Autoimmune Hepatitis (AIH)

Definition, Etiology, PathogenesisTop

Autoimmune hepatitis (AIH) is a chronic necroinflammatory hepatitis of unknown etiology that is associated with hypergammaglobulinemia and the presence of circulating autoantibodies. Possible etiologies include environmental, drug, or infectious triggers in genetically predisposed individuals.

Clinical FeaturesTop

AIH is rare, with an estimated prevalence of 23/100,000 persons in North America, 19/100,000 persons in Europe, and 13/100,000 persons in Asia.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Lv T, Li M, Zeng N, et al. Systematic review and meta-analysis on the incidence and prevalence of autoimmune hepatitis in Asian, European, and American population. J Gastroenterol Hepatol. 2019 May 30. doi: 10.1111/jgh.14746. [Epub ahead of print] PubMed PMID: 31146297. The disease may occur at any age but most commonly develops during adolescence and between the ages of 40 and 60 years. Women are affected 4 times more frequently than men. AIH is also associated with other autoimmune conditions, such as autoimmune thyroiditis, type 1 diabetes mellitus, rheumatoid arthritis, ulcerative colitis, and celiac disease.

AIH can present in many ways, ranging from asymptomatic disease to acute liver failure. Two-thirds of patients have either no symptoms or nonspecific symptoms, such as fatigue, anorexia, jaundice, and abdominal pain. Approximately a quarter of patients have features of cirrhosis and its complications at the time of diagnosis. Untreated AIH leads to the development of decompensated cirrhosis in >80% of patients within 5 years.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests:

1) Biochemical tests: Elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (ranging from minor elevations to >50 × upper limit of normal [ULN]; the AST/ALT ratio is usually <1), elevated bilirubin, and normal or slightly elevated alkaline phosphatase (ALP) levels.

2) Immunologic studies: Elevated serum gamma-globulin levels (polyclonal hypergammaglobulinemia, primarily IgG) are found in 85% of patients. Various autoantibodies are also present, most commonly including antinuclear antibody (ANA), smooth muscle antibody (SMA) and rarely antibodies to type 1 liver/kidney microsomal antigen (LKM1) and perinuclear antineutrophil cytoplasmic antibody (p-ANCA). A small proportion of patients have no detectable autoantibodies or have antibodies that are not routinely assessed (eg, antibodies to liver cytosolic antigen type 1 (LC-1) or antibodies to soluble liver antigen/liver-pancreas (SLA/LP).

2. Histology: Histologic examination of liver biopsy specimens is necessary in patients with suspected AIH to confirm the diagnosis and evaluate for cirrhosis. There are no pathognomonic histologic features but typical findings include interface hepatitis (a necrotic process involving hepatocytes at the lobular/portal interface), lymphocytic plasma cell infiltrates of portal areas, emperipolesis (active penetration by one cell into and through a larger cell), and hepatocellular rosette formation.

Diagnostic Criteria

Diagnostic criteria: Table 1.

There are 2 subtypes of autoimmune hepatitis. Type 1 AIH, which accounts for 80% of cases, is associated with ANAs or SMAs (or both). Type 2 AIH is associated with antibodies to LKM1, LC-1, or both. Type 2 AIH is mainly diagnosed in children.

Among patients with AIH, 10% have an overlap syndrome. This occurs when patients with AIH also have features of either primary sclerosing cholangitis or primary biliary cholangitis.

Differential Diagnosis

Other autoimmune liver diseases (primary biliary cholangitis [formerly known as primary biliary cirrhosis], primary sclerosing cholangitis, and IgG4-associated cholangitis), viral hepatitis (hepatitis virus A, B, and C; Epstein-Barr virus; cytomegalovirus; herpes simplex virus), drug-induced liver injury, alcoholic liver disease, nonalcoholic fatty liver disease, hereditary hemochromatosis, Wilson disease, alpha1-antitrypsin deficiency, celiac disease, systemic lupus erythematosus, cholangiopathy secondary to HIV, and granulomatous hepatitis.

TreatmentTop

General Considerations

1. Immunosuppression is indicated in patients with:

1) AST >10 × ULN.

2) AST >5 × ULN and gamma-globulin level ≥2 × ULN.

3) Bridging or multilobular necrosis.

4) Incapacitating symptoms (eg, fatigue, arthralgia).

Immunosuppression is not indicated in patients with cirrhosis without active inflammation (ie, no inflammatory cells on liver biopsy and normal or slightly elevated serum transaminases).

2. Liver transplant is the treatment of choice in patients with advanced AIH and liver failure.

Pharmacotherapy

Note that there are differences between the usual management of AIH in North America and Europe, mostly reflecting timing of azathioprine introduction and duration of treatment. The information below reflects North American practices. Details regarding European management strategies could be found on the website of the European Association for the Study of the Liver.

The goal of treatment is to achieve biochemical (normalization of serum transaminases and IgG) and histologic remission. The cornerstone of AIH therapy includes prednisone/prednisolone monotherapy or prednisone/prednisolone in combination with azathioprine. Combination therapy is preferred unless there are contraindications to azathioprine (eg, severe leukopenia or thrombocytopenia, thiopurine methyltransferase deficiency). In patients who do not respond to or are intolerant of prednisone and azathioprine, treatment with mycophenolate, cyclosporine (INN cyclosporin), or tacrolimus can be considered.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity, imprecision (small sample sizes) and the risk of bias. De Lemos-Bonotto M, Valle-Tovo C, Costabeber AM, Mattos AA, Azeredo-da-Silva ALF. A systematic review and meta-analysis of second-line immunosuppressants for autoimmune hepatitis treatment. Eur J Gastroenterol Hepatol. 2018 Feb;30(2):212-216. doi: 10.1097/MEG.0000000000001019. Review. PubMed PMID: 29227329.

Combination therapy: Treatment consists of an induction phase followed by a maintenance phase:

1) Induction: The induction period lasts 4 weeks and consists of oral prednisolone/prednisone 30 mg daily for 1 week followed by 20 mg daily for 1 week and 15 mg daily for 2 weeks. Azathioprine 50 mg daily is administered during the entire 4-week induction period. In Europe, prednisolone is preferred over prednisone and the agents are administered in weight-based doses (prednisolone 0.5-1 mg/kg/d) with azathioprine (1-2 mg/kg/d) usually starting after 2 weeks of glucocorticoid treatment.

Alternative treatment with oral budesonide (3 mg bid or tid) in combination with azathioprine has been studied and is associated with fewer adverse effects than prednisolone/prednisone but may involve a higher risk of recurrence.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and imprecision. Manns MP, Woynarowski M, Kreisel W, et al; European AIH-BUC-Study Group. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 2010 Oct;139(4):1198-206. doi: 10.1053/j.gastro.2010.06.046. Epub 2010 Jun 22. PubMed PMID: 20600032. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015 Oct;63(4):971-1004. doi: 10.1016/j.jhep.2015.06.030. Epub 2015 Sep 1. Erratum in: J Hepatol. 2015 Dec;63(6):1543-4. PubMed PMID: 26341719.

2) Maintenance: Maintenance therapy usually consists of prednisone/prednisolone 10 mg daily and azathioprine 50 mg daily. Further slow tapering of prednisone/prednisolone by 2.5 mg/week to 5 mg daily may be performed if tolerated by the patient. There is no minimal or maximal duration of treatment. Maintenance therapy should be continued until biochemical remission and histologic normalization are achieved. Typically 18 to 24 months of maintenance therapy are required. In Europe, treatment is typically continued for a minimum of 2 to 3 years, including 2 years of complete biochemical remission.

3) Management of recurrences: Relapse occurs in 50% to 90% of patients after discontinuation of therapyEvidence 4Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness to different populations. van Gerven NM, Verwer BJ, Witte BI, et al; Dutch Autoimmune Hepatitis Working Group. Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission. J Hepatol. 2013 Jan;58(1):141-7. doi: 10.1016/j.jhep.2012.09.009. Epub 2012 Sep 16. PubMed PMID: 22989569. and is defined as ALT elevation 3 × ULN. Relapse treatment involves the same induction strategy as initial treatment, but maintenance treatment following a relapse should be continued indefinitely.

Follow-UpTop

Biochemical tests (AST, ALT, IgG) are repeated every 1 to 2 weeks (initially weekly) during remission induction and every 3 to 6 months during maintenance treatment. Elevated autoantibody levels have no prognostic value and are not used for monitoring. Patients not receiving treatment require lifelong annual blood tests, as indicated above, to monitor for disease progression and relapse. Patients receiving long-term glucocorticoid therapy should undergo baseline and annual bone mineral density testing as well as receive osteoporosis prophylaxis.

PrognosisTop

In patients who receive appropriate treatment, 10-year survival rates are >80% and life expectancy is close to that of the general population. The prognosis is worse in patients with cirrhosis and in those who do not achieve remission after 2 years of treatment.

TablesTop