The ketogenic diet (KD), characterized by high fat, moderate protein, and very low carbohydrate intake, has gained popularity as a therapeutic intervention for various conditions, including medically refractory epilepsy and metabolic dysfunction-associated steatotic liver disease (MASLD). While the KD has shown promise in promoting weight loss, improving insulin sensitivity, and reducing liver fat, its impact on liver enzymes and overall hepatic health remains a subject of ongoing research and debate. This article aims to provide a comprehensive overview of the effects of the KD on liver enzymes, considering both the potential benefits and risks associated with this dietary approach.
Introduction to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition characterized by hepatic steatosis, which is the accumulation of fat in the liver. MASLD encompasses a spectrum of liver disorders, ranging from nonalcoholic fatty liver (NAFL), characterized by minimal inflammation and damage, to nonalcoholic steatohepatitis (NASH), which involves significant liver inflammation and injury, potentially leading to fibrosis and cirrhosis.
The strong association between MASLD and metabolic disorders has led to the recent update of the terminology from NAFLD to MASLD. MASLD is defined as steatotic liver disease (SLD) occurring in conjunction with at least one of the five cardiometabolic criteria for adults. The global prevalence of SLD is estimated at 32%, highlighting the need for effective treatment strategies.
Management of MASLD: The Role of Weight Reduction and Emerging Therapies
The primary approach to managing MASLD involves weight reduction through lifestyle modifications, including increased physical activity and caloric restriction. However, conventional low-calorie (LC) diets and exercise regimens often fail to achieve sufficient weight loss to resolve hepatic steatosis. Recently, resmetirom has been approved by the FDA combined with diet and physical activity in patients with NASH. However, there are no pharmacological therapies approved for MASLD, highlighting an unmet clinical need for effective treatment strategies. In this context, the very-low-calorie ketogenic diet (VLCKD) has emerged as a promising intervention for MASLD due to its ability to induce rapid weight loss and substantial reductions in hepatic steatosis and visceral adiposity.
The Ketogenic Diet: Mechanisms of Action in Steatotic Liver Disease
The ketogenic diet is characterized by a high-fat intake (60-80/90% of total energy), moderate protein (10-30%), and very low carbohydrate content (5-10%, generally not exceeding 50 g per day). By promoting ketosis, VLCKD may improve insulin resistance and mitigate end-organ damage associated with metabolic dysfunction.
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The liver plays a central role in the synthesis of ketone bodies, a process known as ketogenesis. Ketogenesis is promoted by limited glucose availability, a hallmark of the ketogenic diet, as well as by pathological conditions such as diabetic ketoacidosis. In conditions of glucose deficiency, Acetyl-CoA cannot enter the Krebs cycle, leading to an excess of acetyl-CoA and the activation of ketogenesis, resulting in the production of ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone.
Ketone bodies produced by hepatocytes are utilized by muscle, neural cells, the heart, and the brain for oxidative metabolism to generate energy. A potential pathophysiological basis for employing the ketogenic diet in managing MASLD may relate to the influence of ketogenesis on insulin resistance. Insulin resistance drives de novo lipogenesis, suppresses the oxidation of FFAs and accelerates the breakdown of very low-density lipoproteins (VLDL) in the liver. These mechanisms collectively promote excessive fat accumulation within the liver.
The ketogenic diet has demonstrated significant benefits in improving insulin resistance, independent of weight loss. Hepatic glucose production is influenced partly by hepatic insulin sensitivity, which is impaired by the excessive accumulation of fatty acids in hepatocytes. Patients with hepatic steatosis undergoing a ketogenic diet experience a rapid and substantial reduction in hepatic fat, accompanied by significant weight loss. The reduction in hepatic triglycerides improves hepatic insulin sensitivity by decreasing excessive hepatic glucose production and compensatory hyperinsulinaemia. Furthermore, lower glucose and insulin levels associated with ketogenic diets downregulate cholesterol biosynthesis via reduced activation of β-hydroxy β-methylglutaryl-CoA reductase by insulin.
Clinical Evidence: Ketogenic Diet and Liver Enzymes
The literature occasionally presents conflicting data regarding the ketogenic diet’s impact on metabolic profile and liver function. A key consideration is that, regardless of body weight, obesity-related morbidity and mortality are significant concerns.
Studies in Humans
Studies assessing the effects of ketogenic or low-carbohydrate high-fat diets on liver fat, evaluated by imaging, histology, or biochemical markers, were included. The analysis indicates that ketogenic diets significantly reduce hepatic fat content and improve metabolic parameters, including insulin sensitivity and liver enzyme levels. Evidence further suggests that substituting saturated fats with unsaturated fats or replacing carbohydrates with proteins may enhance these benefits. However, considerable variability exists among studies and long-term data remain limited. Although short-term outcomes are encouraging, potential adverse effects such as dyslipidaemia, gastrointestinal disturbances, and transient ‘keto flu’ symptoms require careful clinical monitoring.
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Studies in Animal Models
Animal studies have provided further insights into the effects of the KD on liver enzymes and hepatic health. One study on male rats investigated the impact of a KD (90% fat, 8% protein, and 2% carbohydrates) on liver structure and function, as well as hepatic inflammatory markers. The results showed that serum cholesterol and alanine transaminase (ALT) levels in the KD group were significantly higher than in the normal diet group. Hepatic inflammatory markers, interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), were also higher in the KD group compared to the normal diet group. Histological examination revealed the presence of macrovesicular steatosis in the liver sections of rats on the KD.
These findings suggest that the KD may have adverse effects on liver health, including increased liver enzyme levels, inflammation, and steatosis. However, it is important to note that these results were obtained in an animal model and may not directly translate to humans.
Case Reports of Acute Hepatocellular Toxicity During Ketogenic Diet Initiation
While hepatic toxicity is generally considered an uncommon side effect of KD, typically associated with long-term use, there have been reports of acute hepatocellular toxicity during the initiation phase of the diet. A case study described two patients who experienced acute, asymptomatic hepatocellular toxicity shortly after starting the KD. The liver enzymes, both AST and ALT, showed significant elevation, corresponding to successive increases in the ratio of ketogenic diet. In one patient, AST showed an 8-fold elevation, and ALT showed a 6-fold elevation. ALP remained stable.
In the second patient, AST showed an 8-fold increase the day after the introduction of the ketogenic diet, and ALT showed a 13-fold increase the day after the introduction of the ketogenic diet. ALP levels continued to be normal. In both cases, the patients remained asymptomatic and tolerated the KD well, with no notable side effects. The liver enzyme elevations rapidly improved once the KD was stopped or tapered off.
These case reports suggest that acute hepatocellular toxicity can occur during the initiation of KD, even in the absence of hepatotoxic medications.
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Potential Adverse Effects and Monitoring Considerations
Despite its potential benefits, concerns have been raised regarding the safety of ketogenic diets, particularly high-fat variants, due to their reported effects on serum cholesterol levels and liver function, which could contribute to the onset or exacerbation of hepatic steatosis. Potential adverse effects such as dyslipidaemia, gastrointestinal disturbances, and transient ‘keto flu’ symptoms require careful clinical monitoring.
Given the conflicting evidence regarding the effects of the KD on liver structure and function, further research is needed to clarify the impact of this diet on hepatic health. Understanding the potential hepatic adverse effects, including steatosis and inflammation, is crucial in assessing the long-term safety of the KD, particularly when used as a therapeutic intervention.
The Importance of Individualized Approaches and Further Research
The impact of the ketogenic diet on liver enzymes and overall health is complex and may vary depending on individual factors, such as genetics, pre-existing conditions, and the specific composition of the diet. While some studies suggest that the KD can improve liver fat and insulin sensitivity, others raise concerns about potential adverse effects on liver enzymes and inflammation.
Therefore, it is crucial to approach the ketogenic diet with caution and under the guidance of a healthcare professional. Regular monitoring of liver enzymes and other relevant markers is essential to assess the individual's response to the diet and to detect any potential liver damage early on. Further research is needed to fully understand the long-term effects of the KD on liver health and to identify the individuals who may benefit most from this dietary approach.