When keto diets backfire and cause health problems

As with all diet trends, they come and go.

However, keto is staying around a bit longer than others now. It turned from the best fat loss diet to the best diet for longevity and health.

But as will all extreme things, it’s not without problems.

In short, a ketogenic diet is a diet that restricts carbs to the point where you start producing ketones for fuel. For some people carb intake needs to be below 20g, for others it can be up to 100g daily.

I’m not going to talk about whether it’s the best diet for longevity and health or not (it’s not), but rather about the harms that can come with it. As with all things, not everyone will suffer side effects. One person can smoke for 70 years and be fine, whereas others just look at a cigarette and get lung cancer.

So let’s dive into some of the problems of the keto diet.

Increase in stress hormones

This one is first and foremost since many other side effects hinge on this one.

Stress hormones are hormones that increase during stress to help buffer the stress. They are helpful. But as we all know, chronic stress is the problem. Chronic stress and chronically elevated stress hormones lead to all kinds of problems such as disease and aging.

Things that act as stressors include hypoglycemia and low carb intake.

When you don’t eat enough carbs, your body has to secrete noradrenaline, adrenaline, cortisol and glucagon.

These hormones stimulate lipolysis (to make more fatty acids available), glycogenolysis (the breakdown of glycogen for fuel) and gluconeogenesis (the production of glucose from amino acids, lactate and glycerol) as of other things. This is all good and well to keep blood sugar stable and provide fuel.

However, when glucose doesn’t become available, these hormones have to stay high to continue to provide fuel. It’s just a matter of fact. No matter how keto-adapted you are, your adrenals will be pumping out more of these hormones compared to if you have carbs (>150g) in your diet.

One of the anticonvulsant benefits of the keto diet is due to an increase in noradrenaline. Block noradrenaline and seizures re-occur (R). Now, if you don’t have seizures, that boost in noradrenaline might be exactly what you don’t need.

A few side effects of excess noradrenaline and adrenaline include:

Cold hands and feet
Feeling wired
ADHD
OCD
Insomnia
Jittery
Anxious
Inner tension
Sweaty palms and pits
etc.

Read here How to identify a stress response and how to stop it.

Cortisol

Some people argue that when they are keto-adapted, cortisol isn’t higher than normal.

However, multiple studies have found that cortisol is higher on a keto diet vs a diet with more carbs. It’s just an inevitable effect of a low carb diet.

During exercise, stimulation of the sympatho-adrenal system, and cortisol secretion with reduced plasma insulin concentration seem to be of importance for the preservation of working capacity (R, R). Exercise in a low carb state leads to significantly higher levels of noradrenaline, adrenaline and cortisol.

A few ways a low carb diet increases cortisol is by (R):

Reducing renal clearance of cortisol
Reducing deactivation of cortisol by 5 alpha and 5 beta reductase
Increasing the synthesis of intracellular cortisol by increasing 11β-HSD1 activity (11β-HSD1 converts cortisone to cortisol).

“Higher cortisol levels may promote adiposity, insulin resistance, and cardiovascular disease, as observed in epidemiological studies.^32–34 In a 6-year prospective, population-based study of older adults in Italy,³⁵ individuals in the highest vs lowest tertile of 24-hour cortisol excretion, with or without preexisting cardiovascular disease, had a 5-fold increased risk of cardiovascular mortality.” (R)

All in all, elevated stress hormones are not a good thing and do enhance disease and aging. Some people might say that ketones protect against excess stress hormones, but that hasn’t been proven.

Read here on how to lower total and intracellular cortisol:

The reason why intracellular cortisol is so important is because a blood test can’t see how much cortisol for example is in the cell. Only what is floating in the blood. This makes it quite an ineffective test when on a low carb diet.

Elevated blood sugar

One of the main reasons why people do a keto diet is because they think it’s great for balancing blood sugar and becoming metabolically flexible.

As mentioned above, glucagon and cortisol are mainly involved in gluconeogenesis, which creates glucose to prevent hypoglycemia. Cortisol breaks down soft tissue to provide amino acids. This puts the body in a catabolic state to the point where it causes an imbalance between anabolic and catabolic. More on that later on.

There is (anecdotal) evidence that long-term ketogenic diets cause hyperglycemia (as shown on a continuous glucose monitor). As insulin remains low, cortisol keeps increasing (insulin is a strong cortisol antagonist). Cortisol in turn inhibits insulin secretion and causes destruction of the pancreas (specifically the beta-cells which secrete insulin) (R, R, R). This leads to progressive higher cortisol and more gluconeogenesis and eventually hyperglycemia.

Some people might even get pancreatitis from a keto diet (R).

Now imagine you want to add carbs back in with a damaged pancreas. Will you be able to secrete enough insulin or at least maintain a good ratio between glucagon and insulin (alpha cell and beta-cell secretions)?

Chances are not.

Insulin resistance caused by keto diet

The pro-keto people say that this state of “insulin resistance” is normal and only temporary. While it is true that the body creates starvation-induced pseudo diabetes on a keto diet, insulin sensitivity doesn’t always recovered right away.

Normally someone can regain complete insulin sensitivity after 1 week or so after reintroducing carbs, some people are not as fortunate. Excess stress hormones cause excess lipolysis and insulin resistance and also epigenetic modifications that lead to “permanent” insulin resistance. They go into a state of adrenal dominance.

Now, I don’t know about you, but to me, metabolic flexibility means being able to switch from one fuel source to the other without any issues. If you have to recover for 1 week or more before you can tolerate carbs normally again, is that metabolically flexible?

And once you do eat carbs, you end up with significant hyperglycemia, because of insulin’s reduced ability to suppress gluconeogenesis (R).

This 1 year low-carbohydrate diet trial found that insulin sensitivity was improved at 6 months but returned to baseline at 1 year (R).

This study in children with epilepsy on a keto diet found that insulin resistance was worse after 1 year on the diet (R). No metabolic flexibility.

Furthermore, a recent meta-analysis showed that reductions in HbA1c achieved with carbohydrate-restricted diets typically wane after a few months and that such diets are not more effective than other diets (R).

Even when you consume carbs before exercise (which being keto-adapted), which enhances glucose utilization and oxidation, doesn’t completely restore normal glucose oxidation (R).

Inhibition of thyroid hormone production and uptake

This is a biggy, but I guess some people argue that on a keto diet, you just don’t need as much thyroid hormone, specifically T3. Nothing is further from the truth, since low T3 gives you hypothyroid symptoms, regardless of the diet you’re on (not everyone gets symptoms if they’re hypothyroid, as with almost everything else).

Multiple studies have shown that a ketogenic diet causes thyroid malfunction and lowers T3 and free T3 and increases fT4 and rT3 (R, R, R, R).

T3 is the active thyroid hormone that is created from T4. On a keto diet, T4 goes up because less is being converted to T3. Instead, T4 is converted to rT3. Reverse T3 blocks the uptake of T3 into a cell. Elevated rT3 is also a sign that the cells are in a low energy state.

Common symptoms of cramping and cold hands and feet are signs of excess catecholamines and low T3.

Thyroid hormone T3 enhances the production of ATP and ATP binds to magnesium, keeping it in the cell. Without enough ATP, your body can’t retain magnesium very effectively, thus enhancing magnesium requirements and increasing the occurrence of cramps.

Feeling cold is also a sign of impaired FGF21 signaling. The ketogenic diet has been shown to impair FGF21 signaling, which reduces energy expenditure and heat (R).

Read more here on the symptoms of being hypothyroid and how to fix it.

Slow to no muscle growth

Not everyone is interested in muscle growth, but this is also applicable to muscle wasting.

Research has shown that muscle growth is either non-existent or much slower than when eating more carbs, even if a surplus is maintained (in both training and untrained lifters) (R, R, R, R).

Protein utilization is also altered on a ketogenic diet; the body shunts as much protein as possible to gluconeogenesis, while the minimum necessary amount is used for tissue repair (R).

Although ketones have been shown to have an anti-catabolic effect in some studies (which makes it good for retaining muscle when in a deficit), others show that a keto diet can cause muscle atrophy.

This animal study showed that “muscle atrophy-related genes Mafbx, Murf1, Foxo3, Lc3b and Klf15 were upregulated in the skeletal muscles of mice fed with the ketogenic diet. In accordance with the reduced expression of anabolic genes such as Igf1, surface sensing of translation (SUnSET) analyses of fast-twitch Ga, TA and Sol muscles revealed that the KD suppressed muscle protein synthesis… In addition to hypercorticosteronemia, hypoinsulinemia and reduced IGF-1, oxidative stress might also be involved in KD-induced muscle atrophy.” (R)

A few reasons why a keto diet might be bad for muscle growth is because of:

Enhanced muscle breakdown for gluconeogenesis
Increased dietary protein breakdown due to enhanced insulin and glucagon secretion by amino acids. Glucagon enhances leucine oxidation, which leads to less TOR activation and reduced muscle protein synthesis stimulation (R).
Low insulin
Reduced IGF-1
Increased oxidative stress
Elevated cortisol
BHB directly inhibit AKT, which is involved in the mTOR pathway (R)

On the other hand, acetoacetate is involved in regulating muscle cell function and has the capability to accelerate muscle regeneration (in normal mice) and prevent muscular dystrophy (R). So I’d say to optimize muscle growth, the ratio of acetoacetate to beta-hydroxybutyrate is what’s important. And you can supplement acetoacetate before or after your workout. That’s exactly what I do by taking the product called Pyrucet. It helps to increase the NAD:NADH ratio and maximize glucose oxidation and ATP production.

Sarcopenia is usually caused by an excess of cortisol and low androgens and thyroid hormone (R). Keto diets lead to an increase in the cortisol to androgen ratio and lower thyroid hormone T3. Doesn’t seem like a good recipe for keeping muscle mass. Also, the animal study above showed enhanced markers of muscle catabolic and reduce anabolism. So this can accelerate muscle wasting.

And long term keto diets might even negatively affect skeletal muscle mitochondrial physiology, which leads to an increase in ROS production (R).

Mental problems

If ketones are the preferred fuel for the brain (as many claims), why do some people still get negative mental effects from it?

Initially, everything might improve a lot and you’ll feel great. Two reasons for this are the elimination of gut-irritating foods (beans, grains, legumes, starches, etc.) and because ketones have pro-GABA effects.

The “mild euphoria often noted with fasting or low-carbohydrate diets may be due to shared actions of BHB and GHB on the brain. Specifically, I propose that BHB, like GHB, induces mild euphoria by being a weak partial agonist for GABA(B) receptors.” (R)

Another reason I didn’t mention is that the increase in noradrenaline can also have anti-depressant effects.

However, too much can lead to anxiety, short temper, irritability, emotional bluntness, emotionally volatile, manic energy (inability to shut off), insomnia, ADHD, restlessness, restless leg syndrome, etc, which are all common symptoms of excess noradrenaline and adrenaline.

This study found that over 1 year, there was a favorable effect of an energy-restricted low diet compared with an isocaloric low carb diet on mood state and affect in overweight and obese individuals (R).

It’s not so much the elimination of a specific macro that improves cognition, but rather the elimination of specific foods/toxins that cause an immune response.

Keto diets on androgens

Carbs are usually good for increasing testosterone, however, the keto diet doesn’t necessarily lower testosterone (at least in the scientific literature) (this can also be sign of reduce testosterone uptake into cells).

Three studies have actually shown that the keto diet can increase testosterone in hypogonadal men (R, R, R). However, the studies have been done on obese individuals while also inducing a deficit, and losing fat by itself has been shown to increase testosterone in overweight individuals. But once you’re lean, then it will not increase T more, but can lead to hypogonadal symptoms.

This one study also looked at SHBG and estrogen, and found that SHBG and estradiol went up by 43% and 56%, while testosterone only increased by 40% (11.5 to 16nmol/l) (R). What concerns me is the ratio between testosterone and estradiol. Obese individuals already have enough/high estradiol, and based on the results, estradiol increased more than testosterone. Although this study found that free T increased by 12%, other anecdotal evidence shows that free T decrease over the long run, due to SHBG increasing even more (R).

And also, the keto diet increases cortisol, and this leads to an increase in the cortisol to testosterone ratio, which is also not a good thing. Cortisol stimulates the aromatase, which leads to more conversion to estrogen.

Thyroid hormone T3 is also intricately involved in steroidogenesis, so the drop in T3, in the long run, will most likely also lower testosterone synthesis.

Long term fat loss

A lot of people do the keto diet for fat loss benefits.

However, although keto diets might seem more effective in the short run on average, long-term data (of about 1 year) show that keto is just as good as any other diet (R, R). No additional benefit.

And this could be due to adherence, or simply because there is no such thing as a superior diet when it comes to fat loss.

In terms of adherence, most people end up eating increasing carb consumption on the keto diet despite getting nutritional counseling. Perhaps because elevated stress hormones don’t feel good and carbs make them feel normal again.

Other problems

Kidney problems

For those without chronic kidney disease (CKD), one of the biggest potential risks of the ketogenic diet is the development of kidney stones (mainly from uric acid (thyroid hormones enhance uric acid excretion)), a finding that has been frequently noted in the pediatric epilepsy literature (R, R).

“Increased risk for kidney stones is well described in patients using the ketogenic diet for
over a 2 year period [17,20,25,26], with complications such as obstructive uropathy, acute
kidney injury, and chronic kidney disease [27–29]. The incidence of kidney stones among patients on the ketogenic diet ranges from 3% to 10%“. (R)

One of the reasons is the significantly elevated free fatty acids, which have a toxic effect on the kidney (R).

Insulin helps with the retention of magnesium and sodium through the kidney, so low insulin induced by a keto diet can lead to hyponatremia and hypomagnesemia, which can cause hypotension, cramps, heart palpitations, etc. (R)

Inflammation

Keto diets are also supported to lower inflammation and one of the predominant benefits is via the SIRT3-UCP2 pathway (R).

Uncoupling protein 2 reduces the production of ROS, which fats are known to cause.

However, pyruvate (or ethyl pyruvate (on the product Pyrucet) has also been shown to increase SIRT3, which will also increase UCP2 and protect against excess ROS, so need for keto for that benefit.

But, the reason keto diets increase antioxidant enzymes like superoxide dismutase, catalase, or UCP2 is because keto diets increase the production of ROS. A higher carb diet will not produce as much ROS so doesn’t need to upregulate antioxidant defense enzymes as much.

Liver problems

In the short term, keto diets have been shown to reduce fatty liver, however, in the long run, it can cause hepatic steatosis/fatty liver.

“KD (ketogenic diet)-fed mice showed signs of hepatic steatosis after 22 wk of diet. … Our data show that long-term KD causes dyslipidemia, a proinflammatory state, signs of hepatic steatosis, glucose intolerance, and a reduction in β- and α-cell mass, but no weight loss.” (R)

“Low-carbohydrate diets have been shown to promote weight loss, decrease intrahepatic triglyceride content, and improve metabolic parameters of patients with obesity. These ketogenic diets also provoke weight loss in rodents. However, long-term maintenance on a ketogenic diet stimulates the development of NAFLD and systemic glucose intolerance in mice. The relationship between ketogenic diets and systemic insulin resistance in both humans and rodents remains to be elucidated.” (R)

Yes, I know it’s only rodent data, but it’s something to keep in mind until more data comes out.

Fatty liver can then also progress into steatohepatitis, which is inflammation of a fatty liver, when it’s under stress by toxins (e.g. endotoxin, heavy metals, pharm drugs, alcohol, etc.). And this can lead to liver fibrosis. “In conclusion, our study demonstrated that feeding a high-fat ketogenic diet may trigger severe steatohepatitis and thereby promote liver fibrosis progression.” (R)

Heart problems

Lately, a few studies have shown how great ketones are as a fuel source for the heart. Regardless whether it’s a good fuel source or not, it can still cause problems. This study found that BHB decreased mitochondrial biogenesis, and increased cardiac fibrosis in human atrial fibrillation heart tissues (R).

Interestingly, “the Inuit has a high prevalence of heart disease that is comparable to Western populations and may be attributable to their high-fat consumption, the lack of carbohydrates in their diet, or another factor“. (R)

Mitochondrial problems

Increased mitochondrial biogenesis is a big reason to do the keto diet as claimed by many enthusiasts.

But mitochondrial biogenesis, which is the synthesis of new mitochondria, doesn’t mean the new mitochondrial will be in tip top shape.

This study found that “unexpectedly, the ketogenic diet aggravated neurodegeneration and mitochondrial deterioration. Electron microscopy showed structurally impaired mitochondria accumulating in neuronal perikarya. We propose that aggravation is caused by increased mitochondrial biogenesis of generally dysfunctional mitochondria” (R).

So you want to make sure that your mitochondria are already in a good state before your start multiplying them like crazy.

Furthermore, BHB can directly cause heart problems through SIRT7 activation.

“In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, increased levels of the ketone body β-hydroxybutyrate (β-OHB), an HDAC2 inhibitor, promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription. This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis. Exogenous β-OHB administration mimicked the effects of a KD in rats. Notably, increased β-OHB levels and SIRT7 expression, decreased mitochondrial biogenesis, and increased cardiac fibrosis were detected in human atrial fibrillation heart tissues.” (R)

Osteoporosis

Another common side effect seen with the keto diet is bone degeneration, osteoporosis, osteopenia and risk of fractures (R).

“After Adaptation, LCHF (low carb high fat) increased fasting CTX (Serum marker of bone breakdown) concentrations above Baseline (p = 0.007, Cohen’s d = 0.69), while P1NP (p < 0.001, d = 0.99) and OC (serum markers of bone formation) (p < 0.001, d = 1.39) levels decreased. Post-exercise, LCHF increased CTX concentrations above Baseline (p = 0.001, d = 1.67) and above HCHO (p < 0.001, d = 0.62), while P1NP (p < 0.001, d = 0.85) and OC concentrations decreased (p < 0.001, d = 0.99) during exercise. Exercise-related area under curve (AUC) for CTX was increased by LCHF after Adaptation (p = 0.001, d = 1.52), with decreases in P1NP (p < 0.001, d = 1.27) and OC (p < 0.001, d = 2.0). CHO restoration recovered post-exercise CTX and CTX exercise-related AUC, while concentrations and exercise-related AUC for P1NP and OC remained suppressed for LCHF (p = 1.000 compared to Adaptation).” (R)

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When keto diets backfire and cause health problems