Tom Wade MD

Today, I review, link to, and excerpt from The ketogenic diet is not for everyone: contraindications, side effects, and drug interactions [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Ann Med. 2026 Dec;58(1):2603016. doi: 10.1080/07853890.2025.2603016. Epub 2026 Jan 4.

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All that follows is from the above article.

• Abstract
• Graphical abstract
• 1. Introduction
• 2. Methodology
• 3. The ketogenic diet and the state of ketosis
• 4. Absolute contraindications to the ketogenic diet (all very rare but important)
• 5. Relative contraindications to the ketogenic diet
• 6. Situations in which special care should be taken when following the ketogenic diet
• 7. KD and drug interactions
• 8. Possible side effects of KD
• 9. Potential problems with the KD in clinical practice
• 10. Strengths and limitations
• 11. Conclusions
• Acknowledgments
• Funding Statement
• Disclosure statement
• Data availability statement
• References
• Associated Data

Abstract

Background: The ketogenic diet (KD), initially developed for the treatment of neurological disorders, has gained increasing attention for its potential role in the management of various metabolic diseases. Alongside its expanding clinical use, concerns have emerged regarding its safety, tolerability, and suitability in specific patient populations. This review summarises key contraindications, clinical situations requiring caution, relevant drug interactions, and commonly reported adverse effects associated with KD.

Discussion: Rare absolute contraindications include selected inborn errors of metabolism affecting pyruvate carboxylase activity, carnitine transport or utilisation, fatty acid oxidation pathways, as well as porphyria. Relative contraindications encompass acute pancreatitis, advanced hepatic or renal disease, familial hypercholesterolaemia, and other conditions that may be aggravated by KD-induced metabolic changes, including concomitant use of propofol. Particular caution is warranted in patients with type 1 or type 2 diabetes receiving specific glucose-lowering therapies, pharmacologically treated hypertension, gallbladder disease or prior cholecystectomy, electrolyte disturbances, cardiac arrhythmias, pregnancy or lactation, underweight status, intense physical activity, significant psychosocial stress, or postoperative recovery.Clinically relevant interactions with medications are reviewed, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, insulin and sulphonylurea derivatives, antiepileptic drugs, diuretics, lipophilic drugs, and corticosteroids. The most frequently reported adverse effects range from transient “keto flu” symptoms (fatigue, headache, nausea) to gastrointestinal disturbances, polyuria, and hypoglycaemia.

Conclusions: KD demonstrates therapeutic potential in the management of a broad range of metabolic and neurological diseases; however, it is not an intervention suitable for all clinical situations. Awareness of existing contraindications, conditions requiring particular caution, and potential drug interactions enables a more responsible, individualised, and safe approach to patient selection and clinical management. In this context, the present paper provides a concise yet comprehensive synthesis to support clinicians and researchers in the rational and effective application of the ketogenic diet in both clinical practice and scientific research.

Keywords: Ketogenic diet (KD); absolute contraindications; diseases; drug interactions; relative contraindications; side effects.

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Keywords: Ketogenic diet (KD), absolute contraindications, relative contraindications, drug interactions, side effects, diseases

Graphical abstract

1. Introduction

The ketogenic diet (KD) has been in clinical use for over a century since 1921, when it was first used in the treatment of epilepsy [1,2]. However, recent years have seen a rapidly growing interest in this dietary model. A manifestation of this trend is the sharp increase in the number of scientific publications on KD, reflecting the intense search for new potential clinical applications. The beneficial antiepileptic effects of KD raise legitimate questions about the effect of this diet in other brain disorders and diseases, such as Alzheimer’s disease (AD) [3], Parkinson’s disease (PD) [4], multiple sclerosis (MS) [5], migraine [6], and brain tumour [7,8]. There is also a growing number of promising findings on the action of KD in mental illnesses including schizophrenia and bipolar affective disorder [9,10], depression [11], and others [12–16]. For many years, research has also been moving beyond neurology, demonstrating the benefits of KD in other conditions such as type 2 diabetes, where it can often lead to a reduction or complete discontinuation of medication, accompanied by a remission [17–20]. Other areas of research include obesity [21–23], metabolic dysfunction-associated fatty liver disease (MAFLD) [24], cardiovascular diseases [25,26], cancer [27,28], and polycystic ovary syndrome (PCOS) [29,30]. Findings in inflammatory bowel disease (IBD) are also promising, albeit still preliminary [31]. The ketogenic diet is also gaining popularity in the context of sports and physical activity. Although its effectiveness compared to traditional dietary models remains a subject of debate, an increasing number of studies are investigating its impact on physical performance, metabolic adaptation, and recovery [32–34].

The multifaceted (and often successful) clinical application of the ketogenic diet and the growing popularity of this nutritional model calls for a discussion of potential contraindications, side effects and situations in which this particular diet should be used with particular care. Like all other dietary models, the ketogenic diet is not right for everyone. By discussing these concerns, specialists can develop a more responsible and reliable approach to the ketogenic diet.

2. Methodology

This manuscript is a narrative review, intentionally chosen due to the heterogeneity of the included evidence (clinical guidelines, mechanistic studies, narrative reviews, case reports, observational studies and expert recommendations), which cannot be synthesised using systematic methods. Searches were primarily conducted in PubMed and Google Scholar. The initial search strategy employed broad combinations of keywords related to the ketogenic diet (e.g. ‘ketogenic diet’, ‘ketosis’), safety considerations (‘absolute contraindications’, ‘relative contraindications ‘, ‘drug interactions’, ‘side effects’, ‘adverse effects’), and clinical conditions potentially affecting ketogenic therapy. To develop a comprehensive review, when individual articles identified a specific contraindication, comorbidity, or safety concern (e.g. acute pancreatitis, primary carnitine deficiency, gallbladder disease, use of SGLT-2 inhibitors), additional targeted searches were performed using the name of the condition or drug together with terms such as ‘ketogenic diet’ or ‘ketosis’. This approach allowed the inclusion of evidence that might not have been captured through broader search strategies.

Selection was based on article titles, abstracts, and full texts.

3. The ketogenic diet and the state of ketosis

Due to its complex and often context-dependent nature, the ketogenic diet has been defined in many different ways. The definition describing KD as a dietary regimen leading to increased endogenous production of ketone bodies, resulting in a metabolic state of ketosis is considered the most accurate [35], as it addresses all relevant contexts and nuances. There are a few ways to induce ketosis, one of which is fasting. In a certain way, KD mimics fasting but without the negative effects of starvation. Thus, unlike fasting, it is feasible for long-term use [36–38]. It is important to note that nutritional ketosis typically occurs in the context of low insulin levels, which lead to increased circulating free fatty acids (FFAs), enhanced mitochondrial uptake of FFAs, and elevated ketone body production. This explains why a ketogenic diet must be very low in carbohydrates [39]. Ketosis involves increased oxidation of fatty acids and the resulting ketone bodies (β-hydroxybutyrate, acetoacetate and acetone) are used as the main energy substrate [37]. This makes the KD different from other diets, in which the body derives energy mainly from glucose. The state of ketosis achieved by the diet can be referred to as nutritional ketosis, which in itself shows a therapeutic potential. Some of its benefits are described in Chapter 1.

Nutritional ketosis is a state achieved by following a low-carbohydrate, high-fat and moderate-protein diet. The macronutrient distribution varies depending on the type of KD and the purpose of the diet. A low-carbohydrate, high-fat and normal-protein diet is the most common type. Depending on the patient’s needs and the intended purpose, the share of energy coming from fat and protein ranges from 60% to 90% and from 6% to 30%, respectively [40]. Conversely, according to the 2024 expert consensus [41], the share of energy from carbohydrates is less than 10%, which in practice corresponds to 20–50 g of carbohydrates per day – this is because higher carbohydrate intake requires higher insulin production, which inhibits ketogenesis, as previously mentioned. Protein sources typically used in the ketogenic diet include meat, fish, eggs, offal and seafood. Fat sources include olive oil, avocado, fatty fish, fatty meats, nuts, seeds, MCT oil (typically used as a supplement), butter, lard, or egg yolks, while carbohydrate sources include mainly vegetables and nuts [42]. However, nutritional ketosis is possible in a variety of dietary models, as long as the right proportions of macronutrients are ensured. Those models include a plant-free ketogenic diet, as well as a plant-based ketogenic diet, although it is helpful to include animal products. Another commonly used diet is the Mediterranean version of KD [43]. The term ‘ketogenic diet’ does not refer to a single standardized dietary pattern; rather, its health effects depend heavily on proper formulation. While certain ultra-processed foods such as diet soda and pepperoni may technically comply with ketogenic macronutrient ratios, they are not necessarily conducive to long-term health.

It is essential to clearly distinguish between nutritional ketosis and ketoacidosis, as the two states may be mistakenly conflated. Nutritional ketosis is a physiological and desirable metabolic condition, whereas ketoacidosis represents a pathological state. The most well-known form is diabetic ketoacidosis (DKA), characterized by markedly elevated blood glucose levels (typically >250 mg/dL) and a high concentration of ketone bodies (15–25 mmol/L), levels that are virtually unattainable in nutritional ketosis. In contrast, nutritional ketosis is defined by ketone levels >0.5 mmol/L—typically within a range of a few mmol/L depending on the depth of ketosis—while blood glucose levels generally remain within the normal laboratory range [19,44–46].

4. Absolute contraindications to the ketogenic diet (all very rare but important)

Absolute contraindications to the use of the ketogenic diet are rare, however, they carry significant clinical importance, as their presence renders the implementation of this dietary intervention unsafe and, in some cases, potentially life-threatening. Most of these conditions are associated with disorders of fat metabolism and are typically diagnosed early in life, most often during infancy.

4.1. Pyruvate carboxylase (PC) deficiency

Pyruvate carboxylase (PC) deficiency is a very rare metabolic disorder, occurring at a frequency of 1 in 250,000 cases [47]. Pyruvate carboxylase deficiency is caused by a mutation in the PC gene (11q13.4-q13.5). The gene plays a role in the conversion of pyruvate to oxaloacetate (an intermediate product in the citric acid cycle and gluconeogenesis). Three types of PC deficiency have been distinguished: type A (infantile PC deficiency), type B (referred to as severe neonatal PC deficiency) and the less common type C (referred to as intermittent or mild PC deficiency). All of these types involve metabolic acidosis [48]. Symptoms of type A include intellectual disability, developmental delay, abdominal pain, vomiting, fatigue, and acid-base imbalance with increased concentrations of lactic acid (lactic acidosis) and increased concentrations of ketone bodies (ketoacidosis). Unfortunately, only some children with type A PC deficiency survive to adulthood. Type B symptoms also include intellectual disability, lactic acidosis and ketoacidosis, as well as hyperammonemia. These are often accompanied by hypotonia, liver failure, seizures, and coma. In these cases, children usually do not survive beyond three months. In contrast, the mildest form, type C, involves mild and intermittent lactic acidosis with normal (or slightly delayed) development and standard life expectancy [49–53].

There have been a series of findings suggesting that the ketogenic diet is contraindicated in each type of PC deficiency as it may aggravate symptoms, for instance by exacerbating metabolic acidosis and further increasing ketone bodies [54–58]. Among other things, this is due to the fact that patients with pyruvate dehydrogenase deficiency are in a way dependent on food-derived glucose, as gluconeogenesis itself is impaired in these individuals [59]. Therefore, in these patients fasting is also contraindicated and their diet should be rich in carbohydrates and protein. Meals should be frequent to prevent the body from becoming dependent on gluconeogenesis [55].

4.2. Disorders of fatty acid β-oxidation

Beta-oxidation is a key process for obtaining energy from fatty acids [60], involving gradual degradation of acyl-CoA to acetyl-CoA in the mitochondria. Long-chain fatty acids (LCFA) must be transported into the mitochondria by carnitine and the enzymes CPT1, CACT, and CPT2, while short and medium chains permeate directly [61]. The resulting acetyl-CoA fuels the Krebs cycle, and the generated NADH and FADH₂ enable ATP production in the respiratory chain. Beta-oxidation becomes critical during starvation, intense exercise and low-carbohydrate diets [60,62]. In individuals with disorders of this pathway, turning to fatty acids as the main energy source is challenging or impossible; restricting carbohydrate supply could lead to serious metabolic complications, therefore, the ketogenic diet is contraindicated in these individuals.

4.2.1. Primary carnitine deficiency (PCD)

Primary carnitine deficiency (PCD) is a rare, autosomal recessively inherited congenital disorder (frequency of 1 per 100,000 cases worldwide). It is caused by mutations in the SLC22A5 gene, which provides information necessary for the synthesis of OCTN2, a protein responsible for carnitine transport into the cell. Carnitine is needed to transport fatty acids into the mitochondria (i.e. the energy centres of the cell), which is particularly important in the heart and muscles, which use fatty acids as the main source of energy. Therefore, mutations in the SLC22A5 gene result in carnitine deficiency in cells and the ensuing consequences [63,64]. Five main spectrums of possible clinical manifestations have been reported in the literature. The first one is metabolic decompensation in infancy (3 months to 2 years) with episodes of hypoketotic hypoglycaemia, hepatomegaly, lethargy, feeding difficulties, elevated hepatic aminotransferase levels and hypoammonemia (induced by fasting or illness, among other things). The second type is childhood myopathy involving the heart and skeletal muscles (with an onset at 2 to 4 years of age); the third type is reduced strength associated with pregnancy or exacerbation of cardiac arrhythmia, the fourth type is fatigue in adulthood and the fifth one is not accompanied by any symptoms [65]. Although the global incidence is estimated at 1 per 100,000 births, it varies significantly from country to country. In Japan, for example, it is 1 in 40,000 births [63], while in China it is as high as 1 in 20,000 births, as a large 2024 meta-analysis involving 10 million newborns demonstrated [66]. The highest incidence (1 in 300 births) has been reported in the Faroe Islands, but the authors of the report point to the efficacy of carnitine treatment for PCD, with patients feeling well 10 years after diagnosis [67]. Levocarnitine (usually at a dose of 100–200 mg/kg/day) is a standard treatment regimen. The therapy is effective, as long as it starts early, before irreversible organ damage occurs [65].

The ketogenic diet is not recommended in primary carnitine deficiency, as discussed in several scientific papers [40,54,68,69]. This is due to the high fat content of the KD, and, as described above, because PCD patients are deficient in cellular carnitine, preventing the efficient use of fats as an energy source. Therefore, contraindications in cases of PCD include high-fat diets, as well as prolonged periods of starvation characterised by increased reliance on fatty acid oxidation [63,65]. In addition, carnitine deficiency inhibits the mitochondrial oxidation of fatty acids to ketone bodies [70], which are the main source of energy in individuals following the ketogenic diet [37]. Moreover, people with PCD are at risk of hypoglycaemia (and hypoketonemia), which may be particularly dangerous if the KD is followed. After a KD meal, blood glucose concentrations rarely spike, and in some cases may even go down [71], which, in the context of hypoglycaemia, is a significant risk. At the same time, due to the nature of PCD, the production of an alternative energy source in the form of ketone bodies is impaired [70]. It is therefore not surprising that in an outpatient setting, PCD patients often use carbohydrate supplementation (mainly in liquid form, orally or by tube). In certain cases, glucose is administered intravenously [65].

4.2.2. Carnitine palmitoyltransferase deficiency

Carnitine palmitoyltransferase deficiency is a rare metabolic disorder caused by a deficiency of either CPT1 or CPT2—enzymes involved in cellular fatty acids uptake and ultimately energy generation [72].

CPT1 (CPT1A) deficiency is an extremely rare, autosomal recessively inherited disorder, with only some 60 cases worldwide reported so far. It is caused by a mutation in the CPT1A gene which encodes carnitine palmitoyltransferase 1 A (CPT1A). The CPT1A enzyme is essential for fatty acid oxidation, as it binds fatty acids to carnitine, which transports them to the mitochondria where they are used for energy generation. Impaired energy production can result in hypoketotic hypoglycaemia (much like in primary carnitine deficiency). Other symptoms of CPT1 deficiency include hyperammonemia, increased blood carnitine levels, increased susceptibility to bleeding, liver failure, seizures, damage to the nervous system, heart and brain, coma and even sudden death [73,74].

Carnitine palmitoyltransferase II (CPT2) deficiency is the most common enzyme disorder, with prevalence estimated at 1 to 9 in 100,000 people [75]). It affects long-chain fatty acid oxidation and is caused by a mutation in the CPT2 gene. It is also the most common cause of recurrent rhabdomyolysis in adults. There are three main phenotypes of primary carnitine deficiency (PCD): the fatal neonatal form, the severe infantile hepatocardiomuscular form and the most common (and mildest) myopathic form, characterised by exercise-induced muscle pain, weakness and myoglobinuria. Interestingly, some individuals may be asymptomatic for most of their lives [72,76]. Much like in CPT1 deficiency, patients with CPT2 deficiency are unable to convert some of the consumed fats into energy [77]. Therefore, the ketogenic diet is considered contraindicated in both CPT1 and CPT2 deficiency [40,78]. The underlying reason is the same as in primary carnitine deficiency. While in PCD the amount of carnitine is insufficient (which impairs energy production from fatty acids), CPT1 and CPT2 deficiency affects the binding of fatty acids to carnitine and their use by the mitochondria as an energy source, as described above. Therefore, a carbohydrate-rich and fat-poor diet is recommended in such patients [72,79]. Frequent meals are also recommended, especially during hypoglycaemic periods, and in cases of severe hypoglycaemia, meals should be accompanied by intravenous administration of dextrose [73]. These strategies prevent the use of fats as an energy source (which is welcome since their oxidation process is impaired), and also prevent hypoglycaemia, to which these patients are particularly vulnerable.

4.2.3. Carnitine-acylcarnitine translocase (CACT) deficiency

Carnitine-acylcarnitine translocase (CACT) is an enzyme found on the inner mitochondrial membrane. It is responsible for carnitine/acylcarnitine translocation across the membrane. Therefore, it is an essential component in the carnitine cycle that regulates the transport of long-chain fatty acids into the mitochondria, where they are beta-oxidised [80,81]. CACT deficiency is an autosomal recessively inherited disorder affecting the beta-oxidation of fatty acids. It is caused by mutations in the SLC25A20 gene [80]. The estimated prevalence in the combined populations of Australia, Germany and the United States is approximately 1 in 750,000 to 1 in 2,000,000 individuals. In Hong Kong and in Taiwan it is estimated at 1 in 60,000 and 1 in 400,000, respectively. Nevertheless, just over 100 cases of CACT deficiency have been diagnosed to date, among which two phenotypes can be distinguished: a severe neonatal-onset form and a later-onset form [81]. The severe neonatal-onset form is far more common and manifests almost immediately after birth. Symptoms include arrhythmias, feeding difficulties, hypotonia, lethargy, hypoketotic hypoglycaemia, elevated liver enzymes, and rhabdomyolysis or hepatomegaly, among other conditions [82–84]. Unless promptly diagnosed and treated, death in the neonatal period is likely, and even if it is diagnosed, the prognosis is still poor, as only a few individuals survive into early and late childhood, and even fewer into early adulthood [82]. In the second, rarer phenotype (a later-onset form), symptoms develop later—after 1 month of age, or sometimes even after 12 months of age. This condition is similar to the first phenotype, but milder. Nevertheless, the prognosis is not promising either, as few people live to adulthood [81–84].

The ketogenic diet is contraindicated in both of these phenotypes, because CACT deficiency impairs the conversion of long-chain fatty acids into energy, and the KD is a high-fat dietary pattern. Similarly, periods of fasting are contraindicated, which is not surprising since they increase reliance on fatty acids [81]. In individuals with CACT deficiency, fasting increases the risk for acute metabolic decompensation [83], and similar symptoms are likely to occur if the KD is followed. This is because maintaining a low LCFA intake on the ketogenic diet is difficult, and in CACT deficiency this particular type of fatty acids is problematic. Therefore, a high-carbohydrate diet is recommended, with more than 60% energy coming from carbohydrates. Conversely, the share of energy coming from LCFAs should be below 10%. Triheptanoin (a special form of fat supplying 25–35% of energy), or medium-chain fatty acids (MCTs) may be used interchangeably [81], as neither MCTs nor triheptanoin require CACT for transport. Therefore, unlike long-chain fatty acids, they are not contraindicated.

4.2.4. 3-hydroxyacyl-coenzyme A (HADH) dehydrogenase deficiency

The 3-hydroxyacyl-coenzyme A (HADH) dehydrogenase enzyme is encoded by the HADH gene. In the mitochondrial matrix it catalyses the oxidation of simple 3-hydroxyacyl-CoA chains as part of the beta-oxidation pathway [85]. HADH deficiency is a rare inherited disorder that prevents the body from converting certain fats into energy, especially during fasting periods [86]. Two main forms of the disorder have been identified: medium-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

4.2.4.1. Medium-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (MHADD)

Medium-chain fatty acid 3-hydroxyacyl-CoA dehydrogenase (MHADD) deficiency is a fairly rare disorder. Since it has only been reported in a small number of people worldwide, its prevalence is unknown [86]. As the name suggests, MHADD involves the deficiency of medium-chain 3-hydroxyacyl-CoA dehydrogenase, an enzyme that processes MCFAs and SCFAs. Without a sufficient supply of 3-hydroxyacyl-CoA dehydrogenase, the body is unable to break down certain fats and convert them into energy [87]. Medium-chain and short-chain fatty acids that are not broken down can accumulate in tissues and damage the liver, heart and muscles, causing serious complications. Typical symptoms of the enzyme’s deficiency include hypoglycaemia and lethargy [86]. In this case, the ketogenic diet is contraindicated for a simple reason: the body of a person suffering from MHADD cannot effectively switch to fats as the main source of energy.

4.2.4.2. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) results from an isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, an enzyme that forms part of the mitochondrial trifunctional protein complex (TFP) [88]. It is a relatively rare disorder, diagnosed in approximately 1 in 250,000 births worldwide. In Poland, the incidence is higher, at around 1 in 120,000 births, with a particularly high incidence in the northern region of Pomerania, where, depending on the source, it is estimated at 1 in 20,000 or even 1 in 16,900 births. This higher prevalence is due to the increased rate of people carrying the pathogenic variant of the HADHA gene, responsible for the development of the disorder [88–90]. The condition usually manifests at any time from a few days to 12 months after birth. In most cases, the phenotype is severe. Possible symptoms and complications include hypoketotic hypoglycaemia, metabolic acidosis, hypotonia, hepatomegaly, encephalopathy, feeding problems, nausea, vomiting, lethargy, arrhythmias and often cardiomyopathy. Sudden heart attack and sudden infant death are also possible, but less common [88,91,92].

The ketogenic diet, as well as other high-fat and low-carbohydrate diets, are contraindicated in people with LCHAD for a simple reason. Namely, these individuals cannot efficiently break down LCFAs, which are abundant in high-fat diets (including ketogenic) [91]. Fasting, caloric deficit during stress, exposure to extreme environmental conditions, intense exercise or even anaesthetics containing high concentrations of long-chain fatty acids (e.g. propofol) are also contraindicated. Conversely, suggested dietary management includes low-fat diets (with particular restriction of LCFAs), increased meal frequency, as well as MCT or triheptanoin supplementation [88,91].

4.2.5. Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

Medium-chain acyl-CoA dehydrogenase (MCAD) is an enzyme required for the breakdown of medium-chain fatty acids (MCFAs). MCADD is a rare genetic disorder caused by mutations in the ACADM gene that lead to a deficiency of the MCAD enzyme. As a result, MCFAs are not properly broken down [93–96]. The average worldwide prevalence of MCADD is estimated at approximately 1 in 14,600 births. There are no symptoms immediately after birth; the first clinical manifestations usually develop between 3 and 24 months of age. However, some patients may be asymptomatic for life [97]. Symptoms and complications include hypoketotic hypoglycaemia (especially in response to prolonged fasting), which in its turn may lead to lethargy, convulsions, vomiting, coma and even death. Metabolic decompensation can also result in elevated liver aminotransferases, hyperammonemia or chronic myopathy [98].

The ketogenic diet, if based solely on long-chain fatty acids LCFAs with no medium-chain fatty acids (MCFAs), could theoretically minimise the metabolic problem characteristic of MCAD deficiency. Nevertheless, the literature lists the disorder among those in which the KD is absolutely contraindicated [68,99,100]. The reason for this precaution is a) the lack of data on KD use in MCAD-deficient patients, and b) the fact that these patients respond well to glucose-based metabolism. In addition, limiting MCFA intake is much easier with a low-fat or standard fat diet. According to the literature, the recommended dietary strategy is to follow a standard carbohydrate-based diet with fat supply restricted to a maximum of 30% of the daily energy intake and to avoid periods of fasting. If necessary, meal intervals in infancy can be reduced to every 2–3 h. In addition, night feedings, a snack before bedtime or maize starch supplementation at 2 g per 1 kg body weight are recommended to maintain adequate blood glucose levels during sleep [97,98].

4.2.6. Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD)

Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), like MCAD deficiency, affects the breakdown of fatty acids. However, in this case, the body is unable to handle very long-chain fatty acids (VLCFA). The underlying cause of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency are mutations in the ACADVL gene [101]. Two forms of VLCADD have been identified: an early (severe) form, which, if not recognised and diagnosed, can lead to cardiomyopathy and be life-threatening; and a later (milder) form, characterised by recurrent bouts of hypoglycaemia [102]. This disorder is also relatively rare, diagnosed in 1:30,000 to 1:100,000 births [103].

The ketogenic diet is listed as an absolute contraindication, which again is a precaution based on a risk-benefit analysis [68,100]. The recommended dietary approach is a carbohydrate-based diet with minimised LCFA intake, increased MCFAs, triheptanoin supplementation, shorter intervals between meals, and avoidance of fasting [103].

4.3. Porphyria

Porphyria is an umbrella term for a group of metabolic disorders that cause a deficiency of enzymes involved in the haem synthesis pathway. Haem is a component of haemoglobin, responsible for oxygen transport in the body. If any of those enzymes is not working properly, porphyrins are not converted to haem and accumulate in the body instead. Their excess is the main problem associated with this condition [104]. Porphyria is relatively rare and mainly affects the skin or the nervous system. In most cases it is hereditary, resulting from mutations in specific genes. Based on the symptoms, porphyrias can be divided into acute (mainly affecting the nervous system) and cutaneous (mainly affecting the skin). Among the former, acute intermittent porphyria is the most common, whereas the most prevalent form of cutaneous porphyria (and at the same time the most common overall) is porphyria cutanea tarda, affecting about 5–10 per 100,000 people; erythropoietic protoporphyria is the most common form in children [105]. Symptoms of acute porphyria are often paroxysmal and continue for days or weeks, often several times over a lifetime. They include pain (abdomen, arms, back, legs), digestive problems (constipation, vomiting, nausea), psychiatric concerns (anxiety, hallucinations, confusion, seizures), muscle weakness, paralysis, respiratory problems, urinary symptoms, skin blistering when exposed to sunlight [105,106]. In cutaneous porphyrias, skin exposure to sunlight can lead to blistering (sometimes with secondary infection), increased skin tenderness (injury proneness and healing disorders), scarring and changes in skin colour [105,107].

Many sources list the ketogenic diet as an absolute contraindication for people with porphyria [68,100,108]. This is because low-carbohydrate diets in general (and KD in particular) are among the factors that may increase the risk and the severity of acute porphyria attacks. Low carbohydrate intake increases the activity of mitochondrial ALA synthase (ALAS1), leading to the excessive production of heme precursors such as ALA and PBG. In the case of enzyme deficiencies further down the pathway (e.g. in acute intermittent porphyria), this results in their accumulation, which promotes the development of neurotoxic symptoms and increases the risk of acute porphyric attacks [109–111]. Other potential aggravating factors include periods of starvation, metabolic stress, and losing weight [105]. Therefore, the recommended strategy is a high-carbohydrate (60–70%) diet, avoidance of fasting, and avoidance of very low-calorie diets [112].

A summary of the absolute contraindications to the use of the ketogenic diet is presented in Table 1.

Table 1.

Absolute and relative contraindications to the use of the ketogenic diet.

Absolute contraindications
Type of contraindication	Rationale for the contraindication	Frequency of occurrence	Sources
Pyruvate carboxylase (PC) deficiency	Due to impaired gluconeogenesis, patients are largely dependent on dietary glucose and therefore cannot safely follow a fat-based ketogenic diet, nor prolonged fasting.	1 in 250,000	[47,49,55]
Primary carnitine deficiency (PCD)	Due to cellular carnitine deficiency, patients cannot efficiently utilize fats for energy, making high-fat ketogenic diets and prolonged fasting unsafe; they are also at risk of hypoglycemia and impaired ketone production	1 in 100,000 (Japan 1 in 40,000 and China 1 in 20,000)	[63–65,70,71]
Carnitine palmitoyltransferase deficiency (CPT1)	Impaired fatty acid oxidation due to defective CPT1A prevents effective energy production from fats, leading to hypoketotic hypoglycemia; ketogenic diets are therefore contraindicated.	60 cases reported worldwide	[72–74]
Carnitine palmitoyltransferase deficiency (CPT2)	Defective CPT2 impairs mitochondrial fatty acid utilization, reducing energy production from fats and increasing risk of hypoglycemia; ketogenic diets are therefore contraindicated.	1–9 in 100,000	[72,75,77–79]
Carnitine-acylcarnitine translocase (CACT) deficiency	Defective CACT impairs long-chain fatty acid oxidation, limiting energy production from fats; ketogenic diets and fasting increase risk of metabolic decompensation and are contraindicated.	1 in 750,000 to 1 in 2,000,000 (Hong Kong 1 in 60,000 and Taiwan 1 in 400,000)	[81,83,84]
Medium-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (MHADD)	The ketogenic diet is contraindicated for a simple reason: the body of a person suffering from MHADD cannot effectively switch to fats as the main source of energy.	unknown	[86,87]
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)	The ketogenic and other high-fat, low-carbohydrate diets are contraindicated in individuals with LCHAD, as they cannot efficiently oxidize long-chain fatty acids, which are abundant in such diets	1 in 250,000 (Poland 1 in 120,000)	[88–91]
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)	Although ketogenic diets based solely on long-chain fatty acids could theoretically minimize the metabolic defect in MCAD deficiency, these diets are contraindicated due to the risk of hypoketotic hypoglycemia, lack of clinical data, and the safety and efficacy of carbohydrate-based diets in these patients	1 in 14,600	[97–100]
Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD)	In VLCAD deficiency, impaired oxidation of very-long-chain fatty acids prevents effective energy production from fats, increasing risk of hypoglycemia and cardiomyopathy; therefore, ketogenic diets are contraindicated.	1 in 30,000 to 1 in 100,000	[100–103]
Porphyria	Ketogenic and other low-carbohydrate diets increase ALAS1 activity, leading to accumulation of heme precursors and risk of acute porphyria attacks; high-carbohydrate diets and avoidance of fasting are recommended.	<200,000 cases in the US; porphyria cutanea tarda: 5–10 per 100,000	[105,109–111]
Relative contraindications
Acute pancreatitis (AP)	In acute pancreatitis, impaired pancreatic enzyme production limits fat digestion; high-fat ketogenic diets may worsen malabsorption and exacerbate symptoms	20 to 40 cases per 100,000	[114,116,120–122]
Acute liver failure (ALF)	The ketogenic diet is contraindicated in acute liver failure due to massive hepatocyte loss, organ dysfunction, and lack of evidence for safety or efficacy; it may also potentially exacerbate liver injury	<10 cases per 1,000,000 per year in developed countries	[128,133]
Chronic kidney disease (CKD) in advanced stages	In advanced CKD (G3b–G5), impaired renal function reduces the ability to excrete ketones and maintain electrolyte balance, increasing the risk of metabolic disturbances; therefore, ketogenic diets are not recommended in these patients.	10.6% of adults globally (CKD stages 3–5; stage 3a and 3b not separated)	[136,138]
Use of propofol	Propofol is considered a relative contraindication during the ketogenic diet because it may impair fatty acid oxidation, increasing the risk of metabolic complications such as acidosis, rhabdomyolysis, or seizure aggravation, although serious events like propofol infusion syndrome are extremely rare.	74% of all anesthesia/ sedation; 90% of general anesthesia	[58,151,153,154]
Familial hypercholesterolaemia (FH)	The ketogenic diet is relatively contraindicated in familial hypercholesterolemia because its effects on lipid profiles are unpredictable-depending on the diet’s composition it may exacerbate high LDL-C levels – and overall safety in these patients has not been established.	1 in 200 to 1 in 1,000	[156,163,164]

PC: Pyruvate carboxylase; PCD: Primary carnitine deficiency; CPT1 or CPT2: Carnitine palmitoyltransferase deficiency; CACT: Carnitine-acylcarnitine translocase; MHADD: Medium-chain acyl-CoA dehydrogenase deficiency; LCHAD: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; MCADD: Medium-chain acyl-CoA dehydrogenase deficiency; VLCADD: Very-long-chain acyl-CoA dehydrogenase deficiency; AP: Acute pancreatitis; ALF: Acute liver failure; CKD: Chronic kidney disease; FH: Familial hypercholesterolemia; ALAS1: Aminolevulinate Synthase 1; LDL-C: Low-Density Lipoprotein Cholesterol.

5. Relative contraindications to the ketogenic diet

5.1. Acute pancreatitis (AP)

Pancreatitis may be acute (which is the focus of this chapter) or chronic. Acute pancreatitis (AP) is an inflammatory response of the pancreas to damage resulting from a variety of aetiological factors, leading to premature activation of pancreatic proenzymes, (mainly trypsin), inside lobular cells. (By contrast, chronic pancreatitis usually develops in response to prolonged ethanol abuse.) The most common causes of acute pancreatitis are gallstones (35–40% of cases, with women >65 years of age being particularly susceptible [113]), and alcohol consumption (30% of cases). Less common forms include autoimmune pancreatitis, hypertriglyceridaemia, genetic mutations, endoscopic retrograde cholangiopancreatography (ERCP) injuries, pancreatic duct injury and certain medications [114,115]. One of the three key diagnostic criteria for AP is a serum lipase or amylase concentration exceeding the normal range by threefold or more [116]. The disease is quite common. In the US alone, it is associated with the hospitalisation of 200,000 to 300,000 patients per year [117,118]. The incidence in Poland is estimated at 72.1/100,000 patients per year, which is one of the highest in Europe [119], while the global annual incidence of acute pancreatitis in the general population ranges from 20 to 40 cases per 100,000 people [120].

The KD is contraindicated in AP because the pancreas plays a key role in fat digestion by synthesising enzymes such as lipase, phospholipase and esterase [121,122]. Increased fat supply could lead to increased stress on the pancreas, and, since pancreatic function is impaired in AP, fat absorption may be affected and symptoms may be exacerbated. Therefore, the standard recommendation is to withhold oral food and fluid intake until abdominal pain, nausea, vomiting, loss of appetite and symptoms of intestinal obstruction have resolved. In a milder course, easily digestible, low-fat meals may be recommended [114,116]. Importantly however, while nutritional management will vary depending on the case [123], high-fat diets are generally discouraged. However, once ultrasound and liver enzyme tests indicate that acute pancreatitis has resolved, or in cases of chronic pancreatitis, the KD may be a reasonable option, but clinical studies are needed to confirm this.

5.2. Acute liver failure (ALF)

Acute liver failure (ALF) is a severe, rapidly progressive condition that leads to hepatic encephalopathy and synthetic dysfunction within 26 weeks or less, and is accompanied by an INR (International Normalized Ratio) of ≥1.5 in patients without cirrhosis and without previous liver diseases [124]. The most common causes of ALF are viral and drug-induced hepatitis. Less common causes include sepsis, poisonous mushrooms, hypoxia-induced liver injury, acute Budd-Chiari syndrome, autoimmune hepatitis, or heat stroke [125,126]. The pathophysiology of ALF is dependent on the initiating factor, but in most cases there is massive hepatocyte death by necrosis or apoptosis, leading to organ failure [124]. Acute liver failure is a rare clinical syndrome, with an incidence of <10 cases per million per year in developed countries. In the U.S., about 2,000 cases are diagnosed annually. ALF often affects younger individuals and carries high morbidity and mortality. It is more common in developing countries due to higher rates of viral hepatitis. The prognosis can be extremely poor and liver transplantation may be required [127,128].

With some liver diseases, KD may have a beneficial effect on the clinical course. One example is metabolic dysfunction-associated fatty liver disease (MAFLD), where KD is not only safe, but may even be one of the more effective therapeutic options [24,129]. Furthermore, the authors of one study [130] showed that KD is promising even in the dietary treatment of patients with nonalcoholic steatohepatitis (NASH), currently more commonly referred to as metabolic dysfunction-associated steatohepatitis (MASH) [131]. There is also a published case study of 2 patients with end-stage liver disease (ESLD) and obesity who were told to reduce body weight in order to qualify for liver transplantation [132]. The patients were put on a very low calorie ketogenic diet (VLCKD) with an energy value of approximately 800 kcal per day. The VLCKD was shown to be well tolerated and safe, and one patient had such a significant improvement in liver function that he could be removed from the liver transplant waiting list. Importantly however, the diet followed by those two patients was not a classic ketogenic diet. Although it did induce a state of ketosis, it was essentially a reduction diet which is not the same as a typical normocaloric ketogenic diet. Furthermore, ESLD involves a chronic, rather than acute, liver failure. For acute liver failure, however, there is no evidence to demonstrate whether KD is effective or not. Therefore, based on indirect evidence and on the pathophysiology of ALF, we feel it is reasonable and responsible to assume that KD is contraindicated in this liver condition, at least until more well-designed clinical studies on the subject become available [133].

5.3. Chronic kidney disease (CKD) in advanced stages

Chronic kidney disease (CKD) is a condition characterised by gradual kidney damage that impairs filtration over long periods of time. As filtration becomes impaired, the body accumulates toxins and unnecessary metabolic products, which can lead to multiple systemic complications [134]. Based on the glomerular filtration rate (GFR), which is measured in ml/min/1.73 m², CKD is divided into six stages: G1 (GFR ≥90), G2 (GFR 60–89), G3a (GFR 45–59), G3b (GFR 30–44), G4 (GFR 15–29) and G5 (GFR <15). In stage G1, filtration may be normal but other abnormalities are present, while G5 indicates end-stage renal failure [135]. Chronic kidney disease (CKD) has a high global prevalence, with an estimated 13.4% of adults affected across all stages. Stages 3–5, which include moderate to advanced disease, affect approximately 10.6% of the adult population globally; however, stage 3 was not subdivided into 3a and 3b, and stages 4 and 5 are relatively rare (0.4% and 0.1%, respectively) [136].

In stages 1–3, a ketogenic diet is not necessarily contraindicated; in fact, available data suggest the KD can have beneficial effects [138–140], even when compared to conventional low-fat diets and the Mediterranean diet [141]. For example, one study in people with mild CKD (or with normal renal function) found that low-carbohydrate diets resulted in a significant improvement in creatinine levels, among other improvements [142]. Additionally, it is known that the two most common causes of CKD are type 2 diabetes (30%-50%) and hypertension (27.2%) [143]. Indeed, the KD is an effective therapeutic option for the treatment of type 2 diabetes [19] (even demonstrating the capacity to achieve remission) [144], and can effectively lower blood pressure as well [19,145]. Furthermore, the KD can halt the progression of diabetic kidney disease (DKD) [146], which is often significantly associated with CKD [147].

It should be noted that the currently available scientific data on the use of KD in advanced stages of CKD (G3b – G5) is still insufficient. One study [148] investigating six obese patients with advanced diabetic nephropathy (estimated GFR <40 ml/min, urinary albumin excretion >30 mg/d) showed that a VLCKD applied for 12 weeks to reduce body weight also improved glomerular filtration markers, diabetes status, and other risk factors associated with kidney disease progression. In addition, the diet improved some other general health and well-being indicators. In another study [149], five haemodialysis patients who required weight reduction prior to planned kidney transplantation were placed on a low-calorie diet (approximately 950 kcal per day). While not a classic KD, it was characterised by a low carbohydrate content and, according to the authors, was effective and safe in this population.

Interestingly, patients in advanced stages of CKD have a reduced ability to excrete ketones in the urine and cope with acid loads. In addition, they also face deteriorating renal function, impaired excretion of sodium, potassium, magnesium or fluids (often excreted in greater amounts during adaptation to KD) and electrolyte imbalance. For all these reasons, KD is not recommended for these patients [69,138]. Despite preliminary evidence suggesting that KD is safe and effective in individual cases, the available data is not representative and remains insufficient. Therefore, guided by the precautionary principle and concern for patient safety, advanced stages of chronic kidney disease should be considered a relative contraindication to the ketogenic diet until more studies become available.

When using propofol, the ketogenic diet is considered a relative contraindication [58,68]. Interestingly, however, this contraindication is based primarily on the case of a 10-year-old boy with epilepsy who developed fatal propofol infusion syndrome (a rare but often fatal complication of this drug) after starting the KD [153]. The authors point out that substances such as propofol, which impair fatty acid oxidation (and are themselves presented in a fatty acid-rich emulsion), may pose an increased risk when combined with the ketogenic diet [58]. It is worth citing a 2023 study that analysed 65 patients with a history of propofol anaesthesia (a total of 165 anaesthesias, including 123 boluses and 42 infusions between 2012 and 2022), while following the ketogenic diet. In bolus dosing, four treatments resulted in acidosis, one in rhabdomyolysis, and one in aggravated seizures. Infusions caused one case of acidosis and one case of seizure aggravation. Importantly, not a single case of propofol infusion syndrome was observed [154]. Therefore, propofol is best considered a relative rather than an absolute contraindication to KD.

5.5. Familial hypercholesterolaemia (FH)

Familial hypercholesterolaemia (FH) is a group of inherited genetic defects leading to increased concentrations of low-density lipoprotein (LDL-C) and, secondarily, total cholesterol (TC), with elevated LDL-C being one of the main diagnostic criteria [155]. The disease is the most common monogenic metabolic disorder globally. Depending on the region and the source, its worldwide prevalence is estimated at 1 in 200 to 1 in 1,000 people [156]. FH is reported to significantly increase the risk of cardiovascular disease (up to 13-fold increase in the risk of coronary heart disease) and shorten life expectancy in both men and women by 10 to 30 years relative to the control population. The main therapeutic goal is to lower LDL-C levels [157,158].

The effect of the ketogenic diet on patients with familial hypercholesterolaemia has not been studied thoroughly. This is not surprising given that the diet’s effect on the lipid profiles of patients without FH is still controversial. This is because LDL-C and TC levels often decrease in individuals on KD who are losing excess body fat, whereas they may rise significantly in some lean individuals following the same diet (this typically happens in people with the so-called ‘lean mass hyper-responder’ (LMHR) phenotype [25,159]. Preliminary data suggest that, in individuals with a LMHR lipid profile, the course of atherosclerosis may be somewhat different [160], although the question definitely requires further research. As Diamond and co-authors (2024) have noted, the notion that LDL-C is inherently atherosclerotic may be incorrect. In their opinion, the question is nuanced and depends on the type of LDL-C. They also note that the FH (familial hypercholesterolemia) consensus ignores the fact that only a subgroup of people with FH (those who develop coagulation disorders, regardless of LDL-C levels) die prematurely from cardiovascular disease [161]. In addition, these authors cite findings indicating that coronary artery calcification score, a numerical measure that assesses the amount of calcium in coronary artery walls based on computed tomography (CT) scanning, is a better predictor of CVD risk and death than LDL-C levels alone. In one study, about half of patients with familial hypercholesterolaemia (FH) had a CAC score of zero, indicating a low risk of developing cardiovascular disease (CVD), despite persistently high LDL-C levels. In contrast, high CAC values and elevated fasting glucose levels (rather than LDL-C levels alone) were significantly associated with heart disease [162]. Certainly, further research is needed to confirm these findings.

The effects of the KD on patients with familial hypercholesterolaemia is uncertain, although some data suggest possible exacerbation of hypercholesterolaemia and uncertain safety levels in these cases [163]. The authors of another publication also suggest that before someone is classified as an FH patient, the effect of the diet as a potential cause of hypercholesterolaemia should be excluded [164]. It is also worth noting that the KD can affect the lipid profile in an individualised way (often by lowering TG but sometimes by raising LDL-C), which may call for adjustment of statin dosage or type (especially in people with FH).

With safety in mind, given the unknown impact of KD on patients with FH and the many potentially conflicting indirect data that may determine that impact, familial hypercholesterolaemia should be considered a relative contraindication to KD until these questions are resolved.

A summary of the relative contraindications to the use of the ketogenic diet is presented in Table 1.

6. Situations in which special care should be taken when following the ketogenic diet

This chapter deals with a selection of the most common situations in which special care should be taken when the ketogenic diet is followed. However, the authors wish to emphasise that these are not the only clinical cases of concern, and that the risks and benefits of the KD should be analysed separately for each individual.

6.1. Patients with type 2 diabetes mellitus (T2DM) taking hypoglycaemic drugs

Evidence suggests that the ketogenic diet may be an effective therapeutic strategy in patients with type 2 diabetes mellitus (T2DM) and may help achieve remission in selected cases [19,144,165]. Indeed, it is known that thanks to KD patients with T2DM can reduce and stabilise glucose levels (fasting, after meals and throughout the day), lower HbA1c and insulin levels, reduce body weight, and reduce (or even wean off) diabetes medication, often achieving full remission. These benefits have been confirmed by a number of meta-analyses and systematic reviews [166–172]. These benefits have been recognised by the American Diabetes Association (ADA), in the 2025 version of Standards of Care in Diabetes (in fact, the effect of KD was noted in earlier editions too). The Standards are considered one of the most important sources of clinical recommendations for the management of diabetes. The most recent version indicates that low-carbohydrate and very-low-carbohydrate diets lead to reductions in HbA1c levels and support dosage reductions of glucose-lowering medications in T2DM patients [173]. These beneficial effects of the KD have also been recognised by other organisations, including the Australian Government in The State of Diabetes Mellitus in Australia in 2024 [174]; the Scientific Advisory Committee on Nutrition (SACN); and Diabetes UK in Lower Carbohydrate Diets for Adults with Type 2 Diabetes [175] and others, such as Diabetes UK [176] or ‘Diabetes Canada’ [177].

Patients with T2DM who take hypoglycaemic drugs (e.g. insulin, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors* and sulphonylureas but NOT metformin or GLP-1 agonists [178] should be particularly cautious when considering the ketogenic diet. However, this is not because the ketogenic diet is contraindicated (in fact, T2DM may be an appropriate indication for the KD), but because the diet is so effective at reducing blood glucose (as described above) that hypoglycaemia may develop if the pharmacotherapy (previously dosed for higher carbohydrate supply) remains unchanged. Therefore, dose adjustments (and often weaning off) of hypoglycaemic drugs by the clinician required to effectively manage T2DM and its remission in the context of the KD [19,177,179–183]. SGLT2 inhibitors also carry a risk for diabetic ketoacidosis when combined with the KD. This is why the American Society of Clinical Endocrinology suggests that patients stop taking these drugs even before starting a ketogenic diet [184].