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Hypercalcemia

Hypercalcemia

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Hypercalcemia

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  1. Hypercalcemia

  2. Introduction • The skeleton contains 99 percent of total body calcium; the remaining 1 percent circulates throughout the body • One half of circulating calcium is free (ionized) calcium, the only form that has physiologic effects. • The remainder is bound to albumin, globulin, and other inorganic molecules • Corrected calcium = (4.0 mg/dl - [plasma albumin]) X 0.8 + [serum calcium]

  3. Definition • Normal serum calcium levels are 8 to 10 mg/dL (2.0 to 2.5 mmol/L) • Normal ionized calcium levels are 4 to 5.6 mg /dL (1 to 1.4 mmol per L) • Hypercalcemia is defined as total serum calcium > 10.5 mg/dl(>2.5 m mol/L ) or ionized serum calcium > 5.6 mg/dl ( >1.4 m mol/L )

  4. Definition Severe hypercalemia is defined as total serum calcium > 14 mg/dl (> 3.5 mmol/L) Hypercalcemic crises is present when severe neurological symptoms or cardiac arrhythmias are present in a patient with a serum calcium > 14 mg/dl (> 3.5 mmol/L) or when the serum calcium is > 16 mg/dl (> 4 mmol/L)

  5. Pathophysiology • Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (calcitriol), and calcitonin control calcium homeostasis in the body • Hypercalcemia is caused by Increased bone resorption, increased gastrointestinal absorption of calcium, and decreased renal excretion of calcium

  6. Pathophysiology • PTH increases osteoclastic bone resorption , increases renal tubular resorption of calcium , increases calcitriol, which indirectly raises serum calcium levels • 1,25-dihydroxyvitamin D3 (calcitriol) increases the absorption of calcium and phosphate in the gut

  7. Pathophysiology • Calcitonin Inhibits osteoclast resorption , promotes Ca++ and PO4 excretion • PTH-related peptide (PTHrP) binds the PTH receptor and mimics the biologic effects of PTH on bones and the kidneys

  8. Clinical Manifestations • Hypercalcemia leads to hyperpolarization of cell membranes • Patients with levels of calcium between 10.5 and 12 mg /dl can be asymptomatic. When the serum calcium level rises above this stage, multisystem manifestations become apparent

  9. Clinical Manifestations • Renal : porlyuria , nephrolithiasis • GI : anorexia , nausea , vomiting , constipation , Pancreatitis , PUD • Neuro- psychiatric : weakness , fatigue , confusion , stupor , coma

  10. Clinical Manifestations • Cardiovascular : Shortened QT interval on electrocardiogram,,bradyarrhythmias and heart block and cardiac arrest • Cornea : band keratopathy

  11. Differential Diagnosis • Hyperparathyroidism : most common • Malignancy : second most common , (severe hypercalcemia and hypercalcemic crises)) squamous carcinoma of the lung、 breast cancer、 renal cell cancer ,head and neck squamous cancer、 multiple myeloma ,hematogenous and lymphomatous malignancies

  12. Differential Diagnosis • The most common cause of hypercalcemia is primary hyperparathyroidism, and malignancy is the second most common cause - together they account for > 90% of cases • primary hyperparathyroidism is usually secondary to a parathyroid adenoma (85%), parathyroid hyperplasia (15%) and rarely due to a parathyroid carcinoma (< 1%)

  13. Differential Diagnosis • Primary hyperparathyroidism rarely produces severe hypercalcemia and/or a hypercalcemic crises, unless renal insufficiency +/- dehydration is superimposed on the underlying hyperparathyroidism • Malignancy accounts for the majority of cases of severe hypercalcemia and hypercalcemic crises

  14. Differential Diagnosis • Malignancy increases osteoclastic activity by two mechanisms - production of a PTH-like substance called PTH-related protein = PTHrP (humoral hypercalcemia of malignancy - HHM - 80% of cases) and due to local osteoclastic activity secondary to bone metastasis (local osteolytic hypercalcemia of malignancy - 20% of cases)

  15. Differential Diagnosis • Granulomatous disease : sarcoidosis、tuberculosis、leprosy 、 berylliosis histoplasmosis/coccidiomycosis disseminated candidiasis/cryptococcosis • Non-parathyroid endocrine disorders : Hyperthyroidism 、adrenal insufficiency pheochromocytoma

  16. Differential Diagnosis • Vitamin D intoxication: increased gastro-intestinal absorption of calcium • Mild alkali syndrome : increased gastro-intestinal absorption of calcium • Drugs : lithium、thiazide diuretics , vitamin A

  17. Differential Diagnosis • Familial hypocalciuric hypercalcemia • Chronic renal insufficiency • Immobilisation and high bone turnover : Pagets disease of bone

  18. Evaluation • Evaluation of a patient with hypercalcemia ( should include a careful history and physical examination focusing on clinical manifestations of hypercalcemia, risk factors for malignancy, causative medications, and a family history of hypercalcemia-associated conditions

  19. Evaluation • Primary hyperparathyroidism : PTH↑ • MALIGNANCY : 1.solid tumors(humoral hypercalcemia):PTHrP↑ , PTH↓ 2.Multiple myeloma and breast cancer(osteolytic hypercalcemia ) : alkaline phosphatase ↑,PTH↓

  20. Evaluation • Granulomatous(sarcoidosis, tuberculosis, Hodgkin's lymphoma): calcitriol (1,25-OH vitamin D3 ) ↑, PTH↓ • Familial hypocalciuric hypercalcemia : 24-hour urinary calcium↓, PTH ↑

  21. Treatment • Saline/fluid hydration : --increases renal calcium excretion ---2 to 4 L IV daily for 1 to 3 days • Biphosphonates : ---inhibition bone resorption ---Pamidronate (Aredia), 60 to 90 mg IVover 4 hours

  22. Treatment • Calcitonin : ----inhibition bone resorption and increases renal calcium excretion ----4 to 8 IU per kg IM or SQ every 6 hours for 24 hours • Plicamycin (Mitharmycin) : ----decreases bone resorption ----25 mcg per kg per day IV over 6 hours for 3 to 8 doses

  23. Treatment • Gallium nitrate : -----inhibition bone resorption -----100 to 200 mg per m2 IV over 24 hours for 5 days • Glucocorticoids : ----Inhibits vitamin D conversionto calcitriol -----Hydrocortisone, 200 mg IV daily for 3 days • Hemodialysis : ---used in patients with renal failure

  24. Treatment • Clinical indications for surgery in patients with primary hyperparathyroidism : 1.significant symptoms of hypercalcemia 2.nephrolithiasis 3.decreased bone mass (> 2 standard deviations below mean for age) 4.serum calcium > 12mg/dl 5.age < 50 years 6.infeasibility of long-term follow-up

  25. Treatment • Medical management of primary hyperparathyroidism : ---medical therapy with drugs have not been shown to affect the eventual outcome ---estrogens (premarin 1.25mg/day) preserve bone mass in post-menopausal females ---well-hydrated by drinking 2 - 3 litres of fluid, and 8 - 10 g of salt daily --dietary restriction of calcium is not necessary , thiazide diuretics must not be used ---oral phosphate should only be used if symptomatic hypercalcemia cannot be corrected surgically

  26. Treatment • Medical management of hypercalcemia in cancer patients : ---2 - 3 litres per day + 8 - 10g of salt/day ---pamridonate can be used prn every few weeks to keep the serum calcium in the normal range ---prednisone (20 - 50 mg bid) is only useful in certain malignancies eg. multiple myeloma and certain lymphomas

  27. Treatment • Medical management of other disorders : --prednisone and low-calcium diet ( < 400 mg/day ) • Medical management of hypercalcemia in sarcoidosis : --a low dose of prednisone (10 - 20 mg/day) is usually adequate