Bartter syndrome

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Bartter syndrome
Classification and external resources

Scheme of renal tubule and its vascular supply. ICD-10 ICD-9 OMIM DiseasesDB eMedicine MeSH E26.8 255.13 601678 241200 607364 602522 1254 med/213 ped/210 D001477

Bartter syndrome is a rare inherited defect in the thick ascending limb of the loop of Henle. It is characterized by low potassium levels (hypokalemia)[1] , increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.

Features
In 90% of cases, neonatal Bartter syndrome is seen between 24 and 30 weeks of gestation with excess amniotic fluid (polyhydramnios). After birth, the infant is seen to urinate and drink excessively (polyuria, and polydipsia, respectively). Life-threatening dehydration may result if the infant does not receive adequate fluids. About 85% of infants dispose of excess amounts of calcium in the urine (hypercalciuria) and kidneys (nephrocalcinosis), which may lead to kidney stones. In rare occasions, the infant may progress to renal failure. Patients with classic Bartter syndrome may have symptoms in the first two years of life, but they are usually diagnosed at school age or later. Like infants with the neonatal subtype, patients with classic Bartter syndrome also have polyuria, polydipsia, and a tendency to dehydration, but normal or just slightly increased urinary calcium excretion without the tendency to develop kidney stones. These patients also have vomiting and growth retardation. Kidney function is also normal if the disease is treated,[2] but occasionally patients proceed to end-stage renal failure. Bartter's syndrome consists of hypokalaemia, alkalosis, normal to low blood pressures, and elevated plasma renin and aldosterone. Numerous causes of this syndrome probably exist. Diagnostic pointers include high urinary potassium and chloride despite low serum values, increased plasma renin, hyperplasia of the juxtaglomerular apparatus on renal biopsy, and careful exclusion of diuretic abuse. Excess production of renal prostaglandins is often found. Magnesium wasting may also occur.

[edit] Diagnosis
People suffering from Bartter syndrome present symptoms that are identical to those of patients who are on loop diuretics like furosemide. The clinical findings characteristic of Bartter syndrome are hypokalemia, metabolic alkalosis, and normal to low blood pressure. These findings may also be caused by:

Chronic vomiting: These patients will have low urine chloride levels (Bartter's will have relatively higher urine chloride levels). Abuse of diuretic medications (water pills): The physician must screen urine for multiple diuretics before diagnosis is made. Magnesium deficiency and Calcium deficiency: These patients will also have low serum and urine magnesium and calcium

Patients with Bartter syndrome may also have elevated renin and aldosterone levels.[3] Prenatal Bartter syndrome can be associated with polyhydramnios.[4]

[edit] Pathophysiology
Bartter syndrome is caused by mutations of genes encoding proteins that transport ions across renal cells in the thick ascending limb of the nephron.[2]

Bartter and Gitelman syndromes can be divided into different subtypes based on the genes involved:[5] Name neonatal Bartter's syndrome neonatal Bartter's syndrome classic Bartter's syndrome Bartter's syndrome with sensorineural deafness Bartter's syndrome associated with autosomal dominant hypocalcemia Gitelman's syndrome Bartter type type 1 type 2 type 3 type 4 type 5 Associated gene Defect mutations NKCC2 Na-K-2Cl symporter thick ascending limb K+ ROMK channel CLCNKB Cl- channel Cl- channel accessory [6] BSND subunit activating mutation of the CASR[7] calcium-sensing receptor SLC12A3 Sodium-chloride (NCCT) symporter

[edit] Treatment
While patients should be encouraged to include liberal amounts of sodium[citation needed] and potassium in their diet, potassium supplements are usually required, and spironolactone is also used to reduce potassium loss.[1] Nonsteroidal antiinflammatory drugs (NSAIDs) can be used as well, and are particularly helpful in patients with neonatal Bartter's syndrome. Angiotensin-converting enzyme (ACE) inhibitors can also be used.

[edit] Prognosis
The limited prognostic information available suggests that early diagnosis and appropriate treatment of infants and young children with Classic Bartter Syndrome may improve growth and perhaps neurointellectual development. On the other hand, sustained hypokalemia and hyperreninemia can cause progressive tubulointerstitial nephritis, resulting in end-stage-renal disease (Kidney failure). With early treatment of the electrolyte imbalances the prognosis for patients with Classic Bartter Syndrome is good.

[edit] History
The condition is named after Dr. Frederic Bartter, who, along with Dr. Pacita Pronove, first described it in 1960 and in more patients in 1962.[3][8][9][10]

[edit] Related conditions

Bartter and Gitelman syndromes are both characterized by hypokalemia, normal to low blood pressure, and hypochloremic metabolic alkalosis.[11]

Pseudo-Bartters syndrome is a syndrome of similar presentation as Bartter syndrome but without any of its characteristic genetic defects. Pseudo-Bartters syndrome has been seen in cystic fibrosis,[12] as well as in excessive use of laxatives.[13]

[edit] References
1. ^ a b "Bartter Syndrome: Tubular and Cystic Kidney Disorders: Merck Manual Home Edition". Retrieved 2007-12-31. 2. ^ a b Rodriguez-Soriano J (1998). "Bartter and related syndromes: the puzzle is almost solved". Pediatr Nephrol 12 (4): 31527. doi:10.1007/s004670050461. PMID 9655365. 3. ^ a b Bartter FC, Pronove P, Gill JR Jr, MacCardle RC (1962). "Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome". Am J Med 33 (6): 81128. doi:10.1016/0002-9343(62)90214-0. PMID 13969763. Reproduced in Bartter FC, Pronove P, Gill JR, MacCardle RC (1998). "Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. 1962". J. Am. Soc. Nephrol. 9 (3): 51628. PMID 9513916.

Friday, July 16, 2010

Hypokalemia/hypomagnesemia might be Gittelman's Syndrome
27y/o Caucasian female ADAF for 30 wk ROB G2 P1. Hx pre-eclampsia, bedrest and delivery baby girl at 35wks wt 5lbs 6 years ago. Current pregnancy was progressing normally except hypokalemic on oral replacement therapy and dietary changes. Today she presents with 15lb weight gain since last ROB visit, elevated BP 150s/110s but HR at her baseline (not tachycardic/still working on the floor and short staffed prior to appt) and complaints of heart burn. BP repeat manual no real improvement; fundal height consistent with dates, FHTs 150s, good fetal movement but patient reports some DOE. CMP ordered to f/u hypokalemia. Results showed continued hypokalemia (slightly improved) and new hypomagnesemia. WHNP consulted with OB MD and patient to start po magnesium supplementation slo-mag which was not available at MTF so civilian prescription given to patient. Patient now considered high risk OB and all future care must be scheduled with MD. Patient reported to provider later in the day that SOB worsening. CXR ordered and results WNL. OB MD consulted with MFM at another facility (not NNMC) and he recommended referral to MFM but order further blood (CBC, full chem. panel, LFTs) and urine electrolytes prior to MFM appt. Her urine electrolytes returned abnormal. Later that week patient had appt with MFM and was placed on bed rest at home with frequent provider appts. Patients previous OB records not available (civilian provider) and patient had consulted with OB provider prior to attempting this pregnancy because she was concerned pre-eclampsia and preterm delivery could occur again. She was told there would be a chance but not likely. MFMs differential diagnoses include Gittelmans syndrome and nephrogenic diabetes insipidus. Needless to say this patient's stress level was elevated from this point forward and she was very concerned about the well being of her unborn child. Luckily she has a strong support network but her family does not live nearby and she now had to drive much further for her OB care. I do not know if she has received a definitive diagnosis yet.

Inherited Tubular Transport Abnormalities

Proximal Tubule Abnormalities
Hypophosphatemic rickets (Vitamin D resistant rickets) o Clinical Features: Presents within 1-2 years of birth with bowing of lower extremities, dental abnormalities, and growth failure o Biochemical features: serum phosphorus, urine phosphate, normal serum calcium and PTH, and inappropriately normal to low 1,25 OH (active) Vitamin D levels. o Similar biochemical abnormality: oncogenic hypophosphatemic osteomalacia: acquired disorder in adults associated with certain tumors; disease resolves after removal of the tumor. o Hypophosphatemic rickets recurs after kidney transplantation therefore, not just kidney involved. o Mutated gene: PHEX = phosphate-regulating gene with homologies to endopetidases on the X chromosome. Expressed in bone; found to be mutated in kindred. o Mode of Inheritance: X-linked inheritance. o Current theory: "unmodified phosphatonin" in the blood vitamin D uptake, degradation of active vitamin D. Bone modified "phosphatonin" usually vitamin D uptake and degradation of active vitamin D; however, mutated PHEX does not modify the "phosphatonin" correctly and get unmodified "phosphatonin".

Loop of Henle and Distal Nephron Abnormalities

Bartter/Gittelman Syndromes o Clinical features: vary, depending on form. Infantile patients. tend to have episodes of dehydration and failure to thrive. o Biochemical features: hypokalemic, hypochloremic metabolic alkalosis. renin and aldosterone. + + Bartters patients: labs look similar to taking loop diuretics; blocks Na , K , 2 Cl pump; including hypercalciuria. + Gittelmans patients: looks like on thiazide diuretics, blocks Na -Cl cotransporter; hypocalcuria and hypomagnesemia. o 3 types: Neonatal, Classic, Gittelman can have history of intimate muscle weakness, chronic dermatitis Neonatal Bartter's "Classic" Bartter's Syndromes Syndrome (type III) ( types I and II) Loop of Henle: NKCC2 (type I) CIC-Kb ROMK (type II) Antenatal/Neonate Very common Rare Normal Very High Infancy/Childhood Common Rare Normal Normal-High Gittelman's Syndrome

Transporter defect (Mutated Gene) Age of presentation Recurrent dehydration Recurrent tetany Serum magnesium Urine calcium o

Distal Convolute Tubule: NCCT Childhood/Adulthood Unusual Often present Low Low

NKCC2 = sodium-potassium-2 chloride cotransporter; ROMK = inwardly rectifying potassium channel; CIC-Kb = renal chloride channel; NCCT = sodium-chloride cotransporter.

Note: Calcium reabsorption decreases with inhibition of NKCC2 channel because there will be less K recycling and a lessening of the lumen-positive electrical gradient which drives the passive reabsorption of calcium in this segment. Familial Hypocalciuric Hypercalcemia (FHH) o Clinical Features: often asymptomatic in heterzygotes. Severe cases seen in homozygotes for the mutation (consanguineous kindred) hyperparathyroidism ++ serum Ca levels and bony abnormalities. ++ o Biochemical features: mildly elevated serum Ca , urine calcium, normal or PTH. Poor response to parathyroidectomy. o Mode of inheritance: Autosomal dominant. (AD) o Mutated gene: Extracellular calcium receptor (Ca-R) Expressed in the PTH gland and kidney (loop of henle) In parathyroid gland mediates extracellular calcium induced suppression of PTH. Kidney inhibits ROMK. Loss of function mutation: ROMK inhibition Na, Ca absorption serum calcium, urine calcium. o Note: if Ca-R undergoes a gain-of-function (activating) mutation: ROMK inhibition + ++ Na , Ca absorption hypocalcemia, hypercalciuria

Collecting Tubule Abnormalities

Liddle syndrome o Clinical features: hypertension. o Biochemical abnormalities: hypokalemia, metabolic alkalosis, renin, aldosterone. o Mode of inheritance: AD with highly variable penetrance o Mutated Gene: Epithelial Sodium Channel (ENaC) composed of alpha, beta, gamma; sensitive to amiloride; gain of function mutations in beta and gamma and produce constitutive activation of the channel and inappropriate sodium retention (Figure 3). Nephrogenic Diabetes Insipidus o Clinical features: massive polyuria, polydipisia, recurrent dehydration (volume depletion) especially in infants, recurrent episodes of hypernatremia (can lead to neurologic symptoms), and growth failure. o Biochemical features: Low urine specific gravity and osmolality, inability to concentrate urine even in the face of volume depletion. No response to exogenous vasopressin. ADH. o Mutated gene: Loss of function mutation in genes encoding aquaporin 2 (AQP2) or the vasopressin (ADH) V2 receptor. (Figure 3) o Mode of Inheritance: X-linked recessive inheritance is the most common form; AD and AR have been described

Gittelmans syndrome (Orphanet Journal of Rare Diseases, 2008) Gitelman syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia.

GS is transmitted as an autosomal recessive trait. Mutations in the solute carrier family12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC), are found in the majority of GS patients. At present, more than 140 different NCC mutations throughout the whole protein have been identified. In a small minority of GS patients, mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb have been identified. Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria). Bartter syndrome (especially type III) is the most important genetic disorder to consider in the differential diagnosis of GS. Genetic counseling is important. Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients. Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesiumsulfate) is recommended. Cardiac work-up should be offered to screen for risk factors of cardiac arrhythmias. All GS patients are encouraged to maintain a high-sodium and high potassium diet. In general, the long-term prognosis of GS is excellent. http://www.ojrd.com/content/3/1/22 (longer more detailed version available at this website) Nephrogenic diabetes insipidus (Nephrogenic diabetes insipidus foundation website, 2010) occurs when the kidney tubules do not respond to a chemical in the body called antidiuretic hormone (ADHADH), also called vasopressin. ADH normally tells the kidneys to make the urine more concentrated. As a result of the defect, the kidneys release an excessive amount of water into the urine, producing a large quantity of very dilute urine. This makes you produce large amounts of urine. Nephrogenic diabetes insipidus is rare. Congenital diabetes insipidus is present at birth as a result of an inherited defect that usually affects men, although women can pass the gene on to their children. Most commonly, nephrogenic diabetes insipidus develops because of other reasons. This is called an acquired disorder. Factors that can trigger the acquired form of this condition include: Blockage in the urinary tract High calcium levels Low potassium levels Use of certain drugs (lithium, demeclocycline, amphotericin B) http://www.ndif.org/public/pages/1-Introduction (more detailed information)

Posted by T Betancourt at 12:19 PM