Divergent Hepatic Outcomes of Chronic Ketone Supplementation: Ketone Salts Preserve Liver Health While Ketone Esters and Precursors Drive Inflammation and Steatosis.

Background/Objectives: Exogenous ketone supplements elevate circulating ketones without carbohydrate restriction, but their long-term hepatic safety remains unclear. This study evaluated the formulation-dependent impact of chronic ketone supplementation on liver histopathology, inflammatory signaling, and systemic biomarkers in rats. Methods: Male Sprague-Dawley rats were orally administered 1,3-butanediol (BD), medium-chain triglycerides (MCTs), ketone ester (KE), ketone electrolytes/salts (KSs), or a ketone salt-MCT combination (KSMCT) for 4 weeks. In a separate arm, animals received standard diet (SD), or SD supplemented with low-dose KE (LKE) or high-dose KE (HKE), for 83 days. Liver structure was assessed by hematoxylin and eosin staining with quantification of red blood cell density and lipid accumulation. Inflammatory and metabolic responses were evaluated by TNF-α and arginase immunohistochemistry. Serum biochemistry included glucose, proteins, electrolytes, and liver and kidney function markers. Results: BD and KE induced macrovesicular steatosis, vascular congestion, and elevated TNF-α and arginase expression, consistent with hepatic stress. MCT caused moderate hepatocellular ballooning and lipid deposition, whereas KS preserved near-normal hepatic morphology. KSMCT produced intermediate effects, reducing lipid accumulation and TNF-α compared with MCT or KE alone. KE supplementation caused dose-dependent reductions in globulin and elevations in creatinine, while HKE reduced sodium and glucose levels. Conclusions: Chronic hepatic responses to exogenous ketones are highly formulation dependent. KS demonstrated the most favorable safety profile under the tested conditions, maintaining normal hepatic structure, while BD and KE elicited adverse changes. Formulation choice is critical for the safe long-term use of exogenous ketones.