Journal of Gastroenterology

, Volume 47, Issue 5, pp 498–503

Autoimmune hepatitis: a review

Authors

    • Mayo Clinic
  • Keith D. Lindor
    • Arizona State University
Review

DOI: 10.1007/s00535-012-0586-z

Cite this article as:
Gossard, A.A. & Lindor, K.D. J Gastroenterol (2012) 47: 498. doi:10.1007/s00535-012-0586-z

Abstract

Autoimmune hepatitis (AIH) is an inflammatory liver disease that predominantly affects females. The disease is characterized histologically by interface hepatitis, biochemically by increased aspartate and alanine aminotransferase levels, and serologically by the presence of autoantibodies and elevated levels of immunoglobulin G. AIH affects both adults and children, and is particularly aggressive in the latter group. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. Treatment is often successful at inducing remission of disease, and this can lead to a normal life expectancy. However, progression to cirrhosis can and does occur in some. For those with advanced-stage disease and complications, consideration of liver transplantation is appropriate.

Keywords

Autoimmune hepatitisAutoimmune liver diseaseLiver diseaseAutoimmune disease

Introduction

Autoimmune hepatitis (AIH) is characterized by chronic inflammation of the liver, interface hepatitis, hypergammaglobulinemia, and the presence of autoantibodies [1]. Disease presentation is varied but typically is based on characteristic aminotransferase elevations, histological abnormalities, elevated levels of serum globulins, and the presence of one or more characteristic autoantibodies. These antibodies include antinuclear antibody (ANA), smooth muscle antibody (SMA), and antibody to liver-kidney microsome (anti-LKM) type 1.

Pathogenesis

The primary cause of AIH is unknown. Pathogenesis may be a result of alterations in immune tolerance, a genetic predisposition, and environmental triggers, which in collaboration induce a T-cell-mediated attack on liver antigens leading to necroinflammation and fibrotic change. In order for the disease to develop, there needs to be genetic susceptibility. Then, presumably, a “trigger” leads to acute disease. Typical environmental triggers, however, have not been identified. Potential offenders include viruses such as measles virus, hepatitis viruses, cytomegalovirus, and Epstein–Barr virus. Other possibilities include medicines such as herbal products, antibiotics such as minocycline or oxafloxacin, and statins [27]. Several recent case studies described a potential association between the use of the anti-tumor necrosis factor agents adalimumab and infliximab and AIH [812]. Identifying a specific trigger has proven very difficult.

Diagnosis and clinical presentation

Information on the natural history of AIH derived from experience prior to the use of immunosuppression as treatment suggests that as many as 40 % of patients, if left untreated, will die within 6 months of diagnosis. Acute onset of the disease is not uncommon (20 %), and for many patients the onset is insidious. AIH may present as acute liver failure. For others, onset of disease causes symptoms such as diffuse arthralgias, fatigue, generalized malaise, and jaundice; some may also have abdominal pain, nausea, and loss of appetite. Up to 25 % of patients are entirely asymptomatic when initially diagnosed [13]. The presence or absence of symptoms does not seem to be related to prognosis. For children, the development of AIH often shortens life-expectancy; however, the presence of cirrhosis at baseline did not seem to affect long-term outcomes in a study of 33 children [14].

Autoimmune hepatitis has an incidence of 1–2 per 100,000 per year, and a prevalence of 10–20/100,000. AIH is seen in all ethnic groups and is a predominantly female disease, at a ratio of 3.6:1 [15]. Peak incidence occurs during adolescence and again at 35–40 years of age. Associations with other autoimmune diseases such as autoimmune thyroiditis, inflammatory bowel disease, rheumatoid arthritis, vitiligo, and celiac disease are common [1621]. A family history of autoimmune disease is present in approximately 40 % of those affected with AIH [22].

Variant syndromes of AIH are not uncommon. There are two major types of AIH, type 1 and type 2. The clinical utility of this classification is limited, however. Type 1 is characterized by the presence of ANA, SMA, or both, and comprises 80 % of all AIH cases. In North American adults, 96 % of patients with AIH will have positive findings for ANA or SMA or both. Type 2 AIH is characterized by the presence of anti-liver/kidney microsomal antibody (LKM type 1) and/or anti-liver cytosol (LC1), and/or anti-LKM type 3. Most type 2 AIH patients are children and female [23].

Patients may exhibit features of both AIH and another autoimmune liver disease, such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or autoimmune cholangitis. This is commonly termed “overlap syndrome” [2430]. Histological findings such as ductopenia or cholangitis may support a concurrent diagnosis of one of these conditions. If the patient has a history of inflammatory bowel disease, a cholangiogram would be indicated to rule out concurrent PSC, particularly if the patient presents with a cholestatic serologic profile.

Interface hepatitis of moderate or severe activity is a key feature of AIH (Fig. 1 ); however, it does not differentiate the disease from viral or drug-induced hepatitis. Panacinar hepatitis is usually seen in acute-onset disease and if relapse occurs after treatment is withdrawn. Lobular hepatitis or central portal bridging necrosis may or may not be present. The presence of bridging necrosis or multiacinar collapse is indicative of more severe disease with a higher risk of progression to cirrhosis. Up to 30 % of newly diagnosed cases have evidence of well-established cirrhosis at the time of diagnosis and this may affect prognosis [31]. Typically there are no biliary lesions or well-defined granulomas, or other prominent changes suggestive of a different etiology such as ductopenia. The presence of these findings would be suggestive of an overlap syndrome.

The diagnosis of AIH is based on a scoring system developed by the International Autoimmune Hepatitis Group in 1999 and revised in 2010 (Table 1). This scoring system is useful particularly in challenging cases of AIH and utilizes treatment response in order to confirm the diagnosis. Most cases of AIH, however, can be made based on histology, serum biochemistries, immunoglobulins, and autoantibodies.
https://static-content.springer.com/image/art%3A10.1007%2Fs00535-012-0586-z/MediaObjects/535_2012_586_Fig1_HTML.jpg
Fig. 1

Histologic image of AIH

Table 1

Simplified scoring system of the International Autoimmune Hepatitis Group

Autoantibodies

 ANA or SMA

≥1:40

+1

 ANA or SMA

≥1:80

+2

 Antibodies to liver kidney microsome type 1

≥1:40

+2

 Antibodies to soluble liver antigen

Positive

+2

 Absent autoantibodies

None

0

Immunoglobulin level

  

 Immunoglobulin G

>UNL

+1

 

>1.1 ULN

+2

 

Normal

0

Histological findings

  

 Morphological features of AIH

Compatible

+1

 

Typical

+2

 

Incompatible

0

Viral disease

 Absence of viral hepatitis

No viral markers

+2

 

Viral markers present

0

Pretreatment aggregate score

Definite diagnosis

≥7

 

Probable diagnosis

6

ANA antinuclear antibodies, SMA smooth muscle antibodies, ULN upper limit of normal range

Management and treatment

Prompt treatment with corticosteroids has been shown to improve the chances for survival significantly [32]. The 10-year life expectancies for treated patients with and without cirrhosis at presentation are 89 and 90 %, respectively. In fact, the life expectancy of patients in clinical remission is similar to that of the general population.

Indications for treatment may be classified into three categories: absolute, relative, and no indication for treatment (Table 2). Absolute indications include serum aspartate aminotransferase (AST) of >10 times the upper limit of normal (ULN), or AST of 5 × ULN and gamma globulin levels of twice normal. Absolute indications histologically include bridging necrosis or multiacinar necrosis. Relative indications include laboratory markers that are less than those described as absolute indications, plus interface hepatitis.
Table 2

Indications for treatment of autoimmune hepatitis

 

Absolute

Relative

None

Clinical

Incapacitating symptoms

Symptoms (fatigue, arthralgia, jaundice, abdominal pain)

Asymptomatic

Laboratory

AST ≥tenfold ULN, AST ≥fivefold ULN and HG ≥twofold ULN

AST or HG less than absolute criteria

Normal or near normal AST and γ globulins

Histology

Bridging necrosis or multiacinar necrosis on histology

Interface hepatitis

Inactive cirrhosis or mild portal hepatitis

Relative contraindications to immunosuppressant therapy: osteopenia, emotional lability, hypertension, diabetes, mild cytopenia

Absolute contraindications to azathioprine or prednisone: vertebral compression, psychosis, uncontrolled hypertension, brittle diabetes, severe cytopenia (WBC count <2.5 × 109/L, platelet count <50 × 109/L), known complete deficiency of thiopurine methyltransferase enzyme (routine testing of TPMT levels is not usually recommended), known intolerance to prednisone or azathioprine

AST aspartate aminotransferase, HG hypergammaglobulinemia, ULN upper limit of normal

Treatment with corticosteroids is effective in suppressing AIH in up to 80 % of patients within 3 years [33]. Response to treatment is generally measured by a reduction in serum aminotransferase levels. Liver biopsy may also be repeated to assess histological response after prolonged biochemical remission has been achieved. Treatment failure is defined as clinical, histological, and biochemical worsening while on therapy. Patients with established cirrhosis tend to have a higher frequency of treatment-related adverse effects and a lower rate of response.

Treatment regimens consist of two equally effective options: prednisone monotherapy starting at 60 mg per day, or combination therapy with prednisone and azathioprine at doses of 30 mg per day and 50 mg per day, respectively (Table 3). Combination therapy is associated with a lower incidence of corticosteroid side effects and is the preferred approach in most cases. In the setting of cytopenias, active malignancies, or pregnancy, however, prednisone monotherapy would be a better choice. Treatment regimens in children are less well established but may be similar to those used in adults. Response to therapy in children is generally excellent with normalization of liver enzymes in 75–90 % of patients after 6–9 months. Rapid response to treatment demonstrated by normalization of hepatic enzymes may be predictive of sustained response to therapy [34].
Table 3

Treatment regimens for adults

 

Prednisone only (mg/day)

Combination

Prednisone (mg/day)

Azathioprine (mg/day)

Week 1

60

30

50

Week 2

40

20

50

Week 3

30

15

50

Week 4

30

15

50

Maintenance until end point

20

10

50

Reasons for preference

Cytopenia

Postmenopausal state

Thiopurine methyltransferase deficiency

Osteoporosis

Brittle diabetes

Pregnancy

Obesity

Malignancy

Acne

Short course (6 months or less)

Emotional lability

 

Hypertension

Following initiation of treatment, the prednisone should be tapered over 4 weeks and then maintained at a steady dose of 20 mg per day if monotherapy is used, or 10 mg per day if used with azathioprine 50 mg per day. The dosage for both therapies is 1–2 mg/kg per day for children. Adults can also be given at 1–2 mg/kg prednisone, but there is no particular advantage to weight-based dosing in adults.

Steroid withdrawal should be performed only after remission is achieved as measured by normalized biochemistries, histologically quiescent disease, and clinical resolution of symptoms. Reductions of prednisone, usually in 2.5- or 5-mg increments, are appropriate if the patient has normal aminotransferases and serum globulins. It is important to remember that 55 % of the patients in complete biochemical remission will still have histological activity and their chance of relapse is greater than 75 % [22]. Therefore, a prolonged consolidation treatment period, lasting for 1–2 years, of either low-dose prednisone (2.5–10 mg/day) or 1.5–2 mg/kg azathioprine is essential before attempting to discontinue all immunosuppression. Demonstration of histologically quiescent disease is recommended by most before discontinuing therapy. For those patients with ongoing interface hepatitis, relapse rates are 75–90 % [35]. Patients in complete remission with normal aminotransferase levels, normal globulins, and no inflammation histologically have a 20–30 % chance of relapse and may be given a trial off of all immunosuppression with careful observation. Although relapse commonly occurs within the first 6 months off treatment, it may occur months or years later. Therefore, continued monitoring of these patients is essential. Only about 20 % of patients will be able to remain off treatment long term. If continued therapy is required, the use of prednisone and azathioprine or azathioprine monotherapy is preferred to prednisone monotherapy [32].

Autoimmune hepatitis responds to monotherapy or combination treatment about 70 % of the time. Of those who “fail” therapy, the most frequent reason pertains to drug toxicity. Less commonly, patients simply do not respond to treatment. In the absence of cirrhosis, the use of budesonide is an alternative option to prednisone as it produces fewer glucocorticoid side effects [36]. In a recent study, prednisone and budesonide were compared [37]. In patients with early disease, budesonide was better at normalizing aminotransferases after 6 months of treatment, and with fewer corticosteroid side effects. If cirrhosis is present, however, efficacy may be lowered and the risk of adverse effects increased. Mycophenolate mofetil is another potential alternative to azathioprine. Several retrospective studies have suggested this may be effective as a second-line treatment of AIH [3845].

The American Association for the Study of Liver Disease developed practice guidelines for the diagnosis and management of AIH. First published in 2002 then revised in 2010, the key points from these guidelines include characteristic diagnostic features of AIH in addition to the diagnostically challenging presentations [46, 47]. The guidelines advise that diagnosis should be based on clinical presentation, the exclusion of other potentially contributing liver conditions (viral hepatitis, drug-induced liver disease, alcohol-induced liver disease), the presence of autoantibodies, and marked elevations of the serum aminotransferase levels. Elevations of gamma globulin are also common.

The guidelines recommend treatment for all patients with serum aminotransferase levels greater than 10 times the ULN, or with serum aminotransferases that are five times the ULN in conjunction with a serum gamma globulin level at least two times the ULN. The use of corticosteroid treatment is the cornerstone of AIH management when there are indications for treatment. The use of azathioprine as a steroid-sparing agent is recommended and will reduce steroid-associated side effects.

Treatment side effects

Treatment-related adverse effects are common with both prednisone and azathioprine and may include weight gain, acne, facial rounding, dorsal hump formation, hirsutism, osteopenia, and diabetes mellitus. In fact, side effects are the most commonly cited reason for treatment withdrawal in AIH. Azathioprine may contribute to cholestatic hepatitis, pancreatitis, nausea, opportunistic infections, and bone marrow suppression. The risk of certain malignancies such as skin cancer is also increased. Patients with low levels of erythrocyte concentrations of thiopurine methyltransferase activity are at particular risk for myelosuppression during treatment. This condition, however, is rare and routine testing for thiopurine methyltransferase activity in AIH prior to treatment is not supported by available evidence.

If treatment is withdrawn after demonstrated remission and relapse occurs, retreatment should begin promptly with prednisone and azathioprine. Future attempts at withdrawal should be carefully considered, as subsequent relapse is common and the potential for inducing remission following relapse is reduced.

Pregnancy in AIH

Given the female predominance and the typical age of presentation, pregnancy is a relatively common conundrum in AIH. Case reports have suggested that successful pregnancy is possible in women diagnosed with AIH [48, 49]. The use of prednisone is a safe option in pregnancy. Azathioprine has also been used and is seemingly a safe option. Close monitoring of mother and fetus is important given the risks of maternal and fetal complications. In one study of 44 pregnancies in 22 women, flares were reported postpartum in 52 % of the pregnancies [49].

Complications of AIH

Despite treatment, AIH may progress to cirrhosis with complications common with advanced-stage liver disease, including hepatocellular carcinoma (HCC) [50]. Particularly in the presence of cirrhosis, HCC surveillance is advisable. HCC occurs in 4 % of patients with type 1 AIH and the 10-year probability for developing this cancer is 2.9 %. Risk factors include male gender, advanced-stage disease as evidenced by portal hypertension, ascites, esophageal varices, and the presence of cirrhosis. Imaging with ultrasonography or computed tomography should be performed every 6–12 months. For patients who progress to liver failure, liver transplantation may be considered [51].

Liver transplantation has a survival rate among adult and pediatric patients 5 years after liver transplantation of 73–85 % [5254]. The 10-year survival rate is approximately 75 %, and the recurrence rate has been reported to be as high as 42 % [55]. Recurrence affects approximately 25 % of liver allografts during the first 5 years after liver transplantation and more than 50 % after 10 years of follow up. Treatment with corticosteroids after transplantation may be warranted [56]. Histological evidence of recurrence may precede clinical and biochemical evidence of recurrence. Recurrence may be related to the immunosuppressive regimen used after transplantation.

Summary

Autoimmune hepatitis is a chronic liver disease with an etiology that is poorly understood. Diagnosis is based on characteristic serologic findings, histological change, and the presence of autoantibodies. Onset of the disease may be acute with features of liver failure at the time of presentation. Prompt treatment with immunosuppressive therapy is critical and requires ongoing monitoring. For many, life-long treatment is required. Progression to advanced-stage liver disease can and does occur. Surveillance for the development of HCC in these patients is essential. Liver transplantation has proven successful for those who progress to liver failure.

Conflict of interest

The authors declare that they have no conflict of interest.

Copyright information

© Springer 2012