Medical Hypotheses I
I
Medtcd Hypotheses (1991) 34.6245 0 Lowman Group UK Ltd 1991
Skeletal Buffer Function and Symptomatic Magnesium Deficiency W.F. LANGLEY and D.J. MANN 175 1 SW 3rd Terr, Pompano, FL 33060,
USA
Abstract - A major factor relating to the oversight of neurological dysfunction and seizures caused by magnesium (Mg + + I depletion, involves the buffer functions of the skeletal system orchestrated primarily by the parathyroid. A Mg + + depleted subject may appear relatively asymptomatic until a short period after homeostatic responses go into effect. The result can be devastating if not recognized promptly and treated appropriately. This series of events can best be demonstrated in veterinary medicine but we propose that analogous syndromes occur in clinical medicine. Evidence is presented to support the hypothesis that in subjects with parathyroid hyperactivity and Mg + + deficiency, the stimulus of a rise in serum ionic calcium (Ca + + I, and the resultant inhibition of parathyroid hormone (PTH) secretion, trigger the transfer of Ca + + , Mg + + and other ions from the extracellular space into the exchangeable bone compartment. More importantly, there is a transfer of Mg + + ions from the cerebrospinal fluid into the blood and ultimately into the bone compartment. If the gradient is large and the stimulus adequate, neurological signs and symptoms may be induced. The degree of Ca + + and Mg+ + depletion of the peripheral bone and the amount and duration of Ca+ + ion increase largely determine the duration and severity of symptoms. The symptom complex is facilitated by sympathetic stimulation. An analogous situation may exist with sodium (Na + I.
Introduction
pears to be a hierarchical order of response by the parathyroid to the major ions stored in the bone (2, 3). This order may be altered by changes in the relative concentrations of the ions in the serum. This has been observed in obstetrical practice. When parenteral Mg+ + sulfate was given to impede labor, the increase inserum Mg + + was followed by a prompt drop in parathyroid hormone (PTH) to imperceptible levels. This was accompanied by a rapid and prolonged reduction in serum Ca+ + levels. The markedly low serum Ca+ + had no effect on PTH secretion
Bone serves as a reservoir for several important ions. Approximately 99% of the Ca + ,897o of the phosphorous, SO- 65% of the Mg + + and 30% of the Na + of the body are found in the skeleton. Large quantities of bicarbonate, potassium (k + ) and hydrogen (H + ) ions are stored in bone (1, 2). During bone formation, not only are Ca+ + and phosphate taken up by the skeletal system, but so are Mg + + , Na + , bicarbonate, and other ions with the release of H+ ions (1). There apL3
SKELETAL BUFFER FUNCTION AND SYMPTOMATIC
MAGNESIUM DEFICIENCY
while the Mg+ + level remained elevated (4, 5). A large increment in serum Na+ may have a similar effect. In experiments on rats, parathyroidectomy impairs the ability of bone to release sodium (6). In the medical literature much concern has been expressed about the rate of correcting low Na+ levels. There are observations indicating that the rapid correction of significant hyponatremia may result in the production of central pontine myelinolysis (CPM) and other central nervous system demyelinating syndromes (7). The neurological symptoms of Mg + + deficiency induced by aberrant homeostasis and those of CPM are amazingly similar. The latter is characterized by disorientation, progressive obtundation, seizures, quadriplegia, muteness, impaired swallowing, coma, and pseudobulbar signs. The clinical settings in which the central demyelinating syndromes occur are those in which Mg + + deficiency most often occur, i.e. alcoholism, hyperaldosteronism, malnutrition, postoperative state with prolonged i.v. treatment, excess vasopressin secretion, SIADH, hyponatremia, prolonged diarrhea, thiazide excess, or most often some combination of the above. The striking increased occurrence in the female in CPM (7,8) is similarly noted in Mg+ + deficiency related to aberrant homeostasis. This is not surprising since, beyond adolescence, depleted Ca + + , Mg + + , and hyperactivity of the parathyroid are much less likely to be found in the male. Mg + + serves as an activator for many enzyme systems of intracellular metabolism. It is necessary for the phosphorylation of adenosine diphosphate to form adenosine triphosphate (ATP). ATP in turn is required for the active transport of Na+ and K+ across cell membranes. All enzyme reactions that are known to be catalyzed by ATP show an absolute requirement for Mg + + . These reactions encompass a very wide spectrum of synthetic processes (9). The consequences of cerebral Mg + + deficiency seem more relevant in explaining CPM than do changes in osmolality associated with the rapid correction of hyponatremia. Aberrant responses to homeostasis or homeostasis gone awry Grass tetany (GT), a condition well known in veterinary medicine, is most illustrative of homeostasis gone awry. Calcium and magnesium deficient farm animals behave normally until they are allowed to graze on the green grass and clover in the spring after being confined indoors dur-
63
ing the winter months. Shortly after grazing on this new pasture, signs of GT may appear. They consist of staggering, muscle spasticity, hyperventilation, hypersalivation, seizures, and on occasion death if not treated adequately with Mg+ + (10). That the animals affected are Ca+ + and Mg+ + deficient, and that Mg+ + will prevent or correct the syndrome when already present, is well documented (10). What instigates the symptom complex has remained an enigma. We postulate that this syndrome is triggered by an increase in serum Ca+ + and that the ensuing response by the parathyroid produces symptoms of central nervous system dysfunction on a Mg+ + deficiency basis. Changes in serum calcium and its relevance to grass tetany The mineral content of grasses and grazing vegetation in grass-tetany-prone areas, when compared with that of the vegetation of the non-grasstetany-prone areas, shows a consistent pattern of higher calcium, and, more strikingly, lower magnesium (11, 12, 13). Moreover, green grass and clover available in the spring generally contain much more Ca+ + than the corn silage and corn grain fed them during the winter months. According to figures compiled by the Penn State Forage Testing Service, legume forage contains four times the Ca + + of corn silage and 30 times the Ca + + of corn grain silage. Grass forage contains 1.8 times as much Ca+ + as does corn silage, and 16 times the Ca + + present in corn grain silage (14). In addition to the effects of nutrition and confinement, birthing and lactation contribute to deficits of Ca+ + and Mg+ + (10). Under these conditions of parathyroid hypertrophy and Mg+ + and Ca+ + deficiency, the conditions are ideal for symptomatic hypomagnesemia to develop (15, 16). The stimulus of a rise in serum ionic Ca + + is known to inhibit PTH secretion. We hypothesize that mineral deficient bone absorbs Ca + + , Mg + + and other ions from the extracellular fluid and that Mg+ + ions diffuse from the brain and cerebrospinal space to restore those taken up by the exchangeable bone compartment. If the gradient is large and the stimulus adequate, neurological signs and symptoms may be induced. Peripheral bone which is markedly depleted of Ca+ + and Mg + + would appear to absorb these ions at a rapid rate for a prolonged period. Neurological dysfunction is thought to persist until the gradient flow or diffusion of Ca+ + and Mg+ + are such
64 that brain Mg + + deficits are restored. With cattle prone to GT, it is not unusual to restore their serum Mg+ + levels to normal with supplements of Mg + + , only to observe a return to hypomagnesemic levels in a day or two if these supplements are not vigorously and continuously administered (22). The quantities of ions that leave the serum in these cases, both the cattle and the obstetrical patients referred to earlier, cannot be readily explained by renal excretion or intracellular shifts of ions alone. The additional absorption of ions into the exchangeable bone compartment via the buffering functions of the skeletal and hormonal systems may account for much of the Mg + + lost from the serum. The delayed clinical response to Mg + + treatment (18), so often observed in clinical medicine, may be explained by the uptake of much of the administered Mg+ + by the bone. Under conditions of Ca+ + and Mg+ + depletion, an increase in serum Mg+ + does not appear to aggrevate or precipitate neurological symptoms. Relative to brain Mg + + , the Mg + + gradient may be little changed despite parathyroid inhibition. However, in instances of severe mineral depletion of bone, a sizeable amount of the administered Mg+ + would be expected to enter the bone rather than to restore brain deficits. If one restored the serum Mg + + level to normal and then observed no clinical improvement, it is understandable why the diagnosis of Mg+ + deficiency might be abandoned prematurely. Serum Na+ , on the other hand, may simulate Ca + + . Rapid correction of hyponatremia is usually accomplished by the infusion of (3% or 5%) hypertonic saline. If parathyroid secretion is inhibited by this increase, the diffusion of Mg+ + ions from the brain and cerebrospinal fluid would likely augment Mg + + deficiency and symptomatology. There appears to be little or no blood brain barrier to the Mg+ + ion under these conditions. Animal experimentation has demonstrated that Mg+ + deficient cerebrospinal levels can be effectively repleted by parenteral Mg+ + (18). Cerebrospinal fluid Mg + + levels have proved to be more accurate indicators for the development of neurological dysfunction, i.e. GT, than have serum Mg+ + levels. Accordingly, symptoms of GT have been recorded in animals with normal serum Mg + + levels whose cerebrospinal fluid levels were low (21). Mg + + has the smallest ionic radius of the biologically important cations, smaller than Ca+ + , phosphate, Na+ , and K+
MEDICAL HYPOTHESES
(19), which may contribute to its unusual mobility and reactivity. It has been demonstrated that the take-up of Mg + + by bone is impaired in parathroidectomized calves (20). These observations suggest an active interchange of Mg + + ions between the several compartments. Human symptomatic magnesium deficiency In man, neurological dysfunction due to Mg+ + deficiency has been recorded after the removal of a parathyroid adenoma. The dysfunction, in this instance dementia, cleared completely with Mg+ + therapy. It was thought that the decline in PTH caused Mg+ + to be taken up by the ‘the hungry bone’ (23). In human subjects with normal renal function, signs and symptoms of Mg + + deficiency are almost impossible to elicit over a short period. Over a longer term, one study revealed that among those who became symptomatic, hypocalcemia was nearly always observed, despite adequate calcium intake. The neurological symptoms that developed were manifested by changes in mentation, tremors, fasciculations, and generalized spasticity. Hypomagnesemia, hypocalcemia, and hypokalemia, were consistently present in all of the affected subjects. Complete relief from symptoms occurred with the reinstitution of Mg+ + (24). Often, in both man and experimental animal studies, there are multiple deficiencies present but the most dramatic results occur in repleting the Mg+ + ion (10, 14, 18). Obfuscating and conditional factors in magnesium deficiency Neurological symptoms of Mg + + depletion may be induced by sympathetic stimulation. It has been demonstrated in many species. Asymptomatic Mg + + depleted cattle and sheep may develop GT seizures after handling. Loud noises cause Mg + + depleted rats to convulse (10, 18). These observations may have relevance to Mg+ + depleted humans making the diagnosis more difficult. Mg+ + deficiency may also be confusing when its loss precedes and overshadows that of calcium. Under normal circumstances the buffering function of the bone and hormones appears to protect the intracellular Mg + + from undue fluctuations (25). However, with long term Mg+ + deficiency, the loss may be so protracted and severe that the integrity of the cell can no longer
SKELETALBUFFER FUNCTION AND SYMPTOMATICMAGNESIUMDEFICIENCY
be maintained. In experiments on rats a fairly constant level of serum Mg+ + depression was reached below which the parathyroid no longer functioned normally (26, 27). In clinical medicine a cirrhotic male patient might have a markedly low serum Mg+ + level and evidence of cardiomyopathy on a Mg+ + deficiency basis. It is conceivable that the parathyroid might also not function normally because of intracellular Mg+ + depletion. In this situation causing a rise in serum Ca+ + might well have no effect on his neurological status. On the other hand, an elderly female with significant mineral depletion of the skeletal system and associated active Mg + + loss, i.e. prolonged diarrhea, SIADH secretin, excessive thiazide usage, etc-in this instance causing an increase in serum Ca+ + or Na+ might well produce serious neurological dysfunction including seizures. References 1. Avioli LK. Bone disease. p 1318 - 19 in Cecil Textbook of
2.
3.
4.
5.
6. 7.
8. 9.
Medicine 14th ed. (Wybgaarden JB, Smith LH Jr, eds.) W B Saunders, Philadelnhia and London. 1982. Habener JF, Potts JT Jr. Relative effectiveness of magnesium and calcium on the secretion and biosynthesis of parathyroid hormone in vivo. Endocrinology 98: 197 - 202, 1976. Anast CS, Gamder DW. Magnesium metabolism. p 423 - 522 in Disorders of mineral metabolism: pathophysiology of calcium, phosphorus and magnesium. 3rd ed (Bonner J, Coburn JW. eds) Academic Press, New York, 1981. Eisenbud E, LoBue CC. Hypocalcemia after therapeutic use of magnesium sulfate. Arch Intern Med 136: 688 - 91, 1976. Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 310: 1221-5. 1984. Nichols G, Nichols N. The effect of parathyroidroidectomy on control of and availability of skeletal sodium in the rat. Am J Physiol 198: 749-753, 1968. Arieff AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med 314: 1529-35, 1986. Naims RG. Therapy of Hyponatremia does haste make waste? N Engl J Med 314: 1573-74, 1986. Mudge GH. Agents Affecting volume and composition of body fluids in Goodman & Gihnan’s The Pharmacological Basis of Therapeutics sixth edition. eds. Goodman AG,
65
Goodman LS, Mayer SE, Melmon KL. p. 879- 883,198l. 10. Littledike ET, Young JW, Beitz DC. Common metabolic diseases of cattle: ketosis, milk fever, grass tetany and downer cow complex. J Dairy Sci 1474 - 82, 1979. 11. Kubota J. How Soils and Climate affect Grass Tetany Crops and Soils Magnesium 33: 15 - 17, 1981. 12. Kubota K, Oberly GH, Naphan EA. Magnesium in Grasses in three selected regions in the United States and its relation to grass tetany. Agronomy J 72: 907 -914, 1980. 13. Turner MA, Neil VE and Wilson GF. Survey of magnesium content of soils and pastures and incidence of grass tetany in three selected areas of Taranaki. N Z Journal of Agricultural Research 21: 583 - 92. 1978. 14. Miler EJ. Dairy Cattle Feeding and Nutrition. p 107 - 8 Table 5.15 Academic Press N.Y. 1979. 15. Maxwell MH, Kleeman CR. p 279-285. in Clinical Disorders of Fluid and Electrolyte Metabolism 3rd ed. McGraw-Hill, 1979. 16. Guyton AC. Textbook of Medical Physiology. 6th ed. p 984 - 5 WB Saunders Co. Philadelphia London Toronto, 1981. 17. Habener JF, Pottsd JT Jr. Relative effectiveness of magnesium and calcium on the secretion and biosynthesis of parathyroid hormone in vivo. Endocrinology. 98: 197 - 202, 1976. 18. Chutkow JG. Clinical chemical correlations in the encephalopathy of magnesium deficiency. Effect of reversal on magnesium deficiency. Mayo Clin Proc 49: 244 - 7, 1974. 19. Windholz M. in The Merck Index; an encyclopedia of chemicals, Drugs and Biologicals. 10th ed. p 5474. Merck & Co Inc. Rahwau. New Jersey, 1983. 20. Smith RH. Calcium and Magnesium Metabolism in Calves and Bone Composition in Magnesium Deficiency and the Control of plasma magnesium. Biochem J 71: 609-614, 1959. 21. Alisop TF and Pauli KV. Responses to lowering Magnesium and Calcium in cerebrospinal fluid of unanesthetized sheep. Australian J Biol Sci 28: 475, 1975. 22. Todd JR. Queens College of Veterinary Medicine. Belfast UK personal communication. 23. Jacobs JK, Merritt CR. Magnesium Deficiency in hyperparathyroidism: Case Report of Toxic psychosis. Ann Surg 163: 260-66, 1966. 24. Shils ME. Experimental human magnesium depletion. Medicine 48: 61-85, 1969. 25. Rude RK, Baker AJ, Watts RB. Renal cortical adenylate cyclase: characterization of magnesium activation. Endocrinology 113: 1348-55, 1983. 26. MacManus J, Heaton FW, Lucas PW. A Decreased Response to parathyroid hormone in Magnesium deficiency. Journal of Endocrinology 49: 253 - 8, 1971. 27. Estrep HL, Martinez GR, Jones D. Hypocalcemia due to hypomagnesemia and reversible parathyroid hormone unresponsiveness. Journal of Clinical Endocrinology 29: 842-5, 1969.
I
Medtcd Hypotheses (1991) 34.6245 0 Lowman Group UK Ltd 1991
Skeletal Buffer Function and Symptomatic Magnesium Deficiency W.F. LANGLEY and D.J. MANN 175 1 SW 3rd Terr, Pompano, FL 33060,
USA
Abstract - A major factor relating to the oversight of neurological dysfunction and seizures caused by magnesium (Mg + + I depletion, involves the buffer functions of the skeletal system orchestrated primarily by the parathyroid. A Mg + + depleted subject may appear relatively asymptomatic until a short period after homeostatic responses go into effect. The result can be devastating if not recognized promptly and treated appropriately. This series of events can best be demonstrated in veterinary medicine but we propose that analogous syndromes occur in clinical medicine. Evidence is presented to support the hypothesis that in subjects with parathyroid hyperactivity and Mg + + deficiency, the stimulus of a rise in serum ionic calcium (Ca + + I, and the resultant inhibition of parathyroid hormone (PTH) secretion, trigger the transfer of Ca + + , Mg + + and other ions from the extracellular space into the exchangeable bone compartment. More importantly, there is a transfer of Mg + + ions from the cerebrospinal fluid into the blood and ultimately into the bone compartment. If the gradient is large and the stimulus adequate, neurological signs and symptoms may be induced. The degree of Ca + + and Mg+ + depletion of the peripheral bone and the amount and duration of Ca+ + ion increase largely determine the duration and severity of symptoms. The symptom complex is facilitated by sympathetic stimulation. An analogous situation may exist with sodium (Na + I.
Introduction
pears to be a hierarchical order of response by the parathyroid to the major ions stored in the bone (2, 3). This order may be altered by changes in the relative concentrations of the ions in the serum. This has been observed in obstetrical practice. When parenteral Mg+ + sulfate was given to impede labor, the increase inserum Mg + + was followed by a prompt drop in parathyroid hormone (PTH) to imperceptible levels. This was accompanied by a rapid and prolonged reduction in serum Ca+ + levels. The markedly low serum Ca+ + had no effect on PTH secretion
Bone serves as a reservoir for several important ions. Approximately 99% of the Ca + ,897o of the phosphorous, SO- 65% of the Mg + + and 30% of the Na + of the body are found in the skeleton. Large quantities of bicarbonate, potassium (k + ) and hydrogen (H + ) ions are stored in bone (1, 2). During bone formation, not only are Ca+ + and phosphate taken up by the skeletal system, but so are Mg + + , Na + , bicarbonate, and other ions with the release of H+ ions (1). There apL3
SKELETAL BUFFER FUNCTION AND SYMPTOMATIC
MAGNESIUM DEFICIENCY
while the Mg+ + level remained elevated (4, 5). A large increment in serum Na+ may have a similar effect. In experiments on rats, parathyroidectomy impairs the ability of bone to release sodium (6). In the medical literature much concern has been expressed about the rate of correcting low Na+ levels. There are observations indicating that the rapid correction of significant hyponatremia may result in the production of central pontine myelinolysis (CPM) and other central nervous system demyelinating syndromes (7). The neurological symptoms of Mg + + deficiency induced by aberrant homeostasis and those of CPM are amazingly similar. The latter is characterized by disorientation, progressive obtundation, seizures, quadriplegia, muteness, impaired swallowing, coma, and pseudobulbar signs. The clinical settings in which the central demyelinating syndromes occur are those in which Mg + + deficiency most often occur, i.e. alcoholism, hyperaldosteronism, malnutrition, postoperative state with prolonged i.v. treatment, excess vasopressin secretion, SIADH, hyponatremia, prolonged diarrhea, thiazide excess, or most often some combination of the above. The striking increased occurrence in the female in CPM (7,8) is similarly noted in Mg+ + deficiency related to aberrant homeostasis. This is not surprising since, beyond adolescence, depleted Ca + + , Mg + + , and hyperactivity of the parathyroid are much less likely to be found in the male. Mg + + serves as an activator for many enzyme systems of intracellular metabolism. It is necessary for the phosphorylation of adenosine diphosphate to form adenosine triphosphate (ATP). ATP in turn is required for the active transport of Na+ and K+ across cell membranes. All enzyme reactions that are known to be catalyzed by ATP show an absolute requirement for Mg + + . These reactions encompass a very wide spectrum of synthetic processes (9). The consequences of cerebral Mg + + deficiency seem more relevant in explaining CPM than do changes in osmolality associated with the rapid correction of hyponatremia. Aberrant responses to homeostasis or homeostasis gone awry Grass tetany (GT), a condition well known in veterinary medicine, is most illustrative of homeostasis gone awry. Calcium and magnesium deficient farm animals behave normally until they are allowed to graze on the green grass and clover in the spring after being confined indoors dur-
63
ing the winter months. Shortly after grazing on this new pasture, signs of GT may appear. They consist of staggering, muscle spasticity, hyperventilation, hypersalivation, seizures, and on occasion death if not treated adequately with Mg+ + (10). That the animals affected are Ca+ + and Mg+ + deficient, and that Mg+ + will prevent or correct the syndrome when already present, is well documented (10). What instigates the symptom complex has remained an enigma. We postulate that this syndrome is triggered by an increase in serum Ca+ + and that the ensuing response by the parathyroid produces symptoms of central nervous system dysfunction on a Mg+ + deficiency basis. Changes in serum calcium and its relevance to grass tetany The mineral content of grasses and grazing vegetation in grass-tetany-prone areas, when compared with that of the vegetation of the non-grasstetany-prone areas, shows a consistent pattern of higher calcium, and, more strikingly, lower magnesium (11, 12, 13). Moreover, green grass and clover available in the spring generally contain much more Ca+ + than the corn silage and corn grain fed them during the winter months. According to figures compiled by the Penn State Forage Testing Service, legume forage contains four times the Ca + + of corn silage and 30 times the Ca + + of corn grain silage. Grass forage contains 1.8 times as much Ca+ + as does corn silage, and 16 times the Ca + + present in corn grain silage (14). In addition to the effects of nutrition and confinement, birthing and lactation contribute to deficits of Ca+ + and Mg+ + (10). Under these conditions of parathyroid hypertrophy and Mg+ + and Ca+ + deficiency, the conditions are ideal for symptomatic hypomagnesemia to develop (15, 16). The stimulus of a rise in serum ionic Ca + + is known to inhibit PTH secretion. We hypothesize that mineral deficient bone absorbs Ca + + , Mg + + and other ions from the extracellular fluid and that Mg+ + ions diffuse from the brain and cerebrospinal space to restore those taken up by the exchangeable bone compartment. If the gradient is large and the stimulus adequate, neurological signs and symptoms may be induced. Peripheral bone which is markedly depleted of Ca+ + and Mg + + would appear to absorb these ions at a rapid rate for a prolonged period. Neurological dysfunction is thought to persist until the gradient flow or diffusion of Ca+ + and Mg+ + are such
64 that brain Mg + + deficits are restored. With cattle prone to GT, it is not unusual to restore their serum Mg+ + levels to normal with supplements of Mg + + , only to observe a return to hypomagnesemic levels in a day or two if these supplements are not vigorously and continuously administered (22). The quantities of ions that leave the serum in these cases, both the cattle and the obstetrical patients referred to earlier, cannot be readily explained by renal excretion or intracellular shifts of ions alone. The additional absorption of ions into the exchangeable bone compartment via the buffering functions of the skeletal and hormonal systems may account for much of the Mg + + lost from the serum. The delayed clinical response to Mg + + treatment (18), so often observed in clinical medicine, may be explained by the uptake of much of the administered Mg+ + by the bone. Under conditions of Ca+ + and Mg+ + depletion, an increase in serum Mg+ + does not appear to aggrevate or precipitate neurological symptoms. Relative to brain Mg + + , the Mg + + gradient may be little changed despite parathyroid inhibition. However, in instances of severe mineral depletion of bone, a sizeable amount of the administered Mg+ + would be expected to enter the bone rather than to restore brain deficits. If one restored the serum Mg + + level to normal and then observed no clinical improvement, it is understandable why the diagnosis of Mg+ + deficiency might be abandoned prematurely. Serum Na+ , on the other hand, may simulate Ca + + . Rapid correction of hyponatremia is usually accomplished by the infusion of (3% or 5%) hypertonic saline. If parathyroid secretion is inhibited by this increase, the diffusion of Mg+ + ions from the brain and cerebrospinal fluid would likely augment Mg + + deficiency and symptomatology. There appears to be little or no blood brain barrier to the Mg+ + ion under these conditions. Animal experimentation has demonstrated that Mg+ + deficient cerebrospinal levels can be effectively repleted by parenteral Mg+ + (18). Cerebrospinal fluid Mg + + levels have proved to be more accurate indicators for the development of neurological dysfunction, i.e. GT, than have serum Mg+ + levels. Accordingly, symptoms of GT have been recorded in animals with normal serum Mg + + levels whose cerebrospinal fluid levels were low (21). Mg + + has the smallest ionic radius of the biologically important cations, smaller than Ca+ + , phosphate, Na+ , and K+
MEDICAL HYPOTHESES
(19), which may contribute to its unusual mobility and reactivity. It has been demonstrated that the take-up of Mg + + by bone is impaired in parathroidectomized calves (20). These observations suggest an active interchange of Mg + + ions between the several compartments. Human symptomatic magnesium deficiency In man, neurological dysfunction due to Mg+ + deficiency has been recorded after the removal of a parathyroid adenoma. The dysfunction, in this instance dementia, cleared completely with Mg+ + therapy. It was thought that the decline in PTH caused Mg+ + to be taken up by the ‘the hungry bone’ (23). In human subjects with normal renal function, signs and symptoms of Mg + + deficiency are almost impossible to elicit over a short period. Over a longer term, one study revealed that among those who became symptomatic, hypocalcemia was nearly always observed, despite adequate calcium intake. The neurological symptoms that developed were manifested by changes in mentation, tremors, fasciculations, and generalized spasticity. Hypomagnesemia, hypocalcemia, and hypokalemia, were consistently present in all of the affected subjects. Complete relief from symptoms occurred with the reinstitution of Mg+ + (24). Often, in both man and experimental animal studies, there are multiple deficiencies present but the most dramatic results occur in repleting the Mg+ + ion (10, 14, 18). Obfuscating and conditional factors in magnesium deficiency Neurological symptoms of Mg + + depletion may be induced by sympathetic stimulation. It has been demonstrated in many species. Asymptomatic Mg + + depleted cattle and sheep may develop GT seizures after handling. Loud noises cause Mg + + depleted rats to convulse (10, 18). These observations may have relevance to Mg+ + depleted humans making the diagnosis more difficult. Mg+ + deficiency may also be confusing when its loss precedes and overshadows that of calcium. Under normal circumstances the buffering function of the bone and hormones appears to protect the intracellular Mg + + from undue fluctuations (25). However, with long term Mg+ + deficiency, the loss may be so protracted and severe that the integrity of the cell can no longer
SKELETALBUFFER FUNCTION AND SYMPTOMATICMAGNESIUMDEFICIENCY
be maintained. In experiments on rats a fairly constant level of serum Mg+ + depression was reached below which the parathyroid no longer functioned normally (26, 27). In clinical medicine a cirrhotic male patient might have a markedly low serum Mg+ + level and evidence of cardiomyopathy on a Mg+ + deficiency basis. It is conceivable that the parathyroid might also not function normally because of intracellular Mg+ + depletion. In this situation causing a rise in serum Ca+ + might well have no effect on his neurological status. On the other hand, an elderly female with significant mineral depletion of the skeletal system and associated active Mg + + loss, i.e. prolonged diarrhea, SIADH secretin, excessive thiazide usage, etc-in this instance causing an increase in serum Ca+ + or Na+ might well produce serious neurological dysfunction including seizures. References 1. Avioli LK. Bone disease. p 1318 - 19 in Cecil Textbook of
2.
3.
4.
5.
6. 7.
8. 9.
Medicine 14th ed. (Wybgaarden JB, Smith LH Jr, eds.) W B Saunders, Philadelnhia and London. 1982. Habener JF, Potts JT Jr. Relative effectiveness of magnesium and calcium on the secretion and biosynthesis of parathyroid hormone in vivo. Endocrinology 98: 197 - 202, 1976. Anast CS, Gamder DW. Magnesium metabolism. p 423 - 522 in Disorders of mineral metabolism: pathophysiology of calcium, phosphorus and magnesium. 3rd ed (Bonner J, Coburn JW. eds) Academic Press, New York, 1981. Eisenbud E, LoBue CC. Hypocalcemia after therapeutic use of magnesium sulfate. Arch Intern Med 136: 688 - 91, 1976. Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 310: 1221-5. 1984. Nichols G, Nichols N. The effect of parathyroidroidectomy on control of and availability of skeletal sodium in the rat. Am J Physiol 198: 749-753, 1968. Arieff AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med 314: 1529-35, 1986. Naims RG. Therapy of Hyponatremia does haste make waste? N Engl J Med 314: 1573-74, 1986. Mudge GH. Agents Affecting volume and composition of body fluids in Goodman & Gihnan’s The Pharmacological Basis of Therapeutics sixth edition. eds. Goodman AG,
65
Goodman LS, Mayer SE, Melmon KL. p. 879- 883,198l. 10. Littledike ET, Young JW, Beitz DC. Common metabolic diseases of cattle: ketosis, milk fever, grass tetany and downer cow complex. J Dairy Sci 1474 - 82, 1979. 11. Kubota J. How Soils and Climate affect Grass Tetany Crops and Soils Magnesium 33: 15 - 17, 1981. 12. Kubota K, Oberly GH, Naphan EA. Magnesium in Grasses in three selected regions in the United States and its relation to grass tetany. Agronomy J 72: 907 -914, 1980. 13. Turner MA, Neil VE and Wilson GF. Survey of magnesium content of soils and pastures and incidence of grass tetany in three selected areas of Taranaki. N Z Journal of Agricultural Research 21: 583 - 92. 1978. 14. Miler EJ. Dairy Cattle Feeding and Nutrition. p 107 - 8 Table 5.15 Academic Press N.Y. 1979. 15. Maxwell MH, Kleeman CR. p 279-285. in Clinical Disorders of Fluid and Electrolyte Metabolism 3rd ed. McGraw-Hill, 1979. 16. Guyton AC. Textbook of Medical Physiology. 6th ed. p 984 - 5 WB Saunders Co. Philadelphia London Toronto, 1981. 17. Habener JF, Pottsd JT Jr. Relative effectiveness of magnesium and calcium on the secretion and biosynthesis of parathyroid hormone in vivo. Endocrinology. 98: 197 - 202, 1976. 18. Chutkow JG. Clinical chemical correlations in the encephalopathy of magnesium deficiency. Effect of reversal on magnesium deficiency. Mayo Clin Proc 49: 244 - 7, 1974. 19. Windholz M. in The Merck Index; an encyclopedia of chemicals, Drugs and Biologicals. 10th ed. p 5474. Merck & Co Inc. Rahwau. New Jersey, 1983. 20. Smith RH. Calcium and Magnesium Metabolism in Calves and Bone Composition in Magnesium Deficiency and the Control of plasma magnesium. Biochem J 71: 609-614, 1959. 21. Alisop TF and Pauli KV. Responses to lowering Magnesium and Calcium in cerebrospinal fluid of unanesthetized sheep. Australian J Biol Sci 28: 475, 1975. 22. Todd JR. Queens College of Veterinary Medicine. Belfast UK personal communication. 23. Jacobs JK, Merritt CR. Magnesium Deficiency in hyperparathyroidism: Case Report of Toxic psychosis. Ann Surg 163: 260-66, 1966. 24. Shils ME. Experimental human magnesium depletion. Medicine 48: 61-85, 1969. 25. Rude RK, Baker AJ, Watts RB. Renal cortical adenylate cyclase: characterization of magnesium activation. Endocrinology 113: 1348-55, 1983. 26. MacManus J, Heaton FW, Lucas PW. A Decreased Response to parathyroid hormone in Magnesium deficiency. Journal of Endocrinology 49: 253 - 8, 1971. 27. Estrep HL, Martinez GR, Jones D. Hypocalcemia due to hypomagnesemia and reversible parathyroid hormone unresponsiveness. Journal of Clinical Endocrinology 29: 842-5, 1969.
