Circulating FGF21 and Ketone Bodies Modify the Risk of MASLD and Mortality: Insights from the PREVEND Cohort Study
Abstract
1. Introduction
2. Results
2.1. Baseline Characteristics of the Study Population
2.2. Logistic Regression Analyses and Interaction Between FGF21 and Ketone Bodies in MASLD
2.3. Longitudinal Analyses and Interaction of FGF21 and Ketone Bodies on All-Cause Mortality
3. Discussion
4. Materials and Methods
4.1. Study Design and Participants
4.2. Data Collection
4.3. Outcome Data
4.4. Statistical Methods
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AcAc | Acetoacetate |
AMPK | AMP-activated protein kinase |
BHB | β-Hydroxybutyrate |
eGFR | Estimated glomerular filtration rate |
FGF | Fibroblast growth factor |
FGF21 | Fibroblast growth factor 21 |
FLI | Fatty Liver Index |
GFR | Glomerular filtration rate |
GGT | Gamma-glutamyltransferase |
HDL | High-density lipoprotein |
ICD-10 | International Classification of Diseases, 10th Revision |
IQ | Interquartile |
MASLD | Metabolic dysfunction-associated steatotic liver disease |
MASH | Metabolic dysfunction-associated steatohepatitis |
NMR | Nuclear magnetic resonance |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
OR | Odds ratio |
PPARα | Peroxisome proliferator-activated receptor alpha |
PREVEND | Prevention of Renal and Vascular End-stage Disease |
SD | Standard deviation |
T2D | Type 2 diabetes |
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Variable | Value |
---|---|
Circulating FGF21 (pg/mL) | 888 [534–1374] |
Ketone bodies (µmol/L) | 176 [139–247] |
Age (years) | 53 ± 12 |
Sex (Male, %) | 2968 (49) |
Waist circumference (cm) | 91 [82–100] |
eGFR (mL/min/1.73 m2) | 97 ± 17 |
Urinary albumin excretion (mg/day) | 9 [6–15] |
Alcohol intake (>1 drink per day/%) | 1558 (26) |
Smoking status (n/%) | 1689 (28) |
Total cholesterol (mmol/L) | 5.4 ± 1.0 |
HDL cholesterol (mmol/L) | 1.3 ± 0.3 |
Systolic blood pressure (mmHg) | 126 ± 19 |
Diabetes (n/%) | 324 (5) |
Fatty Liver Index | 36 [14–67] |
MASLD (n/%) | 1864 (31) |
Circulating FGF21 Concentration | Circulating Ketone Bodies | Interaction Between FGF21 and Ketone Bodies | |||
---|---|---|---|---|---|
Model | OR (95% CI) | p-Value | OR (95% CI) | p-Value | p-Value |
Model 1 | 1.93 (1.81–2.05) | <0.001 | 1.29 (1.19–2.05) | <0.001 | 0.004 |
Model 2 | 1.98 (1.86–2.12) | <0.001 | 1.21 (1.11–2.12) | <0.001 | 0.03 |
Model 3 | 1.91 (1.79–2.05) | <0.001 | 1.17 (1.07–1.28) | <0.001 | 0.03 |
Model 4 | 1.82 (1.64–2.02) | <0.001 | 1.19 (1.03–1.38) | 0.01 | 0.01 |
Events, n (%) | 1864 (31%) | 1864 (31%) |
Analyses of FGF21 with MASLD in Participants with Ketone Bodies Below or Above the Median | |||
Events, n (%) | OR (95% CI) per Doubling | p-Value | |
Subgroup | |||
Ketone bodies < 176 µM | 768 (26%) | 1.58 (1.35–1.85) | <0.001 |
Ketone bodies > 176 µM | 1096 (36%) | 2.05 (1.78–2.37) | <0.001 |
Analyses of Ketone Bodies with MASLD in Participants with Ketone Bodies Below or Above the Median | |||
Events, n (%) | OR (95% CI) per Doubling | p-Value | |
Subgroup | |||
FGF21 < 888 pg/mL | 580 (19%) | 0.98 (0.78–1.23) | 0.86 |
FGF21 > 888 pg/mL | 1283 (43%) | 1.41 (1.73–1.70) | <0.001 |
Circulating FGF21 Concentration | Circulating Ketone Bodies | Interaction FGF21 and Ketone Bodies | |||
---|---|---|---|---|---|
Model | HR (95% CI) | p-Value | HR (95% CI) | p-Value | p-Value |
Model 1 | 1.24 (1.16–1.32) | <0.001 | 1.46 (1.34–1.59) | <0.001 | 0.038 |
Model 2 | 1.13 (1.08–1.30) | <0.001 | 1.18 (1.08–1.30) | <0.001 | 0.044 |
Model 3 | 1.08 (1.01–1.16) | 0.029 | 1.17 (1.06–1.29) | 0.001 | 0.003 |
Model 4 | 1.05 (0.97–1.13) | 0.17 | 1.16 (1.06–1.28) | 0.002 | 0.005 |
Events, n (%) | 843 (14%) | 843 (14%) |
Analyses of FGF21 with Mortality in Participants with Ketone Bodies Below or Above the Median | |||
Events, n (%) | HR (95% CI) per Doubling | p-Value | |
Subgroup | |||
Ketone bodies < 176 µM | 306 (10%) | 1.03 (0.91–1.16) | 0.67 |
Ketone bodies > 176 µM | 537 (18%) | 1.11 (1.02–1.21) | 0.022 |
Analyses of Ketone Bodies with Mortality in Participants with Ketone Bodies Below or Above the Median | |||
Events, n (%) | HR (95% CI) per Doubling | p-Value | |
Subgroup | |||
FGF21 < 888 pg/mL | 334 (11%) | 1.11 (0.96–1.28) | 0.17 |
FGF21 > 888 pg/mL | 508 (17%) | 1.26 (1.11–1.43) | <0.001 |
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Chvatal-Medina, M.; Li, Y.; Dam, W.A.; Connelly, M.A.; Moshage, H.; Bakker, S.J.L.; Dullaart, R.P.F.; Post, A. Circulating FGF21 and Ketone Bodies Modify the Risk of MASLD and Mortality: Insights from the PREVEND Cohort Study. Int. J. Mol. Sci. 2025, 26, 5059. https://doi.org/10.3390/ijms26115059
Chvatal-Medina M, Li Y, Dam WA, Connelly MA, Moshage H, Bakker SJL, Dullaart RPF, Post A. Circulating FGF21 and Ketone Bodies Modify the Risk of MASLD and Mortality: Insights from the PREVEND Cohort Study. International Journal of Molecular Sciences. 2025; 26(11):5059. https://doi.org/10.3390/ijms26115059
Chicago/Turabian StyleChvatal-Medina, Mateo, Yakun Li, Wendy A. Dam, Margery A. Connelly, Han Moshage, Stephan J. L. Bakker, Robin P. F. Dullaart, and Adrian Post. 2025. "Circulating FGF21 and Ketone Bodies Modify the Risk of MASLD and Mortality: Insights from the PREVEND Cohort Study" International Journal of Molecular Sciences 26, no. 11: 5059. https://doi.org/10.3390/ijms26115059
APA StyleChvatal-Medina, M., Li, Y., Dam, W. A., Connelly, M. A., Moshage, H., Bakker, S. J. L., Dullaart, R. P. F., & Post, A. (2025). Circulating FGF21 and Ketone Bodies Modify the Risk of MASLD and Mortality: Insights from the PREVEND Cohort Study. International Journal of Molecular Sciences, 26(11), 5059. https://doi.org/10.3390/ijms26115059