Hypercalcemia Tuesday April 28th

Hypercalcemia

1.     asymptomatic routine evaluation  (most cases)

2.     symptoms: constipation, weakness, fatigue, depression, nephrolithiasis, osteopenia osteoporosis, polyuria

3.     altered mental status

90% will be from hyperparathyroid and malignancy. In the inpatient setting this will likely be related to cancer. In the outpatient setting, this will likely be related to hyperparathyroidism (an adenoma – a little tumor producing the hormone)

Symptoms of hypercalcemia (made this my self, it’s the best):

Kidney: nephrolithiasis, calcium oxalate, nephrocalcinosis, polyuria (DI – inhibits actions of ADH), AKI (afferent vasospasm)

GI: pancreatitis, constipation, ulcers (increased gastrin levels), increased alk phos

CVS: arrhythmias – shortens the qt, vascular calcification, AS, HTN (part of the workup)

Neuro: depression, decreased LOC, hypo-reflexia, band keratopathy in the eyes

MSK: weakness, bony pain, osteoporosis, fragility fractures, pseudogout

Skin: Calciphylaxis (calcific uremic arteriopathy) calcification of small to medium sized blood vessels of dermis and SC fat – ischemia and necrosis, associated with uremia, increased calcium and phosphate. IV sodium thiosulfate and parathyroidectomy controversial

**side note: Fatigue is a non specific primary physicians may be faced with which has a very large differential and a clear cause may not be found (high percentage of psychiatric illnesses). Consider calcium as part of your metabolic cause.

(in addition to consider a TSH, CBC, lytes, BUN, creat, liver enzymes, consider ECG – CHF?, OSA, etc.)

Different sources have different approaches to hypercalcemia, some refer to elevated PTH (or high normal) or low PTH.

Another way (my preference) is the following

1.     PTH related:

a.     primary hyperparathyroidism (consider MEN I and                                                                                                                                            MEN2A workup)

b.     secondary hyperparathyroidism (with calcium supplements)

c.      tertiary hyperparathyroidism

d.     lithium therapy (occurs in 10% of patients)

e.     familial hypocalciuric hypercalcemia (this always gets mentioned in every differential of hypercalcemia, I’ve never seen a case and don’t think I will, this can be considered after the most obvious causes are considered)

2.     hypercalcemia of malignancy

A.     PTH related peptide (squamous cell carcinoma, adenocarcinoma of lung pancreas, kidney)

B.     Osteolytic metastasis: breast, multiple myeloma

C.     Production of calcitriol (hodgkins lymphoma)

3.     Vit D related

A.     hypervitaminosis D

B.     granulomatous disease

C.      

4.     Other:

a.     milk alkali (patients with CKD on tums or patients with GERD taking tums)

b.     hyperthyroidism (increase bone turnover)

c.      immobility (prolonged bed rest)

d.     thiazide diuretics

e.     falsely elevated: hypergammaglobulinemia, hyperalbuminemia

Note: elevated calcium with a normal PTH is suggestive of primary hyperparathyroidism as in 10% of primary hyperparathyroidism PTH is inappropriately NORMAL.

Secondary hyperparathyroidism is when increased secondary to Vit D deficiency, usually in the setting of CKD. This causing elevated calcium is more rare as more commonly you would expect hypocalcemia. But we do know in the setting of CKD, we initially give calcium carbonate (tums) with meals to bind phosphate and get rid of it in gut, and if they absorb calcium while at it… great! It can be on the low side because of vit D deficiency because of CKD.  Patients may then become hypercalcemic from excessive PTH and all the calcium we are giving them! Subsequently we give them phosphate binders that DO NOT contain calcium such as sevalamer.

So how do we treat hypercalcemia? Below is the suspected cancer related hypercalcemia, typically with levels >3.

Treatment:

Fluids is are go to therapy first, NS 200-500 ml/hr. There are some case reports of giving Lasix but no good evidence. This  really is only considered after a patient is becoming overloaded but fluids and other meds  (to be discussed) may be enough.

*Lasix is more often considered in a patient who might have limited capacity to urinate, however, that paiient may be best suitable for dialysis.

If calcium >3 consider bisphosphonate therapy (pamindronate 60 – 90 mg in 500 mL NS over 4 hrs) Or zoledronate 4 mg in 50 mL NS IV over 15 min, lowers bone pain from lytic lesions and bone mets.  Bisphosphonates take around 24-48 hours to take affect, also may cause ATN so caution with renal failure, no RUSH to give as this will take affect after. Also, they may cause hypocalcemia.. so be careful!

Malignancies may respond to steroids, pred 60 mg po daily x 10 days

Calcitonin 4-8 iU/kg IM/SC BID (tachyphylaxis so generally effective in the first 2-3 days.

Often patients with malignancy related hypercalcemia will have known malignancy at presentation, one small study suggested a 50% mortality rate with hypercalcemia related to malignancy.

The opposite end of the spectrum is primary hyperparathyroidism

Indications for parathyroidectomy?

Asymptomatic? Age <50, calcium >0.25 (normal is 2.5) GFR <60 ml/min, osteoporosis, or previous fragility fracture. Urine calcium >400 mg /24 hours is no longer an indication, but this will put them at higher risk of forming kidney stones.

Fragility fracture: vertebral fractures, fractures of the neck of the femur, and Colles fracture of the wrist

Another reason to consider surgery is issues with adherence or follow up, patients would need to get BMD every 2-3 years as well as follow up for calcium.  If you decide to go for surgery, a bisphosphonate or cinacalcet are drugs that can be used to lower calcium in the meantime, although encouraging po fluids may be sufficient. Dr. Kane pointed out that Cinacalcet may be quiet expensive (400 per month!) – may be covered by some insurance?

Is imaging recommended? Yes, as if imaging can identify a parathyroid adenoma, this will usually decrease the amount of time the ENT specialist spends searching for the tumor in the OR. It is also ideal to have a specialist perform the procedure (one that does parathyroidectomies on the regular). If imaging does not show a tumor… does this rule out primary hyperparathyroidism? NO!

Pamidronate maintains normocalcemia for approximately 2-3 weeks (up to 4 weeks), while zoledronic acid works slightly longer ( for about a month or more). If there is no tumor response to treatment, then patient may need regular infusions of bisphosphonates at approximately 2- to 4-week intervals to treat hypercalcemia. 4

This is an article on some rare causes

http://press.endocrine.org/doi/full/10.1210/jc.2005-0675