Vatsalya Vatsalya1, Matthew C Cave2, Maiying Kong3, Leila Gobejishvili4, K Cameron Falkner5, John Craycroft3, Mack Mitchell6, Gyongi Szabo7, Arthur McCullough8, Srinivasan Dasarathy8, Svetlana Radaeva9, Bruce Barton7, Craig J McClain10. 1. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky; Robley Rex VA Medical Center, Louisville, Kentucky; University of Louisville Alcohol Research Center, Louisville, Kentucky; Hepatobiology and Toxicology Program, University of Louisville, Louisville Kentucky. 2. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky; Robley Rex VA Medical Center, Louisville, Kentucky; University of Louisville Alcohol Research Center, Louisville, Kentucky; Hepatobiology and Toxicology Program, University of Louisville, Louisville Kentucky; Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky. 3. Department of Biostatistics and Bioinformatics, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky. 4. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Alcohol Research Center, Louisville, Kentucky; Hepatobiology and Toxicology Program, University of Louisville, Louisville Kentucky; Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky. 5. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky. 6. University of Texas Southwestern Medical Center, Dallas, Texas. 7. University of Massachusetts Medical School, Worcester, Massachusetts. 8. Cleveland Clinic, Cleveland, Ohio. 9. National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland. 10. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky; Robley Rex VA Medical Center, Louisville, Kentucky; University of Louisville Alcohol Research Center, Louisville, Kentucky; Hepatobiology and Toxicology Program, University of Louisville, Louisville Kentucky; Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky. Electronic address: craig.mcclain@louisville.edu.
Abstract
BACKGROUND & AIMS: Acute alcoholic hepatitis (AAH) is a major cause of liver-related morbidity and mortality; there are no good blood biomarkers for diagnosis or determining magnitude of cell death. Keratin 18 (KRT18, also called K18), found in epithelial cells, is released from hepatocytes upon death. We investigated whether level of K18 is a better marker of hepatocyte death than standard biomarkers and might be used to identify patients with AAH at risk for death within 90 days. METHODS: We analyzed data from 173 participants in a large trial performed at 4 medical centers. Participants with AAH were classified as severe (n = 57, model for end-stage liver disease [MELD] scores above 20) or moderate (n = 27, MELD scores from 12 to 19); 38 participants had alcohol use disorder with mild (n = 28) or no liver injury (n = 10); 34 participants had nonalcoholic steatohepatitis; and 17 participants were healthy (controls). We quantified serum levels of K18 using ELISAs and APOPTOSENSE kits. RESULTS: Serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the ratio of AST:ALT did not correlate with MELD scores. Patients with alcohol use disorder had higher serum levels of ALT than patients with severe AAH. Levels of K18M65 and K18M30 had statistically significant increases as liver disease worsened, as did the degree of necrosis (ratio of K18 M65:M30). The ratio of K18M65:ALT was increased in serum from patients with AAH compared with controls. Serum levels of K18 identified patients who died within 90 days with greater accuracy than commonly used static biomarkers. CONCLUSIONS: There is a stronger association between serum level of keratin 18 and amount of hepatocyte death and liver disease severity than for other biomarkers (AST, ALT, and the AST:ALT ratio). The ratio of K18M65:M30 might be used as marker of mechanism of hepatocyte death, and the ratio of K18M65:ALT might be used to distinguish patients with AAH from patients with nonalcoholic steatohepatitis. Serum levels of K18 might be used to identify patients with severe AAH at risk for death. ClinicalTrials.gov identifier # NCT01922895 and NCT01809132.
BACKGROUND & AIMS:Acute alcoholic hepatitis (AAH) is a major cause of liver-related morbidity and mortality; there are no good blood biomarkers for diagnosis or determining magnitude of cell death. Keratin 18 (KRT18, also called K18), found in epithelial cells, is released from hepatocytes upon death. We investigated whether level of K18 is a better marker of hepatocyte death than standard biomarkers and might be used to identify patients with AAH at risk for death within 90 days. METHODS: We analyzed data from 173 participants in a large trial performed at 4 medical centers. Participants with AAH were classified as severe (n = 57, model for end-stage liver disease [MELD] scores above 20) or moderate (n = 27, MELD scores from 12 to 19); 38 participants had alcohol use disorder with mild (n = 28) or no liver injury (n = 10); 34 participants had nonalcoholic steatohepatitis; and 17 participants were healthy (controls). We quantified serum levels of K18 using ELISAs and APOPTOSENSE kits. RESULTS: Serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the ratio of AST:ALT did not correlate with MELD scores. Patients with alcohol use disorder had higher serum levels of ALT than patients with severe AAH. Levels of K18M65 and K18M30 had statistically significant increases as liver disease worsened, as did the degree of necrosis (ratio of K18 M65:M30). The ratio of K18M65:ALT was increased in serum from patients with AAH compared with controls. Serum levels of K18 identified patients who died within 90 days with greater accuracy than commonly used static biomarkers. CONCLUSIONS: There is a stronger association between serum level of keratin 18 and amount of hepatocyte death and liver disease severity than for other biomarkers (AST, ALT, and the AST:ALT ratio). The ratio of K18M65:M30 might be used as marker of mechanism of hepatocyte death, and the ratio of K18M65:ALT might be used to distinguish patients with AAH from patients with nonalcoholic steatohepatitis. Serum levels of K18 might be used to identify patients with severe AAH at risk for death. ClinicalTrials.gov identifier # NCT01922895 and NCT01809132.
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