The ketogenic diet (KD) has shown significant potential in the prevention and treatment of a variety of diseases. It is applicable not only to some neurological disorders but also exerts remarkable effects on multiple metabolic diseases, including obesity, overweight, type 2 diabetes mellitus (T2DM), and metabolic-associated fatty liver disease (MAFLD). It is also gaining recognition in the emerging field of metabolic psychiatry. However, KD has absolute or relative contraindications in certain diseases, pathological conditions, or specific clinical settings.
Due to its high complexity and context dependence, multiple definitions of KD exist in academic literature. The most accurate definition describes KD as a dietary pattern that induces a state of ketosis by increasing endogenous ketone body production, as it covers different application scenarios and their physiological details. There is more than one way to induce ketosis; fasting is one such method. KD metabolically mimics fasting but avoids the adverse effects of prolonged starvation, making it more suitable for long-term implementation. Nutritional ketosis typically occurs under conditions of low insulin levels, where circulating free fatty acid levels rise, mitochondrial fatty acid uptake and oxidation increase, and ketone body production is subsequently enhanced. This mechanism also explains why KD requires strict restriction of carbohydrate intake. In a state of ketosis, fatty acid oxidation is enhanced, and the produced beta-hydroxybutyrate, acetoacetate, and acetone gradually become the primary energy substrates. This makes KD metabolically distinct from conventional diets that rely mainly on glucose for energy.
Achieving nutritional ketosis depends on a dietary structure low in carbohydrates, high in fat, and moderate in protein. However, the specific macronutrient ratios can be adjusted according to different KD types and application purposes. The most common KD pattern is a low-carbohydrate, high-fat, adequate-protein diet, where fat and protein usually contribute 60%–90% and 6%–30% of total energy, respectively. Common protein sources in KD include meat, fish, eggs, offal, and seafood; fat sources include olive oil, avocados, fatty fish, fatty cuts of meat, nuts, seeds, medium-chain triglyceride (MCT) oil, butter, lard, and egg yolks; carbohydrates are mainly derived from vegetables and nuts. Notably, various dietary forms can achieve nutritional ketosis as long as the macronutrient ratios are appropriate, including animal-based KD, plant-based KD, and Mediterranean KD. Thus, “KD” does not refer to a single standardized dietary pattern. Its health benefits largely depend on the overall dietary structure and food quality, rather than being determined solely by macronutrient ratios.
In clinical practice, a clear distinction must be made between nutritional ketosis and ketoacidosis. Nutritional ketosis is a physiological, controllable metabolic adaptation with potential therapeutic value. In contrast, ketoacidosis is a pathological state, most commonly diabetic ketoacidosis, characterized by severely elevated blood glucose (usually >250 mg/dL) and extremely high ketone concentrations (15–25 mmol/L)—levels rarely reached in nutritional ketosis. By comparison, nutritional ketosis is generally defined as a blood ketone level >0.5 mmol/L, typically within a range of several mmol/L, while blood glucose remains within normal laboratory reference ranges. Clear differentiation between these two states is critical for the safe implementation and clinical application of KD.
The absolute contraindications of KD mainly involve rare inherited metabolic defects, especially disorders impairing fat-to-energy conversion, including:pyruvate carboxylase deficiency, fatty acid beta-oxidation disorders (such as primary carnitine deficiency, carnitine palmitoyltransferase deficiency, carnitine-acylcarnitine translocase deficiency, 3-hydroxyacyl-CoA dehydrogenase deficiency, medium-chain and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, medium-chain and very-long-chain acyl-CoA dehydrogenase deficiency, etc.), and porphyria.
Patients with pyruvate carboxylase deficiency have severely impaired gluconeogenesis and rely heavily on exogenous glucose for energy. By restricting carbohydrates, KD forces the body to switch to fat metabolism. However, these individuals cannot perform efficient energy conversion, making them highly susceptible to severe lactic acidosis and ketosis, with a definite risk of death.
Fatty acid beta-oxidation disorders constitute another core set of contraindications. Beta-oxidation is a key process for energy production from fatty acids, involving the stepwise degradation of acyl-CoA to acetyl-CoA within cell mitochondria. Long-chain fatty acids require carnitine and CPT1, CACT, CPT2 for mitochondrial transport, whereas short- and medium-chain fatty acids can enter directly. Acetyl-CoA enters the tricarboxylic acid cycle for energy production, and the generated NADH and FADH participate in ATP synthesis. This pathway is particularly important during starvation, intense exercise, and low-carbohydrate diets. However, for individuals with defects in this metabolic pathway, using fat as the primary energy source is difficult or even impossible. Restricting carbohydrate intake can trigger severe metabolic complications, making KD a clear contraindication for this population.
Porphyria is also an absolute contraindication to KD. Low-carbohydrate diets, especially KD, can increase the risk and severity of acute porphyria attacks. Reduced carbohydrate intake enhances mitochondrial ALA synthase activity, leading to excessive production of heme precursors. In patients with enzyme defects in the downstream synthetic pathway, accumulation of these precursors promotes neurotoxic symptoms and increases the risk of acute attacks. Fasting, metabolic stress, and weight loss may also worsen the condition. Therefore, a high-carbohydrate diet is recommended for these patients, while fasting and very-low-calorie diets should be avoided.