Collagen proportionate area is an independent predictor of long-term outcome in patients with non-alcoholic fatty liver disease.

Elena Buzzetti,Emmanuel A Tsochatzis,Massimo Pinzani,Amar P Dhillon,Stergios Kechagias,Emanuel K Manesis,Gioacchino Leandro,Marta Guerrero Misas,Claudia Covelli,Tuvinh Luong,Roberta Manuguerra,Andrew Hall,Mattias Ekstedt

doi:10.1111/apt.15219

Abstract

Collagen proportionate area (CPA) measurement is a technique that quantifies fibrous tissue in liver biopsies by measuring the amount of collagen deposition as a proportion of the total biopsy area. CPA predicts clinical outcomes in patients with HCV and can sub-classify cirrhosis. To test the ability of CPA to quantify fibrosis and predict clinical outcomes in patients with NAFLD. We assessed consecutive patients with biopsy-proven NAFLD from three European centres. Clinical and laboratory data were collected at baseline and at the time of the last clinical follow-up or death. CPA was performed at two different objective magnifications, whole biopsy macro and ×4 objective magnification, named standard (SM) and high (HM) magnification respectively. The correlation between CPA and liver stiffness was assessed in a sub-group of patients. Of 437 patients, 32 (7.3%) decompensated and/or died from liver-related causes during a median follow-up of 103months. CPA correlated with liver stiffness and liver fibrosis stage across the whole spectrum of fibrosis. HM CPA was significantly higher than SM CPA in stages F0-F3 but similar in cirrhosis, reflecting a higher ability to capture pericellular/perisinusoidal fibrosis at early stages. Age at baseline (HR: 1.04, 95% CI: 1.01-1.08), HM CPA (HR: 1.04 per 1% increase, 95% CI: 1.01-1.08) and presence of advanced fibrosis (HR: 15.4, 95% CI: 5.02-47.84) were independent predictors of liver-related clinical outcomes at standard and competing risk multivariate Cox-regression analysis. CPA accurately measures fibrosis and is an independent predictor of clinical outcomes in NAFLD; hence it merits further evaluation as a surrogate endpoint in clinical trials.

Highlights

Non‐alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome affecting 30% of the population in industrialised countries.[1,2] NAFLD is a complex pathological entity that develops from multiple factors acting synergistically in genetically and/or epigenetically predisposed individuals.[3,4]Despite its high prevalence, only a proportion of subjects with NAFLD develop non‐alcoholic steatohepatitis (NASH) with potential progression to fibrosis and cirrhosis.[1,5] it is important to stratify patients according to their risk of progression in order to tailor the need for interventions and dedicated specialist follow‐up.[6]
We further evaluated a separate cohort of consecutive contemporary patients with biopsy‐proven NAFLD and liver stiffness measurements by transient elastography (FibroScan®), performed within 6 months of the liver biopsy, in order to test the correlation of Collagen proportionate area (CPA) with liver stiffness
We demonstrated that the difference between SM and high magnification (HM) CPA is due to more accurate measurement of peri‐sinusoidal fibrosis using HM (Supplementary material Data S1)

Summary

Introduction

Only a proportion of subjects with NAFLD develop non‐alcoholic steatohepatitis (NASH) with potential progression to fibrosis and cirrhosis.[1,5] it is important to stratify patients according to their risk of progression in order to tailor the need for interventions and dedicated specialist follow‐up.[6] The gold standard to differentiate NAFLD from NASH and accurately stage fibrosis is a liver biopsy, despite the development of several non‐invasive fibrosis assessment tests.[7] This is because the currently available non‐invasive techniques have a satisfactory accuracy for the detection of advanced fibrosis but not for lower fibrosis stages.[8]. Aim: To test the ability of CPA to quantify fibrosis and predict clinical outcomes in patients with NAFLD. Age at baseline (HR: 1.04, 95% CI: 1.01‐1.08), HM CPA (HR: 1.04 per 1% increase, 95% CI: 1.01‐1.08) and presence of advanced fibrosis (HR: 15.4, 95% CI: 5.02‐47.84) were independent predictors of liver‐related clinical outcomes at standard and competing risk multivariate Cox‐regression analysis. Conclusions: CPA accurately measures fibrosis and is an independent predictor of clinical outcomes in NAFLD; it merits further evaluation as a surrogate endpoint in clinical trials

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Conclusion