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. 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. 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. 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.
- Schneider, C. V.
- Hamesch, K.
- Gross, A.
- Mandorfer, M.
- Moeller, L. S.
- Pereira, V.
- Pons, M.
- Kuca, P.
- Reichert, M. C.
- Benini, F.
- Burbaum, B.
- Voss, J.
- Gutberlet, M.
- Woditsch, V.
- Lindhauer, C.
- Fromme, M.
- Kumpers, J.
- Bewersdorf, L.
- Schaefer, B.
- Eslam, M.
- Bals, R.
- Janciauskiene, S.
- Carvao, J.
- Neureiter, D.
- Zhou, B.
- Woran, K.
- Bantel, H.
- Geier, A.
- Dirrichs, T.
- Stickel, F.
- Teumer, A.
- Verbeek, J.
- Nevens, F.
- Govaere, O.
- Krawczyk, M.
- Roskams, T.
- Haybaeck, J.
- Lurje, G.
- Chorostowska-Wynimko, J.
- Genesca, J.
- Reiberger, T.
- Lammert, F.
- Krag, A.
- George, J.
- Anstee, Q. M.
- Trauner, M.
- Datz, C.
- Gaisa, N. T.
- Denk, H.
- Trautwein, C.
- Aigner, E.
- Strnad, P.
- European Alpha-1 Liver Study, Group
Keywords
- Alt
- FibroScan
- Ggt
- Serpina1
