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 Liver
Gross 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 Stain
PAS with diastase digestion shows numerous periportal PAS(+) diastase-resistant globules image in periportal areas.

image
α-1-Antitrypsin Stain
A1AT 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 Micrograph
Electron 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



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