Cancer, hypercalcemia caused

The delicate balance maintained by these factors is altered in patients with cancer by two principal mechanisms tumor production of humoral factors that alter calcium metabolism (humoral hypercalcemia) and local osteolytic activity from bone metastases.27 Humoral hypercalcemia causes around 80% of all hypercalcemia cases and is mediated primarily by systemic secretion of parathyroid hormone-related protein... 

Hypercalcemia causes central nervous system depression, including coma, and is potentially lethal. Its major causes (other than thiazide therapy) are hyperparathyroidism and cancer with or without bone metastases. Less common causes are hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency, and immobilization. With the possible exception of hypervitaminosis D, these latter disorders seldom require emergency lowering of serum calcium. A number of approaches are used to manage the hypercalcemic crisis. 

Cancer and hyperparathyroidism are the most common causes of hypercalcemia. The primary mechanisms are increased bone resorption, increased GI absorption, and decreased renal elimination. 

Breast cancer Androgen therapy may cause hypercalcemia by stimulating osteolysis. 

The mechanism of action of mithramycin (Mithracin) is similar to that of dactinomycin. It is used in patients with advanced disseminated tumors of the testis and for the treatment of hypercalcemia associated with cancer. Mithramycin may cause gastrointestinal injury, bone marrow depression, hepatic and renal damage, and hemorrhagic tendency (see Chapter 62). 

Bisphoshonates are used for treatment of hypercalcemia, fracture prevention and in patients with metastatic cancer. This class of drugs reduce morbidity from hypercalcemia is increasingly recognized to cause nephrotoxicity [14]. Both pamidronate and zoledronate have been associated with nephrotoxicity that features nephrotic syndrome with a collapsing glomerular sclerosis [47]. The mechanism is unkown and the return of renal function is slow. 

Hypercalcemia occurs in 10% to 20% of individuals with cancer. Tumors most commonly cause hypercalcemia by producing PTHrP, which is secreted into the circulation and stimulates bone resorptions and/or by invasion of the bone by metastatic tumor, which produces local factors that stimulate bone resorption. PTHrP binds to the PTH receptor and is the principal mediator of humoral hypercalcemia of malignancy (HHM). Cytokines such as lymphotoxin, interleukin-1, tumor necrosis factor, and PTHrP appear to be important mediators of hypercalcemia in multiple myeloma and other hematological malignancies. Some lymphomas associated with acquired immunodeficiency syndrome or HTLV [ infections cause hypercalcemia by producing 1,25(0H)2D. It is estimated that 5% of patients with hypercalcemic cancer have coexisting primary hyperparathyroidism. 

A second member of the parathyroid hormone family, parathyroid hormone-related protein (PTHrP), is quite similar to PTH in amino acid sequence and protein structure. Like PTH, it activates the parathyroid hormone receptor causing increased bone resorption and renal tubular calcium reabsorption. Increased serum concentrations of parathyroid hormone-related protein are the predominant cause of hypercalcemia in cancer patients with solid tumors. This observation led to its discovery and to the elucidation of its many cellular functions in normal tissues. In contrast to PTH, which is expressed only in parathyroid glands, PTHrP is detected in many tissues in fetuses and adults it is found in epithelia, mesenchymal tissues, endocrine glands, and the central nervous system. This protein is also the principal regulator of placental calcium transport to the fetus. 

Hypercalcemia (total serum calcium >10.5 mg/dL) may be induced by a multitude of causes (Table 49-5). The most common causes of hypercalcemia are cancer and primary hyperparathyroidism. The incidence of primary hyperparathyroidism is approximately 270 new cases per million persons per year. Hypercalcemia of cancer occurs in approximately 20% to 40% of cancer patients at some time during the course of their disease. Cancer-associated hypercalcemia is predominantly encountered in hospitalized patients, while primary hyperparathyroidism accounts for the vast majority of cases in the outpatient setting. ... 

In hospitalized patients, hypercalcemia of malignancy is the major cause of hypercalcemia (26,, , 54). In two separate studies, 9X of all cancer patients had hypercalcemia of malignancy (. 56). Hypercalcemia of malignancy is most common in solid tumors such as carcinomas of the lung, breast, kidney, pancreas and ovary, but also occurs with multiple myeloma and adult T-cell lymphoma/ leukemia. It has been estimated that there is approximately an equal distribution between humoral factors and metastatic bone tumors for causing hypercalcemia of malignancy (26,57,58). 

An unusual example concerns the presence of a PTH-like factor in the circulation of cancer patients. The clinical condition indicated a considerable concentration of PTH-like activity, associated with loss of bone and hypercalcemia (the hypercalcemia of malignancy). Immunoassay detected no elevated PTH levels only the cytochemical bioassay was able to show high concentrations of PTH-like activity, although such activity did not show true parallelism. The material causing this effect has now been isolated and purified it is known as the PTH-related peptide. 

Pamidronate is one of the first drugs that has been proven to reduce the incidence of skeletal complications of metastatic breast cancer and prostate cancer. It also relieves bone pain caused by metastatic bone lesions. Other indications include treatment of osteolytic bone lesions of multiple myeloma, moderate-to-severe hypercalcemia of malignancy, and moderate-to-severe bone lesions due to Paget s disease. 

An excessive quantity of calcium in the blood, above the normal level of 11 mg per 100 ml. Hypercalcemia may be caused by some cancers (especially lung cancer), overactivity of the parathyroid glands, chronic ingestion of large doses of vitamin D, and alkali and milk therapy for peptic ulcers. Affected persons demonstrate a loss of appetite, vomiting, flabby muscles, and possibly kidney stones. 

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