1. Work-up and Management of Hypercalcemia in Hospitalized Patients
Jessica Thom
PGY-3

2. Let’s start with a case
Mrs. S is a 74 year old female with a history of COPD who presents to the ER with confusion and acute renal failure. Her calcium on presentation is 3.13mmol/L with a creatinine of 175micromol/L. Chest X-ray reveals a large right hilar mass.

3. Symptoms of hypercalcemia
Cognitive dysfunction
Confusion, lethargy, coma (in severe cases)
GI disturbances
Constipation, nausea, anorexia
Renal dysfunction
Polyuria, acute/chronic renal failure, nephrolithiasis
Musculoskeletal symptoms
Muscle weakness, bone pain
Patients with calcium levels <3.0mmol/L are often asx
Polyuria – due to decreased concentrating ability in distal tubule
Nephrolithiasis seen more frequently in patients with longstanding hypercalcemia – ex. primary hyperparathyroidism, sarcoidosis

4. What is the most likely cause of hypercalcemia?
Inpatient setting – Malignancy
Outpatient setting – Primary hyperparathyroidism
If no malignancy…how do you approach the work-up of hypercalcemia?

5. PTH independent causes
Start with PTH
PTH-dependent causes
(mid-high normal/elevated levels)
Primary hyperparathyroidism
Familial benign hypocalciuric hypercalcemia
Chronic renal failure (3° hyperparathryoidism)
PTH independent causes
(low levels)
Malignancy
PTHrp (squamous cell ca)
1,25(OH)2D secretion (lymphoma)
Osteolytic (breast, multiple myeloma)
Granulomatous dx (secrete 1,25(OH)2D)
Sarcoidosis
Mycobacerial/fungal dx
Non-parathyroid endocrine dx
HyperT4, pheo, adrenal insufficiency
Medications
Milk-alkali syndrome, vit A/D toxicity, thiazides, lithium
Immobilization
Distinguish familial benign hypocalciuric hypercalemia from primary hyperpara by 24 urine calcium

7. Indications for treatment
No treatment:
Asymptomatic or mildly symptomatic (ex. constipation) with acute calcium levels <3.0mmol/L
Asymptomatic with chronic calcium levels 3.0 to 3.5mmol/L
Treatment:
Symptomatic patients
Acute rise in calcium levels
Calcium levels >3.5mmol/L

8. 4 Main Treatment Strategies for Hypercalcemia
Delivery of calcium to kidneys
 Calcium reabsorption from kidneys (therefore  excretion)
Bone resorption
Calcium absorption from intestines

9. Hypercalcemia Treatment in the Kidney
Increasing calcium delivery to kidney
Isotonic saline – increases GFR (ie. Ca delivery to kidney). 1st line tx for hypercalcemia
Decreasing calcium reabsorption in kidneys
Loop diuretics – Decrease Na & Cl reabsorption, which decreases passive calcium reabsorption
Remember that calcium is re-absorbed passively in the ascending limb of the loop of Henle (via electrochemical gradients created by NaCl absoprtion)

10. Hypercalcemia Treatment in the Bones
Very effective strategy at treating hypercalcemia
Agents that are effective in decreasing bone resorption:
Calcitonin
Bisphosphonates (ex. pamidronate)

11. Hypercalcemia Treatment in the Intestines
Decreasing calcium absorption:
Only effective in the treatment of hypercalcemia secondary to granulomatous diseases and occasionally in lymphomas (where there is increased calcitriol production that enhances intestinal calcium absorption).
Treatments:
Glucocorticoids – Decrease calcitriol production by activating mononuclear cells in the lungs/lymph nodes.
Low calcium diet

12. Other treatments of hypercalcemia
Dialysis
With little or no calcium in dialysate
Reserved for severe, symptomatic hypercalcemia (4.5- 5mmol/L) with neurologic symptoms and severe renal failure (CrCl <10-20ml/min).
Can also be considered severe hypercalcemia and heart failure, in which can not safely give IV fluids.
Target the underlying cause…
Treat the underlying malignancy, sarcoid, stop offending drug etc.

13. How effective are these treatments?
Intravenous fluids
First line treatment
Lowers calcium within hours
Rarely lowers calcium levels in patients with > mild hypercalcemia
Lasix
No randomized controlled trials to assess efficacy. Use based on old case reports/series prior to the use of bisphosphonates.
Not recommended as first line therapy unless patient has or is at risk of fluid overload with hydration.
Case series review published in Ann Intern Med (2008) – 9 case reports/series found. Out of 37 reported patients treated with furosemide, only 14 normalized their calcium levels, and of those, only 2 did so quickly (within 6 to 12 hours).
Last case series published in 1983

14. How effective are these treatments?
Calcitonin
Weak antiresorptive
Works rapidly: reduces calcium levels by 0.5 mmol/L within 4 to 6 hours.
Limited to use within the first 2 days because of risk of tachyphylaxis
Bisphosphonates
More potent than calcitonin
Normalizes calcium in >70% of patients with hypercalcemia of malignancy
Maximum effect in 2-4 days
Particularly useful in reducing bone pain & pathological fractures if administered regularly in patients with skeletal metastases or multiple myeloma.

15. How effective are these treatments?
Bisphosphonates (cont’d)
Zolendronic acid slightly more effective than pamidronate but may have more renal toxicity.
Pamidronate: maintains normocalcemia for 2 to 3 weeks (up to 4 weeks)
Zoledronic acid: lasts for ~ 4 weeks.
Glucocorticoids (Prednisone 20-40mg/day)
Decreases calcium levels within 2-5 days.

16. TO RECAP: Initial treatment of severe hypercalcemia
IV hydration with isotonic saline
Works immediately
Rate of 200 too 300 cc/hr (less in elderly patients)
Target UOP 100 to 150 cc/hr
Salmon calcitonin
Maximal activity in 4 to 6 hrs
Bisphosphonate
Maximal activity 2 to 4 days
Watch for fluid overload!

17. Preventing recurrence of hypercalcemia
Mainstay or therapy is treat underlying cause (ex. malignancy)
If no response to tumor therapy:
Infuse bisphosphonates every 2 to 4 weeks to maintain normocalcemia and prevent skeletal complications.