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Thoughts at large: Controversies in clinical nutrition and functional medicine.

Issue #3

Chronic Low-Grade

Metabolic Acidosis - Part III

The Essentiality of Magnesium in Potassium Metabolism

Given the emphasis on potassium in parts one and two of this series, you may be wondering when the discussion in magnesium will occur. As you will see, that discussion will be prominently featured in this report. However, I deliberately wanted to postpone my discussion on magnesium so that I could review literature that emphasizes the immense importance potassium plays in the optimization of acid/alkaline balance. Why? Because this discussion is going to head in a different direction from the typical review of the literature on magnesium which usually examines magnesium in isolation. As you will see from the papers I am about to present, even though potassium is incredibly important for acid/alkaline optimization, it simply cannot perform all the tasks necessary for this optimization without the presence of optimal levels of magnesium. Therefore, this review will focus not on magnesium in isolation but on its important and multifaceted interaction with potassium. It will be divided into two sections. The first will focus on papers that highlight how often potassium and magnesium are found together in many important human physiological functions. The second will focus on papers that demonstrate how each mineral is dependent on the other for optimal function.

Potassium and magnesium are often found together in human physiology

An excellent paper that highlights this interrelationship is "Potassium, magnesium, and electrolyte imbalance and complications in disease management" by Weglicki et al (Weglicki W et al. Clin Exp Hypertension, Vol. 1, pp. 95-112, 2005). The paper begins with an observation of how often potassium and magnesium deficiencies are found concurrently: "Patients with congestive heart failure ...frequently show hyponatremia, hypokalemia, and hypomagnesemia."

Furthermore: "...very early observations indicated that electrolyte disorders are often coincident with, for example, hypokalemia and hypomagnesemia often occurring together."

This association is also seen with certain cardiovascular irregularities as well as diabetes: "Subclinical magnesium and potassium deficiencies are strongly associated with increased ventricular ectopy and arrhythmias."

In addition: "Hypokalemia and hypomagnesemia are often seen in patients with hypertension, diabetes, and congestive heart failure, which also may be associated with high levels of calcium."

Of course, this relationship is not only seen on a gross level based on clinical diagnosis but in the intracellular milieu also: "The higher the intracellular potassium, the higher the intracellular magnesium and the lower the intracellular calcium"

What about bone metabolism?

"While calcium and vitamin D have been the focus of much attention, potassium and magnesium are emerging as important ions in preserving bone structure in the aging population. Magnesium and potassium depletion is common in elderly subjects and is due to inadequate dietary intake, impairment of renal or gut absorption, hypercalcemia, diabetic acidosis, or diuretic therapy."

Then, of course, there is the issue of diuretic use: "Indeed, volume depletion, hypokalemia, hyperkalemia, metabolic acidosis, metabolic alkalosis, hypomagnesemia, hyponatremia, and hypernatremia are complications that may occur from diuretic use."

Furthermore: "Treating hypertension is a common clinical practice. However, the onset of hypokalemia and hypomagnesemia with thiazides or loop diuretics may lead to increased ventricular ectopy and an increased incidence of sudden death."

Next Weglicki et al comment on diagnostic and treatment aspects of this relationship between potassium and magnesium: "Potassium and magnesium deficiencies coexist in several disease conditions including congestive heart failure. And because serum magnesium testing is seldom done in the clinical setting, hypomagnesemia and hypermagnesemia go unrecognized. Thus, treating hypokalemia also must address magnesium deficiencies."

Weglicki et al conclude their review of the literature with a statement that emphasizes how important it is in the clinical setting to always consider potassium and magnesium jointly: "Several metabolic disorders (e.g., diabetes and obesity, hypertension, and congestive heart failure may be defined based on ion deficiencies, especially related to hypokalemia and hypomagnesemia. Indeed, the two deficiencies are coincident and treatment algorithms must consider this when recommending treatments for conditions that essentially arise from ion imbalances. Reinstitution of electrolyte balance may go a long way in addressing complications in disease management."

Beyond association, how magnesium deficiency contributes to hypokalemia and suboptimal potassium metabolism.

While it is certainly important to note how often potassium and magnesium are found together in human physiology and how often low levels are found together in various disease states, it may be even more important to point out that there is a cause and effect aspect to this relationship that goes beyond mere association. This cause and effect relationship has been emphasized in two papers I have located. The first is entitled "The relationship between disorders of [K.sup.+] and M[g.sup.+] homeostasis" by Solomon (Solomon R. Sem Nephrology, Vol. 7, No. 3, pp. 253-262, September 1987). Two quotes from this paper make it clear that magnesium deficiency must be addressed whenever efforts are being made to replete potassium: "...tissue content of potassium also decreases with magnesium depletion. This potassium depletion occurs rapidly and may or may not be accompanied by a decrease in serum potassium. The degree of potassium depletion and the effect on serum potassium depends in part on the amount of potassium provided in the diet of the magnesium deficient animals. A concomitant deficiency of both dietary potassium and magnesium results in the greatest potassium depletion (greater than that seen with a potassium deficient diet alone) and most consistent hypokalemia."

Why might magnesium deficiency affect potassium levels? "...magnesium deficiency also inhibits the active transport of potassium into the cell."

Then, in the conclusion, Solomon provides more detail on how magnesium deficiency adversely affects potassium physiology: "...primary disturbances in magnesium balance, particularly magnesium depletion, produce secondary potassium depletion. This appears to result from an inability of the cell to maintain the normally high intracellular concentration of potassium, perhaps as a result of an increase in membrane permeability to potassium and/or inhibition of Na+-K-ATPase. As a result, the cells lose potassium, which is excreted in the urine. Repletion of cell potassium requires correction of the magnesium deficit."

The second paper I found that addresses the impact of magnesium deficiency on potassium metabolism is "Mechanism of hypokalemia in magnesium deficiency" by Huang and Kuo (Huang CL & Kuo E. J Am Soc Nephrol, Vol. 18, pp. 2649-2652, 2007). As you will see from the following selection of quotes from this paper, it is well established that optimal levels of magnesium are necessary for optimal potassium metabolism. First, consider the following: "It is estimated that more than 50% of clinically significant hypokalemia has concomitant magnesium deficiency."

Furthermore, this relationship is not just a statistical association but a major cause and effect phenomenon: "Concomitant magnesium deficiency has long been appreciated to aggravate hypokalemia."

Because of this, correcting magnesium deficiency is essen tial for addressing hypokalemia: "Co-administration of magnesium is essential for correcting the hypokalemia."

The next few quotes provide more detail on the biochemistry of this cause and effect issue: "Previous articles suggested that impairment of Na-K-ATPase caused by magnesium deficiency contributes to [K.sup.+] wasting. Magnesium deficiency impairs Na-K-ATPase, which would decrease cellular uptake of [K.sup.+]."

In addition:

"Little [K.sup.+] is excreted by the gastrointestinal tract normally; therefore, hypokalemia in magnesium deficiency is likely associated with enhanced renal [K.sup.+] excretion. To support this idea, Baehler et al. showed that administration of magnesium decreases urinary [K.sup.+] excretion and increases serum [K.sup.+] levels in a patient with Bartter disease with combined hypomagnesemia and hypokalemia. Similarly, magnesium replacement alone (without [K.sup.+]) increases serum [K.sup.+] levels in individuals who have hypokalemia and hypomagnesemia and receive thiazide treatment. Magnesium administration decreased urinary [K.sup.+] excretion is these individuals. Moreover, magnesium infusion decreases urinary [K.sup.+] excretion in normal individuals."

One reason that magnesium supplementation decreases loss of potassium in the urine is its impact on renal function: "Thus, magnesium replacement prevents renal K wasting, at least in part, by decreasing secretion in the distal nephron."

To conclude their paper, Huang and Kuo state the following: "Magnesium and [K.sup.+] are the two most abundant intracellular cations. Because of their predominant intracellular distribution, deficiency of these ions is under recognized. Both magnesium and [K.sup.+] are critical for stabilizing membrane potential and decreasing cell excitability. Magnesium deficiency will not only exacerbate [K.sup.+] wasting but also aggravate the adverse effects of hypokalemia on target tissues. Recognition of concomitant magnesium deficiency and early treatment with magnesium are imperative for effective treatment and prevention of complications of hypokalemia."

Can potassium deficiency cause or exacerbate magnesium deficiency?

As you can see, there is a wealth of data which suggests that magnesium deficiency can cause or contribute to potassium deficiency. Can the reverse by true where potassium deficiency contributes to or causes magnesium deficiency? Unfortunately, I could only find one reference to this relationship in the medical literature. According to Quamme and DeRouffignac (Quamme GA & DeRouffignac C. Renal magnesium handling, in Selden DW & Giebisch G eds., The Kidney: Physiology & Pathophysiology, Volume II, Third Edition, Lippincott Williams Wilkins, Philadelphia, 2000, pp. 1711-1729): "Hypokalemia and potassium depletion is associated with diminished magnesium absorption with the loop and distal tubule, which may lead to increased magnesium excretion."

Is this important interrelationship between potassium and magnesium actually part of a bigger mineral/electrolyte picture?

I feel very strongly that, while discussions such as what I just presented are both clinically important and intriguing, we must never forget that this is just one of many important physiologic and biochemical imbalances that are contributing to the chief complaints we see in chronically ill patients. One aspect of this "big picture" scenario that occurs in both acute and chronically ill patients is that the impact of stress physiology in ailing populations is not limited to potassium and magnesium imbalances. Other key electrolytes and minerals are also affected. This important point was well illustrated in the paper "Stressor states and the cation crossroads" by Weber et al (Weber KT et al. J Am Coll Nutr, Vol. 29, No. 6, pp. 563-574, December 2010): "Stressor state-induced neurohormonal activation involving calcitropic hormones, such as catecholamines, parathyroid hormone, vitamin D, endothelin-1, and angiotensin II, leads to homeostasis gone awry to beget dyshomeostasis at cellular and molecular levels in the heart and systemic organs. This includes a dyshomeostasis of electrolytes and cations. The cation crossroad involves monovalent and divalent cations. It can be schematically envisaged and represented by a complex set of highways, roadways, and byways as frequently invoked by stressor states.

The acute stressor state present in critically ill patients is accompanied by dyshomeostasis of a whole host of electrolytes and trace elements manifested contemporaneously at the time of or shortly after hospital admission. Effector hormones of the HPA axis and the adrenergic nervous system and renin-angiotensin-aldosterone system collectively orchestrate the concordant appearance of hypokalemia, ionized hy-pocalcemia and hypomagnesemia, hypozincemia, and hy-poselenemia."

A Final Thought

In this series I have been doing my best to convey to you the underappreciated issue of potassium deficiency in your chronically ill patients. In part III, though, I wanted to convey that, even though the importance of potassium optimization cannot be over emphasized, we must not forget that issues of magnesium deficiency and a whole host of other mineral deficiencies are intricately intertwined in your chronically ill patients. In part IV, the final installment of this series, I will explore the important but vastly under-appreciated role optimal protein and amino acid metabolism in acid/alkaline balance.

by: Jeffrey Moss, DDS, CNS, DA CBN
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Author:Moss, Jeffrey
Publication:Original Internist
Article Type:Report
Date:Mar 1, 2017
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