Alpha-1-Antitrypsin Deficiency

 Caused by mutations in SERPINA1 gene

• Deficiency is characterized by emphysema and chronic liver disease

Etiology/Pathogenesis

• Mutations result in defective secretion of molecule, accumulation in hepatocytes, and decreased serum A1AT
image Specific mechanism of hepatocyte injury is unknown
• Most common deficiency alleles are PiS and PiZ
image PiZZ phenotype accounts for most cases of severe A1AT deficiency and virtually all cases of liver disease

Clinical Issues

• Most common in Caucasians of Northern European ancestry
• Liver disease is 2nd most common manifestation (after pulmonary disease)
image Bimodal distribution
– Neonatal hepatitis/cholestasis in infants
– Chronic liver disease/cirrhosis in adults

Microscopic

• Eosinophilic globules within periportal/periseptal hepatocytes are characteristic
image Globules are strongly PAS(+), diastase resistant
image Present in periportal/periseptal hepatocytes
image Associated histologic features (inflammation, fibrosis) in adults are variable and nonspecific
• Neonatal hepatitis features cholestasis, hepatocyte injury
image Globules may be difficult to detect in young infants

Diagnostic Checklist

• Consider A1AT deficiency in all cases of neonatal cholestasis or in adults with unexplained chronic liver disease
image
Explanted LiverGross photograph of an explanted liver from an adult with an α-1-antitrypsin (A1AT) deficiency shows nodular capsular and cut surfaces consistent with cirrhosis. Cirrhosis is frequently established at the time of diagnosis in adults.

image
PAS-Diastase StainPAS with diastase digestion shows numerous periportal PAS(+) diastase-resistant globules image in periportal areas.
image
α-1-Antitrypsin StainA1AT immunohistochemical stain confirms the presence of A1AT inclusion bodies within hepatocytes image. 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.
image
Electron MicrographElectron micrograph shows round, electron-dense deposits within the endoplasmic reticulum of a hepatocyte image .

TERMINOLOGY

Abbreviations

• α-1-antitrypsin (A1AT)

Definitions

• Autosomal recessive genetic disorder characterized by mutations in SERPINA1 gene
image A1AT protein synthesized mainly in liver
– Major circulating serine protease inhibitor
– Inhibits neutrophil proteases, thus protecting host tissues from nonspecific injury secondary to inflammation
image Mutations result in defective secretion of molecule
– Most commonly Glu342Lys substitution
– Protein folds abnormally forming insoluble aggregates instead of being secreted
image Deficiency is characterized by emphysema and chronic liver disease
• Most common inherited metabolic disorder leading to liver transplantation in childhood
• Most common genetic cause of liver disease in adults and children

ETIOLOGY/PATHOGENESIS

Inherited Metabolic Disorder

• Highly polymorphic genes with many recognized variants
image Variants comprise protease inhibitor (Pi) system
– Most common variant is PiM
image Present in > 90% of USA population
image Associated with normal serum A1AT levels
– Most common deficiency alleles are PiS and PiZ
image PiZZ phenotype accounts for most cases of severe A1AT deficiency
image ∼ 0.5% of population
image Typically Caucasians of Northern European ethnicity
– ∼ 2% of individuals are heterozygous for Z allele
image Risk of liver disease in heterozygotes is controversial

Accumulation of Mutant Protein

• Coding sequence defects lead to abnormal polymerization of glycoprotein, preventing export from hepatocyte
image Mutant protein accumulates in endoplasmic reticulum of hepatocyte
– Subsequent decrease in serum A1AT
– Specific mechanism of hepatocyte injury is unknown

CLINICAL ISSUES

Epidemiology

• Incidence
image Severe A1AT deficiency is found in ∼ 1 per 3,500 live births

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Apr 20, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Alpha-1-Antitrypsin Deficiency

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