Much Ado About Ketosis: Are The Adverse Effects Really That Adverse?

I recently read a blog post decrying anyone that would recommend a low carbohydrate / ketogenic diet to their patients.


In fact, this particular blog outlined a number of “adverse reactions” to a ketogenic diet, and based upon these perceived reactions, the writer advised severe caution with its use in just about anyone.   It is important to note at the outset that most of the data this blogger quotes are from older studies completed in children for the treatment of epilepsy with specific liquid ketogenic dietary meal replacements. (Not what you’d expect in a low-carb / ketogenic diet for the average obese adult today.)

Diet Confusion
Diet Confusion

Thanks to recent misinformation by a number of medical professionals, including the person writing the blog referenced above, a poor understanding of fatty acid metabolism by the general community, and a distinct lack of understanding of human adaptability recorded over the last 5,000-6,000 years, there is still significant confusion about ketogenic diets.

It is important to recognize the crucial fact that the human body is designed to function quite well when supplied any of three macronutrients: carbohydrates, proteins or fats.  It does so through an amazing series of enzymatic reactions referred to as the Krebs (tricarboxylic acid) cycle, producing needed ATP (adenosine triphosphate) required for our muscles to contract, our heart to beat and our diaphragm to expand our lungs.  What’s even more amazing that that the body was designed to recognize the season we are in based up on the food we eat. That is, until we invented refrigerators in 1913. (Now our bodies think it’s year round summer time . . . wait . . . I live in Arizona where it is year round summer time.)

No, this is not a post about unplugging your refrigerator, living on solar, getting off the grid and saving energy.

Our bodies recognize the seasons we are in based upon inherent hormone release.  The key hormone is insulin.  Insulin can be looked at as the seasonal indicator to our bodies.  Insulin production rises and falls based on our intake of carbohydrates (sugar, starches, some fibers).  Insulin, essentially, tells our bodies when it is a “time of plenty” and when it was a “time of famine.”  Why?  You ask.  We didn’t have refrigerators 100 years ago and you were lucky if you had a root cellar.  The body needs to know when to store for the famine (the winter) that was around the corner. Insulin is that signal.

During the summer, potatoes, carrots, corn and other fruits are readily available.  These are all starchy carbohydrates and they all require the body to stimulate an insulin response so that they can be absorbed.  Insulin stimulates fat storage (J Clin Invest. 2000;106(4):473-481. doi:10.1172/JCI10842).  Just like bears, our bodies were designed to store for the winter.

During the winter, when carbohydrates were less prevalent, insulin production could and would decrease to baseline levels. This also is a natural phenomenon that occurs with fasting and even during lactation.  (Kreitzman SN. Factors influencing body composition during very-low-caloric diets. Am J Clin Nutr. 1992;56(l Suppl):217S–23S.Medical aspects of ketone body metabolism. Mitchell GA, Kassovska-Bratinova S, Boukaftane Y, Robert MF, Wang SP, Ashmarina L, Lambert M, Lapierre P, Potier E, Clin Invest Med. 1995 Jun; 18(3):193-216.)

If you think back in history, your grandparents probably used stored meats & cheeses that could be salted or smoked for preserving during this time of year.  Those crossing the plains were commonly found with pemmican, a concentration of fat and protein used as a portable nutrition source in the absence of other food. (Chapter VIII. Narrative of the Life of David Crockett, of The State of Tennessee, Written by Himself, Sixth Edition [E.L. Carey and A. Hart:Philadelphia] 1834, 1837Marcy, The Prairie Traveler, p. 31.) Think about conversations you may have had with your grandmother when she told you that for Christmas, she received an orange.  A single orange for a gift?! Many of my patients drink 12-15 of them in a glass every morning.  The winter diets of our grandparents were very low in starches and carbohydrates.  When carbohydrate intake is low, little insulin is produced.

Again, insulin is the hormone that tells you that you’re in “a time of plenty” and stimulates weight gain and cholesterol production to prepare for winter.  Those prescribing the use of ketogenic diets understand this innate human adaptive trait, and use it to effect changes in weight, cholesterol and other desired metabolic changes.

Three types of ketones., May 2015

Now, let’s define the difference between ketosis and keto-acidosis and try to clarify the misinformation that is being spread around the blogosphere.

A ketone is a molecule the body produces from the breakdown of fat and some proteins (amino acids).  There are specifically three types of ketones: beta-hydroxybutyric acid, acetoacetic acid and acetone.  If ketosis was “bad,” then why would our bodies produce these molecules?  They are not bad, and in fact, multiple studies show that the body is often more efficient and effective when it functions on ketones rather than glucose as its primary fuel source.  The body can only supply a limited amount of sugar or glucose for fuel.  If you talk to runners, marathoners or triathletes, they will tell you that after about 45-90 minutes of continuous endurance exercise the glucose supply runs out and they will experience what is termed a “bonk” (have a low-blood sugar or hypoglycemic episode).  Unfortunately, our bodies can only store about 18-24 hours of glucose.

Metobolic Changes of Ketogenic Diet (American Journal of Physiology – Endocrinology and Metabolism Published 1 June 2007 Vol. 292 no. 6, E1724-E1739 DOI: 10.1152/ajpendo.00717.2006)

However, the body can store days upon days of fat in the form of triglyceride in the fat cells.  Triglyceride is broken down into ketones.  If glucose is the “unleaded” fuel, you can think of ketones as the “diesel fuel” that is easier to store and runs longer.

The average body functioning on ketones as the primary fuel will have a ketone level measured in the blood somewhere between 0.4 and 4 mmol/L.  Because of a balance that is created by the use of ketones and a feedback mechanism that kicks in when the ketone level rises, the body will maintain a pH of around 7.4.

Ketoacidosis is dramatically different.  If you are a type I diabetic, you don’t produce any insulin.  The feedback mechanism regulating ketone use is broken and the ketone levels and triglyceride breakdown speeds up because the body can’t access glucose and can’t produce insulin.  The ketone levels spike and the level can rise to > 25 mmol/L.  In the presence of a high blood sugar and high ketone level, the acid level in the blood shifts to a pH of less than 7.3.  This is referred to as metabolic acidosis and can be life threatening as the low pH shuts down the bodies’ enzymatic processes and a person becomes critically ill and without treatment, can die. (Kitabchi AE et al., Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults., May 2015.)

If you’re not a type I diabetic, you have nothing to worry about.  Regardless of what the “ketogenic nay-sayers” blog about, your liver makes approximately 240g of glucose per day, this stimulates a basal release of insulin which keeps the pH in check. It’s also what keeps weight loss at a consistent pace of around 2-10 lbs per month.

If you are a type I diabetic, don’t fret.  Carbohydrate restriction can still be used very effectively.  It just takes some balancing and understanding of your individual metabolism.  Talk to your physician and/or medical bariatrician about how to follow a carbohydrate restricted diet while using insulin.

What about all the other “adverse effects” the blogosphere and other so-called experts claim about ketogenic diets?

Let’s take them on one by one.  Are you ready?

Gastrointestinal (GI) disturbances – Yes. Any time you change your diet you may experience diarrhea, constipation or gassiness.  Most of the time, this is because you are either 1) not eating enough leafy greens (fiber) or 2) you’re using a supplement that contains an artificial sweetener.  Most of the studies on ketogenic diets did not incorporate fiber and the studies used to make this point were on children who used a ketogenic fat supplement shake or liquid preparations containing these artificial sweeteners to make them palatable.  If you have spoken to any bariatrician, they will tell you, the best way to follow a ketogenic diet is to eat real food.  If you want to read about the anecdotal GI effects of sweeteners, read the comment section in Amazon about the Haribo Sugar Free Gummy Bears.

Oh, by the way, 65% of patients in my practice following ketogenic diet see improvement in gastroesophageal reflux (GERD) symptoms. (Austin GL, Thiny MT, Westman EC, Yancy WS Jr, Shaheen NJ. A very low carbohydrate diet improves gastroesophageal reflux and its symptoms: a pilot study. Dig Dis Sci 2006;51:1307–2.)

Hair Loss/Thinning – Really?!  It is important to note that hair loss/thinning can occur with any form of weight loss (Novak MA, Meyer JS. Alopecia: Possible Causes and Treatments, Particularly in Captive Nonhuman Primates. Comparative Medicine. 2009;59(1):18-26.)  This is especially true if you are restricting calories, which was occurring in a number of the ketogenic dietary studies previously published.  You do not and should not need to “restrict calories” if you are following a ketogenic diet correctly, and in fact, most people take in more than 1800 calories on a ketogenic diet. (Shai I, et al., N Engl J Med, 2008; 359:229-241.)

Inflammation Risk – In every patient that I have placed on a ketogenic diet in the last 8 years, all inflammatory markers including CRP, Sedimentation Rate and Uric Acid have all decreased.  Inflammation gets better on an appropriately formulated ketogenic diet. The older studies of ketogenic diets in children contain most of their fat from Omega-6 fatty acids from vegetable oil which will increase inflammation and oxidative stress, spike the cortisol levels and have the secondary effect of actually raising the triglycerides. (Simopoulos AP,The importance of the ratio of omega-6/omega-3 essential fatty acids, Biomed Pharmacother., 2002 Oct;56(8):365-79.)

Kidney Stones/Gout – These (Kidney Stones & Gout) are both commonly caused by spikes in uric acid.  As noted above, I’ve seen multiple cases in my practice where a ketogenic diet lowers uric acid. Only a small clinical trial has been published in the literature (and it wasn’t truely ketogenic), but the results point to the potential for ketogenic diets to lower uric acid. (Dessein PH, Shipton EA, Stanwix AE, et al. Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis 2000; 59:539-543.)  Ketogenic diets also have the capacity to lower the formation of calcium oxalate stones through a secondary mechanism I won’t go into here. Are these a risk?  Only if you cheat on your carbohydrate restriction.  So, I warn patients.  Don’t cheat.

Muscle Cramps/Weakness – The process of weight loss occurs by burning fat into CO2 and water. We breathe the CO2 out, but the water produced has to follow salts out through the kidneys.  Hence, we lose salts.  This can cause weakness and muscle cramps.  The solution?  Stop restricting salt on a low carbohydrate diet.  We are the only mammal that restricts salt and we do it because low-fat diets cause us to retain water.  Low carbohydrate diets do the opposite.  Use sea salt or sip beef or chicken bouillon broth with your dinner.  The use of yellow mustard also helps (the small amount of quinine in yellow mustard stops the cramping).  If you have congestive heart failure, talk to your doctor about monitoring your salt intake in balance with your diuretic or water pill.

Hypoglycemia – If you read the ketogenic diet research, most of it was done on epileptic children.  The diets called for a period of starvation, then the use of a ketogenic liquid based on the John’s Hopkin’s protocol.  It is a well-known fact in medicine that starvation in children can frequently cause hypoglycemia, especially in children with other genetic or congenital defects leading to forms of epilepsy.  In clinical practice, with ketogenic diet use in adults, hypoglycemia is rare.

Low Platelet Count (Thrombocytopenia) – Again, this was seen in the epileptic children who were placed into starvation first, then introduced a liquid fat replacement shake to stop intractable seizures. These liquids or shakes were often nutrient deficient in other essentials.  Folic acid, B12 and copper deficiency can occur when not eating “real food.” Low platelet counts are rarely seen on ketogenic diets based around “real food.” Many children in the ketogenic studies had been on or were concomitantly on valproic acid for their seizures.  Valproic acid is commonly known to cause thrombocytopenia (Barry-Kravis E et al, Bruising and the ketogenic diet: evidence for diet-induced changes in platelet function. Ann Neurol. 2001 Jan;49(1):98-103.;  Kraut E, Easy Bruising,, May 2015.)

Impaired Concentration/Mood – A number of patients starting carbohydrate restriction will go through 2-4 weeks of carbohydrate withdrawal.  This can be just as powerful as morphine withdrawal in some patients. Sugar is a drug and effects the same hedonic receptors that morphine does in the brain (Lustig, Robert H, Fructose: Metabolic, Hedonic, and Societal Parallels with Ethanon, Journal of the American Dietetic Association , Volume 110 , Issue 9 , 1307 – 1321.)  Some patients will experience headache, tremor and decreased concentration while “withdrawing” off of starches and carbohydrates. Studies actually show that after a period of adaptation, cognitive function actually improves (Krikorian R, Shidler MD, Dangelo K, Couch SC, Benoit SC, Clegg DJ. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiology of aging. 2012;33(2):425.e19-425.e27. doi:10.1016/j.neurobiolaging.2010.10.006.)

Metabolic Acidosis – As described above, this can occur in a type I diabetic, and metabolic acidosis has also been shown to occur in young children placed on severe carbohydrate and protein restriction, as was the case in some of the ketogenic dietary trials with epileptic patients. (Saxena VS, Nadkarni VV. Nonpharmacological treatment of epilepsy. Annals of Indian Academy of Neurology. 2011;14(3):148-152. doi:10.4103/0972-2327.85870.FreemanThe Ketogenic Diet: One Decade Later, Pediatrics March 2007; 119:3 535543)

Osteoporosis/Osteopenia – If your ketogenic diet is “shake” or “meal replacement” based, you run the risk of mineral deficiency that could lead to Osteoporosis, however, if you are using real food, the opposite is true and most patients have improvement in their Vitamin D levels and bone density. (AG Christina BergqvistJoan I SchallVirginia A StallingsBabette S Zemel, Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic dietAm J Clin Nutr December 2008 88: 16781684; doi:10.3945/ajcn.2008.26099)

Easy Bruising – This is usually due to inadequate protein supplementation as was the case in much of the ketogenic literature where protein levels were also restricted. (Kraut E, Easy Bruising,, May 2015.)

Infections/Sepsis/Pneumonia – These have not been issues in the 8 years I have been using ketogenic diets with my patients.  These issues were seen in the John’s Hopkins protocol with children who had epilepsy and other congenital disorders placed on a diet low in protein and carbohydrate. (Saxena VS, Nadkarni VV. Nonpharmacological treatment of epilepsy. Annals of Indian Academy of Neurology. 2011;14(3):148-152. doi:10.4103/0972-2327.85870.)

Pancreatitis – Patients who are insulin resistant or have impaired fasting glucose commonly have high triglycerides.  Elevation in triglycerides itself is a cause of pancreatitis.  Ketogenic diets lower the triglycerides. However, if a patient has not been following their diet as directed, spikes in the triglycerides can occur placing the person at risk for pancreatitis.

Long QT Intervals/Heart Arrhythmias – The list of things causing Long QT intervals and abnormal heart rhythms is long and variable (Acquired Long QT Syndrome. Berul C et al., May 2015). It is well know that starvation, rapid weight loss and liquid protein diets can cause a delay in the conduction signal in the heart.  Anyone wishing to start any diet should have an electrocardiogram (EKG) through their doctor to ensure that the diet (of any type) doesn’t exacerbate a prolonged QT interval.

Low Carb 71yo male
Three year weight loss and metabolic improvement in a patient on a Low-Carb / Ketogenic diet. Note: Patient admits to not following ketogenic diet during holidays from Nov 2013 – Feb 2014 (see the dramatic changes to the body when cheating happens)

Cardiomyopathy – Prolonged QT intervals have been associated with cardiomyopathy and the former can stimulate the later.  Any diet that has the potential to prolong a QT interval has the potential to cause cardiomyopathy.  Hence the need for regular EKG monitoring on any diet (Acquired Long QT Syndrome. Berul C et al., May 2015).

Lipid/Cholesterol Changes – In the 8 years I have been applying ketogenic diets to patients, I have seen dramatic improvement in the triglycerides and HDL levels.  The only time triglycerides rise over 100 is if the patient is using artificial sweeteners or is cheating on the carbohydrate restriction.  Total cholesterol commonly rises, however, this is indicative of the fact that there is a shift in the LDL particle size and this affects the calculation of both total cholesterol and LDL-C.  In light of this, most of my patients have dramatic improvement in triglycerides and small dense LDL particle number.  I’ve included the common cholesterol changes I seen in my office as a few case reports to demonstrate the effectiveness of a ketogenic diet:

Low Carb 56 yo female
2 year ketogenic dietary labs and weight loss

Myocardial Infarction – It is interesting that one blogger includes this on the list of adverse reactions, however, when you actually read the study, the author of the paper make an “assumption” that there was potential for heart attack due to an elevated total cholesterol, however, a correlation was never made.  Again, in the 8 years I have been using ketogenic diets, I have seen dramatic improvement in cholesterol profiles, inflammatory markers, atherosclerosis and carotid intimal studies (Shai I et al, Circulation 2010; 121:1200-1208).

Low Carb 74 year old male
Three year metabolic history of a Low-Carbohydrate / Ketogenic diet

Menstrual Irregularities / Amenorrhea – It is well known that any diet causing protein or other nutritional deficiency will affect the menstrual cycle first and growth second.  The only time menstrual irregularities occur with a ketogenic or Low-Carb diet is when a patient is not taking in enough protein or is not eating real food.  What amazes me is that a properly applied ketogenic diet causes normalization of the menstrual cycle, and in my practice, I’ve had a number of women successfully be able to conceive after making a ketogenic dietary change.

Death – All cases of death related to ketogenic diets have been documented in children while using liquid formulas for ketosis to treat epilepsy.  These cases revealed the formation of a prolonged QT interval leading to cardiomyopathy due to deficiency in selenium.  This has been solved by the addition of selenium to the ketogenic supplement. (Stewart WA et al., Acute pancreatitis causing death in a child on the ketogenic diet, J Child Neurol. 2001 Sep;16(9):682.;   Bergqvist AG et al, Selenium deficiency associated with cardiomyopathy: A complication of the ketogenic diet. Epilepsia. 2003 Apr;44(4):618-20.;  Kang HC et al., Early and lat onset complications of the ketogenic diet for intractable epilepsy, Epilepsia. 2004 Sep;45(9):1116-23.;  Kang HC et al, Efficacy and Safety of the Ketogenic diet for intractable childhood epilepsy: Korean Multicentric Experience, Epilepsia. 2005 Feb;46(2):272-9.) This does not happen when the diet is based on the use of real food instead of supplementation and has not been seen in adults.

For more details on the nutrient content of a ketogenic diet, see the recent article by a friend of mine, Maria Emmerich.  She’s been creating ketogenic diets for years and has a number of fantastic books my wife and I have been using in our home over the last nine years. She is one among many that can give you some direction on how to devise a healthy, real food based ketogenic diet.  See the page on my website here that will give you some direction in formulating your Ketogenic Lifestyle.

Mothers Day Cheese Cake
Nally Family Low-Carb / Ketogenic Cheese Cake

So, to celebrate Mother’s Day, today, with my family, I am going to indulge in some Low-Carb / Ketogenic Cheese Cake!! Happy Mother’s Day, to all of you and especially to all you mothers out there making a healthy difference in the lives of your families! (You can find the recipe for this delicious cheese cake here)

In the words of Sir William Ostler, “If it were not for the great variability among individuals, medicine might well be a science and not an art.”

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