Alpha-1 Antitrypsin Deficiency

I. Overview

Alpha-1 Antitrypsin Deficiency (AATD) is the most common genetic liver disease in infants and children. It should be considered in:

• Infants with cholestasis
• Children and adults with chronic hepatitis or cirrhosis of unknown etiology

Epidemiology: AATD affects approximately 1 in 12,000 live births, and is associated with chronic liver disease in 10–15% of affected children and 10% of affected adults. Alpha-1 antitrypsin (A1AT) is an acute phase protein and a protease inhibitor that regulates neutrophil elastase and proteinase 3, protecting tissues from enzymatic damage.

II. Genetics and Function

• Gene: SERPINA1 on chromosome 14q31–32.2
• Production: Synthesized in the endoplasmic reticulum of hepatocytes
• Function: Inhibits neutrophil proteases (elastase and proteinase 3)

Inheritance

AATD is inherited in an autosomal codominant pattern. Each allele contributes to the phenotype.

Genotypes and Clinical Impact

III. Pathophysiology

A. Liver: Gain-of-Function Toxicity

• Misfolded AAT accumulates in the endoplasmic reticulum
• Triggers inflammation, fibrosis, and cirrhosis
• Defective autophagy leads to hepatocyte injury

     Classic Liver Biopsy Findings

• PAS-positive, diastase-resistant red hyaline globules in periportal hepatocytes (zone 1)
• Globules often have a clear halo
• May be difficult to detect in early infancy, mimicking idiopathic neonatal hepatitis

B. Lung: Loss-of-Function Damage

• Low AAT fails to inhibit neutrophil elastase and proteinase 3
• Results in parenchymal destruction and early-onset emphysema

C. Skin: Panniculitis

• Tender, erythematous nodules on torso or extremities
• Often ulcerated and draining serosanguinous fluid
• Trauma often precedes onset

IV. Clinical Presentation

A. In Infants and Children

• Small for gestational age (SGA)
  
• Neonatal cholestasis with persistent direct hyperbilirubinemia
• Elevated liver enzymes: AST, ALT, ALP, GGT
• Progression to coagulopathy, poor growth, portal hypertension, ascites
• Fibrosis and cirrhosis in 30–40% of affected individuals

B. In Adults

• Second peak of liver disease in the 50s
• Emphysema in 60–70% of PiZZ adults
• Liver and lung disease may occur independently

V. Diagnosis

A. Laboratory

• Low serum AAT levels (<50–60 mg/dL in PiZZ)
• Phenotyping and genotyping essential
• Always perform AAT level and phenotype before liver biopsy

B. Imaging and Noninvasive Tools

• Fibroscan for liver stiffness and steatosis (CAP)
• APRI and FIB-4 indices: limited sensitivity and specificity

VI. Management

A. Liver Disease

• Fat-soluble vitamin supplementation (A, D, E, K)
• Medium-chain triglyceride (MCT) formula
• Ursodeoxycholic acid (may improve bile flow)
• Liver transplantation for end-stage disease

B. Lung Disease

• Avoid cigarette smoke and pollutants
• Aggressive infection management
• Augmentation therapy with purified human AAT for select patients

C. Emerging Therapies

• Carbamazepine to promote autophagy (clinical trials underway)
• RNA-based therapies in development

D. Screening

• Mandatory for siblings; recommended for all relatives
• Newborn screening not yet implemented

VII. Conclusion

Alpha-1 Antitrypsin Deficiency is a multisystem disorder with distinct pathophysiological mechanisms in the liver and lungs. Early recognition, supportive care, and emerging therapies offer hope for improved outcomes. Continued research into genetic modifiers, noninvasive diagnostics, and targeted treatments will be essential to advancing care for affected children and adults.

Alpha-1 Antitrypsin Deficiency (A1ATD) - REVIEW