Liver & intrahepatic bile ducts nontumor
Metabolic diseases
Alpha-1-antitrypsin deficiency

Topic Completed: 1 April 2012

Minor changes: 16 June 2020

Copyright: 2002-2020,, Inc.

PubMed Search: Alpha-1-antitrypsin deficiency[TI] liver[TI] free full text[sb]

See also: Lung - nontumor chapter

Komal Arora, M.D.
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Cite this page: Arora K. Alpha-1-antitrypsin deficiency. website. Accessed July 13th, 2020.
Definition / general
  • Common cause of neonatal cholestasis
  • Autosomal recessive disease, causing low serum levels of alpha-1-antitrypsin (AAT) and leading to emphysema (80%, usually at age 20 - 39 years) and liver disease
  • AAT is a small, 394 amino acid plasma glycoprotein, synthesized predominantly by hepatocytes, encoded by a gene on #14
  • AAT is a protease inhibitor (Pi), which inhibits neutrophilic elastase released at sites of inflammation; also inhibits trypsin
  • Although there are ~ 120 AAT forms, PiMM (normal phenotype) is present in 90% of population
  • PiZZ: 1 per 7,000; have 10 - 15% of normal AAT levels, are at high risk for clinical disease; accumulate AAT variant Z in endoplasmic reticulum and have slowdown in degradation pathway but only 10% get clinical disease
  • PiZZ hepatic syndromes range from neonatal hepatitis (10%), biliary atresia (intra or extrahepatic), fibrosis, childhood cirrhosis; 2% develop hepatocellular carcinoma, not always associated with cirrhosis
  • PiMZ: intermediate plasma levels of AAT (expression of alleles is autosomal codominant)
  • Pi null: rare variant with no detectable serum AAT
  • PiS: low serum AAT but no disease
  • AAT deficiency variants: secretory protein does not move from endoplasmic reticulum to Golgi; for PiZ, is due to single AA substitution, causing abnormal folding, blocking its movement along the remainder of the secretory pathway
  • Serum protein electrophoresis; liver biopsy to determine extent of histologic damage
Microscopic (histologic) description
  • Round to oval cytoplasmic eosinophilic globular inclusions in periportal hepatocytes
  • Rare Mallory bodies and fatty change
  • Also hepatocellular degeneration, giant cell formation, cholestasis and cholangitis, portal fibrosis and cirrhosis
Microscopic (histologic) images

Images hosted on other servers:

Liver - H&E

Liver - PAS stain with diastase

Liver - various images

Positive stains
  • AAT immunostains
  • Inclusions are strongly PAS+ and diastase resistant
Electron microscopy description
  • Granular material in dilated endoplasmic reticulum
Differential diagnosis
  • AAT that is present in damaged and regenerating hepatocytes (usually diffuse granules, not periportal, no globules, PAS negative), AAT+ globules present in alcoholic hepatitis
Additional references
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