Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers

Schneider, Carolin V.; Hamesch, Karim; Groß, Annika; Mandorfer, Mattias; Moeller, Linda S.; Pereira, Vítor Magno; Pons, Mónica; Kuca, Paweł; Reichert, Matthias; Benini, Federica; Burbaum, Barbara; Voss, Jessica; Gutberlet, Manuela; Woditsch, V; Lindhauer, Cecilia; Fromme, Malin; Kümpers, Julia; Bewersdorf, Lisa; Schäfer, B; Eslam, Mohammed; Bals, Robert; Janciauskiene, Sabina; Carvão, Joana; Neureiter, Daniel; Zhou, Biaohuan; Wöran, Katharina; Bantel, Heike; Geier, Andreas; Dirrichs, Timm; Stickel, Felix; Teumer, Alexander; Verbeek, Jef; Nevens, Frederik; Govaere, Olivier; Krawczyk, Marcin; Roskams, Tania; Haybaeck, Johannes; Lurje, Georg; Chorostowska‐Wynimko, Joanna; Genescà, Joan; Reiberger, Thomas; Zoller, Heinz; Krag, Aleksander; George, Jacob; Anstee, Quentin M.; Trauner, Michael; Datz, Christian; Gaisa, Nadine T.; Denk, Helmut; Trautwein, Christian; Aigner, Elmar; Strnad, Pavel

doi:10.1053/j.gastro.2020.04.058

Cited by 62 publications

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“…In northern Europe, up to 1:2000 is homozygous for the characteristic, disease‐causing variant termed PiZ [9]. While the presence of the homozygous PiZ mutation (referred to as PiZZ) precipitates the development of liver disease [12], the heterozygous PiZ carriage (PiMZ), which has a prevalence of up to 20% in northern Europe, is a well‐established disease modifier [13]. For example, the heterozygous PiZ carriage predisposes patients with cystic fibrosis to the development of severe liver disease [14] and a large genome‐wide study identified PiZ as the variant conferring the highest odds for alcoholic liver disease/non‐alcoholic fatty liver disease (ALD/NAFLD)‐associated liver cirrhosis [15].…”

Section: Introductionmentioning

confidence: 99%

Dual proteotoxic stress accelerates liver injury via activation of p62‐Nrf2

et al. 2021

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Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein‐secretory organ. For example, aggregation of mutated alpha1‐antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs‐PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs‐PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62‐containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin‐2. p62 build‐up led to activation of the p62–Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62–Nrf2 axis. In humans, the PiZ variant was over‐represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15–85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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Section: Introductionmentioning

confidence: 99%

Dual proteotoxic stress accelerates liver injury via activation of p62‐Nrf2

et al. 2021

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“…Hier wird neben der Erhebung der üblichen Leberwerte (Transaminasen, Bilirubin, γGT, AP) auch eine Sonografie sowie eine nichtinvasive Bestimmung der Leberfibrose empfohlen. Unter den gängigen Verfahren ist die transiente Elastografie am besten validiert [8][9][10][11]. Indirekte Fibrose-Scores wie der APRI (AST/Thrombozyten-Index) oder FIB-4-Index (Alter, AST, ALT, Thrombozyten) können weitere Informationen liefern [9].…”

Section: Diagnostikunclassified

Alpha-1-Antitrypsinmangel: Ursache und Kofaktor für Lebererkrankungen

Burbaum

Fromme

Strnad

2021

Dtsch Med Wochenschr

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Was ist neu? Diagnostik Aus gastroenterologischer Sicht hat neben der Bestimmung von Leberenzymen die Untersuchung einer möglichen Fibrose durch nichtinvasive Techniken einen hohen Stellenwert. Besonders zu nennen ist hier die Messung mittels transienter Elastografie (z. B. mittels FibroScan). Bei einem FibroScan-Wert von ≥ 7,1kPa sollte eine detaillierte hepatologische Abklärung folgen, eine Therapie im Rahmen von laufenden Studien kann diskutiert werden. Klinischer Verlauf Ein Zehntel der pädiatrischen Pi*ZZ-Betroffenen weist eine cholestatische Lebererkrankung auf. Nachdem die adulte Lebererkrankung lange vernachlässigt wurde, konnte vor kurzem dessen Ausmaß mit nichtinvasiven Techniken besser bewertet werden. Im Erwachsenenalter entwickeln ein Fünftel bis ein Drittel der Pi*ZZ-Subjekte eine Leberfibrose. Bereits in der heterozygoten Form (Pi*MZ) gilt der AATM als „disease modifier“, der Pi*SZ-Genotyp stellt im Vergleich zu Pi*MZ und Pi*ZZ ein intermediäres Risiko dar. In Anwesenheit von relevanten Risikofaktoren wie Diabetes mellitus, Adipositas (BMI > 30 kg/m2) und Alter > 50 Jahren prädisponiert er für die Entwicklung einer Lebererkrankung. So haben Patienten mit NAFLD/NASH oder einem kritischen Alkoholkonsum bei zusätzlichem AATM ein deutlich erhöhtes Risiko für die Entwicklung einer Leberzirrhose. Ausblick und zukünftige Therapien Bisher existiert für die Leberbeteiligung bei AATM keine medikamentöse Therapie. Einige Pharmaka gegen die Progression der Leberfibrose befinden sich in vielversprechenden Phase-II/III-Studien. Besonders herauszustellen ist die Unterbindung der Alpha-1-Antitypsin (AAT) -Produktion mittels siRNA, für die es erste Hinweise auf eine Wirksamkeit gibt. Zum anderen befindet sich ein Medikament in klinischer Testung, welches versucht, die Z-AAT-Sekretion in den Blutkreislauf zu erhöhen.

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“…Some previous studies have sought to characterise the effect of Z allele heterozygosity and homozygosity on non-respiratory traits, particular liver diseases 2, 3, 4, 5, 6 . However, these have often been carried out in small sample sizes and/or clinical subgroups.…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic effects of heterozygosity for theSERPINA1Z allele in the UK Biobank

Fawcett

Song

Qian

et al. 2020

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Homozygosity for the SERPINA1 Z allele causes alpha-1 antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on non-respiratory phenotypes, and on lung function in the general population, remain unclear. We conducted the largest population-based study to date to determine Z allele effects on >2,400 phenotypes using the UK Biobank study (N>303,353). We detected strong associations between heterozygosity and non-respiratory phenotypes including increased height, increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher lung function in non-smokers, but smoking appears to abolish this protective effect. Individuals heterozygous for the Z allele may therefore have altered risk of smoking-induced lung disease and other, non-respiratory conditions.

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Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers

Abstract: alpha-1 antitrypsin deficiency-related liver disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha-1 Liver,

Cited by 62 publications

References 46 publications

Dual proteotoxic stress accelerates liver injury via activation of p62‐Nrf2

Dual proteotoxic stress accelerates liver injury via activation of p62‐Nrf2

Alpha-1-Antitrypsinmangel: Ursache und Kofaktor für Lebererkrankungen

Pleiotropic effects of heterozygosity for theSERPINA1Z allele in the UK Biobank

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