Severe Hyponatremia and Hypocalcemia in Gitelman

Severe Hyponatremia and Hypocalcemia in Gitelman

Syndrome: A Case Report

Introduction

Gitelman syndrome (GS) is a recessive salt-losing tubulopathy due to a mutation of genes encoding the sodium chloride cotransportersand magnesium channels in the thiazide-sensitive segments of the distal convoluted tubule. In this paper we describe a 45-year old lady with GS who presented with severe hyponatremia and hypocalcemia which are very rare complications associated with this syndrome. We are discussing the mechanisms involved in the development of these rare manifestations in this case report.

CASE REPORT

A 45 years old female was admitted to our hospital with altered sensorium since 1 day. There was no H/O fever, headache, vomiting or head injury. She had complaints of generalized weakness, fatigue, bony pains since 6 months as per the patient’s husband. There was no history of diabetes mellitus or hypertension and was not on any drugs. On examination she was pale and the blood pressure was 90/60 mm Hg. She appeared

adequately hydrated on clinical examination and examination of respiratory, cardiovascular and abdomen were unremarkable.EMV was 12 and there was neither any neurological deficit nor proximal muscle weakness. Neck rigidity was absent and the plantars were flexor.

Laboratory investigations showed following results- Serum potassium 2.8mEq/L (Normal range 3.5-5 mEq/L), serum sodium-108.6 mEq (136-145 mEq), serum chloride-83 mEq/L (96-106 mEq), serum bicarbonate 32mEq/L(24-28),serum ionised calcium 0.69 mmol/L(1.1-1.35 mmol/L),serum magnesium-1.18 mg/dl (1.8-2.4 mg/dl), serum urea-38 mg/dl, serum creatinine-1.4 mg/ dl, blood pH-7.48 (7.35-7.45). The urinary calcium was subnormal at 1.2 m mols/24 hour (2.5-7.5 mmols). Urine sodium is 263.2 meq/L(40-220 mmols), urine potassium 22.5 meq/L (25-120 mmols), urine chloride 310.75 meq/L (20-295 meq/L). Urine specific gravity and urine osmolality were normal. Thyroid function tests (T3, T4, TSH) and serum cortisol levels were normal. Ultrasound of the abdomen did not reveal any abnormality.Chest X-ray was normal and electrocardiogram showed U wavesand flattened T waves.

Since the patient had hypokalemia with hightrans-tubular potassium gradient, metabolic alkalosis, normalblood pressure, hypomagnesemia and high urinary chloride a diagnosis of Gitelman Syndrome was made. In additionto the usual electrolyte abnormalities she also had severe hyponatremia and hypocalcemia.

She was treated with parenteral potassium, calcium andmagnesium initially with indomethacin 25 mg twice daily along with spironolactone 50 mg daily. The sodiumlevel improved with fluid restriction and hypertonic saline,and electrolytes showed improvement after 7 days. She wasdischarged with advice to continue oral potassium, calciumand magnesium supplements.She remains symptom free and normokalemic after one month of followup.

DISCUSSION

Antenatal Bartter’s syndrome, classical Bartter’s syndrome and Gitelman’s syndrome are the three phenotypes of Bartter’s syndrome that have now been recognized. Mutations in several renal tubule transport protein have been shown to be responsible for this syndromes. In Gitelman’s syndrome, mutations have been found in the thiazide sensitive Nacl transporter. The reduced sodium reabsorption in the distal convoluted tubule leads to volume depletion and hypokalemia, though not as severe as would result from a lesion in the loop of Henle. Loss of activity of the thiazide sensitive transport increases tubule calcium reabsortion, leading to the classic finding of hypocalciuria in Gitelman’s syndrome.[1] In our patient, diagnosis of Gitelman’s syndrome was based on clinical findings and laboratory investigation findings like hypocalciuria, hypokalemia, hypermagnesuria, low serum sodium, low serum bicarbonate and alkalosis. Although rarely required for diagnosis, renal biopsy reveals hyperplasia of of the juxta glomerular apparatus and prominence of medullary interstitial cells, with variable degrees of interstitial fibrosis.[1]

Patients with Gitelman’s syndrome do not have symptoms throughout infancy and preschool years other than some febrile seizures, a common disturbance in this age group. In some cases Gitelman’s syndrome is found by chance because of measurement of serum electrolytes for other reason.[2] Chronic vomiting may be a differential diagnosis for Gitelman’s syndrome, which can be easily diagnosed by low urine chloride concentration.[1] Our patient also presented with vomiting.

Serum sodium and calcium are usually normal in patients with GS. In this paper we describe a patientwho had the classical features of GS with severe hyponatremia and hypocalcemia.

Rodriguez-Soriano et al[3] were the first to suggest that hypocalciuria may be useful in distinguishing the Gitelman’s syndrome from classic Bartter’s syndrome. It is less certain whether changes in calcium excretion provide insight into the renal tubular pathophysiology of these syndromes. The greater urinary calcium excretion in patients with classic Bartter’s syndrome is consistent with impaired reabsorption in the ascending limb of loop of Henle. Alternatively the hypocalciuria of Gitelman’s syndrome suggests the involvement of the distal convoluted tubule, where reduced chloride absorption is associated with augmented calcium absorption.[4] Our patient also had hypermagnesuria. Our currentunderstanding of tubular function does not easily explain the dissociation between calcium and magnesium excretion in these disorder. The thick ascending limb of loop of Henle is the major site of magnesium reabsorption, where the reabsorption thought to parallel the reabsorption of calcium. Consequently involvement of thick ascending limb would be expected to promote severe magnesium wasting, which is not usually present in classic Bartter’s syndrome. Paradoxically in Gitelman’s syndrome there is more consistent and severe magnesium wasting, which would not be expected from a tubular defect limited to the distal convoluted tubule. These considerations suggest the possibility of an additional tubular defect in the Gitelman’s syndrome that contributes to magnesium wasting.[4]

Hyponatremia was described with GS for the first timeby Schepkenset al in 2001 in two patients[5]. The phenotypeof GS is identical to that with the chronic use of thiazidediuretics[6].Thiazide induced hyponatremia occurs when theintake of free water is greater than the amount the kidneyscan excrete. In subjects with a moderate impairment of freewaterexcretion, a thiazide will cause hyponatremia if fluidintake is excessive. Hyponatremia can even appear in thosewith more serious impairment of free-water excretion withordinary fluid intake. In patients with GS a similar mechanismmay result in hyponatremia which resembles SIADH.

Thus GS patients are prone to developing hyponatremia in amanner similar to that seen with thiazide diuretics. But hyponatremiais unusual in GS patients since they achieve abalance between water intake and free-water excretion undernormal circumstances. Our patient under study had a normal volume status clinically, hypoosmolarhyponatremia, hypouricemiawith an inappropriately high urinary osmolality andsodium, all consistent with SIADH. So the probable causefor hyponatremia in our patient is likely to be as discussedabove.Patients with GS have significant hypomagnesemia.Chronic hypomagnesemia is closely associated with hypocalcemia,which is caused by impaired parathyroid hormone(PTH) secretion or the refractoriness of bone and renal tubulesto PTH. In general, PTH-induced release of calciumfrom bone is substantially impaired when the plasmamagnesium concentration falls below 0.8 mEq/L (1 mg/Dlor 0.4 mmol/L). In comparison, it appears that more severehypomagnesemiaoccurs only when there is diminishedPTH secretion.Pantanetti et al[7] and Nakamura et al[8]describe twopatients with GS in whom hypocalcemia developed due tohypomagnesemia. The combination of two rare complications,namely hyponatremia and hypocalcemia, in our casemakes this a unique case of GS and throws open scope for more study and research.

Potassium and magnesium supplements are needed in Gitelman’s syndrome. The presence or absence of sodium wasting has important therapeutic implications. Increased delivery of sodium to the distal nephron increases potassium excretion. In sodium wasting or in patients supplemented with sodium in the diet, the augmented potassium excretion will require a large quantity of potassium supplementation and potassium sparing diuretics to maintain the plasma potassium level within the normal range. In the absence of sodium wasting, more modest amounts of potassium supplementation with or without potassium sparing diuretics may be required.

REFERENCES

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2.Bettinelli A, Bianchett MG, Girardin E, Caringella A, Cecconi M, Appiani AC, et al. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter’s and Gitelman’s syndrome. J Pediatr 1992;120:38-43.

3.Rodriguez-Soriano J, Vallo A, Garcia- Fuentis M. Hypomagnesemia of hereditory renal origin. PediatrNephrol 1987;1:465-72.

4.Giteman HJ. Hypokalemia, hypomagnesemia and alkalosis: Arose is a rose- or is it? J Pediatr 1992;120:79-80.

5.Schepkens H, Stubbe J,Hoeben H, Vanholder R, LameireN. Severe hyponatraemia and hypouricaemiain Gitelman’s syndrome. Nephrol Dial Transplant.2001;16(11):2250-2252

6.Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, et al. Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na- Clcotransporter. Nat Genet. 1996;12(1):24-30.

7.Pantanetti P, Arnaldi G, Balercia G, Mantero F, GiacchettiG. Severe hypomagnesaemia-induced hypocalcaemia in a patient with Gitelman’s syndrome. ClinEndocrinol (Oxf). 2002;56(3):413-418.

8.Nakamura A, Shimizu C, Nagai S, Taniguchi S, Umetsu M, Atsumi T, et al. A rare case of Gitelman’ssyndrome presenting with hypocalcemia and osteopenia.J Endocrinol Invest. 2005