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.

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.

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.

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 level^{2 - 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 - 5} Parathyroid 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.

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 ( Article ), 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

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?

Bone 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.

Primary 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

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 adenomas^{41 - 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

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 turnover^{57 - 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.

Calcimimetic 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 failure^{63 - 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

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 - 78} Minimally 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.

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 Article ^{82 - 83} and a brief summary of the evidence base is presented below.

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.

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.

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.