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

• Published in: Hepatology communications 2023-10, Vol.7 (10)
• Main Authors: Karsdal, Morten A, Hallsworth, Kate, Scragg, Jadine, Leeming, Diana J, Villesen, Ida F, Avery, Leah, Haigh, Laura, Govaere, Olivier, Wichmann, Sarah, Taylor, Guy, Cassidy, Sophie, McPherson, Stuart, Anstee, Quentin M
• Format: Article
• Language: English
• Subjects: Biomarkers; Collagen; Complement C3; Complement C4; Humans; Non-alcoholic Fatty Liver Disease; Original; Weight Loss
• ISSN: 2471-254X; 2471-254X
• DOI: 10.1097/HC9.0000000000000254

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. 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. 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. Thus, the likelihood of treatment response may be predicted at baseline by quantification of fibrogenesis biomarkers.