Hypercalcemia is a relatively common clinical problem. It typically manifests as a mild chronic calcium level elevation, although hypercalcemic emergencies do exist. Calcium homeostasis is tightly regulated, and hypercalcemia can affect almost every organ system in the body.

Pathophysiology

Usually, hypercalcemia is reported as elevation of total plasma calcium levels rather than ionized calcium levels. Approximately 50% of total calcium is protein bound, and the total calcium level will vary with protein-binding capacity. This phenomenon may rarely result in pseudohypercalcemia—for example, in patients with hyperalbuminemia secondary to dehydration and in some patients with multiple myeloma. More commonly, lowering of total calcium levels is observed in patients with low levels of binding proteins (hypoalbuminemia). This physiology requires that the total plasma calcium level be corrected for the albumin level. Normal calcium levels may range from 8.5 to 10.5 mg/day, assuming an albumin level of 4.5 g/dL. The calcium concentration [Ca] usually changes by 0.8 mg/dL for every 1.0-g/dL change in plasma albumin concentration. Thus, this formula estimates the actual total plasma calcium level:

Corrected [Ca] = Total [Ca] + (0.8 × [4.5 − albumin level])

Acidosis decreases the amount of calcium bound to albumin, whereas alkalosis increases the bound fraction of calcium. A small amount of calcium (about 6%) is complexed to anions such as citrate and sulfate. The remainder is ionized calcium that is biologically active.

The most common causes of hypercalcemia, affecting 90% of all patients, are primary hyperparathyroidism (HPT) and malignancy. Other causes are summarized in Box 1.

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Signs and symptoms

Symptoms of hypercalcemia ( Table 1) are nonspecific and are related to the severity and rate of change of the serum calcium level. Symptoms are more severe with acute changes than with chronic calcium level elevation. Patients with a chronic calcium level as high as 12 to 14 mg/dL may tolerate those levels well, whereas sudden development of hypercalcemia in this range or higher may lead to dramatic changes in a patient's mental status. Symptoms of underlying diseases causing hypercalcemia may dominate the clinical picture.

A normal extracellular calcium concentration is necessary for normal neuromuscular function, and neurologic dysfunction is the major feature of hypercalcemic states. Changes vary from slight difficulties in concentrating to depression, confusion, and coma. Some of these symptoms may resolve or improve after correction of the hypercalcemia. ¹ Muscle weakness is another clinical manifestation.

Chronic hypercalcemia may result in the formation of renal calculi. Hypercalciuria is the main factor in stone formation, but increased calcitriol production in HPT also plays a role. Nephrogenic diabetes insipidus resulting in polydipsia and polyuria is seen in about 20% of patients. Mechanisms include downregulation of water channels (aquaporin 2) and tubulointerstitial injury caused by calcium deposition. Renal tubular acidosis and renal insufficiency are rare. Chronic hypercalcemic nephropathy may continue to worsen after correction of hypercalcemia.

Hypertension is seen with increased frequency in patients with hypercalcemia and may be caused by renal insufficiency, calcium-mediated vasoconstriction, or both. Hypertension may or may not resolve after correction of hypercalcemia. Cardiac effects include short QT intervals, which may increase sensitivity to digitalis, and deposition of calcium in heart valves, myocardium, or coronary arteries.

Constipation, anorexia, nausea, and vomiting are often prominent symptoms, whereas acute pancreatitis (via activation of trypsinogen in pancreatic parenchyma) and peptic ulcer disease (via stimulation of gastrin secretion) are unusual. Fatigue, musculoskeletal weakness, and pain are the only symptoms known to correlate with increasing levels of serum calcium.

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Primary hyperparathyroidism

Sporadic Primary Hyperparathyroidism

Primary HPT occurs at all ages but is most common in the sixth decade of life. It is three times more common in women than in men. When HPT affects children, it is likely to be a component of familial endocrinopathies such as the multiple endocrine neoplasia (MEN) syndromes type I and II or familial HPT. The incidence of HPT is approximately 4 per 100,000 per year. ²

The underlying pathophysiology of HPT is caused by excessive secretion of parathyroid hormone (PTH), which leads to increased bone resorption by osteoclasts, increased intestinal calcium absorption, and increased renal tubular calcium reabsorption. The consequent hypercalcemia is also often accompanied by low-normal or decreased serum phosphate levels because PTH inhibits proximal tubular phosphate reabsorption.

Most cases of HPT (80%) are discovered accidentally by automated blood sample analyzers that were initially introduced into clinical practice in the 1970s. These cases have minimal or no symptoms, and calcium levels are only mildly elevated (lower than 12 mg/dL). Patients with HPT can present with any of the clinical manifestations summarized in Table 1 , and this diagnosis needs to be considered especially in any patient presenting with kidney stones, bone disease, or hypercalcemic crisis.

Renal calculi are seen in 15% to 20% of patients with HPT and, conversely, about 5% of patients with renal calculi have HPT. Some of these patients may have calcium levels in the upper range of normal. Most calculi are composed of calcium oxalate and the main factor in pathogenesis is hypercalciuria. Although PTH stimulates calcium reabsorption in the distal tubule, the kidney is overwhelmed by the increase in the amount of filtered calcium resulting from increased serum calcium levels. Patients with increased vitamin D levels are more likely to have hypercalcemia and nephrolithiasis.

Classic bone disease of HPT manifests with brown tumors, osteitis fibrosa cystica, and subperiosteal resorption on the radial aspect of middle phalanges. These findings are present only in severe and long-standing disease, and today are seen rarely, usually when disease is caused by parathyroid carcinoma and in secondary or tertiary HPT is associated with chronic renal insufficiency. ³ Low bone mineral density is found in some patients with HPT, but it is unclear whether this occurs more often than in the normal population. Some studies have shown decreased bone mineral density in untreated cases ³ but others have not. ⁴ However, most studies have shown an increased risk for vertebral fractures in patients with HPT. Hip fractures were studied in a cohort of 1800 patients in Uppsala, Sweden, and revealed no extra risk for women but an increased risk in men. ⁵

Hypercalcemic crisis is a rare manifestation and is characterized by calcium levels usually above 15 mg/dL and severe symptoms of hypercalcemia, particularly central nervous system (CNS) dysfunction. Abdominal pain, pancreatitis, peptic ulcer disease, nausea, and vomiting are also seen more commonly in these patients. The mechanism whereby a crisis develops is not clear, but dehydration, intercurrent illness, and possibly infarction of parathyroid adenoma in some patients all play roles.

Several studies have found excessive mortality in patients with HPT, with most of the excess caused by cardiovascular disease. The largest study included 4461 patients and measured an increased mortality risk of 1.71 for men and 1.85 for women. ⁶

Diagnosis

The diagnosis of HPT requires an elevated serum calcium level, with simultaneous demonstration of elevated PTH levels (in 80% to 90% of patients) or within normal limits (in 10% to 20% of patients). Note that patients with hypercalcemia should have their PTH level suppressed and that the “normal” level is inappropriately high in these patients. The PTH elevated should be determined by an assay that measures the intact PTH molecule. The phosphorus level may be low but is usually just in the low-normal range. Urinary calcium excretion is measured by a 24-hour urine collection that should also specify total volume and urine creatinine levels; hypercalciuria should be considered if the urinary calcium level is higher than 400 mg/day. In addition, low calcium excretion (lower than 150 mg/day) may signify familial hypercalcemic hypocalciuria, which is not surgically treatable.

A careful family history is paramount for the recognition of familial forms of primary HPT. In these cases, urinary screening for catecholamine overproduction is important before surgical treatment.

Localization of abnormal parathyroid glands preoperatively by means of ultrasound, Tc 99m-sestamibi scintigraphy, or magnetic resonance imaging (MRI) may offer a possibility for a less invasive surgical approach. The accuracy of these radiologic modalities is variable. They are not required for the diagnosis of HPT, but serve mainly as guides for surgical strategy, and the selection of these tests should be left to the surgeon.

Treatment

Indications for Treatment.

Removal of the abnormal and hyperfunctioning parathyroid tissue results in a long-term cure of HPT in 96% of patients and significant improvement in associated symptoms. The following criteria were proposed as indications for parathyroidectomy based on a National Institutes of Health–sponsored panel and endocrine specialty societies: ⁷

1. Serum Ca level more than 1 mg/dL above the upper limit of normal


2. Marked hypercalciuria higher than 400 mg/day


3. Creatinine clearance reduced more than 30% compared with age-matched controls


4. Reduction in bone mineral density of the femoral neck, lumbar spine, or distal radius of more than 2.5 standard deviations below peak bone mass (T score lower than -2.5)


5. Age younger than 50 years


6. Patients for whom medical surveillance is not desirable or possible


7. Presence of any complications (e.g., nephrolithiasis, overt bone disease)


8. An episode of hypercalcemic crisis

However, because no effective medical therapy for HPT exists, all patients with HPT who are otherwise healthy for surgery should be referred for surgical treatment.

Surgical Treatment.

Parathyroid surgery remains the single most effective treatment option in HPT and requires removal of all abnormal parathyroid tissue. Traditionally, in the vast majority of U.S. practices, this has meant bilateral exploration of the neck to identify all (typically four) parathyroids, assess which ones are abnormal, and remove only the abnormal glands. The setting of multiglandular hyperplasia requires subtotal parathyroidectomy or total parathyroidectomy, with reimplantation of parathyroid tissue into the sternocleidomastoid or forearm muscles. The parathyroids may then also be cryopreserved as a safeguard against future hypocalcemia, in which case the patient may undergo autotransplantation of autogenous, stored parathyroid tissue. In experienced hands, this approach has an exceptional rate of successful long-term cure of HPT (more than 96%) and a low rate of surgical complications (hypocalcemia less than 1%, recurrent laryngeal nerve injury 2% to 5%, neck hematoma or infection less than 1%). ⁸

In recent years, parathyroid procedures have been developed using smaller incisions under sedation and local anesthesia, and with the opportunity for outpatient surgery. Minimally invasive parathyroid surgery has become more frequently requested by patients and primary care physicians alike, even though it does not represent a uniform set of techniques. Depending on regional practices, minimally invasive parathyroid surgery can include laparoscopic, radio-guided or, most frequently, only unilateral neck surgery. The success of these approaches in curing HPT and minimizing complications is relatively unknown because clinical follow-up periods are still short. Minimally invasive parathyroid surgery is appropriate only for patients who have a single, clearly defined parathyroid abnormality on ultrasound, sestamibi scan, or both and when parathyroid hormone levels can be monitored intraoperatively. Bilateral neck exploration is mandatory in all other cases and for patients with familial or genetic syndromes.

Medical Treatment.

Patients who are not treated surgically should be managed to ensure good hydration and to avoid thiazide diuretics. Ambulation should be encouraged. Calcium intake should be average, because excessive intake may aggravate hypercalcemia, especially in patients with high calcitriol levels, whereas low calcium intake may stimulate PTH secretion. Bisphosphonates may be used to lower the serum calcium level in patients with symptomatic hypercalcemia (see later, “Treatment of Hypocalcemia”), although they are usually not effective.

Familial Forms of Hyperparathyroidism

Up to 10% of cases of primary HPT are hereditary forms. Recognition is important because management of many patients and their families may be affected.

The most common familial form is multiple endocrine neoplasia syndrome type I (MEN-I). In this disorder, primary HPT is almost invariably present (in more than 95% of patients) by the age of 65 years, but may be diagnosed in children and even in infants. Indications for surgical intervention are generally the same as for sporadic cases. Pancreatic tumors are present in 30% to 80% of patients. These are usually islet cell tumors secreting gastrin and causing Zollinger-Ellison syndrome in about two thirds of cases. The second most common pancreatic tumor is insulinoma. Tumors secreting various substances have been described.

Pituitary adenomas affect 15% to 50% of patients and are mostly prolactinomas, although tumors causing acromegaly and Cushing's disease also occur. Adrenocortical hyperplasia is seen in about one third of patients.

MEN-I is caused by autosomal dominant mutation of the menin gene on chromosome 11. Genetic testing is cumbersome, and screening of family members should be done by determining serum calcium levels. Some patients develop MEN-1–associated lesions as late as age 35 years.

MEN-II is characterized by the development of medullary thyroid carcinoma, which occurs in almost all patients. Hyperparathyroidism occurs in about one half of affected individuals; most are asymptomatic. Pheochromocytoma or adrenal medullary hyperplasia is an associated feature. The mutated gene is the RET protooncogene. Genetic testing of family members is desirable because it clearly identifies individuals at risk, and timely thyroidectomy is lifesaving.

Other familial syndromes are rare and include the HPT–jaw tumor syndrome and familial isolated primary HPT.

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Other types and causes of hypercalcemia

Tertiary Hyperparathyroidism

In cases of prolonged states of secondary HPT, as seen in patients with end-stage renal disease, vitamin D deficiency, and states of vitamin D resistance, the parathyroid glands undergo hypertrophy and eventually develop autonomous PTH secretion, which in turn leads to hypercalcemia and resembles primary HPT. This condition is called tertiary HPT. The cure requires surgical intervention to reduce the amount of parathyroid tissue.

Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is a rare familial condition caused by an inactivating disorder of calcium-sensing receptors that is expressed in many tissues, but has a major function in regulating calcium metabolism through effects on parathyroid tissue and on handling of renal calcium. The disorder is autosomal dominant, with high penetrance. Several mutations are described, but all decrease the sensitivity of receptors to calcium, requiring higher calcium levels to suppress PTH secretion. Heterozygous patients present with hypercalcemia, hypocalciuria, and mild hypermagnesemia. Fractional excretion of calcium is lower than 1%, despite hypercalcemia. The PTH level is normal or slightly elevated (up to twice the normal in our clinical experience).

The clinical significance of this disease lies mostly in mistaken diagnosis of HPT and referral for parathyroidectomy. A commonly performed subtotal parathyroidectomy cannot correct hypercalcemia, and these patients sometimes undergo multiple surgeries.

Genetic testing is not routinely available and usually is unnecessary. Patients are free of symptoms, a family history will uncover more family members with hypercalcemia, and urinary calcium excretion is low (about 75% of patients excrete less than 100 mg/day). Such a low calcium excretion in the face of hypercalcemia indicates increased renal tubular calcium absorption and low calcium clearance. The ratio of calcium (Ca) clearance to creatinine (Cr) clearance may be used for the diagnosis of FHH using the following formula:

where Ca_u = urinary Ca concentration, Cr_s = serum Cr concentration, Cr_u = urinary Cr concentration, and Ca_s = serum Ca concentration. A ratio of 0.01 or less is typically seen in individuals with FHH.

Hypercalcemia of Malignancy

Humoral Hypercalcemia of Malignancy

Humoral hypercalcemia of malignancy (HHM) is a clinical syndrome in which elevated calcium levels are caused by effects of the humoral factor synthesized by the tumoral process. Usually, this term is applied to patients with excessive tumoral production of PTH-related peptide (PTHrP). However, rare cases characterized by excessive production of PTH and calcitriol have also been described. Patients with HHM constitute about 80% of all patients with hypercalcemia associated with malignancy.

PTHrP and PTH share the same receptor but there are some differences in clinical presentation. HHM patients have a markedly larger degree of renal calcium excretion—PTH potently stimulates tubular calcium resorption and hypercalciuria is less pronounced. HHM is usually associated with low serum calcitriol levels—PTH stimulates calcitriol production and its level is usually elevated. Also, PTH stimulates bone resorption and formation, whereas PTHrP stimulates only bone resorption, with very low osteoblastic activity and therefore usually normal alkaline phosphatase levels.

These patients have suppressed levels of immunoreactive PTH, whereas the immunoreactive PTHrP level is elevated. In addition, patients with HHM are usually dehydrated, in part because of hypercalcemia and in part because of poor oral intake.

Patients with HHM usually have clinically obvious malignant disease and have a poor prognosis. The only exceptions to this rule are patients with small, well-differentiated endocrine tumors (e.g., pheochromocytomas or islet cell tumors). However, these tumors constitute a minority of cases, and HHM is most commonly seen with squamous cell carcinomas (e.g., lung, esophagus, cervix, head and neck), and renal, bladder, and ovarian cancers. The therapy of HHM is aimed at reducing the tumor burden, reducing osteoclastic resorption of the bone, and increasing calcium excretion through the urine.

Most hypercalcemia cases associated with Hodgkin's disease and about one third of those seen in non-Hodgkin's lymphoma are caused by increased production of calcitriol by the malignant cells. Hypercalcemia usually responds well to treatment with corticosteroids.

Hypercalcemia of Malignancy Associated with Localized Bone Destruction

Multiple myeloma affects the skeleton extensively in almost all patients. In addition, common malignant tumors (e.g., breast, prostate, and lung) frequently metastasize to the bone. Most bone metastases are destructive to the bone tissue (osteolytic).

Bone involvement in multiple myeloma may be in the form of discrete lesions or can affect the axial skeleton diffusely. Bone involvement is responsible for pathologic fractures, bone pain (about 80% patients first present with bone pain), and hypercalcemia (seen in 20% to 40% of patients in the course of disease). Myelomas cause bone destruction by cytokine secretion that activates osteoclasts. The exact nature of the responsible cytokines is unknown. In vitro, lymphotoxin produced by myeloma cells accounts for the major portion of bone resorption activity. Interleukin-1, interleukin-6, and PTHrP may also be involved in the process in some patients. The fact that most patients with multiple myeloma demonstrate extensive bone destruction, whereas far fewer develop hypercalcemia, may be explained by impaired glomerular filtration—a result of nephropathy caused by Bence-Jones protein, uric acid nephropathy, amyloidosis, or infection—and the inability to excrete calcium efficiently in those who do develop hypercalcemia.

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