A ketogenic diet (KD) has recently gained popularity amongst the public due to its ability to induce rapid weight loss and for a number of other putative but unproven health benefits. Ketogenic diets also have proven efficacy in resistant cases of seizure disorders. However, due to palatability and adherence issues with KD, alternative diets like the less extreme low glycemic index treatment (LGIT) diet have been effectively used as a seizure disorder treatment option. KD primarily restricts the total amount of carbohydrates in the diet to ≤10% of total caloric intake whereas LGIT primarily restricts high glycemic index foods with total carbohydrates constituting 15% of total energy consumption. While several benefits have been outlined previously, conflicting results have been observed on the effect of diet-induced ketosis on plasma concentrations of the atherogenic low-density lipoprotein cholesterol (LDLc). While some studies showed a significant increase in LDLc with KD treatment, other studies reported the opposite effects with some studies reporting no difference.~Of the studies that reported an increase in LDLc, a review conducted by Chawla et al reported that restricting carbohydrates did not lower LDLc compared to a low-fat diet. In fact, the studies that utilized a low carbohydrate diet reported a significant increase in plasma LDLc concentrations. Similar results were observed by others who reported a significant increase in plasma LDLc within 3 weeks, six months, and 12 months of KD, respectively. Contrary to these findings, Dashti et al reported a significant reduction in plasma LDLc within eight weeks of KD, which remained lower for 24 weeks. Interestingly, in a study conducted by Luukkonen et al, six weeks of KD did not result in any changes in the plasma LDLc. Similar findings were reported by others. With regard to the effect of KD on apoB, limited studies reported that KD increased apoB in the pediatric population but resulted in no change in plasma apoB concentration in adults~. Importantly, there have been concerning case reports of marked elevations of LDL-c in some individuals consuming a KD and Dr. Lewis has been referred a number of these cases to his lipid clinic, some of whom have had extreme elevations of LDL that mimic familial hypercholesterolemia. These marked elevations of LDLc are unique to a ketogenic diet and far exceed the typical mild elevations seen in those consuming a high fat, low carbohydrate LGIT. The investigators speculate that there may be metabolic effects of ketosis per se, independent of the macronutrient composition of the diet that could impair LDL clearance or increase its production. Hence our interest in comparing the effects on LDL metabolism of two low carbohydrate, high-fat diets, differing in their degree of carbohydrate restriction, with and without ketosis. Of course, the investigators cannot completely match the macronutrient composition of the two diets, but the diets will be matched as closely as possible apart from maintaining carbohydrates below or just above the ketogenic threshold, respectively.~Since the popularity of ketogenic diets has increased exponentially amongst the general public in recent years and is commonly used for the treatment of epilepsy, a significant increase in atherogenic LDL-c concentration in those consuming KD could have important public health ramifications. Based on previous literature, at least 1/3rd of the individuals following KD have reported a marked elevation in LDLc levels. Whether this marked elevation in LDLc is due to excess production of LDLc or a defect in clearance is unknown. Due to the complexities and difficulties in quantitating synthesis and clearance rates for LDLc, no studies have been conducted to investigate the changes in LDLc kinetics in response to KD.
There have been concerning case reports of marked elevations of LDL-c in some individuals consuming a KD and Dr. Lewis has been referred a number of these cases to his lipid clinic, some of whom have had extreme elevations of LDL that mimic familial hypercholesterolemia. These marked elevations of LDLc are unique to a ketogenic diet and far exceed the typical mild elevations seen in those consuming a high fat, low carbohydrate LGIT. The degree of elevation of LDL-c suggests that ketosis per se may impair LDL receptor-mediated LDL particle clearance. This clinical observation is a concerning and clinically important issue since millions of people are consuming this popular diet. There are currently no studies that have examined the mechanism of the LDL-raising effect of a ketogenic diet.