Good afternoon, and welcome to the Parathyroid Symposium. In the next hour, we have a lot of exciting updates on parathyroid we'd like to share with you. My name is Jad Sfeir. I'll be your moderator for this afternoon. I'm an endocrinologist and gerontologist at Mayo Clinic in Rochester. Our first speaker, Dr. Alia Khan, unfortunately was unable to join us. She was unable to travel from Canada to the US. But we were very lucky to have her slides shared with us, and I'll be presenting on her behalf her information this afternoon. The reason we asked Dr. Khan to join us to present this is because she was co-chairing the international workshop on parathyroid disease, which occurred in 2021. The last international workshop was in 2014 in Italy, but the 2020 international workshop occurred over Zoom. I was honored to be invited to work with the international group as well. Of course, because I'm on, they do it over Zoom, but instead of going to Italy. Even though I'm presenting for Dr. Khan, I'd like to share with you her credentials. Dr. Khan is a professor of clinical medicine at McMaster University. She's the director of the Calcium Disorder Clinic and the Fellowship in Metabolic Bone Disease at McMaster. She graduated from the University of Ottawa Medical School with honors and completed postgraduate training at the University of Toronto. She has published over 200 scientific papers and numerous chapters and books on osteoporosis and parathyroid diseases. She has received numerous national and international awards, including the Queen's Diamond Jubilee Medal for Excellence, International Hypoparathyroid Award, International Osteoporosis Foundation Award. She was recognized as being in the top 0.1% of the world experts in hyperparathyroidism by Expertscape. We will go over Dr. Khan's talk on updated guidelines on management of primary hyperparathyroidism. And these are Dr. Khan's disclosures. The learning objectives we'll share with you is understanding how to diagnose primary hyperparathyroidism, how to recognize the complications of primary hyperpara and how to manage primary hyperpara. As I mentioned, these are the new guidelines that are currently under review in JBMR. They have not been published yet. A lot of the data that we will share with you this afternoon will be from these new unpublished guidelines. Just to remind everybody in the room and bring everyone up to date, that the key effect of parathyroid hormone are basically on the bone and the kidney. PTH, an increase in PTH will increase renal calcium reabsorption, but also increase bone resorption. In the kidney, it will also increase the conversion from 25 to 125 dihydroxyvitamin D, which itself will increase calcium absorption through the gut, but also have direct effect on bone resorption in the skeleton. As you well know, diagnosing primary hyperpara is typically done with a high serum calcium after correction for albumin, high or inappropriately normal PTH levels. In the absence of drugs that mimic primary hyperpara, the typical culprits that we encounter in the clinic are HTTZ and lithium. We also need a calcium to creatinine clearance ratio that is greater than 0.02, and this is calculated by obtaining urinary calcium and creatinine and serum calcium and creatinine using the equation you have in front of you. The idea here, of course, is to exclude FHH in which case you have an inactivating mutation of the calcium sensing receptor. FHH is typically mildly elevated serum calcium and high normal PTH, but associated with hypocalciuria, and in that setting, your calcium to creatinine clearance ratio will be less than 0.01. So a ratio less than 0.01 will essentially diagnose FHH, a ratio greater than 0.02 will essentially exclude FHH, and then you have the area gray zone in between. This ratio has a sensitivity of 85% and specificity of 88% for diagnosing FHH. So you still have overlap, and you still have cases that can go in between. Imaging, imaging in primary hyperparathyroidism, as you well know, we do not use this to diagnose primary hyperparathyroidism, and this will be stressed in the new guidelines that are coming out. It is mainly for localization to guide surgical approach. Typically, we use sestamibi imaging, which has a sensitivity of 90% and accuracy of 97%. Of course, these are reported numbers, although you have a lot of variability in the literature in terms of accuracy. The idea behind sestamibi is that sestamibi is going to be retained in parathyroid adenomas longer than it is retained in normal parathyroid tissue or in normal thyroid tissue. It's taken up by both, but you do have some confounders there, especially when you have multinodular goiter. You can have more retention. If you have more than one parathyroid adenoma, you will have retention in the adenoma, but you can also have some retention in the normal parathyroid, because what sestamibi is doing is really, it's an electrical binding to the negative charge in the mitochondria, and in the adenoma, you have all these oxyphil cells that are holding onto the sestamibi, which is why it's important to do a delayed imaging in these to be able to see the washout from the normal tissue. Small adenomas can be missed, as I mentioned, with mildly elevated calcium. Ultrasound. Ultrasound is less useful to identify a parathyroid adenoma, but typically in odd locations, the retrotracheal esophagus and ectopic glands in the mediastinum, you're not gonna catch these on ultrasound, but ultrasound is still important because it can also give you some information about the surgical field, particularly the thyroid itself. The sensitivity of an ultrasound is 76 to 87% and accuracy up to 88%. MRI and CT scans have been used with variable sensitivity and accuracy, as you can see on the slides, and then selective venous sampling, much less favored these days for those with repeat surgery or failed prior surgeries. What are the clinical phenotypes of primary hyperpara? Symptomatic primary hyperparathyroidism, typically associated with renal complications, osteitis fibrosa cystica, fractures, chronic kidney disease, nephrolithiasis, and or nephrocalcinosis. These figures show you a brown tumor in the distal radius in the case of primary hyperparathyroidism untreated, and here you can see the osteitis fibrosa cystica, salt and pepper appearance. You can have the diffused demineralization and increased lucency of the inner and outer cortices of the skull. And then we have asymptomatic primary hyperparathyroidism, which was the focus of these guidelines. Patients will have no overt symptoms. Typically, we discover this by biochemical testing. It can have target organ involvement or without any target organ involvement. And then finally, we have normocalcemic primary hyperpara, which is typically normal serum calcium with elevated PTH after excluding secondary hyperparathyroidism. It may or may not have skeletal or renal complication with normocalcemic disease. What are the recommendations to evaluate patients with primary hyperpara? Biochemical testing, obviously we need serum calcium. It's not listed on the slides, but albumin is essential here because you want to correct always for albumin. Phosphate level, intact PTH, vitamin D, and creatinine. For skeletal imaging, the guidelines will recommend three-side DEXA scan, lumbar spine, hip, and distal radius, but also imaging for vertebral fractures, either using VFA or spinal X-rays. And then the guidelines will also recommend if your institution has trabecular bone score, TBS, to have that also done on the lumbar spine, DEXA images. The reason for recommending three-side DEXA, these are the different DEXA at the lumbar spine, at the femoral neck, and at the distal radius. I realize you cannot see my pointer. That the distal radius is the one that's mostly affected because of the preponderance of cortical bone, and the lumbar spine is typically quite preserved in these patients. Fractures in this population, we know that patients with primary hyperpara have a high risk of fracture, both vertebral and non-vertebral fractures, and then the fracture risk decreases significantly after parathyroidectomy. HRPQCT studies showed that there is disturbance in the microarchitecture. It affects actually both the trabecular and the cortical bone with HRPQCT, and HRPQCT correlation with fracture was much better than bone density by DEXA, and that's because even after adjusting for BND, HRPQCT was able to give us a good approximation of the fracture risk. Post-parathyroidectomy, not only does the risk of fracture decrease, but also there is improvement in the microarchitecture of the bone based on HRPQCT studies. And then we talked about asymptomatic disease, and when we talk about symptoms, common things that we get asked in the clinic by patients because they read a lot on the internet is cardiovascular events and cerebrovascular events and cardiovascular disease. This is only to show you that whether we do observation or surgery for patients with primary hyperparathyroidism, there is really no difference in terms of cardiovascular or cerebrovascular mortality or morbidity or events. And medical observation seems to be safe in mild cases of primary hyperparathyroidism. We're going to come back a little bit later to talk about what the guidelines say regarding cardiovascular disease in these patients. Renal monitoring for these patients, you want an estimated GFR based on a creatinine, or if you can actually calculate, a creatinine clearance would be better. 24 hour urinary calcium and biochemical risk factors for stones. And then imaging are recommended for nephrolithiasis or nephrocalcinosis, any type of abdominal imaging that can detect these. So non-classical manifestations, neurocognitive and quality of life and cardiovascular manifestations of primary hyperparathyroidism there is currently no evidence in the literature to routinely evaluate for these in patients diagnosed with primary hyperparathyroidism. So we mentioned briefly kidney stones. So obviously patients with primary hyperparathyroidism have a high risk of kidney stones. The risk is up to 80% incidence of kidney stones. However, this has changed over the years. More recently, we see that in more recent studies that this is actually closer to 10 to 20%. But this is still elevated compared to a background population incidence of about 1.6%. Interestingly, that after parathyroidectomy, the risk of kidney stones decreases, but does not go back to background, does not go back to that 1.6%. So these patients are still at increased risk of kidney stone formation, even after parathyroidectomy. More commonly, these are young men with primary hyperpara. Parathyroidectomy does, however, improve the decline in renal function, improve renal function, prevents further decline. This is based on retrospective cross-sectional data. How about genetic testing? Genetic testing are recommended for all patients with primary hyperpara below the age of 30, those with multiglandular disease, either by history or by imaging, and those with family history of either hypercalcemia, hyperpara, or one of the syndromes. So in patients less than 30 years of age, what are the typical genetic syndromes that have primary hyperpara? Men one, obviously, over 95% of patients by the age of 50 with MEN1 will have hyperparathyroidism. Primary hyperpara typically is the presenting symptom of, presenting disease of MEN1. It can, however, also occur in MEN2 because of the red gene mutation, although at a much lower rate compared to MEN1. In patients with hyperparathyroidism with the jaw tumor, where you have a CDC73 gene mutation, there is a high risk for parathyroid carcinoma, not only parathyroid adenoma or primary hyperpara. And these patients, in addition to the MEN1 patients, it is recommended to have a neck dissection to look for all parathyroid, not only a directed parathyroid surgery. And then down here are the genes that are related to FHH syndromes, FHH1 with calcium sensing receptor, FHH2 and 3, which are much less common. And this is a summary of what I mentioned in terms of biochemical testing that are recommended. This will be featured in the new guidelines coming up hopefully soon. Non-classical manifestation. So neurocognitive symptoms. Currently, there is some form of association between neurocognitive symptoms, quality of life symptoms, and primary hyperparathyroidism. The causality has not been established. The association is not very strong. But more importantly, parathyroidectomy does not improve neurocognitive function, at least based on the limited data that's available. And thus, there is no recommendation regarding testing for neurocognitive diseases or having it to be an indication for surgery. Remember, we're talking about asymptomatic disease, mild primary hyperparathyroidism. We're not talking about symptoms that occur with significantly elevated serum calcium. Cardiovascular disease. There has been association with left ventricular hypertrophy and hypertension in patients with primary hyperpara. There is no evidence that this changes at all after parathyroidectomy. Again, not an indication for assessing it pre-op or using it as an indication for surgery. The studies that looked at hypertension and LVH were confounded by hypertension, essential hypertension. Many of the patients did have essential hypertension to begin with. And then GI, the only association with GI symptoms is in MEN1 and Zollinger-Allison syndrome. What are the indications for surgery? And this is where the changes happen compared to 2014 guidelines. Serum calcium greater than one milligram per deciliter over the upper limit of normal of the lab. Skeletal involvement, which includes a bone density, T-score at either of the three sites, less than negative 2.5, or a presence of vertebral fracture by VFA or vertebral films. Renal involvement, creatinine clearance, or EGFR, less than 60. Presence of nephrocalcinosis or nephrolithiasis by abdominal imaging, which could be via KUB, ultrasound, or other imaging modalities. Hypercalciuria, this is a significant difference compared to the old guidelines. The cutoff for hypercalciuria in women is 250 milligrams or greater, and in men, 300 milligrams or greater would be indication for surgery. And the age less than 50 remains the same. Another indication would be if none of these exist, but the discussion between you and the patient shows that there is preference of the patient to go through surgery, and then they accept the risks of surgery, and there are no contraindications for surgery, then that would be the way to go. Medical management, if the indication is osteoporosis or the patient does have osteoporosis only as their end organ damage, alendronate or denosumab, both have been shown to improve bone density with variable effect on calcium and PTH. Sinacalcet significantly reduces serum calcium and PTH, if there are no contraindications. Remember that in this population, calcium and vitamin D supplementation should follow the general population recommendation. They should not be considered to have a contraindication to be on calcium or vitamin D. Looking at the Institute of Medicine guidelines, depending on age group, would remain the same. Typically, we do recommend the calcium to come from the diet, rather than supplementation, but this may be needed to achieve appropriate calcium intake. This is a study showing us the A benefit of alendronate. These are patients with primary hyperparathyroidism that did not undergo surgery. On top, you see the lumbar spine BMD, and at the bottom, you see the total hip BMD. The first year, in the first 12 months, it was alendronate versus placebo, and the second year, 24 months, those on alendronate continued on alendronate, those on placebo were crossed over to alendronate, showing you that there is significant improvement in bone density with alendronate in patients with primary hyperpara, if there is no room for surgery. And then, how about sinacalcet? This is a study that looked at sinacalcet in patients with primary hyperparathyroidism. It was a placebo-controlled initially, but then was open-label after 28 weeks. The intent was to enroll 140 subjects. However, the recruitment stopped at 67 total subjects after a calculation of sample size showing that over 60-subject recruitment would be enough to show difference. You can see what happens to serum calcium. So with sinacalcet, which is in the black dots, significant decline in serum calcium, normalization of serum calcium on sinacalcet compared to placebo, and then when the open-label happened, all the patients became on sinacalcet, and then you can see the placebo. Previously on placebo, when they were started on sinacalcet, there was reduction in the serum calcium. The dose of sinacalcet in this study started at 30 milligram twice a day, but was titrated every two weeks up to 90 milligrams three times a day. There was about a 15% drop-off in each arm, both placebo and sinacalcet for various reasons. So we talked about vitamin D supplementation. The panel recommends vitamin D to be above 30, but below the upper limit of your lab. Mind you that 50 is generally considered an upper limit of normal in most labs. Recently this has changed over the past few years. Estrogen has been shown to increase bone density, but its effect on serum calcium is inconsistent. Galoxifene has not been shown in any studies to have impact. And this is a summary of everything I talked about, the various medications and supplementation that can be given to these patients. Again, you will find these in the new guidelines. Pregnancy, so special case of pregnancy, what happens in pregnancy? PTHRP is produced by the placenta, and PTHRP will also cause an increase in the conversion of 25 to 125 dihydroxyvitamin D, and then putting us in hyperparathyroid state. But as soon as the placenta is removed after delivery, PTHRP goes rapidly down to previous levels. So these are ungraded recommendations from the panel. Mild cases during pregnancy should be monitored. If there is need for intervention, bisphosphonates and denosumab should not be used in pregnancy, and the data on safety, data on senocalcet is very limited. If you need to do surgery in symptomatic patients with calcium greater than 11, then surgery is recommended in the second trimester. Localization for surgery will have to be limited to ultrasound because of the pregnancy. If surgery is deferred, this neonate at birth should be very closely monitored for hypocalcemia, and that if surgery is deferred, parathyroidectomy should be done after delivery before another pregnancy is planned or unplanned. Management of primary hyperpara during pregnancy, this is just summarizing what we just talked about. So to summarize the talk of Dr. Khan, parathyroidectomy is a very attractive option for asymptomatic primary hyperpara. Those not meeting the guidelines or unable or unwilling to proceed with surgery can be safely followed. We have good evidence there. The guidelines will specifically mention normocalcemic hyperparathyroidism, that in this category, there is currently no evidence to have guidelines or strict indications for surgery in patients with normocalcemic disease. Senocalcet lowers PTH and calcium often into the normal range. Bisphosphonates and denosumab have been shown to improve the bone density and provide skeletal protection. And then for monitoring in those who do not undergo surgery, annual biochemical testing with calcium, creatinine, and BMD every one to two years at all three sites. Vertebral imaging, 24-hour urine, do not have to be repeated in those you are monitored unless clinically indicated. And with that, I thank you for your attention and we'll move on to our next speaker. Our next speaker is Dr. Rob Wormers, who will be talking to us about management of persistent and recurrent hyperparathyroidism. Dr. Wormers is professor of medicine at the Mayo Clinic College of Medicine and Sciences and a consultant in the division of endocrinology and chair of division of endocrinology at Mayo Clinic. Dr. Wormers obtained his undergraduate degree from University of Nebraska and Lincoln, Nebraska, and his doctorate of medicine from the University of Nebraska in Omaha. He completed his training in internal medicine and fellowship in endocrinology at Mayo Clinic. Dr. Wormers. Well, thank you very much for attending the parathyroid session and we're gonna jump right off into an area with less evidence but important clinically. So let me just see here. We'll talk about a couple of off-label uses of different things here, so just to be aware. So we'll talk about what to think about when you get a patient with recurrent or persistent primary hyperparathyroidism. We'll talk about localization strategies. And believe me, we do this, I bet you I see one to two patients every week with this problem, so it's a common problem where we're working at. And we'll talk about what are the risks and benefits about thinking about doing another surgery because the stakes are always gonna be higher in that setting. So just so we're all on the same page for definitions, remember that this is persistent primary hyperparathyroidism is elevated calcium within six months after the parathyroid surgery with an inappropriate PTH. So that's kind of the definition of primary hyperparathyroidism that's persistent. Recurrent is gonna be if you document cure within six months, so after parathyroidectomy, we usually recommend getting a six-month calcium and then annually thereafter. If the calcium normalizes and then becomes elevated with an inappropriate PTH, that's called recurrent primary hyperparathyroidism. Now here's the problem. The problem is that a lot of people, not necessarily me, hopefully not a lot of you, but a lot of people after they have successful parathyroid surgery will often wanna know what their PTH is. So this is data from University of North Carolina where they looked retrospectively at those patients who had a PTH measure within three to 18 months after their parathyroid surgery. And what they identified is that one third of patients will have an elevated PTH. Now if you want some hand-wringing in your office, check a PTH within six months after surgery because this is a problem. Now almost all of those patients, 97%, had a normal serum calcium. And when you looked at predictors of those patients, whoops, who had elevated PTH, what they found was the higher the preoperative PTH and the lower the calcium, the more likely you were to have persistent elevations in PTH. So I generally try to avoid checking PTHs to document cure and I would think you need to be careful. Maybe we should, maybe we shouldn't, but if you check it, you're gonna find elevated PTHs and have anxiety to deal with. Now this is data that's even a little bit more disconcerting from the University of Michigan where they did a retrospective evaluation of labs within six months after parathyroidectomy. And what you can see is that 25% of patients have either an elevated calcium, an elevated PTH, which is about 12% or so in each of those buckets, and then about 3% had an elevation in both, which is persistent primary hyperparathyroidism. So again, if you check both of those, you're gonna have a large number of patients who are gonna have some abnormality in those biomarkers. Now what they found out, and there's really two key points from this kind of, from this table. The first thing is, is the risk of recurrence with this multivariate analysis was the highest if you actually had an increased PTH, but a normal calcium. So maybe we should be checking PTH, I don't know, because those patients may be at higher risk. But then, you know, that isn't how our current definitions go. So about a 20, or 4.3 times increased risk of developing recurrence defined by high calcium and PTH in this particular study. Than if you have a high calcium, but a normal PTH. The other thing I wanna point out, and I think this is, data's gonna be right, because we're looking, we just have submitted for publication on our data over a 45-year period in Rochester. And if you look at the recurrence rate of confirmed recurrent primary hyperparathyroidism, about 10%. And so I think that's probably the right number based on our data and this data. About one in 10 patients at some point will have recurrent primary hyperparathyroidism. So I check a calcium at six months, and then I check a calcium annually thereafter is what I recommend for patients based on data like this. Now, a couple of things to think about. If you're thinking about another surgery, and, you know, it's gonna be a higher stakes situation. It's gonna be more expensive, you're gonna need more localization. You really want an experienced surgeon. But I wanna emphasize, you want an experienced surgeon not only the second time, but the first time. Because, you know, the surgeon makes all the difference in the world. If you have a low-volume parathyroid surgeon, it would be in your patient's best interest to send them somewhere where they do some higher volume of cases. Surgical volume matters. And then there's an increased risk of complications. And the main complications are gonna be hypopara, being the most common, and then vocal cord paralysis. So we do vocal cord checks on all of our patients before they go for another repeat neck surgery. Now what do you think about when you see a patient who has persistent or recurrent disease? You should be thinking not sporadic, original, you know, case of never been operated on. But you need to be thinking the following. First, the patient may not have primary hyperparathyroidism at all. They may have secondary hyperparathyroidism. If you get a patient with an elevated PTH and a normal calcium, and then at the end of the visit they tell you they had a Roux-en-Y gastric bypass 10 years ago, that's not gonna be primary hyperparathyroidism a lot of the time. It's gonna be secondary hyperparathyroidism, right? You have to think about FHH, and there's gonna be clues in your patients to think about FHH. And then you need to think about non-PTH-mediated cause of hypercalcemia. When you have a patient with primary hyperparathyroidism, I like to see that PTH above the 50 percentile normal. Have I seen people with lower PTHs? Yes, but in general they should be on the generous side and not kind of low normal. And then think about multiple gland disease. Often it can be they had one disease gland, but they had another gland that just wasn't identified at the time of surgery. I'll talk a little bit more about my bias on subtypes of primary hyperparathyroidism. Think about ectopic primary hyperparathyroid adenomas. And in general at our institution, we won't operate unless we have a target to go for. We need to have a target on a second or third or fourth, or even fifth surgery sometimes before we're gonna even think about operating on that patient. Think about parathyroid carcinoma or parathyromatosis. And that's why you always wanna get that gland out without rupturing it, because if it ruptures it could seed that tissue and parathyromatosis is a disaster if you see that. And then it could just be the most common scenario is that the surgeon just didn't identify the gland. And so I always go back, look at what the surgeon saw and I review the pathology reports to confirm they found parathyroid tissue when they did the surgery. Now here's kind of an algorithm that I use. Again, this is about as non-evidence-based of a talk as you could give, which is why I like it, because this is what I think. But the first thing you wanna do is, so think about the diagnosis, define the diagnosis, think about the surgical risk, and think about the reason you wanna go to another surgery. Does a patient really need to go to surgery? Dr. Spheer told you about some guidelines that might suggest when to do it. So the second thing is, is if the patient, we'll start generally with a spec CT. Usually we just do a planar spec imaging, which is a functional study, but in this case you wanna do a spec CT. We'll do an ultrasound. And then if that doesn't localize, we'll usually go to a 4D CT. And then another study that we'll often do in this setting is a C11 choline PET CT. And if we localize and we have a good target, we'll generally consider going to surgery if benefits outweigh risks. Sometimes we'll do ethanol ablation in certain subtypes. If we can't find it, we may do selective venous sampling, but generally we don't need to go to that step in the majority of patients, especially with the advent of choline spec CTs. Now, in general, at least in Rochester, we have pretty good success in identifying the disease with usual imaging before we go to more expensive or invasive testing. We can cure most of these patients, 88% of them. We find often they're more likely to have multi-gland disease. And I'm a believer in intraoperative parathyroid hormone. I know there's controversy over that, including in the new guidelines, but in a repeat neck surgery, I think the data's pretty solid in reducing the risk for hypoparathyroidism. If the surgeons are seeing that PTH dropping dramatically in the operating room, they may not wanna take out another gland and it kinda helps guide them on that procedure. And then finally, again, the risk of occipital cord paralysis is pretty low. Now, I just wanna point out that there is controversy. The UK guidelines on intraoperative PTH basically say that the evidence is weak. They don't really recommend doing this routinely. High volume centers have good outcomes irregardless of this, and they challenge the cost effectiveness of this. On the other hand, more recently in JAMA otolaryngology, head and neck journal, they said when they did a meta-analysis that actually they favor doing intraoperative PTH for all cases of primary hyperparathyroidism. And what they identified was is that if you do intraoperative PTH, the patient's more likely to be cured. They are more likely to have a bilateral neck exploration because intraoperative PTH doesn't drop. They're less likely to need another parathyroid surgery. It does increase the OR time, and there's no difference in postoperative mortality, but it does improve cure rates and gives less reoperations. So I think that's a strong argument to do it. And I think because of time purposes, I'm going to not spend too much time since Dr. Spear went over this already, but it's reasonable to think about if they have osteoporosis as the indication, but they don't have a target, or if they have severe hypercalcemia, you don't have a target, that's when you're gonna have to become a real endocrinologist and manage the patient yourself. So this is where you're gonna use Sinecalcet bisphosphonates. I haven't used a lot of Danosumab in this setting, but there is data on that as well. Now, I'm a believer in that a picture's worth a thousand words, so I want to give you a couple of cases here that kind of highlight some of the things that we just went through. So this is a patient that I saw who was a 33-year-old who had hypercalcemia for 10 years. Non-localizing parathyroid surgery, but he underwent surgery and had a three-gland parathyroidectomy with auto-transplantation into the sternocleidomastoid, and it was pathology-confirmed disease, or pathology-confirmed parathyroid tissue, I should say. Calcium was initially normal, but they've been elevated ever since that time, so he had like one normal right after the surgery, but then elevated multiple times after. This is what his labs were. He had calcium levels that were obviously high. PTH was within the normal range, but higher normal, 42. 24-urine calcium was 305 milligrams. He had repeat localization attempts with a scan and a neck ultrasound, and he had really no complications other than when he had a proximal humerus fracture after falling down the stairs, and he had no imaging for stones. Now, he had lithium use six to seven years ago. He denied using any calcium supplements, and his vitamin D level was 22 on some low-dose vitamin D. He had no head or neck radiation and he did have an uncle who had a three and a half gland parathyroidectomy with persistent primary hyperparathyroidism and then his uncle had another surgery. He wasn't sure, but he thinks his mom might have hypercalcemia as well. He was on an albuterol inhaler, medical cannabis for back pain from the state of Illinois. He's able to get off opioids with that. He was on a PPI and he was, after that vitamin D, he was on higher doses of vitamin D then at 5,000 units. On exam, he's a big guy, well-heeled collar scar and thick neck, abdominal obesity, but really otherwise unexciting. These were our Mayo labs. You can see the PTH actually was at the mid-normal mark here on this particular measurement, but these numbers fluctuate. Sometimes patients will perseverate on calcium and phosphorus and I always tell them these things vary from second to second. They can be influenced by vitamin D levels, by calcium intake, by lots of other factors, so we want to look for trends as a general rule and not focus on just single measures. So I always try to encourage patients to just watch the trends over time. So as you think about this person, there's a lot of clues in the history. The history is the most important thing that I do in the office when I see patients. So when you think about this, would you repeat the localization? Would you look for non-PTH-mediated causes of hypercalcemia? Would you assess for complications and do a bone density and check for stones? Would you do the 24-hour urine calcium and creatinine, or would you start doing screening for MEN1, given his family history? So we don't have audience response, but as you think about that, what I ended up doing was just the 24-hour urine calcium and creatinine. Anybody who takes boards know they'll always do the cheapest test, right? So that's usually a good rule of thumb. So he did have a urine calcium that was generous at 232 milligrams, but his urine creatinine was also generous and the ratio was actually less than 0.01. So when you do a 24-hour urine calcium, do a 24-hour urine creatinine. Don't just look at that 300 milligram value. That could lead you astray. We did confirm calcium-sensing receptor mutation for a pathogenic variant in this individual and we advised that he shouldn't have surgery at that point. Now you've heard a little bit about FHH and primary hyperparathyroidism, but what I want you to know is that there's a lot of overlap. There's a lot of overlap. And specifically, although only 25% of patients with FHH have elevated PTHs, that means 25% do have elevated PTHs, 75% will be normal. Calcium tends to be higher in FHH than primary hyperparathyroidism. And there may be some clues, but there's a lot of overlap. And so sometimes it's hard to distinguish on biochemistries. But really, some of the clues in this particular individual is if you hear a story of a three-and-a-half gland parathyroidectomy with persistent primary hyperparathyroidism, that is very unlikely to be primary hyperparathyroidism. That just sounds like FHH. Because if you do a three-and-a-half gland parathyroidectomy in FHH, they'll have persistent hypercalcemia. You don't see that with other forms of primary hyperparathyroidism. The other thing that can be helpful is looking back at the records. Was there ever a normal calcium? When you hear about a 32-year-old, like Dr. Spheer, when do you do genetic screening, and he had calcium for 10 years prior to that in his 20s, you should be thinking about something like FHH. If somebody has persistent primary hyperparathyroidism, you should be thinking about FHH. And so again, this is just something to be aware of. You know, there are some prevalence figures that are pretty scary, to be honest. FHH1 is the most common form of FHH by far, like Dr. Spheer said. If you look at the estimated prevalence from some data from Europe, 74.1 per 100,000 compared to, you know, not that much higher incidence or prevalence of primary hyperparathyroidism in the general population. So I suspect we're missing a lot of FHH. So we just need to have our antennas up in that regard. And again, anytime you have somebody with recurrent or persistent disease, you should be thinking about genetic potential here. We've heard a little bit about this, but you should be thinking about, you know, MEN1. CDC73 mutations are single gland disease. So you're not going to think so much of the only 10% of patients with the CDC73, they have an increased risk of parathyroid carcinoma, but they don't usually have multi-gland disease. Another one to remember is GCM2 mutations. And what we do is I send these patients to clinical genomics because they do a panel, get insurance coverage, and then I don't have to have the heartache of doing that myself, which is always my goal. No heartache for me. So that's one. And I want to show you this last case, because this is, again, a picture's worth a thousand words. So this was a 54-year-old that I saw from South Dakota who had persistent primary hyperparathyroidism. And she had PTH levels that were twice normal, intermittently elevated serum calcium levels. And she went elsewhere and had parathyroid surgery, and she had a right superior parathyroidectomy. And her PTH levels were elevated afterward with a high normal calcium. So in this case, somebody was monitoring PTH. Now, she had no history of head or neck radiation, no lithium or thiazide diuretic use. She did have a BRCA1 mutation and had a hysterectomy and oophorectomy, ultimately. No family history of any parathyroid disease or endocrine syndromes and had well-preserved bone density. No history of stones or fractures. And she was on the most commonly prescribed drug in the U.S., levothyroxine. Just, you know, we've got to be proud as endocrinologists. And she was on calcium, verapamil, and I think she had migraines, and she was on a low dose of vitamin D. And this is the beauty of an endocrinology exam, well-heeled neck collar, otherwise unremarkable. Now, for documentation purposes and billing, please don't do this. But this is what, you know, this is what I like. So her labs, she had mild hypercalcemia. She had a low phosphorus, slightly low, 2.4. She had a PTH that was elevated. And she had a good, thank God she had a normal 25-hydroxyvitamin D. Her 24-hour urine calcium was 824 milligrams. So she had hypercalceria, way above the 250-milligram new threshold that was proposed. Despite that, no stones. And we repeated the 24-hour urine, and it was still high. Now this is kind of one of the messages. So there's two subtypes of patients to think about where you're going to have a higher risk of multigland disease. So most cases are going to be single gland disease, but it's now we're thinking more in the 20% range rather than maybe the used to be 10% was the number. It might be multigland disease is present in up to, you know, a quarter of our patients. And who are the patients you might think about that in? Well, one subtype are patients with mild primary hyperparathyroidism. Now I'd ask you to raise your hand on how many are haunted by mild cases of primary hyperparathyroidism, where either the PTH is normal, the calcium is higher, the calcium is normal, the PTH is higher, because I'm haunted every week about this, and I'm pretty sure you are too. And the problem is a lot of people have pain and other things, and they, you know. But those patients with mild forms of the disease are more likely to have negative localization, more likely to have a negative surgical outcome, and they're more likely to have multigland disease. And that's what I tell patients. You know, if they're thinking they want to do surgery, I always tell them and I always promise them I can't say your symptoms will improve, but I hope they will. Now the other form of multigland disease is hypercalciuric primary hyperparathyroidism after. So if they have persistent hypercalciuria after parathyroid surgery, then that's another subtype where you're going to see more glands diseased more commonly, up to half of those patients. So if you just look at all hypercalciuric patients, and we published a paper a year ago or about two years ago on this now, if you just look at all comers with hypercalciuria, only about 10% will have multigland disease. But if they have persistent hypercalciuria after surgery, many of those will have multigland disease. And so we suspect multigland disease in this individual. So with that being said, what would you do next in this individual? Would you perform localization with referral to an experienced parathyroid surgeon, observe, put them on a thiazide diuretic like chlorothalidone, start her on acinocalcet, or maybe consider alcohol injection? And as you think about that, in this case, you know, she had hypercalciuria. We felt like it was reasonable to proceed with attempting localization. So here's what we did. We did an echo ultrasound, which is very operator dependent. That's an anatomic study. We did a parathyroid scan. In this case, we did spec CT, so anatomic, functional, both with that study. We did a 4D CT as well, and they were all negative. So now what would you do? Would you do selective venous sampling for PTH, observe, start chlorothalidone, put her on acinocalcet, refer to a surgeon? And to save you here, I'm going to go ahead and give you what I did, which you could argue about this. But I went ahead and started her on chlorothalidone. And this is data from Israel showing that it's a retrospective study basically showing that if you put patients on a thiazide diuretic with primary hyperparathyroidism, you really don't see much increase in serum calcium in the right side of this slide. But what you do see is a decrease in 24-hour urine calcium. And so in this particular individual, we put her on chlorothalidone. I started with 25 milligrams. Calcium was 10.5. Phosphorus, 2.4. PTH was 110. And 24-hour calcium was still quite high. Whoops. Oh, man. I gave you the punchline here. So we went next to a C11 petcholine CT. So C11 petcholine CT is the new kid on the block for imaging or localization. Fast imaging time, low-dose radiation compared to a 4D CT, but it's going to be more expensive. And it has a short half-life, so you just happen to need a cyclotron, which is a little bit of a problem. So we did go ahead and do this, and you can see she had a right-sided parathyroid abnormality. Now I just want to, again, point out that the 4D CT, and again, in JAMA otolaryngology, they did a meta-analysis on localization and primary hyperparathyroidism, and actually the C11 petcholine CT was thought to be the most sensitive test to actually identify parathyroid adenomas. Now, it's more expensive, so I would not do this first line. Don't get me wrong. And we have a paper submitted now on our patients with recurrent primary hyperparathyroidism, and it's a good test. So in this individual, we went to surgery. Her intraoperative PTH didn't drop, but we did remove a 290-milligram right superior parathyroid adenoma, and her 24-hour calcium has improved. Since then, we've increased her chlorothalonone to 50 milligrams, and she's been clinically stable. So not all primary hyperparathyroidism is the same, and this is kind of how I think about the different buckets. There's classical, which come in, they get a beautiful light bulb image. They're easily, you know, you got classical biochemistries. That's pretty straightforward. You have mild forms, which are normal parathyroid with hypercalcemia or high calcium with normal PTH. You have mild forms, so I think about those a little bit differently. You have thiazide-associated. I didn't talk about that today. They tend to have more multi-gland disease, at least based on some limited studies. You can see this hypercalceric subtype to think about. Lithium is a very difficult situation. You have familial primary hyperparathyroidism, where you have to think about genetic causes such as FHH or other causes. Recurrent and persistent I also think of a little bit differently than just sporadic. So I do think thiazide as well may be a viable treatment option to consider, especially in those patients where they don't have a good surgical option, where they're high risk for stones or have stones. And then I think C11 choline PET-CT certainly seems to be an image that's going to be utilized more in the future based on the emerging data. So with that, I'll close out, and I thank you for your attention. Thank you, Dr. Wormers. And we'll move on to our next speaker, Dr. Bart Clark, who will be talking about the new guidelines on hypoparathyroidism. Dr. Clark is a consultant at the Metabolic Bone Disease Group in the Division of Endocrinology at Mayo Clinic in Rochester. He is professor of medicine at Mayo Clinic. He completed his medical training at the UCLA School of Medicine, residency and fellowship training at the Mayo Graduate School. His current clinical research interests include parathyroid disorders, including hypoparathyroidism and primary hyperparathyroidism, postmenopausal osteoporosis. He is a previous president of the American Society for Bone and Mineral Research, ASBMR, and a member of the AACE Endocrine Society and ACP. Without further ado, we'll turn it over to Dr. Clark. All right. Well, thank you very much for coming to this session. We thought this would be a great session, because parathyroid disorders are common. We all see them. Depending on what you do, you may see more diabetes, clearly, or thyroid, but you can't escape this. And many of the things that Dr. Wormers just covered are common scenarios that we all see, and we scratch our heads, and we try to do the best we can. Sometimes we do the right thing, and sometimes not. What I'm going to talk to you about in the rest of this symposium here is about hypoparathyroidism. So this is an area that we also get asked to see, probably for many of us, our least favorite patients, because they're difficult. They have many concerns. They want to talk a long time, and your scheduling secretary says, why are you spending an hour and a half, and not just the 45 minutes they were given? So it's all those issues, but what I'm going to try to do today is update you a little bit here on new information, certainly the guidelines, and related issues that are coming. So here's my disclosures. The disclosures really relate to the burgeoning number of products that are being developed to address this rare disease. So thank goodness, sort of like diabetes, we're going to have multiple types of parathyroid hormone. We'll have other products as well that can be used. Hopefully this will make life for us a lot easier, and for our patients specifically. So here's the objectives. We want to talk about the diagnosis a little bit, just kind of reiterate that, because there's patients that are borderline, there are patients who don't quite meet the criteria, but they behave like it, and that sometimes is a challenge. We'll talk about recent advances in the epidemiology of this, because there's multiple studies coming out from countries around the world now that make this a bit clearer. And then finally, we'll talk about coming advances in managing this disorder, because the old-fashioned way of doing this, we still use that, because we have nothing better. And the one product that was approved by the FDA back in 2015 has been taken off the market for manufacturing issues, and there's no sign of when that's going to come back, hopefully within two years. But other products are coming, and maybe some of those will be available by that time. All right, so I'm going to present a case, and this is a typical case that I just took from my case files and, you know, thought it'd be useful to illustrate a few points. This is a 45-year-old patient who comes, and she's referred for evaluation of high bone density on the first time she had a bone density test. So the ordering physician, of course, didn't expect that, and was surprised to find that the T-scores were up in the range of plus three to plus four, quite a bit higher than just, say, normal and good luck with good genetics. So the question is, what's going on? The patient had not had fractures in the past, and she was healthy otherwise. She wasn't taking any calcium or vitamin D supplements at the time, because no diagnosis had been made yet. And she tends to exercise on a regular basis, and she's moderately active, and so she's doing all the right things, but she still has this condition. Now, she takes thyroid hormone, 100-microgram dose for autoimmune thyroiditis. So that's kind of a tip-off that says maybe this is related to the immune system or autoimmunity anyway. So here's her physical exam, height and weight were within normal limits. The basic physical exam was unremarkable. There was no anterior neck scar, which should be the first thing you look at if you're seeing a patient who supposedly has hypoparathyroidism. Not that you would conclude that yet, because you don't know that. But on the screening laboratory studies, trying to figure out why she's got high bone density, she comes back, and she has a low-normal or a low-ish serum calcium. And then, of course, when you ask about this, they volunteer information. They didn't tell you the first time they saw you, because they didn't think it was necessary or related to the bone disease. So she had had low serum calciums for a while. Records are always hard to get, but in the records we had, at least four to five years earlier, she had had this develop. She also had a serum phosphorus that was mildly increased or upper normal. That had also been the case over time with some fluctuation. As Dr. Wormer said, these things change minute to minute, even in this case. So it's not just the hyperpara that does it. It's this also. Now, her alkaline phosphatase was low-normal, 40 units per liter. And if you're a well-trained endocrinologist in this day and age, the first thing you think of is hypophosphatasia, because it's all the rage. Everybody knows about it. We get lots of questions about these people who aren't low enough or that low, but they're in the lower end, and so the question is, do they have it? Many of those patients will get tested, and of course, many of them turn out not to have hypophosphatasia. But that's another thing that this condition can cause. Serum creatinine was normal, no renal dysfunction. Serum 25-hydroxyvitamin D was low normal, 35 nanograms per ml. And our assay, 20 to 50 nanograms per ml is our normal range. PTH was checked, as it oftentimes is in the setting of bone disease, osteoporosis these days. And in this case, of course, it came back detectable, but lower than the normal range. So putting this together, everybody says it's got to be hypoparathyroidism. Her urine calcium also came back on the low end. And this is very typical in patients with hypoparathyroidism, not yet started on supplements. The trouble is, by the time we see them, many of them are on big doses of supplements. And then the urine calcium tends to run high. Some of them get kidney stones. All right, so let's advance. It's not advancing. Maybe it's because, sorry, let's try now. Still not advancing. Can you guys advance the slides? Yeah. It's not doing anything. Oh, boy. We might have to restart it. Which session is this in? This is this one. Let's not even give it an option. OK, do you know what slide you're on? Yeah, I was about to keep going. One back, two back now, I think. OK, all right, good enough. Thank you. All right, so the question that we were faced with is, what should we do? And the question is, what's the best way to treat the low serum calcium? And I've given you a number of options. I'm going to tell you, for time's sake, what I did. Many of these patients end up needing somewhere between 3,000 and 5,000 milligrams of elemental calcium a day in divided doses because they're that sensitive to the calcium. And it takes that much to raise their serum calcium levels up to the range you want. In this case, we said, let's start low and go up. And so we gave her calcium citrate, 600 milligrams, three times a day. The other choices are all reasonable things to do. And of course, sometimes as you go, you get into these other choices, too. But to start with, it made sense to give her calcium. She had not been on any supplements up until this time. So that's what we did. Now, the patient clearly has hypoparathyroidism. And this is what's leading to the high bone density without fractures. It's one of the causes of high bone density because of low PTH. There's low bone turnover. You don't lose bone density in general, although when you hit menopause, you can. And there are patients whose menopausal estrogen deficiency seems to override the lack of PTH on the skeleton, but not all. So some women do lose bone density after menopause. Some don't. Up until menopause, they don't, and men generally don't either. The laboratory studies were consistent with this diagnosis. Her serum calcium was mildly decreased. Serum phosphorus, mildly increased. And of course, that's the tip off for endocrinologists that this is what's going on. Urine calcium was in the normal range due to low calcium intake and low serum calcium as a result. When you supplement with high doses, of course, urine calcium goes right up. And you have to watch that because you can cause kidney stones in some of these patients. There was no evidence of hypo or hypermagnesemia. And this is a very important point because the first time you see a patient who you think has hypoparathyroidism, always check their serum magnesium. I can remember this and tell you this because I did this when I was a junior faculty member without checking the serum magnesium. And the patient was then referred, after I saw the patient, to nephrology. And they said, oh, it's got to be hypomagnesemia. And it was. And that explained all the calcium and PTH and phosphorus abnormalities. So if you don't think of it, you forget. But high or low levels can do this. And if they're normal, then, of course, it's not the issue. So given that the patient had not had neck surgery prior to this, as 75% of these patients do, we said, well, she's probably got autoimmune hypoparathyroidism because that's a fairly common cause. But she could have a genetic cause, too, that we don't know about. We didn't test her for genetic screening back then. And so you could do that, certainly, if you felt the need to or if they had syndromic features that made you think. Now, these are the biochemistries we expect. This paper published by John Belazekian was sort of back at the beginning of this modern era of treatment of hypoparathyroidism, summarizing what we expect. And the top three points, which are the expected findings, those are easy when they're there. Problem is they're not always the same or they're different or they fluctuate over time. What we don't usually check in these patients is what's in the bottom half of the slide. And I put that on there to see because sometimes these patients come in through the back door. They're referred for 125 dihydroxyd mutations or findings that make them think there's a vitamin D disorder. And it turns out that that's the tip off that they've got other things. And when you screen for these things, you find sometimes these other things. Bone markers are always low, for example. Even though they're not checked clinically. So the differential diagnosis is fairly limited, which kind of makes this an easier disorder than the one that Dr. Wormers just showed us of all those different types of primary hyperparathyroidism. This has got a more limited list. Some of the things on the list, though, are harder to figure out because we're not all medical geneticists. We don't recognize syndromes, certainly in adults who had pediatric syndromes, unless the pediatricians made the diagnosis. And so like Dr. Wormers does, I tend to use clinical genomics fairly often, if I'm concerned that there might be a potential genetic cause. But the other things are more common. Post-surgical hypoparathyroidism is responsible for about 75% of these cases. The other 25% have some other on these other versions. And of course, autoimmune is thought to be fairly common. Iron overload, when it's present, it's usually pretty clear because they have genetic background or have had treatments that would make you think of that. Copper overload, on the other hand, I don't think I've ever seen a single case I recognized. And probably that's true for most of us. But if you think about it, checking ceruloplasmin levels would make sense. And so these are the things you have to work your way through. And then, like I said, genetic causes, especially if there's a family history of this, which in some cases there are. So the clinical manifestations these patients always complain about. It's some variation on what's on the slide. There's usually mild to debilitating symptoms of one type or another. Most of these relate to nerve or mental functioning and psychiatric issues. Some of them relate to cramps and tingling paresthesias and things related. But this is a spectrum. And these people basically tell you the first time you meet them, I feel terrible most of the time. Maybe 80% of the day, I'm not functioning the way I want. I can't drive the car. I can't keep a job. I can't take care of my family, et cetera. And so we're stuck with trying to deal with sort of a multifaceted disorder with simply calcium and vitamin D intake. And as you can imagine, that sometimes works, but not very well for many of them. So things that occur, we talked about high bone density already. If this were an ad for an osteoporosis drug, you'd obviously pick the osteoporosis patient is on the right. But in this case, that's the normal patient. The bone density biopsy here on the left is showing a patient with hypoparathyroidism. So instead of having these rods and struts that's on the right side, what you see is more plates and plate-like structure that gives you the idea, this is very dense bone. And there's not much bone marrow space in there, although bone marrow disorders or deficiencies are not a common disorder in this case, as in other bone disease that affect children. What about the epidemiology? So we've divided this into the post-surgical. On this slide, we'll show you the non-surgical. On the next slide, you can see a number of studies produced from around the world, mostly in Europe and the US at this point. But there's studies coming from everywhere that show similar findings. In fact, the study by the Norwegians, Mary Astor and colleagues, showed a lower prevalence figure here than almost all the other studies do. But 20% to 25%, sometimes a bit more or less, is a common figure. Maybe a third to a half of what Dr. Wormer just showed us on primary hyperparathyroidism. So less common. Non-surgical causes, as you'd expect, are much less. They're a small percentage of the total. And these are the studies that we have showing that data. So you know it when you see it. What about mortality? Things that affect serum calcium and make it go down generally might be expected to cause cardiac and other things that would happen to kill the patient. In this case, it turns out most of the studies show no association with increased mortality except for two. And those are bolded in the red. One of them was from Tayside, Scotland. The other one, I can't see from this angle. But it was a well-done study, and they found increased mortality. So the book is still open on this because the initial study showed no evidence of increased mortality, despite all the things symptomatically that they have and their biochemical abnormalities. And yet two studies that were well done have shown increased mortality. What about the risk of complications? So we said earlier, these patients complain of many things beyond just calcium-causing muscle cramps and tingling paresthesias. They have a systemic disease that affects many things. Well, in studies mostly out of the Aarhus in Denmark, they have shown that a number of disorders are increased in patients who've got post-surgical hypoparathyroidism. But they're at least double that in the non-surgical patients. So even basal ganglia calcification down there in the bottom is much more common in the non-surgical patients than it is in the post-surgical. So things to think about when you look at these patients. And like you say, there's cardiovascular on there. There's seizures on there. There's other things on there that could increase mortality. But so far, they've not been convincingly shown to do that. Now, the management guidelines that have been published so far, we have a number of them, including an ACE disease state clinical review that was published back at the beginning in 2015. Want to acknowledge those people. I haven't seen an update yet. Doesn't mean it's coming or not coming, but it may. And then the European Society of Endocrinology has published guidelines as well. And then there's the international conference that was referenced in the talks by Dr. Severe and Dr. Wormers. So all of these are coming together. The common findings of all those guidelines are in the bottom half of the slide. And so the targets for treatment generally are to maintain low normal serum calcium. 8.5 to 9.5 works well for many patients, milligram per deciliter. Others get by with calciums as low as 8, or even sometimes lower. But that's where that's at. And then, of course, we try to maintain high normal to serum or slightly above that for phosphorus. Sometimes it's very difficult to get phosphorus to come down, but we try. And then, of course, maintaining serum calcium, sorry, urine calcium in a range that's acceptable on high doses of supplements, usually with calcium and calcitriol, vitamin D as well. And then finally, the calcium phosphate product should be kept less than 55 milligrams squared per deciliter squared based on renal data. This is from patients with chronic kidney disease. There is not a cutoff yet for hypoparathyroidism, although it's being looked at. And so it turns out, in most of the studies published, even less than 35 milligram squared per deciliter squared causes soft tissue calcification. So we don't know what that threshold should be yet. So here's ways in which we chronically manage these patients. All these things are pretty commonly used, and not a surprise. I won't go through the details of them. But the major burden of treatment is based on calcium supplements and high doses divided, usually. Usually, we typically give D3 or D2 plus calcitriol. And the reason for that is if you can't get calcitriol or it didn't fill the prescription, the insurance denied coverage, all of a sudden, blood vitamin D levels plummet if you don't have a precursor D2 or D3 level. So we maintain D2 and D3 as well as the calcitriol in the normal range. Thiazides can be used sometimes if the low salt diet didn't reduce urine calcium. It does work. Not a lot published on that, but that's also an option. And then, of course, depending on the phosphorus, you may have to use a low phosphate diet. All right, so in terms of how often to check various things, this is a table that kind of summarizes all that. The blood biochemistries we check more often. If you change doses or change therapy, typically three to four days later, you should be checking the blood calcium. If things are stable, you don't have to check blood calcium very often, six months to a year, even, if patients are stable on their doses and you're not changing it. On the other hand, all the other things that we know happen in these patients, it's not clear yet exactly how often they should be done. So clinical judgment is used in the imaging, both for stones and for basal ganglia calcification. And some of these things you would do more often, typically, based on clinical presentation. All right, so updated management based on the new guidelines that are coming. Alia Khan was the lead author on that as well. A number of us worked on that. But here's what is going to be in those guidelines. These are under review right now at JBMR. We just got the first reviews back. And things are being revised. They'll be submitted. And we hope, as the journal reviews things, that eventually, maybe by the fall, these will be published. They plan to publish them, both the hyperparathyroidism guidelines in one issue, and then the hyperparathyroidic guidelines in another issue, with all the supporting evidence, systematic reviews, and other things that are all part of this effort. So you'll see a lot of useful information in there. But you can see here that what we've talked about, basically, things are not changing much. And that's because there's not much evidence. Studies are being done, but this is a rare disease. Only a few centers do these studies. It takes a long time to accumulate data. And so what you can see on here is what we do clinically, probably now most of the time, some variation on that. And then here's the rest. So it's hard to read this from this angle, so I'll skip it. I'll let you guys read it. But there's not a huge amount of revolution in this in terms of what these new guidelines will have. But it kind of refines things based on the evidence that's been published. So my last slide here to summarize chronic hyperparathyroidism, it's a rare disorder. It's characterized by serum calcium and PTH levels that should be low simultaneously at the same time. There's another point. People usually will check calcium once. They find it's low. They check it a second time. It's low again. And then three weeks later, they check the PTH for the first time. And of course, sometimes the PTH isn't low because it fluctuates. And if you don't measure things simultaneously, you don't know that. So in this case, especially when we're checking things, we like to check everything at the same time. Patients with hyperparathyroidism, we've got multiple symptoms and complications caused by surgery. In the vast majority of these cases, a lot could be said about how the surgeons do a better job or should do a better job at doing this. But I can tell you, for having talked to surgeons as part of this guideline effort, it's a tough thing for them because these glands are small. There's other things in the neck. It's hard to know what's parathyroid tissue and what's not, and it's hard. So I am much more, say, lenient on my surgical colleagues than I would have been had I not known all the struggles that they face. But it's a big issue. Standard of care currently includes calcium and calcitriol supplementation, and then with magnesium methiazide diuretics as needed. And then finally, you can use off-label recombinant human PTH 1 to 34, teriparatide, but you're not going to get very far with the insurance paying for that because if they approve it, they typically require renewal every three months ongoing as long as they take it. And in the old days, they would say, these patients can't take teriparatide longer than two years. Well, the lifting of the black box warning by the FDA about cancer now opens the door that you can treat these people longer than two years if you have to. It's a struggle all the way, but this is what we're facing. At that very first slide where he said, there's a lot of companies making very creative products, and I think you'll be impressed as these things get rolled out over the next five to 10 years at the various national meetings. Lots of information, lots of ideas, and everything that diabetes went through to treat it is sort of being recapitulated now in this condition with the same logic and the same efforts to make this better. I think I am two minutes over, so I'll stop there and we'll have the panel discussion. Thank you. Thank you, Dr. Clark. I'll invite Dr. Wormers to join us on the stage. We have six minutes to take a few questions. Please come up to the microphone if you have any questions for our speakers. We're going to talk a little bit later on the new upcoming hypothyroidism medications that are coming on the market in the DSN bone review session this afternoon.

Parathyroid Symposium

primary hyperparathyroidism

diagnosis criteria

imaging techniques

clinical phenotypes

management guidelines

persistent hyperparathyroidism

experienced surgeon

intraoperative parathyroid hormone measurement

hypoparathyroidism

calcium supplements