from the JAMA Network this is JAMA clinical reviews interviews and ideas about Innovations in Medicine Science and clinical practice hello and welcome to this JAMA clinical reviews podcast this is Dr Anne Cappola associate editor for JAMA and professor of medicine at the Perlman school of medicine and director of the Penn medical communication Research Institute today I'm joined by Dr Elizabeth Shane professor of medicine at Columbia University Irving Medical Center we will be discussing her review article entitled hypercalcemia a review Elizabeth thank you so much for joining us and welcome well thank you very much for having me I was so honored to be invited to write the article and I'm very honored also that it's been selected for a podcast so I'm going to start with what should be a straightforward question but perhaps it's not how do you define hypercalcemia I think it really is quite straightforward hypercalcemia is defined according to the measuring laboratory's normal range so if the albumin corrected serum calcium is above the upper normal limit that is considered hypercalcemia there really isn't any universally accepted upper normal limit that would be the same in each and every laboratory so you can't really talk about a physiologic upper normal limit because it's just so different from place to place in practice this is really only a problem when the albumin corrected serum calcium is near the upper limit of normal obviously if you have a serum calcium of 12 milligrams per deciliter that would be abnormal in any Laboratory but a serum calcium of 10.2 milligrams per deciliter could be abnormal in your laboratory but might not be in my laboratory so it's a little straightforward but maybe not so straightforward by and large we should be just looking for the h next to it but also paying attention to the albumin level yes now are there situations where we should be measuring the the ionized calcium level well usually the measuring total serum calcium is enough but if the serum albumin is low then you can correct it using the widely used algorithms that have been in use for many years using it for an elevated albumin is not as well accepted so when the albumin is high that may not be quite as accurate as when the albumin is low I think that the use of an ionized calcium is particularly helpful when there's a lot going on if you have a patient in the ICU who has disturbances in albumin levels and acid-base problems then anionized calcium may be quite helpful particularly when the patient has an acid-base abnormality that affects The Binding of calcium ions to albumin and therefore you can't really tell from the total calcium what is going on with the ionized calcium so then I think if it's available it's very useful to get 99 calcium so it would be fair to say that by and large in outpatients you're not recommending measuring ionized calcium levels yes I think that's fair to say in outpatients you probably don't need to do that especially if they don't have chronic metabolic acidosis or alkalosis people are getting lots of these calcium levels because they're now part of the basic metabolic panel or the comprehensive metabolic panel and sometimes at least I've seen that there's some fluctuations it's not always above the 10.3 or 10.2 whatever the range is for the assay you can see a little bit of fluctuation would you recommend generally looking for a Persistence of abnormalities there or what do you do in the patient where there is some fluctuation between the high nines and the low tens well then I usually follow that patient over time and try and get a sense of what they usually are lots of patients with fairly consistent hypercalcemia will have the odd day when they're normal and conversely perhaps less commonly people may have mostly normal but the occasional elevated calcium level and so I think that it's fine because usually these levels are around the upper limit of the normal range in and out of that normal range and I think that that's not a dangerous level so it's usually safe to follow them until the situation eventually declares itself one way or the other now this may seem like some of a basic question but why do we even worry about hypercalcemia why does it need to be managed I don't necessarily think it always needs to be treated but I always think it's important to try and figure out why the patient has hypercalcemia because it may be an early sign of an underlying undiagnosed problem for example vitamin D toxicity or multiple myeloma that the patient is unaware of and so therefore I think it's something that should be taken seriously in terms of why the patient does have an elevated calcium but it doesn't necessarily need to be treated particularly if it's mild severe hypercalcemia though is kind of a different situation and even if you're dealing with moderate hypercalcemia that is developed rapidly I think that should be treated because it's often very uncomfortable for the patient the patient has symptoms polydipsia polyuria gastrointestinal symptoms and if it's high enough it can be life-threatening for example if mental status is altered or cardiac arrhythmias develop so I think in those situations it is important to treat it certainly you've just described situations where universally there's some complication from it and that would require urgent evaluation and management is it always based on what the clinical situation of the patient is or their absolute levels where you're worried just based on the level that something needs to be done more urgently generally we think of a serum calcium of say 14 milligrams for deciliter as getting into the dangerous range and it should prompt treatment immediately with evaluation preceding concomitantly with treatment like if the patient suddenly presents with a calcium of 14 I would begin treating while I was thinking about why the patient was hypercalcemic that being said though some patients have debilitating or worrisome symptoms even at lower levels and in those patients urgent treatment should be initiated even if it's below 14. I'm not talking about 10.5 here I'm talking about 12.9 or 13.2 and then conversely you can have some patients who will come in with a calcium of 18 milligrams per deciliter and they'll be completely asymptomatic now I still treat them because it's scaryly high but I might take a somewhat less aggressive approach it generally seems to have to do with the relative chronicity or Acuity with which the hypercalcemia develops so if it developed rapidly the patient tends to be much more symptomatic some patients have had hypercalcemia for years such as patients with parathyroid cancer and they may be use or have accommodated to the hypercalcemia so in those patients it may not be so alarming and they may be asymptomatic but generally 14 is the reasonably acceptable cutoff for when you want to jump in with more aggressive treatment and in terms of the symptoms to worry about and those that may have calciums in the high 12s or in the 13s range well are some of the symptoms that would alert you that that would be due to the high calcium potentially and therefore reversible with treatment well polydipsy and polyuria tend to be among the first and also GI symptoms like nausea vomiting constipation the things that are more alarming are mental status changes like a stupor coma maybe just a little difficulty in concentrating is a little subjective so it's a little bit hard to hold your hat on that but I think that anything more than decreased concentration ability should prompt therapy and then of course the EKG with a long PR interval or arrhythmias that's also very concerting all right well let's take a step back and let's just talk broadly about a patient that you see in front of you that has hypercalcemia what is the standard evaluation and then we can move to management but what's the standard evaluation for a patient who presents with hypercalcemia that kind of depends on whether it is mild and or long-standing or whether it's severe if you're dealing with a patient with mild hypercalcemia then the appropriate approach is to take a detailed history including review of old Labs to determine whether this has been there for a while and just hasn't been acted upon or noticed or whether it's a new event and also a medication history to make sure that the patient isn't on excessive thyroid hormone or thiazide diuretics or taking excess numbers of supplements particularly vitamin D and less commonly vitamin A so I think an important thing always is the history and then it's also essential to perform a good fiscal exam looking for Clues such as lymphadenopathy or some such physical trait that might point you in the direction of say neoplasm versus something benign in terms of the diagnostic workup the first step is really to measure pth level and a serum calcium level at the same time on the same blood sample if the pth is high or if it is normal but well within the normal range the upper end or mid-normal range then the diagnosis is probably primary hyperparathyroidism if that patient is young or has a positive family history of hypercalcemia it may be worthwhile considering genetic causes such as familial hypocalceuric hypercalcemia which is better known as fhh that would be the most common of those genetic causes although it's still pretty rare if the parathyroid hormone level is frankly suppressed or if it's at the very lower end of the normal range then it's important to consider other causes thyroid toxicosis vitamin D toxicity malignancy there's a whole multiple tables in the literature of common and not so common causes of hypercalcemia but I think those are the things to be considering when you're evaluating a hypercalcemic patient if the hypercalcemia is severe of Rapid onstat most likely the patient has malignancy although this isn't really certain by any means so I think that it's important in such patients to then focus on diagnosing the type of malignancy as indicated by the history physical and targeted Imaging and laboratory tests so it sounds like history and physical next step is to check the pth and the big decision point is about whether it's parathyroid hormone mediated or not if it is parathyroid hormone mediated then what are the next steps for the patient once you know that the patient has parathyroid hormone mediated hypercalcemia the next step is to evaluate them to determine again just occasionally the patient may have a familial form of hyperparathyroidism also I mean not to be forgotten are rare reports of certain malignancies that actually secrete parathyroid hormones so but these are a tiny tiny tiny proportion of the vast majority so I think that once you have made the diagnosis of primary hyperparathyroidism and you're secure in that diagnosis then I think the next step in my mind is to determine whether the patient meets the guidelines for recommending parathyroid surgery those guidelines would be whether the patient has symptomatic hyperparathyroidism I.E they have symptoms of hypercalcemia or a history or a current kidney stone or nevrocalcinosis or hyperparathyroid bone disease Osteo which is osteitis fibrosis cystica now that's pretty unusual in this day and age and particularly in developed countries so usually we don't see that probably less than five percent of cases if the patient is not symptomatic in any of these ways then the next question would be do they meet other guidelines for surgery to figure that out you need to have the serum calcium which should be as a guideline for surgery a milligram above the upper limit of normal is one of the guidelines you need to do a creatinine clearance because creatinine clearance is below 60 are an indication for surgery and a 24-hour urine calcium should also be done because a level above 250 milligrams in women and 300 milligrams in men for 24 hours is one of the guidelines for surgery it's also important to be sure that the patient does not have kidney stones or nephrocalcinosis so it's important to do an ultrasound or other abdominal Imaging to rule out those issues and it's also important to know that they do not have osteoporosis so you'd get a dexa scan to measure their t-score and also image their vertebral spine to make sure that they don't have vertebral fractures and you can do that either with a vertebral fracture analysis with the dexa if you have that capability or you can get spine films so if all of those things are negative then you can probably follow the patient over time as opposed to operate so if I hear you correctly Elizabeth The Next Step would be to have some laboratory evaluations that would include a 24-hour urine which is not something that any patient likes to do but is an incredibly useful test in this situation yes as well as potentially some other Imaging that might be required to really see if any of the criteria are met for surgery and is age also a Criterion in there yes if the patient is under age 50 that is a an indication for recommending parathyroidectomy what if you have a patient that says they have reflux symptoms and constipation and difficulty concentrating but none of the biochemical or radiologic evaluation meets criteria for surgery and they don't meet the age cut off is that someone that would go to surgery or do they get monitored unless they specifically meet those more objective criteria that are part of the guidelines well let me say you can also recommend surgery for patients who do not meet guidelines and patients who do not make guidelines can also request to have surgery so I think the types of symptoms that you've described are very nondescript symptoms and I think it's highly likely that a patient with constipation and a calcium under one milligram per deciliter higher above the upper limit of normal So within one milligram per decilator it'd probably still be constipated even after the surgery so I think you don't want to set up a situation where mild widely experience signs and symptoms are attributed to hyperparathyroidism when they may just be part of the way the patient is so I don't think you could really assure the patient or be sure yourself that after they had the surgery those things were going to get better you and I are fortunate enough to be at institutions where we have very experienced parathyroid surgeons can you talk a little bit about what someone should look for in a parathyroid surgeon I think you should look for somebody who is very experienced in doing these you don't want somebody who does a couple of these a year doing your parathyroid surgery you want somebody who is at a place where they do this all the time so I think the volume and experience of a surgeon are very important I would absolutely agree because hypoparathyroidism is a hard complication to manage on the other side so much better to have someone that has the appropriate number and amount of parathyroid tissue removed as well as making sure that there's cure afterwards it can be very satisfying when it's a solitary adenoma there's cure afterwards much of what we manage in endocrinology doesn't have a cure at the end of it so that's one of the more satisfying things and we would like to diminish that need to manage those patients who haven't had a successful outcome by making sure that within our power the patients go to people with the most experience but now some patients don't want surgery and they ask about medication is medical therapy an option for someone with primary hyperparathyroidism I tend to not use a lot of medications to lower serum calcium the main medication to do that is cynical set which is a calcium sensing receptor Agonist and it can lower serum calcium into the normal range in patients with primer hyperparathyroidism but I tend to avoid it because it's expensive and it has side effects like nausea and I wouldn't use it unless the hypercalcemia was moderate symptomatic and the patient either refused or could not undergo surgery for some health related reason some physical reason I think my tendency is to try and look for reasons to recommend surgery because I feel that this is a treatable disease and the long-term consequences are unclear but we do know from some small studies but some studies that over 10 to 15 years almost 40 percent of people with hyperparathyroidism are going to develop as surgical indication such as a kidney stone or a more markedly elevated serum calcium and for that reason I always tend to recommend surgery as opposed to Observation reasoning that it's better to operate when the patient's younger and healthier rather than 10 to 15 years later when there's a good chance that they may not be as Stellar a surgical candidate does the patient have to be worried about having parathyroid cancer parathyroid cancer is fairly rare it tends to be associated with some characteristics such as a very high serum calcium and a very high parathyroid hormone level and a palpable neck Mass those are the most defining characteristics I have seen it in people who had relatively mild hypercalcemia but most of the time if the serum calcium is not very high say lesson 14 and the parathyroid hormone level is within a couple of times the upper limit of normal that's pretty unlikely it does occur and when I do suspect it I alert the surgeon that I do suspect it because they would want to perhaps change their approach to the surgery and make sure that no biopsies were done and that they were very careful about evaluating the surgical characteristics of the pathological characteristics and the characteristics of the tumor as they view it when they're looking at it in surgery let's turn to the patient who does not have pth mediated hypercalcemia and let's talk specifically about patients who have hypercalcemia malignancy can you talk a little bit about the evaluation or management in those patients if you have a patient who has hypercalcemia and a low pth and they don't have a known malignancy you evaluate them for common malignancies associated with hypercalcemia such as breast cancer renal cell cancer multiple myeloma but it's also important to consider some non-pth dependent and non-malignant causes that could be associated with hypercalcemia it's like a cyrotoxicosis although that's usually mild vitamin D toxicity you can have very highly elevated serum calcium levels and you'd need to get vitamin D levels to make the diagnosis of that milk Alkali syndrome and to evaluate those patients first before you do a huge malignancy work up with the function tests vitamin D levels Etc if a patient has a low parathyroid hormone and a known malignancy and they could still have other ideologies that could be contributing to or even causing hypercalcemia once you've excluded them I think the focus then ships to a collaboration with our oncology colleagues we won't want to control the malignancy as much as possible if it's certain that they have this malignancy and that it is that malignancy that is causing the hypercalcemia and also a more chronic focus on how to manage the patient to control the serum calcium over time generally this is not a good sign and it usually means that the prognosis is limited but we want to do the best we can to keep every patient comfortable and under control with hypercalcemia malignancy and do you want to just briefly mention some of the therapies for those where it's severe enough so I'm talking about inpatients who have hypercalcemia malignancy that's in that urgent range that we discussed earlier so we often get consulted for this so hypercalcemia malignancy or a patient comes in very hypercalcemic and usually that patient is very volume depleted so we always begin with aggressive hydration with saline generally we try to avoid Loop Diuretics although often on the content service we will see them given anyway and the reason is the patient is already volume depleted and you can just create a negative feedback loop by also giving them a powerful diuretic and it can limit your ability to rehydrate them so we try to stay away from Loop Diuretics until after the patient is hydrated appropriately and then only if there's some need for the Loop Diuretics such as the patient has an issue with renal insufficiency and or heart failure or fluid overload we usually if the patient is very hypercalcemic and symptomatic we often will give salmon calcitonin for a couple of days because it acts very quickly to inhibit osteoclast-mediated bone resorption and it also increases urinary calcium excretion and so for a couple of days while saline hydration and bisphosphonates which I'll come to in a minute are taking to work we can sometimes lower the serum calcium a little bit by milligram or two with salmon calcitonin we only give it for a couple of days because after that point tactical access and Susan it's not effective we usually give intravenous bisphosphonates most typically zolodronic acid for hypercalcemia malignancy usually a dose of four to five milligrams intravenously typically over 15 minutes and that takes probably 36 to 48 hours to lower the serum calcium which is why we hop in with the calcitonin at first that is the typical approach to Mark hypercalcemia in a patient with hypercalcemia malignancy this is new onset I mean if a patient has recurrent then you might set up something where they get sequential doses of solodonic acid as their serum calcium starts to come up again you mentioned that the treatment is aggressive hydration because they're all dehydrated followed by calcitonin and then bisphosphonates what about denosumab does that ever have a role in the treatment of acute hypercalcemia that's severe well there are not a lot of data on this but denosav has been useful in parathyroid crisis and parathyroid carcinoma and it has been shown to lower serum calcium in patients with hypercalcemia malignancy who are refractory to high IV bisphosphonates and for that reason it was approved by the FDA the other place where we consider denosumab is in the patient who has an elevated serum creatinine or acute kidney injury or chronic kidney injury because it is not cleared by the kidney and it does not cause further deterioration of kidney function unfortunately there's not any data to tell us when one might be better off using denosumab than intravenous bisphosinates I use it in patients who have a high creatinine level if I know the kidney problem was present before the hypercalcemia the approved dose is 120 milligrams and I usually start with a lower dose and the reason for that is there's a concern for hypocalcemia that is worse with stenosamab than with ibibus phosphonates great thanks for that clarification before we wrap up is there anything else that you'd like our listeners to know about hypercalcemia and its management I do think it's important to understand that it's particularly if it's consistent hypercalcemia almost always signifies that something is a mess with that patient and so therefore it's important to take it seriously I also think we didn't really touch on how to follow the patient with primary hyperparathyroidism who elects or does not have surgery and they can be followed but they should be followed with annual serum calciums annual estimates of their kidney function they should have bone density every year or every two years and spine Imaging to make sure they haven't had any fractures and 24-hour urine calcium if it's indicated clinically so those would be my points to you can follow patients with primary hyperparathyroidism successfully and that's how to do it and don't ignore hypercalcemia because it usually means something is amiss with the patient great I think that's a great way to wrap up thank you so much that was Dr Elizabeth Shane from Columbia University this has been Dr Ann capola with Jama this episode was produced by Jesse mccorders at the JAMA Network the audio team here also includes Daniel Morrow Shelley Stephens Lisa Harden Audrey foreman and Mary Lynn fercolic to follow this and other Jama Network podcasts please visit us online at jamminetworkaudio.com thanks for listening foreign