Magnesium Deficiency & Cardiovascular Health
Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis
Because serum magnesium does not reflect intracellular magnesium, the latter making up more than 99% of total body magnesium, most cases of magnesium deficiency are undiagnosed. Furthermore, because of chronic diseases, medications decreases in food crop magnesium contents, and the availability of refined and processed foods, the vast majority of people in modern societies are at risk for magnesium deficiency. Certain individuals will need to supplement with magnesium in order to prevent suboptimal magnesium deficiency, especially if trying to obtain an optimal magnesium status to prevent chronic disease. Subclinical magnesium deficiency increases the risk of numerous types of cardiovascular disease, costs nations around the world an incalculable amount of healthcare costs and suffering, and should be considered a public health crisis. That an easy, cost-effective strategy exists to prevent and treat subclinical magnesium deficiency should provide an urgent call to action.
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Magnesium in human biology
‘Magnesium is the seventh most abundant element in the Earth’s crust by mass or molarity…In vertebrates, magnesium is extremely abundant and it is the second most common intracellular cation (potassium being the first). Extracellular magnesium accounts for only ∼1% of total body magnesium, which is found primarily in serum and red blood cells’.
Magnesium is the fourth most common cation in our body, the second most common intracellular cation, and the most common intracellular divalent cation. The human body contains around 25 g of magnesium. Magnesium is necessary for the functioning of over 300 enzymes in human, with 90% of total body magnesium being contained in the muscles and bones (~27% and ~63%, respectively), 90% of which is bound and with only 10% being free. In the serum, 32% of magnesium is bound to albumin, whereas 55% is free.
Some of the main functions of magnesium in human biology include the maintenance of ionic gradients (keeping intracellular sodium and calcium low and potassium high), cellular and tissue integrity, mitochondrial oxidative phosphorylation (ATP production and activation), and DNA, RNA and protein synthesis and integrity.
The elimination of magnesium is mainly controlled by the kidneys, increasing in the urine when there is magnesium surplus and falling to just 1 mEq of magnesium (~12 mg) during deficits. However, despite renal conservation, magnesium can be pulled from the bone (as well as muscles and internal organs) in order to maintain normal serum magnesium levels when intakes are low. Thus, a normal serum magnesium level does not rule out magnesium deficiency, which predisposes to osteopaenia, osteoporosis, and fractures.
An excess of heavy metals due to soil contamination and a lack of minerals due to soil erosion also may predispose to micronutrient deficits. The importance of the mineral content of soil and water, once greatly appreciated, think low iodine levels in soil and the increased prevalence of goiter, has all but been forgotten. Furthermore, refined foods are depleted of magnesium during their processing. In order to prevent chronic diseases, we need to change our mindset away from exclusively treating acute illness and instead focus more on treating the underlying causes of chronic diseases, such as magnesium deficiency.
There are two types of nutrient deficiencies, frank deficiencies (such as scurvy from an ascorbic acid deficiency or goiter from iodine deficiency) and subclinical deficiencies (a clinically silent reduction in physiological, cellular and/or biochemical functions). It is the latter that is most concerning as it is hard to diagnose and predisposes to numerous chronic diseases. And while both result in negative health consequences, the former has obvious symptoms (hence frank deficiency), whereas the latter may have negative or variable health effects that are not so apparent (eg, vascular calcification). The evidence in the literature suggests that subclinical magnesium deficiency is rampant and one of the leading causes of chronic diseases including cardiovascular disease and early mortality around the globe, and should be considered a public health crisis.
‘The homeostatic mechanisms to regulate magnesium balance were developed millions of years ago. Investigations of the macro- and micro-nutrient supply in Paleolithic nutrition of the former hunter/gatherer societies showed a magnesium uptake with the usual diet of about 600 mg magnesium/day, much higher than today’. Our homeostatic mechanisms and genome are still the same as with our ancestors in the Stone Age. This means our metabolism is best adapted to high magnesium intake.
In developed countries, the average intake of magnesium is slightly over 4 mg/kg/day. More than a quarter of obese and non-obese youth have inadequate intakes of magnesium (27% and 29%, respectively). The authors of a study concluded: ‘Even though children may consume an excess of energy, they may not be meeting all of their micronutrient needs’. In other words, children are overfed and undernourished. One expert has argued that a typical Western diet may provide enough magnesium to avoid frank magnesium deficiency, but it is unlikely to maintain high-normal magnesium levels and provide optimal risk reduction from coronary artery disease and osteoporosis. That is, ‘Various studies have shown that at least 300 mg magnesium must be supplemented to establish significantly increased serum magnesium concentrations…’ In other words, most people need an additional 300 mg of magnesium per day in order to lower their risk of developing numerous chronic diseases. So while the recommended daily allowance (RDA) for magnesium (between 300 and 420 mg/day for most people) may prevent frank magnesium deficiency, it is unlikely to provide optimal health and longevity, which should be the ultimate goal.
Importantly, much of the population may not even be meeting the RDA for magnesium. For example, the average magnesium intake in men and women in Taiwan is only 250 mg and 216 mg, respectively, or 68%–70% of the recommended dietary reference intake. The authors of the study concluded: ‘Taiwanese elderly persons had suboptimal levels of dietary magnesium intake, which although may be sufficient to avoid overt magnesium deficiency, may not be sufficient to reduce the risk of diabetes in the elderly’. The National Nutrition Survey in Japan found that for people 15–49 years old the intake of magnesium was below the Japanese RDA. Moreover, around half (48%) of the US population consumes less than the recommended amount of magnesium from food. The US Department of Agriculture states that the average magnesium intake in women and men is 228 mg/day and 323 mg/day, respectively. Based on these data, one group of authors noted: ‘These intake levels suggest that a substantial number of people may be at risk for Mg deficiency, especially if concomitant disorders and/or medications place the individual at further risk for Mg depletion’.7 The most recent published review on magnesium concluded: ‘Approximately 50% of Americans consume less than the Estimated Average Requirement (EAR) for magnesium, and some age groups consume substantially less’.
Lakshmanan et al collected daily food records for 1 year in 34 men and women. They found that the mean magnesium intake was 323 mg/day and 234 mg/day in men and women, respectively (around 4 mg/kg/day). Despite this level of intake, the overall patient population was in negative magnesium balance (−32 and −25 mg/day, respectively). Moreover, 75% of women consumed less than the RDA (300 mg/day) and only one out of the eighteen women were in equilibrium. Considering that the average intake of magnesium in the USA is around 228 mg/day in women and 266 mg/day in men, a large percentage of Americans may be at risk of negative magnesium balance. Indeed, ‘Only American diets containing more than 3000 kcal/day may provide 300 mg or more magnesium’. Another long-term study lasting 50 weeks found that somewhere between 180 mg and 320 mg of magnesium/day is required in order to maintain positive magnesium balance. And since many individuals may be consuming below 320 mg/day of magnesium, this poses a major public health threat.
The data are consistent around the world that magnesium intake may be inadequate. Indeed, the intake of magnesium in Germany was determined to be only 200 mg for women and 250 mg for men. In Kiev a study on 780 men aged 20–59 found that the overall population consumed insufficient magnesium from food rations (10% less than the recommended value). The authors also found a correlation between low magnesium consumption in food and the prevalence of risk factors for ischaemic heart diseases, such as hyperlipoproteinemia, arterial hypertension, and body weight. In 2004, Durlach concluded: ‘About 20% of the population consumes less than two-thirds of the RDA for Mg. Women, particularly, have low intakes. For example, in France, 23% of women and 18% of men have inadequate intakes. Mg deficiency during pregnancy can induce maternal, fetal, and pediatric consequences that might last throughout life’. The median magnesium intake in an elderly population (832 subjects aged 70 years or older) in Southern France was also found to be below the RDA. Another French study on 2373 subjects (4–82 years of age) noted that 71.7% of men and 82.5% of women had an inadequate magnesium intake.
‘Hypomagnesemia is a relatively common occurrence in clinical medicine. That it often goes unrecognized is due to the fact that magnesium levels are rarely evaluated since few clinicians are aware of the many clinical states in which deficiency or excess, of this ion, may occur’.
In developed countries, older data estimated that the prevalence of marginal magnesium deficit is 15%–20% of the population. This corroborates more recent data indicating that around 10%–30% of a given population has subclinical magnesium deficiency based on serum magnesium levels <0.80 mmol/L. The 2006 National Health and Nutrition Survey found low serum concentrations of magnesium in 36.3% and 31% of female and male Mexican adults, respectively. The authors of the study concluded: ‘Low serum concentrations of…magnesium are published for the first time and show significant prevalence of deficiencies’, and up to 20% of the general population has low serum magnesium levels. A systematic review of 37 articles discovered that magnesium deficiency was a possible public health concern for older adults.
Magnesium deficiency has been found in 84% of postmenopausal women with osteoporosis diagnosed by low magnesium trabecular bone content and Thoren’s magnesium load test. Among apparently healthy university students in Brazil, 42% were found to have subnormal magnesium status (based on plasma or erythrocyte magnesium levels). The average magnesium intake was only around 215 mg/day. Magnesium depletion has been found in 75% and 30.8% of patients with poorly controlled type 2 diabetes based on serum and intracellular magnesium status, respectively.
Magnesium deficiency can be present despite normal serum magnesium levels. Approximately 20% of 381 unselected elderly men and women (most of them in their 80s) were found to have low erythrocyte potassium and magnesium levels. The authors of the study concluded: ‘This study underlines the large prevalence of magnesium and potassium deficiencies in the elderly’. Another study concluded: ‘The commonly designated low limit of the normal range…is below levels that exist in patients with marginal deficiencies that can predispose to the development of pathologic findings, so that the prevalence and importance of this disease are insufficiently considered…It is a statistical error to use the confidence limits of the normal population as the exclusion limit for those with abnormal Mg status’. In other words, our normal range of serum magnesium is inaccurate and that serum magnesium levels at the lower end of normal likely suggest marginal magnesium deficiency. Indeed, ‘The magnesium content of the plasma is an unreliable guide to body stores: muscle is a more accurate guide to the body content of this intracellular cation’.
Another study highlighting the discrepancy between serum and body magnesium levels concluded: ‘Although serum-K and serum-Mg values in patients receiving long-term treatment for hypertension or incompensated heart disease usually are normal, muscle-Mg and muscle-K contents are reduced in around 50% of these patients…Evaluation of the K and Mg status during diuretic treatment should be preferentially based on tissue determinations. The muscle biopsy method is rapid, reliable and may reveal conditions of deficiency…oral supplements of Mg have proved to be adequate to restore the normal K/Mg status’.
Among critically ill postoperative patients, 36.5% were found to have magnesium deficiency based on ionized magnesium levels in red blood cells. In one study of patients from a medical intensive care unit (ICU), 65% had hypomagnesemia. The author concluded: ‘The prevalence of normomagnesemic Mg deficiency in critically ill patients may be even higher (than 65%, my insertion) and may contribute to the pathogenesis of hypocalcemia, cardiac arrhythmias and other symptoms of Mg deficiency’. Finally, 6.9%–11% of hospitalized patients have been noted to have hypomagnesemia on routine exam posing on unrecognized need.
The overall incidence of hypomagnesemia in one study was noted to be between 5% and 8% of the overall population, and in young women (aged 18–22) the incidence was approximately 20%. One of the largest studies, a cross-sectional study in an unselected population of more than 16 000 subjects in Germany, found a prevalence of hypomagnesemia (magnesium levels below 0.76 mmol/L) of 14.5%. Over 15% of hospitalized elderly patients have been found with low serum magnesium levels. Another study noted: ‘At ICU admission 52.5% had total hypomagnesemia and 13.5% total hypermagnesemia; with respect to the Mg(2+) 9.7% showed ionized hypomagnesemia and 23.6% ionized hypermagnesemia. Patients who developed ionized hypermagnesemia had higher mortality than patients without ionized hypermagnesemia development (P=0.04)’. And it has been noted that ‘Hypomagnesemia detected at the time of admission of acutely ill medical patients is associated with an increased mortality rate for both ward and medical ICU patients’. Magnesium depletion is present in about half of all ICU patients. More than 50% of those hospitalized with either of the following conditions are likely to be magnesium-deficient based on intravenous retention >20%: hypertension, coronary artery disease, cerebrovascular event, gastrointestinal issues or alcoholism.
Based on 183 peer-reviewed studies published from 1990 to 2008, one group of authors concluded: ‘The perception that ‘normal’ serum magnesium excludes deficiency is common among clinicians. This perception is probably enforced by the common laboratory practice of highlighting only abnormal results. A health warning is therefore warranted regarding potential misuse of ‘normal’ serum magnesium because restoration of magnesium stores in deficient patients is simple, tolerable, inexpensive and can be clinically beneficial’.
One study found that 10 out of 11 apparently healthy women were magnesium-deficient based on the oral magnesium load test. The authors concluded: ‘The results showed there are more frequent deficiencies of magnesium in organisms than it is generally assumed’. Another study showed that 37.6% of patients with type 2 diabetes and 10.9% of age-matched and sex-matched healthy controls have low plasma magnesium levels.
Of patients with severe chronic airway obstruction, 11.6% have serum magnesium levels less than the lower normal limit. The authors of the study concluded: ‘…routine serum magnesium determination is recommended in patients with chronic obstructive lung disease taking diuretic drugs or corticosteroids’
Hypomagnesaemia was identified in 47% of 1033 samples based on both routine magnesium determinations as well as physician-initiated requests for magnesium measurements. Importantly, only 10% of the hypomagnesemia findings were found by physician-initiated requests, underscoring the fact that low magnesium blood levels are an overlooked issue by medical doctors.
About 80% of patients with hypertension treated for at least 6 months with either hydrochlorothiazide or a single non-diuretic drug have been found to have magnesium depletion based on retention of a parenterally administered magnesium load. More troubling is that despite being magnesium-depleted, patients treated with hydrochlorothiazide had high normal serum magnesium. This study underlines how patients can have normal or even higher magnesium levels in the blood despite magnesium depletion. Another study confirmed these findings that ‘thiazides induce a magnesium depletion not detectable by monitoring serum levels’. There is a correlation between low magnesium bone concentrations and increased magnesium retention after an intravenous magnesium load, suggesting that magnesium is retained in the bone after the test.
After several weeks of strenuous physical activity, serum magnesium can increase with no change in erythrocyte magnesium levels despite a reduction in mononuclear cell magnesium levels. The authors of a study concluded that the reduction in mononuclear cell magnesium content ‘reflects a reduction in exchangeable magnesium body stores and the onset of a magnesium deficiency state’. This study also indicates that just 6–12 weeks of strenuous physical activity can lead to magnesium deficiency. Another study concluded: ‘Serum and urinary magnesium concentrations decrease during endurance running, consistent with the possibility of magnesium deficiency. This may be related to increased demand in skeletal muscle’.
One study found low levels of erythrocyte magnesium in 119 of 179 (66%) patients admitted consecutively to the ICU. The prevalence of hypomagnesemia at ICU admission has been estimated at around 51.3%, with a prevalence of ionized hypomagnesemia at ICU admission ranging between 14.4% and 22%.
While normal serum magnesium is considered to be 0.7–1 mmol/L, the optimal serum magnesium concentration has been proposed to be >0.80 mmol/L. Chronic latent magnesium deficiency has been defined as ‘…a serum magnesium concentration of between 0.75 and 0.849 mmol/L (within the reference interval), with a positive magnesium load test indicating magnesium deficiency’.
Story Source: Open Heart - BMJ Journals