hypercalcemia gim academic ½ day, feb 18, 2004 william harper, md, frcpc endocrinology &...

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

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.

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 CreatSCreatU x CaS

CaU: urine Ca (mmol/d)CaS: serum Ca (mmol/L)CreatS: serum creatinine (mmol/L)CreatU: urine creat (mmol/d)

Lithium & PTH

Serum Calcium

PTH

Li

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

Ca Pi PTH 1,25-D

1˚ HPT ↑ ↓ ↑ ↑

2˚ HPT ↓ ↑ ↑↑ ↓

3˚ HPT ↑ ↑ ↑↑ ↓

HPT: 1˚ v.s. 2˚ v.s. 3˚

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 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%

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 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 + ?

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