Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency is a multisystem disorder primarily affecting the lungs and liver. The clinical expression is highly variable and depends on the underlying genotype as well as environmental factors, particularly cigarette smoke exposure. Pulmonary manifestations include emphysema, chronic obstructive pulmonary disease, and bronchiectasis, with lower-lobe-predominant emphysema being characteristic. Respiratory disease is strongly influenced by cigarette smoking, which accelerates disease onset and progression. Hepatic involvement ranges from neonatal cholestasis to chronic liver disease and cirrhosis in adulthood, with an increased risk of hepatocellular carcinoma.

Alpha-1 antitrypsin deficiency is one of the most common metabolic disorders in individuals of northern European descent, with an estimated prevalence of approximately 1 in 5,000–7,000 in North America and higher frequencies of 1 in 1,500–3,000 in Scandinavian populations; it also occurs worldwide at lower frequencies across other populations.

Alpha-1 antitrypsin deficiency is caused by biallelic germline pathogenic variants in SERPINA1 (14q32.13). SERPINA1 encodes alpha-1 antitrypsin, a serine protease inhibitor that protects lung tissue from proteolytic damage by neutrophil elastase.

Disease arises through two distinct molecular mechanisms: a loss-of-function effect in the lung, due to reduced inhibition of neutrophil elastase leading to progressive alveolar elastin degradation and emphysema, and a gain-of-function effect in the liver, caused by intracellular accumulation and polymerisation of misfolded protein, resulting in hepatocellular injury, fibrosis, and an increased risk of hepatocellular carcinoma. The most common deficiency alleles are the Z (Pi*Z) and S (Pi*S) variants. In addition, null alleles leading to complete loss of protein function have been described, as well as rarer variants (e.g., F and I alleles), which may result in functionally impaired protein or mild deficiency.

Alpha-1 antitrypsin deficiency is inherited in an autosomal codominant manner, with both SERPINA1 alleles contributing to circulating alpha-1 antitrypsin levels. Severe disease typically occurs in individuals with biallelic pathogenic variants, consistent with a recessive pattern, while heterozygous carriers may have reduced protein levels and an increased risk of disease depending on the specific genotype and environmental factors.

The diagnosis of alpha-1 antitrypsin deficiency is based on demonstration of reduced serum alpha-1 antitrypsin levels together with confirmatory testing by genotyping or protease inhibitor (PI) typing.

Main differential diagnoses include:

• : bronchiectasis and liver involvement (cholestasis in infancy, later liver disease) with elevated sweat chloride and pancreatic insufficiency.
• Wilson disease: chronic liver disease often presenting in teen years with accompanying neurologic/psychiatric symptoms, Kayser-Fleischer rings, decreased serum ceruloplasmin and increased urinary copper excretion.
• Progressive familial intrahepatic cholestasis (PFIC): prominent cholestasis with infancy presentation, often low/normal gamma-glutamyl transferase and characteristic liver biopsy appearance.

• Establishing the diagnosis: molecular genetic testing confirms the diagnosis of alpha-1 antitrypsin deficiency and provides the basis for accurate classification and genetic counselling.
• Clinical management: identification of the underlying SERPINA1 genotype can inform clinical follow-up and support management, including monitoring for pulmonary and hepatic complications, with care guided by the treating physicians in consultation with the affected individual.
• Therapeutic implications: identification of severe deficiency genotypes may inform eligibility for augmentation therapy in selected individuals with pulmonary disease.
• Family member testing: identification of the familial pathogenic variant(s) enables testing of at-risk relatives and supports clarification of carrier status and informed reproductive decision-making.

• Stoller JK, Hupertz V, Aboussouan LS. Alpha-1 antitrypsin deficiency. 2006 Oct 27 [updated 2023 Jun 1].  In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301692.
• Fromme M, Klebingat F, Ellis P, Strnad P. Alpha-1 antitrypsin deficiency-associated liver disease: from understudied disorder to the poster child of genetic medicine. Hepatol Commun. 2025;9(5). PMID: .