The ketogenic diet (KD), characterized by a high fat, adequate protein, and very low carbohydrate intake, is employed under medical supervision to induce and maintain ketosis. This dietary approach has proven effective in managing pediatric drug-resistant epilepsy (DRE). While the KD offers therapeutic benefits, it also presents potential challenges, including gastrointestinal disturbances and micronutrient deficiencies. This article explores the role of L-carnitine in the context of the ketogenic diet, addressing its functions, potential deficiencies, supplementation strategies, and interactions with essential fatty acids.
Understanding the Ketogenic Diet and Its Nutritional Implications
The ketogenic diet's mechanism involves shifting the body's primary fuel source from glucose to fats, leading to the production of ketone bodies. This metabolic state has demonstrated efficacy in treating drug-resistant epilepsy, surpassing the effectiveness of some anticonvulsant medications. However, the KD's high fat content can lead to adverse effects such as reduced lower esophageal sphincter tone, delayed gastric emptying, and decreased intestinal transit time.
Common side effects of the KD include gastrointestinal disturbances, dyslipidemia, and micronutrient deficiencies. The restrictive nature of the diet may exacerbate pre-existing nutritional deficits, especially in children with disabilities or those on multiple anticonvulsant drugs. Therefore, comprehensive nutritional supplementation with vitamins, minerals, and trace elements is crucial.
Historically, ketogenic diets were not always fully supplemented with micronutrients, however early reports of problems in children date back to 1979. More recently, selenium deficiency was found in nine children on the ketogenic diet, including one who developed cardiomyopathy (Bergqvist et al, 2003). This research group have also reported poor vitamin D status in children on the diet which can compromise bone health because of the resulting loss of bone mineral content (Bergqvist et al, 2007 and 2008). One case report describes a nine year old girl on the ketogenic diet who developed scurvy due to vitamin C deficiency (Willmott & Bryan, 2008). Risk of nutritional deficiency may be increased by a limited food intake pre-ketogenic treatment in a child with severe disability or the effects of multiple anticonvulsant drugs, and the restrictive nature of any type of ketogenic diet makes it necessary to be fully nutritionally supplemented with vitamins, minerals and trace elements. Although the medium chain triglyceride (MCT) ketogenic diet, the modified Atkins diet and the low glycaemic index treatment are less restrictive than the classical ketogenic diet, it is still essential that all children using any of these diets are fully assessed by a dietitian who can advise on their nutritional adequacy and recommend the necessary supplementation based on a child’s nutritional requirements.
L-Carnitine: Role, Sources, and Significance in Ketogenesis
L-carnitine is a water-soluble compound vital for fat metabolism. It facilitates the transport of long-chain fatty acids into the mitochondria, where they undergo oxidation to produce energy. This process, known as the carnitine shuttle, is essential for efficient fat utilization. Carnitine combines with long-chain fatty acids to form acylcarnitines (esters) to enable their transport into the cell mitochondria for oxidation. Once inside the mitochondria, oxidation of fatty acids occurs in stages, with two carbons removed at each stage to form acetyl coA; this either enters the Krebs cycle, or is used to synthesise ketone bodies. The intermediates of this oxidation process can combine with carnitine in the mitochondria, forming acylcarnitines.
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The body obtains carnitine from dietary sources like milk, meat, and eggs, and synthesizes it from the amino acids lysine and methionine. Over 90% of body stores are in muscle. L-carnitine is the biologically active form of carnitine.
On a ketogenic diet, the increased intake of fats elevates the demand for carnitine to transport fatty acids into the mitochondria for oxidation, potentially leading to carnitine depletion. This risk is particularly pronounced in diets high in long-chain fats and may be exacerbated by food restrictions that limit dietary carnitine intake. An additional risk in some individuals is that long term use of the medication sodium valproate also can lead to carnitine deficiency.
Carnitine Deficiency: Assessment and Implications
Carnitine deficiency has been reported in patients with epilepsy being treated with valproic acid and there have been reports that carbamazepine and phenobarbital may also deplete carnitine levels especially if used in combination with valproic acid. It has been suggested that the KD may also induce carnitine deficiency due to the high fat content7. In patients with severe intellectual and motor disabilities, Murata and collaborators reported that the level of free carnitine was significantly correlated with gastric emptying and the severity of constipation and this level was significantly lower in the patients who suffered from constipation. Moreover, the severity of constipation was significantly relieved after supplementation with carnitine8.
Assessing carnitine status involves measuring plasma total carnitine, free carnitine, and the acylcarnitine to free carnitine ratio. Total carnitine includes free carnitine and all acylcarnitines, reflecting the total carnitine pool in the blood. Free carnitine provides an indication of the unbound carnitine available for transport. The acylcarnitine to free carnitine ratio is influenced by the increased fat metabolism and ketosis associated with the ketogenic diet. A consensus paper on carnitine supplementation in childhood epilepsy suggested a free carnitine level of less than 20µmol/litre or an acyl:free carnitine ratio greater than 0.4 (after 1 week post term) indicated a deficiency (DeVivo et al, 1998). These were arbitrary values, and different centres may use other age-dependent ranges, frequently a lower free carnitine cut-off for deficiency.
While plasma levels offer some insight, they may not accurately reflect total body stores, which are primarily located in muscle. The acyl:free ratio does not. Because of the increase in fat metabolism and ketosis that occur while on the diet, as discussed above, levels of acylcarnitines including acetyl carnitine will be greatly increased and this will result in an elevated ratio. This is a normal consequence of being on the ketogenic diet and is likely to reflect the level of ketosis, rather than an indication of carnitine status. Further supplementation with carnitine will have no effect on reducing the ratio and may even cause an increase due to formation of acetyl carnitine.
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Despite current consensus that children on the ketogenic diet should not be routinely supplemented with carnitine unless showing biochemical or symptomatic deficiency (Kossoff et al, 2009), a number of families of children using the diet do choose to use either medically prescribed or bought over-the-counter carnitine supplements, regardless of biochemical status, with reports of improved well-being, energy levels and seizure control. As true carnitine deficiency will impair oxidation of fatty acids in the mitochondria and ketone production, a drop in ketone levels would be expected. Anecdotal reports do suggest ketone levels may improve with additional carnitine supplementation especially if previously showing an unexplained drop, even if plasma carnitine levels are normal, indicating it may be a useful additional tool for dietary fine-tuning.
One study, reported in 2001, looked at plasma total carnitine levels in 46 patients (age range 1-24 years) who were on the classical ketogenic diet; this included 38 who were followed from diet initiation, and an additional eight already on the diet at the time of the study. Of the 38 patients monitored from diet initiation, three were started on carnitine supplementation at baseline due to low levels, and five others needed supplementation later in diet treatment (3 after 1 month, 2 after 6 months). One of the additional eight patients already on the diet needed carnitine supplementation due to low levels after 1 year. So, out of all the ketogenic diet patients who were not started on carnitine when starting the diet, 6 (18%) went on to have low total carnitine levels and need supplementation later. None of them showed any clinical signs of carnitine deficiency, and did not show any worsening of seizure control with low carnitine levels. The average total carnitine in patients who were never carnitine supplemented was lower after one and six months on the diet than at baseline, but this then increased again by 12 and 24 months. One other study, reported in 2005 by Coppola et al, measured plasma free carnitine levels in 164 epilepsy patients (age 1mo-26 years). The two studies discussed above used total and free carnitine.
L-Carnitine Supplementation: Guidelines and Considerations
L-carnitine supplementation in arm I patients was taken after feed in the form of tablets or dissolved tablets with a daily dose of 50 mg/kg/day, up to a maximum of 2 g/day, once per day8,13.Side effects as nausea, diarrhea, and fishy body odor13 were monitored.
If supplementation is deemed necessary, L-carnitine is the preferred form. It should be initiated at a low dose and gradually increased to minimize potential side effects such as poor absorption, diarrhea, or increased seizure frequency. DeVivo et al (1998) recommended supplementing patients with biochemical deficiency at 100mg per kg body weight per day, in three or four divided doses, up to maximum of 2g/day. There may be poor absorption, diarrhoea or an increase in seizures if high doses are started without gradual build-up.
L-Carnitine and Gastric Emptying
Gastric emptying is a complex physiologic process controlled by the physical and chemical composition, sympathetic and parasympathetic innervations of the stomach, and circulating neuro-endocrine transmitters. The type of food, volume, and caloric content significantly affect the rate of gastric emptying9.Gastric emptying can be assessed by ultrasonography which is a non-invasive technique that can be repeatedly performed because of its safety with good correlation to radionuclide estimates of gastric emptying10.
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A randomized controlled clinical trial study was conducted on 30 patients who presented to the Pediatric Clinical Nutrition and Neurology Units, Children`s Hospital, Faculty of Medicine, Ain Shams University (Cairo, Egypt), during the period from January 2023 to November 2023. These units run a multidisciplinary clinic for children with DRE which means failure of two or more well selected and proper dosed AED to achieve sustained seizure freedom2. This clinic supports the use of KD for children with DRE.
The current study comprised 30 patients with DRE who completed the 3 months clinical trial. There were no major side effects that led to withdrawal from the clinical trial prior to the last assessment. Enrolled patients were divided into two groups. Each group included 15 patients and only patients in group one (arm I) received L-carnitine supplementation in addition to KDT.
Significant increase in antral length in the patients who received KD with L-carnitine supplementation after intervention is demonstrated in Table 1. On the other hand, there was no significant difference regarding antral length in the patients who only received KD upon follow up (P-value 0.925).
Additionally, Table 2 shows a significant negative correlation between the antral length by ultrasound and GI symptoms score in all cases and the group who received KD with L-carnitine supplementation indicating that an increase in antral length was associated with clinical improvement of GI symptoms. Additionally, there was a significant positive correlation between the antral length by ultrasound and Bristol stool score in all cases and a distinct positive (almost significant) with the group who received KD with L-carnitine supplementation indicating that an increase in antral length was associated with higher Bristol stool score hence a softer stool consistency. Also, there was a significant positive correlation between the antral length by ultrasound and frequency of defecation in KD with L-carnitine supplementation group only after intervention.
Worth noting here is that no significant difference was detected between the two studied groups regarding initial laxative use. Additionally, the correlation studies showed no significant correlations between the KD ratio and frequency of defecation, Bristol stool scale, vomiting score, GI symptoms` score and antral length after intervention in all patients.
L-Carnitine, Gut Health and Constipation
In patients with severe intellectual and motor disabilities, Murata and collaborators reported that the level of free carnitine was significantly correlated with gastric emptying and the severity of constipation and this level was significantly lower in the patients who suffered from constipation. Moreover, the severity of constipation was significantly relieved after supplementation with carnitine8.
As shown in Table 4, there was highly significant increase in the of frequency of defecation in KD with L-carnitine supplementation group by 50% in comparison to KD only group that showed decrease in frequency of defecation per week by 33%. Although there was a decrease in the median (IQR) of GI symptoms score in the patients on KD with L-carnitine supplementation in comparison to KD only group indicating clinical improvement in GI symptoms, and an increase in the median (IQR) of the Bristol stool scale indicating that the stool was softer, these results didn’t reach statistical significance.
Essential Fatty Acids: Balancing Omega-3 and Omega-6
Essential fatty acids (EFA) are fatty acids that we need for our health but cannot be synthesised in the human body from any other fatty acids provided in our diet. They belong to the class of fatty acids called polyunsaturated fatty acids (PUFAs). There are two types of EFA, omega-3 and omega-6. These names refer to the chemical structure of the fatty acid; both types are unsaturated, that is, they contain carbon-carbon double bonds, the type is determined by the final double bond being either at the n-3 or n-6 position. The main essential omega-3 fatty acid is alpha-linolenic acid (ALA), and the main essential omega-6 fatty acid is linoleic acid. Although the human body cannot synthesise either of these fatty acids from scratch, it can use them to synthesise other essential fatty acids. ALA is a precursor of the longer chain omega-3 fatty acids eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), and linoleic acid is a precursor of the longer chain omega-6 fatty acids gamma-linolenic acid (GLA), dihomogamma-linolenic acid (DGLA) and arachadonic acid (AA).
Both omega-3 and omega-6 EFA have a role in maintaining normal growth and development including that of the brain, and are important components of all cell membranes in the body. However the two classes of EFA are metabolically and functionally separate, and often have important opposing physiological functions. AA (omega-6), DGLA (omega-6), and EPA (omega-3) are used to synthesise eicosanoids in the body, these are signalling molecules that exert complex control over many bodily systems, mainly in inflammation or immunity. There are four families of eicosanoids-the prostaglandins, prostacyclins, the thromboxanes and the leukotrienes. The eicosanoids derived from AA tend to increase inflammation (an important component of the immune response), blood clotting, and cell proliferation, while those derived from EPA and DGLA decrease those functions. The amounts and balance of omega-3 and omega-6 fats in a diet will affect the body’s eicosanoid-controlled functions and are therefore important in maintaining optimum health.
Commonly used polyunsaturated vegetable cooking oils, including sunflower, safflower, corn, cottonseed, and soybean. Processed foods containing these oils. Plant based oils including evening primrose oil, borage seed oil and blackcurrant seed oil. The oil highest in omega-3 fats is flaxseed (linseed), with over 50% of fatty acids as omega-3, and a ratio of 0.3:1 omega-6: omega-3. Hempseed oil also has a good balance, with about 20% omega-3, and a ratio of approximately 3:1 omega-6: omega-3. Eye Q liquid is widely used as a dietary supplement in children. This contains fish oil (EPA and DHA, omega-3), and evening primrose oil (GLA, omega-6), and also vitamin E. Some children on the ketogenic diet may also use the nutritional products Calogen and/or Ketocal (Nutricia).
It is recommended that a healthy diet should consist of approximately 2 - 4 times more omega-6 than omega-3 fatty acids however a typical Western diet tends to contain 15 - 20 times more omega-6 than omega-3 fatty acids due to the amount of vegetable oils and processed foods eaten. Healthy eating guidelines recommend lowering omega-6 intake and increasing omega-3 by reducing processed foods, including oily fish, and replacing some of the commonly used vegetable oils with oils higher in omega-3 fats or olive oil (monounsaturated oil, so contains relatively low amounts of both omega-3 and omega-6 fatty acids, but known to be very beneficial for cardiovascular health) (Simopoulos et al, 2000; Hibbeln et al, 2006). Although there are no recommendations for exact amounts of EFA in the diet of children, current UK department of Health dietary reference values suggest that ALA (omega-3) should provide approximately 0.2% of total dietary energy, and linoleic acid (omega-6) approximately 1% of total dietary energy. There was concern for a number of years that evening primrose oil might cause seizures and advice was given not to use this in epilepsy. Evidence was based on two studies published in the early 1980s on use of evening primrose oil in schizophrenia treatment.
To ensure a good balance between omega-3 and-6 fatty acids, the oil source should be varied wherever possible, and if using large amounts of a polyunsaturated vegetable cooking oil such as those listed in the above table (omega-6 sources), a small amount of an omega-3 source added to the diet as well, such as flaxseed/linseed oil, hempseed oil or walnut oil. The amounts of these omega-3 oils used can be very small, e.g. 2-3ml a day, but this should ensure a child is receiving the correct balance of EFA.