Inherited tubulopathies: Viva

Branch 1: The diagnosis and its segmental basis

The candidate should recognise this as Gitelman syndrome. The combination of a hypokalaemic metabolic alkalosis, a normal or low blood pressure, salt craving, muscle cramps and a low serum magnesium points to an inherited salt-losing tubulopathy of the distal convoluted tubule. The hypomagnesaemia is the key discriminator from Bartter syndrome, and the candidate should state that Gitelman is caused by loss-of-function mutations in SLC12A3, which encodes the thiazide-sensitive sodium chloride cotransporter NCC on the apical membrane of the distal convoluted tubule. The inheritance is autosomal recessive. [1]

If the examiner asks which investigations would confirm the diagnosis, the candidate should propose measuring the renin and aldosterone, which are both raised in Gitelman from the secondary hyperaldosteronism, and the urine calcium-to-creatinine ratio, which is low in Gitelman. The candidate should then arrange genetic testing with a tubulopathy panel covering SLC12A3 and the Bartter genes to settle any overlap. The low urine calcium and the low serum magnesium together, with a high renin and aldosterone and a normal or low blood pressure, are almost pathognomonic before the genetics return. [2]

If pressed on the differential, the candidate should distinguish Gitelman from Bartter syndrome, which presents earlier and with hypercalciuria and nephrocalcinosis, and from Liddle syndrome, which presents with hypertension and suppressed renin and aldosterone. The candidate should mention diuretic abuse as a mimic that requires a urine diuretic screen, and chronic vomiting, which produces a hypochloraemic alkalosis but with a low rather than high urine chloride. [5]

Branch 2: The renin, aldosterone and blood pressure algorithm

If the examiner broadens to the wider algorithm, the candidate should state that a hypokalaemic metabolic alkalosis is sorted first by the blood pressure and then by the renin and aldosterone. A high blood pressure points to Liddle, confirmed by suppressed renin and aldosterone. A high aldosterone with a suppressed renin points to primary hyperaldosteronism. A normal or low blood pressure with high renin and aldosterone points to a salt-losing state, Bartter or Gitelman. [5]

The candidate should explain the mechanism in Liddle. A gain-of-function mutation in SCNN1B or SCNN1G deletes the PY motif that targets the epithelial sodium channel ENaC for degradation, so ENaC accumulates on the apical membrane of the principal cell and reabsorbs sodium constitutively. The extracellular volume expands, potassium and hydrogen are secreted, and the resulting volume expansion suppresses both renin and aldosterone. This is why Liddle produces the same biochemistry as the salt-losing states but through a sodium-retaining mechanism and without raising aldosterone. [4]

The candidate should then split Bartter from Gitelman within the salt-losing group using the urine calcium and the serum magnesium. Bartter runs hypercalciuria because the thick ascending limb is the main site of calcium reabsorption and it has failed, and the magnesium is normal or only mildly low. Gitelman runs hypocalciuria and a characteristically low magnesium. The candidate should note the one exception, that classic Bartter from CLCNKB can mimic Gitelman and may need a gene test. [2]

Branch 3: Management and long-term care

If asked how to manage this girl, the candidate should present oral magnesium as the cornerstone, because the hypomagnesaemia drives much of her symptom burden. Oral magnesium is given as the chloride, lactate or aspartate salt in divided doses to reduce diarrhoea, titrated to the serum magnesium and the symptoms. Potassium chloride is added, and a potassium-sparing diuretic such as amiloride or eplerenone reduces the potassium and magnesium wasting. A liberal salt intake supports the intravascular volume. [1]

The candidate should state which drugs to avoid. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be avoided in Gitelman, because they can precipitate significant hypotension in the salt-losing state. The candidate should contrast this with Liddle, where amiloride is the definitive therapy and spironolactone and eplerenone are ineffective because aldosterone is already suppressed. [4]

If asked about surveillance and prognosis, the candidate should outline monitoring of the serum magnesium and potassium, the electrocardiogram for a prolonged QT interval, growth, and the small but real risk of ventricular arrhythmia from the combined hypokalaemia and hypomagnesaemia. Gitelman is compatible with a normal lifespan but a considerable symptom burden. The candidate should also address the family, because the autosomal recessive inheritance carries a recurrence risk, and genetic counselling and cascade testing of siblings are part of the plan. Adherence to the oral magnesium is the main determinant of quality of life, and it is most often lost in adolescence. [2]