Autoimmune hepatitis

definition and pathophysiology

Immune-mediated liver disease characterized by elevated serum aminotransaminases, liver-associated autoantibodies, and hypergammaglobulinemia.
Pathogenesis involves unknown environmental triggers initiating T cell-mediated immune response against liver autoantigens in genetically predisposed hosts.
Dense mononuclear cell infiltrate invades surrounding parenchyma, causing interface hepatitis.
Cellular injury mediated by cytokines from CD8+ cytotoxic T cells and antibody-mediated cytotoxicity.
Defective regulatory T-cell function impairs control of CD4 and CD8 effector cell proliferation.
Molecular mimicry suspected as potential trigger, showing high amino acid sequence homology between hepatitis C virus polyprotein and CYP2D6.

Characterized by positive smooth muscle antibody (SMA) and/or antinuclear antibody (ANA).
Accounts for 60-70% of pediatric cases.
Typically presents around puberty.
Associated with human leukocyte antigen (HLA) DRB10301 and DRB11301 alleles.
Exhibits isolated partial deficiency of complement component C4.

Characterized by anti-liver kidney microsomal type 1 antibody (anti-LKM-1) and/or anti-liver cytosol type 1 antibody (anti-LC-1).
Represents 20-30% of pediatric cases.
Presents typically at younger age, including infancy.
Partial IgA deficiency common, affecting approximately 40% of patients.
Associated with HLA DRB107 and DRB103 alleles.
Main autoantigen identified as cytochrome P450 2D6.

Clinical features highly variable, ranging from asymptomatic to fulminant liver failure.
Acute hepatitis: Observed in 40-50% of patients. Mimics viral hepatitis with malaise, nausea, vomiting, anorexia, abdominal pain, jaundice, dark urine, and pale stools.
Insidious onset: Observed in 25-40% of patients. Manifests with progressive fatigue, headache, amenorrhea, weight loss, and diarrhea lasting months to years.
Fulminant hepatic failure: Grade II-IV encephalopathy developing weeks to months after symptom onset. More frequent in type 2 (25%) than type 1 (3%).
Late presentation: Complications of cirrhosis and portal hypertension including hematemesis from varices, splenomegaly, bleeding diathesis, and ascites.
Incidental finding: Abnormal transaminases detected without hepatic symptoms.
Extrahepatic manifestations: Arthritis, vasculitis, nephritis, thyroiditis, Coombs-positive anemia, vitiligo, pyoderma gangrenosum, and erythema nodosum.

Elevated serum aminotransferases (100 to >1000 IU/L).
Elevated total bilirubin (2-10 mg/dL) in severe cases.
Normal to slightly increased alkaline phosphatase and gamma-glutamyl transpeptidase. Alkaline phosphatase to aspartate aminotransferase ratio $\geq$ 3 strongly suggests autoimmune sclerosing cholangitis overlap.
Marked polyclonal hypergammaglobulinemia (IgG >16 g/L).
Hypoalbuminemia and prolonged prothrombin time reflect impaired hepatocellular synthetic function in severe disease.
Normochromic normocytic anemia, leukopenia, and thrombocytopenia present in advanced portal hypertension.
Autoantibody detection via indirect immunofluorescence on rodent tissue substrate. Titers of 1:20 for ANA/SMA and 1:10 for anti-LKM-1 clinically relevant in children.

Essential for definitive diagnosis and fibrosis staging.
Interface hepatitis: Dense mononuclear and plasma cell infiltrate in portal tracts disrupting parenchymal limiting plate.
Hepatocyte swelling, pyknotic necroses, and acinar inflammation.
Connective tissue bridging collapse expanding from portal area into lobules.
Hyaline droplets in Kupffer cells positive for IgG by immunohistochemistry.

Goal is complete suppression of hepatic inflammation with minimal medication side effects.
Prednisone or prednisolone initiated at 1-2 mg/kg/day (maximum 60 mg/day).
Monitor liver function tests weekly during first 6-8 weeks. Target 80% reduction of transaminases by 8 weeks.
Taper steroids gradually (5 mg decrements) once biochemical remission achieved.
Azathioprine added at 0.5 mg/kg/day, increasing to 2-2.5 mg/kg/day as steroid-sparing agent.
Thiopurine methyltransferase activity testing recommended before azathioprine initiation to prevent severe myelotoxicity.
Budesonide (9 mg/day) alternative induction agent for patients lacking cirrhosis or severe acute disease.

Required for up to 10% of patients exhibiting standard treatment failure or azathioprine intolerance.
Mycophenolate mofetil (20 mg/kg twice daily) combined with prednisolone.
Calcineurin inhibitors (cyclosporine A, tacrolimus) utilized for refractory cases. Require careful monitoring due to narrow therapeutic index and nephrotoxicity risk.
Rituximab (anti-B lymphocyte monoclonal antibody) and infliximab demonstrating anecdotal success.

Indicated for fulminant hepatic failure unresponsive to steroids, or end-stage liver disease developing despite medical management.
Required in approximately 10% of pediatric patients.
Disease recurrence post-transplantation affects approximately 20% of recipients.
De novo autoimmune hepatitis occurs in 2-5% of pediatric liver transplant recipients transplanted for non-autoimmune indications.

Remission defined as normal transaminases, normal IgG levels, negative or very low autoantibody titers, and histological resolution of inflammation.
Relapse occurs in roughly 40% of patients during treatment tapering, requiring temporary steroid dose increases.
Treatment maintained minimum 2-3 years before attempting withdrawal.
Withdrawal attempted only after 12 months of persistent biochemical/immunological normality and confirmed histological resolution.
Successful drug withdrawal achieved in 20% of type 1 patients, but rarely successful in type 2 patients.
Lifelong monitoring required due to high relapse risk. Avoid withdrawal during puberty.