Liver and intrahepatic bile ducts-nontumor - Alpha-1-antitrypsin deficiency

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Liver and intrahepatic bile ducts-nontumor

Metabolic diseases

Alpha-1-antitrypsin deficiency

Reviewers: Komal Arora, M.D. (see Reviewers page)
Revised: 23 April 2012, last major update April 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

See also Lung-nontumor chapter

General
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● 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
● Pi-S: 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
● Diagnosis: Serum protein electrophoresis; liver biopsy to determine extent of histologic damage

Treatment
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● "Augmentation therapy" (infusion of purified AAT from pooled human plasma, Am J Respir Crit Care Med 2012;185:246, Lancet 2005;365(9478):2225)
● Liver transplantation, avoid cigarette smoking (which causes earlier and more severe emphysema)

Micro description
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● 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

Micro images
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Liver-H&E

Liver-PAS stain with diastase

Liver-various images

Positive stains
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● AAT immunostains
● Inclusions are strongly PAS+ and diastase resistant

EM description
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● Granular material in dilated endoplasmic reticulum

Electron microscopy images
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Liver-various images

Differential diagnosis
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● 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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● J Inherit Metab Dis 2008;31:21

End of Liver and intrahepatic bile ducts-nontumor > Metabolic diseases > Alpha-1-antitrypsin deficiency

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