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alpha-1 antitrypsin deficiency

There are at least 50 inherited variants of alpha-1 antitrypsin. Severe inherited deficiency seen most often as the PiZZ & SZ phenotypes is associated with liver disease, especially in childhood [neonatal hepatitis syndrome & infantile cirrhosis] & with chronic lung disease in adults [emphysema & bronchitis]. Epidemiology: 1) 1/500 births in Sweden 2) prevalence of PiZZ is US is 1:1670 to 1:3000 Pathology: - deficiency in SERPINA1 results in excessive neutrophil elastase resulting in destruction of elastin & diminished recoil in lung - the effect is panacinar pulmonary emphysema - some patients also develop liver disease &/or skin pathology [3,8] - intrahepatic accumulation of variant protein inclusions may lead to cirrhosis [3] Genetics: - autosomal co-dominant - associated with defects in SERPINA1 - phenotyping: (Pi typing, Pi stands for Protease inhibitor) a) PiMM (normal) b) PiMZ (heterozygote) c) PiZZ (homozygote) 1] accumulation of alpha-1 antitrypsin in rough endoplasmic reticulum & in PAS+ globules 2] > 90% show evidence of lung disease d) Pi[null] - make no alpha-1 antitrypsin at all Clinical manifestations: 1) signs & symptoms generally appear during the 3rd or 4th decade of life, but may appear in early childhood 2) early & severe pulmonary emphysema 3) basilar lung predominance of emphysema [3] 4) nephrotic syndrome 5) cholestatic hepatitis in the newborn 6) cirrhosis (3%) 7) necrotizing panniculitis [3] 8) smoking hastens onset of emphysema Laboratory: 1) serum protein electrophoresis - alpha-1 antitrypsin normally accounts for 70% of alpha-1 band 2) serum alpha-1 antitrypsin deficiency 3) alpha-1 antitrypsin genotyping - SERPINA1 gene mutation 4) serum AST & serum ALT modestly increased 5) serum alkaline phosphatase normal to modestly increased 6) serum bilirubin normal 7) see ARUP consult [7] Radiology: basal (lower lobe) emphysema on chest X-ray Differential diagnosis: 1) cystic fibrosis 2) ciliary dyskinesia 3) bronchiectasis Complications: 1) cirrhosis 2) hepatocellular carcinoma Management: 1) stop smoking 2) recombinant alpha-1 antitrypsin a) aerosols helpful for pulmonary symptoms, but not useful for liver disease b) IV administration may be appropriate for patients with homozygous alpha-1 antitrypsin deficiency 3) liver transplantation is curative 4) kidney transplantation

Interactions

disease interactions

Related

alpha-1-antitrypsin; alpha-1 protease inhibitor; alpha-1-antiproteinase; Serpin A1 (SERPINA1, AAT, PI, PRO0684, PRO2209) SERPINA1 gene mutation; alpha-1 antitrypsin gene mutation

General

cirrhosis genetic disease of the liver genetic disease of the lung genetic syndrome (multisystem disorder)

Database Correlations

OMIM 613490

References

  1. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 1452
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 740
  3. Medical Knowledge Self Assessment Program (MKSAP) 14, 15, 16, 18, 19. American College of Physicians, Philadelphia 2006, 2009, 2012, 2018, 2021.
  4. MedlinePLus: Alpha-1 Antitrypsin Deficiency https://medlineplus.gov/alpha1antitrypsindeficiency.html
  5. Genetics Home Reference: Alpha-1 antitrypsin deficiency https://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency
  6. OMIM :accession 613490
  7. ARUP Consult: Alpha-1-Antitrypsin Deficiency - AAT The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/alpha-1-antitrypsin-deficiency
  8. Silverman EK, Sandhaus RA. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med. 2009 Jun 25;360(26):2749-57 PMID: 19553648
  9. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003 Oct 1;168(7):818-900. PMID: 14522813