Gitelman Syndrome

Gitelman syndrome is a rare genetic autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder that affects the sodium-chloride cotransporter in the distal convoluted tubule of the nephron and causes electrolyte abnormalities. The syndrome presents clinically with symptoms of hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia and hypomagnesemia. Diagnosis is based on the clinical presentation of the syndrome with laboratory testing as well as genetic testing for family counseling. The mainstay of management is K+ and Mg2+ supplementation to prevent the development of symptoms. The prognosis is good, but hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia must be monitored to prevent cardiac arrhythmias and potential cardiac arrest Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest.

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Overview

Definition

Gitelman syndrome (GS) is a rare genetic autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder that affects the thiazide-sensitive Na+–Cl cotransporter (NCC) in the distal convoluted tubule (DCT), leading to a salt-wasting tubulopathy. 

Epidemiology

  • Prevalence: 1–10 per 40,000, more common than Bartter syndrome Bartter syndrome Bartter syndrome is a rare autosomal recessive disorder that affects the kidneys and presents either antenatally with severe or life-threatening manifestations or in childhood or adulthood with a milder course, depending on the genetic defect. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb of the loop of Henle. Bartter Syndrome
  • Potentially higher prevalence in Asia
  • Gene mutations are present in > 3% of individuals.
  • No sex predisposition

Etiology

  • Autosomal recessive inheritance: For a person to be affected, a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 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 25% chance of the offspring being affected
    • A 50% chance of the offspring being an unaffected carrier
    • A 25% chance of the offspring being unaffected and not a carrier
  • The mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is present in the SLC12A3 gene (80% of individuals) and rarely in the CLCNKB gene.

Pathophysiology

Normal physiology in the DCT

The DCT is the smallest portion of the duct system in a nephron. It measures about 5 mm in size and starts from the macula densa. Characteristics of the DCT are as follows:

  • Lined with simple cuboidal epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium and without microvilli, giving the appearance of a larger lumen
  • Presence of a large number of mitochondria and Na+/K+-ATPase pump in the basolateral membrane
  • Impermeable to water and urea
  • Contains the NCC, which is the target of many diuretics:
    • Thiazides
    • Aldosterone
    • ARBs
    • ACE inhibitors (ACEis)
  • Functions of the DCT:
    • Regulation of pH by secretion of H+ ions and reabsorption of HCO3, or vice versa
    • Reabsorption of Na+ and secretion of K+
    • Reabsorption of calcium by the action of parathyroid hormone
    • Mg2+ reabsorption by the transient receptor potential channel (TRPM6)

Pathophysiology

Gitelman syndrome leads to the loss of function of the NCC → electrolyte abnormalities due to interference with the normal functioning of the DCT

  • Gene mutations inactivate the NCC:
    • Normally functions to reabsorb Na+ and Cl from the DCT
    • Inactivation prevents reabsorption → ↑ Na+ and Cl delivery to the collecting duct
  • Impaired salt reabsorption → ↑ water loss
  • Volume contraction → activation of RAAS
  • ↑ Renin and aldosterone activity in the collecting duct results in:
    • ↑ K+ excretion → hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
    • ↑ H+ excretion → metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis
  • Additionally, there may be:
    • ↓ Mg2+ reabsorption → renal Mg2+ wasting → hypomagnesemia
    • ↓ Urinary calcium excretion
Gitelman syndrome pathophysiology

Sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) of a nephron: NCC normally helps with the reabsorption of Na+ and chloride from the tubular lumen. In Gitelman syndrome, inactivation of the NCC prevents this absorption, increasing electrolyte delivery to the collecting duct. This phenomenon is similar to the mechanism of action of thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics.
ClC-Kb: chloride channel Kb
TRPM6: transient receptor potential channel

Image: “Gitelman syndrome” by Nine VAM Knoers and Elena N Levtchenko. License: CC BY 2.0
Nephron with gitelman syndrome

Anatomy of a nephron:
Toward the left in red is the distal convoluted tubule, which is affected in individuals with Gitelman syndrome.

Image: “Kidney Nephron” by Holly Fischer. License: CC BY 3.0

Clinical Presentation

Individuals with GS have mild-to-moderate symptoms without limitation in daily activity. These individuals present after the 1st decade of life in adolescence or early adulthood (rarely in infancy).

The classic clinical presentation is the triad of: 

  • Hypokalemia
  • Metabolic alkalosis 
  • Normal or low blood pressure

Other signs and symptoms include:

  • Manifestations of hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia:
    • Muscle twitching, cramps, and weakness
    • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
    • Severe fatigue
    • Polyuria or nocturia
    • Cardiac arrhythmias and cardiac arrest Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest (in severe cases)
  • Manifestations of hypomagnesemia:
    • Paresthesias, especially in the face
    • Muscle cramps
    • Tetany
    • Arthralgias
    • Myalgias
  • Salt cravings
  • Thirst
  • Chondrocalcinosis in adulthood: associated with inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of joints
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures in severe cases
  • Growth delay is seen in individuals affected at a young age.

Diagnosis

A detailed evaluation of GS is necessary when an individual presents with unexplained hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis, and normal or low blood pressure. Because of its rare occurrence compared with other renal disorders with similar symptoms, other causes should be ruled out.

Lab tests

  • Serum electrolyte levels:
    • ↓ Na+
    • ↓ K+
    • ↓ Cl
    • ↓ Mg2+
  • ↑ Renin
  • ↑ Aldosterone
  • ↑ Blood pH (alkalosis)
  • Urinary tests:
    • Na+: ↑ excretion
    • K+: ↑ excretion
    • Cl: ↑ excretion
  • Calcium: ↓ excretion leads to hypocalciuria

Genetic testing

Genetic testing is highly specific and sensitive, and a majority of affected individuals show mutations in 2 particular genes:

  • SLC12A3 (80% of affected individuals)
  • CLCNKB

Management and Prognosis

Management

The goals of management are to minimize the effects of extracellular volume depletion and correct electrolyte deficiencies.

  • Asymptomatic individuals:
    • Need regular physician evaluation for electrolyte imbalances
    • Lab tests for electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes every 6–12 months
  • Hypomagnesemia:
    • Lifelong supplementation with oral magnesium chloride in 3–4 divided doses/day
    • Regular monitoring for serum levels and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea as a side effect
    • Tetany requires IV magnesium chloride.
  • Hypokalemia:
    • K+ levels should be monitored to avoid cardiac arrhythmias.
    • Aldosterone antagonists:
      • Spironolactone
      • Eplerenone
    • K+-sparing diuretic: amiloride
      • In addition to K+ in 3–4 divided doses
      • Affected individuals should be carefully monitored to avoid hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension.
    • ARBs or ACEis may also be used.
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia: Salt intake is encouraged.
  • Chondrocalcinosis (pseudogout):
    • Deposition of calcium pyrophosphate dihydrate (CPPD) crystals in the synovium
    • Reduced by Mg2+ supplementation
    • Treatment includes oral NSAIDs.
  • Growth and puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty delay:
    • Affected individuals are encouraged to maintain a diet high in Na+ and K+.
    • Adequate K+ and Mg2+ supplementation is essential.
    • Indomethacin is shown to have growth-promoting effects.
  • Kidney transplantation:
    • Rare, for individuals with end-stage renal disease
    • Tubular abnormalities resolve without recurrence after kidney transplantation.

Prognosis

  • Generally good
  • The ability to perform daily life activities varies among affected individuals.
  • Progression to renal insufficiency is extremely rare.
  • GS does not affect life expectancy.

Differential Diagnosis

  • Bartter syndrome Bartter syndrome Bartter syndrome is a rare autosomal recessive disorder that affects the kidneys and presents either antenatally with severe or life-threatening manifestations or in childhood or adulthood with a milder course, depending on the genetic defect. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb of the loop of Henle. Bartter Syndrome: a rare genetic disorder that impairs the kidney’s ability to reabsorb salts and causes electrolyte imbalances. Bartter syndrome Bartter syndrome Bartter syndrome is a rare autosomal recessive disorder that affects the kidneys and presents either antenatally with severe or life-threatening manifestations or in childhood or adulthood with a milder course, depending on the genetic defect. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb of the loop of Henle. Bartter Syndrome presents with hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis, and delayed growth/development, but presents with normal serum Mg2+ levels. Diagnosis is by blood and urine testing. Management focuses on treating symptoms and replenishing electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes.
  • Laxative abuse: seen in individuals with eating disorders for weight loss. The 2 main disorders are bulimia and anorexia nervosa Anorexia Nervosa Anorexia nervosa is an eating disorder marked by self-imposed starvation and inappropriate dietary habits due to a morbid fear of weight gain and disturbed perception of body shape and weight. Patients have strikingly low BMI and diverse physiological and psychological complications. Anorexia Nervosa. The associated risks are dehydration, electrolyte abnormalities, constipation, infections, and rectal prolapse Rectal prolapse Rectal prolapse, also known as rectal procidentia, is the protrusion of rectal tissue through the anus. The tissue may include just the mucosa or the full thickness of the rectal wall. Common risk factors include chronic straining, constipation, bowel motility disorders, and weakening of the pelvic floor muscles. Rectal Prolapse. It is important to treat the underlying condition and start CBT.
  • Diuretic abuse: another disorder wherein people attempt to lose weight. Affected individuals take excess diuretics to feel lighter, which leads to dehydration and electrolyte abnormalities. Diuretic abuse is approached with CBT and educating the individual about the complications of diuretic use.
  • Mineralocorticoid excess: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder that results from mutations in the HSD11B2 gene that encodes the kidney isozyme 11β-hydroxysteroid dehydrogenase type 2. Mineralocorticoid excess presents with hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis, and low plasma renin. Diagnosis is made on finding the triad of hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, and suppressed plasma aldosterone levels plus an abnormal urinary cortisol-to-cortisone ratio. Management includes aldosterone antagonists such as spironolactone or renal transplantation.

References

  1. Genetic and Rare Diseases Information Center (GARD). (2021). Gitelman syndrome. Retrieved June 10, 2021, from https://rarediseases.info.nih.gov/diseases/8547/gitelman-syndrome
  2. 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
  3. 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

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