Gitelman's syndrome

Gitelman's syndrome is a primary renal tubular hypokalaemic metabolic alkalosis with hypocalciuria and hypomagnesaemia, a mild variant of Bartter's syndrome.

CASE HISTORY

A man aged 37 had experienced episodes of generalized weakness along with recurrent cramps for the past year. The weakness, which was precipitated by resting after exertion and by a heavy carbohydrate meal, predominantly affected the proximal muscles of all four limbs. Each episode lasted a few hours, and between attacks his only symptoms were polyuria and nocturia. There was no vomiting or diarrhoea and he was not taking any medications. No other family member had a similar illness and there was no history of parental consanguinity.

On examination during an attack the quadriparesis was flaccid and associated with depressed tendon jerks. Muscles of the eyes, face, tongue, pharynx, larynx, diaphragm and sphincters were not involved. Blood pressure was normal. Serum potassium was persistently low even between the attacks—1.7 mmol/L (normal range 3.5-5.0). An excessive loss of potassium, chloride and magnesium was detected in the alkaline urine—potassium 300 mmol/24h (25-125), chloride 650 mmol/24h (110-250), magnesium 56 mmol/24h (2-5). He also had hypomagnesaemia, hypochloraemia and metabolic alkalosis—magnesium 0.5 mmol/L (0.8-1.2), chloride 89 mmol/L (98-106), bicarbonate 33 mmol/L (22-30), blood pH 7.48 (7.35-7.45). The urinary calcium excretion was subnormal at 1.0 mmol/24h (2.5-7.5). Serum calcium was 2.5 mmol/L (2.2-2.6) and sodium 140 mmol/L (136-145). Thyroid function tests (T3, T4, TSH) were normal.

The hypomagnesaemia responded to oral magnesium supplements, but the hypokalaemia persisted despite large doses of oral and parenteral potassium. Oral indomethacin 25 mg 8-hourly was then started empirically and the patient became normokalaemic within 24 hours. He was discharged with advice to continue oral potassium and magnesium supplements along with indomethacin. He remains symptom-free and normokalaemic after four months of follow-up.

COMMENT

Episodic weakness beginning after age 25 is almost never due to primary periodic paralysis¹. Further, a low serum potassium between attacks and absence of a similar family history should raise strong suspicion of a secondary disorder². Thyrotoxicosis can mimic periodic paralysis, especially in Asians, and had to be ruled out here³. Secondary hypokalaemic periodic paralysis with normotension, alkaline urine and metabolic alkalosis is seen in hyperplasia of the juxtaglomerular apparatus with hyperaldosteronism^2,3. Also known as Bartter's syndrome, this condition begins in childhood and presents with short stature, polyuria, polydipsia, and a tendency to dehydration during infancy or before school age. It is associated with polyhydramnios or premature delivery^4,5. Classic Bartter's syndrome is a severe congenital disease that is inevitably recognized before the age of 6 years⁵. Gitelman's syndrome is a milder variant, with more episodes of tetany and a later presentation. It also differs from Bartter's in being associated with hypocalciuria, so these two variants of primary renal tubular hypokalaemic metabolic alkalosis can easily be distinguished by measurement of urinary calcium^4,5. Renal magnesium wasting is seen in all patients with Gitelman's syndrome and in about one-third of those with Bartter's syndrome⁵. The tetany may be attributable to exacerbation of alkalosis and consequent low ionized plasma calcium in the presence of hypomagnesaemia. Usually the underlying condition is obvious, but recurrent episodes of transient weakness can sometimes be difficult to distinguish from primary hypokalaemic periodic paralysis³. The paroxysmal nature of the attacks is unexplained and it is not known whether the ionic shifts during the attacks are the same as in the primary hypokalaemic form. The timing of the attacks may relate to fluctuations in catecholamine levels and associated regulation of sodium potassium ATPase function². Insulin causes movement of potassium into cells which may account for the precipitation of paralysis by large carbohydrate meals.

The laboratory characteristics of classic Bartter's syndrome may be mimicked by treatment with loop diuretics, which bind to and inhibit the luminal sodium-potassium-chloride cotransporter found in the thick ascending limb of loop of Henle. In the case of Gitelman's syndrome the laboratory characteristics resemble those induced by thiazides, which bind to and inhibit the luminal sodium-chloride cotransporter in the distal convoluted tubule⁵. The clinical features of Bartter's syndrome (and possibly also Gitelman's syndrome) are to a large extent caused by raised concentrations of prostaglandins⁶. By direct action and through stimulation of natriuresis, these compounds stimulate renin secretion, thereby promoting potassium wasting. They also have a direct effect on aldosterone biosynthesis. Indomethacin has been used in both syndromes, but especially Bartter's, for the beneficial effects of inhibiting prostaglandin synthesis.