Transcript CPC: 64 y.o. Female with Hypercalcemia & Renal Failure

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
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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:
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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
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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
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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
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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
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Calcitonin
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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
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Bisphosphonates
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Pamidronate
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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
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Useful in Vitamin D intoxication, granuloma,
lymphoproliferative disorders
Prednisone 40-80 mg/d
Takes 5-10d to see treatment effect
Hypercalcemic Crisis: Rx
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Obsolete treatments:
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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
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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
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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
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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:
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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
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2˚ HPT
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3˚ HPT
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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
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
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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
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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
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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
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Gastrointestinal
Neuromuscular
Neuropsychiatric
HTN (↑ risk CV mortality?)
Corneal deposition CaPO4 (band keratopathy)
Pruritis
Asymptomatic!
HPT: Clinical Manifestations
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Hypercalcemic Crisis
Renal Disease
Bone Disease
Gastrointestinal
• Constipation, N/V, Indigestion
• PUD
• Pancreatitis
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Neuromuscular
Neuropsychiatric
HTN (↑ risk CV mortality?)
Corneal deposition CaPO4 (band keratopathy)
Pruritis
Asypmptomatic!
HPT: Clinical Manifestations
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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
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HTN (↑ risk CV mortality?)
Corneal deposition CaPO4 (band keratopathy)
Pruritis
Asypmptomatic!
HPT: Clinical Manifestations
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Hypercalcemic Crisis
Renal Disease
Bone Disease
Gastrointestinal
Neuromuscular
Neuropsychiatric
HTN (↑ risk CV mortality?)
Corneal deposition CaPO4 (band keratopathy)
Pruritis
Asypmptomatic!
HPT: Clinical Manifestations
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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
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Poor F/up compliance
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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:
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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