HYPERCALCEMIA Babak Tamizi Far MD. Assistant professor of internal medicine Al-zahra hospital, Isfahan university of medical sciences
ESSENTIALS OF DIAGNOSIS Serum calcium level > 10.5 mg/dl Serum ionized calcium > 5.3 mg/dl Primary hyperparathyroidism and malignancyassociated hypercalcemia are the most common causes Hypercalciuria usually precedes hypercalcemia Most often, asymptomatic, mild hypercalcemia ( 11 mg/dl) is due to primary hyperparathyroidism, whereas the symptomatic, severe hypercalcemia ( 14 mg/dl) is due to hypercalcemia of malignancy
GENERAL CONSIDERATIONS Primary hyperparathyroidism and malignancy account for 90% of cases Chronic hypercalcemia (over 6 months) or some other manifestations such as nephrolithiasis suggests a benign cause Tumor production of PTH-related proteins (PTHrP) is the most common paraneoplastic endocrine syndrome, accounting for most cases of hypercalcemia in inpatients
GENERAL CONSIDERATIONS Granulomatous diseases, such as sarcoidosis and tuberculosis, cause hypercalcemia from production of active vitamin D3 (1,25 dihydroxyvitamin D3) by the granulomas Milk-alkali syndrome has had a resurgence related to calcium ingestion for prevention of osteoporosis
Etiology Increased intake or absorption Milk-alkali syndrome Vitamin D or A excess Endocrine disorders Primary and secondary hyperparathyroidism Acromegaly Adrenal insufficiency Pheochromocytoma Thyrotoxicosis
Etiology Neoplastic diseases Tumor production of PTHrP (ovary, kidney, lung) Multiple myeloma (osteoclast-activating factor) Lymphoma
Etiology Miscellaneous causes Thiazide diuretics Granulomatous diseases Paget bone disease Hypophosphatasia Immobilization Familial hypocalciuric hypercalcemia Complications of kidney transplantation Lithium intake
Clinical Findings SYMPTOMS AND SIGNS May affect gastrointestinal, kidney, and neurologic function Mild hypercalcemia is often asymptomatic Symptoms usually occur if the serum calcium is > 12 mg/dl and tend to be more severe if hypercalcemia develops acutely
SYMPTOMS AND SIGNS Constipation and polyuria Polyuria is absent in hypocalciuric hypercalcemia Polyuria from hypercalciuria-induced nephrogenic diabetes insipidus can result in volume depletion and acute kidney injury
Other abdominal symptoms include Nausea Vomiting Anorexia Peptic ulcer disease Renal colic Hematuria from nephrolithiasis
Neurologic manifestations may range from mild drowsiness to weakness, depression, lethargy, stupor, and coma in severe cases Ventricular ectopy and idioventricular rhythm occur and can be accentuated by digitalis
Diagnosis LABORATORY TESTS Serum calcium level > 10.5 mg/dl Serum ionized calcium > 5.3 mg/dl The highest serum calcium levels ( 15 mg/dl) generally occur in malignancy A high serum chloride concentration and a low serum phosphate concentration (ratio > 33:1) suggest primary hyperparathyroidism because PTH decreases proximal tubular phosphate reabsorption
LABORATORY TESTS Urinary calcium excretion > 200 mg/day suggests hypercalciuria < 100 mg/day suggests hypocalciuria
LABORATORY TESTS Hypercalciuria from malignancy or from vitamin D therapy frequently results in hypercalcemia when volume depletion occurs Measurements of PTH and PTHrP levels help distinguish between hyperparathyroidism (elevated PTH) and malignancy-associated hypercalcemia (suppressed PTH and elevated PTHrP) Serum phosphate may or may not be low, depending on the cause
IMAGING STUDIES Chest radiograph: to exclude malignancy or granulomatous disease DIAGNOSTIC PROCEDURE ECG: shortened QT interval
Treatment: MEDICATIONS Emergency treatment Establish euvolemia to induce renal excretion of Na+, which is accompanied by excretion of Ca2+ In dehydrated patients with normal cardiac and renal function, infuse 0.45% saline or 0.9% saline rapidly (250 500 ml/h) Furosemide intravenously is often administered but its efficacy and safety were questioned in one meta-analysis
Emergency treatment Thiazides can actually worsen hypercalcemia (as can furosemide if inadequate saline is given
In the treatment of hypercalcemia of malignancy Bisphosphonates are the mainstay, although they may require up to 48 72 hours before reaching full therapeutic effect Calcitonin may be helpful to treat hypercalcemia before the onset of action of bisphosphonates
THERAPEUTIC PROCEDURES In emergency cases, dialysis with low or no calcium dialysate may be needed
Table 347-2 Guidelines for Parathyroid Surgery in Asymptomatic Primary Hyperparathyroidisma Measurement Guidelines, 1990 Guidelines, 2002 Serum calcium (above upper limit of normal) 0.3 0.4 mmol/l(1 1.5 mg/dl) above normal 0.3 mmol/l (1.0 mg/dl) above normal 24-h urinary calcium >400 mg >400 mg Creatinine clearance Reduced by 30% Reduced by 30% Bone mineral density Z-score <-2.0 (forearm) T-score <-2.5 at any site Age <50 <50
Outcome FOLLOW-UP Monitor serum calcium at least every 6 months during medical therapy of hyperparathyroidism
COMPLICATIONS Pathologic fractures Renal calculi Chronic kidney disease Peptic ulcer disease Pancreatitis Precipitation of calcium throughout the soft tissues Gestational hypercalcemia produces neonatal hypocalcemia
PROGNOSIS Depends on the underlying disease Poor prognosis in malignancy
PREVENTION Prevent dehydration that can further aggravate hypercalcemia
WHEN TO REFER Patients with malignancy-related hypercalcemia should be referred to an oncologist Patients with endocrine disorders should be referred to an endocrinologist Patients with granulomatous diseases (eg, tuberculosis and other chronic infections, Wegener granulomatosis, sarcoidosis) may require consultation with infectious disease specialists, rheumatologists, or pulmonologists
WHEN TO ADMIT Patients with symptomatic or severe hypercalcemia require immediate treatment Unexplained hypercalcemia with associated conditions, such as acute kidney injury or suspected malignancy, may also require hospitalization for treatment and expedited evaluation
The End