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Guide: Recommendations for diagnosis and treatment of rare endocrine diseases-Gitelman syndrome.
Gitelman syndrome (Gitelman syndrome, GS; OMIM 263800) is an autosomal recessive genetic disease caused by the dysfunction of the sodium and chloride cotransporter (NCC) in the distal convoluted tubules of the kidney.
The disease was first reported by the American doctor Gitelman in 1966, but it was not until 1996 that the pathogenic gene SLC12A3 was clarified.
The main clinical features are hypokalemia and metabolic alkalosis caused by renal potassium loss, often accompanied by hypomagnesemia, low urine calcium and renin-angiotensin-aldosterone system (RAAS) activation, normal or low blood pressure .
The etiology and epidemiology of Gitelman syndrome Gitelman syndrome is caused by a mutation in the SLC12A3 gene that encodes a thiazide diuretic-sensitive sodium chloride cotransporter (NCC).
Under physiological conditions, the channel protein NCC is located on the lumen side of the epithelial cells of the distal convoluted tubules of the kidney, and participates in the reabsorption of 5%-10% chloride and sodium ions in the glomerular filtrate.
It is a way for the body to maintain the balance of water and electrolytes.
An important line of defense.
When gene mutations cause NCC structure and/or dysfunction, the reabsorption of chloride and sodium ions from the distal renal tubules is reduced, the kidney reabsorption of water is reduced, and secondary RAAS activation, renal potassium loss and calcium reabsorption are reduced.
At present, nearly 500 SLC12A3 gene mutations have been found in patients with Gitelman syndrome (
In addition, mutations in the CLCNKB gene encoding the chloride channel ClC-Kb (Batter syndrome type III) and mutations in the HNF1B gene encoding liver transcription factor 1-β (HNF1-β) can also produce similar clinical manifestations.
Gitelman syndrome is one of the most common hereditary renal tubular diseases, with a prevalence of about 1/4000 to 1/4000, which may be higher in Asian populations.
Because the disease is easily missed or misdiagnosed, it is difficult to determine the true prevalence of the disease in the general population.
At present, no significant difference in the incidence of men and women has been observed.
Clinical manifestations of patients Gitelman syndrome often onset in adolescence or early adulthood.
The clinical manifestations are mainly related to hypokalemia and hypomagnesemia.
Mild patients may be asymptomatic or show mild fatigue and anorexia; severe patients may experience convulsions, paresis, cramps, syncope, and rhabdomyolysis secondary to acute kidney Damage, or even cardiac arrest due to severe ventricular arrhythmia.
It is currently believed that the heterogeneity of the clinical manifestations of Gitelman syndrome is not only related to the type of gene mutations and modified genes, but also related to environmental factors such as the patient's gender and eating habits.
Common clinical manifestations are as follows.
1.
Systemic symptoms: fatigue, thirst, polydipsia, and salt addiction.
2.
Neuro-muscular system muscle weakness, cramps, convulsions, convulsions, numbness, paresthesia, rhabdomyolysis, paralysis, dizziness, vertigo, ataxia, pseudo-brain tumors, etc.
3.
Cardiovascular system palpitations, syncope, normal or low blood pressure, and ventricular arrhythmia.
4.
Digestive system constipation, vomiting, etc.
5.
Urinary system polyuria, nocturia, enuresis, proteinuria and renal insufficiency.
6.
Bone joint system arthralgia, cramps (chondrcalcinosis).
7.
Endocrine and growth retardation, delayed puberty; long-term low potassium and low magnesium, the proportion of diabetes or impaired glucose tolerance is not uncommon.
8.
A few patients with ocular symptoms will have blurred vision and scleral choroidal calcification. The causes of proteinuria and renal damage in patients with Gitelman syndrome are mainly related to long-term hypokalemia.
The latter can lead to tubular interstitial damage and cyst formation.
Proteinuria is mainly derived from tubules; secondly, because of the long-term activation of RAAS, it may be directly or Indirectly lead to glomerular segmental sclerosis, a very small number of cases have other glomerular diseases, such as IgA nephropathy, C1q nephropathy, etc.
, but the correlation between it and Gitelman syndrome is not clear.
Auxiliary examination 1.
Serum (plasma) detection of potassium (K), magnesium (Mg), calcium (Ca), phosphorus (P), uric acid (UA), creatinine (Cr), blood gas, and orthorenin-angiotensin -Aldosterone level, blood sugar or glucose tolerance test.
2.
Urine test urine routine, 24-hour urine protein quantification, 24-hour urine potassium, sodium, chloride, magnesium, calcium, phosphorus, uric acid and creatinine; when serum potassium is less than 3.
5mmol/L, 24-hour urine potassium is more than 25mmol.
In line with renal potassium loss.
3.
ECG assesses whether the QT interval is prolonged and whether it is combined with arrhythmia and other manifestations.
4.
Kidney Ultrasound The kidney morphology is usually normal.
Patients with chronic hypokalemia may develop renal cysts, which can be used to rule out other renal potassium loss caused by abnormal kidney structure.
5.
In the hydrochlorothiazide test, a small dose of hydrochlorothiazide (50mg) was used to directly block NCC, the degree of change in chloride excretion fraction (△FECl) before and after use was observed, and the NCC function was evaluated by comparing it with the normal control.
The sensitivity and specificity for diagnosing Gitelman syndrome in Chinese population when △FECl<2.
86% are 95.
7% and 95.
8%, respectively.
At present, the modified hydrochlorothiazide test is safer, simpler, and less costly.
However, for patients with suspected Batter syndrome, attention should be paid to monitoring the risk of further reduction in serum potassium.
6.
Genetic testing is the gold standard for diagnosing Gitelman syndrome.
The detection of SLC12A3 homozygous mutations or compound heterozygous mutations can be diagnosed.
Patients with single heterozygous mutations need to be combined with the clinic, and newly discovered mutations need in vitro functional tests to determine the pathogenicity of the mutations. Diagnosis of Gitelman syndrome 1.
Hypokalemia caused by chronic renal potassium loss, accompanied by metabolic alkalosis, plasma renin-angiotensin-aldosterone system activation (standing position), but normal or low blood pressure patients , Salt-loss nephropathy should be considered.
2.
If combined with hypomagnesium (<0.
7mmol/L) or low urine calcium (adult urinary calcium to creatinine ratio<0.
2mmol/mmol), NCC dysfunction should be highly suspected.
Further chloride ion scavenging test (hydrochlorothiazide test) can help locate NCC dysfunction and can initially judge the degree of damage.
It should be noted that even if the blood magnesium is normal or the urine calcium is not low, Gitelman syndrome cannot be ruled out.
3.
Except for long-term use of hydrochlorothiazide diuretics or laxatives, other distal tubule dysfunction caused by drugs, immune diseases (such as Sjogren’s syndrome) or monoclonal immunoglobulin disease.
4.
The diagnosis requires genetic diagnosis.
Differential diagnosis of Gitelman syndrome Gitelman syndrome is mainly differentiated from the following two types of diseases: 1.
Other causes of hypokalemia.
First, it is necessary to determine whether renal potassium loss is based on the medical history and the comparison of 24-hour urine potassium and blood potassium levels.
Then check the level of urinary chlorine.
If the level of urinary chlorine excretion is not high (<20mmol/L=, be aware of vomiting, diarrhea, etc.
; otherwise, consider the presence of renal chlorine loss; with hypertension, be alert to primary/secondary aldosterone Hyperplasia, Cushing’s syndrome; if combined with metabolic acidosis, be alert to renal tubular acidosis.
Secondly, exclude other drugs (especially diuretics and traditional Chinese medicine), immune diseases and plasma cell disease secondary to renal potassium loss, you can Identify through corresponding examinations.
2.
Other salt-losing nephropathy such as Batter syndrome.
Classic Batter syndrome (Batter syndrome type III) is caused by mutations in the CLCNKB gene that encodes the chloride channel ClC-Kb, and its onset is relatively more severe.
Early (before 3 years old), the degree of hypokalemia is more severe, and growth retardation and polyuria are more likely to occur.
The patient's blood magnesium level is usually normal, and the urine calcium level is normal or high. The patient responded to the hydrochlorothiazide test, indicating that the NCC function is normal; but the furosemide test did not respond, which is helpful for clinical identification.
Genetic testing can help confirm the diagnosis.
Treatment of Gitelman syndrome Gitelman syndrome is based on symptomatic treatment and electrolyte replacement therapy, in order to achieve the goal of relieving symptoms, improving quality of life, and avoiding serious complications.
The overall treatment principles are as follows: 1.
Alternative treatment recommends a high-salt diet, eating foods rich in potassium and magnesium, oral potassium chloride, potassium magnesium aspartate, magnesium sulfate, and magnesium chloride, and intravenous infusion in emergency or severe cases Injection of potassium salt and magnesium salt.
In 2017, the KDIGO expert controversial consensus recommended that the treatment targets for serum potassium and magnesium be 3.
0mmol/L and 0.
6mmol/L, respectively.
2.
Other treatment potassium-sparing diuretics (such as spironolactone, eplerenone), renin-angiotensin system inhibitors (use with caution in hypotension) inhibit RAAS activation, prostaglandin synthase inhibitors (indomethacin, etc.
) ) Helps reduce the dose of potassium supplements and improve symptoms related to hypokalemia.
However, attention should be paid to monitoring the side effects of related drugs.
3.
Patient management and education.
Emphasize individualized disease management, cultivate and strengthen patients' self-monitoring of symptoms and signs, use drugs on time, seek medical attention at the right time, follow up regularly, and pay attention to the mental health of patients.
4.
Special circumstances For patients with Gitelman syndrome during pregnancy, perioperative period and other diseases, monitoring and active follow-up should be strengthened, and drugs should be adjusted in time to avoid aggravation and serious complications.
Figure 1 Flow chart of diagnosis and treatment of Gitelman syndrome.
Note: GS, Gitelman syndrome; BS, Bartter syndrome.
Figure 2 Flow chart of diagnosis and treatment of hypokalemia.
The above content is taken from: National Health Commission of the People's Republic of China.
Guidelines for the diagnosis and treatment of rare diseases (2019 edition) [J].
The official website of the National Health Commission of the People's Republic of China.
Gitelman syndrome (Gitelman syndrome, GS; OMIM 263800) is an autosomal recessive genetic disease caused by the dysfunction of the sodium and chloride cotransporter (NCC) in the distal convoluted tubules of the kidney.
The disease was first reported by the American doctor Gitelman in 1966, but it was not until 1996 that the pathogenic gene SLC12A3 was clarified.
The main clinical features are hypokalemia and metabolic alkalosis caused by renal potassium loss, often accompanied by hypomagnesemia, low urine calcium and renin-angiotensin-aldosterone system (RAAS) activation, normal or low blood pressure .
The etiology and epidemiology of Gitelman syndrome Gitelman syndrome is caused by a mutation in the SLC12A3 gene that encodes a thiazide diuretic-sensitive sodium chloride cotransporter (NCC).
Under physiological conditions, the channel protein NCC is located on the lumen side of the epithelial cells of the distal convoluted tubules of the kidney, and participates in the reabsorption of 5%-10% chloride and sodium ions in the glomerular filtrate.
It is a way for the body to maintain the balance of water and electrolytes.
An important line of defense.
When gene mutations cause NCC structure and/or dysfunction, the reabsorption of chloride and sodium ions from the distal renal tubules is reduced, the kidney reabsorption of water is reduced, and secondary RAAS activation, renal potassium loss and calcium reabsorption are reduced.
At present, nearly 500 SLC12A3 gene mutations have been found in patients with Gitelman syndrome (
In addition, mutations in the CLCNKB gene encoding the chloride channel ClC-Kb (Batter syndrome type III) and mutations in the HNF1B gene encoding liver transcription factor 1-β (HNF1-β) can also produce similar clinical manifestations.
Gitelman syndrome is one of the most common hereditary renal tubular diseases, with a prevalence of about 1/4000 to 1/4000, which may be higher in Asian populations.
Because the disease is easily missed or misdiagnosed, it is difficult to determine the true prevalence of the disease in the general population.
At present, no significant difference in the incidence of men and women has been observed.
Clinical manifestations of patients Gitelman syndrome often onset in adolescence or early adulthood.
The clinical manifestations are mainly related to hypokalemia and hypomagnesemia.
Mild patients may be asymptomatic or show mild fatigue and anorexia; severe patients may experience convulsions, paresis, cramps, syncope, and rhabdomyolysis secondary to acute kidney Damage, or even cardiac arrest due to severe ventricular arrhythmia.
It is currently believed that the heterogeneity of the clinical manifestations of Gitelman syndrome is not only related to the type of gene mutations and modified genes, but also related to environmental factors such as the patient's gender and eating habits.
Common clinical manifestations are as follows.
1.
Systemic symptoms: fatigue, thirst, polydipsia, and salt addiction.
2.
Neuro-muscular system muscle weakness, cramps, convulsions, convulsions, numbness, paresthesia, rhabdomyolysis, paralysis, dizziness, vertigo, ataxia, pseudo-brain tumors, etc.
3.
Cardiovascular system palpitations, syncope, normal or low blood pressure, and ventricular arrhythmia.
4.
Digestive system constipation, vomiting, etc.
5.
Urinary system polyuria, nocturia, enuresis, proteinuria and renal insufficiency.
6.
Bone joint system arthralgia, cramps (chondrcalcinosis).
7.
Endocrine and growth retardation, delayed puberty; long-term low potassium and low magnesium, the proportion of diabetes or impaired glucose tolerance is not uncommon.
8.
A few patients with ocular symptoms will have blurred vision and scleral choroidal calcification. The causes of proteinuria and renal damage in patients with Gitelman syndrome are mainly related to long-term hypokalemia.
The latter can lead to tubular interstitial damage and cyst formation.
Proteinuria is mainly derived from tubules; secondly, because of the long-term activation of RAAS, it may be directly or Indirectly lead to glomerular segmental sclerosis, a very small number of cases have other glomerular diseases, such as IgA nephropathy, C1q nephropathy, etc.
, but the correlation between it and Gitelman syndrome is not clear.
Auxiliary examination 1.
Serum (plasma) detection of potassium (K), magnesium (Mg), calcium (Ca), phosphorus (P), uric acid (UA), creatinine (Cr), blood gas, and orthorenin-angiotensin -Aldosterone level, blood sugar or glucose tolerance test.
2.
Urine test urine routine, 24-hour urine protein quantification, 24-hour urine potassium, sodium, chloride, magnesium, calcium, phosphorus, uric acid and creatinine; when serum potassium is less than 3.
5mmol/L, 24-hour urine potassium is more than 25mmol.
In line with renal potassium loss.
3.
ECG assesses whether the QT interval is prolonged and whether it is combined with arrhythmia and other manifestations.
4.
Kidney Ultrasound The kidney morphology is usually normal.
Patients with chronic hypokalemia may develop renal cysts, which can be used to rule out other renal potassium loss caused by abnormal kidney structure.
5.
In the hydrochlorothiazide test, a small dose of hydrochlorothiazide (50mg) was used to directly block NCC, the degree of change in chloride excretion fraction (△FECl) before and after use was observed, and the NCC function was evaluated by comparing it with the normal control.
The sensitivity and specificity for diagnosing Gitelman syndrome in Chinese population when △FECl<2.
86% are 95.
7% and 95.
8%, respectively.
At present, the modified hydrochlorothiazide test is safer, simpler, and less costly.
However, for patients with suspected Batter syndrome, attention should be paid to monitoring the risk of further reduction in serum potassium.
6.
Genetic testing is the gold standard for diagnosing Gitelman syndrome.
The detection of SLC12A3 homozygous mutations or compound heterozygous mutations can be diagnosed.
Patients with single heterozygous mutations need to be combined with the clinic, and newly discovered mutations need in vitro functional tests to determine the pathogenicity of the mutations. Diagnosis of Gitelman syndrome 1.
Hypokalemia caused by chronic renal potassium loss, accompanied by metabolic alkalosis, plasma renin-angiotensin-aldosterone system activation (standing position), but normal or low blood pressure patients , Salt-loss nephropathy should be considered.
2.
If combined with hypomagnesium (<0.
7mmol/L) or low urine calcium (adult urinary calcium to creatinine ratio<0.
2mmol/mmol), NCC dysfunction should be highly suspected.
Further chloride ion scavenging test (hydrochlorothiazide test) can help locate NCC dysfunction and can initially judge the degree of damage.
It should be noted that even if the blood magnesium is normal or the urine calcium is not low, Gitelman syndrome cannot be ruled out.
3.
Except for long-term use of hydrochlorothiazide diuretics or laxatives, other distal tubule dysfunction caused by drugs, immune diseases (such as Sjogren’s syndrome) or monoclonal immunoglobulin disease.
4.
The diagnosis requires genetic diagnosis.
Differential diagnosis of Gitelman syndrome Gitelman syndrome is mainly differentiated from the following two types of diseases: 1.
Other causes of hypokalemia.
First, it is necessary to determine whether renal potassium loss is based on the medical history and the comparison of 24-hour urine potassium and blood potassium levels.
Then check the level of urinary chlorine.
If the level of urinary chlorine excretion is not high (<20mmol/L=, be aware of vomiting, diarrhea, etc.
; otherwise, consider the presence of renal chlorine loss; with hypertension, be alert to primary/secondary aldosterone Hyperplasia, Cushing’s syndrome; if combined with metabolic acidosis, be alert to renal tubular acidosis.
Secondly, exclude other drugs (especially diuretics and traditional Chinese medicine), immune diseases and plasma cell disease secondary to renal potassium loss, you can Identify through corresponding examinations.
2.
Other salt-losing nephropathy such as Batter syndrome.
Classic Batter syndrome (Batter syndrome type III) is caused by mutations in the CLCNKB gene that encodes the chloride channel ClC-Kb, and its onset is relatively more severe.
Early (before 3 years old), the degree of hypokalemia is more severe, and growth retardation and polyuria are more likely to occur.
The patient's blood magnesium level is usually normal, and the urine calcium level is normal or high. The patient responded to the hydrochlorothiazide test, indicating that the NCC function is normal; but the furosemide test did not respond, which is helpful for clinical identification.
Genetic testing can help confirm the diagnosis.
Treatment of Gitelman syndrome Gitelman syndrome is based on symptomatic treatment and electrolyte replacement therapy, in order to achieve the goal of relieving symptoms, improving quality of life, and avoiding serious complications.
The overall treatment principles are as follows: 1.
Alternative treatment recommends a high-salt diet, eating foods rich in potassium and magnesium, oral potassium chloride, potassium magnesium aspartate, magnesium sulfate, and magnesium chloride, and intravenous infusion in emergency or severe cases Injection of potassium salt and magnesium salt.
In 2017, the KDIGO expert controversial consensus recommended that the treatment targets for serum potassium and magnesium be 3.
0mmol/L and 0.
6mmol/L, respectively.
2.
Other treatment potassium-sparing diuretics (such as spironolactone, eplerenone), renin-angiotensin system inhibitors (use with caution in hypotension) inhibit RAAS activation, prostaglandin synthase inhibitors (indomethacin, etc.
) ) Helps reduce the dose of potassium supplements and improve symptoms related to hypokalemia.
However, attention should be paid to monitoring the side effects of related drugs.
3.
Patient management and education.
Emphasize individualized disease management, cultivate and strengthen patients' self-monitoring of symptoms and signs, use drugs on time, seek medical attention at the right time, follow up regularly, and pay attention to the mental health of patients.
4.
Special circumstances For patients with Gitelman syndrome during pregnancy, perioperative period and other diseases, monitoring and active follow-up should be strengthened, and drugs should be adjusted in time to avoid aggravation and serious complications.
Figure 1 Flow chart of diagnosis and treatment of Gitelman syndrome.
Note: GS, Gitelman syndrome; BS, Bartter syndrome.
Figure 2 Flow chart of diagnosis and treatment of hypokalemia.
The above content is taken from: National Health Commission of the People's Republic of China.
Guidelines for the diagnosis and treatment of rare diseases (2019 edition) [J].
The official website of the National Health Commission of the People's Republic of China.
