What is significant alpha one anti-trypsin (A1AT) deficiency?

Significant Alpha-1 Antitrypsin Deficiency

Significant alpha-1 antitrypsin (A1AT) deficiency is a hereditary condition characterized by serum A1AT levels below 11 μM (50 mg/dL), most commonly due to the PI*ZZ genotype, which substantially increases risk for developing pulmonary emphysema and liver disease, leading to significant morbidity and mortality. 1, 2

Definition and Pathophysiology

• Alpha-1 antitrypsin is a 52-kD single-chain glycoprotein that functions primarily as a protease inhibitor, with its major biological role being inhibition of neutrophil elastase (NE), an enzyme that degrades elastin and other components of lung tissue 3, 1
• Severe deficiency occurs due to inheritance of two protease inhibitor (Pi) deficiency alleles in the SERPINA1 gene, with PI*ZZ being the most common severe deficiency phenotype, resulting in serum levels typically below 50 mg/dL (11 μM) 3, 2
• The Z mutation causes abnormal protein folding, leading to retention in the endoplasmic reticulum of hepatocytes rather than efficient secretion, resulting in both reduced circulating levels and potential liver damage 4
• This deficiency creates a protease-antiprotease imbalance in the lungs, allowing relatively unopposed destruction of the connective tissue framework of lung parenchyma 2

Clinical Significance and Manifestations

• Pulmonary emphysema of the panacinar type is the most prevalent clinical consequence and the major cause of disability and death in affected individuals 3, 1
• Symptomatic obstructive lung disease typically presents between ages 32 and 41 in individuals with a history of smoking 1
• Liver disease is the second most frequent clinical complication, presenting as cholestasis in infancy (which may resolve by adolescence) or as cirrhosis and hepatocellular carcinoma in 30-40% of patients over age 50 3
• Without treatment, A1AT deficiency can lead to premature disability and death, with 72% of deaths attributed to emphysema 1

Diagnostic Criteria for Significant Deficiency

• Serum A1AT levels below 11 μM (50 mg/dL) are considered the threshold for significant deficiency that increases risk of developing emphysema 2, 5
• The most severe deficiency is associated with the PIZZ phenotype (levels typically 3-7 μM) and PI(null)(null) variant (undetectable protein) 2
• Moderate deficiency (PI*SZ phenotype) results in serum levels of approximately 9-23 μM, which may still confer increased risk for developing emphysema 2
• Testing should be considered in individuals with early-onset emphysema (regardless of smoking history), all subjects with COPD, adults with bronchiectasis without evident etiology, patients with asthma whose spirometry fails to normalize with therapy, liver disease of unknown cause, and family members of known A1AT-deficient patients 1

Clinical Management

• Augmentation therapy with intravenous A1AT protein is the only specific treatment available for patients with severe deficiency and clinically evident emphysema 1, 2
• Weekly infusions aim to maintain serum levels above the protective threshold of 11 μM to slow the progression of emphysema 2
• Smoking cessation and avoidance of environmental irritants are critical as smoking accelerates the development and progression of emphysema in A1AT-deficient individuals 3, 1
• Early antibiotic therapy is recommended for all purulent exacerbations due to the increased elastolytic burden posed by acute infections 3
• Conventional COPD management approaches including bronchodilators, pulmonary rehabilitation, oxygen therapy when indicated, and consideration of lung transplantation for severe disease 3, 1

Important Considerations and Pitfalls

• A1AT deficiency is significantly underdiagnosed despite being one of the most common inherited conditions (affecting approximately 1 in 2,000 to 5,000 people) 6, 5
• Late diagnosis is associated with reduced functional status, quality of life, and worse overall survival, highlighting the importance of early detection 1
• The clinical efficacy of augmentation therapy in affecting the progression of emphysema has not been conclusively demonstrated in large randomized controlled trials, though available evidence suggests it can slow lung function decline 2
• Not all individuals with severe genetic variants of A1AT deficiency develop emphysema or liver disease, indicating variable penetrance and the likely influence of environmental and additional genetic factors 2
• Long-term surveillance for early detection of lung and liver diseases is recommended, and family screening should be encouraged to identify relatives who may be affected 1