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Reversible hypocalciuric hypercalcemia associated with hypothyroidism
CASE REPORTS
Reversible Hypocalciuric Hypercalcemia Associated with Hypothyroidism
GARY P. ZALOGA, M.D. CHARLES EIL, M.D., Ph.D. JOHN T. O’BRIAN, M.D. Bethesda, Maryland
Hypothyroidism is known to affect calcium homeostasis by decreasing bone turnover and serum calcium level, and by increasing parathyroid hormone and 1,25-dihydroxyvitamin D concentrations. A 52-year-old hypothyroid woman is described who had hypercalcemia associated with elevated parathyroid hormone and 1,25dihydroxyvitamin D levels, but decreased 24-hour urinary calcium excretion and ratio of calcium to creatinine clearance. These parameters normalized following thyroid hormone replacement therapy. Hypercalcemia appeared to result from a combination of reduced renal calcium excretion and a change in the “set point” for calcium feedback inhibitton of the parathyroid gtands. These data suggest that thyroid hormone has a direct effect on the parathyroid glands, regulating parathyroid hormone secretion, and on the kidney’s ability to excrete calcium. It is recommended that parathyroid hormone, 1,25-dihydroxyvitamin D, and urinary calcium excretion values be interpreted in light of thyroid hormone status. Hypothyroidism is known to affect calcium homeostasis by decreasing bone turnover [ 1,2], resulting in reduced serum calcium [3,4] and, subsequently, elevated serum parathyroid hormone [3,4] and 1,25dihydroxyvitamin D concentrations [ 51. Urinary calcium excretion is also frequently decreased in hypothyroid patients [4,6-81, reflecting the decreased filtered load of calcium and the effects of increased parathyroid hormone levels. Hypothyroidism also causes increased gastrointestinal absorption of calcium. Hypercalcemia has been reported to occur in hypothyroid patients following oral calcium loads [ 71, probably reflecting the elevated levels of 1,25-dihydroxyvitamin D. However, fasting hypercalcemia in hypothyroidism has not been reported, although rare cases of hypercalcemia in hypothyroidism [7] and cretinism [9] have been described. We describe herein a patient with hypothyroidism who presented with fasting hypercalcemia and hypocalciuria that normalized with thyroid hormone replacement.
From the Endocrinology and Metabolism Branch, Department of Medicine, Naval Hospital, and the Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland. The opinions expressed herein are those of the authors and are not to be construed as reflecting the views of the Navy Department, the Naval Service at large, or the Department of Defense. Requests for reprints should be addressed to Dr. Gary P. Zaloga, Naval Hospital, Bethesda, Maryland 20814. Manuscript accepted April 2, 1984.
CASE REPORT A 52-year-old woman presented for medical evaluation of lethargy, fatigue, anorexia, and constipation. She denied renal stones, peptic ulcer disease, and polyuria. Her past history was significant for hypertension and osteoarthritis. Family history was unremarkable, and she was receiving furosemide 20 mg every other day, clonidine 0.1 mg once daily, and piroxicam 20 mg once daily. Physical examination revealed only mild obesity. Initial laboratory evaluation showed hypercalcemia (10.9 mg/dl) and hypophosphatemia (2.5 mg/dl). Results of subsequent studies, including chest radiography, hand radiography, intravenous pyelography, bone scanning, and liver-spleen
December 1984
The American Journal of Medicine
Volume 77
1101
HYPOCALCIIJRIC
TABLE I
HYPERCALCEMIA-ZALOGA
ET AL
Laboratory Values Date NormalValues
Total calcium Ionized calcium+ Phosphorus Creatinine clearance 24-hour urinary calcium Calcium:creatinine clearance ratio Tubular maximum for phosphate resorption glomerular filtration rate Parathyroid hormonet c-terminal n-terminal 1.25dihydroxyvitamin Dt Thyroxine Thvroid-stimulatino hormone
9130
8.5-10.5 mgldl 4.1-5.1 mgldl 2.5-4.5 mg/dl (ml/minute) (mg) >O.Ol 2.5-4.2
mg/dl
430- 1.860 pg/ml 230-630 pgiml 20-76 pg/ml 5-12 pg/dl <6 &/ml
1015
10/12’
lOl19’
10/21’
9.8 4.9 3.3 99 260 0.018
9.9 5.0 3.4 83 225 0.019
3.0
2.8
10.6 5.6 2.5 100 47 0.002
10.3 5.5 2.7 93 100 0.007
9.7 5.1 3.3 97 173 0.013
2.5
2.2
3.2
-
-
1,550 1,055 84 6.7 16
8.0 6.5
11.4
-
8.3 2.0
10129’ 9.7 4.8 3.5 -
-
1,360 445 12 -
11130’ 9.4 4.6 3.1 108 219 0.012 3.4
1,120 530 59 11.1 2.0
Receiving L-thyroxine 0.15 mg daily. t Measured bv ion-selective electrode (Nova 2, Nova Biomedical, Newton, Massachusetts). t Bioscience Laboratories, Van Nuys, California. l
scanning, calcium
were
all normal.
concentrations
Repeated
were
fasting
total
serum
c-terminal parathyroid hormone (Metpath) was elevated at 1,504 and 1,794 pg/ml (normal less than 885). The patient was referred to the Bethesda Naval Hospital for further work-up and treatment of primary hyperparathyroidism but continued to complain of fatigue, lethargy, and constipation. She denied recent weight gain, cold intolerance, and skin or hair changes. Once again, physical examination revealed only mild obesity. The thyroid gland was symmetric and not enlarged. Following discontinuation of all medications, laboratory evaluation revealed mild anemia (hemoglobin 9.8 g/dl), normal electrolyte levels, magnesium level of 1.21 mg/dl (normal 1.7 to 2.4) normal urinalysis results, creatinine level of 0.5 mg/dl, blood urea nitrogen level of 16 mg/dl, cholesterol level of 239 mg/dl, alkaline phosphatase level of 78 units/ml (normal 30 to 95), total serum calcium level of 10.6 mg/dl, and phosphorus level of 2.5 mg/dl (Table I).
Urine calcium excretion over a 24-hour period was 47 and 100 mg, tubular maximum for phosphate resorption/glomerular filtration rate was 2.5 mg/dl, and ratio of renal calcium clearance to creatinine clearance was 0.002. The serum thyroxine level was 6.7 pg/dl, and the thyroid-stimulating hormone level 16 pU/ml. A thyrotropin-releasing hormone stimulation test revealed an exaggerated thyroidstimulating hormone response consistent with primary hypothyroidism. The 25-hydroxyvitamin D level was 10 ng/ml (normal 10 to 55), 1,25_dihydroxyvitamin D level was 84 pg/ml (normal 20 to 76) c-terminal parathyroid hormone level was 1,550 pg/ml (normal 430 to 1,860), and n-terminal parathyroid hormone level was 1,055 pglml (normal 230 to 630) (Bioscience Laboratories, Van Nuys, California) (Table I). The patient was treated with L-thyroxine 0.15 mg daily. Following therapy (Table I, Figure l), the serum calcium level,
urinary calcium excretion, parathyroid hormone level, 1,25dihydroxyvitamin D level, and ratio of renal calcium clearance to creatinine clearance tient‘s symptoms resolved.
1102
December 1984
COMMENTS
10.3, 10.9, and 10.6 mg/dl, and
normalized, and the pa-
The American Journal of Medicine
The patient in this report presented with nonspecific complaints of fatigue, lethargy, and constipation. initial evaluation demonstrated hypercalcemia and an elevated c-terminal parathyroid hormone concentration. No other cause for hypercalcemia was found, and the initial diagnosis was primary hyperparathyroidism. Upon re-evaluation, the patient was noted to have hypercalcemia with inappropriately elevated parathyroid hormone and 1,25-dihydroxyvitamin D levels compatible with primary hyperparathyroidism. However, decreased 24-hour urinary calcium excretion and a low ratio of calcium clearance to creatinine clearance compatible with familial hypocalciuric hypercalcemia [lo-121 were also noted. It is important to distinguish between these two syndromes since familial hypocalciuric hypercalcemia has little morbidity and usually requires no surgical therapy [ lo- 121. Although familial hypocalciuric hypercalcemia is relatively common, it is diagnosed infrequently [lo], and those affected have mild symptoms, if any, and rarely seek medical attention for hypercalcemia-related problems. Recognition of hypercalcemia usually occurs during routine check-ups or evaluations for problems unrelated to hypercalcemia [ 10,121. Response to subtotal parathyroidectomy has been poor [ 12,131. Total serum calcium and ionized calcium concentrations are similar to those in patients with primary hyperparathyroidism [ 10,111. This syndrome is the only cause of hypercalcemia not associated with hypomagnesemia [ IO,11 1,and half the patients have elevated serum magnesium concentrations. (Our patient had a low serum magnesium level.) Avid renal tubular resorption of calcium characterizes familial hypocalciuric
Volume 77
HYPOCALClURlC
HYPERCALCEMIA-ZALOGA
, .020
nJJ---
Figure 1. Thyroid-stimulating hormone, total serum calcium, n-terminal parafhyroid hormone, 24-hour urinary calcium excretion, and ratio of calcium clearance to creatinine clearance before and after thyroid hormone replacement therapy. The patient began receiving L-thyroxine (0.15 mg per day) on 1016 (arrow).
DATE
+
hypercalcemia and helps distinguish it from other causes of hypercalcemia [ 131. Most patients have 24-hour calcium excretion rates less than 160 mg and ratios of renal calcium clearance to creatinine clearance of less than 0.01 [ 11,121. The ratio of renal calcium clearance to creatinine clearance has been reported to separate patients with familial hypocalciuric hypercalcemia from those with primary hyperparathyroidism or hypercalcemia of malignancy [ 11,121. Patients with familial hypocalciuric hypercalcemia have lower serum parathyroid hormone values than patients with primary hyperparathyroidism. However, considerable overlap between the two groups exists [ 141. Thus, our patient satisfied a number of criteria for familial hypocalciuric hypercalcemia. Family history was negative for known hypercalcemia, although a serum calcium value was measured for only one member. Thyroid hormone and thyroid-stimulating hormone levels were measured in the patient because she complained of fatigue and constipation. Basal thyroidstimulating hormone was elevated and primary hypothyroidism was confirmed by thyrotropin-releasing hormone testing. Hypothyroidism causes decreased bone turnover [ 1,2,15], resulting in lower serum calcium levels [3,4], although values are usually in the normal range. Consequently, parathyroid hormone and 1,25_dihydroxyvitamin D concentrations are elevated [3-5,16,17]. Lekkerkerkeretal [IS] studiedninepatients who had undergone thyroidectomy and three patients who had primary myxedema given oral calcium loads during hypothyroid and euthyroid phases. Patients
ET AL
absorbed more calcium during the hypothyroid phase. When Lowe and co-workers [7] studied 11 patients with hypothyroidism, eight showed greater or more prolonged increases in serum calcium levels following an oral calcium load than did euthyroid subjects. The increased gut calcium absorption most likely resulted from increased 1,25dihydroxyvitamin D levels. To avoid post-absorptive (alimentary) hypercalcemia, we studied our patient in the fasting state. Urinary excretion of calcium is frequently decreased in hypothyroidism [4,6-81. As long ago as 1929, Aub et al [8] noted that urinary calcium excretion was low in patients with myxedema and that calcium excretion returned to normal levels with therapy. Castro et al [4] reported a mean 24-hour urinary calcium excretion of 77 f 14 mg in six hypothyroid patients, whereas a mean of 18 1 f 16 mg was found in six hyperthyroid patients. These authors also compared the changes in serum and urinary calcium and phosphorus levels following exogenous parathyroid hormone in six hypothyroid and six hyperthyroid patients. The hyperthyroid patients had larger increases in serum calcium levels and decreases in serum phosphorus levels compared with the hypothyroid patients, suggesting a decreased sensitivity to parathyroid hormone in hypothyroidism. In addition, this hormone increased urinary excretion of phosphorus (decreased tubular resorption of phosphate) and calcium in the hyperthyroid patients but had little effect in the hypothyroid patients. Guttler and co-workers [ 181 measured the urinary cyclic adenosine monophosphate response to this hormone in hyperthyroid, euthyroid, and
December 1984
The American Journal of Medlclne
Volume 77
1103
HYPOCALCIURIC
HYPERCALCEMIA-ZALOGA
ET AL
hypothyroid patients. Increases in urinary cyclic adenosine monophosphate were highest in hyperthyroid and lowest in hypothyroid subjects, suggesting that there is decreased parathyroid hormone receptor sensitivity in hypothyroidism. Krane et al [6] found decreased urinary excretion of 45Ca in hypothyroid patients compared with euthyroid and hyperthyroid patients. There was a three-fold increase in urinary calcium excretion in the hypothyroid patients following thyroid hormone replacement therapy. Lowe et al [7] compared urinary calcium excretion in five hypothyroid and five euthyroid patients and found four of five hypothyroid patients to have values less than 120 mg per 24 hours, whereas all the euthyroid patients excreted greater than 140 mg. In none of these studies was the decreased urinary calcium excretion associated with hypercalcemia. Indeed, hypercalcemia in hypothyroidism is extremely rare [7,9]. Lowe et al [7] described a case of hypercalcemia (12.6 mg/dl) in a hypothyroid adult on a normal diet. However, no information was provided on this patient’s urinary calcium excretion. Hypercalcemia’normalized following thyroid hormone replacement therapy. It is not clear from this report whether the serum calcium values were measured in the fasting state. Bateson and Chander [9] reviewed nine cases of cretinism associated with nephrocalcinosis. Five of these patients (ages six and a half months to 21 years) had elevated serum calcium values. Again, 24-hour urinary
calcium excretion was not reported, and it is unclear whether calcium concentrations were measured in the fasting state. In this report, we document fasting hypercalcemia in a hypothyroid patient. Mechanisms for the hypercalcemia appear to relate to low renal excretion of calcium secondary to parathyroid gland hyperfunction. Because parathyroid hormone levels were excessive, we postulate a change in the “set point” of parathyroid hormone secretion for calcium feedback inhibition, since, normally, hypercalcemia should suppress parathyroid gland function. In summary, we describe a 52-year-old woman who presented with fatigue and was found to be hypercalcemic and hypothyroid. The hypercalcemia was associated with elevated parathyroid hormone and 1,25dihydroxyvitamin D levels and low urinary calcium excretion. These parameters normalized following thyroid hormone therapy. These data indicate that hypocalciuric hypercalcemia may develop in hypothyroidism and suggest that thyroid hormone has a direct effect upon the parathyroid glands, regulating parathyroid hormone secretion, and on the kidney’s ability to excrete calcium. This defect in hypothyroidism may be analogous to the altered divalent cation metabolism in familial hypocalciuric hypercalcemia [ 1 I]. We recommend that parathyroid hormone and 1,25dihydroxyvitamin D levels and urinary calcium excretion values be interpreted in light of thyroid hormone status.
REFERENCES 1.
2.
3.
4.
5.
6.
7. 8.
9. 10.
1104
Bordier P, Miravet L, Matrajt H, et al: Bone changes in adult patients with abnormal thyroid function. Proc R Sot Med 1967; 60: 1132. Kivirikko KI, Laitinen 0, Lamberg BA: Value of urine and serum hydroxyproline in the diagnosis of thyroid disease. J Clin Endocrinol Metab 1965; 25: 1347. Bouillon R, DeMoor P: Parathyroid function in patients with hyper- or hypothyroidism. J Clin Endocrinol Metab 1974; 38: 999. Castro JH, Genuth SM, Klein L: Comparative response to parathyroid hormone in hyperthyroidism and hypothyroidism. Metabolism 1975; 24: 839. Bouillon R, Muls E, DeMoor P: Influence of thyroid function on the serum concentration of 1,25dihydroxyvitamin D3. J Clin Endocrinol Metab 1980; 51: 793. Krane SM. Brownell GL, Stanbury JB, et al: The effect of thyroid disease on calcium metabolism in man. J Clin Invest 1956; 35: 874. Lowe CE, Bird ED, Thomas WC: Hypercalcemia in myxederna. J Clin Endocrinol Metab 1962; 22: 261. Aub JC, Bauer W, Heath C, et al: Studies of calcium and phosphorus metabolism. Ill. The effect of the thyroid hormone and thyroid disease. J Clin Invest 1929; 7: 97. Bateson EM, Chander S: Nephrocalcinosis in cretinism. Br J Radio1 1965; 38: 58 1. Marx SJ,Spiegel AM, Levine MA, et al: Familial hypocalciuric hypercalcemia: the relation to primary parathyroid hyperplasia. N Engl J Med 1982; 307: 416.
December
1984
The American
Journal of Medicine
11.
12.
13.
14.
15.
16.
17.
18.
Marx SJ, Spiegel AM. Brown EM, et al: Divalent cation metabolism: familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. Am J Med 1978; 65: 235. Marx SJ, Stock JL, Attie MF, et al: Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration. Ann Intern Med 1980; 92: 351. Marx SJ, Attie MF, Levine MA, et al: The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine (Baltimore) 1981; 60: 397. Marx SJ, Spiegel AM, Brown EM, et al: Circulating parathyroid hormone activity: familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. J Clin Endocrinol Metab 1978; 47: 1190. Mosekilde L, Melson F: Morphometric and dynamic studies of bone changes in hypothyroidism. Acta Pathol Microbial Stand 1978; 86: 56. Lekkerkerker JFF, VanWoudenberg F, Beekhuis H, et al: Enhancement of calcium absorption in hypothyroidism. Isr J bled Sci 1971; 7: 399. Adams P, Chalmers TM, Riggs BL: Parathyroid function in spontaneous primary hypothyroidism. J Endocrinol 1968; 40: 467. Guttler RB, Croxsom MS, De Quattro VL, et al: Effects of thyroid hormone on plasma adenosine 3’,5’ monophosphate production in man. Metabolism 1977; 26: 1155.
Volume 77
Reversible Hypocalciuric Hypercalcemia Associated with Hypothyroidism
GARY P. ZALOGA, M.D. CHARLES EIL, M.D., Ph.D. JOHN T. O’BRIAN, M.D. Bethesda, Maryland
Hypothyroidism is known to affect calcium homeostasis by decreasing bone turnover and serum calcium level, and by increasing parathyroid hormone and 1,25-dihydroxyvitamin D concentrations. A 52-year-old hypothyroid woman is described who had hypercalcemia associated with elevated parathyroid hormone and 1,25dihydroxyvitamin D levels, but decreased 24-hour urinary calcium excretion and ratio of calcium to creatinine clearance. These parameters normalized following thyroid hormone replacement therapy. Hypercalcemia appeared to result from a combination of reduced renal calcium excretion and a change in the “set point” for calcium feedback inhibitton of the parathyroid gtands. These data suggest that thyroid hormone has a direct effect on the parathyroid glands, regulating parathyroid hormone secretion, and on the kidney’s ability to excrete calcium. It is recommended that parathyroid hormone, 1,25-dihydroxyvitamin D, and urinary calcium excretion values be interpreted in light of thyroid hormone status. Hypothyroidism is known to affect calcium homeostasis by decreasing bone turnover [ 1,2], resulting in reduced serum calcium [3,4] and, subsequently, elevated serum parathyroid hormone [3,4] and 1,25dihydroxyvitamin D concentrations [ 51. Urinary calcium excretion is also frequently decreased in hypothyroid patients [4,6-81, reflecting the decreased filtered load of calcium and the effects of increased parathyroid hormone levels. Hypothyroidism also causes increased gastrointestinal absorption of calcium. Hypercalcemia has been reported to occur in hypothyroid patients following oral calcium loads [ 71, probably reflecting the elevated levels of 1,25-dihydroxyvitamin D. However, fasting hypercalcemia in hypothyroidism has not been reported, although rare cases of hypercalcemia in hypothyroidism [7] and cretinism [9] have been described. We describe herein a patient with hypothyroidism who presented with fasting hypercalcemia and hypocalciuria that normalized with thyroid hormone replacement.
From the Endocrinology and Metabolism Branch, Department of Medicine, Naval Hospital, and the Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland. The opinions expressed herein are those of the authors and are not to be construed as reflecting the views of the Navy Department, the Naval Service at large, or the Department of Defense. Requests for reprints should be addressed to Dr. Gary P. Zaloga, Naval Hospital, Bethesda, Maryland 20814. Manuscript accepted April 2, 1984.
CASE REPORT A 52-year-old woman presented for medical evaluation of lethargy, fatigue, anorexia, and constipation. She denied renal stones, peptic ulcer disease, and polyuria. Her past history was significant for hypertension and osteoarthritis. Family history was unremarkable, and she was receiving furosemide 20 mg every other day, clonidine 0.1 mg once daily, and piroxicam 20 mg once daily. Physical examination revealed only mild obesity. Initial laboratory evaluation showed hypercalcemia (10.9 mg/dl) and hypophosphatemia (2.5 mg/dl). Results of subsequent studies, including chest radiography, hand radiography, intravenous pyelography, bone scanning, and liver-spleen
December 1984
The American Journal of Medicine
Volume 77
1101
HYPOCALCIIJRIC
TABLE I
HYPERCALCEMIA-ZALOGA
ET AL
Laboratory Values Date NormalValues
Total calcium Ionized calcium+ Phosphorus Creatinine clearance 24-hour urinary calcium Calcium:creatinine clearance ratio Tubular maximum for phosphate resorption glomerular filtration rate Parathyroid hormonet c-terminal n-terminal 1.25dihydroxyvitamin Dt Thyroxine Thvroid-stimulatino hormone
9130
8.5-10.5 mgldl 4.1-5.1 mgldl 2.5-4.5 mg/dl (ml/minute) (mg) >O.Ol 2.5-4.2
mg/dl
430- 1.860 pg/ml 230-630 pgiml 20-76 pg/ml 5-12 pg/dl <6 &/ml
1015
10/12’
lOl19’
10/21’
9.8 4.9 3.3 99 260 0.018
9.9 5.0 3.4 83 225 0.019
3.0
2.8
10.6 5.6 2.5 100 47 0.002
10.3 5.5 2.7 93 100 0.007
9.7 5.1 3.3 97 173 0.013
2.5
2.2
3.2
-
-
1,550 1,055 84 6.7 16
8.0 6.5
11.4
-
8.3 2.0
10129’ 9.7 4.8 3.5 -
-
1,360 445 12 -
11130’ 9.4 4.6 3.1 108 219 0.012 3.4
1,120 530 59 11.1 2.0
Receiving L-thyroxine 0.15 mg daily. t Measured bv ion-selective electrode (Nova 2, Nova Biomedical, Newton, Massachusetts). t Bioscience Laboratories, Van Nuys, California. l
scanning, calcium
were
all normal.
concentrations
Repeated
were
fasting
total
serum
c-terminal parathyroid hormone (Metpath) was elevated at 1,504 and 1,794 pg/ml (normal less than 885). The patient was referred to the Bethesda Naval Hospital for further work-up and treatment of primary hyperparathyroidism but continued to complain of fatigue, lethargy, and constipation. She denied recent weight gain, cold intolerance, and skin or hair changes. Once again, physical examination revealed only mild obesity. The thyroid gland was symmetric and not enlarged. Following discontinuation of all medications, laboratory evaluation revealed mild anemia (hemoglobin 9.8 g/dl), normal electrolyte levels, magnesium level of 1.21 mg/dl (normal 1.7 to 2.4) normal urinalysis results, creatinine level of 0.5 mg/dl, blood urea nitrogen level of 16 mg/dl, cholesterol level of 239 mg/dl, alkaline phosphatase level of 78 units/ml (normal 30 to 95), total serum calcium level of 10.6 mg/dl, and phosphorus level of 2.5 mg/dl (Table I).
Urine calcium excretion over a 24-hour period was 47 and 100 mg, tubular maximum for phosphate resorption/glomerular filtration rate was 2.5 mg/dl, and ratio of renal calcium clearance to creatinine clearance was 0.002. The serum thyroxine level was 6.7 pg/dl, and the thyroid-stimulating hormone level 16 pU/ml. A thyrotropin-releasing hormone stimulation test revealed an exaggerated thyroidstimulating hormone response consistent with primary hypothyroidism. The 25-hydroxyvitamin D level was 10 ng/ml (normal 10 to 55), 1,25_dihydroxyvitamin D level was 84 pg/ml (normal 20 to 76) c-terminal parathyroid hormone level was 1,550 pg/ml (normal 430 to 1,860), and n-terminal parathyroid hormone level was 1,055 pglml (normal 230 to 630) (Bioscience Laboratories, Van Nuys, California) (Table I). The patient was treated with L-thyroxine 0.15 mg daily. Following therapy (Table I, Figure l), the serum calcium level,
urinary calcium excretion, parathyroid hormone level, 1,25dihydroxyvitamin D level, and ratio of renal calcium clearance to creatinine clearance tient‘s symptoms resolved.
1102
December 1984
COMMENTS
10.3, 10.9, and 10.6 mg/dl, and
normalized, and the pa-
The American Journal of Medicine
The patient in this report presented with nonspecific complaints of fatigue, lethargy, and constipation. initial evaluation demonstrated hypercalcemia and an elevated c-terminal parathyroid hormone concentration. No other cause for hypercalcemia was found, and the initial diagnosis was primary hyperparathyroidism. Upon re-evaluation, the patient was noted to have hypercalcemia with inappropriately elevated parathyroid hormone and 1,25-dihydroxyvitamin D levels compatible with primary hyperparathyroidism. However, decreased 24-hour urinary calcium excretion and a low ratio of calcium clearance to creatinine clearance compatible with familial hypocalciuric hypercalcemia [lo-121 were also noted. It is important to distinguish between these two syndromes since familial hypocalciuric hypercalcemia has little morbidity and usually requires no surgical therapy [ lo- 121. Although familial hypocalciuric hypercalcemia is relatively common, it is diagnosed infrequently [lo], and those affected have mild symptoms, if any, and rarely seek medical attention for hypercalcemia-related problems. Recognition of hypercalcemia usually occurs during routine check-ups or evaluations for problems unrelated to hypercalcemia [ 10,121. Response to subtotal parathyroidectomy has been poor [ 12,131. Total serum calcium and ionized calcium concentrations are similar to those in patients with primary hyperparathyroidism [ 10,111. This syndrome is the only cause of hypercalcemia not associated with hypomagnesemia [ IO,11 1,and half the patients have elevated serum magnesium concentrations. (Our patient had a low serum magnesium level.) Avid renal tubular resorption of calcium characterizes familial hypocalciuric
Volume 77
HYPOCALClURlC
HYPERCALCEMIA-ZALOGA
, .020
nJJ---
Figure 1. Thyroid-stimulating hormone, total serum calcium, n-terminal parafhyroid hormone, 24-hour urinary calcium excretion, and ratio of calcium clearance to creatinine clearance before and after thyroid hormone replacement therapy. The patient began receiving L-thyroxine (0.15 mg per day) on 1016 (arrow).
DATE
+
hypercalcemia and helps distinguish it from other causes of hypercalcemia [ 131. Most patients have 24-hour calcium excretion rates less than 160 mg and ratios of renal calcium clearance to creatinine clearance of less than 0.01 [ 11,121. The ratio of renal calcium clearance to creatinine clearance has been reported to separate patients with familial hypocalciuric hypercalcemia from those with primary hyperparathyroidism or hypercalcemia of malignancy [ 11,121. Patients with familial hypocalciuric hypercalcemia have lower serum parathyroid hormone values than patients with primary hyperparathyroidism. However, considerable overlap between the two groups exists [ 141. Thus, our patient satisfied a number of criteria for familial hypocalciuric hypercalcemia. Family history was negative for known hypercalcemia, although a serum calcium value was measured for only one member. Thyroid hormone and thyroid-stimulating hormone levels were measured in the patient because she complained of fatigue and constipation. Basal thyroidstimulating hormone was elevated and primary hypothyroidism was confirmed by thyrotropin-releasing hormone testing. Hypothyroidism causes decreased bone turnover [ 1,2,15], resulting in lower serum calcium levels [3,4], although values are usually in the normal range. Consequently, parathyroid hormone and 1,25_dihydroxyvitamin D concentrations are elevated [3-5,16,17]. Lekkerkerkeretal [IS] studiedninepatients who had undergone thyroidectomy and three patients who had primary myxedema given oral calcium loads during hypothyroid and euthyroid phases. Patients
ET AL
absorbed more calcium during the hypothyroid phase. When Lowe and co-workers [7] studied 11 patients with hypothyroidism, eight showed greater or more prolonged increases in serum calcium levels following an oral calcium load than did euthyroid subjects. The increased gut calcium absorption most likely resulted from increased 1,25dihydroxyvitamin D levels. To avoid post-absorptive (alimentary) hypercalcemia, we studied our patient in the fasting state. Urinary excretion of calcium is frequently decreased in hypothyroidism [4,6-81. As long ago as 1929, Aub et al [8] noted that urinary calcium excretion was low in patients with myxedema and that calcium excretion returned to normal levels with therapy. Castro et al [4] reported a mean 24-hour urinary calcium excretion of 77 f 14 mg in six hypothyroid patients, whereas a mean of 18 1 f 16 mg was found in six hyperthyroid patients. These authors also compared the changes in serum and urinary calcium and phosphorus levels following exogenous parathyroid hormone in six hypothyroid and six hyperthyroid patients. The hyperthyroid patients had larger increases in serum calcium levels and decreases in serum phosphorus levels compared with the hypothyroid patients, suggesting a decreased sensitivity to parathyroid hormone in hypothyroidism. In addition, this hormone increased urinary excretion of phosphorus (decreased tubular resorption of phosphate) and calcium in the hyperthyroid patients but had little effect in the hypothyroid patients. Guttler and co-workers [ 181 measured the urinary cyclic adenosine monophosphate response to this hormone in hyperthyroid, euthyroid, and
December 1984
The American Journal of Medlclne
Volume 77
1103
HYPOCALCIURIC
HYPERCALCEMIA-ZALOGA
ET AL
hypothyroid patients. Increases in urinary cyclic adenosine monophosphate were highest in hyperthyroid and lowest in hypothyroid subjects, suggesting that there is decreased parathyroid hormone receptor sensitivity in hypothyroidism. Krane et al [6] found decreased urinary excretion of 45Ca in hypothyroid patients compared with euthyroid and hyperthyroid patients. There was a three-fold increase in urinary calcium excretion in the hypothyroid patients following thyroid hormone replacement therapy. Lowe et al [7] compared urinary calcium excretion in five hypothyroid and five euthyroid patients and found four of five hypothyroid patients to have values less than 120 mg per 24 hours, whereas all the euthyroid patients excreted greater than 140 mg. In none of these studies was the decreased urinary calcium excretion associated with hypercalcemia. Indeed, hypercalcemia in hypothyroidism is extremely rare [7,9]. Lowe et al [7] described a case of hypercalcemia (12.6 mg/dl) in a hypothyroid adult on a normal diet. However, no information was provided on this patient’s urinary calcium excretion. Hypercalcemia’normalized following thyroid hormone replacement therapy. It is not clear from this report whether the serum calcium values were measured in the fasting state. Bateson and Chander [9] reviewed nine cases of cretinism associated with nephrocalcinosis. Five of these patients (ages six and a half months to 21 years) had elevated serum calcium values. Again, 24-hour urinary
calcium excretion was not reported, and it is unclear whether calcium concentrations were measured in the fasting state. In this report, we document fasting hypercalcemia in a hypothyroid patient. Mechanisms for the hypercalcemia appear to relate to low renal excretion of calcium secondary to parathyroid gland hyperfunction. Because parathyroid hormone levels were excessive, we postulate a change in the “set point” of parathyroid hormone secretion for calcium feedback inhibition, since, normally, hypercalcemia should suppress parathyroid gland function. In summary, we describe a 52-year-old woman who presented with fatigue and was found to be hypercalcemic and hypothyroid. The hypercalcemia was associated with elevated parathyroid hormone and 1,25dihydroxyvitamin D levels and low urinary calcium excretion. These parameters normalized following thyroid hormone therapy. These data indicate that hypocalciuric hypercalcemia may develop in hypothyroidism and suggest that thyroid hormone has a direct effect upon the parathyroid glands, regulating parathyroid hormone secretion, and on the kidney’s ability to excrete calcium. This defect in hypothyroidism may be analogous to the altered divalent cation metabolism in familial hypocalciuric hypercalcemia [ 1 I]. We recommend that parathyroid hormone and 1,25dihydroxyvitamin D levels and urinary calcium excretion values be interpreted in light of thyroid hormone status.
REFERENCES 1.
2.
3.
4.
5.
6.
7. 8.
9. 10.
1104
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