As the science of metabolic therapy evolves, the question of long-term safety around exogenous ketone supplementation has become increasingly important. A new peer-reviewed study by Dr. Csilla Ari D`Agostino and Dr. Dominic D’Agostino, published in Pharmaceuticals (2025), explores how different ketone formulations affect the liver, inflammation, and overall metabolic health. The findings reveal that not all ketone supplements are created equal — and that formulation makes all the difference when it comes to safety and long-term use.
Why Study the Liver?
The liver plays a central role in metabolism — processing fats, producing ketones, and clearing toxins. Because exogenous ketones are metabolized in the liver, understanding how chronic supplementation impacts liver function and structure is critical.
The research team investigated the effects of five different ketone formulations—ketone electrolytes/salts (KS), ketone esters (KE), medium-chain triglycerides (MCT), 1,3-butanediol (BD), and a combined ketone salt–MCT mix (KSMCT)—in Sprague-Dawley rats over several weeks. A separate group was fed low-dose and high-dose ketone esters for 83 days to study long-term exposure.
Using advanced histological imaging and blood chemistry analysis, the team evaluated markers of inflammation (TNF-α), metabolic stress (arginase), and tissue health. This allowed them to compare how each formulation affected the liver’s structure and function.
Key Findings: Formulation Matters
The study revealed striking differences in how each ketone formulation affected the liver:
- Ketone Salts (KS) – Showed the best overall safety profile, preserving normal liver architecture with low inflammation and no fat accumulation. This group most closely resembled the healthy control animals.
- Ketone Esters (KE) – Induced macrovesicular steatosis (fat buildup in liver cells), vascular congestion, and increased inflammatory markers (TNF-α and arginase).
- 1,3-Butanediol (BD) – Produced the most pronounced steatosis and vascular congestion, likely due to its breakdown via alcohol dehydrogenase — a pathway similar to ethanol metabolism — which can generate oxidative stress.
- Medium-Chain Triglycerides (MCT) – Caused moderate lipid accumulation and inflammation, suggesting a mild but noticeable hepatic impact.
- Ketone Salt + MCT Mix (KSMCT) – Displayed intermediate effects, ketone salts seems mitigating some of MCT’s lipid accumulation while maintaining low inflammation, suggesting a potential synergistic or balancing effect.
Interestingly, while histology revealed clear differences, standard blood chemistry markers like ALT, ALP, and bilirubin remained within normal ranges, showing that routine lab tests may not detect early or formulation-specific stress. Instead, histological and molecular markers proved far more sensitive for identifying early hepatic changes.
Blood Biomarkers and Systemic Adaptations
Long-term KE use also altered several blood chemistry markers. High-dose KE groups showed lower globulin (a liver-produced protein involved in immune function) and higher creatinine, a potential indicator of renal stress, although still within physiological limits. Sodium and glucose levels also trended lower at high doses, reflecting metabolic adaptation to chronic ketone exposure.
The Mechanistic Insight: Why Some Formulations Stress the Liver
The differences stem from how each compound is metabolized:
- KE and BD produce rapid, high levels of BHB, generating excess acetyl-CoA that can overwhelm mitochondrial capacity, diverting energy toward triglyceride (fat) synthesis.
- BD, in particular, is metabolized through alcohol dehydrogenase, similar to alcohol, which can disturb redox balance and deplete cellular NAD⁺, increasing oxidative stress.
- MCTs are metabolized quickly, but in excess may lead to fat accumulation if oxidation can’t keep up.
- KS, by contrast, delivers a balanced mix of D- and L-BHB isomers, absorbed more slowly, leading to stable energy production without overwhelming the liver.
This slower release and dual-enantiomer composition appear to make ketone salts the most liver-friendly formulation for chronic use.
Implications for Healthspan and Metabolic Therapy
The findings have important implications for anyone using ketone supplements for health, performance, or therapeutic purposes:
- Ketone Salts (KS) may be the most suitable option for long-term daily use, particularly for healthspan and longevity applications.
- Ketone Esters (KE) and 1,3-Butanediol (BD) should be used with caution, especially at high doses or over extended periods.
- Routine blood tests alone are not sufficient to assess organ-level safety; more detailed metabolic and histological monitoring may be needed in future human studies.
For clinicians and health practitioners, this research emphasizes the need for formulation-specific evaluation — not all ketones behave the same in the body.
The Takeaway
This study provides the first direct comparison of the chronic effects of different exogenous ketone formulations on liver health. The results are clear:
- Ketone salts are safe and well-tolerated.
- Ketone esters and 1,3-butanediol can induce inflammation and fat buildup.
- Formulation selection is key to safe, effective, and sustainable ketone use.
As the use of exogenous ketones expands beyond athletics into longevity medicine and clinical care, these findings help guide both practitioners and consumers toward smarter, safer choices.
🧬 Reference:
Ari, C.; D’Agostino, D.P. Divergent Hepatic Outcomes of Chronic Ketone Supplementation: Ketone Salts Preserve Liver Health While Ketone Esters and Precursors Drive Inflammation and Steatosis. Pharmaceuticals 2025, 18(10), 1436. DOI: 10.3390/ph18101436