PMID- 30138687 OWN - NLM STAT- MEDLINE DCOM- 20191230 LR - 20191230 IS - 1600-0641 (Electronic) IS - 0168-8278 (Linking) VI - 69 IP - 6 DP - 2018 Dec TI - Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort. PG - 1357-1364 LID - S0168-8278(18)32284-0 [pii] LID - 10.1016/j.jhep.2018.08.005 [doi] AB - BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is an uncommonly recognized cause of liver disease in adults, with descriptions of its natural history limited to case series and patient-reported data from disease registries. Liver pathology is limited to selected patients or unavailable. Therefore, we aimed to determine the prevalence and severity of liver fibrosis in an adult AATD population who were not known to have cirrhosis, while defining risk factors for fibrosis and testing non-invasive markers of disease. METHODS: A total of 94 adults with classic genotype 'PI*ZZ' AATD were recruited from North America and prospectively enrolled in the study. Liver aminotransferases and markers of synthetic function, transient elastography, and liver biopsy were performed. RESULTS: The prevalence of clinically significant liver fibrosis (F >/= 2) was 35.1%. Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase values were higher in the F >/= 2 group. Metabolic syndrome was associated with the presence of clinically significant fibrosis (OR 14.2; 95% CI 3.7-55; p <0.001). Additionally, the presence of accumulated abnormal AAT in hepatocytes, portal inflammation, and hepatocellular degeneration were associated with clinically significant fibrosis. The accuracy of transient elastography to detect F >/= 2 fibrosis was fair, with an AUC of 0.70 (95% CI 0.58-0.82). CONCLUSIONS: Over one-third of asymptomatic and lung affected adults with 'PI*ZZ' AATD have significant underlying liver fibrosis. Liver biopsies demonstrated variable amounts of accumulated Z AAT. The risk of liver fibrosis increases in the presence of metabolic syndrome, accumulation of AAT in hepatocytes, and portal inflammation on baseline biopsy. The results support the hypothesis that liver disease in this genetic condition may be related to a "toxic gain of function" from accumulation of AAT in hepatocytes. LAY SUMMARY: Individuals diagnosed with classic alpha-1 antitrypsin deficiency (ZZ) are at risk of liver injury and scarring, because of the accumulation of abnormal alpha-1 antitrypsin in the liver. A liver biopsy in ZZ individuals can demonstrate the accumulation of alpha-1 antitrypsin within the liver and identify if any associated liver scarring is present. Indviduals with large amounts of alpha-1 antitrypsin on biopsy may be at risk of liver injury and fibrosis. Additional common medical conditions of diabetes, obesity, high cholesterol, and hypertension (known as metabolic syndrome) are associated with a greater degree of liver injury. CLINICAL TRIAL NUMBER: clinicaltrials.gov NCT01810458. CI - Copyright (c) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. FAU - Clark, Virginia C AU - Clark VC AD - Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, United States. Electronic address: Virginia.clark@medicine.ufl.edu. FAU - Marek, George AU - Marek G AD - Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States. FAU - Liu, Chen AU - Liu C AD - Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, United States; Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, United States. FAU - Collinsworth, Amy AU - Collinsworth A AD - Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, United States. FAU - Shuster, Jonathan AU - Shuster J AD - Department of Health Outcomes and Policy, University of Florida, United States. FAU - Kurtz, Tracie AU - Kurtz T AD - Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States. FAU - Nolte, Joanna AU - Nolte J AD - Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States. FAU - Brantly, Mark AU - Brantly M AD - Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States. LA - eng SI - ClinicalTrials.gov/NCT01810458 GR - UL1 TR000064/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180821 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (alpha 1-Antitrypsin) SB - IM CIN - J Hepatol. 2019 Dec;71(6):1272-1274. PMID: 31594657 CIN - J Hepatol. 2019 Dec;71(6):1274. PMID: 31606160 MH - Adult MH - Aged MH - Biopsy MH - Canada/epidemiology MH - Comorbidity MH - Cross-Sectional Studies MH - Elasticity Imaging Techniques MH - Female MH - Hepatocytes/metabolism MH - Humans MH - Liver/pathology MH - Liver Cirrhosis/*epidemiology/*etiology MH - Lung Diseases, Obstructive/epidemiology MH - Male MH - Metabolic Syndrome/*complications MH - Middle Aged MH - Phenotype MH - Prevalence MH - Prospective Studies MH - Severity of Illness Index MH - United States/epidemiology MH - alpha 1-Antitrypsin/genetics/*metabolism MH - alpha 1-Antitrypsin Deficiency/*complications/*pathology OTO - NOTNLM OT - Alpha-1 antitrypsin deficiency OT - Elasticity imaging techniques OT - Hepatocytes OT - Liver cirrhosis OT - Metabolic syndrome OT - Prevalence OT - Risk factors EDAT- 2018/08/24 06:00 MHDA- 2019/12/31 06:00 CRDT- 2018/08/24 06:00 PHST- 2017/05/30 00:00 [received] PHST- 2018/07/30 00:00 [revised] PHST- 2018/08/13 00:00 [accepted] PHST- 2018/08/24 06:00 [pubmed] PHST- 2019/12/31 06:00 [medline] PHST- 2018/08/24 06:00 [entrez] AID - S0168-8278(18)32284-0 [pii] AID - 10.1016/j.jhep.2018.08.005 [doi] PST - ppublish SO - J Hepatol. 2018 Dec;69(6):1357-1364. doi: 10.1016/j.jhep.2018.08.005. Epub 2018 Aug 21.