Ketogenic Diet: Which Patients Benefit?John Watson; Reviewed by: Anya Romanowski, MS, RD

March 20, 2018

The Disease-Fighting Diet

When it comes to addressing disease, most diets have a precautionary pitch: Eat better, lose weight, and push back the day you receive an unwanted diagnosis from your doctor. In recent years, the ketogenic diet (KD) has changed this dynamic by being positioned as less preventive and more prescriptive. By committing to this diet, its proponents argue, patients with serious and life-threatening conditions are doing more than practicing healthy eating; they're applying a nonpharmacologic approach that may directly affect their outcomes. In an era defined by soaringdrug costs and a back-to-basics whole food movement, it's an idea that's garnering excitement.

"Ketogenic diets have been used for specialized conditions, such as control of epilepsy, for years," explained David S. Ludwig, MD, PhD, founding director of the Optimal Weight for Life (OWL) program at Boston Children's Hospital and a professor of nutrition at Harvard School of Public Health. "However, interest in this approach for obesity, diabetes, and other chronic conditions has burgeoned in the past decade in light of exciting laboratory data and preliminary clinical trials."

In this overview, we take a closer look at what the latest research shows about the value of KD inseveral conditions.

What Is KD?

The classic KD is composed primarily of fat (80-90%), with the remainder filled in with protein (8%-15%) and, to a minimal degree, carbohydrates (2%-5%).[1] The goal is to mimic the body's state during fasting without impairing its ability for growth. By limiting the amount of carbohydrates and protein metabolized, energy is instead derived from fat within the body or consumed in the diet.[1] As glucose levels decrease, fat-derived ketone bodies begin to take over as the body's main energy source, a metabolic state known as ketosis.[2]

In addition to classic KD, there are three common variations of this diet: a medium-chain triglyceride diet, a modified Atkins diet, and the low-glycemic-index treatment.[3] These give practitioners more variability as they try to offer palatable options to patients by increasing protein, decreasing fat, substituting all but non-starchy vegetable carbohydrates, and other strategies.

Even with a variety of diets to choose from, health concerns remain surrounding their adoption.

"If not done correctly, a ketogenic diet carries important risks, including nutrient deficiencies, hypovolemia, hypokalemia, kidney stones, and gout," said Ludwig. "However, these risks can beminimized with a properly formulated diet."

Food Lists: What's on a Ketogenic Plate?

Defined by its restrictions, KD has a long list of foods that should be limited or avoided, including:

Grains and products made from grains (rice, wheat, rye, oats, barley, quinoa, pasta, cereal, pizza)

Legumes and beans

Starchy vegetables and tubers (peas, corn, potatoes, yams)

High-carb fruits; dried fruit (bananas, apples, oranges)

Low-fat dairy products

Refined fats and oils; vegetable oil

Sugar

Alcohol

When it comes to what you can have, KD still offers an array of options, including beef, pork, poultry, fish, eggs, cheeses, avocados, olive oil, and coconut oil. Also included is a variety of non-starchy vegetables, such as salad greens, green beans, kale, and broccoli.

Ludwig notes that although these diets are highly restrictive, their high intake of fat can also make them "luscious and satisfying," especially given that they usually don't come with the calorie restrictions of so many other diets.

Latest Clinical Data for Various Diseases and Conditions

Epilepsy: An Old Treatment's New Benefits and Risks

KD may be attracting new attention, but its medical roots are nearly a century old. It was first designed as a treatment for epilepsy in 1921,[4] meant to mimic fasting and its known seizure-suppression benefits. The treatment fell out of favor with the advent of antiseizure medications like phenytoin a little over a decade later, but it returned in earnest when anecdotal accounts of children with treatment-resistant epilepsy becoming seizure free after adopting it were confirmedin a seminal 2008 randomized trial.[5]

KD is now widely in use for patients who have failed two mainline drugs,[6] with systematic reviews finding seizure-reduction rates as high as 85% after treatment.[7] Last year, Medscape reported on data that this intervention is just as effective as corpus callosotomy and vagal nerve stimulation in reducing seizures and improving other outcomes in children not responsive to drugs.

The reasons why it is so effective, however, are decidedly less clear. According to Jong M. Rho, MD, section chief of pediatric neurology at Alberta Children's Hospital in Canada, there are key unresolved questions around the direct effects of fatty acids on excitability, restricting glycolysis,and antioxidant activity and a possible role for the gut microbiome. His own recent work suggests that no single mechanism, but instead an array, drives the effects of this diet, including the antiseizure action of ketone bodies.[8]

"The notion that altered or abnormal metabolism is a root cause of epilepsy is growing," said Rho. He added that, in turn, this has increased research into novel targets that work as a "ketogenic diet in a pill," an idea that Rho and a colleague first outlined 10 years ago[9] and which remains elusive.

Despite its resounding success, KD is not without risks. In 2008, researchers reported two cases of sudden cardiac arrest in children on the diet for a period of 3 years.[10] Impaired myocardia function and QT prolongation (as documented on ECG) are complications associated with selenium deficiency from following KD.

Type 2 Diabetes/Obesity: Breaking a Cycle

The historical shift toward promoting low-fat diets, often in the form of high-carbohydrate foods with an increased glycemic burden, is viewed as a major contributor to the current obesity epidemic.[11]

Now researchers are investigating whether KD can help put the genie back in the bottle. The results have been promising, as separate meta-analyses show that KD leads to greater weight lossthan its low-fat counterparts[12] while simultaneously suppressing appetite.[13]

In related efforts, KD has become a focal point for researchers targeting type 2 diabetes.

"By definition, type 2 diabetes is a state of carbohydrate intolerance," said Ludwig. "So it conceptually makes sense that reducing or eliminating carbohydrates would at least improve control (eg, reduce medication requirements) and perhaps help reverse the underlying metabolic problem."

KD's ability to reduce the necessity for antidiabetic drugs by improving glycemic control, weightloss, and other key outcomes has been observed in multiple studies in the past 20-plus years, both alone and in comparison with other dietary interventions.[14,15,16,17,18,19] It was also recently reported that ketogenic drink supplements may improve glycemia and insulin sensitivity, a sign

of the continued desire to provide KD's benefits without the burden of making patients commit toit in full.[20]

Despite these gains, Ludwig reminds clinicians that "no existing trial is of sufficient quality to establish long-term safety and efficacy."

Because patients with diabetes who are restricting carbohydrates are at risk for hypoglycemia, it is recommended that implementation of this diet be accompanied by modification of dosage of insulin and insulin secretagogues.[21]

Cancer: Targeting Tumors Where They Grow

Cancer is a famously heterogeneous disease, though one throughline that connects multiple typesis the Warburg effect, which describes how cancer cells use glucose as their main source of energy.[2] This has made KD an attractive option for supplemental cancer therapy, the theory being that cutting off the tumor's supply of energy will aid in containing its spread.

Fitting for a disease as multifaceted as cancer, the results have been inconsistent.[22] A case series of 78 patients with a variety of tumor types reported a trend toward improved outcomes, including one case of halted progression, among strict adherents to KD in the palliative setting.[23] In patients with glioma, case reports have noted no major side effects to this dietary approach and the achievement of stable disease of up to 6 weeks in certain patients.[24] Recent MR scans have noted the accumulation of ketone bodies in two patients with brain tumors who adhered to this diet.[25]

Building a compelling case for the efficacy of this approach is not currently possible.[22,26] To date, studies have been defined by their inconsistency, and even positive reports suffer from poordesigns. Until these anecdotal reports are submitted to the rigors of randomized trials, KD will remain a promising but unfounded intervention for cancer.

Neurologic Disorders: Building Out From Epilepsy

The unquestionable efficacy of KD in epilepsy has given rise to a number of studies looking into its use for several neurologic disorders. The rationale behind this research is that KD can profoundly affect neuronal plasticity to enhance and normalize function.[27,28]

"The basic premise for using the ketogenic diet is that this therapy may provide neuroprotective effects in a very broad manner," explained Rho .

Results are early and often anecdotal but are impressive in their sheer range of applications. Migraines, thought to be caused in part by an energy deficiency disorder, responded favorably to ketone supplements in a preliminary study. Patients with mild to moderate Alzheimer disease exhibited improved scores on cognitive testing following 3 months of a variation of KD, and those with Parkinson disease also experienced improved function following exposure to this dietary intervention.[27] Behavioral improvements have also been noted in children with autism spectrum disorder who were receiving KD.[28]

Animal data also suggest a role for KD in the treatment of traumatic brain injuries, in that it may mitigate the metabolic changes in the brain caused by such injuries. The same may be true in

amyotrophic lateral sclerosis, for which mitochondrial dysfunction is thought to possibly have a contributory role.[27]

Endurance Athletes -- Does KD Enhance Performance?

The benefits of KD are sought not only by patients but also by otherwise healthy athletes lookingfor a performance advantage.

According to Lorna Doyle, PhD, a lecturer and researcher in nutrition and sports nutrition at Waterford Institute of Technology in Ireland, endurance athletes have moved on from the earlier days of carbo-loading before big events. Aware of the limitations and risks of carbohydrate-heavy diets, many athletes have begun looking for new dietary means of obtaining a performanceedge.

Doyle and colleagues studied 20 male endurance-trained athletes (mean age, 33 years) who committed to either a high-carbohydrate diet or KD, while adopting otherwise identical training regimens, for 12 weeks.[29] They found that the KD group had a significantly greater reduction in body mass (-5.9 kg vs -0.8 kg) and body fat percentage (-5.2% vs -0.7%). Although there was no significant difference in athletic performance on the 100-km time trial between the groups, fat oxidation and 6-second sprint power (+0.8 watts/kg) was significantly higher in those on KD.

"I believe that the improvements in body composition were related to the enhanced usage of fat as energy during the 12 weeks; hence, stored body fat was used for energy," said Doyle. "However, the training employed (endurance, strength, and high-intensity interval training) ensured that muscle mass was retained and possibly helped mitochondrial adaptations to enhancefat usage."

For those hoping to follow in the participants' footsteps, Doyle cautioned that such a select diet necessitates its own considerations.

"Focus and attention must be paid to electrolyte consumption to ensure dietary safety. Sodium and magnesium consumption especially is important, particularly for a person exercising. It can be more difficult to get and absorb some electrolytes on a ketogenic diet."

Key Takeaways

To say that we're in the early stages of learning about a treatment that we can trace back to 1921 may sound counterintuitive but is nonetheless true.

Although the impact of KD in epilepsy is unquestionable, and its promise in treating obesity and type 2 diabetes is backed by a growing body of evidence, much of the case for its application in cancer and neurologic disorders relies on early, anecdotal evidence.

If careful not to overstate the case for KD, experts agree that its promise is sufficient to warrant agreater investment in well-designed trials in these areas. A relatively safe intervention that can beadministered with a trip to the grocery store, not much can halt this explosion of interest in KD for a wide range of conditions.