Thank you. Thank you very much. I appreciate the invitation to be here with you It's my first time in Dubai and it's pretty amazing I hope I have a chance to see some of it when I'm here for the next couple of days My talk today is on hypercalcemia And I'm over those of you in the endocrine space for many years have probably come across some challenging cases in the field of patients who might have high calcium Although the general presentation is pretty straightforward and the evaluation is not that complicated There have been some recent advances that seem to suggest that there are some unique Situations that you may encounter and may have already encountered in your practice That suggests that some of these hypercalcemia cases are actually much more complicated than we have tended to ascribe them to So I am a speaker for several companies I am the bone densitometry endocrine consultant for NASA at the Johnson Space Center and I'll talk to a little bit about issues of Microgravity and bone during this talk just very briefly and I am the faculty writing committee for ISCD bone densitometry course So we'll talk about very briefly the review of calcium metabolism some of the clinical presentation issues with hypercalcemia Evaluation and then some basic approaches to therapeutics. This was presented earlier in the slides upstairs And the fact is is that once we develop some approach to a Disorder it can take up to 17 years for it to actually go downstream into practice so I would emphasize for all of you that are on the front lines of endocrinology to spread what you know to your colleagues so that this Timeline is severely compressed because we want to make sure that information that we have gets translated down to patient care very quickly So as you're well aware very basically low calcium stimulates parathyroid hormone which then causes bone resorption And increased calcium resorption from the kidneys that supposed to increase your calcium back up again That results in an increase GI absorption from increasing levels of 125 hydroxy vitamin D Measuring calcium. We have some caveats. So first of all severe hypercalcemia This is where your intervention is needed right away And these interventions need to be emergent after the calcium is more than 14 milligrams per deciliter in the moderate group We can take a little bit more time to evaluate and find out what's going on and then intervene Appropriately when it's between 12 and 14 and we consider mild hypercalcemia between 10 and 12 milligrams per deciliter Total calcium is divided between the free free calcium space, which is 50 percent. That is the one we worry about That's the one that has the biological physiologic effects that we're concerned about About 40 percent of it is protein bound. This can cause difficulties when there's albumin issues because that may May lead us to underestimate or overestimate the importance of the calcium in that particular patient But it's really the free ionized calcium. That's the important component Physiologically, unfortunately, that's complicated to measure the calcium electrodes are readily available But the longer the specimen sits before it is measured by the electrode the more error is introduced into the system So if you have a good calcium electrode to be able to get a ionized calcium very quickly in your laboratories That is an important adjunct test to consider but it can be quite misleading if there is a delay in time other Organic and inorganic molecules may also bind calcium as well as pair of proteins in the setting of myeloma So those patients with pair of protein emias may have elevated calciums. It may not be reflective of their ionized calcium because of this binding of Calcium by the pair of proteins in addition as you're aware low albumin levels and malnutrition the total calcium may appear Unusually low and so we have a calcium correction equation, which has been well publicized We tend to take the serum calcium total Plus 0.8 times the normal albumin minus the patient albumin. This is a very rough estimate So it's not clear that this is going to be accurate in all cases But it does give you some ballpark figure as to what a corrected calcium may look like in patients who have albumin disorders The presentation of calcium as you probably were from your training was a disorder of stones bones moans and groans To elaborate on that a little bit the stone disease is related to polyurea renal sufficiency and nephrolithiasis In the bone compartment low bone density osteoporosis may result in the more severe cases, which we rarely see these days Osteitis fibrosa cystica where you get these large bone cysts and pain and bone pain may occur as well The disease also can produce moans with anxiety depression lethargy cognitive impairments as the calcium elevations and in the case of hyperparathyroidism PTH may have direct neurocognitive effects as well and This presentation may be quite more common in the elderly And in the setting of rapidly increasing calcium so patients who are in their older age groups who have cognitive impairments Certainly calcium levels is something that should be considered very strongly The groans component of course of the GI manifestations mainly constipation pancreatitis can also increase gastric acid ulcers and produce anorexia The other effects of hypercalcemia may also be reflective in cardiovascular disease with a short QT interval prolonged PR Calcium deposition in arteries I'll be talking about this a little bit more in my plenary session Which is on Sunday and the mortality information that you heard about previously from Bisphosphonates may reduce that may be related to arterial calcification calcium when it appears in other soft tissues Can cause significant harm and in the cardiovascular system especially in blood vessels vascular Calcifications may be responsible for some increase in mortality and this can be associated with disorders in which hypercalcemia is present such as hyperparathyroidism So we'll return to this in the session I will be giving on Sunday the pseudo hypercalcemia presentations again high serum albumins thrombocythemia mainly because as you take the platelet sample in the blood the platelets degenerate in the tube and Release calcium and that can cause a false elevation of calcium in the test tube So patients who have very high levels of platelets in the blood this may cause an artifactual apparent increase in calcium because of the Degeneration of the platelets in the test tube before you're actually measuring the calcium level and as I mentioned before paraprotonemia is in which you can bind calcium and this produces a Elevation in calcium, but it's not reflective of the free calcium, which is really important The basic evaluation is well known to you from your training We're clearly looking at the high calcium in the setting of what the parathyroid hormone levels are doing since parathyroid disorders Are going to be responsible for a large number of these patients PTH in association with calcium is really an important first step in order to determine the evaluation The other steps though you want to know about 125 hydroxy vitamin D since a variety of disorders that we'll talk about May result in increased one alpha hydroxylation of vitamin D causing increased calcium resorption by the gut Resulting in hypercalcemia as well as calcium retention in the kidney these elevations may be produced by granulomatous disease Which is the one you're going to be looking at most frequently But we'll go through the differential as far as other reasons as well certainly if the parathyroid hormone levels are elevated you're looking at either primary hyperparathyroidism or one of the Paraneoplastic syndromes in which PTH levels may be elevated because of neoplastic production of PTH which although is quite rare Nevertheless does occur and needs to be looked at other sources of hypercalcemia. We talked we'll talk about PTH RP Which may be produced neoplastically or in the setting of pregnancy from placental or mammary tissue sources? and in the evaluation of malignancies that reduce PTH RP as well as PTH and The 125 evaluation is going to be very helpful for you in the setting of granulomatous disease so we'll talk about some of the weird and Interesting Causes for hypercalcemia that may not be quite evident in the initial evaluation We know that cancer is probably the major reason for hypercalcemia in the hospitalized patient and the outpatient setting 90% or more is going to be benign causes mainly primary hyperparathyroidism But when you're seeing patients who are sick in the hospital cancer is going to be probably responsible for the vast majority of those patients Hubril hypercalcemia malignancy is going to be most common PTH RP is going to be part of your evaluation Since these tumors can produce PTH RP resulting in the high calcium levels, but also you can have osteolysis so primary osteolysis is generally associated with malignancies involving the bone myeloma breast cancer and lymphoma in particular and 125 vitamin D may be elevated because of lymphoma these lymphatic tissues One alpha hydroxylate so can produce increased levels of one alpha hydroxylation of one vitamin D PTH production although very rare can occur in cancers the major differential that we worry about of course Resulting in unnecessary surgery at times is familial hypocalceric hypercalcemia Well known to you probably is a genetic disorder that results in disordered of calcium Absorb reabsorption by the kidney this causes calcium to be elevated This is not a disorder that usually is amenable to therapy or needs to be treated, but may result in inappropriate parathyroid surgery so looking at the clearance of calcium in the kidney Using a 24-hour urine calcium creatinine ratio is very important in order to distinguish this disorder Granulomatous diseases of any sort macrophages can one alpha hydroxylate so anything that's associated with granulomatous disease, but potentially increased one alpha hydroxylation resulting in 125 elevations and hypercalcemia Such disorders as sarcoidosis tuberculosis Borreliosis fungal diseases and pneumocystis, but also injectables and cosmetic surgery So some patients wind up getting injections of silicone and other things into their bodies that can produce Granulomatous disease Crohn's disease and other granulomatous disorders as well as angiitis can also Produce the same presentation that may be confused with other disorders Endocrine disorders such as hyperthyroidism where you get increased bone turnover can produce hypercalcemia Addisonian crisis and feos are also associated with non pH non PTH dependent hypercalcemia Immobilization so if your patients in the unit and the intensive care unit for any prolonged period of time Even as short as one to two weeks, they will mobilize calcium from their bones I see this in the setting of the astronauts in the space program We see patients in microgravity environments in which they get significant amounts of bone loss with gravity Reinstituted on earth they reverse most of that although the geometry of the bone actually changes over time So these changes can be irreversible in patients who are in long duration weightless states prolonged periods of time What I'll tell you is that you could reverse that at least in the space issue in microgravity using bisphosphonates So our countermeasure for a Mars mission or a long duration moon mission Would be using so ledger Nate prior to mission that would tend to freeze the bones out so that you don't mobilize Calcium from the bones and this is important not just to protect the bones Which we've already demonstrated with a lender Nate on spaceflight, but also because of the risks of kidney stones So one of the concerns we have in anybody who's up in space for a long duration period of time Would be kidney stones since that would be a mission killer someone on a long duration space mission getting a kidney stone in space It's not a good situation So by reducing the hypercalcemia associated with increased bone resorption with weightlessness You can shut that down with bisphosphonates and thereby reduce the risk of kidney stones There's only been one kidney stone on mission that was in a mirror mission early on in the space program from Russia There have been known kidney stones reported since then. However, hypercalceria and Transient hypercalcemia is a notable side effect now This has implications on earth because if you have patients again in hospital settings nursing home settings or other settings They will lose a fair amount of bone and become hypercalcemic early on in their courses So even though they're critical medical condition may dominate your thinking you also want to be aware that this mobilization of calcium May be problematic as far as other effects and possibly Intervening at some point early on may be desirable. Although clearly not part of our guidelines at this point So that's a that's an aside, but it's an interesting aside Milk alkali syndrome some patients drink huge quantities of milk I'll talk about a patient that we saw in our clinics in a short period of time Abnormal protein binding we talked about kidney failure and recovery phases of acute renal failure advanced liver disease and hypophosphatemia Are also things that we will briefly address so milk alkali syndrome excessive calcium carbonate intake a lot of patients take Increased amounts of calcium because they think it's good for their bones and in modest amounts it is but some patients take that to heart And take excessive amounts that may result in significant hypercalcemia, especially if they have some degree of Renal insufficiency we see this also in some unique cases That I'll discuss also soon denosumab discontinuation rebound so we know that stopping Denosumab after some period of time usually more than two years can result in significant amounts of bone loss and increased risk of vertebral fractures But it can also result in hypercalcemia When the denosumab is discontinued the use of vitamin D analogs as you're well aware thiazide diuretics reduce the Excretion of calcium in the kidney and if the patients are having some mild dysfunction of calcium already or taking extra calcium That may also produce hypercalcemia vitamin a toxicity not usually as much of a problem now, but as an aside, I'll tell you that the early explorers in the Arctic, we were just up in the Arctic last week, used to, when they were hungry enough, they would go after polar bears, and sometimes they would eat the polar bear liver, which is extremely high content of vitamin A, and they would die from vitamin A toxicity, which can be also manifested by severe hypercalcemia. So do not eat polar bear liver. That is a bad thing to do. But vitamin A toxicity can also result in patients who are taking retinoids and other things. Lithium use, exogenous PTH we know about, and other things can also be medication and supplement-related hypercalcemia. The most common thing you'll see, other than the parathyroid problem, is usually gonna be 125 vitamin D excess, and this can be associated with granulomatous diseases and a variety of other foreign substances, so things like silicone, paraffin, oil injections. I'm not sure why anybody would do that, but in the cosmetic world, people have tried all sorts of things. Mineral oil injections and talc have also been associated. This can be inhaled, so talc that's inhaled into the lungs can produce granulomatous changes that can produce 125 vitamin D elevations. We'll talk about this syndrome, which I don't, have any of you seen CYP24A1 mutation hypercalcemics? So there are a few of you who have. I will emphasize that point because I think we're seeing them but not noticing them, and I think in your own clinics, you may find that you have patients that may have this rare disorder that can become problematic, and if you recognize it, you can treat it. Neoplastic PTH production can be associated with a wide range of tumors, although extremely rare. These are still mostly case reports more than anything else, but things like lung and ovarian cancers are most common, but other things like Pheos, leukemias, nasopharyngeal tumors, and other cancers can be associated with neoplastic PTH production, so don't get confused if you get your calcium level and then find an elevated PTH. You don't wanna give up on your search for malignancy in the right setting, so you wanna be aware that there is neoplastic production of PTH, even though it is quite unusual. PTHRP, so PTHRP, we don't usually worry about in the normal person. It is a neoplastic-related peroneoplastic syndrome associated with a variety of tumors, but it's also produced normally by the placenta, mammary tissue, and the fetus, and so you will see, oftentimes, in pregnancy or in lactation, elevated calcium levels related to PTHRP, so this is something to be aware of, and this is important also if you have patients with hypoparathyroidism and they get pregnant. They may need to back off on their calcitriol and calcium because their PTHRP production from their placental production and from their mammary production may actually make them hypercalcemic, so just take note that if you have a patient with hypoparahyroidism, that this PTHRP coming from mammary tissue, placental tissue, may actually reverse their problem transiently, and you may need to watch that level of calcium and back off on your therapeutics. Sarcoidosis may also, in rare cases, produce PTHRP, as well as associated with lupus and HIV-related lymphadenopathy. Sarcoid also, obviously, can increase 125 levels, which is a more common reason for hypercalcemia, but it can also, in rare cases, produce PTHRP. Neoplastic origin of PTHRP is one we usually will see in the hospitalized cancer patients. Transitional cell carcinomas, pancreatic neuroendocrine tumors, gastric carcinomas, neuroectodermal tumors are the most common producers of PTHRP, and PTH, so you can have dual production, so if you have PTH elevations, you may also see PTHRP elevations. Again, rare case reports, but just be aware of it because you may actually find it if you look for it. Variety of disorders have unknown mechanisms, so this is probably not really unknown that much as far as the fact that these were described before the advent of the detailed evaluations for hypercalcemia, but patients who have a variety of infections, like leprosy, is associated with an increased risk, and it's beyond just a granulomatous disease with 125 production that patients, even with not high 125 levels, may show up with hypercalcemia. Rheumatoid arthritis, chronic liver disease, and lupus may also be associated with hypercalcemia, and we're still kind of looking into some of the mechanisms. So let's talk about a couple of quick cases. So first of all, 38-year-old woman with prior surgery for hyperparathyroidism. There were no abnormal glands found, and she remains hypercalcemic after surgery. So certainly failure of surgery, parathyroid surgery, in patients with apparent primary hyperparathyroidism is one of the things we worry about a lot because we're sending more and more patients to surgery for hypercalcemia, and unless you're really sure that the diagnosis is primary hyperparathyroidism, you may find that some of these patients get missed. So the disorder you're going to want to look for is familial hypocalceric hypercalcemia. All of you are well aware of this disorder, but unfortunately, it results in significant numbers of patients getting surgery and not being cured. This is an autosomal dominant calcium receptor mutation. Prevalence is about one in 10,000 to one in 100,000. It may be more common than that because we are probably not picking up many of these cases. These patients have asymptomatic lifelong hypercalcemia, so you do not want to be aggressive in intervening with these patients, although rarely some of these patients do require intervention. That is very uncommon. The key test to look at, of course, is the 24-hour urine calcium. They have low urine calcium excretion, so their calcium overcreating clearances are going to be low, generally less than 0.02. These are really the important distinguishing factors, so you don't want to cut corners. You want to make sure you're doing a 24-hour urine calcium in all of these patients with hypercalcemia so you don't miss this disorder because you don't want to subject patients to surgery. Usually in FHH, the magnesium levels may be upper normal. The PTH levels may be a little confusing because it may be normal to mildly elevated in many of these patients, so you may, again, jump on the diagnosis of primary hyperparathyroidism, which would not be a good idea since about 9% of failed parathyroid surgeries are accounted for by FHH. So these are patients who don't need to go to surgery, and unfortunately, they still sometimes go to surgery. These patients generally don't have kidney stones because they're not excreting this high amount of calcium. They're not at increased risk for fractures, and so these are patients that you probably should leave alone. Another quick case, these are all my patients, by the way. 73-year-old with chronic hypercalcemia and low PTH. So this is a patient that lifelong, 73 years old, I picked them up at 73. These patients should be picked up much, much earlier than this, so this is why I'm emphasizing this in this case. So a patient had chronic hypercalcemia all of his life, low PTH levels, elevated levels of 125-dihydroxyvitamin D, and recurrent kidney stones since age 20. So these patients with this syndrome have chronic elevations of calcium, chronic elevations of 125-vitamin D, and kidney stones that really plague them from very early in life. I'll add to this that the valuation for granulomatous disease was negative. He had worsening hypercalcemia with hydrochlorothiazide therapy, and there was no response to glucocorticoids. As you're aware, usually granulomatous disease associated with 125 elevations respond very nicely to glucocorticoids. This patient did not respond to glucocorticoids. So adding a couple of other things here is that there was improvement with ketoconazole. In fact, in my patient, he was changed to fluconazole because he was having side effects from ketoconazole. The key test here, this is a CYP24A1 deficiency. So the key test here is a 2425-dihydroxyvitamin D, which is low, and we'll talk about the mechanism here in a minute. This is a mutation of CYP24A1. This particular patient of mine had a mutation at the E143 deletion. So these patients have problems with their ability to break down 125-vitamin D, so they wind up getting high levels of it. This disorder is also known as infantile hypercalcemia type 1. So CYP24A1 is expressed in renal tubular cells. It's responsible for the production of 2425-vitamin D, which is the inactive form of vitamin D. This is part of the breakdown pathway of 125. So if you can't break it down, it's gonna accumulate, and then it's gonna cause hypercalcemia. The phenotype is variable. Their 125-vitamin D levels are gonna be high. They usually have nephrolithiasis. Hydrochlorothiazide will worsen the hypercalcemia. They don't respond to glucocorticoids, but they do respond to inhibitors such as ketoconazole and fluconazole. And more recently, rifampin has been shown to be useful in some of these patients. So talking about the mechanism here. So vitamin D3 goes through the pathway down to 125-vitamin D, where it is then broken down. The breakdown product is 2425-vitamin D. When you have a deficiency state of the ability to break this down, 125-vitamin D accumulates. So the inability to break down 125-vitamin D causes the 125-vitamin D to go up, and that causes the symptoms that we have just talked about. Imidazole derivatives decrease CYP27B1, which is an alternate pathway. It decreases the breakdown down to 125-vitamin D, and so reduces 125-vitamin D by inhibition at an earlier pathway. So this is why it's important to consider imidazole therapy in these patients with either ketoconazole or fluconazole. And the key test here, of course, is a 2425-vitamin D level in order to diagnose the disorder. Since this breakdown product will wind up being lower since it is not being broken down, the 125 isn't broken down. Rifampin, interestingly, works through a different mechanism. So it increases CYP3A4, which is an alternate pathway that winds up diverting the 125-vitamin D down to a different pathway. Now, I'm just alluding to this briefly for you because of time limits, but you could look this up in order to get some drill-down information on it. But I just want you to emphasize the fact that these patients who have these lifelong histories of elevated calciums, 125-vitamin D elevations, and this is genetic. You'll find other family members that may have the same problem. Looking at the 2425-vitamin D is very important. And this test now is available. It used to be available only at Mayo Clinic. Now it is more readily available, and hopefully you have it available to you here. Looking at another case, a third case. This was a patient of mine, a 21-year-old man, presenting with significant obtundation. A patient had a calcium of 16 milligrams per deciliter. PTH levels were low. His 125-hydroxy-vitamin D level is more than 150 nanograms per mil. Calcium was normal six months ago. And he was taking vitamin D supplements, 50,000 units daily for the past month. Now, I don't know what it's like here in UAE, but in the United States, vitamin D at high doses is available at pharmacies everywhere, just non-prescription. You just walk into a pharmacy and get 10,000 units of vitamin D, sometimes 50,000. You can order them on Amazon. So patients who really think that they are vitamin D deficient, because there was this big hype in the newspapers about everybody's vitamin D deficient, probably a lot of people are, but not to the extent of needing 10,000 or 50,000 units of vitamin D a day. So that is really important to look at in your patients who may be abusing supplements and vitamin D supplements being readily available. Patients may not even realize they're taking them. They may be part of other therapeutic regimens that they're taking for other reasons. So just be aware of that. Classically hyperparathyroidism. So this is something I'm just gonna spend a short amount of time on, because very familiar to you, this is very basic endocrinology, but just to emphasize the fact that primary hyperpara is gonna be probably the more common reason for looking at this. The clinical diagnosis of hyperparathyroidism is clearly well known to you, but there is preclinical disease as well. Patients who develop hyperparathyroidism in the earliest stages may not be well recognized. We recognized parathyroid disease early on because of the invention of the autoanalyzer in 1970, and suddenly we had this big population of parathyroid disease that showed up because now we could measure something. But the preclinical diagnosis is something that we're now more aware of because we are looking for it much more commonly. So I'll just jump to some of the main issues here, which is surgery. And Dr. Bilzekian will be giving a talk, apparently on Sunday, and you'll hear more about it then. But just to point out that surgery is gonna be an option for your hyperparathyroid patients, regardless of the criteria that we have otherwise established. If a patient's symptomatic, they have primary hyperpara, surgery in the hands of a good surgeon is probably the best way of handling this disease long-term. If surgery is not available, management by the use of combinations of sinicalcid and bisphosphonates may help with bone density as well as lowering the calcium levels. And the other disorder that you need to be aware of is normal calcemic primary hyperpara, which is a hodgepodge of disorders. It's controversial, but I will just point out that once you've corrected and found out if they've got secondary hyperparathyroidism or not, if the PTH remains elevated after vitamin D correction and you looked at everything else, then it's probably normal calcemic primary hyperparathyroidism. And that is something that remains controversial, but just to summarize, many of these patients actually do have primary hyperparathyroidism. They're just in an earlier stage. They may have partial PTH resistance or abnormal sensing by the parathyroid. So this is really a hodgepodge of disorders and you should be aware of that. The clinical symptoms are highly variable. Localization is often not consistent. You should make this diagnosis with caution. This is a heterogeneous group of disorders, so you wanna correct secondary hyperpara first. And you really need to limit surgery to those with consistent symptoms and a clear imaging target. So in conclusion, hypercalcemia is a common condition. There are rare causes that you need to be aware of. There are new guidelines that may be helpful in managing this. And normal calcemic hyperpare is an area of controversy still. So if I have time for questions, I'll take some questions.

hypercalcemia

calcium metabolism

diagnosis advancements

familial hypocalciuric hypercalcemia

CYP24A1 deficiency

normocalcemic primary hyperparathyroidism