Low Magnesium levels Lead to Low Blood Calcium Levels in Gitelman’s

Figure 3. Individual circulating levels of intact PTH, 25OHD, and 1,25-(OH) 2 D in 13 patients with Gitelman’s syndrome (*) and 13 healthy subjects ().

between circulating ionized calcium and 1,25-(OH)2 D3 concentrations was also significant ( P < 0.05) in both patients ( y = 966 – 670 x ; r2 = 0.86) and controls ( y = 1345 – 919 x ; r2 = 0.67). The slopes and the intercepts with the x-axis were not significantly different in patients and controls. The relationship between circulating PTH (independent value) and 1,25-(OH)2 D3 (dependent value) was statistically

Figure 4. Relationship between circulating levels of ionized calcium and intact PTH ( upper panel ), between ionized calcium and 1,25-(OH)2 D ( middle panel ), and between intact PTH and 1,25-(OH)2 D ( lower panel ) in 13 patients with Gitelman’s syndrome (*) and 13 control subjects ( and – - -). A significant ( P < 0.05) relationship was observed between circulating ionized calcium (independent variable) and intact PTH (dependent variable) in patients ( y = 29.1 – 20.7 x ; r2 = 0.84) and controls ( y = 39.5 – 27.2 x ; r 2 = 0.75). The slopes of both regressions lines were identical, but the intercepts were significantly ( P < 0.05) different. The relationship between circulating ionized calcium and 1,25-(OH) 2 D was significant ( P < 0.05) in both patients ( y = 966 – 670 x ; r2 = 0.86) and controls ( y = 1345 – 919 x ; r 2 = 0.67). The slopes of both regressions lines were identical, but the intercepts were significantly ( P < 0.05) different. The relationship between circulating PTH (independent value) and 1,25-(OH)2 D (dependent value) was statistically significant and virtually identical in patients ( y = 38.4 + 26.6 x ; r2 = 0.69) and controls ( y = 27.3 + 28.8 x ; r2 = 0.65).

significant and virtually identical in patients ( y = 38.4 + 26.6 x ; r2 = 0.69) and controls ( y = 27.3 + 28.8 x ; r2 = 0.65). No significant relationships were observed between circulating PTH or 1,25-(OH)2 D3 (dependent values) and blood pH or plasma bicarbonate (independent values) in patients or controls.

The BMD values at the lumbar spine were similar in 11 patients with Gitelman’s syndrome (0.953 g/cm2 ; range, 0.893-1.013) and 11 normal subjects (0.934 g/cm2 ; range, 0.818-1.050) matched for sex, age, and body surface area. When compared with healthy adolescents reported previously[17] , the BMD values, expressed as z-scores for age and sex, were 0.17 (-0.33-0.67) in Gitelman patients and 0.24 (-0.26-0.74) in controls. The BMD z-scores for pubertal stage and sex were 0.11 (-0.39-0.61) in Gitelman patients and 0.12 (-0.32-0.56) in control subjects. Individual values are given in Fig. 5.

Discussion

The present study confirms in a relevant cohort the existence of a subset of patients with Bartter’s syndrome who, in addition to hypokalemia and metabolic alkalosis, display mild to moderate magnesium depletion associated with hypocalciuria (1-8). The study also indicates that these patients with so-called Gitelman’s syndrome display normal blood concentrations of PTH, 25OHD3 , and 1,25-(OH)2 D3 , thus raising the question of the origin of hypocalciuria. Finally, the study provides information on two phenomena: one dealing with the interplay between the secretory process of the calciotropic hormones in relation to magnesium deficiency, and the other dealing with bone mass in relation to hypocalciuria and the postulated negative calcium balance of these individuals.

Hypocalcemia is a prominent manifestation in states of chronic magnesium deficiency (9-16). In contrast to patients with hypomagnesemia from other causes, the total plasma calcium concentration has generally been reported to be normal or even high in patients with Gitelman’s syndrome (1-8), the latter because of dehydration-induced hyperproteinemia. The average ionized calcium concentration in blood was also normal in a group of patients with Bartter’s syndrome

Figure 5. Individual values for lumbar mineralometry assessed by dual energy x-ray absorptiometry in 11 patients with Gitelman’s syndrome (*) and 11 normal subjects (). The left panel denotes BMD (grams per cm2 ) in the two groups. The middle panel denotes the z-scores for age and sex; the right panel denotes the z-score for pubertal stage and sex.

and reduced or normal blood levels of magnesium[21] . High total plasma calcium, but low plasma ionized calcium, were observed in our patients with Bartter’s syndrome and magnesium deficiency. The former is accounted for by dehydration-induced hyperproteinemia, with the high albumin concentration in plasma leading to excessive binding of calcium. The latter results from metabolic alkalosis, which leads ionized calcium to excessive complexation with bicarbonate.

The release of PTH is impaired in severe magnesium deficiency; for a given level of ionized calcium in blood, the PTH concentration is lower in such patients than in their control counterparts[9] [10] [11] [12] [13] [14] [15] [16] . In the present study, as in others, the serum PTH concentration was similar in Gitelman patients and healthy subjects[6] ,[21] . However, the relationship between PTH and ionized calcium concentrations clearly was blunted in the patients, thus providing the first evidence that patients with Gitelman’s syndrome have a disturbed secretion of PTH. Although not proven by maneuvers of magnesium repletion, the finding is probably accounted for by the renal magnesium depletion encountered in these patients. The identity of the relationship between 1,25-(OH) 2 D3 and PTH levels in patients and controls is noteworthy; it shows that mild to moderate renal magnesium deficiency does not interfere with the action of PTH on 1alpha-hydroxylase.

Finally, severe hypocalciura is a prominent feature in Gitelman’s syndrome[1] [2] [3] [4] [5] [6] [7] [8] . Several mechanisms must be envisioned to account for this finding. The first of these is a low dietary intake of calcium, but in our patients this has been excluded as a potential cause. Secondly, hypomagnesemia is known to promote tubular calcium reabsorption[22] ,[23] , but in Gitelman’s syndrome, urinary calcium has been shown to remain low even after correction of hypomagnesemia[6] . Thirdly, insufficient intestinal absorption of calcium[24] , inasmuch as in this study there was a trend for 1,25-(OH)2 D 3 levels to be low for a given blood level of ionized calcium. Clearly, balance studies with direct measurement of intestinal calcium absorption have to be carried out to address this issue. However, normal BMD results, which are new information in the field, speak against chronically sustained negative calcium balance. One might argue that 12 of our 13 patients with Gitelman’s syndrome had received magnesium supplementation or treatment with inhibitors of prostaglandin synthesis for 5-42 months; however, such a short period of treatment is unlikely to have consistently corrected or prevented a tendency toward low BMD.

In summary, the present investigations in patients with Gitelman’s syndrome confirm the renal origin of magnesium depletion and disclose the suppressed relationship between calcium and PTH levels with a tendency toward hypocalcemia, which seems to be due to chronic hypomagnesemia.

Journal of Clinical Endocrinology and Metabolism
Volume 80 Number 1 January 1, 1995
Copyright 1995 The Endocrine Society

M. G. BIANCHETTI,  A. BETTINELLI, J. P. CASEZ, E. BASILICO,  M. G. METTA,  I. SPICHER,  C. SANTERAMO,  M. BIGONI, PH. JAEGER

Abteilung fuur Nephrologie, Universitaatskinderklinik (M.G.B., I.S.), and Medizinische Universitaatspoliklinik (J.P.C., P.J.), Bern, Switzerland; and Istituto di Clinica Pediatrica II (A.B., E.B., M.G.M.) and Istituto di Scienze Mediche, Ospedale Policlinico (M.B.), Universitaa di Milano, and Laboratorio di Ricerche Cliniche, Istituti Clinici di Perfezionamento (C.S.),
Milan, Italy

Received May 14, 1994. Revision received September 12, 1994. Accepted September 16, 1994. Address all correspondence and requests for reprints to: Dr. Ph. Jaeger, Policlinic of Medicine, University Hospital, CH-3010 Bern, Switzerland.

References

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