Alpha 1 Antitrypsin Disease

Question 1

Overview

Answer 1

• AR
• Single base substitution in SERPINA1 -<> mutant Z protein (PIZZ).
• A1AT: serine protease inhibitor, inhibits neutrophil elastase
  Z-protein is mis-folded: polymerizes and accumulates in ER of hepatocytes
  -results in low serum A1AT levels.
  ONLY PISZ and PIZZ develop significant liver disease.

Question 2

Effects of PIZZ on Liver

Answer 2

PAS positive, diastase resistant globules.
-Gain of function: proteotoxicity in the liver.

Question 3

Histology slide of A1AT

Answer 3

Question 4

Epidemiology

Answer 4

PIZZ 1:2,000 to 1:5,000 live births
10-20% of PIZZ children develop clinical liver disease. Another 10% develop cirrhosis later in life. Most do not develop clinical liver disease. Emphysema in 40s and 50s, especially among smokers.

Question 5

Diagnosis

Answer 5

• suspect in all cases of neonatal cholestasis
• most common genetic causes of cholestasis in Caucasians.
  PI phenotype or SERPINA1 genotype, ?A1AT serum level.