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Under Appreciated Issues in the Treatment of Chronic Illness - Low Grade, Chronic Acidosis Combined with Potassium Deficiency-Part 1

Is Metabolic Acidosis Really That Important?


05/01/2018 - Moss Nutrition Report #279

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Introduction

At the beginning of 2018 I started to think about all of the supplements and metabolic imbalances I have written and talked about over the years that, despite overwhelming research, clinical, and anecdotal evidence about their major importance in terms of improving quality of life in chronically ill patients, continue to be almost completely ignored by the public, the vast majority of nutritional practitioners, and, much to my surprise and chagrin, all too many in the functional medicine community.  With these thoughts in mind, I wrote about protein and docosahexaenoic acid (DHA) deficiencies and the value of supplementation of each earlier this year, discussing research I had found since my previous publications on these subjects. 

Now I would like to write again about two different but tightly integrated subjects about which I have written extensively over the years but, still to my surprise and chagrin, continue to attract much less attention than what I feel they deserve.  These issues are low-grade, chronic metabolic acidosis and potassium deficiency.  Of course, given the shear amount of pages I have written on these subjects over the years, you may wonder why I would still desire to devote several more pages of the Moss Nutrition Report on these subjects.  For me, the answer is simple.  Even though it was not all that long ago that I wrote on these subjects, a staggering amount of research papers have been published on them, all of which emphasize their extreme importance clinically.  Yet, despite all of this research, as with protein and DHA, I am, quite frankly, both baffled and dumbfounded that these subjects do not receive more attention.  Can continuing to write about all of this research contribute to a mass awakening among the public and health care practitioners that did not occur after my previous writings?  I don't know.  However, because I have long had a glass half-full attitude about the value of providing a forum for little read and vastly under-appreciated research, I feel compelled to try yet again.  Before I do so, though, I would like to share some thoughts as to why some compelling research on understanding and improving quality of life in chronically ill patients captures the fancy of the public and health care practitioners and why some equally compelling research on this subject does not. 

My theories as to why some research on nutritional and metabolic imbalances in chronically ill patients gets attention and why some does not

Concerning the public and the average health care practitioner, I feel the reasons are fairly simple and straight-forward.  My experience suggests that, for this group, simplicity, which means the ability to distill the concept to a simple, newsworthy sound bite, cost, profitability for the manufacturers, and marketing, are, overwhelmingly, the deciding factors on what nutritional and metabolic research on chronic illness gets the most attention.  However, for the group with which I am most familiar and most intimately involved, functional medicine practitioners, I feel the reasons are more complicated.

Simplicity versus complexity - Given the incredible intellect of those in the functional medicine community and their passionate desire to learn more about sometimes complex issues, the complexity of some of the research on low-grade chronic metabolic acidosis and potassium deficiency, does not, in contrast to the public and the average health care practitioner, explain the comparative lack of emphasis I see on this issue.

Novelty - I feel this is a big issue for many in the functional medicine community.  All of us in the functional medicine community have an intense desire to see "What's new."  However, I am increasingly concerned that our desire to learn about "What's new" is so intense that we sometimes lose sight of what we have traditionally learned and practiced.  In turn, we often mistakenly take on an attitude that the increasing complexity of today's chronically ill patient could never be addressed, even partially, with the boringly simplistic, low-cost, patient-friendly, traditional knowledge base of the past.  We start to believe that complex problems must have complex solutions.  As I have made clear in this forum over the years, I strongly disagree.  I am a big believer in the need for functional medicine practitioners to continually strive to balance "back to basics" thinking with the very admirable desire to learn and incorporate "What's new." 

As I have been pointing out about protein and DHA and will be pointing out about low-grade, chronic metabolic acidosis and potassium deficiency in this newsletter series, the research community has and continues to make it clear that what we have known about these concepts for years, almost to the point of taking them for granted and ignoring them like old toys in the toy chest, is more relevant than ever to addressing the increased complexity of chronic illness.

Over reliance on functional medicine testing - For me, this issue for functional medicine practitioners as to why some nutritional and metabolic research attracts and does not attract attention may not only be the most significant but the most controversial and sensitive.  Why am I addressing this issue knowing that some of you may be alarmed by what I write?  While there may be many ways to answer this question, the best I can offer is that it provides one very good reason why all the research that follows in this series gets comparatively little attention.

Over the last few years I have attended several functional medicine symposiums that featured many excellent presentations on functional medicine testing.  Has our love affair with functional medicine testing gone too far?  Of course, the value of functional medicine tests is the ability to objectively evaluate and determine whether complex issues revolving around immune function, gut function, food sensitivities, detoxification, etc. are relevant to the needs of any particular chronically ill patient.  However, are we so enamored with these tests that we are forgetting to gain knowledge from simple, low-cost, traditional diagnostic modalities such as routine blood chemistry, grip strength, percent body fat testing, first-morning urine pH, and, last but not least, history?  Given that the best way to learn about the need to address protein intake, low-grade, chronic metabolic acidosis, and potassium deficiency is with these traditional diagnostic modalities, I feel that the answer to this question may, disturbingly, be "Yes".  Like you, I greatly enjoy hearing seminars about the complexities of gut function, immunology, neurotransmitter activity, food sensitivities, etc. that are sponsored by the functional medicine labs underwriting the costs of the various functional medicine symposia.  However, just because these subjects are emphasized in these presentations, they are not more important than the nutritional and metabolic issues that do not lend themselves to functional medicine lab testing and therefore are not discussed in these presentations.  These would include issues such as protein need and what I am going to discuss in this series, chronic, low-grade metabolic acidosis and potassium deficiency, all of which are best diagnosed by the simple and low-cost diagnostic modalities we have been using for years.

WHY WE NEED TO PAY MORE ATTENTION TO CHRONIC, LOW-GRADE METABOLIC ACIDOSIS WHEN ADDRESSING THE CONCERNS OF CHRONICALLY ILL PATIENTS

As we all know, it has become increasingly evident over the last few years that, more than any one single factor, the metabolic foundation of virtually every chronic illness chief complaint is chronic inflammation.  Some compelling research is now making it clear that there is an intimate relationship between inflammation and metabolic acidosis.  To introduce this concept, consider the following quote from the paper "Relationship between acid-base status and inflammation in the critically ill" by Zampieri et al (1):

"A complex interplay between acid-base abnormalities and inflammation has been suggested."

Similar findings were noted by Casimir et al in their paper "The acid-base balance and gender in inflammation: A mini-review" (2):

"Acidosis is observed in numerous inflammatory processes, primarily acute conditions such as sepsis, trauma, or acute respiratory distress where females tend to exhibit better prognosis compared with males."

In addition:

"During acute inflammatory processes, particularly infections and even more dramatically sepsis, the acid-base balance is usually severely challenged."

Concerning the nature of the inflammation/acidosis relationship, what is the primarily causational factor?  In other words, does inflammation create an acidotic scenario or vice versa?  While there has been some suggestion that inflammation contributes to an acidotic state, most of the literature I found suggested that an acidotic state is a powerful contributor to the creation and/or exacerbation of an inflammatory response.  Casimir et al (2) state:

"There is evidence favoring the existence of links between acid-base balance and cytokine concentrations, with acidosis as a potential unifying factor for the trigger threshold of the inflammatory response."

In "Metabolic acidosis treatment as part of a strategy to curb inflammation" by Rubens de Nadai et al (3) this relationship is taken one step further with the suggestion that resolution of metabolic acidosis should be an integral aspect of efforts to reduce inflammation.  The authors begin their discussion of this subject by stating:

"Metabolic acidosis is one of the most common abnormalities in patients suffering from serious diseases.  There have been numerous etiologies and treatment of the underlying disease as the basis of therapy.  However, there is growing evidence suggesting that acidosis itself has profound effects on the host, particularly in immune function."

Rubens de Nadai et al (3) then go on to present evidence of this by pointing out a relationship between two key indicators of acidosis, higher anion gap and lower serum bicarbonate, with key inflammatory markers, leukocyte count and C-reactive protein:

"It was shown that a higher anion gap and a lower level of serum bicarbonate (despite being within the normal range) were associated with higher levels of several inflammatory markers, including leukocyte count and levels of C-reactive protein."

With the above in mind, the authors recommend that addressing acidosis should be part of the anti-inflammatory protocol:

"Most often, metabolic acidosis is present in acute systemic inflammatory response in which the control of acid-base balance is part of the treatment protocol.  Thus, evaluation of the role of metabolic acidosis is mandatory."

In addition:

"The correction of metabolic acidosis as an isolated marker needs to be abandoned and considered as being an essential part of the systemic inflammatory response."

It has become increasingly clear that the reduction of inflammation is a central objective with virtually every chronically ill patient.  In turn, the above research makes it clear that another equally important central objective, particularly for those patients who are not responding well to our usual anti-inflammatory efforts, is the recognition that metabolic acidosis may be a major, under-appreciated factor in contributing to ongoing production of inflammatory mediators.  With this in mind, our priorities about the need to address metabolic acidosis must be transformed from the typical attitude of an interesting but ancillary side concern to an attitude of importance that has equal ranking with core issues such as gut dysfunction, dysbiosis, food allergies, toxicology, infection, and all of the other metabolic issues that are at the forefront of today's functional medicine practice.

IS DIET ALWAYS THE CAUSE OF METABOLIC ACIDOSIS IN CHRONICALLY ILL PATIENTS?

Traditionally, most nutritional researchers and practitioners would probably answer yes to this question.  Later on in this series, though, I will present research that makes it clear that this is not always the case.  However, to begin this discussion I will examine the metabolic acidosis-diet connection.  The relationship between diet and acid/alkaline balance has been extensively examined by Lynda Frassetto and her primary colleague, Anthony Sebastian, in several different publications over the years.  What follows are key highlights from a few of these publications. 

Specifically, what exactly is "metabolic acidosis" and "metabolic alkalosis?"

I find it interesting that, given all that has been written and stated in the nutritional community over the years about being too acid or too alkaline, it is still difficult to find a definition of metabolic acidosis and alkalosis that is universally agreed upon.  Therefore, I would like to begin this discussion of the work by Frassetto and colleagues with their thoughts on the definition of these terms.  In "An evolutionary perspective on the acid-base effects of diet" by Sebastian et al (4) the following is stated:

"Somewhat surprisingly, we cannot define 'metabolic acidosis' and 'metabolic alkalosis' simply and unambiguously.  Clinicians define them as disorders initiated by primary changes in plasma bicarbonate (HCO3-) (decreased in metabolic acidosis; increased in metabolic alkalosis)."

The authors then go on to point out a reality about which most of us are aware concerning interpretation of blood chemistries in chronically ill patients.  The laboratory ranges for plasma bicarbonate we see on the lab report may not be an accurate reflection of what level is too high or too low for any individual patient:

"We point out, however, that in individual cases, clinicians have no unambiguous reference point against which to judge whether increases or decreases in serum (HCO3-) have occurred with the wide range of clinically accepted 'normal' values."

More simply, even though an individual patient's bicarbonate level may fall within normal laboratory ranges, it may be too low for him or her, suggesting that the patient is acidotic even though the lab report suggests otherwise.  How then, if we cannot depend on serum bicarbonate to reliably tell us if any given patient is too acid, can we determine what parameters to use to make this decision?  Frassetto, who was part of the group of authors who created the book chapter discussed above, states the following in "Dietary contributions to metabolic acidosis" (5):

"There are at least three independent determinants of the set point for blood hydrogen ion concentration ([H+]): the partial pressure of carbon dioxide (PCO2), excretion of which is controlled by the lungs; diet acid or base load, including chloride intake from the salt content of the diet; and the kidney, which declines in functioning with advancing age.  In healthy adult humans eating ordinary American diets, these factors help insure that systemic acid-base equilibrium is maintained within narrow limits."

In simpler terms, acid/alkaline status is determined by three major factors - the lungs, the kidneys, and the diet.  Furthermore, as noted in the book chapter by Sebastian et al (4), a better determinant of whether a patient is too acid is the level of net endogenous acid production (NEAP).  Of the three factors mentioned above, what is the most important determinant of excessive NEAP?  As you will see, diet.  Sebastian et al (4) state:

"...we conclude that otherwise healthy humans who habitually eat ordinary net acid-producing diets typically sustain a chronic low-grade metabolic acidosis, the severity of which varies directly with the magnitude of the diet-determined NEAP.  Accordingly, the blood [H+] and the plasma [HCO3-] at which a healthy person would have neither metabolic acidosis nor metabolic alkalosis manifests when the diet yields a zero net acid load.  We therefore propose the plasma acid-base composition at zero NEAP as the reference point for the diagnosis of metabolic acid-base disturbances."

With the above in mind, a patient can be metabolically acid even though the plasma bicarbonate is within normal laboratory ranges:

"...one cannot rule out a potentially clinically significant metabolic acidosis by the routine laboratory finding of a plasma [HCO3-] within the clinically accepted normal range."

What is the key takeaway point from the quotes highlighted above?  Even though a low or low-normal plasma bicarbonate is suggestive of metabolic acidosis a better determinant, which is also easier to ascertain clinically, is whether the diet is too acid. 

The specific factors in the diet that have the largest impact in creating a state of metabolic acidosis or alkalosis

What are the factors in the diet that are most responsible for creating a state of metabolic acidosis or alkalosis in any particular patient?  Frassetto (5) states:

"...the net acid production was the sum of (1) the oxidation of organic sulfur to sulfates (2) the net liberation of protons from organic phosphate radicals, and (3) the endogenous formation of unmetabolized organic acids."

Concerning the primary precursors of an alkaline environment, Frassetto (5) points out:

"Dietary bases come from the ingestion of organic anions such as citrate or malate that are metabolizable to bicarbonate."

More simply, much endogenous acid production comes from foods such as proteins that yield sulfur and phosphate metabolites plus the body's own production of organic acids.  Furthermore, foods that yield citrate or malate, which are mainly fruits and vegetables, contribute to an alkaline environment.  Before continuing, I would assume that those of you who are familiar with organic acids testing probably recognize many of the factors mentioned above.  In turn, based on the above, the key message is what we are measuring in the organic acids test are the main factors, both from diet and endogenous production, that determine whether a patient is too acid or too alkaline. 

Metabolic acidosis from a Paleolithic perspective

While the above discussion examined metabolic acidosis and metabolic alkalosis from relatively equal theoretical perspectives, we all know that, from a more realistic and practical standpoint, a state of excessive acidity is the norm for virtually all patients we encounter and a state of excessive alkalinity is virtually non-existent.  A notable exception, of course, is those who ingest excessive amounts of alkaline water that have become more popular as of late.  

Why is metabolic acidosis the norm for most patients?   Sebastian et al (4) provide an excellent answer to this question with their examination of acid-base status from a historical, Paleolithic perspective.  The authors begin this discussion by stating:

"We describe here acid-base physiology in humans who eat typical modern American diets, and argue that, owing to the nature of those diets and the effects of aging, many otherwise healthy adults suffer chronically from a state of progressively worsening, pathogenically significant, low-grade hyperchloremic metabolic acidosis."

However, the authors go on to note that a state of metabolic acidosis is not just a state of excessive ingestion of acid-forming foods, it is also a state of low ingestion of alkalizing foods:

"We also argue that the same individuals suffer chronically from the absence of a low-grade diet-induced potassium-replete metabolic alkalosis for which natural selection has genetically adapted them but for which the modern diet does not nutritionally enable."

Before continuing, I would like to emphasize two key points from the above quote.  First, notice the presence of the word "potassium."  Interestingly, even though the word "potassium" is included in the title of this series, it is the first time I have mentioned it in this monograph.  The reason is that the role of potassium in the acid/alkaline story is quite controversial.  Does potassium play an integral role in creating a more alkaline state or is it merely a neutral carrier of alkalizing elements?  I will explore this question in great detail later in this series.

Second, notice again the statement above about "natural selection."  As I will point out shortly, Sebastian et al (4) make it clear that the Paleolithic world from which we came and largely determined our current genetic profile was intensely alkaline from a dietary standpoint.  Because of this, we are simply unable to metabolically cope with the realities of the overwhelmingly acidotic diets of today's modern society. 

The next quote from the Sebastian et al (4) book chapter provides more detail on how the modern diet creates an acidic metabolic environment:

"The tonic metabolic acidosis induced by the modern diet results from an imbalance in the supply of nutrient precursors of HCO3_ and H+, resulting in the net delivery of H+ to the systemic circulation each day."

Before continuing, please note that "HCO3_" denotes the alkaline bicarbonate ions and "H+" denotes the acid hydrogen ions.  The authors continue:

"Specifically, it results from insufficient endogenous generation of HCO3_ from the metabolism of dietary inorganic salts of organic acids (e.g., potassium citrate) - insufficient to keep pace with the body's daily generation of H+ from noncarbonic acids (e.g., sulfuric acid, citric acid).  The body produces noncarbonic acids either as end products of metabolism of ingested acid precursors (e.g., amino acids that produce sulfuric acid), or as incompletely oxidized dietary supplied or metabolically produced organic acids (e.g., citric acid).  The systemic H+/HCO3_ imbalance produced by the modern diet reflects an inadequate supply of HCO3_-precursor-rich plant foods."

Another important factor in determining the impact of diet on the creation of metabolic acidosis, which was mentioned briefly above, is kidney function.  As noted in the following quote by Sebastian et al (4), age-related loss of kidney function will increase the impact of an acid-based diet on contributing to metabolic acidosis:

"The kidney mitigates the severity of the academia and hypobicarbonatemia induced by eating the modern diet.  That renal mitigation, however, diminishes as renal function declines progressively with age, resulting in progressively worsening academia and hypobicarbonatemia.  Accordingly, the modern-diet-dependent metabolic acidosis qualifies partly as an 'acid-load, base deficiency' acidosis and partly as a 'renal' acidosis."

Next, the authors return to their premise that modern-day acidosis is largely related to the fact that the modern-day acid based diet differs markedly from the traditional, hunter-gatherer highly alkaline diet:

"We argue that the modern diet's induced metabolic acidosis reflects a shift from the preagricultural hunter-gatherer-type net base-producing diet to a modern agriculturally based net acid-producing diet, a diet in which the most common plant food ingested - cultivated cereal grains - happens to yield net acid on metabolism."

Because of the above, the authors conclude:

"From an evolutionary perspective, we consider the biologically natural and presumably optimal acid-base status of humans as mild metabolic alkalosis, which one would expect to result from the daily delivery to the body of a diet net load of base."

The next quote from Sebastian et al (4) I would like to feature provides still more detail on the role of potassium in the creation of an alkaline state:

"Because dietary HCO3- precursors consist predominantly of K+ salts (e.g., K+ citrate), we consider that both the chronic acidosis and the absent alkalosis produced by the modern diet co-occur with a state of chronic nutritional deficiency of K+ as well as of HCO3-."

The above quote brings up an interesting, clinically relevant controversy that I will explore in more detail later.  Is potassium, in and of itself, a key alkalizing agent, or does it merely function as delivery agent for important dietary alkalizers such as citrate and bicarbonate?  As suggested above, Sebastian et al (4) feel that potassium deficiency is associated with acidosis not because potassium directly affects acid/alkaline balance but because it is a delivery agent of alkalizing factors.  However, as you will see, other authors suggest that potassium plays a dual role in contributing to acid/alkaline balance by both delivering alkalizing factors such as citrate and bicarbonate and acting as a primary alkalizing agent.  More on that controversy later.

The last quote I would like to feature from the discussion by Sebastian et al (4) on acid/alkaline balance from a Paleolithic perspective strongly suggests that many of the chronic illnesses that plague modern society are directly contributed to by the fact that our modern potassium deficient, acid-based diet differs so markedly from the potassium replete, alkaline-based diet of the hunter-gatherer:

"We...argue that diet-induced age-amplified low-grade metabolic acidosis, and the absence of diet-induced low-grade metabolic alkalosis, coupled with an unavoidably suboptimal dietary K+, contribute to the pathogenesis of age-related disorders, including osteoporosis, sarcopenia, nephrolithiasis, hypertension, stroke, and renal insufficiency."

More on the role of the kidney in the creation of acid/alkaline balance

As was mentioned above, as we age, the kidneys lose the ability to contribute to an alkaline state.  Therefore, the acid-based diet with which we could cope from a pH standpoint at a younger age, may contribute to a marked metabolic acidosis as we age.  Sebastian et al (4) state:

"Because renal function declines over age (over years), blood [H+] increases and plasma [HCO3_] decreases with age for any given diet net acid load, exacerbating the already present low-grade diet-induced metabolic acidosis."

Furthermore:

"Renal insufficiency induces metabolic acidosis, variably due to reduced conservation of filtered HCO3- and reduced excretion of acid.  Old humans have impaired acid-excretory ability in response to acute exogenous acid loading."

Thus, whether or not your patient demonstrates clinical evidence of suboptimal kidney function, aging will make focusing on the acid/alkaline balance of the diet much more vital in terms of gaining improvements in patient chief complaints.  If suboptimal renal function is clinically evident, focus on the acid/alkaline balance of the diet will be virtually mandatory in order to gain notable quality of life improvements.

Why is it not more obvious in the routine clinical setting that an acid-based diet is contributing to chief complaints?

One answer to this question is that, very often, as suggested previously, routine laboratory measurements on the chronically ill patient ingesting a highly acid diet indicate a "normal" acid-base balance.  Therefore, we as clinicians tend to regard metabolic acidosis as a severely pathological state that occurs in the sickest of sick largely found in a hospital setting, not in chronic illness patients we typically see in the outpatient setting.  Sebastian et al (4) provide a powerful argument that this line of thinking does not reflect reality:

"Understandably most clinicians find it difficult to think 'metabolic acidosis' when plasma acid-base composition falls in the range traditionally considered normal.  Clinicians think of metabolic acidosis as a 'disorder' that results from the buffering of excess noncarbonic acid in the systemic circulation, or from abnormal bicarbonate losses.  Its presence implies pathophysiological sequelae.  If diet-induced acidosis has no such sequelae, one might rightly remain skeptical about using the term despite the arguments presented above."

In fact, the usual American, acid-based diet can contribute to patient chief complaints even though routine laboratory measurements of acid/alkaline status are "normal":

"But in fact many acidosis-induced pathophysiological sequelae do develop as consequences of the normal diet acid load, indicated by their improvement on neutralizing the diet net acid load with small amounts of exogenous base."

Why would a patient suffering from the consequences of a high acid diet demonstrate normal blood values?  Sebastian et al (4) point out that this is due to the numerous compensatory mechanisms the body uses to cope with a high acid diet.  Unfortunately, these compensatory mechanisms, while largely benign from a patient symptom standpoint in the short term, will, based on allostatic load concepts, have serious clinical implications when active for long periods of time:

"In conditions causing metabolic acidosis, the severity of the acidosis, as reflected in plasma acid-base composition, may underestimate the severity of the tissue injury attributable to the acidosis.  With diet-dependent chronic metabolic acidosis, homeostatic adaptations occur that serve to minimize disturbances in extra- and intracellular [H+] and [HCO3-].  Those adaptations at the same time have detrimental 'trade-off' effects when operating over long periods of time.  The adaptations include decreased renal citrate excretion, dissolution of bone, hypercalciuria and hyperphosphaturia, skeletal muscle protein catabolism, reduction in intracellular K+, and renal proliferative and hypertrophic growth.  The negative 'trade-offs' include increased risks for renal calcification and stone formation, osteoporosis, muscle wasting, sequelae of K+ depletion, and progression of renal disease."

In part II of this series I will continue my review of the book chapter by Sebastian et al (4), focusing on the massive clinical effects of chronic, diet-induced metabolic acidosis that were introduced in the above quote.

REFERENCES

  1. Zampieri FG et al. Relationship be tween acid-base status and inflammation in the critically ill. Critical Care. 2014;18.
  2. Casimir GJ et al. The acid-base balance and gender in inflammation: A mini-review. Frontiers in Immunology. 2018;9(March).
  3. Rubens de Nadai et al. Metabolic acidosis treatment as part of a strategy to curb inflammation. Int J Inflammation. 2013;2013.
  4. Sebastian A et al. An evolutionary perspective on the acid-base effects of diet. In: Gennari FJ et al, ed. Acid-Base Disorders and Their Treatment Boca Raton: Taylor & Francis; 2005:241-92
  5. Frassetto LA. Dietary contributions to metabolic acidosis. In: Wessen DE, ed. Metabolic Acidosis: A Guide to Clinical Assessment and Management. New York: Springer; 2016:65-75.

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