Hyperparathyroidism (pth-mediated hypercalcemia)
Classification
Primary hyperparathyroidism Primary hyperparathy-roidism is the most common cause of hypercalcemia in outpatients. Current estimates place the annual incidence at approximately four per 100,000 population; the incidence peaks in the fifth to sixth decade of life, and there is a female-to-male ratio of 3:2.4 The most common clinical presentation is that of asymptomatic mild hypercalcemia. Pathologically, a solitary parathyroid adenoma is present in 80% to 85% of cases; hyperplasia involving multiple glands is found in 15% to 20% of cases, and parathyroid carcinoma is found in less than 1%. Occasionally, double adenomas are found. Patients with type I MEN (MEN I) or MEN II usually have parathyroid hyperplasia.5
Lithium therapy can change the set point for the calcium-sensing receptor such that a higher serum calcium concentration is needed to inhibit PTH secretion. This can lead to biochemical abnormalities (e.g., high levels of calcium and high-normal to elevated PTH levels) that mimic primary hyper-parathyroidism. Patients on lithium will often have very low urinary calcium excretion.
Secondary hyperparathyroidism Conditions that tend to decrease serum calcium increase PTH secretion as a corrective measure. This increase of PTH secretion is termed secondary hy-perparathyroidism. Once circulating PTH is elevated, the serum calcium may return to normal or remain low. Common causes of secondary hyperparathyroidism include chronic renal insufficiency, vitamin D deficiency, intestinal malabsorption, renal calcium losses, and severe dietary inadequacy. Correction of the underlying calcium abnormality will return serum PTH concentrations to normal.
Familial hypocalciuric hypercalcemia Familial hypocalci-uric hypercalcemia (FHH), also referred to as benign familial hy-percalcemia, is a rare inherited condition caused by various inactivating mutations in the CaSR. This results in inappropriately increased PTH secretion and a higher set point for the extracellular ionized calcium concentration. Patients with FHH have chronic asymptomatic hypercalcemia associated with relatively depressed urinary calcium excretion.
Tertiary hyperparathyroidism In some patients with prolonged secondary hyperparathyroidism, hyperplasia or neopla-sia of the parathyroid glands develops. These parathyroids no longer respond appropriately to serum calcium; instead, they produce excess PTH at all times, leading to chronic hypercal-cemia. This is most often seen in patients with chronic kidney disease. More than one parathyroid gland is usually affected.
Diagnosis
Clinical manifestations The clinical manifestations of hy-perparathyroidism depend, in part, on the severity of the hyper-calcemia. When hyperparathyroidism was first described more than 50 years ago, most patients presented with late-stage complications of prolonged and severe hypercalcemia, such as abnormalities of bone (osteitis fibrosa cystica)6 or kidneys (nephro-calcinosis, renal failure). Since the development more than 30 years ago of laboratory equipment for measuring serum chemistry, hyperparathyroidism is often diagnosed by routine blood testing, before the development of symptoms. It also may be uncovered during the evaluation of osteoporosis or during the workup of renal stone disease.
When symptomatic, patients with hyperparathyroidism demonstrate clinical manifestations of hypercalcemia (see above).
Physical examination In general, parathyroid tumors are too small to be palpable. Indeed, a palpable parathyroid tumor should be suspected as a malignancy until proved otherwise. Evidence of the consequences of hyperparathyroidism should be sought, such as osteoporosis (kyphosis) or nephrolithiasis (costovertebral angle tenderness).
Laboratory tests Currently, most patients with hyper-parathyroidism have a serum calcium concentration of less than 12 mg/dl (unless coexisting volume contraction is present), and they may have mild to moderate hypophosphatemia and a non-anion gap metabolic acidosis (from renal tubular acidosis). Urinary calcium excretion is often increased; in these patients, the reduction of fractional calcium excretion by PTH is overcome by the high filtered calcium load. This may result in nephrocalcinosis or nephrolithiasis.
Renal stones in patients with hyperparathyroidism are usually composed of calcium oxalate and tend to occur bilaterally, especially when urinary calcium excretion is high. Rarely, nephro-calcinosis and azotemia develop, usually in those with the most severe and protracted hypercalcemia, especially if dehydration or other renal insult is superimposed. Because PTH increases both osteoclast and osteoblast activity, there are increases in serum and urinary concentrations of biochemical markers of bone turnover, including bone alkaline phosphatase.
Elevation of both the serum calcium and the PTH concentrations (in the absence of low urinary calcium excretion) supports a diagnosis of primary hyperparathyroidism. PTH levels are usually increased to less than five times the upper limit of normal. In certain mild cases, the calcium level is only slightly high, and the PTH is minimally elevated or inappropriately normal. Rarely, patients with primary hyperparathyroidism have serum calcium levels in only the high-normal range. In fact, most such patients have elevated serum ionized calcium values and therefore are not actually normocalcemic. The diagnosis in such patients can be extremely challenging.
When the PTH level is normal or mildly elevated and the 24hour urinary calcium level is low, consideration should be given to the possibility of FHH.7 The relatively low urinary calcium output seen in FHH may help distinguish this condition from primary hyperparathyroidism, although low urinary calcium excretion may also occur in hyperparathyroidism.
The possibility of FHH is raised when there is a strong family history of symptomatic, stable hypercalcemia, especially in patients younger than 40 years; when family members have undergone unsuccessful parathyroid surgery; or when the patient’s urinary calcium output is unexpectedly low. When this diagnosis is suspected, further evaluation is necessary, such as the screening of other family members. Unfortunately, specific genetic testing is not currently widely available from commercial laboratories. In some cases, FHH cannot be distinguished confidently from primary hyperparathyroidism. However, in most such patients, expectant management is safe and avoids unnecessary parathyroid exploration. When there is trouble distinguishing between primary hyperparathyroidism and FHH, parathyroid imaging is sometimes useful. In primary hyper-parathyroidism, enlarged parathyroid glands are easily found, whereas parathyroid size is usually normal in FHH.
Once the diagnosis of primary hyperparathyroidism is secured, it will usually already be apparent whether the patient is a candidate for parathyroidectomy. If the patient does not meet criteria for surgery on the basis of age, renal function, urinary calcium excretion, history of fractures, or renal stones/nephro-calcinosis, then measurement of bone density with a dual-energy x-ray absorptiometry (DXA) scan may be useful. In addition to the standard left hip and lumbar spine measurements, assessment at the distal radius may be particularly helpful, because hyperparathyroidism may affect this predominantly cortical site more than the other locations, which have a greater percentage of trabecular bone.6
Other diagnostic studies are usually not necessary. Consideration should also be given to the possibility of one of the MEN syndromes, particularly if the patient is young or has a personal or family history of a related endocrinopathy.5 This information will be helpful to the surgeon, because the patient with primary hyperparathyroidism in the setting of a MEN syndrome usually has multigland parathyroid hyperplasia, and in such patients a surgical procedure beyond a single parathyroidectomy is necessary. If MEN II is suspected, medullary thyroid cancer should be considered, and pheochromocytoma must be excluded before the patient goes to surgery.
Treatment
Previous controversy over which patients with hyperparathy-roidism require surgical intervention has been largely resolved. Those without symptoms or complications clearly related to hy-perparathyroidism can be followed safely for long periods. Treatment of the patient with primary hyperparathyroidism must take into account the degree of the hypercalcemia, the presence of symptoms, and the severity of any end-organ damage.8 Understandably, it is widely agreed that patients with symptoms clearly attributable to hypercalcemia should undergo surgery.
Guidelines for surgical intervention in patients with primary hyperparathyroidism were developed at a National Institutes of Health workshop in 2002.9 The indications for surgical intervention are as follows:
1. Significant bone, renal, gastrointestinal, or neuromuscular symptoms typical of primary hyperparathyroidism.
2. Elevation of serum calcium by 1 mg/dl or more above the normal range (i.e., > 11.5 mg/dl in most laboratories).
3. Marked elevation of 24-hour urine calcium excretion (e.g., > 400 mg).
4. Decreased creatinine clearance (i.e., reduced by > 30% compared with age-matched normal persons.
5. Significant reduction in bone density (i.e., > 2.5 standard deviations below peak bone mass [T score < -2.5 at the lumbar spine, proximal femur, or distal radius]).
6. Consistent follow-up is not possible or is undesirable because of coexisting medical conditions.
7. Age younger than 50 years.
Those patients with mild hypercalcemia who are truly asymptomatic can be followed clinically for the subsequent development of surgical indications. Most will likely remain asymptomatic and will not require intervention.9
Preoperative localization Imaging studies to locate parathyroid adenomas have become more widely used, particularly as more centers have started offering minimally invasive surgery with intraoperative PTH assays (see below).10,11 In most cases of adenoma in a single gland, precise knowledge of the location of the adenoma may decrease operative time by allowing the surgeon to direct attention to the area of suspicion. It is important to remember, however, that in good hands, parathyroidectomy for primary hyperparathyroidism has a cure rate in the range of 90% to 95%, even without such localization studies. Thus, it is unlikely that preoperative localization will ever be demonstrated to improve overall surgical outcomes. Localization studies are mandatory before minimally invasive parathyroidectomy, in the setting of a second neck exploration for persistent or recurrent hyperparathyroidism, or if previous thyroid surgery has been performed. The localization test of choice is technetium-99m sestamibi scintigraphy.12,13 This is often followed by a neck ultrasound of the region demonstrating scintigraphic activity to confirm the location of an enlarged parathyroid gland. An additional benefit of ultrasound at this stage in the evaluation is to provide the opportunity for any coexisting thyroid abnormalities to be addressed.
Surgical management The surgical procedure required in patients with hyperparathyroidism resulting from a solitary parathyroid adenoma is resection of that gland. If intraoperative PTH assays show a drop in the PTH level by more than 50% a few minutes after resection, no further neck exploration is required. Intraoperative measurement of PTH is considered by some experts to be critical in the case of ectopic parathyroid adenoma (which would not be easily found during routine neck exploration) and in reoperations. If an intraoperative PTH assay is not used, the other three glands must be directly inspected to ensure that a second adenoma or generalized hyperplasia is not present.14 If a second adenoma is found, it too should be excised. If hyperplasia is encountered, the surgeon performs a subtotal parathyroidectomy: removal of approximately three to three and one half glands. In some centers, this is followed by auto-transplantation of remaining parathyroid tissue to the forearm, which may simplify follow-up surgical exploration in the event of recurrent hypercalcemia. Additional parathyroid tissue may be frozen in case future need develops. Parathyroid autotrans-plantation is a controversial treatment, because some patients experience aggressive regrowth of parathyroid tissue within the forearm muscles. This can require challenging and disfiguring surgery to correct.
At certain centers, so-called minimally invasive parathy-roidectomy is being offered in conjunction with intraoperative PTH measurements.11 This approach is best suited for a good surgical candidate in whom both history and preoperative imaging studies suggest a single adenoma (which is, in fact, the most common situation in primary hyperparathyroidism). With information from scintigraphy and ultrasound already in hand, the diseased gland can be excised through a smaller, unilateral incision, under local nerve block, in an ambulatory setting. Success is gauged by the drop in PTH levels intraoperatively. This approach usually provides a better cosmetic result, quicker recovery time, and a lower incidence of postoperative hypocal-cemia. Minimally invasive surgery may not be appropriate in suboptimal surgical candidates, in patients who may have multigland disease, and in reoperative cases. However, it is quite likely that the majority of parathyroidectomies will be performed in this fashion in the future.
Table 2 2002 NIH Working Group Recommendations Regarding Follow-up Testing for Patients with Primary Hyperparathyroidism Who Do Not Undergo Surgery9
|
Measurement |
Frequency |
|
Serum calcium |
Biannually |
|
24-hour urine calcium |
At initial evaluation only |
|
Creatinine clearance |
At initial evaluation only |
|
Serum creatinine |
Annually* |
|
Bone mineral density |
Annually (lumbar spine, femur, and forearm) |
|
Abdominal radiograph (or ultrasound) |
At initial evaluation only |
* If the serum creatinine suggests a change in renal function, measurement of creatinine clearance is recommended.
Hyperparathyroidism occasionally persists after operative intervention, usually because of failure to identify the culprit gland, occasionally because of undiagnosed multigland hyper-plasia, and rarely because of undiagnosed parathyroid carcino-ma.15-17Scar tissue and the sometimes unexpected location of remaining pathologic parathyroid tissue make second surgeries notoriously more challenging and prone to complications. Consequently, preoperative imaging studies are invaluable in patients undergoing repeat surgery for persistent hyperparathy-roidism. Catheterization studies with venous sampling may also be helpful in certain difficult cases. The identity of putative parathyroid glands can be confirmed by fine-needle aspiration with real-time PTH assay.
Nonsurgical management Although there is as yet no recognized medical therapy for primary hyperparathyroidism, patients who do not meet the criteria for surgical intervention or who refuse surgery can be followed expectantly. This involves periodic monitoring of serum and urine calcium levels, renal function, and BMD, as well as evaluation for nephrocalcinosis or nephrolithiasis. The extent and frequency of this monitoring should be tailored to the individual patient’s disease and comor-bidities. [see Table 2].9 Drugs that have a tendency to raise serum calcium levels, such as thiazides and lithium, should be avoided. Calcium and excessive vitamin D supplementation should generally be avoided. Dietary calcium should not be restricted, because such restriction may lead to further elevation of PTH and may possibly have detrimental effects on bone mass. Vitamin D deficiency should be identified and treated with gradual supplementation, because vitamin D deficiency will enhance the adverse effects of hyperparathyroidism on bone. Good hydra-tion should be maintained at all times to avoid the development of renal insufficiency and renal stones, especially in patients with hypercalciuria. In patients with low BMD, a bisphospho-nate will help to slow bone loss. In patients who are very hyper-calcemic but cannot or will not have surgery, calcimimetic agents have been used to control hypercalcemia, although they re not approved by the Food and Drug Administration for use in this particular setting. For example, the calcimimetic agent cinacalcet is approved for the treatment of secondary hyper-parathyroidism in patients with chronic kidney disease who are on dialysis, as well as for the treatment of hypercalcemia in patients with parathyroid cancer. Calcimimetic agents activate the CaSR and thus diminish PTH production. The high cost of these agents and the relative ease of parathyroid surgery make their widespread use in the future unlikely.18
Pth-independent hypercalcemia
Cancer remains the most common cause of PTH-indepen-dent, persistent, substantial hypercalcemia and is most frequently to blame when an acutely elevated calcium level is discovered in a hospitalized patient. Other causes include sar-coidosis, certain endocrine disorders, and various drugs and supplements.
Etiology
Malignancy Malignancy-associated hypercalcemia has two forms: humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia (LOH).
HHM results from the elaboration by the tumor of a circulating factor that has systemic effects on skeletal calcium release, renal calcium handling, or GI calcium absorption. Rarely, it can be caused by the unregulated production of calcitriol (usually by B cell lymphomas). However, the best-recognized mediator responsible for HHM is parathyroid hormone-related protein (PTHrP).19 Normally, PTHrP appears to serve as a paracrine factor in a variety of tissues (e.g., bone, skin, breast, uterus, and blood vessels); it is involved in cellular calcium handling, smooth muscle contraction, and growth and development. The amino terminus of PTHrP is homologous with that of PTH, and they share a common receptor. When PTHrP circulates in supra-physiologic concentrations, it induces most of the metabolic effects of PTH, such as osteoclast activation, decreased renal calcium output, and increased renal phosphate clearance.
Tumors that produce HHM by secreting PTHrP are usually squamous cell carcinomas (e.g., lung, esophageal, laryngeal, oropharyngeal, nasopharyngeal, or cervical carcinomas).20 Other tumor types that occasionally produce PTHrP include adenocar-cinoma of the breast and ovary, renal cell carcinoma, transitional cell carcinoma of the bladder, islet cell tumors of the pancreas, T cell lymphomas, and pheochromocytoma. All tumors that elaborate PTHrP do so in relatively small amounts; thus, the syndrome typically develops in patients with a large tumor burden. It is also unusual for HHM to be the presenting feature of the cancer.
LOH occurs when a tumor growing within bone itself causes the local release of calcium through the production of cytokines that activate osteoclasts; there is no production of a systemic factor in these cases. The classic tumor associated with this syndrome is multiple myeloma, although other neoplasms, such as adenocarcinoma of the breast and various lymphomas, may also cause LOH. Local factors produced by bone cells may further enhance the growth of such tumors; this results in the skeleton inadvertently working in concert with the tumor to promote progressive bone resorption and calcium release and further advancement of the cancer. (This is the basis of the success of bis-phosphonates in the treatment of multiple myeloma.)
Other causes PTH-independent hypercalcemia may be caused by sarcoidosis and other granulomatous diseases, such as tuberculosis, in which granulomas produce calcitriol. Endocrine conditions that may occasionally lead to hypercalcemia include hyperthyroidism (which stimulates bone turnover) and Addison disease (in which volume contraction reduces calcium clearance). Immobilization may increase calcium levels, usually in persons with active bone turnover, such as adolescents or those with previously unrecognized hyperparathyroidism or Paget disease of bone (see below). Use of drugs and dietary supplements (e.g., vitamin D and vitamin A) may be associated with hypercalcemia. The association of thiazides with hypercal-cemia is now thought to occur when a thiazide-induced reduction in calcium excretion unmasks previously unrecognized primary hyperparathyroidism. Although only rarely encountered today, the so-called milk-alkali syndrome results from the long-term consumption of large quantities of milk and antacids; milk and antacids were the standard treatment of peptic ulcers in the days before the development of H2 receptor blockers and proton pump inhibitors.
Diagnosis
If the serum calcium concentration is elevated but the PTH level is very low, the patient has PTH-independent hypercal-cemia. Possible causes include malignancy, granulomatous disease, thyrotoxicosis, and vitamin D intoxication. These cases require further laboratory assessment, with the choice of tests depending on the clinical situation.
In malignancy-associated hypercalcemia, the degree of calcium elevation is usually moderate or severe. Evidence of significant volume depletion and generalized debility may dominate the clinical picture, along with other cancer-related symptoms. Typically, the diagnosis of malignancy has already been established. The diagnosis of malignancy-associated hypercalcemia should be suspected in cancer patients with hypercalcemia who have abnormally low PTH concentrations. In patients with tumors associated with HHM, measurement of PTHrP is indicated. Radioimmunoassays for PTHrP are commercially available; an elevation of PTHrP concentration will essentially confirm the diagnosis of most cases of HHM. Special care should be taken to ensure that blood for PTHrP levels is drawn and handled correctly to avoid spuriously low results. In HHM from B cell lym-phomas, circulating plasma concentrations of calcitriol are increased. In local osteolytic disease, PTHrP and calcitriol are within normal ranges, and there is definitive evidence of bony metastases.
When the PTH is low and the patient is not known to have a malignancy, diagnostic possibilities include granulomatous diseases, other endocrine disorders, drugs or dietary supplements, and immobilization. Possible laboratory studies in such patients might include measurement of vitamin D metabolites, thyroid hormone levels, or 24-hour urine calcium excretion. If investigation of these diagnoses proves unrewarding, the very rare possibility of unrecognized malignancy may be considered, especially if measurement of PTHrP is performed and shows elevated values. Further imaging studies are indicated in such cases, including a plain chest radiograph or a computed tomographic scan of the thorax as the initial study. If the results are negative, consideration should be given to a comprehensive otolaryngo-scopic examination, esophagoscopy, or CT of the abdomen. Should such further assessment be unrevealing, radiographic or endoscopic assessment of the genitourinary tract should be considered.
Treatment
Acute hypercalcemia A nonparathyroid disorder, often a malignancy, is responsible for most cases of acute hypercal-cemia [see Table 1]. When the serum calcium level is substantially elevated, treatment includes attempts to increase renal calcium excretion while simultaneously attenuating either bone re-sorption or intestinal calcium absorption, depending on which is the primary source of calcium. Because most patients have at least moderate volume contraction, which further exacerbates their ability to excrete calcium, the initial intervention should be expansion of the intravascular volume with an intravenous infusion of normal saline [see Table 3]. This will augment the delivery of sodium and water to the distal nephron, both of which will, in turn, increase urinary calcium excretion. Once the intravascular volume is repleted, adding a loop diuretic such as furosemide will allow continued aggressive saline hydration and may further increase calcium excretion. If the serum calcium concentration does not normalize quickly with intravenous fluid and diuresis, pharmacologic therapy is indicated.21 Because almost all causes of severe hypercalcemia involve some degree of increased osteoclast activation, drugs that decrease bone turnover are favored. The treatment of choice is a bisphosphonate, such as pamidronate or zoledronic acid, both of which are available for intravenous infusion. Pamidronate is given in a dosage of 60 to 90 mg intravenously over several hours; it is generally well tolerated. Typically, serum calcium levels begin to decrease within 24 to 48 hours of the infusion, although the peak effect may not occur for several days. The action of pamidronate may persist for up to several weeks; treatment can be repeated as needed if renal function will allow. Zoledronic acid is given at a dosage of 4 mg intravenously over no less than 15 minutes. It appears to have a higher potency and an even longer duration of action than pamidronate. A repeat dose may be provided after 7 days. Use of intravenous bisphophonates, especially zole-dronic acid, is often associated with an acute-phase response after the first dose, with flulike symptoms. Caution should be employed with these agents in the setting of renal dysfunction. In addition, if parathyroidectomy is planned, use of bisphospho-nates should be considered carefully, because they may make postoperative hypocalcemia management more difficult. When more rapid action is desired, subcutaneous injection of calci-tonin can be tried, either alone or in conjunction with a bisphos-phonate. Calcitonin is given at a dosage of 4 IU/kg twice daily. Calcitonin is a relatively weak hypocalcemic agent; tachyphy-laxis to the effects of calcitonin is common and limits its use to a few days. Other possible therapies are plicamycin and gallium nitrate, although certain toxicities limit their use as first-line agents. In severe or refractory cases, hemodialysis against a low-calcium bath may also be undertaken.
In the more unusual situation of hypercalcemia resulting from an increase in gut calcium absorption, such as in vitamin D intoxication or granulomatous diseases, glucocorticoid therapy may have an integral role. Glucocorticoids directly impede intestinal calcium transport and also decrease renal or granuloma-tous 1a-hydroxylase activity, which results in a decrease in concentrations of calcitriol. In patients with lymphoma, steroids may also have an antineoplastic effect.
Contributing factors to hypercalcemia, such as the use of oral calcium or vitamin D supplements, diuretic therapy, or immobilization, should be corrected, if possible.
In malignancy-associated hypercalcemia, effective surgery, chemotherapy, or radiotherapy targeted at the tumor itself will reduce the hypercalcemia. However, because hypercalcemia is often an end-stage complication, further chemotherapy or radiotherapy may be neither possible nor desired.
|
Table 3 Therapy for Acute Hypercalcemia |
|
Fluids |
|
0.9% NaCl I.V. |
|
Loop diuretic (forced diuresis) |
|
Medications |
|
Bisphosphonates |
|
Pamidronate (60-90 mg I.V.) |
|
Zolendronic acid (4 mg I.V.) |
|
Calcitonin (4 IU/kg S.C. q. 12 hr) |
|
Plicamycin (15-25 |Ag/kg I.V.) |
|
Gallium nitrate (200 mg/m2/day continuous infusion for 5 days) |
|
Glucocorticoids (20-100 mg of prednisone a day) |
|
Other |
|
Primary therapy directed at tumor |
|
Surgery |
|
Chemotherapy |
|
Radiation |
|
Decrease calcium and vitamin D intake |
|
Maintain adequate hydration |
|
Mobilize patient |
Hypocalcemia
Hypocalcemia is defined as a serum calcium level below the reference range for the laboratory. As with hypercalcemia, an ionized calcium determination on a correctly collected sample is the best way to confirm hypocalcemia.
