Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

Abstract

ObjectiveAlpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the ‘Pi*Z’ variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous ‘Pi*Z’ carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common ‘Pi*S’ variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.DesignBaseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.ResultsAmong UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8–53.7)) and primary liver cancer (aOR=44.5 (10.8–183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2–2.2)) and cholelithiasis (aOR=1.3 (1.2–1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1–8.2)) and primary liver cancer (aOR=6.6 (1.6–26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.ConclusionOur study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Shear Wave Elastography and Shear Wave Dispersion Imaging in the Assessment of Liver Disease in Alpha1-Antitrypsin Deficiency

“…As recently reported by Fromme et al, the PiZZ genotype harbors the highest pre disposition for liver fibrosis/cirrhosis and liver cancer in AATD [27]. Hence, we speculate that a higher degree of liver injury could be detected noninvasively among PiZZ individ uals in our cohort.…”

Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder

“…After excluding individuals with pathological alcohol consumption and viral J o u r n a l P r e -p r o o f 8 hepatitis, the cohort was left with >17,000 Pi*MZ, >800 Pi*SZ, and ~140 Pi*ZZ individuals. 18 Although the lack of a detailed assessment of liver fibrosis is a limitation of this cohort, the population-based recruitment of participants independently of their AATD genotype constitutes a major advantage, given that most individuals with AATD remain undiagnosed their whole life. 1 Second, the EASL AATD consortium recruited >400 Pi*MZ individuals, ~240 Pi*SZ individuals, and nearly 600 Pi*ZZ study participants from fourteen European countries, the US, and Australia.…”

“…It affects 1:500 J o u r n a l P r e -p r o o f 5 Caucasians, displays intermediate AAT serum concentrations, and moderately increases susceptibility to lung disease (Table 2, Figure 2). 17,18 The Pi*SS genotype (i.e., homozygous Pi*S allele) is approximately as common as Pi*SZ but does not seem to constitute a clinically relevant risk factor for the development of liver disease. 18…”

“…17,18 The Pi*SS genotype (i.e., homozygous Pi*S allele) is approximately as common as Pi*SZ but does not seem to constitute a clinically relevant risk factor for the development of liver disease. 18…”

Alpha-1-Antitrypsinmangel: Ursache und Kofaktor für Lebererkrankungen

“…Abhängig vom Genotyp und weiteren Risikofaktoren (insbesondere Rauchen) wird eine pneumologische Anbindung empfohlen [5,6]. [15]. Sowohl bei Pi*SZ-als auch Pi*ZZ-Betroffenen gelten Übergewicht, Alter ≥ 50 Jahre sowie das männliche Geschlecht als etablierte Risikofaktoren [8,13].…”