We discussed a case of hypercalcemia this morning and reviewed the mechanisms by which malignancy can cause hypercalcemia.
1. Direct metastases to bone: These mets trigger the production of inflammatory cytokines and stimulate ostoclasts. Sometimes osteoclasts are directly stimulated by tumor cells via Osteoclast Activating Factors (eg IL6) in multiple myeloma or lymphoma.
2. PTH related peptide: this is the most common cause of hypercalcemia from non-metastatic solid tumors. Classically in squamous cell lung Ca
3. PTH: this is rare! only a few case reports of PTH being released from tumors
4. Calcitriol: a very common mechanism for hypercalcemia in the lymphomas.
Here is a great review article. *CT scan of a patient presenting with Ca=3.1, who subsequently was found to hav have small cell lung cancer.
Corrected Calcium:
The physiologically important calcium (Ca2+) is ionized calcium. This can be measured in the lab, however, total calcium is the value most commonly reported.
Calcium is bound to serum proteins, most importantly albumin. Therefore, in patients with low serum albumin concentration, the fraction of total serum Ca2+ that exists as ionized Ca2+ will be higher. When we are correcting calcium it is not because of a lab error, but rather to help us put the measured lab value into proper physiologic context in terms of possible causes, associated symptoms and need for treatment
It is important to know the serum albumin when interpreting total serum calcium levels. A correction for total serum calcium can be made using the following formula (alternatively ionized Ca2+ could be measured):
Ca = SerumCa + 0.02 * (NormalAlbumin - PatientAlbumin) (SI UNITS) - basically means that for every decrease of albumin by 10, add 0.2 to the total calcium.
Pseudohypercalcemia can occur when patients are hyperalbuminemic or have a multiple myeloma with a paraprotein that binds calcium (rare) - in these cases total CA2+ will be high, but ionized CA2+ will be normal.
DIFFERENTIAL DIAGNOSIS:
Most commonly either HyperPTH or Malignancy related. Malignancy related often presents with higher calcium levels, more symptoms and a more acute rise in calcium level (if previous values are known.
Other causes are out there - look them up if in doubt
Treatment:
TREATMENT
FLUIDS!!!!!!!!
Infusion rate depends on volume status, heart function, etc, but should target 100-150 cc urine output/hr - do not need to hydrate beyond euvolemia.
If severe/symptomatic consider: Bisphosphonates (IV) - will not take effect for 48-72 hrs, but will help maintain normal calcium when achieved.
Calcitonin - subQ is also very effective.
If hyperCa2+ is from sarcoid or lymphoma consider steroids (20-40 mg/day) - this works by decreasing calcitriol production from activated mononuclear cells in the lung and lymph nodes. Trying to get tissue before giving steroids if hypercalcemia not overly severe/symptomatic is a good idea.
AVOID LASIX since most patients are profoundly volume depleted initially and once replete can cause hypokalemia, hypomagnesemia, and lead to recurrence of volume depletion. A recent Annals of Internal Medicine article reviews the use/concerns regarding Lasix in hypercalcemia. If Lasix is need for pulmonary edema etc., it can certainly be given, just monitor lytes and volume status.
Dialysis should be considered if the above fail/can't be done because of renal failure or heart failure.
RENAL CELL CARCINOMA and PARANEOPLASTIC SYNDROMES
Hypercalcemia - from lytic bone mets, PTHrP or increased production of prostaglandins that promote bone resorption.
Polycythemia - from EPO overproduction
Hepaitc Dysfunction - "Stauffer syndrome" - in the abscence of mets, increased ALP (+/- fever, wt.loss, fatigue), often improves after nephrectomy
1) High PTH- expect high Ca, low PO4. A) primary/secondary/teriary hyperparathydoidism, parathyroid hyperplasia B) lithium C) familial hypercalcemic hypocalciuria
2) Low PTH PTHrP from malignancy (esp. SCC- lung, H+N) hypervitaminosis D- expect high Ca and high PO4- from granulomatous disease, lymphoma) OAF = IL6 (local paracrine effect; in breast and hematological cancers) Direct effect of mets (e.g. prostate, lung, etc.) Myeloma Medications- HCTZ, Ca, vit. D Milk alkali syndrome Hyperthyroidism
As inpatient, #1 cause = malignancy As outpatient, #1 cause = primary hyperpara
Tx: Fluids!. Consider bisphosphonate if malignancy-related or v. high (but takes days to work) Calcitonin by nasal spray or subq. If hyper D from sarcoid or lymphoma, possible steroids. Avoid lasix since most patients are profoundly volume depleted. Last resort is dialysis
Milk-Alkali syndrome
Triad of hypercalcemia, met alk, renal failure assoc with ingestion of large amts calcium, alkali
Once common because of PUD treatement. Making resurgence b/c of calcium for osteoporosis, and prevention of secondary hyperparathyroidism in CKD
Sequence: hypercalcemia, dec GFR, met alkalosis ("contraction"). Hypercalcemia per se stimulates renal bicarb fomation.
Pts on vit D, thiazides, vol contraction, CKD are at higher risk
Some links:
Click here for NEJM clinical problem solving case on hypercalcemia
Click here for a review of calcium disorders in renal disease
