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α1-Antitrypsin deficiency (AATD) is a
relatively common inherited disorder. It primarily presents with early-onset
panacinar lung emphysema and with liver cirrhosis in a minority of the
patients. Cardiac arrest in association with general anesthesia has been
described.
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α1-Antiprotease Deficiency; Hereditary
Pulmonary Emphysema; AATD.
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Worldwide, approximately 1:2000 to 1:4000 newborns have
AATD. This disorder is found in all ethnic groups but most frequently in
Caucasians.
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AATD is inherited in an autosomal recessive
pattern. In the majority of patients, the parents are carriers (heterozygous
for the defect) but show no symptoms of the disease. A gene called
SERPINA1 (Serine [or cysteine] proteinase inhibitor,
clade A [AAT], member 1) is responsible
for production of AAT and has been mapped to 14q32.1.
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The SERPINA1 gene comes in many alleles (>100 different phenotypic variants
of AATD have been identified). Most people (approximately 90%) are
homozygous for the M version (PiMM, where Pi = proteinase inhibitor), which is
characterized by normal levels of AAT (serum levels 20-60 mmol/l). Two
altered alleles of the SERPINA1 gene result in moderately low to very low
AAT levels and are called the S and Z allele, respectively. Individuals with
a PiZZ (AAT serum level 3.3-7 mmol/l) or PiSZ phenotype are at high risk to
develop AATD. In fact, the PiZZ phenotype is responsible for almost all the
cases of AAT-related emphysema and liver disease. In general, individuals
with a PiMS or PiSS genotype can produce enough AAT to prevent lung damage.
In general, a serum level of approximately 11 mmol/l and higher is
considered sufficient to prevent lung damage. However, patients with the
PiMZ genotype (carrier) who smoke are at increased risk for lung disease. In
a rare variant, termed the 00 (null-null) phenotype, no AAT is produced.
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AAT is a glycoprotein with a molecular weight of
54 kDa. It is produced in hepatocytes and mononuclear phagocytes. The
genetic defect in AATD alters the molecule (misfolding secondary to
substitution of alanine for valine at amino acid residue 213 and
substitution of lysine for glutamate at amino acid residue 342 of AAT) such
that, although synthesized, it cannot be released from the endoplasmic
reticulum, where a significant part is degraded but the rest accumulates in
the form of insoluble intracellular globular inclusions. The inclusion can
easily be identified on routine (H and E) and periodic acid-Schiff
(PAS)-stained liver biopsies (except in the Pi00 genotype, where AAT
production is completely absent). AAT serum levels in PiZZ patients are
approximately 10 to 15% of normal values, meaning that 85 to 90% of
AAT produced remains intracellularly, of which a significant part is
degraded; the rest accumulates. The major function of AAT is inhibition of
several mainly neutrophil-derived proteases, particularly at sites of
inflammation where high amounts of active serine proteases (elastase,
trypsin, cathepsin G, proteinase 3) are released from infiltrating
polymorphonuclear cells. ...