Monte Minute‎ > ‎Monte Minute‎ > ‎

Hypercalcemia and Primary Hyperparathyroidism - 8/13/2012

posted Aug 13, 2012, 8:07 AM by Rohit Das   [ updated Dec 27, 2012, 7:13 AM by Purnema Madahar ]

At resident report today, Elena Lebduska was kind enough to present a case of primary hyperparathyroidism. Elena had noticed asymptomatic hypercalcemia on her patients labs following a brief admission for atypical chest pain. Further diagnostics ultimately revealed the diagnosis. So, how do we approach hypercalcemia?        

  • First off, always remember that the patient’s Calcium level on a BMP is their total calcium, both free and bound. Almost 50% of Calcium is bound to albumin, so the serum Calcium must always be corrected for a patient’s albumin level (or just measure their ionized Calcium…)         
  • 90% of hypercalcemia is due to either primary hyperparathyroidism (PHPT - the predominant cause in the outpatient world) or malignancy (the predominant cause in the inpatient world). There are several other, much less common, etiologies that I think is too much for my little ol’ daily (but worth reviewing!!!)         
  • Hypercalcemia of malignancy has many different pathologic etiologies, but in nonmetastatic solid tumors, the majority are due to secretion of PTH-related protein (PTHrP). The Calcium levels are usually >13, and is overall a very, very poor prognostic marker, regardless of etiology.        
  •  The single, most useful test in the workup of hypercalcemia is intact PTH. It is very important to note that the PTH is normal in up to 20% of patients with PHPT – BUT, in this situation, a “normal” PTH isn’t actually normal (i.e., it should be suppressed), and is still pretty much diagnostic of PHPT.         
  • Though the differential for non-PTH related hypercalcemia is very broad, the differential for PTH-related hypercalcemia is very limited – PHPT, Familial Hypocalciuric Hypercalcemia (FHH), and Tertiary Hyperparathyroidism. To differentiate PHPT from FHH, check a 24-hour Urine Calcium (should be low in the latter…hence the name). Tertiary HPT is a rare diagnosis these days, and is seen in very late stage CKD patients who have not been treated adequately for secondary hyperparathyroidism (yea..getting a bit complicated…read up!)

Focusing on PHPT, most cases are due to solitary adenomas (80%), with a minority due to hyperplasia (10-15%, sometimes part of a “MEN” syndrome), and very rarely due to parathyroid carcinoma (<1%). Dr. Epstein very nicely went through the pathophysiology of why elevated PTH causes hypercalcemia, which is basically via 3 mechanisms:       

  • Activating osteoblasts, which subsequently activate osteoclasts leading to increased bone resorption.         
  • Increases calcium reabsorption in the kidneys, via the distal convoluted tubule (corrected, thanks to Dr. Epstein - I previously wrote "via the ascending loop of Henle")        
  • Increased conversion of 25-Hydroxy Vitamin D to the active 1,25-Hydroxy form, which promotes Calcium and Phosphorus absorption in the intestine.

So, what do we do with patients with hypercalcemia? Well, it depends. Asymptomatic patients with mildly elevated levels (10-12) or moderately high levels chronically (12-14) don't need treatment. Depending on the rate of the rise, and how elevated, some patients will develop symptoms – remember?..."bones, stones, abdominal moans and psychic groans." Symptomatic patients, and those with a level > 14-15 should be treated – intravenous NS and calcitonin (efficacy limited to only the first 48 hours) are our mainstays, and bisphosphonates (longer-acting, but also a longer onset – usually 2-4 days) should be reserved for refractory cases in which the diagnosis has been made.         

  • Several bisphosphonates have been well studied. The most potent is Zoledronic acid (87-88% efficacy in normalizing Ca levels), followed by Pamidronate and Ibandronate (70-75% efficacy).
  • Bisphosphonates are especially important in patients with bone metastases. In this setting, bisphosphonates have been shown to also prevent “skeletal-related events” – particularly fractures and cord compression.         
  • Though, in patients on chronic bisphosphonates, always be wary of jaw osteonecrosis (…just sounds bad…), which has about a 2% incidence, after a median of 14 months of therapy. Bisphosphonates have a myriad of other adverse effects, which are also worth reviewing.

Regarding treatment of PHPT specifically – all symptomatic patients should be referred for parathyroidectomy, which is very effective – about a 95-98% cure rate, with an adverse event rate of 1-3%. Definitive management for asymptomatic patients is a matter of debate. In a NEJM observational study (attached) from 1999, 73% of patients with asymptomatic PHPT did not have disease progression after 10 years of follow-up. So – who should get surgery? Here are the guidelines from PHPT gurus (meeting ANY of the criteria):         

  • Serum Calcium >1.0 above the upper limit of normal         
  • Creatinine Clearance < 60 (uhh…isn’t this the entire Bronx…?)         
  • T score of -2.5 DS at any site, and/or previous fracture       
  •  Age < 50 years
  • Evidence of nephrolithasis, even if asymptomatic

Wow, a lot to know about a little divalent cation -- I've attached some good review articles, so please review...Until tomorrow…

Primary Hyperparathyroidism
Marocci et. al., NEJM 2011, Volume 365(25): 2389-97

Endres, Clin Biochemistry 2012, Volume 45: 954-963

Silverberg et. al., NEJM 1999, Volume 341 (17): 1249-55
Comments