CASE REPORT

Renal Refractoriness to Phosphaturic Action of Parathyroid Hormonein a Patient with Hypomagnesemia Masahiro Mihara, Keita Kamikubo, Keiko Hiramatsu, Satomi Itaya, Tom Ogawa and Shigeki Sakata*

A 50-year-old tetanic womanwith hypomagnesemiais described. She had partial resection of the stomach and thejejunum at the age of20 years. Lack of (PTH) function was indicated by , hyperphosphatemia and high tubular reabsorption of . However, both plasma concentration of PTHand nephrogenous CAMPwere normal. Administra- tion of magnesiumsulfate completely normalized serum phosphate and tubular transport of phosphate with only a modest increase in nephrogenousCAMP.The present findings suggest that phosphaturic action of PTHis impaired in magnesiumdeficiency and that steps distal to CAMP production may be responsible for the renal refractoriness to the hormonal action. (Internal Medicine 34: 666-669, 1995) Key words: , hyperphosphatemia, hypocalcemia, nephrogenous CAMP

Introduction Case Report Hypocalcemia and much less frequently hyperphosphatemia A 50-year-old womanwas admitted to our hospital because develop in severely hypomagnesemic patients (1). There are of tetany. She had had an appendectomy at the age of 15 years several possible mechanismsproposed for these abnormalities and partial resection of the stomach and thejejunum due to ileus in calcium and phosphate metabolismdue to magnesiumdefi- at the age of 20 years. She had been having paresthesia in ciency. The secretion of parathyroid hormone (PTH) is sup- bilateral legs for a month prior to admission. Three days before pressed in chronic hypomagnesemia(2- 1 2). The refractoriness admission the paresthesia also developed in bilateral forearms. of target organs, kidney and bone, to PTHactions has also been On the day of admission she manifested symptomsof tetany. reported in some hypomagnesemic subjects (5, 7, 9, 12-19). In Trousseau's sign and Chvostek's sign were positive. the kidney, PTHreduces phosphate reabsorption at the proxi- Someblood chemical and endocrinological findings are mal tubules via a CAMP-dependentprocess (20-22). Little is presented in Table 1. Serumcalcium concentration corrected knownabout impaired steps of phosphaturic PTHaction in with serum albumin level, serum inorganic phosphate, and hypomagnesemichyperphosphatemia, a rare complication of serum magnesium were low. Serum potassium (3.0 mEq/1) magnesium deficiency. In this report we describe a tetanic was also low. Arterial blood gas analysis revealed metabolic patient with hypomagnesemiaand hypocalcemia whoshowed alkalosis (pH 7.52, HCO3~30.1 mM, base excess 7.6 mM). hyperphosphatemia and high tubular reabsorption of phosphate Creatinine clearance was 1 14 I/day, Plasma intact PTHlevel despite normal plasma concentrations of PTHand nephro- (Allegro Intact PTH Kit, Japan Mediphysics, Tokyo, Japan) genous CAMP.Administration of magnesiumcompletely nor- and mid-portion PTH level (210 pg/ml) (PTH Kit Yamasa, malized serum phosphate and tubular transport of phosphate Yamasa, Choshi, Japan: normal, 160 to 520 pg/ml) were nor- with only a modest increase in nephrogenous CAMP.The mal. NephrogenousCAMPwaswithin the normal range. Per- present findings suggest that the phosphaturic action of PTHis centage of tubular reabsorption of phosphate and Tmpo4/GFR impaired in magnesium deficiency and that steps distal to were high. Urinary magnesium excretion (0.9 mEq/day) was CAMPresponse maybe responsible for the renal refractoriness low. FEca was 2.0%. Plasma 1,25(OH)2 D3 concentration to PTHaction. (1,25(OH)2 D3 Kit SRL, Yamasa) was low. Plasma 25(OH)D3

From the Department of Internal Medicine, Takayama Red Cross Hospital, Takayama and *the Third Department of Internal Medicine, Gifu University School of Medicine, Gifu Received for publication October 3 1, 1994; Accepted for publication March 20, 1995 Reprint requests should be addressed to Dr. Keita Kamikubo, the Department of Internal Medicine, Takayama Red Cross Hospital, 3- 1 1 Tenman-cho, Takayama 506

666 Internal Medicine Vol. 34, No. 7 (July 1995) PTHResistance in Magnesium Deficiency Table 1. Laboratory Findings Vari abl e D a y 1 D a y 6 D a y 1 2 D a y 3 0 N o r m a l rang e

C a l c i u m ( m E q / 1 ) 2.9 3. 3 3. 7 4. 5 4 . 0- 5 . 0 M a g n e s i u m ( m E q / 1 ) 0. 6 0. 9 1. 0 1. 6 1. 6 - 2 . 1 P h o sp h a te (m g /d l) 5.4 4. 4 3. 1 3. 8 2 . 7 ^ . 4 In t a c t P T H ( p g /m l ) 17 6 9 3 8 1 5 - 5 0 1 , 25 ( O H) 2 D 3 ( p g/ m l ) 9 .6 17 2 3 2 2 -6 5 n - C A M P ( n m o l / d l ) 0. 71 0 . 80 0. 4-2. 8 % T R P 9 5 9 1 8 7 - 9 3 T m P O 4 / G F R ( m g / d l ) 8.7 3. 1 2 .5 - 4 . 2

calcium: serum calcium concentration corrected with serum albumin level, n- cAMP: nephrogenous CAMP.

1 i MgSO4

| Calcium gluconate | == 8r -.4- -i80

\ o- A. iS" "^ 5-5 6- /à""~~J^\/ -. "3X -60^

^e 4å /'' ^*\ ^^-^-^=^"21 "40i f| <^>^^>-^^» à"^^ | E Is2- .-'' ^_« å å å à"--å _]s -20S || t-^*-*^ | £ <^^ o1 ' à" ' ' ' ' ' '-"o h 2 4 6 8 10 12 14 16 Day Figure 1. Clinical course after admission. Serumconcentrations of magnesium(å ), inorganic phosphate ( à") and calcium corrected with serum albumin ( O) are indicated. Plasma intact PTHlevels (A) are also shown. The patient was given calcium gluconate (1,700 mg/day) and magnesium sulfate (500 to 1,500 mg/day) as indicated. level ( 1 0. 1 ng/ml) was normal (Special Reference Laboratories, cal Industry, Tokyo, Japan) (23) was performed on the 12th day Tokyo, Japan: normal, 9 to 35 ng/ml) and 24,25(OH)2 D3 level when baseline nephrogenous CAMP,%TRPand Tmpo^GFR (0.45 ng/ml) was also normal (Special Reference Laboratories: were normal (Table 1 ). The test indicated a normal response for normal, 0.40 to 2.0 ng/ml). Plasma calcitonin concentration both urinary CAMPand urinary phosphate (Fig. 2). The serum (18 pg/ml) was normal (Calcitonin Kit Mitubishiyuka, calcium level was restored to normal on the 16th day. Serum Mitubishiyuka, Tokyo, Japan: normal, 17 to 58 pg/ml). magnesium, calcium, inorganic phosphate, plasma intact PTH The patient was given calcium gluconate intravenously and 1 ,25(OH)2D3 were normal one month after admission with (1,700 mg/day) as well as magnesium sulfate orally later (500 magnesium supplementation (Table 1 ). to 1,500 mg/day) (Fig. 1). Plasma intact PTH level (30 pg/ml) wasagain normal on the third day. Hyperphosphatemiacontin- Discussion ued for five days after admission. Onthe sixth day, the plasma intact PTH level was slightly high and the plasma 1 ,25(OH)2 D3 Onadmission, serumcalcium waslow, and serumphosphate concentration was still low (Table 1). Intravenous calcium and tubular reabsorption of phosphate were abnormally high administration was terminated on the nineth day. Standardized despite the normal plasma PTHlevel and nephrogenous CAMP. Ellsworth-Howard test using human PTH1-34 (Asahi Chemi- With supplementation of magnesiumand calcium, serum phos-

Internal Medicine Vol. 34, No. 7 (July 1995) 667 Mihara et al

PTH increased slightly. Cyclic AMPis thought to mediate the tubular phosphaturic action of PTH(20-22). Although other 50r -,5 possibilities, such as the possibility that normal nephrogenous CAMPwas brought about by increased leakage of low tubular intracellular CAMPlevel, are not completely eliminated, the 40- / -4 present findings suggest that steps distal to the CAMPresponse in renal PTHaction may have been impaired in this patient. 1 f/ l Tubular resistance to phosphaturic PTHaction at points distal |¥30- / -3£| to CAMPproduction is also knownin dietary phosphate depri- vation (28). There have been discrepancies in renal responsiveness to E / 1 ^= PTHin magnesiumdeficiency. Renal hyporesponsiveness to the phosphaturic action of PTHhas been reported in some 10å / -1 patients with magnesium deficiency (5, 13, 16). Nodata on urinary CAMPis available in these patients. Other patients with hypomagnesemia,however, shownormal renal responses to PTH(3, 4, 6). Hyperphosphatemia is a rare complication in ol_J 1 1 1 1 1-lo magnesium deficiency (16, 29), whereas hypocalcemia has -3 -2 -1 0 1 2 been reported frequently. In the present case, serum phosphate Time(hour) and tubular reabsorption of phosphate returned to normal before serumcalcium was restored. These findings maysuggest Figure 2. Renal response to PTH. The results of Ellsworth- that the renal phosphaturic action is more resistant to magne- Howardtest are shown. sium deficiency than the hypercalcemic action of PTH. In addition to severity and duration of magnesiumdeficiency, accompanying abnormalities in other electrolytes and genetic predisposition may account for the patient-to-patient variation phate and renal phosphate transport returned to normal and in renal responsiveness to PTH. serumcalcium wasrestored later. After calcium administration Plasma level of 1,25(OH)2 D3 was low despite normal had been terminated, serum calcium and phosphate were main- plasma concentrations of 25(OH) D3. This suggests that la- tained at the normal levels with magnesiumsupplementation. hydroxylation of 25 (OH) D3 was impaired. Hyperphosphatemia These results suggest that hypomagnesemiawas the pricnipal seems to be responsible for the reduced la-hydroxylation at causative factor responsible for the hypocalcemia and least in part (30). Hypomagnesemic patients without hyperphosphatemia in this patient. Since the urinary magne- hyperphosphatemia, however, frequently show a low 1 ,25 (OH)2 sium excretion was low, low magnesiumabsorption probably D3 level (3 1). Since intracellular magnesium is required for 1a- due to the partial resection of the jejunum seems to be respon- hydroxylation (32), magnesium deficiency itself may impair sible for the magnesium deficiency. the enzymereaction. The pathophysiological consequence of There are at least two possible mechanisms for the develop- low 1 ,25(OH)2 D3 in magnesium deficiency is not clear. There ment of hypocalcemia and hyperphosphatemia in this patient. have been conflicting reports on roles of low 1,25(OH)2 D3 in First, the plasma PTH level was within normal range but the development of hypocalcemia in magnesium deficiency inappropriately low in the presence of hypocalcemia indicating (33, 34). impaired secretion of PTH.After magnesiumadministration In summary,wehave presented a tetanic patient with the plasma PTHlevel increased. An acute increase in extracel- hypocalcemia and hyperphosphatemia secondary to magne- lular magnesiumconcentration inhibits PTHsecretion both in sium deficiency. Impairment of PTHsecretion and renal PTH vitro (24, 25) and in vivo (26, 27). In chronic severe action partly accounts for the hypocalcemia and hypomagnesemia, however, PTH secretion is paradoxically hyperpho sphatemia. diminished and replenishment of magnesium stimulates PTH secretion (2-12). Mechanisms underlying the impaired PTH References secretion in chronic magnesiumdeficiency are not clear. 1) Wacker WEC,Parist AF. Magnesium metabolism. N Engl J Med 278: Secondly, responsiveness of target organs to PTHseems to 658, 1968. have been reduced in this patient. At the time of admission when 2) Anast CS, Mohs JM, Kaplan SL, Burns TW. Evidence for parathyroid severe hypomagnesemiawas present, serum calcium was low failure in magnesiumdeficiency. Science 177: 606, 1972. despite normal levels of plasma PTHand nephrogenous CAMP. 3) Suh SM, Tashjian AH, Matsuo N, Parkinson DK, FraserD. Pathogenesis Furthermore, serum phosphate and tubular reabsorption of of hypocalcemia in primary hypomagnesemia: Normal end-organ re- sponsiveness to parathyroid hormone, impaired parathyroid gland func- phosphate were abnormally high indicating a lack of renal PTH tion. J Clin Invest 52: 153, 1973. action. After magnesiumsupplementation, tubular phosphate 4) Chase LR, Slatopolsky E. Secretion and metabolic efficacy of parathyroid transport was completely normalized while nephrogenousCAMP hormone in patients with severe hypomagnesemia. J Clin Endocrinol

668 InternalMedicine Vol. 34, No. 7 (July 1995) PTHResistance in MagnesiumDeficiency Metab38: 363, 1974. and reduced responsiveness to calcitropic hormones. Intern Med31 : 820, 5) Levi J, Massry SG, Coburn JW, Llach F, Kleeman CR. Hypocalcemia in 1992. magnesium-depleted dogs: Evidence for reduced responsiveness to par- Dennis VW,Brazy PC. Divalent anion transport in isolated renal tubules. athyroid hormone and relative failure of parathyroid gland function. Kidney Int 22: 498, 1982. Metabolism 23: 323, 1974. Caverzasio J, Rizzoli R, Bonjour JP. Sodium-dependent phosphate trans- 6) Anast CS, Winnacker Jl, Forte LR, Burns TW. Impaired release of port inhibited by parathyroid hormone and cyclic AMPstimulation in an parathyroid hormone in magnesium deficiency. J Clin Endocrinol Metab opossum kidney cell line. J Biol Chem 261: 3233, 1986. 42: 707, 1976. QuammeG, Pfeilschifter J, Murer H. Parathyroid hormone inhibition of 7) Rude RK, Oldham SB, Singer FR. Functional and Na+/phosphate cotransport in OKcells: generation of second messengers parathyroid hormone end-organ resistance in human magnesiumdefi- in the regulatory cascade. Biochem Biophys Res Commun158: 951, ciency. Clin Endocrinol 5: 209, 1976. 1989. 8) Rude RK, Oldham SB, Sharp CF, Singer FR. Parathyroid hormone Ogata E, YamamotoM, Matsumoto T, et al. Standard procedure and the secretion1978. in magnesium deficiency. J Clin Endocrinol Metab 47: 800, diagnostic criteria for the Ellsworth-Howard test using humanPTH-( 1 - 34). Folia Endocrinol Jpn 60: 971, 1984. 9) Jacob AI, Pennell JP, Lambert PW, Gavellas G. Vitamin D metabolites Care AD, Sherwood LM, Potts JT, Aurbach GD. Perfusion of the isolated and parathyroid hormone in hypomagnesemic hypocalcemia. parathyroid gland of the goat and sheep. Nature 209: 55, 1966. Electrolyte Metab 6: 316, 1981. Sherwood LM, Herman I, Bassett CA. Parathyroid hormone secretion in 10) Ralston S, Boyle IT, Cowan RA, Crean GP, Jenkins A, Thomson WS. vitro: Regulation by calcium and magnesium ions. Nature 225: 1056, PTHand vitamin D responses during treatment of hypomagnesemic 1970. hypoparathyroidism. Acta Endocrinol 103: 535, 1983. Buckle RM, Care AD, Cooper CW, Gitelman HJ. The influence of plasma ll) Chiba T, Okimura Y, Inatome T, Inoh T, Watanabe M, Fujita T. magnesiumconcentration on parathyroid hormonesecretion. J Endocrinol Hypocalcemic crisis in alcoholic fatty liver: Transient hypoparathy- 42: 529, 1968. roidism due to magnesium deficiency. AmJ Gastroenterol 82: 1084, Cholst IN, Susan FS, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The 1987. influence of on serum calcium and parathyroid hor- 12) Mune T, Yasuda K, Ishii M, Matsunaga T, Miura K. Tetany due to mone levels in human subjects. N Engl J Med 310: 1221, 1984. hypomagnesemia induced by cisplatin and doxorubicin treatment for Bonjour JP, Troehler U, Preston C, Fleisch H. Parathyroid hormone and synovial sarcoma. Intern Med 32: 434, 1993. renal handling of Pi: effect of dietary Pi deprivation and diphosphonate. 13) Estep H, Shaw WA, Watlington C, Hobe R, Holland W, Tucker SG. Am J Physiol 234: F497, 1978. Hypocalcemia due to hypomagnesemia and reversible parathyroid hor- Shils ME. Experimental human magnesium depletion. Medicine (Balti- moneunresponsiveness. J Clin Endocrinol 29: 842, 1969. more) 48: 61, 1969. 14) MacManusJ, Heaton FW,Lucas PW.A decreased response to parathy- Fraser DR. Regulation of the metabolism of vitamin D. Physiol Rev 60: roid hormone in magnesium deficiency. J Endocrinol 49: 253, 1971. 551, 1980. 15) Woodard JC, Webster PD, Carr AA. Primary hypomagnesemia with Rude RK, AdamsJS, Ryzen E, et al. Lowserum concentrations of 1 ,25- secondary hypocalcemia, diarrhea and insensitivity to parathyroid hor- dihydroxyvitamin D in human magnesium deficiency. J Clin Endocrinol mone. Dig Dis 17: 612, 1972. Metab61: 933, 1985. 16) Medalle R, Waterhouse C. A magnesium-deficient patient presenting Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biologically with hypocalcemia and hyperphosphatemia. Ann Intern Med79: 76, active vitamin D metabolite. Nature 228: 764, 1979. 1973. Selby PL, Peacock M, Bambach CP. Hypomagnesemia after small bowel 17) WiegmannT, Kaye M. Hypomagnesemic hypocalcemia. Arch Intern resection: treatment with la-hydroxylated vitamin D metabolites. Br J Med137: 953, 1977. Surg 71: 334, 1984. 18) Allgrove J, Adami S, Fraher L, Reuben A, O'Riordan JLH. Hypomagne- Fuss M, Cogan E, Gillet C, et al. Magnesium administration reverses the saemia: Studies of parathyroid hormonesecretion and function. Clin hypocalcemia secondary to hypomagnesemia despite low circulating Endocrinol 21: 435, 1984. levels of 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D. Clin 19) Mori S, Harada S, Okazaki R, Inoue D, Matsumoto T, Ogata E. Endocrinol 22: 807, 1985. Hypomagnesemiawith increased metabolism of parathyroid hormone

Internal Medicine Vol. 34, No. 7 (July 1995) 669