title: Serum cell death biomarkers for prediction of liver fibrosis and poor prognosis in primary biliary cirrhosis.
abstract: The development of simple, noninvasive markers of liver fibrosis is urgently needed for primary biliary cirrhosis (PBC). This study examined the ability of several serum biomarkers of cell death to estimate fibrosis and prognosis in PBC. A cohort of 130 patients with biopsy-proven PBC and 90 healthy subjects were enrolled. We assessed the utility of the M30 ELISA, which detects caspase-cleaved cytokeratin-18 (CK-18) fragments and is representative of apoptotic cell death, as well as the M65 and newly developed M65 Epideath (M65ED) ELISAs, which detect total CK-18 as indicators of overall cell death, in predicting clinically relevant fibrosis stage. All 3 cell death biomarkers were significantly higher in patients with PBC than in healthy controls and were significantly correlated with fibrosis stage. The areas under the receiver operating characteristic curve for the M65 and M65ED assays for differentiation among significant fibrosis, severe fibrosis, and cirrhosis were 0.66 and 0.76, 0.66 and 0.73, and 0.74 and 0.82, respectively. In multivariate analysis, high M65ED (hazard ratio 6.13; 95% confidence interval 1.18-31.69; P = 0.031) and severe fibrosis (hazard ratio 7.45; 95% confidence interval 1.82-30.51; P = 0.005) were independently associated with liver-related death, transplantation, or decompensation. High serum M65ED was also significantly associated with poor outcome in PBC (log-rank test; P = 0.001). Noninvasive cell death biomarkers appear to be clinically useful in predicting fibrosis in PBC. Moreover, the M65ED assay may represent a new surrogate marker of adverse disease outcome.
authors.affiliation: Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sekiguchi
authors.affiliation: Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Takeji
authors.initials: T
authors.lastname: Umemura
authors.affiliation: Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Fujimori
authors.affiliation: Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ichikawa
authors.affiliation: Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Joshita
authors.affiliation: Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Michiharu
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.affiliation: Department of Legal Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Ota
mesh_terms: D000368:Aged; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood*; D001706:Biopsy; D016022:Case-Control Studies; D016923:Cell Death; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D053538:Keratin-18 / Q000097:blood; D008103:Liver Cirrhosis / Q000097:blood* / Q000175:diagnosis*; D008105:Liver Cirrhosis, Biliary / Q000097:blood* / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012372:ROC Curve; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C488421:KRT18 protein, human; D053538:Keratin-18