Growth differentiation factor 15 predicts advanced fibrosis in biopsy‐proven non‐alcoholic fatty liver disease

• Published in: Liver international Vol. 38; no. 4; pp. 695 - 705
• Main Authors: Koo, Bo Kyung, Um, Sung Hee, Seo, Dong Soo, Joo, Sae Kyung, Bae, Jeong Mo, Park, Jeong Hwan, Chang, Mee Soo, Kim, Jung Ho, Lee, Jieun, Jeong, Won‐Il, Kim, Won
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.04.2018
• Subjects: Actin; Adult; Aged; Animals; Aspartate aminotransferase; Biomarkers; Biomarkers - blood; Biopsy; Body mass; Body mass index; Body size; Cells, Cultured; Collagen (type I); Confidence intervals; Cross-Sectional Studies; Diabetes mellitus; Differentiation; Fatty liver; Female; Fibrosis; Gene expression; growth differentiation factor 15; Growth Differentiation Factor 15 - blood; Growth Differentiation Factor 15 - genetics; Hepatocytes; Humans; Hypertension; Immunoassays; Insulin; Insulin resistance; Kupffer cells; Liver; Liver - pathology; Liver Cirrhosis - blood; Liver Cirrhosis - diagnosis; Liver diseases; Logistic Models; Male; Men; Mice; Middle Aged; Muscles; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - pathology; Palmitic acid; Patients; Pharmacology; Phosphorylation; Prospective Studies; Republic of Korea; Risk Factors; RNA, Messenger - analysis; sarcopenia; Severity of Illness Index; Skeletal muscle; SMAD; Smad2 protein; Smad3 protein; Smoking; Smooth muscle; Stiffness; Republic of Korea; fibrosis; SMAD; growth differentiation factor 15; sarcopenia
• ISSN: 1478-3223; 1478-3231; 1478-3231
• DOI: 10.1111/liv.13587

Background & Aims We explored whether growth differentiation factor 15 (GDF15) affects the histological severity of non‐alcoholic fatty liver disease (NAFLD) independent of insulin resistance. Methods In a biopsy‐proven NAFLD cohort, we measured serum GDF15 levels using enzyme‐linked immunosorbent assays. Results Among 190 subjects (mean age, 53 ± 14 years; men, 52.1%), 72 (men, 65.3%) and 78 (men, 44.9%) were diagnosed with biopsy‐proven non‐alcoholic fatty liver (NAFL) and non‐alcoholic steatohepatitis (NASH) respectively. GDF15 levels were significantly higher in NASH patients than in controls (P = .010) or NAFL patients (P = .001). Subjects with advanced fibrosis (≥F3) also showed higher GDF15 levels compared to the others (F0‐2; P < .001). Among NAFLD patients, the highest quartile of GDF15 levels was significantly associated with a risk of advanced fibrosis even after adjustment for age, gender, body mass index, smoking status, hypertension, diabetes, aspartate aminotransferase, platelet, albumin, insulin resistance and low skeletal muscle mass (odds ratio, 4.27; 95% confidence interval, 1.04‐17.63), but not with NASH risk. GDF15 levels showed a significant positive correlation with liver stiffness (Spearman's ρ, .525; P < .001). Palmitate treatment increased the GDF15 mRNA expression level significantly in Kupffer cells, but not in hepatocytes. In LX‐2 cells, GDF15 treatment resulted in enhanced expression of α‐smooth muscle actin and collagen I, as well as phosphorylation of SMAD2 and SMAD3. Conclusions Our findings suggest that GDF15 may serve as a novel biomarker of advanced fibrosis in NAFLD, thereby indicating the need for urgent anti‐fibrotic pharmacotherapy.