As this session is recorded, I'll stop waiting and I would like to welcome all of our endocrine fellows who will join in the virtual version afterwards to this ASAP Live 2022 on pituitary, adrenal and neuroendocrine disorders. Next slide please. I would like to introduce our leadership, ACE Board Review course leadership here, Dr. Suraj and Dr. Gopalakrishnan. Next slide please. And today, you will be together with Dr. Gregory Hong and myself, Irina Bengus. Dr. Hong is Associate Professor of Medicine and he is Program Director of the Endocrine Fellowship Program. He is also in charge of the Pituitary Program at the Division of Endocrinology at the University of Virginia Health Center. And I'm a Journal Endocrinologist, also serve as a Social Program Director for Endocrine Fellowship at Mayo Clinic in Rochester, Minnesota. Next slide please. These are disclosures not pertinent to this presentation. A few items to remember, please type your questions in the Q&A box anytime during the case presentation. You can see or upload questions both by other participants as well. When the Zoom poll opens, please select your answer. You'll have around 30 seconds to choose that answer. And questions from the audience will be addressed at the end of each case discussion. We will try to go through six cases today. And one of us will be moderating Q&A sessions. So we are hoping to see a lot of questions. Thank you. Next. And I would like to introduce our speaker, Dr. Hong, who will start with case number one. Thank you, Irina. And then welcome everyone. So we'll get going with case number one here. This is a 62 year old man who was seen in the emergency department. He has a history of widely metastatic melanoma and recently completed his third cycle of chemotherapy with nivolumab and epilimumab. He's had a week of increasing fatigue with complaints of nausea, myalgias, and a mild headache. He's not had changes in vision or bowel habits. He's been able to maintain his oral intake at normal levels. Otherwise, he has type 2 diabetes and hypertension. He's on basal insulin, 50 units of bedtime, metformin, and lisinopril. Fasting blood glucoses have been 70 to 80 milligrams per deciliter over the past week, which is lower than normal for him. On exam, his BMI is 28. He's normotensive with a normal heart rate. He does appear tired. His extraocular motions are intact. Pupils are reactive. Visual fields are full. He does not have thyromegaly. He does appear euvolemic. The only other notable exam finding is a healed incision on the back where his initial melanoma lesion was removed. These are his relevant laboratory studies that you can see here. The bolded results are abnormal. And the reference ranges you can see here on the right. So we can see here that his sodium is modestly low. His A1C is 8. ACTH is 6 with a cortisol of 1.1 at 1030 in the morning. TSH is 1 with a free T4 of 0.3 and a uranosm of 400. This is a sagittal version of his post-contrast T1 MRI performed in the emergency room. And this is the question. Which of the following is the most appropriate next step in the management of this patient? A, discontinuation of his nivolumab, ipilimumab chemotherapy. B, treat him with physiologic dose hydrocorazone, roughly 15 to 20 milligrams per day, with subsequent initiation of levothyroxine afterwards. C is stress dose hydrocorazone, so approximately 150 to 200 milligrams per day with subsequent initiation of levothyroxine. And answer choice D is transplantal biopsy of the pituitary for diagnostic purposes. So we'll give everyone 30 seconds or so to make their choices. And once we see the answer choices slowing down, Beth will end the poll. Okay, so it looks like, based on our poll results, that majority of the participants chose answer choice B, which is physiologic dose hydrocorazone with subsequent initiation of levothyroxine, about 77% of the audience. And about 23% chose answer C, which is stress dose hydrocorazone with subsequent initiation of levothyroxine. No one chose answer A or D. The majority of people did choose the right answer, and we'll go through briefly why, and then we'll open it up to questions. So I think we all recognize that this patient likely has immune checkpoint inhibitor hypophysitis. This is a very, I guess, more prevalent condition that we see these days, given the widespread use of these immune checkpoint inhibitors. The highest risk seems to be with combination therapy with CTLA-4 inhibitors and or PD-1, PD-L1 inhibitors. Monotherapy CTLA-4 inhibitors seems to have a higher rate than the PD-1 and PD-L1 inhibitors. There's been a meta-analysis in GM several years ago that suggests the rate in combination therapy may be greater than 6%. The clinical presentation is hypopituitarism affecting multiple axes. You can also have mass effect symptoms related to inflammation or enlargement of the pituitary gland. Classically, we think of things like headache or cranial nerve 2 neuropathy. Potentially, the cranial nerves in the cavernous sinus, the individual field, or X shock or motion deficits. Many patients commonly have hyponatremia, presumably a result of the secondary adrenal insufficiency and or secondary hypothyroidism seen at the time of diagnosis. MRI can demonstrate a moderately enlarged or enhancing pituitary gland, which was seen in this patient. However, it's important to remember that MRI can appear normal in about 30% of cases. That's because essentially you can have a volume increase with hypophysitis, but that volume increase may not get big enough to the point where you exceed the normal dimensions of the pituitary gland within the cell. Really, what's most helpful is if you actually have a pretreatment MRI to compare it to, but we often don't have that, as you might expect. Management typically involves supportive care and appropriate hormonal replacement. If you have hemodynamic instability from adrenal crisis or if you have very severe mass effect symptoms, then high-dose glucocorticoids would be a reasonable option. Since this patient did not have those, that's why that answer choice or answer choice C was incorrect. We do have some limited retrospective data that suggests that high-dose glucocorticoid treatment actually may cause worse outcomes. This may be because if you think about it, the whole goal of immune checkpoint inhibitor chemotherapy is to kind of dysregulate the immune system to allow the immune system to attack the cancer. High-dose glucocorticoids are going to suppress the immune system, going to downmodulate that inflammation or that immune response. Obviously, that's going to lead to decreased efficacy against the tumor cells. As we just talked about, since he does not have severe symptoms of adrenal crisis, physiologic-dosed hydrocortisone followed by levothyroxine is the most appropriate strategy. Finally, this diagnosis is typically made clinically. We often never pursue a transplantal biopsy. Then why don't we stop chemotherapy in this patient? Well, if you look at the oncology guidelines, you can stop chemotherapy if someone has a very severe adverse event, whether it's endocrine or another organ. However, this patient would not meet criteria for a severe event. The hormonal deficits that we see here are easily treated with replacement medications. Furthermore, discontinuing the chemotherapy could lead to progression of disease. He has stage four melanoma. In a patient like this, it actually makes sense to just treat the endocrinopathy by replacing the hormones and then continuing the chemotherapy to treat his metastatic malignancy. We do know that from limited data, the risk of another recurrence of hypophysitis, if you continue or re-challenge with chemotherapy, is not zero, but it seems to be low, less than a one in eight chance. It would be reasonable to continue this patient on chemotherapy moving forward. With that, if anyone has any questions, if you would like to put them in the webinar box or in the chat box, I'd be happy to address those. If you think of them later, you can still put them in. I'll do my best to address them either in writing or at some point later in the presentation. Well, I hope we see at least one question. Well, it may take some time for people to get warmed up. Well, can I ask one? Sure. What is the chance of this person to recover from adrenal insufficiency? Yeah, it's a great question. It depends on the study you look at, and you have to keep in mind that these studies are maybe not done super rigorously, because in order to tell someone has recovered from adrenal insufficiency, you have to go through the process of tapering them off steroid, which sometimes the patients don't like. They feel poorly, and sometimes providers feel like maybe it's not worth the effort to try to get them off. But in general, the recovery of corticotroph function after hypophysitis is quite low, and some studies would suggest that it doesn't occur at all. It's likely less than 15% to 20% from what I've seen, and in most cases, it's the one axis that does not recover. The other axes, you can see a slightly better chance, maybe 40%, 50% chance of recovery than before. That's good to know when we counsel the patients, because that's probably what they ask. It will be forever that I'll have to take cortisol supplements. Right. Well, there are no questions for now, so I guess we move on for now, and hopefully people will engage a bit more. So it's my turn, and because Dr. Hong is the one who is driving the slides, I may have to say next slide, but we'll try to be smooth about it. So case number two is a 39-year-old man with a medical history significant for hypertension of 13 years duration, presented for follow-up after adrenal vein sampling. He's currently taking lozartan, amlodipine, flortalidone, and metoprolol. So a few things to point out here, that it's a young man who had hypertension since he was very young, in his 20s, and someone already diagnosed this person, it seems like, with primary aldosterone, because he comes to see us after adrenal vein sampling on four drugs. So this is his laboratory data from four weeks, two weeks, and one week ago. So some things to point out here is, if you look at his potassium, it was low or borderline. It was 3.24 weeks ago, and just on the border of normal two weeks ago. So that certainly is consistent with primary aldosterone. Also, I would like to point out to abnormal creatinine, which suggests that this person has primary aldosterone for quite some time, because some sort of kidney dysfunction already occurred. Aldosterone was elevated and renin plasma activity was suppressed both times it was measured. Not only this person had two positive case detection tests and hypokalemia, this patient also had confirmatory tests that some people would argue is not needed. But here you are, you have it. 24-hour urinaldosterone was above 12, when sodium was above 200. So with appropriate salt loading, urinaldosterone was inappropriately high, above 12. So I would say the diagnosis is crystal clear here. This person indeed has primary aldosterone. Next slide. And these are his results from adrenal vein sampling performed under casentropin stimulation. And that's important to know because every institution has their own protocol. So in this case, casentropin was administered. And the results are cortisol in the anterior vena cava was 17.9, left adrenal vein 514, right adrenal vein 20, and aldosterone was 29 in anterior vena cava, 96 in left adrenal vein, and right adrenal vein 25. So I read it intentionally because I think it's important for you to think a little bit about these numbers, because you may want to calculate the ratios and consider some other things here before interpreting the results. OK, next slide. So I hope everyone had some time to think about it. So what are the questions here? Which of the following is a correct interpretation of this patient's results? Is it A, failed cannulation of left adrenal vein? Is it B, no lateralization, source of excess aldosterone is bilateral in this case? Is it C, left adrenal lateralization? Or is it D, failed cannulation of right adrenal vein? So I think you have around 30 seconds, depending on how quick you answer it here. Oh, and I'm glad that we went back to this table. I had to remember myself what it says. People are still thinking, I see. OK, it's a tough one, isn't it? We have a bit more sort of like discordance here. The majority of you voted for left adrenal lateralization. Then the second most common answer was failed cannulation of the right adrenal vein. Then we have failed cannulation of left adrenal vein and no lateralization for the other answers. And before we go to the rationale, I just would like to stay a little bit on this table. And rather than me reading from the slide, I just want to go over this. I think the first step you have to do in interpreting adrenal vein sampling is to see whether this cannulation was successful in both right and left adrenal vein. The easiest way to do that would be to calculate the ratio between IVC cortisol and adrenal vein cortisol. Usually, a sign of successful lateralization is seeing cortisol ratio of around 5 to 1. For example, if you look at left adrenal vein cortisol, it's 514. If you look at IVC cortisol, it's 18. It's definitely more than 5 to 1. But if you look at the right adrenal vein cortisol, it's really very similar to what was measured in IVC. That already tells me that it is unlikely that the right adrenal vein was cannulated. So I would say right now, okay, right adrenal cannulation, failed right adrenal cannulation is one of the right answers. We actually could sometimes determine whether it's left or right adrenal disease. For example, in this particular case, it does not seem to be a left disease. But that's another question. So let's move on to the rationale. So again, I guess it's important to underline the fact that this patient did undergo appropriate workup for resistant hypertension. Someone eventually thought of primary aldosterone and did that case detection testing. He had hypokalemia, and he did have elevated aldosterone in the setting of suppressed renin plasma activity, despite the fact that he was on some medication that may interfere with renin plasma activity. I should also mention that if you suspect primary aldosterone, you can just go ahead with case detection testing for primary aldosterone, which is aldosterone and renin in the morning, without stopping any medications, including spredalactam or pleridine. This patient also had an elevated 24-hour urinaldosterone concentration in the setting of elevated sodium, which again reinforces the diagnosis. So based on the most recent guidelines, you don't have to do confirmatory testing in a person with hypokalemia and clear-cut positive case detection tests. So because this patient desired potential surgical cure, he underwent adrenal vein sampling to determine the source. So now that we've summarized the situation, let's go to the next slide. So, to remind you, the first step in interpreting adrenal vein sampling is confirming successful catheterization. And if it's done on the gesynthropin, the ratio of 5 to 1 is usually what you would see between IVC and either of the adrenal veins. It's only after that, when you calculate the value for each side, and then determine lateralization. So here, we did not even have to proceed with that because of the very first step telling us that it's not an interpretable test. Next slide, please. So, and this is just underlying what went wrong. In this particular case, this ratio between right adrenal vein cortisol and IVC was almost 1 to 1. Next. Okay, so given that the right adrenal vein to IVC cortisol was less than 5 to 1, cannulation of the right adrenal vein failed, so option D is correct. This is actually quite common, especially in centers that do not do a lot of ABS, because of the anatomy of the right adrenal vein and this variable angle at which it flows into the IVC. So, I guess option A is wrong, because cannulation of the left actually was successful. It was, I believe, 400 to 17, so way above 5 to 1. So once successful cannulation is confirmed, we calculate cortisol corrected aldosterone ratio to adjust for the dilutional effect of the inferior phrenic vein flow into the left adrenal vein. So in this case, you will see in the column number four that, oh sorry, the last column, cortisol corrected aldosterone ratio on the left was 0.19. Next slide. Contralateral suppression is seen when aldosterone to cortisol ratio from a correctly cannulated adrenal vein is less than or equal to 0.5. So the left adrenal vein in this case was successfully cannulated, and it's actually very informative what we found in this left adrenal cannulated vein. We found that aldosterone to cortisol ratio was 0.19, which is under 0.5. And that sort of excludes this adrenal gland being the culprit lesion. And if you know that the left one is not the one producing aldosterone, it remains to conclude that the right one is the one that is producing aldosterone and is the culprit lesion. This is why in this particular case repeating IBS is not absolutely necessary. You can just actually proceed directly with right adrenalectomy. Next. So, and I guess this is what it's saying here. Contralateral suppression is associated with high incidence of postoperative hyperkalemia, improved blood pressure, requirement of less antihypertensive treatment. This is a very serious contralateral disease. Therefore, this patient should undergo right adrenalectomy. After surgery, potassium should be monitored every week for four weeks because in around 6% of cases with this low of contralateral suppression, hyperkalemia can develop. In about half of these cases, hyperkalemia is transient and treatment is required in the other half. I have to say that from the personal experience, I've had one single patient who developed such profound hyperkalemia and myelocorticoid deficiency that this patient is on low-dose fludrocortisone three months now after surgery. Okay, I think we've over-discussed this case. It's just a lot of things to discuss. Next slide, please. This is just references in support of what we discussed. And if there are any questions about this, please let me know. It's a complicated thing to ask questions about, right? But I hope, I'm hoping people will. Well, Irina, while we're waiting for the audience to potentially submit a question, so just to clarify, the effect of contralateral suppression, that is 100% specificity, so you can go to adrenalectomy when you see that. You don't have to worry about not cannulating the other adrenal gland thus far. Because I don't know that that's actually in the guidelines. Is it, if I remember correctly? I don't think it's in the guidelines unless I'm also forgetting. Well, you know, never say never or 100% in endocrinology. I've learned that. So we love unusual things happening. But what it does tell us, assuming that all the labeling was done correctly, and again, in an institution that you trust the results coming from, it tells us that that adrenal gland was contralateral suppression index under 0.5. It's not the one producing aldosterone. And if you know that, let's say the left adrenal gland is not doing that, it really remains only, it leaves only two possibilities. Either it's the right adrenal gland, or it's ectopic source of aldosterone. And at Mayo Clinic, at least, we've never seen an ectopic source of aldosterone. I suppose it is possible, but it's just so very unlikely that, yes, I would probably, after discussion of all of this, proceed directly with contralateral adrenalectomy. That was my question. Is there such a thing as ectopic aldosterone? It sounds like, if you haven't seen it, probably it doesn't exist. A few case reports out there, yeah. But not at Mayo, at least. Okay, well, I guess maybe we should continue then. Okay. So far, we're going according to the plan. All right. This is case three. 36-year-old woman evaluated as a new patient to establish care. She has a history of Cushing's disease diagnosed a decade ago. She had a transmodal resection, initially achieved remission, but then had a recurrence. MRI did not demonstrate an obvious surgical target, and as such, she completed radiation therapy to the entire cell six years ago. She did achieve biochemical remission, but developed panhypotutism four years ago. She feels relatively well. She has regular menses, stable weight, and moods. She's on levothyroxine 100, hydrocortisone, ethinyl estrogal, norethindrone, oral contraceptive pill, and growth hormone at 1.2 milligrams sub-q every day. She only has another otherwise notable medical history of hysterectomy for uterine fibroids relatively recently, several months ago. She's normotensive with a BMI of 25. She does not appear Cushingoid or acromegalic. She has full visual fields, normal proximal muscle length, normal reflexes, normal skin. She has a free T4 of 0.8 with a reference range of 0.7 to 1.5. Her IGF-1 is 217 with a Z-score of 1.2 standard deviations above the mean. She would like to avoid the progestin component of her contraceptive pill. You instruct her to stop the oral contraceptive pill and then prescribe transdermal estradiol instead for her estradiol replacement moving forward. Which of the following represents the best next step in this patient's management? A, decrease her growth hormone dose, B, decrease her levothyroxine dose, C, increase her growth hormone dose, or D, increase her levothyroxine dose. So we'll give people 30 seconds or so to answer this question. Okay, looks like we have a somewhat of a spread here. We have the majority wanting to decrease her growth hormone dose. The next most popular answer is increase her levothyroxine dose. And then the least popular answers are either decrease levothyroxine or increase growth hormone. So this question gets at how do hormonal replacements for hypopituitarism interact with each other and what are the factors or the considerations we need to keep in mind in someone who's panhypopituitary. So as we go through the rationale here, the critical thing to remember is that oral estrogen induces several protein changes at the level of the liver which could impact replacement dosing of hormones. So because you have first met past metabolism oral estrogen, you do have a degree of hepatic growth hormone resistance leading to a decreased level of IGF-1 that's made by the liver. And so typically in someone on oral estrogen, you will need a higher dose of growth hormone to maintain a similar IGF-1 level compared to those who are taking transdermal estrogen. So transdermal estrogen obviously bypasses those first past metabolism effects. And so that's something to keep in mind in this patient. So this patient currently has a relatively substantial dose of growth hormone for her weight, so 1.2 milligrams. Typically we start at 0.3 to 0.4. Her Z-score is quite robust at 1.2. And so the likelihood is if we transition this patient off oral estrogen, there may be a good chance that if we keep her growth hormone dose the same, she'll have enhanced production of IGF-1, potentially leading to iatrogenic acromegaly. Likewise, increasing the growth hormone dose would not be necessary in this situation for reasons we just discussed. I personally like to keep the IGF-1 level right around 1.0 or the Z-score right around 1.0. She's already at that sweet spot, and so if we make this change without making the corresponding decrease in growth hormone, it's likely that that Z-score is going to increase to potentially abnormal ranges. We obviously should remember that oral estrogen includes this TBG production from the liver. This could potentially lead to increased dose requirements of levothyroxine. We know that oral estrogen therapy slightly increases mean levothyroxine dose requirements in people with central hypothyroidism. And in this patient, if we stop oral estrogen, we may actually need to decrease her levothyroxine. However, since this patient has a free T4 level near the lower limit of normal, it's unlikely that this situation would apply to her. It's important to remember that growth hormone can have potential effects on levothyroxine or glucocorticoid dosing, so growth hormone can enhance conversion of T4 to T3. And so if you're following the free T4 as the parameter, which a lot of times is the best we have in someone with central hypothyroidism, you may have to adjust the levels of levothyroxine placement if you're looking at free T4 only. And growth hormone can also increase metabolism of cortisol. So if you start someone who has adrenal insufficiency on growth hormone, you may need to increase their dose of hydrocortisone as well. All right. So increasing levothyroxine for the reasons we just discussed would likely not be reasonable in this patient because she's actually stopping oral estrogen. Typically, if we do need to make a change, we just monitor again four to six weeks. And you can make an argument, well, is free T4 measured the standard way, really the best way to assess for levothyroxine adequacy in people who are potentially having TBG binding protein or TBG level adjustments? And maybe it's not, but oftentimes we don't go through the expense and the hassle of doing it via equilibrium dialysis. So the endocrine society does recommend just using free T4 in a normal assay to base your levothyroxine dose amount. Okay. I believe that is the summary for this patient. So, or for this question, I'm happy to take any questions from the audience, if anything wasn't clear or if anyone has any comments on that. Don't be shy. And again, to fill in the time, I have one question of my own while maybe someone is type typing. So a bit of a different question, but let's say in a woman was pituitary deficiency, would have to be partially pituitary deficiency on stable pituitary hormone replacement therapy who becomes pregnant. How would you monitor or change hormone replacement therapy during pregnancy? Yeah, it's a great question. So one of the things to remember is that the placenta oftentimes will make a lot of hormones, right? So oftentimes that's kind of a fail safe or a backup to help us in the hypopituitary sense. And one of the things to remember is that someone with central hypothyroidism has a normal thyroid gland and can presumably respond to HCG that's made during pregnancy, right? So you may see during the first part of pregnancy, as those HCG levels rise, that they may actually need a lot less supplemental levothyroxine than they otherwise would. Glucocorticoid replacement tends to stay roughly similar for the most part. It's hard to really monitor the adequacy of that. You kind of have to go just based on symptoms, which is obviously difficult if someone has morning sickness. And then finally, growth hormone. In general, it's not FDA approved during pregnancy. In general, the further along someone goes during pregnancy, the more the placenta actually makes growth hormone. So some people have advocated, well, it might be fine to continue it for the first trimester, but then once you hit the second and third trimester where placental growth hormone really picks up, you can probably stop it and the fetus will have adequate exposure to growth hormone based on placental production. So it gets very complicated. And so to be honest, a lot of times we don't even worry about growth hormone in the pregnancy study. So let's address some of these questions here. So apologies if this wasn't clear. So the correct answer in this question is to decrease the growth hormone dose because as you stop the oral estrogen, you'll lose that growth hormone resistance at the level of the liver and that growth hormone dose, which is already relatively robust, may end up being too much. So I hope that's clear. The second question is, should we titrate the dose right away or can we repeat labs after a few weeks and then titrate our doses? So I think you could probably do either. I think for the sake of this question and for the sake of just routine clinical practice, we would probably expect this patient with an IGF-1 and a Z-score of 1.2 is almost certainly going to become acromegalic if you stop that oral estrogen. And so rather than, you know, potentially causing a problem like that, I think it makes sense to proactively decrease the dose. You can always decrease the dose and if the IGF-1 falls too much, you can always go back up and that way you avoid any type of super therapeutic dose dosing, even if it's for a short amount of time. So good questions, good questions. And then I think there's one last question in the chat. Would there be atrophy of the thyroid if they have central hypothyroidism? If there is atrophy, would the thyroid respond to HTG? So yes, in the absence of any TSH simulation, you probably do have some degree of thyroid atrophy. I don't know if it's clinically significant the same way that you see adrenal cortex atrophy in the absence of ACTH. We definitely do see pregnant women be able to respond to endogenous HCG despite not having had TSH for a while. So it's a great question. I don't know that I have a firm formula or calculation exactly predict how much it's going to atrophy over what period of time, but there probably is some degree of that. So excellent question. Okay, Irina, I'll turn it over to you for the next case. Yes, I'm so excited. We are starting to have some questions. Okay, case number four on adrenal medulla. Next slide. And this is a 33-year-old man with no significant medical history who comes to the emergency room with acute abdominal pain and vomiting. His gastrointestinal symptoms spontaneously resolve with hydration and observation. However, computed tomography scan obtained in emergency room is abnormal, demonstrating bilateral adrenal tumors. And it is at that time he's referred for endocrine evaluation. At that time, his blood pressure is borderline 131 over 87, and heart rate is 68 beats per minute. He has mild freckling on the face, but not in the axilla, and no evidence of cafe au lait spots. Siren's examination reveals no palpable nodules, and he does not know of a family history of pheochromocytoma paragangliomas. Next slide. And this is a CT scan from the emergency room. You will see, hopefully, on this slide, an 8.8-centimeter right adrenal mass, heterogeneous, nasty-looking, I would say, and a 5.8-centimeter left adrenal mass. Again, heterogeneous with areas of necrosis from what I see here. On an enhanced CT scan, the Hounsfield unit is 36 on the right and 24 on the left, and this definitely places his tumors in indeterminate range. We cannot really exclude either malignancy or pheochromocytoma. On contrast enhanced CT scan, and this is what you're looking at, both adrenal tumors are heterogeneous and lobular in appearance. And in addition to adrenal tumors, this person also has a 6-millimeter pancreatic lesion, most consistent with neuroendocrine tumor, which I think is in this stem because we would like you to come up with differential diagnosis here. So remember this pancreatic lesion. Next slide. So laboratory findings included elevated norepinephrine and noremetanephrines, pretty significantly elevated, five times normal. Concentration of dopamine, epinephrine, metanephrine are all within normal ranges. So I hope you would agree that this is consistent with catecholamine-secreting pheochromocytomas, noradrenergic phenotype because epinephrine and metanephrines are normal. So this patient was prepared with two-week alpha-adrenergic and beta-adrenergic blockade, and after that underwent bilateral adrenalectomy. Pathology, not surprisingly, confirmed bilateral pheochromocytomas. So to summarize the case, before we go to the question, this is a person who has bilateral pheochromocytoma. So right away, we have to think genetic. This is a person who is noradrenergic by a chemical phenotype. So catecholamine excess is purely noradrenergic. And I hope you remember my reminder that this person has a pancreatic neuroendocrine tumor as well. And armed with this information, we are ready to answer the next question. So which of the following genetic predispositions is most likely associated with this patient's presentation? Is it neurofibromatosis type I? Is it von Hippolyndo syndrome? Is it multiple endocrine aplasia type A? Or is it succinate dehydrogenase B or SDHB-associated pheochromocytomas? So think a little bit about that. All four of these conditions can present with bilateral pheochromocytomas. You have to think about other things in this step to help you answer this. Of course, in the day of next-generation sequencing, which is autogenetic testing, we don't have to guess. But let's say it's very expensive and you have to choose one single genetic test. Which one is that? So the most popular answer is multiple endocrine aplasia type A. It's actually the wrong answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. It's not the right answer. Hepatitis B1, though, is almost always present with neurodegenerative biochemical phenotype. And pancreatic neuroendocrine tumor was another big sign because 17% of patients with VHL have pancreatic neuroendocrine tumor and the rest have cystic pancreatic, so pancreatic cysts. Other manifestations include hemangioblastomas of the brain and spine, retinal hemangioblastomas, glial cell, renal cell carcinomas, cereocystodenomas of pancreas and endolymphatic sac tumors. In fact, this particular patient afterwards did undergo MRI of brain and spine and was diagnosed with also hemangioblastomas, but not at that time. Next slide. So once a diagnosis of VHL is established, this patient should be tested for associated conditions that I've described. Patients with VHL chromosome associated with MEN2 and NF1 usually have an adrenergic biochemical phenotype. I would say 99.9% of situation is adrenergic biochemical phenotype, meaning both adrenaline and noradrenaline or metanephrine and normetanephrine are elevated. Next slide. Associated conditions in MEN2 include mainly medullary thyroid cancer and primary hyperparathyroidism. Patients with NF1 also demonstrate neurofibromas, optic pathway gliomas, other central nervous system neoplasm, and sarcomas. Again, MEN2 and NF1 could have been excluded just based on a neuroendocrinogenic phenotype. Patients with genetic predisposition to SDHB or D also have neuroendocrinogenic profile, but are much less likely to have bilateral pheochromocytomas or pancreatic neuroendocrine tumors. Bilateral pheo is certainly possible, but most of the time, these people present with extradrenal barogangliomas. So bilateral pheochromocytomas occur in around 20% of patients with NF1 and 40% of patients with MEN2 and VHL. Now to conclude, genetic testing is recommended for any patient with pheochromocytoma, whether it's unilateral or bilateral, but absolutely certainly if it's bilateral. Most pheochromocytomas are discovered incidentally, 60% in fact, and may not present with hypertension, tachycardia, or other symptoms. This person presented incidentally, despite the fact that he had two huge pheochromocytomas. Next slide. And I think this is it, these are the references, and I am happy to answer questions. So Irina, there's two, I guess, questions or comments that came in the chat about the lack of renal tumors in this patient. How common would that be in someone with VHL, and would that be something that's very uncharacteristic of a VHL patient, I guess, is the way to put it? Yeah, so actually only a minority of people with VHL have renal cell tumors, and it's a lifelong accumulation of events. So it is very possible that this person eventually will develop renal cell carcinoma as well. But I would not exclude VHL, just because you don't have renal cell cancer. Now, unfortunately, I do not recall the exact percentage of patients with VHL presenting or never developing renal cell carcinoma, but I bet it's a minority who do. What I mean by minority, certainly under 50%. Thank you. Could I ask, maybe, patient has two very large pheochromocytomas, but based on the question stemmed, sounded relatively asymptomatic. Is that also an unusual presentation, or is that enough? Yeah, that's a good question. So I would say once you have such a bulk of disease, it is unusual. I would have expected at least some symptoms. But overall, like all comers with pheochromocytomas, with no unilateral most of the times, median size is usually like four centimeters. It's not uncommon that pheochromocytomas are incidentally discovered. And even when you ask the person in retrospect, there is just mild symptoms. So the era of spells of pheochromocytomas and multiple P's, five P's, or whatever else is gone. We live in an era when most pheochromocytomas are discovered incidentally, all by genetics critic, actually. Any last questions for Dr. Bankos before I move on? Sure, good questions. Yeah. Can you have MEN2 just secreting norepinephrine? You can, but I would say it's very rare. I believe when we looked at our data, we found only one patient. And I'm not sure why, but 99% of MEN2 would have adrenergic profile. Okay. Thank you. Thank you. Well, we will move on here. All right. Case five is a 28-year-old female with a history significant for bipolar disorder. She was referred for a further evaluation of urinary frequency. She drinks five 32-ounce water bottles, which roughly equates to five liters per day due to significant thirst. And she's had some headaches as well as nocturia up to four times per night over the past month. She did take lithium previously, but is now maintained on a different mood stabilizer. Family history is unremarkable. Her PCP does urine quantification, and she does have a 24-hour urine volume of 3.5 liters. So it does meet the definition of polyuria. These are her referral laboratory tests that come with her to her visit. Her sodium is minimally elevated with a normal A1c. Calcium is also normal, and her urine osmium is 200, obtained simultaneously as the sodium. A MRI of the brain is ordered given chronic headaches. These are the findings that are shown here. The question is, what is the best next step in the management of this patient? Should we obtain early morning ADH and vasopressin levels? Should we perform an overnight water restriction test? Should we obtain a random copeptin measurement? Should we advise drinking only to thirst and then returning for longitudinal follow-up? So let's take 30 seconds and see what the audience thinks. Okay. The majority of people want to do a water restriction test. A smaller percentage of people either want a random copeptin or to assess ADH levels in the morning. So let us go through this. The correct answer is actually B, as the majority chose. And we'll go through why here in the rationale. So this patient has polyuria, and the differential for diagnosis for this is broad, obviously. This could be central or nephrogenic DI, psychogenic polydipsia, and solute diuresis. However, the constellation of lab findings we have so far, so hypernatremia would inappropriately dilute urine osmium, is consistent with diabetes insipidus. And for diabetes insipidus, really the water restriction test or the water deprivation test is the gold standard for establishing this diagnosis, at least historically. Central DI is suggested based on her enlargement of the pituitary gland. This suggests potentially an infiltrative process. Nephrogenic DI obviously could be suggested by her previous use of lithium. It's probably unlikely she has some of these rare inherited causes of DI, given her family history is negative. As we all know, you can administer synthetic ADH during the water deprivation test to distinguish between central and nephrogenic DI. Bipolar disorder is kind of the classic board answer for psychogenic polydipsia. But remember, that's a state of water excess, and so you should have hyponatremia, not hypernatremia like this patient has. If you have a solute diuresis, either from hypercalcemia or glucocerea, then you would expect an elevated urine osmium, which this patient also does not have. What about measuring ADH or copeptin? Because that's potentially a theoretical way we could look for central DI. ADH typically isn't done all that often in the clinical setting, just because a lot of times we don't have access to accurate and easily available assays for ADH. For that reason, it's not typically included in the recommendations for the diagnosis of central DI. Copeptin, we do know, is a prohormone that contains ADH or a prohormone that contains ADH and copeptin is secreted. Basically, that cleavage project results in copeptin, which can be measured relatively accurately in most laboratory settings. However, if you remember from the New England Journal paper that looked at copeptin as a use in the diagnosis of diabetes insipidus, that needs to be done in the setting of hypernatremia. You don't do that randomly. The reason that that was not the right answer is because the answer option was to measure it in a random fashion, which is not how it typically should be done to make the diagnosis of DI. Obviously, advising the patient to drink only to thirst doesn't really get at the diagnostic reason for DI. It's probably important to get at the diagnostic reason for central DI, at least, because that could be from an infiltrated process that may need some either ongoing management longitudinally or maybe a diagnostic evaluation. In this particular patient, she did have an overnight water restriction test for potentially four to six hours. I don't exactly remember. This is not my patient, but she did have hypernatremia with a plasma osmum of 298, so elevated and inappropriately low urine osmum, which did respond to death suppressants. So she has classic central DI and was found to have GPA with pituitary gland involvement as the cause. You know, the quick teaching point unrelated to this is anytime someone has central DI, it's never from a pituitary adenoma. It's always from some sort of infiltrative process or a supercell or lesion like craniopharyngioma. Run-of-the-mill pituitary adenomas almost never present with DI. OK, these are the references, and I will take any questions if anyone has any. So as people are typing, I'm curious, how was the diagnosis made? Was it through biopsy? I don't know. This was not my patient. Another physician submitted this case, but I'm almost certain that it would be biopsy. I mean, you can get the ANCAs and the serologic studies, but in a case like this, and whenever someone presents with DI or any degree of hypopitutism and emerald like that, we always biopsy to rule out things like germinome or some things that could be very, very bad. It would need quick treatment. Yeah, I'm always concerned about biopsy damaging the pituitary gland some more in this case. That's all my concern, especially someone who does not present with panhypopituitaries. I think it's a very valid concern, Irina. And I think you have to have a surgeon that's very cautious and prudent and only takes out a small part of the anterior lobe. Let's just put it that way. But it's a valid concern. Well, Irina, I think we have maybe time for one last case. Eight minutes left. Should we try? Yes, we'll try. Okay, adrenal incidentaloma, my favorite. 65-year-old woman with bilateral adrenal mastitis is being evaluated, and she has history of type 2 diabetes, hypertension. Also diagnosed with multiple myelomas three years ago, for which she underwent autologous hematopoietic cell transplantation. Recent PET scan for evaluation of right hip pain revealed unchanged bone lesions and bilateral adrenal notches, measuring 1.5 centimeters in maximum diameter with SCV max of 7.46 on the left and 6.32 on the right. Next slide. And this is not my case as well, but I guess I do see the PET positivity in both adrenal glands on the figure on the left. And I see some nodular appearing adrenal glands on the right. Next slide. Review of the pre-transplantation abdominal CT images showed that adrenal nodules were similar in size. And on physical examination, her blood pressure was elevated, heartbeat 72. She's obese, but has no cushion good features. Next slide. And this is her biochemical workup. So clearly demonstrating some hyperglycemia in the range of diabetes, normal potassium. I see that plasma metanephrines were negative, but one milligram dexmedezone suppression test was abnormal at 2.6 microns per deciliter, so above 1.8. I see that baseline ACTH supposedly performed on a different day from dexmedezone suppression test was suppressed under 10 picograms per milliliter. Also DHA sulfate was very low at 12 microns per deciliter. So both ACTH and DHA sulfate was low. 17-OH progesterone was mildly elevated. And I see that aldosterone and retinoplasmic activity sort of excluded primary aldosterone. So we have autonomous cortisol secretion and ACTH-independent autonomous cortisol secretion here. Next slide. What is the most likely diagnosis for this patient? Is it congenital adrenal hyperplasia? Is it metastatic adrenal disease? Is it bilateral macronodular adrenal hyperplasia? Or is it bilateral pheochromocytoma? I guess this question happened a bit too fast. People are taking some time to think about it. So I guess CAH is here because 17-OH progesterone was elevated and bilateral nodular disease, metastatic adrenal disease because of this history of multiple myeloma, bilateral macronodular adrenal hyperplasia because of autonomous cortisol secretion, and bilateral pheochromocytoma because of uptake on PET scan. Okay, so majority said bilateral macronodular adrenal hyperplasia with the two other answers being CAH and metastatic adrenal disease. No one voted for bilateral pheochromocytoma. Okay, next slide. So it is bilateral macronodular adrenal hyperplasia or BEMA. This patient has enlarged adrenal glands with bilateral nodular lesions, which are apparently stable in size because the stem told us that adrenal nodules were of similar size for several years. So this does support the diagnosis of benign tumors. Based on the size criteria, these are consistent with macroadenomas. The investigational functionality of bilateral adrenal tumors include the same hormonal evaluation to exclude hormone excess as recommended in unilateral adrenomas. As we've discussed before, aldosterone and radiin excluded primary aldosterone, but the lower CTH, incomplete cortisol suppression after one milligram dexamethasone suppression test, as well as low DHA sulfate are all supportive of autonomous cortisol secretion. Next slide. So the frequent finding in PEMA is this positivity on PET scan. So these are cortisol producing nodules. So it's frequently in the false positive range, where should this person have PET scan for any other reason, I usually, for example, get a referral for possible adrenal metastasis. Most of you did not go on that, but it's just important to be aware that maximum SUV of 3.3 and 8.9 have been described not only in bilateral macronodular adrenal hyperplasia, but in any other functioning benign adrenal nodule. Another thing to comment on is 17-hydroxyprogesterone. So macronodular adrenal hyperplasia has slightly impaired stereogenesis. So you could see elevation in 17-hydroxyprogesterone and also some of the other steroids, immature steroids, if you measure them. Next slide. Both incomplete suppression of cortisol after dexamethasone and undetectable ACTH level helps distinguish between CAH and PEMA. In CAH, you would actually find elevated DHA sulfate in untreated CAH, and you would find elevated ACTH, or at least high normal ACTH. So low ACTH indicates that our pituitary or this person's pituitary gland is sensing too much cortisol. But remember, in congenital adrenal hyperplasia, it's cortisol deficiency that is driving ACTH production from the pituitary gland and subsequently androgen excess. And as you all picked up, while pheochromocytomas can present with high FTG uptake in PET scan, negative plasma tenebris just makes this diagnosis unlikely. Adrenal involvement in multiple myeloma has been described in very advanced disease, but it's just very unlikely in someone with otherwise very stable myeloma to have this adrenal involvement. So most of you chose right here. Next slide. And I think this is just references. And we have just one minute for a question or so. So Irina, I think that the question of the day, and this is a doozy, is how would you treat this patient? There's evidence of maybe autonomous glucocorticoid secretion, there's hypertension, diabetes. What would you recommend in this situation? Well, I struggle with the answer to this question every day, because I'm an adrenal endocrinologist. So most of the patients I see, you know, have some sort of adrenal nodules. Well, so first, I think it's important to sort of like conclude that we are concerned about autonomous cortisol production in this patient. Why? Because she does have obesity, she has diabetes, she has hypertension, I believe some other possible cortisol related morbidity. So once we decided we are concerned, I think the next step is to decide how concerned. Do we want to just conservatively manage each of that comorbidity separately and aggressively? Do we want to remove just one of the adrenal glands? And in this particular case, it's more or less equal. So whatever is easiest to remove, because by removing one adrenal gland, we are decreasing autonomous cortisol production by 50%. In someone who is without Avert-Cushing syndrome, this could be sufficient for years to come, as far as stopping progression of cortisol-induced morbidity. Biolateral adrenalectomy is the mainstay of therapy for this patient, but I frankly don't do that unless a person has pretty severe hypercortisolis. Or we've exhausted other options. And finally, we do have medical therapy for cortisol excess, but I also don't think it's an excellent option because it's expensive, has a lot of side effects, needs a lot of monitoring, and to expose someone to medical therapy, which is still sort of like very new. Basically, it's not yet spironolactin for primary aldosterone. Possibly when we have an agent like spironolactin for primary aldosterone for this patient, I'll change my mind. But for now, I think most of my patients would probably be considered for unilateral adrenalectomy. Thanks, Serena. That's a tough question. I will say that there is nifeprestone, which is a glucocorticoid receptor antagonist or blocker that sometimes we'll use in the Cushing setting that does maybe analogous to what spironolactin does, but then you have a bunch of side effects with that as well, which we won't get into. I think we're at 8.02, so I think we're out of time, but we would like to thank all of you who have participated with us. We hope you found this useful and informative, and we wish you the best of luck studying on the boards. I don't know if anyone saw the recent board pass rates for the endocrine exam, but it was pretty grim this year, so you have your studying cut out for you. Oh, that's not the good way to end it. I'm sure everyone will do fine, and you'll do better than the people that weren't here tonight. Let's put it that way. Thank you. It was a pleasure speaking about adrenal inflammatory today. Okay, thank you, everyone.

endocrine disorders

live session

pituitary

adrenal

neuroendocrine disorders

case scenarios

diagnostic tests

management approaches

patient cases

healthcare professional