OVERVIEW

What is Gitelman Syndrome?

Gitelman syndrome was first reported by Gitelman in 1966, hence the disease is named after him.

This is a rare autosomal recessive genetic disorder, primarily associated with mutations in the SLC12A3 gene located at the 13q locus of chromosome 16. This leads to dysfunction of the sodium-chloride cotransporter in the distal convoluted tubules of the kidneys, thereby affecting the reabsorption and excretion of electrolytes (such as potassium and magnesium) in the body.

The disease is considered a benign renal tubular disorder, typically manifesting in adolescence or adulthood. Clinical symptoms include hypokalemia, hypochloremic metabolic alkalosis, hypomagnesemia, hypocalciuria, and activation of the renin-angiotensin-aldosterone system (RAAS), but with normal or low blood pressure.

Treatment mainly involves symptomatic and supportive care, with some cases potentially requiring kidney transplantation.

Is Gitelman Syndrome Common?

Gitelman syndrome is uncommon. In Western populations, the incidence is approximately 1 in 40,000 individuals. The prevalence may be higher in Asian populations, though there are no statistical data on its incidence in China.

SYMPTOMS

What are the common manifestations of Gitelman syndrome?

The symptoms of Gitelman syndrome vary in severity, typically presenting as hypokalemia, alkalosis, hypomagnesemia, and hypotension. Symptoms range from being asymptomatic to weakness, fatigue, salt craving, thirst, nocturia, constipation, hand and foot spasms, convulsions, quadriplegia, joint and muscle pain, palpitations, and even sudden death in severe cases:

• Most common manifestations (occurring in over 50% of patients): muscle cramps, muscle weakness, fatigue, dizziness, nocturia, thirst, polydipsia, paresthesia, limb numbness, palpitations, hypotension, etc.
• Relatively common manifestations (occurring in 20%–50% of patients): syncope, polyuria, arthralgia, chondrocalcinosis, prolonged QT interval on electrocardiogram, etc.
• Less common manifestations (occurring in fewer than 20% of patients): early-onset (before age 6), growth retardation, delayed puberty, vertigo, tetany, nausea, constipation, paralysis, etc.
• Rare manifestations (only isolated reports): epilepsy, ventricular tachycardia, rhabdomyolysis, blurred vision, etc.

What diseases can Gitelman syndrome cause?

Complications of Gitelman syndrome include:

• Deposition of calcium salts in joints and sclera, leading to chondrocalcinosis and choroidal calcification;
• Growth retardation, delayed puberty, and short stature, which may occur in non-adult-onset patients;
• Prolonged QT interval, increasing the risk of ventricular arrhythmias;
• Glucose intolerance or insulin resistance;
• Tubulointerstitial nephritis, proteinuria, etc.

CAUSES

What is the cause of Gitelman syndrome?

Gitelman syndrome is a genetic disorder caused by gene mutations, primarily associated with mutations in the SLC12A3 gene located at chromosome 16q13. This leads to dysfunction of the sodium-chloride cotransporter in the distal convoluted tubules of the kidneys, affecting the reabsorption and excretion of electrolytes (such as potassium and magnesium) in the body.

Who is commonly affected by Gitelman syndrome?

Gitelman syndrome has a low incidence rate and typically manifests in adolescents or adults. As a monogenic inherited disorder, it may exhibit familial clustering.

Is Gitelman syndrome contagious?

Gitelman syndrome is not contagious; it is a genetic disease.

Is Gitelman syndrome hereditary?

Gitelman syndrome is hereditary and follows an autosomal recessive inheritance pattern.

DIAGNOSIS

How is Gitelman syndrome diagnosed?

When diagnosing Gitelman syndrome, doctors primarily rely on the patient's clinical manifestations, laboratory findings of "five lows and one high," and metabolic alkalosis—specifically, hypokalemia, hypomagnesemia, hypochloremia, hypocalciuria, low or normal blood pressure, and increased activity of the renin-angiotensin-aldosterone system (RAAS).

The definitive diagnostic criterion for Gitelman syndrome is the identification of pathogenic mutations in the SLC12A3 gene.

What tests are needed to diagnose Gitelman syndrome?

Generally, tests such as blood pressure measurement, biochemical analysis, blood gas analysis, hormone testing, imaging, and genetic testing are required.

• Blood pressure measurement: Blood pressure is normal or low, aiding in diagnosis.

• Biochemical tests: Confirm hypokalemia, hypomagnesemia, hypochloremia, hypocalciuria, etc. Hypomagnesemia and hypocalciuria are particularly valuable for diagnosis. Blood and urine samples should be collected simultaneously, preferably 2–3 times.

  If the patient is undergoing potassium or magnesium supplementation and electrolyte levels are normal or near-normal, discontinue the medications 48 hours before testing to avoid interference.

• Blood gas analysis: Identifies metabolic alkalosis, excludes renal tubular acidosis and Fanconi syndrome, and assists in diagnosis.

• Hormone testing: Plasma direct renin concentration, plasma renin activity, angiotensin II, and aldosterone levels—elevated renin levels and activated RAAS help exclude primary aldosteronism and Liddle syndrome. Thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), total triiodothyronine (T3), and total thyroxine (T4) levels—normal results rule out hypokalemia caused by thyroid disorders. Adrenocorticotropic hormone (ACTH) and cortisol—physiological rhythms exclude hypokalemia due to hypercortisolism.

• Imaging: Renal ultrasound showing no significant abnormalities supports the diagnosis.

• Genetic testing: Detection of pathogenic mutations in the SLC12A3 gene serves as the definitive diagnostic evidence.

Which diseases is Gitelman syndrome easily confused with? How to differentiate them?

Gitelman syndrome shares similarities with Bartter syndrome and can be easily confused. Key distinguishing features include:

• Age of onset: Gitelman syndrome typically presents in adolescents or adults, whereas Bartter syndrome often manifests in childhood.
• Electrolyte abnormalities: Hypocalciuria and hypomagnesemia are unique to Gitelman syndrome.
• Growth retardation: Bartter syndrome is frequently associated with growth retardation.
• Genetic testing: Provides definitive differentiation between the two conditions.

TREATMENT

Which department should I visit for Gitelman syndrome?

Endocrinology or Pediatrics.

Can Gitelman syndrome resolve on its own?

No, Gitelman syndrome cannot resolve on its own. It is an inherited congenital disorder where the dysfunction of the renal tubules cannot be corrected unless a kidney transplant is performed. Therefore, treatment for Gitelman syndrome is lifelong and primarily focuses on symptom management.

How is Gitelman syndrome treated?

Treatment for Gitelman syndrome mainly includes medication and surgery.

Medications include:

• Potassium and magnesium supplements:

  • Oral or intravenous potassium supplementation is the primary treatment. Patients with low magnesium levels also require magnesium supplementation. Treatment varies based on individual conditions and often requires lifelong management.
  • Follow the principle of "dietary + medicinal supplementation." It is recommended to maintain serum potassium levels above 3.0 mmol/L and serum magnesium levels above 0.6 mmol/L.
  • Encourage consumption of potassium-rich foods. Potassium chloride extended-release tablets can be used for medicinal supplementation, preferably taken with meals to reduce gastrointestinal irritation. The dosage can be gradually increased until an appropriate maintenance level is achieved. Intravenous potassium is necessary if the patient cannot eat or experiences severe hypokalemia leading to arrhythmias, rhabdomyolysis, limb paralysis, or difficulty breathing.
  • Encourage magnesium-deficient patients to consume magnesium-rich foods like nuts and dark chocolate. Oral magnesium supplementation is preferred, with a recommended starting dose of 300 mg per day (as elemental magnesium), divided and taken with meals, adjusted based on serum magnesium levels and gastrointestinal tolerance. Intravenous magnesium (e.g., magnesium sulfate or magnesium chloride) is required for severe complications or intolerance to oral supplementation.

• Nonsteroidal anti-inflammatory drugs (NSAIDs): Such as indomethacin or celecoxib, which may be effective for some patients.

• Potassium-sparing diuretics: Such as the aldosterone antagonist spironolactone, with doses up to 300 mg daily. It reduces urinary potassium excretion and raises serum potassium but has anti-androgenic side effects like gynecomastia in males and menstrual irregularities in females, requiring caution in adolescents and young adults.

  The selective aldosterone antagonist eplerenone has fewer side effects, with doses up to 150 mg daily. Amiloride is also effective, with doses up to 40 mg daily. Sodium supplementation is necessary when using these drugs, and hypotension should be monitored.

  • Renin-angiotensin system inhibitors include renin inhibitors, ACE inhibitors (e.g., enalapril), and angiotensin II receptor blockers (ARBs). ACE inhibitors are preferred, starting at low doses and gradually increasing. Hypotension should be monitored, especially during acute sodium loss (e.g., vomiting or diarrhea), when these drugs should be avoided.

Surgical treatment primarily involves kidney transplantation, which has been performed in very few cases, with no reported recurrence post-transplant.

Can Gitelman syndrome be completely cured?

Gitelman syndrome is an inherited congenital disorder, and the renal tubular dysfunction cannot be corrected unless a kidney transplant is performed, which has only succeeded in very few cases. Therefore, Gitelman syndrome is currently incurable, and treatment is lifelong.

DIET & LIFESTYLE

What should patients with Gitelman syndrome pay attention to in their diet?

In addition to oral medication supplementation, patients with Gitelman syndrome can increase their intake of potassium- and magnesium-rich foods, such as meat (pork), fish (cod and tuna), milk, yogurt, beans, carrots, bananas, nuts, dark chocolate, etc.

Does Gitelman syndrome affect fertility?

Generally, Gitelman syndrome does not impair fertility, and most pregnant women with the condition can successfully deliver healthy babies.

With proper treatment and monitoring during pregnancy, maternal and fetal outcomes are favorable. Occasional complications such as oligohydramnios or fetal growth restriction may occur, but miscarriage and stillbirth are rare.

It is important to note that the demand for potassium and magnesium supplementation usually increases during pregnancy. In addition to normal nutritional needs, patients with Gitelman syndrome should increase their intake of sodium chloride and potassium- and magnesium-rich foods. Regular blood potassium monitoring is necessary, and oral supplements should be adjusted accordingly. Blood potassium levels do not need to be strictly maintained within the normal range and can be kept between 2.8–3.3 mmol/L during pregnancy.

Drugs that block the renin-angiotensin system are typically contraindicated during pregnancy, and nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended. Multiple case reports suggest that spironolactone, amiloride, and/or eplerenone can be safely used during pregnancy.

During the perinatal period, blood potassium should ideally be maintained above 4.0 mmol/L, with electrolyte checks every 2 days. Hypokalemia and hypomagnesemia alone are not indications for cesarean delivery. However, if severe complications such as fetal growth restriction or fetal distress occur, cesarean section may be considered. Intraoperative electrolyte monitoring is essential to assess potassium and magnesium levels for timely supplementation. Postpartum follow-up with an endocrinologist is recommended to address any electrolyte deficiencies.

PREVENTION

Can Gitelman Syndrome Be Prevented? How to Prevent Gitelman Syndrome?

Prenatal genetic counseling and assessing the risk of offspring developing Gitelman syndrome are of certain significance in preventing the disease.

How Can Gitelman Syndrome Patients Prevent Other Diseases?

Actively pursuing prenatal diagnosis is crucial. For cases of polyhydramnios, ultrasound diagnosis or alpha-fetoprotein testing should be performed. If no cause is identified, amniocentesis may be necessary to collect fetal cells from the amniotic fluid for genetic testing, enabling early diagnosis and treatment before birth. For suspected cases, prompt diagnosis and active treatment are essential to prevent complications.