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At a glance

Alpha1-Antitrypsin deficiency (AATD) primarily presents with early-onset panacinar lung emphysema and with liver cirrhosis in a minority of the patients. Cardiac arrest associated with general anesthesia has been described.

Synonyms

Alpha1-Antiprotease Deficiency; Hereditary Pulmonary Emphysema; AATD Syndrome.

Incidence

Worldwide, approximately 1:2,000 to 1:4,000 newborns have AATD. This disorder is found in all ethnic groups, but most frequently in Caucasians. It has been estimated that the PiZZ mutation (see below) is found in roughly 250,000 people worldwide.

Genetic inheritance

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 the production of AAT and has been mapped to chromosome 14q32.1. The SERPINA1 gene occurs 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 denotes 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 of developing AATD. In fact, the PiZZ phenotype is responsible for almost all cases of AAT-related emphysema and liver disease. In general, individuals with a PiMS or PiSS genotype can produce sufficient AAT to prevent lung damage. 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.

Pathophysiology

AAT is a glycoprotein with a molecular weight of 52 kDa produced in hepatocytes and mononuclear phagocytes. The genetic defect in AATD alters the α1-Antitrypsin 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) in a way that, although synthesized, it cannot be released from the endoplasmic reticulum, where a significant part is degraded while the rest accumulates in the form of insoluble intracellular globular inclusions. These inclusions can easily be identified on routine (HE-staining) 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 stored intracellularly, of which—as mentioned above—a significant proportion is degraded, while the rest accumulates. The major function of AAT is inhibition ...

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