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Guest Researcher Explores Epidemiology of AAT Deficiency

By Eddy Ball
January 2007

Since his own diagnosis with the genetic disease alpha-1 antitrypsin (AAT) deficiency in 1997, NIEHS Guest Researcher Frederick de Serres, Ph.D., has published a series of studies examining the prevalence of the disease and its link to respiratory and other conditions. His studies have developed a central theme articulated in the title of his 2003 commentary in Environmental Health Perspectives: "Alpha-1 antitrypsin (AAT) deficiency is not a rare disease but a disease that is rarely diagnosed."

de Serres' work has challenged the medical community to revise its notions about how widespread AAT deficiency is and how much of the world's population is actually affected. Once considered a rare disease of white Europeans, where it is the most prevalent, AAT, according to de Serres' research, "may actually be one of the most common single-locus genetic diseases in the world."

Based on meta-analyses of genetic epidemiological data from around the world, de Serres has estimated incidence of the deficiency among 4.7 billion people in the 69 countries he has studied. He concludes that there are at least 286 million carriers of the two most prevalent phenotypes (PI MS and PI MZ) and an additional 3.8 million with deficiency allele combinations (PI SS, PI SZ and PI ZZ), indicating that approximately one person in every 25 is either a carrier or a homozygote/heterozygote for these two deficiency alleles. de Serres estimates that in the United States there may be as many as one carrier or deficiency allele combination phenotype for every 11.3 individuals. The rate varies from country to country and is as high as one in 4.5 among people from the Iberian peninsula.

AAT is produced mainly in the liver by hepatocytes and, under normal conditions, is continuously released into the blood stream. There it acts as a serine protease inhibitor to give the lungs lifelong protection from the proteolytic damage of neutrophil elastase (NE), which causes inflammation in tissues. In people who have AAT deficiency, the protease inhibitor is not readily released into the blood stream. The resulting deficiency can reduce the lungs' defense against NE and lead to early onset of panlobular pulmonary emphysema, especially in smokers.

In addition, AAT can aggregate in the liver, leading to liver disease. AAT deficiency has been linked to neonatal cholestasis that may progress to infant and juvenile cirrhosis. In adults, AAT accumulation in hepatocytes can result in slowly progressing liver disease. In a recent study of the causes of death in persons with AAT deficiency, researchers concluded that severe airflow obstruction and liver disease account for excess mortality in affected individuals.

In his collaborative research with Spanish physicians, de Serres has explored the association between AAT deficiency and patients with chronic obstructive pulmonary disease and estimated the distribution of the genetic mutation worldwide. He and his colleagues have examined Caucasian populations in Europe, North America, Australia and New Zealand, where AAT deficiency is most common. In earlier studies, the researchers estimated rates in Africa and the Middle East. Their most recent meta-analysis, published in the December 2006 issue of European Respiratory Journal, evaluated data from 20 Asian countries and found a significant incidence of AAT deficiency among people there.


de Serres FJ, Blanco I, FernÁndez-Bustillo E. 2006. Estimated numbers and prevalence of PI*S and PI*Z deficiency alleles of {alpha}1-antitrypsin deficiency in Asia. Eur Respir J 28(6):1091-1099.

de Serres FJ, Blanco I, FernÁndez-Bustillo E. 2006. Estimating the risk for alpha-1 antitrypsin deficiency among COPD patients: evidence supporting targeted screening. COPD: Journal of Chronic Obstructive Pulmonary Disease 3:133-139. (Not PubMed indexed; contact the author at

Blanco I, de Serres FJ, FernÁndez-Bustillo E, Lara B, Miravitlles M. 2006. Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries. Eur Respir J 27(1):77-84.

de Serres FJ. 2003. Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed. Environ Health Perspect 111(16):1851-1854.

AAT/World Trade Center Link?

Recent research suggests that the AAT mutation may help explain World Trade Center cough and the chronic diseases that a number of 9/11 first responders developed after the attack. Historically, a significant portion of members of the New York Police and Fire Departments have been members of ethnic groups, such as Irish and Italians, who have a high incidence of AAT deficiency.

In a presentation at Chest 2006, the annual meeting of the American College of Chest Physicians, David Prezant, M.D., of New York's Montefiore Medical Center reported preliminary findings that firefighters with an AAT deficiency had significantly faster declines in lung function than those with normal AAT levels. Prezant and his colleagues have been studying 12,000 of the New York firefighters who were at Ground Zero in the aftermath of the attack and for whom lung function tests both before and after are available.

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