Is Nutritional Ketosis Safe?

Post by Cliff Harvey
There has been a lot in the media recently slamming the high fat, low carb diet suggesting that it is not safe and could put you at increased risk of disease.
Individual results to different diets will vary and a ketogenic diet may not be applicable to everyone, but nutritional ketosis is generally considered to be safe by most researchers in the field. 

Why may people think ketosis is dangerous? 

Ketosis elicited by dietary intervention has been described variously as ‘functional ketosis’ (1) or more commonly ‘nutritional ketosis’. It has been claimed that Jeff Volek and Stephen Phinney coined the term ‘nutritional ketosis’ however the term can be found in the medical and scientific literature predating Drs Volek and Phinney, for example in the work of Sargent and colleagues (2). However in many of the earlier texts ketosis, even if nutritionally induced (i.e. absent pathological aetiology) is considered to be a disadvantaged or dangerous state. As early as 1960 Hans Krebs began to elucidate some of the mechanisms of interdependence between fatty acid and carbohydrate metabolism (for instance the effects on fatty acid metabolism and ketone production of reductions in oxaloacetate) (3). This investigation and others began to more aptly differentiate the state of nutritional ketosis versus that of a far greater levels hyperketonaemia seen in pathologies such as diabetic ketoacidosis (DKA). In 1966 Krebs differentiated this ‘physiologic’ ketosis from pathological ketosis (4).

Jeff Volek and Stephen Phinney considered the ten-fold physiologic range between 0.5mmol/L or greater of BOHB to 5mmol/L as the functional definition for ‘nutritional ketosis’  (5,6). 

Ketoacidosis may also occur in the alcoholic. In alcoholic ketoacidosis gluconeogenesis is inhibited, creating an ‘energy crisis’, requiring increased fatty acid metabolism and ketone body formation.

So is ketosis safe? 

Ketonaemia and nutritional ketosis resulting from ketogenic diets have been demonstrated to be safe when used in the treatment of: 
Epilepsy (7; 8; 9) (and in combination with valproate) (10) and case evidence suggests that type 1 diabetes does not preclude the use of a ketogenic diet for epilepsy (11); infantile spasms (12); and spinal cord injury (13). 

Pilot data suggests that ketogenic diets are safe in the adjunctive treatment for various cancers  (14; 15) and that they are safe and feasible for even advanced cancer patients (16).

Serious side effects have not been noted during studies for ketogenic diets and obesity (17), hyperlipidaemia (18)  and diabetes (19) and they appear to be safe for cardiovascular disease and may be cardio-protective by modulating artherogenic factors (namely HDL and TAG levels and LDL lipid sub-fractions) (20; 21). 


Differentiating a functional, nutritional induced ketosis from DKA and other pathology associated ketosis

We often learn in University that ketosis is ‘dangerous’ because it is equated to acidosis. However Diabetic ketoacidosis (DKA) (a potentially fatal condition characterised by a triad of: hyperglycaemia, increased total body ketone concentration, and metabolic acidosis) (22). DKA results from uncontrolled diabetes mellitus and an inability of peripheral tissue to uptake glucose effectively NOT from normal, nutritional ketosis. 

A functional, nutritional ketosis (one absent of pathology) on the other hand is an adaptive response allowing the utilization of ketone bodies (in particular BOHB) by neurons and other tissue and reducing the need for carbohydrate (glucose) as a primary fuel substrate in periods of carbohydrate scarcity. For example, it has been demonstrated that insulin induced hypoglycaemic coma can be reversed by intravenous administration of BOHB (23) and that BOHB and acetoacetate effectively replace glucose as fuel for neurons during starvation (24) and preserves synaptic function even in the presence of glucose deprivation and reduction of glycolysis (25).

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​References

1. Royer, P. (1954). Periodic functional ketosis in children. Vie médicale (Paris, France: 1920), 35(1), 9. 

2. Sargent, F., Johnson, R. E., Robbins, E., & Sawyer, L. (1958). THE EFFECTS OF ENVIRONMENT AND OTHER FACTORS ON NUTRITIONAL KETOSIS. Quarterly Journal of Experimental Physiology and Cognate Medical Sciences, 43(4), 345-351. doi: 10.1113/expphysiol.1958.sp001347

3. Krebs, H. (1960). Biochemical aspects of ketosis. Proceedings of the Royal Society of Medicine, 53(2), 71. 

4. Krebs, H. A. (1966). The regulation of the release of ketone bodies by the liver. Advances in Enzyme Regulation, 4(0), 339-353. doi: http://dx.doi.org/10.1016/0065-2571(66)90027-6

5. Volek, J. S., & Phinney, S. D. (2011). LOW CARBOHYDRATE LIVING. 

6. Volek, J. S., & Phinney, S. D. (2013). The art and science of low carbohydrate living: beyond obesity.

7. Chul Kang, H., Joo Kim, Y., Wook Kim, D., & Dong Kim, H. (2005). Efficacy and Safety of the Ketogenic Diet for Intractable Childhood Epilepsy: Korean Multicentric Experience. Epilepsia, 46(2), 272-279. doi: 10.1111/j.0013-9580.2005.48504.x

8. Kang, H.-C., Lee, Y.-M., Kim, H. D., Lee, J. S., & Slama, A. (2007). Safe and Effective Use of the Ketogenic Diet in Children with Epilepsy and Mitochondrial Respiratory Chain Complex Defects. Epilepsia, 48(1), 82-88. doi: 10.1111/j.1528-1167.2006.00906.x

9. Suo, C., Liao, J., Lu, X., Fang, K., Hu, Y., Chen, L., . . . Li, C. Efficacy and safety of the ketogenic diet in Chinese children. Seizure - European Journal of Epilepsy, 22(3), 174-178. doi: 10.1016/j.seizure.2012.11.014

10. Lyczkowski, D. A., Pfeifer, H. H., Ghosh, S., & Thiele, E. A. (2005). Safety and Tolerability of the Ketogenic Diet in Pediatric Epilepsy: Effects of Valproate Combination Therapy. Epilepsia, 46(9), 1533-1538. doi: 10.1111/j.1528-1167.2005.22705.x
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11. Dressler, A., Reithofer, E., Trimmel-Schwahofer, P., Klebermasz, K., Prayer, D., Kasprian, G., . . . Feucht, M. (2010). Type 1 diabetes and epilepsy: Efficacy and safety of the ketogenic diet. Epilepsia, 51(6), 1086-1089. doi: 10.1111/j.1528-1167.2010.02543.x

12. Kossoff, E. H., Pyzik, P. L., McGrogan, J. R., Vining, E. P. G., & Freeman, J. M. (2002). Efficacy of the Ketogenic Diet for Infantile Spasms. Pediatrics, 109(5), 780-783. doi: 10.1542/peds.109.5.780

13. Guo, C., Zhou, J., Wu, X., Jiang, H., Lu, K., Chen, J., . . . Zhu, Q. (2014). [A clinical trial of ketogenic diet in patients with acute spinal cord injury: safety and feasibility]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 34(4), 571-575. 

14. Fine, E. J., Segal-Isaacson, C. J., Feinman, R. D., Herszkopf, S., Romano, M. C., Tomuta, N., . . . Sparano, J. A. (2012). Targeting insulin inhibition as a metabolic therapy in advanced cancer: A pilot safety and feasibility dietary trial in 10 patients. Nutrition, 28(10), 1028-1035. doi: http://dx.doi.org/10.1016/j.nut.2012.05.001

​15. Rieger, J., Baehr, O., Hattingen, E., Maurer, G., Coy, J., Weller, M., & Steinbach, J. (2010). The ERGO trial: A pilot study of a ketogenic diet in patients with recurrent glioblastoma. J Clin Oncol (Meeting Abstracts), 28(15_suppl), e12532-. 

16. Schmidt, M., Pfetzer, N., Schwab, M., Strauss, I., & Kämmerer, U. (2011). Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial. Nutr Metab (Lond), 8(1), 54. 

17. Johnstone, A. M., Horgan, G. W., Murison, S. D., Bremner, D. M., & Lobley, G. E. (2008). Effects of a high-protein ketogenic diet on hunger, appetite, and weight loss in obese men feeding ad libitum. The American journal of clinical nutrition, 87(1), 44-55. 

18. Yancy, J. W. S., Olsen, M. K., Guyton, J. R., Bakst, R. P., & Westman, E. C. (2004). A Low-Carbohydrate, Ketogenic Diet versus a Low-Fat Diet To Treat Obesity and HyperlipidemiaA Randomized, Controlled Trial. Annals of Internal Medicine, 140(10), 769-777. doi: 10.7326/0003-4819-140-10-200405180-00006

19. Yancy Jr, W. S., Foy, M., Chalecki, A. M., Vernon, M. C., & Westman, E. C. (2005). A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutr Metab (Lond), 2, 34. 

20. Sharman, M. J., Kraemer, W. J., Love, D. M., Avery, N. G., Gómez, A. L., Scheett, T. P., & Volek, J. S. (2002). A Ketogenic Diet Favorably Affects Serum Biomarkers for Cardiovascular Disease in Normal-Weight Men. The Journal of Nutrition, 132(7), 1879-1885. 

21. Westman, E. C., Yancy Jr, W. S., Olsen, M. K., Dudley, T., & Guyton, J. R. (2006). Effect of a low-carbohydrate, ketogenic diet program compared to a low-fat diet on fasting lipoprotein subclasses. International Journal of Cardiology, 110(2), 212-216. doi: http://dx.doi.org/10.1016/j.ijcard.2005.08.034

22. Kitabchi, A. E., Umpierrez, G. E., Miles, J. M., & Fisher, J. N. (2009). Hyperglycemic Crises in Adult Patients With Diabetes. Diabetes Care, 32(7), 1335-1343. doi: 10.2337/dc09-9032

23. Thurston, J. H., Hauhart, R. E., & Schiro, J. A. (1986). Beta-hydroxybutyrate reverses insulin-induced hypoglycemic coma in suckling-weanling mice despite low blood and brain glucose levels. Metab Brain Dis, 1(1), 63-82. 

24. Owen, O. E., Morgan, A. P., Kemp, H. G., Sullivan, J. M., Herrera, M. G., & Cahill, G. F., Jr. (1967). Brain Metabolism during Fasting*. J Clin Invest, 46(10), 1589-1595. doi: 10.1172/JCI105650

25. Izumi, Y., Ishii, K., Katsuki, H., Benz, A. M., & Zorumski, C. F. (1998). beta-Hydroxybutyrate fuels synaptic function during development. Histological and physiological evidence in rat hippocampal slices. J Clin Invest, 101(5), 1121-1132. doi: 10.1172/jci1009