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Hypercalcemia GIM Academic ½ Day, Feb 18, 2004 William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine McMaster University Hamilton General Hospital www.drharper.ca Objectives 1. 2. 3. Review management of emergent hypercalcemia Understand diagnostic approach to hyercalcemia Understand physiology of calcium homeostasis and parathyroid hormone action Reference: Medical Progress: Hyperparathyroid and Hypoparathyroid Disorders Marx S. J., NEJM 2000; 343:1863-1875, 2000. Case 1 • 72 y.o. male ER: confusion & constipation • Patient lived alone, visiting family member called 911 • PMHx: CRF unknown etiology • Meds: ativan qhs, OTC laxatives • O/E: • • • • • 90/50, P110 (supine) 80/40, P130 (sitting) Dry mucus membranes, JVP < SA H&N: no goitre or neck masses Liver 10 cm, Castelle’s + but no palpable spleen No lymphadenopathy Case 1 • • • • • • • Hb 110, WBC 7.1, ptl 222 Na 136, K 4.3, Cl 98, HCO3 29, creat 268 Calcium 4.33, Pi 1.04, Mg 0.92, albumin 46 Ionized Ca 2.11 (1.18-1.32) 24h urine Ca 16.4 mM/d (1-7.5 mM/d) PTH 14 pg/mL (10-65) IV NS, IV pamidronate: • Resolution of ECFv , hypercalcemia, ARF Case 1 • • • • SPEP, IEP normal. Urine: + Bence Jones Bone marrow Bx: normal x 2 CXR normal Abdominal CT: • Enlarged spleen, 50% of spleen abnormal heterogeneity • Skeletal survey normal • Bone scan: • No metastases • Increased activity @ distal femur suggesting HPT Case 1 • Heme: unlikely to be Lymphoproliferative Dx • Sestamibi Neck Scans: • Dual-Phase: normal PTH glands • Pertechnetate subtraction: normal PTH glands • Repeated admissions for Hypercalcemic crisis • • • • • Ca > 4.0 mM, Creat 300-350, contracted ECFv Responded IV NS, IV pamidronate every 4 weeks Prednisone reduced bisphosphonate requirements On 3rd occasion: PTH level overtly low (< 10 pg/mL) PTHrP level elevated! Case 1: Splenectomy Hypercalcemic Crisis: Rx 1. Volume: IV NS 300-500 cc/h (slower if elderly, cardiac or renal disease) 2. Loop diuretic: Only give if ECFv overloaded. Lasix 20-40 mg IV q4-6h. Monitor I/O carefully, keep patient in positive fluid balance 3. Replace electrolyte depletion from saline diuresis as needed (K, Mg, Pi, etc.) Hypercalcemic Crisis: Rx • Calcitonin • • • • • 1 IU SC test dose: skin rxn by 15 min 4 IU/kg SC/IM q12h If no response by 24-48h increase to max dose 8 IU/kg q6h Rapid effect (begins 4-6h) but transient (2-3d) due to tachyphylaxsis Effective in 60-70% of cases, lowers Ca by 0.3-0.5 mM Hypercalcemic Crisis: Rx • Bisphosphonates • Pamidronate – – • • Ca < 3.0 mM: 30 mg in 500cc NS IV over 4h Ca > 3.0 mM: 60-90 mg in 500cc NS IV over 24h Effect peaks @ 2-4d, lasts 1-6 wk (can retreat q1-6wk) Steroids • • • Useful in Vitamin D intoxication, granuloma, lymphoproliferative disorders Prednisone 40-80 mg/d Takes 5-10d to see treatment effect Hypercalcemic Crisis: Rx • Obsolete treatments: • • • • Mithramycin: + + N/V & other toxicities Gallium nitrate: nephrotoxic Chelators: IV EDTA, IV or PO phosphate Identify & Rx underlying cause of hypercalcemia! Hypercalcemia Ddx • PTH Mediated • Non-PTH Mediated Case 1: PTH 14 (10-65) Hypercalcemia Ddx • PTH Mediated • • • • 1˚HPT: PTH adenoma/hyperplasia/carcinoma 3˚ HPT Familial Hyopcalciuric Hypercalcemia (FHH) Lithium • Non-PTH Mediated FHH • Inactivating mutation of Calcium sensor: • Parathyroid cell: higher serum Ca needed to shut off PTH secretion • Renal tubular cell: increase urinary Ca reabsorption • Autosomal dominant inheritance • Homozygous: severe neonatal hypercalcemia • Heterozygotes: asymptomatic mild hypercalcemia • Distinguish HPT from FHH by FECa • FHH: FECa < 0.01 • HPT: FECa > 0.01-0.02 • Autosomal dominant hypocalcemia • Activating mutation of Ca sensor • Mirror image of FHH FECa: Fractional Excretion Ca FECa = CaCl / CrCl = CaU x CreatS CreatU x CaS CaU: urine Ca (mmol/d) CaS: serum Ca (mmol/L) CreatS: serum creatinine (mmol/L) CreatU: urine creat (mmol/d) Lithium & PTH PTH Li Serum Calcium Hypercalcemia Ddx • PTH Mediated • Non-PTH Mediated • Malignancy » PTHrP (SCC, hypernephroma, etc.) » Osteolysis (myeloma, breast Ca) » 1-alpha hydroxylase of Vitamin D (lymphoma) • Granulomatous Disease • Drugs » Vitamin D, A » Calcium antacids (milk alkali) » Thiazides • AI, Pheo, Thyrotoxicosis, Paget’s (immobility) • ARF Case 2 • • • • 65 y.o. female PMHx: Schizophrenia, no prior use of Lithium Medications: Loxapine, ativan, benztropine prn Admit to psych ward under Form 1 for inability to self-care. • Previously lived with mother (CVA LTC) • Serum Ca 3.08 Endo referral from Psych! • No past hx of renal stones or hypercalcemic crises Case 2 • • • • • • • O/E: normal Ca 3.08, albumin 39, Pi 0.9, ALP 68 Ca ion 1.63 PTH 45.6 pM (1.2-7.6 pM) 24h urine: Ca 3.2 mmol/d, Creat 8.3 mmol/d FECa = 0.017 ( > 0.01) Tc-99m Sestamibi PTH scan: activity L upper Case 2 • Rx with NS and IV pamidronate normalized serum calcium but no improvement in psychotic symptoms • Surgery: L upper PTHectomy, L lower PT biopsy • Postop Ca nadir 2.19 (postop day 5) • D/C home: f/up with Psych, Sx, GIM amb clinic 1˚ HPT • Etiology: • • • • • • • • • Single Adenoma 85% Multiple Adenomas 5% Hyperplasia 10% Carcinoma < 1% Incidence 42/100,000 Prevalence 1/1000 Female:male = 2-3:1 Incidence increases with age Postmenopausal women: • Incidence 5x general population • Prevalence 4/1000 HPT: 1˚ v.s. 2˚ v.s. 3˚ Ca Pi PTH 1,25-D 1˚ HPT ↑ ↓ ↑ ↑ 2˚ HPT ↓ ↑ ↑↑ ↓ 3˚ HPT ↑ ↑ ↑↑ ↓ HPT Diagnosis • Elevated serum Ca (total, ionized) • Serum intact PTH: • Double-antibody immunoassays (IRMA or ICMA) • Elevated or inappropriately high normal • Normal 10-65 pg/mL (1.2-7.6 pmol/L) • Serum Pi decreased, Serum ALP increased • Hyperchloremic metabolic acidosis • Urine Ca normal (1-7.5 mM/d) to slight increased • FECa > 0.01-0.02 • Urinary Ca less than that of non-PTH mediated hypercalcemic patient with an equivalent serum calcium HPT Diagnosis 1) Dual Phase Exam 10-20 mCi Technetium-99m (Tc99m) Sestamibi. Scan neck & chest @ 15 min and 2-4h post injection. Agent clears faster from thyroid than parathyroid so PTH adenoma more clear on the 2-4h scan. SEN 45-95% (ave 73%) PPV 97% 2) Subtraction Exam Tc99m-pertechnetate outlines the thyroid only and this image is subtracted from the Tc99m-sestamibi image. SEN 89% HPT: Clinical Manifestations • • • • • • • • • • Hypercalcemic Crisis Renal Disease Bone Disease Gastrointestinal Neuromuscular Neuropsychiatric HTN (↑ risk CV mortality?) Corneal deposition CaPO4 (band keratopathy) Pruritis Asypmptomatic! Hypercalcemic/Parathyroid Crisis • Pathogenesis poorly understood • 40% have intercurrent illness and/or predisposition for dehydration • In a few patients, the crisis was ascribed to infarction of a parathyroid adenoma • Usually severe ↑ serum Ca > 3.8 mM • PTH usually 20x ULN • Marked symptoms from ↑ serum Ca: especially CNS dysfn • Polyuria ECFv contraction renal insufficiency Parathyroid Carcinoma • Approx 400 reported cases since 1920 • Mean age presentation 44-54 years • More likely to have symptoms than PTH adenoma • • • • • • 65-75% have serum Ca > 3.7-4.0 mM 12% present with hypercalcemic/parathyroid crisis 34-52% have a neck mass 34-73% have bone disease 32-70% have renal disease Only 2-7% asymptomatic • Suspect if RLN palsy Parathyroid Carcinoma • Diagnosis based on histology • Uniform sheets of cells • Arranged in lobular pattern seperated by dense fibrous trabeculae • Capsular and vascular invasion (sometimes seen in adenomas) • Local invasion, lymph node or distant mets • Pathogenesis • RB gene, p53 gene • Hypercalcemia principle cause of M&M • 5y survival 50-70%, 10y survival 13-35% HPT: Clinical Manifestations • Hypercalcemic Crisis • Renal Disease • Nephrolithiasis • Nephrocalcinosis • Renal Insufficiency, Nephrogenic DI • • • • • • • • Bone Disease Gastrointestinal Neuromuscular Neuropsychiatric HTN (↑ risk CV mortality?) Corneal deposition CaPO4 (band keratopathy) Pruritis Asymptomatic! Nephrocalcinosis • Development of renal insufficiency in 1˚ HPT is related to degree & duration of hypercalcemia • Long-standing hypercalcemia & hypercalciuria leads to chronic nephropathy. • Calcification, degeneration, and necrosis of the tubular cells leads to cell sloughing and eventual tubular atrophy and interstitial fibrosis and calcification (nephrocalcinosis) HPT: Clinical Manifestations • Hypercalcemic Crisis • Renal Disease • Bone Disease • Osteitis fibrosa cystica – Subperiosteal resorption (phalanges) – Salt & Pepper skull XR – Bone Cysts, Osteoclastomas (Brown Tumors) • Osteopenia/Osteoporosis (Cortical bone > Trabecular bone) • Pathological # • Dental resorption of lamina dura • • • • • • • Gastrointestinal Neuromuscular Neuropsychiatric HTN (↑ risk CV mortality?) Corneal deposition CaPO4 (band keratopathy) Pruritis Asymptomatic! HPT: Clinical Manifestations • • • • Hypercalcemic Crisis Renal Disease Bone Disease Gastrointestinal • Constipation, N/V, Indigestion • PUD • Pancreatitis • • • • • • Neuromuscular Neuropsychiatric HTN (↑ risk CV mortality?) Corneal deposition CaPO4 (band keratopathy) Pruritis Asypmptomatic! HPT: Clinical Manifestations • • • • • Hypercalcemic Crisis Renal Disease Bone Disease Gastrointestinal Neuromuscular • Proximal muscle weakness/atrophy, gait disturbance • Hyperreflexia • Neuropsychiatric • Fatigue, apathy, poor concentration, memory loss • Depression, irritability, emotional liability • Frank Psychosis • • • • HTN (↑ risk CV mortality?) Corneal deposition CaPO4 (band keratopathy) Pruritis Asypmptomatic! HPT: Clinical Manifestations • • • • • • • • • • Hypercalcemic Crisis Renal Disease Bone Disease Gastrointestinal Neuromuscular Neuropsychiatric HTN (↑ risk CV mortality?) Corneal deposition CaPO4 (band keratopathy) Pruritis Asypmptomatic! HPT: Clinical Manifestations • • • • • • • • • • Hypercalcemic Crisis Renal Disease Bone Disease Gastrointestinal Neuromuscular Neuropsychiatric HTN (↑ risk CV mortality?) Corneal deposition CaPO4 (band keratopathy) Pruritis Asypmptomatic! July 1974: introduction of automated serum Ca measurements HPT Treatment • Surgery: still the treatment of choice • 95% success rate • Vocal cord paralysis 1%, Permanent hypoparathyroidism 4% • Medical • Bisphosphonates – IV for acute severe hypercalcemia – Some trials showing benefit with po bisphosphonates • Oral phosphate (may ppt calciphylaxsis) • Postmenopausal women: HRT? • Calcimimetic agents: Ca receptor agonists NIH Consensus for Asymptomatic 1˚ HPT 1991 2002 Serum Ca > 2.85-3.0 mM > 2.85 mM CrCl < 70% normal < 70% normal 24 Urinary Ca > 10 mmol/d > 10 mmol/d (“shouted down”) < 2 SD (z-score) < 2.5 SD (t-score) < 50 < 50 Pt. Prefers Sx + ? Poor F/up compliance + ? BMD Age Calciphylaxis • Associated with but not just metastatic soft-tissue calcifications • Systemic medial calcification of the arteries and tissue ischemia • Calcium Phosphate Product • Serum Ca x Pi < 5 • ESRD, HPT at greatest risk • Clinical Manifestations: • • • • • Ischemic necrosis of skin, subcutaneous fat, less often muscle/viscera Livedo reticularis plaques/papules ischemic/necrotic ulcers Ishcemic myopathy without skin necrosis can occur (rare) High mortality (58%) due to sepsis Calcified heart myocardium, valves, cardiac vessels • Diagnosis: tissue biopsy • Arterial occlusion, calcification, no vasculitic changes Coronoary artery calcification in a patient with renal failure END