Key Facts

Alpha-1 antitrypsin (AAT) deficiency is the most common genetic cause of emphysema and liver disease in adults and children. It results from mutations in the SERPINA1 gene, leading to reduced circulating levels of the serine protease inhibitor alpha-1 antitrypsin.

Epidemiology

• PiZZ homozygosity: ~1 in 2,000-5,000 in Northern Europeans
• PiMZ heterozygotes: ~1 in 25 (usually asymptomatic carriers)
• Often underdiagnosed; average delay to diagnosis ~5-7 years
• Accounts for ~1-2% of COPD cases

Aetiology

• Mutations in SERPINA1 gene (chromosome 14)
• Normal allele: Pi*M (produces normal AAT levels)
• Deficient alleles: PiZ (Glu342Lys — most common severe), PiS (Glu264Val — moderate)
• PiZZ: AAT levels ~10-15% of normal (high risk of lung and liver disease)
• PiSZ: intermediate risk
• PiMZ: usually normal AAT function, slight increased risk with smoking

Pathophysiology

• Lung: AAT normally inhibits neutrophil elastase in the lungs; deficiency allows unopposed elastase activity → alveolar wall destruction → panacinar emphysema (basal predominant)
• Smoking massively increases neutrophil recruitment and oxidative inactivation of remaining AAT
• Liver: misfolded Z-protein aggregates in hepatocyte endoplasmic reticulum → hepatocyte injury → cirrhosis (gain-of-function mechanism)

Pulmonary Presentation

• Early-onset COPD/emphysema (<45 years)
• Progressive breathlessness and wheeze
• Basal predominant emphysema (unlike smoking-related apical emphysema)
• Disproportionate breathlessness for smoking history
• Recurrent chest infections
• May present as "difficult asthma" in younger patients

Hepatic Presentation

• Neonatal cholestasis (10-15% of PiZZ neonates)
• Childhood cirrhosis
• Adult cirrhosis (15-20% of PiZZ adults)
• Hepatocellular carcinoma risk

Other Manifestations

• Panniculitis: painful subcutaneous nodules, typically on thighs/buttocks
• Granulomatosis with polyangiitis (c-ANCA positive vasculitis — rare association)

Red Flags

• COPD/emphysema onset <45 years
• Emphysema in a non-smoker or minimal smoker
• Basal predominant emphysema on CT
• Family history of early COPD or liver disease
• Unexplained liver cirrhosis
• Panniculitis

Bedside

• Spirometry: obstructive pattern (FEV₁/FVC <0.7); may show significant gas trapping
• Pulse oximetry: baseline and exercise desaturation

Bloods

• Serum alpha-1 antitrypsin level: <11 µmol/L (or <0.8 g/L) confirms deficiency
• AAT phenotyping (isoelectric focusing) or genotyping: identifies allele combination (PiMM, PiMZ, PiSZ, PiZZ)
• LFTs: elevated in liver involvement
• FBC: polycythaemia if chronic hypoxia

Imaging

• HRCT chest: panacinar emphysema with basal predominance; bronchiectasis may coexist
• CT liver/USS liver: cirrhosis assessment

Special Tests

• TLCO: reduced (emphysema)
• Full lung function tests: increased RV/TLC (gas trapping)
• Liver biopsy: PAS-positive, diastase-resistant globules in hepatocytes (accumulated Z-protein)
• Liver elastography (FibroScan): non-invasive cirrhosis assessment
• Family screening: offer genotyping to first-degree relatives

Non-pharmacological

• Smoking cessation: absolutely essential — most important single intervention
• Avoidance of occupational dust/fume exposure
• Annual influenza and pneumococcal vaccination
• Pulmonary rehabilitation
• Registration with national AAT deficiency registry (ADAPT in UK)

Pharmacological

• Standard COPD management per NICE NG115 (bronchodilators, ICS if eosinophilic)
• IV augmentation therapy: pooled human alpha-1 antitrypsin (Respreeza 60mg/kg IV weekly)
  • RAPID trial: slowed progression of CT-measured emphysema
  • NICE HST24: approved for non-smoking adults with FEV₁ 35-70% predicted and evidence of progressive disease
  • Specialist centre initiation only
• Hepatoprotection: avoid hepatotoxic drugs, alcohol abstinence
• Ursodeoxycholic acid for cholestatic liver disease (limited evidence)

Surgical/Interventional

• Lung transplantation: for end-stage emphysema; AAT deficiency is a common indication for lung transplant in younger patients
• Liver transplantation: for end-stage liver disease (curative — donor liver produces normal AAT)
• Lung volume reduction surgery: selected cases

Referral Criteria

• All patients with confirmed AAT deficiency should be referred to a specialist centre
• Hepatology referral for liver involvement
• Genetic counselling for family members
• Transplant assessment when appropriate

• PiZZ smokers: mean age of emphysema onset ~32-41 years; significantly reduced life expectancy
• PiZZ non-smokers: may not develop clinically significant emphysema until 50-60 years
• Smoking is the strongest modifiable risk factor — cessation improves survival dramatically
• FEV₁ decline ~70-130 mL/year in PiZZ smokers vs ~50 mL/year in non-smoking PiZZ
• Liver cirrhosis develops in 15-20% of PiZZ adults
• Liver transplant is curative for both liver and lung disease (normalises AAT levels)
• 5-year survival post-lung transplant: ~50-60%
• Augmentation therapy slows CT emphysema progression by ~30%

AAT Phenotypes and Clinical Risk

Key Distinguishing Features from Smoking COPD