Hospital Medicine

Bartter/Gitelman syndrome

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I. What every physician needs to know.

Bartter syndrome and Gitelman syndrome are autosomal recessive disorders of renal tubular electrolyte transport characterized by metabolic alkalosis, hypokalemia and low to normal blood pressure despite hyperaldosteronism and hyperreninemia.

There are multiple genetic mutations associated with these syndromes (Bartter I-IV and Gitelman) and although there can be significant overlap, they are often divided into three separate clinical entities - classic Bartter syndrome, antenatal Bartter syndrome and Gitelman syndrome. The age of onset and severity of symptoms can vary significantly.

Bartter syndrome refers to several clinical disorders that result from defective sodium chloride (NaCl) reabsorption in the thick ascending limb of the loop of Henle, the site of action of loop diuretics. Gitelman syndrome results from a defect in the NaCl cotransporter in the distal convoluted tubule, where thiazide diuretics exert their effects, leading to similar but milder physiologic changes.

Failure to reabsorb NaCl in these two areas of the kidney leads to excess salt and water loss and stimulation of the renin-angiotensin-aldosterone system. Elevated aldosterone leads to increased potassium and hydrogen exchange for sodium in the distal tubule and results in the hypokalemia and metabolic alkalosis seen in both syndromes.

Antenatal Bartter syndrome (type I, II, IV, also called hyperprostaglandin E syndrome) is the most severe clinical variant. It is generally associated with prenatal polyhydramnios and premature delivery. Patients are noted to have severe electrolyte abnormalities, including significant hypercalciuria, which can lead to nephrocalcinosis. Elevated angiotensin II leads to increased renal vasoconstriction and markedly elevated prostaglandin E levels.

Untreated patients suffer from growth failure as well as life-threatening episodes of fevers, vomiting and diarrhea. A small subset of patients (those with type IV Bartter) also have sensorineural deafness because their genetic defect is in the barttin protein found in chloride channels in the inner ear as well as the kidney.

Classic Bartter syndrome (type III) is usually diagnosed in childhood or early adolescence and has highly variable clinical manifestations and lack of nephrocalcinosis. Patients with this variant may have mildly increased urinary prostaglandin levels and growth failure may occur.

Gitelman syndrome (also called familial hypokalemia-hypomagnesemia) is generally milder than Bartter syndrome, often presents in adolescence and early adulthood and may be found in asymptomatic patients. These patients usually have hypocalciuria and hypomagnesemia. Adult patients may have chondrocalcinosis from longstanding hypomagnesemia.

II. Diagnostic Confirmation: Are you sure your patient has Bartter/Gitelman syndrome?

N/A

A. History Part I: Pattern Recognition:

Bartter and Gitelman syndromes

  • Unexplained hypokalemia, metabolic alkalosis

  • Normotension or mild hypotension

Bartter syndrome

  • Polyuria

  • Polydipsia

  • Fatigue

  • Failure to thrive

  • Salt cravings

  • Muscle weakness

  • Impaired urinary concentrating ability

  • Growth retardation or short stature (if untreated)

  • Hypercalciuria

  • Hypomagnesemia (in approx 10-20%)

  • May have developmental delay

  • May have sensorineural hearing loss (linked to the mutations of the barttin protein in Bartter syndrome IV)

Gitelman syndrome

  • Fatigue

  • Polyuria

  • Salt cravings

  • Muscle weakness and/or cramping

  • Tetany

  • Facial paresthesias

  • Hypomagnesemia

  • Chondrocalcinosis (in adults)

B. History Part 2: Prevalence:

Both Bartter and Gitelman syndromes are rare autosomal recessive disorders. According to a report from the Framingham Heart Study, the estimated prevalence was approximately 1 per 40,000 for Gitelman syndrome and 1 per million for Bartter syndrome. There is no gender or racial preference in these syndromes.

C. History Part 3: Competing diagnoses that can mimic Bartter/Gitelman syndrome.

The lab abnormalities common to these disorders are much more likely to be caused by surreptitious vomiting (such as in bulimia) or diuretic abuse than by a salt-losing tubulopathy. The absence of hypertension can help differentiate Bartter or Gitelman syndromes from other conditions with elevated renin and/or aldosterone such as renal artery stenosis and Conn's syndrome.

Presence of hypocalciuria and hypomagnesemia is usually used to distinguish Gitelman syndrome from classic or later-onset Bartter syndrome.

D. Physical Examination Findings.

  • Hypotension - may be symptomatic or asymptomatic based on volume status

  • Tetany - positive Chvostek's and Trouseau's signs may be present in the setting of hypomagnesemia and hypocalcemia

E. What diagnostic tests should be performed?

N/A

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

  • BMP to confirm hypokalemia and metabolic alkalosis and for estimation of glomerular filtration rate (GFR)

  • Serum calcium and magnesium

  • Urine potassium (looking for evidence of elevated excretion in the setting of hypokalemia)

  • Urine chloride (looking for elevated excretion)

  • Urine screen for diuretics (to rule out diuretic abuse)

  • Urine calcium excretion (elevated in Bartter, decreased in Gitelman)

There are no widely available genetic tests for these syndromes.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

  • Antenatal Bartter may be suspected in patients with polyhydramnios by prenatal ultrasound

  • Patients with hypercalciuria should have a renal ultrasound to look for nephrocalcinosis

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Serum renin and aldosterone levels are unhelpful because these levels are increased in both Bartter and Gitelman syndromes as well as surreptitious vomiting and diuretic use.

III. Default Management.

Acute treatment involves correction and management of electrolyte abnormalities and hypovolemia. Long-term management is directed at limiting the effects of increased aldosterone and prostaglandins as well as treating potential complications such as growth failure, nephrocalcinosis and chondrocalcinosis.

A. Immediate management.

  • Patients with significant hypokalemia and/or hypocalcemia should have a 12 lead electrocardiogram (EKG) and be placed on telemetry and may require significant amounts of electrolytes for replacement.

  • Intravenous (IV) or per os (PO) magnesium should be given prior to or with potassium if there is concomitant hypomagnesemia.

B. Physical Examination Tips to Guide Management.

N/A

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Serialelectrolyte monitoring.

D. Long-term management.

Bartter syndrome

  • Non-steroidal anti-inflammatory drugs (NSAIDs) are used due to their anti-prostaglandin effects and are especially important in antenatal Bartter syndrome. They may improve polyuria, salt wasting and growth failure.

  • Potassium supplements, aldosterone antagonists, angiotensin-converting enzyme (ACE) inhibitors and potassium-sparing diuretics are used to keep the potassium above 3.0mg/dL in adult patients.

  • Exogenous growth hormone, typically managed by a pediatric or adult endocrinologist, may be needed in patients who suffer from growth failure.

Gitelman syndrome

  • Lifelong magnesium supplementation (even in asymptomatic patients) - as chondrocalcinosis is suspected to be from chronic hypomagnesemia.

  • Aldosterone antagonists, ACE inhibitors or potassium-sparing diuretics can be used to treat symptomatic hypokalemia not improved with magnesium supplementation.

  • Prolonged QT interval corrected for heart rate (QTc) and sudden cardiac arrest have been reported. Abnormal EKG should lead to a more thorough cardiac evaluation. Medications known to prolong the QT interval should be avoided.

E. Common Pitfalls and Side-Effects of Management

Bartter syndrome

Side effects of NSAIDs can include gastrointestinal (GI) toxicity and interstitial nephritis. Indomethacin has been shown to be efficacious and is used commonly. The use of cyclooxygenase 2 (COX-2) inhibitors can also be considered but have been less well studied and may increase cardiovascular risk.

The addition of proton-pump inhibitors or other drugs for gastric mucosal protection should be considered.

Potassium supplements are often needed in high doses (up to several hundred mEq/day in adult patients), depending on tolerance of ACE inhibitors, aldosterone antagonists and potassium sparing diuretics, the use of which can be limited by hypotension.

Gitelman syndrome

Magnesium chloride has more oral bioavailability than other forms of magnesium and can be dosed at 4-5mg/kg/24hrs. It should be divided into 3-4 daily doses to avoid diarrhea. Dosing needs to be adjusted according to serum magnesium levels and should be increased in times of infection.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

Close monitoring of electrolytes is necessary in patients taking potassium supplements, potassium sparing diuretics, ACE inhibitors, and aldactone because of the risks of hyperkalemia and acute kidney injury, particularly in the setting of intercurrent illness.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

Careful consideration of the use of digoxin is indicated because of the potential for toxicity in patients with hypokalemia. Careful use of diuretics is warranted.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Patients with Bartter syndrome and Gitelman syndrome are at high risk of electrolyte abnormalities in the hospital. Arrhythmias on telemetry, reports of muscle cramping, etc. should prompt a basic metabolic panel (BMP).

B. Anticipated Length of Stay.

Not applicable - hospitalization would be primarily for another diagnosis.

C. When is the Patient Ready for Discharge.

When volume status and electrolytes have been stabilized, the patient should be ready for discharge from the standpoint of underlying Bartter or Gitelman syndrome.

D. Arranging for Clinic Follow-up

N/A

1. When should clinic follow up be arranged and with whom.

  • Follow-up with a pediatric or adult nephrologist is indicated in all patients soon after hospital discharge or diagnosis to reassess electrolytes and adjust medications as necessary.

  • Antenatal Bartter syndrome - patients are likely to need frequent follow-up with nephrology

  • Gitelman syndrome - asymptomatic patients need every 6-month evaluations with BMP and serum magnesium.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

BMP, calcium, magnesium.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

BMP, calcium, magnesium.

E. Placement Considerations.

N/A

F. Prognosis and Patient Counseling.

Both Bartter and Gitelman syndromes are autosomal recessive inherited disorders, and genetic counseling of parents with an affected child is important. Neither syndrome can be cured, but treatments aimed at correcting the electrolyte disturbances can improve quality of life and limit long-term complications.

In the setting of illness where rapid changes in electrolytes are possible, patients should be promptly evaluated with laboratory monitoring.

Bartter syndrome

Nephrocalcinosis may lead to chronic renal insufficiency. In the absence of nephrocalcinosis, renal function usually remains normal.

Gitelman syndrome

Gitelman syndrome has an excellent long-term prognosis without progression to renal failure (unless from comorbid conditions).

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

N/A

VII. What's the evidence?

Kleta, R, Bockenhauer, D. "Bartter Syndromes and Other Salt-Losing Tubulopathies.". Nephron Physiol. vol. 104. 2006. pp. 73-80.

Knoers, N. "Gitelman syndrome.". Orphanet J Rare Dis. vol. 3. 2008. pp. 22.

Naesens, M. "Bartter's and Gitelman's Syndromes: From Gene to Clinic.". Nephron Physiol. vol. 96. 2004. pp. 66-78.

Nozu, K. "The Pharmacological Characteristics of Molecular-Based Inherited Salt-Losing Tubulopathies.". J Clin Endocrinol Metab. vol. 95. 2010. pp. E511-E518.

"Long-term follow-up of patients with Bartter syndrome type I and II". Nephrol Dial Transplant. vol. 25. 2010. pp. 2976-81.

Roser, M. "Gitelman Syndrome.". Hypertension. vol. 53. 2009. pp. 893-7.

Seyberth, HW. "Bartter and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects.". Pediatr Nephrol,. 2011.

Seyberth, HW. "An improved terminology and classification of Bartter-like syndrome.". Nat Clin Pract Nephrol. vol. 4. 2008.

Shaer, A. "Inherited Primary Renal Tubular Hypokalemic Alkalosis: A Review of Gitelman and Bartter Syndromes.". Am J Med Sci. vol. 322. 2001. pp. 316-322.

"Bartter syndrome: benefits and side effects of long-term treatment". Pediatr Nephrol. vol. 19. 2004. pp. 858.

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