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Can you handle a high protein diet? The answer may be genetic

Article at a Glance
  • Protein metabolism results in waste products that are toxic to the body, so nature has given us a built in solution, known as the urea cycle, which is the metabolic chain of events we use to rid our bodies of ammonia, urea and uric acid, protein’s main waste products.
  • Properly digesting protein requires the urea cycle enzymes, which spring into action in 4 stages. Your ration of these enzymes (not everyone has the same amount to work with) is driven be genetics, with the CPS1 gene being a good example. It’s the enzyme produced by this gene that carries out the first step of the urea cycle, breaking down nitrogen into ammonia.
  • From there, protein waste is filtered by the liver and kidneys and we pee it out in urine. However, very high protein diets, especially diets high in animal protein, can cause health issues when they overload the body’s natural ability to remove the waste produced from consuming protein.
  • It’s not just the urea cycle and ammonia that is at issue when we’re talking about digesting and using protein. If I can convince you to read on, you’ll see how protein consumption impacts wide ranging health issues, from heart health, to urinary tract infections, to mental health.
Genes Mentioned
steak and high protein diets

Just like I think it’s fair to say that New York City is a “drinking town,” I think it’s also fair to say that America is a “protein country.”

Men in particular are encouraged to eat high protein diets to build muscle.

If you look at movie stars from a few generations back, or even professional athletes, you notice a major change in appearance. There has been a shift toward bulk. Yesterday’s action heroes are today’s leading men. The Rock eats like 100 pounds of cod a day, or something crazy like that. Everyone wants to get “ripped,” and protein is the fuel (in addition to some other things) they’re using to do it.

For purposes of this post, I will define a high protein diet as 100g per day on a 2,000 calorie diet, or more. Having said that, some people may have problems processing smaller daily protein intakes.

How much protein is too much?

Our American obsession with protein begs the question: how much protein is too much protein? What do our bodies do with all the protein we eat? When does it become toxic, if at all?

I will attempt to answer those questions and more in this post.

To begin, it’s important to say that we need protein to be healthy. Proteins are the building blocks of cells. In fact, genes aren’t much more than a section of the DNA sequence coded to make a protein. So, I’m not here to say that protein, or even large amounts of protein, are necessarily “bad.”

However, high protein diets do not suit everyone, and how your body handles protein is driven, in part, by your genetics.

For example, the human body breaks down the nitrogen molecules found in protein into ammonia, and finally to urea, which is then cleared by the liver and kidneys. Your body’s ability to process and clear this ammonia/urea cocktail is a large driver of how much protein your body can handle.

The Urea Cycle

Enter the urea cycle, the process our bodies use to break down ammonia in the liver and turn it into urea, which is then excreted in urine. When the urea cycle is functioning at 100%, large amounts of protein are easier to handle.

The first step in the urea cycle is governed by the CPS1 gene. CPS1 stands for carbamoyl phosphate synthase. When our urea cycle is compromised, like it can be with diminished CPS1 function, we might not do as good of a job dealing with ammonia. To quote the National Urea Cycle Disorders Foundation:

Normally, the urea is transferred into the urine and removed from the body. In urea cycle disorders, the nitrogen accumulates in the form of ammonia, a highly toxic substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death.

To be clear, the scenario described above is not what I am talking about when I say that a high protein diet is sub-optimal for some people.

I’m analyzing the issue on a spectrum.

Tragically, on one side of that spectrum, are children born with severe CPS1 deficiency, who rapidly develop hyperammonemia and become very ill. (R) However, the disorder is very rare. My interest for this post is: what happens when CPS1 activity is functional, but reduced due to diminished enzyme activity?

For example, what happens if someone has just 50% CPS1 function?

Are ammonia levels elevated in these people? How do these increased ammonia levels impact physical and mental health? Does a high protein diet, which by definition means a high ammonia diet, create a toxic load the body can’t handle?

This Harvard article is the jumping off point for my theory. In essence the idea is that what constitutes the “toxic” dose of protein varies from individual to individual based on how efficient their urea cycle is (and I would extend beyond the urea cycle to other areas that impact ammonia levels).

Urea cycle disorders are viewed as rare and primarily pediatric conditions, but there might be a whole range of unrecognized, genetically determined problems with protein metabolism experienced by adults. Some people may have mild mutations that compromise a gene’s function and cause slight symptoms. This may explain why one person eschews meat while another loves nothing more than a steak meal. Defects in protein metabolism may also explain why some people have bad reactions to high-protein diets like the Atkins diet.

A quick note on blood type and protein

Aaron just published a very interesting post to our blog about the blood type diet. His conclusion is that the blood type diet has largely been debunked, however, one glimmering piece of credible science can be found in the diet: hydrochloric acid levels vary based on blood type. Type A has the least, type O, the most.

We know that hydrochloric acid is essential to digesting protein. While there aren’t studies which demonstrate a link between blood type and what constitute healthy protein levels, it’s something worth noting when evaluating protein intake based on what we know about digestion.

People with type A blood would seem to be at a disadvantage in handling a high protein diet, especially if they have gene expression linked to reduced urea cycle function.

With that out of the way, let’s keep moving on to ammonia.

Ammonia levels and protein

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High levels of ammonia wreak havoc on the body. Ammonia is a neurotoxin, that readily crosses the blood brain barrier. (R) Elevated ammonia alone is an issue in itself.

The analysis could stop there: higher protein, combined with lower urea cycle function, can lead to elevated ammonia, and elevated acid load on the kidneys, which can cause health issues. And I’ve written about previously, there are other factors, such as Candida and CBS gene SNPs which can also contribute to elevated ammonia. Perhaps all of these factors work in tandem in some people to create a perfect storm that requires a lower protein diet, or the cycling of protein to ensure that the body has the chance to clear its toxic load.

In my experience, diets that advocate for consuming meat, and full disclosure, I do consume animal products despite flirting with a vegan diet lately, rarely mention limiting protein to a day a week, or a few days a week. For those folks in the Paleo camp, do you really believe it’s “primal” to eat 10 ounces of meat at each meal throughout the day, 7 days a week?

Probably not.

In the more realistic scenario, our cave man ancestors would have had a “feast or famine” relationship with meat, gorging when there was a kill, then going days or weeks without. (R)

All that aside, if you’ve read this far and are wondering how to test your ammonia levels, the gold standard is a serum ammonia test, a blood test that must be taken fasting.

And while ammonia is a big issue, it’s certainly not the only one when it comes to high protein diets. Below, I will delve into some of the health problems overloading on protein can/could cause.

List of high protein health problems

Hypertension, lack of circulation, free radical production

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(This one will be the most controversial on the list based on the theory).

We could have stopped at high protein and elevated ammonia, however, to flush out my theory, this post relies on an “ammonia plus” theory of high protein advanced by Dr. Amy Yasko.

It is important to point out that the information I share on BH4 being used to neutralize ammonia comes from her clinical experience. There isn’t much else in the literature to support her theory, which she advances in her book Feel Good Nutrigenomics. If you decide not to trust Dr. Yasko, or think she’s a quack, you’re on solid ground, and the analysis stops with the urea cycle variability I mention above, plus the rest of the “protein problems” health list below.

I wanted to dive in on the nitric oxide stuff first, because it’s really interesting.

Dr. Yasko has this to say about BH4 and ammonia on page 125-126 of Feel Good Nutrigenomics:

A very high protein diet can also affect BH4 levels. Ammonia is generated from the intake of high protein foods. The body uses two molecules of BH4 to detoxify one molecule of ammonia to urea. This is an “expensive” way to use our BH4.

If Yasko is right, it means that when our urea cycle is compromised, an important chemical our body uses to make neurotransmitters, such as serotonin and dopamine, called Tetrahydrobiopterin (BH4), rushes to neutralize the harmful ammonia.

When the body uses BH4 to fight ammonia, it doesn’t have as much to make the chemicals in our brains that make us feel good, or to make nitric oxide. In this way, BH4 is like a urea cycle “backup.” However this presents a problem as we need BH4 for other important functions. BH4 deficiency has been linked to anxiety and depression. (R) When a high protein diet causes elevated ammonia, mood issues can follow if the individual’s BH4 is running on empty.

BH4 is a Nitric Oxide Co-factor

In addition to its role in producing neurotransmitters, we also need BH4 to keep nitric oxide (“NO”) flowing.

BH4 is a co-factor for NOS, or nitric oxide synthase. (R) Without NOS, your body can’t produce NO.

Why is this important?

Because NO is a vasorelaxant, an anti-thrombotic, and it is anti-inflammatory. eNOS, or endothelial nitric oxide synthase, is responsible for making the NO that makes our blood vessels relax so they can receive oxygenated blood. (R) Without NO, your endothelial health suffers, and a decline in endothelial health is one of the first signs of heart disease. Diminished eNOS activity is also linked to erectile dysfunction, which is why the mechanism of action for the popular ED drug, Cialis, is to increase NO production. (R)

Yikes.

Reduced BH4 can cause NOS to “uncouple,” meaning, rather than producing NO, NOS produces super oxide, a dangerous free radical. (R)

For more on superoxide, see: SOD2 A16V: the oxidative stress gene?

In this way, NOS can be either great for us, or bad for us, and some of its role is determined by how much protein we eat and the state of our urea cycle to handle it. In cases where BH4 is used to neutralize ammonia, thereby increasing the likelihood of eNOS uncoupling, high dietary protein could cause vasoconstriction, which could lead to higher blood pressure for some people, or problems in the bedroom for others. (R)

The CPS1 T1405N polymorphisms have been linked to reduced NO levels. Greater ammonia, reduced BH4, reduced NOS synthesis equals diminished (not necessarily total loss) endothelial health. (R) Presumably, lifestyle and diet can reverse these issues.

Although the state of our urea cycle plays a role, BH4 levels aren’t totally governed by ammonia, there are also genetic and lifestyle factors that determine how much BH4 our bodies have available at any given time.

The BH4 genes

As we’ve talked about above, BH4 helps get rid of excess ammonia, and when it does, levels are depleted for its other important functions: NO and neurotransmitter production.

What genes are associated with BH4 production and maintenance? The data here is scarce, but I will highlight the latest theories below.

BH4 Biosynthesis

BH4 is formed from the simple molecule GTP in a three step process, each step catalyzed by a different enzyme; GTP cyclohydrolase I (encoded for by the gene GCH1), pyruvoyltetrahydropterin synthase (PTS) and sepiapterin reductase (SPR).

For all three enzymes there are severe clinical mutations which result in complete or significant loss of function. Of the three only GCH1 contains any SNPs which are associated with a reduction in function, with a subsequent small reduction in BH4 levels. (R)

CBS C699T

In a previous post, I talked about “up-regulated” CBS enzyme activity, and the biomarkers you can look to to determine whether you are a fast metabolizer of sulfur, namely low homocysteine and high serum ammonia. These two markers, presumably combined with a good chunk of CBS SNPs, especially C699T, means you could be moving nutrients through the transsulfuration pathway at a rapid pace, and losing sulfur amino acids your body needs to make glutathione in the process. The transsulfuration pathway removes sulfur amino acids, when they are in excess. If not enough are removed, they pool, in extreme cases causing conditions like homocystinuria. Up-regulation takes things in the opposite direction, causing the body to rip through sulfur amino acids. As sulfur metabolism results in the production of ammonia, CBS C699T is listed as a gene that impacts BH4, the ammonia neutralizer. The bottom line is that up-regulated CBS activity could result in higher serum ammonia. Many of the blogs discussing this topic talk about going on an extreme low sulfur diet with the presence of these SNPs, and maybe that’s a good thing for some people.

BHMT

Information here is scarce and there are very few studies to support any of the BHMT theories, however, Dr. Amy Yasko has written, based on clinical observations in her own practice, that homozygous BHMT-02 and BHMT-04 SNPs can act in a similar fashion to the CBS up-regulation pathway, pushing homocysteine through the system faster, potentially resulting in higher ammonia levels.

BHMT-08 is said by Yasko to be linked to attention deficit symptoms and stress.

SHMT2

Yasko theory, little data outside of blogs.

MTHFR A1298C

Methylfolate is a BH4 co-factor. (R)

Urinary Tract Infection (UTI)

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Similarly, would you have guessed that a high protein diet could be to blame for recurrent urinary tract infections?

I wouldn’t have thought so, however a study out of Washington University in St. Louis found a potential link. Researchers at Wash U found that a person’s susceptibility to UTI is heightened when their urine becomes acidic, as it does when we eat animal protein. (R) Those with more acidic urine had a higher likelihood of contracting recurrent UTI.

In the Wash U study, the urine samples that prevented bacterial growth were more alkaline. As the urine grew more acidic, the bacteria known to cause UTI, such as E. Coli, thrived.

Food for thought if you have issues with UTI, especially in light of the next study on the list concerning prostate health.

Prostatitis

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In a study of 1,000 men with prostatitis, a condition marked by recurrent inflammation of the prostate, 80% responded with significant improvement in symptoms with a regimen of a popular anti-fungal drug and potassium citrate, a mineral used to alkalize urine.

Very interesting in light of Candida’s (yeast) tendency to make the stomach more alkaline (so that protein is more difficult to digest), which creates a greater acid load on the kidney, lowering the PH of urine.

Both the UTI and prostatitis studies link in nicely with Yasko’s BH4 theory, namely that these regions of the body became prone to infection because a lack of NO allowed an anaerobic environment to form.

In the case of the anti-fungal regimen having success treating prostatitis, the study author’s point out that it’s an E. Coli infection which is often the “door” Candida and pathogenic yeast use to invade these regions of the body.

Begs the question: can a high protein diet cause a “perfect storm of acidity” in the genitourinary region which allows bacteria to flourish?

Cancer?

Science Score*: 

It’s well established that protein rich diets increase insulin like growth factor 1 (IGF-1), a marker for cancer growth (R), and you may have heard of T. Colin Campbell and The China Study, a series of extensive epidemiological studies that link eating animal protein (casein) to cancer.

A quick note on China Study critics: one of the most visible is Chris Kresser, a clinician, blogger and Paleo advocate in Northern California, who is thoughtful and well prepared. However, when you click through the sources for Chris’ post “debunking” the China Study, they’re less than credible. T. Colin Campbell’s work in the China Study was peer reviewed at excellent, world renowned universities. Kresser’s critique relies on very young, part time statisticians.

This does not necessarily mean these critiques are wrong!

I make this point because I was surprised that Kresser and the Paleo community didn’t have more established counter punchers in their corner.

In any event, this post is intended as a survey of issues for the reader to conduct further research, not as a dispositive statement on a complicated issue. I am not taking a side here, at Gene Food we advocate in favor of bio-individuality, I am presenting credible schools of thought.

The China Study certainly has its detractors, and I do not believe for a second that eating small amounts of quality meat and fish a handful of times a week causes cancer. I’m not so sure about heavier levels of consumption, as you can probably tell from reading this post.

Bottom line is there are serious commentators who believe that the link between animal protein and cancer is so strong that it should not be consumed under any circumstances, where others, see a benefit in seriously restricting its consumption.

Even Dr. Mercola, Titan of the functional world and certainly no vegan, has written about the benefits of cycling / limiting protein intake.

See: Why Too Much Protein Triggers Aging and Cancer

* Caveat for this science score being that a high protein diet correlates with cancer, the science is much less clear for a low or cycled protein intake.

Osteoporosis

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As I’ve written about before in my post on Veganism and Vitamin A, the active form of Vitamin A, retinol, is derived from animal products. You eat animal protein, you get vitamin A as retinol. If you eat a yam, a plant that is high in beta-carotene, the body must convert the beta carotene into vitamin A, and this process is driven by the BCO1 gene.

Studies have shown, including a New England Journal of Medicine Study, that higher dietary intake of Vitamin A (and most vitamin A comes from foods that also include animal protein) is associated with lower bone density and greater risk of fracture. (R) When you do a Google search for “high sources of dietary vitamin A,” you get lists of foods high in beta carotene, which requires a conversion to retinol. It’s beef, chicken, cheese and dairy, and eggs that have the highest retinol count.

The China Study folks have also claimed that eating animal protein reduces bone mineral density leading to osteoporosis, however, this American Journal of Clinical Nutrition Article advocates for higher protein intake, especially for seniors.

Seems as though the jury is still out on this one, but a very high protein diet probably doesn’t strengthen bones, even if some protein is necessary to maintain muscle mass as we age.

Heart Disease

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This is an interesting one, and not because of the tired arguments over saturated fat. No, the issue here is how our intestinal flora metabolizes L-carnitine, an amino acid found in all meat, from red meat to fish. When we eat meat, the microbes in our gut break down the carnitine into a metabolite known as trimethylane-N-oxide, or “TMAO.” Elevated serum TMAO levels have been linked to heart disease and are thought to be an independent risk factor, along other markers like Lp(a). (R)

I touched on this already in my curcumin and phospholipids post, because choline produces TMAO as well.

The authors of these studies, including the one that appeared in the New England Journal of Medicine, do not advocate eating zero meat. Instead, they advocate for moderation. When we take days off from eating animal products, our bodies can cycle through TMAO and excrete it, lowering our chances for heart disease. This is impossible with a daily mega dose of protein.

Closing thoughts

Again, it’s important to emphasize that the science on these topics is emerging. We have some promising theories, but more data is needed. Having said that, if you find a number of SNPs surrounding the CBS, CPS1, NOS, MTHFR A1298C, and the BH4 precursors (least amount of data here), it is worth doing some lab testing for low homocysteine and high ammonia, or to experiment with diet to see how you feel when you eat different amounts of protein.

Remember, that while a high protein diet isn’t for everyone, protein is a necessary component of a healthy diet. When I say high protein, I mean “meathead” levels of 100 grams or more on a 2,000 calorie base, not normal consumption. The trick is not to go to either extreme. That, and realize that one size fits all advice is worthless. The intent of this article is to shed light on the complex processes our bodies use to metabolize protein, and how genetic variants could influence how much we should be eating.

I have a handful of CPS1 SNPs, and a heterozygous MTHFR A1298C mutation, but am not affected by most of these SNPs. Even still, I am experimenting with protein cycling right now to give my liver a break each week, and I take methyl folate almost as much for BH4 support as I do to support MTHFR.

For a good article on protein cycling, check out this Bodybuilding.com article.

Or you can just go with well known longevity doctor, Peter Attia’s advice, and eat no more protein than your body needs to maintain muscle mass.

Whatever you decide, a little experimentation never hurt anyone.

John O'Connor

John O'Connor is the founder of Gene Food and an Integrative Health Coach, trained at Duke IM. He lives in Austin, Texas.

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  1. Anusha says:

    Hi
    I am vegetarian but I want to eat egg as a protein source bt whenever I eat egg I M facing gasetic problem very badly do me suggestion

  2. Sheri Parr says:

    I am homozygous for the CBS A360A gene as well as DAO, BHMT -08, FUT 2. I have hashimotos thyroiditis, I produce too much ammonia and cannot take Omega fatty acids. I also have trouble eating nightshades, grains and legumes unless soaked and cooked well. Cruciferous vegetable in large doses makes me very ill. Just wanted to add this because the gene is not mentioned but a very real problem for me.

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