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Serum levels of fibrogenesis biomarkers reveal distinct endotypes predictive of response to weight loss in advanced nonalcoholic fatty liver disease

Lookup NU author(s): Dr Kate HallsworthORCiD, Jadine Scragg, Dr Leah Avery, Laura HaighORCiD, Dr Olivier GovaereORCiD, Dr Guy Taylor, Dr Sophie Cassidy, Professor Stuart McPhersonORCiD, Professor Quentin AnsteeORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023 Lippincott Williams and Wilkins. All rights reserved.Background: NAFLD is associated with activation of fibroblasts and hepatic fibrosis. Substantial patient heterogeneity exists, so it remains challenging to risk-stratify patients. We hypothesized that the amount of fibroblast activity, as assessed by circulating biomarkers of collagen formation, can define a "high-risk, high-fibrogenesis" patient endotype that exhibits greater fibroblast activity and potentially more progressive disease, and this endotype may be more amendable to dietary intervention. Methods: Patients with clinically confirmed advanced NAFLD were prescribed a very low-calorie diet (VLCD) intervention (800 kcal/d) to induce weight loss, achieved using total diet replacement. Serum markers of type III (PRO-C3) and IV collagen (PRO-C4) fibrogenesis were assessed at baseline every second week until the end of the VLCD, and 4 weeks post-VLCD and at 9 months follow-up. Results: Twenty-six subjects had a mean weight loss of 9.7% with VLCD. This was associated with significant improvements in liver biochemistry. When stratified by baseline PRO-C3 and PRO-C4 into distinct fibrosis endotypes, these predicted substantial differences in collagen fibrogenesis marker dynamics in response to VLCD. Patients in the high activity group (PRO-C3 11.4 ng/mL and/or PRO-C4 236.5 ng/mL) exhibited a marked reduction of collagen fibrogenesis, ranging from a 40%-55% decrease in PRO-C3 and PRO-C4, while fibrogenesis remained unchanged in the low activity group. The biochemical response to weight loss was substantially greater in patients a priori exhibiting a high fibroblast activity endotype in contrast to patients with low activity. Conclusions: Thus, the likelihood of treatment response may be predicted at baseline by quantification of fibrogenesis biomarkers.

Publication metadata

Author(s): Karsdal MA, Hallsworth K, Scragg J, Leeming DJ, Villesen IF, Avery L, Haigh L, Govaere O, Wichmann S, Taylor G, Cassidy S, McPherson S, Anstee QM

Publication type: Article

Publication status: Published

Journal: Hepatology Communications

Year: 2023

Volume: 7

Issue: 10

Print publication date: 01/10/2023

Acceptance date: 21/06/2023

Date deposited: 09/04/2024

ISSN (electronic): 2471-254X

Publisher: Lippincott Williams and Wilkins


DOI: 10.1097/HC9.0000000000000254

PubMed id: 37756043


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Funder referenceFunder name
777377European Commission
European Union Horizon 2020 Research and Innovation Programme
Innovative Medicines Initiative 2 Joint Undertaking
National Institute for Health Research
Newcastle NIHR Biomedical Research Centre