Autoimmune Hepatitis

• Andreea M. Catana, M.D.
• Kittichai Promrat, M.D.

 Basic Information

Definition

Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver characterized by elevated serum globulin levels (IgG), presence of circulating autoantibodies, interface hepatitis on histology, and plasma cell rich infiltrate. Two types have been described:

1. Type 1, or “classic,” autoimmune hepatitis is the most predominant form in the U.S. and worldwide (80%) and has a bimodal age distribution with peaks between 10 and 20 and 45 and 70 years of age. Patients are positive for antinuclear antibodies (ANA) and/or antismooth muscle antibodies (ASMA) and have specific associated HLA haplotypes: B8, DR3, DR4.

2. Type 2 is rare in the U.S., primarily affects young children between 2 and 14 years of age, and is characterized by the presence of antibodies to liver/kidney microsomes (anti-LKM-1) or liver cytosol 1. Patients have associated HLA haplotypes: B14, DR. This form is generally more advanced at presentation and is more difficult to treat.

Synonyms

1. Autoimmune chronic active hepatitis

2. AIH

3. Chronic active hepatitis

4. Lupoid hepatitis

5. Plasma cell hepatitis

ICD-10CM CODES
K75.4	Autoimmune hepatitis
K73.2	Chronic active hepatitis, not elsewhere classified

Epidemiology & Demographics

1. Annual incidence (estimated): 0.2 to 2.0 cases per 100,000, similar to PBC, more common than PSC.

2. Point prevalence (estimated): 16.9 per 100,000.

3. Type 1: age of onset has a bimodal distribution with peaks between 10 and 20 and 45 and 70 years.

4. Type 2: more common in young children 2-14 years of age.

5. Female/male ratio is 3.6:1; type 1 has an 80% female predominance, whereas type 2 has a 90% female predominance.

6. Approximately 100,000 to 200,000 persons affected in the U.S.

7. Accounts for 4% to 6% of liver transplants in the U.S.

8. Associated with HLA-DRB1∗0301 and HLA-DRB1∗0401 alleles.

Clinical Presentation

1. Varies from intermittent asymptomatic elevations of liver enzymes to advanced cirrhosis. Cirrhosis is often the presenting stage. AIH can also present initially as a fulminant hepatitis.

2. Symptoms may include fatigue, anorexia, nausea, abdominal pain, pruritus, and arthralgia.

3. Autoimmune findings may include arthritis, xerostomia, keratoconjunctivitis, cutaneous vasculitis, and erythema nodosum.

4. Patients with advanced disease can show hepatosplenomegaly, ascites, peripheral edema, abnormal bleeding, and jaundice.

Etiology

1. Exact etiology is unknown; liver histology demonstrates cell-mediated immune attack against hepatocytes.

2. Presence of a variety of autoantibodies suggests an autoimmune mechanism.

3. There are likely two components involved: genetic predisposition and an inciting environmental trigger.

4. Potential triggering agents such as viruses (hepatitis A, B, C) or drugs (minocycline, nitrofurantoin) likely possess some homology similar to liver-specific antigens.

Diagnosis

1. A simplified diagnostic criteria for routine clinical practice has been developed by the International Autoimmune Hepatitis Group (see Table 1).

   TABLE1 Simplified Diagnostic Criteria for Autoimmune Hepatitis

   Variable	Cutoff	Points	Cutoff	Points
   ANA or SMA	≥1:40	1	≥1:80	2
   LKM			≥1:40	2
   SLA			Positive	2
   IgG	≥ULN	1	≥1.1 × ULN	2
   Histology	Compatible with AIH	1	Typical of AIH	2
   Absence of viral hepatitis			Yes	2
   Maximum number of points for all antibodies = 2, total = 8. Probable AIH ≥6 points, definite AIH ≥7 points. 88% sensitivity and 97% specificity. AIH, Autoimmune hepatitis; ANA, antinuclear antibody; IgG, immunoglobulin G; LKM, liver/kidney microsomes; SLA, soluble liver antigen; SMA, smooth muscle antibody; ULN, upper limit of normal.

2. Histology: lymphoplasmacytic infiltrate invading the hepatocyte boundary surrounding the portal triad (limiting plate). Also, a periportal infiltrate may be seen (interface hepatitis).

3. The European Association for the Study of the Liver guidelines do require liver biopsy as part of the diagnostic evaluation.

4. The American Association for the Study of Liver Disease (AASLD) approach is to obtain a liver biopsy if the diagnosis is unclear or to assess disease activity prior to initiating treatment.

Differential Diagnosis

1. Acute viral hepatitis (A, B, C, D, E, cytomegalovirus, Epstein-Barr, herpes)

2. Chronic viral hepatitis (B, C)

3. Toxic hepatitis (alcohol, drugs)

4. Primary biliary cirrhosis

5. Primary sclerosing cholangitis

6. Hemochromatosis

7. Nonalcoholic steatohepatitis

8. Systemic lupus erythematosus

9. Wilson’s disease

10. Alpha-1 antitrypsin deficiency

Workup

1. History and physical examination with attention to the presence of autoimmune abnormalities such as autoimmune thyroiditis, Graves’ disease, inflammatory bowel disease, celiac sprue, and rheumatoid arthritis. Fig. 1 illustrates a diagnostic algorithm for autoimmune hepatitis.

   

2. Liver function tests and serum gamma-globulins.

3. Tests for autoantibodies: ANA, ASMA, anti-LKM.

4. Liver biopsy for establishing diagnosis and disease severity.

Laboratory Tests

1. Aminotransferases generally elevated and may fluctuate

2. Bilirubin and alkaline phosphatase moderately elevated or normal

3. Elevation of gamma globulin (>2.0 g/dl [20 g/L]) and immunoglobulin G

4. Circulating autoantibodies (Table 2) often present:

   1. Rheumatoid factor

   2. ANAs

      1. Present in two thirds of patients

      2. Typical pattern is homogeneous or speckled

      3. Titer does not correlate with the stage, activity, or prognosis

   3. Anti-SMAs

      1. Present in 87% of patients

      2. Titer does not correlate with course or prognosis

   4. Anti-LKM antibodies

      1. Typically found in patients who are ANA negative and SMA negative

      2. Characterizes type 2 AIH

      3. Present in pediatric population and up to 20% of adults in Europe; also present in patients with drug-induced hepatitis

   5. Autoantibodies against soluble liver antigen and liver-pancreas antigen (anti-SLA/LP)

      1. Present in 10% to 30% of patients

      2. Associated with higher rate of relapse after corticosteroid therapy

      3. Several studies suggest that patients with anti-SLA/LP have a more severe course

   TABLE2 Serologic Markers of Autoimmune HepatitisFrom Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fortran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

   Autoantibodies	Antigenic Target	Clinical Implications
   ANA	Multiple nuclear antigens	Type 1 AIH Variably expressed with SMA
   SMA	Actin (F and G) Nonactin components (14%)	Type 1 AIH Variably expressed with ANA
   Anti-LKM1	CYP2D6 (main epitope, 193-212 amino acid sequence)	Type 2 AIH Usually exclusive of ANA, SMA Mainly in children Associated with HLA DRB1∗07
   Anti-SLA	Transfer ribonucleoprotein (tRNP(ser)sec); renamed Sep [O-phosphoserine] tRNA:Sec [selenocysteine] tRNA synthase (SEPSECS)	Diagnostic specificity of 99% for AIH Associated with HLA DRB1∗0301 and anti-Ro/SSA Of prognostic value (severe disease, relapse, treatment dependence)
   Atypical pANCA	Nuclear lamina proteins	Present in 50%-92% of type 1 AIH Absent in type 2 AIH Associated with PSC and UC
   Anti-actin	Actin (F and G)	Present in 86% of AIH with SMA Of possible prognostic value (assay dependent) Double reactivities to actin and α-actinin are associated with severe disease
   Anti-asialoglycoprotein receptor	Asialoglycoprotein receptor (recombinant H1 subunit in investigational EIA)	Associated with histologic activity and relapse after drug withdrawal Disappears with effective treatment
   Anti-liver cytosol type 1	Formiminotransferase cyclodeaminase	Frequently concurrent with anti-LKM1 (32%) Mainly in young patients (≤20 years of age) Associated with concurrent immune diseases, severe liver inflammation, and rapid progression to cirrhosis Rare in North American patients
   Anti-LKM1, antibodies to liver kidney microsome type 1; anti-SLA, antibodies to soluble liver antigen; AIH, autoimmune hepatitis; ANA, antinuclear antibodies; CYP2D6, cytochrome P450 2D6; EIA, enzyme immunoassay; pANCA, perinuclear antineutrophil cytoplasmic antibodies; Ro/SSA, ribonucleoprotein/Sjögren’s syndrome A protein; SMA, smooth muscle antibodies.

Serum p-ANCA levels are useful for diagnosis of the 10% to 15% of patients with negative ASMA, negative ANA, and low gamma globulin levels.

1. Hypoalbuminemia and prolonged prothrombin time with advanced disease.

2. There is a well-described overlap syndrome with primary biliary cirrhosis (7%), primary sclerosing cholangitis (6%), and autoimmune cholangitis (11%). In patients who do not respond to therapy after 3 months, consider cholangiographic studies to evaluate for primary sclerosing cholangitis.

Imaging Studies

1. Ultrasound of liver and biliary tree to rule out obstruction or hepatic mass.

2. Cirrhosis secondary to AIH is a risk factor for development of hepatocellular carcinoma (although less so than viral hepatitis). Patients with cirrhosis should get ultrasonography and AFP every 6 months.

Treatment

Nonpharmacologic Therapy

1. Avoid alcohol and hepatotoxic medications.

2. Liver transplantation is an option for end-stage disease or fulminant hepatic failure.

Pharmacologic Therapy

1. Initial treatment:

   1. Prednisone or prednisolone 40 to 60 mg/day PO or combination treatment with prednisone 30 mg PO daily plus azathioprine 50 mg PO daily, with a gradual taper to prednisone 10 mg PO daily over 2 to 3 months as liver function test (LFT) results normalize. A combination of oral budesonide (6-9 mg/day) and azathioprine (1-2 mg/kg/day) can be used to induce and maintain remission in patients with non-cirrhotic AIH, with a lower rate of steroid-specific side effects. Steroids are contraindicated in brittle diabetes mellitus, uncontrolled hypertension, prior steroid intolerance, severe osteopenia, and psychosis. Azathioprine is contraindicated by thiopurine S-methyltransferase (TPMT) deficiency, leukopenia, or thrombocytopenia. Budesonide is contraindicated in cirrhosis because portal systemic shunting and abnormal hepatic metabolism prevent complete hepatic first-pass extraction, reducing therapeutic efficacy and causing systemic steroid side effects.

   2. Combination therapy allows lower prednisone doses, fewer steroid side effects, and faster normalization of LFTs.

2. The primary goal of therapy in AIH is to achieve remission. The 2010 AASLD Practice Guideline (2010 PG) redefined remission to require: normal levels of AST, ALT (optimally <19 U/L in women and <30 U/L in men), total bilirubin, gamma-globulin or IgG and absence of inflammatory activity on liver biopsy. Secondary goals of therapy are the prevention of progression of fibrosis to cirrhosis and reversion of cirrhosis to a lower stage of fibrosis, which has been documented.

3. Indications for treatment:

   1. Serum aminotransferases >10 times the upper limit of normal

   2. Serum aminotransferases >5 times the upper limit of normal, with serum gamma-globulin level twice the upper limit of normal

   3. Histologic features of bridging necrosis

   4. Symptomatic disease: incapacitating symptoms such as fatigue and arthralgia

4. Relative indications:

   1. Asymptomatic patients with elevated liver enzymes or limited histological activity

5. Treatment not indicated:

   1. Inactive cirrhosis

6. Evaluation of treatment response:

   1. Goals are the absence of symptoms, normalization of liver function tests, and absence of inflammatory activity on liver biopsy. Generally, this is a steroid-responsive condition, but up to 20% do not respond.

   2. Patients whose transaminase levels normalize may continue to have ongoing active hepatitis involving inflammation and fibrosis.

   3. Histologic improvement may lag behind clinical and laboratory improvement by as much as 6 months. Because of this, repeat liver biopsy should be considered after normalization of transaminase levels. A review of AIH studies between 1972 and 2013 shows that hepatic fibrosis improves in 53% to 57% of cases and that progressive fibrosis slows or is prevented in 79% of patients.

   4. After initial remission is achieved, one may consider tapering medications. Steroid withdrawal should be done only if liver function tests normalize and histologic quiescence is achieved. About 50% to 86% of patients will relapse after this and require long-term maintenance medications.

   5. Complete normalization on biopsy is associated with a 15% to 20% risk of relapse, whereas persistent interface hepatitis is associated with a 90% risk of relapse. Do not attempt multiple treatment withdrawals. The risk of developing cirrhosis with single relapse is 9.5%, whereas multiple relapses are associated with 37.5% risk of developing cirrhosis. The patient with sustained remission has a risk of cirrhosis of 4.5%.

Disposition

1. Long-term treatment may be necessary for sustained remission in individuals who continuously relapse and in partial responders.

2. Sixty-five percent of patients achieve remission by 18 months; 80% achieve remission by 3 years.

3. Approximately 10% to 15% of patients do not respond to conventional therapy. The risk factors for nonresponse include presence of underlying cirrhosis, younger age, or longer duration of disease, HLA-B8 or DR3. High-dose therapy can achieve remission in 70%: prednisone 60 mg or dual therapy with prednisone 30 mg and AZA 150 mg. Other alternatives such as mycophenolate, the calcineurin inhibitors (CNIs), tacrolimus (TAC) and cyclosporine (CSA), sirolimus (SIR), everolimus (EVR), rituximab, and infliximab, have been used successfully. However, none of the alternative therapies has been studied in multicenter, randomized, controlled trials.

4. Orthotopic liver transplantation (OLT) is a life-saving option for AIH patients with acute liver failure, decompensated cirrhosis, or HCC. Allograft and patient survival are excellent; however, AIH recurs in the allograft in a minority (25% probability in first 5 years, 50% in 10 years).

Referral

Patients with advanced cirrhosis or who progress to end-stage liver disease are candidates for liver transplantation and should be referred to appropriate medical centers that provide liver transplantation services.

Pearls & Considerations

Comments

1. ANA and SMA are observed together in 60% of cases. Serum titers >1:40 suggest autoimmune hepatitis.

2. A variety of autoimmune conditions can be seen in association with autoimmune hepatitis, including thyroiditis, Graves’ disease, ulcerative colitis, rheumatoid arthritis, uveitis, pernicious anemia, Sjögren’s syndrome, mixed connective tissue disease, CREST syndrome, and vitiligo.

3. Variant forms of autoimmune hepatitis (overlap syndrome) have clinical and serologic findings of autoimmune hepatitis plus features of other forms of chronic liver disease such as primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC).

Prevention

None

Patient & Family Education

1. American Liver Foundation (ALF): Phone: 800-GO-LIVER (465-4837); Internet: www.liverfoundation.org

2. National Digestive Diseases Information clearinghouse: http://digestive.niddk.nih.gov/ddiseases/pubs/autoimmunehep

Suggested Readings

• E. Björnsson, et al.: Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 51 (6):2040–2048 2010 20512992

• A.J. Czaja: Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther. 39 (4):385–406 2014 24387318

• A.J. Czaja, M.P. Manns: Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis. Gastroenterology. 139 (1):58–72 2010 20451521

• European Association for the Study of the Liver: EASL clinical practice guidelines: autoimmune hepatitis. J Hepatol. 63 (4):971 2015 26341719

• A.A. Gossard, K.D. Lindor: Autoimmune hepatitis: a review. J Gastroenterol. 47 (5):498–503 2012 22526272

• M.A. Heneghan, et al.: Autoimmune hepatitis. Lancet. (12):S0140–S6736 June 2013

• M.P. Manns, et al.: American Association for the Study of Liver Diseases: Diagnosis and management of autoimmune hepatitis. Hepatology. 51 (6):2193–2213 2010 20513004

• M.P. Manns, et al.: European AIH-BUC-Study Group. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 139 (4):1198–1206 2010 20600032

• M.P. Manns, A.J. Czaja, J.D. Gorham, et al.: Diagnosis and management of autoimmune hepatitis. Hepatology (Baltimore, Md). 51 (6):2193–2213 2010 20513004

• J.M. Vierling: Autoimmune hepatitis and overlap syndromes: diagnosis and management. Clin Gastroenterol Hepatol. 13 (12):2088–2108 2015 26284592

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