0021-972X/90/7105-1305$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright© 1990 by The Endocrine Society
Vol. 71, No. 5 Printed in U.S.A.
Primary Hyperparathyroidism and Severe Hypercalcemia with Low Circulating 1,25Dihydroxyvitamin D JOSEPH L. SHAKER, KONRAD W. KRAWCZYK, AND JAMES W. FINDLING Departments of Medicine and Family Practice, St. Luke's Medical Center, Milwaukee, Wisconsin 53215
ABSTRACT. We report a postmenopausal woman with primary hyperparathyroidism (PHPT) and severe hypercalcemia while her total calcium intake was more than 2 g daily. Despite a markedly elevated intact PTH level, her serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] level was low (17 pmol/L; 7 pg/mL). With reduced calcium intake, her serum calcium normalized, and 1,25-(OH)2D increased to 122 pmol/L (51 pg/mL). At the
P
RIMARY hyperparathyroidism (PHPT) is a common disorder, particularly in postmenopausal women (1). This condition is usually associated with normal or elevated 1,25-dihydroxyvitamin D [1,25(OH)2D] levels (2-4), because PTH directly stimulates renal 25-hydroxyvitamin D (25OHD)-la-hydroxylase activity. PHPT with low circulating levels of 1,25-(OH)2D is unusual but can occur (4-6). Hypercalcemia, however, may directly lower 1,25-(OH)2D levels in animals (7-10), and there is evidence that this phenomenon may also occur in humans (9). We know of only one previously reported case of PHPT and low circulating 1,25-(OH)2D in which correction of hypercalcemia (removal of a parathyroid adenoma) resulted in normalization of 1,25(OH)2D (5). We report a postmenopausal woman with PHPT and severe hypercalcemia while her total calcium intake from diet and supplements was greater than 2 g daily. Her serum PTH level was markedly elevated, and 1,25-(OH)2D was low. With calcium restriction alone, her serum calcium level normalized at the same time her circulating 1,25-(OH)2D level increased into the high normal range. These changes provide further evidence for a direct suppressive effect of severe hypercalcemia on circulating 1,25-(OH)2D levels in humans. Furthermore, this direct effect can overcome the stimulatory effect of PTH on renal 25OHD-la-hydroxylase activity. Received March 5, 1990. Address all correspondence and requests for reprints to: Joseph L. Shaker, M.D., Department of Medicine, St. Luke's Medical Center, HS Suite 503, 2901 West Kinnickinnic River Parkway, Milwaukee, Wisconsin 53215.
same time, intact PTH decreased to 32% of the initial value. PHPT may be associated with low circulating 1,25-(OH)2D levels. Furthermore, low 1,25-(OH)2D levels in PHPT may be due to a direct effect of severe hypercalcemia arid be reversible with correction of hypercalcemia. (J Clin Endocrinol Metab 7 1 : 1305-1309, 1990)
Materials and Methods Serum calcium, creatinine, and phosphorus were measured using an automated analyzer (American Monitor Parallel, American Monitor, Indianapolis, IN). Ionized calcium was measured using an ion-selective electrode (Nova 8, Nova Biomedical, Waltham, MA). Intact PTH was measured by a two-site immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA). Vitamin D metabolites were measured by radiobinding assays (Nichols Institute).
Case Report A 73-yr-old white woman was referred for evaluation of hypercalcemia. Six days before evaluation, her serum calcium was 3.74 mmol/L (15.0 mg/dL). At that time calcium supplements she had been taking were stopped. There had been some recent memory impairment, and she admitted to nocturia and polydipsia. Her dietary calcium intake was estimated to be 1250 mg/day. In addition, she had been taking calcium supplements to prevent osteoporosis for about 1 yr. Initially, she was taking 500 mg elemental calcium daily, but increased this to 1000 mg daily 2 months before presentation. Review of her records revealed a serum calcium level of 2.62 mmol/L (10.5 mg/dL) and phosphorus of 0.71 mmol/L (2.2 mg/dL) 4 yr earlier. Four months before presentation her serum calcium level was 2.57 mmol/L (10.3 mg/dL), phosphorus was 0.58 mmol/L (1.8 mg/ dL), and creatinine was 150 /miol/L (1.7 mg/dL). Her past history was significant for atrial fibrillation, for which she was treated with digoxin. She had a hysterectomy and oophorectomy at age 55 yr and took estrogen replacement for 8 yr. On physical examination her height was 154 cm, and weight was 64 kg. There were no neck masses. Laboratory data included the following: calcium, 3.39 mmol/ 1305
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 01:47 For personal use only. No other uses without permission. . All rights reserved.
SHAKER, KRAWCZYK, AND FINDLING
1306
L (13.6 mg/dL; normal, 2.20-2.54 mmol/L); phosphorus, 0.84 mmol/L (2.6 mg/dL; normal, 0.74-1.52 mmol/L); ionized calcium, 2.05 mmol/L (normal, 1.17-1.31); creatinine, 141 /anol/ L (1.6 mg/dL; normal, 62-115 /umol/L); alkaline phosphatase, 90 IU/L (normal, 50-136); intact PTH, 938 ng/L (normal, 1065); 1,25-(OH)2D, 17 pmol/L (7 pg/mL; normal, 36-144 pmol/ L); and 25OHD, 42 nmol/L (17 ng/mL; normal, 22-130 nmol/ L). A 24-h urine collection contained 9.36 mmol (375 mg) of calcium. A bone mineral density study by dual photon absorptiometry (Lunar, Madison, WI) revealed the following: lumbar spine, 1.08 g/cm2 (109% of value in age-matched controls); femoral neck, 0.61 g/cm2 (85% of values in age-matched controls); and greater trochanter, 0.46 g/cm2 (71% that in agematched controls). A low calcium diet (estimated to be less than 250 mg daily) was initiated, and serum calcium, phosphorus, creatinine, intact PTH, and vitamin D metabolites were followed (Table 1). Over the next 10 weeks, her calcium level decreased to 2.34 mmol/L (9.4 mg/dL), while her 1,25-(OH)2D increased into the high normal range (122 pmol/L; 51 pg/mL). At the same time her intact PTH level decreased to 32% of its initial value. Her dietary calcium was liberalized slightly (estimated to be 250-500 mg daily), and 2 months later her calcium was 2.44 mmol/L (9.8 mg/dL), ionized calcium was 1.37 mmol/ L, phosphorus was 0.87 mmol/L (2.7 mg/dL), creatinine was 150 Mm/L (1.7 mg/dL), and 1,25-(OH)2D, was 89 pmol/L (37 pg/mL; Table 1). She did well with calcium restriction (250-500 mg daily) until 1 yr after presentation. At that time she was hospitalized with a nontransmural myocardial infarction. Four days after admission her serum calcium was 2.67 mmol/L (10.7 mg/dL), creatinine was 168 ^mol/L (1.9 mg/dL), intact PTH was 328 ng/L, and 1,25-(OH)2D was 106 pmol/L (44 pg/mL). While immobilized during her hospitalization the serum calcium level increased to 3.69 mmol/L (14.8 mg/dL). A parathyroid scan using thallium and pertechnetate was negative. A magnetic resonance imaging study revealed a 3-cm area of increased signal intensity on T2 weighted images posterior to the junction of the left clavicle and manubrium. At neck exploration this was found to be a 5.0 x 1.5 X 0.5-cm mass. Because the other
JCE & M • 1990 Vol 71 • No 5
parathyroid glands were felt to be slightly enlarged, the patient underwent a 3.5 gland parathyroidectomy. The pathological findings were consistent with hyperplasia. Subsequent to surgery the patient has required calcium (1500 mg daily as calcium carbonate) and 1,25-(OH)2D (Rocaltrol, Roche Laboratories, Nutley, NJ; 0.25 ng twice daily) to maintain a normocalcemic state.
Results Levels of intact PTH, vitamin D metabolites, calcium, ionized calcium, phosphorus, and creatinine during 20 weeks of observation are shown in Table 1. Concentrations of calcium, intact PTH, and 1,25-(OH)2D are also shown in Fig. 1. Initial levels of calcium (3.39 mmol/L) and ionized calcium (2.05 mmol/L) were markedly elevated. During the 10 weeks of calcium restriction, the calcium level decreased into the normal range (2.34 mmol/L), and the ionized calcium decreased to slightly supranormal (1.32 mmol/L). At the same time the circulating 1,25-(OH)2D level, which was initially very low, increased into the high normal range (122 pmol/L; 51 pg/mL). The intact PTH level, which was initially markedly elevated (938 ng/L), decreased to 32% of its initial value, but remained clearly elevated. With a modest increase in calcium intake, there was a slight increase in calcium and ionized calcium and a slight decrease in 1,25-(OH)2D. Regression analyses revealed inverse relationships between calcium and 1,25-(OH)2D (r = 0.91; P = 0.03; Fig. 2) as well as ionized calcium and 1,25-(OH)2D (r = 0.90; P = 0.04). There was also a tendency toward an inverse relationship between intact PTH and 1,25(OH)2D; however, this did not reach statistical significance (r = 0.86; P = 0.06). The serum 25OHD level was initially normal and did not change. There were no consistent changes in serum phosphorus or creatinine,
TABLE 1. Serum chemistries before and during calcium restriction 6/28/88° Calcium (mmol/L; normal range, 2.20-2.54) Ionized calcium (mmol/L; normal range, 1.17-1.31) Phosphorus (mmol/L; normal range, 0.74-1.52) Intact PTH (ng/L; normal range, 10-65) 1,25-(OH)2D (pmol/L; normal range, 36-144) 25-OHD (nmol/L; normal range, 22-130) Creatinine (jtmol/L; normal range, 62-115)
7/7/88
7/14/88
7/21/88
7/28/88
9/6/88"
11/15/88
3.39
2.97
2.54
2.4
2.34
2.34
2.44
2.05
1.69
1.44
1.33
1.32
1.32
1.37
0.84
0.65
0.78
0.68
0.68
0.9
0.87
938
395
345
297
259
17
58
113
122
89
42
50
141
168
45 159
150
168
"Dietary calcium restriction started (
Vol. 71, No. 5 Printed in U.S.A.
Primary Hyperparathyroidism and Severe Hypercalcemia with Low Circulating 1,25Dihydroxyvitamin D JOSEPH L. SHAKER, KONRAD W. KRAWCZYK, AND JAMES W. FINDLING Departments of Medicine and Family Practice, St. Luke's Medical Center, Milwaukee, Wisconsin 53215
ABSTRACT. We report a postmenopausal woman with primary hyperparathyroidism (PHPT) and severe hypercalcemia while her total calcium intake was more than 2 g daily. Despite a markedly elevated intact PTH level, her serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] level was low (17 pmol/L; 7 pg/mL). With reduced calcium intake, her serum calcium normalized, and 1,25-(OH)2D increased to 122 pmol/L (51 pg/mL). At the
P
RIMARY hyperparathyroidism (PHPT) is a common disorder, particularly in postmenopausal women (1). This condition is usually associated with normal or elevated 1,25-dihydroxyvitamin D [1,25(OH)2D] levels (2-4), because PTH directly stimulates renal 25-hydroxyvitamin D (25OHD)-la-hydroxylase activity. PHPT with low circulating levels of 1,25-(OH)2D is unusual but can occur (4-6). Hypercalcemia, however, may directly lower 1,25-(OH)2D levels in animals (7-10), and there is evidence that this phenomenon may also occur in humans (9). We know of only one previously reported case of PHPT and low circulating 1,25-(OH)2D in which correction of hypercalcemia (removal of a parathyroid adenoma) resulted in normalization of 1,25(OH)2D (5). We report a postmenopausal woman with PHPT and severe hypercalcemia while her total calcium intake from diet and supplements was greater than 2 g daily. Her serum PTH level was markedly elevated, and 1,25-(OH)2D was low. With calcium restriction alone, her serum calcium level normalized at the same time her circulating 1,25-(OH)2D level increased into the high normal range. These changes provide further evidence for a direct suppressive effect of severe hypercalcemia on circulating 1,25-(OH)2D levels in humans. Furthermore, this direct effect can overcome the stimulatory effect of PTH on renal 25OHD-la-hydroxylase activity. Received March 5, 1990. Address all correspondence and requests for reprints to: Joseph L. Shaker, M.D., Department of Medicine, St. Luke's Medical Center, HS Suite 503, 2901 West Kinnickinnic River Parkway, Milwaukee, Wisconsin 53215.
same time, intact PTH decreased to 32% of the initial value. PHPT may be associated with low circulating 1,25-(OH)2D levels. Furthermore, low 1,25-(OH)2D levels in PHPT may be due to a direct effect of severe hypercalcemia arid be reversible with correction of hypercalcemia. (J Clin Endocrinol Metab 7 1 : 1305-1309, 1990)
Materials and Methods Serum calcium, creatinine, and phosphorus were measured using an automated analyzer (American Monitor Parallel, American Monitor, Indianapolis, IN). Ionized calcium was measured using an ion-selective electrode (Nova 8, Nova Biomedical, Waltham, MA). Intact PTH was measured by a two-site immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA). Vitamin D metabolites were measured by radiobinding assays (Nichols Institute).
Case Report A 73-yr-old white woman was referred for evaluation of hypercalcemia. Six days before evaluation, her serum calcium was 3.74 mmol/L (15.0 mg/dL). At that time calcium supplements she had been taking were stopped. There had been some recent memory impairment, and she admitted to nocturia and polydipsia. Her dietary calcium intake was estimated to be 1250 mg/day. In addition, she had been taking calcium supplements to prevent osteoporosis for about 1 yr. Initially, she was taking 500 mg elemental calcium daily, but increased this to 1000 mg daily 2 months before presentation. Review of her records revealed a serum calcium level of 2.62 mmol/L (10.5 mg/dL) and phosphorus of 0.71 mmol/L (2.2 mg/dL) 4 yr earlier. Four months before presentation her serum calcium level was 2.57 mmol/L (10.3 mg/dL), phosphorus was 0.58 mmol/L (1.8 mg/ dL), and creatinine was 150 /miol/L (1.7 mg/dL). Her past history was significant for atrial fibrillation, for which she was treated with digoxin. She had a hysterectomy and oophorectomy at age 55 yr and took estrogen replacement for 8 yr. On physical examination her height was 154 cm, and weight was 64 kg. There were no neck masses. Laboratory data included the following: calcium, 3.39 mmol/ 1305
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 01:47 For personal use only. No other uses without permission. . All rights reserved.
SHAKER, KRAWCZYK, AND FINDLING
1306
L (13.6 mg/dL; normal, 2.20-2.54 mmol/L); phosphorus, 0.84 mmol/L (2.6 mg/dL; normal, 0.74-1.52 mmol/L); ionized calcium, 2.05 mmol/L (normal, 1.17-1.31); creatinine, 141 /anol/ L (1.6 mg/dL; normal, 62-115 /umol/L); alkaline phosphatase, 90 IU/L (normal, 50-136); intact PTH, 938 ng/L (normal, 1065); 1,25-(OH)2D, 17 pmol/L (7 pg/mL; normal, 36-144 pmol/ L); and 25OHD, 42 nmol/L (17 ng/mL; normal, 22-130 nmol/ L). A 24-h urine collection contained 9.36 mmol (375 mg) of calcium. A bone mineral density study by dual photon absorptiometry (Lunar, Madison, WI) revealed the following: lumbar spine, 1.08 g/cm2 (109% of value in age-matched controls); femoral neck, 0.61 g/cm2 (85% of values in age-matched controls); and greater trochanter, 0.46 g/cm2 (71% that in agematched controls). A low calcium diet (estimated to be less than 250 mg daily) was initiated, and serum calcium, phosphorus, creatinine, intact PTH, and vitamin D metabolites were followed (Table 1). Over the next 10 weeks, her calcium level decreased to 2.34 mmol/L (9.4 mg/dL), while her 1,25-(OH)2D increased into the high normal range (122 pmol/L; 51 pg/mL). At the same time her intact PTH level decreased to 32% of its initial value. Her dietary calcium was liberalized slightly (estimated to be 250-500 mg daily), and 2 months later her calcium was 2.44 mmol/L (9.8 mg/dL), ionized calcium was 1.37 mmol/ L, phosphorus was 0.87 mmol/L (2.7 mg/dL), creatinine was 150 Mm/L (1.7 mg/dL), and 1,25-(OH)2D, was 89 pmol/L (37 pg/mL; Table 1). She did well with calcium restriction (250-500 mg daily) until 1 yr after presentation. At that time she was hospitalized with a nontransmural myocardial infarction. Four days after admission her serum calcium was 2.67 mmol/L (10.7 mg/dL), creatinine was 168 ^mol/L (1.9 mg/dL), intact PTH was 328 ng/L, and 1,25-(OH)2D was 106 pmol/L (44 pg/mL). While immobilized during her hospitalization the serum calcium level increased to 3.69 mmol/L (14.8 mg/dL). A parathyroid scan using thallium and pertechnetate was negative. A magnetic resonance imaging study revealed a 3-cm area of increased signal intensity on T2 weighted images posterior to the junction of the left clavicle and manubrium. At neck exploration this was found to be a 5.0 x 1.5 X 0.5-cm mass. Because the other
JCE & M • 1990 Vol 71 • No 5
parathyroid glands were felt to be slightly enlarged, the patient underwent a 3.5 gland parathyroidectomy. The pathological findings were consistent with hyperplasia. Subsequent to surgery the patient has required calcium (1500 mg daily as calcium carbonate) and 1,25-(OH)2D (Rocaltrol, Roche Laboratories, Nutley, NJ; 0.25 ng twice daily) to maintain a normocalcemic state.
Results Levels of intact PTH, vitamin D metabolites, calcium, ionized calcium, phosphorus, and creatinine during 20 weeks of observation are shown in Table 1. Concentrations of calcium, intact PTH, and 1,25-(OH)2D are also shown in Fig. 1. Initial levels of calcium (3.39 mmol/L) and ionized calcium (2.05 mmol/L) were markedly elevated. During the 10 weeks of calcium restriction, the calcium level decreased into the normal range (2.34 mmol/L), and the ionized calcium decreased to slightly supranormal (1.32 mmol/L). At the same time the circulating 1,25-(OH)2D level, which was initially very low, increased into the high normal range (122 pmol/L; 51 pg/mL). The intact PTH level, which was initially markedly elevated (938 ng/L), decreased to 32% of its initial value, but remained clearly elevated. With a modest increase in calcium intake, there was a slight increase in calcium and ionized calcium and a slight decrease in 1,25-(OH)2D. Regression analyses revealed inverse relationships between calcium and 1,25-(OH)2D (r = 0.91; P = 0.03; Fig. 2) as well as ionized calcium and 1,25-(OH)2D (r = 0.90; P = 0.04). There was also a tendency toward an inverse relationship between intact PTH and 1,25(OH)2D; however, this did not reach statistical significance (r = 0.86; P = 0.06). The serum 25OHD level was initially normal and did not change. There were no consistent changes in serum phosphorus or creatinine,
TABLE 1. Serum chemistries before and during calcium restriction 6/28/88° Calcium (mmol/L; normal range, 2.20-2.54) Ionized calcium (mmol/L; normal range, 1.17-1.31) Phosphorus (mmol/L; normal range, 0.74-1.52) Intact PTH (ng/L; normal range, 10-65) 1,25-(OH)2D (pmol/L; normal range, 36-144) 25-OHD (nmol/L; normal range, 22-130) Creatinine (jtmol/L; normal range, 62-115)
7/7/88
7/14/88
7/21/88
7/28/88
9/6/88"
11/15/88
3.39
2.97
2.54
2.4
2.34
2.34
2.44
2.05
1.69
1.44
1.33
1.32
1.32
1.37
0.84
0.65
0.78
0.68
0.68
0.9
0.87
938
395
345
297
259
17
58
113
122
89
42
50
141
168
45 159
150
168
"Dietary calcium restriction started (
![[Severe hypercalcemia after substitution of prolonged deficiency of vitamin D in a patient with primary hyperparathyroidism].](/assets/img/hold.png)
