Epidemiology

AAT deficiency is frequently under-recognised by clinicians. Direct population-based screening has estimated that prevalence of the PI*ZZ phenotype in the US is 1 in 4455 people.[13] The largest prospective screening study of newborns was performed in Sweden and reported a PI*Z phenotype prevalence of 1 in 1639.[14] One indirect genetic survey in the US determined the frequency of the Z allele and estimated that 59,047 individuals carry the genotype.[15]

Although the two greatest disease-associated alleles (S and Z) have been documented in every racial group, people with northern European ancestry carry the greatest frequencies of these alleles.[3][16] Z allele frequency is highest (20-40 per 1000) in northwestern Europe and decreases towards the east of the continent.[17] The prevalence of PI*ZZ phenotype in people with COPD is 1 in 408 in northern Europe and 1 in 944 in western Europe.[18]

A self-reported allelic frequency study utilising direct-to-consumer testing investigated the frequency of S and Z alleles in almost 200,000 people. The study demonstrated an allele frequency of 15.1% for PI*S and 6.5% for PI*Z. The PI*ZZ genotype was present in 0.63% of participants, half of whom had been diagnosed with AAT deficiency.[19]

There is limited evidence to suggest that symptomatic lung disease is more prevalent in PI*ZZ males than in PI*ZZ females. However, this result is likely to be confounded by other variables, such as smoking and occupational exposure.[20][21][22][23] The mean age at which smokers with AAT deficiency typically present with symptomatic pulmonary disease is 32 to 41 years.[24]

Liver involvement may be evident in neonates, and is the second most common cause of liver transplant in children.[14][25] Mortality is high in those with severe liver disease, and death may occur in the first decade of life.[26] Liver disease is also the most common manifestation in non-smoking older adults with AAT deficiency who do not manifest pulmonary symptoms.[27] Liver fibrosis has been detected in 20% to 36% of asymptomatic adults with PI*ZZ AAT deficiency, while the reported prevalence of cirrhosis ranges from 2% to 43%.[6][28][29]

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