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Hypercalcemia
GIM Academic ½ Day, Feb 18, 2004
William Harper, MD, FRCPCEndocrinology & Metabolism
Assistant Professor of Medicine
McMaster University
Hamilton General Hospital
www.drharper.ca
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Objectives
1. Review management of emergent hypercalcemia2. Understand diagnostic approach to hyercalcemia3. Understand physiology of calcium homeostasis and
parathyroid hormone action
Reference:Medical Progress: Hyperparathyroid and Hypoparathyroid DisordersMarx S. J., NEJM 2000; 343:1863-1875, 2000.
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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
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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
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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
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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!
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Case 1: Splenectomy
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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.)
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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
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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
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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!
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Hypercalcemia Ddx
• PTH Mediated
• Non-PTH Mediated
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Case 1:PTH 14 (10-65)
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Hypercalcemia Ddx
• PTH Mediated• 1˚HPT: PTH adenoma/hyperplasia/carcinoma
• 3˚ HPT
• Familial Hyopcalciuric Hypercalcemia (FHH)
• Lithium
• Non-PTH Mediated
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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
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FECa: Fractional Excretion Ca
FECa = CaCl / CrCl = CaU x CreatSCreatU x CaS
CaU: urine Ca (mmol/d)CaS: serum Ca (mmol/L)CreatS: serum creatinine (mmol/L)CreatU: urine creat (mmol/d)
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Lithium & PTH
Serum Calcium
PTH
Li
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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
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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
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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
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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
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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
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Ca Pi PTH 1,25-D
1˚ HPT ↑ ↓ ↑ ↑
2˚ HPT ↓ ↑ ↑↑ ↓
3˚ HPT ↑ ↑ ↑↑ ↓
HPT: 1˚ v.s. 2˚ v.s. 3˚
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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
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HPT Diagnosis1) Dual Phase Exam10-20 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 ExamTc99m-pertechnetate outlines the thyroid only and this
image is subtracted from the Tc99m-sestamibi image.
SEN 89%
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HPT: Clinical Manifestations
• Hypercalcemic Crisis• Renal Disease• Bone Disease• Gastrointestinal• Neuromuscular• Neuropsychiatric• HTN (↑ risk CV mortality?)• Corneal deposition CaPO4 (band keratopathy)• Pruritis• Asypmptomatic!
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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
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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
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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%
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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!
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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)
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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!
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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!
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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!
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HPT: Clinical Manifestations
• Hypercalcemic Crisis• Renal Disease• Bone Disease• Gastrointestinal• Neuromuscular• Neuropsychiatric• HTN (↑ risk CV mortality?)• Corneal deposition CaPO4 (band keratopathy)• Pruritis• Asypmptomatic!
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HPT: Clinical Manifestations
• Hypercalcemic Crisis• Renal Disease• Bone Disease• Gastrointestinal• Neuromuscular• Neuropsychiatric• HTN (↑ risk CV mortality?)• Corneal deposition CaPO4 (band keratopathy)• Pruritis• Asypmptomatic!
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July 1974: introduction of automated serum Ca measurements
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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
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NIH Consensus for Asymptomatic 1˚ HPT
1991 2002Serum 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”)
BMD < 2 SD (z-score) < 2.5 SD (t-score)
Age < 50 < 50
Pt. Prefers Sx + ?
Poor F/up compliance + ?
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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
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Coronoary artery calcification in a patient with renal failure
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END