Autoimmune hepatitis

Autoimmune hepatitis (AIH) is a rare form of chronic hepatitis that predominantly affects women. Although the etiology is unclear, it is commonly associated with other autoimmune conditions (e.g., thyroid disease, type 1 diabetes mellitus, celiac disease). The clinical presentation ranges from asymptomatic transaminitis to acute liver failure. Diagnosis is established based on the detection of autoantibodies (e.g., antinuclear antibodies, anti-smooth muscle antibodies) and the histologic findings of interface hepatitis on liver biopsy. Treatment consists of immunosuppressive medications such as prednisone and azathioprine. The prognosis is favorable with treatment; without treatment, patients may develop cirrhosis and liver failure.

• Type 1 AIH (80% of cases): characteristic autoantibodies include antinuclear antibodies (ANAs), anti-smooth muscle antibodies (ASMAs) anti-soluble liver antigen antibodies (anti-SLA)
• Type 2 AIH: characteristic autoantibodies include anti-liver-kidney microsomal-1 antibodies (anti-LKM-1), anti-liver cytosol antibodies-1 (ALC-1)

• Prevalence: 0.1–2/100,000 white adults in the US, even less so in other ethnicities [1]
• Bimodal distribution: 10–20 years and 40–60 years [2]
  • Type 1 AIH: most common in adults
  • Type 2 AIH: most common in children
• Sex: ♀ > ♂
  • Type 1 AIH: (∼ 4:1) [3]
  • Type 2 AIH: (∼ 10:1)

Epidemiological data refers to the US, unless otherwise specified.

• Idiopathic [4]
• AIH is commonly associated with other autoimmune conditions
  • Type 1 AIH: Hashimoto thyroiditis, Graves disease, ulcerative colitis, celiac disease, rheumatoid arthritis
  • Type 2 AIH: Hashimoto thyroiditis, type 1 diabetes mellitus, vitiligo

AIH has an insidious onset in most patients and its presentation varies widely, ranging from asymptomatic disease to severe symptoms or even acute liver failure.

• Nonspecific symptoms
  • Fatigue
  • Upper abdominal pain
  • Weight loss
• Signs of acute liver failure (∼ ⅓ of patients)
• Signs of chronic liver disease

Approach [5]

• Consider AIH in patients with unexplained liver disease.
• Rule out other causes of hepatitis; see “Differential diagnoses.”
• Establish the diagnosis of AIH with laboratory studies and liver histology.
• Consider utilizing the Autoimmune Hepatitis Diagnosis calculator to facilitate the diagnosis. [6]
• Consult hepatology for guidance on further diagnostic testing.

The diagnosis of AIH is based on positive autoantibodies (e.g., ANA, ASMA) and histological findings of interface hepatitis on biopsy.

Initial studies [5]

Laboratory tests [7][8]

• Liver chemistries: ↑↑↑ ALT and ↑↑ AST; , ↑ GGT, normal or ↑ ALP, and ↑ bilirubin
• Serum antibodies
  • ANA, ASMA: combination is highly specific for type 1 AIH [7]
  • Anti-LKM-1: typically positive in type 2 AIH
• SPEP: hypergammaglobulinemia (↑ IgG)
• CBC: normochromic anemia, thrombocytopenia, mild leukopenia
• Inflammatory markers: ↑ ESR

Liver biopsy [7]

• Perform following the detection of AIH antibodies to confirm the diagnosis.
• Histological findings:
  • Lymphoplasmacytic interface hepatitis: ongoing inflammatory process with lymphocytic infiltration, bridging or multiacinar necrosis, and fibrotic changes
  • Centrilobular perivenulitis and necrosis
  • Hepatocyte emperipolesis [7]
  • Hepatocyte rosettes
  • Bile duct changes (e.g., cholangitis, ductal injury)

Additional evaluation [5]

• Obtain further serum antibodies to clarify diagnosis if initial antibody testing is negative.
  • ALC-1 (type 2 AIH), anti-SLA (type 1 AIH)
  • Antimitochondrial antibody: rare in AIH; may indicate AIH-PBC overlap
  • pANCA: may be present in type 1 AIH or AIH-PSC overlap
• Screen all patients for concomitant celiac disease (with anti-tTG) and thyroid disease (with TSH).
• Assess for other common comorbidities (e.g., rheumatoid arthritis, diabetes mellitus, inflammatory bowel disease) based on clinical suspicion.

• Viral hepatitis (e.g., hepatitis C)
• Primary sclerosing cholangitis
• Primary biliary cholangitis
• Alcohol-associated liver disease
• Metabolic dysfunction-associated steatohepatitis
• Drug-induced liver injury
• Drug-induced autoimmune-like hepatitis (DIAH)
• Hemochromatosis
• Wilson disease

The differential diagnoses listed here are not exhaustive.

General principles [5][7]

• Initiate management of acute liver failure if necessary.
• Refer patients to a hepatologist for management.
• Immunosuppression is the mainstay of treatment.
  • Provide age-appropriate immunizations and pretreatment counseling.
  • Prevent complications of glucocorticoid therapy.
• Liver transplantation is indicated in patients with decompensated liver cirrhosis.

Pharmacotherapy [5]

• Indication: active disease (i.e., elevated transaminases, elevated IgG, and/or histological disease)
• Goals of treatment
  • Reduce symptoms.
  • Reverse liver inflammation and fibrosis.
  • Achieve remission.
• Induction therapy
  • First line: glucocorticoids (e.g., prednisone or prednisolone) with or without azathioprine (AZA)
  • Alternatives: mycophenolate, tacrolimus, infliximab, rituximab
• Maintenance: glucocorticoid discontinuation after gradual tapering; continue AZA.
• Monitoring
  • Check ALT, AST, IgG levels to assess for biochemical response and remission. [5]
  • Conduct transient elastography at least 6 months after successful treatment to assess for advanced fibrosis or cirrhosis
• Treatment withdrawal
  • Consider in patients with biochemical remission for ≥ 2 years.
  • Consider repeat liver biopsy to exclude active inflammation prior to withdrawal.
  • Relapse is common; obtain AST, ALT, and IgG levels at regular intervals. [5]

Do not use azathioprine in patients with decompensated cirrhosis or acute severe AIH (i.e., jaundice, INR > 1.5). [5]

• 10-year survival rate with treatment: > 90% [9]
  • Lifelong therapy is usually required.
  • Increased risk of developing hepatocellular carcinoma (HCC): Follow-ups are recommended.
• Type 2 AIH is associated with more severe disease, a worse response to corticosteroids, and more frequent relapses.
• Increased risk of liver cirrhosis if left untreated