Alpha-1 Antitrypsin (AAT) Deficiency — Complete MD Exam Answer (15 Marks)

1. Introduction & Historical Background

2. Normal Function of AAT

• Cathepsin G
• Proteinase 3
• Trypsin, chymotrypsin, thrombin

3. Genetics and Molecular Basis

Pi Allele Nomenclature

Genotypes and Serum AAT Levels

4. Pathogenesis

4a. Lung Disease — Protease–Antiprotease Imbalance

1. In PiZZ individuals, circulating AAT is severely reduced (<15% of normal)
2. Neutrophils recruited to the lung release elastase unchecked
3. Elastase destroys alveolar walls → panacinar (panlobular) emphysema, predominantly involving the lower lobes (unlike smoking-related centrilobular emphysema which is upper lobe)
4. Tobacco smoking greatly worsens the process: cigarette smoke oxidizes the active methionine residue on AAT, inactivating it — further tipping the protease–antiprotease balance
5. This explains the gene–environment interaction: ZZ smokers develop severe emphysema by the 4th decade; ZZ non-smokers may not develop symptoms until the 5th–6th decade

4b. Liver Disease — Gain-of-Function Toxic Accumulation

• The Z-AAT protein polymerizes and accumulates within hepatocyte endoplasmic reticulum (ER) rather than being secreted
• This intracellular accumulation triggers ER stress, apoptosis, and chronic inflammation → hepatic fibrosis and cirrhosis
• This is a gain-of-function mechanism (toxic protein aggregation), distinct from the loss-of-function lung mechanism
• Null alleles do NOT cause liver disease (no protein to accumulate) — confirming this mechanism

5. Clinical Features

5a. Pulmonary Manifestations

• Chronic obstructive pulmonary disease (COPD): emphysema most common
• Also: chronic bronchitis, bronchiectasis
• Panacinar (panlobular) emphysema — predominantly lower lobe distribution
• Onset: smokers in their 30s–40s; non-smokers in 40s–50s
• Progressive dyspnoea, reduced exercise tolerance, barrel chest, prolonged expiration
• Hyperinflation on CXR; reduced DLCO; obstructive spirometry

5b. Hepatic Manifestations

5c. Other Manifestations

• Panniculitis: necrotizing lobular panniculitis — tender erythematous nodules and plaques, especially on trunk/thighs; may ulcerate and drain oily fluid; associated with severe AATD
• Vasculitis: c-ANCA-positive vasculitis (e.g., granulomatosis with polyangiitis)
• Wegener-like syndromes reported

6. Diagnosis

Step 1: Serum AAT Level

• First-line test: quantitative serum AAT level by nephelometry or immunoturbidimetry
• Low levels in carriers; very low in ZZ homozygotes
• Note: AAT is an acute-phase reactant — may be falsely normal during infection, pregnancy, OCP use; serial measurements or protein phenotyping needed

Step 2: Pi Phenotyping (IEF)

• Gold standard: Isoelectric focusing (IEF) of serum proteins
• Identifies variant isoforms by migration pattern
• Can detect all alleles including rare variants
• Reports phenotype as PiZZ, PiMZ, PiSZ, etc.

Step 3: DNA Genotyping

• Targets S and Z mutations specifically
• Advantage: can test dried blood spots, family members, prenatal diagnosis
• Disadvantage: misses rare/null alleles
• Sequencing of entire SERPINA1 gene if rare alleles suspected

Step 4: Additional Investigations

• Spirometry: obstructive pattern (↓FEV₁, ↓FEV₁/FVC, ↑TLC, ↑RV)
• DLCO (transfer factor): reduced — reflects loss of alveolar surface area
• Chest CT: panacinar emphysema predominantly lower lobe; hyperinflation
• Liver function tests, liver biopsy (PAS-positive, diastase-resistant globules in hepatocytes — hallmark of Z-AAT accumulation)
• Liver biopsy histology: PAS-positive intracytoplasmic inclusions in periportal hepatocytes

7. Management

7a. General Measures

• Smoking cessation — single most important intervention; drastically slows lung disease progression
• Alcohol avoidance — minimizes hepatic progression
• Vaccination: influenza and pneumococcal vaccines
• Genetic counselling for family members

7b. Lung Disease Management

• Standard COPD management: bronchodilators (SABA, LABA, LAMA), inhaled corticosteroids
• Pulmonary rehabilitation: improves exercise capacity and quality of life
• Supplemental oxygen for hypoxaemia

7c. AAT Augmentation (Replacement) Therapy

• Indication: PiZZ (or equivalent) patients with established lung disease (not for heterozygotes)
• Agent: pooled human plasma-derived purified AAT concentrate (e.g., Prolastin, Zemaira, Aralast)
• Dose: 60 mg/kg IV weekly infusion
• Mechanism: raises serum and lung AAT levels above the "protective threshold" (~11 µmol/L)
• Evidence: slows CT-measured lung density decline; reduces exacerbations
• Not indicated for liver disease (will not reduce intrahepatic protein accumulation)
• Not recommended for heterozygous patients

7d. Surgical Options

• Lung volume reduction surgery: selected patients with heterogeneous emphysema, upper lobe predominance (less common in AATD)
• Lung transplantation: for end-stage lung disease; ~25% of lung transplants are for COPD/emphysema
• Liver transplantation: for end-stage liver disease; restores normal AAT phenotype (donor liver)

7e. Novel/Future Therapies

• Gene therapy: SERPINA1 gene delivery (under investigation)
• Small molecule polymer blockers: prevent Z-AAT polymerization in hepatocytes
• RNA interference (siRNA): reduce Z-AAT production in liver — clinical trials ongoing
• Liver-directed AAT gene therapy: promising for simultaneous treatment of liver and lung disease

8. Prognosis and Monitoring

• Annual spirometry and 6-minute walk test
• CT lung density measurement every 2–3 years in augmentation therapy candidates
• Regular LFTs and hepatic ultrasound

9. Screening and Genetic Counselling

• Targeted screening of first-degree relatives of known AATD patients (autosomal recessive; 25% risk in siblings of ZZ proband)
• Population screening remains controversial; however, international guidelines (ATS/ERS) recommend testing all patients with COPD, asthma with irreversible airflow obstruction, cryptogenic liver cirrhosis, and unexplained bronchiectasis
• Carrier frequency (PiMZ): approximately 1 in 50 in the general population; PiMS ~1 in 20

10. Summary Table