Macrominerals: exploring the role of inorganic macronutrients | Nursing Times

Introduction

The previous four articles in this series have explored organic micronutrients, highlighting both the nature and functions of the major vitamins. In this penultimate article in our series, we begin to explore inorganic micronutrients. Unlike vitamins – which, by definition, are organic and synthesised by living organisms (animals, plants and fungi) – minerals are inorganic and found preformed in the environment. Despite this, most of the minerals that humans obtain come from dietary plant, fungal and animal sources.

Plants and fungi can get most of their minerals directly from the soil or dissolved in water, while animals primarily obtain them through the food chain. Additionally, humans get minerals from drinking water, fortified foods, condiments (for example, by adding salt to meals) and dietary supplements.

Around 96% of the total body weight is accounted for by the common elements carbon, nitrogen, oxygen and hydrogen (Du et al, 2021). However, as these elements are usually found together forming the body’s organic molecules – for example, carbohydrates, fats, proteins, nucleic acids and vitamins – they are not generally referred to as minerals.

Calcium, phosphorus, sulphur, sodium, potassium, chloride and magnesium are needed in relatively large amounts and are referred to as macrominerals (Sousa et al, 2019). In this first of two articles reviewing key minerals, we begin to examine calcium, phosphorus, sulphur, sodium, potassium and chloride. Each of these is examined in turn; for each, refer to Table 1 for information on the UK recommended daily allowance (RDA), dietary sources and the terminology used to describe deficiency and excess.

Calcium

Calcium is the fifth most abundant element in the human body and the most abundant mineral. A body weighing 70kg contains ~1kg of calcium, with around 99% of this concentrated in the skeleton (Drake and Gupta, 2024). In addition to forming the structural mineral matrix of bone (in the form of calcium phosphate), calcium is vital to human health. It plays a key role in several physiological processes including:

• Blood coagulation;
• Muscle contraction;
• Cell division;
• Glandular secretion;
• Synaptic transmission;
• Acting as cofactor for many enzymes.

Calcium homeostasis

As calcium is vital to so many physiological functions, it is one of the most tightly regulated variables in the human body and maintained within a narrow normal range of 2.2-2.6mmol/L (Knight et al, 2020). Levels of calcium are primarily regulated by the action of two antagonistic hormones – calcitonin and parathyroid hormone – and vitamin D.

Calcitonin is released from the thyroid gland when plasma calcium levels rise (Fig 1). As an example, when a calcium-rich food is being consumed, calcitonin decreases plasma calcium by directing excess calcium into the skeleton and encourages the loss of calcium in the urine.

Parathyroid hormone (PTH) is released from the parathyroid glands when blood calcium levels fall. PTH stimulates osteoclasts (bone-digesting cells) to break down bone and release calcium into the plasma (Fig 1). PTH also encourages calcium retention by the kidneys to reduce loss in urine.

While also considered to be a hormone, vitamin D plays a key role in calcium homeostasis (see the third article in this series), with its most active form (1,25-dihydroxyvitamin D3, also known as calcitriol) increasing calcium absorption in the gut (Drake and Gupta, 2024).

Hypocalcaemia

Decreased blood calcium (hypocalcaemia) is diagnosed if blood calcium concentrations fall below the normal range (that is, <2.2mmol/L). There are several causes, including:

• Reduced PTH secretion (hypoparathyroidism);
• Vitamin D deficiency, which reduces calcium absorption in the gut;
• Calcium malabsorption syndromes;
• Medications, including denosumab and bisphosphonates (both common treatments for osteoporosis), and etelcalcetide and cinacalcet (both hyperparathyroidism treatments).

Many patients who have hypocalcaemia stay asymptomatic, but more-severe cases are associated with muscle cramps, muscle twitching/spasms, arrhythmias, tiredness, confusion, memory loss and depression. Treatments include oral calcium carbonate or calcium citrate and, if necessary (in cases of severe hypocalcaemia), intravenous (IV) calcium gluconate or calcium chloride. Vitamin D supplements may also be recommended to enhance gut calcium absorption (Tinawi, 2021a).

Hypercalcaemia

Elevated blood calcium (hypercalcaemia) is diagnosed if blood calcium concentrations rise above the normal range (that is, >2.6mmol/L). As with hypocalcaemia, there are multiple causes, including:

• Primary hyperparathyroidism, in which too much PTH is produced, commonly as a result of a tumour in the parathyroid glands;
• Paget’s disease (a condition associated with excessive bone breakdown);
• Immobility, which encourages bone loss;
• Certain medications, such as diuretics, lithium (which is commonly used to treat bipolar disorder) and theophylline (an asthma medication).

Early signs and symptoms include weakness, fatigue, drowsiness and anxiety, commonly progressing to nausea, vomiting, abdominal pain, constipation and polyuria (increased urination). There is also an increased risk of kidney stones (renal calculi) forming. Other manifestations include shortened QT interval (on an electrocardiogram), bone pain, headache, hypertension and, more rarely, stupor and coma.

Treatment is usually initially with isotonic saline and, if necessary, calcitonin and bisphosphonates (which inhibit the release of further calcium from the skeleton) (Tinawi, 2021a).

Phosphorus/phosphate

Phosphorus is the second most abundant mineral; the average human body contains ~700g of phosphorus. The vast majority of phosphorus is found associated with oxygen in the form of phosphate (PO4). This accounts for ~1% of total body weight, with approximately 85% of the total phosphate located in the skeleton (Tinawi, 2021b).

Phosphorus has multiple functions in the human body. In the form of phosphate, it forms a major component of the mineral matrix of bone (Fig 2). Human bone consists predominantly of organic collagen fibres and inorganic crystals of calcium phosphate (hydroxyapetite).

Adequate levels of phosphorus are also needed for the formation of:

• Phospholipids, which make up the phospholipid bilayer of cell membranes;
• The energy storage and signalling molecules, adenosine diphosphate, adenosine triphosphate and cyclic adenosine monophosphate.

Additionally, phosphate is essential for the formation of nucleotides, which form the building blocks of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) molecules (Du et al, 2021).

Phosphate forms the ‘backbone’ of DNA and RNA molecules and is essential to maintaining their structural integrity (Fig 2). Phosphate molecules also act as essential pH buffers in the blood and other bodily fluids contributing to effective acid–base balance (Tinawi, 2021b).

Phosphate homeostasis

There is some variation in the normal plasma phosphate levels quoted in the literature, but values of 0.70-1.50mmol/L are typical of those cited (as in Van der Vaart et al (2022)). The homeostatic control of phosphate is complex, primarily involving PTH, fibroblast growth factor 23 (FGF23) and vitamin D.

In addition to its role in calcium homeostasis, PTH increases the release of phosphate from the mineral stores in bone, while simultaneously enhancing the elimination of phosphate in the urine. Similarly, FGF23 also enhances renal elimination of phosphate; together PTH and FGF23 collectively reduce plasma phosphate concentrations. Conversely, vitamin D acts antagonistically to PTH and FGF23, increasing the plasma phosphate concentration by enhancing phosphate absorption in the gut (Brown and Razzaque, 2018).

Hypophosphataemia

Hypophosphataemia occurs when phosphate levels fall below the normal range. It is most often associated with alcoholism and malnutrition. Other causes include:

• Vitamin D deficiency;
• Bariatric surgery (such as the removal of a portion of the stomach to enhance weight loss or as a result of diseases such as stomach cancer);
• Malabsorption disorders;
• Hungry bone syndrome (sometimes seen after thyroid or parathyroid surgery, which stops or significantly reduces PTH secretion);

Hypophosphataemia can also occur during continuous renal replacement therapy (a form of slow continuous renal dialysis) and some medications – such as diuretics, acyclovir (a cold sore treatment) and corticosteroids (commonly used to treat chronic inflammatory diseases) – are associated with an increased risk of it.

Mild hypophosphataemia is usually asymptomatic. Symptoms usually appear when hypophosphataemia becomes moderate to severe; these include:

• Haemolysis (bursting of erythrocytes);
• Metabolic encephalopathies (conditions in which metabolic imbalances inflict damage to neural tissue in the brain);
• Seizures;
• Thrombocytopenia (reduced platelets);
• Reduced appetite;
• Myopathy (damage to skeletal muscle structure).

If not treated, hypophosphataemia can become more severe and progress to respiratory depression and respiratory acidosis. Treatment is usually through oral phosphate replacements. If mild hypophosphataemia is present, milk may be sufficient; K-Phos® Neutral tablets may also be used. More-severe cases usually require slow IV phosphate solutions (Tinawi, 2021b).

Hyperphosphataemia

Hyperphosphataemia occurs when the plasma phosphate concentration rises above the normal range. It is most commonly seen in patients with compromised renal function.

Even when there are high dietary levels of phosphate, hyperphosphataemia rarely develops because the kidneys are so effective at eliminating excess phosphate. Other causes include:

• Rhabdomyolysis, a condition in which muscle tissue breaks down, releasing its intracellular components (including phosphate) into the blood;
• Vitamin D toxicity (in which excess phosphate can be absorbed from food in the gut).

Patients with hyperphosphataemia are often asymptomatic, but some may develop itching (pruritus). In the long term, hyperphosphataemia can lead to blood vessel calcifications and calciphylaxis (a condition in which calcium accumulates in the small blood vessels of the skin and fat tissues). Severe hyperphosphataemia may indirectly trigger hypocalcaemia by causing significant calcium phosphate precipitation in soft tissues; this reduction in calcium can potentially lead to arrhythmias, muscle cramps and seizures.

Treatment usually initially aims to address any underlying cause, such as vitamin D toxicity or rhabdomyolysis. Other treatments include IV dextrose and insulin to move excess phosphate into cells, as well as drugs that promote renal phosphate elimination, such as acetazolamide (a diuretic). Renal dialysis may also be used if necessary (Tinawi, 2021b).

Sulphur

Sulphur is the third most abundant mineral in the human body. Currently, there is no UK RDA for sulphur as most of it is obtained indirectly from amino acids derived from dietary protein. Two amino acids – cysteine and methionine – are rich in sulphur. Methionine is an essential amino acid; it cannot be synthesised by humans and, therefore, must be obtained through diet.

Other dietary sources of sulphur include taurine (derived from cysteine), which is found in many types of meat, and glutathione, which is an antioxidant found in fruits and vegetables. As many foods are rich in sulphur (Table 1), adequate amounts are usually acquired through a balanced diet. However, it has been suggested that modern agricultural techniques have led to a decline in the sulphur content of some foods (Hewlings and Kalman, 2019).

As sulphur is associated with amino acids, most sulphur in humans resides in the proteins that are used to build organs and tissues. Sulphur provides stability to proteins, primarily through the formation of disulphide bridges, which stabilise protein structure. Sulphur is vital to structure keratin, where it strengthens, hardens and helps maintain structure in the epidermis (outer layer of skin), hair and nails (Kovacs et al, 2015).

Sulphur also has many other roles, including:

• Maintaining the integrity of tendons, ligaments and cartilage;
• Insulin biosynthesis;
• Acting as an antioxidant to protect against free radicals;
• Participating in detoxification reactions in the liver (Hewlings and Kalman, 2019).

Sodium

Sodium has multiple roles in the body. Together with potassium, it is essential for the generation of nerve impulses (action potentials) in neurons and other electrochemical tissues. Sodium also plays a key role in helping to maintain osmotic balance in the body. Most cells have a sodium/potassium pump, which pumps potassium into cells and sodium out of them. As a result of this, most of the sodium in the body is found outside of cells and the normal plasma sodium concentration is relatively high at 135-145mmol/L (Knight et al, 2020).

Sodium homeostasis

Plasma sodium concentration is primarily regulated by the steroid hormone aldosterone (Fig 3), which is produced by the adrenal cortex (Knight et al, 2020).

Hyponatraemia

When sodium levels fall below their normal plasma concentrations (that is, <135mmol/L) this leads to hyponatraemia. This triggers the release of aldosterone, which stimulates the kidneys to retain sodium in the blood to help restore levels (Andrade et al, 2021).

Hyponatraemia is often associated with the use of diuretic medications, which can flush out electrolytes; other causes include adrenal insufficiency (in which insufficient aldosterone is released), hypovolaemia caused by vomiting and diarrhoea (flushing of electrolytes) and heart failure.

Symptoms are not always obvious but, where they are present, they may include nausea, vomiting, fatigue, tissue oedema and ascites (accumulation of excess fluid in the abdominal cavity).

Treatments typically include IV salines. Isotonic or hypertonic salines may be used to restore sodium levels, depending on severity. If blood volume is normal, fluid restriction may also be used to help concentrate sodium in the plasma (Hoorn and Zietse, 2017).

Dilutional hyponatraemia is most often caused by excess water consumption and is also commonly known as water intoxication. This is considered a medical emergency as water can rapidly enter the body’s cells by osmosis, leading to organ swelling. As the brain is encased in the bones of the cranial vault, swelling of the brain raises the intracranial pressure. This results in a severe headache, confusion and eventually loss of consciousness, coma and, potentially, death.

Treatments involve carefully normalising the blood electrolyte concentration using saline boluses; aggressive therapies for dilutional hyponatraemia are avoided as they can lead to devastating osmotic demyelination syndrome, in which the insulatory myelin sheaths of nerve cells (neurons) are damaged (Peechakara and Gupta, 2023).

Hypernatraemia

Sodium levels rising above their normal range (that is, >145 mmol/L) results in hypernatraemia. In order to normalise the plasma sodium concentration, less aldosterone is released from the adrenal cortex and excess sodium can be eliminated by the kidneys into the urine (Andrade et al, 2021).

Hypernatraemia is most commonly associated with dehydration and hypovolaemia (low blood volume). This can occur in patients displaying persistent vomiting, burn injuries (in which burn blisters burst) and prolonged sweating. Symptoms include lethargy, irritability, increased thirst and, if hypovolaemia is present, postural hypotension and tachycardia.

Treatment involves normalising the blood concentration by increasing fluid intake. This usually involves simply encouraging the patient to drink more water. In severe hypernatraemia, isotonic saline infusions are typically used initially, before the patient can be encouraged to drink water (Sonani et al, 2023).

Potassium

Potassium, like sodium, is vital for the generation of nerve impulses and plays a role in osmotic balance in the body. Due to the activity of the sodium potassium pump, most of the body’s potassium is located inside the cells of the body and, consequently, plasma levels are relatively low at 3.5-5mmol/L (Knight et al, 2020).

Potassium homeostasis

As with sodium, potassium homeostasis is regulated primarily by the hormone aldosterone (Fig 3). In many respects the control mechanism is the opposite of that seen with sodium (Knight et al, 2020).

Hypokalaemia

When potassium levels fall below their normal range (that is, <3.5mmol/L), this is termed hypokalaemia. To normalise the plasma potassium concentration, the release of aldosterone is inhibited and the kidneys reduce elimination of potassium in the urine, ensuring more potassium is retained in the blood (Andrade et al, 2021).

Hypokalaemia occurs most commonly due to a lack of potassium in the diet and through diuretic use. Diuretics are used to treat hypertension and fluid retention in conditions such as heart failure; they function by significantly increasing urine output but, unfortunately, this can lead to potassium loss. This is such an issue that potassium-sparing diuretics (for example, amiloride) have been developed; these allow increased urine output to be induced without significant loss of potassium.

Symptoms of hypokalaemia include muscle weakness that typically begins in the legs and moves upwards through the body, nausea, muscle cramps, vomiting and cardiac arrhythmias. Treatment involves restoring plasma potassium. In mild-to-moderate hypokalaemia, this is usually achieved using oral potassium supplements; severe deficiency needs to be urgently addressed with higher oral doses and IV infusion (Castro and Sharma, 2023).

Hyperkalaemia

Hyperkalaemia is when potassium levels rise above the normal range (that is, >5mmol/L). To maintain homeostasis, aldosterone is secreted from the adrenal cortex and stimulates the kidneys to secrete excess potassium into the urine for elimination; this normalises the blood concentration (Andrade et al, 2021).

Hyperkalaemia can be caused by consuming foods containing excess potassium or supplements; it is also often seen in patients with kidney disease who typically have a reduced ability to eliminate excess potassium. Moderate to severe hyperkalaemia can often occur after extensive cellular damage, such as following a physical injury, which can disrupt the cell membranes and lead to potassium leaking from damaged cells into the blood.

Mild hyperkalaemia is often asymptomatic but, as potassium levels rise, symptoms such as palpitations and muscle weakness may become apparent. Severe hyperkalaemia can be life-threatening as it can disrupt the electrical conductive tissues of the heart; this can lead to dangerous arrhythmias and potentially cardiac arrest.

Treatments include removing excess potassium from the diet. Calcium can be used to help manage any cardiac symptoms; insulin (often given with glucose) and beta2 adrenergic agents (used to treat asthma) help to shift excess extracellular potassium back into cells. Thiazide diuretics may be used as these encourage loss of potassium in the urine (Simon et al, 2023).

Chloride

Chloride is the second most abundant ion (electrolyte) in the plasma (after sodium). The average body is estimated to have ~85-115g, with the normal plasma range maintained at 97-107mmol/L (Turck et al, 2019). Most chloride is obtained in the form of sodium chloride (table salt), which is common in many foods. Chloride plays a role in acid–base balance, fluid–osmotic balance, renal function, blood-pressure control and normal muscle function, and is needed to generate hydrochloric acid in the stomach (Astapenko et al, 2020).

Chloride is vital for the efficient transport of carbon dioxide (CO2) in the blood. Most CO2 is transported in plasma in the form of bicarbonate ions (HCO3-). CO2 is continually produced by tissues as a waste product of cellular respiration; this rapidly diffuses into erythrocytes (red blood cells) across their cell membranes.

Erythrocytes contain an enzyme called carbonic anhydrase, which combines CO2 with H2O (water) to produce carbonic acid (H2CO3). This molecule is unstable and rapidly dissociates (breaks down) into HCO3- and hydrogen ions (H+). HCO3- quickly diffuses out of the erythrocyte into the plasma for transport to the lungs. However, as each bicarbonate ion has a negative electrical charge associated with it, the movement of bicarbonate into the plasma leaves the erythrocyte with a positive electrical charge. To restore electrical neutrality to the erythrocyte, chloride ions (Cl-) diffuse in from the plasma; this movement of chloride ions is referred to as “the chloride shift” (VanPutte et al, 2017).

Chloride enters cells through dedicated chloride transporter proteins; mutations that result in chloride channel abnormalities are associated with several diseases, including cystic fibrosis, chronic pancreatitis and cataracts (Astapenko et al, 2020).

Chloride homeostasis

The kidneys play the major role in regulating the plasma concentration of chloride by excreting excess chloride when plasma levels rise above normal, and increasing chloride reabsorption into the blood when chloride levels fall. Aldosterone, which primarily regulates the plasma sodium and potassium concentrations, can influence chloride levels by promoting reabsorption of chloride in the kidney (Scott et al, 2023).

Hypochloraemia

Low blood chloride is referred to as hypochloraemia and is commonly caused by vomiting, which results in significant chloride loss from purged hydrochloric acid. It can also be caused by:

• Dilution of the blood through excessive consumption of hypotonic fluids, such as water;
• Inadequate chloride reabsorption by the kidneys – as as example, this may be due to renal disease or use of loop diuretics, such as thiazides and acetazolamide, which cause chloride loss (Astapenko et al 2020; Pfortmueller et al, 2018).

Symptoms are diverse and include the potential for developing metabolic alkalosis (in which the pH of the blood rises), apathy, confusion, cardiac arrhythmias and increased muscle irritability (Astapenko et al, 2020).

The usual treatment of hypochloraemia is isotonic 0.9% NaCl saline, which can be given intravenously to normalise chloride levels (Lobo and Awad, 2014). It is important to treat hypochloraemia effectively as persistently low chloride levels have been shown to be associated with adverse outcomes and increased mortality in patients with hypertension, heart failure, sepsis and chronic kidney disease (Nozaki et al, 2023; Valga, et al 2023).

Hyperchloraemia

Elevated blood chloride is termed hyperchloraemia. It is often seen after the ingestion of sea water, excessive use of saline solutions, renal disease, watery diarrhoea (in which large volumes of water are lost, leading to dehydration), fevers (in which much water can be lost from sweating) and in people with very high dietary salt intakes (Nagami, 2016).

Symptoms include fluid retention, decreased levels of consciousness, muscle weakness, muscle spasms/twitching and laboured breathing (Sharma, 2016). Treatment involves restoring normal chloride concentrations, mainly through increased fluid intake. Patients are encouraged to increase water intake, and IV fluids and diuretics may be used to help flush out excess chloride. Medications to treat underlying causes, such as vomiting and diarrhoea, may also be prescribed (Sharma, 2016).

Conclusion

In this article, we have outlined the physiological roles of the macrominerals calcium, phosphate, sulphur, sodium, potassium and chloride.