Pseudohypoparathyroidism Showing Positive Phosphaturic and Negative Cyclic AMP Excretion Response to Parathyroid Hormone

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1 Pseudohypoparathyroidism Showing Positive Phosphaturic and Negative Cyclic AMP Excretion Response to Parathyroid Hormone KIICHIRO HIGASHI, KENICHI HONDA*, MITSUO MORITA*, TERUHISA UMEDA*, TATSUYA SHIMADA, KEISHI KIMURA, TADAHIRO SHIDO, ISAO ARITA AND TATSUO SATO* Department of Internal Medicine, Kumamoto National Hospital and The Third Department of Internal Medicine, Kumamoto University Medical School* Abstract We report a patient with pseudohypoparathyroidism (PHP) in whom parathyroid hormone (PTH) infusion failed to produce an increase in urinary adenosine 3',5' monophosphate (camp) excretion in spite of the positive urinary phosphate excretion. The dbcamp infusion test showed almost the same increase in phosphate as in the E-H test, although high urinary camp excretion was detected. Furthermore, a PTH infusion test in combination with calcium antagonist (diltiazem) administration markedly increased phosphate excretion, whereas the response of urinary camp excretion also remained negative. After treatment with la(oh)d3, phosphaturic response increased by at least 14.3 mg/2 h compared with that in the pretreatment period. Therefore, intra and extra cellular calcium seem to affect the phosphaturic response induced by PTH. Received October 13, 1988 Reprint requests to Department of Internal Medicine, Kumamoto National Hospital, Ninomaru 1-5, Kumamoto, 860, Japan (Dr. KTICHIRO HIGASHI). Pseudohypoparathyroidism (PHP) is divided into two groups, type I and type II. PHP type I is characterized by failure to increase urinary excretion of adenosine 3', 5' monophosphate (camp) and phosphate in response to parathyroid hormone (PTH) (Chase et al., 1969). In PHP type II, resistance to the phosphaturic effect of PTH is associated with normal urinary camp excretion (Drezner et al., 1973). In the untreated patient with PHP, positive phosphaturic and negative camp response to PTH has not been reported. After treatment with vitamin D, however, there were several reports showing positive phosphaturic and negative camp excretion response which was occasionally called PHP type III (Ogata et al., 1984). Recently, increasing evidence indicates that calcium is a second messenger in PTH dependent events (Rasmussen, 1970). Therefore, we also examined whether or not calcium could influence response in the E-H test.

2 HIGASHI et al. Endocrinol. Japon. August 1989 Report of a case Table 1. Urinary excretion of creatinine, phosphate and camp A 44-year-old woman was hospitalized for evaluation of hypocalcemia. She had brachymetacarpia, brachymetatarsia and dispropotionated growth retardation (145 cm, 34 kg). There was no family history of short stature or hand or foot abnormality. Roentgenographic examination revealed basal ganglia calcifications. Her karyotype was 46, XX. Laboratory results included decreased serum calcium (5.6mg/dl) and incresed serum immunoreactive PTH (C- PTH 0.6ng/ml; normal<0.5ng/ml, M-PTH 780pg/ml; pg/ml, N-PTH 700pg/ ml; pg/ml), and serum inorganic phosphate was increased (6.5mg/dl). There were no symptoms of steatorrhea or renal disease. Normal renal function was determined by urinalysis and creatinine clearance (89 ml/min). Serum 1,25 (OH) 2D3 and 25 (OH)D were 23pg/ml (20-76pg/ml) and 15ng/ml (10-55ng/ml), respectively. Serum alkaline phosphatase (76p/i), magnesium (2.1mg/dl) and thyroid stimulating hormone (2.1pU/ml) were within the normal range. The Plasma camp concentration increased from 13pg/ml to 780pg/ml after glucagon infusion (0.03USP/kg). Ellsworth-Howard (E-H) tests were repeated three times at at least 2 week intervals before treatment. She had not been treated with vitamin D or other drugs to increase serum calcium, and was in a hypocalcemic state throughout these studies. Urine was collected at hourly intervals from 1100h to 1500h during a control day and experimental days (1100h to 1200h; U 1, 1200h to 1300h; U2, 1300h to 1400h; U3, 1400h to 1500h; U4). Urine specimens were stored at-20 Ž before the determination of camp. One hundred units of human (h) PTH (1-34) was injected intravenously at 1300h. Urinary data were shown in Table 1 and Table 2. The ratio of creatinine during the 2 hours Urine was collected at 1 hour time intervals (1100 h-1200 h; U 1, 1200 h-1300 h; U2, 1300h h; U3, 1400 h-1500 h; U4). 100 units of human PTH (1-34) or dbcamp (2.5mg/kg) was injected intravenously at 1300 h. C; control, D; Diltiazem (90mg) was given at 1000h. Urine was collected at 1 hour intervals in the same way as in the Ellsworth-Howard (E-H) test. E-H 1, 2, 3; E-H test performed before treatment. E-H4; E-H test performed after treatment with la(oh)d3. E-H5; diltiazem administration +E-H test, which was performed before treatment with la(oh)d3. Diltiazem (90 mg) was given at 1000h. before PTH to that after PTH administration was (n, 4). The increase in (U3-U2) and ratio (U3/U2) of 1hour total urinary camp excretion in response

3 PHP SHOWING INTERESTING PTH RESPONSE Table 2. Urinary excretion of phosphate and camp The criteria of positive response in the Ellsworth-Howard test (E-H test) are defined as follows. 1) phosphaturic response: increase in 2-hour urinary phosphate excretion; more than 35mg/2hr. 2) camp response: increase in 1-hour urinary excretion; more than 1ƒÊmol/h, ratio of 1-hour urinary excretion; more than 10 times. Urine was collected at 1 hour intervals. 100 units of human PTH (1-34) or dbcamp (2.5mg/kg) was injected intravenously at 1300h. Diltiazem (90mg) was administered at 1000h. E-H 1, 2, 3; Ellsworth-Howard test performed before treatment, E-H 4; E-H test performed after treatment with la (OH) D3, E-H 5; diltiazem administration+e-h test, which was performed before treatment with lƒ (OH) D3. Diltiazem (90mg) was given at 1000h. D; Diltiazem (90mg) was given at 1000h. Urine was collected at 1 hour intervals in the same way as in the E-H test. to h PTH (1-34) were pmol/ hr (mean+sd, n=3) and 2.3 }0.5 (n=3), respectively. The increase in 2 hour urinary phosphate excretion (U3+U4-U-1-U2) was 38.8 }2.6mg/2h (n=3). Urinary phosphate excretion was further increased by diltiazem administration (90 mg) 3 hours before PTH injection (U3+U4- whether the phosphaturic and urinary camp excretion response might change or not. The results were as follows. P: U3+U4 U2=0.173 pmol/h, U3/U2 = A negative camp response and positive phosphaturic response were also shown after treatment with la (OH) D3. The phos- U1-U2=84.4mg/2hr), although diltiazem phaturic increase was at least 14.3mg/2h administration alone could not increase urinary phosphate excretion (U3+U4-U1-U2= responses in E-H tests performed during more than each of the three phosphaturic pretreatment condition. concentration (207.0ng/ml) appeared at 3.5 hours after diltiazem administration. In addition, increased urinary phosphate excretion was found after dibutyryl camp Discussion (dbcamp) administration (2.5mg/kg). The diagnosis of PHP was established After completing these tests, we treated on the basis of the typical physical signs the patient with la (OH) D3. When serum compatible with Albright's hereditary osteodystrophy (AHO)(Albright et al., 1942), calcium returned to normal (Ca 8.7mg/dl), the last E-H test was done to confirm the lowered serum calcium and increased

4 HIGASHI et al. Endocrinol. Japon. August 1989 serum PTH and phosphate, and the resistance of urinary camp excretion to PTH. Renal failure and Turner's syndrome were excluded because of the normal renal function and the normal karyotype. Ogata et al. reported the standard procedum and diagnostic criteria of positive responses. to the E-H test with hpth (1-34) (Ogata et al., 1984). The diurnal variation in phosphate excretion was small, and the accuracy of timed urine collection was confirmed by urinary excretion of creatinine. The increase in 2hour urinary phosphate excretion (U3+U4-U1-U2) was always greater than 35mg/2h, indicating a positive phosphaturic response. On the other hand, the increase in 1 hour urinary camp excretion (U3-U2) and the ratio (U3/U2) of 1 hour urinary camp excretion showed a negative response. These results clearly indicated that resistance to urinary camp excretion was associated with normal phosphaturic response to PTH. The normal phosphaturic response associated with negative urinary camp is very interesting, but it seems to be difficult to explain the mechanism of this response completely. Firstly, phosphaturia may be caused by hypersensitivity to intracellular camp. However, the result of the dbcamp infusion test was contrary to our expectations. The dbcamp test showed almost the same increase in phosphate as in the E-H test in spite of extremely high urinary camp excretion. Although it was confirmed that phosphaturia could be induced by camp as Bell et al. reported (Bell et al., 1972), it remained uncertain why an extremely great increase in phosphate could not be attained in a dbcamp infusion test. Several possible explanations may be considered. For one thing, there might really be no hypersensitivity to camp in this patient, and for another, there might be some problems involved in the method of metabolism of dbcamp. Most of the dbcamp might be metabolized in organs other than the kidneys, and the amount of intracellular camp in the renal tubules might not be enough to induce extremely high phosphate excretion. Anyway, we could not confirm by the dbcamp infusion test that this patient was hypersensitive to camp. Secondly, hyper-response of phophate excretion may be caused by the supplementary help of, or cooperation with, another mechanism. Although camp has been considered to be the intracellular second messenger for PTH action in the renal tubular cell (Chase and Aurbuch, 1967), there is evidence to suggest that many PTH effects on the kidney are calcium dependent (Rasmussen and Tenenhouse, 1968; Borle and Uchikawa, 1978; Pushett, 1981; Somermeyer et al., 1983). Therefore, we performed an E-H test associated with calcium antagonist in order to clarify whether or not intracellular calcium played a role in phospate excretion. Borle et al. reported that PTH stimulated calcium influx or increased intracellular calcium in cultured kidney cells (Borle, 1970; Borle and Uchikawa, 1978). If PTH really acted as a calcium influx stimulator or as an intracellular calcium increasing factor in the kidney, calcium antagonist with PTH would seem to decrease or inhibit phosphate excretion interfering with the effect of PTH. However, Dolson et al. recently demonstrated that exposure of the renal tubules to PTH resulted in a significant decrease rather than an increase in the calculated cytosolic concentration of calcium (Dolson et al., 1985). This suggests the possibility that diltiazem may help the effect of PTH by further decreasing the intracellular calcium concentration. After treatment with 1 a(oh)d3, 2-hour urinary phosphate excretion in the E-H test had increased by at least 14.3mg/2h compared with that in the pretreatment period. The increased phosphaturic change

5 PHP SHOWING INTERESTING PTH RESPONSE is in line with previous reports (Suh et al., 1970; Ogata et al., 1984). In addition, according to Stogmann, phosphaturia could be induced by parathyroid extract without urinary excretion of camp after normalization of calcium (Stogmann and Fischer, 1975). Therefore, it seems that there may be a relation between the serum calcium concentration and the phosphaturic effect of PTH. In conclusion, we report here a patient with PHP. She showed positive phosphaturic and negative camp respose to PTH. The reason why the unique response occurred in the E-H test remains uncertain. However, the calcium antagonist might have worked as a helper of camp in this case. References Albright, F. et al.(1942). Pseudohypoparathyroidism: an example of "Seabright-Bantam Syndrome". Endocrinology 30, Bell, N. H. et al.(1972). Effects of dibutyryl cyclic adenosine 3', 5' monophosphate and parathyroid extract on calcium and phosphorus metabolism in hypoparathyroidism and pseudohypoparathyroidism. J. Clin. Invest. 51, Borle, A. B.(1970). Kinetic analyses of calcium movements in cell cultures. Endocrinology 86, Borle, A. B. and T. Uchikawa(1978). Effect of parathyroid hormone on the distribution and transport of calcium in cultured kidney cells. Endocrinology 102, Chase, L. R. and G. D. Aurbach (1967). Parathyroid function and the renal excretion of 3', 5'-adenylic acid. Proc. Natl. Acad. Sci. U. S. A. 58, Chase, L. R. et al.(1969). Pseudohypoparathyroidism: Defective excretion of 3' 5'-AMP in response to parathyroid hormone. J. Clin. Invest. 48, Dolson, G. M. et al.(1985). Relationship among parathyroid hormone, camp, and calcium on proximal tubule sodium transport. Am. J. Physiol. 249, F409-F416. Drezner, M. et al.(1973). Pseudohypoparathyroidism type II: A possible defect in the reception of the cyclic AMP signal. N. Eng. J. Med. 289, Ogata, E. et al.(1984). Standard procedure and the diagnostic criteria for the Ellsworth- Howard test using human PTH-(1-34). Folia Endocrinol. 60, Puschett, J. B. et al.(1981). Study of the renal tubular sites and mechanisms of action of parathyroid hormone. Mineral Electrolyte Metab. 6, Rasmussen, H. and A. Tenenhouse(1968). Cyclic adenosine monophosphate, calcium and membranes. Proc. Natl. Acad. Sci. U. S. A. 59, Rasmussen, H.(1970). Cell communication, calcium ion, and cyclic adenosine monophosphate. Science 170, Somereyer, M. et al.(1983). Characterization of Ca transport in rat renal bruch-border membranes and its modulation by phosphatidic acid. Biochem. J. 214, Stogman, W. and J. A. Fischer (1975). Pseudohypoparathyroidism. disappearance of resistance of parathyroid extract during treatment with vitamin D. Amer. J. Med. 59, Suh, S. M. et al.(1970). Pseudohypoparathyroidism responsiveness to parathyroid extract induced by vitamin D therapy. J. Clin. Endocrinol. Metab. 30,