Caused by mutations in SERPINA1 gene
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Deficiency is characterized by emphysema and chronic liver disease
Etiology/Pathogenesis
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Mutations result in defective secretion of molecule, accumulation in hepatocytes, and decreased serum A1AT
Specific mechanism of hepatocyte injury is unknown
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Most common deficiency alleles are PiS and PiZ
PiZZ phenotype accounts for most cases of severe A1AT deficiency and virtually all cases of liver disease
Clinical Issues
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Most common in Caucasians of Northern European ancestry
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Liver disease is 2nd most common manifestation (after pulmonary disease)
Bimodal distribution
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Neonatal hepatitis/cholestasis in infants
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Chronic liver disease/cirrhosis in adults
Microscopic
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Eosinophilic globules within periportal/periseptal hepatocytes are characteristic
Globules are strongly PAS(+), diastase resistant
Present in periportal/periseptal hepatocytes
Associated histologic features (inflammation, fibrosis) in adults are variable and nonspecific
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Neonatal hepatitis features cholestasis, hepatocyte injury
Globules may be difficult to detect in young infants
TERMINOLOGY
Abbreviations
Definitions
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Autosomal recessive genetic disorder characterized by mutations in
SERPINA1 gene
A1AT protein synthesized mainly in liver
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Major circulating serine protease inhibitor
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Inhibits neutrophil proteases, thus protecting host tissues from nonspecific injury secondary to inflammation
Mutations result in defective secretion of molecule
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Most commonly Glu342Lys substitution
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Protein folds abnormally forming insoluble aggregates instead of being secreted
Deficiency is characterized by emphysema and chronic liver disease
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Most common inherited metabolic disorder leading to liver transplantation in childhood
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Most common genetic cause of liver disease in adults and children
ETIOLOGY/PATHOGENESIS
Inherited Metabolic Disorder
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Highly polymorphic genes with many recognized variants
Variants comprise protease inhibitor (Pi) system
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Most common variant is PiM
Present in > 90% of USA population
Associated with normal serum A1AT levels
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Most common deficiency alleles are PiS and PiZ
PiZZ phenotype accounts for most cases of severe A1AT deficiency
∼ 0.5% of population
Typically Caucasians of Northern European ethnicity
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∼ 2% of individuals are heterozygous for Z allele
Risk of liver disease in heterozygotes is controversial
Accumulation of Mutant Protein
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Coding sequence defects lead to abnormal polymerization of glycoprotein, preventing export from hepatocyte
Mutant protein accumulates in endoplasmic reticulum of hepatocyte
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Subsequent decrease in serum A1AT
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Specific mechanism of hepatocyte injury is unknown
CLINICAL ISSUES
Epidemiology
in periportal areas.
. The peripheral pattern of staining of each globule is characteristic. In neonates, there is typically more granular cytoplasmic staining, as well-formed globules are not usually present in this age group.
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