Good afternoon everyone. Welcome to this session. I also welcome all the attendees who are virtually attending. We have over 300 people online as well to this session about hypo and hyperparasitism. My name is Dr. Stan Van Umen. I'm an endocrinologist in London, Ontario, Canada, and I'm delighted to have two great speakers present to us today. Just from a housekeeping perspective, Dr. Alia Khan was not able to come into this session. She's still in Canada and she's pre-recorded on video her session, so that will be done primarily using virtual presentation. As a start, I want to welcome Dr. John Belizekian, who's going to talk to us about primary hyperparasitism and the updates from the workshop that has happened over the last several years. I'm going to keep the intro short. Please read his bio online, but I don't want to take time away from our valuable presentation. Dr. Belizekian, please go ahead. So Stan, thank you very much and thank you all for coming to this session on the latest and greatest, maybe not the greatest, but the revised guidelines for the two most important parathyroid diseases, namely primary hyperparathyroidism and hypoparathyroidism. My presentation will not be actually case-based, but it will be phenotypically based. That is, we will be describing a lot of different forms of primary hyperparathyroidism and also give you an update on the activities of the workshop that has been working very hard and very long for the past two years. Professor Kahn will follow me and give a similar presentation on this international workshop, which will focus on hypoparathyroidism. The rationale for having these workshops at this time with specific reference to primary hyperparathyroidism is that it's been nine years since the last international workshop, and over the past nine years there have been major advances in many aspects of this disease, as noted on this slide. It seemed to me and my steering committee members that it was timely to revisit these new data from an evidence-based point of view. The steering committee included our illustrious honorary chair, John Potts, my co-chair, Alia Khan, and Marie-Louise Brandy, Bart Clark, who is in the audience, and Michael Mondstadt, and others who are part of this workshop are also in the audience, and I want to thank them in advance for all the work that they have done. This was a big effort. There are 17 countries represented on the various task forces. In those 17 countries, 45 different institutions were represented, and in total over a hundred participants, all of whom are true experts in the parathyroid diseases. Wanting this to be an international effort, we reached out to a number of international organizations, as you see on the left, including the Endocrine Society. We reached out to regional surgical societies, as well as patient advocacy groups. The Hypoparathyroidism Association is here at this meeting, and they, of course, are a very important proponent of hypoparathyroidism from a patient-oriented point of view. Again, the outreach included over a hundred regional societies that we asked to review our work and hopefully to endorse it. These over a hundred societies are including over 50 countries, and to date, we have 65 international and regional societies that, upon their own review of our guidelines, have endorsed these guidelines. So when they are published, this effort will represent, we think, the greatest international consortium of societies that have signed on to these two diseases. We employed several different ways of reviewing, and this is pertinent both to primary hypoparathyroidism as well as to hypoparathyroidism. Using grade methodology, when possible, we were able to look at the literature from that rigorous point of view. And to this end, we want to acknowledge Gordon Guyette, who is the master of grade methodology, who actually oversaw all aspects of this review. And for the hyperparathyroidism efforts, Zhikang Ying, a PhD student of Gordon's, was extremely helpful. Recognizing that the rigor of grade methodology necessarily excludes a lot of noteworthy evidence, and recognizing that some of our questions did not lend themselves to this more rigorous approach, and still wanting to canvas the world's literature so that we didn't miss anything, many of our task forces did narrative reviews, and as a result, of course, would not grade these recommendations, but nevertheless offer them as guidelines for management. The search engines I note here, the reviews included all the usual reviews, including original publications. Historically, we went back to the beginning of the disease as it was recognized, but more evidently over the past 50 years. There were seven papers submitted to the Journal of Bone and Mineral Research simultaneously in February 2022. There were an equal number of papers submitted simultaneously to the Journal of Bone and Mineral Research on hypoparathyroidism. So on one day, the JBMR got 15 or 16 papers, quite a tour de force, and they had their own challenge to review all these papers. We have received their reviews, and we are in the midst of finalizing the response. So although it says publication is expected in spring 2022, it will not be publicly available until the summer, hopefully, of this year. Nevertheless, I am pleased to present these guidelines to you because already some of these guidelines have been presented and are in the public domain as per the ASBMR meeting last fall. I want to acknowledge the four task forces on primary hypoparathyroidism. Aaliyah will acknowledge the four task forces that addressed itself to hypoparathyroidism, and you can see each of the task forces had two co-chairs, and each of the task forces had a large group of dedicated experts, all of whom worked collegially and, I would say, tirelessly over the past two years to develop the data in a way that we can apply to our practices. In the case of primary hyperparathyroidism, there are many areas that we reviewed, and for this presentation, I am noting in the upper left-hand corner of the slides where there are particularly noteworthy comments or conclusions. I thought this was a great idea, but then I realized that all my slides are going to have a star in the upper left-hand corner. But let's start with the disease itself. We define it as a common endocrine disorder characterized by incompletely regulated excessive secretion of parathyroid hormone from one or more of the four parathyroid glands. The forms pathologically are a single benign adenoma most of the time, but we do see multiglandular disease, and very, very rarely we see parathyroid cancer. This nomogram we are very familiar with that relates the serum calcium to the parathyroid hormone level, and in the hypercalcemic variant, the parathyroid hormone level is typically either, frankly, above normal or in the upper range of normal. It is fairly obvious, although there is a differential diagnosis of hypercalcemia with high or inappropriate PTH, but we're typically dealing with primary hyperparathyroidism. We are defining it in these terms along with having these measurements done on at least two occasions and at least two weeks apart. That differential diagnosis I referred to includes familial hypocalceric hypercalcemia. Some people have trouble with this as a differential point, but I don't. This genetic disease has very high penetrance, usually before the age of 30 and almost always before the age of 40, with a very low urinary create calcium to creatinine clearance ratio, and often if there can be a family history obtained, there is a family history of hypercalcemia. We know about thiazide diuretics, we know about lithium, and we also know that the ectopic secretion of authentic parathyroid hormone is exceedingly rare. The epidemiology of primary hyperparathyroidism changed. Sorry about that. I have to go back to where I was. It changed in 1970 when the multi-channel screening test became widely used in the United States, and soon thereafter, and you can see that the incidence of primary hyperparathyroidism increased by about four to five-fold, and because these individuals were being discovered accidentally, the blood calcium was measured, we called them asymptomatic, and thus we had two groups of individuals. The larger group, those with asymptomatic hyperparathyroidism, and the more traditional group, those who had clear evidence for target organ involvement. The disease is a disease of women by a ratio of three or four to one. There is a genetics of primary hyperparathyroidism. About 10% of patients will show a mutation in one of 10 genes that have been implicated. Genetic testing can facilitate the syndromic or non-syndromic forms, but we don't use genetic testing to make a diagnosis. We use genetic testing in certain cases, such as the hyperparathyroidism jaw tumor syndrome, MEN1, MEN2, or as I said before, if FHH is expected or suspected. There is a physiology and pathophysiology dysregulated overgrowth of a clone of parathyroid cells, leading to the excessive secretion of parathyroid hormone. Associated with, but not necessarily etiologically related, is a reduced expression of the calcium sensing receptor, with the pathophysiological consequences of an altered set point, accelerated bone resorption, facilitated renal tubular reabsorption of calcium, reduced renal reabsorption of phosphate, and indirectly enhanced absorption of calcium from the gastrointestinal tract. Many of you have seen this slide. This is always worth noting that the clinical phenotype of primary hyperparathyroidism, as shown on the left, is the Captain Charles Martel, who a few years after getting this disease, showed the devastating potential of parathyroid hormone to destroy the skeleton. The radiographic features are shown on the right, with the salt and pepper degranulation of the skull. The distal clavicle radiologically is missing. The subperiosteal bone resorption is evident, and there is osteoitis fibrosa cystica in the pelvis of this woman. Again, we're more familiar with the biochemical and densitometric signatures of primary hyperparathyroidism. And since 2000, we're familiar now with the third phenotype, namely subjects who have persistently normal adjusted serum calcium and normal ionized calcium, but have higher PTH levels in the absence of secondary causes. So these three phenotypes of primary hyperparathyroidism have been described chronologically, as we just mentioned. But actually, these three phenotypes of primary hyperparathyroidism coexist throughout the world. And depending on where you are in the world, you'll either see symptomatic disease, as is frequently still seen in India, or asymptomatic hyperparathyroidism, as seen in countries where multi-channel screening is common. Or you might see, more often these days, normal calcimic hyperparathyroidism in medical centers where bone disease is a specialty, and where parathyroid hormone is typically measured, even in subjects who have a normal serum calcium. Now, the workshop has refined the definitions of these three phenotypes. I won't spend time on the symptomatic form, because I think we're all familiar that there's evident bone disease, there's evident kidney disease, and rarely, but still seen, is the classic proximal myopathy of primary hyperparathyroidism. The workshop, however, did refine this terminology of asymptomatic primary hyperparathyroidism, now referring to two different forms after patients have been evaluated. After they have been evaluated, if there's no evidence for target organ involvement, we are going to refer to these individuals as asymptomatic without, or after evaluation, if there is target organ involvement, namely bones and kidney or kidney, we would define these individuals as having target organ involvement. Normal calcimic primary hyperparathyroidism, as I mentioned before, we are maintaining that definition, and we're also emphasizing to pay particular attention to the secondary causes for a high PTH, particularly vitamin D deficiency, and as you'll notice here, we are taking liberties with the Institute of Medicine. We're saying the level should be less than 30 nanograms per ml. Renal insufficiency can be associated with a higher PTH. We've mentioned thiazide, diuretic, lithium, hypercalciuria, any form of malabsorption, and other metabolic bone disease could be associated with an elevated level of PTH. Unfortunately, we still don't have a lot of information, and the published literature on normal calcimic hyperparathyroidism have not always used consistent definitions or shown data in regular follow-up, but we do appreciate that normal calcimic hyperparathyroidism can be symptomatic. Normal calcimic primary hyperparathyroidism can be asymptomatic, and when asymptomatic, it may or may not have target organ involvement. With regard to biochemical evaluation, everyone needs a 25-hydroxyvitamin D. We need an assessment of renal function, preferably by a measured creatinine clearance. A 24-hour urine for calcium is preferred over a fasting sample. We're not strongly recommending serum phosphorus, although it might be helpful, and we're not strongly recommending measurement of bone turnover markers. In terms of the skeletal evaluation, we all subscribe to the three-site DEXA, recognizing that classic primary hyperparathyroidism has a proclivity to be catabolic at cortical bones, such as the distal third radius, and based on these data from our work many, many years ago, there seemed to be a protective effect in this disease on sites of primarily trabecular bone, like the lumbar spine. This pattern is a classical pattern, but not the only pattern. We recognize that if that were predictive of fracture risk in hyperparathyroidism, you wouldn't see much of a difference compared to controls in terms of vertebral fractures, but would see an increase in incidence of non-vertebral fractures, which is really essentially cortical bone. The data from the Mayo Clinic, however, shown on the left, more recently from PISA Italy on the right, show that those predictions by DEXA are not borne out. There is an increased incidence of all fractures, as shown on the left, in primary hyperparathyroidism, and as shown on the right, there's an increase in vertebral fractures, whether determined by x-rays or vertebral fracture assessment. So the reality of fracture risk in hyperparathyroidism is not synced with the measurements of bone density. The explanation for why we see increased fractures at all sites, I think, is from our studies and other studies that have looked more carefully into the microstructure of bone, using HRPQCT in particular. We have obviously confirmed the cortical thinning, but also have been able to show that the trabecular compartment of bone has involvement that is quite significant, and this microarchitectural deterioration, I think, helps to explain why there is a global increase in fractures in primary hyperparathyroidism. As a result, we are recommending that we go beyond 3-site DEXA in all of our patients with some form of vertebral imaging, whether it be VFA or vertebral x-rays. If you have trabecular bone score on your dexa, that can be helpful. Renal involvement, kidney stones and hypercalciuria continue to be the major aspects of this target organ. And we know that hypercalciuria is a risk factor, but we also recognize that there are many other risk factors that contribute to stone risk in primary hyperparathyroidism. More recently, Claudio Marcoci has shown that hypomagnesuria is an independent risk factor for stone disease in primary hyperparathyroidism. We think that a threshold value of 60 cc per minute might be useful to target because those who have parathyroid surgery and levels below that seem to stabilize while those who do not have surgery seem to show continued declines in the EGFR. Those continued declines in EGFR are associated, as shown by Marcella Walker, with an increased risk of fracture. However, we still do not know whether reduced renal function in primary hyperparathyroidism is due to the disease itself or to independent factors. So we are recommending, again, a good measurement of creatinine clearance, the 24-hour urine for calcium, and, if clinically indicated for other stone risk factors, imaging for nephrolithiasis or nephrocalcinosis, as shown by these various imaging modalities. The atypical or non-classical manifestations of hyperparathyroidism have vexed us for years and continue to vex us. This work from Jens Bolestef, recently published, was a 10-year prospective randomized trial of parathyroidectomy or observation looking at two quality-of-life scales tested at baseline 2 years, 5 years, and 10 years thereafter. And what Jens was able to show, that parathyroidectomy was associated with biochemical cure, while observation was not associated with biochemical cure. That is obvious. But what wasn't obvious to me was that, looking at these two quality-of-life scales, they really didn't change, or, if they did change, both groups changed in the same way. So that, in the conclusion of this study, parathyroidectomy did not actually improve quality-of-life, and those who did not have parathyroidectomy did not show worsening quality-of-life. So it continues to be a problem. I am not going to mention the cardiovascular issues, because we don't have time, but that also is unclear. And the bottom line is, we need more research. Now, with regard to vitamin D, the hypothesis of double trouble, that in the presence of vitamin D deficiency, patients may have worsening hyperparathyroidism. Our work with our friends in Beijing, China, where hyperparathyroidism was virtually always a symptomatic disease, as shown in this slide, helped to underscore the point that, in China, the average 25-hydroxyvitamin D level was 8, while our group had an average 25-hydroxyvitamin D level of 21. Not great, but certainly better than 8. And even in our group of subjects who had mild hyperparathyroidism, those whose 25-hydroxyvitamin D level was less than 30, sorry, 20, had a markedly higher level of parathyroid hormone than this cohort of patients with 25-hydroxyvitamin D levels greater than 20 nanograms per ml. So the panel conclusions are that we really want to ensure vitamin D sufficiency, and we are talking about greater than 20 nanograms per ml, or 15 nanomoles per liter. And in terms of calcium intake, subjects should be taking in an adequate amount of calcium, preferably from the diet. The 50-year dilemma is as shown here. And we're not speaking about symptomatic hyperparathyroidism. That's not the dilemma. The dilemma is in the asymptomatic subjects, who needs surgery and who can be followed safely without surgery. And to that end, clearly, and the data are absolutely unequivocal, that in the hands of experienced surgeons, surgery achieves a biochemical cure in actually this number that came from the graded review, 97.8% of patients. Surgery is virtually always associated with a significant increase in bone density at all sites, and by inference, that increase is likely to be associated with a reduction in fracture. We still do not have evidence, as I briefly summarized, about whether surgery affects in a positive way renal function, neurocognitive function, quality of life, or cardiovascular indices. So these are the panel conclusions. These are going to be the guidelines. Any one of these, Matt, would be sufficient to recommend parathyroidectomy. They aren't much changed from the earlier ones. We've refined them a little bit more in terms of what are the criteria, particularly those additional imaging modalities in terms of skeletal involvement or in terms of renal involvement. Hypercalciuria has been made simpler by noting the conventional number of 300 milligrams per day in men or greater than 250 milligrams per day in women. And age has continued to be a criterion. And let me underscore the point that any one of these criteria is sufficient. I've had colleagues who say, well, doctor, my patients don't meet any of the criteria except one. Well, that's enough. The other point we're going to emphasize is that if the patient meets no criteria, parathyroidectomy is not the wrong decision. It's a perfectly acceptable choice if the patient and the physician concur and there are no medical contraindications. If the patient is going to have surgery, we are recommending preoperative imaging, and which preoperative imaging test you use should depend on which one you are most familiar with. At Columbia, we have become enamored of 4DCT, but you may choose another form of parathyroid imaging. Again, let me point out that we don't image the neck unless the decision for surgery has been made. Some surgeons still adhere to intraoperative measurement of the parathyroid hormone level. There is some controversy over this. But there are criteria for a cure in those who have minimally invasive parathyroidectomy. Other surgeons use a more traditional foregland exploration. We want to emphasize not only preoperative localization of the parathyroid gland, but preoperative localization of the parathyroid surgeon. That parathyroid surgeon should be experienced with an outstanding track record. I'm going to say it again. I'm going to say it again. And I'm going to quote Dr. John Dottman, who was actually the pioneer in endocrine imaging, who said many, many years ago, as I just said, the most important preoperative localization challenge in hyperparathyroidism is to locate the parathyroid surgeon. After successful parathyroid surgery, the biochemical indices all normalize. And that's pretty clear in some patients who have parathyroidectomy. That is the end of the story. But there is a medical therapeutics. There are many subjects who are not going to have parathyroid surgery, either because they don't meet one of those guidelines or there are medical contraindications or they don't want parathyroid surgery. And yet you want to reduce the serum calcium because it is higher than you want it to be, and or you want to increase bone density because it's lower than you would like it to be. There are a number of pharmacological approaches listed here. And one of the papers will go into great detail into these various medical alternatives. To increase bone density, we're recommending abysphosphonate, with the most experience being alendronate. To reduce the serum calcium, we're recommending sinecalcet. And in those who have very high calcium and very low bone density, there is some data with combinations in a calcet and bisphosphonate. Very recently, there are a couple of papers using denosumab that seems to be effective to increase bone density in this disease and maybe even more effectively than in postmenopausal women. So this is just a summary of what I said about the pharmacological approaches. Again, calcium intake should follow Institute of Medicine guidelines. And the hope that vitamin supplementation would be adequate. You can see there's a little bit of inconsistency here because some of us are arguing for levels greater than 30 nanograms per ml. In normal calcimic primary hyperparathyroidism, we're very uncertain. There's more multiglandular disease. Some patients after parathyroid surgery will have an improvement in bone density. But like the hypercalcemic variant, we really don't know how parathyroidectomy improves or doesn't, renal, cardiovascular, or quality of life. And after much discussion, the ungraded panel recommendations are first to refer these individuals to one of us who is said to be experienced. We are not issuing any guidelines for the management of normal calcemic hyperparathyroidism. In those who you feel need parathyroidectomy, obviously preoperative localization is recommended, although it's less successful than the hypercalcemic disease. In terms of those who are not going to have parathyroidectomy, the recommendation for monitoring will include annual serum calcium, a 25-hydroxyvitamin D, yearly or every two-year DEXA, and further imaging if clinically indicated, a creatinine clearance or estimated GFR annually, and again imaging of the kidneys if clinically indicated, as also the case to repeat the 24-hour urine for calcium. When should parathyroid surgery be recommended in either hypercalcemic or normal calcemic disease when they're being monitored? And these are pretty obvious. They basically say if the patient meets any one of those guidelines that the patient didn't meet earlier, then of course you would recommend parathyroid surgery because they would now fit into that surgical cohort. We have a section on primary hyperparathyroidism in pregnancy. It is a rare event. We don't know what the true incidence is. Typically in pregnancy the hyperparathyroidism is mild. However, there is an increased risk of miscarriage, prematurity, and low birth weight in the older forms of hyperparathyroidism, particularly if the serum calcium is greater than 11.4 milligrams per deciliter. Most of these individuals can be managed throughout their pregnancy by maintaining good hydration and monitoring serum calcium levels. We don't use pharmacological agents, as noted here. They either don't cross the placenta, or you don't want them to cross the placenta. But there are individuals who really should have parathyroid surgery when they're pregnant. And if the decision is made, the best time to do that is in the second trimester. Obviously preoperative imaging is limited to ultrasound. We will pay particular attention to the neonate for hypocalcemia that is worse than usual. And if that woman is not to have parathyroid surgery when pregnant, we recommend parathyroidectomy soon after the pregnancy and before the next one to take care of the problem. Now although we covered a lot of data, and I presented just a little tidbit of it for you today, for every point we make there are about 10 points of information that we would like to have. And we do have a, if you will, a long list of research questions that we are setting forth for the next decade. And in order to gain more insight into this disease, we're recommending a number of additional studies that hopefully will be done by us in order for us to gain more insight into this disease. So let me summarize my formal comments. We're dealing with a common endocrine disorder. Dr. Khan is going to talk to you about a rare endocrine disorder. Asymptomatic hyperparathyroidism is most often seen in developed countries. Symptomatic hyperparathyroidism, normal calcemic hyperparathyroidism, and asymptomatic hypercalcemic disease exist throughout the world simultaneously. And pointing out again, the relative proportion of these three phenotypes depends upon the points I made earlier. And you want to bear that in mind. Surgery can be recommended even for patients who do not meet guidelines if there are no medical contraindications and the patient and the physician concur. For patients who are not going to have surgery, conservative medical management is appropriate. Pharmacological intervention is generally reserved for those whose serum calcium is high, and I mean higher than that threshold, and or whose bone density is low, lower than that threshold of minus 2.5, and surgery is not an option. And finally, the data argue that long-term conservative management beyond 10 years is advised with caution because we're beginning to see some of those complications surface in those who are followed conservatively for longer than 10 years. So let me end my comments. This evidence-based review hopefully will aid us in our collective quest to apply the best evidence available to understand, evaluate, and management hyperparathyroidism. And I hope this effort will be helpful to us in our never-ending search for new knowledge. Thank you very much for your attention. Thank you. Thank you, Dr. Bilizekian, for that outstanding review. I'm going to open it up for questions for Dr. Bilizekian, so please stay at the microphone. I can have a bit of difficulty seeing if there's any questions in the audience. If you have a question, please come to the microphone. In the meantime, I'll start to list some of the questions that have come online. We have, by the way, over 400 attendants online now. So first two questions relate to 24-hour urine calcium. The questions are, number one, if a patient is on hydrochlorothiazide, how long do you have to stop that before you measure the 24-hour urine calcium? And the second question is, hypercalciuria is listed as something that should be excluded as a potential cause of secondary hyperparathyroidism in the setting of normal calcemia. With patients with calcium levels in the upper end of the normal range, can hypercalciuria not be a consequence of that calcium level in that upper range? So those two questions I should ask Dolores Schoback to answer. Dolores is here, and she's a real expert in this discussion. So thiazide diuretics don't have a long half-life, in my opinion. I would wait at least a month and maybe six weeks before repeating the testing. And some people would even wait a little bit longer. The issue of primary hypercalciuria as a cause of secondary hyperparathyroidism is a difficult one. If the patient has a urinary calcium excretion of 450 or 500 milligrams and the serum calcium is normal and the PTH is high, then that's when you begin to wonder about a tubular defect in handling. But the so-called mild hypercalciuria that we typically see in normal calcemic disease, I don't think we're arguing that that's an etiology for the high PTH. But I admit it can be unclear sometimes. Thank you. I see a question at the microphone on my right. Please go ahead. Thanks. Can you clarify the 10-year warning? So does that mean anyone with a life expectancy beyond 10 years should just go ahead and have surgery? Just clarify a little bit. Thank you for that question. No, I'm not saying that. What are the data to argue that we be careful after 10 years? It's actually from our work looking at the serum calcium level, but more importantly looking at bone density. We published this work. Very interestingly, over the first 10 years of our conservative monitoring, bone density is rock stable. Lumbar spine, total hip, femoral neck, distal third radius. The next five years, from years 10 to 15, although lumbar spine bone density continues to be stable, the femoral neck bone density falls significantly and the distal third radius bone density plummets, really does drop. And there are other studies that have supported this notion. So I'm not saying that it's going to happen. How likely is it to happen? Not the majority. About 40% of our patients followed for over 10 years had either worsening hypercalcemia or effects on bone density. So it's not so clear that you should say, the patient has a life expectancy for 20 years, 40 years, do it now. But I would urge those who are the patient under the age of 50, and this also factors in to this discussion, patients who are under the age of 50, followed for the same period of time, had actually a 60% risk of one of those complications. So those are the boundaries of why we are making that recommendation. Thank you. My microphone on my left. Hi. Mimi Hu from MD Anderson in Houston, Texas. Hi, Dr. Velazquez. Hi. How are you? Amazing talk. Amazing effort. So thank you all. Looking forward to the publication. So my question is really, in someone who's normal calcemic referred to us for bone health, what really is the utility of checking that PTH if even the guidelines were not recommending acting upon it from a parathyroid perspective surgically? So just wondering about your perspective on getting that PTH in normal calcemic patients. Yeah. So very good question. Why are we looking for trouble? Yeah, I think we should measure PTH because if I say don't measure PTH, I will be countermanding my whole life. But why are we looking for it? We are looking for etiologies of osteoporosis. And you could say, well, measure the 25-hydroxyvitamin D. That's enough. But again, there are people in the audience like Dolores and others who might want to make a comment about this. But I think these thresholds of 25-hydroxyvitamin D, whether you say 30 nanograms per mL or 20, there's a real wide spectrum. So if you have a patient with a PTH, let's say a 25-hydroxy of 30, but the PTH is elevated, this still may be vitamin D deficiency. In fact, there are some papers that have argued that getting such patients up to 40 nanograms per mL is actually the problem, and that there's a relative vitamin D resistance. So I do think it's reasonable to do it, particularly if the patient has been referred to a center like yours or mine, where we're supposed to be the last word and we want to be as complete as possible. There are some more questions online relating to normocalcemic hyperparasitism. The questions are, number one is, if a patient has complications, would you still recommend surgery? And number two is, what is the evidence that surgery helps in that situation? Normocalcemic hyperparasitism, that surgery helps. Well, there isn't a lot of evidence that it helps, except some studies have shown postoperative improvements in bone density. The PTH will drop if you find the adenoma. So that is, to the extent that we know, that that's a point. Now, having said we aren't stating any guidelines, if you won't tell anybody, but having said this in public, everybody's going to say I said it, but I'm going to use the same guidelines. I mean, you have a patient with normocalcemic hyperparathyroidism and has a kidney stone or has a fracture, or has low bone density. It seems to me, although we don't have the evidence, that's where we're hung up, we don't have the evidence, but it seems to me that the wisest thing to do is to take it seriously and link the classic complication to the disease, even though we're saying not necessarily. And follow up on that, is there a risk for hypocalcemia for surgery in that setting? After surgery for normocalcemic hyperparasitism? I haven't seen, you mean the post-operative reduction in calcium in normocalcemic? I don't think, I haven't seen that there's much of a difference. We don't see a lot of hypocalcemia after traditional parathyroid surgery these days. And it isn't necessarily that patients wouldn't become hypocalcemic, but it's because our surgical colleagues give our patients a lot of calcium and vitamin D post-op so that they won't be woken up at night. So we don't see a lot of post-operative hypocalcemia, except in those people who have an overt skeletal disease. Question on my left. Hi. Thank you so much for the very nice presentation. Again, my question is about normocalcemic hyperparathyroidism. I was initially under the impression that those patients do not go for surgery, but having listened to the end of this presentation, I came to understand that if there are any of the manifestations, we may consider surgery. So in a case scenario where we have a post-menopausal woman with a fragility fracture and a normocalcemic hyperparathyroidism, how can I infer or confirm that the normocalcemic hyperpara is the cause of this patient's osteoporosis as opposed to being post-menopausal woman? Right. It's a wonderful question, and you never know. And you never know, actually, even if the patient had hypercalcemic disease. And even more to the point, patients who have a kidney stone. We say that's a surgical guideline. But kidney stones are so common. 95% of kidney stones are not at all associated with hyperparathyroidism. And the patient may have a kidney stone for other reasons, and yet we're saying there is an association. So you're absolutely right. We're just looking at the likelihood of the association, and you're using your clinical judgment to say, let's take care of this problem, recognizing that it is a post-menopausal woman, and this may be estrogen-related bone loss and not related to the disease itself. I wish I could be more definitive, but we're at the state-of-the-art as opposed to the state-of-science. So in the interest of time, I'm going to take one more online question, one more question from the audience. The online question is, is there any evidence that medical treatment of hyperparathyroidism reduces complication, including fracture risk? Is there any evidence that medical therapy of hyperparathyroidism reduces complications? Well, I don't know if it reduces complications. It certainly takes care of some of those features. For example, those of you who have had experience with Sinocalcet, even the 30 milligram once a day dose, in my experience, the calcium becomes normal. The PTH will drop not to normal. The PTH will drop maybe by about 20%. Now, does that prevent complications? I don't know. If you use alendronate, and more recently, the studies with denosumab, bone density will go up. Well, does that mean you'll reduce the risk of fracture? I don't know. But all of this is inferential because of the association of the surrogate markers with the known complications. But it seems reasonable, Stan, that you do what you can to deal with those features and expect that things will be better. So this makes us understand why the most busy slide was the one about further research. Last question here in the audience. Hello. Thank you very much for the presentation. I have a question regarding the normal calcemic hyperparathyroidism. The patient, according to the new guidelines, qualifies for surgery, and we have nothing seen on the imaging. We cannot find any particular source of the parathyroid hormone. So the patient meets, again, as I said, we're not going to be so clear on what we think about the guidelines. But I think you're going to all conclude that we're going to use those guidelines for normal calcemic. So your question is if the patient meets the guideline and their preoperative localization is not suggested. The patient studies are inconclusive. So this is a good question because it is more likely that the imaging will be negative in normal calcemic than in hypercalcemic. But we see negative imaging in hypercalcemic disease as well. So there are a couple of points about that. What imaging study did you use? Is your site that does imaging really top notch? I have had 40 CT images sent to me from elsewhere. It was reported out as negative. And I've had my people look at it, and it's obvious. So again, the reader of these imaging studies may miss it. So you don't really know if it's true, negative, no, you can't see it. But let's say it's negative, negative. It clearly can't be visualized. Remember, you're too young to remember this. And I'm too young to remember this, believe it or not. But in the old days, before imaging, parathyroid surgery was not done with imaging. And the old literature had this disease cured 95% of the time. Not different. Now, granted, it was a more serious disease in those days, and the parathyroid glands were much bigger. So you would go to the surgeon and say, look, we can't find the gland, but I'm sure it's there. Go to it. And your surgeon is going to say, I don't want to do it. Even though it's one of the world's best parathyroid surgeons, they don't want to operate on people who have negative imaging. So you get to an impasse. That's it. And then you do the best you can. Okay. Fair enough. Thank you. Thank you, Dr. Belizekian, for great responses. And I apologize that we didn't get a chance to answer all the questions, because there's still about a dozen online as well. We're going to switch to hypoparathyroidism now. This session, as like I said before, will be done primarily using video. But before doing that, there's a couple of cases that Dr. Khan would like to present to you. So I encourage you all to take this picture and go to this online ability to answer the question to the response questions. This will also provide you the ability to ask questions to Dr. Khan. She's online, and she will, as we go along, try to respond to the questions while her presentation is ongoing. So I suggest that when she starts the presentation, as much as possible, that you ask your questions while ongoing, rather than waiting to the end. And this will still come back once more. So this is the case that she asked me to present. So this is of a 37-year-old female who has had surgery and now is having hypoparathyroidism. She had a total cytodectomy for papillary cytokines when she was 34, so three years ago. She is on calcium and calcitriol and is now pregnant. And at 12 weeks of gestation, she's experiencing numbness and tingling in the face and the hands, as well as muscle cramps in the lower extremities. Her current medications are the following, calcium carbonate, one gram, three times a day, calcitriol, 0.5, twice a day, vitamin D, and centroid, as well. And she's on hydrochlorothiazide, 12.5 milligrams daily. On examination, she has trussex times negative and trousseau's negative, with a blood pressure of 110 over 65, and no thyroid tissue on examination. Here is the laboratory evaluation given in SI units on the left and imperial units on the right, showing that the ionized calcium is low, parathyroid hormone is low, consistent with the diagnosis, vitamin D is at 40 and 16 low, phosphate is just above the upper limit of normal, magnesium normal, and the creatinine clearance is given as 111 milliliters per minute. I'll let you look at that for a moment. So which of the following is true? Low calcium and low PTH confirm hypoparasyroidism, slightly high phosphate also reflects low PTH. Option two, vitamin D insufficient is causing the low serum calcium and high phosphate. Pregnancy is associated with increased initiation of PTRRP and may lower the need for calcium and vitamin D. Close monitoring is required during pregnancy in all except two. And we see the responses coming in at about, I want to try to get to 100 responses. We have probably a couple of hundred people here and 400 online. We'll see how far we get. But I think that the trend is that most people choose option, the last option and a few, the first option, okay? Next question, her serum calcium is low, which of the following is true? And you read, I think you guys are faster than I am in reading it. Calcium is low, pregnancy is important to maintain normal, hyperglycemia is dangerous and hyperglycemia can result in stimulation of the fetal parasyroid glands. And again, there's already a number of questions coming in with the trends looking at all are true. Okay. And then the next question, how should she be treated? Supplements calcium and calcitriol are safe, adjustments need to be made aiming for serum calcium in the mid to normal reference range. Stop hydrochlorothiazide, vitamin D should be normalized and all of the above. Again, we're going mostly with the all of the above. It seems like we want to have a comprehensive treatment. Here is the scan again for those of you who need it. And now we will start to look at the video. Please look at the screen for the presentation videotaped by Dr. Alia Khan. She is a professor of endocrinology at McMaster University and has been instrumental in many studies relating to osteoporosis and parathyroid disease. Dr. Khan, please take it away. Thank you very much, Dr. van Oom. And it really is my pleasure to present on our new hypoparathyroidism guidelines. And I would like to thank Endocrine Society for this opportunity. And we will have a very interactive section. So I'm looking forward to everybody's responses. These are my disclosures. I have received research funding from a number of the industry partners for the development of new molecules for parathyroid disease and metabolic bone disease. So our new guidelines are under review right now. And we expect that they will be published later this year. And these are recommendations from the second international workshop. And as you can see, this was truly a global effort. We had international experts from around the world working collectively together. Our guideline methodologist was Gordon Guyette, the founder of Evidence-Based Medicine. And he is at McMaster University with his team of PhD students. So in the guidelines, we had systematic reviews, which led to graded recommendations, and narrative reviews, which led to non-graded recommendations. And just to remind everybody that a graded recommendation follows a structured process of framing questions in the PICO format, conducting a systematic evidence search, and then presenting the recommendations as strong or weak with the corresponding quality of evidence. A strong recommendation can be made if the desirable effects are much greater than the undesirable effects, or vice versa, and is worded as we recommend. A weak recommendation, on the other hand, is made in the presence of low certainty of evidence, or a close balance between the desirable and the undesirable effects, and is worded as we suggest. And the ungraded recommendations from the narrative reviews did not involve any of the structured approaches, and are presented as descriptions of the practice of the panelists in managing patients with hypoparathyroidism. And the ungraded recommendations, we present them as we propose. So let's begin with the diagnosis of hypoparathyroidism. How do we diagnose hypoparathyroidism? Well, the diagnosis can be confirmed in the presence of hypocalcemia. Corrected serum calcium has to be low, or an ionized calcium could be low in the presence of a low or inappropriately normal PTH. And we have to have confirmation of this on a second occasion at least two weeks apart. Other abnormalities which would support the diagnosis of hypoparathyroidism are hyperphosphatemia. Remember, PTH has a phosphaturic effect, and so in the presence of low PTH levels, or inadequate levels of PTH, phosphate levels will climb. PTH also converts 25D to 125D, and so patients can have low levels of 125D. There is a reduction in bone remodeling, and there can be elevations in the fractional excretion of calcium, as PTH enhances calcium reabsorption through the kidney. A word of caution, human anti-mouse antibodies can lead to spurious elevations in PTH, and high biotin intake in a few assays can lead to falsely low PTH levels. And so we do ask patients to stop biotin if they're taking high doses of biotin prior to measuring PTH. Post-surgical hypoparathyroidism can be confirmed if patients have features of hypoparathyroidism which persist beyond 12 months following surgery. And these recommendations are provided in much more detail in one of the manuscripts dedicated to diagnosis and evaluation by Michael Manstad and colleagues. Now, it is important for us to understand why our patient has hypoparathyroidism. Seventy to 75% of patients with hypoparathyroidism have this on the basis of post-surgical disease. There are other conditions, however, and it is important for us as endocrinologists to identify the underlying cause for the hypoparathyroidism. Autoimmune conditions are the next most common cause of hypoparathyroidism, and they may occur in isolation or as part of autoimmune polyendocrine syndrome 1 in association with mutations in the air gene. And in this situation, the parathyroid glands will be infiltrated with lymphocytes, and they will be circulating antibodies. We need to look for other features of APS1. Does our patient have chronic mucocutaneous candidiasis? Do they have adrenal insufficiency? Do they have the minor features of APS1? It is important for us to understand why our patient has hypoparathyroidism. Genetic variants can result in abnormal formation of the parathyroid gland, secretion of PTH, or destruction of the parathyroid glands, and we would be looking for features of an underlying genetic abnormality. Remember, infiltrative conditions can result in hypoparathyroidism, such as granulomatous disease, sarcoidosis, amyloidosis, and these are conditions that we're looking for. Mineral deposition with copper or iron, mineral deposition in the parathyroid glands can destroy the parathyroid glands. Metastatic disease is a very rare cause of hypoparathyroidism, but has been reported in patients with breast cancer, leukemia, lymphoma, skin, and lung tumors as well have been associated with hypoparathyroidism due to metastatic disease. Radiation can destroy parathyroid tissue. And remember, magnesium can stimulate the calcium sensing receptor. It can bind to the calcium sensing receptor and turn off PTH. So excess magnesium can result in a functional hypoparathyroidism. And it's also important to remember that magnesium deficiency can also result in hypoparathyroidism because magnesium is a cofactor for adenylate cyclase. So intracellular magnesium deficiency can result in a resistance to PTH as well. They can be transient hypoparathyroidism. This can happen in the ICU with acute illness or severe burns. Mothers with hyperparathyroidism may have babies born with hypoparathyroidism because the hypercalcemia will prevent the development of the fetal parathyroid tissue. So if we exclude all of these potential causes of hypoparathyroidism in our patient, and we do not identify a cause, then we can say that our patient has idiopathic hypoparathyroidism. Now, can we predict who is more likely to develop chronic hypoparathyroidism following thyroidectomy? And this was one of the questions that was asked. And we did a systematic review and meta-analysis and evaluated the use of PTH and or calcium after total thyroidectomy to predict chronic hypoparathyroidism. And the study is detailed in Michael Manstead and Maria Luisa's manuscript summarizing the results of this particular systematic review. And what was seen was that measuring PTH 12 to 24 hours following total thyroidectomy provides higher sensitivity and specificity than measuring serum calcium for predicting permanent hypoparathyroidism. So if the PTH in the 12 to 24 hours after total thyroidectomy is more than 10 picograms per mil or 1.05 picomoles per liter, that would essentially exclude the possibility of permanent hypoparathyroidism. But if it is less than this value, there is a higher likelihood of permanent hypoparathyroidism, but it is still less than 50%. So our graded recommendation is that we recommend measuring PTH levels after total thyroidectomy for predicting which patients will not develop permanent post-surgical hypoparathyroidism. And this is a strong recommendation based on moderate quality evidence. So if the PTH is more than 10 picograms per mil or 1.05 picomoles per liter, 12 to 24 hours post-surgery, the development of permanent hypoparathyroidism is very unlikely. And if it is less than this value, it is still a possibility, the possibility remains, but it is still less than 50%. And these people need to be followed very closely. Now, what should be our approach in establishing the genetic etiology of hypoparathyroidism? And this is also detailed in the paper led by Michael Manstad and Maria Luisa Brandi. And we recommend that we first of all look at the biochemical profile and confirm, does our patient meet the criteria for hypoparathyroidism, exclude post-surgical hypoparathyroidism, check magnesium, exclude infiltrative disorders, and then look for the presence of other endocrinopathies or features of a syndromic cause for the hypoparathyroidism. And if we have features of coexisting diseases or a syndromic cause, then our DNA analysis will include a large panel of genes, including the AIR gene. We're going to be looking for DiGeorge syndrome, CHARGE syndrome, Kenny Caffey syndrome, Sanjit Sakadi, and there's a number of syndromes that we're going to be looking for. Barakat syndrome with deafness and renal abnormalities in association with hypoparathyroidism, that is associated with GATA3 mutations. They may be mitochondrial defects as well that could be present. So we're going to do a larger genetic panel. If we're suspecting the presence of a syndromic cause, it looks like a syndromic cause, then we're going to be looking at all of these genes. If it looks like it is isolated hypoparathyroidism with no other abnormalities, then the mutation may be in the GCM2 gene that can result in familial isolated hypoparathyroidism, or the PTH gene, or the X-linked SOX3 gene. Or our patient might have a mutation, an activated mutation, in the calcium-sensing receptor gene, or the GNA11 gene, and they may have autosomal dominant hypocalcemia type 1 or type 2. So the way that we would narrow down which genes we're going to look at is by the presence of a syndromic cause or coexisting diseases. Remember, a genetic etiology is more likely to be present in the presence of a positive family history or consanguinity. So we made an ungraded recommendation that in patients with hypoparathyroidism who have a positive family history of nonsurgical hypoparathyroidism, who present with syndromic features, or are younger than 40, we recommend genetic testing. In nonsurgical hypoparathyroidism with features of autoimmune polyendocrine syndrome 1, we recommend evaluation of the AIR gene for variants. And if we don't find any of the genetic causes to be present that we are aware of, then we would label this patient as having idiopathic hypoparathyroidism. And in post-surgical hypoparathyroidism, we would describe this as being permanent if the hypoparathyroidism persists for 12 months or longer following neck surgery. Now what are the complications seen in patients with hypoparathyroidism? This was the question that was asked in one of the systematic reviews. What are appropriate monitoring strategies in patients with hypoparathyroidism? This was the question asked in a second systematic review. And which treatment is best for patients with hypoparathyroidism? PTH replacement versus no PTH replacement? And that was the question that was asked in the third systematic review. So I will provide further detail regarding this. So what are the complications? So we did a systematic review, and we ended up with 81 studies and 82 reports that were included in the meta-analysis. And a complication was confirmed as a complication of hypoparathyroidism if it was reported by at least three studies and found to have a statistically significant pooled relative risk estimate in comparison to people with normal parathyroid function. And so the prevalence of the complication was evaluated by conducting a meta-analysis, and then we looked at three groups. We looked at the post-surgical group, we looked at the non-surgical group, and we also looked at children. And these are the confirmed complications following this GRADE approach. And we found cataracts were more commonly seen in patients with hypoparathyroidism, infections were more commonly seen, nephrocalcinosis, nephrolithiasis, renal impairment, seizures, depression, ischemic heart disease, and cardiac arrhythmias. These were the most common symptoms and complications of chronic hypoparathyroidism reported in the literature. Now, what is the optimal monitoring strategy for chronic hypoparathyroidism? And we only came up with two studies. So we elected to ask our panel members, our international group of experts, what their practice pattern was. And we based these recommendations on the practice of more than 70% of the respondents completing this at least 70% of the time. And so what we recommend is that patients have a measure of serum creatinine, calcium, either ionized or albumin-corrected, magnesium, phosphate, and vitamin D. A 24-hour urine for creatinine and calcium is recommended. And patients should be monitored, depending on whether they are stable or unstable. And if they're stable, they could be monitored every three to 12 months. Vitamin D would also be monitored every possibly six to 12 months. And we recommend that the urine calcium be monitored possibly every six months to up to two years. In unstable patients, they obviously need to be clearly monitored more closely. That might be daily if necessary, or it could be weekly or monthly. But the monitoring will be based on the degree of stability for the patients. The panel members also suggest completing a baseline assessment for the presence of kidney stones or nephrocalcinosis, calcification of the renal parenchyma. And we recommend that if there is a change made in the management of the patient, that the serum calcium be measured, again, within a few days or a week of that change and not be left for longer time periods because we may overshoot or undershoot. And the details of this important manuscript are summarized by the paper led by Dr. Stan Van Uum. So what does conventional therapy consist of? Well, we can certainly provide our patients with calcium carbonate or calcium citrate, and the dose may range from 500 milligrams three times a day to three grams three times a day. Some patients are even on higher doses. We recommend giving the calcium with meals so that it can also bind to the phosphate in the food and reduce serum phosphate levels. Calcium citrate is preferred in the presence of PPI use. We do recommend correcting vitamin D levels with cholecalciferol. And if our patients have vitamin D deficiency and they require higher doses, if the 25 D is like below 25 nanomoles per liter, then patients could be offered ergocalciferol 50,000 units once a week, or even twice a week, or more frequently based on the vitamin D levels. We do recommend active vitamin D. They could be given either calcitriol or alpha calcidol. And the dose could be 0.25 micrograms daily up to three micrograms daily total dose administered in divided doses. Remember the half-life of calcitriol is five to eight hours, so we prefer to give it twice a day. And alpha calcidol is half as potent as calcitriol. I actually never use alpha calcidol. It does have a longer half-life as well in tissues and it can take a longer time to wash out if our patient becomes hypercalcemic. So I actually prefer to use calcitriol, but alpha calcidol can be used as well. And thiazide diuretics can be helpful as they enhance calcium reabsorption through the kidney. A word of caution, avoid use of thiazide diuretics in patients with autosomal dominant hypocalcemia. These patients already have significant problems with hypomagnesemia and so thiazide diuretics can be a problem. Remember steady state is reached in five to six half-lives. So if we make a change in calcium or active vitamin D or the dose of the thiazide diuretic, we should be following this up with a repeat blood calcium within a few days to see how our patient is doing. So that we can make further adjustments in the dose of their conventional therapy. Now we did do a systematic review and looked at PTH therapy versus conventional therapy or standard of care for managing chronic hypoparathyroidism. What are the desirable and the undesirable consequences? And to qualify for the systematic review and meta analysis, the study had to be a randomized controlled trial and compare PTH therapy with placebo and patients could also be on standard of care. And we looked at evaluating patient important outcomes, adverse events, improving quality of life, what was the impact on the pill burden, and the surrogate markers were evaluated as well. Serum calcium, urine calcium, phosphate, renal function. And we had six studies that were included in this systematic review and meta analysis. And these are the studies and I'll briefly review these with you. So in the replace study, patients were treated with recombinant human PTH 1 to 84 and the dose was 50 to 100 micrograms a day in comparison to active vitamin D and calcium. And there was the placebo arm. The study duration was seven months. And what was seen was that eucalcemia was maintained and the phosphate levels and the calcium phosphate product declined with PTH therapy. Urine calcium declined in both groups, both the PTH and the control group. So, this did not show a reduction in urine calcium in comparison to placebo. In another study looking at recombinant human PTH, the dose that was used was 100 micrograms a day in comparison to placebo. And this was added to active vitamin D and conventional therapy. The study duration was six months and patients were able to maintain a normal serum calcium. Phosphorus levels declined with PTH therapy. There was no change in the calcium phosphate product and there was no change in urine calcium with PTH therapy. Karen Weiner has conducted a series of trials evaluating synthetic PTH 1 to 34 and comparing this with active vitamin D and calcium conventional therapy in varying durations of study. And what was seen was that eucalcemia was maintained and urine calcium declined in two of these three studies. And then we did a trial looking at transcon PTH in varying doses between 15 to 21 micrograms per day. And this was in comparison to placebo, active vitamin D and calcium. And in the RCT study in the phase two trial, over one month we demonstrated a maintenance of eucalcemia and reductions in the fractional excretion of calcium with PTH therapy. And transcon PTH is PTH 1 to 34 with a polyethylene glycol molecule attached to it, providing it with a longer half life. And at this meeting we will be presenting the results of the phase three trial. And so this is also very exciting information and this will be presented later. So when we look at the meta analysis, comparing PTH and standard of care, what did we see? What was the relative difference or the mean difference? And what we saw was that phosphorus levels declined with PTH therapy. However, there were more cases of hypercalcemia with PTH in comparison to standard of care. So it is very important when we're titrating that PTH that we be cutting back on conventional therapy and ensuring that our patients do not become hypercalcemic. And then we provide the summary of the findings, but essentially we did see some small improvements in quality of life in terms of the physical score. And we did see a dramatic reduction in the pill burden. There was 50% or greater reduction in the doses of active vitamin D and calcium and discontinuation rates or serious adverse events were very few. The drug was well tolerated in general. So if we look at the six studies that we included in our systematic review, these were relatively small. They were of short duration. They did not report on patient important outcomes of nephrocalcinosis, nephrolithiasis, seizures, arrhythmias, ischemic heart disease, cataracts, fractures and infections, but PTH did decrease phosphate. And it may have important benefits in decreasing the long-term complications of chronic hypoparathyroidism. We want to avoid ectopic calcification, basal ganglia calcification, cataracts. We want to avoid renal calcification and comprises, compromises in renal function. And PTH did allow reductions in the dose of calcium and active vitamin D. So we are able to reduce the pill burden. But in these six studies that we demonstrated, we were not able to show a very significant impact on quality of life. And the adverse events were limited to a higher incidence of hypercalcemia. So the panel graded recommendation for hypoparathyroidism is that the panel suggests conventional therapy as first-line therapy. This is a weak recommendation based on low quality of evidence. And when conventional therapy is deemed unsatisfactory, the panel considers use of PTH. But we recognize that we need longer and larger studies with patient important outcomes, and these are coming. So in patients with hypoparathyroidism, these are ungraded recommendations. We propose treating patients with calcium and active vitamin D analog therapy. Our goal is to raise that calcium into the target range in the lower half of the normal reference range or just below the normal reference range. And it is not clear right now whether we should focus more on active vitamin D with less calcium or more calcium with meals and less active vitamin D. We need more evidence to provide for the guidelines along that perspective. It is important to alleviate symptomatic hypocalcemia while avoiding hypercalcemia. And we also want to avoid hypercalciuria. Now, we don't have comparable data in the hypoparathyroidism patient population confirming a relationship between hypercalciuria and the development of kidney stones. We do have this in the general population, but we're inferring that hypercalciuria may be associated with a higher risk of renal stones in hypoparathyroid patients as well. And we would want to avoid hypercalciuria. We want to avoid hyperphosphatemia. We want to avoid the ectopic calcification. And we feel that it is likely an important factor in the development of ectopic calcification. However, currently we need more evidence to support this. We need to normalize magnesium levels, and we recommend normalizing vitamin D levels. We recommend treating hypercalciuria, possibly with thiazide diuretics, as well as a low-salt diet, and monitoring blood pressure, magnesium, potassium, and renal function. And we recommend considering PTH therapy in patients who are not adequately controlled by conventional therapy. So if they have symptomatic hypocalcemia, if they have hyperphosphatemia, if they have renal impairment, hypercalciuria, or wide fluctuations in their serum calcium, and they have poor quality of life, we definitely recommend considering PTH replacement therapy in these patients. What about our patients who are pregnant? Well, it's important to remember that the breast and the placenta produce PTHRP, and this begins to rise as early as three weeks of gestation, and it will reach three times the pre-pregnancy levels by term. And the rises in PTHRP will result in increases in bone remodeling, and will also up-regulate 125D, which in turn will increase intestinal calcium and phosphate absorption, and this will result in increases in urine calcium. And so this is important information because in our pregnant patient, it may mean that our pregnant patient may not require an increase in the dose of calcium and active vitamin D to meet the fetal requirements because there will be endogenous production of PTHRP. But this is not always the case. Our patient may or may not require higher doses. They may require a reduction in the dose, but the important point is that we need to follow our patients closely because there is a change in calcium homeostasis during pregnancy. So calcium requirements during pregnancy increase due to the fetal demand, but because of the rises in 125D and PTHRP, our patient's requirements for active vitamin D and calcium may not increase, or they may be the same, or they may increase, depending on how much of a rise they experience in PTHRP and active vitamin D. And so patients need to be closely followed. We recognize that hypocalcemia is harmful in pregnancy, and it is associated with significant morbidity for the mother as well as the fetus. Hypocalcemia can result in uterine contractions and preterm labor. And for the fetus, it is associated with stimulation of the parathyroid glands, and the fetus may develop primary hyperparathyroidism in utero and demineralization of the fetal skeleton and intrauterine fractures. So hypocalcemia is a problem for both the mother and the fetus. And we need to ensure that our patient is not hypocalcemic during pregnancy. We also need to ensure that our patient is not hypercalcemic during pregnancy, because if we give too much calcium and active vitamin D, and if our patient becomes hypercalcemic, then this will suppress the fetal parathyroid glands and contribute to fetal hypoparathyroidism. So too much calcium and too little calcium, both of them are problems in pregnancy. So in the non-pregnant patient, we're recommending that the serum calcium be at the low end of the normal range or below the normal reference range. But in the pregnant patient, we recommend that it be in the mid to the low normal reference range and not below the normal reference range. We need to normalize phosphorus, magnesium and vitamin D and closely monitor our patients every three to four weeks during pregnancy and lactation with increased frequency in the month preceding and following parturition, as well as in the presence of symptoms. So if our patient have symptoms of hypercalcemia or hypocalcemia, check serum calcium. And I give my patients lab requisitions and say, if you're not feeling well, please get your calcium checked with albumin. And I put stat on it and I want them to call my office and confirm what the results are, or we'll follow up on that as well. We need to work closely with the obstetrician and the pediatrician in order to optimize pregnancy outcomes. We want to avoid thiazide diuretics and PTH analogs during pregnancy. But calcium and active vitamin D is safe during pregnancy. So what about emerging therapies? And we have a number of new molecules which will become available very soon. We have the long acting PTH analog, which is PTH, PTHRP hybrid molecule. And this has been shown to normalize serum calcium in early phase two A data and result in independence from calcium and active vitamin D and has also been associated with reductions in urine calcium and phosphorus. And this AZP3601 molecule, there will be data presented at endocrine society meeting regarding this. The PTH receptor agonist was discontinued because of hepatotoxicity. Calcilitics are very interesting molecules and these molecules are negative allosteric modulators of the calcium sensing receptor. So they will block the calcium sensing receptor and they will increase PTH levels. And they have been shown to result in increases in calcium and PTH and reductions in phosphorus and urine calcium have been seen in patients with autosomal dominant hypocalcemia type one. And there will be data presented at the endocrine society meeting. And then with transcon PTH, PTH1 to 34, transiently conjugated to polyethylene glycol, we will be presenting the phase three data week 26. And in this RCT study, we demonstrated achievement of independence from conventional therapy in 93% of patients with reductions in phosphate and urine calcium. So there's a lot of important information coming out and emerging therapies are looking very promising for hypoparathyroidism. So let's come back to our case that was presented by Dr. Van Oum. And so our 37 year old female, post-surgical hypoparathyroidism. She has been on calcium and active vitamin D following surgery. She's now 12 weeks pregnant and she is experiencing numbness and tingling in the face and hands, as well as muscle cramps in the lower extremities. Her medications include calcium and active vitamin D. She's also on hydrochlorothiazide and she's taking her levothyroxine. And on examination, her blood pressure seems to be stable. And the Shvostak sign is negative, Trousseau sign is negative. There's no thyroid tissue palpable. She's now on examination and this is what her lab profile showed. So her ionized calcium is low. Her PTH is low. And look at her vitamin D levels. Her vitamin D levels are low and her phosphate is high. Serum magnesium is indeed normal and her renal function is well-maintained. So which of the following is true? Does the low calcium and the low PTH confirm hypoparathyroidism and the elevated PTH? Would that be in keeping with a diagnosis of hypoparathyroidism? Yes. So she has low PTH. She's not able to mobilize calcium from her skeleton. She's not able to reabsorb calcium through the kidney. She's not able to excrete phosphate and her serum calcium is low and her phosphate is high. And this is all reflecting low PTH. So that is correct. Is it because of her vitamin D insufficiency that she has a low serum calcium and a high phosphate? Well, the vitamin D insufficiency can certainly contribute to low calcium, but vitamin D helps us to absorb calcium and phosphate from the bowel. So if vitamin D insufficiency was the cause, the sole cause, and it's not low enough to be the sole cause of the hypocalcemia, we would have expected to see a high PTH and phosphate levels would be low. They would not be high because we absorb calcium and phosphate with vitamin D. So inadequate levels of vitamin D would result in reductions of calcium and phosphate. In pregnancy, do we have increased formation of PTHRP? And would that lower the need for calcium and active vitamin D potentially? Yes, that is a potential manifestation of elevations of PTHRP, but not all women are able to have significant elevations in PTHRP with elevations in endogenous 125D so that they can meet the fetal requirements. And many may still require higher doses of calcium and vitamin D, active vitamin D, or they may require the same dose, or they may require a reduction in the dose. So to know where our patient is, we need to follow our patient closely. So close monitoring is required to see which direction our patient will go. So which is true? All of these are true except number two, vitamin D insufficiency is not the cause of the high phosphate. Which of the following is true? Her serum calcium is low, and in pregnancy, it is important to maintain a calcium in the mid-normal to low-normal reference range in order to avoid hypocalcemia? That is true. Hypocalcemia is dangerous in pregnancy as it increases the risk of preterm labor? That is true. Hypocalcemia can stimulate the development of the fetal parathyroid glands and result in primary hyperparathyroidism in the newborn? That is true. So all three are correct. So we want to avoid hypocalcemia, and our patient is hypocalcemic. So that's not good. And we want to correct this urgently. And we also want to avoid hypercalcemia because hypercalcemia in the mother will result in the fetal parathyroid glands not developing. So it's very important for us to maintain a normal serum calcium in pregnancy. So how should she be treated? During pregnancy, calcium and calcitriol supplements are safe and can be continued? Yes. Do we need to make adjustments in the dose of the calcium and the calcitriol, aiming for a mid-normal to low-normal level? Correct. Hydrochlorothiazide should be stopped? Absolutely. Hydrochlorothiazide is not safe and should not be continued. PTH and PTH analogs are not recommended during pregnancy. And vitamin D should be normalized? Correct. We need to normalize her vitamin D. So all of these are correct. So let's come back to our case. So what did we do? So we increased the dose of the calcitriol. And so we asked our patient to take 0.75 micrograms in the morning. And we continued the evening dose at 0.5 micrograms. And we asked her to take calcium supplement with each meal and to take extra calcium if she had numbness or tingling in the face or hands or muscle cramping. And we also asked her to monitor uterine contractions, which can increase with hypocalcemia. And we asked her to stop the hydrochlorothiazide. And we asked her to get her blood work done in three days. We want to keep a close watch on this lady to make sure that her serum calcium does not fluctuate widely. Want to normalize that serum calcium. If you have any concerns about compliance or how your patient will do, then you can always measure the calcium daily for three days. That's one of the things that I do for our pregnant patients is I might just check calcium daily for three days, make sure that our patient is doing well. So with that, I would like to thank you for your attention and open up for questions. Thank you. Thank you. Thank you so much, Dr. Khan for putting this together in the video and presenting a comprehensive overview as well as clarity in the approach to the clinical patients. I noticed that online, there are still about a couple of dozen of questions. And I imagine Dr. Khan frantically sitting to type and answer those questions. So I invite you to go back to those questions a little bit later and look at her responses. In the interest of time, I would like to conclude this session, but not before thanking both Dr. Khan and Dr. Bilizekian for leading the effort for the international workshop and the presentations today. Thank you and wish you a good evening.

video transcript

hypo

hyperparasitism

Dr. Stan Van Umen

primary hyperparasitism

surgical removal

parathyroid gland

treatment

normocalcemic hyperparasitism

diagnosis

hypoparathyroidism

complications

conventional therapy

pregnant patients