Introduction

Gitelman syndrome is an autosomal recessive, salt-losing tubulopathy characterised by renal potassium wasting, hypokalaemia, metabolic alkalosis, hypocalciuria, hypomagnesaemia, and the hyperactivity of the renin-angiotensin system, RAAS (hyperreninemic hyperaldosteronism). The majority of patients who suffer from Gitelman syndrome are considered asymptomatic, and clinical symptoms are variable and depend on age, but a few individuals can experience mild to severe symptoms, which include:¹

• Salt craving
• Muscle weakness/fatigue
• Cramps, fainting episodes, paraesthesia
• Growth retardation, pubertal delay, short stature
• Sudden changes in drinking behaviour or thirst
• Abdominal pain
• Dizziness, polyuria, and joint pain
• Cardiac arrhythmias
• Polydipsia

More severe specific symptoms are also present, like rhabdomyolysis, a rare muscle injury, and chondrocalcinosis, a painful type of arthritis where crystals are deposited in the joints.¹

Epidemiology

Gitelman syndrome is a rare disorder; the prevalence ratio is 25 cases for a population of 1,000,000 or 1 in 40,000 people. However, only 1% of the heterozygous white population has Gitelman syndrome, while the prevalence of cases is higher in the Asian population. It was found that most males carry one copy of the defective gene.

Cause of gitelman syndrome

Gitelman syndrome is caused by mutations of genes that normally produce sodium chloride and magnesium carriers in the apical membrane of the distal convoluted tubule of the kidney’s nephron. The mutations involve the SLC12A3 gene, which encodes the thiazide-sensitive sodium chloride (NaCl), and the TRPM6 (cation channels subfamily 6 of the protein claudin 16) gene, which handles the magnesium ion transport. More than 350 mutations affected the SLC12A3 gene in patients who suffer from Gitelman syndrome. Further mutations also affect the CLCNKB gene, which encodes the chloride voltage-gated channel CLC-Kb; they transport ions into and out of cells and regulate the membrane potential and volume of apical membrane cells. All of these channels can cause the downregulation of sodium chloride and magnesium reabsorption, which can lead to the clinical symptoms described above.¹

Physiology of the distal convoluted tubule

The function of the kidney’s nephron is to filter blood by removing waste and reabsorbing substances like glucose. The distal convoluted tubule (DCT) is responsible for 7% to 10% of the tubular reabsorption of electrolytes.² They reabsorb roughly 5%–10% of the sodium, which was filtered out before it arrived at the DCT, mainly done by the NaCl cotransporter (NCC).

Any abnormalities in the distal convoluted tubule can cause changes to the volume of extracellular fluid and the balance between sodium, chloride, and potassium ions. NaCl transporter (NCC) is mediated by epithelial sodium channels (ENaC), as they can turn the lumen of the kidney nephron into a negatively charged area, in turn causing the movement of other ions like chloride back into the blood.³

The DCT reabsorbs about 10% of the magnesium, which is filtered out initially. DCT is the primary site for magnesium reabsorption. Mediated by the TRMP6, which is a voltage-cation channel similar to another cation channel called TRPV5, which reabsorbs calcium instead of magnesium. A receptor called the EGF receptor has been shown to regulate the reabsorption activity of magnesium. The receptor triggers a signalling cascade to stimulate TRMP6.³

The main cell in the DCT in which potassium is absorbed is the alpha-intercalated cell. The main protein channel that is responsible for the majority of the secretion of potassium is the renal outer medullary potassium channel. Magnesium is a regulator of the ROMK channel, blocking the channel pore to prevent K+ from being secreted. The only reason why potassium isn’t lost is that the potassium is recycled by the basolateral K+ channel, acting as a channel for the potassium absorbed by the Na+/K+ ATPase in cells to be excreted back out in the blood.³

Hormones effect on DCT reabsorption

Hormones like aldosterone and angiotensin II can play a major role in regulating the DCT reabsorption of magnesium and sodium chloride. For example, renin is released when the macula densa cells, which monitor the concentrations of sodium chloride, can cause them to release renin, in turn releasing angiotensin II, which can cause the release of aldosterone, allowing for the reabsorption of more sodium chloride when the body lacks it. Furthermore, aldosterone is released when hyperkalaemia occurs, which causes activation of the potassium channel, which causes an increase in potassium secretion. This results in increased ENaC activity, which increases the absorption of sodium.⁴

Pathophysiology of gitelman syndrome

Hypokalemia and metabolic alkalosis

So, Gitelman syndrome begins when the mutation causes the loss of function of the sodium chloride transporter, which results in a decrease in the sodium and chloride reabsorption, so more of the sodium chloride is lost and ends up in the collecting duct of the kidney and leads to an overall reduction in vascular volume activity. This dysregulation causes an unnecessary increase in the secretion of renin and aldosterone, it causes ENaC to increase sodium reabsorption and also increase the number of ROMK channels, which increases the excretion of potassium (K+) and can also increase the excretion of hydrogen (H+) ions. This can cause a lack of potassium ions in the blood (hypokalaemia) and an elevation of pH in the body due to the lack of acidic ions like chloride (metabolic alkalosis). 

Gitelman syndrome also affects the chloride transport in the DCT. Metabolic alkalosis is associated with the clinical symptoms of muscle cramps, tetany, and paresthesias. Muscle weakness can be caused by hypokalaemia as a result of the dysregulation of the channels.⁴

Hypomagnesemia

Additionally, the downregulation of TRPM6 channels in the distal tubules and duodenum results in the affected individuals losing magnesium. Hypomagnesaemia can be problematic because it impairs the function of calcitropic hormones like parathyroid hormone (PTH), which regulate the levels of calcium and phosphate in human bones. So, this downregulation can reduce the skeletal sensitivity to PTH and impair calcium transport in the intestine even when calcium levels are normal. 

Furthermore, hypomagnesemia can reduce pyrophosphatase activity, which functions as a regulator of connective tissue, bone, cartilage, etc. This reduced activity can promote pyrophosphate crystallisation in the joints, which causes the symptoms of joint pains and chondrocalcinosis. Also, a study (1994) has observed that increased aldosterone levels have been linked with increased excretion of magnesium in the urine by downregulating the TRMP6 channel. Moreover, hypokalemia has some link with the development of hypomagnesemia due to magnesium wasting.⁴

Arterial hypertension

The clinical manifestation of arterial hypotension can be explained by the depletion of extracellular volume as the collecting duct accumulates salt and other ions. The water and electrolyte waste can enhance weakness, fatigue, and muscle cramps. Furthermore, electrolyte and water wasting can also lead to the clinical manifestation of polydipsia, which means excessive production of urine. Also, hypokalemia and hypomagnesemia can contribute to the clinical symptoms of cardiac arrhythmia because the lack of potassium and magnesium can prolong the duration of the action potential of cardiac cells. The meaning of action potential is a rapid change in the voltage of the cardiac cell membrane, which allows the heart to contract and pump blood.⁴

Hypocalciuria

Hypocalciuria, which means the lack of calcium in the urine, can be the result of the lack of sodium chloride reabsorption. it was found that both calcium and sodium chloride reabsorption are tightly associated with each other in the DCT. The reduction of the sodium chloride channel can reduce the intracellular sodium levels, which in turn increases calcium excretion across the basolateral membrane via the sodium-calcium exchanger of the DCT. This low level of intracellular calcium can lead to an increase in calcium entry into the DCT cells via the TRPV5.⁴

Hypophosphatemia

Another important ion is wasted due to Gitelman syndrome. One of them is hypophosphatemia, whose mechanism isn’t very clear, but it’s theorised that the increase in aldosterone levels is due to decreased sodium chloride reabsorption or other conditions like hypokalemia and metabolic alkalosis. Furthermore, hypophosphatemia can increase calcium reabsorption and cause hypercalcemia and hypocalciuria.⁴

Summary

In summary, Gitelman syndrome is a genetic disorder in which the mutated genetic trait is autosomal recessive from parent to offspring. The main clinical manifestations are hypokalemia, metabolic alkalosis, and hypomagnesemia. The physical symptoms present would be muscle cramps, cardiac arrhythmias, growth retardation, thirst, etc. The pathophysiology of Gitelman syndrome involves the mutation of the genes that encode the transporter channels, like the thiazide-sensitive sodium chloride channel, which reabsorbs sodium and magnesium, which in turn causes the loss of other ions like calcium, potassium, and phosphate. The loss of magnesium and potassium can cause cardiac arrhythmias and muscle cramps. The loss of sodium can cause salt cravings, and the increase in calcium reabsorption can cause the crystallisation of joints.