Metabolic Alkalosis and Tubulopathies
On this page
Direct answer
Metabolic alkalosis is a primary rise in serum bicarbonate with a compensatory rise in PaCO2, and it is classified by urine chloride into chloride-responsive and chloride-resistant forms. Vomiting, nasogastric suction and remote diuretic use cause the chloride-responsive kind, with urine chloride below about 20 mmol/L, while primary aldosteronism and the inherited tubulopathies Bartter and Gitelman syndromes cause the resistant form, with urine chloride above that level.
What you must remember
- Chloride-responsive causes: vomiting, nasogastric drainage, past loop or thiazide diuretic use (urine chloride is high while the drug is acting) and post-hypercapnia; urine chloride is typically low.
- Chloride-resistant causes: primary hyperaldosteronism, Cushing syndrome, exogenous mineralocorticoids, liquorice ingestion, and Bartter and Gitelman syndromes, with raised urine chloride.
- Bartter syndrome: a defect in the NKCC2 cotransporter of the thick ascending limb, causing hypokalaemic alkalosis, hypercalciuria, raised renin and aldosterone, and normal or low blood pressure.
- Gitelman syndrome: a defect in the thiazide-sensitive NCC of the distal convoluted tubule, causing hypokalaemia, hypomagnesaemia and hypocalciuria, with normal blood pressure and usually a later presentation.
- Liddle syndrome: gain of function of the epithelial sodium channel gives hypertension with hypokalaemia and suppressed renin and aldosterone, and it responds to amiloride.
- Correction: isotonic saline for the chloride-responsive form, with potassium and magnesium replacement in tubulopathies and aldosterone antagonists for hyperaldosteronism.
- Antenatal Bartter: presents with polyhydramnios and preterm birth.
A vomiting patient and a hypertensive with low potassium
A 35-year-old woman has five days of vomiting, with a pH of 7.52, bicarbonate 34 mmol/L, chloride 84 mmol/L, potassium 2.9 mmol/L and urine chloride 8 mmol/L.
- Confirm the primary alkalosis: The alkalosis is primary, and the low urine chloride identifies a chloride-responsive cause.
- Replace volume and chloride: Isotonic saline is given.
- Replace potassium: Potassium is replaced carefully while the kidneys recover.
- Check for hidden diuretics: A quick check for furosemide or thiazide use is worthwhile, since covert diuretic use also causes alkalosis, though urine chloride is high while the drug is acting.
Now a second patient: a 40-year-old man with hypertension, bicarbonate 33 mmol/L and potassium 2.6 mmol/L, not taking diuretics, has a urine chloride of 45 mmol/L. Raised urine chloride with hypertension points to a chloride-resistant mechanism, so aldosterone and renin are measured, with an aldosterone-to-renin ratio raised in primary hyperaldosteronism.
A young patient with unexplained hypokalaemia and normal blood pressure leads instead to Bartter or Gitelman testing.
| Feature | Bartter syndrome | Gitelman syndrome |
|---|---|---|
| Defective transporter | NKCC2 in the thick ascending limb | Thiazide-sensitive NCC in the distal convoluted tubule |
| Urinary calcium | Raised | Low |
| Blood pressure | Normal or low | Normal |
| Usual presentation | Often childhood | Usually later |
Urinary calcium is the discriminator.
Where the examiner tries to catch you
The examiner's favourite errors involve the tubulopathy pair, the hidden diuretic and the wrong drug for Liddle syndrome.
- Trap: confusing Bartter with Gitelman syndrome Correct: Bartter has hypercalciuria and a more severe early presentation, while Gitelman has hypocalciuria, hypomagnesaemia and normal blood pressure, and it is the more common of the two in adults.
- Trap: mistaking diuretic abuse for genuine tubulopathy Correct: surreptitious diuretic use gives a Bartter or Gitelman-like picture with high urine chloride while the drug is acting, so a urine diuretic screen separates them.
- Trap: forgetting that hypokalaemia itself causes alkalosis Correct: hypokalaemia shifts hydrogen ions into cells and increases renal bicarbonate reabsorption and ammonium production, so potassium repletion is part of correction.
- Trap: using spironolactone for Liddle syndrome Correct: Liddle syndrome responds to amiloride and not to spironolactone, the usual first choice in hyperaldosteronism.
Frequently asked questions
What is the urine chloride cutoff in metabolic alkalosis?
A urine chloride below about 20 mmol/L indicates a chloride-responsive metabolic alkalosis, such as vomiting or past diuretic use. Values above about 20 mmol/L point to a chloride-resistant cause, such as primary hyperaldosteronism, Bartter syndrome or Gitelman syndrome.
How does Bartter syndrome differ from Gitelman syndrome?
Bartter syndrome results from a defect in the thick ascending limb transporter and causes hypercalciuria with normal or low blood pressure, often presenting in childhood. Gitelman syndrome results from a defect in the distal convoluted tubule transporter and causes hypocalciuria, hypomagnesaemia and normal blood pressure, usually presenting later.
Why is saline used in chloride-responsive metabolic alkalosis?
Saline is used in chloride-responsive metabolic alkalosis because it replaces the extracellular volume and chloride that the kidney needs in order to excrete the excess bicarbonate. Once chloride is restored, the kidney can clear bicarbonate, and the alkalosis resolves, while potassium is replaced in parallel.
Which tubulopathy causes hypocalciuria with hypomagnesaemia?
Gitelman syndrome causes hypocalciuria with hypomagnesaemia, because the defect in the thiazide-sensitive transporter in the distal convoluted tubule increases magnesium and potassium loss while reducing calcium excretion.
How is Liddle syndrome treated?
Liddle syndrome is treated with amiloride, which blocks the overactive epithelial sodium channel and corrects the hypertension and hypokalaemia. Spironolactone is ineffective because the defect is downstream of the aldosterone receptor.