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Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation

dc.contributor.authorHamesch, Karim
dc.contributor.authorMandorfer, Mattias
dc.contributor.authorPereira, Vítor Magno
dc.contributor.authorMoeller, Linda S.
dc.contributor.authorPons, Monica
dc.contributor.authorDolman, Grace E.
dc.contributor.authorReichert, Matthias C.
dc.contributor.authorSchneider, Carolin V.
dc.contributor.authorWoditsch, Vivien
dc.contributor.authorVoss, Jessica
dc.contributor.authorLindhauer, Cecilia
dc.contributor.authorFromme, Malin
dc.contributor.authorSpivak, Igor
dc.contributor.authorZoller, Heinz
dc.contributor.authorAigner, Elmar
dc.contributor.authorReiberger, Thomas
dc.contributor.authorWetzel, Martin
dc.contributor.authorSiegmund, Britta
dc.contributor.authorSimões, Carolina
dc.contributor.authorGaspar, Rui
dc.contributor.authorMaia, Luís
dc.contributor.authorCosta, Dalila
dc.contributor.authorBento-Miranda, Mário
dc.contributor.authorvan Helden, Josef
dc.contributor.authorYagmur, Eray
dc.contributor.authorBzdok, Danilo
dc.contributor.authorStolk, Jan
dc.contributor.authorGleiber, Wolfgang
dc.contributor.authorKnipel, Verena
dc.contributor.authorWindisch, Wolfram
dc.contributor.authorMahadeva, Ravi
dc.contributor.authorBals, Robert
dc.contributor.authorKoczulla, Rembert
dc.contributor.authorBarrecheguren, Miriam
dc.contributor.authorMiravitlles, Marc
dc.contributor.authorJanciauskiene, Sabina
dc.contributor.authorStickel, Felix
dc.contributor.authorLammert, Frank
dc.contributor.authorLiberal, Rodrigo
dc.contributor.authorTrautwein, Christian
dc.contributor.authorStrnad, Pavel
dc.contributor.authorEuropean Alpha1-Liver Study Group
dc.date.accessioned2019-10-17T10:19:24Z
dc.date.available2019-10-17T10:19:24Z
dc.date.issued2019
dc.description.abstractBACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation- associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%–36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or g-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter 280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-lowdensity lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Zoverexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosispt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationGastroenterology Vol. 157, No. 3pt_PT
dc.identifier.doidoi.org/10.1053/j.gastro.2019.05.013pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.26/29961
dc.language.isoengpt_PT
dc.subjectliver fibrosispt_PT
dc.subjectmetabolic alterationspt_PT
dc.subjectalpha-antitrypsin deficiencypt_PT
dc.subjectPi*ZZ Mutationpt_PT
dc.titleLiver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage719pt_PT
oaire.citation.startPage705pt_PT
person.familyNameMandorfer
person.familyNamePereira
person.familyNameZoller
person.familyNameReiberger
person.familyNameMahadeva
person.givenNameMattias
person.givenNameVítor
person.givenNameHeinz
person.givenNameThomas
person.givenNameRavi
person.identifier.orcid0000-0003-2330-0017
person.identifier.orcid0000-0002-9854-086X
person.identifier.orcid0000-0003-1794-422X
person.identifier.orcid0000-0002-4590-3583
person.identifier.orcid0000-0001-6111-5555
person.identifier.scopus-author-id24315181000
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationc5120c49-3221-42bb-9056-2ec3fa4a22a0
relation.isAuthorOfPublication206b8104-6d62-49eb-ac05-5649bcc1b4b6
relation.isAuthorOfPublication7419af9c-3089-48ae-bc96-b2cf22c150f9
relation.isAuthorOfPublication54718bc9-5541-433f-9ed6-dcbc8c943243
relation.isAuthorOfPublication178d3e73-8a16-4f4f-8b7f-142d3691d153
relation.isAuthorOfPublication.latestForDiscovery206b8104-6d62-49eb-ac05-5649bcc1b4b6

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