Primary hyperparathyroidism affects 1% of the US population and is commonly under recognized and underdiagnosed. In this case based panel conference, experts from across Penn Medicine discuss current recommendations for diagnostic evaluation and clinical decision making with a multidisciplinary team of experts. We also cover the management strategies for hypoparathyroidism, a less common and important condition. Key takeaways are easily applied to your clinical practice. Note CME credits are no longer available for this recording.
Good morning. Hello everyone. Welcome to the CMI approved webinar sponsored by the endocrine disease team at the Abramson Cancer Center here at Penn medicine. Today we will focus on parathyroid disease which presents an opportunity for a robust discussion regarding management options for primary hyper parathyroid ism including diagnostic evaluation, surveillance and indications for surgery. In addition to raising awareness of key management strategies for patients with hypothyroidism, a less common condition. My name is Heather Wachtel and I will serve double roles today as the moderator and in my professional role as an endocrine surgeon. I am joined by four fantastic colleagues whose disciplines represent the multidisciplinary collaboration essential for care of the patient population. First from primary care and dr martin Pfeiffer from nuclear medicine dr Sophie O'brien and from endocrinology. Dr Amna Khan and Deepika Pradhan. Together our goal is to define and review the approach to a patient bound to have hyper parathyroid is um with it which is both evidence based and patient centered. We will focus on the initial diagnostic evaluation and surveillance and treatment options as indicated by the course of disease. We will address the issues that are related to the role of imaging in the planning of treatment. We will adjust other less common variants of primary hyper parathyroid is um including the so called normal hormonal and normal calcium IQ variants as well as the less common clinical condition of hypothyroidism. This webinar will discuss and highlight points of care relevant to the management of these patients across their care team because our focus is on management decisions. We will be sharing three clinical vignettes and verbally providing them. The pathology and radiology results are vignettes will include a common patient presentation. Normal hormonal primary hyperthyroidism and hypothyroidism. These are our speakers today. Um My colleagues dr khan Pradhan O'brien and King of Pfeiffer and our learning objectives today are to review the diagnostic evaluation of hyperthyroidism and hypothyroidism to discuss an evidence based approach for decision making for surgical intervention versus surveillance and to illustrate key management strategies for patients with hypothyroidism. We have no disclosures. This webinar is live and will be conducted as a panel discussion at any time. During the Webinar. You can submit questions using the chat box. Please feel free to send to all. We have reserved 10 minutes for questions at the end of the session. This session is being recorded and a link will be available for future listening. So we're going to start with our very first case here Today. A 65 year old woman presents to her primary care physician after a recent emergency department visit for a low impact risk fracture On her basic metabolic panel. She is found to have an elevated calcium at 11.1 mg per deciliter. On review of her prior biochemical testing. Her calcium level has been rising over time from 9.8 mg per deciliter. Two years prior to 10.3 mg per deciliter last year. Her creatinine is normal. Her past medical history is significant only for hypercholesterolemia On one medication. I'm going to put our first question to dr Pfeiffer to marty here, marty. Could you please take us through your evaluation when you first see this patient with new onset hyper calc mia and a fracture. What's your most likely diagnosis? Talk to us a little bit about the symptoms that your your patients come to you within your diagnostic evaluation. Sure heather thanks so much and thanks so much for having us here. We really enjoy um this experience. So this patient has a fragility fracture and because of her fragility fracture, she'll meet the diagnosis of osteoporosis. Um remember we diagnosed osteoporosis by the presence of a fragility fracture and they're commonly in the vertebrae, like a stress fracture of the vertebrae, the hip, the risk, the humerus, the ribs or the pelvis, or it could be diagnosed by a bone density with less than 2.5 less than or equal to 2.5 standard deviations from normal. Uh we want to explore why she has osteoporosis at the age of 65 and the emergency department helped us out a lot, as they often do by revealing that her elevated her calcium is elevated. And that would make us concerned about primary hyperthyroidism related to her her osteoporosis. So I would want to learn more about her risk factors for osteoporosis as well as her risk factors for primary hyper parathyroid is um and be sure that we evaluated her thoroughly so that we could address all of her risk factors. So, in her medical history we would look for um concerns such as malabsorption, history of bariatric surgery, spruance, inflammatory bowel disease, chronic conditions like rheumatoid arthritis, hyperthyroidism, hyperthyroidism and diabetes. And then we'd also ask about concerns or conditions related to hyper parathyroid is um not knowing from the emergency department and her prior records that her calcium is not only elevated but it's also on the rise. So we I usually added um probably from medical school of bones, stones, groans and moans. Some things just never go away. Um so I would check on kidney stones if she had abdominal pain, headaches and then her just her general sense of wellness. Um, I would also ask about our family history of the same because oftentimes that can be revealing, um you mentioned that our patient is only treated for hypercholesterolemia. Sometimes people don't tell us about over the counter medications such as proton pump inhibitors for ulcers. And then also sometimes people don't tell us about their historical medications, such as recurrent steroids for asthma or um, you know, rheumatoid arthritis or any of the conditions that people might have. So I would specifically ask about her over the counter medications as well as historical medications and and in particular with osteoporosis. We want to know about her social history, um does she smoke, does she drink a lot of alcohol. Um and her level of activity if her level of activity is low that sometimes can be revealing. I'd want to go a little bit further and ask her why her level of activity is low on her physical exam. We would pay attention to our vital signs of course. And in particular we'd be interested in a person that has a low B. M. I. Since that also is is a risk factor for osteoporosis. Um We know that we could we'd review the labs from the emergency department and then my checklist would be to make sure that any of that weren't done would get done at the time that I get to see her. So we believe she had a BMP because her kidney function was found to be normal, we would check her glucose and considering a one c if she either had risk factors for diabetes or if it were elevated at that time. And then the other test that I usually do when a person has osteoporosis would be her thyroid function test, make sure her liver functions okay her vitamin D. Level, her parathyroid hormone and I usually get the BMP at the same time. Um Because we're making this diagnosis based on a fragility fracture rather than their texas scan, I would want to get a texas scan if one hadn't been done in the past two years. Um And then naturally since she has lost your process will begin to treat her while we continue her evaluation and most commonly we treat them we treat with this Austin eight. Great. Well I'm gonna happen right there. Thank you marty. That was a really fantastic overview. Um and very helpful particularly to consider the differential diagnoses which you look to rule out or rule in in the initial evaluation. I'm gonna ask you a little bit more. You know if you're looking at things from a really comprehensive perspective um What are the what really is then your threshold for um you know referral on what are some of the red flags that you consider? Things that need to have additional testing or diagnose diagnostic valuation at that point. Well for this patient once we get our p th she'll probably end up being referred. So I can I can pass the Topeka because we're I can see that the p th if you like me to reveal is 200. Um And her she also has vitamin D. Deficiency with the vitamin D. Level of 20. We have the fastest lab in the world. So we're lucky that way. And I wonder if I can pass to Topeka and she can help us from there. Yes. So so for this patient we're gonna have the world's most straightforward patient to start out with. She has no other medical comorbidities. Her biochemical testing is going to show that she has hyperpower thyroid is um so her P. T. H. Is 200 picograms per ml. Um She has moderate vitamin D. Deficiency. Her 25 oh. H. Vitamin D. Is is 20 with a normal being 30 or above. So typical. What are some of the common causes of secondary hyper parathyroid ism that you see particularly in the ambulatory population. What are your what is your strategy for repeating vitamin D. Deficiency? And the hyper calcium impatient. Sure heather thank you so much for organizing this. It's a pleasure. So um in terms of causes of secondary hyper parathyroid is um well in secondary hyper parathyroid is um the parathyroid glands are doing what they're supposed to do which is basically defending your body against hyper calc mia. So hyper calc mia is one of the important trigger for parathyroid hormone secretion. So any condition that can lead to hyper calc mia in your body, whether that is chronic dietary deficiency malabsorption conditions like celiac disease, inflammatory bowel disease recently um gastric bypass surgery or any surgery that involves the terminal intestine affects the absorption of calcium can lead to hyper calc mia. Which in turn will trigger parathyroid secretion causing secondary hyper parathyroid ism. Otherwise if your body is losing too much calcium like we would see in renal calcium wasting idiopathic hyper calc area you can have second secondary hyper parathyroid. Is um from that now vitamin D plays a very important role in regulating calcium uh if you remember vitamin D. Is converted to active vitamin D. 1 25 D. In your kidneys and then 1 25 D. Is gonna help you absorb calcium from your gut as well as bowels. So if your vitamin D. If you're deficient in vitamin D, you lose that function and that in turn is going to lead to hyper calcium in your body and that's going to trigger parathyroid hormone secretions. So therefore vitamin D. Deficiency is a very important cause of secondary hyper parathyroid is um now in chronic kidney disease, you're not able to convert your vitamin D. To 1 25 vitamin D. And therefore again similarly you would see elevation and parathyroid hormone also in CKD, you're not able to excrete your phosphate. So hyper foster Tamia being a second important trigger for parathyroid secretions. So these are common conditions where you would see secondary hyper parathyroid is um I should also talk about magnesium. So magnesium deficiency. Remember magnesium is important both for parathyroid hormone secretion and action. And if your magnesium deficient you can have parathyroid hormone resistance. So often magnesium deficiency can lead to secondary hyper parathyroid is um some medicine that can cause secondary hyper parathyroid includes loop diuretics bisphosphonates and denosumab rare condition that can cause secondary hyper parathyroid is um are 25 hydroxy deficiency. One alpha hydroxy deficiency environment. The resistance. So these are the list of secondary causes of hyper parathyroid is um now coming to vitamin D. Deficiency. So our patient has elevated parathyroid hormone and high calcium. So this poor patient likely has primary hyper parathyroid ism but also has vitamin D. Deficiency. So remember we just talked about how I how vitamin D. Can cause secondary hyper parathyroid is. Um so the concern is is that an overlap of secondary hyper parathyroid is um on top of primary hyper parathyroid is. Um So when you have vitamin D. Deficiency that we know that especially in hyper calcium IQ patient uh you find aggravated disease increased bone turnover markers, reduced bone mineral density and there's an increased risk of post operative hyper calcium a in this patient group. So we obviously favor vitamin D. Replacement in this patient. Now initially at least we had some concerns about worsening hyper calc mia and hyper calc area and patient uh we're we're hyper calcium IQ. And vitamin D. Deficient with vitamin D. Replacement. But recently multiple studies um and now a meta analyzes which included 10 studies and over 300 patients were studied were hyper calcium IQ. With different level of vitamin D. Deficiency and different doses of vitamin D. From 800 international units which is considered very low to a robust dose of 50,000 weekly dose was used and the study so that there was no worsening of hyper calc hyper calcium in these patients. So this tells us that we can safely replete vitamin D. In our hyper calcium patient as well. That's a great point there I think that's really worth emphasizing because we see this a lot. You know from the surgical perspective is there's there's a little bit of uncertainty about whether vitamin D. Should be stopped, whether it should be repeated. So could you just summarize for our audience what your your practice pattern is for those patients who have common and vitamin D. Deficiency and primary hyperthyroidism or suspected primary hyper parathyroid is um Sure. So based on vitamin D. Level, if the patient is severely vitamin D deficient, say their vitamin D. Levels below 10, then um I usually prescribe higher strength of vitamin D 50,000 weekly to achieve vitamin D. Level of 30. Now we obviously measure their uh we follow the calcium level uh in patients who are hyper calcium especially above 12 I might be slightly hesitant to give higher dose and might do a moderate dose. But for most patients who are between 20 to 30 I give them about 2000 to 4000 units. For a patient above 30 I use the maintenance dose about 1000 units daily. Um So that's what I use in my practice heather. That's fantastic. Thank you for sharing that. Um As a follow up question for this, you know, the concern is that you may precipitate hyper calc mia or worse, you know, a hyper calcium. It crisis are in in the unlikely event that that something like that would develop or you know something else precipitates severe hyper calc mia. Are there medical therapies that you would use potentially for temporary control of hyper calc MIA. So in the setting of vitamin D. Deficiency, if you notice that their calcium is trending up of course you want to lower your vitamin D. Uh make sure the patient is staying hydrated often. It's recommended that they drink at least 6 to 8 glasses of water. Um Now if the hyper calcium is worsening with primary hyper parathyroid is um then we will we will use a group of medicines called calcium a medics. The most common one is the cynical set. These medicine mimics calcium and works through the calcium sensing receptor activates them, reduces parathyroid hormone secretion and therefore improves their parathyroid hormone level and calcium level. So sometimes pre operatively we might use the medicine uh does is the medicine is called that's a brand name. Now we have generic available. So cost wise it is much better. Previously we're worried about the cost of censorship are often I would start with 30 mg dose and then I will check their calcium again in about a week and then based on the calcium response, I can titrate their sense of our great well that's a fantastic clinical parole. And I think it's also worth mentioning that this is a temporary. The calcium a medics are temporary. Um and not a lifelong medication as they would be for in stage renal. Uh secretary hyper parathyroid is um So we're gonna come back to our patients? So our 65 year old patient with a fragility fracture, as marty had called out earlier, one of the most important parts of her evaluation is going to be a Texas scan. So the texas can that marty orders shows severe osteoporosis with the lowest score of minus 4.2 in the distal radius. Um For for ana. Um can you please discuss for us the patterns of bone mineral density loss in patients with primary hyper parathyroid is um When do you order four? Armed X. In addition to an axial Dexia and maybe talk a little bit about your strategy for treating bone disease? Thank you heather and thank you for including me in this very fun webinar. Actually I'm really enjoying heading the going through this flow. So let me tell you a little bit about parathyroid and bone hill. So we know that fracture risk is increased in patients with primary hypothyroidism at the vertebral and non vertebral sights. Hence the bone density assessment with the Dexia is routinely recommended for all patients for the past decade. As you may have seen from the workshop from the fifth workshop for primary hypothyroidism. Asymptomatic primary hypothyroidism. A T score of minus 2.5 at any of the three sites which includes lumber, spine, hip and wrist and or a vertebral fracture has been considered as one of the surgical criteria. Now as we review the patterns of bone loss and primary hyper parathyroid is um please note that the spine is predominantly a counselor or Trebek collarbone while risk comprises mostly of cortical bone and the hip is a mix of cortical and Trebek collarbone. Now P. T. H. Is known to be cata bolic to the cortical bone. Hence the greater bone loss as seen at the wrist. As you can see in this study as well, lumbar spine primarily composed of Trebek labone is generally preserved by the decks and primary hypothyroidism as seen in the decks. A studies in hyper parathyroid patients. Um An opposite pattern is seen in postmenopausal bone density loss. So as you can see in this graph over here as well, um over time there's lots of radios presents with the lower bone density as compared compared to the other sites. But this is all based on the B. M. D. And dexter studies in this population heather next line. So despite data showing preservation of kinsella's BmD by bone density, metreon, primary hypothyroidism. Several studies now indicate an increased risk of vertebral fractures in primary hypothyroidism. We've actually learned a lot from new imaging techniques such as the high resolution peripheral quantitative demography Trebek labone score that is achievable from Alexa which has provided insight into this paradoxical increase in vertebral fracture risk and primary hyper parathyroid despite relatively preserved BmD by Dexia. So by these new studies, these new high resolution pacific you cities, women with primary hyper parathyroid conditions demonstrate decreased Rebecca and cortical volumetric densities, they have thinner cortex is as you can see in the second diagram over here and more widely spaced Rebecca at both radial and trivial sites confirming the involvement of the Tribeca labone as well. So these studies appear to be more representative of the schedule features in primary hyper parathyroid than the dexter and the translate bone biopsies. Tribeca labone score. I just wanted to comment a little bit about that. It's it's a it's a qualitative assessment of the spine that is achieved from texas. Um It is available on most of the decks is at penn sites. Um And it's an add on software to the decks. A so if anybody in the audience has a deck sir, with the Tribeca ball has not been added, you you should be able to request through radiology for the software to be added. So as a Tribeca labone score, several studies have shown that they correlate with the skeletal abnormalities and primary hypothyroidism, presence of vertebral fracture was associated with the tbs of less than 1.2 in some studies. However, not all studies have confirmed this association which is why we can't use Trebek labone score alone in making our medical decisions to answer heather's second question as to when do we consider a risk? Exa it should always be considered based on the C. D guidelines in a hyper parathyroid state in very obese individuals exceeding the weight limit of the decks. A table because of the impact of fat mass over the bone bone mass that is being analyzed. And if hip or spine cannot be assessed or interpreted, uh answer the third question. My strategy for treating this bone disease. Well, I would always I'm a proponent of surgery if the patient is able to undergo surgery. And of course if no contraindications, knowing that significant bone density gains post para thyroidectomy, especially given the low surgical risk when referred to a high volume surgeon. Long term follow up of individuals with primary hyper parathyroid without intervention comes from a 15-year observational study evaluating about 57 patients in which they reported that spine bone density remains stable while significant bone loss occurred at the distal radius and femoral neck after eight years of follow up um A longer randomized control trial conducted in mild asymptomatic primary hyper parathyroid also showed a significant decrease in bone density at all sites except the lumbar spine. After five years, with the corresponding benefit of para thyroidectomy and bone density at all sites except for the radius. New vertebral fractures have also reported if we take the observation route. So para thyroidectomy provides skeletal protection. However, the natural history of this condition appears to indicate relative skeletal stability. However, my strategy is that if somebody can undergo while they're at at a younger age and they're in good surgical condition. Um I would be favorable for proceeding with surgery. Great. Well, fantastic, thank you so much for that really. Um Fantastic overview and I know your expertise is in bone mineral density loss and you could probably give us a full hour's lecture just on this area. Um I think that you bring up a couple of really important points about the cross sectional imaging here and some of the new imaging modalities. We're really fortunate to have Sophia o'brien with us who is a expert in nuclear medicine and radiology and Sofia. Can you you talked to us a little bit about the role of cross sectional and functional imaging now in this patient with a known diagnosis of primary hyperthyroidism and if you can particularly comment on the the risk and the benefits of the different types of imaging modalities, that would be fantastic. I would love to. And I also want to extend my thanks for including me in this webinar. Um so I'll give a brief overview of the most commonly used imaging modalities and patients with primary hyperthyroidism. Um Although primary hyperthyroidism is primarily a clinical and biochemical diagnosis, imaging is key to the localization of parathyroid adenomas which can lie in conventional locations adjacent to our posterior to the thyroid or less commonly in ectopic sites anywhere throughout the macromedia steinem accurate localization of the hyper functioning parathyroid adenoma facilitates the use of minimally invasive or targeted surgical approach. Standard of care for imaging in the United States includes ultrasound a nuclear medicine system. Maybe scan and or four D. C. T. Ultrasound is inexpensive, readily available and free of ionizing radiation sensitivities for single gland disease range anywhere between seventies and 89%. But these are affected by the operator. Ultrasound is a very operator dependent examinations. You want to go to an expert center. Normal parathyroid glands are small and flat and usually not well seen. Um So an easily visible parathyroid gland is suspicious for underlying disease. Abnormal glands are typically hippo coke as we can see here posterior to the thyroid. We have this um ovoid structure which is hip ochoa compared to the adjacent thyroid tissue. Um Thank you and can have a well defined hyper ochoa capsule at times. Cystic degeneration can also be seen. Um Ultrasound can simultaneously depict thyroid nodules which may mimic parathyroid adenomas or may actually represent intra thyroid and parathyroid adenomas. Um And then ultrasound guided FM. A can be performed in these nodules with parathyroid hormone testing to evaluate them to see if they are an intra thyroid uh intra thyroid parathyroid adenoma. Good Lord. Um switching to the nuclear medicine side of things technician 99 access to many um is a radio tracer which accumulates in mitochondria rich cells including myocardial cells malignant cells and in overactive parathyroid glands. Um technician 99 testimony has increased and prolonged uptake in parathyroid adenomas compared to its uptake in the adjacent thyroid tissue and this forms the basis of what we call dual phase imaging. So here we see on the left side images from the early phase which was performed about 10 to 30 minutes after radio pharmaceutical administration. And on the right side of the supremacy delayed phase imaging which is performed about an hour and a half or 2.5 hours later. And if you click this side I should have arrows popping up hopefully. So we can see that there is accumulation on the early phase. In this midline area. We see gland accumulation above and we see a little bit of thyroid accumulation below. And then if you click again on the delayed imaging that thyroid uptake, there's the thyroid, the thyroid uptake washes out and we see persistent uptake in what is apparently a parathyroid adenoma posterior to the thyroid gland we have in common in cT imaging to help with localization and we can see in the bottom right corner, I'm sorry, these are a little too small. Um but we can see that there is an avid lesion posterior to the thyroid gland. In keeping with the parathyroid adenoma. Um in a meta analysis that pooled sensitivity of technician 99 and testament respect for single Gland disease was about 79% compared to the sensitivity of ultrasound. In that study of approximately 76%. Another study demonstrated that pool sensitivities of spect ct, the combination of the functional radio tracer with a low dose ct for anatomy approached about the mid 80% for sensitivity. And at penn we would always do a spect ct for an atomic localization. Um Another study identified that the combination of ultrasound and spect ct with the system and the radio trace or improve sensitivity overall as compared to ultrasound. The system, maybe nuclear medicine scan can depict potential ectopic sites because we can image from the base of the head down to the upper media sign and really this one goes to the upper abdomen so we can see ectopic parathyroid glands anywhere from the angle of the mandible down to the media steinem. Alright. And our final imaging modality that we typically use is something called four D. C. T. This is a three phase imaging protocol of the neck. We have a pre contrast phase and early arterial phase and a delayed venus phase. And the fourth dimension of this is time enhancement patterns throughout these phases. Act as a surrogate for perfusion and parathyroid adenomas are very vascular more so than thyroid nodules or lymph nodes which can be mimic ear's of parathyroid adenomas. On imaging a classic adenoma will show enhancement greater than the thyroid on the arterial phase. Um With washout on the venus phase and I think if we click we'll see some arrows pointing to this very small structure again posterior to the thyroid. This one is medial to the carotid artery. We can see very strong enhancement on the arterial phase and then that enhancement very quickly washes out on the delayed phase. The effective radiation dose is higher with 40 CT than with the nuclear medicine system OBI scan. And more of the dose goes to the thyroid gland than in the nuclear medicine scan. In a small study, 40 Ct had higher sensitivity for single gland disease, approaching the low nineties compared to mid seventies or eighties for system OBI scans. And then next slide um one additional benefit for ultrasound. In addition to identifying possible intra thyroid parathyroid adenomas, we can just perform assessment of the thyroid gland itself and assessment of any thyroid nodules because if there is a suspicious bilateral intra thyroid nodule, we You can further characterize it before surgeon goes in um to remove the parathyroid adenoma. So this is an example of a patient with primary hyper parathyroid is um I'm actually showing a tie rods for thyroid nodule here, which would typically have continued to undergo imaging um follow up because it is less than 1.57 m in size but greater than 1.1 cm. But since this patient was already planned to undergo a para thyroidectomy, um the decision was made to sample this nodule. It came back as follicular neo plasm and the surgeon was able to both remove the parathyroid adenoma and do a very easy nuclearization of this particular neo plasm in the same surgery. Great, thank you for that. Really thorough overview. This is it's always exciting and fantastic to hear about all of the new technologies? I think it's worthwhile to note that practice patterns differ and the availability of these studies may be different depending on the local center. And so people will often use a combination of different studies to achieve the desired results. I think it is worth reiterating that the diagnosis here was a very clear biochemical diagnosis. And so the imaging is fantastic for operative and management planning, but it actually doesn't change that biochemical diagnosis. Um, so this is this is purely uh icing on the cake as it were. That's a great point. Whether I wanted to quickly mention typically when I'm doing nuclear medicine and radiology imaging, I want to be very, very certain about my impression and my assessment of what I'm seeing for this case. I'm a little bit different in how I approach. And particularly for me when I'm reading assessed, maybe scan any inkling of a possible parathyroid adenoma is enough for me to raise. Like make me take extra care to look at, you know, the left inferior lobe because I know a surgeon is going in anyway, so I can only help the surgical search. Um, and so it's a slightly different, like you said, we're kind of the icing on the cake here rather than extension. The diagnosis. Thank you. Great. Um well, we'll put our next question to Deepika, you know what we know that this patient has a diagnosis of hyper parathyroid is um we have now some imaging to suggest that we may have a parathyroid adenoma. But when is surgery really indicated? We've talked a lot about para thyroidectomy. What are your general indications for surgery? And when do you alternatively consider surveillance? Thank you heather. If you don't mind pulling up the slide with the guideline? Thank you so much. Uh so this is the guideline that was published in journal of bone and mineral research fairly recently, August of 2022 on the very right corner. You have the indication for parathyroid um surgery. Um so which I'll be going over. So if your calcium level is greater than one mg per deciliter, your upper limit of normal, which is usually 10.3 in our lab. That is one criteria to consider surgery. Now you don't have to meet all these criteria. If you meet just one criteria, you will be a candidate for surgery. The second one is of course skeletal indication which is osteoporosis based on t score of negative 2.5 in lumber spine, femoral neck or distal one third of the radius or a vertebral fracture. By imaging. Um uh An estimated G fr of career than sorry, less than 60 per minute. Again a lot of patient might have their G. F. R. Less than 60 for different reasons like diabetes. But the thought behind that is if a patient has primary hyper parathyroid is um and their G. F. R. Is already lower irrespective of the ideology. I mean this patient is at high risk of developing kidney stone infection. Need for procedure which might further decline their G. F. R. So this is the criteria uh If they're 24 hour urine calcium is over 2 50 in women and over 300 men. Now this is somewhat different from our previous guideline um which was which gave the cut off of over 400. Um And then the second one is of course a kidney stone network al cyanosis which is basically calcium deposits in the kidney tissue. Um Either by X ray ultrasound or cat scan. The is has not changed throughout this period with the guideline which is less than 50. So now if you go back to our case, this patient is 65 years old woman so is wise is not meeting criteria for surgery. Uh See her calcium level was 11.1. It is elevated but not quite over one mg per deciliter cut off range. However, in this patient with T score of negative 3.4 um in her radius that definitely meets the criteria. So in our patient facility factor and osteoporosis would be the indication for surgery. Now. Um coming to your next question, when would you prefer surveillance over referring someone to surgery? So parathyroid surgery offers cure. So I always have this discussion with the patient that even if you're not meeting criteria for surgery, they might opt for surgery because it offers cure. Some people who do not meet criteria for surgery for example, um If their bone density is an osteo Penick range, but they have been declining over time or their calcium has been high but not quite one mg per deciliter of arrange. These patients can still choose to go for surgery. Um Similarly, patients who are meeting criteria for surgery but do not want to go for surgery either for medical region or personal choice. Um They might prefer to just undergo surveillance or medical management. So it's a shared decision making heather. But usually, I mean for these patients are meeting guidelines would recommend that they go for surgery. Great. Well I think that's a really excellent summary and there and it's important to emphasize that it is a shared decision making. You know, the emphasis of this webinar is really on the management um and decision making. So we're not gonna spend a lot of time on on the surgical approach. Um However, I do like to emphasize with all my colleagues and I know everybody on the panel knows this is that the parathyroid surgery is a very short and very safe um Uh surgery which can almost always be done as an outpatient based on patient comorbidities. Generally speaking, it takes about an hour. It is under general anesthesia. We make a small incision in the neck and remove any abnormal parathyroid Gland or glands. And about 85% of cases. It's just a single bland. We hear a pen are very fortunate in that we have a lot of inter operative adjuncts that we can use if we have a missing or or non localized parathyroid glands, glands. Uh So some of the tools that we use in addition to you know expert training are going to be inter operative ultrasound, inter operative parathyroid hormone monitoring so that we know that we can achieve biochemical cure on the day of of surgery um nerve monitoring as as uh it's indicated. Um and additionally if we need to we can do parathyroid jugular venous sampling. So we have a lot of interactive adjuncts that we can use. Our pathology colleagues will often offer us frozen section or quick look pathology although this is almost always benign disease, it's often very reassuring to patients. Um and typically the cure rates for parathyroid surgery are excellent. So those range from 98.5 to 99% And most patients will do very very, very well with this with this surgery, one of the major considerations that we do have is there peri operative management. All patients who have a pair of thyroidectomy are then going to be at risk of developing postoperative HIPPA calc mia. Typically this can be transient but in order to prevent or to or to cushion this, we will often place them on a temporary calcium replacement and or vitamin D replacement after surgery. There are certain patient populations which are at higher risk of developing hungry bone syndrome. And my colleagues have commented a little bit on folks with bone disease. And so that's always an important discussion to have with the referring provider, either the primary care physician or the endocrinologist. And so I think that in the interest of time we will actually then talk about the with the postoperative management, particularly the patients with bone disease. I do note that in the chat we have a couple of questions about secondary and uh primary hyper parathyroid is and the differential diagnosis and we will address these at the end of the session. Um So in terms of the bone disease for omni, before we move on to our next case, can you comment on how you follow patients after a successful para thyroidectomy? Absolutely. Um so basically biochemical work up. I just quickly comment on that. I'd like to see patients at four week follow up just to ensure that they don't have hypoglycemia and their vitamin D. And the vitamin D. Levels are optimal as well. I do like to check p th at that time because that kind of gives me a roadmap as to a resolution of para thyroidectomy or you know, what am I forcing generally, if there are any stunt lands, they will recover by six months. The next follow up would be at four or six months. I will check a cmp vitamin D. N. A. P. Th only if it was abnormal at four weeks and then I would just if everything looks stable. Vitamin D calcium all looks in the optimal range. I just do annual follow ups with the cmp vitamin D. P. Th, maybe year one if and then just annually if they have underlying bone disease for which I'm following them as well. Now, when do I recheck? The decks are for patients with severe bone mineral density loss. The decks a decision is basically based on the pre surgery dexter age of the patient severity of the disease, absence or presence of additional risk factors below BmD and high fracture risk first. So keep in mind that the patient population that we see in our clinic, a lot of them have the traditional risk factors for low bone density as well, such as post menopausal caucasian females. These are like very typical scenarios that we see in our clinic. Um um Men with osteoporosis may have history of prostate cancer. Previously treated with androgen deprivation therapy. So they're they're relatively frequently. There will be traditional risk factors as well. However, for example, in a 40 year old premenopausal female with a normal bone density, I will not consider repeating till she's menopausal. On the other hand, if I have a postmenopausal, female age 70 with a pre surgery T score of minus 2.5 or less or osteopenia with a fragility fracture at one year. I would like to check her bone density change to see what the improvement or worsening has been. Generally I would I would expect an improvement in a bone density. Um And then if somebody has normal bone density we can make decisions for longer interval for bone density assessment. We know from several studies that bone density increases after para thyroidectomy. As you can see in this in these two studies which were one was like a 10 year study and 14 year follow up as well. And these have been confirmed by short term randomized trials as well as these long term observational data. A cumulative increase of about 12% at the lumbar spine and femoral neck have been reported and known to sustain after for many years after para thyroidectomy. So factors leading to significant bone density increases are considered to be severe disease, young age, good renal function. And I would like to reinforce a point here that the same decks A facility should be used to do the follow up texas because otherwise if they're going to different texas, I mean you really cannot make a comment or a decision on you know what the bone density changes are. So it's very important that they go back to the same decks a facility and ideally to the same machine and ideally to the same tech but which is kind of hard to control. But at least the same decks a facility. And just as for people at penn I mean none of the machines across deliberated. So if somebody is getting the decks at Radnor you please send them back to Radnor and not to Pearlman. Um So we did have a few cases during the pandemic when people could not access the Pearlman dexter or so they were being sent to P. Mark or they were being sent out to red. Now we had to like make special requests for them to go back and do the decks is at the same facility. So again even within a system um please ensure that you know they're going back to the same text facility. I think that's an important parole is is the cross calibration. Um Sophia can you comment a little bit on how the texas scores? How the scoring system for dexter scores are actually calculated. Sure. And I'm also going to address a comment that came up questioning timing for the three modalities that I talked about previously Just to reiterate the technician 99 M. System IBI scan has the dual time points. The second time point being about 2.5 hours after radio pharmaceutical administration. So that imaging study probably takes about three hours plus the check in and wait time and check out time um versus an ultrasound. Is your checking and wait time. But the scan itself is probably closer to about 20 minutes and then a four D. C. T. Is the scan itself is probably just within minutes um With administration of I. V. Contrast. Uh So now going back to Dexia, I'm just going to. So dual energy X ray absorption geometry. Um It's an imaging test that measures bone density in the mineral content of bone. And we know that decreased mineral density over time increases of patients risk for fractures. It uses there's two types of low level X. Rays to measure density. Um And again to reiterate unlike normal X ray machines. No two decks and machines are the same. And so it is very important that patients go to the same exact machine that they were previously measured on if at all possible. Most patients loved X. A. Scans performed on their hip or spine. But studies have shown that patients with primary hyperthyroidism have the lowest decks. A score T. Scores you score in their forearms. So patients with primary hyperthyroidism where most were taking very close consideration of their radius um scores and there are two scores that this machine will sit out. It'll tell us the T. Score which compares the patient's own density to that of a healthy young adult. This is used in post menopausal women and older men. There's also a Z score which compares bone mineral density to those of people of this patient's same age sex and size. Um This is typically used in Children, premenopausal females, younger males essentially anyone who is expected to have a normal bone mineral density and that their age appropriate cohort, would I also have a normal bone mineral density from the majority of patients that we see. Typically postmenopausal women, we focus on the T score and we can click to the next slide actually because they're normal cohort also probably also have abnormal bone mineral cortical density and so comparing to age appropriate um Cohort is not going to be the most useful in evaluating and assessing their frisk fracture. So, as was mentioned before, the T score, postmenopausal women, anything less than one standard deviation from the young healthy mean is considered osteopenia and anything less than 2.5 standard deviations away as osteoporosis. And then looking at the score, if we had a premenopausal woman, a child or a younger man, anything below two standard deviations away from the mean is below expected for their age range. Uh that's a great overview, I think that these are always challenging to incorporate, particularly as you're looking at different age populations. Um so as we focused to our next case, we've covered a lot of the primary management principles and all the understanding of primary hyperthyroidism. We now want to consider an alternative scenario here. So instead of our our 65 year old postmenopausal woman presenting to the emergency department, She's actually coming into the her primary care physician for her annual physical exam on her routine, annual basic metabolic panel. She now has new onset hyper calc mia. This is relatively mild at 10.9, she had been 9.82 years ago and 10.3 last year her creatinine is not normal. Um for dr uh Pfeiffer she actually checks the parathyroid hormone level and finds that this is actually inappropriately un suppressed. At 55 picograms per ml. With a normal range being 14 to 65 her vitamin D level is normal marty. How do you discuss these results with a patient? What is what is your diagnosis? What's your differential diagnosis And when do you perform additional evaluation for this patient? Thanks heather. This is a really common challenge and independently. And without regard to age, the p th and the calcium could be completely normal. But together they're not normal. Um In this case the calcium is actually a little bit high, patients grasp this sort of inverse relationship really well. More commonly. I explained this in the context of hypothyroidism and I appreciate the naming of the thyroid stimulating hormone because it helps me out a lot in the explanation. Um So it makes sense that when the thyroid hormone falls or I'm not giving them enough supplement, then the TSH will increase. And when there's too much thyroid hormone, the thyroid stimulating hormone will decrease. Parathyroid hormone doesn't help us out with the naming quite as much but it's the same sort of relationship. So if the calcium is high, I explained to them that the parathyroid hormone should be lower because they don't need the parathyroid hormone to increase the calcium. Which is more of its like direct relationship. But if there's too much calcium with their customers on the high end and particularly for a person of that age, then we would really expect the p th to be lower. So in their situation while the lab printout might say that it's normal um that it really isn't normal together. Um There's the Noma graham from the site parathyroid dot com and I use that um no mammogram. And also I use that as a great resource for myself and for clinicians as well as for my patients. But if we use if we go to the, oh thank you so much. If we go to the Noma graham and we follow the levels that have been described, you can see that in the relationship this will fall into the primary hyper parathyroid is um range. So I believe that the diagnosis here is is hyper parathyroid is um and I'd be sure that this patient had the work up that we talked about previously as well as the ultrasound of her of her thyroid. Um as was discussed previously by our group. Um and then I would communicate with either your group heather and endocrine surgery or endocrinology to see if any other tests would be useful prior to the visit or people would prefer to have tests at the visit. Right well let's check in with our endocrinology colleagues then for on non and for when you know, when do you consider ruling out additional mimics of primary hyperthyroidism. Um And can you talk a little bit about the non classic variants of primary hyperthyroidism? Sure, heather. Um So I'll be talking about the nonclassical videos of primary hyper parathyroid is um so remember in classic, primary hyper parathyroid hormone is high and the calcium is high. So it's pretty clear cut that this is primary hyper parathyroid is um unless proven otherwise. Now in some condition you're just like the one that marty discussed. Your calcium is high but the p th is within normal range. But the most important take home point here is for most hyper calc mia, which is not p th driven like malignancy or grandma matters disease sarcoidosis, you expect your parathyroid hormone to be less than 20 in most cases less than 10. So just because the p th is normal, doesn't mean that you don't have primary hyper parathyroid is um this is still primary hyper parathyroid is um so this is again, hyper calc mia with inappropriately un suppressed. P th and that's sometimes called normal hormonal, although we really don't like using this term because it just caused confusion and dichotomy. Uh So that's one nonclassical variants. The other variant is what we call you calc emmick hyper parathyroid ism or normal. Normal calcium is hyper parathyroid is um this can be a little bit tricky. So and this is usually found when someone is working up a patient for secondary causes of like osteopenia, osteoporosis or kidney stone in this case is your parathyroid hormone is found to be elevated but your calcium is normal. So then we need to make sure that we have ruled out all causes of secondary hyper parathyroid is um because before we really contribute this to primary hyper parathyroid is um so the management and surveillance is a little bit a little bit different. So for primary have clear cut, classic primary hyper parathyroid is um or or um in un suppressed I mean um inappropriately un suppressed. PCH with hyper calcium in the management is about the same. But in patients who have normal calcium IQ hyper parathyroid is um you really, I mean follow them through, make sure that they are taking a good amount of calcium supplement. We deplete their vitamin D. If they have hyper calc area, we often treat them with a diuretic. So we there might be a little bit more follow up and proper work up before we diagnose this with primary hyper parathyroid and refer them to surgery. Great. I just want to add a little bit on the differential here. So as Deepika says, you know, so in endocrinology we used inappropriately normal relatively frequently. So if you're seeing an inappropriately normal p th that that would more likely be hyper parathyroid is um unless proven otherwise we do want to see a very suppressed ph and calcium eras of other condition. I just wanted to quickly touch on the very important condition that is very rare. However, it's always on our differential when we're seeing these patients with asymptomatic primary hypothyroidism called familial hyper calc urich hyper calc mia. It's a rare artisanal dominant disorder with three identified variants leading to abnormal function in the calcium sensing receptor. And surgery is not indicated in the press F. H. H. Because it can actually worsen the condition. So it's very important to make this differentiation when we see these patients. Um So I uh the importance of calcium creating clearance ratio is I cannot emphasize more hair. We typically would do a 24 hour urine collection for calcium and creating um in the F. H. H. You would expect that Ratio to be less than .01 and about 80% of the people. However you can still see um uh greater than .02, which is more so in primary hypothyroidism. Now, the problem is that um patients in our clinics don't come with like the typical presentations that we always were stuck in the gray zone, which is .012.02. Uh So unfortunately we are in an era where genetic testing has primed to a great extent. So we do have the facility to send them to genetics or even just send them directly for genetics through. And um there are companies out there. But my go to is the invitation which is online which is very easily doable and very user friendly. And so so we are doing routinely through this uh genetic uh these tests through this genetic company. Of course you want to rule out vitamin D. Inadequacy, low calcium intake and curated use before you're looking at the 24 hour urine collection. There's some racial factors as well which can impact about 44% of primary hyper parathyroid patients of african descent have had a noted to have calcium excretion less than 100 mg per day. So keeping all this in mind, we must consider FH on our differential and I think that's a really important point and something that should be taken into consideration for sure. Um We are running close to time and I do want to make sure that we have time to see some of these questions. We've gotten a lot of fantastic questions from our audience here. Um And our last case is really one of hypo parathyroid is um this is really something that's relatively rare. So we're gonna address this very briefly. We I often see this in the context of via tra genic hypothyroidism. So classic case might be a young person who's had graves hyperthyroidism undergoes a thyroidectomy. And then after surgery we'll have a parathyroid hormone levels ranging from zero undetectable to five with a calcium of 7-7.5 and a normal phosphate. Um If uh Deepika and nina might be up to comment very briefly on how you know what types of repression that we use. And then we will transition to our discussion of some of the comments that we've received. Would you like to start your I think you're on mute. Sorry? Yeah sure. So this patient post thyroidectomy has it tra genic or post surgical hyper calcium iAN due to hypothyroidism. So oftentimes we start treatment by oral replacement calcium carbonate or calcium citrate calcium carbonate needs acidic environment for absorption although it has higher elemental calcium about 40%. So 1000 mg of calcium carbonate. T. I. D. Is a good start. Or calcium citrate can be used again about 1000 mg of elemental calcium is what we want to get them started on. Uh And then usually after 24 hours we check their calcium. If their calcium is still not coming up then we add roux cultural which is active vitamin D. About 0.5 micrograms once a day or twice a day and monitor their calcium level. We also checked their 24 hour urine is if that's above 1 50. We might start them into on diuretics which help them absorb calcium and improve the calcium level. Uh Now most of the hyper calcium is transient and they recover quickly mostly from the standing of the parathyroid gland. Very really the parathyroid parathyroid is um might last for over six months. Then we are worried about a long term or persistent hypothyroidism. Uh So usually these are my management strategies for permanent permanent hyper parathyroid, sorry hyper parathyroid. We often monitor the calcium level. We monitor their 24 hour urine calcium because they are at increased risk of necro calc no sis uh calcium, kidney stone and callous evil axis. Um I'm gonna let I'm not talk a little bit about recombinant human P th that has been approved for patients who have resistant hyper parathyroid is um. Alright so so basically um just to piggyback on d because things. So first we try with the conventional therapies and however we know that the convention therapy can lead to new locale stenosis or nephrology. Isis within the renal system deposition of calcium in the soft tissues. And it does not directly address the concerns caused by the lack of P. T. H. And hyper parathyroid patients especially as regards to quality quality of life neurocognitive complaints and decrease skeletal turnover. So p th formulations became available. Um We do have P. T. H. 1-85. And you may have heard about net para which was approved by us by the FDA in 2015 for the treatment of adults with chronic hepatitis. Um So we're talking about permanent hyper parathyroid patients most of the time. These are surgical complex, surgical hyper patas small uh population can have genetic mutations as well. So unfortunately. Um this was recalled back in 2019. Um due to some issue with rubber particulates originating from the rubber septum. And so I when I was reading up, there is an update from october 3rd 2022 the company is going to be discontinuing this altogether by 2024. So we're really not left with. I think the only choice left is now terry parasite, which can be used as a twice a day dosing and these people um net part is still available under the special use for special use population that is still being supplied. But eventually I think that supply is going to be um finished and so we'll be left with unless we have a new option here, wow. Well that's really hot off the presses. Thank thank you for sharing that. I think that's really important for for people who see these types of patients and will be a challenge going forward. But good to know that it's still available at least for a time under compassionate use. So we have covered a ton of ground here. I think we're incredibly fortunate to have such an expert panel. We're gonna try and field a couple of the questions right now that have been put into the chat and we've received beforehand. Um, if we do not address your specific question, I'll be following up with you by email. If you put contact information when you submitted a question also, please feel free to email us directly. My my email address is heather dot Wachtel at penn medicine dot u penn dot e d u. And I'll put that in the chat at the end. Um We have a number of questions that have sort of addressed about question concerns for differentiating secondary hyperthyroidism. In the setting of end stage renal or chronic kidney disease from primary hyperthyroidism marty, you probably have to untangle this in the primary care setting a great deal. Do you want to comment on on how you start that work up and when you, you know, work in in conjunction with a colleague from endocrinology or from nephrology? Um Sure, but I think the nama graham is really useful in this situation. So the parathyroid hormone oftentimes typically is elevated in um chronic kidney disease and kidney failure. And it's though for a totally different reason. And if you can look at the nama graham, you'll see that typically the phosphorus will be elevated, but the calcium will be on the lower side um and usually are endocrinologists and I guess I'll pass comments to our endocrinologist team here, but I think this is a nice display of really, there's two separate groups with just a little bit of overlapping, completely different physiology to the, to the two reasons for the p th being elevated. So I know Topeka, if you have any comments, I think you might be on mute. Topeka. Sorry I was talking without muting so oftentimes when we see such high level of P th with normal calcium we're leaning towards the diagnosis of um secondary hyper parathyroid especially in the background of CKD. So we usually work with our renal colleague regarding management of this and often times I've seen them. Used cultural to help the I I. P. T. H. Level. Um Do you have any comment on this case? I think I I um no further comments I would support what Deepika is saying. Alright well great. Thank you. This has been a fantastic webinar. I really appreciate the expertise of all my colleagues here. I'm gonna hand things over to AMY and we're gonna put information up on obtaining your cmI credit. Please feel free to email or contact any of us. We're always happy to chat and if we can help in any way, don't hesitate to reach out. So thank you so much to all my colleagues, Amna Deepika and marty and Sophia for joining today for the A. C. C. Staff for organizing and to all of you for making the time to log on. Thank you heather It was a wonderful experience and thank you everybody