Etiology of hypercalcemia

INTRODUCTION — Hypercalcemia is a relatively common clinical problem. It results when the entry of calcium into the circulation exceeds the excretion of calcium into the urine or deposition in bone. This occurs when there is accelerated bone resorption, excessive gastrointestinal absorption, or decreased renal excretion of calcium [1]. In some disorders, however, more than one mechanism may be involved. As examples, hypervitaminosis D increases both intestinal calcium absorption and bone resorption, and primary hyperparathyroidism increases bone resorption, tubular calcium reabsorption, renal synthesis of calcitriol (1,25-dihydroxyvitamin D, the most active metabolite of vitamin D), and intestinal calcium absorption.

Among all causes of hypercalcemia, primary hyperparathyroidism and malignancy are the most common, accounting for greater than 90 percent of cases (table 1).

This topic will review the etiology of hypercalcemia. The clinical manifestations, diagnostic approach, and treatment are reviewed separately. (See "Clinical manifestations of hypercalcemia" and "Diagnostic approach to hypercalcemia" and "Treatment of hypercalcemia".)

PARATHYROID MEDIATED

Primary hyperparathyroidism — Hypercalcemia in primary hyperparathyroidism is due to parathyroid hormone (PTH)-mediated activation of osteoclasts, leading to increased bone resorption and elevated intestinal calcium absorption (table 1). Primary hyperparathyroidism is most often due to a parathyroid adenoma. Patients typically have relatively minor elevations in serum calcium concentrations (less than 11 mg/dL or 2.75 mmol/L), and some patients have mostly high-normal values with intermittent hypercalcemia. Occasionally, however, patients have more severe hypercalcemia with levels over 12 mg/dL. When one suspects primary hyperparathyroidism (eg, patient with calcium nephrolithiasis), and the serum calcium is high-normal, it may be necessary to obtain serial measurements of serum calcium to detect hypercalcemia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

Tertiary hyperparathyroidism — Patients with severe chronic kidney disease may develop parathyroid hyperplasia. Such patients usually have frankly low or low-normal serum calcium concentrations (secondary hyperparathyroidism).

In some patients with advanced and prolonged renal failure, parathyroid hyperplasia may gradually progress to autonomous overproduction of PTH that is not suppressible by elevated serum calcium concentrations. In such cases, elevated serum PTH levels are associated with hypercalcemia, a disorder called tertiary hyperparathyroidism. The rise in plasma calcium may be exacerbated by concomitant adynamic bone disease and markedly reduced bone turnover, which results in marked reduction in the skeletal uptake of calcium after a calcium load, such as occurs when calcium carbonate is used as a phosphate binder to treat hyperphosphatemia [2]. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Abnormalities in bone turnover, mineralization, volume linear growth, or strength'.)

If the patient with severe chronic kidney disease undergoes renal transplantation, the parathyroid gland hyperplasia usually subsides, although this may require months to years. In some patients, transient hypercalcemia may develop after renal transplantation; this occurs because correction of the renal failure normalizes phosphate balance and increases calcitriol production, thereby raising serum calcium concentrations until the parathyroid hyperplasia subsides. Often, parathyroid hyperplasia may not resolve completely and some patients have elevated parathyroid hormone levels indefinitely. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation", section on 'Hypercalcemia'.)

Familial hypocalciuric hypercalcemia — Familial hypocalciuric hypercalcemia is a rare autosomal dominant disorder characterized by mild hypercalcemia, hypocalciuria (suggesting a contribution from increased renal tubular calcium reabsorption), normal to moderately elevated serum magnesium concentrations, and normal to slightly increased serum PTH concentrations. The majority of these patients have few, if any, symptoms of hypercalcemia and require no therapy; subtotal parathyroidectomy does not correct the hypercalcemia.

The primary defect in this disorder is a loss-of-function mutation in the calcium-sensing sensor on the parathyroid cells and in the kidneys so that higher than normal serum calcium concentrations are needed to suppress PTH release. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

A rare acquired form of hypocalciuric hypercalcemia due to autoantibodies directed against the calcium-sensing receptor has been described. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Acquired disorders of the calcium-sensing receptor'.)

Metaphyseal chondrodysplasia — A rare form of dwarfism, Jansen-type metaphyseal chondrodysplasia, is associated with asymptomatic but significant hypercalcemia and hypophosphatemia. The parathyroid glands are normal, and serum PTH and PTH-related protein (PTHrP) concentrations are normal or low. The primary defect in this condition is a mutation in the PTH-PTHrP receptor gene, resulting in continuous activation of the receptor at normal or low levels of PTH secretion [3].

NON-PARATHYROID MEDIATED

Malignancy — Hypercalcemia occurs in patients with many malignancies, both solid tumors and leukemias (table 1). In general, serum calcium levels are higher in patients with malignancy than in those with primary hyperparathyroidism, although this is not always the case. Values above 13 mg/dL (3.25 mmol/L) are less commonly seen in primary hyperparathyroidism and, in the absence of another apparent cause, are more likely due to malignancy.

The mechanism of increased bone resorption with malignancy depends upon the cancer. In patients with bone metastases, direct induction of local osteolysis by the tumor cells is common. Cytokines such as tumor necrosis factor and interleukin-1 appear to play an important role by stimulating the differentiation of osteoclast precursors into mature osteoclasts, which then cause increased bone resorption.

In patients with multiple myeloma, hypercalcemia is similarly due to the release of osteoclast activating factors, such as lymphotoxin, interleukin-6, hepatocyte growth factor, and receptor activator of nuclear factor kappa B ligand (RANKL). (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis" and "Normal skeletal development and regulation of bone formation and resorption", section on 'Osteoclasts'.)

The most common cause of hypercalcemia in patients with nonmetastatic solid tumors is secretion of parathyroid hormone (PTH)-related protein (PTHrP). In contrast, hypercalcemia is caused by PTH-independent, extrarenal production of calcitriol from calcidiol by activated mononuclear cells (particularly macrophages) in patients with lymphoma. Although rare, a few patients with ectopic nonparathyroid cancers that secreted PTH, not PTHrP, have been reported.

Hypercalcemia of malignancy is reviewed in more detail elsewhere. (See "Hypercalcemia of malignancy: Mechanisms".)

Hypervitaminosis D — High serum concentrations of either 25-hydroxyvitamin D (25[OH]D; calcidiol) or 1,25-dihydroxyvitamin D (calcitriol) can cause hypercalcemia by increasing calcium absorption and bone resorption. (See "Overview of vitamin D", section on 'Metabolism'.)

Intestinal transport of calcium is primarily regulated by 1,25-dihydroxyvitamin D, which is more potent than 25(OH)D. However, hypercalcemia does occur in patients with markedly elevated serum 25(OH)D concentrations, for example, those who ingest high doses of either vitamin D (which is converted to calcidiol in the liver), calcidiol itself, or use topical calcipotriol, a vitamin D analog used in the treatment of some dermatologic disorders [4-6]. In some patients with hypervitaminosis D, the excess intake was unknown to the patients because milk was inadvertently excessively fortified with vitamin D [4]. In some patients, hypervitaminosis D may be due to taking "over-the-counter" supplements that contain extremely large doses of vitamin D [7].

High serum 1,25-dihydroxyvitamin D concentrations are usually due to ingestion of calcitriol as treatment for hypoparathyroidism or for the hypocalcemia and secondary hyperparathyroidism of renal failure. Calcitriol-induced hypercalcemia usually lasts only one to two days because of the relatively short biologic half-life of calcitriol. Thus, stopping the calcitriol, increasing salt and fluid intake, or perhaps hydration with intravenous saline may be the only therapy that is needed.

Hypercalcemia caused by vitamin D or calcidiol lasts longer because vitamin D may be stored in fat and released over time. More aggressive therapy such as glucocorticoids and intravenous bisphosphonates may be necessary [8].

Hypercalcemia can also be caused by increased endogenous production of 1,25-dihydroxyvitamin D, as can occur in patients with malignant lymphoma (see "Hypercalcemia of malignancy: Mechanisms"), chronic granulomatous disorders (especially sarcoidosis) (see "Hypercalcemia in granulomatous diseases"), and, less frequently, in other illnesses characterized by granuloma formation, such as granulomatosis with polyangiitis (GPA) [9] or in association with silicone injections for cosmetic purposes [10].

Finally, a rare cause of hypercalcemia is spontaneous idiopathic excess production of calcitriol in the apparent absence of granulomatous disease. These patients have high serum concentrations of angiotensin-converting enzyme and calcitriol and a presumed increase in calcitriol production by macrophages. The hypercalcemia responds to prednisone but continuous therapy is required [11].

Immobilization — Immobilization causes hypercalcemia due to a non-parathyroid-mediated increase in bone resorption [12-15]. PTH and PTHrP are appropriately low, and the vitamin D level is normal.

MEDICATIONS

Lithium — Patients receiving chronic lithium therapy often develop mild hypercalcemia, most likely due to increased secretion of parathyroid hormone (PTH) due to an increase in the set point at which calcium suppresses PTH release. The hypercalcemia usually, but not always, subsides when the lithium is stopped. Lithium can also unmask previously unrecognized mild hyperparathyroidism. Lithium can also raise serum PTH concentrations without raising serum calcium concentrations. (See "Primary hyperparathyroidism: Pathogenesis and etiology", section on 'Lithium therapy'.)

Thiazide diuretics — Thiazide diuretics lower urinary calcium excretion, an effect that is useful in the treatment of patients with hypercalciuria and recurrent calcium nephrolithiasis (see "Kidney stones in adults: Prevention of recurrent kidney stones" and "Diuretics and calcium balance"). This effect rarely causes hypercalcemia in otherwise normal persons but can lead to hypercalcemia in patients with underlying hyperparathyroidism. (See "Primary hyperparathyroidism: Pathogenesis and etiology", section on 'Thiazide therapy'.)

PTH or PTHrP analogs — Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) analogs belong to a class of osteoporosis drugs called "anabolic" agents because they increase bone formation. Hypercalcemia is a side effect of both types of treatment and is due to a transient increase in bone resorption and in renal tubular calcium reabsorption. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Adverse events'.)

Increased calcium intake — A high calcium intake alone is rarely a cause of hypercalcemia because the initial elevation in serum calcium concentration inhibits both the release of PTH and, in turn, the synthesis of calcitriol. However, in patients who have decreased urinary calcium excretion due to reduced glomerular filtration, increased calcium intake can cause hypercalcemia. This combination of high calcium intake and low urine calcium excretion occurs in two clinical situations: chronic kidney disease and the milk-alkali syndrome.

●Chronic kidney disease – Renal failure alone, although associated with decreased calcium excretion, does not lead to hypercalcemia, because of the calcium-lowering effects of concurrent hyperphosphatemia and decreased calcitriol synthesis. However, hypercalcemia is not unusual in patients who are given calcium carbonate or calcium acetate to bind dietary phosphate, particularly if they have adynamic bone disease or are also treated with calcitriol (or another form of vitamin D) in an attempt to reverse both hypocalcemia and secondary hyperparathyroidism [2]. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Phosphate binders'.)

●Milk alkali syndrome – In the absence of renal failure, hypercalcemia can be induced by a high intake of milk or more commonly, calcium carbonate, leading to hypercalcemia, metabolic alkalosis, and renal insufficiency (the milk-alkali syndrome). The milk-alkali syndrome typically occurs in the setting of excess calcium carbonate supplementation to treat osteoporosis or dyspepsia. Calcium is absorbed in the small intestine via both active and passive transport. The former is more important physiologically and is stimulated by vitamin D metabolites. On the other hand, when calcium intake is greater than 2 grams daily or more, substantial amounts of calcium may be absorbed passively. (See "The milk-alkali syndrome".)

The metabolic alkalosis augments the hypercalcemia by directly stimulating calcium reabsorption in the distal tubule, thereby diminishing calcium excretion. A calcium-induced decline in renal function, due to renal vasoconstriction and, with chronic hypercalcemia, structural injury, can also contribute to the inability to excrete the excess calcium. Renal function usually returns to baseline after cessation of milk or calcium carbonate intake, but irreversible injury can occur in patients who have prolonged hypercalcemia. (See "The milk-alkali syndrome".)

Hypervitaminosis A — Hypervitaminosis A (in which there is prolonged ingestion of more than 50,000 international units per day) [16,17] or the administration of retinoic acid to patients with certain tumors, as either cis-retinoic acid [18] or all-trans retinoic acid [19,20]. Retinoic acid causes a dose-dependent increase in bone resorption, resulting in an overall incidence of hypercalcemia of approximately 30 percent [18]. All-trans retinoic acid inhibits cell growth in part by downregulation of interleukin 6 receptors; the subsequent rise in serum interleukin 6 concentrations may be responsible for increased bone resorption and hypercalcemia [19]. (See "Differentiation syndrome associated with treatment of acute leukemia".)

Theophylline toxicity — Theophylline toxicity has been associated with mild hypercalcemia [9]. As in hyperthyroidism, the hypercalcemia usually subsides in response to administration of a beta-adrenergic antagonist. (See "Theophylline poisoning".)

ENDOCRINE DISORDERS

Thyrotoxicosis — Mild hypercalcemia occurs in up to 15 to 20 percent of thyrotoxic patients, due to a thyroid hormone-mediated increase in bone resorption [21,22]. It typically resolves following correction of hyperthyroidism [21,23]. If the hypercalcemia persists after the restoration of euthyroidism, serum parathyroid hormone (PTH) should be measured to assess for concomitant hyperparathyroidism. (See "Bone disease with hyperthyroidism and thyroid hormone therapy", section on 'Mineral metabolism'.)

Pheochromocytoma — Hypercalcemia is a rare complication of pheochromocytoma. It can be due to concurrent hyperparathyroidism (in multiple endocrine neoplasia type 2 [MEN2]) or to the pheochromocytoma itself (see "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2"). The hypercalcemia in the latter patients appears to be due to tumoral production of PTH-related protein (PTHrP) [24-26]. Serum PTHrP concentrations in these patients can be reduced by alpha-adrenergic blockers, suggesting a mediating role for alpha-stimulation [27].

Adrenal insufficiency — Hypercalcemia occurs in occasional patients with Addisonian crisis [28,29]. Multiple factors appear to contribute to the hypercalcemia including increased bone resorption, volume contraction and increased proximal tubular calcium reabsorption, hemoconcentration, and perhaps increased binding of calcium to serum proteins. Cortisol administration reverses the hypercalcemia within several days [28]. Hypercalcemia has also been reported in patients with secondary adrenal insufficiency [30-32]. The increased release of calcium from bone occurs despite appropriate suppression of PTH and calcitriol release and appears to be mediated, at least in part, by thyroid hormone via a process normally inhibited by glucocorticoids [30].

MISCELLANEOUS CAUSES

Rhabdomyolysis associated with acute renal failure — Hypercalcemia has been described during the diuretic phase of acute renal failure, most often in patients with rhabdomyolysis. Hypercalcemia in this setting is primarily due to the mobilization of calcium that had been deposited in the injured muscle. Correction of hyperphosphatemia (induced by the rise in glomerular filtration rate), mild secondary hyperparathyroidism induced by the renal failure, and an unexplained increase in serum calcitriol concentrations all appear to contribute to the hypercalcemia. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Clinical features and diagnosis of heme pigment-induced acute kidney injury", section on 'Calcium'.)

A similar mechanism of mobilization of calcium phosphate as renal failure-induced hyperphosphatemia is corrected plus persistent secondary hyperparathyroidism may account for the transient hypercalcemia that can occur after successful renal transplantation. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Congenital lactase deficiency — Hypercalcemia and medullary nephrocalcinosis have been described in infants with congenital lactase deficiency [33]. The hypercalcemia resolves rapidly after institution of a lactose-free diet, but the nephrocalcinosis may persist. The hypercalcemia may be due to an increase in calcium absorption in the ileum in the presence of nonhydrolyzed lactose.

SUMMARY AND RECOMMENDATIONS

●Pathophysiology of hypercalcemia – Hypercalcemia is a relatively common clinical problem. It results when the entry of calcium into the circulation exceeds the excretion of calcium into the urine or deposition in bone. This occurs when there is accelerated bone resorption, excessive gastrointestinal absorption, decreased renal excretion of calcium, or a combination of these mechanisms. (See 'Introduction' above.)

●Etiology of hypercalcemia – Among all causes of hypercalcemia, hyperparathyroidism and malignancy are the most common. (See 'Primary hyperparathyroidism' above and 'Malignancy' above.)

The many other causes of hypercalcemia occur less frequently but are important to consider in clinical situations when hypercalcemia is not caused by hyperparathyroidism or malignancy (table 1).