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A 64-Year-Old Woman With Primary Hyperparathyroidism

A 64-Year-Old Woman With Primary Hyperparathyroidism DR BURNS: Ms Q is a 64-year-old woman with a history of mild hypercalcemia and hyperparathyroidism. She has managed care insurance. Ms Q states that on a routine blood test 7 years ago she was noted to have a calcium level of 10.1 mg/dL (2.5 mmol/L). She has subsequently had her calcium checked on a biannual basis and it has ranged from 10.4 to 11.3 mg/dL (2.6-2.8 mmol/L). Ms Q was referred to an endocrinologist in December 2002 after her calcium was higher than 11 mg/dL (2.7 mmol/L) on 3 occasions. Her laboratory studies just prior to her visit revealed a calcium level of 11.1 mg/dL (2.8 mmol/L), a parathyroid hormone (PTH) level of 102 pg/mL, and a phosphate level of 3.4 mg/dL. At the time of her visit, she reported a history of constipation since childhood with no recent change. She denied any history of cancer, thyroid disease, parathyroid disease, or radiation to her neck. She had never had any fractures and had no history of renal stones. She denied having any depression, anxiety, or mood swings. She reported lactose intolerance, although she was able to eat 1 serving of cheese daily. She did not take calcium, vitamin D, or any other supplements. She was postmenopausal and had not been taking hormone therapy. She is married and has 3 children who are alive and well. She has never smoked cigarettes and drinks alcohol socially. She otherwise reported that she felt well and had no complaints. She had a normal bone density in May 2000 (T-score: −0.88 spine and −0.09 total hip). Her only current medication was lorazepam for long-standing insomnia. She has no known drug allergies. On physical examination her thyroid gland was normal. She was believed to have primary hyperparathyroidism. Her physician’s plan was to exclude other causes of hyperparathyroidism, to repeat her bone mineral density (BMD) test, and to obtain a sestamibi scan of her parathyroid glands to localize a possible parathyroid adenoma. She returned for follow-up 6 months later. She continued to feel well. Her calcium level was 10.4 mg/dL (2.6 mmol/L) with an albumin level of 4.1 g/dL, phosphate level of 3.4 mg/dL, and a PTH level of 101 pg/mL. Her creatinine clearance was 81 mL/min (1.3 mL/s). A 24-hour urine calcium measurement was 226 mg. Her thyrotropin level was 1.4 mIU/mL and her 25-hydroxyvitamin D level was 27 ng/mL (67.4 nmol/L). Her bone density had decreased by 7.3% at the spine and 5.2% at the femoral neck. She underwent a sestamibi scan of the neck that revealed slightly increased uptake in the lower pole of the thyroid bilaterally. Ms Q was believed to have mild primary hyperparathyroidism. Ms Q was referred to a parathyroid surgeon for consideration of a parathyroidectomy. Ms Q is uncertain how to proceed. She feels well and would like to avoid a surgical procedure. She wonders whether there are any alternatives to surgery and what factors would necessitate her having to have a surgical procedure. Ms q: her view I was aware that there was a problem perhaps 6 or 7 years ago. I was at a spa and had a routine blood check and I had a calcium level of about 10.1. Before that I didn’t even realize I had a problem. From that time until perhaps a year ago, I just had annual blood checks. In the past year I went to see an endocrinologist. The endocrinologist suggested that I could possibly have surgery or I could wait. I have friends who have had parathyroid surgery, and I’d like to know what is the determining factor—whether it’s your calcium level or other deciding factors. I would prefer not to have surgery unless it’s absolutely necessary. If there is a medical way to treat this I would certainly prefer that. My ideal solution to this would be if I could take some kind of medication to lower my blood calcium. Either that, or if the calcium stays within a range that’s safe, then I just watch it going forward, because it doesn’t seem to be advancing very quickly. It just seems to be a very, very slow process. I would like to ask that there be a conclusion to the issue, whether I need surgery or I don’t need surgery, and perhaps through further discussion and examination this can be determined. At the crossroads: questions for dr strewler What is the epidemiology and underlying pathophysiology of hypercalcemia? What evaluation should be performed for a patient with hypercalcemia? What are the end-organ effects of primary hyperparathyroidism? What medical treatment options are available and how effective are they? When should a patient be referred to a surgeon and what are the surgical treatment options? What are the current clinical guidelines for treatment of primary hyperparathyroidism? What do you recommend for Ms Q? DR STREWLER: Ms Q, who presents for consideration of parathyroidectomy after a 7-year history of mild hypercalcemia, clearly has primary hyperparathyroidism. She was suspected of having progressive disease, because her serum calcium level was higher than 11.0 mg/dL on 3 consecutive occasions over an 18-month period, but 6 months after her referral to an endocrinologist for treatment consideration, her serum calcium had returned to 10.4 mg/dL (institutional normal range, 8.4-10.2 mg/dL). She is relatively asymptomatic and is uncertain about the benefits and risks of parathyroid surgery. Epidemiology and Pathophysiology Ms Q is typical of patients who present with primary hyperparathyroidism in the United States. Although there are no population-based data on the prevalence of the disease in North America, the estimate from a clinical series was about 1 per 1000,1 and the prevalence is highest in postmenopausal women. Although 2% to 10% of patients present with renal stone disease,2 most are identified by multiphasic screening of the serum calcium level2,3 and have no symptoms specifically referable to primary hyperparathyroidism. Hyperparathyroidism in all its forms is characterized by an increase in the set point for serum calcium; this resetting of the sensitivity of the parathyroid gland to calcium leads to regulation of the serum calcium at a level above the normal range (Figure 1A).4,5Quiz Ref IDParathyroid hormone increases the serum calcium level by actions at all 3 of the interfaces of the extracellular fluid —the bone, the gut, and the kidney. The level of calcium in serum is set primarily by control of calcium fluxes between bone and the extracellular fluid (rather than by osteoclastic bone resorption), and PTH shifts these fluxes by a poorly understood mechanism.6 However, the level of hypercalcemia is influenced by calcium absorption from the diet, which can increase in primary hyperparathyroidism because of increased 1,25-dihydroxyvitamin D levels and by enhanced renal reabsorption of calcium. Evaluation There is almost no doubt that Ms Q has hyperparathyroidism because she has an inappropriately elevated level of PTH in the presence of hypercalcemia.7-9 In all forms of nonparathyroid hypercalcemia (Box 1), PTH is suppressed. This means that only measurement of calcium, phosphate, creatinine, and PTH is necessary to make the diagnosis of primary hyperparathyroidism. Serum 25-hydroxyvitamin D should be measured as well to exclude vitamin D deficiency, which can exacerbate hyperparathyroidism while blunting hypercalcemia because of impaired absorption of calcium from the diet.9 Box 1. Differential Diagnosis of Hypercalcemia Primary hyperparathyroidism and variants  Sporadic primary hyperparathyroidism  Familial primary hyperparathyroidism   Associated with multiple endocrine neoplasia type 1 (MEN-1)   Associated with multiple endocrine neoplasia type 2A (MEN-2A)  Familial benign hypocalciuric hypercalcemia  Tertiary hyperparathyroidism   In chronic renal failure   After renal transplantation  Associated with lithium therapy Malignancy-associated hypercalcemia Sarcoidosis and other granulomatous diseases Endocrinopathies  Thyrotoxicosis  Adrenal insufficiency  Pheochromocytoma  Vasoactive intestinal peptide-producing tumor (VIPoma) Immobilization-associated Milk-alkali syndrome Vitamin D intoxication Vitamin A intoxication Acute renal failure Ms Q has either primary hyperparathyroidism or one of its variants. In familial benign hypocalciuric hypercalcemia (FBHH), a mutation in the parathyroid calcium receptor reduces the sensitivity of the gland to calcium and thereby increases the set point for serum calcium (Figure 1A).10,11 The resultant hypercalcemia is lifelong and asymptomatic, PTH levels are in the normal range, urinary calcium excretion is typically decreased (because the receptor also sets the level of calcium reabsorption in the renal tubule), and 50% of first-degree relatives are hypercalcemic. Ms Q had a previously normal serum calcium level and has a relatively high normal urinary calcium, excluding FBHH in her case. Primary hyperparathyroidism also occurs as part of the familial syndrome multiple endocrine neoplasia type 1 (MEN-1) and more rarely in other familial endocrine tumor syndromes.12 Lithium treatment causes hypercalcemia by shifting the set point for PTH secretion to the right and may be viewed as a phenocopy of FBHH.13-15 There is no accepted medical treatment of primary hyperparathyroidism but it generally can be cured surgically. It is not clear whether every patient with the diagnosis requires surgery, however, and Ms Q presents the typical therapeutic dilemma. To make an evidence-based recommendation to her for surgery or observation, several questions must be answered.9 What are the end-organ effects of primary hyperparathyroidism? Is the disorder or its effects likely to be progressive? What are the risks of surgery and how can they be minimized? Does surgery often improve the general well-being of a patient without obvious manifestations of hyperparathyroidism? End-Organ Effects Quiz Ref IDBone is one of the classic target organs of PTH. Severe hyperparathyroid bone disease, osteitis fibrosa cystica, is rarely seen in the United States today, but osteoporosis is common in primary hyperparathyroidism.16-18 Cortical bone is lost preferentially because of endocortical bone resorption and intracortical tunneling, and BMD is consequently lowest at predominately cortical sites in the skeleton, such as the forearm. Trabecular bone (eg, in the lumbar spine) is relatively preserved, despite rates of bone turnover several times normal. The reasons for preservation of trabecular bone mass have been studied by quantitative histomorphometry of bone biopsies from hyperparathyroid patients.19-21 Resorption pits in primary hyperparathyroidism are frequent but relatively shallow and can be completely filled by new bone formation so that trabecular architecture is preserved. Primary hyperparathyroidism is probably associated with a relatively small increased risk of forearm and spine fractures, although not all studies agree.22-24 The stimulation of new bone formation by PTH is useful therapeutically. When PTH is administered once daily by subcutaneous injection, there is active bone formation with less bone resorption and net accretion of bone occurs. Bone mass and bone strength are increased, most strikingly in cancellous bone, and osteoporotic fractures are prevented.25 The synthetic PTH fragment teriparatide was approved for treatment of osteoporosis in 2002 and is the first anabolic agent available for the disorder. Quiz Ref IDPrimary hyperparathyroidism causes nephrolithiasis and occasionally nephrocalcinosis and progressive renal insufficiency. To assess for clinically significant end-organ effects of primary hyperparathyroidism, it is reasonable to measure serum creatinine, alkaline phosphatase, urinary calcium, and BMD and to obtain an abdominal film to identify asymptomatic urolithiasis. Fatigue, weakness, depression, and memory problems are common complaints in patients referred for treatment of primary hyperparathyroidism,26 but it has been difficult to ascertain whether these nonspecific symptoms are caused by hyperparathyroidism. Two recent studies in which the outcome of parathyroidectomy was compared with the outcome of thyroid surgery suggest an improvement in fatigue, but both lacked objective measures using well-defined instruments.27,28 In the only randomized trial of parathyroid surgery, involving 53 patients, there was a postoperative difference in annual change in 2 of the 9 domains of the 36-Item Short Form Health Survey (SF-36), social functioning and emotional role functioning.29 The difference resulted from a decline in function in the control group rather than an increase in surgically treated patients. Several European studies have found an adverse effect of primary hyperparathyroidism on mortality, largely attributable to excess mortality from cardiovascular disease.30-33 Mortality was increased both in a population-based survey of hypercalcemic patients30 and in long-term postoperative follow-up of more than 13 300 patients.31-33 A population-based case-control study in Rochester, Minn, did not confirm an adverse effect of primary hyperparathyroidism onoverall mortality.2 Comparison of the populations studied suggests that hyperparathyroidism was more severe in the European countries, and in some studies mortality was correlated with the level of serum calcium. Consistent with this trend, increased mortality was observed in the upper quartile of serum calcium (>11.2 mg/dL [2.8 mmol/L]) in the Rochester study.23 The pathophysiological basis of these observations is not understood.26 Hypertension is more prevalent in primary hyperparathyroidism than matched controls,34 although it is not clear whether hypertension responds to surgery.35 Left ventricular hypertrophy and myocardial and valvular calcifications are reported in primary hyperparathyroidism,36,37 and cardiovascular disease is accelerated in patients with severe secondary hyperparathyroidism as a complication of chronic renal failure.38 In addition, many of the molecular features of vascular calcification and bone formation are similar.39 Natural History and Pathogenesis Primary hyperparathyroidism does not progress in most patients. In 10-year prospective studies,16,40 serum calcium and PTH levels were stable in most patients, and serum creatinine and BMD did not change. Four percent of patients had substantial worsening of hypercalcemia, 15% developed marked hypercalciuria (>400 mg/24 h), and 12% had progressive declines in BMD to a predetermined threshold for surgery (z -score less than −2.0). It is unclear whether Ms Q has progressed significantly. She appears to have had a slight upward trend in the serum calcium level, but the most recent result was barely above the upper limit of normal. She has had a significant decline in BMD but remains above the mean for her age with a T-score of −1.5. Her renal function is normal for her age. The stability of primary hyperparathyroidism in most cases is surprising, considering the neoplastic nature of the disorder. About 90% of cases result from a parathyroid adenoma; most of the remainder have hyperplasia of all 4 parathyroid glands. (Parathyroid carcinoma is rare and presents with severe and progressive hypercalcemia, so it is unlikely in Ms Q.) The pathogenesis of parathyroid adenomas is similar to that of other tumors: an oncogenic mutation provides a growth advantage to a clone of cells that gradually expands to become a tumor. Overexpression of the cell cycle regulator cyclin D1 is found in 20% to 40% of sporadic parathyroid adenomas41,42; loss of function of the MEN1 tumor suppressor gene (the gene that is mutated in MEN-1) accounts for an additional 15% to 20%43-45; and inactivation of HRPT2, the gene implicated in the hereditary hypercalcemia-jaw tumor syndrome, occurs in rare cystic parathyroid adenomas.46 Why do these tumors stop growing47 despite mutations that abrogate growth control? As proposed by Parfitt,48 this behavior can be explained by a set point hypothesis. An increase in the set point for secretion of PTH is characteristic of most parathyroid adenomas,49,50 that is, secretion of PTH from tumors can be suppressed by calcium, but it requires more calcium to suppress adenomatous than normal glands. It is hypothesized that parathyroid adenomas typically grow until the serum calcium reaches the set point for secretion of PTH, then essentially stop growing (Figure 1B). Thus, the negative growth influence of ambient calcium concentrations above the set point dominates the control of parathyroid cell growth, even when the cells have a fundamental abnormality of growth control. If correct, the set point hypothesis has an important potential implication for medical therapy of hyperparathyroidism: drugs such as bisphosphonates, which reduce the serum calcium level by inhibiting bone resorption, may cause not only increased secretion of PTH, but also enlargement of the parathyroid adenoma, once they lower the serum calcium level below the set point.51 Medical Treatment Options Estrogens and bisphosphonates have been used as medical treatments for primary hyperparathyroidism.51 Treatment with high estrogen doses modestly reduces the serum calcium level, averaging 0.5 mg/dL (0.12 mmol/L).52,53 The dose of conjugated equine estrogen that is required averages 1.25 mg,52 and treatment with 0.625 mg does not consistently lower the serum calcium level, although bone remodeling is slowed.54 Parathyroid hormone levels do not change, suggesting that the predominant effect of estrogen is on bone resorption, rather than secretion of PTH. In view of the adverse effects of combined estrogen-progesterone treatment on breast cancer risk and cardiovascular disease,55 the use of estrogens cannot be recommended for Ms Q or most other postmenopausal women. Bisphosphonates inhibit osteoclastic bone resorption. They have little benefit for control of hypercalcemia in primary hyperparathyroidism,56-59 probably because PTH secretion tends to rise as bone resorption falls to maintain the serum calcium level at its high set point. However, alendronate treatment for 24 months significantly improves BMD and reduces bone turnover57-60 and may be useful in patients with osteoporosis who are not surgical candidates. Whether long-term bisphosphonate treatment will eventually lead to enlargement of parathyroid tumors and worsening of hyperparathyroidism remains to be determined. Quiz Ref IDCalcimimetic agents, a new class of drugs, provide the first effective medical therapy for primary hyperparathyroidism.51,61 They increase the sensitivity of the parathyroid calcium receptor to calcium and thereby reduce the set point for the serum calcium.62 Calcimimetic treatment prevents the development of secondary hyperparathyroidism in animal models of chronic renal failure63,64 and reduces PTH and calcium levels in patients with chronic renal insufficiency.65,66 In a 1-year randomized placebo-controlled trial in 78 patients, cinacalcet reduced serum calcium levels by at least 0.5 mg/dL (0.12 mmol/L) to a level of 103 mg/dL (2.57 mmol/L) or below in 73% of patients without serious adverse events.67 In theory, a reduction in the set point for serum calcium might permit involution of parathyroid glands, but a calcimimetic closely related to cinacalcet was ineffective in reducing gland size in a model of established secondary hyperparathyroidism,68 although it prevented the development of parathyroid hyperplasia when used early in the course of disease.63 It thus might be speculated that, used in a patient like Ms Q, cinacalcet would provide chronic control of hypercalcemia but would induce involution of a parathyroid adenoma slowly, if at all. Patients should take in 700 to 1400 mg of calcium daily. Calcium restriction is not advisable and may worsen hyperparathyroidism. Vitamin D–deficient patients can be supplemented with vitamin D, 400 to 800 U daily.9 While at one time vitamin D repletion was believed to exacerbate hypercalcemia, a recent study in 21 patients suggests that vitamin D repletion in patients with mild hypercalcemia (calcium level <12 mg/dL [3 mmol/L]) does not exacerbate hypercalcemia and may decrease PTH and bone turnover.69 Surgical Treatment Options As John Doppman quipped in the 1990 Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism,70 the greatest challenge in preoperative localization of a parathyroid adenoma is locating an experienced surgeon. A skilled parathyroid surgeon will cure hyperparathyroidism in more than 95% of cases, even without resorting to modern localizing techniques. The standard procedure is a bilateral neck exploration; the aim is to identify an enlarged parathyroid gland and at least 1 normal gland. The latter is important because parathyroid hyperplasia—hyperparathyroidism associated with enlargement of all 4 parathyroid glands—occurs in about 10% of cases; hence, the first enlarged gland the surgeon encounters may not be an isolated adenoma. Surgical complications of laryngeal paralysis and hypoparathyroidism are uncommon in skilled hands but are correlated with the experience of the surgeon. In a survey of members of the American Association of Endocrine Surgeons, the major complication rate was 3.76% for surgeons who perform fewer than 15 cases annually, compared with 1.48% for surgeons who perform more than 50 parathyroidectomies per year.71 A new technique, minimally invasive parathyroidectomy, uses a combination of preoperative localization and intraoperative strategies to directly guide the exploration for an adenoma.72,73 Scanning with 99technicium Tc-99m–labeled sestamibi (Figure 2) using single-photon emission computed tomography localizes a parathyroid adenoma in 60% to 89% of cases, depending on the skill of the center.74,75 If an adenoma is localized preoperatively, a limited incision is made under regional or general anesthesia and the adenoma is identified. Rapid intraoperative assay of PTH can be used to confirm that resection of an adenoma has removed the source of PTH.76-78Quiz Ref IDMinimally invasive parathyroidectomy reduces morbidity, saves operating room time, and, if performed under regional anesthesia, can markedly reduce hospital stay and cost, particularly if it eliminates an overnight stay.79 It is not clear that success rates are improved or complications averted. Surgical treatment of primary hyperparathyroidism reduces the postoperative incidence of renal stones by about 90%.80,81 Bone mineral density improves markedly, with sustained increases of more than 10% at 10 years at the lumbar spine and hip and smaller gains at the radius.16 Nonspecific symptoms may improve.27-29 The objective outcomes of surgery are not controversial, but how minimally symptomatic patients should be selected for surgery has been, leading to the development of clinical practice guidelines. Clinical Treatment Guidelines A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases in 2002 asked a panel of experts to review and update previous clinical guidelines from 199070 for treatment of asymptomatic primary hyperparathyroidism. Their recommendations are summarized in Box 282,83 and a brief summary of the evidence base is presented below. Box 2. Treatment of Asymptomatic Primary Hyperparathyroidism: Recommendations of 2002 National Institutes of Health Workshop Surgery was recommended for patients with the following:  Serum calcium >1 mg/dL (0.25 mmol/L) above upper limit of normal  Urinary calcium excretion >400 mg/24 h  Impaired renal function (creatinine clearance reduced by 30% from age-matched healthy patients)  T-score less than −2.5 (matching the World Health Organization definition of osteoporosis)  Age younger than 50 years  Follow-up likely to be unreliable The panel favored surgery in patients with serum calcium levels more than 1 mg/dL (0.25 mmol/L) above the upper limit of normal, which is lower than the previous threshold of serum calcium (>1-1.6 mg/dL [0.25-0.40 mmol/L] higher than normal). The intuitive notion that severe hyperparathyroidism is more likely to progress is buttressed by studies indicating that the level of serum calcium is a determinant of progressive decline in BMD16 or of mortality,2,31 but there is no firm evidence base for choosing either the previous threshold or the new one. Surgery was recommended for patients with urinary calcium excretion greater than 400 mg/24 h. There is no direct evidence of a relationship between hypercalciuria and stone formation in primary hyperparathyroidism, and urinary calcium is a poor predictor of stone risk in patients who have not previously formed stones.84 The threshold level of urinary calcium that was defined by the consensus panel is not sex- or race-specific, even though men excrete 25% to 30% more urinary calcium than women, and whites excrete 20% to 25% more calcium than blacks, but 400 mg/d is set well above the upper limit of normal. Impaired renal function (creatinine clearance 30% less than age-matched healthy patients) was also considered an indication for surgery. Primary hyperparathyroidism leads to progressive nephron loss in some individuals.16,40 Renal insufficiency from other causes would increase calcium handling per nephron and could thereby predispose to renal damage from hyperparathyroidism, but there is no evidence this occurs. In some patients, primary hyperparathyroidism leads to progressive bone loss. The panel recommended that surgery be considered when the T-score is less than −2.5 (matching the World Health Organization definition of osteoporosis). This is a change from the previous recommendation of a Z-score threshold of less than −2. A T-score of less than −2.5 is an accepted threshold to treat for fracture prevention in osteoporosis, although there is no evidence that the relationship of BMD and fracture risk is the same in primary hyperparathyroidism and osteoporosis. Surgery was recommended in patients younger than 50 years. The evidence for this recommendation is not substantial, but there is evidence that premenopausal women who are not treated through menopause have an increased risk of losing BMD.16 In practice, endocrine surgeons tend to be more aggressive than the guidelines recommend in older asymptomatic patients but somewhat reluctant to operate based on age alone.71 Finally, the panel recommended that patients who might not be reliable for follow-up for the possible future development of complications undergo parathyroidectomy. This reasonable recommendation is not evidence-based. Recommendations for ms q Ms Q has asymptomatic hyperparathyroidism. According to the current guidelines, she does not have an indication for parathyroidectomy. I am concerned, however, that 2 aspects of her case suggest that she may be one of the approximately 25% of women who progress: there are suggestions both of increasing hypercalcemia compared with 7 years ago and of declining BMD. I would obtain a baseline abdominal film to rule out asymptomatic calcium urolithiasis. If that is negative, I recommend that medical follow-up be continued for 1 to 2 years because the patient needs to gain confidence about surgery and because the data on progression are inconclusive. She should have twice-yearly determinations of serum calcium and creatinine levels, and a BMD test should be repeated annually. If the apparent decline in BMD is confirmed or if calcium levels rise, I would recommend surgery. I would not wait until she is frankly osteoporotic, per the clinical practice guidelines, because it seems clear (although the guidelines do not explicitly address this point) that patients who have disease progression are in a poor prognostic group for whom surgical intervention is appropriate. Questions and comment A PHYSICIAN: Ms Q seems to be asymptomatic, but don’t asymptomatic patients come back and volunteer improvement in energy level and cognitive function? Do you believe there can be an improvement? DR STREWLER: There are patients who feel unexpectedly better after parathyroidectomy. They tell the internist and the surgeon, “I never knew what feeling good was until I had this operation.” The problem is that one can’t pick them out prospectively, and it’s therefore hard to recommend surgery solely on that basis. A PHYSICIAN: My question relates to the assumption that the effect of hyperparathyroidism on mortality is due to calcium. Is it possible that there is another action of parathyroid hormone that is unrelated to calcium and that perhaps has to do with mortality? DR STREWLER: I think hypercalcemia in these patients may be a marker for the severity of hyperparathyroidism. In secondary hyperparathyroidism, there is a clear association with cardiovascular mortality. There is every reason to imagine that parathyroid hormone turns on a program of gene expression in the cells of the vascular wall that produces a predisposition to coronary disease and stroke. A PHYSICIAN: Should Ms Q be offered alendronate? DR STREWLER: Ms Q has mild osteopenia at age 64. Alendronate would prevent rapid bone loss due to hyperparathyroidism, but it would not control her hypercalcemia and it could worsen her hyperparathyroidism. If she has continued loss of bone mass, then parathyroidectomy would be a much more effective treatment for her osteoporosis than a bisphosphonate like alendronate. MS Q: Would you recommend that I wait for this new medication to come on the scene and take that? DR STREWLER: Cinacalcet was approved for the treatment of secondary hyperparathyroidism in chronic renal failure, but little information is available about its long-term safety and efficacy in primary hyperparathyroidism. If there is a clear indication to treat your hyperparathyroidism, I would recommend surgery as a curative treatment. Back to top Article Information Corresponding Author: Gordon J. Strewler, MD, Tosteson Medical Education Center, Harvard Medical School, 260 Longwood Ave, Room 232A, Boston, MA 02115 (gordon_strewler@hms.harvard.edu). Financial Disclosure: Dr Strewler is a consultant to Abgenix Inc, manufacturer of a new drug for treatment of hyperparathyroidism that is in clinical trials in patients with secondary hyperparathyroidism. Funding/Support: This Clinical Crossroads is made possible in part by a grant from The Florence and Richard Koplow Charitable Foundation. 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Neer RM, Arnaud CD, Zanchetta JR. et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434-144111346808Google ScholarCrossref 26. Silverberg SJ. Non-classical target organs in primary hyperparathyroidism. J Bone Miner Res. 2002;17:(suppl 2) N117-N12512412788Google Scholar 27. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: a case-control study. Ann Surg. 1995;222:402-4127677469Google ScholarCrossref 28. Pasieka JL, Parsons LL. Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg. 1998;22:513-5189597921Google ScholarCrossref 29. Talpos GB, Bone HG III, Kleerekoper M. et al. Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey. Surgery. 2000;128:1013-102011114637Google ScholarCrossref 30. Lundgren E, Lind L, Palmer M, Jakobsson S, Ljunghall S, Rastad J. Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years. Surgery. 2001;130:978-98511742326Google ScholarCrossref 31. Hedback G, Oden A. Increased risk of death from primary hyperparathyroidism–an update. Eur J Clin Invest. 1998;28:271-2769615902Google ScholarCrossref 32. Walgenbach S, Hommel G, Junginger T. Outcome after surgery for primary hyperparathyroidism: ten-year prospective follow-up study. World J Surg. 2000;24:564-56910787077Google ScholarCrossref 33. Nilsson IL, Yin L, Lundgren E, Rastad J, Ekbom A. Clinical presentation of primary hyperparathyroidism in Europe–nationwide cohort analysis on mortality from nonmalignant causes. J Bone Miner Res. 2002;17:(suppl 2) N68-N7412412780Google Scholar 34. Nainby-Luxmoore JC, Langford HG, Nelson NC, Watson RL, Barnes TY. A case-comparison study of hypertension and hyperparathyroidism. J Clin Endocrinol Metab. 1982;55:303-3067085856Google ScholarCrossref 35. Bradley EL III, Wells JO. Primary hyperparathyroidism and hypertension. Am Surg. 1983;49:569-5706638692Google Scholar 36. Stefenelli T, Mayr H, Bergler-Klein J, Globits S, Woloszczuk W, Niederle B. Primary hyperparathyroidism: incidence of cardiac abnormalities and partial reversibility after successful parathyroidectomy. Am J Med. 1993;95:197-2028356983Google ScholarCrossref 37. Stefenelli T, Abela C, Frank H. et al. Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up. J Clin Endocrinol Metab. 1997;82:106-1128989242Google ScholarCrossref 38. Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int. 2001;60:472-47911473629Google ScholarCrossref 39. Bostrom K, Demer LL. Regulatory mechanisms in vascular calcification. Crit Rev Eukaryot Gene Expr. 2000;10:151-15811186330Google ScholarCrossref 40. Scholz DA, Purnell DC. Asymptomatic primary hyperparathyroidism: 10-year prospective study. Mayo Clin Proc. 1981;56:473-4787266058Google Scholar 41. Hemmer S, Wasenius VM, Haglund C. et al. Deletion of 11q23 and cyclin D1 overexpression are frequent aberrations in parathyroid adenomas. Am J Pathol. 2001;158:1355-136211290553Google ScholarCrossref 42. Hsi ED, Zukerberg LR, Yang WI, Arnold A. Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study. J Clin Endocrinol Metab. 1996;81:1736-17398626826Google ScholarCrossref 43. Heppner C, Kester MB, Agarwal SK. et al. Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Genet. 1997;16:375-3789241276Google ScholarCrossref 44. Carling T, Correa P, Hessman O. et al. Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. J Clin Endocrinol Metab. 1998;83:2960-29639709976Google ScholarCrossref 45. Farnebo F, Teh BT, Kytola S. et al. Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab. 1998;83:2627-26309709922Google ScholarCrossref 46. Carpten JD, Robbins CM, Villablanca A. et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet. 2002;32:676-68012434154Google ScholarCrossref 47. Parfitt AM, Wang Q, Palnitkar S. Rates of cell proliferation in adenomatous, suppressed, and normal parathyroid tissue: implications for pathogenesis. J Clin Endocrinol Metab. 1998;83:863-8699506741Google ScholarCrossref 48. Parfitt AM. Parathyroid growth: normal and abnormal. In: Bilezikian JP, Marcus R, Levine MA, eds. The Parathyroids: Basic and Clinical Concepts. San Diego, Calif: Academic Press; 2001:293-329 49. Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab. 1983;56:572-5816822654Google ScholarCrossref 50. Brown EM, MacLeod RJ. Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev. 2001;81:239-29711152759Google Scholar 51. Strewler GJ. Medical approaches to primary hyperparathyroidism. Endocrinol Metab Clin North Am. 2000;29:523-53911033759Google ScholarCrossref 52. Marcus R, Madvig P, Crim M, Pont A, Kosek J. Conjugated estrogens in the treatment of postmenopausal women with hyperparathyroidism. Ann Intern Med. 1984;100:633-6406324624Google ScholarCrossref 53. Selby PL, Peacock M. Ethinyl estradiol and norethindrone in the treatment of primary hyperparathyroidism in postmenopausal women. N Engl J Med. 1986;314:1481-14853754618Google ScholarCrossref 54. Grey AB, Stapleton JP, Evans MC, Tatnell MA, Reid IR. Effect of hormone replacement therapy on bone mineral density in postmenopausal women with mild primary hyperparathyroidism: a randomized, controlled trial. Ann Intern Med. 1996;125:360-3688702086Google ScholarCrossref 55. Rossouw JE, Anderson GL, Prentice RL. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33312117397Google ScholarCrossref 56. Reasner CA, Stone MD, Hosking DJ, Ballah A, Mundy GR. Acute changes in calcium homeostasis during treatment of primary hyperparathyroidism with risedronate. J Clin Endocrinol Metab. 1993;77:1067-10718408454Google ScholarCrossref 57. Chow CC, Chan WB, Li JK. et al. Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab. 2003;88:581-58712574184Google ScholarCrossref 58. Parker CR, Blackwell PJ, Fairbairn KJ, Hosking DJ. Alendronate in the treatment of primary hyperparathyroid-related osteoporosis: a 2-year study. J Clin Endocrinol Metab. 2002;87:4482-448912364423Google ScholarCrossref 59. Rossini M, Gatti D, Isaia G, Sartori L, Braga V, Adami S. Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism. J Bone Miner Res. 2001;16:113-11911149474Google ScholarCrossref 60. Khan AA, Bilezikian JP, Kung AW. et al. Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2004;89:3319-332515240609Google ScholarCrossref 61. Antoniucci DM, Shoback D. Calcimimetics in the treatment of primary hyperparathyroidism. J Bone Miner Res. 2002;17:(suppl 2) N141-N14512412791Google Scholar 62. Nemeth EF, Steffey ME, Hammerland LG. et al. Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci U S A. 1998;95:4040-40459520489Google ScholarCrossref 63. Wada M, Nagano N, Furuya Y, Chin J, Nemeth EF, Fox J. Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism. Kidney Int. 2000;57:50-5810620187Google ScholarCrossref 64. Wada M, Nagano N. Control of parathyroid cell growth by calcimimetics. Nephrol Dial Transplant. 2003;18:(suppl 3) iii13-iii1712771292Google Scholar 65. Quarles LD, Sherrard DJ, Adler S. et al. The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol. 2003;14:575-58312595492Google ScholarCrossref 66. Goodman WG. Calcimimetic agents and secondary hyperparathyroidism: rationale for use and results from clinical trials. Pediatr Nephrol. 2003;18:1206-121014586685Google ScholarCrossref 67. Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2005;90:135-14115522938Google ScholarCrossref 68. Chin J, Miller SC, Wada M, Nagano N, Nemeth EF, Fox J. Activation of the calcium receptor by a calcimimetic compound halts the progression of secondary hyperparathyroidism in uremic rats. J Am Soc Nephrol. 2000;11:903-91110770968Google Scholar 69. Grey A, Lucas J, Horne A, Gamble G, Davidson JS, Reid IR. Vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency. J Clin Endocrinol Metab. doi:10.210/jc2004-1772. Published online January 11, 2005. Accessed March 16, 2005 70. Proceedings of the NIH Consensus Development Conference on diagnosis and management of asymptomatic primary hyperparathyroidism, Bethesda, Maryland, October 29-31, 1990. J Bone Miner Res. 1991;6:(suppl 2) S1-S1661763659Google ScholarCrossref 71. Sosa JA, Powe NR, Levine MA, Udelsman R, Zeiger MA. Profile of a clinical practice: thresholds for surgery and surgical outcomes for patients with primary hyperparathyroidism: a national survey of endocrine surgeons. J Clin Endocrinol Metab. 1998;83:2658-26659709928Google ScholarCrossref 72. Udelsman R. Surgery in primary hyperparathyroidism: the patient without previous neck surgery. J Bone Miner Res. 2002;17:(suppl 2) N126-N13212412789Google Scholar 73. Sosa JA, Udelsman R. Minimally invasive parathyroidectomy. Surg Oncol. 2003;12:125-13412946483Google ScholarCrossref 74. Civelek AC, Ozalp E, Donovan P, Udelsman R. Prospective evaluation of delayed technetium-99m sestamibi SPECT scintigraphy for preoperative localization of primary hyperparathyroidism. Surgery. 2002;131:149-15711854692Google ScholarCrossref 75. Denham DW, Norman J. Cost-effectiveness of preoperative sestamibi scan for primary hyperparathyroidism is dependent solely upon the surgeon’s choice of operative procedure. J Am Coll Surg. 1998;186:293-3059510260Google ScholarCrossref 76. Irvin GL III, Dembrow VD, Prudhomme DL. Clinical usefulness of an intraoperative “quick parathyroid hormone” assay. Surgery. 1993;114:1019-10228256205Google Scholar 77. Haciyanli M, Lal G, Morita E, Duh QY, Kebebew E, Clark OH. Accuracy of preoperative localization studies and intraoperative parathyroid hormone assay in patients with primary hyperparathyroidism and double adenoma. J Am Coll Surg. 2003;197:739-74614585407Google ScholarCrossref 78. Garner SC, Leight GS Jr. Initial experience with intraoperative PTH determinations in the surgical management of 130 consecutive cases of primary hyperparathyroidism. Surgery. 1999;126:1132-113710598198Google ScholarCrossref 79. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg. 2002;235:665-67011981212Google ScholarCrossref 80. Deaconson TF, Wilson SD, Lemann J Jr. The effect of parathyroidectomy on the recurrence of nephrolithiasis. Surgery. 1987;102:910-9133686354Google Scholar 81. Mollerup CL, Vestergaard P, Frokjaer VG, Mosekilde L, Christiansen P, Blichert-Toft M. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. BMJ. 2002;325:80712376441Google ScholarCrossref 82. Bilezikian JP, Potts JT Jr, Fuleihan G. et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab. 2002;87:5353-536112466320Google ScholarCrossref 83. Proceedings of the NIDDK Workshop program. Asymptomatic primary hyperparathyroidism: a perspective for the 21st century, Bethesda, Maryland, USA, April 8-9, 2002. J Bone Miner Res. 2003;17:(suppl 2) N1-N16212708458Google Scholar 84. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126:497-5049092314Google ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

A 64-Year-Old Woman With Primary Hyperparathyroidism

JAMA , Volume 293 (14) – Apr 13, 2005

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American Medical Association
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Copyright © 2005 American Medical Association. All Rights Reserved.
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0098-7484
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1538-3598
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10.1001/jama.293.14.1772
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Abstract

DR BURNS: Ms Q is a 64-year-old woman with a history of mild hypercalcemia and hyperparathyroidism. She has managed care insurance. Ms Q states that on a routine blood test 7 years ago she was noted to have a calcium level of 10.1 mg/dL (2.5 mmol/L). She has subsequently had her calcium checked on a biannual basis and it has ranged from 10.4 to 11.3 mg/dL (2.6-2.8 mmol/L). Ms Q was referred to an endocrinologist in December 2002 after her calcium was higher than 11 mg/dL (2.7 mmol/L) on 3 occasions. Her laboratory studies just prior to her visit revealed a calcium level of 11.1 mg/dL (2.8 mmol/L), a parathyroid hormone (PTH) level of 102 pg/mL, and a phosphate level of 3.4 mg/dL. At the time of her visit, she reported a history of constipation since childhood with no recent change. She denied any history of cancer, thyroid disease, parathyroid disease, or radiation to her neck. She had never had any fractures and had no history of renal stones. She denied having any depression, anxiety, or mood swings. She reported lactose intolerance, although she was able to eat 1 serving of cheese daily. She did not take calcium, vitamin D, or any other supplements. She was postmenopausal and had not been taking hormone therapy. She is married and has 3 children who are alive and well. She has never smoked cigarettes and drinks alcohol socially. She otherwise reported that she felt well and had no complaints. She had a normal bone density in May 2000 (T-score: −0.88 spine and −0.09 total hip). Her only current medication was lorazepam for long-standing insomnia. She has no known drug allergies. On physical examination her thyroid gland was normal. She was believed to have primary hyperparathyroidism. Her physician’s plan was to exclude other causes of hyperparathyroidism, to repeat her bone mineral density (BMD) test, and to obtain a sestamibi scan of her parathyroid glands to localize a possible parathyroid adenoma. She returned for follow-up 6 months later. She continued to feel well. Her calcium level was 10.4 mg/dL (2.6 mmol/L) with an albumin level of 4.1 g/dL, phosphate level of 3.4 mg/dL, and a PTH level of 101 pg/mL. Her creatinine clearance was 81 mL/min (1.3 mL/s). A 24-hour urine calcium measurement was 226 mg. Her thyrotropin level was 1.4 mIU/mL and her 25-hydroxyvitamin D level was 27 ng/mL (67.4 nmol/L). Her bone density had decreased by 7.3% at the spine and 5.2% at the femoral neck. She underwent a sestamibi scan of the neck that revealed slightly increased uptake in the lower pole of the thyroid bilaterally. Ms Q was believed to have mild primary hyperparathyroidism. Ms Q was referred to a parathyroid surgeon for consideration of a parathyroidectomy. Ms Q is uncertain how to proceed. She feels well and would like to avoid a surgical procedure. She wonders whether there are any alternatives to surgery and what factors would necessitate her having to have a surgical procedure. Ms q: her view I was aware that there was a problem perhaps 6 or 7 years ago. I was at a spa and had a routine blood check and I had a calcium level of about 10.1. Before that I didn’t even realize I had a problem. From that time until perhaps a year ago, I just had annual blood checks. In the past year I went to see an endocrinologist. The endocrinologist suggested that I could possibly have surgery or I could wait. I have friends who have had parathyroid surgery, and I’d like to know what is the determining factor—whether it’s your calcium level or other deciding factors. I would prefer not to have surgery unless it’s absolutely necessary. If there is a medical way to treat this I would certainly prefer that. My ideal solution to this would be if I could take some kind of medication to lower my blood calcium. Either that, or if the calcium stays within a range that’s safe, then I just watch it going forward, because it doesn’t seem to be advancing very quickly. It just seems to be a very, very slow process. I would like to ask that there be a conclusion to the issue, whether I need surgery or I don’t need surgery, and perhaps through further discussion and examination this can be determined. At the crossroads: questions for dr strewler What is the epidemiology and underlying pathophysiology of hypercalcemia? What evaluation should be performed for a patient with hypercalcemia? What are the end-organ effects of primary hyperparathyroidism? What medical treatment options are available and how effective are they? When should a patient be referred to a surgeon and what are the surgical treatment options? What are the current clinical guidelines for treatment of primary hyperparathyroidism? What do you recommend for Ms Q? DR STREWLER: Ms Q, who presents for consideration of parathyroidectomy after a 7-year history of mild hypercalcemia, clearly has primary hyperparathyroidism. She was suspected of having progressive disease, because her serum calcium level was higher than 11.0 mg/dL on 3 consecutive occasions over an 18-month period, but 6 months after her referral to an endocrinologist for treatment consideration, her serum calcium had returned to 10.4 mg/dL (institutional normal range, 8.4-10.2 mg/dL). She is relatively asymptomatic and is uncertain about the benefits and risks of parathyroid surgery. Epidemiology and Pathophysiology Ms Q is typical of patients who present with primary hyperparathyroidism in the United States. Although there are no population-based data on the prevalence of the disease in North America, the estimate from a clinical series was about 1 per 1000,1 and the prevalence is highest in postmenopausal women. Although 2% to 10% of patients present with renal stone disease,2 most are identified by multiphasic screening of the serum calcium level2,3 and have no symptoms specifically referable to primary hyperparathyroidism. Hyperparathyroidism in all its forms is characterized by an increase in the set point for serum calcium; this resetting of the sensitivity of the parathyroid gland to calcium leads to regulation of the serum calcium at a level above the normal range (Figure 1A).4,5Quiz Ref IDParathyroid hormone increases the serum calcium level by actions at all 3 of the interfaces of the extracellular fluid —the bone, the gut, and the kidney. The level of calcium in serum is set primarily by control of calcium fluxes between bone and the extracellular fluid (rather than by osteoclastic bone resorption), and PTH shifts these fluxes by a poorly understood mechanism.6 However, the level of hypercalcemia is influenced by calcium absorption from the diet, which can increase in primary hyperparathyroidism because of increased 1,25-dihydroxyvitamin D levels and by enhanced renal reabsorption of calcium. Evaluation There is almost no doubt that Ms Q has hyperparathyroidism because she has an inappropriately elevated level of PTH in the presence of hypercalcemia.7-9 In all forms of nonparathyroid hypercalcemia (Box 1), PTH is suppressed. This means that only measurement of calcium, phosphate, creatinine, and PTH is necessary to make the diagnosis of primary hyperparathyroidism. Serum 25-hydroxyvitamin D should be measured as well to exclude vitamin D deficiency, which can exacerbate hyperparathyroidism while blunting hypercalcemia because of impaired absorption of calcium from the diet.9 Box 1. Differential Diagnosis of Hypercalcemia Primary hyperparathyroidism and variants  Sporadic primary hyperparathyroidism  Familial primary hyperparathyroidism   Associated with multiple endocrine neoplasia type 1 (MEN-1)   Associated with multiple endocrine neoplasia type 2A (MEN-2A)  Familial benign hypocalciuric hypercalcemia  Tertiary hyperparathyroidism   In chronic renal failure   After renal transplantation  Associated with lithium therapy Malignancy-associated hypercalcemia Sarcoidosis and other granulomatous diseases Endocrinopathies  Thyrotoxicosis  Adrenal insufficiency  Pheochromocytoma  Vasoactive intestinal peptide-producing tumor (VIPoma) Immobilization-associated Milk-alkali syndrome Vitamin D intoxication Vitamin A intoxication Acute renal failure Ms Q has either primary hyperparathyroidism or one of its variants. In familial benign hypocalciuric hypercalcemia (FBHH), a mutation in the parathyroid calcium receptor reduces the sensitivity of the gland to calcium and thereby increases the set point for serum calcium (Figure 1A).10,11 The resultant hypercalcemia is lifelong and asymptomatic, PTH levels are in the normal range, urinary calcium excretion is typically decreased (because the receptor also sets the level of calcium reabsorption in the renal tubule), and 50% of first-degree relatives are hypercalcemic. Ms Q had a previously normal serum calcium level and has a relatively high normal urinary calcium, excluding FBHH in her case. Primary hyperparathyroidism also occurs as part of the familial syndrome multiple endocrine neoplasia type 1 (MEN-1) and more rarely in other familial endocrine tumor syndromes.12 Lithium treatment causes hypercalcemia by shifting the set point for PTH secretion to the right and may be viewed as a phenocopy of FBHH.13-15 There is no accepted medical treatment of primary hyperparathyroidism but it generally can be cured surgically. It is not clear whether every patient with the diagnosis requires surgery, however, and Ms Q presents the typical therapeutic dilemma. To make an evidence-based recommendation to her for surgery or observation, several questions must be answered.9 What are the end-organ effects of primary hyperparathyroidism? Is the disorder or its effects likely to be progressive? What are the risks of surgery and how can they be minimized? Does surgery often improve the general well-being of a patient without obvious manifestations of hyperparathyroidism? End-Organ Effects Quiz Ref IDBone is one of the classic target organs of PTH. Severe hyperparathyroid bone disease, osteitis fibrosa cystica, is rarely seen in the United States today, but osteoporosis is common in primary hyperparathyroidism.16-18 Cortical bone is lost preferentially because of endocortical bone resorption and intracortical tunneling, and BMD is consequently lowest at predominately cortical sites in the skeleton, such as the forearm. Trabecular bone (eg, in the lumbar spine) is relatively preserved, despite rates of bone turnover several times normal. The reasons for preservation of trabecular bone mass have been studied by quantitative histomorphometry of bone biopsies from hyperparathyroid patients.19-21 Resorption pits in primary hyperparathyroidism are frequent but relatively shallow and can be completely filled by new bone formation so that trabecular architecture is preserved. Primary hyperparathyroidism is probably associated with a relatively small increased risk of forearm and spine fractures, although not all studies agree.22-24 The stimulation of new bone formation by PTH is useful therapeutically. When PTH is administered once daily by subcutaneous injection, there is active bone formation with less bone resorption and net accretion of bone occurs. Bone mass and bone strength are increased, most strikingly in cancellous bone, and osteoporotic fractures are prevented.25 The synthetic PTH fragment teriparatide was approved for treatment of osteoporosis in 2002 and is the first anabolic agent available for the disorder. Quiz Ref IDPrimary hyperparathyroidism causes nephrolithiasis and occasionally nephrocalcinosis and progressive renal insufficiency. To assess for clinically significant end-organ effects of primary hyperparathyroidism, it is reasonable to measure serum creatinine, alkaline phosphatase, urinary calcium, and BMD and to obtain an abdominal film to identify asymptomatic urolithiasis. Fatigue, weakness, depression, and memory problems are common complaints in patients referred for treatment of primary hyperparathyroidism,26 but it has been difficult to ascertain whether these nonspecific symptoms are caused by hyperparathyroidism. Two recent studies in which the outcome of parathyroidectomy was compared with the outcome of thyroid surgery suggest an improvement in fatigue, but both lacked objective measures using well-defined instruments.27,28 In the only randomized trial of parathyroid surgery, involving 53 patients, there was a postoperative difference in annual change in 2 of the 9 domains of the 36-Item Short Form Health Survey (SF-36), social functioning and emotional role functioning.29 The difference resulted from a decline in function in the control group rather than an increase in surgically treated patients. Several European studies have found an adverse effect of primary hyperparathyroidism on mortality, largely attributable to excess mortality from cardiovascular disease.30-33 Mortality was increased both in a population-based survey of hypercalcemic patients30 and in long-term postoperative follow-up of more than 13 300 patients.31-33 A population-based case-control study in Rochester, Minn, did not confirm an adverse effect of primary hyperparathyroidism onoverall mortality.2 Comparison of the populations studied suggests that hyperparathyroidism was more severe in the European countries, and in some studies mortality was correlated with the level of serum calcium. Consistent with this trend, increased mortality was observed in the upper quartile of serum calcium (>11.2 mg/dL [2.8 mmol/L]) in the Rochester study.23 The pathophysiological basis of these observations is not understood.26 Hypertension is more prevalent in primary hyperparathyroidism than matched controls,34 although it is not clear whether hypertension responds to surgery.35 Left ventricular hypertrophy and myocardial and valvular calcifications are reported in primary hyperparathyroidism,36,37 and cardiovascular disease is accelerated in patients with severe secondary hyperparathyroidism as a complication of chronic renal failure.38 In addition, many of the molecular features of vascular calcification and bone formation are similar.39 Natural History and Pathogenesis Primary hyperparathyroidism does not progress in most patients. In 10-year prospective studies,16,40 serum calcium and PTH levels were stable in most patients, and serum creatinine and BMD did not change. Four percent of patients had substantial worsening of hypercalcemia, 15% developed marked hypercalciuria (>400 mg/24 h), and 12% had progressive declines in BMD to a predetermined threshold for surgery (z -score less than −2.0). It is unclear whether Ms Q has progressed significantly. She appears to have had a slight upward trend in the serum calcium level, but the most recent result was barely above the upper limit of normal. She has had a significant decline in BMD but remains above the mean for her age with a T-score of −1.5. Her renal function is normal for her age. The stability of primary hyperparathyroidism in most cases is surprising, considering the neoplastic nature of the disorder. About 90% of cases result from a parathyroid adenoma; most of the remainder have hyperplasia of all 4 parathyroid glands. (Parathyroid carcinoma is rare and presents with severe and progressive hypercalcemia, so it is unlikely in Ms Q.) The pathogenesis of parathyroid adenomas is similar to that of other tumors: an oncogenic mutation provides a growth advantage to a clone of cells that gradually expands to become a tumor. Overexpression of the cell cycle regulator cyclin D1 is found in 20% to 40% of sporadic parathyroid adenomas41,42; loss of function of the MEN1 tumor suppressor gene (the gene that is mutated in MEN-1) accounts for an additional 15% to 20%43-45; and inactivation of HRPT2, the gene implicated in the hereditary hypercalcemia-jaw tumor syndrome, occurs in rare cystic parathyroid adenomas.46 Why do these tumors stop growing47 despite mutations that abrogate growth control? As proposed by Parfitt,48 this behavior can be explained by a set point hypothesis. An increase in the set point for secretion of PTH is characteristic of most parathyroid adenomas,49,50 that is, secretion of PTH from tumors can be suppressed by calcium, but it requires more calcium to suppress adenomatous than normal glands. It is hypothesized that parathyroid adenomas typically grow until the serum calcium reaches the set point for secretion of PTH, then essentially stop growing (Figure 1B). Thus, the negative growth influence of ambient calcium concentrations above the set point dominates the control of parathyroid cell growth, even when the cells have a fundamental abnormality of growth control. If correct, the set point hypothesis has an important potential implication for medical therapy of hyperparathyroidism: drugs such as bisphosphonates, which reduce the serum calcium level by inhibiting bone resorption, may cause not only increased secretion of PTH, but also enlargement of the parathyroid adenoma, once they lower the serum calcium level below the set point.51 Medical Treatment Options Estrogens and bisphosphonates have been used as medical treatments for primary hyperparathyroidism.51 Treatment with high estrogen doses modestly reduces the serum calcium level, averaging 0.5 mg/dL (0.12 mmol/L).52,53 The dose of conjugated equine estrogen that is required averages 1.25 mg,52 and treatment with 0.625 mg does not consistently lower the serum calcium level, although bone remodeling is slowed.54 Parathyroid hormone levels do not change, suggesting that the predominant effect of estrogen is on bone resorption, rather than secretion of PTH. In view of the adverse effects of combined estrogen-progesterone treatment on breast cancer risk and cardiovascular disease,55 the use of estrogens cannot be recommended for Ms Q or most other postmenopausal women. Bisphosphonates inhibit osteoclastic bone resorption. They have little benefit for control of hypercalcemia in primary hyperparathyroidism,56-59 probably because PTH secretion tends to rise as bone resorption falls to maintain the serum calcium level at its high set point. However, alendronate treatment for 24 months significantly improves BMD and reduces bone turnover57-60 and may be useful in patients with osteoporosis who are not surgical candidates. Whether long-term bisphosphonate treatment will eventually lead to enlargement of parathyroid tumors and worsening of hyperparathyroidism remains to be determined. Quiz Ref IDCalcimimetic agents, a new class of drugs, provide the first effective medical therapy for primary hyperparathyroidism.51,61 They increase the sensitivity of the parathyroid calcium receptor to calcium and thereby reduce the set point for the serum calcium.62 Calcimimetic treatment prevents the development of secondary hyperparathyroidism in animal models of chronic renal failure63,64 and reduces PTH and calcium levels in patients with chronic renal insufficiency.65,66 In a 1-year randomized placebo-controlled trial in 78 patients, cinacalcet reduced serum calcium levels by at least 0.5 mg/dL (0.12 mmol/L) to a level of 103 mg/dL (2.57 mmol/L) or below in 73% of patients without serious adverse events.67 In theory, a reduction in the set point for serum calcium might permit involution of parathyroid glands, but a calcimimetic closely related to cinacalcet was ineffective in reducing gland size in a model of established secondary hyperparathyroidism,68 although it prevented the development of parathyroid hyperplasia when used early in the course of disease.63 It thus might be speculated that, used in a patient like Ms Q, cinacalcet would provide chronic control of hypercalcemia but would induce involution of a parathyroid adenoma slowly, if at all. Patients should take in 700 to 1400 mg of calcium daily. Calcium restriction is not advisable and may worsen hyperparathyroidism. Vitamin D–deficient patients can be supplemented with vitamin D, 400 to 800 U daily.9 While at one time vitamin D repletion was believed to exacerbate hypercalcemia, a recent study in 21 patients suggests that vitamin D repletion in patients with mild hypercalcemia (calcium level <12 mg/dL [3 mmol/L]) does not exacerbate hypercalcemia and may decrease PTH and bone turnover.69 Surgical Treatment Options As John Doppman quipped in the 1990 Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism,70 the greatest challenge in preoperative localization of a parathyroid adenoma is locating an experienced surgeon. A skilled parathyroid surgeon will cure hyperparathyroidism in more than 95% of cases, even without resorting to modern localizing techniques. The standard procedure is a bilateral neck exploration; the aim is to identify an enlarged parathyroid gland and at least 1 normal gland. The latter is important because parathyroid hyperplasia—hyperparathyroidism associated with enlargement of all 4 parathyroid glands—occurs in about 10% of cases; hence, the first enlarged gland the surgeon encounters may not be an isolated adenoma. Surgical complications of laryngeal paralysis and hypoparathyroidism are uncommon in skilled hands but are correlated with the experience of the surgeon. In a survey of members of the American Association of Endocrine Surgeons, the major complication rate was 3.76% for surgeons who perform fewer than 15 cases annually, compared with 1.48% for surgeons who perform more than 50 parathyroidectomies per year.71 A new technique, minimally invasive parathyroidectomy, uses a combination of preoperative localization and intraoperative strategies to directly guide the exploration for an adenoma.72,73 Scanning with 99technicium Tc-99m–labeled sestamibi (Figure 2) using single-photon emission computed tomography localizes a parathyroid adenoma in 60% to 89% of cases, depending on the skill of the center.74,75 If an adenoma is localized preoperatively, a limited incision is made under regional or general anesthesia and the adenoma is identified. Rapid intraoperative assay of PTH can be used to confirm that resection of an adenoma has removed the source of PTH.76-78Quiz Ref IDMinimally invasive parathyroidectomy reduces morbidity, saves operating room time, and, if performed under regional anesthesia, can markedly reduce hospital stay and cost, particularly if it eliminates an overnight stay.79 It is not clear that success rates are improved or complications averted. Surgical treatment of primary hyperparathyroidism reduces the postoperative incidence of renal stones by about 90%.80,81 Bone mineral density improves markedly, with sustained increases of more than 10% at 10 years at the lumbar spine and hip and smaller gains at the radius.16 Nonspecific symptoms may improve.27-29 The objective outcomes of surgery are not controversial, but how minimally symptomatic patients should be selected for surgery has been, leading to the development of clinical practice guidelines. Clinical Treatment Guidelines A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases in 2002 asked a panel of experts to review and update previous clinical guidelines from 199070 for treatment of asymptomatic primary hyperparathyroidism. Their recommendations are summarized in Box 282,83 and a brief summary of the evidence base is presented below. Box 2. Treatment of Asymptomatic Primary Hyperparathyroidism: Recommendations of 2002 National Institutes of Health Workshop Surgery was recommended for patients with the following:  Serum calcium >1 mg/dL (0.25 mmol/L) above upper limit of normal  Urinary calcium excretion >400 mg/24 h  Impaired renal function (creatinine clearance reduced by 30% from age-matched healthy patients)  T-score less than −2.5 (matching the World Health Organization definition of osteoporosis)  Age younger than 50 years  Follow-up likely to be unreliable The panel favored surgery in patients with serum calcium levels more than 1 mg/dL (0.25 mmol/L) above the upper limit of normal, which is lower than the previous threshold of serum calcium (>1-1.6 mg/dL [0.25-0.40 mmol/L] higher than normal). The intuitive notion that severe hyperparathyroidism is more likely to progress is buttressed by studies indicating that the level of serum calcium is a determinant of progressive decline in BMD16 or of mortality,2,31 but there is no firm evidence base for choosing either the previous threshold or the new one. Surgery was recommended for patients with urinary calcium excretion greater than 400 mg/24 h. There is no direct evidence of a relationship between hypercalciuria and stone formation in primary hyperparathyroidism, and urinary calcium is a poor predictor of stone risk in patients who have not previously formed stones.84 The threshold level of urinary calcium that was defined by the consensus panel is not sex- or race-specific, even though men excrete 25% to 30% more urinary calcium than women, and whites excrete 20% to 25% more calcium than blacks, but 400 mg/d is set well above the upper limit of normal. Impaired renal function (creatinine clearance 30% less than age-matched healthy patients) was also considered an indication for surgery. Primary hyperparathyroidism leads to progressive nephron loss in some individuals.16,40 Renal insufficiency from other causes would increase calcium handling per nephron and could thereby predispose to renal damage from hyperparathyroidism, but there is no evidence this occurs. In some patients, primary hyperparathyroidism leads to progressive bone loss. The panel recommended that surgery be considered when the T-score is less than −2.5 (matching the World Health Organization definition of osteoporosis). This is a change from the previous recommendation of a Z-score threshold of less than −2. A T-score of less than −2.5 is an accepted threshold to treat for fracture prevention in osteoporosis, although there is no evidence that the relationship of BMD and fracture risk is the same in primary hyperparathyroidism and osteoporosis. Surgery was recommended in patients younger than 50 years. The evidence for this recommendation is not substantial, but there is evidence that premenopausal women who are not treated through menopause have an increased risk of losing BMD.16 In practice, endocrine surgeons tend to be more aggressive than the guidelines recommend in older asymptomatic patients but somewhat reluctant to operate based on age alone.71 Finally, the panel recommended that patients who might not be reliable for follow-up for the possible future development of complications undergo parathyroidectomy. This reasonable recommendation is not evidence-based. Recommendations for ms q Ms Q has asymptomatic hyperparathyroidism. According to the current guidelines, she does not have an indication for parathyroidectomy. I am concerned, however, that 2 aspects of her case suggest that she may be one of the approximately 25% of women who progress: there are suggestions both of increasing hypercalcemia compared with 7 years ago and of declining BMD. I would obtain a baseline abdominal film to rule out asymptomatic calcium urolithiasis. If that is negative, I recommend that medical follow-up be continued for 1 to 2 years because the patient needs to gain confidence about surgery and because the data on progression are inconclusive. She should have twice-yearly determinations of serum calcium and creatinine levels, and a BMD test should be repeated annually. If the apparent decline in BMD is confirmed or if calcium levels rise, I would recommend surgery. I would not wait until she is frankly osteoporotic, per the clinical practice guidelines, because it seems clear (although the guidelines do not explicitly address this point) that patients who have disease progression are in a poor prognostic group for whom surgical intervention is appropriate. Questions and comment A PHYSICIAN: Ms Q seems to be asymptomatic, but don’t asymptomatic patients come back and volunteer improvement in energy level and cognitive function? Do you believe there can be an improvement? DR STREWLER: There are patients who feel unexpectedly better after parathyroidectomy. They tell the internist and the surgeon, “I never knew what feeling good was until I had this operation.” The problem is that one can’t pick them out prospectively, and it’s therefore hard to recommend surgery solely on that basis. A PHYSICIAN: My question relates to the assumption that the effect of hyperparathyroidism on mortality is due to calcium. Is it possible that there is another action of parathyroid hormone that is unrelated to calcium and that perhaps has to do with mortality? DR STREWLER: I think hypercalcemia in these patients may be a marker for the severity of hyperparathyroidism. In secondary hyperparathyroidism, there is a clear association with cardiovascular mortality. There is every reason to imagine that parathyroid hormone turns on a program of gene expression in the cells of the vascular wall that produces a predisposition to coronary disease and stroke. A PHYSICIAN: Should Ms Q be offered alendronate? DR STREWLER: Ms Q has mild osteopenia at age 64. Alendronate would prevent rapid bone loss due to hyperparathyroidism, but it would not control her hypercalcemia and it could worsen her hyperparathyroidism. If she has continued loss of bone mass, then parathyroidectomy would be a much more effective treatment for her osteoporosis than a bisphosphonate like alendronate. MS Q: Would you recommend that I wait for this new medication to come on the scene and take that? DR STREWLER: Cinacalcet was approved for the treatment of secondary hyperparathyroidism in chronic renal failure, but little information is available about its long-term safety and efficacy in primary hyperparathyroidism. If there is a clear indication to treat your hyperparathyroidism, I would recommend surgery as a curative treatment. Back to top Article Information Corresponding Author: Gordon J. Strewler, MD, Tosteson Medical Education Center, Harvard Medical School, 260 Longwood Ave, Room 232A, Boston, MA 02115 (gordon_strewler@hms.harvard.edu). Financial Disclosure: Dr Strewler is a consultant to Abgenix Inc, manufacturer of a new drug for treatment of hyperparathyroidism that is in clinical trials in patients with secondary hyperparathyroidism. Funding/Support: This Clinical Crossroads is made possible in part by a grant from The Florence and Richard Koplow Charitable Foundation. 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Journal

JAMAAmerican Medical Association

Published: Apr 13, 2005

Keywords: surgical procedures, operative,hyperparathyroidism, primary,hyperparathyroidism,calcium,hypercalcemia

References