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

Work-up and Management of Hypercalcemia in Hospitalized Patients

Jessica ThomPGY-3

Let’s start with a caseMrs. 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.

Symptoms of hypercalcemiaCognitive dysfunction

Confusion, lethargy, coma (in severe cases)

GI disturbancesConstipation, nausea, anorexia

Renal dysfunctionPolyuria, acute/chronic renal failure, nephrolithiasis

Musculoskeletal symptomsMuscle weakness, bone pain

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?

Start with PTHPTH-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

Indications for treatmentNo 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 patientsAcute rise in calcium levelsCalcium levels >3.5mmol/L

4 Main Treatment Strategies for Hypercalcemia

1. Delivery of calcium to kidneys

2. Calcium reabsorption from kidneys (therefore excretion)

3. Bone resorption

4. Calcium absorption from intestines

1. Increasing calcium delivery to kidney

Isotonic saline – increases GFR (ie. Ca delivery to kidney). 1st line tx for hypercalcemia

2. Decreasing calcium reabsorption in kidneys

Loop diuretics – Decrease Na & Cl reabsorption, which decreases passive calcium reabsorption

Hypercalcemia Treatment in the Kidney

Remember that calcium is re-absorbed passively in the ascending limb of the loop of Henle (via electrochemical

gradients created by NaCl absoprtion)

Hypercalcemia Treatment in the Bones

Very effective strategy at treating hypercalcemia

Agents that are effective in decreasing bone resorption:CalcitoninBisphosphonates (ex. pamidronate)

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

Other treatments of hypercalcemia

DialysisWith little or no calcium in dialysateReserved 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.

How effective are these treatments?

Intravenous fluidsFirst line treatmentLowers calcium within hoursRarely lowers calcium levels in patients with >

mild hypercalcemia

LasixNo 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.

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.

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.

TO RECAP: Initial treatment of severe hypercalcemia

IV hydration with isotonic salineWorks immediatelyRate of 200 too 300 cc/hr (less in elderly patients)Target UOP 100 to 150 cc/hr

Salmon calcitoninMaximal activity in 4 to 6 hrs

BisphosphonateMaximal activity 2 to 4 days

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.