Bartter Syndrome

Bartter syndrome is a rare 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 kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. 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, where 30% of filtered salt is normally reabsorbed. Bartter syndrome is characterized by salt wasting and 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 presents with electrolyte abnormalities and their consequences, such as vomiting and dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration. Diagnosis is made by lab testing that shows the typical hypokalemic 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 hypercalciuria. Additional lab abnormalities include increased serum renin and aldosterone, but patients clinically have normal blood pressure. Management is focused on normalizing serum electrolyte levels. ACE inhibitors and angiotensin receptor blockers are used to improve 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 limit proteinuria.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Bartter syndrome (BS) is a rare genetic (autosomal recessive) disorder that results from a defect in sodium chloride reabsorption in the thick ascending limb of the loop of Henle, leading to 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 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. The disorder mimics long-term ingestion of a loop diuretic.

Epidemiology

  • Prevalence: 1 in 1 million people in the United States
  • BS is less common than Gitelman syndrome Gitelman syndrome Gitelman syndrome is a rare genetic autosomal recessive disorder 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 and hypomagnesemia. Gitelman Syndrome (a similar disorder of the renal tubule, which is seen in 1–10 in 40,000 people).
  • The prevalence of heterozygotes with one of the genetic mutations that cause BS is > 1% in the United States and as high as 3% in Asia.

Pathophysiology and Classification

Normal physiology in the Loop of Henle

In the cells lining the loop of Henle:

  • The sodium/potassium–adenosine triphosphatase (Na+/K+-ATPase) pump on the basolateral membrane brings 3 Na+ out of the cell (into the blood) and 2 K+ into the cell, resulting in:
    • ↓ Intracellular Na+ concentration
    • ↑ Intracellular K+ concentration
  • The Na+/K+-2Cl cotransporter (also known as NKCC2) on the apical membrane reabsorbs 1 Na+, 1 K+, and 2 Cl from the tubular lumen.
    • Electroneutral (2 positive and 2 negative charges moving in the same direction)
    • Driven by the low Na+ concentration within the cell
  • Na+ that is brought in through the NKCC2 is pumped out through the Na+/K+-ATPase
  • Cl that is brought in through the NKCC2 leaves primarily through the NKCC2 on the basolateral membrane (called chloride channel B (ClC-Kb))
    • ClC-Ka (chloride channel Ka) is another chloride channel thought to have redundant functionality
    • A small protein subunit called barttin is required for both ClC-Kb and ClC-Ka to function properly
    • Note: These same chloride channels are found in the ear, and mutations in these channels can lead to deafness.
  • K+ that is brought into the cell through NKCC2 is recycled back into the lumen through the renal outer medullary potassium (ROMK) channels → allows for continued NaCl reabsorption
  • Calcium and magnesium reabsorption:
    • The movement of positively charged K+ into the lumen and negatively charged Cl out of the lumen (and into the blood) causes the lumen to become more positively charged than the peritubular space.
    • This positive charge drives the paracellular reabsorption of Na+, Ca2+, and Mg2+.
Ion transport in the thick ascending limb of the loop of henle

Ion transport in the thick ascending limb of the loop of Henle
ATPase: adenosine triphosphatase
ClC-Ka: chloride channel Ka
ClC-Kb: chloride channel Kb
NKCC2: Na+/K+-Cl cotransporter 2
ROMK: renal outer medullary potassium

Image by Lecturio.

Pathophysiology in Bartter syndrome

Because of one of several 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 Inheritancegenetic defects, there is a variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables renal tubular disorder characterized by salt-wasting and 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 in all subtypes. 

  • Bartter syndrome is characterized by impairment of NKCC2, which is found in the thick ascending limb of the loop of Henle (TAL). 
  • Impairment of this transporter will ↓ reabsorption in the TAL of:
    • Sodium
    • Potassium
    • Chloride 
  • ↓ Reabsorption of ions →  leads to ↑ distal delivery of these ions 
    • These ions remain in the tubular lumen as the urine travels distally 
    • ↑ Distal delivery of Na+ → ↑ the electronegative gradient across the luminal membrane → ↑ excretion of K+ 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
    • ↑ Distal delivery of K+ → ↑ exchange of K+ for H+ in the collected duct → ↑ 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
  • ↑ Na+ in the urine → ↑ free water in the urine, resulting in:
    • Impaired ability to concentrate the urine
    • Volume depletion Volume depletion Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Volume depletion can be caused by GI losses, renal losses, bleeding, poor oral Na intake, or third spacing of fluids. Volume Depletion and Dehydration → causes activation of the RAAS and leads to secondary hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism
      • Long-term stimulation of the RAAS causes hyperplasia of the juxtaglomerular apparatus and increased renin levels.
  • ↑ Renal release of prostaglandin E2
    • ↑ Renal blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure and GFR 
    • ↑ Renin secretion
    • ↑ Na+ and free water excretion  
  • Also urinary loss of calcium and magnesium.
    • ↓ NaCl reabsorption → ↓ Ca2+ and Mg+ reabsorption
    • Calcium wasting in the urine can lead to nephrocalcinosis.
  • Activating mutations in the calcium-sensing receptor (CaSR) on the basolateral membrane can also impair NaCl transport → generates a mild form of BS
    • ↑ CaSR function → ↓ K+ efflux through ROMK → ↓ activity of NKCC2
    • This 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 autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance.
    • Also leads to a downward “resetting” of the normal serum calcium range → results in ↓ parathyroid hormone (PTH) and hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia

Classification by mutations

There is significant genetic heterogeneity in BS; it may result from homozygous or mixed heterozygous mutations in any of the genes that reduce the activity of electrolyte transporters in the TAL. Thus, the severity and clinical presentation of BS vary with each type.

Table: Summary of 5 Bartter syndrome subtypes depending on the gene involved and the transporter being affected
Name Type Defective protein Severity of presentation
Neonatal Bartter syndrome (hyperprostaglandin E syndrome) I NKCC2 Severe
Neonatal Bartter syndrome II ROMK channel Severe
Classic Bartter syndrome III ClC-Kb Mild
Classic Bartter syndrome with sensorineural deafness (hyperprostaglandin E syndrome) IVa Barttin (the β-subunit of ClC-Ka and ClC-Kb) Severe
IVb Simultaneous mutations in ClC-Ka and ClC-Kb Severe
Bartter syndrome with hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia (also called autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism) V CaSR Mild
Different channelopathies in bartter’s syndrome

Different channelopathies in Bartter’s syndrome
ATPase: adenosine triphosphatase
ClC-Ka: chloride channel Ka
ClC-Kb: chloride channel Kb
NKCC2: Na+/K+-Cl cotransporter 2
ROMK: renal outer medullary potassium

Image by Lecturio.

Clinical Presentation

The clinical manifestations of BS are mostly due to electrolyte imbalances and their consequences. Symptoms are much less pronounced in heterozygotes. The tubular defects in ion transport produce a clinical disorder that appears similar to that seen with long-term ingestion of a loop diuretic (e.g., furosemide).

Presentations in neonates

Typically seen in types I, II, IVa, and IVb. Common findings include:

  • Polyhydramnios Polyhydramnios Polyhydramnios is a pathological excess of amniotic fluid. Common causes of polyhydramnios include fetal anomalies, gestational diabetes, multiple gestations, and congenital infections. Patients are often asymptomatic but may present with dyspnea, extremity swelling, or abdominal distention. Polyhydramnios antenatally
  • Preterm birth Preterm birth Preterm labor refers to regular uterine contractions leading to cervical change prior to 37 weeks of gestation; preterm birth refers to birth prior to 37 weeks of gestation. Preterm birth may be spontaneous due to preterm labor, preterm prelabor rupture of membranes (PPROM), or cervical insufficiency. Preterm Labor and Birth
  • Sensorineural deafness (types IVa and IVb)
  • Electrolyte abnormalities:
    • Hypokalemia
    • Metabolic alkalosis
    • Hypercalciuria
  • Polyuria
  • Vomiting
  • 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
  • Emaciation/ failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive 
  • Growth and developmental delay
  • Abnormal facial features
    • Prominent forehead
    • Large eyes
    • Strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus
    • Protruding ears
    • Drooping mouth
Child with bartter syndrome before treatment

Child with Bartter syndrome showing severe dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration before treatment

Image: “Bartter’s child before treatment showing severe dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration” by Sampathkumar K et al. License: CC BY 2.0

Presentations in children, adolescents, and adults

Common findings include:

  • Electrolyte abnormalities:
    • Hypokalemia
    • Metabolic alkalosis
    • Hypercalciuria
    • Hypophosphatemia in occasional patients with secondary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism
    • Normal or mildly decreased serum magnesium level
  • Vomiting
  • Polyuria and polydipsia due to decreased urinary concentrating ability
  • Abdominal cramping
  • Dehydration/hypovolemia
  • 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
  • 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
  • Muscle weakness
  • Renal dysfunction (late manifestation): 
    • Proteinuria
    • ↓ GFR

Diagnosis

The diagnosis of BS is made by lab findings after clinical suspicion arises from the history and physical examination.

History and exam

  • Evaluate for surreptitious vomiting; findings may include:
    • Scarring on the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand from insertion into the mouth
    • Dental erosion
    • Parotitis
  • Rule out unprescribed diuretic use.
  • Ask about family history of nephrocalcinosis.
  • Look for characteristic facial features.
  • 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 (Primary hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism will typically present 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.)

Laboratory

  • Serum 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:
    • 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 (a key diagnostic feature of BS)
    • Metabolic alkalosis
    • Hypomagnesemia
    • Hypophosphatemia
  • Urine 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:
    • ↑ Urinary chloride (differentiates BS from surreptitious vomiting, which will have a ↓ urine Cl)
    • ↑ Urinary calcium (differentiates BS from Gitelman syndrome Gitelman syndrome Gitelman syndrome is a rare genetic autosomal recessive disorder 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 and hypomagnesemia. Gitelman Syndrome, which will have a ↓ urine Ca2+)
    • ↑ Urinary sodium
    • ↑ Urinary potassium
  • Additional lab abnormalities:
    • ↑ Serum renin
    • ↑ Serum aldosterone
    • ↑ Prostaglandin E2
    • ↑ PTH
  • Genetic testing can be considered to look for specific mutations.
  • Prenatal testing:  
    • Amniotic fluid chloride levels may be elevated.
    • Alpha-fetoprotein level is low in antenatal BS.

Management and Complications

The tubular defects in BS cannot be corrected (except by kidney transplantation). The goal of management is to decrease the effects of elevated prostaglandins, renin, and angiotensin in types I, II, and IV.  In the milder adult form, or classic BS, the primary goal is to normalize serum potassium levels.

Prenatal Bartter syndrome with severe polyhydramnios

  • NSAIDs to antagonize the effects of the ↑ prostaglandins 
    • Avoid NSAIDs after 32 weeks of gestation (may cause premature closure of the ductus arteriosus).
    • If NSAIDs are used, repeated ultrasound assessment for the development of tricuspid regurgitation Tricuspid regurgitation Tricuspid regurgitation (TR) is a valvular defect that allows backflow of blood from the right ventricle to the right atrium during systole. Tricuspid regurgitation can develop through a number of cardiac conditions that cause dilation of the right ventricle and tricuspid annulus. A blowing holosystolic murmur is best heard at the left lower sternal border. Tricuspid Regurgitation
  • Consider intermittent amniocentesis in the 3rd trimester to treat severe polyhydramnios by draining excessive amniotic fluid.

Neonatal Bartter syndrome types I, II, and IV

  • IV saline infusion may be needed to treat dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration.
  • Oral potassium supplementation will likely needed.

Childhood or adult Bartter syndrome type III

  • Oral supplementation of 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:
    • To correct fluid and electrolyte imbalances
    • Most likely to require:
      • Potassium
      • Sodium
      • Magnesium
  • NSAIDs:
    • Antagonize the effects of increased prostaglandins
    • Examples: indomethacin, celecoxib
  • Potassium-sparing diuretics Potassium-sparing diuretics Potassium-sparing diuretics are medications that act in the principal cells in the collecting ducts to induce diuresis that does not result in excretion of potassium. These diuretics include 2 subclasses: sodium channel blockers and aldosterone antagonists. Potassium-sparing Diuretics:
    • Blocks distal tubule sodium–potassium exchange → can ↑ serum K+ and reverse 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
    • Examples: amiloride, spironolactone 
  • ACE inhibitors and angiotensin receptor blockers: 
    • Decrease elevated angiotensin II and aldosterone levels
    • Limit proteinuria
    • Increase serum potassium 
  • Kidney transplantation:
    • For rare patients with end-stage renal disease and/or nephrocalcinosis
    • Tubular abnormalities resolve after kidney transplantation, without recurrence.

Complications

  • Cardiac arrhythmias and sudden cardiac death due to electrolyte imbalances
  • Failure to thrive
  • Developmental delay
  • Osteopenia or osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis due to calcium loss in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones

Differential Diagnosis

  • Gitelman syndrome Gitelman syndrome Gitelman syndrome is a rare genetic autosomal recessive disorder 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 and hypomagnesemia. Gitelman Syndrome: 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 caused by one of several mutations in the genes encoding sodium chloride and magnesium transporters in the thiazide-sensitive segments of the distal nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys. Gitelman syndrome Gitelman syndrome Gitelman syndrome is a rare genetic autosomal recessive disorder 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 and hypomagnesemia. Gitelman Syndrome is characterized by renal potassium loss, 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, hypocalciuria, hypomagnesemia, and hyperreninemic hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism with normal blood pressure. A key feature differentiating Gitelman syndrome Gitelman syndrome Gitelman syndrome is a rare genetic autosomal recessive disorder 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 and hypomagnesemia. Gitelman Syndrome from Bartter syndrome is the urine calcium level, which will typically be high-normal in BS and low in GS. 
  • Diuretic abuse with loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics: target the TAL and increase the excretion of sodium, potassium, chloride, calcium, magnesium, and water. Hypokalemia is a common side effect and can be significant. Loop diuretics are used mainly to treat edematous conditions, such as heart failure and cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, and they may also be used in the management 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.
  • Cyclic vomiting syndrome: condition characterized by recurrent, prolonged episodes of severe nausea and vomiting.  Metabolic alkalosis and 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 may result from GI losses. The cause is unknown and can begin at any age. Episodes of vomiting may last hours or days with symptom-free intervals in between for weeks. Diagnosis is made clinically after ruling out other conditions. Management is aimed at controlling symptoms and avoiding triggers, as well as medications to prevent or relieve nausea.
  • Bulimia nervosa Bulimia nervosa Bulimia nervosa is an eating disorder marked by recurrent episodes of binge eating accompanied by inappropriate compensatory behaviors (laxatives or diuretics use, self-induced vomiting, fasting, or excessive exercise) to counteract the effects of binge eating and prevent weight gain. Bulimia Nervosa: eating disorder characterized by recurrent episodes of binge eating with inappropriate compensatory behavior, often including self-induced vomiting and/or diuretic, laxative, or thyroid hormone abuse. Bulimia nervosa Bulimia nervosa Bulimia nervosa is an eating disorder marked by recurrent episodes of binge eating accompanied by inappropriate compensatory behaviors (laxatives or diuretics use, self-induced vomiting, fasting, or excessive exercise) to counteract the effects of binge eating and prevent weight gain. Bulimia Nervosa frequently involves comorbid psychopathology. Treatment consists of psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy and often psychopharmacologic agents.
  • Pyloric stenosis: obstruction of outflow from the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach due to hypertrophy and hyperplasia of the pyloric sphincter muscle. Pyloric stenosis is the most common cause of GI obstruction in infants. Affected newborns typically present after the 3rd to 5th week of life with progressive nonbilious vomiting and a firm olive-like mass in the epigastrium. Diagnosis is by ultrasonography, and management consists of fluid resuscitation, correction of electrolyte imbalances, and surgery.
  • Hyperaldosteronism: defined as increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary or may be secondary to other causes. Classically, primary hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism 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, and 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.  Diagnosis is made by lab testing and imaging of the adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands.  Management involves the use of aldosterone receptor antagonist medications and surgical excision of any aldosterone-secreting tumors.

References:

  1. Emmett, M., Ellison, D. H. (2019).  Bartter and Gitelman syndromes. UpToDate. https://www.uptodate.com/contents/bartter-and-gitelman-syndromes
  2. Bartter syndrome. Retrieved May 5, 2021, from https://rarediseases.info.nih.gov/diseases/5893/bartter-syndrome#:~:text=Bartter%20syndrome%20is%20a%20group%20of%20very%20similar,volume%20of%20fluid%20surrounding%20the%20fetus%20%28amniotic%20fluid%29
  3. Online Mendelian Inheritance in Man. (n.d.). Bartter syndrome, Retrieved May 5, 2021, from https://www.omim.org/entry/607364
  4. Al Shibli, A., Narchi, H. (2015). Bartter and Gitelman syndromes: spectrum of clinical manifestations caused by different mutations. World Journal of Methodology 5(2):55–61.
  5. Bokhari, S.R.A., et al. (2021). Bartter syndrome. StatPearls. Retrieved May 5, 2021, from: https://www.ncbi.nlm.nih.gov/books/NBK442019/

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