Understanding Electrolytes

Introduction

Electrolytes are substances that have a natural positive or negative electrical charge when dissolved in water. Since around 60% of body weight of an adult is water, electrolytes are present all over the body, both intracellularly and extracellularly. Examples of electrolytes are sodium, potassium, calcium, magnesium, phosphate, chloride and bicarbonate (“the electrolyte panel”). They are unevenly distributed in the body fluids compartments, separated by semi-permeable membranes (Fig.1). It is difficult to measure intracellular electrolytes, but measurement of serum electrolytes is an important investigation that is often part of a routine blood screening or a comprehensive metabolic panel.

Fig.1- Distribution of electrolytes in body fluids compartments ( Source- Fluid/electrolyte balance. Austin Community College )

Functions of electrolytes

Electrolytes help to regulate chemical reactions, maintain fluid balance and also have specific functions such as conduction of electrical impulses along cell membranes in neurons and muscles; stabilizing enzyme structures, and releasing hormones from endocrine glands. The ions in plasma also contribute to the osmotic balance that controls the movement of water between cells and their environment. Imbalances of these ions can result in various problems in the body, and their concentrations are tightly regulated. Aldosterone and angiotensin II control the exchange of sodium and potassium between the renal filtrate and the renal collecting tubule. Calcium and phosphate are regulated by PTH, calcitriol, and calcitonin.1.

Functions of sodium and potassium

Sodium is sometimes referred to as the “salt of life” because severe losses can be life-threatening. It is the principal cation in the extracellular fluid and its main functions are related to blood volume maintenance, water balance and cell membrane potential;

Sodium contributes to 90% of plasma osmolality (280+ 5 mOsm/kg) as can be seen in the formula:

Potassium is the major intracellular cation and is important in repolarization of cell membrane. The restoration of resting membrane potential is crucial for keeping cells ready to respond to excitation. Irregularities in membrane stability can cause abnormalities in heart contraction and muscle contractility.

Functions of calcium and phosphate

Calcium is the major structural element in the vertebrate skeleton, existing as calcium phosphate Ca5 ( PO4 ) 3(OH) orhydroxy apatite in bone and teeth. Ionized calcium is essential for excitation-contraction coupling, generation of action potential in the heart, blood coagulation, and regulation of excitability in nerve. It also plays a role in regulation of release of some hormones.

Phosphate is important for bone and teeth formation, structure of DNA, RNA, ATP and takes part as co-enzymes in metabolism.

Functions of magnesium²

Magnesium is a cofactor in more than 300 enzyme systems that regulate diverse biochemical reactions in the body, including protein synthesis, muscle and nerve function, blood glucose control, and blood pressure regulation. Magnesium is required for energy production, oxidative phosphorylation, and glycolysis. It contributes to the structural development of bone and is required for the synthesis of DNA, RNA, and the antioxidant glutathione. Magnesium also plays a role in the active transport of calcium and potassium ions across cell membranes, a process that is important to nerve impulse conduction, muscle contraction, and normal heart rhythm

Functions of chloride and bicarbonate

Chloride is the second most abundant electrolyte in serum, with a key role in the regulation of body fluids, electrolyte balance, the preservation of electrical neutrality, acid-base status. It is also required for formation of gastric HCl. The main source of chloride is from dietary salt.

Bicarbonate is responsible for keeping the plasma pH alkaline ensuring optimal functioning of cells and enzyme systems.

Regulation of electrolytes

Sodium homeostasis

The physiological need for sodium in acclimatized adults is about 165-230 mg sodium per day. The human species evolved in the warm climate of Africa, a salt-poor continent, on a low-salt diet (as low as 50 mg sodium per day).³ but as civilization evolved, sodium intake has increased beyond their physiological needs so depletion of body sodium in healthy individuals is very unlikely although some pathological conditions could cause hyponatraemia. Incidentally, arterial blood pressure is not seen to rise with age in cultures with low salt intake ⁴. Animals go to salt licks when sodium-deprived; humans also have neural mechanisms that regulate salt appetite5 so that sodium deficiency is rare under physiological conditions.

More than 95% of ingested salt is absorbed by the gut and the kidneys reabsorb most of the filtered sodium, adjusted to the body’s needs. Aldosterone and angiotensin II are salt-retaining hormones and atrial natriuretic peptide (ANP) , produced by the atria with ECF volume expansion, inhibits sodium reabsorption. Large amounts may also be lost in sweat, unrelated to body fluids volume homeostasis but catered to loss of excess heat.

Sodium regulation is so precise that serum sodium level is not influenced by dietary intake. Healthy kidneys can excrete excess sodium ingested within the next 24 hours . Hyponatraemia does not ensue even on zero intake of sodium.

Potassium homeostasis

It has been recommended that 3,500- 4,700 mg of potassium is ingested per day. However, potassium intake is low in most cultures and very few people around the world get enough potassium6. Potassium from food and drink is readily absorbed and potassium in the ECF equilibrates with that in the cells and the bones. It is kept mainly in the cells, and potassium that leaves the cell during the action potential is pumped back into the cells by the ubiquitous 2K/3Na pump. In acidosis, hydrogen ions enter the cells, displacing potassium, resulting in hyperkalaemia. Insulin favours potassium influx and may be life-saving in severe hyperkalaemia as in strenuous exercise when cells break down, releasing potassium into the blood. In the kidneys, filtered potassium is reabsorbed in the proximal convoluted tubules (urinary potassium is flow-dependent and excretion is reduced at night i.e. there is a diurnal variation). In the distal tubules, potassium is secreted in exchange for sodium reabsorption under the influence of aldosterone. In thethick ascending limb of the loop of Henle, potassium is reabsorbed together with sodium and chloride through the1K/1 Na/ 2 Cl pump which is inhibited by loop diuretics.

Calcium &phosphate homeostasis

Calcium has an inverse relationship to phosphorus. As levels of phosphorus in the blood rise, levels of calcium in the blood fall because phosphorus binds to calcium reducing the available free calcium in the blood. Thus, the (Ca x PO₄) product is kept constant under normal conditions.

Calcium homeostasis is controlled by bidirectional calcium fluxesoccurring at the levels of intestine, bone and kidney, controlled by parathormone (PTH), calcitonin, and calcitriol ( or 1,25 dihydroxycholecalciferol, a vitamin D metabolite.). The ionized form is the physiologically active form. Hypercalcemia is defined as an ionized Ca⁺ concentration greater than 2.7 mEq/L or a total serum Ca+ concentration greater than 10.5 mg/dl.

PTH is released from the parathyroid glands when serum calcium falls. It raises serum calcium level by (1) stimulating osteoclast activity, and conversion of osteoblasts into osteoclasts (2) increasing reabsorption of filtered calcium and inhibiting phosphate reabsorption in the proximal convoluted tubules (phosphaturic action) (3) stimulating 1-alpha hydroxylase enzyme essential for conversion of the less active calcidiol into the active form calcitriol in the kidney. Calcitriol increases calcium reabsorption in the distal tubules via calbindin D. It also increases calcium absorption in the small intestines. Hypercalcaemia stimulates release of calcitonin from the thyroid. It reduces serum calcium level by inhibiting osteoclast activity and inhibition of PTH action on the kidney.

Fig.2- Hormonal Control of Calcium and Phosphate Metabolism and the Physiology of bone ( Source- Review of Medical Physiology.WF Ganong)

Fig.3- Physiologyof calcium homeostasis – Actions of parathormone PTH
( Source- Review of Medical Physiology.WF Ganong)

Magnesium homeostasis²

An adult body contains approximately 25 g magnesium, with 50% to 60% present in the bones and most of the rest in soft tissues. Less than 1% of total magnesium is in blood serum, and these levels are kept under tight control. Normal serum magnesium concentrations range between 0.75 and 0.95 millimoles (mmol)/L Hypomagnesaemia is defined as a serum magnesium level less than 0.75 mmol/L . Magnesium homeostasis is largely controlled by the kidney, which typically excretes about 120 mg magnesium into the urine each day. Urinary excretion is reduced when magnesium status is low

Chloride & bicarbonate homeostasis

Bicarbonate, together with H⁺ , is a product of dissociation of H₂CO₃ formed from hydration of carbon dioxide. Seventy percent of CO2 is carried from tissues to the lungs as bicarbonate. Bicarbonate and chloride levels have a reciprocal relationship, with exchange of the two occurring across cell membranes (“chloride shift” or “Hamburger phenomenon” in red blood cells and “reverse chloride shift” in alveoli). Chloride follows sodium into the ECF, maintaining electroneutrality.

The “ aniongap” is calculated as (Na+ + K+) – (Cl- + HCO3-) , Na ⁺ + K⁺ is more than the bicarbonate + chloride and this gap refers to the unmeasured anions like keto acids produced in acidosis.

Causes of electrolyte disturbances⁷

The most common electrolytes imbalances are hypo- and hypernatraemia, hypo- and hyperkalaemia Altered levels may be merely reflecting water imbalance, haemodilution causing low levels and haemoconcentration causing raised levels. True imbalances can occur with body fluids disturbances seen in diarrhoea and kidney disease or due to endocrine disorders. Bicarbonate level is altered in acid-base imbalance. Electrolyte disturbances can present with a wide range of symptoms including irregular heartbeat, confusion, fatigue, light- headedness, blood pressure changes, muscle weakness or twitching, numbness and seizures.

There are many causes of an electrolyte imbalance, including:

• Loss of body fluids from vomiting, diarrhoea, sweating or high fever
• Chemotherapy
• Medications such as furosemide (Lasix®)
• Antibiotics, such as AmBisome® and Cancidas®
• Immunosuppressants, such as cyclosporine.
• Poor diet or not getting enough vitamins from food

Endocrine disorders may also cause electrolyte imbalance. Disorders of adrenal cortical function present with symptoms of hypo – or hyperaldosteronism. Sodium and potassium levels are altered in opposite directions because aldosterone retains sodium and favours potassium secretion. (If both are reduced, it is indicative of haemodilution; and both are raised in haemoconcentration). Ingestion of large quantities of liquorice (in candy or chewing on the roots) mimics hyperaldosteronism because liquorice has mineralocorticoid activity. Tumours may release a PTH-like protein, causing hypercalcaemia. Tumours of the parathyroids cause hypercalcaemia. Secondary hyperparathyroidism, resulting from low phosphate of chronic renal disease, causes hypercalcaemia.

Hyponatreamia

Hyponatraemia does not result from low intake of sodium, but results when loss of sodium is more than loss of water (e.g. as in diuretic use, diarrhoea, heart failure, liver disease, renal disease, or when water is retained in excess of the body’s needs e.g. in the syndrome of inappropriate antidiuretic hormone secretion (SIADH). or there is altered distribution of body fluids. Blood volume falls as water leaves the IVF to enter the ISF and thence into the ICF. The volume contraction stimulates ADH release. Symptoms occur when serum sodium falls below 120 mEq/l and seizures can occur at 113 mEq/l. Water shifts into the brain cells, causing headache, apathy, confusion, altered consciousness, seizures, coma⁸.

The cause of hyponatraemia may be identified if the plasma osmolality is also considered. For example, hyponatraemia associated with high plasma osmolality is probably caused by water from the ICF drawn into the ECF by osmotically active substances e.g. glucose. Hyperglycaemia is the most common cause of this type of hyponatraemia. It is estimated that serum sodium falls by 1.6 meq;l for every 100 mg;l rise of blood glucose. Hyponatraemia associated with normal plasma osmolality is called “pseudo hyponatraemia” and is an artifact in measurement caused by hyperlipidaemia and high levels of proteins. Hyponatraemia associated with low plasma osmolality may be hypovolaemic (loss of salt and water), euvolaemic (SIADH, wate intoxication, glucocorticoid deficiency etc) or hypervolaemic (renal isufficiency)..

Hyponatraemia, even when relatively mild, leads to increased morbidity and mortality in diverse clinical scenarios. In particular, hyponatraemia has been shown to increase gait instability, falls, and fracture risk. It now appears likely that at least part of the fracture risk is because of the adverse effects of hyponatraemia on bone density and quality. The mechanisms through which this occurs are not yet completely understood, but prominently involve increased bone osteoclast formation and activity. An additional direct effect of AVP on bone remodelling has also been recently suggested. ⁷

Hypernatraemia

The main cause of hypernatraemia is haemoconcentration caused by loss of water in excess of sodium (burns, sweating, peritoneal dialysis) or inadequate intake of water . The sodium in the blood pulls water out of the cells and acute symptoms of CNS involvement are seen when the serum sodium exceeds 158 mmol/l. These include restlessness, irritability, tremulousness, ataxia, twitching, spasticity, hyperreflexia and may be fatal.

Hypokalaemia

Hypokalaemia is associated with alkalosis, loss through the gastrointestinal tract, primary hyperaldosteronism, excessive use of potassium-losing diuretics, liquorice consumption. Potassium shifts into cells as plasma pH rises, in exchange for H+ efflux. Aldosterone (and liquorice, which has aldosterone-like actions) cause sodium retention and potassium loss from the kidneys.

Clinical features start to appear at levels lower than 2.5 mmol/l, presenting with orthostatic hypotension, dysrhythmias, ECG abnormalities (flat T waves, prominent U waves, S-T depression), muscle weakness, hyporeflexia, cramps, reduced GFR (retention of ammonia leading to encephalopathy), ileus.

Hyoerkalaemia

Serum potassium > 5.5 mmol;l . Causes include oliguric renal failure, potassium-sparing diuretics, NSAIDs, ACE inhibitors (failure to excrete potassium) , potassium released from cells due to tissue breakdown, , haemolysis, Other causes include potassium efflux into ECF due to acidosis, beta blockade, insulin deficiency, digitalis intoxication and increased potassium load from diet, blood transfusion, rhabdomyolysis . False results can be obtained if potassium is not measured promptly in blood samples due to potassium released from breakdown of red blood cells.

Hyperkalaemia affects heart function, presenting as ventricular fibrillation, heart block, asystole. ECG changes are seen (tall T waves, short QT, prolonged PR interval, widening of QRS, flat P). Weakness, areflexia, paraesthesia, nausea & vomiting, diarrhoea are also presentations of hyperkalaemia.

Hypcalcaemia

Hypocalcaemia refers to a condition of serum calcium < 8.5 mg/dl (ionized calcium< 2.0 mg/dl). Causes are shock, sepsis, pancreatitis, renal failure, hypoalbuminaemia, vitamin D deficiency (hypoparathyroidism, hyperphosphataemia), drugs (cimetidine, loop diuretics, cisplatin, aminoglycosides, theophylline, heparin, phenobarbital etc). Neurological presentations are circumoral and digital paraesthesia, tetany, Chvostek/s sign, Trousseau sign, hallucinations, dementia, seizures. Muscle weakness, cramps and spasms may be seen. Dry, scaly skin, coarse brittle hair and hyperpigmentation are also features of hypocalcaemia. The cardiovascular effects include heart failure, vasoconstriction, prolonged QT. Effects on bone are osteodystrophy, rickets, osteomalacia. X-ray findings are similar to those seen in vitamin D deficiency. Transient hypocalcaemia can result from hyperventilation, presenting as alkalotictetany.

Hypophosphataemia and hyperphosphataemia

Phosphate is mainly an intracellular cation. The serum level is 2.5-4.5 mg/dl. Low levels are caused by low intake (alcoholism, malnutrition) or shifts into the cells in alkalosis, hyperparathyroidism, DKA and symptoms appear at levels lower than 1 mg/dl. These are paraesthesias, progressive muscle weakness and tremors, hyperventilation, anorexia.

Serum level >4.5 mg/dl. Causes include increased intake, renal dysfunction, shift out of cells, hypoparathyroidism. Symptoms are similar to renal failure, hypocalcaemia and hypomagnesaemia.

Hypercalcaemia

Serum calcium >10.5 mg/dl (ionized calcium > 2.7 mg/dl). The majority of cases (>90%) are caused by malignancy and endocrinopathies (hyperparathyroidism, phaeochromocytoma, adrenal insufficiency). Drugs like lithium and hydrochlorthiazide and immobilization may cause hypercalcaemia. The clinical presentations are traditionally memorised as “Stones, bones, moans and groans” , referring to renal calculi, osteolysis, psychiatric disorders and abdominal pain (PUD, pancreatitis) .Other presentations are general weakness, malaise, nausea and vomiting, anorexia, weight loss, constipation, polyuria, polydipsia.

Hypo- and hypermagnesaemia

The normal serum magnesium level is 1.5-2.5 mEq/l. Hypomagnesaemia is often associated with hypocalcaemia and hypokalaemia; similarly, hypermagnesaemia coexists with hyperkalaemia and hypercalcaemia.

Hypomagnesaemia can occur due to low intake, redistribution in the body fluids, increased loss in the kidneys (drugs like loop diuretics, aminoglycosides, cisplatin; SIADH, hyperthyroidism, hyperparathyroidism) or extrarenal losses (burns, lactation, sweating, sepsis). The neuromuscular manifestations are muscle weakness, tetany, apathy, paraesthesias, seizures, abnormalities of cerebellar function like ataxia, nystagmus, vertigo). GI symptoms include dysphagia, anorexia, nausea. Cardiovascular effects are seen as heart failure, dysrhythmias, hypotension, ECG changes (prolonged PR and QT,wide QRS, inverted T, depressed ST).

The most common cause of hypermagnesaemia is renal failure. Increased loads of magnesium (laxatives, antacids, untreated DKA, rhabdomyolysis) or increased reabsorption in the kidneys (hypothyroidism, hyperparathyroidism, adrenal insufficiency) are also causes. Nausea, somnolence are the first clinical features, occurring at levels of 2,0 or 3.0 mEq/l. ECG changes are seen around 5 mEq/l (prolonged PR,QT,QRS). Respiration is compromised, with apnoea observed at levels around 8,0mEq/l. Heart block and hypotension can occur at >15 mEq/l.

Hyperchloraemia

Low chloride levels are uncommon, and is due to low intake. A plasma chloride concentration of >110 mg/dl hyperchloraemia. The most common cause of hyperchloraemia is the administration of chloride-rich intravenous fluid, particularly 0.9% saline. It can also be caused by dehydration, severe diarrhoea, ureteric diversion, hyperalimentation. Excessive extracellular Cl− concentration leads to a hyperchloraemic metabolic acidosis (HCMA), with a risk of reduced renal blood flow and injury to the kidney. The anion gap is normal although it is a condition of metabolic acidosis.

High and low bicarbonate

Bicarbonate is a product of dissociation of carbonic acid into hydrogen ions and bicarbonate ions. Carbonic acid is formed by hydration of carbon dioxide, a reaction catalysed in both directions by carbonic anhydrase (CA). CA is abundant in the red blood cells, gastric mucosa, brain and kidney.

Hydrogen and bicarbonate contribute to the pH of body fluids as depicted in the Handerson-Hasselbalchequation:

Bicarbonate binds to added acid and hydrogen ions bind with added anions to minimise pH changes. Thus, bicarbonate level falls in metabolic acidosis and rises in respiratory acidosis (because the lungs cannot get rid of the carbon dioxide resulting from dissociation of carbonic anhydrase formed by HCO3 and H+.A general rule to remember: when pH and bicarbonate go in the same direction, it is metabolic acidosis / alkalosis. If they go in opposite directions, it is respiratory acidosis/alkalosis.

Principles of Management

• Treat the patient; not the laboratory values.
• The rate of correction should mirror the rate of change.
• Correct in orderly fashion
  • Volume
  • pH
  • potassium, calcium, magnesium
  • sodium, chloride .
  • Consider overall impact of interventions

Assessing electrolytes

When assessing electrolytes, it is wise to ascertain whether it is a true alteration or a result of water imbalance (haemodilution and haemoconcentration). This can be gauged from the plasma and urine osmolality. Once it is certain that the alteration is true, work out the cause, to treat accordingly. There are many algorithms available on the net. Samples of sodium imbalance are given here.

Source: GrammatikiM,Rapti, E, Mousiolis A , Kotsa K. .Research Gate 2016

Source: JakubZiegElectrolyte Disorders Research Gate . 2014.

References

1. Chapter Review of Fluid, Electrolyte, and Acid-Base Balance https://www.labxchange.org
2. Magnesium. NIH Fact Sheet https://ods.od.nih.gov/factsheets/Magnesium
   HealthProfessional/
3. Sodium in diet. Medline Plus. https://medlineplus.gov/ency/article/002415.htm
4. Alderman MH. 2000, “Salt, blood pressure, and human heath”.Hypertension.36; 890-898
5. Hurley SW & Johnson AK. 2015. “The biopsychology of salt hunger and sodium
   deficiency”Pflugers Arch. 467(3): 445–456.( Published online 2015 Jan 10.
   doi: 10.1007/s00424-014-1676-y)
6. Raman R. 2020. “How-much-potassium do you need per day?”
   https://www.healthline.com/nutrition/how-much-potassium-per-day
7. https://www.cooperhealth.org/sites/default/files/pdfs/Electrolyte Imbalance.pdf
8. Dang Thanh Tuan. 2010. “Electrolytes disorders”.
   https://www.slideshare.net/dangthanhtuan/electrolytes-disorders
9. Hannon MJ &Verbals JG. 2014. “Sodium homeostasis and bone”.CurrOpinNephrol
   Hypertens 23(4):370-6.

Author information

Hla Yee Yee
MB,BS (Rgn); M.Sc(Mdy); PhD(Lond); FRCP(Edin)(Hon);Cert.in Leadership for Physician Educators ( Harvard Business School)
Honorary Professor, University of Medicine 1, Yangon.