| Title: | Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers |
| Journal: | Gastroenterology |
| Published: | 4 May 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32376409/ |
| DOI: | https://doi.org/10.1053/j.gastro.2020.04.058 |
| URL: | http://www.gastrojournal.org/article/S0016508520305771/pdf |
Publication 5332
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Abstract
BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease.</p>
METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank.</p>
RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals.</p>
CONCLUSIONS: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.</p>
20 Keywords
- Adult
- Aged
- Counseling
- Cross-Sectional Studies
- Elasticity Imaging Techniques
- Female
- Heterozygote
- Homozygote
- Humans
- Liver
- Liver Cirrhosis
- Liver Function Tests
- Longitudinal Studies
- Male
- Middle Aged
- Phenotype
- Prospective Studies
- United Kingdom
- alpha 1-Antitrypsin
- alpha 1-Antitrypsin Deficiency
53 Authors
- Carolin V. Schneider
- Karim Hamesch
- Annika Gross
- Mattias Mandorfer
- Linda S. Moeller
- Vitor Pereira
- Monica Pons
- Pawel Kuca
- Matthias C. Reichert
- Federica Benini
- Barbara Burbaum
- Jessica Voss
- Marla Gutberlet
- Vivien Woditsch
- Cecilia Lindhauer
- Malin Fromme
- Julia Kümpers
- Lisa Bewersdorf
- Benedikt Schaefer
- Mohammed Eslam
- Robert Bals
- Sabina Janciauskiene
- Joana Carvão
- Daniel Neureiter
- Biaohuan Zhou
- Katharina Wöran
- Heike Bantel
- Andreas Geier
- Timm Dirrichs
- Felix Stickel
- Alexander Teumer
- Jef Verbeek
- Frederik Nevens
- Olivier Govaere
- Marcin Krawczyk
- Tania Roskams
- Johannes Haybaeck
- Georg Lurje
- Joanna Chorostowska-Wynimko
- Joan Genesca
- Thomas Reiberger
- Frank Lammert
- Aleksander Krag
- Jacob George
- Quentin M. Anstee
- Michael Trauner
- Christian Datz
- Nadine T. Gaisa
- Helmut Denk
- Christian Trautwein
- Elmar Aigner
- Pavel Strnad
- European Alpha-1 Liver Study Group
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