Association between ketone body levels and chronic liver disease: Epidemiological studies and potential mechanisms

Zeping Liu; Yihu Zheng; Yi Li; Zeping Liu; Yihu Zheng; Yi Li

doi:10.3934/publichealth.2026006

AIMS Public Health

2026, Volume 13, Issue 1: 82-104. doi: 10.3934/publichealth.2026006

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Association between ketone body levels and chronic liver disease: Epidemiological studies and potential mechanisms

1.
West China School of Medicine, Sichuan University, Chengdu, China
2.
College of Computer Science, Sichuan University, Chengdu, China
3.
Department of General Surgery, the First Affiliated Hospital of Wenzhou Medical University, China
4.
Department of Laboratory Medicine, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Wuhou District, Chengdu, Sichuan, China

Received: 15 September 2025 Revised: 09 December 2025 Accepted: 15 December 2025 Published: 07 January 2026

Chronic liver disease encompasses conditions such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, alcohol-related liver disease, and chronic viral hepatitis, being a major cause of cirrhosis and hepatocellular carcinoma. Ketone bodies, crucial hepatic energy substrates, may serve as biomarkers in CLD progression. This review investigated the association between chronic liver diseases and ketone body levels. Studies indicate that ketone body levels may serve as biomarkers for chronic liver diseases. Patients with metabolic dysfunction-associated steatotic liver disease have elevated ketone levels. However, findings are inconsistent in obese populations and metabolic dysfunction-associated steatohepatitis. The relationship between ketone body levels and other chronic liver diseases, such as alcohol-related liver disease and chronic viral hepatitis, remains unclear, necessitating further research. The review also discussed potential mechanisms linking ketone metabolism abnormalities to chronic liver disease pathogenesis. Understanding the role of ketone bodies in chronic liver disease is essential for developing targeted interventions, and future research should employ large-scale databases and causal inference methods to clarify these associations.
- chronic liver disease,
- ketone body,
- acetone,
- acetoacetates,
- β-hydroxybutyrate
Citation: Zeping Liu, Yihu Zheng, Yi Li. Association between ketone body levels and chronic liver disease: Epidemiological studies and potential mechanisms[J]. AIMS Public Health, 2026, 13(1): 82-104. doi: 10.3934/publichealth.2026006

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Abstract

Chronic liver disease encompasses conditions such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, alcohol-related liver disease, and chronic viral hepatitis, being a major cause of cirrhosis and hepatocellular carcinoma. Ketone bodies, crucial hepatic energy substrates, may serve as biomarkers in CLD progression. This review investigated the association between chronic liver diseases and ketone body levels. Studies indicate that ketone body levels may serve as biomarkers for chronic liver diseases. Patients with metabolic dysfunction-associated steatotic liver disease have elevated ketone levels. However, findings are inconsistent in obese populations and metabolic dysfunction-associated steatohepatitis. The relationship between ketone body levels and other chronic liver diseases, such as alcohol-related liver disease and chronic viral hepatitis, remains unclear, necessitating further research. The review also discussed potential mechanisms linking ketone metabolism abnormalities to chronic liver disease pathogenesis. Understanding the role of ketone bodies in chronic liver disease is essential for developing targeted interventions, and future research should employ large-scale databases and causal inference methods to clarify these associations.

Abbreviations

CLD

Chronic liver disease

MASLD

metabolic dysfunction-associated steatotic liver disease

MASH

metabolic dysfunction-associated steatohepatitis

ALD

alcohol-related liver disease

HCC

hepatocellular carcinoma

HBV

hepatitis B virus

HCV

hepatitis C virus

AKBR

arterial ketone body ratio

BMI

body mass index

Acknowledgments

This study was supported by the Sichuan Natural Science Foundation (24NSFSC3735) and the Sichuan Science and Technology Program (2024NSFSC1540).

Authors' contributions

Zeping Liu: Investigation, Data Curation, Writing-Original Draft. Yihu Zheng: Conceptualization. Yi Li: Writing-Review & Editing.

Conflict of interest

The authors declare no conflicts of interest.

References

[1]	Dabos KJ, Parkinson JA, Sadler IH, et al. (2015) ¹H nuclear magnetic resonance spectroscopy-based metabonomic study in patients with cirrhosis and hepatic encephalopathy. World J Hepatol 7: 1701-1707. https://doi.org/10.4254/wjh.v7.i12.1701
[2]	Cao D, Cai C, Ye M, et al. (2017) Differential metabonomic profiles of primary hepatocellular carcinoma tumors from alcoholic liver disease, HBV-infected, and HCV-infected cirrhotic patients. Oncotarget 8: 53313-53325. https://doi.org/10.18632/oncotarget.18397
[3]	Post A, Garcia E, van den Berg EH, et al. (2021) Nonalcoholic fatty liver disease, circulating ketone bodies and all-cause mortality in a general population-based cohort. Eur J Clin Invest 51: e13627. https://doi.org/10.1111/eci.13627
[4]	Hwang CY, Choe W, Yoon KS, et al. (2022) Molecular mechanisms for ketone body metabolism, signaling functions, and therapeutic potential in cancer. Nutrients 14: 4932. https://doi.org/10.3390/nu14224932
[5]	Kimura I, Inoue D, Maeda T, et al. (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci 108: 8030-8035. https://doi.org/10.1073/pnas.1016088108
[6]	Lee AK, Kim DH, Bang E, et al. (2020) β-Hydroxybutyrate suppresses lipid accumulation in aged liver through GPR109A-mediated signaling. Aging Dis 11: 777-790. https://doi.org/10.14336/AD.2019.0926
[7]	Lund TM, Ploug KB, Iversen A, et al. (2015) The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity. J Neurochem 132: 520-531. https://doi.org/10.1111/jnc.12975
[8]	Juge N, Gray JA, Omote H, et al. (2010) Metabolic control of vesicular glutamate transport and release. Neuron 68: 99-112. https://doi.org/10.1016/j.neuron.2010.09.002
[9]	Mooli RGR, Ramakrishnan SK (2022) Emerging role of hepatic ketogenesis in fatty liver disease. Front Physiol 13: 946474. https://doi.org/10.3389/fphys.2022.946474
[10]	Loomba R, Friedman SL, Shulman GI (2021) Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184: 2537-2564. https://doi.org/10.1016/j.cell.2021.04.015
[11]	Satapati S, Kucejova B, Duarte JA, et al. (2015) Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest 125: 4447-4462. https://doi.org/10.1172/JCI82204
[12]	Grattagliano I, Montezinho LP, Oliveira PJ, et al. (2019) Targeting mitochondria to oppose the progression of nonalcoholic fatty liver disease. Biochem Pharmacol 160: 34-45. https://doi.org/10.1016/j.bcp.2018.11.020
[13]	Solinas G, Borén J, Dulloo AG (2015) De novo lipogenesis in metabolic homeostasis: More friend than foe?. Mol Metab 4: 367-377. https://doi.org/10.1016/j.molmet.2015.03.004
[14]	Sunny NE, Satapati S, Fu X, et al. (2010) Progressive adaptation of hepatic ketogenesis in mice fed a high-fat diet. Am J Physiol Endocrinol Metab 298: E1226-E1235. https://doi.org/10.1152/ajpendo.00033.2010
[15]	Satapati S, Sunny NE, Kucejova B, et al. (2012) Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J Lipid Res 53: 1080-1092. https://doi.org/10.1194/jlr.M023382
[16]	Croci I, Byrne NM, Choquette S, et al. (2013) Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease. Gut 62: 1625-1633. https://doi.org/10.1136/gutjnl-2012-302789
[17]	Mey JT, Erickson ML, Axelrod CL, et al. (2020) β-Hydroxybutyrate is reduced in humans with obesity-related NAFLD and displays a dose-dependent effect on skeletal muscle mitochondrial respiration in vitro. Am J Physiol Endocrinol Metab 319: E187-E195. https://doi.org/10.1152/ajpendo.00058.2020
[18]	Fletcher JA, Deja S, Satapati S, et al. (2019) Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver. JCI Insight 4: e127737. https://doi.org/10.1172/jci.insight.127737
[19]	Asif S, Kim RY, Fatica T, et al. (2022) Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis. Mol Metab 61: 101494. https://doi.org/10.1016/j.molmet.2022.101494
[20]	Buzzetti E, Pinzani M, Tsochatzis EA (2016) The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65: 1038-1048. https://doi.org/10.1016/j.metabol.2015.12.012
[21]	Chen Y, Ouyang X, Hoque R, et al. (2018) β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway. J Hepatol 69: 687-696. https://doi.org/10.1016/j.jhep.2018.04.004
[22]	Peng Z, Borea PA, Varani K, et al. (2009) Adenosine signaling contributes to ethanol-induced fatty liver in mice. J Clin Invest 119: 582-594. https://doi.org/10.1172/JCI37409
[23]	Yokoyama A, Yokoyama T, Mizukami T, et al. (2014) Alcoholic ketosis: Prevalence, determinants, and ketohepatitis in Japanese alcoholic Men. Alcohol Alcohol 49: 618-625. https://doi.org/10.1093/alcalc/agu048
[24]	Becker HC (2012) Effects of alcohol dependence and withdrawal on stress responsiveness and alcohol consumption. Alcohol Res Curr Rev 34: 448-458. https://doi.org/10.35946/arcr.v34.4.09
[25]	Rachdaoui N, Sarkar DK (2013) Effects of Alcohol on the Endocrine System. Endocrinol Metab Clin North Am 42: 593-615. https://doi.org/10.1016/j.ecl.2013.05.008
[26]	Liu Y, Hong Z, Tan G, et al. (2014) NMR and LC/MS-based global metabolomics to identify serum biomarkers differentiating hepatocellular carcinoma from liver cirrhosis: Serum Biomarkers in Hepatocellular Carcinoma. Int J Cancer 135: 658-668. https://doi.org/10.1002/ijc.28706
[27]	Jaworski DM, Namboodiri AM, Moffett JR (2016) Acetate as a metabolic and epigenetic modifier of cancer therapy. J Cell Biochem 117: 574-588. https://doi.org/10.1002/jcb.25305
[28]	Sullivan LB, Gui DY, Hosios AM, et al. (2015) Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162: 552-563. https://doi.org/10.1016/j.cell.2015.07.017
[29]	Fotakis C, Kalafati IP, Amanatidou AI, et al. (2023) Serum metabolomic profiling unveils distinct sex-related metabolic patterns in NAFLD. Front Endocrinol 14: 1230457. https://doi.org/10.3389/fendo.2023.1230457
[30]	Robinson EJ, Taddeo MC, Chu X, et al. (2021) Aqueous metabolite trends for the progression of nonalcoholic fatty liver disease in female bariatric surgery patients by targeted 1H-NMR metabolomics. Metabolites 11: 737. https://doi.org/10.3390/metabo11110737
[31]	Männistö VT, Simonen M, Hyysalo J, et al. (2015) Ketone body production is differentially altered in steatosis and non-alcoholic steatohepatitis in obese humans. Liver Int 35: 1853-1861. https://doi.org/10.1111/liv.12769
[32]	Kotronen A, Seppälä-Lindroos A, Vehkavaara S, et al. (2009) Liver fat and lipid oxidation in humans. Liver Int 29: 1439-1446. https://doi.org/10.1111/j.1478-3231.2009.02076.x
[33]	Amathieu R, Triba MN, Nahon P, et al. (2014) Serum 1H-NMR metabolomic fingerprints of acute-on-chronic liver failure in intensive care unit patients with alcoholic cirrhosis. PLoS One 9: e89230. https://doi.org/10.1371/journal.pone.0089230
[34]	Saibara T, Maeda T, Onishi S, et al. (1994) The arterial blood ketone body ratio as a possible marker of multi-organ failure in patients with alcoholic hepatitis. Liver 14: 85-89. https://doi.org/10.1111/j.1600-0676.1994.tb00053.x
[35]	Stewart A, Johnston DG, Alberti KG, et al. (1983) Hormone and metabolite profiles in alcoholic liver disease. Eur J Clin Invest 13: 397-403. https://doi.org/10.1111/j.1365-2362.1983.tb00120.x
[36]	Meoni G, Lorini S, Monti M, et al. (2019) The metabolic fingerprints of HCV and HBV infections studied by nuclear magnetic resonance spectroscopy. Sci Rep 9: 4128. https://doi.org/10.1038/s41598-019-40028-4
[37]	Embade N, Mariño Z, Diercks T, et al. (2016) Metabolic characterization of advanced liver fibrosis in HCV patients as studied by serum 1H-NMR spectroscopy. PLoS One 11: e0155094. https://doi.org/10.1371/journal.pone.0155094
[38]	Sato C, Saito T, Misawa K, et al. (2013) Impaired mitochondrial β-oxidation in patients with chronic hepatitis C: Relation with viral load and insulin resistance. BMC Gastroenterol 13: 112. https://doi.org/10.1186/1471-230X-13-112
[39]	Lim K, Kang M, Park J (2021) Association between fasting ketonuria and advanced liver fibrosis in non-alcoholic fatty liver disease patients without prediabetes and diabetes mellitus. Nutrients 13: 3400. https://doi.org/10.3390/nu13103400
[40]	Sasaki R, Taura N, Miyazoe Y, et al. (2018) Ketone bodies as a predictor of prognosis of hepatocellular carcinoma after transcatheter arterial chemoembolization. Nutrition 50: 97-103. https://doi.org/10.1016/j.nut.2017.12.015
[41]	Teilhet C, Morvan D, Joubert-Zakeyh J, et al. (2017) Specificities of human hepatocellular carcinoma developed on non-alcoholic fatty liver disease in absence of cirrhosis revealed by tissue extracts 1H-NMR spectroscopy. Metabolites 7: 49. https://doi.org/10.3390/metabo7040049
[42]	Yan LN, Chen XL, Li ZH, et al. (2007) Perioperative management of primary liver cancer. World J Gastroenterol 13: 1970-1974. https://doi.org/10.3748/wjg.v13.i13.1970
[43]	Younossi ZM, Koenig AB, Abdelatif D, et al. (2016) Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64: 73-84. https://doi.org/10.1002/hep.28431
[44]	BMJ Best PracticeAlcohol-related liver disease (2024). [cited 2025 December 15]. Available from: https://bestpractice.bmj.com/topics/zh-cn/1116
[45]	Cui F, Blach S, Manzengo Mingiedi C, et al. (2023) Global reporting of progress towards elimination of hepatitis B and hepatitis C. Lancet Gastroenterol Hepatol 8: 332-342. https://doi.org/10.1016/S2468-1253(22)00386-7
[46]	Yang X, Li Q, Liu W, et al. (2023) Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: From pathogenesis to treatment. Cell Mol Immunol 20: 583-599. https://doi.org/10.1038/s41423-023-01010-3
[47]	Dong Z, Wang Y, Jin W (2024) Liver cirrhosis: molecular mechanisms and therapeutic interventions. MedComm 5: e721. https://doi.org/10.1002/mco2.721
[48]	Choudhury A, Adali G, Kaewdech A, et al. (2024) Liver transplantation in chronic liver disease and acute on chronic liver failure- indication, timing and practices. J Clin Exp Hepatol 14: 101347. https://doi.org/10.1016/j.jceh.2024.101347
[49]	Rumgay H, Ferlay J, de Martel C, et al. (2022) Global, regional and national burden of primary liver cancer by subtype. Eur J Cancer 161: 108-118. https://doi.org/10.1016/j.ejca.2021.11.023
[50]	Johnson PJ, Kalyuzhnyy A, Boswell E, et al. (2024) Progression of chronic liver disease to hepatocellular carcinoma: Implications for surveillance and management. BJC Rep 2: 39. https://doi.org/10.1038/s44276-024-00050-0
[51]	Serviddio G, Bellanti F, Vendemiale G, et al. (2011) Mitochondrial dysfunction in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 5: 233-244. https://doi.org/10.1586/egh.11.11
[52]	Cotter DG, Ercal B, Huang X, et al. (2014) Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia. J Clin Invest 124: 5175-5190. https://doi.org/10.1172/JCI76388
[53]	Kaluba FC, Rogers TJ, Jeong YJ, et al. (2025) An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells. Nat Metab 7: 2033-2044. https://doi.org/10.1038/s42255-025-01366-y
[54]	Li K, Wang WH, Wu JB, et al. (2023) β-hydroxybutyrate: A crucial therapeutic target for diverse liver diseases. Biomed Pharmacother 165: 115191. https://doi.org/10.1016/j.biopha.2023.115191
[55]	Ristic-Medic D, Kovacic M, Takic M, et al. (2020) Calorie-restricted mediterranean and low-fat diets affect fatty acid status in individuals with nonalcoholic fatty liver disease. Nutrients 13: 15. https://doi.org/10.3390/nu13010015
[56]	Moore MP, Cunningham RP, Dashek RJ, et al. (2020) A fad too far? Dietary strategies for the prevention and treatment of NAFLD. Obesity 28: 1843-1852. https://doi.org/10.1002/oby.22964
[57]	O'Neill B, Raggi P (2020) The ketogenic diet: Pros and cons. Atherosclerosis 292: 119-126. https://doi.org/10.1016/j.atherosclerosis.2019.11.021
[58]	Luukkonen PK, Dufour S, Lyu K, et al. (2020) Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease. Proc Natl Acad Sci 117: 7347-7354. https://doi.org/10.1073/pnas.1922344117
[59]	McKenzie AL, Athinarayanan SJ, McCue JJ, et al. (2021) Type 2 diabetes prevention focused on normalization of glycemia: A two-year pilot study. Nutrients 13: 749. https://doi.org/10.3390/nu13030749
[60]	Lan Y, Jin C, Kumar P, et al. (2022) Ketogenic diets and hepatocellular carcinoma. Front Oncol 12: 879205. https://doi.org/10.3389/fonc.2022.879205
[61]	Sarkar A, Jin Y, DeFelice BC, et al. (2023) Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver. eLife 12: e82311. https://doi.org/10.7554/eLife.82311
[62]	Miyauchi T, Uchida Y, Kadono K, et al. (2019) Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury. Proc Natl Acad Sci 116: 13533-13542. https://doi.org/10.1073/pnas.1820282116
[63]	Bae HR, Kim DH, Park MH, et al. (2016) β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget 7: 66444-66454. https://doi.org/10.18632/oncotarget.12119

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