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Thoughts at large: Controversies in clinical nutrition and functional medicine: issue #4 chronic low-grade metabolic acidosis - part IV.

The Role of Proteins and Amino Acids in Acid/Alkaline Balance

Introduction

As we all know concerning acid/alkaline/fluid and electrolyte issues, the controlling factors we tend to emphasize are water, minerals such as sodium, potassium, magnesium, and calcium, and regulatory hormones such as insulin, Cortisol, aldosterone, and parathyroid hormone. However, as you will see from the paper I am about to review, there is another incredibly important factor. Interestingly, though, I would guess that most of you are like me in that, even though you are well aware of this factor and many of its physiologic functions, you are comparatively unaware of its role in fluid and electrolyte metabolism and acid/alkaline balance. What is this factor? Protein and amino acids.

Of course, even though you may not be aware, we have all seen evidence of the impact of proteins and amino acids on fluid and electrolyte metabolism. Where have we seen this? We have all seen the classic pictures of starving children in third-world countries suffering from a form of extreme protein deficiency called kwashiorkor where one of the key clinical findings is a distended belly. This distended belly is the result of massive fluid accumulation that results from the equally massive fluid and electrolyte regulation disturbances caused by extreme protein/calorie malnutrition.

Could kwashiorkor be an extreme example of a metabolic imbalance we see very often in our chronically ill patients? Could it be that, even though we are not seeing distended bellies, we are seeing disturbances in fluid and electrolyte metabolism caused by too much or too little dietary protein and amino acids? As I hope to demonstrate in this review, the answer to these questions is an emphatic "Yes!" In turn, if this relationship is as important as I am about to suggest, we must expand our thinking on acid/alkaline imbalance beyond the usual water and electrolyte issues to another key issue, suboptimal protein intake. Before delving into this paper, though, I would like to issue a warning of sorts. Partially due to the complexity of the issue and partially due to our significant unfamiliarity, what I am about to present is somewhat complex, or, at least it is for me. Therefore, I will do my best to simplify as much as possible. However, if you are like me, even with simplification you may have to read the quotes I am about to present more than once to fully understand the concepts contained within them. Hopefully, even though reading the following may take more effort than usual, you can take satisfaction in knowing that you have a much better understanding of a key, vastly under appreciated metabolic imbalance that can contribute to many of the signs and symptoms seen routinely in our chronically ill patients. Finally, with this understanding, you will hopefully have a better idea of what to do next when optimizing levels of water consumption and intake of minerals such as magnesium and potassium either through diet or supplements is not correcting low grade, chronic metabolic acidosis as measured by first morning urinary pH.

The Impact of Protein and Amino Acids on Acid/Alkaline Balance

In this discussion I would like to present highlights from the paper "Impact of the diet on net endogenous acid production and acid-base balance" by Poupin et al (Poupin N et al. Clin Nutr, published online ahead of publication, 2012). To begin this paper, the authors point out that the low-grade chronic metabolic acidosis we are seeing in our patients can be caused by many different types of acids, not all of which come from the diet:

"The acids in the body are classified as volatile acids (carbonic acid, [H.sub.2][CO.sub.3]) and fixed acids, which are nonvolatile acids ingested from the diet or produced within the body as intermediary or end products of metabolism. It is also important to distinguish between metabolizable acids (or bases), which are organic acids that can be consumed and transformed by endogenous metabolism, and non-metabolisable acids which consist mainly of inorganic acids and some organic acids, such as those that cannot be disposed of by metabolism and are excreted in the urine."

Of course, given that amino acids are "acids," it would seem likely that every time an amino acid is metabolized, there would be a contribution to an acid-forming pool. Poupin et al point out that this is not, in actuality, what happens:

"As for amino acids, their catabolism consists mainly in the conversion of their carbon skeleton to glucose or triglycerides, which globally consumes [H.sup.+], and in the synthesis of urea from their ammonium ion, which consumes HC[O.sub.-3] or produces [H.sup.+]. Consequently, the metabolism of amino acids does not result in a net production of acid except sulphur, cationic and anionic amino acids."

Please note again the last sentence in the above quote which suggests that sulphur-containing amino acids can contribute to the systemic acid pool. The authors elaborate:

"The oxidation of sulphur-containing amino acids from dietary proteins or endogenous tissue proteins during starvation results in the production of H* ... This production is reported to account for 25 to 70 mEq/day of [H.sup.+] production. Depending on the composition of the diet and considering protein intakes of 100 g/day, the intake of sulphur-containing amino acids is about 3g/day, which would lead to [H.sup.+] production of approximately 20 mEq/day."

What about the cationic and anionic amino acids mentioned above? Which amino acids are they and how do they contribute to acid/alkaline balance?

"Cationic amino acids (i.e. mainly arginine and lysine) contain an additional amino group, which is protonated at body pH, and their metabolism leads to the production of acid."

Concerning the anionic amino acids the following is stated:

"Conversely, anionic amino acids (glutamate, aspartate), which contain an additional carboxyl group, contribute to the production of alkali (or consumption of acid) when they are metabolized."

Giving the increased popularity of organic acids testing, more and more of those in the alternative medicine community have become aware of these acids. Of course, based on this type of functional medicine testing we tend to think of organic acids as metabolic indicators and indicators of micronutrient deficiency. Unfortunately, with the above in mind, we tend to forget the obvious, that organic acids are "acids" and can also contribute to acid/alkaline balance. In this regard Poupin et al state: "... some ingested organic acids cannot be fully metabolized in the body (e.g. uric, oxalic or hippuric acids) and their organic anions are formed as end products of metabolism with an equivalent consumption of HC[O.sub.-3](bicarbonate) and retention of [H.sup.+]. In both cases, HC[O.sub.-3] is not generated, which represents a loss of potential base."

What is the result of this loss of bicarbonate in terms of acid production?

"The loss of bicarbonate due to the incomplete metabolism of organic acids is reported to be equivalent to an [H.sup.+] addition/retention of 40 mEq."

What are the most important sources of alkaline-forming elements in the diet? The authors state:

"The most important organic sources of alkalis in the diet are organic acids that are ingested in the form of salts or organic anions (e.g. citrate, malate and lactate). They lead to the production of HCO)-[.sub.3] when they are oxidized in the course of metabolism..."

As suggested in the introduction, protein as well as individual amino acids contribute acid/alkaline balance. Poupin et al note:

"Proteins are also buffers because of their amine (N[H.sub.2]) and carboxylic acid (COOH) groups."

How does the body eliminate acids produced from protein and amino acids?

The lungs and kidneys are the major organs involved in elimination of acids. The authors note:

"The kidneys are involved in the disposal of the fixed acids that are produced daily. Cells generate such fixed acids mainly in the form of [H.sub.2]S[O.sub.4] (from sulphur amino acids) and HCl (from cationic amino acids), which dissociate into [H.sup.+] and the corresponding anions S[O.sup.2]-[.sub.4] or Cl-Hydrogen ions are usually buffered by HC[O.sub.-3] excreted as C[O.sub.2] by the lungs."

What about ammonia? As we all know, that is eliminated via the kidneys. What is less well known is that ammonia elimination requires the involvement of an amino acid:

"Ammonium (N[H.sup.+.sub.4]) is excreted in urine through the metabolism of glutamine by the kidneys."

In addition to being a major organ of acid elimination, the kidneys also play a role in controlling acid/alkaline balance by producing buffers:

"To assure disposal of the fixed acids by the kidneys and to sustain the bicarbonate buffer system, the blood concentration of HC[O.sub.-3] must be sustained and HC[O.sub.-3] must be regenerated, which is the other role of the kidneys. They both reabsorb filtered bicarbonate and generate 'new ' bicarbonate to replace that lost during buffering mechanisms."

As with elimination of ammonia, glutamine is required by the kidneys as one way to generate bicarbonate:

"The other way to generate 'new bicarbonates' occurs through glutamine catabolism in the kidneys."

In addition, as you might expect, very little glutamine is used by the kidneys to generate bicarbonate buffers in a healthy state. However, in your chronically ill patients who demonstrate low-grade, chronic metabolic acidosis, loss of glutamine through this pathway can be significant:

"In normal acid-base balance, the kidneys extract and catabolize very little of the plasma glutamine, but during acute and chronic acidosis the extraction of glutamine by the kidneys increases significantly."

With this important point in mind, a diagnostic procedure as simple as the first morning urine pH gains even more utility. For, when the patient reports to us that the first morning urine pH is in the acid range, not only can we suspect electrolyte imbalances in general and potassium and magnesium need specifically, we can also safely postulate that the patient may require glutamine supplementation or a protein supplement such as whey powder that contains significant amounts of glutamine.

What Specific Compounds in the Diet are Most Responsible for Contributing to Low-Grade Chronic Metabolic Acidosis?

As we all know, our chronically ill patients tend to ingest many dietary substances that have acidifying potential. However, according to Poupin et al, certain amino acids bear most of the responsibility:

"Sulphur amino acids are thought to be responsible for most of the acidifying potential of the diet. The end product of their metabolism is sulphate (S[O.sup.2.sub.4]-), which is excreted in the urine. Since sulphate is rarely ingested in another form than sulphur amino acids, urinary sulphate excretion is proportional to [H.sup.+] production from the oxidation of sulphur amino acids. However, it has been noticed that the percentage of sulphate recovered in the urine after ingestion of sulphur amino acids may be less than 100%, as sulfates participate in several reactions and may be retained in the body."

I feel this quote makes two clinically important points that deserve to be highlighted. First, when your patient reports to you that first morning urine pH is significantly in the acid range, still another "red flag" that should occur to us besides the need for magnesium, potassium, and glutamine, is that intake of foods that contain significant amounts of sulphur amino acids, such as red meat products, may be excessive. Second, and very fortunately, not all sulphur amino acids in the diet are excreted, since they supply sulphur that is used to create glutathione and function in many important enzymatic pathways such as sulfation.

What other factors in the diet have a significant impact on acid/alkaline balance? The authors point out:

"Most diets contain inorganic acids (e.g. N[H.sub.4]Cl), inorganic alkalis (e.g. NaHC[O.sub.3], Al(OH)[.sub.3] and potential alkalis in the form of inorganic cationic salts of metabolizable organic anions, such as potassium citrate or calcium acetate."

Is There any Way of Determining how Much of Any Key pH Controlling Dietary Compoinds is Present in the Urine.?

While technology does exist to make this determination, it is not practical for use in a routine clinical setting. However, Poupin et al do provide a general formula to determine how much of any particular constituent is present based on rates of GI absorption:

"The amount of urinary excretion of each cation and anion is considered equal to the amount absorbed from the gastrointestinal tract and therefore can be estimated by the amount ingested from the diet, corrected by the net intestinal absorption rates estimated as 75% for protein, 63% for phosphorus, 95% for chloride, 95% for sodium, 80% for potassium, 25% for calcium and 32% for magnesium."

Can the amount of sulphate in the urine be calculated? According to the authors this can be estimated from the amount of methionine and cysteine in the diet:

"Sulphate is considered to come from the metabolism of methionine and cysteine, the ingested amounts of which are estimated as 2.4% and 2% of total dietary protein, respectively."

Fortunately, as those of you who routinely use organic acids testing know, urinary sulfate is part of that profile and is very often elevated in chronically ill patients.

General Overview on the Relationship Between Diet and Acid Production

In concluding their paper, Poupin et al review key points about diet and the production of metabolic acids:

"Metabolism of endogenous and dietary substrates results in a net production of volatile and fixed acids. To maintain constant [H.sup.+] and HC[O.sub.-3] plasma concentrations, daily net acid production is balanced by an equivalent rate of acid consumption or neutralization within the body and removal from the body. The bicarbonate buffer system, which is the main body buffer, neutralizes a large part of the fixed produced or ingested acids, while producing carbonic acid. Remaining fixed acids are removed from the body by the kidneys and excreted in the urine, while volatile acids produced by metabolic processes and the bicarbonate buffer system are eliminated via the lungs."

Some Final Thoughts on the Poupin et al Paper

As you could see by title of the paper and some of the subjects discussed, Poupin et al intended to discuss diet in general and its impact on acid/alkaline balance. However, much of the paper was devoted to a relationship about which many in the alternative medicine community, including me, have little more than a superficial knowledge, the impact of protein and amino acids on systemic pH. Typically, we have used a simple sound bite to describe the relationship, stating that protein and amino acid-based foods tend to be "acid forming" or "acid ash." However, as I hope you realize from the Poupin et al paper, this relationship is much more complex and deserves more than a casual, all-inclusive sound bite. Therefore, we should consider protein and amino acids in relationship to systemic pH expansively in the same way we consider protein and amino acids in relation to issues such as sarcopenia. With this type of perspective, we can now use protein and amino acid modulation along with water and electrolyte modulation to fine-tune the many chronically ill patients who demonstrate low-grade, chronic metabolic acidosis.

by: Jeffrey Moss, DDS, CNS, DACBN
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Author:Moss, Jeffrey
Publication:Original Internist
Article Type:Report
Date:Jun 1, 2017
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