What is alpha-1 antitrypsin (A1AT) disease?

What is Alpha-1 Antitrypsin Deficiency?

Alpha-1 antitrypsin deficiency (AATD) is a hereditary genetic disorder characterized by severely low serum levels of alpha-1 antitrypsin protein, which predisposes affected individuals to early-onset panacinar emphysema (the leading cause of disability and death) and liver disease (the second most common complication). 1

Genetic Basis and Inheritance Pattern

• AATD results from inheritance of two deficiency alleles from the SERPINA1 gene located on chromosome 14q31-32.3, transmitted in an autosomal codominant pattern 1
• The PIZ allele is the most common deficiency variant; homozygous PIZZ individuals have serum AAT levels below 50 mg/dL (less than 11 μM), representing only 15% of normal levels 1
• The PIS allele is more prevalent in Mediterranean populations, with PISS homozygotes maintaining approximately 60% of normal AAT levels 1
• Null alleles (PI*QQ) produce no functional AAT protein and confer the most severe deficiency 1
• Approximately 100 allelic variants have been identified, with varying degrees of protein deficiency and clinical manifestations 1, 2

Protein Structure and Function

• AAT is a 52-kD single-chain glycoprotein composed of 394 amino acid residues with 3 asparagine-linked carbohydrate side chains 1, 2
• Normal serum concentrations range from 120-200 mg/dL 1
• The protein's primary biological role is inhibiting neutrophil elastase (NE), a 29-kD enzyme that degrades elastin, basement membrane, and other matrix components in lung tissue 1
• Hepatocytes are the primary source of AAT production, though mononuclear phagocytes and intestinal/lung epithelial cells also synthesize the protein 1
• AAT functions by forming stable 1:1 equimolar complexes with serine proteinases at its active site (Met358-Ser359) 1

Clinical Manifestations

Pulmonary Disease

• Panacinar emphysema is the most prevalent clinical consequence and the major cause of disability and death in AATD 1
• Symptomatic obstructive lung disease typically presents between ages 32-41 in smokers 3
• Clinical features include dyspnea, chronic cough, and progressive airflow obstruction 4
• A protective serum threshold exists at 11 μM (approximately 35% of normal levels); levels below this significantly increase emphysema risk 1
• Cigarette smoking dramatically accelerates disease progression and reduces life expectancy from 69 years in non-smokers to 49 years in smokers 3

Liver Disease

• Liver disease is the second most frequent clinical complication, often presenting in infancy as cholestasis with conjugated hyperbilirubinemia, which typically resolves by adolescence 1
• Cirrhosis and hepatocellular carcinoma affect 30-40% of patients over age 50 and represent a significant cause of death in non-smoking PI*ZZ individuals 1
• The PI*Z mutation causes AAT protein polymerization and retention in hepatocyte endoplasmic reticulum, leading to hepatocyte injury 1
• Null alleles paradoxically protect the liver because no abnormal protein accumulates in hepatocytes 1

Other Manifestations

• Necrotizing panniculitis occurs rarely as a skin manifestation 4, 5
• Secondary vasculitis has been reported in rare cases 4

Epidemiology

• Prevalence in Western Europe and the USA is approximately 1 in 2,500 to 1 in 5,000 newborns, with higher rates in populations of Scandinavian descent 4
• AATD is one of the most common inherited conditions but remains significantly underrecognized and underdiagnosed 6

Pathophysiology

• The most common severe deficiency mutation (PI*Z) involves substitution of glutamic acid by lysine at codon 342 (p.E342K), causing profound conformational changes and protein polymerization 1, 7
• This mutation decreases extracellular hepatocyte AAT secretion, markedly reducing circulating and lung AAT levels 1
• Inadequate AAT levels fail to inhibit neutrophil elastase, allowing unopposed proteolytic destruction of lung elastin and other structural proteins 1, 2
• Environmental factors (cigarette smoking, dust exposure, respiratory infections) act as additional risk factors that accelerate disease progression 4, 5

Diagnostic Approach

• Initial screening involves measuring serum AAT levels; levels ≥23 mmol/L (≥1.2 g/L) exclude severe deficiency 3
• Levels <11 mmol/L (<0.57 g/L) indicate severe deficiency requiring confirmatory testing 3
• Definitive diagnosis requires isoelectric focusing for phenotyping or genetic testing (genotyping/sequencing) to identify specific alleles 1
• The 2025 Canadian Thoracic Society guidelines recommend using standard Human Genome Variation Society (HGVS) nomenclature alongside traditional PI typing during the transition period 1

Who Should Be Tested

• All individuals with early-onset emphysema (regardless of smoking history) 3
• All patients with COPD 3
• Adults with bronchiectasis of unknown etiology 3
• Patients with asthma whose spirometry fails to normalize with therapy 3
• Individuals with liver disease of unknown cause 3
• All first-degree relatives (parents, siblings, children) of individuals with confirmed AATD should undergo testing 1, 3

Treatment Considerations

• Augmentation therapy with intravenous AAT is FDA-approved for individuals with clinically evident emphysema due to severe hereditary AAT deficiency 8
• The effect of augmentation therapy on pulmonary exacerbations and emphysema progression has not been conclusively demonstrated in randomized controlled trials 8
• Smoking cessation is the single most critical intervention to slow disease progression 1, 3
• Standard COPD management includes bronchodilators, inhaled corticosteroids, pulmonary rehabilitation, and oxygen therapy when indicated 1
• Liver transplantation is the only treatment for severe liver disease 4, 5
• Lung transplantation may be considered for end-stage pulmonary disease 1

Prognosis

• Without treatment, AATD leads to premature disability and death, with 72% of deaths attributable to emphysema 3
• Early diagnosis enables implementation of preventive measures that can significantly improve outcomes 3, 6
• Life expectancy approaches normal in non-smoking individuals who avoid occupational exposures 3
• Prognosis is generally grave in patients who develop cirrhosis 4