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Autoimmune Hepatitis

This PatientPlus article is written for healthcare professionals so the language may be more technical than the condition leaflets. You may find the abbreviations list helpful.

Autoimmune hepatitis (AIH) is a chronic disease of unknown cause, characterised by continuing hepatocellular inflammation and necrosis, which tends to progress to cirrhosis. Immune serum markers are often present and the disease is often associated with other autoimmune diseases.

  • Autoimmune hepatitis is associated with the complement allele C4AQO and with the HLA haplotypes B8, B14, DR3, DR4, and Dw3.
  • The autoantibodies present include antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-liver-kidney microsomal-1 (anti-LKM-1) antibody, antibodies against soluble liver antigen (anti-SLA), antimitochondrial antibody (AMA) and antiphospholipid antibodies.

AIH is an heterogeneous disorder and it can be divided into two types, depending on which autoantibodies are present:1

  • Type 1: associated with the presence of ASMA or ANA. Accounts for about 75% of patients.2
  • Type 2: associated with the presence of either anti-LKM-1 or anti-liver cytosolic-1 (anti-LC-1) antibodies.

Epidemiology

  • The prevalence of autoimmune hepatitis (AIH) in Europe is estimated as being in the range of 10-17 cases per 100,000 persons.3
  • It is m common in those aged between 10 and 30 years and those between 40 and 50 years but can occur at any age.
  • Type 2 is more frequent in Southern Europeans.
  • AIH accounts for about 3% of liver transplantations in Europe.
  • Women are affected three to four times more often than men.

Presentation

Autoimmune hepatitis (AIH) may present as acute hepatitis, chronic hepatitis or established cirrhosis.

Subclinical disease often precedes the onset of symptoms and many patients have histological evidence of cirrhosis at the onset of symptoms. Common symptoms include:

  • Fatigue, myalgia, mild pruritus.
  • Nausea (often a prominent symptom).
  • Upper abdominal discomfort.
  • Anorexia, diarrhoea.
  • Arthralgias.
  • Skin rashes (including acne), hirsutism.
  • Oedema.
  • Amenorrhoea.
  • Chest pain (pleuritis).
  • Weight loss and intense pruritus (unusual).

Signs

Common findings on physical examination are as follows:

Investigations

No pathognomonic features exist for autoimmune hepatitis (AIH) and therefore the diagnosis rests on a combination of compatible biochemical, immunological and histological features together with exclusion of other liver diseases.3

Diagnosis of autoimmune liver disease requires the exclusion of common viral, drug-induced and metabolic liver disease.

  • Autoantibodies (see above).
  • Serum protein electrophoresis and quantitative immunoglobulins:
    • An immunoglobulin G (IgG)-predominant polyclonal hypergammaglobulinaemia is a common finding in patients with untreated AIH.
    • Increased gammaglobulin and IgG levels are found in around 85% of patients.
    • Immunoglobulin levels typically return to normal during treatment.
  • Aminotransferases:
    • Serum aminotransferases: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually elevated at initial presentation.
    • Aminotransferase values correlate poorly with the degree of hepatic necrosis but very high levels may indicate acute hepatitis or a severe flare of pre-existing disease.
    • Continued elevation of the aminotransferases during therapy is a reliable marker for ongoing liver inflammation but active liver inflammation is present in more than 50% of patients with normal LFTs. Biochemical remission may precede true histological remission by 3-6 months.
    • Serum aminotransferases may normalise either on treatment or spontaneously, even with continuing severe hepatic inflammation on biopsy.
  • Serum alkaline phosphatase is normal or only mildly raised. A more than two-fold elevation suggests an alternative or additional diagnosis.
  • Hypoalbuminaemia and prolongation of prothrombin time are markers of severe hepatic synthetic dysfunction.
  • FBC and blood film: findings include mild leukopenia, normochromic anaemia, Coombs-positive haemolytic anaemia, thrombocytopenia, eosinophilia.
  • Imaging studies are not usually helpful in reaching a definitive diagnosis of AIH but may suggest the presence of active inflammation or necrosis. The appearance of an irregular nodular liver may confirm the presence of cirrhosis. Imaging studies may also be used to rule out the presence of hepatocellular carcinoma.
  • Liver biopsy:
    • Liver biopsy is the most important diagnostic procedure in patients with AIH.
    • Liver biopsy should be performed as early as possible in all patients with acute hepatitis who are thought to have AIH. Confirmation of the diagnosis enables initiation of treatment at an early stage in the disease process.
    • Liver biopsy also provides information on prognosis. Up to a third of patients have cirrhosis at presentation.2 Patients with cirrhosis and those with bridging necrosis at diagnosis have a poorer prognosis than those without.

Associated diseases

Autoimmune hepatitis (AIH), especially type 2, is associated with a wide variety of other disorders:

Management3

  • Patients with moderate or severe inflammation (defined as one or more of serum AST >5 times normal, serum globulins >2 times normal, liver biopsy showing confluent necrosis) should be offered immunosuppressive treatment.
  • Patients with symptoms, established cirrhosis on biopsy and younger patients should also be considered for treatment with immunosuppressive treatment.
  • There is less proven benefit of treating older, asymptomatic patients with mild autoimmune hepatitis (AIH). These patients should be monitored regularly.
  • Prednisolone in conjunction with azathioprine is the treatment of choice in patients with AIH. Prednisolone alone is sometimes used.
  • One study showed that budesonide plus azathioprine achieved normalisation of serum transaminases more quickly and had fewer side-effects compared with prednisolone plus azathioprine. This regime may be considered in non-cirrhotic patients with severe steroid-related side-effects such as psychosis, poorly controlled diabetes or osteoporosis.4
  • The target for remission therapy should be normalisation of serum AST/ALT, gammaglobulin, IgG and, ideally, histological evidence of cessation of active liver inflammation.
  • Other drugs, including ciclosporin A, tacrolimus and mycophenolate are used as second-line therapy. However, these drugs only control the disease in around 50% of patients.
  • Liver transplantation is an effective form of therapy for patients with decompensated cirrhosis caused by AIH or to rescue patients who present with fulminant hepatic failure secondary to AIH.
  • About 10-20% of patients with AIH will require liver transplantation during their lifetime.
  • Recurrence of AIH may occur after liver transplantation.

Monitoring

  • Patients should be tested for hepatitis A and B immunity and vaccinated if needed.
  • Regular blood testing including LFTs, glucose and FBC should be performed.
  • All patients should receive calcium and vitamin D supplements.
  • Dual-energy X-ray absorptiometry (DEXA) scans should be performed prior to starting steroids and repeated at 1-2-yearly intervals.
  • Screening for glaucoma and cataracts should be considered after 12 months' prednisolone treatment.

Complications

  • Hyperviscosity syndrome secondary to high IgG levels may occur.
  • Hepatocellular carcinoma may occur. It is more common in patients with cirrhosis. There is a 10-20% risk of hepatocellular carcinoma in patients with cirrhosis.5
  • Six-monthly surveillance is recommended to be undertaken in otherwise healthy patients with cirrhosis, using ultrasound and serum alpha-fetoprotein.6

Prognosis

  • Without treatment, nearly 50% of patients with severe autoimmune hepatitis (AIH) die in approximately five years.7
  • Outlook for treated patients with AIH is generally very good.
  • Within one year of stopping treatment following histological and biochemical remission, 50-90% of patients have a disease relapse.
  • Following reintroduction of the initial treatment regime, more than 80% of patients who relapsed achieve a biochemical remission, usually within a few months.
  • Some patients receive a maintenance dose of azathioprine or azathioprine and prednisolone which has been shown to reduce the risk of relapse.8
  • Cirrhosis develops in 30-50% of patients.

Document references

  1. Wolf DC et al, Autoimmune Hepatitis, Medscape, Aug 2011
  2. Al-Chalabi T, Underhill JA, Portmann BC, et al; Impact of gender on the long-term outcome and survival of patients with J Hepatol. 2008 Jan;48(1):140-7. Epub 2007 Oct 22. [abstract]
  3. Guidelines for the Management of Autoimmune Hepatitis, British Society of Gastroenterology (May 2011)
  4. Manns MP, Woynarowski M, Kreisel W, et al; Budesonide induces remission more effectively than prednisone in a controlled Gastroenterology. 2010 Oct;139(4):1198-206. Epub 2010 Jun 22. [abstract]
  5. Montano-Loza AJ, Carpenter HA, Czaja AJ; Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis. Am J Gastroenterol. 2008 Aug;103(8):1944-51. Epub 2008 Jun 28. [abstract]
  6. Manns MP, Czaja AJ, Gorham JD, et al; Diagnosis and management of autoimmune hepatitis. Hepatology. 2010 Jun;51(6):2193-213.
  7. Decock S, McGee P, Hirschfield GM; Autoimmune liver disease for the non-specialist. BMJ. 2009 Sep 8;339:b3305. doi: 10.1136/bmj.b3305.
  8. Lamers MM, van Oijen MG, Pronk M, et al; Treatment options for autoimmune hepatitis: a systematic review of randomized J Hepatol. 2010 Jul;53(1):191-8. Epub 2010 Mar 30. [abstract]

Internet and further reading

The clinicians responsible for the production of this document are:
Original Author: Dr Colin Tidy
Last Checked: 13 Jan 2012		Current Version: Dr Louise Newson
Document ID: 12577  Version: 3		Peer Reviewer: Dr John Cox
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