Hypercalcemia (1 of 9) 1 Routine blood test reveals hypercalcemia or patient presents w/ signs & symptoms which suggest hypercalcemia 2 DIAGNOSIS Is hypercalcemia parathyroid-dependent or parathyroid- independent? Parathyroid-dependent Parathyroid-independent hypercalcemia hypercalcemia 3 TREATMENT TREATMENT DECISION See next page Should patient be treated surgically? Yes No A Parathyroidectomy B Measures to lower serum calcium • In asymptomatic patients C Pharmacological therapy • Estrogen replacement in menopausalMIMS patients D © Follow-up Not all products are available or approved for above use in all countries. Specifi c prescribing information may be found in the latest MIMS. B127 © MIMS 2019 Hypercalcemia (2 of 9) PARATHYROID INDEPENDENT HYPERCALCEMIA 2 HYPERCALCEMIA DIAGNOSIS Determine etiology HYPERCALCEMIA VITAMIN D GRANULOMATOUS OF MALIGNANCY INTOXICATION DISEASES • Usually presents as • eg Sarcoidosis severe hypercalcemia B Measures to lower serum calcium B Measures to lower serum calcium C Pharmacological therapy C Pharmacological therapy • Loop diuretics • Corticosteroid hormones • Bisphosphonates • Calcitonin • Corticosteroid hormones 1 HYPERCALCEMIA • Normal serum Ca level: 8-10 mg/dL (2-2.5 mmol/L) • Hypercalcemia: Serum Ca >10.5 mg/dL (>2.5 mmol/L) - Use total serum Ca level corrected for albumin concentration, by adding 0.8 mg/dL to the total serum Ca level for every 1 g/dL drop in serum albumin <4 g/dL Signs & Symptoms Mild Hypercalcemia • Usually asymptomatic More Severe Hypercalcemia • Symptoms usually become more severe as serum Ca levels rise • e constellation of clinical manifestations are commonly described as “bones, abdominal moans, stones & groans” • Neurological • Gastrointestinal • Renal • Cardiovascular - Mild drowsiness - Constipation - Nephrogenic - Increased - Weakness - Nausea & vomiting diabetes insipidus myocardial MIMS(DI) contractility - Depression - Anorexia - Lethargy - Peptic ulcer disease - Decreased - Shortened glomerular ventricular systole - Stupor (PUD) fi ltration rate (GFR) - Hypotension - Coma - Nephrolithiasis - Syncope from - Hypotonia, - Nephrocalcinosis arrhythmias hyporefl exia - Polyuria, nocturia - Hypertension © - Dehydration - Cardiomyopathy Not all products are available or approved for above use in all countries. Specifi c prescribing information may be found in the latest MIMS. B128 © MIMS 2019 Hypercalcemia (3 of 9) 2 DIAGNOSIS Lab Tests, Physical Exam & History Confi rm Hypercalcemia • Measure total serum Ca & ionized Ca at least twice Obtain Detailed History, Physical Exam, Review Prior Routine Chemistry Results • Inquire about: HYPERCALCEMIA - Past kidney stones - Fractures - Weight loss - Bone pain - Fatigue - Vitamin & mineral ingestion - Lithium or thiazide diuretic use Measure Serum Parathyroid Hormone (PTH) • Immunoassays specifi c for intact molecules using double antibody is preferred (intact parathyroid hormone) • Diagnosis: Elevated or inappropriately normal serum parathyroid hormone w/ hypercalcemia usually indicates primary hyperparathyroidism - Exceptions: Familial hypocalciuric hypercalcemia (FHH), autonomous parathyroid secretion & rarely ectopic malignant neoplasm • Diagnosis: Low-undetectable serum parathyroid hormone suggests parathyroid-independent hypercalcemia - Evaluate patient for malignancy (many times, malignancy will already be known) - If malignancy is not present, search for unusual causes of hypercalcemia Measure 24-hour Urinary Calcium & Creatinine (Cr) Excretion • In patients w/ familial hypocalciuric hypercalcemia, the urinary Ca excretion is low • Calculation of the Ca/Cr clearance ratio is believed to be preferable in diagnosing familial hypocalciuric hypercalcemia - e ratio is calculated from the results of 24-hour urine collection & simultaneously measured total serum Ca & Cr concentrations using the below formula: Ca/Cr clearance ratio = [24-hr urine CA x serum Cr] / [Serum CA x 24-hr urine Cr] - A ratio of <0.01 usually indicates familial hypocalciuric hypercalcemia, while a ratio of >0.02 is present in patients w/ hyperparathyroidism Etiologies Parathyroid-Dependent Hypercalcemia • Primary hyperparathyroidism - Leading cause of hypercalcemia - Some primary hyperparathyroidism are part of multiple endocrine neoplasia (MEN) syndrome Parathyroid-Independent Hypercalcemia • Malignancy - Parathyroid hormone-related peptide (PTHrP)-dependent - Other humoral syndromes - Multiple myeloma & osteolytic metastases • Increased vitamin D/1,25(OH)2D - Vitamin D ingestion - Topical vitamin D analogues MIMS - Calcitriol intoxication - Granulomatous disease - Williams syndrome • yrotoxicosis • Adrenal insuffi ciency (AI) • Immobilization • Medications - Vitamin A - Milk-alkali syndrome - iazide© diuretics - eophylline Not all products are available or approved for above use in all countries. Specifi c prescribing information may be found in the latest MIMS. B129 © MIMS 2019 Hypercalcemia (4 of 9) 3 TREATMENT DECISION - INDICATIONS FOR SURGERY • Surgery is the treatment of choice for patients w/ classic symptoms or complications of primary hyperparathyroidism • Surgery is indicated for asymptomatic patients w/ primary hyperparathyroidism if any of the following are present: - Serum Ca >0.25 mmol/L (1 mg/dL) above upper limit of normal HYPERCALCEMIA - Urinary Ca >400 mg/24 hr - CrCl reduced by >30% - W/ complications of primary hyperparathyroidism including osteoporosis (T score <-2.5 SD at any site), nephrocalcinosis or severe psychoneurologic disorder - Patient <50 years old A PARATHYROIDECTOMY • An option for patients w/ primary hyperparathyroidism • Controversy of medical vs surgical management of asymptomatic hypercalcemic patients - Cost, compliance & long-term follow-up are some arguments against medical management - Surgery is the only permanent cure • e following are used to facilitate targeted or minimally invasive parathyroidectomy: 99mTc-sestamibi scanning for preoperative localization, ultrasound & intraoperative measurement of circulating intact parathyroid hormone • Eff ects: 95% of patients achieve normocalcemia if performed by experienced surgeon & pathologist • Complications: Vocal cord paralysis, permanent hypoparathyroidism MIMS © B130 © MIMS 2019 Hypercalcemia (5 of 9) B MEASURES TO LOWER SERUM CALCIUM Mild Asymptomatic Hypercalcemia • Patients w/ primary hyperparathyroidism often have mild & prolonged hypercalcemia, which results in mild or no symptoms • Start measures to decrease serum Ca - Stop any medications that may cause hypercalcemia eg thiazide diuretics HYPERCALCEMIA - Patient should avoid all diuretics • Counsel patient to: - Avoid prolonged immobilization - Maintain adequate hydration - Patient should seek immediate medical attention for illness that may cause dehydration especially severe vomiting or diarrhea • If patient becomes symptomatic, they should be referred to a surgeon immediately Acute Severe Hypercalcemia • Monitor patient closely preferably in ICU setting especially if using forced diuresis - Monitor central venous pressure, plasma or urine electrolytes, may need to catheterize the bladder • Diagnostic testing should occur while aggressive Ca-lowering treatment is initiated • Primary hyperparathyroidism will benefi t from immediate surgery Fluids • Restore normal hydration - Patient is usually dehydrated from vomiting, inanition or defective urinary concentrating ability • If serum Ca >2.8 mmol/L (11.2 mg/dL), patient needs to be instructed to drink 2-3 L/day of low Ca liquids • If serum Ca >3 mmol/L (12 mg/dL) - Infuse NaCl 0.9% at 2-6 L/day IV which will increase calciuria - Loop diuretic may be added to improve diuresis • K & Mg depletion needs to be prevented If diuresis proves unsuccessful: • Hemodialysis is the treatment of choice • Dialysis bath should be free of or low in Ca • Eff ects of dialysis: Ca-free peritoneal dialysis can remove 5-12.5 mmol (200-500 mg) of Ca in 24-48 hours - Serum Ca may be lowered by 0.7-3 mmol/L (3-12 mg/dL) • Phosphate concentration needs to be monitored - Add phosphate supplements to diet if necessary C PHARMACOLOGICAL THERAPY • ere is no convincing data to support the eff ectiveness of medical therapy in long-term management of primary hyperparathyroidism Primary Hyperparathyroidism Estrogen Replacement • In postmenopausal women, estrogen replacement may lower serum Ca w/ no eff ect on parathyroid hormone • Protects against bone loss Bisphosphonates MIMS • Further study is needed to prove usefulness in mild hypercalcemia caused by primary hyperparathyroidism Acute Severe Hypercalcemia Loop Diuretics • Administer as aggressively as patient’s cardiac status will allow • Eff ects: Stimulates natriuresis which is accompanied by calciuresis - Direct calciuretic eff ects may be achieved w/ high doses (Furosemide 100 mg/hr) - Serum Ca may decrease by ≥1 mmol/L (4 mg/dL) within 24 hours - Urine Ca© excretion may exceed >25 mmol/dL Not all products are available or approved for above use in all countries. Specifi c prescribing information may be found in the latest MIMS. B131 © MIMS 2019 Hypercalcemia (6 of 9) C PHARMACOLOGICAL THERAPY (CONT’D) Acute Severe Hypercalcemia (Cont’d) Bisphosphonates • Actions: High affi nity for bone especially in areas of increased bone turnover where they inhibit bone resorption • Useful for hypercalcemia due to enhanced osteoclastic bone resorption HYPERCALCEMIA • Eff ects: Depending on agent used may take a few days to reach normocalcemia - Normocalcemia is prolonged (depending on agent, may be for a month or longer) • ough related structurally,