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Concomitant graves' disease and primary hyperparathyroidism. Influence of hyperthyroidism on serum calcium and parathyroid hormone
Concomitant Graves' Disease and Primary Hyperparathyroidism Influence of Hyperthyroidism on Serum Calcium and Parathyroid Hormone
RIDHA AREM, M.D. MARY ANNE LIM-ABRAHAN, M.D. LAWRENCE E. MALLETTE, M.D., Ph.D. Houston, Texas
From the Division of Endocrinology and Metabolism, Baylor College of Medicine and the Veterans Administration Medical Center, Houston, Texas. This work was supported by the Veterans Administration. Requests for reprints should be addressed to Dr. Ridha Arem, Bayior College of Medicine, One Baylor Plaza, Houston, Texas 77030. Manuscript accepted December 13, 1984.
Two patients with coexistent Graves' disease and primary hyperparathyroidism were studied during medical treatment of their hyperthyroidism. Serum free calcium level was initially quite elevated (1.61 and 1.71 mM, normal 1.12 to 1.28 mM), but immunoreactive parathyroid hormone values were only slightly increased. The immunoreactive parathyroid hormone values of 153 and 173 nleq/ml (normal less than 150 nleq/ml) were far lower than expected in hyperparathyroid patients with a similar degree of hypercalcemia. As the patients became euthyroid during thionamide treatment, calcium values decreased to 1.39 and 1.61 mM, respectively, and parathyroid hormone increased to values clearly suggestive of hyperparathyroidism (454 and 229 nleq/ml, respectively). Parathyroidectomy and subtotal thyroidectomy cured both the hyperparathyroidism and the thyrotoxicosis in each case. These observations suggest that thyroid hormone had potentiated the osteoclastic effects of parathyroid hormone and that the resulting exacerbation of hypercalcemia had produced a relative suppression of hormone secretion by the abnormal parathyroid tissue. The occurrence of hypercalcemia in a thyrotoxic patient may present an interesting diagnostic problem. A high serum calcium value may be noted during the course of hyperthyroidism in as many as 22 percent of cases [ 1]. Excess thyroid hormone is thought to produce hypercalcemia and hypercalciuria by activating osteoclastic bone resorption [2]. The severity of hyperthyroidism correlates positively both with urinary hydroxyproline excretion [3] and with osteoclastic activity in trabecular and cortical bone [4]. Furthermore, thyroid hormone has been shown to increase the responsiveness of bone to administered parathyroid hormone [5], but whether endogenous parathyroid hormone plays a role in the exaggerated osteoclastic activity of hyperthyroidism remains controversial, since parathyroid hormone values have been reported to be elevated [6-8], diminished [4,9,10], or normal [1 1]. Primary hyperparathyroidism has also been reported in several hyperthyroid patients [8,12-31], but probably accounts for hypercalcemia in no more than 1 percent of thyrotoxic patients [32]. In such cases, however, it would be desirable to detect the parathyroid lesion before definitive therapy is chosen, since treatment of the thyroid disease with radioiodine might be deferred and neck surgery used to treat both diseases. We describe two patients with concomitant hyperparathyroidism and hyperthyroidism in whom serum free calcium levels, immunoreactive
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parathyroid hormone levels, and thyroid function were monitored during therapy with anti-thyroid medications. The data suggest that hyperthyroidism can exacerbate the hypercalcemia of primary hyperparathyroidism and thereby suppress immunoreactive parathyroid hormone levels. Treatment to lower free calcium levels may facilitate the diagnosis by increasing immunoreactive parathyroid hormone to a level more clearly indicating primary hyperparathyroidism. CASE REPORTS Patient 1. A 71-year-old black man was admitted because of dyspepsia and epigastric pain of six months' duration, not associated with hunger or relieved by food intake. He had lost 40 pounds over the previous six months, despite a good appetite. He was chronically constipated and had recently noted polydipsia, polyuria, and nocturia. He denied palpitations, dyspnea, nervousness, or heat intolerance. His medical record revealed that 38 and two months earlier, his serum calcium level had been 11.1 and 10.8 mg/dl, respectively. Hypertension diagnosed six years earlier was being treated with propranolol, 80 mg three times a day, hydrochlorothiazide, 50 mg daily, and hydralazine, 50 mg twice daily. He was an aesthenic black man weighing 176 pounds (ideal body weight 190 pounds). His blood pressure was 115/90 mm Hg, pulse 96 beats per minute and regular, respirations 14 per minute, and temperature 98.6°F orally. There was no band keratopathy. The thyroid was twice normal size, with a smooth surface and firm consistency. No bruit was appreciated. Results of chest, heart, and abdominal examinations were unremarkable. The proximal muscles were weak and tendon reflexes brisk. Laboratory values were as follows: serum sodium 149 meq/liter, potassium 3.7 meq/liter, chloride 107 meq/liter, bicarbonate 30 meq/liter, and creatinine 0.8 mg/dl; total serum calcium ranged from 11.3 to 11.8 mg/dl, with albumin 3.6 g/dl, phosphate 3.8 mg/dl, alkaline phosphatase 130 mlU/ml (normal less than 100 mlU/ml), bilirubin 0.7 mg/dl, serum glutamic oxaloacetic transaminase 30 mlU/ml (normal less than 40), serum glutamic pyruvic transaminase 33 mlU/ml (normal less than 40), lactic dehydrogenase 209 mlU/ml (normal less than 200), hematocrit 35.5 percent, serum thyroxine 29 #g/dl (normal 5 to 12), triiodothyronine resin uptake 44 percent (normal 25 to 35 percent), and free thyroxine 6.2 ng/ml (normal 0.7 to 2.3 ng/ml). Thyroidal radioactive iodine uptake was 17 percent at 24 hours, and thyroid scanning showed homogeneous uptake by a slightly enlarged gland. Because of the dyspepsia and anemia, esophagogastroscopy was performed, revealing multiple gastric polyps, which were removed. Findings on histologic examination were compatible with gastric hamartomas. The patient was treated with propranolol 80 mg and propylthiouraci1200 mg orally every eight hours and hydralazine, 50 mg orally twice a day. Hydrochlorothiazide was discontinued on admission, with no immediate change in serum calcium level. During the next several weeks, as his hyperthyroid state came under control, immunoreactive
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parathyroid hormone and free calcium values were monitored serially and are presented later. With treatment he gained weight progressively, and four months after initiation of the anti-thyroid therapy he was clinically and biochemically euthyroid. He then underwent subtotal thyroidectomy and parathyroid exploration, with excision of an adenoma of the right superior parathyroid gland. Histologically, the thyroid tissue was diffusely hyperplastic. Hypercalcemia has not recurred during two years of follow-up. Patient 2. A 59-year-old black man was admitted because of a 50-pound weight loss over the previous nine months, with anorexia, intermittent diarrhea, fever, and left upper quadrant discomfort. He had been admitted three months earlier for diverticulitis, which was treated with antibiotics. He denied insomnia, palpitations, heat intolerance, nervousness, or diaphoresis. Atrial fibrillation had been treated with digoxin 0.125 mg orally daily for the past year. Two years earlier, a multiphasic chemical determination during admission for a ruptured appendix had shown a serum calcium value of 11.0 mg/dl that was not evaluated. He was a thin black man weighing 124 pounds (ideal body weight 180 pounds). His blood pressure was 120/80 mm Hg, pulse 104 beats per minute and irregular, oral temperature 100°F, and respirations 18 per minute. The skin was warm and smooth with several areas of vitiligo on the abdnominal wall, and the hair was of fine texture. He displayed lid lag, but no exophthalmos. The thyroid gland was of normal size, with a firm consistency but no bruit. Results of chest and cardiovascular examinations were remarkable only for the irregular pulse. The abdomen was tender in the left upper quadrant. A fine tremor and hyperactive reflexes with a brisk relaxation phase were noted. Levels of serum electrolytes and creatinine were normal. Other values were as follows: total serum calcium 12.5 mg/dl, albumin 2.7 g/dl, phosphate 2.2 mg/dl, alkaline phosphatase 101 mlU/ml (normal less than 80 mlU/ml), serum glutamic oxaloacetic transaminase 17 mlU/ml (normal less than 40), serum glutamic pyruvic transaminase 26 mlU/ml (normal less than 40), lactic dehydrogenase 186 mlU/ml (normal less than 200), hematocrit 33.6 percent, serum thyroxine 16.5 #g/dl (normal 5 to 12), triiodothyronine resin uptake 39.9 percent (normal 25 to 35 percent), free thyroxine index 6.6 (normal 1.2 to 4.2), and free thyroxine 7.0 ng/ml (normal 0.7 to 2.3). The radioiodine uptake was 52.6 percent at 24 hours and thyroid scanning showed a normal-sized gland with homogeneous uptake. Ultrasound and gallium scanning suggested the presence of a left upper quadrant abdominal abscess. He was treated with propylthiouracil 100 mg orally every six hours and propranolo140 mg orally every eight hours, as well as with parenteral antibiotics. Free calcium and immunoreactive parathyroid hormone values during treatment are presented later. He became euthyroid within about three weeks and then underwent surgical drainage of the abdominal abscess. After three months of recuperation, he underwent subtotal thyroidectomy and parathyroid exploration. The right and left inferior parathyroid glands were grossly enlarged and were excised. Histologic examination revealed diffuse hyperplasia of both thyroid and parathyroid tissue. Postoperatively, the total calcium level fell to 8.7
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Figure 1. Ionized calcium (Ca++), immunoreactive parathyroid hormone (iPTH), and serum thyroxine ( T4) and triiodothyronine ( T3) values during therapy with propylthiouracil (PTU) in Patient 1. The time in weeks represents the time elapsed since initiation of therapy.
mg/dl and phosphorus level to 3 mg/dl with an albumin level of 3 g/dl. Two years later, he was asymptomatic and weighed 183 pounds. His serum calcium value was 10.1 mg/dl, albumin level 3.6 g/dl, and phosphorus level 4.0 mgldl. METHODS
Parathyroid hormone was measured with two different midregion-specific radioimmunoassay systems using goat antiserum to native human parathyroid hormone. The first employed anti-serum BG-6 with 1251-labeledbovine parathyroid hormone-(37-84) as radioligand [33]. This assay system has precisely the same performance characteristics as the previously described assay that used bovine parathyroid hormone-(41-84) as radioligand [34], except that the nonspecific binding value is lower, approximately 6 percent. The second assay system employed anti-serum NG-5 with radiolabeled tyr43-human parathyroid hormone-(44-68) as radioligand [35,36]. Crude human parathyroid hormone served as standard for each assay [34]. The concentration of the free calcium ion in serum was measured anaerobically by ion-selective electrode (Nova 2, Nova Biomedical, Newton, Massachusetts), as described [34].
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Serum immunoreactive parathyroid hormone and free calcium were measured in each patient at the time of initial diagnosis and during treatment with propylthiouracil. Values for immunoreactive parathyroid hormone, free calcium, thyroxine, and triiodothyronine as a function of time are given in Figure 1 and Table I. In Patient 1,
TABLE I
Laboratory Values before and after Three W e e k s of Propylthiouracil in Patient 2 Before After Therapy Therapy
Thyroxine (#g/dl) 16.5 Triiodothyronine resin uptake (percent) 39.9 Free thyroxine index 6.6 Total calcium (mg/dl) 12.5 Albumin (g/dl) 2.9 Free calcium (mM) 1.71 Immunoreactive parathyroid hormone (nleq/ml) 173
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INFLUENCE OF HYPERTHYROIDISM ON PRIMARY HYPERPARATHYROIDISM--AREM ET AL
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Figure 2. Serum parathyroid hormone immunoreactivity in each of two patients with Graves' disease and concomitant primary hyperparathyroidism was measured serially with each of two radioimmunoassays and is plotted as a function of the simultaneous serum free calcium ion activity. The upper limits of normal for calcium ion a'ctivity and for immunoreactive parathyroid hormone (iPT~ in each assay are indicated by the vertical and horizontal lines, respectively. The curved line in the upper panel outlines the domain that contains data points from over 99 percent of patients with uncomplicated primary hyperparathyroidism. Numbers beside each symbol represent weeks of treatment with propylthiouracil.
thyroxine level declined progressively, from 29 to 7.6 #g/dl after 12 weeks of treatment, whereas triiodothyronine level fell from 509 to 169 ng/dl (Figure 1). Serum free calcium level was initially 1.61 mM (normal 1.11 to 1,28), but immunoreactive parathyroid hormone value was just at the upper limit of normal, 153 nleq/ml (normal less than 150). As the hyperthyroidism came under control, serum free calcium level progressively declined and immunoreactive parathyroid hormone value increased markedly, making the diagnosis of primary hyperparathyroidism clear. A similar sequence of events occurred in Patient 2 (Table I). After three weeks of treatment, serum immunoreactive parathyroid hormone level rose from 696
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173 to 229 nleq/ml, whereas free calcium level fell from 1.71 to 1.61 mM. In Figure 2, the serial changes in immunoreactive parathyroid hormone level are plotted as a function of the simultaneous free calcium value, in order to illustrate the reciprocal relationship between immunoreactive parathyroid hormone and free calcium and the manner in which the immunoreactive parathyroid hormone-free calcium points entered the domain for primary hyperparathyroidism after treatment had lowered free calcium level significantly. Values from the two parathyroid hormone assay systems were essentially parallel, demonstrating that the change in immunoreactive parathyroid hormone value was not an artifact of a single parathyroid hormone assay system.
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Hypercalcemia occurs in up to 22 percent of patients with hyperthyroidism [ 1]. In only a small percentage of cases is the hypercalcemia attributable to concomitant parathyroid disease [32]. The best laboratory clue to the presence of primary hyperparathyroidism has been the serum phosphate value, which tends to be high-normal in thyrotoxicosis [2], but tends to be decreased or low-normal in primary hyperparathyroidism. The phosphate value may, however, be misleading, as in our Patient 1. Because serum phosphate is subject to the influence of a number of factors including dietary phosphorus intake and intrinsic renal tubular function, a more direct measurement of parathyroid function would be desirable. The radioimmunoassay for parathyroid hormone unfortunately has given variable results in patients with uncomplicated thyrotoxicosis, with various groups reporting high [6-8], low [4,9,10], or normal [ i l ] values. We have Shown, however, that the results are highly dependent on the particular assay employed [37]. The new homologous, mid-region-specific assays used herein give lower mean irnmunoreactive parathyroid hormone values in patients With thyrotoxicosis than in normal subjects [37]. Although an increased clearance of biologically inactive parathyroid hormone fragments due to the thyrotoxic state could also lower immunoreactive parathyroid hormone values, we believe that the low values seen with this more sensitive assay probably reflect the true status of parathyroid function in uncomplicated thyrotoxicosis. On the aforementioned background, the borderline elevated parathyroid hormone levels in our two hypercalcemic patients did suggest increased parathyroid function. Renal insufficiency can elevate mid-region immunoreactive parathyroid hormone values in Subjects with nonparathyroid forms of hypercalcemia [34], but both of our subjects showed normal serum creatinine values. Since there is always the possibility of nonspecific effects on any peptide radioimmunoassay, and since radioactive iodine would otherwise have constituted adequate treatment, we were reluctant to recommend neck exploration
INFLUENCE OF HYPERTHYROIDISM ON PRIMARY HYPERPARATHYROIDISM--AREM ET AL
without stronger proof of excessive parathyroid function. The observation of reciprocal changes in immunoreactive parathyroid hormone values as free calcium levels fell allowed us to recommend surgery with confidence. The fact that the early immunoreactive parathyroid hormone values had apparently been suppressed by the high levels of serum calcium is analogous to the effect of calcium infusion, which has been shown to decrease immunoreactive parathyroid hormone values in most cases of primary hyperparathyroidism [38]. As free calcium levels declined, immunoreactive parathyroid hormone values began to increase markedly while free calcium levels were still far above normal, suggesting that the abnormal parathyroid tissue in our patients possessed an increased set-point for inhibition by calcium, as has been observed during studies of parathyroid adenomas in vitro [39]. The possibility should also be considered that changes in magnesium balance may have influenced the immunoreactive parathyroid hormone and free calcium changes during treatment. Severe magnesium depletion can inhibit parathyroid hormone secretion and lead to hypocalcemia, and repletion will increase immunoreactive parathyroid hormone and calcium levels [40]. Although serum magnesium was not measured in our patients, serum magnesium in thyrotoxicosis is not usually depressed to the very low levels needed to inhibit parathyroid hormone secretion [41]. Furthermore, if magnesium depletion did play a role in inhibiting our patients' immunoreactive parathyroid hormone secretion, the degree of their hypercalcemia should also have been lessened, and repletion of magnesium would have blunted the fall in free calcium levels while.also contributing to the increase in immunoreactive parathyroid hormone values. Measurements of serum magnesium will be needed to test these possibilities. Several authors have reported the coexistence of primary hyperparathyroidism and hyperthyroidism [8,12-31]. Some have suggested that it may occur more frequently than by chance alone [32] and that the parathyroid diSease might be produced by a long-standing effect of excess thyroid hormone on adrenergic receptors [7]. If this were the case, parathyroid hyperplasia should be almost universal in thyrotoxicosis, whereas the parathyroids are usually histologically normal [42]. Also, the acute increase in immunoreactive parathyroid hormone level in response to EDTA-induced hypocalcemia is blunted in thyrotoxic patients [32], and a decreased biologic effect of parathyroid hormone on the kidney is suggested by the
increased fractional renal calcium excretion [2]. The occurrence of primary hyperparathyroidism in thyrotoxicosis is, therefore, probably coincidental. It seems likely that the primary effect of thyrotoxicosis is to stimulate osteoclastic bone resorption [4,43], and that the resulting small increment in serum calcium level chronically tends to suppress parathyroid secretion. Overt hypercalcemia would then occur only in the most severe cases or when another factor, such as dehydration, immobilization, or hyperparathyroidism interfered with calcium clearance or further accelerated bone resorption. Correction of the thyrotoxicosis was probably the main factor that lowered serum calcium levels in these patients. In Patient 1, hydrochlorothiazide was discontinued upon admission, but without significant change in serum calcium level. In Patient 2, the introduction of propranolol may have contributed to the fall in calcium level, since the drug may sometimes lower calcium values in thyrotoxic patients [44], probably by inhibiting bone resorption [45]. Since thyroid hormone is not known to have direct effects on the intestinal or renal transport of calcium, the parallel fall in levels of serum calcium and thyroid hormones suggests that the excess thyroid hormone had been stimulating osteoclastic activity, either directly or by potentiating the effect of parathyroid hormone. Measurement of 1,25-dihydroxyvitamin D in future cases of concomitant primary hyperparathyroidism and thyrotoxicosis would be of interest. In uncomplicated thyrotoxicosis, 1,25-dihydroxyvitamin D levels are reduced [46] and intestinal calcium absorption is decreased [47], whereas hyperparathyroidism tends to increase both parameters. It is possible that the protective decrease in intestinal calcium absorption in thyrotoxicosis might be lost when primary hyperparathyroidism is also present. In summary, we have observed two patients with concomitant thyrotoxicosis and primary hyperparathyroidism. Treatment with thionamide led to a decrease in serum calcium levels, and an increase in immunoreactive parathyroid hormone to values that allowed a firm diagnosis of primary hyperparathyroidism. Surgical treatment corrected both diseases. ACKNOWLEDGMENT
Dr. R. McGregor kindly furnished bovine parathyroid hormone-(37-84) for use as radioligand. We would like to thank Mrs. Rosemary Telder for her secretarial assistance in the preparation of the manuscript.
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RIDHA AREM, M.D. MARY ANNE LIM-ABRAHAN, M.D. LAWRENCE E. MALLETTE, M.D., Ph.D. Houston, Texas
From the Division of Endocrinology and Metabolism, Baylor College of Medicine and the Veterans Administration Medical Center, Houston, Texas. This work was supported by the Veterans Administration. Requests for reprints should be addressed to Dr. Ridha Arem, Bayior College of Medicine, One Baylor Plaza, Houston, Texas 77030. Manuscript accepted December 13, 1984.
Two patients with coexistent Graves' disease and primary hyperparathyroidism were studied during medical treatment of their hyperthyroidism. Serum free calcium level was initially quite elevated (1.61 and 1.71 mM, normal 1.12 to 1.28 mM), but immunoreactive parathyroid hormone values were only slightly increased. The immunoreactive parathyroid hormone values of 153 and 173 nleq/ml (normal less than 150 nleq/ml) were far lower than expected in hyperparathyroid patients with a similar degree of hypercalcemia. As the patients became euthyroid during thionamide treatment, calcium values decreased to 1.39 and 1.61 mM, respectively, and parathyroid hormone increased to values clearly suggestive of hyperparathyroidism (454 and 229 nleq/ml, respectively). Parathyroidectomy and subtotal thyroidectomy cured both the hyperparathyroidism and the thyrotoxicosis in each case. These observations suggest that thyroid hormone had potentiated the osteoclastic effects of parathyroid hormone and that the resulting exacerbation of hypercalcemia had produced a relative suppression of hormone secretion by the abnormal parathyroid tissue. The occurrence of hypercalcemia in a thyrotoxic patient may present an interesting diagnostic problem. A high serum calcium value may be noted during the course of hyperthyroidism in as many as 22 percent of cases [ 1]. Excess thyroid hormone is thought to produce hypercalcemia and hypercalciuria by activating osteoclastic bone resorption [2]. The severity of hyperthyroidism correlates positively both with urinary hydroxyproline excretion [3] and with osteoclastic activity in trabecular and cortical bone [4]. Furthermore, thyroid hormone has been shown to increase the responsiveness of bone to administered parathyroid hormone [5], but whether endogenous parathyroid hormone plays a role in the exaggerated osteoclastic activity of hyperthyroidism remains controversial, since parathyroid hormone values have been reported to be elevated [6-8], diminished [4,9,10], or normal [1 1]. Primary hyperparathyroidism has also been reported in several hyperthyroid patients [8,12-31], but probably accounts for hypercalcemia in no more than 1 percent of thyrotoxic patients [32]. In such cases, however, it would be desirable to detect the parathyroid lesion before definitive therapy is chosen, since treatment of the thyroid disease with radioiodine might be deferred and neck surgery used to treat both diseases. We describe two patients with concomitant hyperparathyroidism and hyperthyroidism in whom serum free calcium levels, immunoreactive
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parathyroid hormone levels, and thyroid function were monitored during therapy with anti-thyroid medications. The data suggest that hyperthyroidism can exacerbate the hypercalcemia of primary hyperparathyroidism and thereby suppress immunoreactive parathyroid hormone levels. Treatment to lower free calcium levels may facilitate the diagnosis by increasing immunoreactive parathyroid hormone to a level more clearly indicating primary hyperparathyroidism. CASE REPORTS Patient 1. A 71-year-old black man was admitted because of dyspepsia and epigastric pain of six months' duration, not associated with hunger or relieved by food intake. He had lost 40 pounds over the previous six months, despite a good appetite. He was chronically constipated and had recently noted polydipsia, polyuria, and nocturia. He denied palpitations, dyspnea, nervousness, or heat intolerance. His medical record revealed that 38 and two months earlier, his serum calcium level had been 11.1 and 10.8 mg/dl, respectively. Hypertension diagnosed six years earlier was being treated with propranolol, 80 mg three times a day, hydrochlorothiazide, 50 mg daily, and hydralazine, 50 mg twice daily. He was an aesthenic black man weighing 176 pounds (ideal body weight 190 pounds). His blood pressure was 115/90 mm Hg, pulse 96 beats per minute and regular, respirations 14 per minute, and temperature 98.6°F orally. There was no band keratopathy. The thyroid was twice normal size, with a smooth surface and firm consistency. No bruit was appreciated. Results of chest, heart, and abdominal examinations were unremarkable. The proximal muscles were weak and tendon reflexes brisk. Laboratory values were as follows: serum sodium 149 meq/liter, potassium 3.7 meq/liter, chloride 107 meq/liter, bicarbonate 30 meq/liter, and creatinine 0.8 mg/dl; total serum calcium ranged from 11.3 to 11.8 mg/dl, with albumin 3.6 g/dl, phosphate 3.8 mg/dl, alkaline phosphatase 130 mlU/ml (normal less than 100 mlU/ml), bilirubin 0.7 mg/dl, serum glutamic oxaloacetic transaminase 30 mlU/ml (normal less than 40), serum glutamic pyruvic transaminase 33 mlU/ml (normal less than 40), lactic dehydrogenase 209 mlU/ml (normal less than 200), hematocrit 35.5 percent, serum thyroxine 29 #g/dl (normal 5 to 12), triiodothyronine resin uptake 44 percent (normal 25 to 35 percent), and free thyroxine 6.2 ng/ml (normal 0.7 to 2.3 ng/ml). Thyroidal radioactive iodine uptake was 17 percent at 24 hours, and thyroid scanning showed homogeneous uptake by a slightly enlarged gland. Because of the dyspepsia and anemia, esophagogastroscopy was performed, revealing multiple gastric polyps, which were removed. Findings on histologic examination were compatible with gastric hamartomas. The patient was treated with propranolol 80 mg and propylthiouraci1200 mg orally every eight hours and hydralazine, 50 mg orally twice a day. Hydrochlorothiazide was discontinued on admission, with no immediate change in serum calcium level. During the next several weeks, as his hyperthyroid state came under control, immunoreactive
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parathyroid hormone and free calcium values were monitored serially and are presented later. With treatment he gained weight progressively, and four months after initiation of the anti-thyroid therapy he was clinically and biochemically euthyroid. He then underwent subtotal thyroidectomy and parathyroid exploration, with excision of an adenoma of the right superior parathyroid gland. Histologically, the thyroid tissue was diffusely hyperplastic. Hypercalcemia has not recurred during two years of follow-up. Patient 2. A 59-year-old black man was admitted because of a 50-pound weight loss over the previous nine months, with anorexia, intermittent diarrhea, fever, and left upper quadrant discomfort. He had been admitted three months earlier for diverticulitis, which was treated with antibiotics. He denied insomnia, palpitations, heat intolerance, nervousness, or diaphoresis. Atrial fibrillation had been treated with digoxin 0.125 mg orally daily for the past year. Two years earlier, a multiphasic chemical determination during admission for a ruptured appendix had shown a serum calcium value of 11.0 mg/dl that was not evaluated. He was a thin black man weighing 124 pounds (ideal body weight 180 pounds). His blood pressure was 120/80 mm Hg, pulse 104 beats per minute and irregular, oral temperature 100°F, and respirations 18 per minute. The skin was warm and smooth with several areas of vitiligo on the abdnominal wall, and the hair was of fine texture. He displayed lid lag, but no exophthalmos. The thyroid gland was of normal size, with a firm consistency but no bruit. Results of chest and cardiovascular examinations were remarkable only for the irregular pulse. The abdomen was tender in the left upper quadrant. A fine tremor and hyperactive reflexes with a brisk relaxation phase were noted. Levels of serum electrolytes and creatinine were normal. Other values were as follows: total serum calcium 12.5 mg/dl, albumin 2.7 g/dl, phosphate 2.2 mg/dl, alkaline phosphatase 101 mlU/ml (normal less than 80 mlU/ml), serum glutamic oxaloacetic transaminase 17 mlU/ml (normal less than 40), serum glutamic pyruvic transaminase 26 mlU/ml (normal less than 40), lactic dehydrogenase 186 mlU/ml (normal less than 200), hematocrit 33.6 percent, serum thyroxine 16.5 #g/dl (normal 5 to 12), triiodothyronine resin uptake 39.9 percent (normal 25 to 35 percent), free thyroxine index 6.6 (normal 1.2 to 4.2), and free thyroxine 7.0 ng/ml (normal 0.7 to 2.3). The radioiodine uptake was 52.6 percent at 24 hours and thyroid scanning showed a normal-sized gland with homogeneous uptake. Ultrasound and gallium scanning suggested the presence of a left upper quadrant abdominal abscess. He was treated with propylthiouracil 100 mg orally every six hours and propranolo140 mg orally every eight hours, as well as with parenteral antibiotics. Free calcium and immunoreactive parathyroid hormone values during treatment are presented later. He became euthyroid within about three weeks and then underwent surgical drainage of the abdominal abscess. After three months of recuperation, he underwent subtotal thyroidectomy and parathyroid exploration. The right and left inferior parathyroid glands were grossly enlarged and were excised. Histologic examination revealed diffuse hyperplasia of both thyroid and parathyroid tissue. Postoperatively, the total calcium level fell to 8.7
INFLUENCE OF HYPERTHYROIDISMON PRIMARYHYPERPARATHYROIDISM--AREMET AL
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Figure 1. Ionized calcium (Ca++), immunoreactive parathyroid hormone (iPTH), and serum thyroxine ( T4) and triiodothyronine ( T3) values during therapy with propylthiouracil (PTU) in Patient 1. The time in weeks represents the time elapsed since initiation of therapy.
mg/dl and phosphorus level to 3 mg/dl with an albumin level of 3 g/dl. Two years later, he was asymptomatic and weighed 183 pounds. His serum calcium value was 10.1 mg/dl, albumin level 3.6 g/dl, and phosphorus level 4.0 mgldl. METHODS
Parathyroid hormone was measured with two different midregion-specific radioimmunoassay systems using goat antiserum to native human parathyroid hormone. The first employed anti-serum BG-6 with 1251-labeledbovine parathyroid hormone-(37-84) as radioligand [33]. This assay system has precisely the same performance characteristics as the previously described assay that used bovine parathyroid hormone-(41-84) as radioligand [34], except that the nonspecific binding value is lower, approximately 6 percent. The second assay system employed anti-serum NG-5 with radiolabeled tyr43-human parathyroid hormone-(44-68) as radioligand [35,36]. Crude human parathyroid hormone served as standard for each assay [34]. The concentration of the free calcium ion in serum was measured anaerobically by ion-selective electrode (Nova 2, Nova Biomedical, Newton, Massachusetts), as described [34].
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Serum immunoreactive parathyroid hormone and free calcium were measured in each patient at the time of initial diagnosis and during treatment with propylthiouracil. Values for immunoreactive parathyroid hormone, free calcium, thyroxine, and triiodothyronine as a function of time are given in Figure 1 and Table I. In Patient 1,
TABLE I
Laboratory Values before and after Three W e e k s of Propylthiouracil in Patient 2 Before After Therapy Therapy
Thyroxine (#g/dl) 16.5 Triiodothyronine resin uptake (percent) 39.9 Free thyroxine index 6.6 Total calcium (mg/dl) 12.5 Albumin (g/dl) 2.9 Free calcium (mM) 1.71 Immunoreactive parathyroid hormone (nleq/ml) 173
April 1986
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Volume80
10.8 25.9 2.8 11.7 2.6 1.61 229
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INFLUENCE OF HYPERTHYROIDISM ON PRIMARY HYPERPARATHYROIDISM--AREM ET AL
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Figure 2. Serum parathyroid hormone immunoreactivity in each of two patients with Graves' disease and concomitant primary hyperparathyroidism was measured serially with each of two radioimmunoassays and is plotted as a function of the simultaneous serum free calcium ion activity. The upper limits of normal for calcium ion a'ctivity and for immunoreactive parathyroid hormone (iPT~ in each assay are indicated by the vertical and horizontal lines, respectively. The curved line in the upper panel outlines the domain that contains data points from over 99 percent of patients with uncomplicated primary hyperparathyroidism. Numbers beside each symbol represent weeks of treatment with propylthiouracil.
thyroxine level declined progressively, from 29 to 7.6 #g/dl after 12 weeks of treatment, whereas triiodothyronine level fell from 509 to 169 ng/dl (Figure 1). Serum free calcium level was initially 1.61 mM (normal 1.11 to 1,28), but immunoreactive parathyroid hormone value was just at the upper limit of normal, 153 nleq/ml (normal less than 150). As the hyperthyroidism came under control, serum free calcium level progressively declined and immunoreactive parathyroid hormone value increased markedly, making the diagnosis of primary hyperparathyroidism clear. A similar sequence of events occurred in Patient 2 (Table I). After three weeks of treatment, serum immunoreactive parathyroid hormone level rose from 696
April 1986
173 to 229 nleq/ml, whereas free calcium level fell from 1.71 to 1.61 mM. In Figure 2, the serial changes in immunoreactive parathyroid hormone level are plotted as a function of the simultaneous free calcium value, in order to illustrate the reciprocal relationship between immunoreactive parathyroid hormone and free calcium and the manner in which the immunoreactive parathyroid hormone-free calcium points entered the domain for primary hyperparathyroidism after treatment had lowered free calcium level significantly. Values from the two parathyroid hormone assay systems were essentially parallel, demonstrating that the change in immunoreactive parathyroid hormone value was not an artifact of a single parathyroid hormone assay system.
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Hypercalcemia occurs in up to 22 percent of patients with hyperthyroidism [ 1]. In only a small percentage of cases is the hypercalcemia attributable to concomitant parathyroid disease [32]. The best laboratory clue to the presence of primary hyperparathyroidism has been the serum phosphate value, which tends to be high-normal in thyrotoxicosis [2], but tends to be decreased or low-normal in primary hyperparathyroidism. The phosphate value may, however, be misleading, as in our Patient 1. Because serum phosphate is subject to the influence of a number of factors including dietary phosphorus intake and intrinsic renal tubular function, a more direct measurement of parathyroid function would be desirable. The radioimmunoassay for parathyroid hormone unfortunately has given variable results in patients with uncomplicated thyrotoxicosis, with various groups reporting high [6-8], low [4,9,10], or normal [ i l ] values. We have Shown, however, that the results are highly dependent on the particular assay employed [37]. The new homologous, mid-region-specific assays used herein give lower mean irnmunoreactive parathyroid hormone values in patients With thyrotoxicosis than in normal subjects [37]. Although an increased clearance of biologically inactive parathyroid hormone fragments due to the thyrotoxic state could also lower immunoreactive parathyroid hormone values, we believe that the low values seen with this more sensitive assay probably reflect the true status of parathyroid function in uncomplicated thyrotoxicosis. On the aforementioned background, the borderline elevated parathyroid hormone levels in our two hypercalcemic patients did suggest increased parathyroid function. Renal insufficiency can elevate mid-region immunoreactive parathyroid hormone values in Subjects with nonparathyroid forms of hypercalcemia [34], but both of our subjects showed normal serum creatinine values. Since there is always the possibility of nonspecific effects on any peptide radioimmunoassay, and since radioactive iodine would otherwise have constituted adequate treatment, we were reluctant to recommend neck exploration
INFLUENCE OF HYPERTHYROIDISM ON PRIMARY HYPERPARATHYROIDISM--AREM ET AL
without stronger proof of excessive parathyroid function. The observation of reciprocal changes in immunoreactive parathyroid hormone values as free calcium levels fell allowed us to recommend surgery with confidence. The fact that the early immunoreactive parathyroid hormone values had apparently been suppressed by the high levels of serum calcium is analogous to the effect of calcium infusion, which has been shown to decrease immunoreactive parathyroid hormone values in most cases of primary hyperparathyroidism [38]. As free calcium levels declined, immunoreactive parathyroid hormone values began to increase markedly while free calcium levels were still far above normal, suggesting that the abnormal parathyroid tissue in our patients possessed an increased set-point for inhibition by calcium, as has been observed during studies of parathyroid adenomas in vitro [39]. The possibility should also be considered that changes in magnesium balance may have influenced the immunoreactive parathyroid hormone and free calcium changes during treatment. Severe magnesium depletion can inhibit parathyroid hormone secretion and lead to hypocalcemia, and repletion will increase immunoreactive parathyroid hormone and calcium levels [40]. Although serum magnesium was not measured in our patients, serum magnesium in thyrotoxicosis is not usually depressed to the very low levels needed to inhibit parathyroid hormone secretion [41]. Furthermore, if magnesium depletion did play a role in inhibiting our patients' immunoreactive parathyroid hormone secretion, the degree of their hypercalcemia should also have been lessened, and repletion of magnesium would have blunted the fall in free calcium levels while.also contributing to the increase in immunoreactive parathyroid hormone values. Measurements of serum magnesium will be needed to test these possibilities. Several authors have reported the coexistence of primary hyperparathyroidism and hyperthyroidism [8,12-31]. Some have suggested that it may occur more frequently than by chance alone [32] and that the parathyroid diSease might be produced by a long-standing effect of excess thyroid hormone on adrenergic receptors [7]. If this were the case, parathyroid hyperplasia should be almost universal in thyrotoxicosis, whereas the parathyroids are usually histologically normal [42]. Also, the acute increase in immunoreactive parathyroid hormone level in response to EDTA-induced hypocalcemia is blunted in thyrotoxic patients [32], and a decreased biologic effect of parathyroid hormone on the kidney is suggested by the
increased fractional renal calcium excretion [2]. The occurrence of primary hyperparathyroidism in thyrotoxicosis is, therefore, probably coincidental. It seems likely that the primary effect of thyrotoxicosis is to stimulate osteoclastic bone resorption [4,43], and that the resulting small increment in serum calcium level chronically tends to suppress parathyroid secretion. Overt hypercalcemia would then occur only in the most severe cases or when another factor, such as dehydration, immobilization, or hyperparathyroidism interfered with calcium clearance or further accelerated bone resorption. Correction of the thyrotoxicosis was probably the main factor that lowered serum calcium levels in these patients. In Patient 1, hydrochlorothiazide was discontinued upon admission, but without significant change in serum calcium level. In Patient 2, the introduction of propranolol may have contributed to the fall in calcium level, since the drug may sometimes lower calcium values in thyrotoxic patients [44], probably by inhibiting bone resorption [45]. Since thyroid hormone is not known to have direct effects on the intestinal or renal transport of calcium, the parallel fall in levels of serum calcium and thyroid hormones suggests that the excess thyroid hormone had been stimulating osteoclastic activity, either directly or by potentiating the effect of parathyroid hormone. Measurement of 1,25-dihydroxyvitamin D in future cases of concomitant primary hyperparathyroidism and thyrotoxicosis would be of interest. In uncomplicated thyrotoxicosis, 1,25-dihydroxyvitamin D levels are reduced [46] and intestinal calcium absorption is decreased [47], whereas hyperparathyroidism tends to increase both parameters. It is possible that the protective decrease in intestinal calcium absorption in thyrotoxicosis might be lost when primary hyperparathyroidism is also present. In summary, we have observed two patients with concomitant thyrotoxicosis and primary hyperparathyroidism. Treatment with thionamide led to a decrease in serum calcium levels, and an increase in immunoreactive parathyroid hormone to values that allowed a firm diagnosis of primary hyperparathyroidism. Surgical treatment corrected both diseases. ACKNOWLEDGMENT
Dr. R. McGregor kindly furnished bovine parathyroid hormone-(37-84) for use as radioligand. We would like to thank Mrs. Rosemary Telder for her secretarial assistance in the preparation of the manuscript.
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Baxter JD, Bondy PK: Hypercalcemia of thyrotoxicosis. Ann Intern Med 1966; 65: 429-442. Mosekilde L, Melsen F, Bagger JP, Myhre-Jensen O, Sorensen NS: Bone changes in hyperthyroidism: interrelationships between bone morphometry, thyroid function and calcium phosphorus metabolism, Acta Endocrinol 1977; 85: 515-525.
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