. Autoimmune hepatitis can present at any age and in all ethnic groups. The disease may begin as acute hepatitis and gradually progress to chronic liver disease and cirrhosis.1 Autoimmune hepatitis has a wide spectrum of clinical presentations. Although this disorder had previously been known by a variety of names, the International Autoimmune Hepatitis Group determined that autoimmune hepatitis is the most appropriate term for this disease.1
For type 1 autoimmune hepatitis, the female-to-male ratio is 4:1, but for type 2 autoimmune hepatitis, the ratio is 10:1.2 According to studies from Europe, the incidence is 0.9 to 2 per 100,000 population per year, with a prevalence of 11 to 25 per 100,000 population. No prevalence data on autoimmune hepatitis exist for the United States.2
Many scientists believe that the pathogenesis of the disease is due to an environmental trigger in a genetically predisposed individual. The exact relationships between genes and the autoimmune process remain largely unknown, but at the molecular level, they are thought to involve the autoantigen, the major histocompatibility complex, and the T-cell receptor.2
Autoimmune hepatitis may present as either an acute or chronic disease with a fluctuating pattern. However, there are occasions that include asymptomatic patients. At the highest level, patients can present with considerable and sometimes debilitating symptoms such as anorexia, fatigue, and weight loss. In addition, long periods of subclinical disease may occur before or after presentation.3
The age of presentation has a pattern, with a peak in the second decade and another peak between the fifth and sixth decades. Physical findings range from a normal physical examination to findings suggestive of cirrhosis or liver failure such as jaundice, ascites, and splenomegaly.2,3
Asymptomatic patients may be identified when they undergo screening examinations. At this time, the finding of an elevated aminotransferase level (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) may be the only sign of liver disease. On occasion, an asymptomatic patient is discovered when an unrelated abdominal surgery is performed and the surgeon notes an abnormal, sometimes cirrhotic-appearing liver.
At the far end of the spectrum are the patients who present with acute liver failure, jaundice, and coagulopathy, but such a presentation is generally uncommon. In addition to asymptomatic disease and an acute presentation, some patients present with a range of mild-to-severe to nonspecific symptoms (e.g., fatigue, anorexia, nausea, abdominal pain, itching). Arthralgia involving the small joints or a transient erythematous rash may also be present with patients.4
In acute presentations, elevations in aminotransferases may exceed 10 to 20 times the upper limit of the reference range, and the ratio of alkaline phosphatase to AST (or ALT) is often <1:5 and in some cases is <1:10.4 The major laboratory feature of autoimmune hepatitis is an elevation in gamma globulins, particularly immunoglobulin G (IgG). Levels of IgA and IgM are typically normal. Hypergammaglobulinemia is generally associated with circulating autoantibodies. For adults with suspected autoimmune hepatitis, higher antibody titers (>1:160) provide greater support for the diagnosis compared with lower titers.3,4 The major autoantibodies that may be present in patients with autoimmune hepatitis are in type 1 and type 2 hepatitis. However, some patients may lack circulating autoantibodies.
On the basis of the autoantibody profiles, patients can be categorized into two disease subtypes: type 1 or type 2; however, these subtypes have not been established as distinct clinical or pathological groups.5,6
Type 1 Autoimmune Hepatitis
Autoantibodies characteristic of type 1 autoimmune hepatitis are the following:
• Antinuclear antibody (ANA)
• Antismooth muscle antibody (ASMA; approximately 65% of patients)
• Antiactin antibodies
• Antimitochondrial antibodies
• Antisoluble liver antigen/liver pancreas antibody antigen (anti-SLA/LP; approximately 10%-30% of adults)
• Antisingle-stranded and antidouble-stranded DNA (25%-35% of patients)
• Atypical perinuclear antineutrophil cytoplasmic antibodies.
Type 2 Autoimmune Hepatitis
Autoantibodies characteristic of type 2 autoimmune hepatitis are the following:
• Antibodies to liver-kidney microsome (LKM-1) alone or accompanied by antiliver cytosol antibody-1 (ALC-1). Positive titers are defined as >1:20 for ANA and ASMA, whereas titers of 1:10 may be considered positive for anti-LKM-1. However, some patients have only ALC-1 antibodies. In addition, approximately 10% to 30% of patients with type 2 disease will have anti-SLA/LP antibodies.
• Antibodies to liver-kidney microsome-3 (LKM-3) are rarely seen in type 2 disease and are not useful in clinical practice.
The diagnosis of autoimmune hepatitis can be made in a patient with a compatible clinical presentation when the following features are present6-8:
1) A minimum of one elevated serum aminotransferase, typically (but not always) an AST and/or ALT level at least two times the upper limit of the reference range;
2) A minimum of one positive laboratory test: increased total IgG or gamma-globulin levels, and/or serologic markers (ANAs), ASMA at a titer of at least 1:40, anti-LKM-1 antibodies, ALC-1, or anti-SLA/LP antibodies;
3) Exclusion of other diseases that have a similar presentation, particularly viral hepatitis, drug-induced liver injury, and alcoholic liver disease.
When a liver biopsy is obtained, the diagnosis can be confirmed by histology showing interface hepatitis and/or a predominantly lymphoplasmacytic infiltrate.
Autoantibody-Negative Autoimmune Hepatitis
Approximately 20% of patients who present with all of the features of autoimmune hepatitis lack circulating ANA, ASMA, or anti-LKM-1 antibodies. These patients are usually regarded as having autoantibody-negative autoimmune hepatitis. The differential diagnosis of autoimmune hepatitis includes various conditions associated with either acute hepatitis or chronic inflammation that may also be accompanied by liver cirrhosis.
The diagnostic evaluation for children with suspected autoimmune hepatitis is similar to the evaluation in adults, although, magnetic resonance cholangiopancreatography is obtained in all children to exclude autoimmune sclerosing cholangitis. In addition, antibody titers of 1:20 or greater (for all antibodies) are regarded as positive in children. Some clinical features of autoimmune hepatitis (e.g., elevated transaminases) may be found in patients who present with inflammatory liver disease from a different etiology such as viral hepatitis, drug-induced hepatitis, nonalcoholic steatohepatitis, systemic lupus erythematosus–associated liver disease, acute liver failure, and iron overload.2,8
The goal of treatment is to slow or stop the immune system from attacking the liver, no matter which type of autoimmune hepatitis is present.6,9,10 Steroids are the initial treatment for autoimmune hepatitis, typically with or without azathioprine or 6-mercaptopurine. This combination may help slow down the progression of the disease. The initial treatment is usually prednisone, which decreases immune system activity. Prednisone, however, especially when it is taken for a long time, can cause serious side effects, such as diabetes, osteoporosis, osteonecrosis, high blood pressure, cataracts, glaucoma, and weight gain. Prednisone is typically given at a high dose for about the first month of treatment. To minimize the risk of side effects, the dose is gradually reduced over the next several months until reaching the lowest possible dose that controls the disease. The addition of azathioprine also helps avoid prednisone’s side effects.
Many patients may experience remission a few years after starting treatment, but the disease often returns if the drug is discontinued. Patients may need lifelong treatment. If medications do not stop the progress of the disease or if the patient develops irreversible scarring (cirrhosis) or liver failure, the alternative option is a liver transplant. The diseased liver is removed and replaced with a healthy liver from a donor. The procedure often uses livers from deceased organ donors, but in some cases, a living-donor liver can be used. During a living-donor liver transplant, a patient receives only a portion of a healthy liver from a living donor. Both livers begin regenerating new cells almost immediately.
1. Manns MP, Lohse AW, Vergani D. Autoimmune hepatitis. Update 2015. J Hepatol. 2015;62:S100-5111.
2. Heneghan MA. Overview of autoimmune hepatitis. Wolters Kluwer 2022. www.uptodate.com/contents/overview-of-autoimmune-hepatitis?search=overview-of-autoim-mune-hepatitis&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4. Accessed May 4, 2022.
3. Heneghan MA, Yeoman AD, Verma S, et al. Autoimmune hepatitis. Lancet. 2013;382:1433-1444.
4. Krawitt EL. Autoimmune hepatitis. N Engl J Med. 2006;354:54-66.
5. Rust C, Beuers U. Overlap syndromes among autoimmune liver diseases. World J Gastroenterol. 2008;14:3368-3373.
6. Anand L, Choudhury A, Bihari C, et al. Flare of autoimmune hepatitis causing acute on chronic liver failure: diagnosis and response to corticosteroid therapy. Hepatology. 2019;70:587-596.
7. Wies I, Brunner S, Henninger J, et al. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis. Lancet. 2000;355:1510-1515.
8. Mack CL, Adams D, Assis DN, et al. Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American Association for the Study of Liver Diseases. Hepatology. 2020;72:671-722.
9. Ngu JH, Bechly K, Chapman BA, et al. Population-based epidemiology study of autoimmune hepatitis: a disease of older women? J Gastroenterol Hepatol. 2010;25:1681-1686.
10. Mayo Clinic. Autoimmune hepatitis. www.mayoclinic.org/diseases-conditions/autoimmune-hepatitis/diagnosis-treatment/drc-20352158. Accessed May 4, 2022.
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