Hypercalcemia  is defined by serum calcium value above the upper limit of the normal range.

Hypercalcemia develops when calcium entry into the serum exceeds skeletal deposition and/or kidney excretion.

Hypercalcemia affects approximately 2% of patients with cancer.

Approximately 90% of people with hypercalcemia have primary hyperparathyroidism or malignancy.

The annual incidence is 0.09% to 0.6% of varying by population screened.

In ESRD is hazardous since such patients have associated hyperphoshatemia, which can result in precipitation of calcium salts in various organs.

Rapid development with moderately, severe hypercalcemia causes kidney, afferent arterial, vasoconstriction, reduced GFR, and impaired kidney function.

Hypercalcemia also causes nephrogenic, diabetes, insipidus by down regulating aquaporin  and impairing osmotic gradient  generation: exacerbating volume contraction, and reduces GFR rate, worsening hypercalcemia.

Moderate to severe hypercalcemia, once established, initiates a self perpetuating cycle.

Precipitation of calcium phosphate salts in hypercalcemia worsens renal insufficiency, accelerates atherosclerosis, valvular heart disease, leads to metastatic calcification and calciphylaxis.

The pathophysiology of hyperglycemia: increased bone, resorption, reduced kidney calcium clearance, increased, G.I., calcium absorption, or a combination may contribute.

Approximately 90% of patients with hypercalcemia have primary hyperparathyroidism or hypercalcemia of malignancy.

Mild hypercalcemia followed in patients for decades is accompanied by premature vascular death.

Associated with hypertension, left ventricular hypertrophy, vascular calcification, shortened QT interval, and arrhythmias.

In sarcoidosis associated with elevated vitamin D levels.

Accounts for 0.23-1.5% of cases of pancreatitis.

Most common life threatening metabolic disorder in patients with cancer with an overall incidence of 10-20%.

Incidence can be as high as 30-40% in patients with breast cancer, multiple myeloma and lung cancer.

May be the presenting symptom in cancer, but is usually seen in patients with an established diagnosis.

Secondary to myeloma, breast cancer, lung cancer and lymphomas is a result of bone invasion with bone resorption.

Treatment depends on the severity of symptoms and the underlying cause.

The goal of therapy is to treat the hypercalcaemia first and then to treat the underlying cause.

Initial therapy is fluids and diuretics so bood volume expansion and saline diuresis is typical management.

Hydration is needed because many patients are dehydrated due to vomiting or renal defects in concentrating urine.

Increasing salt intake increases the body fluid volume as well as increasing urine sodium excretion, which further increases urinary calcium excretion as calcium and sodium are handled in a similarly by the kidney.

Following rehydration, a loop diuretic is given to permit continued large volume intravenous salt and water replacement while minimizing the risk of volume overload.

Loop diuretics diminish renal calcium reabsorption and further lower blood calcium levels by 1–3 mg/dL within 24 hours.

Bisphosphonates inhibit osteoclastic bone resorption to lower calcium levels and include etidronate, tiludronate, IV pamidronate, alendronate, zoledronate and risedronate.

All patients with cancer-associated hypercalcaemia should receive treatment with bisphosphonates.

The use of calcitonin blocks bone resorption and also increases urinary calcium excretion by inhibiting renal calcium reabsorption.

Calcitonin can be given intramuscularly or subcutaneously, and is usually used in life-threatening hypercalcaemia with other modalities of treatment.

Calcitonin helps prevent recurrence of hypercalcaemia.

Calcitonin dose is 4 Units per kg via subcutaneous or intramuscular route every 12 hours.

Glucocorticoid therapy increases urinary calcium excretion and decreases intestinal calcium absorption,and effective in hypercalcaemia due to osteolytic malignancies, in hypervitaminosis D and sarcoidosis.

Dialysis reserved for severe hypercalcaemia complicated by renal failure.

Volume depletion tends to exacerbate or perpetuate the hypercalcemia by increasing Na+ reabsorption in the thick ascending limb of the loop of Henle.

Immobilization aggravates hypercalcemia and weightbearing mobilization is encouraged.

Reduction of dietary calcium and vitamin D intake is effective for treating hypercalcemia due to increased intestinal calcium absorption.

In vitamin D toxicity or extrarenal synthesis of 1,25(OH) D3 as is seen in sarcoidosis , steroids may be beneficial.

Calcitonin can be given intramuscularly or subcutaneously.

Mithramycin blocks osteoclastic function and can be given for severe malignancy-related hypercalcemia.

Peritoneal or hemodialysis is highly effective in lowering plasma calcium levels.

Bisphosphonates inhibit bone resorption and are used for treatment of cancer related hypercalcemia.

Pamidronate (Aredia) and zoledronate (Zometa) commonly used bisphosphonates in hypercalcemia.

Particularly associated with squamous cell carcinoma via ectopic production of PTHrP (PTH-related peptide).

3 pathologic types of cancer related hypercalcemia-1-humoral hypercalcemia of malignancy-often mediated by PTHrP,2- local bone destruction resulting in release of cytokines, and 3- tumor production of vitamin D analogues.

Related to malignancy is associated with a survival of less than 1 year and is particularly common in patients with refractory advanced disease.

In patients with cancer associated with an approximate 50% mortality rate within 30 days.

Leads to impaired mentation and renal failure.

Rarely due to high calcium intake but when combined with decreased urinary excretion as in chronic renal insufficiency or milk-alkali syndrome this may occur.

Granulomatous diseases such as sarcoidosis, disseminated fungal disease and tuberculosis cause hypercalcemia by unregulating calcitriol production by the granulomas.

Normocalcemic response range from 40-100% with pamidronate.

Gallium nitrate used for hypercalcemia that has not responded to hydration, but has limited usefulness since it requires continuous intravenous infusion.

Gallium nitrate may be more effective in the management of epidermoid carcinoma induced hypercalcemia.

Hypercalcemic crisis arbitrarily defined as in albumin-corrected serum calcium level of 14 mg/dL and or greater, associated with multi organ dysfunction.

Primary hyperparathyroidism is the most common underlying etiology of hypercalcemic crisis.

Hypercalcemia crisis: majority are female at 65%, all age groups affected, 4% occur during pregnancy, almost 90% have a single parathyroid adenoma.

In hypercalcemic crisis 8% of adenomas are ECT opic and in old series mortality rate approaches 1 hundred percent, while modern-day series it is 7%.

Hypercalcemia crisis is rare accounting for 1.6% of patients presenting with primary hyperparathyroidism.

In a series of 1310 consecutive hyperparathyroid patients who underwent parathyroidectomy over 40 years reported a 6.7% incidence of crisis (Canon JJ et al).

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