Parathyroid Hormone Status and Renal Responsiveness in Familial Hypophosphatemic Rickets T. J. HAHN, C. R. SCHARP, L. R. HALSTEAD, J. G. HADDAD, D. M. KARL, AND L. V. AVIOLI Department of Medicine, Washington University School of Medicine, The Jewish Hospital of St. Louis, St. Louis, Missouri 63110 ABSTRACT. Basal serum and urinary biochemical parameters and their response to PTH or calcium infusion were examined in 14 untreated patients with familial hypophosphatemic rickets (FHR) from 5 kindreds and 9 normal control subjects after a period of dietary equilibration. FHR subjects exhibited significantly elevated basal serum iPTH levels (FHR: 11.4 ±0.8, controls: 5.1 ± 0.5 ng/ml,P < 0.001) and urinary cAMP excretion (FHR: 7.83 ± 0.8.1, controls: 3.78 ± 0.46 nmol/mgereatinine P < 0.001). In response to PTH infusion (6 units/ kg over 4 hours) FHR subjects exhibited a mean 34% decrease in TRP and a 22-fold increase in cAMP excretion, both comparable to the control response. Calcium infusion (10 nig/kg over 1 h) rapidly suppressed serum iPTH and urinary cAMP values in FHR subjects. However, TRP remained inappropriately low for the level of serum phos-
F
AMILIAL hypophosphatemic rickets (FHR) is an X-linked dominant disorder characterized by hypophosphatemia, reduced renal tubular reabsorption of phosphate, decreased intestinal absorption of calcium and inorganic phosphate, and varying degrees of rickets or osteomalacia (1,2). The most consistently observed biochemical abnormality is hypophosphatemia, with affected (hemizygous) males exhibiting more marked hypophosphatemia and bone disease than heterozygous females (2). Two opposing theories of the pathogenesis of this disorder have been proposed. On the one hand, it has been suggested that the primary defect is a disordered conversion of vitamin D to 25-hydroxyvitamin D (25OHD) with a presumed deficiency of biologically active metabolites, consequent calcium malabsorption, and secondary hyperparathyroidism resulting in a decreased renal tubular reabsorption of phosphate, hypophosphatemia, and rickets Received May 13, 1975.
phate. Basal and post-calcium infusion serum iPTH levels correlated positively with urinary cAMP in FHR subjects and controls. Pie- and postcalcium infusion iPTH levels correlated with serum calcium in FHR subjects. Mean salivary phosphate concentration was significantly reduced in FHR subjects (FHR: 12.68 ± 0.87, controls: 22.47 ± 2.16 mg/100 ml, P < 0.001). However, calculated salivary phosphate clearance rates were similar in FHR and control subjects. PTH or calcium infusion did not significantly alter salivary phosphate concentration or clearance rates in either patients or controls. We concluded that untreated FHR patients exhibit a state of mild secondary hyperparathyroidism and an at least normal renal phosphaturic response to PTH. In addition, there is no evidence for increased salivary phosphate excretion in FHR. (J Clin Endocrinol Metab 41: 926, 1975)
(3,4). However, it has been recently demonstrated that serum 25OHD levels measured by competitive protein-binding assay are normal in patients with FHR and rise normally following vitamin D administration (5). Furthermore, administration of 25OHD or 1,25 dihydroxyvitamin D does not correct the hypophosphatemia or decreased renal tubular reabsorption of phosphate (6-9). Data on serum immunoreactive parathyroid hormone (iPTH) levels in patients with FHR is conflicting, with various groups reporting low (10), normal (11), high normal (12), or elevated (13,14) iPTH levels in these individuals. The alternate hypothesis is that FHR is due to a primary defect in the membrane transport of inorganic phosphate in the proximal renal tubule and intestinal mucosa with subsequent phosphate malabsorption and renal phosphate wasting (15-17). Glorieux and Scriver have reported that renal tubular reabsorption of phosphate appears to be mediated through two separate mechanisms, a parathyroid 926
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PTH STATUS AND RESPONSE IN FHR hormone-sensitive system responsible for reabsorption of approximately two-thirds of the filtered phosphate, and a parathyroid hormone-insensitive, calcium-responsive system responsible for reabsorption of the remaining one-third of filtered phosphate (16). Based on their observation that hemizygote males with FHR did not exhibit a phosphaturic response to parathyroid hormone, these authors have concluded that the parathyroid hormone-sensitive system is defective in FHR (16). In addition, they have reported that following intravenous phosphate infusion in hemizygote males with FHR, renal excretion of phosphate often exceeds the filtered load, suggesting net tubular phosphate secretion. The presence of a normal calcium-sensitive renal phosphate transport component in FHR patients would explain the observed ability of calcium infusion to decrease phosphatuiia in these individuals. The observed intestinal calcium malabsorption might then be postulated to be the result of a primary disturbance in intestinal phosphate transport leading to the formation of insoluble calcium-phosphate complexes in the intestinal lumen (17). The purpose of the present study was to investigate the parathyroid hormone-mineral metabolism status in previously untreated hemizygotes and heterozygotes with FHR by examining a) the interrelationships of basal biochemical parameters, b) renal tubular responsiveness to parathyroid hormone and calcium infusion, as measured by urinary phosphate and 3'5'-cyclic adenosine monophosphate (cAMP) excretion, and c) salivary phosphate excretion, the latter to test for a possible generalized membrane phosphate transport defect. Materials and Methods Nine female and five male patients with Xlinked FHR, ranging in age from 10 to 43 years (mean 20.2 ± 3.5 years), from five separate kindreds were studied. The diagnosis of FHR was based on a characteristic family history of X-linked FHR, radiographic findings of rickets
927
or osteopenia, absence of other intrinsic intestinal or renal disease, and persistent hypophosphatemia. All patients were previously untreated with the exception of S.H. and R.H., who had each received a brief course of vitamin D therapy (50,000-100,000 IU/day) approximately five years prior to study. All patients were hospitalized in the Clinical Research Centers of Barnes and St. Louis Children's Hospitals and equilibrated for one week prior to study on a diet containing 800 nig calcium, 1200 mg phosphate and 400 IU vitamin D per day. This diet in most cases was quite comparable to the patient's normal intake. Subsequently, serum calcium, phosphate, alkaline phosphatase, albumin, and 24-hour urinary calcium and creatinine excretion, determined by Technicon AutoAnalyzer (18), were measured daily for four days. Fasting serum 25OHD levels were measured by competitive protein-binding assay (19). Nine normal subjects, 5 female and 4 male, ranging in age from 11 to 33 years, were studied under similar conditions following a similar period of dietary equilibration. Parathyroid hormone (PTH) and calcium infusion studies were performed following an overnight fast, and oral hydration with 4 ml water/kg ideal body weight/hour, starting 2 hours before and continuing through the test infusion periods. At the beginning of the test period, an infusion of 0.45 N saline at a rate of 50 ml/h was begun and continued through the test period. During the parathyroid hormone infusion test, urines were collected at hourly intervals for six hours for determination of phosphate, creatinine, and cAMP, and blood samples were obtained at the mid-point of each collection period for determination of serum total calcium, phosphate, and creatinine. Urinary cyclic AMP excretion was determined by radio-immunoassay employing a Schwarz-Mann kit (Schwarz-Mann, Orangeburg, New Jersey) according to previously described techniques (19). After two baseline collection periods, parathyroid extract (Eli Lilly, lot no. 6NK02A) was administered intravenously in a total dose of 6 units/kg ideal body weight with a maximum of 400 units given. One-third of the total dose was given immediately intravenously over 10-15 seconds while the remainder was added to 0.45 N saline and infused over the remaining four hours. At the beginning of the infusion, salivary collection cups were placed over one parotid duct and saliva collected in 15 minute periods starting 30 and 15 minutes
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JCE & M • 1975 \'ol 41 • No 5
HAHN ET AL.
928
before, and 0 and 45 minutes after parathyroid extract administration according to previously described techniques (20). Total volume was measured and aliquots taken for microdetermination of phosphate (21). For the calcium infusion studies, patients were similarly fasted overnight and hydrated with 4 ml water/kg ideal body weight/hour for two hours prior to and during the infusion. At the beginning of the infusion period 0.45 N saline at a rate of 50 ml/hour was begun and continued throughout the infusion period. Urines were collected at 30 minute intervals for three hours with blood samples obtained at the mid-point of each collection period. After two baseline collections, calcium (10 mg/kg body weight), as calcium glucoheptonate, was infused over a one-hour period. Salivary cups were placed as described above and saliva collected in 15-minute periods starting 30 and
15 minutes before, and 0 and 30 minutes after initiation of the calcium infusion. Serum immunoreactive parathyroid hormone (iPTH) levels were measured after the initiation of calcium infusion by the ininiunoassay technique of Slatopolsky et al. (22) employing an antibody (Chicken-9) which recognizes both the amino and carboxyl terminal ends of the PTH molecule. Statistical significance was determined by the Student's t test, correlation coefficient were determined by Pearson's formula, and the reduced major axis of correlation determined by the method of Kermack and Haldane (23).
Results Basal biochemical parameters Serum values in the fasting non-hydrated state showed many of the characteristic
TABLE 1. Basal fasting biochemical parameters in FHR subjects and normal controls 24-Hour urine enilciuin excretion
Serum values
Age
Patient Kindred I KE MB
JB KB CB Kindred II HM TM \VM
RM
(y«)
Race
Sex
22 17 12 9 43
W W VV W W
F
40 15 12 10
W
F
w
12
Calcium (mg/lOOml)
Inorganic phosphate mg/lOOml
Creatinine (mg/lOOml)
Alkaline phosphatase mil/ml
25OHD (ng/ml)
mg/24 h
9 6 12
1.75 ± 0.06 2.00 + 0.24 1.50 + 0.24 1.85 ±0.21 1.25 + 0.13
+ 7 ± 16 ± 8 ± 4
0.42 ± 0.07 1.60 ± 0.20 1.15 + 0.20 2.13 + 0.17
8.74 ± 8.27 ± 9.48 ± 9.60 ± 8.80 ±
0.13 0.19 0.41 0.52 0.13
2.16 ±0.10 2.90 ± 0.19 2.75 ± 0.19 2.87 ± 0.18 2.13 + 0.17
0.58 ± 0.06 0.81 + 0.07 0.71 + 0.10 0.78 ± 0.15 1.11 + 0.06
49+2 64+12 345 + 16 235 + 20 87+2
8.2 36.8 8.5 35.7 29.5
110 ± 92 i: 56 + 53 + 113 ±
VV VV
F M M
8.78 ± 8.92 ± 9.05 ± 9.33 ±
0.14 0.18 0.35 0.26
2.50 + 0.08 2.56 + 0.15 2.30 ± 0.35 2.17 ± 0.17
0.83 + 0.03 0.53 ± 0.03 0.50 + 0.04 0.40 ± 0.02
112 ± 3 183+ 4 486 + 32 420 ± 23
9.0 18.7 17.0 16.4
45 128 46 49
F
F F
M
mg/kg body weight
7
12
Kindred III SH RH TH
12 45
VV VV VV
F F M
9.60 ± 0.08 9.70 ± 0.08 9.53 ± 0.15
1.91 ± 0.18 1.81 ±0.15 1.79 ± 0.05
0.73 ± 0.06 0.71 ± 0.05 0.85 + 0.03
541 ± 6 485 ± 1 69+8
26.7 18.3 10.3
10 + 5 3+ 1 94 ± 15
0.37 + 0.18 0.12 i 0.04 1.02 + 0.16
Kindred IV MW
10
VV
M
9.15 ± 0.17
2.60 ±0.14
0.52 ± 0.05
401 + 31
20.4
15 +
4
0.66 ± 0.18
Kindred V PH
24
VV
F
9.22 =
2.46 + 0.04
0.75 ± 0.08
56+ 1
14.0
26 ±
3
0.38 + 0.04
9.67 + 0.18 (9.25 - 10.35)
3.59 + 0.16 (3.15 - 4.10)
0.96 ± 0.08 (0.85- 1.15)
57+8 (36 - 71)
14.9+ 3.5 (9.5 - 28.4)
149 ± 11 (115- 201)
(1.98-2.61)
9.00- 11.00
3.00 - 4.50
0.40- 1.20
30-80 (adults) 75 - 250 (children)
8-40
1 1 0 - 240
Normal subjects (5WF and 23.3 4WM) ;±2.1
.011
2.45 + 0.18
Normal values
Values for the FHR subjects represent the mean ± SEM of at least four determinations. Values for the normal subjects are given as the mean ± SEM for two determinations in 9 subjects with ranges in parentheses.
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929
PTH STATUS AND RESPONSE IN FHR changes previously noted in FHR subjects (Table 1). Serum calcium values ranged from normal to mildly decreased with a mean serum calcium of 9.28 ± 0.09 mg/100 ml significantly below the mean of 9.67 ± 0.18 mg/100 ml observed in the 9 normal subjects (P < 0.01). Mean serum calcium concentrations in male and female FHR subjects were not significantly different. Serum albumin was normal in all subjects. Varying degrees of hypophosphatemia were observed among the 5 kindreds with the most marked hypophosphatemia occurring in Kindred III which was the most severely involved clinically. Within each kindred lowest serum phosphate levels were observed in the males. Serum creatinine was normal in all subjects. Alkaline phosphatase ranged from normal to moderately elevated, with the highest values observed in the two children in Kindred III. Serum 25OHD levels were normal in all subjects, in keeping with previous observations (5),
and showed no correlation with serum calcium or phosphorus values. Twenty-fourhour urine calcium excretion was generally quite low, averaging 58 ± 8 mg on an 800 mg calcium diet, significantly below the mean of 149 ± 1 1 mg/24 h observed in normal subjects(P < 0.001), with the lowest values again observed in Kindred III. Response to PTH infusion and infusion
calcium
Basal serum and urine chemistries in the hydrated state, prior to PTH or calcium infusion showed striking differences between FHR and normal subjects (Table 2). There were no significant differences between mean basal values in the FHR subjects on the two test infusion days, hence basal values from these two days were combined for analysis. Basal serum calcium levels were slightly but not significantly higher and serum phosphate levels
TABLE 2. Comparison of basal values in the hydrated state prior to provocative infusion in FHR and control subjects P values Males vs. Females FHR
Normals
FHR
Normals
FHR vs. normals
Serum calcium (mg/100 ml) Males Females
9.04 ± 0.10 8.84 ± 0.07
9.69 ± 0.20 9.48 ± 0.10
NS
NS
F
AMILIAL hypophosphatemic rickets (FHR) is an X-linked dominant disorder characterized by hypophosphatemia, reduced renal tubular reabsorption of phosphate, decreased intestinal absorption of calcium and inorganic phosphate, and varying degrees of rickets or osteomalacia (1,2). The most consistently observed biochemical abnormality is hypophosphatemia, with affected (hemizygous) males exhibiting more marked hypophosphatemia and bone disease than heterozygous females (2). Two opposing theories of the pathogenesis of this disorder have been proposed. On the one hand, it has been suggested that the primary defect is a disordered conversion of vitamin D to 25-hydroxyvitamin D (25OHD) with a presumed deficiency of biologically active metabolites, consequent calcium malabsorption, and secondary hyperparathyroidism resulting in a decreased renal tubular reabsorption of phosphate, hypophosphatemia, and rickets Received May 13, 1975.
phate. Basal and post-calcium infusion serum iPTH levels correlated positively with urinary cAMP in FHR subjects and controls. Pie- and postcalcium infusion iPTH levels correlated with serum calcium in FHR subjects. Mean salivary phosphate concentration was significantly reduced in FHR subjects (FHR: 12.68 ± 0.87, controls: 22.47 ± 2.16 mg/100 ml, P < 0.001). However, calculated salivary phosphate clearance rates were similar in FHR and control subjects. PTH or calcium infusion did not significantly alter salivary phosphate concentration or clearance rates in either patients or controls. We concluded that untreated FHR patients exhibit a state of mild secondary hyperparathyroidism and an at least normal renal phosphaturic response to PTH. In addition, there is no evidence for increased salivary phosphate excretion in FHR. (J Clin Endocrinol Metab 41: 926, 1975)
(3,4). However, it has been recently demonstrated that serum 25OHD levels measured by competitive protein-binding assay are normal in patients with FHR and rise normally following vitamin D administration (5). Furthermore, administration of 25OHD or 1,25 dihydroxyvitamin D does not correct the hypophosphatemia or decreased renal tubular reabsorption of phosphate (6-9). Data on serum immunoreactive parathyroid hormone (iPTH) levels in patients with FHR is conflicting, with various groups reporting low (10), normal (11), high normal (12), or elevated (13,14) iPTH levels in these individuals. The alternate hypothesis is that FHR is due to a primary defect in the membrane transport of inorganic phosphate in the proximal renal tubule and intestinal mucosa with subsequent phosphate malabsorption and renal phosphate wasting (15-17). Glorieux and Scriver have reported that renal tubular reabsorption of phosphate appears to be mediated through two separate mechanisms, a parathyroid 926
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PTH STATUS AND RESPONSE IN FHR hormone-sensitive system responsible for reabsorption of approximately two-thirds of the filtered phosphate, and a parathyroid hormone-insensitive, calcium-responsive system responsible for reabsorption of the remaining one-third of filtered phosphate (16). Based on their observation that hemizygote males with FHR did not exhibit a phosphaturic response to parathyroid hormone, these authors have concluded that the parathyroid hormone-sensitive system is defective in FHR (16). In addition, they have reported that following intravenous phosphate infusion in hemizygote males with FHR, renal excretion of phosphate often exceeds the filtered load, suggesting net tubular phosphate secretion. The presence of a normal calcium-sensitive renal phosphate transport component in FHR patients would explain the observed ability of calcium infusion to decrease phosphatuiia in these individuals. The observed intestinal calcium malabsorption might then be postulated to be the result of a primary disturbance in intestinal phosphate transport leading to the formation of insoluble calcium-phosphate complexes in the intestinal lumen (17). The purpose of the present study was to investigate the parathyroid hormone-mineral metabolism status in previously untreated hemizygotes and heterozygotes with FHR by examining a) the interrelationships of basal biochemical parameters, b) renal tubular responsiveness to parathyroid hormone and calcium infusion, as measured by urinary phosphate and 3'5'-cyclic adenosine monophosphate (cAMP) excretion, and c) salivary phosphate excretion, the latter to test for a possible generalized membrane phosphate transport defect. Materials and Methods Nine female and five male patients with Xlinked FHR, ranging in age from 10 to 43 years (mean 20.2 ± 3.5 years), from five separate kindreds were studied. The diagnosis of FHR was based on a characteristic family history of X-linked FHR, radiographic findings of rickets
927
or osteopenia, absence of other intrinsic intestinal or renal disease, and persistent hypophosphatemia. All patients were previously untreated with the exception of S.H. and R.H., who had each received a brief course of vitamin D therapy (50,000-100,000 IU/day) approximately five years prior to study. All patients were hospitalized in the Clinical Research Centers of Barnes and St. Louis Children's Hospitals and equilibrated for one week prior to study on a diet containing 800 nig calcium, 1200 mg phosphate and 400 IU vitamin D per day. This diet in most cases was quite comparable to the patient's normal intake. Subsequently, serum calcium, phosphate, alkaline phosphatase, albumin, and 24-hour urinary calcium and creatinine excretion, determined by Technicon AutoAnalyzer (18), were measured daily for four days. Fasting serum 25OHD levels were measured by competitive protein-binding assay (19). Nine normal subjects, 5 female and 4 male, ranging in age from 11 to 33 years, were studied under similar conditions following a similar period of dietary equilibration. Parathyroid hormone (PTH) and calcium infusion studies were performed following an overnight fast, and oral hydration with 4 ml water/kg ideal body weight/hour, starting 2 hours before and continuing through the test infusion periods. At the beginning of the test period, an infusion of 0.45 N saline at a rate of 50 ml/h was begun and continued through the test period. During the parathyroid hormone infusion test, urines were collected at hourly intervals for six hours for determination of phosphate, creatinine, and cAMP, and blood samples were obtained at the mid-point of each collection period for determination of serum total calcium, phosphate, and creatinine. Urinary cyclic AMP excretion was determined by radio-immunoassay employing a Schwarz-Mann kit (Schwarz-Mann, Orangeburg, New Jersey) according to previously described techniques (19). After two baseline collection periods, parathyroid extract (Eli Lilly, lot no. 6NK02A) was administered intravenously in a total dose of 6 units/kg ideal body weight with a maximum of 400 units given. One-third of the total dose was given immediately intravenously over 10-15 seconds while the remainder was added to 0.45 N saline and infused over the remaining four hours. At the beginning of the infusion, salivary collection cups were placed over one parotid duct and saliva collected in 15 minute periods starting 30 and 15 minutes
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JCE & M • 1975 \'ol 41 • No 5
HAHN ET AL.
928
before, and 0 and 45 minutes after parathyroid extract administration according to previously described techniques (20). Total volume was measured and aliquots taken for microdetermination of phosphate (21). For the calcium infusion studies, patients were similarly fasted overnight and hydrated with 4 ml water/kg ideal body weight/hour for two hours prior to and during the infusion. At the beginning of the infusion period 0.45 N saline at a rate of 50 ml/hour was begun and continued throughout the infusion period. Urines were collected at 30 minute intervals for three hours with blood samples obtained at the mid-point of each collection period. After two baseline collections, calcium (10 mg/kg body weight), as calcium glucoheptonate, was infused over a one-hour period. Salivary cups were placed as described above and saliva collected in 15-minute periods starting 30 and
15 minutes before, and 0 and 30 minutes after initiation of the calcium infusion. Serum immunoreactive parathyroid hormone (iPTH) levels were measured after the initiation of calcium infusion by the ininiunoassay technique of Slatopolsky et al. (22) employing an antibody (Chicken-9) which recognizes both the amino and carboxyl terminal ends of the PTH molecule. Statistical significance was determined by the Student's t test, correlation coefficient were determined by Pearson's formula, and the reduced major axis of correlation determined by the method of Kermack and Haldane (23).
Results Basal biochemical parameters Serum values in the fasting non-hydrated state showed many of the characteristic
TABLE 1. Basal fasting biochemical parameters in FHR subjects and normal controls 24-Hour urine enilciuin excretion
Serum values
Age
Patient Kindred I KE MB
JB KB CB Kindred II HM TM \VM
RM
(y«)
Race
Sex
22 17 12 9 43
W W VV W W
F
40 15 12 10
W
F
w
12
Calcium (mg/lOOml)
Inorganic phosphate mg/lOOml
Creatinine (mg/lOOml)
Alkaline phosphatase mil/ml
25OHD (ng/ml)
mg/24 h
9 6 12
1.75 ± 0.06 2.00 + 0.24 1.50 + 0.24 1.85 ±0.21 1.25 + 0.13
+ 7 ± 16 ± 8 ± 4
0.42 ± 0.07 1.60 ± 0.20 1.15 + 0.20 2.13 + 0.17
8.74 ± 8.27 ± 9.48 ± 9.60 ± 8.80 ±
0.13 0.19 0.41 0.52 0.13
2.16 ±0.10 2.90 ± 0.19 2.75 ± 0.19 2.87 ± 0.18 2.13 + 0.17
0.58 ± 0.06 0.81 + 0.07 0.71 + 0.10 0.78 ± 0.15 1.11 + 0.06
49+2 64+12 345 + 16 235 + 20 87+2
8.2 36.8 8.5 35.7 29.5
110 ± 92 i: 56 + 53 + 113 ±
VV VV
F M M
8.78 ± 8.92 ± 9.05 ± 9.33 ±
0.14 0.18 0.35 0.26
2.50 + 0.08 2.56 + 0.15 2.30 ± 0.35 2.17 ± 0.17
0.83 + 0.03 0.53 ± 0.03 0.50 + 0.04 0.40 ± 0.02
112 ± 3 183+ 4 486 + 32 420 ± 23
9.0 18.7 17.0 16.4
45 128 46 49
F
F F
M
mg/kg body weight
7
12
Kindred III SH RH TH
12 45
VV VV VV
F F M
9.60 ± 0.08 9.70 ± 0.08 9.53 ± 0.15
1.91 ± 0.18 1.81 ±0.15 1.79 ± 0.05
0.73 ± 0.06 0.71 ± 0.05 0.85 + 0.03
541 ± 6 485 ± 1 69+8
26.7 18.3 10.3
10 + 5 3+ 1 94 ± 15
0.37 + 0.18 0.12 i 0.04 1.02 + 0.16
Kindred IV MW
10
VV
M
9.15 ± 0.17
2.60 ±0.14
0.52 ± 0.05
401 + 31
20.4
15 +
4
0.66 ± 0.18
Kindred V PH
24
VV
F
9.22 =
2.46 + 0.04
0.75 ± 0.08
56+ 1
14.0
26 ±
3
0.38 + 0.04
9.67 + 0.18 (9.25 - 10.35)
3.59 + 0.16 (3.15 - 4.10)
0.96 ± 0.08 (0.85- 1.15)
57+8 (36 - 71)
14.9+ 3.5 (9.5 - 28.4)
149 ± 11 (115- 201)
(1.98-2.61)
9.00- 11.00
3.00 - 4.50
0.40- 1.20
30-80 (adults) 75 - 250 (children)
8-40
1 1 0 - 240
Normal subjects (5WF and 23.3 4WM) ;±2.1
.011
2.45 + 0.18
Normal values
Values for the FHR subjects represent the mean ± SEM of at least four determinations. Values for the normal subjects are given as the mean ± SEM for two determinations in 9 subjects with ranges in parentheses.
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929
PTH STATUS AND RESPONSE IN FHR changes previously noted in FHR subjects (Table 1). Serum calcium values ranged from normal to mildly decreased with a mean serum calcium of 9.28 ± 0.09 mg/100 ml significantly below the mean of 9.67 ± 0.18 mg/100 ml observed in the 9 normal subjects (P < 0.01). Mean serum calcium concentrations in male and female FHR subjects were not significantly different. Serum albumin was normal in all subjects. Varying degrees of hypophosphatemia were observed among the 5 kindreds with the most marked hypophosphatemia occurring in Kindred III which was the most severely involved clinically. Within each kindred lowest serum phosphate levels were observed in the males. Serum creatinine was normal in all subjects. Alkaline phosphatase ranged from normal to moderately elevated, with the highest values observed in the two children in Kindred III. Serum 25OHD levels were normal in all subjects, in keeping with previous observations (5),
and showed no correlation with serum calcium or phosphorus values. Twenty-fourhour urine calcium excretion was generally quite low, averaging 58 ± 8 mg on an 800 mg calcium diet, significantly below the mean of 149 ± 1 1 mg/24 h observed in normal subjects(P < 0.001), with the lowest values again observed in Kindred III. Response to PTH infusion and infusion
calcium
Basal serum and urine chemistries in the hydrated state, prior to PTH or calcium infusion showed striking differences between FHR and normal subjects (Table 2). There were no significant differences between mean basal values in the FHR subjects on the two test infusion days, hence basal values from these two days were combined for analysis. Basal serum calcium levels were slightly but not significantly higher and serum phosphate levels
TABLE 2. Comparison of basal values in the hydrated state prior to provocative infusion in FHR and control subjects P values Males vs. Females FHR
Normals
FHR
Normals
FHR vs. normals
Serum calcium (mg/100 ml) Males Females
9.04 ± 0.10 8.84 ± 0.07
9.69 ± 0.20 9.48 ± 0.10
NS
NS
