Gitelman Syndrome: What the Clinician Needs to know

Abstract

Gitelman syndrome has a prevalence of 1-10/40,000, representing the most common inherited disease of renal tubules. It is due to inactivating mutations of the SLC12A3 gene that encodes the thiazide-sensitive Sodium Chloride Cotransporter (NCC) located in the apical membrane of the distal convoluted tubules, resulting in hypokalemic metabolic alkalosis associated with hypomagnesemia and hypocalciuria. Although it is generally considered a benign tubular disease, a number of complications have been observed in some patients. Increased sodium intake along with a diet rich in potassium and magnesium is essential, but a number of patients requires intravenous potassium or magnesium infusion. In certain patients, amiloride, spironolactone, eplerenone, or renin angiotensin system blockers can be administered.

Keywords

Gitelman syndrome, Potassium, Hypokalemia, Metabolic alkalosis, Hypomagnesemia, Hypocalciuria

Gitelman syndrome is the most common autosomal recessive inherited disease of renal tubules with a prevalence of 1-10/40,000. It is characterized by hypokalemic metabolic alkalosis associated with hypomagnesemia and hypocalciuria [1-4]. The disease is due to inactivating mutations of the SLC12A3 gene that encodes the thiazide-sensitive Sodium Chloride Cotransporter (NCC) located in the apical membrane of the distal convoluted tubules [5-7]. Less often, the condition results from mutations in the CLCNKB gene encoding the chloride channel ClC-Kb, the cause of classic Bartter syndrome [1]. The detection of biallelic inactivating SLC12A3 mutations (currently used methods have high sensitivity and specificity) is crucial for the diagnosis of Gitelman syndrome, but in patients who do not have two mutations in SLC12A3 the clinical sensitivity (proportion of positive tests if the disease is present) is 65% to 80%. Available next generation sequencing gene panels should at least include the SLC12A3, CLCNKB, and HNF1B genes [1]. Certain founder mutations are observed in populations such as European Gypsies and genetic testing can establish the diagnosis [8-10]. It should be mentioned that there is weak association between genotype and clinical phenotype in Gitelman syndrome.

Gitelman syndrome is usually detected during adolescence or adulthood in patients with symptoms related to the coexisting electrolyte abnormalities (Table 1) [1,11]. Most of these clinical findings are related to chronic hypokalemia and hypomagnesemia which can be identified in serum chemistry and can help in the diagnosis of the syndrome (Table 2) [1,12,13]. It should be mentioned that even though it was initially regarded as a benign tubular disease, a number of complications have been observed in some patients with Gitelman syndrome (Table 3) [1,14-23].

Gitelman syndrome should be differentiated from acquired causes of hypokalemic nonperiodic paralysis, tubulopathies due to diuretic abuse, bulimia nervosa or chronic vomiting, autoimmune disorders and drugs, from genetic disorders such as Bartter syndrome as well as diseases arisen from mutations in the KCNJ10 and HNF1β genes (Table 4) [24-31].

Increased sodium intake along with a diet rich in potassium and magnesium is essential for patients’ management. Additionally, oral potassium and magnesium supplementation is needed in most patients aiming at increasing serum potassium and magnesium levels (> 3 mmol/l and 0.6 mmol/l, respectively) [1,32-34].The dose of these supplements should be carefully individualized to avoid their side effects. In severe electrolyte imbalances, intravenous potassium or magnesium infusion is indicated. In some patients with persistent hypokalemia, potassium sparing diuretics, such as amiloride, spironolactone or eplerenone can be administered [35-37]. Other drugs, such as renin angiotensin system blockers or nonsteroidal anti-inflammatory agents have been used in case reports [36,38,39]. Chronic hypokalemia-induced interstitial nephropathy increases the risk of chronic renal failure that requires clinical and laboratory monitoring. Finally, special care is indicated in pregnant women with Gitelman syndrome as well as in patients undergoing anesthesia because in these populations electrolyte derangements increase complications risk [40,41]. The family character of the affection should lead clinicians to also test family members of patients with Gitelman syndrome (Table 5).

Conflict of Interest

This review was written independently. Professor MS Elisaf reports personal fees from ASTRA ZENECA, grants and personal fees from MSD, personal fees from PFIZER, ABBOTT, SANOFI, BOEHRINGER INGELHEIM, ELI LILLY, GSK. The authors have given talks and attended conferences sponsored by various pharmaceutical companies, including Bristol-Myers Squibb, Pfizer, Lilly, Abbott, Amgen, AstraZeneca, Novartis, Vianex, Teva and MSD.

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