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Hypercalcemia and Multiple Myeloma

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Hypercalcemia and Multiple Myeloma 7/16/08 Morning Report * * * * * * * * * * * * * * * * * * * * * * The Others Gallium nitrate- osteoclast inhibitor, not cytotoxic ... – PowerPoint PPT presentation

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Title: Hypercalcemia and Multiple Myeloma


1
Hypercalcemia and Multiple Myeloma
  • 7/16/08
  • Morning Report

2
Overview
  • Calcium metabolism (13 slides)
  • Hypercalcemia
  • Presentation (3)
  • Differential diagnosis (4)
  • Work-up (2)
  • Acute treatment (7)
  • Multiple Myeloma diagnosis/treatment if we have
    time (7)

3
Calcium metabolism
  • 1st and 2nd year Med School Style!

4
Calcium Metabolism
  • PTH, 1,25-vitamin D (calcitriol), calcitonin
  • parathyroid, C-cells of thyroid bone, small
    intestine, kidney
  • PO intake 0.4-1.5g/d, excretion in feces
    0.3-1.0g/d, excretion in urine 0.15-0.3g/d. In
    ECF 1-2g. In bone 1000-2000g.
  • ECF is 10,000x ICF
  • 50 ionized, 40 bound to protein, 10 compounded
    with inorganic anions

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8
PTH
  • Made and released by parathyroid glands.
  • Calcium sensing receptor (CaSR) suppresses
    release of PTH when activated by calcium binding.
  • Low calcium causes increase in PTH. Then PTH
    raises ionized Calcium.
  • PTH targets 1. bone (osteoclasts), causing
    resorption, releasing calcium into blood. 2.
    Kidney, causing 1a hydroxylation of 25 vit D, and
    decreasing calcium excretion (increase distal
    tubule resorption).

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11
Vitamin D
  • Not a vitamin!
  • Steroid in skin turns into cholecalciferol (D3)
    with sun exposure, liver hydroxylates at 25, then
    kidney hydroxylates at 1. End result is
    Calcitriol (active form)
  • Can take PO cholecalciferol or ergocalciferol
    (D2, derived from plants), need liver and kidneys
    to become active.
  • 1,25 vit D target small intestine lumen,
    increase active calcium absorption.

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13
  • 1,25 Vit D has intracellular target
  • Forms transcription factors
  • turns on genes to stimulate active Ca transport
    in small intestines.

14
Calcitonin
  • Made and released by parafollicular c-cells in
    the thyroid (have CaSR).
  • Target bone, inhibiting the action of PTH there.

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17
Hypercalcemia
18
Presentation
  • Hx N/V, AMS, constipation, lethargy, depression,
    weakness and vague myalgias, polyuria, headache
  • Elderly are more likely symptomatic
  • Hyperparathyroid is more symptomatic than
    malignancy.
  • PE abdominal tenderness, LE proximal muscle
    weakness (if chronic), boney tenderness,
    hyperreflexia, tongue fasciculations, and
    findings from underlying disease.

19
  • Central nervous system drowsiness, lethargy,
    depression, psychosis to stupor/coma
  • Neuromuscular weakness, proximal myopathy,
    hypotonia, decreased DTR
  • Cardiovascular HTN, bradycardia, cardiac
    arrhythmia, short QT
  • Renal polyuria, hypercalciuria,
    nephrocalcinonsis
  • Gastrointestinal nausea, vomiting, anorexia,
    constipation, pancreatitis
  • Metastatic calcification

20
Labs
  • Total calcium On WebCIS, WNL 8.5-10.2 (12.2 is
    red).
  • lt12 is mild, gt14 is life-threatening.
  • Ionized calcium WNL 4.4-5.4 (6.39 is purple).
  • lt8 is mild, gt10 is life threatening.
  • Correction for albumin
  • corrected Ca (4-albumin)(o.8) total Ca

21
Differential Diagnosis
  • PTH mediated
  • primary hyperPTH- hyperplasia (10) or adenoma
    (90), (25/100,000) mostly from increased Ca
    absorption from small intestine.
  • tertiary hyperPTH- chronic secondary hyperPTH
    leads to hyperplasia, then hypercalcemia develops
    after transplant or HD.
  • benign familial (hypocalciuric) hypercalcemia-
    autosomal dominant, Ca-sensing receptor mutation
    leads to high PTH (mild, asymptomatic)

22
Non-PTH Mediated
  • Humoral hypercalcemia of malignancy (PTHrP)
    affects bone and kidney
  • Squamous cell carcinoma lung, head and neck,
    cervix, penis, skin
  • Ovarian, breast, renal cell, transitional cell,
    etc.
  • Lymphomas VitD 1,25 generation
  • Multiple myeloma, lymphoma, and solid mets to
    bone, often breast CA local cytokine osteoclast
    activation.
  • Meds thiazides, Lithium, Milk Alkali Syndrome
    (take in gt3g Ca/day), Vit D intox, Vit A intox,
    theophylline
  • Granulomas macrophage production of calcitriol.
    sarcoid, TB, histo-, coccidio-, beryliosis,
    leprosy
  • Hyperthyroid (direct effect on bone), adrenal
    insufficiency/crisis (volume contraction, new PTH
    set-point)
  • Immobilization, rhabdomyolysis

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24
In Reality
  • Outpatients
  • 90 have primary hyperparathyroidism
  • Inpatients
  • 65 have cancer
  • 25 have primary hyperparathyroidism

25
This patient- Hypercalcemia crisis perfect storm
  • Multiple myeloma
  • Immobility
  • Thiazide use
  • Excessive PO calcium
  • Renal insufficiency (2/2 diuretic, ACE-I, Bence
    Jones proteins, hypercalcemia, ?BPH)

26
Work-Up
  • Check albumin or ionized calcium
  • BUN/Cr, phosphate, EKG,
  • Check (intact) PTH. If elevated, check 24 hr
    urinary calcium
  • If low, eval for cancer, granulomatous disease,
    drug induced, thyroid or adrenal disease.
  • PTHrP
  • 25 and 1,25 Vit D levels, serum ACE
  • PSA, DRE
  • Myeloma panel SPEP, UPEP, immunofixation,
    quantitative immunoglobulins. Serum free light
    chains will pick up Bence Jones Myeloma when SPEP
    is negative.
  • Mammogram, myeloma skeletal survey, CT C/A/P if
    PTHrP.
  • TSH, ACTH stim test

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28
Acute Treatment
  • Adequately rehydrate patient!
  • Increase urine Ca excretion
  • Saline diuresis /- loop diuretic
  • Inhibit osteoclasts
  • calcitonin
  • bisphosphonates
  • gallium nitrate
  • Plicamycin no longer available, bad side-effects
  • D/C inciting drugs
  • Treat the underlying cause
  • Surgery, chemo, steroids, low Ca diet

29
Hydration
  • Aggressive normal saline hydration (3-6L in 24h,
    then 100-300ml/h) in patient with functioning
    kidneys, without CHF
  • Maintain UOP 100-150 ml/h
  • Will dilute serum Ca, and increase urinary
    excretion. Effect lasts 2-3 days.
  • If kidney failure, will need HD against a low Ca
    bath.

30
Diuretics
  • D/C and avoid thiazides!
  • Lasix with IV hydration if hypervolemic or at
    risk (CHF).
  • Routine use of lasix and IVF when euvolemic has
    fallen out of favor
  • Calcitonin and bisphosphonates now available
  • Need for frequent careful monitoring of fluid
    status, electrolytes (can cause hypokalemia,
    hypomag
  • Body, JJ. Hypercalcemia of Malignancy. Semin
    Nephrol 2004 2428.

31
  • Calcium filtered in glomerulus
  • Reabsorbed passively in proximal tubule and
    ascending limb of loop of Henle
  • Active calcium reabsorption due to PTH in distal
    tubule.
  • Volume expansion with NS will inhibit Na
    reabsorption in proximal and loop, thus reducing
    passive Ca reabsorption.
  • Loop diuretic will inhibit Ca reabsorption in
    loop of Henle (loops lose Ca)

32
Bisphosphonates
  • Non-hydrolyzable analogs of inorganic
    pyrophosphate, adsorb to surface of bone,
    interfere with osteoclasts
  • Maximum effect in 2-4 days
  • Pamidronate 60-90 mg IV over 2h. Dont repeat
    for 7 days
  • Less responsive if PTHrP
  • Zoledronate 4mg IV over 15 min.
  • More potent. Lasts longer. More low grade
    nephrotoxicity.
  • Ibandronate 4mg IV
  • Osteonecrosis of the jaw in cancer patients
    getting chronic IV therapy

33
Calcitonin
  • Also increase renal calcium excretion
  • 4 units/kg IM or SC q12
  • Can lower Ca by 1-2 mg/dL in 4-6 hours.
  • Only good for 48 hours, then tachyphylaxis (from
    down-regulation of receptors)
  • Concurrent steroids may prevent/delay
    tachyphylaxis, unclear clinical benefit

34
The Others
  • Gallium nitrate- osteoclast inhibitor, not
    cytotoxic
  • if PTHrP or
  • IV continuous infusion, 200 mg/m2/day x5days
  • Also risk for nephrotoxicity
  • Corticosteroids- in granulomatous disease and
    lymphomas that over-produce calcitriol.
  • Prednisone 20-40 mg/day PO
  • Will decrease calcitriol production
  • Works in 2-5 days
  • Also limit PO Calcium, vit D, and sun exposure.

35
Multiple Myeloma
36
Multiple Myeloma
  • Proliferation of malignant plasma cells, and
    overabundance of monoclonal paraprotein
  • No cure
  • 9.6/100,000 yearly incidence in black men
  • Complications renal failure, cord compression,
    pathologic fractures, hypercalcemia
  • Presentation bone pain 70, lumbar vertebrae
    most common
  • Also bleeding, hyperviscosity, infection

37
Bone marrow aspirate, biopsy
38
Diagnosis combinations of
  • Plasmacytoma on tissue biopsy
  • BMBx gt30 plasma cells
  • SPEP w/ monoclonal globulin spike, IgG gt3.5g/dL
    or IgA gt2g/dL
  • UPEP w/ amyloid and Uprotein gt1g/24h
  • Lytic bone lesions
  • Less plasma cells or lower Ig levels

39
Work-up
  • CBC, Chem 10, albumin, total protein, uric acid
  • SPEP, UPEP, and immunofixation
  • 24h urine for light chains, Cr, protein
  • Quantitative immunoglobulins
  • Beta-2 microglobulin, CRP prognostic
  • Serum viscosity if neuro symptoms, nose bleeds,
    high M protein
  • Skeletal series, MRI spine, bone marrow aspirate,
    biopsy, and cytogenetics

40
Staging
  • Stage I Hgb gt 10, Ca lt 12, normal x-rays, low M
    protein
  • Stage III any of Hgb lt 8.5, Ca gt 12, lytic bone
    disease, high M-protein
  • Stage II neither I or II
  • Subclass A Cr lt 2
  • Subclass B Cr gt 2

41
Treatment
  • Melphalan inhibits mitosis by cross-linking DNA
    strands
  • Prednisone
  • M and P
  • PO x 4-7 days

42
Hypercalcemia in Multiple Myeloma
  • Most common metabolic complication
  • From wide-spread tumor-induced bone destruction
  • Cytokines from myeloma cells and
    microenvironment RANKL, MIP-1a, TNFa, TNFb
  • Bisphosphonates reduce skeletal complications
  • Fractures, bone pain, need for analgesics

43
Thanks!
  • UpToDate.com
  • eMedicine.com
  • The Washington Manual
  • MKSAP 13
  • Oyajobi, BO, Multiple myeloma/hypercalcemia.
    Arthritis Research Therapy, 2007.
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