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Liver disease in adults with ?1-antitrypsin deficiency.

ABSTRACT: The natural history of adult liver disease due to ?1-antitrypsin deficiency (A1AD) remains poorly understood.We investigated whether heterozygosity for the Z-allele predisposes for the development of clinically significant portal hypertension (CSPH). Moreover, we aimed to non-invasively assess the prevalence of liver fibrosis and hepatic steatosis in adults with A1AD treated by pulmonologists.SERPINA1 rs28929474 (Z-allele) was genotyped in 315 patients with CSPH (hepatic venous pressure gradient ?10?mmHg; cases) and 248 liver donors (controls). In addition, 31 adults with A1AD (Pi*ZZ/Pi*SZ) and 11 first-degree relatives (Pi*MZ/Pi*MS) underwent liver stiffness and controlled attenuation parameter (CAP) measurement.Heterozygosity for the Z-allele was observed in 6.7% of patients with CSPH and 2.8% of liver donors. Thus, harboring the Z-allele was associated with increased odds of CSPH (odds ratio: 2.47; 95% confidence interval: 1.03-5.9; P?=?0.042). Among Pi*ZZ/Pi*SZ patients, 23%/3% had liver stiffness values indicative of liver fibrosis (??F2/??F3). Interestingly, 65%/52% of Pi*ZZ/Pi*SZ patients had CAP values indicative of hepatic steatosis (??S1/??S2).Heterozygosity for the Z-allele predisposes for the development of CSPH, confirming its role as a genetic (co)factor in liver disease. Pi*ZZ/SZ patients rarely develop liver fibrosis??F3 during adulthood; however, liver fibrosis??F2 is common. Elevated CAP values hint at underlying hepatic steatosis, which might promote liver fibrosis progression.

SUBMITTER: Mandorfer M

PROVIDER: S-EPMC6068794 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Liver disease in adults with α1-antitrypsin deficiency.

Mandorfer Mattias M Bucsics Theresa T Hutya Veronika V Schmid-Scherzer Karin K Schaefer Benedikt B Zoller Heinz H Ferlitsch Arnulf A Peck-Radosavljevic Markus M Trauner Michael M Ferenci Peter P Kneussl Meinhard M Reiberger Thomas T

United European gastroenterology journal 20180228 5

<h4>Background</h4>The natural history of adult liver disease due to α1-antitrypsin deficiency (A1AD) remains poorly understood.<h4>Objective</h4>We investigated whether heterozygosity for the Z-allele predisposes for the development of clinically significant portal hypertension (CSPH). Moreover, we aimed to non-invasively assess the prevalence of liver fibrosis and hepatic steatosis in adults with A1AD treated by pulmonologists.<h4>Methods</h4>SERPINA1 rs28929474 (Z-allele) was genotyped in 315 ...[more]

PMID: 30083333

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Project description:BackgroundPathological mutations in Alpha-1 Antitrypsin (AAT) protein cause retention of toxic polymers in the hepatocyte endoplasmic reticulum. The risk for cirrhosis in AAT deficiency is likely directly related to retention of these polymers within the liver. Polymers are classically identified on liver biopsy as inclusion bodies by periodic acid schiff staining after diastase treatment and immunohistochemistry. However, characterization of the polymer burden within a biopsy sample is limited to a semi-quantitative scale as described by a pathologist. Better methods to quantify polymer are needed to advance our understanding of pathogenesis of disease. Therefore, we developed a method to quantify polymer aggregation from standard histologic specimens. In addition, we sought to understand the relationship of polymer burden and other histologic findings to the presence of liver fibrosis.MethodsLiver samples from a well-categorized AATD cohort were used to develop histo-morphometric tools to measure protein aggregation.ResultsWhole-slide morphometry reliably quantifies aggregates in AATD individuals. Despite very low levels of inclusions present (0-0.41%), accumulation of globules is not linear and is associated with higher fibrosis stages. Immunohistochemistry demonstrates that fibrosis is associated with polymer accumulation and not total AAT. A proportion of patients were found to be "heavy accumulators" with a polymer burden above the upper 25% of normal distribution. Males had significantly more liver inclusions and polymer than females. These measurements also highlight interrelated phenotypes of hepatocellular degeneration and autophagy in AATD liver disease.ConclusionQuantitative inclusion analysis measures AAT accumulation in liver biopsy specimens. Quantification of polymer may identify individuals at risk for progressive disease and candidates for therapeutic interventions. Furthermore, these methods may be useful for evaluating efficacy of drugs targeting accumulation of AAT.

Dataset Information

Liver disease in adults with ?1-antitrypsin deficiency.

Publications

Liver disease in adults with α1-antitrypsin deficiency.

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