Dr. Yulong Li, MD focuses on clinical evaluation and treatment or referral of hyperparathyroidism and addressed differences in guidelines and practice.
OK. So doctor Yulong Le earned her medical degree at Shanghai Medical University in Shanghai, China and then completed her Master of Bioinformatics at University of Medicine and Dentistry of New York, New Jersey, and New York, New Jersey. Doctor Yulong is a bim board certified in endocrinology. Is currently an assistant professor of medicine in the division of endocrinology with the washi physicians. She sees patients at the Center for Advanced Medicine at Barnes Jewish Hospital and Village Square in North County for General endocrinology and endocrine tumors, including but not limited to diabetes, thyroid disorder, osteoporosis, parathyroid disease, tumor, and thyroid pituitary and adrenal tumor. So, thank you so much for your time today and I will let you um take the floor. Uh So the I showed the presentation mode. Is that the correct on your screen? We're seeing the present the presentation mode on our screen. Yes. OK. OK. Wonderful. Thank you. Absolutely. Uh Thank you very much and for coming today. So today, my topic is uh hypercalcemia and hyperparathyroidism. I have nothing to disclose and uh I will not be able to cover every topic and the focus will be on evaluation treatment, referral for primary hyperparasite, I will address differences in guidelines and the parties in treatment and referral of primary hyperparathyroidism, persistent and recurrent hyper parasitism after parasite surgery and hypercalcemia and in malignancy including etiologies and management. So first, uh there are three cases and I put it here intentionally. The first two cases, they have a similar uh clinical features except uh uh gender and age are different. And the third case is quite different than the first two cases. So you can see that the first two cases, they have a mildly elevated calcium level. The third case has moderate elevated calcium level and the first two cases, their PTH were elevated. And the third case, the PTH was um inappropriate normal. So that means um usually in that situation, the calcium level is more than 12 PTH should be surprised or be very low, low normal range. But this patient is uh uh in the mid normal range which which is inappropriate and they all have uh uh relatively normal uh vitamin D level. And uh the first two patients, they have uh borderline or normal high 125 vitamin D. And the third patient has elevated 125 vitamin D. The first two patients uh has kidney function, normal kidney function. And the third patient has uh kidney compromised. And the um when people has uh CKD, especially uh stage four or above, there's no need to do the urine calcium collection and evaluation because it wouldn't be accurate. And the first two patient, they have normal kidney function. Their urine calcium evaluation was in the normal range. They do not have ultrasound or didn't. It's not available for uh parathyroid nodule evaluation. Uh The third patient has a system maybe scan and the suspect have a parathyroid adenoma. And the first two, they have a normal bone density and the last one has osteoporosis demonstrated in the bone density scan. So just uh uh give like five seconds and uh look at those patients uh by chemistry report and their clinical features and what you would do regarding referral for the surgery and we will come back to those cases. And in the later presentation, primary hyper parasitism is uh a very common endocrine disorder. Um about 12,000 paray were done each year and the peak instance is in post menopausal woman and the patient. Um if you just look at absolute number uh woman patients and double female patient, double the uh male patients. Other risk factors has been reported including previous radiation exposure, race, gender differences and dietary intake and the supplement of Caling. So, the primary hyper parasitism is considered the pathetic gland disease in the neck. Usually 90% of the time is a single adenoma but sometimes can be hyper cellular, um pancreatic uh I'm sorry, uh hyper cellular uh parasitic gland changes and in the neck and causing increased autonomous secretion of PTH and elevated calcium level and then cause complications in the kidney cardiovascular system, musculoskeletal system, gastrointestinal system and the neurological system. Uh The traditional typical clinical manifestation of hypercalcemia are not commonly seen right now because of routine screening for calcium level. And during the physical exam and the, the uh just occasionally we still will see some patient with very high elevated calcium level. And we had a patient die from hyperglycemia due to parasite carcinoma. And autopsy show that there's uh extensive calcium deposition in the heart and in all the uh vascular system in the brain and in the pancreas and in the liver. So almost organs, all the organ system has a significant extensive calcium deposition. And that's the uh elevated calcium. Actually, it's the reason that causing complications and the mortality, usually it's not the elevated parasite hormone. So occasionally, if a patient has a very significant calcium elevation and the two things that you probably should pay attention is uh um patient's neurological status and the patient cardiovascular status because other things can wait and take time. But these two things and require uh urgent care and uh immediate management for hypercalcemia. Regarding uh primary hyper parasitism evaluation, there are many guidelines and also algorithm and uh uh tables of figures that um giving illustration how to do the assessment. Here, I will only focus on three. First is calcium evaluation. Then parasite hormone evaluation and the phosphorous evaluation, the calcium evaluation, the total calcium were measured in the B MP and C MP including a 50% of free analyzed calcium. So the free analyzed calcium is active form of calcium. However, uh to measure analysed calcium, especially in the outpatient setting is uh technically difficult. So that's why we use a total calcium, total calcium, including free analyzed calcium and also including the calcium binded to the protein and uh uh majority binded to albumin but also can bind it to other protein and um uh chemicals. Then it comes the question if a patient has a significant liver problems, kidney problems are building a normality and critically ill and the total calcium might not be accurate. Then at that time, the A S calcium can be utilized. And also there is a formula developed to correct the total uh calcium or analyzed calcium and based on the factors that can affect its level. And there are in addition, uh many literatures and published different calculations and corrections and formulations that nobody can really remember it. So my recommendation is uh uh just to focus on the total calcium and the calcium value without correction. So this is a graph and uh plotted uh 13,000 paired total calcium and the calcium from thousands of uh hyperparathyroidism patient. So you can see that the total calcium and RNS, the calcium, they correlated very well and with very significant significant P value and very high correlation coefficient and uh uh 0.919. And there are only few occasions that the total calcium and NNS calcium are not correlated by well. And in that case, you may consider all both. But uh most of the time the total calcium without the correction uh can represent the patients true calcium status. The next is uh uh parasite hormone level. The parasite hormone level, the parasite hormone half left for parasite hormone is about two minutes. And uh um it, it, it has uh uh it fluctuates like very frequently and also can be affected by certain medications naturally. It's also have a diurnal rhythm. So if you just pick up random pth level, it's elevated, it's low in the normal range. It really doesn't tell you too much. So because of uh pth, the half life is just two minutes and it fluctuate very frequently and we should interpret the PTH and in the context of calcium level. So here is uh you can see the X axis is uh total calcium level and the y axis is um the serum pth level. So if I draw a line here, uh PTH equal to 60 or draw a line here, pth equal to 20 depends on their calcium level and their PTPTH represented a different thing. It could be normal uh subjects, it could be hyperparasite patient and it also could be hypercalcemia malignancy or primary hyperparasite patients. So that's why the PTH interpretation must be in context of calcium. And ideally, the PTH and the calcium level should be drawn at the same time and sometimes the patient will be referred and uh I receive re referral of the patient some of the times and the PTH and the calcium, they were ordered on the different day and sometimes even on different month so that I cannot correlate this pth with calcium level. So the individual random pth high and the low sometimes cannot represent um significant uh diagnosis if patient, calcium level is persistently elevated and the pth level is normal or especially increased. And usually it is a pth media hypercalcemia. However, if a patient's calcium level is persistently elevated and the PTH is surprised and you should consider other differential diagnosis including PT Hr P mediated 125 vitamin D me and the other type of um uh hypocalcemia secondary causes phosphorus. Um Actually, it's um uh very important and uh sometimes can be helpful and for diagnosis and the differential diagnosis, the both PTH and the PT hr P hormone, they can inhibit renal rabs sop of phosphorus. So, um there will be more excretion and the phosphorous level will be low. So, if phos uh if calcium level is elevated and the phosphorous level is low, you can consider the PTHPT hr P mediated hypercalcemia. If phosphorous is high normal or even elevated, and it's more likely to be vitamin D intoxification, thyroids and other type of uh etiology mediated hypocalcemia because uh vitamin D level, uh this is a vitamin D level can increase false absorption through G I system causing P level to be elevated, uh thyroid function, high causing bone reabsorption. So the force level can be elevated. So there are other mechanism can causing phos level to be abnormal uh for the localization studies. And um sometimes when patient refer to me, they already have ultrasound or the maybe scan study done. And there's one patient even have uh a neck ct completed. And before referral to me. And I think uh for me and you uh for us to consider localized study. And uh the most important thing uh sa a very famous radiologist said, I think the most localization consideration is to localize a good parasite surgeon. And it is uh uh also a topic and um a title for paper and published in a GS. The best local localization is uh experienced parasite surgeon. So that is the most important thing that we should consider the imaging study to localize the tumor. But the imaging study should not be used to make primary hyperparathyroidism diagnosis. The uh even the surgeon agree with me that the primary hypoparathyroid diagnosis should be by chemistry, clinical diagnosis. It should not be based on imaging diagnosis and the imaging should be used and utilized after primary hyperparasite diagnosis is made and the imaging is used to localize the tumor and the and the preparation for the surgery. So my preference is that I usually don't not order the uh ultrasound or uh system, maybe scan or even ct I will let the our experienced surgeon to decide and what it will be the appropriate localization studies they want to order. So I leave this option to the surgeon. The reason is uh the parasite gland kind uh be a Utopic and also ectopic. So it's located in different locations. So experienced surgeon when they do ultrasound, actually, they do better than the radiologist. They know where they should look for the uh parathyroid gland and all the uh endocrine surgeon I work with, they do the bad side ultrasound during the clinic visit. So they will check the ultrasound themselves and to see that if they can visualize enlarged uh para gland. And this is also helped them to form the surgical roadmap and for the surgery, this is a 2018 New England Journal of Medicine, published the radiology investigation for parasite disease. And you can see ultrasounds such maybe scan and four DC T scan and the MRI they will have a relatively good positive predictive values and it's uh commonly used um in our Institute ultrasound system may be scanned and sometimes also for the CT imaging. And the reason the publication, they uh some of European country, they even use the PC T and they found that the pi city has a higher sensitivity and the positive predictive value than the previous um modality mentioned. But again, I think this is will be um I will leave it to the experienced surgeon and usually the 40 ct and the pet CT in my opinion, to identify the path gland that is very challenging to localize the definitive measurement for primary hyperparasite is means surgery because the cure rate is very high. And after surgical resection of parasite tumor or hyper cellular lesion. Then here comes a different uh guideline regarding how to refer patients to the surgeon. So, on the left side, this is uh the uh endocrine Society. So that is um Internal Medicine guideline. Endocrine Society endocrinologist guideline. Regarding what's the criteria to refer uh hyperparasite patient for surgery. And this a AES represent the American Association of Endocrine Surgeons. So this is uh endocrine surgeons guideline and how to refer the patient to the endocrine surgeon. And for the hyperparathyroidism. A very interesting finding is that if I follow the surgical guideline, I will be referral every patient I see. And for the hypocalcemic hyperparathyroidism. So it is a very inclusive and including like almost everyone will meet one of the criteria and the most endocrinologists um uh practicing, they follow this endocrine society guideline. So, criteria listed here and also has a similarity with the surgical guideline including age less than 50 years old. So younger the age, the better the surgical outcome. And also because of this patient, if you don't treat them with a surgical operation, they will develop a complication and there was a long term um consequences. So the young patients, we should refer them and consider them and for surgical referral and also uh criteria including calcium level above 1 mg per deciliter above the uh normal limits. And for the renal involvement, if a patient has a chronic kidney disease with JFR less than 60 or if a patient has um uh kidney stone histories and the image finding of uh uh nephrocalcinosis or urine, calcium level is uh significantly elevated. I think the reason the guideline is not 400 anymore, it's uh 302 150. And so those are the criteria for, for as well. And regarding the uh bone density, if a patient has uh osteoporosis, it's a criteria for referral and if a patient has um vertebral factor, it's a criteria for referral. So we have discussed the referral criterias and those, all those are similar as the surgical uh guidelines regarding referral. So next, let's see, the um three patients we discussed earlier. So this is the first two patients, their calcium level does not meet the criteria for referral and they do not have a kidney impairment. Their urine calcium level was not significantly elevated and uh their bone density were normal. So if you just look at those, they seems like they don't meet the uh either uh endocrine society or the endocrine surgeon guideline for referral. Uh But I actually referred both of them because of the um I wrote the all the secondary causes, I consider them to have a primary even they don't meet the criteria. But if I consider they have primary hyperparasite without the secondary causes and I can refer. So the in addition, this patient, the age is less than 50. So actually, that meet the referral criteria and both of them actually has low falls and some kind, some symptoms related with hypercalcemia. So I referred both of them and they had a successful uh parasite surgery and the intraoperative parasite hormone dropped significantly into the normal range. And the post op calcium level were in normal range. And during the follow up and the pathology showed they have both of them actually have a hyper cellular parathyroid gland. So this is the first two patient and um one of the very important uh consideration is uh before surgical referral is um uh when we refer patient for parathyroid disease, we should consider if uh evaluating if a patient has any thyroid disease because uh if a patient has coexisting thyroid disease, and it will be a good opportunity to take care of the med at the same time. So that's why the third function certainly need to be tested. And also uh if they anybody order imaging test, the uh third condition need to be evaluated to see if there's any third disease or third condition that can be taken care at the same surgery. Second thing is that when the patient has been returned to primary care. Uh after the surgery, the calcium level should be monitored and uh uh especially in the first year, at least that six months after the surgery, in order in order to establish the cure, because later on, we will discuss recurrent and persistent hyperparasite and we will discuss this again. The third case we discussed, the patient has a moderate elevated calcium level and there's a kidney impairment and uh image showing possible parasite tumor and the bone density osteoporosis. So, patient has actually four criteria and meet the referral um guideline. But this patient, if you look at the further uh for the past years, their uh calcium GFR vitamin D, parathyroid hormone change, you can see that the GFR is gradually go down and the correlates with uh the parathyroid hormone level. The parathyroid hormone level has always been in the normal range and uh has never been checked multiple times, has never been elevated and the patient's calcium level has been elevated, there's some fluctuation but it has always been elevated. And uh the patient's 125 vitamin D has been checked the at least twice and uh it has been uh significant elevated in both times, but it's more elevated. And now. So actually, I did not refer this patient for uh surgical uh evaluation. This PTH in the inappropriate normal could reflect the GFR situation. So PTH was abnormal but the if patient truly have the primary hyperparasite, I should see PTH level and gradually going up with time. And because this is a several years follow up and the PTH did not really uh gradually go up significantly. And instead the 125 vitamin D has go up significantly. So these patients uh I uh initial diagnosis and official diagnosis that can start secondary hypocalcemia. And uh there's a possibility of secondary hypopara and I will evaluate first evaluate the possibility of 125 vitamin D mediated hypercalcemia. Um So the we know that again, we go back to this uh surgical referral for the primary hyperparasite. They uh regarding the complications, they mentioned both of the guideline, they mentioned that the kidney impairment is uh considered for referral. Uh elevated kidney stones is considered for referral osteoporosis and the vertebral fracture fragility fracture considered as a criteria for referral. So the next we will look at the instance and the prevalence of those in general population. So in general population, kidney stone is actually uh quite prevalent. If you look at the 45 50 60 years old, those are the common age diagnosis. Hypercalcemic hyperparasite. Their prevalence of kidney stone range from 4% to 10%. So it's a prevalent in the general population and for the vertebral fracture, it is also prevalent in the elderly population. And you can see that the uh percentages range again, close to 5% to 10 and even 15%. So it's quite high in the elderly population. And it's the same story for osteoporosis. Um osteoporosis prevalence uh increase with age and the female is more dominant than the male. And then you can see the rate is uh about 3 to 4% and to like 12 and even higher, 6 to 12 and even higher percentage in the general population. So all those things, osteoporosis and the kidney stones and the pupil factor, they are quite prevalent in general population. However, the primary hyper param in general population is about 1% and to 5%. So much lower than osteoporosis, vertebral fracture, kidney stones prevalence. So the sometimes when people present with those conditions, osteoporosis, kidney disease or kidney stones, it could be just a coexisting condition instead of uh casual complication because of uh hypercalcemic hyper power because those conditions more prevalent in the primary hyperparathyroidism. So sometimes we need to be aware of that and uh so that the referral when we consider referral, we should put that into consideration next renal disease. So this is uh from National Kidney Foundation. And uh uh the chronic kidney disease is uh also very prevalent in the general population. About 10% of us population has chronic kidney disease. And if you look at this is the GFR levels, so you look at GFR levels. The blue bar is um uh percentage of patient with uh elevated parasite hormone level. So you can see that for people with chronic kidney disease. But the GFR is more than 60 even in this group, there's a significant amount of patient percentage of patients, more than 15% has elevated parathyroid hormone level. And if you look at the CKD in stage three or even higher, the percentage of parathyroid hormone elevation and it's uh significantly high and uh more than 50% 60%. And in the stage three B and the stage four disease. So it is true that the in my clinic and uh mm most like most patient referred for elevated parasite hormone level and the majority of them actually a secondary cause, it's not the primary cause. And because um the uh especially if a patient has uh the compromised kidney function, the elevated parathyroid hormone is quite prevalent and in those populations. So, in their kidney um guidelines, they have discussed that the pth uh parasite hormone evaluation and they consider the uh increase of parathyroid hormone can represent appropriate response to declining kidney functions. And however, for people with JFR, less than 60 not on dialysis, the optimal pth level, we don't know about that. And for people with end stage renal disease and the parathyroid hormone level can be in the range 2 to 9 times of upper limit normal and considered to be appropriate response and compensation. And the only referral uh patient for parathyroid surgery is for those patients with severe hyperparathyroidism and who failed to respond to medical treatment. And those patient has a progressive increase of calcium and the parathyroid hormone level that is suggest the parathyroidectomy. Otherwise, it will be monitoring and uh uh observation and using vitamin D supplements and also cic acid for treatment in this group of patients. So again, um the regarding this uh referral guideline for the surgery and uh uh be aware that those uh renal conditions and also osteoporosis and the vertebral fracture. They are quite frequent and in the elderly patient population, so not necessarily everyone with the GFR less than 60 I will refer a patient. It must put into the clinical context. And also even patient does not meet any of those criteria. If the patient's investigation and the clinical picture is uh consistent with the primary hyperparathyroidism and the secondary causes were ruled out and we can refer a patient even they don't meet any of the criteria for reform. So this part of the summary is uh the uh hyperparathyroidism majority due to um primary hyperparasite. And uh also CKD because I have seen a lot of patients with CKD with the elevated parathyroid hormone level and the parathyroid hormone level. Uh evaluation should be in the context of calcium level and the false. And uh and 125 vitamin D sometimes can be useful in making differential diagnosis. Indication for surgery are not absolute indications. And uh uh the patient you need to be uh individualized and personalized and the decision making. And for the surgical referral and the treatment. Next, I will discuss a concept about normal calm hyper parasitism. So the uh definition is persistent and the parasite hormone elevation with normal total and ana the calcium, a very another very important thing to consider is it is a diagnosis of exclusion. So all the other secondary hyperparasite need to be ruled out because that is a common reason to have a normal classic normal calm uh parasite from. So this is a proposed, this is European uh endocrine society proposed uh guideline regarding what the secondary causes. So there are many different secondary causes medication can cause parasite hormone to be elevated, including some of the uh diabetes medication, GLT two and the PP I and the uh osteoporosis treatment medication also show that it can increase uh parasite hormone level, the hypercalciuria. So this is in this way, the people with the primary hyperparathyroidism, they can have elevated calcium in the urine. But the people with normal calcium level, we are talking about normal calm hyper, they should not have elevated calcium in the urine. In the other side. The uh people with elevated calcium and due to genetic reasons due to other reasons, kidney problems, they have a hypercalciuria, they can stimulate the parasite gland and um uh causing parasite hormone elevation. So this is a secondary cause for elevated parasite hormone. Of course, vitamin D, we know vitamin D, we discuss renal insufficiency and they all can causing all can stimulate parasite gland causing parasite hormone to be elevated. And another group is uh low diary calcium intake and or has absorption issues. So the there's a um low absorption and those can stimulate the parasite gland and causing parasite hormone elevation, abnormal f uh metabolism also can causing the calcium and also parasite form and level of abnormalities. So those are the common things to consider and rule out before proceed and to um further investigation. So, diagnosis of normal calm hyper power is a diagnosis of exclusion. And that is a very important point to remember. Um There are a lot of uh controversies regarding management of uh normal calm hypopara. So I summarized the the point they uh give the recent guidelines. So the normal calm hyper can be considered maybe a early stage of primary hyperparasite. However, the evidence is lacking for progression. So they didn't see this is a progression to the primary hyperparasite for majority of the cases. And um uh we mentioned it's a diagnosis of exclusion and the uh evidence on the effect of a parasite, parasite is uh very limited and there's no clear data on natural history of normal calm hyperparathyroidism. So in that case, we actually really didn't, don't have a guideline to follow if we should refer or not. So a lot of times that uh the I think the initial work up will be looking for secondary causes and for some of those patient, I referred and some of the patient I didn't refer. But I must uh be honest that the the patient I referred for the normal calm hyperparasite is for the several patients they do not get surgical cure. So after the surgery, their levels still elevated. So their possibility is that there's still a secondary causes. It's just we couldn't identify that secondary causes. Um The surgical intervention should be considered only after full endocrine review and only if there's a compelling indications and a surgical target, that means they can localize uh abnormal gland. And uh they there will be a more possibility for surgical c recurring and the persistent um hyperparathyroidism. So the recurrent and persistent hyperparathyroidism is the definition of elevated calcium level, not elevated parathyroid hormone level. It's elevated calcium level after six months, it is a recurrent within six months. It's persistent. So that is a recurrent and persistent disease. It is an elevated cain. So for those patient, uh if it has recurred um primary hyper parasitism, we should consider review the previous uh medical history lab and the pathology information, review family history, what genetic uh condition that we probably missed that the initial diagnosis and what medication the secondary causes and that is very important too. The prevalence is quite high. So the surgical cure is not 100% it's 1 90%. So there's a uh certain recurrent uh conditions here. That's why this uh we recommend those patient when we discharge from hospital and then they return to primary care. Uh their calcium level need to be continued followed up. And because of their potential recurrence from like 3 to 2% to 10%. And they will find out those uh recurrent patients again, uh significant amount of them actually have uh developed another like uh adenoma and some are due to multi gland disease that is not uh very successful by the surgery. So after initial parasite surgery, if repeat surgery is considered a more sensitive imaging test should be recommended again. I would let the surgeon to decide and which modality to use. The persistent elevated parasite hormone level has been observed in one third of the patient. Uh After the surgery, the mechanism is not very clear. We don't know why it's a persistent and the surgery looks like uh successful because calcium level has been reduced to normal range and persistently in the normal range. But the parathyroid hormone levels is still elevated. So that could be again, due to there's a secondary causes we didn't know. And uh we need to ensure patient has uh adequate calcium vitamin D intake. We should monitor the calcium level because some of those patients with elevated uh persistent elevated parasite hormone level, they eventually develop a recurrent disease. So we need to monitor calcium level and we can, if calcium level is elevated, we can consider s acid treatment. Uh but we can consider repeat surgery and if calcium is elevated in the future. And those patient has a high risk for developing hypopara for repeated surgery. Uh So, reoperation need to be considered carefully and needed through assessment. So other differential diagnosis for hypocalcemia, we mentioned hypercalcemia related with hyper paray. And uh uh there are other etiology can cause hypoglycemia in clinical settings. And the patient taking uh excessive amount of calcium, especially uh in Tums because uh a lot of times they think the Tums is medicine for treating uh author and the peptic disease. But they don't consider the tum is actually calcium supplements. So that we have seen occasionally in the clinic. And we see the patient with a hyperthyroidism because of the bone tumor increase. So their calcium level can be temporarily elevated. If their hyperthyroidism is adequately treated, the calcium level will go ba back down to normal range. Um 125 vitamin D induced uh hypercalcemia with seed seed from time to time and sometimes the sarcoidosis, not just the sarcoidosis. Sometimes we see even for very systemic fungal infections, they form granuloma disease and that can cause in 125 vitamin D level elevation. And we treated the fungal disease aggressively and uh controlled and the calcium back to the normal range, multiple myeloma. Uh we screen it like if a patient has elevated calcium level, we routinely screen multiple myeloma. Um Yes, I actually, one or two patients did identify multiple myeloma because of the screening. And so those are the some other causes for elevated calcium level. But the most commonly you see and the encounter and IC encounter probably a solid tumor malignancy causing hypercalcemia. So that is uh another category of diagnosis, hypercalcemia of malignancy. Actually a majority of cases due to PT hr P mediate hypercalcemia. So if you check PDH RP, it will be elevated. But sometimes those malignancy can do to other hormone uh and or other chemicals and uh uh conditions causing elevated calcium level. So it is not all the malignancy cases we have for PDH RP elevated, there's only like uh 80% another 20% there's other reason for calcium to be elevated. So PDH RP um is uh uh produced normally by a lot of organ systems and associated with a lot of solid tumors. And uh also lymphoma as well. Uh similar as a parathyroid hormone. It activate bone reabsorption. So that can cause calcium level to be elevated. It also act similar as a PTH and act in the kidney and inhibit the phosphorus reabsorption. So, uh so the calcium re absorption will be increased, calcium level will be high force re absorption will be decreased and the force level will be low. So this is similarity with the parathyroid hormone different than parathyroid hormone. Is uh this uh para parathyroid hormone related protein does not stimulate uh one alpha hydroxylase does not stimulate conversion from 25 vitamin D to 125 vitamin D and that does not increase calcium absorption through the G I system. That's the difference between PT hr P and PTH regarding calcium metabolism. So, this is again, there are structures similar at the terminal, both of them combined with uh parasite hormone receptors and causing downstream activities. Um So that's the reason causing calcium level to be elevated. And this is another group of uh uh etiology for hypercalcemia in malignancy. And um in those cases, and the patient has uh osteolytic metastasis and the cytokine released by the tumor can increase calcium re uh release from the bone. Uh for those patients, the there's also localized pro production of PDH RP, but you can't measure it in the serum because it's just uh uh action locally. So for those patients, you probably don't have really um bad chemical evidence of the etiology. But you mean uh radiology uh image should show that the patient has osteolytic lesions, um mentioned this before 125 vitamin D and this is can be uh secreted and usually there's a ectopic activation and stimulation of one hydroxylase. So, increase 125 vitamin D production and the mechanism is similar as uh hyperglycemia in granuloma. Uh It's commonly seen in the lymphoma uh type of the disease, very rarely. It's uh uh malignancy hypercalcemia. In malignancy also can be pth mediated that you see parasite carcinoma or um lung cancer, which has ectopic protection of parasite form then treatment of hypercalcemia of malignancy and of course target is treating malignancy. However, uh a lot of times we cannot cure malignancy. So the calcium level actually were gradually trend up uh in those cases. And it's a poor prognosis for uh malignancy because people malignancy with elevated calcium level and the pro prognosis is poor than the m malignancy without elevated calcium level. So, in those patients, because we the likelihood of treating hypercalcemia and maintain calcium in the normal range is very, very low. So, a realistic goal is uh we keep them to be lessened to a milligram per deciliter and most of patient reported tolerance. And if calcium can be treated less than to a milligram per deciliter and manage other complications. Uh The hypercalcemia treatment in malignancies uh uh has some similarity for hypercalcemia treated in primary hyperpartisan use a saving. It's only for mild hypocalcemia. The advocacy in severe hypercalcemia is very limited. And plus, there are limitations that you if a patient has renal disease, cardiac disease, you cannot load patient with a lot of fluid. And then the mechanism is to expand intravascular volume and increase renal perfusion and calcium excretion. But again, it's only for uh possibly a short period of time and uh uh for the IV fluid and the IV fluid loading. And it's only for mild hypercalcemia, Lasix and uh furosemide. The proposed mechanism is uh increased calcium expression through the urine and inhibit calcium reabsorption. Uh However, a lot of research done on this didn't show that it's the case. They, there are no solid evidence support Lasix used in uh malignant hypercalcemia and the hybrid is commonly used. And in this case, calcitonin uh mechanism of calcitonin is uh uh decrease the bone absorption, increased calcium, urinary excretion is approved by FDA for hypocalcemia. However, the uh the efficacy limited to two days and um uh it is a weak agent. That means again, this is for just a mild hypocalcemia cannot be used to treat successfully, treat severe hypocalcemia. Sometimes it depends on how the calcitonin was produced and there's a hypersensitivity test and you need to check the patient do the skin test before you give patients. Calcitonin depends on the manufacturing uh indications. The skin test for the caston is like a PPD test. And uh usually the uh the label will show like how to do this test to provide hypersensitivity reaction. Uh Glucocorticoids, it's um uh usually used for the patient with uh 125 vitamin D overproduction. And this FDA approved for hypercalcemia of malignancy. Uh they don't have really a dedicated dose but the expert opinions, 20 to 40 mg daily predniSONE. But the other hydrocortisone dexamethasone high dose all have been used and reported in the literature. In the past. Of course, we know there's many limitations and uh uh it, those are not going to be long term. The a treatment for patient dialysis can be used for severe hypercalcemia and uh with the neurological symptoms and for, for whom that the calcium level need to be corrected immediately, counter indicated in renal insufficiency, heart failure, we cannot tolerate a large volume of uh resuscitation and the mechanism. Of course, if you use a dialysis food with a little no calcium, yet, you will be successful, uh get rid of the calcium in the blood. Again, suggest the short term for very severe hypoglycemia. Next, we discuss the three medication can be used for long term hypercalcemia in malignancy and even in non malignant situation, uh who is not a surgical candidate. So first is sac acid. So the sinic acid combined the calcium sensing receptor on the cell membrane of parasite gland. So that increase uh calcium binding with the calcium sensor receptor. And when calcium binded with the calcium sensory receptor, it interrupted this signal and reduce parathyroid hormone secretion and production. And then consequently, and reduce calcium production. Sin calcium is uh FDA approved for parasite carcinoma. Also approved for primary and secondary hyperparasite is mass indicated. Uh the dosage start with 30 mg daily and it can go up to uh in total uh 360 mg daily. So it's a very large dose dosage range. So there are a lot of uh limitations. There's a tla that means uh with time and the patient develop a tolerance to the medication. Uh Also patient can have some sensitive um uh sensitivities and it can cause nausea, vomiting, vomiting, skin lesions, and there's also liver function impairment. The most intolerance is caused by nausea, vomiting, abdominal discomfort, but 30 mg daily sometimes can be effective. And also patient tolerated 30 mg quite well. It is just when we titrate them up and they develop intolerance. So, this is one of the medication we can use long term and this is uh uh literature regarding use this medication for parasite carcinoma, we can see the calcium level nicely and trend it down with uh uh the treatment. And uh again, we can use these two medications long term and to treat hypercalcemia in malignancy, you can see the dosage is different than the dosage treating osteoporosis for zoic acid. And using 4 mg, you can repeat the treatment after seven days and usually the interval is recommended 3 to 4 weeks. And if GFR is uh less than 16. And for denosumab, the osteoporosis treatment is 60 mg every six months. But for treating malignancy with the hypercalcemia is 120 mg, much higher dose and plus much more frequent uh monthly. So those can be used the long term and they are effective and they also can be combined with a cac acid and with the increased e uh efficacy for hypercalcemia treatment. So, this is uh bisphosphonate approved and actually uh both uh medication has been approved, but Zoledronic acid is preferred and is more potent in uh pomegranate and both can be renal toxic. And the limitation you're aware of. Denosumab is FDA approved and for patient treating, prevent uh the uh relative co complications from the bone metastasis. And 1 20 mg every four weeks limitation is similar as the um zygotic acid except that the renal uh problems. So, denosumab and the patient with a severe hyper uh calcemia and the calcium level will gradually uh turn it down. So, um I think this is uh at the end. So basically, um the important thing I think is uh we discuss the evaluation, we discuss the referral, it should be individualized and we discuss uh several concepts uh related with the primary hyperparasite. And thank you very much for your uh time. And uh if you have any questions, I think there are a couple of minutes left. There was a question and thank you very much, Doctor Lee. Thank you in the Q and A uh the 50 year age cut off seems quite young. Would you please expound on the rationale for that? So I think the uh uh consideration is that those young patient, we should refer them early. Uh otherwise they may develop a long term complication because some of the complications, they were, it's not reversible, uh such as cardiovascular changes and uh high blood pressure, those complications are not reversible um after the surgery or cannot be completely reversible. That's why if we can identify the disease earlier and we should consider refer them. However, if you have a patient come to your clinic at 20 years old, 30 years old and they have uh um elevated calcium, elevated parathyroid hormone and your first impression should that you need to rule out the genetic uh gemini mutations. So that is um a different story. We have a patient with um uh just uh uh primary hyperparasite is sporadic, developed in forties. But we also have seen patients develop in 20 thirties and those 20 thirties are germline notated. Patients need to be ruled out. Ok. Thank you very much, Doctor Lee. Thank you. I don't see any other questions but if anyone has any questions, um you feel free to email me and I can get those answered for you from Doctor Lee. Thank you very much. Have a nice day. You too. Thank you.
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