Hypercalcemia: Are You Sure the Patient Has Primary Hyperparathyroidism?

The problem, simply stated, is how can you be sure that the patient who presents with hypercalcemia has primary hyperparathyroidism? On statistical grounds, it is most likely that the diagnosis will be Primary Hyperparathyroidism because it is the most common cause of hypercalcemia. In fact, primary hyperparathyroidism is a common endocrine disease with incidence figures that can be as high as 1 in 1000 in the United States. While the disease used to present with symptoms of hypercalcemia such as polyuria, polydypsia, altered mental status, at times, kidney stones and overt skeletal disease, such findings are unusual because the hypercalcemia is discovered usually in the course of a routine biochemical screening test.

Most patients and their doctors do not even know that they have hypercalcemia. The majority of patients with PHPT, therefore, are asymptomatic, in that they have neither signs nor symptoms that are classically associated with hypercalcemia. The non-specific manifestations of primary hyperparathyroidism have been a topic of much discussion but not consistent research results. Some patients will complain of weakness, easy fatigability, intellectual weariness, and a sense of not feeling well. Despite attempts to track these symptoms before and after surgery, it has not been possible to determine that these non-specific features are an intrinsic component of the disease.

The incidence of kidney stones in primary hyperparathyroidism is 15-20% which makes it the most frequent overt target organ complication of primary hyperparathyroidism. Fractures are rarely reported. Neuromuscular function does not appear to be abnormal. Cardiovascular indices, such as vascular stiffness, left ventricular size can be different from controls, but these measurements require highly sophisticated approaches. As a result of the difficulty with these cardiovascular measurements, and, more important, uncertainty about whether they are directly related to the disease process, such testing is not routinely performed or recommended.

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The key laboratory findings are an elevated serum calcium and high parathyroid hormone concentration.

While most patients do have levels of parathyroid hormone that are clearly above the upper limits of normal (> 65 pg/mL in most laboratories), a substantial number of patients will show a PTH level that is within the normal laboratory limits. The physiology of calcium as a regulator of PTH dictates, however, that in hypercalcemia due to a non-parathyroid etiology, the PTH level should be completely suppressed. Thus, a detectable level of PTH in the mid- to upper normal range is entirely compatible with the diagnosis of primary hyperparathyroidism.

This discussion focuses upon the hypercalcemic patient, but it is noteworthy that primary hyperparathyroidism presents also with normal calcium levels and high parathyroid hormone. This variant of primary hyperparathyroidism is called ‘normocalcemic primary hyperparathyroidism.’ It is being increasingly recognized in the context of evaluations in metabolic bone diseases centers for reduced bone density in which a PTH level is often drawn. Normocalcemic primary hyperparathyroidism is characterized by normal total and ionized serum calcium along with consistently elevated PTH levels in the absence of other causes for a high PTH.

What Else Could the Patient Have?

Primary Hyperparathyroidism with hypercalcemia

A patient with hypercalcemia and a high PTH level does not present a major problem in the differential diagnosis of hypercalcemia because most other causes of hypercalcemia are associated with a suppressed PTH level. However, there are individuals who appear to have primary hyperparathyroidism but are on a thiazide diuretic or lithium. These two drugs can be associated with an elevated serum calcium and PTH level. It used to be said that taking patients off either of these two drugs and retesting in 3 months would show, in many cases, a return to normal of serum calcium and PTH. While withdrawing a thiazide diuretic and retesting in 3 months is reasonable, it can be problematical for those who are dependent upon lithium for their mental health. In addition, it has become clear that patients who are withdrawn from these medications and are retested thereafter invariably continue to show biochemical evidence for primary hyperparathyroidism with elevated serum calcium and PTH levels.

In the differential diagnosis of the elevated serum calcium and PTH, the rare genetic disorder, Familial Hypocalciuric Hypercalcemia (FHH) should be considered. This possibility is usually not difficult to rule out, if there is no family history of hypercalcemia, the time of onset of the hypercalcemia occurs after the age of 40, and the urinary calcium excretion is greater than 100 mg on a normal calcium diet. Much is made of the calcium/creatinine ratio which should be less than 0.01 if the diagnosis of FHH is to be seriously entertained. On the other hand, if there is a family history of hyperparathyroidism, particularly if associated with failed parathyroidectomies, time of onset occurred before the age of 40, and the 24-hour urinary calcium excretion is low, FHH does become a possibility. Commercial laboratories can routinely measure the calcium sensing receptor and determine whether an inactivating point mutation is present. While much is made of FHH in the differential diagnosis of primary hyperparathyroidism, it is important to appreciate that it is a rare disease.

Normocalcemic Primary Hyperparathyroidism

It is important to rule out other causes for a high PTH, a situation that is called secondary hyperparathyroid state. One of the most important causes of secondary hyperparathyroidism is a low vitamin D level There is controversy over what constitutes vitamin D deficiency or inadequacy. The recent Institute of Medicine guidelines suggest a concentration of <20 ng/mL of 25-hydroxyvitamin D is insufficient. While there is not unanimity on this value, for normocalcemic primary hyperparathyroidism, I feel that it is important to ensure, without any doubt, that the patient has adequate Vitamin D stores. To this end, therefore, the 25-hydroxyvitamin D level should be > 30 ng/mL. If the patient’s vitamin D level is < 30 ng/mL, provide supplemental vitamin D and retest in 3 months.

If vitamin D adequacy has been achieved and the PTH level is still elevated, vitamin D insufficiency has been ruled out as the etiology of the hyperparathyroidism. Another secondary hyperparathyroid state to rule out in the setting of a normal serum calcium is renal insufficiency. While the level of renal function at which PTH levels uniformly rise is not clearly known, and probably varies among patients, a clearance of < 60 cc/min (stage 3 CKD) is considered by many to be a threshold clearance. Levels of PTH can be elevated when the creatinine clearance is < 60 cc/min. Other causes for a secondary rise in PTH are primary hypercalciuria, and other metabolic bone diseases such as Paget’s disease. Despite ruling out these secondary causes for a high PTH level, there is often still doubt as to the diagnosis. Nevertheless, normocalcemic primary hyperparathyroidism is clearly a form of primary hyperparathyroidism.

Key Laboratory and Imaging Tests

Key laboratory testing in someone with primary hyperparathyroidism includes bone densitometry because even in asymptomatic disease, there is a typical pattern of bone loss. Cortical bone is at risk. In order to ascertain the status of cortical bone, a thick envelope of bone that is also called compact bone, the distal 1/3 site must be measured. This site is predominantly cortical bone and typically shows a reduction in bone mineral density In primary hyperparathyroidism. The lumbar spine, a site that is enriched in cancellous bone, typically shows relative preservation. The hip regions (total hip or femoral neck) show values that are intermediate between the lumbar spine and the distal 1/3 radius, because those hip regions are a more even admixture of cortical and cancellous bone. All patients being evaluated for primary hyperparathyroidism should have bone mineral densitometry with testing at all 3 sites.

A 24-hour urine collection for calcium is highly recommended. While the decision for or against surgery is not dependent upon urinary calcium excretion, the measurement is helpful to rule out FHH. It can also be helpful to measure directly the creatinine clearance, a point of importance if renal function is estimated to be in the neighborhood of 60 cc/min.

Other Tests That May Prove Helpful Diagnostically

The serum phosphate is usually normal in primary hyperparathyroidism but in the low normal range. The physiological actions of PTH include a phosphaturic effect. When primary hyperparathyroidism was a symptomatic disorder, hypophosphatemia was common. Now, however, frankly low serum phosphate levels are not common.

Bone turnover markers are usually high or in the upper range of normal. Both bone formation markers (e.g., osteocalcin, bone-specific alkaline phosphatase) and bone resorption markers (e.g., urinary N-telopeptide of collagen-NTX; or serum C-terminal peptide of collagen- CTX) are at the upper limits of normal or frankly elevated. These bone turnover markers are helpful in ascertaining the activity of the disease.

Abdominal imaging. In the patient who has no history of nephrolithiasis or nephrocalcinosis, most endocrinologists do not order an abdominal flat plate or a CT scan, to look for calcifications.

Imaging of the neck and mediastinum. If the patient is a candidate for parathyroid surgery (see below), preoperative parathyroid imaging is indicated. If the patient is not a candidate for parathyroid surgery, preoperative imaging is not indicated. The only reason for obtaining an imaging test is as a preoperative test. It is not used for diagnostic purposes. The exact kind of imaging modality to be used is, in part, determined by local expertise. 99T-labeled sestamibi often will locate the abnormal parathyroid gland. In patients who have a thyroid gland, double-labeling with 123I and 99T-sestamibi can be highly effective because the 123I iodine is picked up only by thyroid tissue. Subtraction imaging leaves only the non-thyroidal accumulation of 99T-sestamibi. Invariably, the sestamibi positive image will be that of the abnormal parathyroid gland. Ultrasound and computed tomography with so-called 4-dimensional imaging can also be highly specific in locating the parathyroid gland(s). Other imaging modalities include magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning.

Management and Treatment of the Disease

Operative management. The Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism lists any one of the following criteria for parathyroid surgery:

  • Serum calcium > 1 mg/dL above normal limits

  • Creatinine clearance < 60 cc/min

  • Bone mineral density at any site < -2.5; age < 50

If the patient meets any one of these criteria, surgery is generally recommended. It is important to note that even if the patient does not meet any of these criteria for surgery, but desires surgical removal of the abnormal parathyroid gland, it is appropriate to do so, as long as there are no medical contraindications. It is also important to note that if the patient is symptomatic of primary hyperparathyroidism, namely has had a kidney stone or a fragility fracture, surgery is clearly indicated.

The surgery is commonly performed with a minimally invasive approach. Successful preoperative localization directs the surgeon to the gland. A small incision under local anesthesia and conscious sedation, usually delivers the offending gland readily. Intraoperative monitoring of the PTH level just prior to and following removal of the enlarged parathyroid gland helps to assure success of the surgery. The post-operative PTH level should fall by >50% into the normal range.

In patients who do not meet any criteria for surgery, a conservative, non-surgical approach is acceptable. Annual monitoring of the serum calcium and a calculated creatinine clearance are recommended. In addition, 3-site bone mineral densitometry should be conducted annually, at least until stability can be assured. The frequency of bone mineral density testing may depend upon local insurers but since this is not osteoporosis, the rules of more widely spaced bone density measurements (e.g. every 2 years) do not necessarily apply.

In patients who do or do not meet criteria for surgery, but in whom surgery is not desired or possible, medical management can include pharmacological therapy. Estrogen is an option although there are the usual caveats about its use. The bisphosphonates have been shown to increased bone density of the lumbar spine. The serum calcium and PTH levels do not change. The calcimimetic, cinacalcet, has been shown to reduce the serum calcium, often to normal levels, while reducing the PTH level by approximately 30%. Bone mineral density does not change. Cinacalcet can be very effective in subjects whose serum calcium is beyond the mild range in whom control is medically indicated.

What’s the Evidence?/References

Khan, AA, Bilezikian, JP, Kung, AWC, Ahmed, MM, Dubois, SJ. “Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial”. J Clin Endocrinol Metab. vol. 89. 2004. pp. 3319-25. (This paper describes the effect of a bisphosphonate to improve bone mineral density in primary hyperparathyroidism. It provides evidence for bisphosphonate use in subjects whose bone density is low but are not candidates for parathyroid surgery.)

Ambrogini, E, Cetani, F, Cianferotti, L. “Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial”. J Clin Endocrinol Metab.. vol. 92. 2007. pp. 3114-21. (This paper is one of several to seek in a controlled manner changes in traditional and non-traditional aspects of primary hyperparathyroidism after successful parathyroid surgery.)

Rubin, MR, Bilezikian, JP, McMahon, DJ. “The Natural History of Primary Hyperparathyroidism With or Without Parathyroid Surgery after 15 Years”. J Clin Endocrinol Metab. vol. 93. 2008. pp. 3462-70. (Rubin and her colleagues describe the longest prospective history of primary hyperparathyroidism in the modern era. It demonstrates clearly the benefits of surgery as well as the natural history of those who are treated conservatively.)

Bilezikian, JP, Khan, A, Potts Jr, JT. “Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Third International Workshop”. J Clin Endocrinol Metab. vol. 94. 2009. pp. 335-9. (The proceedings of the 3rd International Workshop on the Management of Primary Hyperparathyroidism are described in this paper. Guidelines for surgery are summarized as well as non-surgical options.)

Walker, MD, McMahon, DJ, Inabnet, WB. “Neuropsychological features in primary hyperparathyroidism: a prospective study”. J Clin Endocrinol Metab. vol. 94. 2009. pp. 1951-8. (The vexing issue of neurocognitive features of primary hyperparathyroidism is addressed in this prospective study of subjects who underwent detailed neuropsychological testing before and after successful parathyroid surgery.)

Silverberg, SJ, Bilezikian, JP, DeGroot, LJ, Jameson, JL. “Primary hyperparathyroidism”. Endocrinology. 2010. pp. 1176-97. (A detailed and comprehensive discussion of primary hyperparathyroidism in all of its classical and non-traditional manifestations.)

Bilezikian, JP, Silverberg, SJ. “Normocalcemic primary hyperparathyroidism”. Brazilian Archives of Endocrinology and Metabolism. vol. 54. 2010. pp. 106-9. (In this paper, Bilezikian and Silverberg summarize the features of normocalcemic primary hyperparathyroidism.)

Lewiecki, EM. “Management of skeletal health in patients with asymptomatic primary hyperparathyroidism”. J Clin Densitom. vol. 12. 2010. pp. 324-34. (This report by Lewiecki provides an accurate summary of the skeleton in primary hyperparathyroidism and management questions pertinent to this major target organ.)

Peacock, M, Bilezikian, JP, Bolognese, MA, Borofsky, M, Scumpia, S. “Cinacalcet HCI reduces hypercalcemia in primary hyperparathyroidism across a wide spectrum of disease severity”. J Clin Endocrinol Metab. vol. 96. 2011. pp. E9-E18. (The efficacy of cinacalcet to control the hypercalcemia associated with Primary Hyperparathyroidism across a spectrum of involvement from mild to severe disease is provided by Peacock et al.)

Udelsman, R, Lin, Z, Donovan, P. “The superiority of minimally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism”. Ann Surg. vol. 253. 2011. pp. 585-91. (Udelsman summarizes his extensive and impressive experience with minimally invasive parathyroidectomy.)

Rosen, CJ. “Vitamin D insufficiency”. N Engl J Med. vol. 364. 2011. pp. 248-54. (Issues relevant to vitamin D economy and definitions of adequacy are provided in this clear exposition written for experts and practicing clinicians.)

Cetani, F, Marcocci, C. “Primary Hyperparathyroidism”. N Engl J Med. vol. 365. 2011. pp. 2389-97. (A recent description of management issues related to the care of subjects with Primary Hyperparathyroidism is provided in this paper by Cetani and Marcocci.)

Eldeiry, LS, Ruan, DT, Brown, EM, Gaglia, JL, Garber, JR. “Primary hyperparathyroidism and familial hypocalciuric hypercalcemia: relationships and clinical implications”. Endocr Pract. vol. 18. 2012. pp. 412-7. (Familial hypocalciuric hypercalcemia is an important but rare disorder to be considered in the differential diagnosis of hypercalcemia with elevated PTH levels. This paper summarizes key clinical issues about the distinction between these two hypercalcemic states.)

Walker, MD, Rundek, T, Homma, S. “Effect of parathyroidectomy on subclinical cardiovascular disease in mild primary hyperparathyroidism”. Eur J Endocrinol. vol. 167. 2012. pp. 277-85. (Demonstration of cardiovascular manifestations of mild primary hyperparathyroidism requires a rather sophisticated set of detection tools. This paper describes how some of these manifestations are improved after successful parathyroid surgery.)

Bilezikian, JP, DeGroot, L, Singer, F. “Primary hyperparathyroidism”. . (A recent, comprehensive discussion of virtually all aspects of Primary Hyperparathyroidism.)