Sarah Rice BSc. (Hons), MCOptom (UK), MHP, NNP

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD)* is a common chronic liver disease that is strongly associated with metabolic dysfunction, often seen alongside metabolic syndrome, obesity, and type 2 diabetes. Formerly known as non-alcoholic fatty liver disease (NAFLD), MASLD more accurately captures the core attribute of metabolic dysfunction with the accumulation of fat in the liver (not associated with alcohol consumption). This chronic condition affects around 30% of the global population and tracks with the increasing burden of obesity and type 2 diabetes (1). Despite the significant clinical burden, pharmacological options remain limited (there is little effect on fibrosis and unfavourable side-effect profiles), and lifestyle interventions are at the forefront of treatment (1).

Pathophysiology

Individuals with fatty liver disease demonstrate abnormalities in glucose and lipid metabolism in line with general metabolic dysfunction observed in this population. Fat accumulation in the liver, namely diacylglycerol (DAG) or triglyceride accumulation, drives lipotoxicity, which damages hepatocytes and promotes inflammation (1,2). Visceral adiposity is strongly linked to increased liver fat. A proposed mechanism is that the proximity of visceral fat to the portal vein enables free fatty acids and adipokines to flow directly to the liver (2). Consumption of carbohydrates and insulin resistance contribute to fatty liver via gluconeogenesis and increased de novo lipogenesis (DNL) (1,2). In particular, a high fructose intake promotes excessive liver fat accumulation as it stimulates lipogenesis independently of insulin, rapidly producing substrates for triglyceride synthesis. It is suggested that ‘fructose metabolism supports DNL more strongly than [a high-fat diet] and hepatic DNL is a central abnormality in NAFLD’ (Softic et al., 2016)(3). Our current food landscape, heavily featuring high fructose corn syrup and processed carbohydrates, would appear to be a key driver of this chronic condition.

Therapeutic carbohydrate restriction

Reduced carbohydrate approaches are emerging as promising interventions for MASLD, with several recent studies adding to the growing evidence base.

In a recent systematic review and meta-analysis, Pi et al. (2025) looked at 16 RCTs representing data from 1,056 participants (1). They analysed the effects of low-carbohydrate diets (LCDs – defined as <45% total energy from carbohydrates) on cardiovascular (CVD) risk factors in patients with MASLD. LCDs produced significant reductions in HbA1c, triglycerides (TG), body weight (BW), and BMI. Carbohydrate restriction of <26% resulted in further improvements in blood pressure, HOMA-IR, BW, BMI, and waist circumference. Another systematic review and meta-analysis of 20 randomised-controlled trials examined the effect of a ketogenic diet on liver function and found improved liver enzymes, though it found no significant changes to liver stiffness (4).

In a study from Rotolo et al. (2025), a four-month, 2-phase, low-carbohydrate approach was used in 474 patients with MASLD (2). The intervention used 25% carbohydrate (25% protein, 50% fat) for 1 month, increasing to 40% carbohydrate (25% protein, 35% fat) for 3 months. Carbohydrate reduction according to their protocol led to reduced visceral adipose tissue in all groups, with the strongest response in those with moderate steatosis. The MASLD status improved for all groups, and some people moved to the “absent” category (63 out of 474). There were statistically significant improvements for all blood and anthropometric values (2).

These studies build on earlier studies showing the benefits of carbohydrate reduction for fatty livers. In particular, a small study from 2020, Luukkonen et al., demonstrated a remarkable reduction in fatty liver over just 6 days using a ketogenic diet, delivering key insights into potential mechanisms (5). The diet was hypocaloric (∼1,440 kcal energy per day) and very low in carbohydrates (≤25 g/day, or ∼6% total energy intake [TEI]). Fat content was ∼64% and protein ~28% TEI. Their data reflected key changes in mitochondrial metabolism leading to a rapid reversal of MAFLD in their subjects. Metabolic shifts led to increased hydrolysis of liver triglycerides, decreased endogenous glucose production, and reduced serum insulin. These changes reduced intrahepatic triglycerides (-31%) despite an increase in circulating nonesterified fatty acids (NEFA); this change is thought to occur in part due to a partitioning of these fatty acids towards ketogenesis (+232%), with reduced insulin being a key driver of these changes (5).

Proposed mechanisms are further explored in a recent review which explores the role of exogenous ketones, as well as endogenous ketones, in MASLD (6). Preclinical studies using ketone esters demonstrate improvements in steatosis, inflammation, and fibrosis independently of carbohydrate restriction. While more studies are needed to determine the therapeutic potential of ketone esters, nutritional interventions, which may include nutritional ketosis, have already demonstrated the potential to significantly improve fatty liver and associated metrics (1, 2, 4).

Conclusion

MASLD represents a significant disease burden globally and carbohydrate reduction strategies offer a promising intervention that targets the core pathophysiological mechanisms driving the disease. In addition, nutritional therapies in the ketogenic range may offer additional benefits in promoting hepatoprotective effects by attenuating hepatic steatosis and inflammation. More research will help define optimal approaches but removing high fructose corn syrup and reducing carbohydrates appears to be an effective strategy for mitigating fatty liver disease.

*Another term in use is metabolic dysfunction-associated fatty liver disease (MAFLD), and there is some controversy over which term is the best, depending on the diagnostic criteria. While some advocate for MAFLD as being superior, I have used MASLD, as this term is used in the papers referenced.

References

1. Pi, S. et al. (2025) ‘Low-carbohydrate diets reduce cardiovascular risk factor levels in patients with metabolic dysfunction-associated steatotic liver disease: a systematic review and meta-analysis of randomized controlled trials’, Frontiers in Nutrition, 12. Available at: https://doi.org/10.3389/fnut.2025.1626352.

2. Rotolo, O. et al. (2025) ‘The Effect of a Four-Month Low-Carbohydrate Diet on Visceral Adipose Tissue in Obese Subjects with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)’, Nutrients, 17(17), p. 2905. Available at: https://doi.org/10.3390/nu17172905.

3. Softic, S., Cohen, D.E. and Kahn, C.R. (2016) ‘Role of Dietary Fructose and Hepatic de novo Lipogenesis in Fatty Liver Disease’, Digestive diseases and sciences, 61(5), pp. 1282–1293. Available at: https://doi.org/10.1007/s10620-016-4054-0.

4. Qu, Y. et al. (2025) ‘The Effect of a Ketogenic Diet on Liver Health: A Systematic Review and Meta-Analysis’, Nutrition Reviews, p. nuaf197. Available at: https://doi.org/10.1093/nutrit/nuaf197.

5. Luukkonen, P.K. et al. (2020) ‘Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease’, Proceedings of the National Academy of Sciences of the United States of America, 117(13), pp. 7347–7354. Available at: https://doi.org/10.1073/pnas.1922344117.

6. Kelty, T.J., Krause, A. and Rector, R.S. (2025) ‘Ketone metabolites in metabolic dysfunction-associated steatotic liver disease progression: optimizing keto-therapeutic strategies’, American Journal of Physiology-Endocrinology and Metabolism, p. ajpendo.00178.2025. Available at: https://doi.org/10.1152/ajpendo.00178.2025.