Alpha-1 Antitrypsin (AAT) Deficiency

Summary

Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder characterized by reduced levels or dysfunction of the protease inhibitor AAT, leading to unopposed neutrophil elastase activity. This results in early-onset emphysema (particularly panacinar type affecting lower lobes) and liver disease (cirrhosis, hepatocellular carcinoma). The condition follows an autosomal codominant inheritance pattern, with the most severe form (PiZZ genotype) causing 10-15% of normal AAT levels.

Patients typically present with COPD symptoms at a young age (30-40 years), often with minimal smoking history. Liver manifestations include neonatal jaundice, hepatitis, and cirrhosis. Diagnosis is confirmed by measuring serum AAT levels followed by genotyping. Management includes AAT replacement therapy for lung disease, standard COPD treatment, and liver transplantation for end-stage liver disease.

Overview

• Definition: Genetic disorder causing deficiency or dysfunction of alpha-1 antitrypsin → uninhibited neutrophil elastase → tissue destruction
• Prevalence: Most common genetic cause of liver disease in children and emphysema in adults
  • Affects 1 in 1,600-2,000 live births
  • Highest incidence in individuals of European descent (especially Northern Europeans)
  • Often underdiagnosed - many cases remain undetected
• Key concept: AAT is a serine protease inhibitor (SERPIN) produced mainly by hepatocytes
  • Normal function: Protects lung tissue from neutrophil elastase
  • In deficiency: Unopposed elastase activity → alveolar destruction

Genetics and Pathophysiology

• Inheritance: Autosomal codominant ➜ مهم جداً
  • SERPINA1 gene on chromosome 14
  • Over 150 known alleles identified
• Common alleles and their significance:
  • M allele: Normal (wild type)
  • S allele: Moderate decrease in AAT production
  • Z allele: Most important pathologic allele → severe decrease + polymerization in hepatocytes

Clinical Features

Pulmonary Manifestations (Most Common Presentation)

• Age of onset:
  • Smokers: 30s (accelerated disease) ➜ مهم
  • Non-smokers: 40-50s
  • Compare to typical COPD: 60-70s
• Symptoms:
  • Progressive dyspnea on exertion
  • Chronic cough with mucoid sputum
  • Wheezing
  • Recurrent respiratory infections
  • Spontaneous pneumothorax (especially in young adults)
• Physical examination:
  • Decreased breath sounds (especially at bases)
  • Hyperresonance to percussion
  • Barrel chest
  • Prolonged expiration

Hepatic Manifestations

• In neonates/children:
  • Prolonged neonatal jaundice (cholestatic pattern)
  • Hepatomegaly
  • Failure to thrive
  • Bleeding (vitamin K deficiency)
• In adults:
  • Often asymptomatic until advanced
  • Elevated liver enzymes (mild)
  • Cirrhosis
  • Hepatocellular carcinoma

Other Manifestations

• Necrotizing panniculitis: Painful red nodules on trunk/thighs
• Vasculitis: Granulomatosis with polyangiitis (rare)

Diagnosis

When to Suspect AAT Deficiency

• COPD at age < 45 years ➜ أهم نقطة
• COPD with minimal/no smoking history
• Basilar-predominant emphysema on imaging
• Family history of emphysema or liver disease
• Unexplained liver disease
• Necrotizing panniculitis

Diagnostic Tests

• Step 1: Serum AAT level ➜ Initial screening test
  • Normal: 100-300 mg/dL (20-60 μmol/L)
  • Deficiency: < 100 mg/dL (< 20 μmol/L)
  • Severe deficiency: < 60 mg/dL (< 11 μmol/L)
  • Note: AAT is an acute phase reactant → may be falsely elevated during inflammation
• Step 2: Phenotyping or Genotyping ➜ Confirmatory test
  • Identifies specific alleles (MM, MZ, ZZ, etc.)
  • Required for definitive diagnosis

Imaging Findings

• Chest X-ray:
  • Hyperinflation
  • Flattened diaphragm
  • Basilar hyperlucency (vs apical in smoking-related emphysema)
• Chest CT:
  • Panacinar emphysema with lower lobe predominance ➜ مهم جداً
  • Bronchiectasis possible
  • Bullae formation

Other Tests

• Pulmonary Function Tests:
  • Obstructive pattern (↓ FEV1/FVC ratio < 70%)
  • ↑ Residual volume
  • ↓ DLCO
• Liver Tests:
  • Mild ↑ AST, ALT
  • ↑ PT if advanced liver disease
• Liver Biopsy (if indicated):
  • PAS-positive, diastase-resistant globules in periportal hepatocytes ➜ Pathognomonic finding

Treatment

General Measures

• Smoking cessation: Most important intervention
• Avoid environmental irritants (dust, fumes)
• Vaccinations:
  • Annual influenza vaccine
  • Pneumococcal vaccine
  • Hepatitis A & B vaccines
• Minimize alcohol consumption
• Avoid hepatotoxic medications

Specific Therapy for Lung Disease

• AAT Replacement (Augmentation) Therapy:
  • Goal: Maintain AAT levels > 11 μmol/L
  • Slows decline in FEV1 but doesn't reverse damage
  • Note: Expensive, lifelong therapy
• Standard COPD management:
  • Bronchodilators (LABA, LAMA)
  • Inhaled corticosteroids if indicated
  • Pulmonary rehabilitation
  • Oxygen therapy if hypoxemic
• Lung transplantation:
  • For end-stage lung disease
  • Good outcomes reported

Treatment for Liver Disease

• Monitoring:
  • Regular liver function tests
  • Ultrasound surveillance for HCC (every 6 months if cirrhotic)
  • Alpha-fetoprotein levels
• Liver transplantation:
  • Definitive treatment for liver disease
  • Corrects AAT deficiency (liver produces normal AAT)
  • Indications: Decompensated cirrhosis, HCC

Complications

• Pulmonary complications:
  • Respiratory failure
  • Pneumothorax
  • Pulmonary hypertension
  • Cor pulmonale
• Hepatic complications:
  • Cirrhosis (10-15% of PiZZ adults)
  • Hepatocellular carcinoma ➜ Regular surveillance needed
  • Portal hypertension with varices

High-Yield Points for Exams

• أفكار الأسئلة الشائعة:
  • مريض شاب (35-40 سنة) + ضيق نفس + تاريخ تدخين قليل أو معدوم = AAT deficiency
  • COPD + تاريخ عائلي لأمراض الكبد = AAT deficiency
  • انتفاخ رئوي في الفصوص السفلية = AAT deficiency (عكس التدخين في الفصوص العلوية)
  • يرقان حديثي الولادة طويل الأمد = فكر في AAT deficiency
  • زراعة الكبد تصحح نقص AAT لكن لا تعكس ضرر الرئة