Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C

Gut doi:10.1136/gut.2010.207423

Robert J Fontana 1, Jules L Dienstag 2, Herbert L Bonkovsky 3, Richard K Sterling 4, Deepa Naishadham 5, Zachary D Goodman 6, Anna S F Lok 1, Elizabeth C Wright 7, Grace L Su 1, the HALT-C Trial Group

+ Author Affiliations

1 Department of Internal Medicine, University of Michigan Medical School, Michigan, USA
2 Gastrointestinal Unit (Medical Services), Massachusetts General Hospital and the Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
3 Departments of Medicine and Molecular & Structural Biology and The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, Connecticut, USA
4 Hepatology Section, Virginia Commonwealth University Medical Center, Virginia, USA
5 New England Research Institutes, Massachusetts, USA
6 Armed Forces Institute of Pathology, Division of Hepatic Pathology and Veterans Administration Special Reference Laboratory for Pathology, Washington, USA
7 Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Maryland, USA

Correspondence to
Robert J Fontana, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, Ann Arbor, Michigan, USA; rfontana@med.umich.edu

Revised 17 May 2010
Accepted 18 May 2010
Published Online First 30 July 2010

 Abstract

Objectives The aim of this study was to explore the association of serum fibrosis marker levels with the risk of clinical and histological disease progression in a large cohort of patients with chronic hepatitis C (CHC).

Methods 462 prior non-responders to peginterferon and ribavirin enrolled in the randomised phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial had baseline and annual serum samples tested for hyaluronic acid (HA), N-terminal peptide of procollagen type 3, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and YKL-40. All patients underwent a pretreatment liver biopsy and follow-up biopsies at years 2 and 4. Histological progression was defined as a ≥2 point increase in Ishak fibrosis score in patients without cirrhosis. Clinical outcomes included development of decompensation, hepatocellular cancer, death or an increase in the CTP (Child–Turcotte–Pugh) score to ≥7.

Results Mean patient age was 49.5 years and 39% had histological cirrhosis at entry. Baseline HA, YKL-40 and TIMP-1 levels combined with other laboratory parameters were all significantly associated with clinical outcomes in the 69 (15%) patients with disease progression (p<0.0001). The best multivariate model to predict clinical outcomes included baseline bilirubin, albumin, international normalised ratio (INR) and YKL-40 levels. All of the baseline serum fibrosis marker levels were also significantly associated with histological fibrosis progression that developed in 70 (33%) of the 209 patients with cirrhosis (p <0.0001). However, baseline HA and platelet counts were best at predicting histological progression (area under the curve (AUC)=0.663).

Conclusion Pretreatment serum fibrosis marker levels are significantly increased in patients with CHC at risk of clinical and histological disease progression. If validated in additional cohorts, measurement of these markers could help identify patients with CHC who would benefit from more frequent and intensive monitoring.

Trial Registration Number NCT00006164.

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