Circulating Angiopoietin-like protein 8 (ANGPTL8) and steatotic liver disease related to metabolic dysfunction: an updated systematic review and meta-analysis

Farah Abdelhameed ^1,2 Lukasz Lagojda ^1,3 Chris Kite ^1,4,5 Alexander Dallaway ^1,4 Attia Mustafa ^1,2,6,7 Nwe Ni Than ⁸ Eva Kassi ^10,9 Harpal Singh Randeva ^1,11,2,6* Ioannis Kyrou ^{1,11,12,13,14,2,6*}

• ¹ Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
• ² Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
• ³ Sheffield Centre for Health and Related Research (SCHARR), School of Medicine and Population Health, University of Sheffield, Sheffield, United Kingdom
• ⁴ School of Health and Society, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, United Kingdom
• ⁵ Faculty of Health, Medicine and Society, Division of Public Health, Sport and Wellbeing, University of Chester, Chester, United Kingdom
• ⁶ Warwick Medical School, University of Warwick, Coventry, United Kingdom
• ⁷ Internal Medicine Department, Faculty of Medicine, Omar Almukhtar University, Al-Bayda, Libya
• ⁸ Gastroenterology and Hepatology Department, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
• ⁹ Department of Biological Chemistry, National and Kapodistrian University of Athens Medical School, Athens, Greece
• ¹⁰ Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
• ¹¹ Centre for Sport, Exercise and Life Sciences, Faculty of Health and Life Sciences, Coventry University, Coventry, West Midlands, United Kingdom
• ¹² Aston Pharmacy School, School of Life & Health Sciences, Aston University, Birmingham, West Midlands, United Kingdom
• ¹³ College of Health, Psychology and Social Care, University of Derby, Derby, United Kingdom
• ¹⁴ Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, Athens, Greece

Background: Steatotic liver disease related to metabolic dysfunction is the most common cause of chronic liver disease globally. The spectrum of this condition includes steatosis and steatohepatitis and was previously referred to as non-alcoholic fatty liver disease (NAFLD), but has been renamed as metabolic dysfunction-associated fatty liver disease (MAFLD) and more recently as metabolic dysfunction-associated steatotic liver disease (MASLD). Angiopoietin-like protein 8 (ANGPTL8), also known as betatrophin or lipasin, regulates triglycerides and has emerged as a potential novel biomarker for steatosis/steatohepatitis. Therefore, this systematic review aimed to identify and synthesize the evidence on the possible association of circulating ANGPTL8 concentrations with NAFLD, MAFLD or MASLD.Methods: PubMed/MEDLINE, Cochrane Library, EMBASE, and Web of Science were searched for studies published in English reporting circulating ANGPTL8 concentrations in adults with NAFLD or MAFLD or MASLD and controls. A meta-analysis was performed, reporting the standardized mean difference (SMD) of circulating ANGPTL8 concentrations between these two groups. Study quality and risk of bias were assessed using the NIH quality assessment tool and RoBANS 2, respectively.Results: Of the 104 identified publications, eight studies were eligible for this systematic review, whilst seven were also eligible for meta-analysis (543 NAFLD or MAFLD cases vs. 352 controls). Circulating ANGPTL8 concentrations were significantly higher in patients with NAFLD or MAFLD compared with controls (SMD: 0.62, 95%CI: 0.28-0.97; p<0.001). Considerable heterogeneity was noted among these studies, with six studies having high risk of bias in at least one RoBANS 2 domain.Conclusion: These findings present up-to-date comprehensive evidence indicating that adults with steatotic liver disease related to metabolic dysfunction exhibit higher circulating ANGPTL8 concentrations compared with controls. Given the need for novel screening/diagnostic biomarkers for steatosis/steatohepatitis, as well for additional drug targets, large and prospective studies are required to confirm this association and explore its temporal direction, particularly under the new MASLD diagnosis/term.