Gitelman Syndrome

Article Author:
Malvinder Parmar
Article Author:
Vijayadershan Muppidi
Article Editor:
Khalid Bashir
Updated:
7/17/2020 7:10:02 AM
PubMed Link:
Gitelman Syndrome

Introduction

Gitelman syndrome (GS) is an autosomal recessive, salt-losing tubulopathy characterized by renal potassium wasting, hypokalemia, metabolic alkalosis, hypocalciuria, hypomagnesemia, and hyperreninemic hyperaldosteronism. Gitelman syndrome is also referred to as Gitelman’s syndrome and Familial hypokalemia-hypomagnesemia.

Gitelman syndrome is caused by mutation of genes encoding the sodium chloride cotransporter(NCCT) and magnesium transporters in the thiazide-sensitive segments of the distal convoluted tubule (DCT) of the nephron. [1]

Etiology

GS is an autosomal recessive tubular disorder caused by mutations of some of the genes encoding the sodium, chloride, and magnesium carriers in the apical membrane of the distal convoluted tubule, which is responsible for 7% to 10% of electrolyte tubular absorption. Magnesium channels are also down-regulated in the duodenal cells.

The mutations involve:

  1. SLC12A3 gene which encodes the thiazide-sensitive sodium chloride cotransporter (NCCT).[2]
  2. TRPM6 (cation channels subfamily 6 of the protein Claudin 16) gene handles the distal tubular magnesium transport.[3][4]

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.[5] Though rare, Gitelman syndrome is the most common inherited salt-losing renal tubulopathy. [6]

Pathophysiology

The handling of sodium, chloride, magnesium, calcium, and potassium ions by the kidney is a complex process and depends on the molecular activity of various renal tubular channels. The distal convoluted tubular channels play an important role in handling the ions. Alterations in the activity of these channels result in a variable degree of electrolyte abnormalities. There is also significant phenotypic variability in the affected members of the family with identical genetic defects.[6]

SLC12A3 encodes the NCCT channel in the apical membrane of the first part of the DCT. NCCT helps in the absorption of sodium and chloride ions from the tubular lumen. Mutations in the SLC12A3 gene results in loss of function of NCCT, which in turn, results in increased sodium and chloride delivery to the collecting tubule and volume contraction. This leads to increased renin and aldosterone secretion. Aldosterone, through its effect on the epithelial sodium channels (ENaC) in the collecting tubule, increases sodium reabsorption along with increased excretion of potassium and hydrogen ions. These effects cause hypokalemia and metabolic alkalosis. A minority of Gitelman syndrome patients do not have a mutation in SLC12A3 but have a mutation in the CLCNKB gene that encodes the chloride channel in the basolateral membrane (CLC-kb). [5]

The relationship between calcium and magnesium is definitely complex and still not well defined. TRPM6 magnesium-permeable channels are located at the apical domain of the distal convoluted tubules and brush border of the duodenal magnesium-transporter cells. In Gitelman syndrome, there is a reduced expression of TRPM6 channels. Downregulation of these channels in the distal tubule and duodenum results in urinary and intestinal magnesium wasting leading to hypomagnesemia seen in Gitelman syndrome.[6]

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 calcitropic hormones is shown in calcium pool studies. Compared to thiazide-treated subjects, the Gitelman 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 a lack of parathyroid hyperfunction. In addition, metabolic alkalosis plays a vital role in calcium abnormalities in these patients.[7]

Hypomagnesemia may also result in a reduction of pyrophosphatase activity that could promote pyrophosphate crystallization in joints causing joint pains and chondrocalcinosis.[8]

The increased sodium chloride load in the collecting duct stimulates the aldosterone-driving transcellular sodium across the epithelial sodium channels of the principal cell luminal membrane. This tubular sodium transport generates an electronegative transmembrane voltage that is neutralized either by chloride-transmembrane diffusion 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.[9]

Both the overstimulation of the renin-angiotensin system in response to increased delivery of distal tubular sodium at the macular zone and the stimulation of baroreceptors from hypovolemia may result in polydipsia.[10]

In Gitelman syndrome, there is increased passive reabsorption of calcium in the proximal convoluted tubule, which is likely a reason for hypocalciuria 

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 can be seen in many but not in all cases. The biochemical findings are similar to an individual taking a thiazide diuretic.[11]

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. Also, some cases of chondrocalcinosis and nephrocalcinosis have been reported.[12]

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.[13]

Evaluation

Clinically, most of the patients have an unremarkable physical examination or have subtle clinical findings. Patients have normal or low blood pressure. There could be a bunch of lab findings. The serum potassium is low (hypokalemia). Serum magnesium may be low (hypomagnesemia)or normal. The serum bicarbonate is usually high in keeping with(metabolic alkalosis). Plasma renin and aldosterone are high (hyper-reninemic hyperaldosteronism). The urinary calcium excretion is low (hypocalciuria). [14][15]

The lab 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 chloride excretion in response to thiazide diuretics help distinguish Gitelman syndrome patients who have a blunted chloride fractional excretion.[16]

Laxative abuse is another differential diagnosis to consider in patients with hypokalemia. However, there can be a metabolic acidosis with a urine potassium/creatinine ratio of less than 1.5.[17]

Treatment / Management

Treatment is symptomatic, which 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 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 primary issue.[6]

Magnesium replacement by magnesium sulfate or oxide may result in diarrhea. Magnesium chloride is better tolerated than sulfate or oxide 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.[18][19]

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) as well as 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.[20]

Prognosis is good, except a few patients may be at risk for cardiac arrhythmias.[21]

Differential Diagnosis

The differential diagnosis includes various disorders and salt losing tubulopathies. The important conditions to be considered for differential diagnosis in Gitelman syndrome include Bartters syndrome, Pseudo Bartters-Gitelman's syndrome, surreptitious vomiting, laxative abuse, licorice, Congenital chloride diarrhea. Labs are essential in differentiating the disorders. Both serum and urine electrolytes should be carefully examined.

Pearls and Other Issues

Diuretic abuse and surreptitious vomiting are important conditions to consider in the differential diagnosis of patients presenting with hypokalemia.[22]

The risk of transmitting the disease genetically to offspring is 25%. [23]

Enhancing Healthcare Team Outcomes

Gitelman syndrome is a rare genetic disorder and is best managed by an interprofessional team that includes a nephrologist, cardiologist, internist, and the primary care physician. The treatment is based on symptoms, and most patients require correction of hypokalemia. Both the nurse and pharmacist should educate the patient on compliance with therapy; otherwise, there is a risk of developing arrhythmias. The prognosis for most patients is excellent.[24][25]


References

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