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Concurrent renal hypomagnesemia and hypoparathyroidism with normal parathormone responsiveness
Concurrent Renal Hypomagnesemia and Hypoparathyroidism with Normal Parathormone Responsiveness
MICHAEL J. DURAN, M.D. GEORGE C. BORST, III, M.D. ROBERT C. OSBURNE, M.D. CHARLES EIL, M.D., Ph.D. Bethesda, Maryland
From the Endocrinology Branch, Department of Medicine, Naval Hospital Bethesda and Uniformed Services University of the Health Sciences, Bethesda, Maryland. The opinions and assertions expressed herein are the private ones of the authors and are not to be construed as official or reflecting the view of the Navy Department, the Naval Service at large, or the Department of Defense. Requests for reprints should be addressed to Dr. Charles Eil, Box 396, National Naval Medical Center, Bethesda, Maryland 20814. Manuscript accepted March 8, 1983.
A 24-year-old woman presented with clinical features suggesting hypoparathyroidism: tetany, basat ganglia cak#ication, and a history of a seizure disorder. Hypocalcemia was present on admission despite therapy with calcium and vitamin D. Hormonal evaluation revealed undetectable parathormone levels and a normal cyclic AMP and phosphaturic response to parathormone infusion, suggesting the diagnosis of idiopathic hypoparathyroidism. Additional testing, however, revealed hypomagnesemia and elevated urinary magnesium levels. Normomagnesemia could not be consistently achieved despite oral magnesium administration. When the serum magnesium level was temporarily normalized via intravenous magnesium supplementation, parathormone levels rose into the normal range. These data indicate that the patient’s hypomagnesemia was most likely due to renal magnesium loss. The normalization of her parathormone level during magnesium replenishment, along with the parathormone infusion data, suggests that this patient’s hypomagnesemia was responsible for decreased parathormone synthesis and/or secretion, while target tissue responsiveness to parathormone was maintained. The effects of hypomagnesemia on calcium and parathyroid hormone metabolism have been studied extensively during the past decade. Although it is generally agreed that hypomagnesemia is often associated with a lowering of serum calcium levels, controversy remains regarding the role of decreased magnesium in producing impaired parathormone secretion versus target organ unresponsiveness to parathormone. Some investigators have found elevated parathormone levels and impaired end-organ responsiveness to exogenous parathormone infusion in magnesiumdeficient patients [l-4]. On the other hand, low or inappropriately normal parathormone levels with a normal target tissue response to parathormone have also been reported in such patients [5- 111. In this report, we describe a woman with hypomagnesemia due to a severe renal tubular defect. Her hypomagnesemia could not be overcome with normal replacement therapy. This patient also had hypoparathyroidism, but she had a completely normal response to parathormone infusion (Ellsworth-Howard test). Moreover, when serum magnesium levels were transiently corrected by intravenous magnesium supplements, parathormone levels, which were initially unmeasurable, rose to within the range of detection of the assay. Thus, the data on this patient would support the critical role of serum magnesium in parathormone secretion, not in parathormone action on the kidney.
January 1984
The American Journal of Medicine
Volume 76
151
HYPOMAGNESEMIA
AND
HYPOPARATHYROIDISM-DURAN
ET AL
CASE REPORT A 24-year-old white woman was referred to the National Naval Medical Center for evaluation of hypocalcemia that had been discovered two years previously as a result of finding calcified basal ganglia on skull films performed for head trauma. At that time, the serum calcium level was 6.9 mg/dl, serum phosphate level 5.6 rng/dl, and the parathormone level reported as “below normal.” She was subsequently treated with varying dosages of oral calcium and several vitamin D preparations, but experienced wide fluctuations in serum calcium levels, the most recent known value being 7.2 mg/dl about eight months prior to admission. Medications at the time of admission included calcium lactate, 7.8 g twice daily, dihydrotachysterol, 0.375 mg daily, oral contraceptives, and multivitamins, which had been a stable regimen for about nine months. There was a history of a seizure disorder from age 2 to age 6, and the patient reported having carpopedal spasms with exercise since age 8. There was no family history of endocrinopathy, with the exception of diabetes mellitus in two uncles and short stature in her grandmother. Findings on physical examination were within normal limits, including normal stature and metacarpal length. Chvostek and Trousseau signs were negative and there was no evidence of candidiasis. There was normal calcification of the teeth and no cataract formation. Laboratory evaluation revealed a serum calcium level of 6.8 mg/dl and a serum phosphate level of 4.7 mg/dl. The following values were normal: albumin, 4.3 g/dl; alkaline phosphatase, 52 units/liter (normal 30 to 115 units/liter); serum creatinine, 0.8 mg/dl; and 24-hour urinary calcium, 158 mg. Electrolyte levels and results of urinalysis were normal. The serum thyroxine level was 11.9 pg/dl, resin triiodothyronine uptake, 0.77 (normal 0.8 to 1.2), and an A.M. cortisol level was 21 pg/dl. Serum carotene and fecal fat levels were normal at 64 pgldl and 5.6 g per 24 hours, respectively. The serum parathormone level was undetectable (below 0.022 ng eq/ml with a normal upper limit of 0.24 ng eq/ml). The baseline serum magnesium level, measured by atomic absorption, was 0.93 mg/dl (normal 1.7 to 2.9) and urinary magnesium excretion rate was 56 mg per 24 hours. Following oral magnesium replacement therapy (1.8 g magnesium oxide once daily for a week), the serum magnesium level was 1.09 mg/dl with a urinary magnesium
TABLE I
Response to Parathormone
Infusion*
Serum Time Ca++ (minutes) (mgldl) o+ 30 60 120 180 240
Urine Ca++ Phosphate CyclicAMP Phosphate (mg/total (mg/total (nmollmg
7.6 7.9 7.7 7.7 7.7 8.2
(mgldl) 4.7 4.3 3.9 3.9 4.0 4.2
volume) 2.3 1.8 4.8 4.7 3.4 5.3
volume) 7.2 3.6 36.0 55.8 46.6 29.7
creatinine) 3.4 570 250 9.3 4.1 -
250 units bovine parathormone extract (Lilly) given intravenously over 10 minutes at time 0. At this time, serum electrolyte levels included a Mg++ value of 0.93 mg/dl. + Preinfusion baseline parathormone level undetectable. l
152
January 1984
The American Journal of Medicine
excretion rate of 211 mg per 24 hours. The patient had received a single dose of 650 mg of magnesium oxide prior to undergoing an Ellsworth-Howard test. The results of an Ellsworth-Howard test with intravenous administration of bovine parathormone extract (250 units, Lilly) are shown in Table I, revealing a normal nephrogenous cyclic AMP and phosphaturic response. The patient’s oral magnesium replacement was limited to a maximum dose of 4 g of magnesium oxide daily, due to the development of diarrhea. When the serum magnesium level was transiently normalized with intravenous magnesium replacement (4 g magnesium sulfate per day for four days), the parathormone level became detectable (0.066 ng eq/ml). Subsequently, the serum magnesium level again declined, and the patient was essentially asymptomatic when discharged on a regimen of magnesium, calcium, and 1,25dihydroxyvitamin D3. Over the next year, she was hospitalized once for hypercalcemia, and treatment was switched to 50,000 units of vitamin D daily, with which she has done well. There was no apparent decrease in vitamin D requirements due to the magnesium replacement. Cyclic AMP and parathormone levels were measured by
radioimmunoassay as previously described [ 12,131. The parathormone assay reliably differentiated low-normal parathormone levels from absent levels, as demonstrated with control hypoparathyroid serum. COMMENTS The presence of calcifications in the basal ganglia as well as a history of a seizure disorder and occasional episodes of carpopedal spasms in her early years strongly suggest that the hypoparathyroidism in this woman was of long duration [ 141. This would imply that this patient’s hypomagnesemia, if it was responsible for the hypoparathyroidism, was congenital or acquired very early in life. The patient’s hypomagnesemia was associated with, and most likely caused by, renal magnesium wasting. Normal subjects are able to conserve magnesium effectively (urinary magnesium excretion rate less than 20 mg per day) when dietary intake of magnesium is curtailed or the serum magnesium level drops [ 15,161. In contrast, our patient excreted greater than 55 mg of magnesium per 24 hours despite hypomagnesemia. In addition, oral magnesium supplementation resulted in even greater urinary magnesium excretion. Idiopathic renal magnesium wasting with otherwise normal renal function has been reported by others [17-l 91. Although intestinal magnesium absorption per se was not evaluated, there was no evidence of any other form of malabsorption in this patient. Numerous specific causes for hypomagnesemia have been detailed elsewhere [20], but none of these was present in our patient. Hypomagnesemia is not a usual finding in patients with hypoparathyroidism [ 2 11. This patient demonstrated hypoparathyroidism with undetectable basal parathormone levels and normal
Volume 76
HYPOMAGNESEMIA AND HYPOPARATHYROIDISM--DURAN
renal cyclic AMP and phosphaturic responsiveness to exogenous parathormone. Further, when her serum magnesium level was temporarily normalized, the serum parathormone level rose into the detectable range. These findings are consistent with those in a number of other patients who have been reported with both hypomagnesemia and hypocalcemia [5-g]. Anast et al [lo] and Rude et al [ 1 l] have shown in their patients that parathormone ‘levels rise within minutes after parenteral magnesium replacement. This would seem to pinpoint the defect at the level of parathormone secretion rather than at parathormone synthesis, and provides in vivo corroboration for the in vitro findings of Targovnik et al [22] that low magnesium levels in the incubation media decrease parathormone secretion, but not synthesis, by bovine parathyroid glands [23]. The dependence of parathormone release on magnesium-dependent adenylate cyclase in the parathyroid gland would provide a possible biochemical explanation for these observations [24]. Interestingly, however, Cohan et al [25] have shown that the release of cortisol, thyrotropin, and gonadotropins following hormonal stimulation, presumably also mediated by magnesium-dependent adenylate cyclase, was not impaired by magnesium deficiency. Alternatively, several other investigators have found elevated parathormone levels in magnesium-deficient patients, as well as end-organ unresponsiveness to exogenous parathormone [l-4]. For instance, Estep et al [l] showed that in a group of alcoholic patients with magnesium deficiency, there was an extremely blunted calcemic and phosphaturic response to exogenous parathormone, which was corrected following magnesium replacement. Skeletal resistance to parathormone action was clearly demonstrated by Freitag et al [26], who showed in isolated bone from magnesium-deficient dogs that both parathormone extraction and cyclic AMP generation were decreased. Reconciliation of these two lines of divergent data is not easy.
ET AL
Multiple factors may play a role in producing the different results: degree of magnesium depletion, varying tissue sensitivity of enzyme systems to magnesium, and unaccounted biochemical variabilities. Grades of partial resistance of target tissues to parathormone most likely exist, and the sensitivity of bone and kidney to parathormone in magnesium deficiency may well differ [26]. Further, normal or even moderately elevated serum parathormone levels may be inappropriately low in hypocalcemic patients. It appears likely, nonetheless, that both parathormone deficiency and partial or complete parathormone unresponsiveness play a role in producing the hypocalcemia seen in hypomagnesemic patients. Additional factors, most notably an alteration in the equilibrium for calcium between bone and extracellular fluid favoring calcium retention in bone, may also play a role [ 271. The patient presented herein demonstrated both hypomagnesemia and parathormone deficiency. Although a cause and effect relationship cannot be proved, the apparent restoration of parathormone secretory activity during magnesium replacement therapy suggests that hypomagnesemia may have played an etiologic role in this patient’s hypoparathyroidism and hypocalcemia. Regardless of causality, the association between these two entities remains an interesting one, whose further understanding awaits evaluation of other patients with hypomagnesemia and hypocalcemia. ACKNOWLEDGMENT We are grateful to Dr. James C. LaRocque for referring the patient to us, and to Dr. Stephen J. Marx and the Metabolic Diseases Branch, National Institute of Arthritis, Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland, for measuring serum parathormone levels and urinary cyclic AMP levels, as well as for providing the bovine parathormone. We also wish to thank Harriet Harryman and Cathy Morris for expert secretarial assistance.
REFERENCES 1.
2.
3.
4.
5.
EstepIi, ShawWA, Watlington C, Hobe R, Holland W, Tucker SG: Hypocalcemia due to hypomagnesemia and reversible parathyroid hormone unresponsiveness. J Clin Endocrinol Metab 1969; 29: 842-848. Connor TB, Toskes P, Mahaffey J, Martin LG, Williams JB, Walser M: Parathyroid function during chronic magnesium deficiency. John Hopkins Med J 1972; 131: 100-117. Muldowney FP, McKenna TJ, Kyle LH, Freaney R, Swan M: Parathormone-like effect of magnesium replenishment in steatorrhea. N Engl J Med 1970; 282: 61-68. MacManus J, Heaton FW, Lucas PW: A decreased response to parathyroid hormone in magnesium deficiency. J Endocrinol 1971; 49: 253-258. Bar RS, Wilson HE, Mazzaferri EL: Hypomagnesemic hypocalcemia secondary to renal magnesium wasting. Ann In-
January
6.
7.
8.
9.
10.
1984
tern Med 1975; 82: 646-649. Suh SM, Tashjian AH, Matsuo N, Parkinson DK, Fraser D: Pathogenesis of hypocalcemia in primary hypomagnesemia. J Clin Invest 1973; 52: 153-160. Anast CS, Mohs JM, Kaplan SL, Burns TW: Evidence for parathyroid failure in magnesium deficiency. Science 1972; 177: 606-608. Chase LR, Slatopolsky E: Secretion and metabolic effect of parathyroid hormone in patients with severe hypomagnesemia. J Clin Endocrinol Metab 1974; 38: 363-371. Suh SM, Csima A, Fraser D: Pathogenesis of hypocalcemia in magnesium depletion: normal end-organ responsiveness to parathyroid hormone. J Clin Invest 1971; 50: 26682678. Anast CS, Winnacker JL, Forte LR: Impaired release of
The American
Journal of Medicine
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AND HYPOPARATHYROIDISM-DW)AN
ET AL
parathyroid hormone in magnesium deficiency. J Clin Endocrinol Metab 1976; 42: 707-715. 11. Rude RK, Oldham SB, Sharp CF Jr, Singer FR: Parathyroid hormone secretion in magnesium deficiency. J Clin Endocrinol Metab 1978: 47: 800-806. 12. Steiner AL, Parker CW, Kipnis DM: Radioimmunoassay for cyclic nucleotides. I. Preparation of antibodies and iodinated cyclic nucleotkles. J Biol Chem 1972; 247: 1106-1113. 13. Marx SJ, Sharp ME, Krudy A, Rosenblatt M, Mallette LE: Radioimmunoassay for the mkldle region of human parathyroid hormone: studies with a radioiodinated synthetic peptlde. J Clin Endocrinol Metab 1981: 53: 76-84. 14. Aurbach GD, Marx SJ, Spiege.AM: Parathyroid hormone, calcitonin, and the calciferofs. In: Williams RH, ed. Textbcok of endocrinology, 6th ed. Philadelphia: WB Saunders, 1981; 922-1031. 15. Shils ME: Experimental human magnesium deficiency. Medicine (Baltimore) 1969; 48: 61-85. 16. Heaton FW: The kidney and magnesium homeostasis. Ann NY Acad Sci 1969; 169: 775-785. 17. Gitelman HJ, Graham JB, Welt LG: A familial disorder characterized by hypokalemia and hypomagnesemia. Ann NY Acad Sci 1969; 169: 856-864. 16. Runeberg L, Collan Y, Jokinen E, Lahdevirta J, Aro A: Hypornagnesemia dus to renal disease of unknown etiology. Am J Med 1975; 59: 873-881. 19. Evans RA, Carter JN, George CRP. et al: The congenital ‘magnesium-losing” kidney: repcft of two patients. Q J Med 1981; 197: 39-52.
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20. 21.
22.
23.
24.
25.
26.
27.
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Massry SG, Seelig MS: Hypomagnesemla and hypermag nesemia. Clin Nephrol 1977; 7: 147-153. Rude RK, Bethune JE, Singer FR: Renal tubular maximum for magnesium in normal, hyperparathyroid and hypoparathyroid man. J Clin Endocrinol Metab 1980; 51: 14251431. Targovnik JH, Rodman JS, Sherwood LM: Regulation of parathyroid hormone secretion in vitro: quantitatfve aspscts of calcium and magnesium ion control. Endocrinology 1971; 88: 1477-1482. Hamilton JW, Spierto FW, MacGregor RR, Cohn DV: Studies on the biosynthesis in vitro of parathyroid hormone. II. The effect of calcium and magnesium on synthesis of parathyroid hormone isolated from bovine parathyroid tissue and incubation media. J Biol Chem 1971; 246: 32243233. Abe M, Sherwood LM: Regulation of parathyroid hormone secretion by adenylate cyclase. Biochem Biophys Res Commun 1972; 48: 396-402. Cohan BW, Singer FR, Rude RK: End-organ response to adrenocorticotropin, thyrotropin, gonadotropin-releasing hormone, and glucagon in hypocalcemic magnesium deficient patients. J Clin Endocrinol Metab 1982; 54: 975979. Freitag JJ, Martin KJ, Conrades MB, et al: Evidence for skeletal resistance to parathyroid hormone in magnesium deficiency: studies in isolated perfused bone. J Clin Invest 1979; 64: 1238-1244. Massry SG: Pharmacology of magnesium. Annu Rev Pharmacol Toxicol 1977; 17: 67-82.
MICHAEL J. DURAN, M.D. GEORGE C. BORST, III, M.D. ROBERT C. OSBURNE, M.D. CHARLES EIL, M.D., Ph.D. Bethesda, Maryland
From the Endocrinology Branch, Department of Medicine, Naval Hospital Bethesda and Uniformed Services University of the Health Sciences, Bethesda, Maryland. The opinions and assertions expressed herein are the private ones of the authors and are not to be construed as official or reflecting the view of the Navy Department, the Naval Service at large, or the Department of Defense. Requests for reprints should be addressed to Dr. Charles Eil, Box 396, National Naval Medical Center, Bethesda, Maryland 20814. Manuscript accepted March 8, 1983.
A 24-year-old woman presented with clinical features suggesting hypoparathyroidism: tetany, basat ganglia cak#ication, and a history of a seizure disorder. Hypocalcemia was present on admission despite therapy with calcium and vitamin D. Hormonal evaluation revealed undetectable parathormone levels and a normal cyclic AMP and phosphaturic response to parathormone infusion, suggesting the diagnosis of idiopathic hypoparathyroidism. Additional testing, however, revealed hypomagnesemia and elevated urinary magnesium levels. Normomagnesemia could not be consistently achieved despite oral magnesium administration. When the serum magnesium level was temporarily normalized via intravenous magnesium supplementation, parathormone levels rose into the normal range. These data indicate that the patient’s hypomagnesemia was most likely due to renal magnesium loss. The normalization of her parathormone level during magnesium replenishment, along with the parathormone infusion data, suggests that this patient’s hypomagnesemia was responsible for decreased parathormone synthesis and/or secretion, while target tissue responsiveness to parathormone was maintained. The effects of hypomagnesemia on calcium and parathyroid hormone metabolism have been studied extensively during the past decade. Although it is generally agreed that hypomagnesemia is often associated with a lowering of serum calcium levels, controversy remains regarding the role of decreased magnesium in producing impaired parathormone secretion versus target organ unresponsiveness to parathormone. Some investigators have found elevated parathormone levels and impaired end-organ responsiveness to exogenous parathormone infusion in magnesiumdeficient patients [l-4]. On the other hand, low or inappropriately normal parathormone levels with a normal target tissue response to parathormone have also been reported in such patients [5- 111. In this report, we describe a woman with hypomagnesemia due to a severe renal tubular defect. Her hypomagnesemia could not be overcome with normal replacement therapy. This patient also had hypoparathyroidism, but she had a completely normal response to parathormone infusion (Ellsworth-Howard test). Moreover, when serum magnesium levels were transiently corrected by intravenous magnesium supplements, parathormone levels, which were initially unmeasurable, rose to within the range of detection of the assay. Thus, the data on this patient would support the critical role of serum magnesium in parathormone secretion, not in parathormone action on the kidney.
January 1984
The American Journal of Medicine
Volume 76
151
HYPOMAGNESEMIA
AND
HYPOPARATHYROIDISM-DURAN
ET AL
CASE REPORT A 24-year-old white woman was referred to the National Naval Medical Center for evaluation of hypocalcemia that had been discovered two years previously as a result of finding calcified basal ganglia on skull films performed for head trauma. At that time, the serum calcium level was 6.9 mg/dl, serum phosphate level 5.6 rng/dl, and the parathormone level reported as “below normal.” She was subsequently treated with varying dosages of oral calcium and several vitamin D preparations, but experienced wide fluctuations in serum calcium levels, the most recent known value being 7.2 mg/dl about eight months prior to admission. Medications at the time of admission included calcium lactate, 7.8 g twice daily, dihydrotachysterol, 0.375 mg daily, oral contraceptives, and multivitamins, which had been a stable regimen for about nine months. There was a history of a seizure disorder from age 2 to age 6, and the patient reported having carpopedal spasms with exercise since age 8. There was no family history of endocrinopathy, with the exception of diabetes mellitus in two uncles and short stature in her grandmother. Findings on physical examination were within normal limits, including normal stature and metacarpal length. Chvostek and Trousseau signs were negative and there was no evidence of candidiasis. There was normal calcification of the teeth and no cataract formation. Laboratory evaluation revealed a serum calcium level of 6.8 mg/dl and a serum phosphate level of 4.7 mg/dl. The following values were normal: albumin, 4.3 g/dl; alkaline phosphatase, 52 units/liter (normal 30 to 115 units/liter); serum creatinine, 0.8 mg/dl; and 24-hour urinary calcium, 158 mg. Electrolyte levels and results of urinalysis were normal. The serum thyroxine level was 11.9 pg/dl, resin triiodothyronine uptake, 0.77 (normal 0.8 to 1.2), and an A.M. cortisol level was 21 pg/dl. Serum carotene and fecal fat levels were normal at 64 pgldl and 5.6 g per 24 hours, respectively. The serum parathormone level was undetectable (below 0.022 ng eq/ml with a normal upper limit of 0.24 ng eq/ml). The baseline serum magnesium level, measured by atomic absorption, was 0.93 mg/dl (normal 1.7 to 2.9) and urinary magnesium excretion rate was 56 mg per 24 hours. Following oral magnesium replacement therapy (1.8 g magnesium oxide once daily for a week), the serum magnesium level was 1.09 mg/dl with a urinary magnesium
TABLE I
Response to Parathormone
Infusion*
Serum Time Ca++ (minutes) (mgldl) o+ 30 60 120 180 240
Urine Ca++ Phosphate CyclicAMP Phosphate (mg/total (mg/total (nmollmg
7.6 7.9 7.7 7.7 7.7 8.2
(mgldl) 4.7 4.3 3.9 3.9 4.0 4.2
volume) 2.3 1.8 4.8 4.7 3.4 5.3
volume) 7.2 3.6 36.0 55.8 46.6 29.7
creatinine) 3.4 570 250 9.3 4.1 -
250 units bovine parathormone extract (Lilly) given intravenously over 10 minutes at time 0. At this time, serum electrolyte levels included a Mg++ value of 0.93 mg/dl. + Preinfusion baseline parathormone level undetectable. l
152
January 1984
The American Journal of Medicine
excretion rate of 211 mg per 24 hours. The patient had received a single dose of 650 mg of magnesium oxide prior to undergoing an Ellsworth-Howard test. The results of an Ellsworth-Howard test with intravenous administration of bovine parathormone extract (250 units, Lilly) are shown in Table I, revealing a normal nephrogenous cyclic AMP and phosphaturic response. The patient’s oral magnesium replacement was limited to a maximum dose of 4 g of magnesium oxide daily, due to the development of diarrhea. When the serum magnesium level was transiently normalized with intravenous magnesium replacement (4 g magnesium sulfate per day for four days), the parathormone level became detectable (0.066 ng eq/ml). Subsequently, the serum magnesium level again declined, and the patient was essentially asymptomatic when discharged on a regimen of magnesium, calcium, and 1,25dihydroxyvitamin D3. Over the next year, she was hospitalized once for hypercalcemia, and treatment was switched to 50,000 units of vitamin D daily, with which she has done well. There was no apparent decrease in vitamin D requirements due to the magnesium replacement. Cyclic AMP and parathormone levels were measured by
radioimmunoassay as previously described [ 12,131. The parathormone assay reliably differentiated low-normal parathormone levels from absent levels, as demonstrated with control hypoparathyroid serum. COMMENTS The presence of calcifications in the basal ganglia as well as a history of a seizure disorder and occasional episodes of carpopedal spasms in her early years strongly suggest that the hypoparathyroidism in this woman was of long duration [ 141. This would imply that this patient’s hypomagnesemia, if it was responsible for the hypoparathyroidism, was congenital or acquired very early in life. The patient’s hypomagnesemia was associated with, and most likely caused by, renal magnesium wasting. Normal subjects are able to conserve magnesium effectively (urinary magnesium excretion rate less than 20 mg per day) when dietary intake of magnesium is curtailed or the serum magnesium level drops [ 15,161. In contrast, our patient excreted greater than 55 mg of magnesium per 24 hours despite hypomagnesemia. In addition, oral magnesium supplementation resulted in even greater urinary magnesium excretion. Idiopathic renal magnesium wasting with otherwise normal renal function has been reported by others [17-l 91. Although intestinal magnesium absorption per se was not evaluated, there was no evidence of any other form of malabsorption in this patient. Numerous specific causes for hypomagnesemia have been detailed elsewhere [20], but none of these was present in our patient. Hypomagnesemia is not a usual finding in patients with hypoparathyroidism [ 2 11. This patient demonstrated hypoparathyroidism with undetectable basal parathormone levels and normal
Volume 76
HYPOMAGNESEMIA AND HYPOPARATHYROIDISM--DURAN
renal cyclic AMP and phosphaturic responsiveness to exogenous parathormone. Further, when her serum magnesium level was temporarily normalized, the serum parathormone level rose into the detectable range. These findings are consistent with those in a number of other patients who have been reported with both hypomagnesemia and hypocalcemia [5-g]. Anast et al [lo] and Rude et al [ 1 l] have shown in their patients that parathormone ‘levels rise within minutes after parenteral magnesium replacement. This would seem to pinpoint the defect at the level of parathormone secretion rather than at parathormone synthesis, and provides in vivo corroboration for the in vitro findings of Targovnik et al [22] that low magnesium levels in the incubation media decrease parathormone secretion, but not synthesis, by bovine parathyroid glands [23]. The dependence of parathormone release on magnesium-dependent adenylate cyclase in the parathyroid gland would provide a possible biochemical explanation for these observations [24]. Interestingly, however, Cohan et al [25] have shown that the release of cortisol, thyrotropin, and gonadotropins following hormonal stimulation, presumably also mediated by magnesium-dependent adenylate cyclase, was not impaired by magnesium deficiency. Alternatively, several other investigators have found elevated parathormone levels in magnesium-deficient patients, as well as end-organ unresponsiveness to exogenous parathormone [l-4]. For instance, Estep et al [l] showed that in a group of alcoholic patients with magnesium deficiency, there was an extremely blunted calcemic and phosphaturic response to exogenous parathormone, which was corrected following magnesium replacement. Skeletal resistance to parathormone action was clearly demonstrated by Freitag et al [26], who showed in isolated bone from magnesium-deficient dogs that both parathormone extraction and cyclic AMP generation were decreased. Reconciliation of these two lines of divergent data is not easy.
ET AL
Multiple factors may play a role in producing the different results: degree of magnesium depletion, varying tissue sensitivity of enzyme systems to magnesium, and unaccounted biochemical variabilities. Grades of partial resistance of target tissues to parathormone most likely exist, and the sensitivity of bone and kidney to parathormone in magnesium deficiency may well differ [26]. Further, normal or even moderately elevated serum parathormone levels may be inappropriately low in hypocalcemic patients. It appears likely, nonetheless, that both parathormone deficiency and partial or complete parathormone unresponsiveness play a role in producing the hypocalcemia seen in hypomagnesemic patients. Additional factors, most notably an alteration in the equilibrium for calcium between bone and extracellular fluid favoring calcium retention in bone, may also play a role [ 271. The patient presented herein demonstrated both hypomagnesemia and parathormone deficiency. Although a cause and effect relationship cannot be proved, the apparent restoration of parathormone secretory activity during magnesium replacement therapy suggests that hypomagnesemia may have played an etiologic role in this patient’s hypoparathyroidism and hypocalcemia. Regardless of causality, the association between these two entities remains an interesting one, whose further understanding awaits evaluation of other patients with hypomagnesemia and hypocalcemia. ACKNOWLEDGMENT We are grateful to Dr. James C. LaRocque for referring the patient to us, and to Dr. Stephen J. Marx and the Metabolic Diseases Branch, National Institute of Arthritis, Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland, for measuring serum parathormone levels and urinary cyclic AMP levels, as well as for providing the bovine parathormone. We also wish to thank Harriet Harryman and Cathy Morris for expert secretarial assistance.
REFERENCES 1.
2.
3.
4.
5.
EstepIi, ShawWA, Watlington C, Hobe R, Holland W, Tucker SG: Hypocalcemia due to hypomagnesemia and reversible parathyroid hormone unresponsiveness. J Clin Endocrinol Metab 1969; 29: 842-848. Connor TB, Toskes P, Mahaffey J, Martin LG, Williams JB, Walser M: Parathyroid function during chronic magnesium deficiency. John Hopkins Med J 1972; 131: 100-117. Muldowney FP, McKenna TJ, Kyle LH, Freaney R, Swan M: Parathormone-like effect of magnesium replenishment in steatorrhea. N Engl J Med 1970; 282: 61-68. MacManus J, Heaton FW, Lucas PW: A decreased response to parathyroid hormone in magnesium deficiency. J Endocrinol 1971; 49: 253-258. Bar RS, Wilson HE, Mazzaferri EL: Hypomagnesemic hypocalcemia secondary to renal magnesium wasting. Ann In-
January
6.
7.
8.
9.
10.
1984
tern Med 1975; 82: 646-649. Suh SM, Tashjian AH, Matsuo N, Parkinson DK, Fraser D: Pathogenesis of hypocalcemia in primary hypomagnesemia. J Clin Invest 1973; 52: 153-160. Anast CS, Mohs JM, Kaplan SL, Burns TW: Evidence for parathyroid failure in magnesium deficiency. Science 1972; 177: 606-608. Chase LR, Slatopolsky E: Secretion and metabolic effect of parathyroid hormone in patients with severe hypomagnesemia. J Clin Endocrinol Metab 1974; 38: 363-371. Suh SM, Csima A, Fraser D: Pathogenesis of hypocalcemia in magnesium depletion: normal end-organ responsiveness to parathyroid hormone. J Clin Invest 1971; 50: 26682678. Anast CS, Winnacker JL, Forte LR: Impaired release of
The American
Journal of Medicine
Volume 76
153
HYPOMAGNESEMIA
AND HYPOPARATHYROIDISM-DW)AN
ET AL
parathyroid hormone in magnesium deficiency. J Clin Endocrinol Metab 1976; 42: 707-715. 11. Rude RK, Oldham SB, Sharp CF Jr, Singer FR: Parathyroid hormone secretion in magnesium deficiency. J Clin Endocrinol Metab 1978: 47: 800-806. 12. Steiner AL, Parker CW, Kipnis DM: Radioimmunoassay for cyclic nucleotides. I. Preparation of antibodies and iodinated cyclic nucleotkles. J Biol Chem 1972; 247: 1106-1113. 13. Marx SJ, Sharp ME, Krudy A, Rosenblatt M, Mallette LE: Radioimmunoassay for the mkldle region of human parathyroid hormone: studies with a radioiodinated synthetic peptlde. J Clin Endocrinol Metab 1981: 53: 76-84. 14. Aurbach GD, Marx SJ, Spiege.AM: Parathyroid hormone, calcitonin, and the calciferofs. In: Williams RH, ed. Textbcok of endocrinology, 6th ed. Philadelphia: WB Saunders, 1981; 922-1031. 15. Shils ME: Experimental human magnesium deficiency. Medicine (Baltimore) 1969; 48: 61-85. 16. Heaton FW: The kidney and magnesium homeostasis. Ann NY Acad Sci 1969; 169: 775-785. 17. Gitelman HJ, Graham JB, Welt LG: A familial disorder characterized by hypokalemia and hypomagnesemia. Ann NY Acad Sci 1969; 169: 856-864. 16. Runeberg L, Collan Y, Jokinen E, Lahdevirta J, Aro A: Hypornagnesemia dus to renal disease of unknown etiology. Am J Med 1975; 59: 873-881. 19. Evans RA, Carter JN, George CRP. et al: The congenital ‘magnesium-losing” kidney: repcft of two patients. Q J Med 1981; 197: 39-52.
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20. 21.
22.
23.
24.
25.
26.
27.
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Massry SG, Seelig MS: Hypomagnesemla and hypermag nesemia. Clin Nephrol 1977; 7: 147-153. Rude RK, Bethune JE, Singer FR: Renal tubular maximum for magnesium in normal, hyperparathyroid and hypoparathyroid man. J Clin Endocrinol Metab 1980; 51: 14251431. Targovnik JH, Rodman JS, Sherwood LM: Regulation of parathyroid hormone secretion in vitro: quantitatfve aspscts of calcium and magnesium ion control. Endocrinology 1971; 88: 1477-1482. Hamilton JW, Spierto FW, MacGregor RR, Cohn DV: Studies on the biosynthesis in vitro of parathyroid hormone. II. The effect of calcium and magnesium on synthesis of parathyroid hormone isolated from bovine parathyroid tissue and incubation media. J Biol Chem 1971; 246: 32243233. Abe M, Sherwood LM: Regulation of parathyroid hormone secretion by adenylate cyclase. Biochem Biophys Res Commun 1972; 48: 396-402. Cohan BW, Singer FR, Rude RK: End-organ response to adrenocorticotropin, thyrotropin, gonadotropin-releasing hormone, and glucagon in hypocalcemic magnesium deficient patients. J Clin Endocrinol Metab 1982; 54: 975979. Freitag JJ, Martin KJ, Conrades MB, et al: Evidence for skeletal resistance to parathyroid hormone in magnesium deficiency: studies in isolated perfused bone. J Clin Invest 1979; 64: 1238-1244. Massry SG: Pharmacology of magnesium. Annu Rev Pharmacol Toxicol 1977; 17: 67-82.