What Is Bartter Syndrome?

Bart syndrome, or Bartter syndrome, is characterized by hypokalemia, renin, aldosterone, but normal blood pressure, juxtaglomerular hyperplasia, and hypertrophy. Early manifestations of polyuria, thirst, constipation, anorexia and vomiting, more common in children under 5 years of age, have been thought to be clinical syndromes caused by mutations in ion channel genes.

Bart syndrome

Bart syndrome disease information

Chinese name: Bart syndrome

English name: Bartter syndrome

Alias: Bartter-Gietlman syndrome; Bartter syndrome; Bartle syndrome; Heterotype secondary aldosteronism syndrome; Secondary aldosteronism syndrome; Juxtaglomerular hyperplasia syndrome; Juxtaglomerular cell hyperplasia; Conjunctival alkalosis; congenital hypokalemia; congenital hyperaldosteronism; diffuse juxtaglomerular cell hyperplasia; Bart's syndrome; normotensive hyperaldosteronism. ^[1]

Bart syndrome epidemiology

In 1962, Bartter reported two cases for the first time, and similar reports have since been reported. This disease is rare. Hundreds of cases have been reported so far, and dozens of cases have been reported in China. But more cases may be missed. According to a retrospective study of 28 cases in Sweden, the estimated incidence is 19/1 million worldwide and all races have been reported, but the incidence of blacks is relatively high, and women are slightly older than men. The earliest age of diagnosis is 20 weeks to 50 years of age. The disease is common in children, and more than half of those who have symptoms before the age of 5 have a significant familial tendency, but rare vertical inheritance. It has been reported that 4 patients in 2 families of a family inherited an autosomal recessive inheritance pattern.

Causes of Bart syndrome

The cause of this pathogen is inconclusive. Most scholars consider it an autosomal recessive disease. There have been reports of 5 out of 9 siblings and 4 outbreaks in a second generation. The possible reasons are:

Sodium chloride loss renal tubular defect: proximal tubular defect, distal tubular defect, distal and proximal tubular defect, thick segmental defect of the ascending branch of the myelin, and part of the membrane defect.

Loss of potassium tubular defects.

Renal prostaglandins are produced too much.

The response of the vessel wall to angiotensin II is low.

Primary juxtaglomerular hyperplasia.

Primary atrial natriuretic peptide increased.

Pathogenesis of Bart syndrome

There are many hypotheses, and no theory has successfully explained the pathogenesis of the disease.

Impairment of transport of chloride and sodium and potassium ions in renal tubules Most scholars believe that this disease is caused by renal tubular reabsorption of Cl- and Na + ion disorders. Defective reabsorption sites are:

Proximal renal tubules: mostly without NH4 + and HCO3 + reabsorption disorders.

Both distal and proximal renal tubules have dysfunction: Na +, Cl- loss is increased, Na + is negatively balanced, resulting in decreased blood volume, increased renin, angiotensin and aldosterone secretion and increased distal K + -Na + exchange , K + increased, leading to hypokalemia.

(3) Defective Na + -2Cl- and K + common transport function in the ascending branch of the medullary ridge: Cl- is actively reabsorbed in this segment, and Na + is then passively reabsorbed. Cl- active reabsorption plays an important role in the mechanism of urine concentration. And the reduction of Cl-, Na + reabsorption in this section also reduces the K + reabsorption (normally K + 30% to 40% of the filtrate is reabsorbed in this section), resulting in hypokalemia. Hypokalemia stimulates the production of prostaglandin E2 and increases blood renin and angiotensin . After prostaglandin E2 is elevated, blood vessels are not sensitive to angiotensin , so blood pressure is normal. Impaired renal dilution is reported in patients with this disease, supporting this hypothesis.

Renal tubule Modern molecular biology techniques have also revealed that Bartter syndrome is an autosomal recessive disease caused by mutations in the ion transporter gene on renal tubular epithelial cells. It has been found that infantile Batter syndrome has mutations in the NKCI2 gene. The gene is located at 15q12-21, has 16 exons, encodes 1,099 amino acids for the Na + -K + -2C1-channel, and more than 20 mutations have been found. Classical Bartter syndrome is caused by a mutation in the CICNKB gene, which is located at 1q38 and encodes a Cl-channel on the basal side of a cell containing 687 amino acids. About 20 mutation types have been found in adult Bartter syndrome, also known as Bartter-Gietlman. The syndrome is caused by mutations in the thiazide-sensitive Na + -K + channel gene (SCI12A3), which is located at 16q913 and encodes 1021 amino acids. Up to 40 mutations have been found. In addition, some patients found mutations in the potassium channel gene (ROWK). Therefore, Batter syndrome can be identified as a clinical syndrome caused by the mutations of the above-mentioned ion channel genes.

Low response to angiotensin in blood vessels Bartter originally believed that the low response to angiotensin in the vessel wall was the cause of the disease. This results in reduced vascular tone, decreased renal perfusion, stimulated compensatory hypertrophy and hypertrophy of the juxtaglomerular apparatus, increased renin, angiotensin, and aldosterone secretion, increased K +, and produced hypokalemia. Because blood vessels respond to angiotensin II poorly, blood pressure is normal, but it does not explain why patients have no sodium retention and increased blood volume

Excessive production of prostaglandins in the kidney Dunn proposed in 1981 that excessive production of prostaglandins in the kidney may be the cause of the disease. Prostaglandins increase renin secretion through direct action or by promoting sodium excretion, thereby promoting angiotensin to produce aldosterone Release and release K +, prostaglandins have a direct effect on aldosterone synthesis, and can also reduce vascular tone and change the response of blood vessels to vasoactive substances, including angiotensin II. Although prostaglandin's increased urinary Na + excretion may be due to non-specific hemodynamic effects (similar to other vasodilators), prostaglandin E2 can prevent the collection of Na + reabsorption from the collecting duct and the thickening of the renal medullary branch to C1-weighted Absorption is reduced, thus causing increased K + excretion and hypokalemia. However, some scholars believe that this is not the primary pathogenesis of the disease, because prostaglandin production and excretion are not increased in some patients, and most patients can only partially improve symptoms when using prostaglandin synthesis inhibitors. Even when urinary prostaglandin E2 is completely discharged during steroidal anti-inflammatory drugs, the loss of Cl and urinary concentration dysfunction have not been reversed. Therefore, the increase in prostaglandin is more likely to be secondary to angiotensin , renin, and vasopressors. May stimulate phospholipase A to increase prostaglandin production in the kidney, hypokalemia can also increase the prostaglandin E2 synthesis in the kidney, which can return to normal after water restriction, which suggests that the increase in prostaglandin excretion in this disease is due to polyuria. Because the application of indomethacin can sometimes restore all the abnormal manifestations of the disease to normal, some patients may determine the existence of excessive primary prostaglandin production, which plays an important role in the pathogenesis of the disease.

Clinical manifestations of Bart syndrome

The clinical manifestations of this disease are complex and diverse, mainly hypokalemia symptoms. Fetal Bartter syndrome is manifested as intermittent onset of polyuria, resulting in polyhydramnios at 22 to 24 weeks of pregnancy. Repeated pumping of amniotic fluid is required to prevent preterm birth.

The most common symptoms in children are growth retardation (51%), muscle weakness (41%), weight loss (3l%), polyuria (28%), convulsions (26%), and thirst (26%).

Renal tubular reabsorption The most common symptoms of the adult type are muscle weakness (40%), followed by fatigue (21%) and convulsions (26%). Rare symptoms include paresis, paresthesia, polyuria at night, constipation, nausea, vomiting and even bowel. Obstruction, short-standing erect hypotension with salt, vinegar, or sour pickles, short stature, gout, hypercalciuria, mental calcification, progressive renal failure, rickets, magnesium deficiency, erythrocytosis, etc.

It is worth noting that some patients (10% of pediatrics, 37% of adults) are asymptomatic and were diagnosed at other consultations. Two patients with this disease have been reported to have special faces, large heads, prominent foreheads, triangular ears, large eyes, and drooping corners.

Bart syndrome complications

Electrolyte disorders are complicated by hyperuricemia, renal calcification, gout, kidney stones, intestinal obstruction, and mental immature. The main complications in children are developmental disorders, vitamin D deficiency, mental retardation, and special facial features, and severe renal failure may occur in severe cases.

Bart syndrome diagnosis

The main points of diagnosis of this disease are:

Body fluid index table Hypokalemia (1.5 2.5mmol / L).

High urine potassium (> 20mmol / L).

Metabolic alkalosis (plasma HCO3-> 30mmol / L)

Hyperreninemia.

Hyperaldosteroneemia.

Not sensitive to exogenous vasopressin

Juxtaglomerular hyperplasia

Hypochloremia (urine chlorine> 20mmol / L).

Normal blood pressure.

Clinically, the disease can be gradually diagnosed according to the diagnosis steps of Bartter syndrome shown in Figure 1.

Differential diagnosis of Bart syndrome

Primary aldosteronism may appear hypokalemia and hyperaldosteroneemia, but have hypertension and hyporeninemia, and are sensitive to angiotensin response.

figure 1 Pseudohyperaldosteronism (IAddle syndrome) also presents hypokalemia with metabolic alkalosis but has hypertension, hyporeninemia, and hypoaldosteronemia.

Pseudo-Bartter syndrome caused by abuse of diuretic laxatives or long-term diarrhea, loss of potassium and chloride, hypokalemia, hyperreninemia, and hyperaldosteroneemia, but the symptoms were improved after stopping the above drugs.

Bart syndrome test

Laboratory inspection:

Most cases have significant hypokalemia, generally below 2.5mmol / L, and the lowest can reach 1.5mmol / L. Metabolic alkalosis is also a common manifestation. Blood HCO3- is increased (28-45mmol / L). Blood H + value is increased or normal due to the effects of metabolic mechanisms, hypokalemia, or renal insufficiency, and low sodium or low chloride may also appear Hypoxemia, infants and young children with hypochloremia and alkalosis are the most serious, blood chlorine can be as low as (62 ± 9) mmol / L. Hyperreninemia, hyperaldosteroneemia, and insensitivity to angiotensin and vasopressin are also laboratory features of this disease. There are also reports of increased blood urinary prostaglandin, increased excretion of bradykinin and renal relaxin, hypotonic urine, pH is alkaline, and renal concentration and dilution function are often reduced. About 30% of patients have proteinuria, and some patients have reduced renal function . Some patients may also have hypercalcemia, hypophosphatemia, increased sodium concentration in hypoxeocytes and decreased sodium outflow, with occasional hypercalciuria.

Renal biopsy showed pathological changes such as membranoproliferative glomerulonephritis, interstitial nephritis, and renal calcification. The proliferation and hypertrophy of the juxtaglomerular apparatus are the main pathological abnormalities of the disease. From these cells, all signs of increased renin synthesis can be seen. Electron microscopy showed that rough endoplasmic reticulum and Golgi complex hypertrophy may be renin deposition and increased renin synthesis. Immunocytochemistry has confirmed that the dense plaque cells atrophy and abnormally flat compact plaque structure abnormalities cause abnormal renin secretion due to inability to feedback regulation. Glomerular mesangial cells proliferate, forming fibrosis around the glomeruli of the crescent, especially arterial and small arterial smooth muscle cells are replaced by juxtaglomerular cells, and thickening and sclerosis of the renal arteries make the arterioles Decreased perfusion can also promote increased renin secretion, which in turn acts on vascular smooth muscle to contract blood vessels, renal tubular atrophy and vacuole formation, and renal medullary stromal cell proliferation can be seen, but it can quickly disappear after potassium supplementation.

Other auxiliary inspections:

B-ultrasound Routine imaging examinations, such as X-ray examination, B-ultrasound and ECG, etc., if necessary, EEG and brain CT.

Related tests: pH (urine) prostaglandin salivary aldosterone urine prostaglandin uroaldosterone urine potassium urine magnesium antidiuretic cortisol plasma renin activity angiotensin 1

Bart syndrome treatment

Potassium supplementation for a long time in large doses of oral potassium chloride to correct hypokalemia. The dose is> 10mmol / (kg · d), sometimes as high as 500mmol / d in older children.

Potassium-sparing diuretics can use spironolactone (Ansutone) 10-15mg / (kg · d) or ampicillin 10mg / (kg · d).

Prostaglandin synthase inhibitors such as indomethacin (indomethacin) ibuprofen and aspirin can improve clinical symptoms and correct hyperreninemia and hyperaldosteroneemia. Indomethacin (indomethacin) is the most effective. The dosage is 2-5 mg / (kg · d). To avoid water and sodium retention, it should be started in small doses. Cases resistant to indomethacin (indomethacin) can be replaced with ibuprofen (isobutyric acid). Of the 10 patients reported by Dillan, 6 patients treated with indomethacin (indomethacin) for 6 to 24 months significantly improved the condition and accelerated growth, but one patient developed duodenal ulcer after high-dose application.

Angiotensin transferase inhibitors such as captopril (mercaptoproline), have a certain effect, the dosage is 0.5 ~ 1mg / (kg · d), orally divided into 3 times.

Propranolol (propranolol) beta-adrenergic blockers can reduce renin activity but its effectiveness has not been confirmed.

Magnesium chloride is used to correct hypomagnesemia.

It is believed that the combined use of the above drugs, such as potassium supplementation, potassium diuresis, and low-dose indomethacin (indomethacin), is more effective than one drug alone.

Prognosis for Bart syndrome

Prognosis:

Symptoms in infants are severe, 1/3 have mental retardation, and can die after dehydration, electrolyte disturbances and infection. Almost all of them have growth retardation. Some patients have progressive renal insufficiency and even develop acute Renal Failure. Of the 11 deaths reported, 10 were younger than one year old, mostly due to dehydration, electrolyte disturbances, or repeated infections, and older and adults mostly died of chronic renal failure.

prevention:

The cause is inconclusive and there are no exact precautions. After the diagnosis of this disease should be actively symptomatic treatment to prevent complications.