Magnesium and microminerals: roles, deficiency and excess | Nursing Times

Introduction

This final article in a six-part series about vitamins and minerals concludes our exploration of macrominerals (minerals needed in relatively large amounts) by highlighting the physiological roles of magnesium. It then explores microminerals, which are trace elements needed in much smaller amounts. Each mineral is explored in turn and the recommended daily allowances, dietary sources, and terminology used to describe deficiency and excess are shown in Table 1.

Magnesium

A typical adult body contains ~25g of magnesium, with the bulk of this (50-60%) in the skeleton (National Institutes of Health Office of Dietary Supplements (NIH ODS), 2022). Magnesium has been identified as an essential cofactor for the normal functioning of around 600 enzymes (Morrison, 2023). These are involved in diverse physiological processes, including:

• Nucleic acid (deoxyribonucleic acid (DNA) and ribonucleic acid) synthesis;
• Protein synthesis;
• Blood-pressure control;
• Heart function;
• Blood–glucose homeostasis;
• Cellular metabolism;
• Muscle and nerve function (NIH ODS, 2022).

In health, plasma concentrations of magnesium are maintained at 0.75-0.95mmol/L (NIH ODS, 2022). Unlike calcium – which is tightly regulated by calcitonin, parathyroid hormone and also vitamin  D – there is thought to be minimal hormonal involvement in maintaining magnesium homeostasis (Reddy et al, 2018). Instead, plasma magnesium levels are maintained by a combination of:

• Efficient absorption of dietary magnesium across the gut;
• Release of magnesium from the large pool stored in the skeleton;
• Stringent control of the elimination/reabsorption of magnesium by the kidneys (Fiorentini et al, 2021).

Hypomagnesaemia

Low plasma magnesium is called hypo-magnesaemia and is most commonly associated with dietary deficiency, gastro-intestinal (GI) tract problems (such as vomiting, diarrhoea or malabsorption syndromes) and renal disease. It is also common in people using diuretics and proton pump inhibitors (used to reduce stomach acid production) (Oost et al, 2023).

As magnesium is vital to the functioning of many enzymes, symptoms of deficiency are diverse. They include muscle fasciculation (twitching), tremors, tetany, seizures, tiredness, apathy and delirium (Pham et al, 2014). Cardiac arrhythmias are also common, with postulated links to premature atrial and ventricular contractions, atrial fibrillation and, more dangerously, ventricular arrhythmias (Negru et al, 2022).

Treatments for hypomagnesaemia involve magnesium replacement. For mild-to-moderate deficiency, oral magnesium oxide, magnesium chloride, magnesium lactate or magnesium chloride tablets are used. More serious deficiency, particularly when associated with symptoms such tetany and seizures, is usually treated with intravenous (IV) magnesium sulphate infusion (Rosner et al, 2023).

Hypermagnesaemia

Elevated plasma magnesium is a fairly rare disorder called hypermagnesaemia. It is usually associated with acute or chronic renal disease, in which the kidneys have become less efficient at excreting excess magnesium. It is also seen when excessive magnesium is consumed via food or supplements, and can be caused by disorders that enhance magnesium absorption and those that reduce transit times in the gut, such as inflammatory bowel diseases and constipation.

Opioid medications for pain relief can increase the risk of hypermagnesaemia by slowing gut movements, which increases the risk of constipation. Many medications used to treat constipation are also rich in magnesium and can raise the plasma concentration further (Aal-Hamad et al, 2023).

As with hypomagnesaemia, symptoms of hypermagnesaemia are incredibly diverse. They include nausea, dizziness, confusion, muscle weakness, depression and decreased blood pressure. Severe hypermagnesaemia may be associated with muscle paralysis, sinus bradycardia, atrioventricular node block, seizures, coma and cardiac arrest (Aal-Hamad et al, 2023).

Treatments usually involve using isotonic salines and IV calcium chloride or gluconate; these calcium compounds act to antagonise some of the effects of excess magnesium, particularly in the heart and muscle tissues. Loop diuretics, such as furosemide, can also help to ‘flush out’ excess magnesium. Renal dialysis may be needed in patients with compromised renal function or when symptoms are severe (Cascella and Vaqar, 2023).

Microminerals

Many minerals are needed by the body in smaller amounts. These are termed microminerals or trace elements; they include iron (Fe), copper (Cu), zinc (Zn), manganese (Mn) and iodine (I). Some microminerals are needed at extremely low concentrations (some <1µg per day) and are referred to as ultra-trace minerals. These include selenium (Se), molybdenum (Mo), cobalt (Co) and chromium (Cr). While essential to human physiology, many microminerals can be toxic at high concentrations (Sousa et al, 2019). The key microminerals and ultra-trace minerals are explored below.

Iron

Dietary iron is divided into:

• Non-haem iron, which comes from plants and animals;
• Haem iron, which is primarily derived from the haemoglobin and myoglobin molecules present in animal meats.

Iron is absorbed across the gut wall of the small intestine (mainly in the duodenum). As highlighted in the first article of this series, absorption of iron in the gut is enhanced by vitamins A and C, and may be significantly reduced when these are deficient. Iron crosses into the enterocytes (epithelial cells lining the small intestine), utilising a cell membrane protein called ferroportin. This iron-transport protein is also found in many other cell types that take up iron, including:

• Macrophages – large phagocytic cells that are important to immunity and are also present in the liver, in the form of Kupffer cells);
• Hepatocytes – the major liver cells that form the bulk of the liver’s mass (Wang and Babitt, 2019).

Once iron has crossed the gut into the plasma, it binds to the plasma protein transferrin; this acts as a vehicle for transporting iron to the liver, bone marrow and other tissues that need iron (Fig 1) (Wang and Babitt, 2019; Yiannikourides and Latunde-Dada 2019).

The average man has 50-60mg of iron per kilogram of body weight (Yiannikourides and Latunde-Dada, 2019); women have less at ~38mg/kg (European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies, nd). Around 65% of the body’s total iron is associated with haemoglobin in erythrocytes, and 10% is associated with the myoglobin within muscles (Yiannikourides and Latunde-Dada, 2019). Both haemoglobin and myoglobin have a strong affinity for oxygen, which is essential to their role in oxygen transport (VanPutte et al, 2017).

As free iron is toxic at high levels, it is stored in liver hepatocytes and other cells bound to a specialised protein called ferritin; this acts as an intracellular reservoir for iron, so it can then be accessed as needed (Yiannikourides and Latunde-Dada, 2019).

Transferrin and a structurally related protein called lactoferrin play an important role in the body’s non-specific immune responses and help protect against a broad range of infections. Both proteins bind to free iron, making it unavailable for micro-organisms that need iron for many internal metabolic processes. This withholding of iron slows down pathogen replication, potentially reducing the spread and severity of infection (Ganz, 2018).

Iron has many other key physiological functions, including participating in:

• The biochemical reactions of cellular respiration within mitochondria (Xu et al, 2021);
• Cell signalling;
• The replication of nucleic acids, including DNA (Wang and Babitt, 2019).

Iron levels are mainly regulated by a peptide hormone called hepcidin, which is produced by the liver hepatocytes. When released into the blood, hepcidin inhibits both the absorption of iron in the gut and the release of iron from the liver stores. This is primarily achieved by hepcidin promoting the degradation and reduced activity of the ferroportin iron transporters (Wang and Babitt, 2019). Conversely, when iron levels drop, less hepcidin is released. Absorption of iron in the gut is enhanced, and the release of stored iron from the liver is increased (Yiannikourides and Latunde-Dada, 2019).

Iron deficiency
The most common issue associated with lack of iron is iron-deficiency anaemia. Without sufficient iron, the red bone marrow cannot manufacture enough healthy erythrocytes to efficiently transport oxygen around the body. Iron-deficiency anaemia is the most common form of anaemia; each year, it is responsible for >57,000 emergency admissions to UK hospitals (Snook et al, 2021).

The key symptoms of iron-deficiency anaemia include:

• Tiredness and lack of energy;
• Shortness of breath;
• Heart palpitations;
• Skin pallor;
• Headaches;
• Tinnitus;
• Food tasting strange;
• Itchiness;
• A sore tongue;
• Hair loss (NHS, 2024).

All of these symptoms are caused by a lack of healthy, circulating red blood cells in the body and the inability to effectively transport sufficient oxygen around the body (NHS, 2024).

Iron-deficiency anaemia is treated by increasing the amount of iron in the patient’s diet – this is done through the consumption of iron-rich foods and, where necessary, iron supplements. It should be noted, however, that iron supplements must be used with caution, because they can cause constipation, diarrhoea, abdominal pain, acid reflux, nausea and black stools (NHS, 2024).

Iron toxicity
Iron toxicity is one of the most common toxic ingestions seen in clinical practice and is potentially fatal, particularly in children (Yuen and Becker, 2023). As iron supplements are commonly prescribed medications, they are often ingested to excess, either accidently or deliberately.

Iron toxicity can be classified as:

• Corrosive iron toxicity – this occurs when high levels of ingested iron physically corrode the epithelial tissues of the gut; this results in caustic injury, leading to vomiting, diarrhoea, abdominal pain and, potentially, hypovolaemia (reduced blood volume);
• Cellular iron toxicity – this occurs when excess iron is taken up into the cells of the body (Yuen and Becker, 2023).

Iron levels of >60mg per kilogram of body weight are toxic, and very high levels are associated with high morbidity and mortality. Excessive iron is toxic to many organs in the body, accumulating in the mitochondria and disrupting cellular respiration; this can eventually result in multiple organ failure and death (Yuen and Becker, 2023).

Treatments include IV saline, for patients showing hypovolaemia, and deferoxamine (an iron-chelating agent that binds to and removes iron from the plasma and tissues). When appropriate, gastric lavage and bowel irrigation may be used to help flush excess iron residues from the GI tract (Yuen and Becker, 2023).

Hereditary haemochromatosis (HH), also known as iron overload, is a genetic disorder characterised by hepcidin deficiency due to inheritance of abnormal hepcidin genes. Without hepcidin to limit both the absorption of iron from food and the release of iron from stores in the liver, iron begins to accumulate to toxic levels. Symptoms include feeling tired all the time, joint pain, brain fog, mood swings, depression, erectile dysfunction and irregular periods.

Without treatment, HH can lead to liver cirrhosis, cardiomyopathy, diabetes mellitus, arthropathies (joint disorders) and abnormal skin pigmentation. HH is most often treated by phlebotomy, which is effective at removing 200-250mg of iron per unit of blood taken. Iron chelators (molecules that bind to iron, reducing the level of free iron) may also be used, particularly in patients who refuse, or cannot undergo, phlebotomy (Xu et al, 2021).

Copper

Copper is a cofactor to many enzymes, including those involved in cellular respiration (Hofmann et al, 2021). It is vital for the formation of haemoglobin and healthy erythrocytes, and also plays an important role in the immune system (NHS, 2020), skin pigmentation and neurotransmitter synthesis (Hofmann et al, 2021). Additionally, it contributes to bone strength and brain development (NHS, 2020).

Excess copper is stored in the liver and can be released as needed by the body. Copper deficiency can lead to:

• Anaemia;
• Neurological symptoms;
• Reduced melanin synthesis, leading to skin and hair depigmentation (Hofmann et al, 2021).

Copper deficiency is typically treated with 4-8mg oral or IV copper per day (Berger et al, 2022).

Copper toxicity is associated with stomach pains, vomiting, diarrhoea, and liver and kidney damage (NHS, 2020). Wilson’s disease is a genetic disorder in which copper accumulates to toxic levels in the liver hepatocytes; it eventually leaks into the blood, where it circulates and can accumulate in other organs, such as the brain, kidneys and corneas. Wilson’s disease and copper toxicity can be managed by avoiding foods with a high copper content and through the use of copper-chelating agents (Immergluck and Anilkumar, 2023).

Zinc

More than 85% of the body’s zinc is found in skeletal muscle and bone, with <0.1% circulating in the plasma (Berger et al, 2022). Like copper, zinc is an essential cofactor for multiple enzymes, including:

• Carbonic anhydrase, which is essential for the transport of carbon dioxide (as discussed in the previous article in the series),
• Carboxypeptidase, which is involved in protein digestion;
• Alcohol dehydrogenase, which breaks down ethanol in the liver (Godswill et al, 2020).

Zinc also plays a role in wound healing, glucose homeostasis and immunity; it is essential to DNA and protein synthesis, and is a structural component of many proteins (Berger et al, 2022).

Zinc deficiency is relatively common. Mild deficiency does not usually produce symptoms, but more severe deficiency is associated with immune dysfunction, poor wound healing, growth retardation, alopecia and skin rashes (Berger et al, 2022). Treatment involves dietary adjustments and supplementation.

Because zinc is generally considered a non-toxic metal, toxicity is rare; however, consuming large amounts can lead to epigastric pain, nausea, vomiting, lethargy and fatigue (Sousa et al, 2019). If needed, chelating agents may be used with whole-bowel irrigation (Berger et al, 2022).

Manganese

Manganese is a cofactor for enzymes involved in glucose and lipid metabolism; it is also essential for bone health, normal growth and blood coagulation. It concentrates primarily in bone, liver and glandular tissues, including the pancreas, pituitary and adrenal glands (Berger et al, 2022). Deficiency is rare, because it is fairly ubiquitous in the diet and needs for it are very low. Toxicity is also rare, although it has been reported in metal workers, such as welders (Lahhob et al, 2023).

Iodine

Unlike many other minerals, excess iodine is not stored in large amounts in the body. Most excess dietary iodine is eliminated in the urine; this allows a person’s current iodine status to be accurately assessed using urine samples (Dei-Tutu et al, 2020). Small amounts of iodine can be stored in the tissues of the stomach and salivary glands, then released as needed (Mégier et al, 2023). However, it is generally accepted that a continual supply of iodine in the diet is needed to maintain health.

The major role of iodine in the human body is the synthesis of the iodine-containing thyroid hormones that regulate metabolism. Around 90% of dietary iodine is absorbed in the stomach and duodenum; it then circulates in the plasma, before being taken up by the follicular cells of the thyroid gland.

Initially, iodine is conjugated (joined) to a large protein called thyroglobulin and stored in the thyroid follicles as a homogenous suspension termed a colloid. Thyroglobulin is rich in the amino acid tyrosine, which, together with the stored iodine, is used to synthesise two iodine-containing hormones called T3 and T4, each of which contains two molecules of tyrosine. Each molecule of T3 contains three atoms of iodine and is called triiodothyronine; each molecule of T4 has four iodine atoms and is called tetraiodothyronine or thyroxine (Fig 2).

Both the iodine-containing hormones regulate the metabolic rate, which is the rate at which food molecules, such as glucose, are broken down to release energy in cells (VanPutte et al, 2017). The thyroid releases approximately 80% T4 and 20% T3; T3 has approximately four times the potency of T4 (Knight et al, 2021). Many of the target cells for these hormones have enzymes called deiodinases; these rapidly remove a single atom of iodine from T4 molecules, thereby generating greater amounts of the more-potent T3 (Shahid et al, 2023).

As with vitamins A, C, E and K (discussed in earlier articles in this series), iodine is also known to function as a scavenger of damaging free radicals in the body and is thought to play a role as an anticancer agent. Additionally, when combined with oxygen to form hypoiodite (IO-), iodine has antimicrobial effects, showing activity against bacteria, fungi and viruses (Sorrenti et al, 2021).

Iodine deficiency
Serious iodine deficiency can result in a swelling of the thyroid gland, referred to as goitre (Fig 3). It can also cause hypothyroidism (low T3 and T4 production), and chronic iodine deficiency is associated with an increased risk of the follicular form of thyroid cancer (Zimmermann and Galetti, 2015).

As iodine is most abundant in seafood, deficiency is more likely in geographical regions far from the coast. However, iodine deficiencies leading to goitre can even be present in island locations, such as the UK. Indeed, in the 1920s, a “goitre belt” was identified, extending from the West Country (Devon, Cornwall, Somerset and Dorset) through Gloucestershire and Derbyshire and into parts of Wales; goitre became common in these areas and was often referred to as “Derbyshire neck” (Bath and Rayman, 2013).

Unlike many other countries, the UK has never formally had an iodisation programme, such as the common practice of iodising table salt. However, iodine deficiency decreased substantially with the introduction of iodine into cattle feeds, which considerably increased the amount of iodine consumed via milk and other dairy products. This led to a threefold increase in iodine intake between the 1950s and 1980s; as a result, the UK population was considered to be iodine sufficient and cases of goitre declined (Bath and Rayman, 2013). Globally, however, iodine deficiency remains a major problem, affecting ~40% of the world’s population (Mégier et al, 2023).

During pregnancy and when breastfeeding, the need for iodine increases (Dei-Tutu et al, 2020). It is essential for the normal development of the embryonic/foetal nervous system, so mild-to-moderate iodine deficiency during pregnancy can negatively affect a child’s cognitive capabilities (Mégier et al, 2023; Dei-Tutu et al, 2020). Severe iodine deficiency is the most common cause of congenital hypothyroidism (previously known as cretinism). This can lead to abnormalities in brain development, resulting in serious intellectual disability, mutism, spastic diplegia (a form of cerebral palsy) and stunted growth (Mégier et al, 2023).

Iodine toxicity
It has been estimated that ingestion of >1.1mg of iodine per day is harmful, potentially leading to acute or chronic toxicity (Southern and Jwayyed, 2023). Iodine toxicity is most often associated with overconsumption of dietary supplements or iodised table salt. It has many symptoms, including burning of the mouth, nausea, vomiting, fever and thyroid dysfunction. There is no recognised antidote for iodine poisoning; treatment usually involves managing symptoms and monitoring vital signs until iodine levels normalise again (Southern et al, 2024).

Ultra-trace minerals

Selenium

Selenium is needed to produce the amino acid selenocysteine, which is a component of selenium-containing proteins; currently 25 selenoproteins have been identified. Some have antioxidant activity and documented roles in immunity and thyroid hormone physiology (Berger et al, 2022). In many of its target tissues, the thyroid hormone T4 is converted into more biologically active T3 by selenium-dependent iodinases (Fig 2) (Shahid et al, 2023).

Severe selenium deficiency can result in an abnormal thyroid hormone profile, with reduced levels of the highly active T3 and greater levels of the less-potent T4. Selenium deficiency can adversely affect skin and nail health, and lead to immune dysfunction, with increased risk of viral infections of greater virulence. It is also associated with an increased risk of type 2 diabetes and some forms of cancer. Deficiency is treated with oral or IV selenium supplementation (Berger et al, 2022).

Selenium toxicity is rare, but elevated levels have been associated with an increased risk of type 2 diabetes, high-grade prostate cancer and Parkinson’s disease (Berger et al, 2022).

Molybdenum

Molybdenum is a cofactor for four enzymes involved in cellular metabolism and the metabolism of drugs and toxins in the liver. Neither dietary deficiency nor dietary toxicity have been reported in humans (Berger et al, 2022).

Cobalt

Cobalt is a component of cobalamin (vitamin B12), which is needed for normal erythrocyte production (as discussed in the second article of this series) (Lahhob et al, 2023). It is largely acquired through the diet, from foods rich in vitamin B12; some can potentially be obtained from industrial exposure (Berger et al, 2022).

As cobalt is acquired via vitamin B12, dietary deficiency is usually associated with vitamin B12 deficiency. Dietary toxicity is rare, but can occur with overuse of dietary supplements. Elevated cobalt levels can also occur as a result of industrial exposure, as well as due to surgical implants containing cobalt (such as metal hip replacements). Cobalt toxicity is associated with increased erythrocyte mass (polycythaemia), damage to cardiac muscle (cobalt-related cardiomyopathy) and congestive heart failure (Berger et al, 2022).

Chromium

Chromium plays an important role in blood–glucose homeostasis and enhances the actions of insulin by:

• Increasing the number of insulin receptors on target cells;
• Improving the movement of glucose transporter proteins onto cell membranes (Berger et al, 2022).

These glucose transporter proteins enhance the uptake of glucose into cells, lowering the blood–glucose concentration (Knight et al, 2020).

Chromium deficiency is relatively common in industrialised countries. It appears to be associated with an increased risk of changes to glucose metabolism; studies have shown lower chromium levels in patients with type 2 diabetes compared with the general population (Berger et al, 2022). Deficiency is also associated with elevated triglyceride and cholesterol levels, as well as increased risk of heart disease (Lahhob et al, 2023). Additionally, deficiencies may occur in burns and trauma patients, and in individuals who have had bowel resection, which reduces absorption (Berger et al, 2022).

Deficiency can be treated with chromium replacement therapy, which can be given orally or intravenously. This can minimise insulin resistance, thereby reducing the risk of type 2 diabetes (Lahhob et al, 2023).

Chromium toxicity can occur through excessive use of supplements, but it is very rare due to the naturally poor absorption of chromium in the gut. Where necessary, chelating agents, antioxidants and plasmapheresis (an intervention in which chromium is removed from the plasma) can be used to treat severe toxicity (Berger et al, 2022).

Conclusion

This final article of the series has completed the exploration of macrominerals and microminerals. It has discussed magnesium, iron, copper, zinc, manganese, iodine, selenium, molybdenum, cobalt and chromium in terms of their role in human physiology, and the pathological consequences of deficiency and excess.

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