Alpha-1-antitrypsin (AAT) deficiency is a hereditary metabolic disorder. It is the most common metabolic liver disease in children and results in the unopposed action of neutrophil elastase and subsequent severe basal emphysema and respiratory symptoms.
The classic presentation of the disease is with dyspnoea in the 4th to 5th decades of life. Two-thirds of individuals show clinical features but most carriers are asymptomatic.
AAT is a protein that prevents enzymes such as elastase from degrading normal host tissue. Over 90% of the AAT protein is produced in hepatocytes by codominant gene expression on chromosome 14. The AAT protein inhibits neutrophil elastase. In patients with severe deficiency, the neutrophil elastase acts unopposed resulting in damage to the lower respiratory tract. This damage is predominantly basal because of the gravitational distribution of pulmonary blood flow.
- cirrhosis with increased risk of hepatocellular carcinoma 19
- AAT deficiency carriers are at 70-100% increased risk of lung cancer 20
Radiograph and CT
- the emphysema pattern was traditionally thought to be pan-lobular although more recent studies have also suggested a variable pattern to the emphysema
- emphysema may develop in 75-85% of cases 12
- bronchiectasis: up to 40% 9
- frank bullae formation: non-specific feature 13
- bronchial wall thickening: non-specific feature 13
- hepatopulmonary syndrome
Reduced perfusion and ventilation in the lower zones on a V/Q study.
Hepatic manifestations of this disease are those of cirrhosis.
Treatment and prognosis
Emphysema and cirrhosis are usually considered the most common causes of death 8.
Survival is substantially worse in smokers, who have a 20-year decrease in longevity relative to non-smokers. According to one study, the overall median survival time was ~ 55 years 7.
AAT replacement therapy, most often by weekly intravenous infusions of AAT purified from human plasma, has been used in some situations to partially correct the biochemical defect 14-15.
While randomised, placebo-controlled clinical trials have confirmed a reduction in the decline in lung density in patients receiving augmentation therapy 14. It's efficacy in reducing mortality, however, is uncertain 16. Other management strategies include avoidance of smoking and other risk factors for cirrhosis.
The differential will depend on the organ involved:
- 1. Meyer CA, White CS, Sherman KE. Diseases of the hepatopulmonary axis. Radiographics. 20 (3): 687-98. Radiographics (full text) - Pubmed citation
- 2. Mcmahon MA, O'mahony MJ, O'neill SJ et-al. Alpha-1 antitrypsin deficiency and computed tomography findings. J Comput Assist Tomogr. 29 (4): 549-53. J Comput Assist Tomogr (link) - Pubmed citation
- 3. King MA, Stone JA, Diaz PT et-al. Alpha 1-antitrypsin deficiency: evaluation of bronchiectasis with CT. Radiology. 1996;199 (1): 137-41. Radiology (abstract) - Pubmed citation
- 4. Parr DG, Stoel BC, Stolk J et-al. Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment. Am. J. Respir. Crit. Care Med. 2004;170 (11): 1172-8. Am. J. Respir. Crit. Care Med. (full text) - doi:10.1164/rccm.200406-761OC - Pubmed citation
- 5. Shaker SB, Stavngaard T, Stolk J et-al. Alpha1-antitrypsin deficiency. 7: Computed tomographic imaging in alpha1-antitrypsin deficiency. Thorax. 2004;59 (11): 986-91. Thorax (full text) - doi:10.1136/thorax.2003.006569 - Free text at pubmed - Pubmed citation
- 6. Seersholm N, Kok-Jensen A. Clinical features and prognosis of life time non-smokers with severe alpha 1-antitrypsin deficiency. Thorax. 1998;53 (4): 265-8. Free text at pubmed - Pubmed citation
- 7. Seersholm N, Kok-Jensen A, Dirksen A. Survival of patients with severe alpha 1-antitrypsin deficiency with special reference to non-index cases. Thorax. 1994;49 (7): 695-8. Free text at pubmed - Pubmed citation
- 8. Tanash HA, Nilsson PM, Nilsson JA et-al. Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ). Thorax. 2008;63 (12): 1091-5. Thorax (full text) - doi:10.1136/thx.2008.095497 - Pubmed citation
- 9. King MA, Stone JA, Diaz PT et-al. Alpha 1-antitrypsin deficiency: evaluation of bronchiectasis with CT. Radiology. 1996;199 (1): 137-41. Radiology (abstract) - Pubmed citation
- 10. Shin MS, Ho KJ. Bronchiectasis in patients with alpha 1-antitrypsin deficiency. A rare occurrence?. Chest. 01;104 (5): 1384-6. Pubmed citation
- 11. Parr DG, Guest PG, Reynolds JH et-al. Prevalence and impact of bronchiectasis in alpha1-antitrypsin deficiency. Am. J. Respir. Crit. Care Med. 2007;176 (12): 1215-21. Am. J. Respir. Crit. Care Med. (full text) - doi:10.1164/rccm.200703-489OC - Pubmed citation
- 12. Ranes J, Stoller JK. A review of alpha-1 antitrypsin deficiency. Semin Respir Crit Care Med. 2005;26 (02): 154-66. doi:10.1055/s-2005-869536 - Pubmed citation
- 13. Guest PJ, Hansell DM. High resolution computed tomography (HRCT) in emphysema associated with alpha-1-antitrypsin deficiency. Clin Radiol. 1992;45 (4): 260-6. Pubmed citation
- 14. Miravitlles M. Alpha-1-antitrypsin and other proteinase inhibitors. Curr Opin Pharmacol. 2012;12 (3): 309-14. doi:10.1016/j.coph.2012.02.004 - Pubmed citation
- 15. Abboud RT, Ford GT, Chapman KR. Emphysema in alpha1-antitrypsin deficiency: does replacement therapy affect outcome?. Treat Respir Med. 2005;4 (1): 1-8. Pubmed citation
- 16. Russi EW. Alpha-1 antitrypsin: now available, but do we need it?. Swiss Med Wkly. 2008;138 (13-14): 191-6. doi:2008/13/smw-11991 - Pubmed citation
- 17. Tonelli AR, Brantly ML. Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies. Ther Adv Respir Dis. 2010;4 (5): 289-312. Ther Adv Respir Dis (abstract) - doi:10.1177/1753465810373911 - Pubmed citation
- 18. Kelly E, Greene CM, Carroll TP et-al. Alpha-1 antitrypsin deficiency. Respir Med. 2010;104 (6): 763-72. doi:10.1016/j.rmed.2010.01.016 - Pubmed citation
- 19. Hong WK, Jr. RCB, Hait WN et-al. Holland-Frei Cancer Medicine, 8/e. pmph usa. ISBN:1607950146. Read it at Google Books - Find it at Amazon
- 20. Yang P, Sun Z, Krowka MJ et-al. Alpha1-antitrypsin deficiency carriers, tobacco smoke, chronic obstructive pulmonary disease, and lung cancer risk. Arch. Intern. Med. 2008;168 (10): 1097-103. doi:10.1001/archinte.168.10.1097 - Free text at pubmed - Pubmed citation