Gitelman syndrome: pathophysiological and clinical aspects

Graziani, G.; Fedeli, Carlo; Moroni, Luca; Cosmai, Laura; Badalamenti, Salvatore; Ponticelli, Claudio

doi:10.1093/qjmed/hcq123

Cited by 69 publications

(77 citation statements)

References 34 publications

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“…In Gitelman syndrome, renin and Ang II are increased, but aldo may be normal to low because of aldo suppression by marked hypokalemia. Patients with Gitelman syndrome show cardiac arrhythmias but no structural CV alteration 42 or increase in CV risk. 43 Conversely, patients with apparent mineralocorticoid excess, in which impaired activity of 11-β-hydroxysteroid dehydrogenase 2 allows glucocorticoids to activate MR despite low plasma aldo, have hypertension and early vascular complications.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Effects of Aldosterone

Escoubet

Couffignal

Laisy

et al. 2013

Circ Cardiovasc Genet

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A ldosterone (aldo) plays a key role in the control of sodium and potassium balance in the distal tubule of the kidney, thus regulating water body content and blood pressure (BP). Aldo acts through the mineralocorticoid receptor (MR), which is a ligandactivated transcription factor. Alteration of the aldo and MR signaling cascade leads to salt-wasting syndromes or hypertension. Clinical Perspective p 390In addition to their role in fluid and electrolyte homeostasis, aldo and MR are important factors for organ damage in cardiovascular (CV) and chronic kidney disease. [2][3][4] This is supported by the beneficial effects of MR antagonism in acute myocardial infarction and heart failure, [5][6][7] although mechanisms underlying the CV effects of aldo are still under debate. Chronic activation of the renin-angiotensin-aldo system (RAAS) is associated with progressive cardiac, vascular, and kidney injury, and aldo per se has deleterious CV effects that are independent of BP levels. In familial hyperaldosteronism type 1 (also known as glucocorticoid remediable aldosteronism), increased aldo levels lead to cardiac and vascular damage in young patients, before the onset of hypertension. 8 In common forms of primary aldosteronism, patients display more CV complications (stroke, nonfatal myocardial infarction, atrial fibrillation) than hypertensive subjects.9,10 MR signaling has been shown to be directly involved in macrophage-dependent cardiac remodeling and fibrosis, 11,12 salt-induced hypertension, 3 vascular remodeling,Background-High plasma aldosterone has deleterious cardiovascular effects that are independent of blood pressure, but the role of the mineralocorticoid receptor remains unclear. Renal pseudohypoaldosteronism type 1 is a rare autosomaldominant disease caused by NR3C2 loss-of-function mutations, which is characterized by renal salt loss and compensatory high renin and aldo secretion. We aimed to assess the cardiovascular outcomes in adults carrying NR3C2 mutations. Methods and Results-In this case-control study, 39 NR3C2 mutation carriers were compared with sex-and age-paired noncarriers. Patients underwent cardiac and vascular ultrasound, cardiac MRI with gadolinium injection, measurement of pulse wave velocity, extracellular water, 24-hour ambulatory blood pressure, and autonomous nervous system activity. Mutation carriers showed increased aldo and renin plasma levels (4. and stroke. 13 In most clinical situations, the respective contributions of renin, angiotensin II (Ang II), aldo, and MR are difficult to assess because of their simultaneous involvement and interaction.14,15 Indeed, experimental models have illustrated a crosstalk between Ang II and aldo signaling in cardiac remodeling and progression of kidney damage. [15][16][17][18] Type 1 pseudohypoaldosteronism (PHA1) is a rare disease of mineralocorticoid resistance.19-21 Despite extremely high plasma renin and aldo levels, patients present with neonatal salt wasting and failure to thrive, hyponatremia, hyperkalemia, and metabolic acidosis...

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Section: Discussionmentioning

confidence: 99%

Cardiovascular Effects of Aldosterone

Escoubet

Couffignal

Laisy

et al. 2013

Circ Cardiovasc Genet

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“…In patients with TD abuse, NCCT is inhibited [34]. Abnormalities in electrolyte tubular transport are similar to those seen in GS [4,13,15,34]. Sometimes the creatinine level is elevated [4,35].…”

Section: Discussionmentioning

confidence: 97%

“…Sometimes the creatinine level is elevated [4,35]. TD abuse is often found in cases of eating disorders, weight-loss attempts and sport doping [30][31][32][33][34]36].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Gitelman syndrome DD thiazide diuretics abuse

Keller

Beule²,

Dippold³

2014

Open Medicine

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AbstractIntroduction. Gitelman syndrome (GS) is a rare inherited disorder. Mutations in SLC12A3 gene that encode tubular Na+Cl-cotransporter (NCCT) cause hypokalemic metabolic alkalosis, salt loss, hypomagnesaemia and hypocalciuria. The symptoms include weakness, vertigo, hypotension, tetany, paresthesia and nausea. Diagnostic criteria are a normal urine concentrating ability, normal glomerular filtration rate (GFR), hypomagnesaemia (<0,65mmol/l), hypokalemia (<3,6mmol/l) and hypocalciuria (<0,1mmol/mmol creatinine). Previously, the diagnosis was made by exclusion. Today, genetic analysis can ensure diagnosis. Thiazide diuretics (TD) abuse with similar abnormalities can make the differential diagnosis difficult. Causal therapy of GS does not exist. The substitution of potassium and magnesium are therapeutic strategies. Case presentation. A 41-year-old obese woman presented at the emergency department with recurrent episodes of hypokalemia with concomitant weakness, muscle cramps, polyuria and collapse. The results of laboratory testing of blood and urine led to the suspected diagnosis of GS. In the follow-up examinations, the results were inconsistent. Therefore, a transient thiazide diuretics abuse was assumed. Discussion. This case demonstrates the difficulties in making the diagnosis of GS on the basis of only clinical and laboratory tests, without the use of genetic analysis. The differentiation between GS and thiazide diuretic abuse is especially difficult.

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“…Besides, the complex relationship between the calcium metabolism and magnesium metabolism in GS patients is not completely clear, hypomagnesemia may impair the function of calciotropic hormones; despite the fact that GS patients have normal calcitriol plasma level, their bones have a decreased sensitivity to parathyroid hormone (PTH) and their intestinal calcium transport is impaired, both of which would cause a low reaction to hypocalcinuria [8], which could be relieved by redressing the blood magnesium levels [9]. Some GS patients suffer from chondrocalcinosis, it may be related to the decreased pyrophosphatase activity caused by metabolic alkalosis and hypomagnesemia, the impaired enzymatic activity aggravates pyrophosphate salt crystallization in the peripheral portion of the joint and causes arthralgia [10]. Related studies have found that male GS patients have more severe symptoms than female patients do, which is related to female hormone [11,12].…”

Section: Discussionmentioning

confidence: 99%