- Email: [email protected]
Normocalcemic hyperparathyroidism in patients with osteoporosis
Normocalcemic hyperparathyroidism in patients with osteoporosis Jack M. Monchik, MD, and Emre Gorgun, MD, Providence, RI
Background. Diagnosing primary hyperparathyroidism (PHP) in patients with osteoporosis is important because of the benefits of surgery. Screening patients with osteoporosis for PHP with only total serum calcium level will fail to diagnose PHP in patients with intermittent or no elevation of the total calcium level. Methods. This is a retrospective study of 140 patients who had a preoperative bone density study of the 223 patients who had surgery for PHP from January 1995 to June 1999. Normocalcemic hyperparathyroidism was defined as having all normal total calcium values or only intermittent elevation defined as at least 40% of the total calcium values in the normal range. Results. Osteoporosis was identified in 64 of these 140 patients (46%). Fifteen patients with osteoporosis and PHP had normocalcemic hyperparathyroidism. Six of these patients had all preoperative total calcium values in the normal range, and the remaining 9 patients had intermittent elevation of the total calcium. This group consisted of 12 women and 3 men aged 55 to 79 years. Forty-four concomitant ionized and total calcium values were available in the patients with all normal preoperative total serum calcium values. Forty-two serum ionized calcium values (95%) were elevated. Fifty-one concomitant values were available in the patients with intermittent elevation of the total calcium, and only 20 total calcium values (39%) were elevated and 47 of ionized values (92%) were elevated (P< .01). Intact parathyroid hormone was also significantly better than total calcium in identifying PHP. Twenty of 23 intact serum parathyroid hormone values (87%) were elevated (P< .05). Conclusions. Screening patients with osteoporosis for PHP with only total calcium levels will fail to identify patients with no elevation of total calcium level and many patients with only intermittent elevation of the total calcium level. Ionized calcium and intact parathyroid hormone were comparable and significantly better than total calcium level in the detection of PHP in patients with osteoporosis. Ionized calcium and intact parathyroid hormone should be used to diagnose hyperparathyroidism in patients with osteoporosis and normal serum total calcium levels. (Surgery 2004;136:1242-6.) From the Division of Endocrine Surgery, Rhode Island Hospital, and Brown University School of Medicine, Providence, RI
WIDESPREAD USE OF BONE DENSITY for screening postmenopausal women has resulted in the diagnosis of osteoporosis with increasing frequency. Previous studies from Rhode Island Hospital have identified an important group of symptomatic patients with primary hyperparathyroidism (PHP) with normal or only intermittent elevation of the total calcium.1,2 Most of these patients had renal calculi. This retrospective study assesses the role of ionized calcium and intact parathyroid hormone in the
Presented at the 25th Annual Meeting of the American Association of Endocrine Surgeons, Charlottesville, Virginia, April 4-6, 2004. Reprint requests: Jack M. Monchik, MD, Department of Surgery, Rhode Island Hospital, Brown University School of Medicine, 154 Waterman St, Providence, RI 02906. 0039-6060/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.surg.2004.06.052
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diagnosis of PHP in patients with osteoporosis who have no elevation of the total calcium or intermittent elevation of the total calcium. Intermittent elevation of the total calcium is defined as at least 40% of all preoperative total serum calcium values in the normal range. Normocalcemic hyperparathyroidism, for the purpose of this article, is defined as patients who have no elevation or only intermittent elevation of the total calcium.
PATIENTS AND METHODS From January 1995 to June 1999, 223 patients underwent parathyroid surgical procedures for PHP at the Rhode Island Hospital. There were 167 female and 56 male patients who ranged in age from 29 to 86 years. Patients with familial forms of hyperparathyroidism or renal failure were excluded. A preoperative bone density was available for 140 of these patients.
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Table I. Total preoperative serum calcium values categorized by normal, intermittent, or elevated in all patients with PHP Normal calcium (n) 22 (9%)
Intermittent calcium (n)*
Elevated calcium (n)
Total (n)
28 (12%)
173
223
*At least 40% of the serum total calcium values in the normal range.
Total and ionized calcium determinations were obtained by venipuncture without stasis into a 7-mL vacutainer tube. Samples were taken immediately to the laboratory, centrifuged, and stored anaerobically at 4°C. Serum total and ionized calcium values were determined within 24 hours. Samples from outpatients were obtained while the patient was seated. Total calcium concentration was measured by atomic absorption spectroscopy in serum that was diluted 1:50 with lanthanum by automatic diluter. The result was reported to the nearest 0.1 mg/dL. The normal range for total and ionized calcium at the Rhode Island Hospital are 8.5 to 10.5 mg/dL and 4.2 to 5.2 mg/dL, respectively. The reported ionized calcium values represent the mean of 2 determinations that agree within 0.6 mg/dL. A total of at least 3 concomitant preoperative serum ionized and total calcium values were available for each patient with minimal, intermittent or no elevation of the total calcium. All patients had at least 1 preoperative serum intact parathyroid hormone value. Intact parathyroid hormone level was measured by immunoradiometric assay with a kit supplied by the Nichols Institute for Endocrinology (San Pedro, Calif). The normal values with this assay are 12 to 65 mg/dL. The bone mineral density was performed with dual energy x-ray absorptiometry scan and expressed as grams per square centimeter. Comparison with a sex-matched young adults database is given as standard deviations from the mean, expressed as a T score. A T score between ÿ1.0 and ÿ2.5 is defined as osteopenia, and a score <ÿ2.5 is defined as osteoporosis. RESULTS The 223 patients who underwent parathyroid surgical procedures for PHP had a broad range of symptoms and/or hypercalcemia. Sixty-two of these patients (28%) had a history of at least 1 renal calculus. A preoperative bone density was available in 140 of the 223 patients; 64 of these patients were found to have osteoporosis. Intermittent or no elevation of the serum total calcium value was not uncommon. All 223 patients
who were categorized by preoperative total serum calcium values that were all in the normal range, intermittently elevated, or elevated are depicted in Table I. Fifty of the 223 patients had either all preoperative serum calcium values in the normal range or at least 40% of all total calcium values in the normal range. Fifteen of these 50 patients did not have a bone density scan; 3 patients had a normal bone density; 17 patients had osteopenia, and 15 patients had osteoporosis. These 15 patients with osteoporosis and normocalcemic hyperparathyroidism are the subject of this review. Six of these patients had all preoperative total values in the normal range. The remaining 9 patients had only intermittent elevation of the total calcium value. This group consisted of 12 female and 3 male patients who ranged in age from 55 to 79 years. Ten of these 12 female patients had osteoporosis that was found on a screening bone density. The remaining 2 female patients had muscle and bone pains and fatigue; osteoporosis was found as part of diagnostic studies for these symptoms. All 3 male patients with osteoporosis and normocalcemic hyperparathyroidism had at least 1 renal calculus, and osteoporosis was found in the course of the workup for hyperparathyroidism. Table II shows results of the bone density and the serum total calcium category of normal, intermittent, or elevated in the 140 patients who had a preoperative bone density. Eight of the 39 patients (20%) with osteopenia had all preoperative total calcium values in the normal range. Nine of the patients (23%) with osteopenia had only intermittent elevation of the total calcium. Fifteen of the 64 patients (23%) with osteoporosis had all normal or only intermittent elevation of the total calcium value. Therefore, 32 of the 103 patients (31%) with decreased bone density that was defined as osteopenia or osteoporosis had either all normal or only intermittent elevation of the serum total calcium value. A total of 95 concurrent preoperative measurements for total and ionized calcium were available in the 15 patients with osteoporosis. The 6 patients who had all preoperative normal total calcium values had a total of 44 concomitant ionized and total calcium values; ionized values in 42 patients (95%) were elevated. The remaining 9 patients with intermittent elevation of total calcium values had 51 concomitant ionized and total calcium values. Only 20 total calcium measurements (39%) were elevated, but 47 ionized values (92%) were elevated (P < .01). A total of 20 of the 23 preoperative intact parathyroid values (87%) in these patients were elevated. This is significantly greater than the
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Table II. Total serum calcium and bone densitometry results in the 140 patients who had a preoperative bone density Variable
Normal calcium (n)
Intermittent calcium (n)*
Elevated calcium (n)
Total (n)
Osteoporosis Osteopenia Normal bone density
6 (9%) 8 (20%) 2
9 (14%) 9(23%) 1
49 22 34
64 39 37
*At least 40% of the serum total calcium values in the normal range.
Table III. Age, sex, symptoms, disease, and weight of the hyperfunctional parathyroid glands in 15 patients with osteoporosis with normal or intermittent elevation of the total calcium Age
Sex
Symptom
Total calcium
Disease
Weight of gland (mg)
79 55 68 57
F F F M
Normal Normal Normal Normal
Adenoma Adenoma Adenoma Adenoma
360 126 110 98
77 79 75
F F M
Fatigue, peptic ulcer Osteoporosis, fatigue Osteoporosis Osteoporosis, renal calculus, bone pain Osteoporosis Osteoporosis Renal calculus, fatigue
Intermittent Intermittent Intermittent
64 63 73 76 74 58 55 64
M F F F F F F F
Renal calculus Osteoporosis Osteoporosis Osteoporosis Osteoporosis Osteoporosis Muscle aching, fatigue Osteoporosis
Intermittent Intermittent Intermittent Normal Normal Intermittent Intermittent Intermittent
Adenoma Adenoma First operation, Second operation Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma
154 222 810 200 784 760 510 439 660 730 440 715
M, Male; F, female.
number of elevated total calcium values (P < .05). Fourteen of these 15 patients had at least 1 elevated preoperative intact parathyroid hormone value. One of these patients had all intact parathyroid hormone values in the normal range. These values were 45, 48, and 61 mg/mL (normal, 12-65 mg/mL). This patient had a positive oral calcium loading test. The mean intact parathyroid hormone in the patients with all normal total calcium values was 87 mg/mL (range, 45-144 mg/mL). The mean intact parathyroid hormone value for patients with fluctuating total calcium values was 119 mg/mL (range, 67-385 mg/mL). This difference was not statistically significant. Dual energy x-ray absorptiometry scan of the hip and spine was performed in all 15 patients with osteoporosis and in the forearm in 3 patients. In these 15 patients, the T score was <ÿ2.5 in the spine and hip in 6 patients, in the hip only in 8 patients, and in the spine and forearm in 1 patient. All 15 patients underwent a bilateral exploration by 1 of the authors (J.M.M.). Fourteen patients were cured by resection of a single en-
larged parathyroid gland. Each of these patients had correction of their elevated ionized calcium. One patient demonstrated persistent elevation of serum ionized calcium and intact parathyroid hormone. This patient subsequently underwent a mediastinal exploration with resection of a second enlarged parathyroid gland, which resulted in the correction of the serum ionized calcium and intact parathyroid hormone values. The mean weight of the enlarged parathyroid glands in all 15 patients was 507 mg (range, 98-1440 mg). The mean weight of the enlarged parathyroid glands in the patients with all normal preoperative total calcium values was 228 mg (range, 98-660 mg). The mean weight of the enlarged parathyroid glands for the 9 patients with intermittent elevation of the total calcium value was 632 mg (range, 154-1440 mg). This difference in mean weight between the patients with all preoperative normal total calcium values and patients with intermittent value elevation was significant (P < .05). The age, sex, initial symptom, total calcium value, pathologic finding, and weight of the excised parathyroid glands are listed in Table III.
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DISCUSSION The increased use of bone density for screening postmenopausal women for osteoporosis has resulted in finding an increasing population of asymptomatic patients with osteoporosis. Twelve of these 15 individuals in this study with normocalcemic hyperparathyroidism and osteoporosis were postmenopausal women whose workup for hyperparathyroidism was initiated because of osteoporosis that was discovered on a routine bone density. The diagnosis of PHP should be pursued in patients with osteoporosis because of the favorable outcome of parathyroid surgery. Correction of PHP results in stoppage of the accelerated bone loss and a 8% and 6% increase in the lumbar spine and femoral neck, respectively, at 1 year and 12% and 14% at 10 years, respectively.3 A substantial increase in cortical bone and trabecular bone has been reported, which indicates that surgical correction of PHP involves a generalized increase in bone mass.4 One hundred forty of the total 223 patients (63%) who underwent parathyroid operation for PHP had a bone density. A substantial number of these patients (31%) had either osteopenia or osteoporosis and had either all normal or only intermittent elevation of the serum total calcium values. A single serum calcium determination, therefore, would fail to identify hyperparathyroidism in a significant number of these patients. This study showed no significant advantage of ionized calcium over intact parathyroid hormone in the diagnosis of hyperparathyroidism. Ionized calcium, however, is less expensive than intact parathyroid hormone. Subsequent experience in our hospital and by others have demonstrated that there is an increasing number of patients with symptomatic hyperparathyroidism with only an elevated intact parathyroid hormone level and no elevation of the total or ionized calcium concentration. Some symptomatic patients have normal ionized total calcium and intact parathyroid hormone but an inappropriate elevation of the intact parathyroid relative to the serum calcium concentration.5-8 The oral calcium loading study may be helpful in some patients who have no elevation of the ionized or total calcium and minimal or no elevation of the intact parathyroid hormone.9-11 The combination of an elevated total and/or ionized calcium concentration and intact parathyroid hormone is satisfactory to make the diagnosis of PHP. One must be cautious in making the diagnosis when only the intact parathyroid hormone level is elevated because this can be due
to other factors. Vitamin D deficiency (defined as a low serum 25-hydroxyvitamin D level), which is not uncommon in the northeastern part of the United States, can cause an elevated intact parathyroid hormone.12 Secondary factors that can cause an elevated intact parathyroid must be ruled out. These include familial hypocalciuric hypercalcemia, liver disease, renal disease, gastrointestinal malabsorption, or medications such as lithium or thiazide diuretics. Patients who were found to have osteoporosis by bone density scan should be evaluated for PHP. Screening these patients with only total calcium value will fail to identify patients with no elevation of the total calcium value and a substantial proportion of patients with intermittent elevation of the total calcium value. Intact parathyroid hormone level is more specific and was comparable to ionized calcium values in the diagnosis of hyperparathyroidism in this study. This study suggests that both ionized calcium and intact parathyroid hormone should be used to minimize the risk of missing the diagnosis of PHP in patients with osteoporosis.
REFERENCES 1. Monchik JM, Martin HF. Ionized calcium in the diagnosis of primary hyperparathyroidism. Surgery 1980;82:185-92. 2. McLeod MK, Monchik JM, Martin HF. The role of ionized calcium in the diagnosis of subtle hypercalcemia in symptomatic primary hyperparathyroidism. Surgery 1984;95: 667-73. 3. Silverberg SJ, Shane E, Jacobs TP, Bilezikian JP. A ten-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249-55. 4. Abugassa S, Nordenstrom J, Eriksson S, Mollerstrom G, Alveryd A. Skeletal remineralization after surgery for primary and secondary hyperparathyroidism. Surgery 1990;107:128-33. 5. Marvani G, Hertig A, Paillard M, Houillier P. Normocalcemic hyperparathyroidism: evidence for a generalized targettissue resistance to parathyroid hormone. J Clin Endocrinol Metab 2003;88:4641-8. 6. Muldowney FP, Freaney R, McMullin JP, Towers RP, Spillane A, O’Connor P, et al. Serum ionized calcium and parathyroid hormone in renal stone disease. Q J Med 1976;45:75-86. 7. Silverberg SJ, Bilezikian JP. ‘‘Incipient’’ primary hyperparathyroidism: a ‘‘forme fruste’’ of an old disease. J Clin Endocrinol Metab 2003;88:5348-52. 8. Glendenning P, Gutteridge DH, Retallack RW, Stuckey BG, Kermode DG, Keating GN. High prevalence of normal total calcium and intact PTH in 60 patients with proven primary hyperparathyroidism. Aust N Z J Med 1998;2:173-8. 9. McHenry CR, Rosen IB, Walfish PG, Pollard A. Oral calcium load test: diagnostic and physiologic implications in hyperparathyroidism. Surgery 1990;108:1026-32. 10. Broadus AE, Horst RI, Littledike FT, Mahaffey JE, Rasmussen H. Primary hyperparathyroidism with intermittent hypercalcemia: serial observation and simple diagnosis by means of an oral calcium tolerance test. Clin Endocrinol 1980;12:225-35.
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11. Monchik JM, Lamberton RP, Roth U. Role of the oral calcium loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. Surgery 1992;112:1103-10. 12. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy adults. Am J Med 2002;112:659-62.
DISCUSSION Dr Rick J. Schmidt (Safety Harbor, Fla). The osteoporotic patient who is sent to your office with an intact parathyroid hormone level that is mildly elevated and an ionized calcium concentration that is a high normal (let’s say it is 5), how do you handle that patient? In other words, the patient in whom you can never document an elevated calcium or elevated ionized calcium concentration, but their elevated intact PTH level was picked up when the battery of tests for osteoporosis was sent. Dr Monchik. Most of the patients you describe do not have hyperparathyroidism. Many of these patients will have vitamin D deficiency. Vitamin D deficiency is not uncommon in patients who live in the Northeastern part of the United States or in other areas that have reduced sunlight exposure. You should measure the 25 vitamin D level, and if this is low the patient should be treated with vitamin D, which will result in the correction of the elevated serum intact parathyroid hormone. The other causes of an elevated serum intact parathyroid hormone noted in the paper should be ruled out. The oral calcium loading study may be helpful in cases with minimal or no elevation of the serum ionized or total calcium. Dr Richard A. Prinz (Chicago, Ill). I had a little difficulty understanding your paper because you did not give us any absolute values for total calcium or ionized calcium concentration or the ranges that were involved. Hopefully, that information is in the article because it is necessary to allow us to interpret your findings. Is there a level of total calcium at which you can say the patient does not have hyperparathyroidism? What are you recommending as the evaluation for hyperparathyroidism in patients with osteoporosis? Should we be getting an intact parathyroid hormone value on all these patients? Do we really need an ionized calcium concentration? What are your recommendations? Dr Monchik. There is no clearly defined level of total calcium that one could state that the patient does not have PHP. I have had patients who have had some of their preoperative total calcium values in the mid to high 8 mg/dL range. Patients who have osteoporosis and elevated total calcium levels only need an elevated intact parathyroid hormone to confirm the diagnosis. Patients who have osteoporosis and a normal total calcium level should have both an intact parathyroid hormone and ionized calcium. I would suggest 3 consecutive days of concomitant ionized and total calcium levels (fasting) and an intact parathyroid hormone on 1 of these days. Dr Gary B. Talpos (Detroit, Mich). We have used corrected calcium levels and ionized calcium levels for years and think that this is very, very important in
Surgery December 2004
diagnosing PHP. I have a question about the other patients. Most adults, including a lot of us in this room, do not have the recommended dietary calcium intake every day. Half of my patients are black and frequently lactose intolerant because they lose their lactose enzyme at an earlier age. These individuals have nutritional hyperparathyroidism, and I see a few people every month who are sent for surgical procedures who have an elevated PTH and borderline calcium level because they do not have enough dietary calcium. As you know, the condition responds to oral calcium and vitamin D. Surgery is not necessary. How long do you follow those people when you put them on vitamin D and calcium therapy? Do you have a protocol for these patients? Dr Monchik. The endocrinologist at our institution would treat patients with an elevated serum intact parathyroid hormone level and normal total calcium and vitamin D deficiency with 50,000 units of vitamin D every 2 weeks and oral calcium supplementation of 1000 mg of elemental calcium. The intact parathyroid hormone would again be determined in 2 to 3 months. Dr Roger John Tabah (Montreal, Quebec, Canada). A question to Dr. Monchik and maybe the audience. Why are we still measuring total calcium levels when we know that ionized calcium is the business end both in diagnosing mild PHP and in following patients who are hypocalcemic after the operation. Dr Monchik. Ionized calcium is the biologically active component of the serum calcium. The measurement of the serum ionized calcium, however, is not necessary in the diagnosis of PHP when the total calcium level is elevated. The important role of ionized calcium is as a screening test for patients who demonstrate complications of hyperparathyroidism. Our initial studies with ionized calcium identified a group of patients with PHP who had recurrent renal calculi. These patients had only an occasional or no elevation of the total calcium. The patients in the current study had osteoporosis. Patients with renal calculi or osteoporosis should be screened for hyperparathyroidism. I would suggest screening with 3 consecutive days of ionized and total calcium and on 1 of these days a serum intact parathyroid hormone. This will identify most patients with hyperparathyroidism. The measurement of ionized calcium is more difficult than total calcium, and it is therefore important to use a laboratory that frequently performs this study. There would be no additional benefit in using ionized calcium to follow postoperative patients who are hypercalcemic as determined by the serum total calcium level. Dr Geoffrey B. Thompson (Rochester, Minn). The overwhelming majority of your patients had a single adenomas. How many of those patients had preoperative sestamibi scans, and of those, how many results were positive? Dr Monchik. Sestamibi was not used routinely in the period of this study, which was 1995 to 1999; a bilateral exploration procedure was done in all of these patients. Only 3 patients had a preoperative sestamibi study, which correctly identified the site of the adenoma in 2 of 3 patients.
Background. Diagnosing primary hyperparathyroidism (PHP) in patients with osteoporosis is important because of the benefits of surgery. Screening patients with osteoporosis for PHP with only total serum calcium level will fail to diagnose PHP in patients with intermittent or no elevation of the total calcium level. Methods. This is a retrospective study of 140 patients who had a preoperative bone density study of the 223 patients who had surgery for PHP from January 1995 to June 1999. Normocalcemic hyperparathyroidism was defined as having all normal total calcium values or only intermittent elevation defined as at least 40% of the total calcium values in the normal range. Results. Osteoporosis was identified in 64 of these 140 patients (46%). Fifteen patients with osteoporosis and PHP had normocalcemic hyperparathyroidism. Six of these patients had all preoperative total calcium values in the normal range, and the remaining 9 patients had intermittent elevation of the total calcium. This group consisted of 12 women and 3 men aged 55 to 79 years. Forty-four concomitant ionized and total calcium values were available in the patients with all normal preoperative total serum calcium values. Forty-two serum ionized calcium values (95%) were elevated. Fifty-one concomitant values were available in the patients with intermittent elevation of the total calcium, and only 20 total calcium values (39%) were elevated and 47 of ionized values (92%) were elevated (P< .01). Intact parathyroid hormone was also significantly better than total calcium in identifying PHP. Twenty of 23 intact serum parathyroid hormone values (87%) were elevated (P< .05). Conclusions. Screening patients with osteoporosis for PHP with only total calcium levels will fail to identify patients with no elevation of total calcium level and many patients with only intermittent elevation of the total calcium level. Ionized calcium and intact parathyroid hormone were comparable and significantly better than total calcium level in the detection of PHP in patients with osteoporosis. Ionized calcium and intact parathyroid hormone should be used to diagnose hyperparathyroidism in patients with osteoporosis and normal serum total calcium levels. (Surgery 2004;136:1242-6.) From the Division of Endocrine Surgery, Rhode Island Hospital, and Brown University School of Medicine, Providence, RI
WIDESPREAD USE OF BONE DENSITY for screening postmenopausal women has resulted in the diagnosis of osteoporosis with increasing frequency. Previous studies from Rhode Island Hospital have identified an important group of symptomatic patients with primary hyperparathyroidism (PHP) with normal or only intermittent elevation of the total calcium.1,2 Most of these patients had renal calculi. This retrospective study assesses the role of ionized calcium and intact parathyroid hormone in the
Presented at the 25th Annual Meeting of the American Association of Endocrine Surgeons, Charlottesville, Virginia, April 4-6, 2004. Reprint requests: Jack M. Monchik, MD, Department of Surgery, Rhode Island Hospital, Brown University School of Medicine, 154 Waterman St, Providence, RI 02906. 0039-6060/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.surg.2004.06.052
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diagnosis of PHP in patients with osteoporosis who have no elevation of the total calcium or intermittent elevation of the total calcium. Intermittent elevation of the total calcium is defined as at least 40% of all preoperative total serum calcium values in the normal range. Normocalcemic hyperparathyroidism, for the purpose of this article, is defined as patients who have no elevation or only intermittent elevation of the total calcium.
PATIENTS AND METHODS From January 1995 to June 1999, 223 patients underwent parathyroid surgical procedures for PHP at the Rhode Island Hospital. There were 167 female and 56 male patients who ranged in age from 29 to 86 years. Patients with familial forms of hyperparathyroidism or renal failure were excluded. A preoperative bone density was available for 140 of these patients.
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Table I. Total preoperative serum calcium values categorized by normal, intermittent, or elevated in all patients with PHP Normal calcium (n) 22 (9%)
Intermittent calcium (n)*
Elevated calcium (n)
Total (n)
28 (12%)
173
223
*At least 40% of the serum total calcium values in the normal range.
Total and ionized calcium determinations were obtained by venipuncture without stasis into a 7-mL vacutainer tube. Samples were taken immediately to the laboratory, centrifuged, and stored anaerobically at 4°C. Serum total and ionized calcium values were determined within 24 hours. Samples from outpatients were obtained while the patient was seated. Total calcium concentration was measured by atomic absorption spectroscopy in serum that was diluted 1:50 with lanthanum by automatic diluter. The result was reported to the nearest 0.1 mg/dL. The normal range for total and ionized calcium at the Rhode Island Hospital are 8.5 to 10.5 mg/dL and 4.2 to 5.2 mg/dL, respectively. The reported ionized calcium values represent the mean of 2 determinations that agree within 0.6 mg/dL. A total of at least 3 concomitant preoperative serum ionized and total calcium values were available for each patient with minimal, intermittent or no elevation of the total calcium. All patients had at least 1 preoperative serum intact parathyroid hormone value. Intact parathyroid hormone level was measured by immunoradiometric assay with a kit supplied by the Nichols Institute for Endocrinology (San Pedro, Calif). The normal values with this assay are 12 to 65 mg/dL. The bone mineral density was performed with dual energy x-ray absorptiometry scan and expressed as grams per square centimeter. Comparison with a sex-matched young adults database is given as standard deviations from the mean, expressed as a T score. A T score between ÿ1.0 and ÿ2.5 is defined as osteopenia, and a score <ÿ2.5 is defined as osteoporosis. RESULTS The 223 patients who underwent parathyroid surgical procedures for PHP had a broad range of symptoms and/or hypercalcemia. Sixty-two of these patients (28%) had a history of at least 1 renal calculus. A preoperative bone density was available in 140 of the 223 patients; 64 of these patients were found to have osteoporosis. Intermittent or no elevation of the serum total calcium value was not uncommon. All 223 patients
who were categorized by preoperative total serum calcium values that were all in the normal range, intermittently elevated, or elevated are depicted in Table I. Fifty of the 223 patients had either all preoperative serum calcium values in the normal range or at least 40% of all total calcium values in the normal range. Fifteen of these 50 patients did not have a bone density scan; 3 patients had a normal bone density; 17 patients had osteopenia, and 15 patients had osteoporosis. These 15 patients with osteoporosis and normocalcemic hyperparathyroidism are the subject of this review. Six of these patients had all preoperative total values in the normal range. The remaining 9 patients had only intermittent elevation of the total calcium value. This group consisted of 12 female and 3 male patients who ranged in age from 55 to 79 years. Ten of these 12 female patients had osteoporosis that was found on a screening bone density. The remaining 2 female patients had muscle and bone pains and fatigue; osteoporosis was found as part of diagnostic studies for these symptoms. All 3 male patients with osteoporosis and normocalcemic hyperparathyroidism had at least 1 renal calculus, and osteoporosis was found in the course of the workup for hyperparathyroidism. Table II shows results of the bone density and the serum total calcium category of normal, intermittent, or elevated in the 140 patients who had a preoperative bone density. Eight of the 39 patients (20%) with osteopenia had all preoperative total calcium values in the normal range. Nine of the patients (23%) with osteopenia had only intermittent elevation of the total calcium. Fifteen of the 64 patients (23%) with osteoporosis had all normal or only intermittent elevation of the total calcium value. Therefore, 32 of the 103 patients (31%) with decreased bone density that was defined as osteopenia or osteoporosis had either all normal or only intermittent elevation of the serum total calcium value. A total of 95 concurrent preoperative measurements for total and ionized calcium were available in the 15 patients with osteoporosis. The 6 patients who had all preoperative normal total calcium values had a total of 44 concomitant ionized and total calcium values; ionized values in 42 patients (95%) were elevated. The remaining 9 patients with intermittent elevation of total calcium values had 51 concomitant ionized and total calcium values. Only 20 total calcium measurements (39%) were elevated, but 47 ionized values (92%) were elevated (P < .01). A total of 20 of the 23 preoperative intact parathyroid values (87%) in these patients were elevated. This is significantly greater than the
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Table II. Total serum calcium and bone densitometry results in the 140 patients who had a preoperative bone density Variable
Normal calcium (n)
Intermittent calcium (n)*
Elevated calcium (n)
Total (n)
Osteoporosis Osteopenia Normal bone density
6 (9%) 8 (20%) 2
9 (14%) 9(23%) 1
49 22 34
64 39 37
*At least 40% of the serum total calcium values in the normal range.
Table III. Age, sex, symptoms, disease, and weight of the hyperfunctional parathyroid glands in 15 patients with osteoporosis with normal or intermittent elevation of the total calcium Age
Sex
Symptom
Total calcium
Disease
Weight of gland (mg)
79 55 68 57
F F F M
Normal Normal Normal Normal
Adenoma Adenoma Adenoma Adenoma
360 126 110 98
77 79 75
F F M
Fatigue, peptic ulcer Osteoporosis, fatigue Osteoporosis Osteoporosis, renal calculus, bone pain Osteoporosis Osteoporosis Renal calculus, fatigue
Intermittent Intermittent Intermittent
64 63 73 76 74 58 55 64
M F F F F F F F
Renal calculus Osteoporosis Osteoporosis Osteoporosis Osteoporosis Osteoporosis Muscle aching, fatigue Osteoporosis
Intermittent Intermittent Intermittent Normal Normal Intermittent Intermittent Intermittent
Adenoma Adenoma First operation, Second operation Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma
154 222 810 200 784 760 510 439 660 730 440 715
M, Male; F, female.
number of elevated total calcium values (P < .05). Fourteen of these 15 patients had at least 1 elevated preoperative intact parathyroid hormone value. One of these patients had all intact parathyroid hormone values in the normal range. These values were 45, 48, and 61 mg/mL (normal, 12-65 mg/mL). This patient had a positive oral calcium loading test. The mean intact parathyroid hormone in the patients with all normal total calcium values was 87 mg/mL (range, 45-144 mg/mL). The mean intact parathyroid hormone value for patients with fluctuating total calcium values was 119 mg/mL (range, 67-385 mg/mL). This difference was not statistically significant. Dual energy x-ray absorptiometry scan of the hip and spine was performed in all 15 patients with osteoporosis and in the forearm in 3 patients. In these 15 patients, the T score was <ÿ2.5 in the spine and hip in 6 patients, in the hip only in 8 patients, and in the spine and forearm in 1 patient. All 15 patients underwent a bilateral exploration by 1 of the authors (J.M.M.). Fourteen patients were cured by resection of a single en-
larged parathyroid gland. Each of these patients had correction of their elevated ionized calcium. One patient demonstrated persistent elevation of serum ionized calcium and intact parathyroid hormone. This patient subsequently underwent a mediastinal exploration with resection of a second enlarged parathyroid gland, which resulted in the correction of the serum ionized calcium and intact parathyroid hormone values. The mean weight of the enlarged parathyroid glands in all 15 patients was 507 mg (range, 98-1440 mg). The mean weight of the enlarged parathyroid glands in the patients with all normal preoperative total calcium values was 228 mg (range, 98-660 mg). The mean weight of the enlarged parathyroid glands for the 9 patients with intermittent elevation of the total calcium value was 632 mg (range, 154-1440 mg). This difference in mean weight between the patients with all preoperative normal total calcium values and patients with intermittent value elevation was significant (P < .05). The age, sex, initial symptom, total calcium value, pathologic finding, and weight of the excised parathyroid glands are listed in Table III.
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Surgery Volume 136, Number 6
DISCUSSION The increased use of bone density for screening postmenopausal women for osteoporosis has resulted in finding an increasing population of asymptomatic patients with osteoporosis. Twelve of these 15 individuals in this study with normocalcemic hyperparathyroidism and osteoporosis were postmenopausal women whose workup for hyperparathyroidism was initiated because of osteoporosis that was discovered on a routine bone density. The diagnosis of PHP should be pursued in patients with osteoporosis because of the favorable outcome of parathyroid surgery. Correction of PHP results in stoppage of the accelerated bone loss and a 8% and 6% increase in the lumbar spine and femoral neck, respectively, at 1 year and 12% and 14% at 10 years, respectively.3 A substantial increase in cortical bone and trabecular bone has been reported, which indicates that surgical correction of PHP involves a generalized increase in bone mass.4 One hundred forty of the total 223 patients (63%) who underwent parathyroid operation for PHP had a bone density. A substantial number of these patients (31%) had either osteopenia or osteoporosis and had either all normal or only intermittent elevation of the serum total calcium values. A single serum calcium determination, therefore, would fail to identify hyperparathyroidism in a significant number of these patients. This study showed no significant advantage of ionized calcium over intact parathyroid hormone in the diagnosis of hyperparathyroidism. Ionized calcium, however, is less expensive than intact parathyroid hormone. Subsequent experience in our hospital and by others have demonstrated that there is an increasing number of patients with symptomatic hyperparathyroidism with only an elevated intact parathyroid hormone level and no elevation of the total or ionized calcium concentration. Some symptomatic patients have normal ionized total calcium and intact parathyroid hormone but an inappropriate elevation of the intact parathyroid relative to the serum calcium concentration.5-8 The oral calcium loading study may be helpful in some patients who have no elevation of the ionized or total calcium and minimal or no elevation of the intact parathyroid hormone.9-11 The combination of an elevated total and/or ionized calcium concentration and intact parathyroid hormone is satisfactory to make the diagnosis of PHP. One must be cautious in making the diagnosis when only the intact parathyroid hormone level is elevated because this can be due
to other factors. Vitamin D deficiency (defined as a low serum 25-hydroxyvitamin D level), which is not uncommon in the northeastern part of the United States, can cause an elevated intact parathyroid hormone.12 Secondary factors that can cause an elevated intact parathyroid must be ruled out. These include familial hypocalciuric hypercalcemia, liver disease, renal disease, gastrointestinal malabsorption, or medications such as lithium or thiazide diuretics. Patients who were found to have osteoporosis by bone density scan should be evaluated for PHP. Screening these patients with only total calcium value will fail to identify patients with no elevation of the total calcium value and a substantial proportion of patients with intermittent elevation of the total calcium value. Intact parathyroid hormone level is more specific and was comparable to ionized calcium values in the diagnosis of hyperparathyroidism in this study. This study suggests that both ionized calcium and intact parathyroid hormone should be used to minimize the risk of missing the diagnosis of PHP in patients with osteoporosis.
REFERENCES 1. Monchik JM, Martin HF. Ionized calcium in the diagnosis of primary hyperparathyroidism. Surgery 1980;82:185-92. 2. McLeod MK, Monchik JM, Martin HF. The role of ionized calcium in the diagnosis of subtle hypercalcemia in symptomatic primary hyperparathyroidism. Surgery 1984;95: 667-73. 3. Silverberg SJ, Shane E, Jacobs TP, Bilezikian JP. A ten-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249-55. 4. Abugassa S, Nordenstrom J, Eriksson S, Mollerstrom G, Alveryd A. Skeletal remineralization after surgery for primary and secondary hyperparathyroidism. Surgery 1990;107:128-33. 5. Marvani G, Hertig A, Paillard M, Houillier P. Normocalcemic hyperparathyroidism: evidence for a generalized targettissue resistance to parathyroid hormone. J Clin Endocrinol Metab 2003;88:4641-8. 6. Muldowney FP, Freaney R, McMullin JP, Towers RP, Spillane A, O’Connor P, et al. Serum ionized calcium and parathyroid hormone in renal stone disease. Q J Med 1976;45:75-86. 7. Silverberg SJ, Bilezikian JP. ‘‘Incipient’’ primary hyperparathyroidism: a ‘‘forme fruste’’ of an old disease. J Clin Endocrinol Metab 2003;88:5348-52. 8. Glendenning P, Gutteridge DH, Retallack RW, Stuckey BG, Kermode DG, Keating GN. High prevalence of normal total calcium and intact PTH in 60 patients with proven primary hyperparathyroidism. Aust N Z J Med 1998;2:173-8. 9. McHenry CR, Rosen IB, Walfish PG, Pollard A. Oral calcium load test: diagnostic and physiologic implications in hyperparathyroidism. Surgery 1990;108:1026-32. 10. Broadus AE, Horst RI, Littledike FT, Mahaffey JE, Rasmussen H. Primary hyperparathyroidism with intermittent hypercalcemia: serial observation and simple diagnosis by means of an oral calcium tolerance test. Clin Endocrinol 1980;12:225-35.
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11. Monchik JM, Lamberton RP, Roth U. Role of the oral calcium loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. Surgery 1992;112:1103-10. 12. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy adults. Am J Med 2002;112:659-62.
DISCUSSION Dr Rick J. Schmidt (Safety Harbor, Fla). The osteoporotic patient who is sent to your office with an intact parathyroid hormone level that is mildly elevated and an ionized calcium concentration that is a high normal (let’s say it is 5), how do you handle that patient? In other words, the patient in whom you can never document an elevated calcium or elevated ionized calcium concentration, but their elevated intact PTH level was picked up when the battery of tests for osteoporosis was sent. Dr Monchik. Most of the patients you describe do not have hyperparathyroidism. Many of these patients will have vitamin D deficiency. Vitamin D deficiency is not uncommon in patients who live in the Northeastern part of the United States or in other areas that have reduced sunlight exposure. You should measure the 25 vitamin D level, and if this is low the patient should be treated with vitamin D, which will result in the correction of the elevated serum intact parathyroid hormone. The other causes of an elevated serum intact parathyroid hormone noted in the paper should be ruled out. The oral calcium loading study may be helpful in cases with minimal or no elevation of the serum ionized or total calcium. Dr Richard A. Prinz (Chicago, Ill). I had a little difficulty understanding your paper because you did not give us any absolute values for total calcium or ionized calcium concentration or the ranges that were involved. Hopefully, that information is in the article because it is necessary to allow us to interpret your findings. Is there a level of total calcium at which you can say the patient does not have hyperparathyroidism? What are you recommending as the evaluation for hyperparathyroidism in patients with osteoporosis? Should we be getting an intact parathyroid hormone value on all these patients? Do we really need an ionized calcium concentration? What are your recommendations? Dr Monchik. There is no clearly defined level of total calcium that one could state that the patient does not have PHP. I have had patients who have had some of their preoperative total calcium values in the mid to high 8 mg/dL range. Patients who have osteoporosis and elevated total calcium levels only need an elevated intact parathyroid hormone to confirm the diagnosis. Patients who have osteoporosis and a normal total calcium level should have both an intact parathyroid hormone and ionized calcium. I would suggest 3 consecutive days of concomitant ionized and total calcium levels (fasting) and an intact parathyroid hormone on 1 of these days. Dr Gary B. Talpos (Detroit, Mich). We have used corrected calcium levels and ionized calcium levels for years and think that this is very, very important in
Surgery December 2004
diagnosing PHP. I have a question about the other patients. Most adults, including a lot of us in this room, do not have the recommended dietary calcium intake every day. Half of my patients are black and frequently lactose intolerant because they lose their lactose enzyme at an earlier age. These individuals have nutritional hyperparathyroidism, and I see a few people every month who are sent for surgical procedures who have an elevated PTH and borderline calcium level because they do not have enough dietary calcium. As you know, the condition responds to oral calcium and vitamin D. Surgery is not necessary. How long do you follow those people when you put them on vitamin D and calcium therapy? Do you have a protocol for these patients? Dr Monchik. The endocrinologist at our institution would treat patients with an elevated serum intact parathyroid hormone level and normal total calcium and vitamin D deficiency with 50,000 units of vitamin D every 2 weeks and oral calcium supplementation of 1000 mg of elemental calcium. The intact parathyroid hormone would again be determined in 2 to 3 months. Dr Roger John Tabah (Montreal, Quebec, Canada). A question to Dr. Monchik and maybe the audience. Why are we still measuring total calcium levels when we know that ionized calcium is the business end both in diagnosing mild PHP and in following patients who are hypocalcemic after the operation. Dr Monchik. Ionized calcium is the biologically active component of the serum calcium. The measurement of the serum ionized calcium, however, is not necessary in the diagnosis of PHP when the total calcium level is elevated. The important role of ionized calcium is as a screening test for patients who demonstrate complications of hyperparathyroidism. Our initial studies with ionized calcium identified a group of patients with PHP who had recurrent renal calculi. These patients had only an occasional or no elevation of the total calcium. The patients in the current study had osteoporosis. Patients with renal calculi or osteoporosis should be screened for hyperparathyroidism. I would suggest screening with 3 consecutive days of ionized and total calcium and on 1 of these days a serum intact parathyroid hormone. This will identify most patients with hyperparathyroidism. The measurement of ionized calcium is more difficult than total calcium, and it is therefore important to use a laboratory that frequently performs this study. There would be no additional benefit in using ionized calcium to follow postoperative patients who are hypercalcemic as determined by the serum total calcium level. Dr Geoffrey B. Thompson (Rochester, Minn). The overwhelming majority of your patients had a single adenomas. How many of those patients had preoperative sestamibi scans, and of those, how many results were positive? Dr Monchik. Sestamibi was not used routinely in the period of this study, which was 1995 to 1999; a bilateral exploration procedure was done in all of these patients. Only 3 patients had a preoperative sestamibi study, which correctly identified the site of the adenoma in 2 of 3 patients.