The Ketone Craze - Who Really Benefits From High Ketone Levels?

When trawling recent "Keto forums" and reading people's experience with the diet, it's very noticeable that there is some sort of "ketone craze" happening.

Meaning that generally healthy people who want to shed a few pounds, have more energy or improve their mental clarity are convinced that pushing their blood ketone levels to levels of 5 mmol/l or beyond would benefit them—or help them lose weight faster. The goal of this article is to look at the rationale behind elevated ketones (or not) and what to aim for in various different "health situations".

A Brief History of Ketones

There is no doubt that ketones can have a very powerful effect on our metabolism, particularly in the brain (1, 2, 3).

This was discovered indirectly a long time ago: in 500 BC (or possibly even earlier), fasting and other dietary regimes were used to treat life-threatening conditions like for instance epilepsy (4).

In 1921, the endocrinologist Rollin Woodyatt first mentioned the term "ketones" that were produced in times of starvation, fasting or carbohydrate restriction. In the same year, a Mayo Clinic physician, Dr Russel Wilder, defined a dietary therapy that drastically reduced carbohydrates and replaced most of the calories by fat. He hoped that this so-called "ketogenic diet" would provide the benefits of fasting without restricting calories so drastically, making it more sustainable in the long term.

What Are Ketones?

Ketones are a by-product of fat metabolism in the body: when glucose drops through carbohydrate restriction or fasting, for instance, insulin production will also decrease. These form the ideal conditions for the liver to start producing ketone bodies. This happens—more or less quickly depending on the individual—once beta-oxidation of fatty acids has increased to a point where fatty acids can't be utilized directly for adenosine triphosphate (ATP) production. ATP is the "energy currency" of the cell and is found in all forms of life: Without ATP, there is no life!

The major types of ketone bodies are:

• Acetoacetate
• B-hydroxybutyrate
• Acetone

Why does ketone production actually happen, you might ask? The main reason is to provide the brain with an alternative fuel when glucose is scarce. Ketone bodies, which are water-soluble and can cross the blood brain barrier (5), can supply the brain with up to 70% of total energy required. But most other body tissues can utilize ketone bodies in a very efficient, and in some tissues even preferential, way (5).

So, in short: If humans weren't able to burn fat and at some point also ketones as a by-product of fat oxidation, we probably wouldn't be here any more. Tapping into our glycogen stores—yielding approximately 2,000 Kcal—wouldn't get us very far if we couldn't access the 40,000+ Kcal (in many people this is a lot more!) stored as fat.

How Are the Different Ketone Bodies Related?

As you might imagine, the three ketone bodies outlined above need to be measured in different ways:

• Acetoacetate can be measured in urine (it is also in the blood but cannot be easily measured with a home test kit)
• B-hydroxybutyrate is tracked in the blood
• Acetone levels are detectable in the breath

Currently, the "gold standard" in testing is undoubtedly β-hydroxybutyrate in the blood (6), while acetoacetate in urine can be a useful tool in the first few weeks of following a carbohydrate-restricted diet. It indicates that you are producing ketones, but it doesn't tell you anything about whether you're actually using them.

In most people acetoacetate in urine is not detectable any more after adapting to a lower carb, higher fat diet. This is for very good reasons: The body is undergoing a range of metabolic adaptations in the first few days and weeks of changing the diet. Muscle cells initially oxidize both β-hydroxybutyrate and acetoacetate. However, after some weeks, they start reducing the acetoacetate to β-hydroxybutyrate and return it back into circulation (7).

If somebody is still measuring large amounts of acetoacetate in their urine after a good while on a properly implemented low carb diet, this needs to be looked at and analyzed.

Acetone, which can be measured in the breath, indicates metabolic usage of ketones. In other words, the level of acetone tells us whether ketones went into the energy production cycle to generate ATP. Contrary to popular belief, acetone and β-hydroxybutyrate very rarely correlate (meaning: if one is high, the other one is high, too). One tool to measure acetone in the breath is for instance the Ketonix.

In my clinical experience, I've made some observations and have discussed the topic of correlation of different ketone bodies at length with colleagues. Especially when it comes to long term keto adaptation, when dramatic metabolic changes can happen. But let's leave this for a future post to avoid getting distracted!

"Healthy Fats Are Good" - a Statement That Should Come With a Disclaimer

It's certainly very positive that more and more mainstream media have started reporting on fats and how they've been demonized wrongly for the past 40 years or so. But contrary to what some people think, the "battle of carbs versus fats" will probably never have a clear winner.

Various factors determine whether somebody will lose weight more effortlessly on a LCHF or HCLF approach. One thing I observe in clinical practice - and also by reading forum posts on the internet - is that people read the headlines of a magazine article and simplify the message without digging deep into the research. Which is totally understandable—who has time for this!

Instead of realizing that a higher healthy fat approach most likely only leads to healthful results if carbohydrates are (drastically) reduced at the same time, they start adding dollops of butter to their coffee and pouring copious amounts of olive oil over every meal. On top of eating their pasta, bread and fruit. And then wonder why the pounds are not falling off. In some cases, they even pile up.

What many people seem to be most confused by is that it might not be enough to simply "eat more healthy fat" and then watch the pounds shed. It can happen in some people, but they're a minority. I'm not a proponent of the simplified, so-called "calorie in—calorie out model" that suggests we should just eat the amount of calories that we actually burn to maintain weight. Hormonal triggers and other factors make this a much more complex and nuanced matter.

But calories do still matter, especially in the mid to long term. Some people certainly get away with a high fat, high calorie diet—at least in the short term. My guess is that these are mostly young, metabolically healthy individuals.

In the same way, some people are convinced that higher ketone levels will lead to more fat loss. While there are studies demonstrating this for the short term of a few weeks, my clinical experience shows that this is certainly not always the case (8).

The Need to Chase Ketones

If you're planning to use—or you're already using—a low carb lifestyle to feel better, have more energy and possibly shape up a bit, I don't see a valid reason why you'd want ketones to reach incredibly high levels. Or why you'd have to measure them on a regular basis.

Reducing Insulin Levels is a Better Strategy

There are always exceptions, of course, and if you have any medical conditions or concerns, it's certainly a good idea to monitor very closely what's going on in your body.

Lipolysis is the breakdown of (stored) fats to release fatty acids and glycerol. It is, for obvious reasons, a very important step in fat loss. There is evidence that high ketones—and this probably also true for exogenous ketones in the form of supplements—may inhibit lipolysis (9). This is another reason why focusing on avoiding insulin spikes (remember - insulin is a very potent inhibitor of lipolysis) rather than obsessing with high ketone levels might be a more successful strategy if your goal is to shed a few—or a lot of—pounds.

Low to Moderate Ketone Levels Can Help Regulate Appetite

Don't get me wrong—producing ketones means you're oxidising fat in the absence of significant carbs or excess protein, so it's a certainly an indicator that the right processes are in place to lose fat.

Many people find that a low to moderate level of ketosis can help regulate their appetite, make them more focused and give them more energy. These are likely to be very important aspects for improving vitality but also for achieving and maintaining weight loss.

Calories Matter

As explained earlier, calories certainly still matter when using a low carb approach for health and a trim body. You basically have two choices: Getting the body to use dietary fat from your plate or "forcing" it to break down stored fat via lipolysis. If you happen to eat all the fat you're oxidizing (i.e. using for energy production), then obviously fat loss won't be happening to the extent you might be wishing for.

Fat Burners Typically Have Lower Ketone Levels

Over time, another interesting phenomenon can be observed: Your number of monocarboxylic acid transporters (MCTs, not to be confused with "medium-chain triglycerides", also called MCT!) increases (10).

MCTs facilitate the uptake of ketone bodies into your tissues, thereby lowering ketones in your blood. In other words—lower β-hydroxybutyrate in the blood might be an indication that you've become a more efficient fat burner. This is another reason why aiming for high ketones in the blood is unlikely to lead to better results - you'd have to eat copious amounts of fat to get them back up to a higher level. The result? Weight gain, in most cases.

Who SHOULD Measure Ketones?

There are three broad categories of disease where ketones may have therapeutic effects (9):

• diseases of substrate insufficiency or insulin resistance: e.g. GLUT1 deficiency
• diseases resulting from free radical damage: e.g. Parkison's disease or
• disease resulting from hypoxia: e.g. following a stroke.

In her excellent book "The Alzheimer's Antidote", Amy Berger provides an overview of the various metabolic states and corresponding blood ketones:

Metabolic State	Blood Ketones (bOHB, mmol/L)
Mixed (high-carb) diet	0.1-0.2
Overnight fast on mixed diet	< 0.5
Nutritional ketosis	0.5-5.0
Medically therapeutic ketosis	2.0-7.0
Total starvation	5.0-8.0
Diabetic ketoacidosis	15-25

Ketones and Epilepsy

As explained earlier, the most evidence-based application of a ketogenic diet is in epilepsy, especially in children. Here are some notes of Matthew's Friends "Keto College", where I participated in 2016, on ketone levels:

"Blood ketones between 2 and 5 mmol/l (once full diet is established) are usually required but vary individually. It is advisable to avoid ketones consistently higher than 5 mmols/l to avoid symptoms of hyperketosis (lethargy, fatigue, irritability, facial flushing, vomiting and panting)."

You will notice that the "appropriate" level of ketosis might be even more conservative than in the table depicted above. The recommendation is to monitor levels above 5 mmol/l and associated symptoms very closely for epileptic patients.

Interestingly, studies using the so-called Medium Chain Triglyceride Ketogenic diet show equally beneficial effects to a very strict 4:1 ratio. This is a very rigorous approach to ketosis where fat is usually around 90% of total energy intake, whereas the MCT ketogenic diet contains "only" about 70% fat.

A 4:1 ratio can be very difficult to sustain in the mid to long term without running into trouble (e.g. nutrient deficiencies, gut issues or also boredom with food choices). It's reassuring and encouraging to see that more "moderate" approaches where carbohydrate and protein intake are significantly higher can achieve very similar clinical outcomes (11).

Ketones and Cancer

For cancer patients, the evidence remains pre-clinical but compelling as to whether a ketogenic diet as an adjunct to conventional cancer treatment is effective (12, 13). For on-going clinical trials into the ketogenic diet for cancer, you can check out the website Clinicaltrials.gov.

The Glucose/ Ketone Index

Thomas Seyfried and his team ([14) developed the so-called "Glucose/Ketone index" to monitor cancer patients. By dividing glucose measurements (in mmol/l) and ketone measurements (also in mmol/l), an index can be calculated. As an example: If your glucose is at 5 mmol/l and your ketones measure 2.5 mmol/l, you have achieved a ratio (GKI) of 2. Thomas Seyfried states that "the zone of metabolic management is likely entered with GKI values between 1 and 2 for humans. Optimal management is predicated for values approaching 1.0".

This is incredibly challenging to achieve, especially in the long term, and many factors apart from food can influence this number. Stress, age, medication (especially steroid hormones that raise your blood glucose), surgery, cancer treatment, hormones and lack of sleep are of particular importance. And for cancer patients, these are all very real concerns. If somebody is getting very stressed out "chasing" this optimal range, it's important to take a step back. It's valuable for tracking trends but shouldn't discourage patients.

Other Promising Areas of Application

Here are some examples of other conditions where ketones might have an important role to play:

• Traumatic brain injury (15)
• Alzheimer's disease (16)
• GLUT1 deficiency, a rare genetic disorder that interferes with brain metabolism. Because there is a lack of one of the proteins (GLUT1) responsible to transfer glucose from the blood into the brain, an alternative fuel source in the form of ketones can bring relief for the patients (17).
• Overall health and body composition in endurance athletes (18). It is still debatable whether athletes benefit from ketones or a low carb approach when it comes to performance - it probably very much depends on the individual. What emerging research has been showing, though, is that general wellbeing can be improved.

Take Home Message

Simply put, if you're using a low carb approach to be slim, trim and feel well, there is no need to measure your ketones several times a day and try to push them as high as possible.

In the short term, you might be able to increase ketones with more fat in your diet, but this will likely lead to metabolic issues or even weight gain in the future: If your fat intake is higher than necessary, you'll be far less likely to tap into your own energy stores.

The best fat loss will probably be from eating a nutrient dense diet while keeping your carbohydrates low, your protein at very adequate levels BUT achieving a caloric deficit from watching your fat intake.

Ketogenic diets for epilepsy or other medical conditions are not necessarily supposed to lead to weight loss, but the goal is to elevate ketones. This is why fat intake is kept high.

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