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Hypercalcemia


Summary of Key Points

  • Incidence

  • Hypercalcemia is a common metabolic complication associated with malignant disease.

  • Hypercalcemia is frequently seen in more advanced malignancy and is associated with poorer prognosis.

  • Etiology

  • The three main mechanisms are tumor secretion of parathyroid hormone–related peptide (PTHrP); production of 1,25(OH) 2 D by autonomous 1α-hydroxylase; and increasing bone resorption by osteolytic metastases through the RANKL pathway.

  • Evaluation of the Patient

  • Determine of the severity of hypercalcemia and underlying malignancy.

  • The total calcium concentration must be corrected for serum albumin concentration.

  • Close attention to volume status and renal function is mandatory.

  • Causes of hypercalcemia other than malignancy should be considered.

  • Patients with symptoms caused by their hypercalcemia should be treated as severely affected, irrespective of the absolute calcium level.

  • Treatment

  • Antitumor therapy should be implemented to treat underlying malignancy.

  • Volume expansion with intravenous fluids is important for calciuresis and treatment of associated renal insufficiency.

  • Antiresorptive therapy and bisphosphonates are first-line therapy.

  • Other therapies targeting underlying or additional causes can be second-line therapy.

Hypercalcemia is a common complication in patients with malignancy, often seen in more advanced disease, and is associated with a poorer prognosis. Although the overall annual prevalence of hypercalcemia of malignancy in patients with stage IV cancer is 1.46 to 2.74, the incidence varies widely with the type of malignancy. Adult T-cell leukemia and lymphoma have the highest incidence, as high as 70% in some reports. Other malignancies such as multiple myeloma have rates of hypercalcemia around 30%. Solid tumors such as lung and breast cancers are associated with hypercalcemia about 12% and 30% of the time, respectively. Hypercalcemia of malignancy results from abnormal handling of calcium from bone resorption, intestinal absorption, or renal excretion.

Calcium Physiology

The body's supply of calcium is divided into three separate and distinct compartments, with the skeleton having the largest calcium reserve ( Fig. 35.1 ). The other two compartments are the intracellular fluid (ICF) and extracellular fluid (ECF). The movement of calcium between compartments is regulated by physical constraints (i.e., cell membranes and calcium-binding proteins) and by hormonal regulation (parathyroid hormone [PTH] and vitamin D). The main concern in this chapter is a high level of calcium in the ECF and how to prevent and/or treat it in the setting of malignancy. Under normal physiologic conditions, the extracellular calcium level is highly regulated to maintain the calcium levels within a very narrow range despite constant input and outflow from other organs.

Figure 35.1, Normal calcium homeostasis. Ca, Calcium; ECF, extracellular fluid.

The organs that control the ECF calcium levels are the gastrointestinal (GI) tract, kidney, and bone. Calcium intake and the resulting absorption through the GI tract is one source for increased ECF calcium (prevalent in malignancies that produce 1,25[OH] 2 D, which increases the absorption of calcium). Failure by the kidney to excrete calcium in large enough amounts is one of the primary mechanisms of hypercalcemia in malignancies that produce parathyroid hormone–related peptide (PTHrP), and osteoclastic resorption of bone tissue with the release of calcium into the ECF can be a direct or indirect effect of some cancers.

In normal calcium physiology, the ECF calcium is maintained in a very narrow therapeutic range. A slight drop in ECF calcium signals the release of PTH from the parathyroid glands. PTH's immediate effect is to raise the renal threshold for calcium excretion, increasing calcium reabsorption. The stimulation of 1α-hydroxylase enzyme increases the production of 1,25(OH) 2 D, which stimulates calcium absorption from the GI tract and may also stimulate the release of calcium from bone. PTH also has a direct effect on osteoblasts signaling to osteoclasts, resulting in bone tissue remodeling and calcium release. Once the ECF calcium level is restored to normal, the PTH release ceases.

The osteoclast is responsible for increasing bone resorption, and this process is tightly linked to the osteoblasts' function of bone formation. One mechanism for keeping these processes tightly linked is signaling between the cells through the RANK/RANKL/OPG pathway. RANKL is the receptor activator of nuclear factor–κB ligand. It is produced by osteoblasts and other cells by the confluence of several hormones and cytokines. RANKL stimulates osteoclast precursors to form osteoclasts; osteoprotegerin (OPG) is a natural decoy for RANKL, keeping the delicate balance between bone resorption and bone formation.

There are three main mechanisms that result in hypercalcemia of malignancy. First, the most common (80%) is tumor secretion of PTHrP, which can act similarly to PTH, resulting in hypercalcemia. Second, production of 1,25(OH) 2 D by autonomous 1α-hydroxylase in the tumor results in increased absorption of calcium. Third, osteolytic metastases can directly or indirectly increase bone resorption, mainly through the RANKL pathway.

Parathyroid Hormone–Related Peptide

The most common cause of hypercalcemia in patients with solid tumors is the secretion of PTHrP. This is also known as humoral hypercalcemia of malignancy. This can occur with lung, head and neck, renal, bladder, breast, or ovarian cancer; non-Hodgkin lymphoma, chronic myeloid leukemia; and adult T-cell lymphoma. Release of PTHrP into the circulation results in stimulation of the PTH receptor in the bone and kidney. This increases bone resorption and increases the distal tubular calcium reabsorption, resulting in release of calcium from the bone as well as a decreased ability to excrete it. It is interesting to note, however, that it does not increase production of 1,25(OH) 2 D.

1,25(OH) 2 D Production

Under normal circumstances, many cells in the body have the machinery to convert 25(OH)D to 1,25(OH) 2 D with intracellular 1α-hydroxylase. Intracellular 1,25(OH) 2 D is for the cell's internal use, and after it is used it is catabolized by 24-hydroxylase to inactive 1,24,25(OH) 3 D; it is then further metabolized and excreted. It has no effect on the systemic calcium regulation, which is under the tight control of PTH. This intracellular 1α-hydroxylase production of 1,25(OH) 2 D becomes a risk for hypercalcemia when it is released into the circulation. This is an important cause of hypercalcemia in granulomatous disease, but also in Hodgkin and non-Hodgkin lymphoma. The elevated 1,25(OH) 2 D increases GI calcium absorption and possibly bone resorption.

Bone Resorption

The tumors that are classically associated with hypercalcemia of malignancy from increased bone resorption and the resultant release of calcium are breast cancer and multiple myeloma. Also, non–small cell lung, renal, and thyroid cancers, as well as lymphoma and melanoma, can cause osteolytic lesions. The bone resorption that occurs is primarily a result of various factors produced by tumors acting to increase osteoclast activity. For example, myeloma cells can produce RANKL, the key stimulator of physiologic osteoclast activity. Also, factors such as interleukin (IL)-6 and other cytokines directly increase osteoclast function. Breast cancer has a similar effect on osteoclasts through the production of locally produced PTHrP, which binds to marrow stromal cells that produce RANKL, which in turn stimulates osteoclasts. Because this is local production of PTHrP, it does not result in measurable systemic levels of PTHrP as in some other cancers.

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