Liver Phenotypes of European Adults Heterozygous or Homozygous for PiZ Variant of AAT (PiMZ vs Pi*ZZ genotype) and Noncarriers

被引：58

作者：

Schneider, Carolin, V ^{[1
]}

Hamesch, Karim ^{[1
,2
,3
]}

Gross, Annika ^{[1
]}

Mandorfer, Mattias ^{[4
,37
]}

Moeller, Linda S. ^{[5
]}

Pereira, Vitor ^{[6
]}

Pons, Monica ^{[7
,8
]}

Kuca, Pawel ^{[9
]}

Reichert, Matthias C. ^{[10
]}

Benini, Federica ^{[11
]}

Burbaum, Barbara ^{[1
]}

Voss, Jessica ^{[1
]}

Gutberlet, Marla ^{[1
]}

Woditsch, Vivien ^{[1
]}

Lindhauer, Cecilia ^{[1
]}

Fromme, Malin ^{[1
]}

Kumpers, Julia ^{[1
]}

Bewersdorf, Lisa ^{[1
]}

Schaefer, Benedikt ^{[12
]}

Eslam, Mohammed ^{[13
,14
]}

Bals, Robert ^{[15
]}

Janciauskiene, Sabina ^{[16
]}

Carvao, Joana ^{[6
]}

Neureiter, Daniel ^{[17
]}

Zhou, Biaohuan ^{[1
]}

Woeran, Katharina ^{[18
]}

Bantel, Heike ^{[19
]}

Geier, Andreas ^{[20
]}

Dirrichs, Timm ^{[21
]}

Stickel, Felix ^{[22
]}

Teumer, Alexander ^{[23
,24
]}

Verbeek, Jef ^{[25
]}

Nevens, Frederik ^{[25
]}

Govaere, Olivier ^{[26
,27
]}

Krawczyk, Marcin ^{[10
,28
]}

Roskams, Tania ^{[29
]}

Haybaeck, Johannes ^{[30
,38
]}

Lurje, Georg ^{[31
,32
]}

Chorostowska-Wynimko, Joanna ^{[9
]}

Genesca, Joan ^{[7
,8
]}

Reiberger, Thomas ^{[4
,37
]}

Lammert, Frank ^{[10
]}

Krag, Aleksander ^{[5
]}

George, Jacob ^{[13
,14
]}

Anstee, Quentin M. ^{[26
,27
]}

Trauner, Michael ^{[4
,37
]}

Datz, Christian ^{[33
]}

Gaisa, Nadine T. ^{[34
]}

Denk, Helmut ^{[35
]}

Trautwein, Christian ^{[1
,2
,3
]}

机构：

[1] Univ Hosp RWTH Aachen, Gastroenterol Metab Dis & Intens Care, Med Clin 3, Aachen, Germany

[2] Univ Hosp Aachen, Coordinating Ctr Alpha 1 Antitrypsin Deficiency R, European Reference Network ERN Rare Liver, Pauwelsstr 30, D-52074 Aachen, Germany

[3] Univ Hosp Aachen, European Assoc Study Liver EASL Registry Grp Alph, Pauwelsstr 30, D-52074 Aachen, Germany

[4] Med Univ Vienna, Dept Internal Med 3, Div Gastroenterol & Hepatol, Vienna, Austria

[5] Odense Univ Hosp, Dept Gastroenterol & Hepatol, Odense, Denmark

[6] Ctr Hosp Funchal, Dept Gastroenterol, Madeira, Portugal

[7] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst VHIR, Liver Unit, Barcelona, Spain

[8] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain

[9] Natl Inst TB & Lung Dis, Dept Genet & Clin Immunol, Warsaw, Poland

[10] Saarland Univ, Med Ctr, Dept Med 2, Homburg, Germany

[11] Spedali Civili & Univ, Dept Med, Gastroenterol Unit, Brescia, Italy

[12] Med Univ Innsbruck, Dept Internal Med, Innsbruck, Austria

[13] Westmead Hosp, Storr Liver Ctr, Westmead Inst Med Res, Sydney, NSW, Australia

[14] Univ Sydney, Sydney, NSW, Australia

[15] Saarland Univ, Dept Internal Med 5, Med Ctr, Homburg, Germany

[16] Hannover Med Sch, Clin Pneumol, Hannover, Germany

[17] Paracelsus Med Univ, Inst Pathol, Salzburger Landeskliniken SALK, Salzburg, Austria

[18] Med Univ Vienna, Dept Pathol, Vienna, Austria

[19] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany

[20] Univ Wurzburg, Dept Hepatol, Wurzburg, Germany

[21] RWTH Aachen Univ Hosp, Dept Diagnost & Intervent Radiol, Aachen, Germany

[22] Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland

[23] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[24] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany

[25] Univ Hosp KU Leuven, Dept Gastroenterol & Hepatol, Leuven, Belgium

[26] Newcastle Univ, Fac Med Sci, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[27] Newcastle Upon Tyne Hosp NHS Fdn Trust, Newcastle NIHR Biomed Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[28] Med Univ Warsaw, Dept Gen Transplant & Liver Surg, Ctr Pre Clin Res, Lab Metab Liver Dis, Warsaw, Poland

[29] Univ Hosp KU Leuven, Dept Pathol, Leuven, Belgium

[30] Med Univ Innsbruck, Dept Pathol Neuropathol & Mol Pathol, Innsbruck, Austria

[31] Univ Hosp RWTH Aachen, Dept Surg & Transplantat, Aachen, Germany

[32] Charlie Univ Med Berlin, Dept Surg, Campus Charite Mitte 1,Campus Virchow Klinikum, Berlin, Germany

[33] Paracelsus Private Univ Salzburg, Hosp Oberndorf, Dept Internal Med, Teaching Hosp, Oberndorf, Austria

[34] Univ Hosp RWTH Aachen, Inst Pathol, Aachen, Germany

[35] Med Univ Graz, Inst Pathol, Graz, Austria

[36] Paracelsus Med Univ, Dept Med 1, Salzburg, Austria

[37] Med Univ Vienna, Rare Liver Dis RALID Ctr European Reference Netwo, Vienna, Austria

[38] Med Univ Graz, Diagnost & Res Ctr Mol Biomed, Inst Pathol, Graz, Austria

来源：

GASTROENTEROLOGY | 2020年 / 159卷 / 02期

基金：

欧盟地平线“2020”; 瑞士国家科学基金会;

关键词：

FibroScan; SERPINA1; GGT; ALT; ALPHA-1-ANTITRYPSIN DEFICIENCY; TRANSIENT ELASTOGRAPHY; DISEASE; FIBROSIS; PERFORMANCE; HEPATITIS; BIOLOGY; COHORT; DAMAGE; AGE;

D O I：

10.1053/j.gastro.2020.04.058

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 gammaglutamyl 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.

引用

页码：534 / +

页数：26

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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

Liver Phenotypes of European Adults Heterozygous or Homozygous for PiZ Variant of AAT (PiMZ vs Pi*ZZ genotype) and Noncarriers