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Approach to hypercalcemia

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  1. Approach to hypercalcemia Elevated serum calcium Confirm elevation Look for clinical clues of hypercalcemia

  2. Approach to hypercalcemia Elevated serum calcium You’ve confirmed hypercalcemia. You only get to order one test to continue your work-up, what do you choose?

  3. Approach to hypercalcemia Elevated serum calcium PTH HIGH -Primary hyper-parathyroidism-Familial hypocalciuric hypercalcemia

  4. Approach to hypercalcemia Elevated serum calcium PTH HIGH HIGH-NORMAL -Primary hyper-parathyroidism-Familial hypocalciuric hypercalcemia High normal is never normal in the setting of hypercalcemia!!

  5. Approach to hypercalcemia Elevated serum calcium PTH HIGH HIGH-NORMAL -Primary hyper-parathyroidism -FHH Primary hyperparathyroidism, consider Familial hypocalciuric hypercalcemia *differentiate with 24-hour urine calcium

  6. Approach to hypercalcemia Elevated serum calcium PTH HIGH or HIGH-NORMAL LOW Non-PTH mediated hypercalcemia -Primary hyper-parathyroidism -FHH

  7. Mechanisms of non-PTH mediated hypercalcemia • Malignancy • PTH-related peptide • Osteolytic metastases • (1,25)-OH2 vitamin D • Granulomatous disease • (1,25)-OH2 vitamin D • Vitamin D intoxication • 25-OH vitamin D • Others: • Unrecognized calcium intake • Thiazide diuretics • Hyperthyroidism

  8. Approach to hypercalcemia Elevated serum calcium PTH LOW PTH-related peptide (1,25)-OH2 vitamin D (25)-OH vitamin D

  9. Approach to hypercalcemia Elevated serum calcium PTH (25)-OH vitamin D (1,25)-OH2 vitamin D LOW PTH-rp -Lymphoma -Granulomatous disease (infectious, non-infectious) Vitamin D intoxication Humoral hypercalcemia of malignancy *if all normal, consider SPEP/UPEP to evaluate for multiple myeloma

  10. Approach to hypercalcemia: Summary Elevated serum calcium HIGH or HIGH-NORMAL LOW PTH 1.) Humoral hypercalcemia of malignancy 2.) Lymphoma or granulomatous disease 3.) Vitamin D intoxication PTH-rp (1,25)-OH2 vitamin D (25)-OH vitamin D HIGH 1.) Primary hyper parathyroidism 2.) FHH NORMAL SPEP, UPEP, serum free light chains HIGH Multiple myeloma NORMAL Assess for other diagnosis: milk-alkali syndrome, vitamin A intoxication, hyperthyroidism

  11. Cholecalciferol Vitamin D Metabolism 25-hydroxylase Calcifediol = Major circulating metabolite Extra-Renal 1α-hydroxylase Renal 1α-hydroxylase 1α-hydroxylase Calcitriol = Active metabolite Imaged adapted from:Hollis BW, Wagner CL. Nutritional Vitamin D Status During Pregnancy: Reasons for concern. CMAJ. 2006;174(9), 1287-1290. PMID 16636329.

  12. Granulomatous-associated hypercalcemia

  13. Cholecalciferol Granulomas & Vitamin D 25-hydroxylase Calcifediol = Major Circulating metabolite Extra-Renal 1α-hydroxylase Active metabolite (calcitriol)

  14. Endogenous 1,25-OH Vitamin D-mediated Hypercalcemia • Chronic Granulomatous Diseases • Lymphoma-associated • **HewisonM, et al. Vitamin D-Mediated Hypercalcemia in Lymphoma: Evidence for Hormone Production by Tumor-Adjacent Macrophages. Journal of Bone and Mineral Research. 2003; 18:3, pg 579-582. PMID 12619944.

  15. Acute Hypercalcemia Treatment • Asymptomatic and calcium <14.0 mg/dL: • Does not require urgent therapy. • Calcium >14mg/dL or symptomatic: Urgent therapy • #1. Isotonic saline. Rate to maintain urine output of 100-150mL/hr.* • #2. Bisphosphonates: • Zoledronic acid or Pamidronate • #3. Calcitonin (if within first 48hrs)** • In rare cases: Hemodialysis. • Depending on underlying cause: • Primary hyperparathyroidism: Parathyroidectomy. • Multiple myeloma or Granulomatous-mediated: Corticosteroids.