Synopsis
Identify alpha-1 antitrypsin deficiency across liver and lung phenotypes, confirm genotype and prevent avoidable cofactors while staging complications.
- Alpha-1 antitrypsin is produced mainly by hepatocytes and protects lung connective tissue from neutrophil elastase.
- The common Z variant misfolds and polymerises within hepatocytes, causing toxic gain-of-function liver injury while low circulating protein creates loss-of-function lung risk.
- Severe Pi*ZZ disease can present as neonatal cholestasis, childhood fibrosis or adult cirrhosis and hepatocellular carcinoma, with widely variable penetrance.
- Pi*MZ and Pi*SZ states carry lower average liver risk but can modify fibrosis when alcohol, obesity, diabetes or another liver disease is present.
- Serum A1AT is an acute-phase reactant; inflammation can conceal deficiency and a concentration alone cannot define genotype or hepatic risk.
- Confirm a low or suspicious level with phenotype or SERPINA1 genotyping through the current NHS genomic pathway.
- Liver tests may be normal despite advanced fibrosis, so elastography, platelet count and imaging matter more than reassurance from ALT alone.
- Smoking avoidance is the most important preventable pulmonary intervention, and occupational dust or fume exposure should also be reduced.
- Intravenous A1AT augmentation does not remove hepatic polymers and NICE does not recommend replacement therapy for COPD in the UK.
- There is no established routine liver-specific medicine; treat cofactors and cirrhosis, coordinate respiratory care and refer advanced disease for transplantation.
Key red flags
Prolonged conjugated jaundice, hepatomegaly, pale stool, poor growth or coagulopathy occurs in infancy after urgent obstructive and metabolic causes are considered.
Ascites, variceal bleeding, jaundice, sarcopenia, encephalopathy or kidney dysfunction requires urgent cirrhosis care and transplant review.
Investigation priorities
Screen for reduced circulating protein in unexplained liver or early lung disease.
Management branches
A1AT is low or clinical suspicion remains despite a borderline concentration.
- Check CRP, liver synthesis and protein-loss context and repeat a potentially inflammation-confounded concentration when appropriate.
- Request phenotype or common SERPINA1 genotyping under the current NHS pathway and seek broader analysis if results do not explain the level or phenotype.
- Assess both organs with liver fibrosis testing and respiratory history, spirometry and smoking exposure instead of referring to only one specialty.
- Explain codominant inheritance and variable penetrance and offer proportionate family testing with reproductive and insurance questions directed to genetics.
Key medicines
Licensed smoking-cessation pharmacotherapySelect nicotine replacement, varenicline, cytisinicline or another current NICE-supported option at its BNF regimen according to dependence, contraindications, pregnancy and local service availability, combined with behavioural support.Match adverse effects, renal function, mental-health history and interactions to the chosen medicine. Pharmacotherapy does not replace continued follow-up or occupational exposure reduction.
Inhaled COPD therapyUse short- and long-acting bronchodilator or inhaled corticosteroid combinations only according to the current NICE NG115 symptom, exacerbation and spirometry pathway, with inhaler teaching and review.Check technique, adherence, tachycardia, tremor, urinary retention, glaucoma and pneumonia or oral candidiasis risk by class. Do not prescribe inhaled corticosteroid solely because the genotype is Pi*ZZ.