Alpha 1 Antitrypsin Deficiency

Alpha 1 antitrypsin deficiency (AATD) is an autosomal codominant disorder of the SERPINA1 gene causing low serum alpha 1 antitrypsin, with early onset emphysema and liver disease.

Most severe genotype is PiZZ (Glu342Lys): 1 in 2000 to 5000 in people of European ancestry. Z protein polymerises in hepatocytes (liver injury) and leaves lungs unprotected from neutrophil elastase.

Other alleles: S (mild), null (no protein), M (normal). PiSZ has intermediate risk.

Lung: panacinar, lower lobe predominant emphysema in the 3rd to 5th decade (earlier with smoking), chronic bronchitis, bronchiectasis. Smoking dramatically accelerates decline.

Liver: neonatal cholestasis (10 to 15% of PiZZ infants), childhood cirrhosis, adult cirrhosis and hepatocellular carcinoma.

Other: panniculitis, granulomatosis with polyangiitis (c ANCA), vasculitis, fibromuscular dysplasia.

Underdiagnosed; average delay of 5 to 8 years.

• Dyspnoea, wheeze, cough, sputum, recurrent chest infection in a patient under 45 to 50 years or non smoker with COPD.
• Family history of COPD or liver disease; panniculitis (painful skin nodules).
• Hepatomegaly, jaundice, portal hypertension in liver disease; neonatal cholestasis.

• Serum alpha 1 antitrypsin level (below 11 µM or 57 mg/dL, 80 mg/dL by nephelometry) then phenotyping (isoelectric focusing) or genotyping (PCR for S and Z alleles; sequencing for rare variants).
• Screening recommended for all patients with COPD, asthma with fixed obstruction, cryptogenic liver disease, bronchiectasis, panniculitis, ANCA vasculitis, and first degree relatives.
• Pulmonary function tests (obstruction, reduced DLCO), CT chest (basal emphysema).
• Liver evaluation: liver enzymes, elastography, ultrasound, biopsy (PAS positive diastase resistant globules in periportal hepatocytes).

Lung disease

• Smoking cessation (essential), avoid occupational dusts, vaccinations (influenza, pneumococcal, COVID 19, RSV).
• Standard COPD therapy: long acting bronchodilators (tiotropium 18 micrograms, indacaterol, olodaterol), inhaled corticosteroid for exacerbators, rehabilitation, oxygen.
• Augmentation therapy with weekly IV pooled human alpha 1 proteinase inhibitor 60 mg/kg for adults with FEV1 30 to 65% predicted and PiZZ (slows CT lung density loss by about 34%; RAPID trial); stops in smokers; infusion reactions; also 120 mg/kg every 2 weeks being studied.
• Lung volume reduction surgery/endobronchial valves for selected; lung transplantation for end stage.

Liver disease

• Surveillance (annual ultrasound and elastography; alpha fetoprotein), vaccination (hepatitis A and B), alcohol avoidance, weight control.
• Management of cirrhosis complications; liver transplantation for decompensation or hepatocellular carcinoma (corrects deficiency).
• Emerging therapies: siRNA fazirsiran 200 mg SC every 3 months (reduces liver Z AAT), gene therapy.

Family

• Screen siblings and offspring; genetic counselling; PiMZ carriers have modest risk if smoke.
• Neonatal cholestasis: supportive therapy, fat soluble vitamins, ursodeoxycholic acid 15 to 20 mg/kg.
• Panniculitis: dapsone 100 mg daily, augmentation therapy.