What are some of the clinical applications for ketogenic diets?

By Cliff Harvey

Much of the latest research is suggesting positive effects of consuming a ketogenic diet for individuals with disease. These include epilepsy, neurodegenerative disorders and obesity just to name a few. 

​​Epilepsy
VLCKDs have been used to successfully treat childhood epilepsy since the 1920s with reviews of uncontrolled studies showing efficacy (1, 2) along with one more recent randomised controlled trial (3). A 2012 Cochrane Database review of four randomised controlled trials,  along with seven prospective and four retrospective studies (4). found ketogenic diets to be comparable to medication  for the treatment of epilepsy (although the authors noted a high attrition rate for the diet in one long term study suggesting it may be difficult for children to tolerate, or integrate a classical ketogenic diet.)
It has been postulated based on animal research that some of the neuroprotective and anti-seizure benefits of a ketogenic diet may be derived from an increased provision of polyunsaturated essential fatty acids inherent within a higher fat dietary protocol (5).
 
Neurodegenerative disorders
High carbohydrate diets are hypothesised to play a role in the causation of Alzheimer’s Disease (AD) (6).
A stratified random sample of 815 community residents aged 65 or older in which 131 persons developed AD within the follow-up period (3.9 years) indicated a positive correlation in trends between the incidence of AD and both saturated and trans-fats, with inverse correlation shown for MUFAs and PUFAs. However there were significant interquintile variations.
A feasibility trial of five participants found reduced Parkinson’s Disease (PD) activity after use of a ketogenic diet, which was tolerable and found suitable for the participants. Placebo effects cannot be ruled out as the trial was uncontrolled (7). Again, positive effects from higher-fat diets may result wholly or partially from a greater intake of PUFAs in a diet inherently higher in total fat. In the Rotterdam Study a prospective cohort (n=5289) of people age greater or equal to 55 years, 51 participants with PD were identified. Intakes of MUFAs, PUFAs and total fat were correlated with lower risk of PD, with no association shown for cholesterol, saturated or trans-fats (8).
 
Obesity
Current dietary recommendations for obesity are centred on strategies that promote a lower calorie intake in order to reduce weight in accordance with the first law of thermodynamics (the law of energy conservation). Position statement on low-carbohydrate diets by Dietitians NZ states: “Dietitians New Zealand also considers there not to be any evidence that a diet high in fat and low in carbohydrates is more beneficial for sustained weight loss than any other dietary regimen that results in a lower intake of kilojoules.”(9) This statement according to the first law of thermodynamics cannot be disputed. The roles of satiety, taste and potential metabolic advantage of diet are not recognised by a simple ‘calories in vs. calories out’ proposition however and authors have begun to more recently speculate as to the metabolic efficiencies and inefficiencies of various diets and the role this may play in creating metabolic advantage for weight loss (10). It has been demonstrated that LCHF diets are more effective for early weight-loss  than a standard low-fat, high-carbohydrate protocol (11-14) and that ad-libitum LCHF diets are as effective for weight control as calorie-restricted low-fat diets (15). And that this may be due to an auto-regulation of energy intake due to the greater satiating effect of fats and protein, compared to carbohydrate.  This work is further supported by findings of Shai and colleagues (16) who investigated weight loss and cardiometabolic markers in people on either an energy restricted low-fat regime, an energy restricted Mediterranean regime, or an unlimited energy low-carbohydrate regime.  After 24 months, the low-carbohydrate regime had produced the greatest overall weight loss compared to the other two regimes, with more favourable changes to cardiometabolic markers including HDL cholesterol, triglycerides, and ratio of total cholesterol to HDL cholesterol. Notwithstanding that effects observed are due to caloric restriction (or in the examples of increased EE, caloric expenditure), a key point not mentioned by Dietitians NZ and other organisations is that improved satiety, satisfaction and EE may play a crucial role in both achieving results and compliance. This is amply demonstrated in any rational setting by the results seen in the previously mentioned ad libitum vs. energy restricted diets irrespective of post-hoc analysis of calories consumed.
 
Diabetes
Obesity is closely linked with diabetes (type 2). Reduced bodyweight, BMI, blood glucose, total cholesterol, LDL cholesterol, triglycerides and urea levels were reduced in 64 patients following a ketogenic diet for 56 weeks with significant increase in HDL (P<0.0001) (17).
A controlled trial by Hussain and colleagues compared over 24 weeks the effect of a low calorie (2200 calorie) ‘best-practice’ diet with a low-carbohydrate ad libitum, ketogenic diet in both diabetic and non-diabetic participants with significantly increased reductions in weight, BMI, waist circumference, glycated haemoglobin in both diabetic and non-diabetics following a VLCKD versus a low-calorie diet. Interestingly blood lipid profiles were improved for TAG, LDL and total cholesterol (all reduced), and HDL (increased) significantly only in the VLCKD group (D2 and ND) with some worsening in those following a low-calorie diet – significantly there was noted a worsening of total cholesterol and triglycerides in non-diabetics following a standard calorie-restricted diet (18). A 44 month follow up of 16 diabetic patients following a low-carbohydrate diet (50% fat, 20% carbohydrate, 30% protein) showed statistically significant (P<0.001) improvements in weight, BMI, HbA1C, HDL-C and HDL – total cholesterol ratio (19).
 
Cancer
Cancer cells are predominantly glycolytic.  The shift from normal aerobic metabolism to glycolysis in cancer cells is known as the ‘Warburg Effect’ as elucidated by Otto Warburg (20). Mutations and further growth in tumours may be related to disturbed energy metabolism, and due to the reliance on higher carbohydrate diets in dietary guidelines for health, some standards of current care may contribute to progression of tumours. Calorie restricted or ketogenic diets may be effective to reduce these metabolic maladies. (21)
Reviews of the published literature in both animal and human studies suggest a role for the ketogenic diet as it appears to be potentially toxic to cancer cells, effectively ‘starving’ them of priority fuel for continued growth and progression, and is well tolerated and safe for patients (22, 23).
 
Autism
Very early (and highly speculative) preliminary evidence suggests a possible adjunct treatment role of a ketogenic diet in the reduction of seizures in autistic children (24) and more broadly in reducing symptoms of autism  (25).

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​References
 
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