The Fat Fad: Assessing the Ketogenic Diet and its Applications

The Fat Fad: Assessing the Ketogenic Diet and its Applications

The classic ketogenic diet is characterized by consuming a high fat, low protein, and low carbohydrate diet to mimic the fasting state and utilize fats as the primary source of fuel in the body (Meira et al., 2019).  This lifestyle first gained traction in the early 1920s when similar to starvation, it displayed the ability to produce ketone bodies and reduce seizure incidence and severity in individuals with epilepsy (Meira et al., 2019).  While the ketogenic diet’s effects on seizure disorders are well-documented, it is important to ask: Is this diet safe for everyone?  Let’s explore.

The ketogenic diet is not without adverse effects.

Children who are placed on a long-term ketogenic diet have an increased risk of growth deficiency, kidney stones, skeletal fractures, dyslipidemia, vitamin D deficiency, acute pancreatitis, and prolonged QT intervals (Vining, 2008).  In their study of children who followed the ketogenic diet from 2003 to 2012, Wibisono et al. (2015) reported that constipation, hypertriglyceridemia, and hypercholesterolemia were the most common side effects, whereas diarrhea, lethargy, iron deficiency, and vomiting occurred less frequently.  Similarly, Liu et al. (2018) stated that adults adhering to this diet tended to display elevated low-density lipoprotein (LDL) and total cholesterol in addition to menstrual irregularities in female patients. 

Furthermore, Asrih, Altirriba, Rohner-Jeanrenaud, and Jornayvaz (2015) found that, after just four weeks on a ketogenic diet, inflammation as well as lipid and macrophage accumulation in the liver had increased.  Interestingly, the authors also found that inflammation was decreased in white adipose tissue, which suggests that the ketogenic diet may produce favorable effects in one body tissue and less-than-desirable effects in another.

Due to the restrictive nature of the ketogenic diet, it is recommended that individuals supplement with vitamin D, calcium, and B vitamins, among other micronutrients (Kossoff et al., 2018).  Additionally, supplementing with potassium citrate may help to ameliorate the occurrence of kidney stones (Wibisono et al., 2015). 

The ketogenic diet can impact our biochemistry and gene expression.

According to Kossoff et al. (2018), it is of the utmost importance to screen a child for disorders of fatty acid transport before beginning a ketogenic diet.  These include several inborn errors that can be found in organic acids testing, porphyrin testing, and in genomic evaluations:

  • Carnitine deficiency (primary)
  • Carnitine palmitoyltransferase (CPT) I or II deficiency
  • Carnitine translocase deficiency
  • ß-oxidation defects
  • Medium-chain acyl dehydrogenase deficiency (MCAD)
  • Long-chain acyl dehydrogenase deficiency (LCAD)
  • Short-chain acyl dehydrogenase deficiency (SCAD)
  • Long-chain 3-hyroxyacyl-CoA deficiency
  • Medium-chain 3-hydroxyacyl-CoA deficiency
  • Pyruvate carboxylase deficiency
  • Porphyrias

Often times, many of our modern idiopathic diseases are heterozygous or partial presentations of some of our more well-known metabolic disturbances. Unfortunately, due to their heterogenous presentation, they often go misdiagnosed for many years, leaving parents confused and individuals at risk for long term consequences.

In addition to these inborn errors, the FTO, APOE, and PPAR genes also influence fat metabolism, so it is vital that SNPs in these genes are assessed before prescribing the ketogenic diet.  Variations in APOE genotypes may explain differences in fat metabolism, as carriers of E4 tend to experience more significant lowering of total cholesterol and apolipoprotein B levels when dietary saturated fat is replaced with low-glycemic carbohydrates (Griffin et al., 2018).  Furthermore, Asrih et al. (2015) found that the ketogenic diet downregulated FGFR4 and KLB and impaired FGF21 signaling in the liver, all of which may play a role in the onset and progression of liver inflammation and altered lipid metabolism. 

In addition to impacts on mitochondrial function and lipid metabolism, the ketogenic diet has been shown to increase adenosine and diminish or even block methylation (Boison, 2017).  Thus, those with detoxification deficiencies or genomic impairments in methylation should likely avoid this diet unless otherwise supported.

Ultimately, caution must be exercised when prescribing or following the ketogenic diet, especially for the long term.  It is highly recommended that functional testing is performed prior to placing an individual on this diet, and, at the very least, he or she should be screened regularly for any adverse effects. 

Diet is never a one-size-fits-all approach, and the ketogenic diet is no exception to that rule.


Asrih, M., Altirriba, J., Rohner-Jeanrenaud, F., & Jornayvaz, F.R.  (2015).  Ketogenic diet impairs FGF21 signaling and promotes differential inflammatory responses in the liver and white adipose tissue.  PLoS One, 10(5), e0126364.

Boison, D.  (2017).  New insights into the mechanisms of the ketogenic diet.  Current Opinion in Neurology, 30(2), 187-192.

Griffin, B.A., Walker, C.G., Jebb, S.A., Moore, C., Frost, G.S., Goff, L.,…Lovegrove, J.A.  (2018).  APOE4 genotype exerts greater benefit in lowering plasma cholesterol and apolipoprotein B than wild type (E3/E3), after replacement of dietary saturated fats with low glycaemic index carbohydrates.  Nutrients, 10(10), 1524.

Kossoff, E.H., Zupec-Kania, B.A., Auvin, S., Ballaban-Gil, K.R., Christina Bergqvist, A.G., Blackford, R.,…Wirrell, E.C.  (2018).  Optimal clinical management of children receiving dietary therapies for epilepsy: updated recommendations of the International Ketogenic Diet Study Group.  Epilepsia Open, 3(2), 175-192.

Liu, H., Yang, Y., Wang, Y., Tang, H., Zhang, F., Zhang, Y.,…Zhao, Y.  (2018).  Ketogenic diet for treatment of intractable epilepsy in adults: a meta-analysis of observational studies.  Epilepsia Open, 3(1), 9-17.

Meira, I.D., Romao, T.T., Pires do Prado, H.J., Kruger, L.T., Paiva Pires, M.E., & da Conceicao, P.O.  (2019).  Ketogenic diet and epilepsy: what we know so far.  Frontiers in Neuroscience, 13, 5.

Vining, E.P.G.  (2008).  Long-term health consequences of epilepsy diet treatments.  Epilepsia, 49(s8), 27-29.  Wibisono, W., Rowe, N., Beavis, E., Kepreotes, H., Mackie, F.E., Lawson, J.A.,…Cardamone, M.  (2015).  Ten-year single-center experience of the ketogenic diet: factors influencing efficacy, tolerability, and compliance.  The Journal of Pediatrics, 166(4), 1030-1036.