Key learning points
- Autoimmune hepatitis is uncommon
- It affects women more than men and can affect people at any age
- Early diagnosis of AIH is important as untreated patients rapidly develop liver cirrhosis
- Many patients are asymptomatic at the onset of the disease
- Patients may have raised titres of antinuclear antibody (ANA) or smooth muscle antibody (SMA)
- Hypergammaglobulinaemia is common in patients
- The prognosis of effectively treated patients is excellent
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that can rapidly lead to cirrhosis in untreated patients.
Aetiology
The autoimmune aetiology of AIH is now generally accepted. The hypothesis is that individuals with a genetic predisposition may suffer from an autoimmune process triggered by autoreactive T-cells that leads to chronic hepatitis.
Autoimmune hepatitis is uncommon. It affects around 1 in 10,000 people in the UK.
AIH can occur in every ethnic group but seems to be more frequent in Japan than in Europe. The medium age at presentation is 45 years but AIH can affect all age groups from young infants to the elderly. Women are affected more often than men (ratio 3:1).
People with autoimmune hepatitis have a greater chance of also having one or more other autoimmune diseases.
Symptoms
In most patients the symptoms develop gradually over weeks or months. At the onset of the disease, many patients have no symptoms at all. The most common early symptoms include fatigue, feeling generally unwell and also myalgia and joint pains that are usually worse in the mornings.
Without treatment, in time the persistent inflammation causes liver damage and can lead to cirrhosis. In some cases, the symptoms develop quickly over a few days with an acute hepatitis. This can cause a fairly sudden onset of fever, abdominal pain, jaundice, nausea and vomiting. This may progress to liver cirrhosis and liver failure.
Diagnosis
As many people with autoimmune hepatitis have no or only vague symptoms, the diagnosis is often made when tests are performed for an unrelated condition. There is no pathognomonic test for patients with AIH.
AIH should to be considered in the differential diagnosis of any patient (at any age) with elevated and/or fluctuating liver enzymes.
It is important that other causes of hepatitis are excluded in these patients. Patients with viral hepatitis (e.g. chronic hepatitis C, chronic hepatitis B infection) may present with similar clinical symptoms and may have positive autoantibody titres (10-15%).
Liver function tests in untreated AIH often show an undulating course, misleading clinicians that the condition may resolve on its own as might occur in an acute viral hepatitis.
In 1993 the International Autoimmune Hepatitis Group first formulated diagnostic criteria for Autoimmune Hepatitis1. Simplified criteria for AIH have been proposed by the International Autoimmune Hepatitis Group. Further validation of these criteria is ongoing.
Physical examination
In most patients with AIH physical examination will be unremarkable. However, patients might show signs of acute or chronic liver disease. Patients with chronic liver disease may develop spider naevi or have palmar erythema, jaundice, ascites, asterixis, and features of portal hypertension.
Figure 1: A patient with chronic hepatitis with characteristic spider naevi.
Investigations
Hypergammaglobulinaemia is the most common serological finding in patients presenting with AIH. Selective elevation of IgG is common in patients with AIH.
Raised levels of antinuclear antibody (ANA) and/or smooth muscle antibody (SMA) can be found in patients. ANA, however, are not specific for AIH as they can be found in chronic viral hepatitis, in alcoholic or non-alcoholic steatohepatitis, in drug induced liver injury, in primary biliary cirrhosis and primary sclerosing cholangitis.
SMA is present in 87% of AIH patients but also in several other liver diseases. Anti-liver/kidney microsomal (LKM)-1 antibodies are positive in about 4% of AIH patients. They usually appear when SMA and ANA are negative. LKM may also be positive in patients with hepatitis C.
Soluble liver antigen/liver pancreas antibodies (SLA/LP) are detectable in 20−25% of AIH patients. Antibodies to SLA/LP are directed against an intracellular enzyme and are only by sensitive and specific immunoassays (ELISA, Blot). These antibodies have been found to occur exclusively in patients with AIH2.
However, up to 10% of AIH patients have no antibodies detectable at the time of initial presentation.
AIH patients can be differentiated according to their autoantibody profile (Type I: ANA and/or SMA positive, Type 2: LKM positive, Type 3: SLA/LP positive). However, differences in course of disease or response to therapy do not seem to be clinically relevant so this is more academic than practical.
Ultrasound of the liver should be performed to grade liver morphology, to exclude the presence of liver neoplasm and to look for portal hypertension.
Liver histology from a liver biopsy may be needed for making the diagnosis of AIH if there is diagnostic uncertainty. It may also give important information for staging disease severity. If the patient has positive SMA, elevated IgG, and elevated transaminases that respond to a trial of corticosteroid, liver biopsy may not always be necessary.
Figure 2: A liver biopsy showing in a patient with hepatitis.
Management
Autoimmune hepatitis was the first liver disease in which drug treatment has proven to be life saving. AIH patients who are treated efficiently with immunosuppression can be have a normal life expectancy. A prompt diagnosis of AIH is therefore very important.
In patients presenting with fulminant disease rapid diagnosis and induction of immunosuppressive therapy are essential3.
The aim of immunosuppressive therapy is induction and maintenance of remission. Remission is defined as normalisation of transaminases, IgG and histological activity.
The indication for induction of immunosuppressive therapy in patients with mild disease is not as well established as for those with severe AIH as there are no trials examining these patients.
Patients are usually treated when transaminases are outside the normal range, IgG is elevated or liver histology shows inflammatory infiltrates and fibrosis.
Corticosteroids alone or in conjunction with azathioprine is the treatment of choice in patients with AIH and results in remission induction in over 80% of patients4. Regimens used vary from centre to centre. Most centre start on 40mg prednisolone daily for 1 month before tapering the course. Azathioprine is only normally started once the results of the enzyme to degrade Azathioprine are available (TPMT). The dose is mormally increased to a target dose of 2mg/Kg.
In maintenance of remission, azathioprine is well established as the drug of choice. Steroids at a low dose may be added when there is an insufficient response. In some cases steroids can be withdrawn completely.
Treatment works well for most patients. Usually, the inflammation settles and symptoms improve within a few months of starting treatment. However, it may take a year or more to get the disease totally under control. Azathioprine is usually given for at least three years. In around 30% of cases the disease burns itself out and all treatment can gradually be withdrawn and finally stopped. Liver histology is required to prove absence of inflammatory activity before treatment is stopped as otherwise relapse within a year usually occurs.
Only a minority of patients cannot tolerate azathioprine or respond insufficiently to treatment. Mycophenolate mofetil (MMF) is often given as an alternative, as its side effects are usually mild. Other alternatives include cyclophosphamide, methotrexate, cyclosporin A and tacrolimus. All of these agents have been only been tested in small trials.
Liver transplantation
For the few people who do not respond to drug treatment or are diagnosed in the late stage of the disease with severe cirrhosis or liver failure, a liver transplant may be an option. AIH actually accounts for 2.6% of liver transplantations in Europe. 5-year survival is between 75 and 85%.
Autoimmune hepatitis recurs after transplantation in at least 17% of patients, and it does often improve with treatment with immunosuppressive drugs5.
Prognosis
It is very important that the diagnosis is explained clearly to the patient as compliance with long term immunosuppressive therapy is essential. Patients should know that their disease is chronic, but the prognosis of effectively treated patients is excellent. Even if cirrhosis is already present at diagnosis, life expectancy can be normal. Patients should be made aware that stopping treatment too early would almost certainly result in relapse.
Female patients need to know that pregnancy is possible with AIH but detailed discussion of risks and continuous surveillance are necessary.
References
1. Papamichalis PA, Zachou K, Koukoulis GK, Veloni A, et al. The revised international autoimmune hepatitis score in chronic liver diseases including autoimmune hepatitis/overlap syndromes and autoimmune hepatitis with concurrent other liver disorders. J Autoimmune Dis 2007;4:3.
2. Zachou K, Rigopoulou E, Dalekos GN. Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease. J Autoimmune Dis 2004;1:2.
3. Strassburg CP, Manns MP; Treatment of autoimmune hepatitis. Semin Liver Dis. 2009 Aug;29(3):273-85.
4. Granito A, Muratori P, Ferri S, et al; Diagnosis and therapy of autoimmune hepatitis. Mini Rev Med Chem. 2009;9(7):847-60.
5. Czaja AJ; Current and future treatments of autoimmune hepatitis. Expert Rev Gastroenterol Hepatol. 2009;3(3):269-91.
Author and reviewers competing interests: none.
Images: Wellcome.
