Hypercalcemia of malignancy

Second leading cause of hypercalcemia after primary hyperparathyroidism.

May result from bone destruction or production of humoral mediated calcium factors by malignant cells, as parathyroid hormone-related peptide.

May be an oncologic emergency .

In humeral hypercalcemia of malignancy, tumors, secrete parathyroid, hormone related protein, a protein with homology to parathormone, which binds to and activates, the parathyroid1 receptor.

Malignancy associated hypercalcemia involves increased bone resorption, and kidney calcium resorption, and one involves focal skeleton osteoclastic bone resorption.

About 23% of palliative care cancer patients may have this process.

Occurs it up to 30% of patients with cancer during the course of their disease.

Hypercalcemia has been reported in association with most cancers, but is most common with non-small cell lung cancer, breast cancer, multiple myeloma, squamous cell cancers of the head and neck, urothelial carcinoma‘s, or ovarian cancers.

Its  prevalence is declining going to the prophylactic use of bisphosphonates or denosumab in patients with bone metastases  (prevalence 2-3%).

Mild elevations of calcium may be asymptomatic, but when levels exceed 3 mmol per liter/L symptoms are usually present.

Head and neck squamous cell carcinoma associated hypercalcemia is mainly mediated by humeral factors.

The prevalence of hypercalcemia in early-stage head and neck squamous cell carcinoma is low and increases with the advanced stages.

In some hematologic malignancies and lymphoma hypercalcemia is caused by ectopic overproduction of calcitriol from macrophages in response to malignant cells.

Treatment of symptomatic disease by bisphosphonates improve symptoms and quality of life.

Associated with poor prognosis in patients with head and neck squamous cell carcinoma with a median survival ranging from 31 to 74 days.

Cancer associated hypercalcemia is a complication advanced cancer and portends a poor prognosis, with older studies showing a median survival of 30 days after the onset of hypercalcemia.

Classified into four subtypes: humoral, local osteolytic, 1,25 – dihydroxy vitamin D – mediated, and ectopic hyperparathyroidism.

Humoral hypercalcemia of malignancy is usually caused by tumor secretion of parathyroid hormone:Typically associated with squamous cell cancer of the lung  and head and neck, urothelial carcinomas and breast cancers.

Humoral hypercalcemia of malignancy is typically associated with few or no bone metastases.

patients with local osteolytic hypocalcemia have extensive bone metastasis, most often from breast cancer or multiple myeloma.

Tumor cells in bone produce cytokines that act locally to increase osteoclastic bone resorption and suppress osteoblastic bone formation.

With a large skeletal tumor burden, the calcium outflow from the bone exceeds renal calcium clearance, causing hybrid calcium.

Other humoral causes arevrelated to the production of hormones involved in bone remodeling which may be responsible for converting 25 hydroxy vitamin D to the active hormone 1,25 dihydroxy vitamin D which increases intestinal calcium absorption as well as bone resorption leading to hypercalcemia.

Ectopic hyperparathyroidism is caused by tumors that produce PTH instead of parathyroid hormone related peptide.

Parathyroid cancer can also cause hypercalcemia by secreting. PTH.

Humoral hypercalcemia of malignancy and local osteolyric hypercalcemia represent a spectrum that includes the vast majority of patients with hypercalcemia of malignancy; cases of hypercalcemia, mediated by 1,25 dihydroxyvitamin D, or PTH account for less than 1% of the cases.

Treatment of hypercalcemia of malignancy has three basic principles: correcting volume depletion, inhibiting bone resorption, and addressing the underlying malignancy.

Hypercalcemia is associated with anorexia, nausea, vomiting , and nephrogenic diabetes insipidus, that often produces extreme dehydration, leading to reduce GFR rate, limiting the ability of the kidney to excrete calcium.

Sodium delivery to the distal tubule increases urinary calcium excretion by the kidney.

The administration of intravenous saline where do without loop diuretics can typically lower serum calcium levels 1 to 2 mg/dL.

Because most instances of cancer associated hypercalcemia occurs as a result of excessive bone resorption, the  mainstay of therapy is the administration of anti-resorptive agents: primarily bisphosphonates, or denosumab, and in some instances calcitonin.

Bisphosphonates work by interrupting the recruitment, maturation, and attachment of osteoclasts, and induce apoptosis in osteoclasts and plasma cells.

Pamidromate,  zoledronate and ibandronate intravenously transiently normalize calcium levels in 60 to 90% in patients with cancer associated hypercalcemia.

Denosumab, a fully human monoclonal antibody that binds to RANKL and prevents it from binding to the receptor activator of nuclear factor kB on osteoclastic precursors and mature osteoclasts normalizing serum calcium levels in 70% of patients with cancer associated hypercalcemia.

In an analysis of three phase 3 trials involving patients with multiple myeloma and bone metastasis, denosumab delayed the time to first hypercalcemic event, and reduced the risk of recurrent hypercalcemia as compared with zoledronate.

Calcitonin, a peptide hormone secreted by the parafollicular cells of the thyroid gland, inhibit osteoclast activity and promotes renal calcium excretion:when is ministered can lower serum calcium levels rapidly within 12 to 24 hours, but the reductions are small.

Calcitonin is useful in the initial lowering of a very high calcium level while awaiting more prolonged onset of action of other anti-resume up to agents.

Corticosteroids can reduce hypercalcemia associate with 1 25 dihydroxyvitamin D overproduction that is typically seen in patients with lymphoma.

The presence  of hypercalcemia and acute kidney injury with oligoria may warrant hemodialysis or peritoneal dialysis to lower calcium levels.

The calcimimetic agent cinacalcet reduces parathormone secretion and blocks renal tubular reabsorption of calcium by binding to the calcium sensing receptors on the parathyroid glands and kidneys.









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