Gitelman Syndrome

Article Author:
Malvinder Parmar
Article Editor:
Khalid Bashir
Updated:
11/10/2018 9:20:21 PM
PubMed Link:
Gitelman Syndrome

Introduction

Gitelman syndrome is an autosomal recessive, salt-losing tubulopathy characterized by renal potassium wasting, hypokalemia, metabolic alkalosis, hypocalciuria, hypomagnesemia, and hyporeninemic hyperaldosteronism. It is caused by mutation of genes encoding sodium chloride (NCCT) and magnesium transporters in the thiazide-sensitive segments of the distal nephron.

Etiology

It is an autosomal recessive tubular disorder caused by mutations of some of the genes encoding the sodium chloride and Mg carriers in the apical membrane of the distal convoluted tubule (NCCT), that is responsible for 7% to 10% of tubular absorption.

The mutations may involve:

  1. SLC12A3 gene that encodes the thiazide-sensitive sodium chloride cotransporter (NCCT)
  2. TRPM6 (cation channels subfamily 6 of the protein Claudin 16) gene promotes the distal tubular magnesium transport

Epidemiology

Gitelman syndrome is a rare disorder, and its prevalence is estimated at 25 cases per one million population. However, the prevalence of heterozygous persons is approximately 1% in the Caucasian population (Knoers NV and Levtchenko EN, Orphanet J Rare Dis 2008).

Pathophysiology

The handling of sodium, chlorine, magnesium, calcium, and potassium ions by the kidney is a complex process and depends on the molecular activity of various distal tubular channels. Alterations in the activity of these channels result in a variable degree of electrolyte abnormalities. There is also a significant phenotypic variability in the affected members of the family with identical genetic defects.

The relationship between calcium and magnesium is complex and still not well defined. The discovery of a mutation of chromosome 9q.21.13 encoding the TRPM6 Mg channels in families with hypomagnesemia and secondary hypocalcemia led to the identification of a defective expression of TRPM6 Mg-permeable channels, localized not only at the apical domain of the distal convoluted tubules but also at the brush border of the duodenal Mg-transporter cells. In Gitelman syndrome, there is a reduced expression of TRPM6 Mg channels, so it is likely that downregulation of these channels both in the distal tubule and duodenum results in urinary and intestinal magnesium wasting leading to hypomagnesemia seen in Gitelman syndrome.

Hypomagnesemia can also impair the function of calcitropic hormones and there is an inverse association between ionized calcium, parathyroid hormone (PTH) and calcitriol. This is down-regulated in these patients and results in reduced skeletal sensitivity to PTH and an impaired intestinal calcium transport despite normal calcitriol levels. This blunted response possibly also explains the lack of hypercalcemic response to hypocalciuria in these patients. The hypomagnesemia induced lower intestinal and skeletal sensitivity to the calciotropic hormones is shown in calcium pool studies. Compared to thiazide-treated subjects, the Gentleman syndrome patients do not show changes in bone mineral content related to hypocalciuria. The normal serum phosphate and fractional excretion of phosphate in these patients suggest lack of parathyroid hyperfunction. In addition, metabolic alkalosis plays an important role in calcium abnormalities in these patients.

Hypomagnesemia may also result in a reduction of pyrophosphatase activity that could promote pyrophosphate crystallization in joints causing joint pains and chondrocalcinosis.

The increased sodium chloride load the collecting duct stimulates the transcellular sodium across epithelial sodium channels of the principal cell luminal membrane. This tubular sodium transport generates an electronegative transmembrane voltage that is neutralized either by chlorine-transmembrane diffuse across the paracellular pathway or by a coupled potassium ion and hydrogen ion cellular secretion, resulting eventually in metabolic alkalosis and hypokalemia. In addition, the low effective extracellular volume activates the renin-angiotensin-aldosterone system and under the effect of aldosterone results in potassium secretion through apical potassium channels.

Both the overstimulation of the renin-angiotensin system in response to increased distal delivery of sodium and the stimulation of baroreceptors from hypovolemia may result in polydipsia.

History and Physical

The clinical manifestations of Gitelman syndrome are highly variable and depend on age at presentation, the severity of symptoms, and biochemical abnormalities. Patients often are asymptomatic and noted to have hypokalemia on routine laboratory testing or may have nonspecific symptoms of fatigue and generalized malaise. Some patients may experience muscle cramps. Many patients have low blood pressure. Tetany and hypokalemic paralysis have been reported, the latter being more common in Asian populations. In addition to hypokalemia, metabolic alkalosis and hypocalciuria are common. Hypomagnesemia is present in many but not all cases. The biochemical findings are similar to an individual taking a thiazide diuretic.

Increased thirst and salt craving were noted in three-fourths of patients. Many patients have a preference for pickle brine, salted cucumbers, oranges, and lemons.

Some patients may have joint pains and cases of chondrocalcinosis and nephrocalcinosis have been reported.

Cardiac arrhythmias are common, palpitations in about 60% of patients, prolonged QTc in about 50%, but sudden death is rare. The classic electrocardiographic manifestations of hypokalemia and hypomagnesemia (U wave greater than 1 mm, ST depression greater than 0.5 mm, flattened T waves) were not observed in patients with Gitelman syndrome.

Evaluation

Clinically, patients have normal or low blood pressure and absence of sodium retention. The serum potassium is low (hypokalemia), serum magnesium may be low or normal. The serum bicarbonate is high in keeping with metabolic alkalosis. Plasma renin and aldosterone are high. The urinary calcium excretion is low (hypocalciuria), and findings may mimic thiazide diuretic use, and a urinary diuretic screen may be helpful in difficult cases in the absence of family history.

Increased urinary sodium and even more of chloride excretion in response to thiazides, may help to identify Gitelman patients who have a blunted chloride fractional excretion.

Laxative abuse is another differential diagnosis to consider in patients with hypokalemia. However, there is metabolic acidosis with urine potassium/creatinine ratio of less than 1.5.

Treatment / Management

Treatment is symptomatic, that is supplementation with potassium and magnesium.

Correction of hypokalemia may require large doses of potassium chloride. It is important to use potassium chloride and not other salts that are linked with poorly absorbable anions such as gluconate or aspartate, as these do not correct hypokalemia and may worsen the associated metabolic alkalosis. The poor gastric tolerability of potassium chloride is often the major issue.

High doses of magnesium sulfate or oxide may cause diarrhea. Magnesium chloride is better tolerated and can be given at a daily dosage of 4 mg/kg to 5 mg/kg per day divided into four to six doses to avoid diarrhea.

If tolerated, consider aldosterone antagonists, potassium-sparing diuretics, like amiloride (5 mg to 10 mg per day) and spironolactone (200 mg to 300 mg per day), inhibitors of the renin-angiotensin system. However, in patients with low blood pressure, these agents may not be well-tolerated and should be administered with caution.

Correction of hypokalemia may require large doses of potassium chloride. It is important to use potassium chloride than other salts that are linked with poorly absorbable anions such as gluconate or aspartate, as these do not correct hypokalemia and may worsen the associated metabolic alkalosis. The poor gastric tolerability of potassium chloride is often the major issue.

Prognosis is good, except a few patients may be at risk for cardiac arrhythmias.

Pearls and Other Issues

Diuretic abuse and surreptitious vomiting are important conditions to consider in the differential diagnosis of sick patients presenting with hypokalemia.

The risk of transmitting the disease to offspring is 25%.