Liver & intrahepatic bile ducts

• Immune mediated inflammatory liver disease of uncertain cause (Hepatology 2020;72:671)

• Previously known as lupoid hepatitis

• Incidence is highest in North America (42.9/100,000), followed by Europe (10.7 - 23.9/100,000) (J Gastroenterol Hepatol 2015;30:1230)
• M:F = 1:4 - 6
• Usual age of presentation depends on subtype:
  • Type 1: bimodal (10 - 25 years and 45 - 70 years)
  • Type 2: < 15 years

• Unknown; genetic and environmental factors may play roles in pathogenesis (J Hepatol 2015;62:S100)
• Genetic predisposition:
  • North America / Europe: HLA-DR3 (DRB1*0301) and HLA-DR4 (DRB1*0401)
  • China / Japan: HLA-DR4 (DRB1*0405)

• Serum autoantibodies (J Autoimmun 2013;46:17):
  • Antinuclear antibody: positive in 75% of type 1 autoimmune hepatitis; not associated with disease course or outcome
  • Anti smooth muscle antibody: positive in 95% of type 1 autoimmune hepatitis; not associated with disease course or outcome
  • Anti liver kidney microsomal: diagnostic for type 2 autoimmune hepatitis; associated with younger age at presentation, fulminant hepatic failure and partial IgA deficiency
  • Anti liver cytosol type 1: diagnostic for type 2 autoimmune hepatitis; associated with more severe inflammation and rapid progression to cirrhosis
  • Antisoluble liver antigen / liver pancreas: positive in 20 - 50% of autoimmune hepatitis; associated with more severe disease, treatment dependence, relapse after drug withdrawal and need for transplantation
• Elevated liver enzymes; ALT / AST > ALP
• Serum immunoglobulin G (IgG): marker for diagnosis (> 1.1 x upper limit of normal [ULN]) and monitoring treatment response (Hepatology 2010;51:2193)

• Typical morphological changes:
  • Portal plasma cell rich inflammation
  • Interface hepatitis, formerly referred to as piecemeal necrosis: portal inflammatory cells eroding through the limiting plate between the portal tract and liver parenchyma
  • Emperipolesis: active penetration of lymphocytes into and through a hepatocyte
  • Hepatocyte rosettes
  • Variable fibrosis (about 10% of autoimmune hepatitis does not show any fibrosis at initial presentation)
  • Lobular necroinflammatory activity: usually accompanied by portal and periportal inflammation
• Uncommon morphological changes:
  • Perivenular necrosis: up to 17% of autoimmune hepatitis with or without typical portal and periportal changes; associated with more severe disease activity and lower histological stage
  • Intrahepatic cholestasis (bilirubinostasis)
  • Syncytial multinucleated giant cells: autoimmune hepatitis is the most common cause (30%) of postinfantile giant cell hepatitis, which is rare in adults (0.1 - 0.25% of all hepatitis) (Hepat Res Treat 2013;2013:601290)
  • Mild bile duct injury / inflammation: present in up to 24% of classical autoimmune hepatitis (Hepatology 2001;34:659)
  • Chronic biliary disease or overlap syndrome only need to be considered in the presence of more extensive bile duct injury, florid duct lesions, ductular reaction, ductopenia, chronic cholestasis, portal granulomas or periductal fibrosis (clinical and laboratory findings must separately be met for both autoimmune hepatitis and primary sclerosing cholangitis / primary biliary cholangitis)
  • IgG4 associated autoimmune hepatitis: > 10 IgG4 positive plasma cells/high power field
• Simplified International Autoimmune Hepatitis Group scoring system:
  • Typical of autoimmune hepatitis (sensitivity: 40 - 59%; specificity: 55 - 96%) (Mod Pathol 2017;30:773, Hepatology 2008;48:169)
    • Interface hepatitis with lymphocytic or lymphoplasmacytic infiltrate
    • Hepatocyte rosettes
    • Emperipolesis
  • Compatible with autoimmune hepatitis
    • Chronic hepatitis with lymphocytic infiltrate
    • Without all 3 typical features
• Recent studies have suggested hepatocyte rosettes and emperipolesis are not specific features of autoimmune hepatitis (Hum Pathol 2018;82:51, Mod Pathol 2017;30:773)
• Grading and staging is usually performed according to systems developed for viral hepatitis, such as Batts and Ludwig

Contributed by Anthony W.H. Chan, M.B.Ch.B.

• Clinical presentation, including serology, is very important for resolving the differential diagnosis
• Chronic hepatitis C:
  • Portal lymphocytic infiltrate with lymphoid follicles
  • Less severe interface hepatitis
  • Mild bile duct injury
  • Mild steatosis
• Drug / toxin reaction:
  • No reliable histological features differentiating autoimmune hepatitis and drug induced liver injury
  • Clinical correlation with drug history is essential
• Hepatitis A:
  • May resemble acute / early phase of autoimmune hepatitis (prominent plasma cells and interface hepatitis)
  • No fibrosis
  • Viral serology is crucial
• Overlap syndromes (Ulster Med J 2011;80:15)
• Primary biliary cholangitis:
  • Unequivocal bile duct injury with chronic cholatestasis
  • Only mild interface hepatitis and lobular necroinflammatory activity
  • Cholestatic liver enzyme derangement or seropositivity of antimitochondrial antibody
• Primary sclerosing cholangitis:
  • Periductal fibrosis with chronic cholatestasis
  • Only mild interface hepatitis and lobular necroinflammatory activity
  • Cholestatic liver enzyme derangement or seropositivity of antineutrophil cytoplasmic antibodies
  • Classic liver imaging findings helpful to establish this diagnosis
  • More common in male patients

• Best Pract Res Clin Gastroenterol 2011;25:689, Ann Hepatol 2005;4:6, Minerva Gastroenterol Dietol 2007;53:43

Which of the following features are considered typical for autoimmune hepatitis?

1. Florid duct lesion and seropositivity for antimitochondrial antibody
2. Interface hepatitis and seropositivity for smooth muscle antibody
3. Pericellular fibrosis and seropositivity for antinuclear antibody
4. Periductal concentric onion skin fibrosis and seropositivity for antineutrophil cytoplasmic antibodies

B. Interface hepatitis and seropositivity for smooth muscle antibody

Comment Here

Reference: Autoimmune hepatitis

A middle aged woman without significant past medical history presents with acute onset of fatigue and jaundice. Blood tests show markedly elevated aspartate aminotransferase and alanine aminotransferase and high titer antinuclear antibody. Serology for smooth muscle antibody and antimitochondrial antibody are both negative. A liver biopsy demonstrates the above finding. Which of the following laboratory results should be assessed before issuing the diagnosis of consistent with autoimmune hepatitis?

1. Elevated serum IgG
2. Negative serology for viral hepatitis A
3. Normal serum alkaline phosphatase
4. Positive serology for liver kidney microsomal

B. Negative serology for viral hepatitis A. Portal plasmacytic infiltration with interface hepatitis may also occur in viral hepatitis A.

Comment Here

Reference: Autoimmune hepatitis