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P46 The prediction of liver related outcomes using histological tools as an endpoint for studies evaluating anti-fibrotic therapies
  1. G E Dolman1,
  2. G Li2,
  3. G Burgess3,
  4. T Gray4,
  5. A M Zaitoun4,
  6. W Irving5,
  7. I N Guha1
  1. 1Nottingham Digestive Diseases Centre/Biomedical Research Unit, University of Nottingham
  2. 2Pfizer Inc, China
  3. 3Pfizer Ltd, UK
  4. 4Department of Histopathology, Nottingham University Hospitals NHS Trust
  5. 5Department of Microbiology, Nottingham University Hospitals NHS Trust

Abstract

Introduction Liver related outcomes (LRO) represent a meaningful end-point for future anti-fibrotic therapies. Staging of liver fibrosis on histology is a surrogate for these outcomes but may not be an ideal tool.

Aim Our initial aim was to determine liver related outcomes and survival from the individual stages of significant fibrosis. Our second aim was to assess the value of morphometric collagen quantification within cirrhosis to predict clinical outcomes.

Method The study cohort was selected from a single centre within the Trent HCV study, a prospective cohort which began in 1991 to address the natural history of chronic hepatitis C. Inclusion criteria for this study were the presence of significant fibrosis (at least Ishak Stage (IS) three on biopsy) and at least 3-year follow-up post biopsy. LRO was defined as decompensation (variceal bleeding, ascites, encephalopathy), HCC, liver transplant and liver-related death. Automated morphometry was performed to measure the Collagen Area Fraction (CAF). Survival at 3, 5 and 7 years respectively was evaluated.

Results The study cohort comprised 155 patients (70% male; mean age 49 years). The median follow-up time was 78 months. A LRO occurred in 48 patients (31.0%, estimated annual incidence 5.2%). HCC developed in 16 patients (10.6%, estimated annual incidence 1.6%) liver-related death occurred in 34 patients (21.9%, estimated annual incidence 3.3%); clinical decompensation developed in 20 patients (13.3%, estimated annual incidence 2.1%). See Abstract P46 table 1. CAF was measured in a subgroup of 89 patients. The median CAF was calculated for each Ishak stage and increased progressively towards the more advanced stages. (IS 3: median CAF 3.7%, IQR 1.5–5.1; IS 4: median CAF 5.2%, IQR 2.8–7.4; IS 5: median CAF 6.8%, IQR 3.4–9.5; IS 6: median CAF 9.9%, IQR 6.2–15.7). Within Ishak stage 6 the median CAF scores predicting LRO were higher (13.89, 12.48 and 12.69%) compared to median CAF scores in patients with no outcomes (8.59, 8.32 and 8.10%) at years 3, 5 and 7 respectively.

Abstract P46 Table 1

LRO and survival by Ishak Stage

Conclusion Clinical outcomes represent realistic and meaningful end-points for future trials evaluating anti-fibrotic agents once advanced fibrosis has developed. Further development and validation of morphometry within advanced fibrosis could enable better identification of patients at risk of more rapid progression of liver disease than Ishak stage alone.

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