00~~-9~~x/92/i,s06-1514~03.00/0 .Jrmrnal of Clinical Endocrinology and Metabolism Copyright CC)1992 hy The Endocrine Society
Tertiary Therapy
Vol. 75, No. 6 Printed in U.S.A.
Hyperparathyroidism during of Familial Hypophosphatemic
SCOTT A. RIVKEES, GHADA AND JOHN D. CRAWFORD
EL-HAJJ-FULEIHAN,
EDWARD
High Phosphate Rickets*
M. BROWN,
Pediatric Endocrine Unit, Massachusetts General Hospital (S.A.R., J.D.C.), and the EndocrineHypertension Division and Department of Medicine, Brigham and Women’s Hospital (G.E.-H.F., Boston, Massachusetts 02114
E.M.B.),
ABSTRACT We report the development of severe tertiary hyperparathyroidism in three girls treated for familial hypophosphatemic rickets and characterize parathyroid function in uiuo and in uitro. All patients had been previously treated with relatively large doses of inorganic phosphorus (125 mm/day) and ergocalciferol or calcitriol for several years and had radiographic evidence of long-standing hyperparathyroidism. Even in the presence of extremely elevated PTH levels, oral phosphate lowered serum calcium levels in uiuo and further stimulated PTH secretion.
Profound multiglandular parathyroid hyperplasia was found in each patient at surgery. Examination of the secretory characteristics of the excised parathyroid tissue revealed that either relatively high calcium concentrations were generally needed to suppress PTH secretion or PTH secretion was not suppressible. Caution is recommended when relatively large doses of phosphate are used to treat familial hypophosphatemic rickets. (J Clin Endocrino2 Metab 75: 1514-1518, 1992)
F
dihydroxyvitamin D3) and large doses of phosphate. Our findings suggest that even in the presence of vitamin D therapy, high dose phosphate therapy may lead to the development of hyperparathyroidism in FHR.
AMILIAL hypophosphatemic rickets (FHR) is characterized by renal phosphate wasting, hypophosphatemia, skeletal deformity, and growth failure in the untreated state (1, 2). With oral phosphate and vitamin D therapy, serum phosphate levels can be normalized, skeletal deformity prevented, and normal stature achieved (2, 3). During correction of hypophosphatemia, phosphate therapy may induce slight depressions in serum ionized calcium levels and trigger the release of PTH (4-7). Secondary (reversible) hyperparathyroidism has been described in children and adults receiving phosphate therapy (4-9), and hypercalcemic hyperparathyroidism requiring parathyroidectomy has been reported after long term phosphate therapy (see Ref. 8 for review). Although the risk of hyperparathyroidism during treatment of FHR is generally appreciated, reports of children who have developed autonomous parathyroid hyperfunction during treatment of FHR are rare (8). With adjunctive vitamin D therapy, phosphate-induced secretion of PTH can be attenuated (3, 4, 6, 7). This may reflect the maintenance of higher serum calcium levels during vitamin D therapy than in the untreated state (3, 4, 6, 7) or a direct inhibitory effect of vitamin D metabolites on parathyroid function (10). Combination vitamin D and phosphate therapy is, thus, recommended for treatment of FHR (6, 11). In this report we describe the development of severe hyperparathyroidism in three girls with FHR who had been treated with ergocalciferol (vitamin D2) or calcitriol (1,25-
Materials
and Methods
Patients Patients 1 and 2 were sisters referred with hyperparathyroidism and hypercalcemia at 10 and 13 yr of age, respectively (Table 1). FHR was diagnosed during infancy, when hypophosphatemia (CO.6 mM) and renal phosphate wasting were detected (tubular reabsorption of phosphorus, 2 X 1 X 0.5 cm/gland; normal adult size, 0.6 X 0.5 X 0.2 cm/gland (13)] eutopic parathyroid glands were located and completely excised. In both cases,a fragment of one gland was transplanted into the left forearm. In patient 2, three glands (2 X 1 X 0.7 cm/ gland) were located and completely excised; autotransplantation was not performed. Diffuse chief cell hyperplasia and absenceof stromal fat was observed in all surgical parathyroid specimensby microscopy. Immediately after surgery, each patient experienced hypocalcemia, and PTH levels fell to undetectable levels. In patient 3, after 1 week of iv calcium infusions, calcium levels could be maintained at asymptomatic levels (-2.0 mM) with
FIG. 1. X-Ray appearance of bones at the time of surgery (A) and 3 months after parathyroidectomy (B) in patient 1. Note cystic abnormalities in distal phalanges, coarse and irregular trabeculae, and osteopenia before surgery and their apparent resolution 3 months later.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 13:53 For personal use only. No other uses without permission. . All rights reserved.
1516
RIVKEES
ET
0
FIG. 2. Postsurgical serum calcium levels (lower panel) and the amount of calcium infused iv (top panel) in patient 1. The open horizontal bar in the top panel depicts calcium infusions during the day; the shaded vertical bar depicts calcium infusions during the night.
JCE & M. 1992 Vol75.No6
AL.
60
90
60
9-o
30
f
I
I
0
30
,
POSTOPERATIVE
containing meal. Blood samples were obtained via an indwelling antecubital catheter at specified times (Fig. 3). 2000 1
soo-
5
A
2000
B
1
1500 1000 PT 1
2
3
4
0
2.0
2.0
1.5
1.5
1.0
1.0
1
2
3
4
d 0.5
0.5 c--
O0
G---
1
i
1
4 Time
(hrs)
O’ 0
4
1 Time
Before phosphate administration, hypophosphatemia and hypercalcemia were present. Thirty minutes after the dose, serum phosphorus levels increased and remained above baseline for at least 4 h. Concomitantly, serum calcium levels fell, and PTH levels increased. After a period of elevated PTH levels, the concentration of the hormone fell to below baseline levels in each patient. In
soo-
Cl
DAYS
vitro
studies
The functional characteristics of the excised parathyroid tissue were examined in tissue from one gland from patient 1, one gland from patient 2, and each of the four glands removed from patient 3. In patient 1 (who had the highest serum calcium and PTH concentrations), PTH secretion was partially suppressiblewith 1.25 mM Ca’+, but increased and was not suppressible at higher calcium concentrations (Fig. 4). Paradoxical increases in PTH secretion with increasing extracellular calcium levels have been observed in primary hyperparathyroidism (16). In patient 2, PTH secretion was suppressiblewith increasing concentrations of calcium (Fig. 4). However, the set-point (1.25 mM) was higher than that required to achieve half-maximal suppressionof PTH release from normal parathyroid tissue [0.99 mM (17)]. In three of the four glands excised from patient 3, more than 50% suppressionof PTH releasewas achieved with high calcium concentrations (set-points of 1.O, 1.25, and 1.3 mM), whereas PTH secretion from one gland was suppressedby only 45% with 3 mM Ca*+ (Fig. 5). In addition to the heterogeneity in the set-points, these glands exhibited a heterogenous maximal PTH releaseper 10’ cells/h.
(hn)
FIG. 3. Changes in serum PTH, calcium, and phosphorus concentrations after a single oral dose of phosphorus (45 mm). Data obtained from patients 2 (A) and 1 (B) are shown. Oral phosphate was administered immediately after obtaining the initial blood sample at 0 h.
Discussion
Hyperparathyroidism of the magnitude described in this report is extremely rare in children treated for FHR. Our
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 13:53 For personal use only. No other uses without permission. . All rights reserved.
HYPERPARATHYROIDISM
IN FHR
1517
FIG. 4. PTH secretion by dispersed parathyroid cells in vitro as related to external calcium concentration. Data from tissue obtained from patients 1 (B) and 2 (A) are shown. Each point represents the mean + SEM of triplicate observations, each assayed in duplicate. Open arrowa depict the normal set-point (17); the solid arrow represents the cells’ set-point.
0
I.0
2.0 C02+,,M
200
RU
LU
t50
-9
(00
T
50
0 200
1.0
2.0
0
2.0
0
4.0
2.0
-
h
01 0
1% Co2+,
mM
1.0 Co’+,
2.0 mM
FIG. 5. PTH secretion by dispersed parathyroid cells in uitro as related to external calcium concentration from all four glands from patient 3. RU, Right upper; LU, left upper; RL, right lower; LL, left lower. Symbols are explained in Fig. 4. Note the difference in the y-axis calculated for the LL gland. Each point represents the mean rt SEM of triplicate observations, each assayed in duplicate. Open arrows depict the normal set-point (17); the solid arrow represents the cells’ setpoint.
findings suggest that high dose phosphate therapy was a critical factor in the pathogenesis of profound multiglandular parathyroid hyperplasia. High dose phosphate therapy appeared to contribute to
3.0
0
t.0
2.0 Ca2+,
3s
mM
the development of severe parathyroid disease in two ways. First, oral phosphate therapy decreased serum calcium levels in the presence of high PTH levels. This may have delayed the recognition of hyperparathyroidism, allowing further parathyroid hyperplasia. Second, we observed that even in the presence of considerable parathyroid hyperplasia and dysfunction, oral phosphate further stimulated parathyroid activity, possibly leading to the further hyperplasia. The doses of phosphate the patients received were generous [50-75 mm/day inorganic phosphorus is recommended (18)] and maintained serum phosphorus levels at high levels for age. As first directly demonstrated by Arnaud et al. (4) and subsequently confirmed (2, 3, 5-9), oral phosphate induces slight decrements in serum calcium levels, stimulating PTH release. Thus, it is likely that the large doses of phosphate induced secondary hyperparathyroidism, which, in turn, evolved into tertiary hyperparathyroidism. The profound degree of demineralization present in patients 1 and 2 supported the idea that the hyperparathyroid state was indeed long-standing. We estimate that the amount of iv calcium given within the first 2 months of surgery (520 mm/ kg) to these patients was equivalent to 70% of the calcium content of the normal skeleton (18). Reversibility of the hyperparathyroid state in FHR has been demonstrated in some patients after the initiation of vitamin D (calcitriol) therapy (6). However, in our patients a trial of calcitriol while the phosphate dose was reduced resulted in hypercalcemia and did not lower PTH levels. Presumably, this reflected the large mass of parathyroid tissue and the advanced stages of parathyroid dysfunction present in each patient. The circulating PTH levels in patients 1 and 2 and the parathyroid gland volumes of each of the patients were among the highest values that have been encountered at our institution (Segre, G., and C. A. Wang, personal communication). Thus, a prolonged trial and/or a higher dosage of calcitriol treatment did not appear to be justified. In addition to excessive amounts of parathyroid tissue, defective regulation of PTH release appeared to contribute to the high circulating levels of the hormone. In vitro studies revealed that either the set-points for PTH secretion were elevated, or clear suppressibility could not be documented.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 13:53 For personal use only. No other uses without permission. . All rights reserved.
RIVKEES
1518
In the only patient in which multiple glands were studied, a spectrum of suppressibility and set-points was documented. This suggests that in the presence of high dose phosphate therapy, the parathyroids proceed through stages of progressive calcium insensitivity analogous to the development of hyperparathyroidism in renal failure (19, 20). Since the father of patients 1 and 2 underwent parathyroidectomy at 45 yr of age, we also considered whether familial factors were involved in the pathogenesis of hyperparathyroidism. However, the patients’ father had been treated with phosphate for FHR for many years and may have similarly developed hyperparathyroidism as a complication of therapy. There was also no evidence for recognized causes of familial hyperparathyroidism, e.g. multiple endocrine adenomatosis (21) or familial neonatal hypercalcemia
(2-4. The development of severe hyperparathyroidism after combination high dose phosphate and vitamin D therapy of FHR highlights the need to carefully monitor serum phosphorus levels during treatment of this disorder and avoid large doses of phosphate. It is also important to note that patients 1 and 2 had sonographic evidence of nephrocalcinosis, which may also be associated with phosphate therapy (23). Since oral phosphate therapy may mask the recognition of hyperparathyroidism by lowering serum calcium levels, routine assessment of parathyroid activity in FHR should be considered to detect parathyroid hyperactivity. Detection of hyperparathyroidism at early stages may lead to its successful treatment (with calcitriol and reduction of the phosphate dose) before the hyperparathyroid state leads to significant skeletal demineralization and becomes irreversible. The use of noncalcemic vitamin D analogs that suppress PTH secretion without any effect on serum calcium levels (24) may also be promising in the management of these patients.
Acknowledgments We thank Janice Erlander, Christina M. Rivkees, and Drs A. Arnold, C. A. Wang, D. Ryan, and R. Gaz for their assistance in the care and investigation of these patients. The authors are also indebted to Drs. Catherine Upchurch and Stanley Mackowiac for discovering hyperparathyroidism in the patients studied.
References 1. Albright F, Butler AM, Bloomberg E. 1937 Rickets resistant to vitamin D therapy. Am J Child Dis. 54:529-547. 2. Glorieux FH, Striver CR, Reade TM, Goldman H, Roseborough A. 1972 Use of phosphate and vitamin D to prevent dwarfism and rickets in X-linked hypophosphatemia. N Engl J Med. 287:481-487. 3. Balsan S, Tieder M. 1990 Linear growth in patients with hypophosphatemic familial hypophosphatemic rickets: influence of treatment regimen and parental height. J Pediatr. 116:365-371. 4. Arnaud C, Glorieux F, Striver C. 1971 Serum parathyroid hor-
ET AL.
JCE & M. 1992 Vol’I5.No6
mone in X-linked hypophosphatemia. Science. 173:845-847. 5. Reitz RE, Weinstein RL. 1973 Parathyroid hormone secretion in familial vitamin-D-resistant rickets. N Engl J Med. 289:941-945. 6. Glorieux FH, Marie PJ, Pettifor JM, Devlin EE. 1980 Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic familial hypophosphatemic rickets. N Engl J Med. 303:1023-1031. A, Bianchi ML, Mazzucchi E, Gandolin G, Appoani AC. 7. Bettinell 1991 Acute effects of calcitriol and phosphate salts on mineral metabolism in children with hypophosphatemic rickets. J Pediatr. 118:372-376. 8. Firth RG, Grant CS, Riggs BL. 1985 Development of hypercalcemic hyperparathyroidism after long-term phosphate supplementation in hypophosphatemic osteomalacia. Report of two cases. Am J Med. 78~669-673. 9. Falls WF, Carter NW, Rector Jr FC, Seldin DW. 1968 Familial hypophosphatemic rickets. Study of six cases with evaluation of the pathogenic role of secondary hyperparathyroidism. Ann Intern Med. 68:553-560. 10. Slatopolskv E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ. 1984-Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihvdroxvcholecalciferol in uremic patients, J Clin Invest. 74:2136-2143. ’ HE. 1977 Vitamin D and the metabolism of calcium, 11. Harrison phosphate, and bone. In: Rudolf AM, ed. Pediatrics. New York: Appleton-Century-Crofts; pp 235-245. 12. El-Hajj-Fuleihan G, Chen CJ, Rivkees SA, et al. 1989 Calciumdependent release of N-terminal fragments and intact immunoreactive parathyroid hormone by human pathological parathyroid tissue in vitro. J Clin Endocrinol Metab. 69:860-867. 13. Dufour DR, Wilkerson SV. 1982 The normal parathyroid revisited: percentage of stromal fat. Hum Pathol. 92:814-821. 14. Albright F, Reifenstein Jr EC. 1948 The parathyroid glands and metabolic bone disease. Baltimore: Williams At Wilkins; p 113. 15. Brasier AR, Nussbaum SR. 1988 Hungry bone syndrome: clinical and biochemical predictors of its occurrence after parathyroid surgery. Am J Med. 84:654-660. 16. Brown EM, Broadas AE, Brennan MF, et al. 1979 Direct comparison in uivo and in vitro of suppressibility of parathyroid function by calcium in primary hyperparathyroidism. J Clin Endocrinol Metab. 48:604-610. EM, Wilson RE, Thatcher JG. 1981 Abnormal calcium 17. Brown regulated PTH release in normal parathyroid tissue from patients with adenoma. Am J Med. 71:565-571. 18. Harrison HE, Harrison HC. 1964 Hereditary metabolic bone disease. Clin Orthop. 33:147-158. 19. Parfitt AM. 1982 Hypercalcemic hyperparathyroidism following renal transplantation: differential diagnosis, management, and implications for cell population control in the parathyroid gland. Mineral Electrolyte Metab. 8:92-112. 20. Brown EM, Wilson RE, Eastmant RC, Pallota J, Marynick SP. 1982 Abnormal regulation of parathyroid hormone release by calcium in secondary hyperparathyroidism due to chronic renal failure. I Clin Endocrinol Metab. 54:172-179. 21. Marx SJ, Powell D, Shimkin PM, et al. 1973 Familial hyperparathyroidism. Mild hypercalcemia in at least nine members of a kindred. Ann Intern Med. 78:371-377. DA, Striver CR, Pedvis S, Shragovitch I. 1964 Neonatal 22. Hillman familial primary hvperparathvroidism. N Engl J Med. 270:483-490. 23. Verge CF, Lam AL, Simpson JM, Cowell CT; Howard NJ, Silink M. 1991 Effects of therauv in X-linded hvpoohosohatemic rickets. ,I1 . N Engl J Med. 325:1843ff848. 24. Brown AJ, Rtitter CR, Finch JL, et al. 1989 The non calcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion. J Clin Invest. 84:728-732.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 13:53 For personal use only. No other uses without permission. . All rights reserved.
Tertiary Therapy
Vol. 75, No. 6 Printed in U.S.A.
Hyperparathyroidism during of Familial Hypophosphatemic
SCOTT A. RIVKEES, GHADA AND JOHN D. CRAWFORD
EL-HAJJ-FULEIHAN,
EDWARD
High Phosphate Rickets*
M. BROWN,
Pediatric Endocrine Unit, Massachusetts General Hospital (S.A.R., J.D.C.), and the EndocrineHypertension Division and Department of Medicine, Brigham and Women’s Hospital (G.E.-H.F., Boston, Massachusetts 02114
E.M.B.),
ABSTRACT We report the development of severe tertiary hyperparathyroidism in three girls treated for familial hypophosphatemic rickets and characterize parathyroid function in uiuo and in uitro. All patients had been previously treated with relatively large doses of inorganic phosphorus (125 mm/day) and ergocalciferol or calcitriol for several years and had radiographic evidence of long-standing hyperparathyroidism. Even in the presence of extremely elevated PTH levels, oral phosphate lowered serum calcium levels in uiuo and further stimulated PTH secretion.
Profound multiglandular parathyroid hyperplasia was found in each patient at surgery. Examination of the secretory characteristics of the excised parathyroid tissue revealed that either relatively high calcium concentrations were generally needed to suppress PTH secretion or PTH secretion was not suppressible. Caution is recommended when relatively large doses of phosphate are used to treat familial hypophosphatemic rickets. (J Clin Endocrino2 Metab 75: 1514-1518, 1992)
F
dihydroxyvitamin D3) and large doses of phosphate. Our findings suggest that even in the presence of vitamin D therapy, high dose phosphate therapy may lead to the development of hyperparathyroidism in FHR.
AMILIAL hypophosphatemic rickets (FHR) is characterized by renal phosphate wasting, hypophosphatemia, skeletal deformity, and growth failure in the untreated state (1, 2). With oral phosphate and vitamin D therapy, serum phosphate levels can be normalized, skeletal deformity prevented, and normal stature achieved (2, 3). During correction of hypophosphatemia, phosphate therapy may induce slight depressions in serum ionized calcium levels and trigger the release of PTH (4-7). Secondary (reversible) hyperparathyroidism has been described in children and adults receiving phosphate therapy (4-9), and hypercalcemic hyperparathyroidism requiring parathyroidectomy has been reported after long term phosphate therapy (see Ref. 8 for review). Although the risk of hyperparathyroidism during treatment of FHR is generally appreciated, reports of children who have developed autonomous parathyroid hyperfunction during treatment of FHR are rare (8). With adjunctive vitamin D therapy, phosphate-induced secretion of PTH can be attenuated (3, 4, 6, 7). This may reflect the maintenance of higher serum calcium levels during vitamin D therapy than in the untreated state (3, 4, 6, 7) or a direct inhibitory effect of vitamin D metabolites on parathyroid function (10). Combination vitamin D and phosphate therapy is, thus, recommended for treatment of FHR (6, 11). In this report we describe the development of severe hyperparathyroidism in three girls with FHR who had been treated with ergocalciferol (vitamin D2) or calcitriol (1,25-
Materials
and Methods
Patients Patients 1 and 2 were sisters referred with hyperparathyroidism and hypercalcemia at 10 and 13 yr of age, respectively (Table 1). FHR was diagnosed during infancy, when hypophosphatemia (CO.6 mM) and renal phosphate wasting were detected (tubular reabsorption of phosphorus, 2 X 1 X 0.5 cm/gland; normal adult size, 0.6 X 0.5 X 0.2 cm/gland (13)] eutopic parathyroid glands were located and completely excised. In both cases,a fragment of one gland was transplanted into the left forearm. In patient 2, three glands (2 X 1 X 0.7 cm/ gland) were located and completely excised; autotransplantation was not performed. Diffuse chief cell hyperplasia and absenceof stromal fat was observed in all surgical parathyroid specimensby microscopy. Immediately after surgery, each patient experienced hypocalcemia, and PTH levels fell to undetectable levels. In patient 3, after 1 week of iv calcium infusions, calcium levels could be maintained at asymptomatic levels (-2.0 mM) with
FIG. 1. X-Ray appearance of bones at the time of surgery (A) and 3 months after parathyroidectomy (B) in patient 1. Note cystic abnormalities in distal phalanges, coarse and irregular trabeculae, and osteopenia before surgery and their apparent resolution 3 months later.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 13:53 For personal use only. No other uses without permission. . All rights reserved.
1516
RIVKEES
ET
0
FIG. 2. Postsurgical serum calcium levels (lower panel) and the amount of calcium infused iv (top panel) in patient 1. The open horizontal bar in the top panel depicts calcium infusions during the day; the shaded vertical bar depicts calcium infusions during the night.
JCE & M. 1992 Vol75.No6
AL.
60
90
60
9-o
30
f
I
I
0
30
,
POSTOPERATIVE
containing meal. Blood samples were obtained via an indwelling antecubital catheter at specified times (Fig. 3). 2000 1
soo-
5
A
2000
B
1
1500 1000 PT 1
2
3
4
0
2.0
2.0
1.5
1.5
1.0
1.0
1
2
3
4
d 0.5
0.5 c--
O0
G---
1
i
1
4 Time
(hrs)
O’ 0
4
1 Time
Before phosphate administration, hypophosphatemia and hypercalcemia were present. Thirty minutes after the dose, serum phosphorus levels increased and remained above baseline for at least 4 h. Concomitantly, serum calcium levels fell, and PTH levels increased. After a period of elevated PTH levels, the concentration of the hormone fell to below baseline levels in each patient. In
soo-
Cl
DAYS
vitro
studies
The functional characteristics of the excised parathyroid tissue were examined in tissue from one gland from patient 1, one gland from patient 2, and each of the four glands removed from patient 3. In patient 1 (who had the highest serum calcium and PTH concentrations), PTH secretion was partially suppressiblewith 1.25 mM Ca’+, but increased and was not suppressible at higher calcium concentrations (Fig. 4). Paradoxical increases in PTH secretion with increasing extracellular calcium levels have been observed in primary hyperparathyroidism (16). In patient 2, PTH secretion was suppressiblewith increasing concentrations of calcium (Fig. 4). However, the set-point (1.25 mM) was higher than that required to achieve half-maximal suppressionof PTH release from normal parathyroid tissue [0.99 mM (17)]. In three of the four glands excised from patient 3, more than 50% suppressionof PTH releasewas achieved with high calcium concentrations (set-points of 1.O, 1.25, and 1.3 mM), whereas PTH secretion from one gland was suppressedby only 45% with 3 mM Ca*+ (Fig. 5). In addition to the heterogeneity in the set-points, these glands exhibited a heterogenous maximal PTH releaseper 10’ cells/h.
(hn)
FIG. 3. Changes in serum PTH, calcium, and phosphorus concentrations after a single oral dose of phosphorus (45 mm). Data obtained from patients 2 (A) and 1 (B) are shown. Oral phosphate was administered immediately after obtaining the initial blood sample at 0 h.
Discussion
Hyperparathyroidism of the magnitude described in this report is extremely rare in children treated for FHR. Our
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 13:53 For personal use only. No other uses without permission. . All rights reserved.
HYPERPARATHYROIDISM
IN FHR
1517
FIG. 4. PTH secretion by dispersed parathyroid cells in vitro as related to external calcium concentration. Data from tissue obtained from patients 1 (B) and 2 (A) are shown. Each point represents the mean + SEM of triplicate observations, each assayed in duplicate. Open arrowa depict the normal set-point (17); the solid arrow represents the cells’ set-point.
0
I.0
2.0 C02+,,M
200
RU
LU
t50
-9
(00
T
50
0 200
1.0
2.0
0
2.0
0
4.0
2.0
-
h
01 0
1% Co2+,
mM
1.0 Co’+,
2.0 mM
FIG. 5. PTH secretion by dispersed parathyroid cells in uitro as related to external calcium concentration from all four glands from patient 3. RU, Right upper; LU, left upper; RL, right lower; LL, left lower. Symbols are explained in Fig. 4. Note the difference in the y-axis calculated for the LL gland. Each point represents the mean rt SEM of triplicate observations, each assayed in duplicate. Open arrows depict the normal set-point (17); the solid arrow represents the cells’ setpoint.
findings suggest that high dose phosphate therapy was a critical factor in the pathogenesis of profound multiglandular parathyroid hyperplasia. High dose phosphate therapy appeared to contribute to
3.0
0
t.0
2.0 Ca2+,
3s
mM
the development of severe parathyroid disease in two ways. First, oral phosphate therapy decreased serum calcium levels in the presence of high PTH levels. This may have delayed the recognition of hyperparathyroidism, allowing further parathyroid hyperplasia. Second, we observed that even in the presence of considerable parathyroid hyperplasia and dysfunction, oral phosphate further stimulated parathyroid activity, possibly leading to the further hyperplasia. The doses of phosphate the patients received were generous [50-75 mm/day inorganic phosphorus is recommended (18)] and maintained serum phosphorus levels at high levels for age. As first directly demonstrated by Arnaud et al. (4) and subsequently confirmed (2, 3, 5-9), oral phosphate induces slight decrements in serum calcium levels, stimulating PTH release. Thus, it is likely that the large doses of phosphate induced secondary hyperparathyroidism, which, in turn, evolved into tertiary hyperparathyroidism. The profound degree of demineralization present in patients 1 and 2 supported the idea that the hyperparathyroid state was indeed long-standing. We estimate that the amount of iv calcium given within the first 2 months of surgery (520 mm/ kg) to these patients was equivalent to 70% of the calcium content of the normal skeleton (18). Reversibility of the hyperparathyroid state in FHR has been demonstrated in some patients after the initiation of vitamin D (calcitriol) therapy (6). However, in our patients a trial of calcitriol while the phosphate dose was reduced resulted in hypercalcemia and did not lower PTH levels. Presumably, this reflected the large mass of parathyroid tissue and the advanced stages of parathyroid dysfunction present in each patient. The circulating PTH levels in patients 1 and 2 and the parathyroid gland volumes of each of the patients were among the highest values that have been encountered at our institution (Segre, G., and C. A. Wang, personal communication). Thus, a prolonged trial and/or a higher dosage of calcitriol treatment did not appear to be justified. In addition to excessive amounts of parathyroid tissue, defective regulation of PTH release appeared to contribute to the high circulating levels of the hormone. In vitro studies revealed that either the set-points for PTH secretion were elevated, or clear suppressibility could not be documented.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 13:53 For personal use only. No other uses without permission. . All rights reserved.
RIVKEES
1518
In the only patient in which multiple glands were studied, a spectrum of suppressibility and set-points was documented. This suggests that in the presence of high dose phosphate therapy, the parathyroids proceed through stages of progressive calcium insensitivity analogous to the development of hyperparathyroidism in renal failure (19, 20). Since the father of patients 1 and 2 underwent parathyroidectomy at 45 yr of age, we also considered whether familial factors were involved in the pathogenesis of hyperparathyroidism. However, the patients’ father had been treated with phosphate for FHR for many years and may have similarly developed hyperparathyroidism as a complication of therapy. There was also no evidence for recognized causes of familial hyperparathyroidism, e.g. multiple endocrine adenomatosis (21) or familial neonatal hypercalcemia
(2-4. The development of severe hyperparathyroidism after combination high dose phosphate and vitamin D therapy of FHR highlights the need to carefully monitor serum phosphorus levels during treatment of this disorder and avoid large doses of phosphate. It is also important to note that patients 1 and 2 had sonographic evidence of nephrocalcinosis, which may also be associated with phosphate therapy (23). Since oral phosphate therapy may mask the recognition of hyperparathyroidism by lowering serum calcium levels, routine assessment of parathyroid activity in FHR should be considered to detect parathyroid hyperactivity. Detection of hyperparathyroidism at early stages may lead to its successful treatment (with calcitriol and reduction of the phosphate dose) before the hyperparathyroid state leads to significant skeletal demineralization and becomes irreversible. The use of noncalcemic vitamin D analogs that suppress PTH secretion without any effect on serum calcium levels (24) may also be promising in the management of these patients.
Acknowledgments We thank Janice Erlander, Christina M. Rivkees, and Drs A. Arnold, C. A. Wang, D. Ryan, and R. Gaz for their assistance in the care and investigation of these patients. The authors are also indebted to Drs. Catherine Upchurch and Stanley Mackowiac for discovering hyperparathyroidism in the patients studied.
References 1. Albright F, Butler AM, Bloomberg E. 1937 Rickets resistant to vitamin D therapy. Am J Child Dis. 54:529-547. 2. Glorieux FH, Striver CR, Reade TM, Goldman H, Roseborough A. 1972 Use of phosphate and vitamin D to prevent dwarfism and rickets in X-linked hypophosphatemia. N Engl J Med. 287:481-487. 3. Balsan S, Tieder M. 1990 Linear growth in patients with hypophosphatemic familial hypophosphatemic rickets: influence of treatment regimen and parental height. J Pediatr. 116:365-371. 4. Arnaud C, Glorieux F, Striver C. 1971 Serum parathyroid hor-
ET AL.
JCE & M. 1992 Vol’I5.No6
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