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S2D: The Symptom to Diagnosis Podcast - Episode 22: Hypercalcemia
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S2D: The Symptom to Diagnosis Podcast - Episode 22: Hypercalcemia
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Language: EN.
Segment:0 .
[upbeat intro music] [upbeat intro music] [upbeat intro music]
DR. CIFU: I'm Adam Cifu.
DR. STERN: And I'm Scott Stern.
DR. CIFU: And we're here with another episode of S2D, the Symptom to Diagnosis podcast. This podcast teaches evidence-based strategies for diagnosing common medical symptoms. We begin each episode with a case unknown to one of us. We then discuss five high yield features that help to accurately diagnose the cause of the symptom at hand. We then return to our case before finishing up with a discussion of fingerprints, common misconceptions, pet peeves, and other random pearls of knowledge pertaining to the week's symptom.
DR. CIFU: The cases that we discuss are drawn from our clinical experiences, but because protecting patient privacy is part of our oath, we never discuss actual patients, and most cases are composites.
DR. STERN: You know, it crosses my mind that we're going to have to change fingerprints to like DNA analysis. No one's going to know pretty soon what a fingerprint is.
DR. CIFU: I was thinking that someday when I'm like, completely demented, I will just be repeating that intro over and over again.
DR. STERN: [chuckles] Something to look forward to.
DR. CIFU: So what are we talking about today, Scott?
DR. STERN: Our topic today is hypercalcemia. And you are the expert of the day. Do you have a case to present to me?
DR. CIFU: I do.
DR. STERN: All right, well hit it.
DR. CIFU: Picture this.
DR. STERN: Okay.
DR. CIFU: You're sitting in your office, it's the afternoon, you just had a cup of coffee, and you have a new patient on your schedule. You're excited because you have a little bit more time for the new patient than your usual patient. The patient is 60. She has not seen a doctor in 10 years. And she considers herself quite healthy, and quite knowledgeable about medicine. And she admits that she does not particularly like doctors, she finds them self-important.
DR. CIFU: She comes in now because she knows she's due for her second colonoscopy. She had one at 50, which was normal. She is having worsening constipation. She now says she used to drink prune juice daily, and that enables her to go to the bathroom at most every other day. She also would like to get the Shingrix vaccine, which she knows has been approved since the last time she saw a doctor.
DR. CIFU: You see her, everything seems fine, you convince her that some blood work would be helpful. You send a CMP, a TSH, lipids and an A1C. Although your colleague, Dr. Cifu sitting next to you is like, [scoffs] "Why are you sending all these blood tests?" They all look great, except the calcium is 11, her albumin is normal.
DR. CIFU: Thoughts?
DR. STERN: Well, actually, in a real visit, I'd have a lot of thought. So before I get to the calcium, there's a lot of interesting dialogue that you just had. So first, she hasn't seen a doctor in 10 years. I will say that you have to be very careful with patients who really haven't seen a doctor in 10 years because oftentimes, something's really wrong with them. They haven't seen a doctor for 10 years because they don't like going to doctors and something, even if they don't admit it, has pushed them to feel badly enough that they've come in.
DR. STERN: And so I've often called that Stern's rule, if someone's coming in, they haven't been seen in 10 or 20 years, something's wrong. The other thing I'd mentioned is boy, I have to check my emotional karma at the door with this patient because it sounds like she's going to at least trigger me a little bit. She doesn't like doctors, she seems to think that she knows what's going on, and so sometimes you have to be aware of what you're thinking and just take care of the patient.
DR. STERN: But, all right, so let's get to her calcium. So she's 11. And you have a patient who is basically apparently well-looking. You haven't mentioned that she looks sickly or is losing weight, who's hypercalcemic. And you know, retrospect, her constipation is probably a symptom of this, it'd be nice to know how long it's gone on so that you have a sense of maybe how long she's been hypercalcemic which can be helpful, as would her any prior labs, but she hasn't had any because she hasn't seen anyone in 10 years.
DR. STERN: A family history can also be helpful. Other clues to chronicity, which can be helpful are prior kidney stones or if she's ever been diagnosed with osteoporosis. I think I definitely want to know whether she's taking calcium and vitamin D, she does say she's cognizant of her health, so it's quite possible she's taking too much calcium and vitamin D and it's quite simple and she just needs to stop those.
DR. STERN: But if all of that's negative, my first step would be to get a PTH level on her because clearly primary hyperparathyroidism is going to be the most common of the various disorders that we're going to talk about. Her thyroid function tests are normal, arguing against hyperthyroidism, and it doesn't sound like she's on thiazide, because she hasn't seen anyone in 10 years, which is another common cause.
DR. STERN: If all of that is negative, the PTH is normal, then we'd have to think about cancer, if she was a smoker, maybe a paraneoplastic syndrome from a cancer or multiple myeloma could do this, but those fortunately will be less likely and I'm not going to order those in the initial steps. So what do you got for me?
DR. CIFU: That sounds great. I really liked the idea that she seems to be very aware of her health. And so thinking about, you know, maybe she's using calcium and vitamin D, I think is a great thought, especially in the COVID era where half the world decided that maybe taking vitamin D was going to prevent COVID. And you also alluded to the symptoms of hypercalcemia, And you also alluded to the symptoms of hypercalcemia, which is classically described by, I don't know, this mnemonic, I guess? Bones, abdominal groans, thrones and psychiatric overtones.
DR. CIFU: Bones talking about usually PTH related bone disease, Bones talking about usually PTH related bone disease, abdominal groans, the kind of constipation and achy that people can get, thrones, which I had forgotten until I looked it up for this which is from sitting on the toilet, either because of constipation or polyuria. And then psychiatric overtones, anxiety, depression, that goes along with hypercalcemia.
DR. CIFU: Well, yeah, I'll give you what you want, so you asked for PTH, is that correct?
DR. STERN: I did.
DR. CIFU: And her PTH comes back at 135, with normal I think going up to 70-75.
DR. STERN: So presumably if her creatinine is normal, then this is not secondary or tertiary hyperparathyroidism. So pretty much confirms the diagnosis of primary hyperparathyroidism. And the real decision is going to be, does she need treatment or not, which we can get to later but I think the diagnosis is fortunately relatively clear.
DR. CIFU: So you're feeling pretty good about yourself?
DR. STERN: I'm feeling quite good about myself. Thank you very much.
DR. CIFU: [chuckles] Okay, so I'm going to move on with my five points here. So point one, for me hypercalcemia is one of those diagnoses that I think about the differential with a framework, and then the clinical evaluation of the patient with a whole different algorithm. So I'm going to start with the differential and the differential, I think very much like you expressed, I think of totally in terms of PTH related causes of hypercalcemia, hypercalcemia of malignancy, vitamin D related and other causes.
DR. CIFU: So parathyroid related is overwhelmingly primary hyperparathyroidism. But you mentioned some of the other things, secondary, tertiary hyperparathyroidism. Hypercalcemia of malignancy, actually the most common cause of hypercalcemia in our hospitalized patients. And that can also be a couple of different things. There can be PTHrP related, there can be hypercalcemia from osteolytic mets, or there can actually be production of vitamin D by tumors.
DR. CIFU: That's mostly seen with lymphoma. There's vitamin D related causes in today's world, that's mostly just people taking too much vitamin D, but granulomatous disease can do that. And then there are some other relatively common causes of hypercalcemia that I just keep in the back of my mind, milk-alkali syndrome, hyperthyroidism, stuff like that.
DR. STERN: Great.
DR. CIFU: My second key point is, to organize your differential of a patient around the PTH. So most patients you see with hypercalcemia will not have symptoms, you'll just get a calcium, it'll be elevated, the PTH will be elevated, the creatinine will be normal, and your diagnosis will be primary hyperparathyroidism. And you kind of can't say that enough, because you don't want to get too into the weeds in your differential diagnosis, because most the time, this is easy.
DR. CIFU: Third key point, once you diagnosed primary hyperparathyroidism, and you alluded to this, Scott, you have to remind yourself that not every patient needs surgical treatment. I always love this talking to medical students, because medical students coming off of internal medicine, generally think that you just monitor primary hyperparathyroidism.
DR. CIFU: Medical students coming off the surgical service think that you just operate on primary hyperparathyroidism.
DR. STERN: It's not minor surgery.
DR. CIFU: It's not minor surgery. And really, I think it's one of those surgeries that you have to be in good hands, right, to have it done.
DR. STERN: Absolutely, totally.
DR. CIFU: So the indications for surgery are symptoms, which are sometimes, given how non-specific symptoms of hypercalcemia are, sometimes a tough call, osteoporosis, which can be a tough call in older people, because, is it because of their hyperparathyroidism, or is it because they're a 75-year-old woman? Creatinine clearance or GFR less than 60, right? And so, I should say, without another cause, so that's probably nephrocalcinosis, right? CKD related to hypercalcemia.
DR. CIFU: Interesting one, age less than 50. It turns out that if you got hypercalcemia at a young age, that's A, much more likely to progress to hypercalcemia that requires treatment. It also costs so much to monitor those people over the course of their life that's actually cost efficient to just surgically treat their primary hyperparathyroidism. And then a calcium over 11.2 because if your calcium is that high, those people are also more likely to progress too.
DR. STERN: The age makes sense to me. If you think about the long term impact of even mild hyperparathyroidism over decades, you have to imagine that's going to mess with your bones, even if you're not osteoporotic then.
DR. CIFU: Right, I'd be worried about that. I'd be worried about that from a bone perspective. I think I'd be worried about that from a vascular perspective as well, right?
DR. STERN: And kidneys as well, right, totally.
DR. CIFU: Fourth key point, if your PTH is low, the diagnosis is likely cancer, I think anybody who's gone to medical school has seen that old graph of like low and high PTH and what the causes are. But mostly that's in patients who've already been diagnosed with cancer, it's relatively uncommon for someone to present with hypercalcemia, and that lead to the diagnosis of their cancer.
DR. CIFU: Maybe myeloma is the only thing that stands out from that. Maybe myeloma is the only thing that stands out from that. I don't know what you think.
DR. STERN: I'm not sure. I was wondering if the level of the calcium impacted your thinking about that. Is there value in saying, boy, if it's 14, I'm really worried about cancer? Does the data bear that out?
DR. CIFU: That data does bear that out. And if you look at people who are hospitalized for hypercalcemia who obviously, by the fact that they're hospitalized in 2021, those are people who must have really high calcium. Those people overwhelmingly have malignancies. So I think you're onto something there.
DR. STERN: Okay.
DR. CIFU: But other possibilities for this low PTH hypercalcemia are milk-alkali syndrome, okay? That's actually the second leading cause of hospitalized patients for hypercalcemia, hypervitaminosis D, hyperthyroidism, granulomatous disease and thiazide use.
DR. STERN: All right. And so do you have one more for us?
DR. CIFU: I have a final key point.
DR. STERN: Go ahead.
DR. CIFU: And that's-
DR. CIFU: We spend a whole lot of time thinking about and measuring calcium and phosphate levels in people with CKD. It helps me to remember the story of what happens to calcium metabolism when the kidneys fail. So the first step is that as kidney function worsens, the kidneys produce less vitamin D and excrete less phosphate. And the body's response to this is perfect, okay? The body makes more PTH, this leads to more excretion, which is actually decreased resorption of phosphate, and it also increases production of vitamin D, thus more calcium is absorbed and more calcium is released from the bone, okay?
DR. CIFU: So initially things are working great. The problem is, that as the CKD worsens, the PTH no longer helps. The kidneys sort of say, "Yeah, I know there's PTH, but I can't make any more vitamin D, and I can't excrete more phosphate." And so all that happens is the PTH pulls calcium out of the bones, which weakens the bones, phosphate levels rise, and you end up with someone with low calcium, high PTH, renal osteodystrophy and hyperphosphatemia and it's just a bad place to be.
DR. STERN: Okay, so we don't want to get that. That makes sense, all right.
DR. CIFU: So let's go back to our case.
DR. STERN: But just to make that simple, the reality is, we only have to worry about that if someone's creatinine is significantly elevated. If their PTH is elevated and their creatinine is normal, we're done with that, correct?
DR. CIFU: You got it, you got it. So when you're thinking about primary hyperparathyroidism, generally, you shouldn't be sending a PTH, unless you already have a creatinine or some measure of kidney function.
DR. STERN: Great. All right, so let's go back to our case. You said her PTH was over 100-
DR. CIFU: Yep.
DR. STERN: -and despite the hypercalcemia. So she has a high calcium and a high PTH, pretty much confirming hyperparathyroidism. So what happened to her?
DR. CIFU: So I'll throw that back at you. So you know, we talked about reasons to treat her and treat her is send her to surgery. So she's convinced that she's having no symptoms of this. She thinks her constipation is chronic and unchanged. You urge her to have a bone density study, you know, generally we start that at 65, but here's a woman and she refuses, because she's not supposed to have that until she's 65. Her renal function is fine.
DR. CIFU: She's 60, so she's over 50, and her calcium is not quite 11.2. So what do you tell her?
DR. STERN: Well, that's a good question. I probably wouldn't push her very hard, frankly, I'd probably say we should keep an eye on it, I would try to explain to her the rationale for doing a bone density because she is leaching calcium from her bones at a much higher rate, and hope I could persuade her with time to do that, because it might affect my therapy. But other than that, I don't think that- Would I put her on anything for her bones now, with the absence of a bone mineral density?
DR. STERN: I probably would not, although maybe some people would. So Dr. Cifu, I need your expertise in this. What would you do in the absence of deciding you're going to do surgical therapy?
DR. CIFU: I think what you said is perfect. And I think it shows that you are, you know, an experienced internist, and recognize it like yeah, you don't have to finish that on today's visit. I mean, I think if you can get her to come back in six months or a year to continue this conversation, rechecking her calcium, you know, making the argument about the bone density study, boy, that would be terrific. You threw me for a second, talking about treatment of this.
DR. CIFU: And it's interesting, certainly there are people who don't want to have surgery, whose only symptom is some osteopenia and osteoporosis whose only symptom is some osteopenia and osteoporosis that you might treat that. And then we can treat primary hyperparathyroidism with cinacalcet, right? Certainly, I think at this point with someone without symptoms and a calcium of 11, you wouldn't even think about doing that.
DR. CIFU: But it's an interesting thought.
DR. STERN: All right, well, that was an interesting case. So we're going to go on now to our next section, which is fingerprints/DNA analysis-
DR. CIFU: [chuckles]
DR. STERN: -common misconceptions, pet peeves and other random pearls of knowledge. Adam, what do you have for fingerprints?
DR. CIFU: Nothing.
DR. STERN: Okay, I don't have anything either, as is often the case. All right, so how about common misconceptions?
DR. CIFU: So I kind of mentioned this before. So maybe the misconception that milk-alkali syndrome is a rare syndrome only of historical importance, and it's people with peptic ulcer disease, who are ingesting some crazy mix of milk and bicarbonate, right? I've actually printed out the JAMA article about this from like 1917, that I occasionally hand out in the hospital just to-
DR. STERN: From 1917?
DR. CIFU: 1917, isn't that cool?
DR. STERN: Wow.
DR. CIFU: So that's not true. Milk-alkali syndrome, second leading cause of hospitalization from hypercalcemia, these days it's not related to Sippy powders or whatever it was back then, but it's related to people using calcium carbonate, which is really a terrific source of both calcium and an alkali. You'd like people to have some, you know, AKI, CKD, but even just hypovolemia, which could get them some level of hypercalcemia and get them into the hospital.
DR. STERN: That's great.
DR. CIFU: How about you, misconception?
DR. STERN: I have one. So when we think about cancer causing hypercalcemia we often look to the alkaline phosphatase to see if it's elevated because the idea is that as the bone is invaded, the alk phos will go up. The one exception to that to remember is multiple myeloma. It turns out that multiple myeloma releases something that's been called osteoclast-activating factor that reabsorbs bone but does not elevate alk phos.
DR. STERN: So if you ever worry about multiple myeloma, the alk phos will not usually be elevated.
DR. CIFU: I had completely forgotten about that. But I have to say it is true that for me hypercalcemia of malignancy very often if I see an elevated alk phos very often if I see an elevated alk phos and I go to that next step of okay, while I'm working this up, I'm going to send serum protein electrophoresis, urine protein electrophoresis, PSA, you know, it's generally not myeloma, and in my practice, it's often unfortunately, prostate cancer.
DR. STERN: Right, sure. All right, so let's go on to pet peeves. These are our favorite I think. What do you-
DR. CIFU: These are.
DR. STERN: I have several of these I have to admit.
DR. CIFU: Yeah, so mine is the diagnosis, normocalcemic primary hyperparathyroidism, okay? normocalcemic primary hyperparathyroidism, okay? And I tweeted this once and an endocrine colleague, who I very much respect, just got all over me about this because he's like, "It exists! What are you doing?" And it was interesting, where our disagreement was, comes from this. So normocalcemic primary hyperparathyroidism is very rare. It's generally found when the PTH is checked in people with a normal calcium, but you're working up osteoporosis in someone who shouldn't really have osteoporosis, okay?
DR. CIFU: You know, you got a 50-year-old woman, 50-year-old man, and I don't know, maybe they fracture something, you find out they're osteoporotic, you start working it up, and you're like, where does this come from? So you could conceivably have normocalcemic primary hyperparathyroidism, but there are just a whole lot of other things which might be causing hyperparathyroidism in patients, which might be causing hyperparathyroidism in patients, that's actually not normocalcemic primary hyperparathyroidism.
DR. CIFU: So chronic kidney disease for instance, right? And in that case, it's actually secondary hyperparathyroidism, but just not so severe that you have hypocalcemia. It could be decreased calcium intake, right? And the body is responding to the decreased calcium by secreting PTH. It could be calcium malabsorption, which could be from a whole number of things, right?
DR. CIFU: Vitamin D deficiency, past bariatric surgery, celiac disease, pancreatic exocrine insufficiency, maybe this is someone who had a history of alcoholism and has had pancreatitis in the past, renal calcium loss, there's idiopathic hypercalciuria, there are people who are on long-term loop diuretics, or I don't even know how to fit this in there, but I wrote this down as a possibility, so bisphosphonates, right?
DR. CIFU: Bisphosphonates inhibit bone resorption but I have no idea how you get to a patient where you're concerned about normocalcemic primary hyperparathyroidism when they're on a bisphosphonate, unless they're taking the bisphosphonate without telling you about it. So let's not even talk about that.
DR. STERN: So, I'm a little worried about getting into the weeds further on this particular entity, but it does occur to me that if you really were going to say, they had normocalcemic primary hyperparathyroidism, the argument would have to be that they're putting out too much PTH and the serum calcium is normal because they're hypercalciuric.
DR. CIFU: Right.
DR. STERN: And most of these other entities, they're not hypercalciuric, right?
DR. CIFU: You got it, you got it. And usually what this is, or what the theory is, is that these are people who you've sort of just caught really early in their primary hyperparathyroidism. And so, you know, their parathyroids are secreting too much either from hyperplasia or an adenoma, but it's just not high enough yet that it's made them hypercalcemic. But I think the message is, work up the other things, because it's important that you figure out if this person has chronic kidney disease.
DR. CIFU: And if you ignore that you've ignored the most important part of it all.
DR. STERN: Well, that's for sure. All right, well, I have a pet peeve, and it actually pertains a little bit more to hypocalcemia than hypercalcemia. Again, we're in the weeds, but it's relevant. So you do have to correct the serum calcium for the albumin. So as everyone remembers, calcium binds to albumin, and what the body is trying to regulate is the ionized calcium. So if, for instance, for some reason your albumin was quite high, the body would allow the serum calcium to be high so that the ionized calcium was normal.
DR. STERN: And you might be mistaken into thinking someone's hypercalcemic. I have to say it's pretty unusual. But the opposite is worth emphasizing, that happens all the time in hospitalized patients, which is their serum calcium is low, 7.5 to 8 or even 7, and it turns out, it's because their albumin is low. So for every gram your albumin goes down, as a rule, your calcium is going to go down by .8.
DR. STERN: So if your albumin moves down by one point, you could add .8 to your measured calcium and estimate what your truly normal calcium would be. And I have to say, that's pretty common in the hospital.
DR. CIFU: Absolutely. I mean, I think these days, basically, nobody with normal albumin gets admitted to the hospital, right? Because you have to be so sick that almost everybody's hyperalbuminemic for some reason. that almost everybody's hyperalbuminemic for some reason.
DR. STERN: Yeah, true. All right, so let's close up with some pearls. What do you have for me?
DR. CIFU: Okay, so my clinical pearl is treatment. So these are usually patients who come into the hospital with hypercalcemia, right? They have an underlying disease, prostate cancer, breast cancer, multiple myeloma, maybe milk-alkali syndrome, and they come in with a calcium of, let's say, 14, or 15, feeling awful. So what do you do? First, you hydrate them, because these people are pretty much always hypovolemic. So you're going to start normal saline.
DR. CIFU: Once you have them euvolemic, you're going to add on a loop diuretic that causes calcium uresis, and then you're going to do things which will act over the next 24 to 48 hours. And that's generally starting a bisphosphonate, stabilize the bones, prevent calcium egress from the bones, maybe use calcitonin, and then you'll treat the underlying cause.
DR. CIFU: Maybe it's treating the tumor, maybe if it's from sarcoid, you'll start steroids, maybe if it's from hypervitaminosis D, from vitamin D intoxication, you will take them off their vitamin D. And then slowly, hopefully, their calcium will get better, and they'll feel better.
DR. STERN: Well, my pearl is to think about thiazide diuretics as a cause of hypercalcemia, even if they've been on it for quite a while because patients can develop, interestingly enough, hypercalcemia after they've been on a thiazide for a while. So it should be high on your differential.
DR. CIFU: I'm so happy you brought that up, because when I was working on the hypercalcemia chapter, for the latest, the 4th edition of Symptom to Diagnosis, I found a study, which is like, you know, when you have a question, and then you find a study, which sort of perfectly answers that question? Well, this was a study out of Mayo Clinic published in 2016, in the Journal of Clinical Endocrinology and Metabolism. And what they did is, they looked back on all the patients that they had in their system, who had been diagnosed with hypercalcemia, related to thiazide diuretics.
DR. CIFU: And what they found is that the average presentation of thiazide induced hypercalcemia was five years after starting thiazide diuretics.
DR. STERN: Wow, five years?
DR. CIFU: Five years.
DR. CIFU: So really just as you said. Upon discontinuation, about a third of the patients actually returned to normal calcium levels. So you stop the thiazide, they get better. And of the remaining two thirds of patients, those patients who stopped the thiazide and they remained hypercalcemic, 80% of those people had primary hyperparathyroidism.
DR. STERN: So and how long did you say it takes? Or maybe you didn't say, how long does it take when you stop the thiazides for the calcium to go back to normal?
DR. CIFU: Right, so for that first third, it's quick, it's a couple of weeks. So I think that if you said, "Stop your thiazide, come back in a month, let's recheck levels," great. And if their calcium at that point's high, you check a PTH, their PTH is probably going to be high and then you've made your diagnosis.
DR. STERN: Perfect.
DR. CIFU: So we hope you found this episode of S2D, the Symptom to Diagnosis podcast useful, and a bit enjoyable. As a reminder, our textbook, Symptom to Diagnosis: An Evidence-Based Guide, takes a much deeper dive into how to think about and reason through the diagnosis of medical presentations. It's amazing that we take a deeper dive than our podcast.
DR. STERN: Deeper dive.
DR. CIFU: Yeah.
DR. STERN: [chuckles] Okay, go ahead.
DR. CIFU: Need a wetsuit for that. The book is available in print, on your handheld device, and in a fully searchable mode via the Access Medicine website available worldwide from McGraw Hill. The music for this, the S2D podcast, is courtesy of Dr. Maylyn Martinez.
DR. STERN: Thank you. [upbeat outro music] [upbeat outro music fading]