Alpha-1 antitrypsin deficiency
Alpha-1 antitrypsin deficiency is an autosomal codominant disorder in which a deficient or misfolded protease inhibitor causes unopposed neutrophil elastase activity in the lung and toxic protein accumulation in the liver, producing early basilar-predominant panacinar emphysema and, in some patients, cirrhosis. Diagnosis rests on a low serum level confirmed by phenotype or genotype testing, and management centers on smoking cessation, standard COPD therapy, and, for qualifying patients, weekly IV augmentation with pooled alpha-1 proteinase inhibitor.
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What this article covers
- Overview
Definition: alpha-1 antitrypsin (AAT) deficiency is an autosomal codominant disorder (gene on chromosome 14; normal allele M, abnormal S and Z alleles) in which a misfolded or reduced antiprotease…
- Epidemiology
Age of clinical presentation: patients with deficient genotypes typically present with emphysema in the third or fourth decade of life, decades earlier than typical smoking-related COPD.
- Risk factors
Deficient genotype (PIZZ, PISZ, or null/null): the dominant risk factor for early emphysema; PIZZ carries the highest risk for both organs.
- Pathophysiology
Antiprotease function is lost in the lung: AAT is the principal inhibitor of neutrophil elastase; when circulating AAT is reduced or dysfunctional, elastase acts unopposed on the alveolar wall.
- Clinical features
Early-onset dyspnea and airflow obstruction: the hallmark presentation is emphysema-type dyspnea in the third or fourth decade of life, often with minimal or absent smoking history, which should raise suspicion above typical COPD.
- Differential diagnosis
Smoking-related (usual) COPD: shares dyspnea, cough, and airflow obstruction; distinguished by older age at onset, extensive smoking history, an upper-lobe centriacinar pattern, and a normal AAT level.
- Diagnosis
The diagnosis is confirmed by a low quantitative serum AAT level plus AAT phenotype (Pi typing) or genotype testing identifying a deficient allele combination (for example PIZZ, PISZ, or null/null)…
- Management
First, address smoking status at every encounter: counsel every smoker to quit and start pharmacotherapy, since continued smoking is the single most modifiable driver of accelerated FEV1 decline.
- Complications
Progressive airflow obstruction and respiratory failure, accelerated by continued smoking; manage acute worsening as acute exacerbation of COPD.
- Prognosis
Smoking status is the dominant modifiable determinant of survival: continued smoking accelerates FEV1 decline far beyond genotype alone, making cessation the single highest-impact intervention.
- Prevention
Universal one-time case-finding: obtain a quantitative AAT level once in every patient diagnosed with COPD, regardless of age, so undiagnosed patients are identified before disease is advanced.
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