Gitelman syndrome (GS) is a rare genetic autosomal recessive disorder that affects the thiazide-sensitive Na+–Cl– cotransporter (NCC) in the distal convoluted tubule (DCT), leading to a salt-wasting tubulopathy.
- Prevalence: 1–10 per 40,000, more common than Bartter syndrome
- Potentially higher prevalence in Asia
- Gene mutations are present in > 3% of individuals.
- No sex predisposition
- Autosomal recessive inheritance: For a person to be affected, a mutation must be present on both genes encoding the NCC.
- Carrier: A person with only 1 mutated gene remains unaffected.
- When 2 unaffected carriers have children, there is:
- A 1 in 4 chance (25%) of the children being affected
- 50% unaffected carriers
- 25% unaffected and not carriers
- The mutation is present in the SLC12A3 gene (80% of the individuals) and rarely in the CLCNKB gene.
Normal physiology in the distal convoluted tubule
The DCT is the smallest portion of the duct system in the nephron, about 5 mm in size, and starts from the macula densa. The DCT:
- Is lined with simple cuboidal epithelium, and microvilli are absent, giving the appearance of a larger lumen
- Has a large number of mitochondria and a Na+/K+-ATPase pump in the basolateral membrane
- Is impermeable to water and urea
- Contains the NCC, which is the target of many diuretics:
- The functions of the DCT are:
- Regulation of pH by secretion of H+ ions and reabsorption of bicarbonate, or vice versa
- Reabsorption of sodium and secretion of potassium
- Reabsorption of calcium by the action of parathyroid hormone
- Magnesium reabsorption by the transient receptor potential channel (TRPM6)
Gitelman syndrome leads to the loss of function of the NCC → electrolyte abnormalities due to interference of the normal functioning of the DCT
- Gene mutations inactivate the thiazide-sensitive cotransporter.
- Na+/K+-ATPase acts continuously on the basolateral membrane due to the inactivation of the transporter → favorable sodium gradient across membranes → ↑ sodium reabsorption and ↑ calcium absorption
- Reduction of NCC activity is similar to thiazide diuretic action →
- Volume contraction
- Increased renin activity
- Hypokalemia due to renal potassium wasting
- Hypomagnesemia due to renal magnesium wasting
- Decreased urinary calcium excretion
Patients with GS have mild-to-moderate symptoms without limitation in daily activity. These patients present after the 1st decade of life in adolescence or early adulthood (rarely in infancy).
The classic clinical presentation is the triad of:
- Metabolic alkalosis
- Normal or low BP
Other signs and symptoms include:
- Manifestations of hypokalemia:
- Muscle twitching, cramps, and weakness
- Severe fatigue
- Polyuria or nocturia
- Cardiac arrhythmias and cardiac arrest (in severe cases)
- Manifestations of hypomagnesemia:
- Paresthesias, especially in the face
- Muscle cramps
- Salt cravings
- Chondrocalcinosis in adulthood—associated with inflammation of joints
- Seizures in severe cases
- Growth delay is seen in patients who present at a young age.
A detailed evaluation of GS is necessary when a patient presents with unexplained hypokalemia, metabolic alkalosis, and normal or low BP. Because of its rare occurrence compared to other renal disorders with similar symptoms, other causes should be ruled out.
- Serum electrolyte levels
- ↓ Sodium
- ↓ Potassium
- ↓ Chloride
- ↓ Magnesium
- ↑ Renin
- ↑ Aldosterone
- ↑ Blood pH (alkalosis)
- Urinary tests:
- Sodium: ↑ excretion
- Potassium: ↑ excretion
- Chloride: ↑ excretion
- Calcium: ↓ excretion leads to hypocalciuria
Genetic testing is highly specific and sensitive, and a majority of patients show mutations in 2 particular genes:
- SLC12A3 (80% of patients)
Management and Prognosis
The goals of management are to minimize the effects of extracellular volume depletion and correct the electrolyte deficiencies.
- Asymptomatic patients:
- Need regular physician evaluation for electrolyte imbalances
- Lab tests for electrolytes every 6–12 months
- Lifelong supplementation with oral magnesium chloride in 3–4 divided doses/day
- Regular monitoring for serum levels and side effect of diarrhea
- Tetany requires IV magnesium chloride.
- Potassium levels should be monitored to avoid cardiac arrhythmias.
- Aldosterone antagonists:
- Potassium-sparing diuretic: amiloride
- In addition to potassium in 3–4 divided doses
- Patients should be carefully monitored to avoid hypotension.
- ARBs or ACEis may also be used.
- Hyponatremia: Salt intake is encouraged.
- Chondrocalcinosis (pseudogout):
- Deposition of calcium pyrophosphate dihydrate (CPPD) crystals in the synovium
- Reduced by magnesium supplementation
- Treatment includes oral NSAIDs.
- Growth and puberty delay:
- Patients are encouraged to maintain high-sodium, high-potassium diet.
- Adequate potassium and magnesium supplementation is essential.
- Indomethacin is shown to have growth-promoting effects.
- Kidney transplantation:
- For rare patients with end-stage renal disease
- Tubular abnormalities resolve without recurrence after kidney transplantation.
- Generally good
- Ability to perform daily life activities varies with each patient.
- Progression to renal insufficiency is extremely rare.
- GS does not affect life expectancy.
- Bartter syndrome: rare genetic disorder that impairs the kidney’s ability to reabsorb salt and causes electrolyte imbalances. Bartter synddrome presents with hypokalemia, metabolic alkalosis, and delayed growth/development but a normal serum magnesium level. Diagnosis is by blood and urine testing. Management focuses on treating symptoms and replenishing electrolytes.
- Laxative abuse: seen in patients with eating disorders for weight loss. The 2 main disorders are bulimia and anorexia nervosa. The associated risks are dehydration, electrolyte abnormalities, constipation, infections, and rectal prolapse. It is important to treat the underlying condition and start CBT.
- Diuretic abuse: another disorder wherein people attempt to lose weight. Patients take excess diuretics to feel lighter, which leads to dehydration and electrolyte abnormalities. Diuretic abuse is approached with CBT and educating the patient about the complications of diuretics.
- Mineralocorticoid excess: autosomal recessive disorder that results from mutations in the HSD11B2 gene that encodes the kidney isozyme 11β-hydroxysteroid dehydrogenase type 2. Mineralocorticoid excess presents with hypertension, hypokalemia, metabolic alkalosis, and low plasma renin. Diagnosis is made on finding the triad of hypertension, hypokalemia, and suppressed plasma aldosterone levels plus an abnormal urinary cortisol-to-cortisone ratio. Management includes aldosterone antagonists such as spironolactone or renal transplantation.
- Genetic and Rare Diseases Information Center (GARD). (2021). Gitelman syndrome. Retrieved June 10, 2021, from https://rarediseases.info.nih.gov/diseases/8547/gitelman-syndrome
- LaRosa, C.J. (2020). Bartter syndrome and Gitelman syndrome. MSD Manual. https://www.msdmanuals.com/en-in/professional/pediatrics/congenital-renal-transport-abnormalities/bartter-syndrome-and-gitelman-syndrome
- Emmett, M. & Ellison, D.H. (2019). Bartter and Gitelman syndromes. UpToDate. Retrieved June 10, 2021, from https://www.uptodate.com/contents/bartter-and-gitelman-syndromes