Insights from JCM Case Reports Lecture

well welcome everyone to clinical pearls from jcm case reports this is the second year we're holding this special Forum my name is Bill Young I'm the editor and chief of the journal and our co-chair is Dr Adina turku who is the Deputy editor for the journal we have three presentations they're going to be fairly short about 7 minutes followed by a Q&A with the author and then we're going to invite up an expert on the topic to expound some pearls for you on that particular case so we're going to start our first presenter is Dr Lauren Doyle uh she did her training at Bowmont Hospital the r rcsi in Dublin Ireland she basically just completed the equivalent of Internal Medicine Residency in the US and is now moving on to her endocrine Fellowship the title of her paper is clinical utility of g& analoges in female andren exess highlighting Diagnostic and therapeutic applications Lauren thanks very much Dr Young And so thanks very much for the invitation to present today um so I delighted to be um here to talk everyone through our management experience of using GnRH analoges in uh diagnosing and treating female Androgen excess there we go H so I have no conflicts of interest to declare but just to highlight that we are discussing um an off Lael use for trypan and other medications within the GnRH analog class so before we dive into our cases I think it's important to highlight the principle of GnRH analog testing so this relies on the principle that um ovarian derived anen excess will remain under the control of the hpg axis but adrenal Androgen excess will not um so following administration of a 3 milligram trip Talent OR similar IM we'll get initial pituitary receptor binding and a downstream U regulation of gadal products but at about two to three weeks we'll see a result in desensitization and downregulation of these receptors due to loss of pulsatility and we'll see a 50% reduction in serum testosterone at day 28 following Administration so our first case we had a 68-year-old woman who presented with a three to four year history um of evolving facial her heroism and Alesia C doesn't seem to be working on this for me there okay perfect yeah that's working better now um so she had rapidly she had some alarming features including rapidly Progressive vocal deepening and reported changes in the external genitalia and the immediate months prior to presentation her past medical history was largely insignificant and she had no previous reproductive concerns expressed her initial biochemistry was quite alarming so we can see a massive elevation in her serum test off poone and so and quite inappropriately suppressed ganat tropins for a postmenopausal woman interestingly she also had elevations in her seramal and elevations at both her hemoglobin and hematocrit which have been reported in cases of virilization previously so naturally this woman underwent urgent radiological workup to try and ascertain where exactly the source of her Anin excess was was so she had normal adrenal um Imaging um but an ultrasound pelvis showed a large R ofar in hypo aoic MK so while she was awaiting Gynecology review she underwent an adjunctive investigation in the form of a GnRH analog suppression test and we can see the results of this here so the benefit of doing this was to try and ascertain whether or not hpg access regulation was maintained which would be more reassuring for a benign etiology to her andren excess so here we can see full suppression of her serum testosterone um at day 28 in addition to suppression of her andr Dion so this lady was referred onwards to gynecology had a benign aarian steroid cell tumor identified following bilateral cell Piner rectomy and most notably had full Androgen suppression day6 post operatively our second case had a much more indolent uh presentation so this was the 67y old woman who is referred with the 15year history of heroism with some Associated frontal hair thinning similarly had no significant past medical history clinically on exam she did have evidence of an increased body mass but no cushingoid features or insulin resistance were evident her initial biochemistry while abnormal was not as significantly alarming as our first case but we did see a testosterone of 2.5 on her initial um biochemistry and an eastra dial of 130 in terms of ascertaining where exactly this was coming from she did normal overnight dxms his own suppression test and an incidental left-sided adrenal my lipoma was identified on CT Imaging and she normal transvaginal ultrasound with no evidence of any ovarian pathology given her overall biochemical pattern um her indolent clinical history and normal Imaging it was felt that this woman most likely had a benign ovarian source for her anren excess and most likely in keeping with an ovarian hyperthecosis so she had a 50% reduction in her serum testosterone following 28 days um after a GnRH analog suppression test which would be indicative of a confirmatory test given the chronicity of her symptoms the absence of any features of feralization it was felt that she most likely had a benign aarian pathology most likely an ovarian hyperthecosis given her initial symptomatic relief following administration of the G analog she declined further referral for surgical intervention instead opting to continue with regular trip to rein therapy which was ultimately transition to a long acting Depot preparation and due to successful symptom suppression our final case discusses a benign use or premenopausal um case of a 25-year-old woman referred with significant heroism and secondary amen ARA her past medical history was significant for a juvenile dermatomyositis and an overall adverse metabolic phenotype as indicated by her steroid induced typer glycemia iously and hypertension and obstructive sleep apnea clinically she'd EV evidence of a partial lipo distrophy with relative trunkal sparing and stigma of severe insulin resistance her initial biochemistry showed an elevated LH to FSH ratio and then very significant elevations in her serum testosterone and andrine jion she also had massive hyperinsulinemia so the working diagnosis here was a severe insulin resistance syndrome most likely an acquired partial hpid distrophy in the setting of her Juvenile dermala Myositis she had normal Imaging overall with no Source identified for andren excess so she underwent a 3 milligram trip toin Administration to try and ascertain whether this was ovarian um or adrenal in origin and she had confirmatory testing here with full suppression of her testosterone H following 28 days she also had very significant symptom resolution um so in as a result of this she opted to trial regular GnRH analog therapy with addback sequential combined HRT for bone and um phas of motor symptom alleviation unfortunately this had to be temporarily disc continued following an es schic stroke um however this was felt more than likely to be in the setting of her systemic vascular resistance and um unrelated to her um her g& orh analog therapy given that she's no desire for future fertility she's opted for a Gynecology referral for an elective bilateral Singo rectomy so in terms of take- Home messages we proposed that the GnRH analoges would be potentially useful adjuncts and the diagnosis of suspected over VAR Androgen excess with the potential to reduce Reliance on any invasive procedures in the correct context therapeutically um they offer a potential non-operative um management option for postmenopausal women again with clear benign sources for anren excess who wish to avoid surgery or indeed for premenopausal again with C clear benign sources um who with very significant symptoms who wish to have a fertility sparing alternative it's very careful that careful case selection is undertaken and that features of viralization or indicators of malignancy are not overlooked thank you [Applause] thank you Lauren for that presentation you you kept right on time for those who have questions or comments for Lauren we have a microphone in the aisle over here just come to the microphone introduce yourself and ask your question in the meantime Lauren I would like to ask you a question in your first case where you had an ovarian tumor you decided to use this test to differentiate between a potential malignant versus benign cause have you used uh PET Imaging or no so we had news pad Imaging in this case um another kind of potential Imaging that may have been useful in terms of identifying potential tumor versus aian hyperthecosis maybe would have been MRI they seem to have reasonable sensitivity but we didn't have Pet Imaging available in our Institution for for that type of indication interesting so I wanted some adrenal tumors have LH receptor do you have any experience from your review of literature of how they might respond to this analog um an interesting question I have no personal um experience around that um particular indication um but I know particularly in the in the cases of the insulin resistance syndromes um with our partial life p distrophy and that they can get some stimulation by the excess insulin as well to give them adrenal andren production but I wouldn't have any any direct experience um in terms of um LH and adrenal andrin Richard Quinton Newcastle Mick said to come and say hi um I can answer that question um yes um they they if an adrenal um um adoma um expressing the lhg receptor yeah they shut down perfectly with um gen analog treatment um but my question was um Peter Lou uh Los Angeles so in your third case um the person had sleep up and there's evidence that if you re reverse the the hyper engine and the sleep app can actually improve did that actually happen in this in that case so she didn't we've only I think had maybe 12 months since we've commenced therapy and given the kind of interruption particularly around the time of her um the concern around the stroke we haven't had a sustained period of time long enough to really ascertain whether or not we got Improvement the question I was going to really ask before I bulldo peed out of the way sorry was in ter it's a great treatment but in terms of Diagnostics what does it add above um nothing in the adrenals and low dhas I suppose um in in terms of what it adds I think in our experience in in terms of um reassuring Imaging um it gave us kind of some additional reassurance that there may have been a purely ovarian benign Source going on here rather than anything adrenal Al rogal Charlottesville Virginia uh Little Wrestler so that's those are good hands um especially with ad Dena on the uh uh at the as chair the issue that you're trying to do is to distinguish between ovarian and adrenal so is there a uh place for measuring Oxo testosterone or Oxo DHT I think down the line that that would be something that we'd like to include but in terms of um assay availability and resource allocation that can be quite challenging particularly in some of the contexts that we're working within um so hopefully down the line when we have greater availability of those type of Diagnostics it would be great to include that but in terms of the resources that that uh we have at our disposal this could be an additional benefit in that context thank you any uh words of wisdom Adina so in the US uh Lab Corp at least and I think maybe Quest is incorporating these assays but I know they offer Lab Corp offers 11 keto testosterone great Lauren thank you very much now I'd like to invite up our expert on this topic Dr Francis Hayes from Mass General at Harvard right here in Boston Francis thank you very much Bill and congrats to Lauren for an excellent presentation um so the question here as Dr Quinton um sort of um raised is what is the utility of generate analoges as both a an um therapeutic and diagnostic modality when you're faced with that patient who has significant hyperandrogenism so the first question is um as um Al asked is the excess Androgen coming from the uh ovary or is it coming from the adrenal as Lauren mentioned the hormone profile the Baseline hormone profile can be helpful in that if there's a predominant increase in testosterone um over and above anderen diione or DHEA uh that favors an ovarian source and can be confirmed um if there is significant suppression um the question then is whether you need to do this test on everybody that you see with um significant hiber androgenisation if you have a normal adrenal CT you have effectively um excluded a functioning either benign or malignant adrenal nodule now in one of Lauren patients there was an adrenal myo lipoma not traditionally considered to be functioning but if you did have um a lesion in the adrenals you weren't sure if it was an incidentaloma or not potentially a GNR uh analog suppression test could be useful or you might consider adrenal vein sampling um there's a poster from the Mayo Clinic group on Monday though that shows that in a study of 22 women where they did combined ovarian and adrenal ovarian sampling uh there was no evidence of an adrenal Source uh in those patients um so if the adrenal Imaging is normal then you focus on the ovary and here the question is is there bilateral uh or unilateral um adrenal or uh Androgen production and if it's unilateral um which side is it coming from and here unfortunately a g analog is not particularly helpful it doesn't help you to lateralize and it really doesn't distinguish between a benign Source like ovarian hyperthecosis um and a tumor sources because there's overlap in the degrees um of suppression um I would also add as a clinical Pearl beware of a report that says normal ovaries in a post-menopausal woman if it doesn't give you an actual volume because the ovaries do uh decrease significantly with age the average volume is about 2.2 um MLS so a an ovarian volume of 5 mls in a postmenopausal woman could certainly raise suspicion for ovarian hyperthecosis um so the real conundrum I think is the premenopausal woman where there's a short history there's concern for a tumor but the ovarian Imaging is unrevealing and this I think is the situation where um ovarian um vein sampling if it's available in in your institution H can be very helpful so my feeling is that the GNR analogs do have a role um but more from a therapeutic uh uh perspective as opposed to Diagnostic and Lauren showed an excellent response in her premenopausal patient um pending bilateral ectomy and in the postmenopausal patient who declined um uh definitive surgery I don't know if we have time for questions questions or comments for Dr Hayes okay Francis thank you very much for sharing those insights our next uh case presenter is Dr Lauren walish who comes from Mel University in monreal Canada she will be talking about a case of Moler pregnancy induced hyperthyroidism and the importance of early recognition and timely pre-operative management Laurel perfect thank you um so I'm super excited to be here and to walk you through this case of this rare presentation that we had at our hospital so our patient she was a 32-year-old female first time pregnant at 10 weeks dation previously healthy did not take any medications and she presented to a community hospital with a two-e history of bloating abdominal pain and nausea on further history there was no bleeding no symptoms of hyper or hypothyroidism which was thoroughly in uh question and no family history of thyroid disorders either so on exam her vitals were completely stable she wasn't Taki cardic her thyroid was completely normal as well she had no Tremor um nothing else on her extremities she did have an abdomen that appeared pregnant um but the rest of her exam was unremarkable so on investigations her beta HCG was over 420 million and yes that's the right amount of zeros and so I um for a patient who is about 10 weeks gation it should be about 60,000 her beta HCG so that was very surprisingly high and so this was her pelvic ultrasound here and so you could see there's some kind of mass um but for people who aren't used to interpreting pelvic ultrasounds um it was reported as a 10 cm molar pregnancy invading to the posterior myometrium so her thyroid profile her TSH was not detectable and her T4 was 43 and at this time there was no trab or T3 that was sent or available just yet so this whole clinical picture at this moment is concerning for a biochemical hyperthyroidism with no clinical evidence of thyrotoxicosis um but it was concerning for an impending thyroid storm so she was transferred to our quinary care center and right away many services were involved so of course OB Endo anesthesia and ICU so all of these Services sat down together had a discussion and so she was planned for an urgent um laparoscopy with uterine evacuation so essentially they took a peak into her belly and also did a DNC um so through the vaginal route and so of course with the um laparoscopic surgery she needed general anesthesia to go through this and there was a post-operative ICU plan for the patient to be transferred there after her surgery so from an Endo point of view she was started on hydrocortisone PTU and beta blockers were on standby her vitals were stable at this moment she had her surgery it was non-complicated she was transferred to the ICU uh clinically stable and her medications were continued there while she was closely monitored after 24 hours uh her PTU was reduced to 200 uh twice daily and her steroids were stopped and given the very very high beta HCG on presentation the Gynecology service gave her a prophylactic dose of chemo uh just to ensure that nothing else was going on or to happen her trab came back negative and her final pathology was a complete hyap form mole so she as she was stable she was able to go home on day three posttop she continued her PTU and she had close follow-up arranged with both gy and endo so her follow-up so here um is a graph of her thyroid hormones I'll just Orient us a little bit so oh you don't see my cursor um so anyways there's you see her day before surgery um on the xaxis zero that's her day of her surgery oh sorry I don't know how to use this oops sorry oh there it is maybe I'm better off not using it um and anyways so her TSH here so you could see um it was undetectable before her surgery at her surgery and then around day 13 um it started to rise you could see her in Orange her T4 um so it started to come down very nicely after her surgery and we got her T3 the first one was on the day of her o so it was also a little elevated and then came down um so then at two weeks posttop um when she came in for her followup with Endo her free T4 had actually been hypo um thyroid she was clinically totally normal um but at that point her PTU was stopped and she might have also had some symptoms of a rash so we she was stopped for both reasons so her beta HCG on the other hand so this graph just to orient you as well um for scale the 400 million is not on here it comes down um but the Y AIS is like an increment of 20,000 so it did come down very nicely um but you could see starting at day 19 it kind of took a turn and started to increase so at this point uh Gynecology did a repeat dilation and curage um they made sure there was no evidence of metastatic disease on Imaging and they gave her methotraxate uh as chemotherapy and throughout all this her thyroid was not a problem so you could see here on this graph um the trend of her beta HCG it came down quite nicely um after uh the second treatment so some learning points to take out of this um so it's essential to recognize the link um between gestational trophoblastic disease and thyrotoxicosis and it's important to anticipate this early because thyroid toxicosis can happen especially undergoing surgery and general anesthesia um could trigger a thyroid storm and obviously severe consequences can occur um if this is left untreated so a multidisiplinary approach especially when there's no guidelines to treat such a case is very important to prevent um poor outcomes and make sure the safety of the patient so thank you if you have questions about this case you can come to the microphone and ask your questions I think this session is cursed I just about tripped over somebody um Carol weam from Spokane Washington nice presentation I was just curious as to the rationale of continuing the PTU after the evacuation of the mole so I I we got this question when we published the the paper as well um so so I it was it was just done out of preventative measures just no real no real reason that I could give you linking into this question I would like to ask you a non obgym person how long are you supposed to follow the beta ECG I saw you followed for at least n by 19 days it returned at higher levels so they were following it until it normalized so it still hadn't normalized on the graph it was still like 10,000 even though it came down significantly it kind of looked like it was normal um but it was still not yet at zero is this a common thing for a pregnan a m pregnancy to recur after DNC for or some residual tissue to be left so requiring a second D DMC like in this case I don't know the exact statistics um but I I would think it's something that's rare God it we're we're Endocrinology it's okay thank you so if there no other questions right now I'd like to invite our um expert Dr another local again from Boston Dr Elizabeth Pierce from Boston University School of Medicine so thank you Laurel interesting case beautifully presented um and I think this raises a few issues that are sort of helpful to think about um that we may see in more common contexts than than the one you saw it in so anytime we see HCG mediated hyperthyroidism uh typically patients don't have a lot of hyperthyroid symptoms and that was true in the patient that you presented and that's probably because unlike Graves disease which is going to be the the other common cause of hyperthyroidism in somebody a woman of reproductive age uh the primary sort of clinical sign uh in HCG mediated hyperthyroidism is nausea and vomiting because HCG is what mediates the nausea and Pregnant and so women present with that the predominant symptom and therefore you get kind of an overlay of non-thyroidal illness so when you look at the thyroid function tests you see relatively lower t3s than you might expect uh which is effectively sort of the the body's response to starvation so she's not very thyroid toxic um and that's what I would expect we see this more frequently in women not with molar pregnancy but with gational transient thyroid toxicosis in the early pregnancy when HCG is typically not as high as you would see in AAR pregnancy like this uh but still um either very elevated as in a twin or triplet gestation or maybe women with somehow more bioactive HCG we can see patients who present with thyroid toxicosis and the challenge is often to distinguish that from graves disease in early gation uh so the TSH receptor stimulating antibody which you did eventually get in this patient uh can be very helpful in that context presence or absence of nausea presence or absence of thyroid toxic symptoms all are really helpful in making that distinction and then the challenge in this patient was to prepare her for surgery needing general anesthesia at a time when she was really pretty profoundly hyperthyroid uh you don't want to delay a surgery for a molar pregnancy women can get severe bleeding they can get preeclampsia um so there was some urgency to getting this done and you didn't have the luxury of waiting for her anti-thyroid drug to bring the thyroid hormone levels down so we have to think about rapid surgical preparation um again probably more commonly in different settings often it's the the patient with severe Graves disease who can't tolerate anti-thyroid drug where we need to get them to the O and get them through the surgery safely and we always worry about the anesthesia inducing thyroid storm so we've got a bunch of things in the toolkit that we can use some of them were used here um in this patient she could get anti-thyroid drug PTU was selected over mimisol because of sort of the theoretic Advantage I think of blocking T4 to T3 conversion as well as decreasing thyroid hormone synthesis I'm not honestly sure how much difference that makes in in most clinical contexts but it's probably the right textbook answer and the way to go um she also got glucocorticoid at high doses because that will as a potent um inhibitor of T4 to T3 conversion again and the whole goal here is to try and knock down those circulating T3 levels as quickly as possible before the operation um she got IV hydrocortisone um b 1 milligram dexamethasone actually works just fine um in in um preparing patients for for Rapid surgery when they're thyroid tox other things she could have considered um beta blocker particularly Propranolol which again decreases T4 to T3 conversion um was considered in this case but not felt to be needed and she did just fine with the surgery without it and then other possibilities and could have considered would have been um highd do iodine lugols or sski to induce the acute wolf chof effect and sort of rapidly um decrease thyroid hormone synthesis um and could have considered cholestyramine uh which will decrease circulating thyroid hormone by interrupting the enterohepatic circulation and when all else fails one can consider plasmapheresis but happily this patient did fine with glucocorticoid an anti-thyroid drug alone so with that I think we maybe got a few minutes for questions if if there are any oh and another comment about why continue the PTU um after uh the pregnancy T4 has a long halflife but the PTU obviously you know it's I as I said I don't think it's doing that much to to decrease T4 T3 circulations so I'm not sure that there would have been a huge benefit thank you so much we're actually right on time but if anybody has one or two extra questions we can take them if not we thank you very much okay our next and last perer is Dr Salman bot who recently completed his ocran fellowship at John's Hopkins University in Baltimore Maryland the title of his paper is type B insulin resistance syndrome a rare cause of hypoglycemia Salon good afternoon everyone uh thank you for the opportunity and thank you for everyone for coming so um today I we going to present a interesting case of hypoglycemia that we saw in the inpatient consult service who was uh diagnosed to be uh from type B insulin resistance syndrome so um we have this 59y old black female with the history of SLE and Insulin dependent diabetes metis who presented with altered mental status she was found to have a blood glucose of uh finger stick glucose of 30 which was resolved with administration of IV dextrose um this was the first known episode of hypoglycemia she also reported 100 pound weight loss and no recent changes in her dietary patterns or insulin dosing her avany was 7.7% at the time of admission this was the medication list on admission as you can see she was on both on Long acting and short acting insulin uh none of the doses were changed and the other medication lists did not have any uh medications which with a high evidence of hypoglycemia risk um subsequently on physical examination the pertinent positives were a BMI of 29.3 she also had gingival hyperplasia with many of her teeth missing along with axillary ecosis nigricans and axillary adenopathy she had no uh significant evidence of facial uh hair or any other heroism as you can see on the left side uh she has axillary acantosis nigricans but none in the of the neck subsequently during the hospital course initial our initial thought was um exogenous insulin mediated hypoglycemia insulin use was stopped uh however Patient continued to develop multiple overnight hypoglycemic episodes which were confirmed both by finger stick testing as well as by blood glucose checks um subsequently we underwent she underwent a 72-hour fasting test to make sure all the labs were appropriately obtained as we can see here um we did the 72-hour fasting test and 12 hours into fasting she had a blood glucose of 44 with an significantly elevated insulin and pro insulin level and a detectable C you know inappropriately detectable C peptide um we also did a oral hypoglycemic agent panel and an insulin Auto anti Auto antibody testing both of which were negative um other lab evaluation also showed serum trius Rites of 71 and an high which was normal and an adonin of 28 which was high normal in a typical type 2 diabetic we would have expected a significantly higher triglyceride level and a low adiponectin level her adrenal and thyroid function was uh normal SLE antibody titer were elevated subsequently uh we she underwent Imaging of her abdomen um her CT uh abdomen pelvis showed widespread liid opathy um we also obtained an MRCP which showed an 11 mm cystic leion in the pancreas um with T2 hypointensity um which was more consistent with an intrapapillary mous neoplasm we also did uh Li um core needle biopsy of the lymphadenopathy which showed reactive lymphadenopathy at this point uh we had a wide differential diagnosis uh the initial was one was insulinoma along with these other ones which were most of which were ruled out with previous biochemical testing um at this point because of the characteristics of the tumor on the MRCP which it did not meet insulinoma it was a cystic lesion which was less likely to be an insulinoma and this patient had multiple other characteristics which are seen in this R rare case of type B insulin resistant syndrome which included her history of SLE along with uh being black subsequently we underwent she underwent further testing her blood was sent to Dr sh hur's lab in Germany which who has a validated assay for testing um this disease um and the testing was strongly positive for anti-insulin receptor antibodies which was diagnostic of type B insulin resistance syndrome as you can see here uh there was a negative control in the lab and then there was a positive control with the binding index of 38 a binding index of greater than 10 is highly positive for type B insulin resistance syndrome and as you can see in our patient it was 248 um which was sign significantly positive um our patient uh was treated by cessation of insulin therapy we provided dietary modifications with corn starch at night and continued the use of CGM um Rheumatology service was also consulted and she was continued on the hydroxy chloroquin along with addition of Bellum map 3 months after index admission uh the patient was not on any diabetic therapy uh her A1C was 5.4% and she continued to have midnight o overnight mild hypoglycemia um as you can see in the CGM tracing there was around 13.8% hypoglycemia um along with 1.6% very low hypoglycemia all of which was manageable for the patient and the graph shows this overnight hypoglycemia continuing to occur so um The Learning points um in our case uh so TYB insulin resistance syndrome is primarily um presents with uh severe insulin resistance and uh SE diabetes malius requiring a very high dose of insulin and very rarely can cause a hyperinsulinemic hypoglycemia this happens in around 20 to 40% of the patients at at some point in their clinical history diagnostic pointers towards H type B insulin resistance syndrome include black women with a history of autoimmune dis disease biochemical pointers include a normal triglyceride level and a high normal to high adiponectin levels in a typical type to diabetic patient with metabolic syndrome we would expect a normal or an elevated triglyceride level or a high adiponectin or low adipine nectin level anti-insulin receptor antibodies are diagnostic of TBS and AES are not frequently available um this was sent to Germany there are other places we can send to and I think there was a recent an paper which also discussed an aay new assay formed um which could be tested in the US and uh typically in TBS we see elevated serum insulin levels and undetectable C peptide levels our patient did have detectable C peptide levels the source of this discordance is uh the differing methods of clearance of insulin and C peptide the insulin clearance is driven by uh the receptor mediated endocytosis whe whereas C peptide is not so um in addition one point we I want to mention is the treatment protocol so NIH has a treatment protocol for this disease Which con consists of multiple imuno supressant medications um this was not followed in this patient because she had good response um to dietary modifications and you know we did not go ahead with that moreover this treatment protocol was mostly tested in hyperglycemic patients thank you [Applause] questions comments for Salon I I have one question um you know I'm an adrenal guy um I I guess I don't understand why is insulin high if you have an antibody uh triggering the receptor shouldn't shouldn't insulin levels be low so the body compensates so there is significant insulin resistance um in the body so the pancreas just continues to produce insulin it's not getting the insulin does not move away because it depends on receptor mediated endocytosis which is blocked by the high receptor levels The receptors the the antibodies are binding to the receptor and preventing this breakdown of insulin that's that's the reason got it thank you Steve so is the uh black race predisposition related to the predisposition to lupus or is there something else about the black right um so good question we don't know much about what is causing that as you rightly said autoimmune disease is you know seen more slle is seen more in African-Americans that's a pretty rare disease so we really don't have much data most of the data comes from you know large case studies but we really haven't had that connection but that's a good question hi jackit are at Total Health I'm lucky enough to work with Dr bot now um why did this happen now as opposed to or what triggered it as opposed to a year or two earlier that's a good question also so um it can the presence of hypoglycemia or onp of hypoglycemia can be very variable um it can be dependent on the antibody titer so high antibody tiers in this disease are linked with hypoglycemia low antibody titter are linked with hypoglycemia um so it could be very variable that her disease was going into remission a lot of patient around 20 to 30% of these patients do go into remission so that could have been a possible cause that she was slowly coming down her antibody titos were coming down and she developed this now thank you last question when there is insulin resistance generally trigly level should be high here the trigly level is normal so that's a very good question and I I did read about it so the effect of U the insulin receptor antibodies is dependent on where they act so in this case they really don't have much effect on the liver so it's not a postreceptor defect it's a you know pre-receptor defect or you know defect at the receptor itself and this does not affect the you know receptors in the liver as much and that is where the trius rides arise don't try to explain by the differential insulin resistance on the yes sir various organs in respect compared to lipo distrophy where you have a you know more generalized post receptor defect Thank You Salon thank you very much thank you so our expert discussion is Dr David delesio at Duke University School of Medicine Durham North Carolina David thanks Bill and uh thanks very much for a really nice case Dr bot I um being called an expert here it's a little euphemistic since I've seen one case in my life and it was the year before I started my endocrine Fellowship uh I was Gunther boo I was at Temple University where Gunther Bowden was head of metabolism and he was trying to convince me to go into Endocrinology so he brought me to the Research Unit and showed me how to do a glucose clamp and the patient he didn't tell me had type B insulin resistance and he was showing me that you could give virtually infinite amounts of insulin to this patient and the blood sugar wouldn't move it did make me curious it uh uh and I did go into Endocrinology uh I I'm a little nervous that somebody in the audience has seen two cases and that that they may demolish my credibility um this is a actually a a really interesting um condition historically um the first cases were described at by the NIH group in the early 70s um and it it really was led to a lot of fundamental discoveries about the insulin receptor about insulin signaling so that for for a uh cause of hypoglycemia that's very rare had a big impact scientifically and if you look at the people who reported these cases and did the evaluations flyer uh KH Taylor these were all the people that then went out and worked on insulin resistance and the the the 80s were uh a decade where insulin resistance came to the four as a pathogenic mechanism and as as essential in type two diabetes and it's this syndrome I think that drove a lot of the research put a lot of the tools in the hands of people to study the insulin receptor this particular patient is right out of Central Casting from that the cohort that the NIH assembled they they have 40 some patients and then if you look at the rest of the literature there's there's less than a hundred case reports of this so I guess my one case may not be that puny um the patients that the ni had seen were uh disproportional African-American disproportionately female and had lupus about half the time or some other autoimmune disease most of the time now that being said if you look at reports from the rest of the world in in Japan again they put together a case series that was mostly male um so I think I think making uh too many uh demographic or predisposing conclusions is probably um premature and I would say again that the the the big problem with this syndrome um is that we we don't have a great way great detection mechanism right the NIH uh people came up with an imuno precipitation assay that's very similar to what we use now clinically in Graves disease a trab mechanism where you take a recombinant protein and you use that to capture antibodies from the serum that's never been standardized and put into clinical practice so uh it ends up being a a really difficult diagnosis to make and I was really impressed that Dr bot and his colleagues were able to sort through this and come to this diagnosis because almost seemed like a madeup case with one red herring after another looking you in the face um I think a commercially available assay would be useful um you know as endocrinologists we what we when we see a case of bonafide hypoglycemia somebody that's not taking medications insulinoma is at the top of the list and you can say well the CT didn't show insulinoma that that happens about 20 or 30% of the time um so that you know the probabilities were were in this case was that even with a negative CT insulinoma might have been more common than um than type B insulin resistance although we we we don't really know what the epidemiology of the latter is um so I you know to me the things that would make me um think about something like an autoimmune mechanism would be the really high levels of of insulin and C peptide often times what we see are kind of inappropriately normal levels of insulin and C peptide and insulinoma and and in these cases where you have essentially a circulating snc of antibodies that are holding the insulin the the levels can can be really high um again just to talk about the pathogenesis again the antibodies are in high tighter whether they're true Agonist or whether they just mediate clearance of the receptor from the membrane when they bind to the receptor it's the clearance is increase so you actually have a downregulation of insulin receptors and that may be the insulin resistance they're partial agonists and the partial agonism effect seems to be present as Dr bot says at low titer so it's a it's a very confusing but again the analogy to Graves disease where you have antibodies to the TSH receptor that do different things is is not far-fetched um let me just finish by thanking Bill and Adena not only for inviting me to this really interesting session but for forwarding this journal um case reports you know oftentimes get short shrift but um if you work in a setting where you get a lot of referrals to have good case reports and a a good source for them is aen so thank you both David oh we have one question from Al but it has to be short because we're well I am short so it's EAS yeah Dave I'm as expert as you are I have a series of one I was trained at the NIH uh with Ron uh in the group with Ron Khan I sat with a patient uh with this condition I gave gave her she started out with a blood sugar of 300 I gave her 50,000 units of insulin sitting by the bedside I finished her blood sugar was still 300 yeah scared the hell out of me the whole six hours I was there it when I saw my case I Didn't Know Better 10,000 units just seemed like what you gave some well I I want to thank David for the plug for the journal Aden and I encourage you all to consider submitting your interesting challenging cases to jcm case reports with that we conclude our session thank you all for coming

well welcome everyone to clinical pearls from jcm case reports this is the second year we&#39;re holding this special Forum my name is Bill Young I&#39;m the editor and chief of the journal and our co-chair is Dr Adina turku who is the Deputy editor for the journal we have three presentations they&#39;re going to be fairly short about 7 minutes followed by a Q&amp;A with the author and then we&#39;re going to invite up an expert on the topic to expound some pearls for you on that particular case so we&#39;re going to start our first presenter is Dr Lauren Doyle uh she did her training at Bowmont Hospital the r rcsi in Dublin Ireland she basically just completed the equivalent of Internal Medicine Residency in the US and is now moving on to her endocrine Fellowship the title of her paper is clinical utility of g&amp; analoges in female andren exess highlighting Diagnostic and therapeutic applications Lauren thanks very much Dr Young And so thanks very much for the invitation to present today um so I delighted to be um here to talk everyone through our management experience of using GnRH analoges in uh diagnosing and treating female Androgen excess there we go H so I have no conflicts of interest to declare but just to highlight that we are discussing um an off Lael use for trypan and other medications within the GnRH analog class so before we dive into our cases I think it&#39;s important to highlight the principle of GnRH analog testing so this relies on the principle that um ovarian derived anen excess will remain under the control of the hpg axis but adrenal Androgen excess will not um so following administration of a 3 milligram trip Talent OR similar IM we&#39;ll get initial pituitary receptor binding and a downstream U regulation of gadal products but at about two to three weeks we&#39;ll see a result in desensitization and downregulation of these receptors due to loss of pulsatility and we&#39;ll see a 50% reduction in serum testosterone at day 28 following Administration so our first case we had a 68-year-old woman who presented with a three to four year history um of evolving facial her heroism and Alesia C doesn&#39;t seem to be working on this for me there okay perfect yeah that&#39;s working better now um so she had rapidly she had some alarming features including rapidly Progressive vocal deepening and reported changes in the external genitalia and the immediate months prior to presentation her past medical history was largely insignificant and she had no previous reproductive concerns expressed her initial biochemistry was quite alarming so we can see a massive elevation in her serum test off poone and so and quite inappropriately suppressed ganat tropins for a postmenopausal woman interestingly she also had elevations in her seramal and elevations at both her hemoglobin and hematocrit which have been reported in cases of virilization previously so naturally this woman underwent urgent radiological workup to try and ascertain where exactly the source of her Anin excess was was so she had normal adrenal um Imaging um but an ultrasound pelvis showed a large R ofar in hypo aoic MK so while she was awaiting Gynecology review she underwent an adjunctive investigation in the form of a GnRH analog suppression test and we can see the results of this here so the benefit of doing this was to try and ascertain whether or not hpg access regulation was maintained which would be more reassuring for a benign etiology to her andren excess so here we can see full suppression of her serum testosterone um at day 28 in addition to suppression of her andr Dion so this lady was referred onwards to gynecology had a benign aarian steroid cell tumor identified following bilateral cell Piner rectomy and most notably had full Androgen suppression day6 post operatively our second case had a much more indolent uh presentation so this was the 67y old woman who is referred with the 15year history of heroism with some Associated frontal hair thinning similarly had no significant past medical history clinically on exam she did have evidence of an increased body mass but no cushingoid features or insulin resistance were evident her initial biochemistry while abnormal was not as significantly alarming as our first case but we did see a testosterone of 2.5 on her initial um biochemistry and an eastra dial of 130 in terms of ascertaining where exactly this was coming from she did normal overnight dxms his own suppression test and an incidental left-sided adrenal my lipoma was identified on CT Imaging and she normal transvaginal ultrasound with no evidence of any ovarian pathology given her overall biochemical pattern um her indolent clinical history and normal Imaging it was felt that this woman most likely had a benign ovarian source for her anren excess and most likely in keeping with an ovarian hyperthecosis so she had a 50% reduction in her serum testosterone following 28 days um after a GnRH analog suppression test which would be indicative of a confirmatory test given the chronicity of her symptoms the absence of any features of feralization it was felt that she most likely had a benign aarian pathology most likely an ovarian hyperthecosis given her initial symptomatic relief following administration of the G analog she declined further referral for surgical intervention instead opting to continue with regular trip to rein therapy which was ultimately transition to a long acting Depot preparation and due to successful symptom suppression our final case discusses a benign use or premenopausal um case of a 25-year-old woman referred with significant heroism and secondary amen ARA her past medical history was significant for a juvenile dermatomyositis and an overall adverse metabolic phenotype as indicated by her steroid induced typer glycemia iously and hypertension and obstructive sleep apnea clinically she&#39;d EV evidence of a partial lipo distrophy with relative trunkal sparing and stigma of severe insulin resistance her initial biochemistry showed an elevated LH to FSH ratio and then very significant elevations in her serum testosterone and andrine jion she also had massive hyperinsulinemia so the working diagnosis here was a severe insulin resistance syndrome most likely an acquired partial hpid distrophy in the setting of her Juvenile dermala Myositis she had normal Imaging overall with no Source identified for andren excess so she underwent a 3 milligram trip toin Administration to try and ascertain whether this was ovarian um or adrenal in origin and she had confirmatory testing here with full suppression of her testosterone H following 28 days she also had very significant symptom resolution um so in as a result of this she opted to trial regular GnRH analog therapy with addback sequential combined HRT for bone and um phas of motor symptom alleviation unfortunately this had to be temporarily disc continued following an es schic stroke um however this was felt more than likely to be in the setting of her systemic vascular resistance and um unrelated to her um her g&amp; orh analog therapy given that she&#39;s no desire for future fertility she&#39;s opted for a Gynecology referral for an elective bilateral Singo rectomy so in terms of take- Home messages we proposed that the GnRH analoges would be potentially useful adjuncts and the diagnosis of suspected over VAR Androgen excess with the potential to reduce Reliance on any invasive procedures in the correct context therapeutically um they offer a potential non-operative um management option for postmenopausal women again with clear benign sources for anren excess who wish to avoid surgery or indeed for premenopausal again with C clear benign sources um who with very significant symptoms who wish to have a fertility sparing alternative it&#39;s very careful that careful case selection is undertaken and that features of viralization or indicators of malignancy are not overlooked thank you [Applause] thank you Lauren for that presentation you you kept right on time for those who have questions or comments for Lauren we have a microphone in the aisle over here just come to the microphone introduce yourself and ask your question in the meantime Lauren I would like to ask you a question in your first case where you had an ovarian tumor you decided to use this test to differentiate between a potential malignant versus benign cause have you used uh PET Imaging or no so we had news pad Imaging in this case um another kind of potential Imaging that may have been useful in terms of identifying potential tumor versus aian hyperthecosis maybe would have been MRI they seem to have reasonable sensitivity but we didn&#39;t have Pet Imaging available in our Institution for for that type of indication interesting so I wanted some adrenal tumors have LH receptor do you have any experience from your review of literature of how they might respond to this analog um an interesting question I have no personal um experience around that um particular indication um but I know particularly in the in the cases of the insulin resistance syndromes um with our partial life p distrophy and that they can get some stimulation by the excess insulin as well to give them adrenal andren production but I wouldn&#39;t have any any direct experience um in terms of um LH and adrenal andrin Richard Quinton Newcastle Mick said to come and say hi um I can answer that question um yes um they they if an adrenal um um adoma um expressing the lhg receptor yeah they shut down perfectly with um gen analog treatment um but my question was um Peter Lou uh Los Angeles so in your third case um the person had sleep up and there&#39;s evidence that if you re reverse the the hyper engine and the sleep app can actually improve did that actually happen in this in that case so she didn&#39;t we&#39;ve only I think had maybe 12 months since we&#39;ve commenced therapy and given the kind of interruption particularly around the time of her um the concern around the stroke we haven&#39;t had a sustained period of time long enough to really ascertain whether or not we got Improvement the question I was going to really ask before I bulldo peed out of the way sorry was in ter it&#39;s a great treatment but in terms of Diagnostics what does it add above um nothing in the adrenals and low dhas I suppose um in in terms of what it adds I think in our experience in in terms of um reassuring Imaging um it gave us kind of some additional reassurance that there may have been a purely ovarian benign Source going on here rather than anything adrenal Al rogal Charlottesville Virginia uh Little Wrestler so that&#39;s those are good hands um especially with ad Dena on the uh uh at the as chair the issue that you&#39;re trying to do is to distinguish between ovarian and adrenal so is there a uh place for measuring Oxo testosterone or Oxo DHT I think down the line that that would be something that we&#39;d like to include but in terms of um assay availability and resource allocation that can be quite challenging particularly in some of the contexts that we&#39;re working within um so hopefully down the line when we have greater availability of those type of Diagnostics it would be great to include that but in terms of the resources that that uh we have at our disposal this could be an additional benefit in that context thank you any uh words of wisdom Adina so in the US uh Lab Corp at least and I think maybe Quest is incorporating these assays but I know they offer Lab Corp offers 11 keto testosterone great Lauren thank you very much now I&#39;d like to invite up our expert on this topic Dr Francis Hayes from Mass General at Harvard right here in Boston Francis thank you very much Bill and congrats to Lauren for an excellent presentation um so the question here as Dr Quinton um sort of um raised is what is the utility of generate analoges as both a an um therapeutic and diagnostic modality when you&#39;re faced with that patient who has significant hyperandrogenism so the first question is um as um Al asked is the excess Androgen coming from the uh ovary or is it coming from the adrenal as Lauren mentioned the hormone profile the Baseline hormone profile can be helpful in that if there&#39;s a predominant increase in testosterone um over and above anderen diione or DHEA uh that favors an ovarian source and can be confirmed um if there is significant suppression um the question then is whether you need to do this test on everybody that you see with um significant hiber androgenisation if you have a normal adrenal CT you have effectively um excluded a functioning either benign or malignant adrenal nodule now in one of Lauren patients there was an adrenal myo lipoma not traditionally considered to be functioning but if you did have um a lesion in the adrenals you weren&#39;t sure if it was an incidentaloma or not potentially a GNR uh analog suppression test could be useful or you might consider adrenal vein sampling um there&#39;s a poster from the Mayo Clinic group on Monday though that shows that in a study of 22 women where they did combined ovarian and adrenal ovarian sampling uh there was no evidence of an adrenal Source uh in those patients um so if the adrenal Imaging is normal then you focus on the ovary and here the question is is there bilateral uh or unilateral um adrenal or uh Androgen production and if it&#39;s unilateral um which side is it coming from and here unfortunately a g analog is not particularly helpful it doesn&#39;t help you to lateralize and it really doesn&#39;t distinguish between a benign Source like ovarian hyperthecosis um and a tumor sources because there&#39;s overlap in the degrees um of suppression um I would also add as a clinical Pearl beware of a report that says normal ovaries in a post-menopausal woman if it doesn&#39;t give you an actual volume because the ovaries do uh decrease significantly with age the average volume is about 2.2 um MLS so a an ovarian volume of 5 mls in a postmenopausal woman could certainly raise suspicion for ovarian hyperthecosis um so the real conundrum I think is the premenopausal woman where there&#39;s a short history there&#39;s concern for a tumor but the ovarian Imaging is unrevealing and this I think is the situation where um ovarian um vein sampling if it&#39;s available in in your institution H can be very helpful so my feeling is that the GNR analogs do have a role um but more from a therapeutic uh uh perspective as opposed to Diagnostic and Lauren showed an excellent response in her premenopausal patient um pending bilateral ectomy and in the postmenopausal patient who declined um uh definitive surgery I don&#39;t know if we have time for questions questions or comments for Dr Hayes okay Francis thank you very much for sharing those insights our next uh case presenter is Dr Lauren walish who comes from Mel University in monreal Canada she will be talking about a case of Moler pregnancy induced hyperthyroidism and the importance of early recognition and timely pre-operative management Laurel perfect thank you um so I&#39;m super excited to be here and to walk you through this case of this rare presentation that we had at our hospital so our patient she was a 32-year-old female first time pregnant at 10 weeks dation previously healthy did not take any medications and she presented to a community hospital with a two-e history of bloating abdominal pain and nausea on further history there was no bleeding no symptoms of hyper or hypothyroidism which was thoroughly in uh question and no family history of thyroid disorders either so on exam her vitals were completely stable she wasn&#39;t Taki cardic her thyroid was completely normal as well she had no Tremor um nothing else on her extremities she did have an abdomen that appeared pregnant um but the rest of her exam was unremarkable so on investigations her beta HCG was over 420 million and yes that&#39;s the right amount of zeros and so I um for a patient who is about 10 weeks gation it should be about 60,000 her beta HCG so that was very surprisingly high and so this was her pelvic ultrasound here and so you could see there&#39;s some kind of mass um but for people who aren&#39;t used to interpreting pelvic ultrasounds um it was reported as a 10 cm molar pregnancy invading to the posterior myometrium so her thyroid profile her TSH was not detectable and her T4 was 43 and at this time there was no trab or T3 that was sent or available just yet so this whole clinical picture at this moment is concerning for a biochemical hyperthyroidism with no clinical evidence of thyrotoxicosis um but it was concerning for an impending thyroid storm so she was transferred to our quinary care center and right away many services were involved so of course OB Endo anesthesia and ICU so all of these Services sat down together had a discussion and so she was planned for an urgent um laparoscopy with uterine evacuation so essentially they took a peak into her belly and also did a DNC um so through the vaginal route and so of course with the um laparoscopic surgery she needed general anesthesia to go through this and there was a post-operative ICU plan for the patient to be transferred there after her surgery so from an Endo point of view she was started on hydrocortisone PTU and beta blockers were on standby her vitals were stable at this moment she had her surgery it was non-complicated she was transferred to the ICU uh clinically stable and her medications were continued there while she was closely monitored after 24 hours uh her PTU was reduced to 200 uh twice daily and her steroids were stopped and given the very very high beta HCG on presentation the Gynecology service gave her a prophylactic dose of chemo uh just to ensure that nothing else was going on or to happen her trab came back negative and her final pathology was a complete hyap form mole so she as she was stable she was able to go home on day three posttop she continued her PTU and she had close follow-up arranged with both gy and endo so her follow-up so here um is a graph of her thyroid hormones I&#39;ll just Orient us a little bit so oh you don&#39;t see my cursor um so anyways there&#39;s you see her day before surgery um on the xaxis zero that&#39;s her day of her surgery oh sorry I don&#39;t know how to use this oops sorry oh there it is maybe I&#39;m better off not using it um and anyways so her TSH here so you could see um it was undetectable before her surgery at her surgery and then around day 13 um it started to rise you could see her in Orange her T4 um so it started to come down very nicely after her surgery and we got her T3 the first one was on the day of her o so it was also a little elevated and then came down um so then at two weeks posttop um when she came in for her followup with Endo her free T4 had actually been hypo um thyroid she was clinically totally normal um but at that point her PTU was stopped and she might have also had some symptoms of a rash so we she was stopped for both reasons so her beta HCG on the other hand so this graph just to orient you as well um for scale the 400 million is not on here it comes down um but the Y AIS is like an increment of 20,000 so it did come down very nicely um but you could see starting at day 19 it kind of took a turn and started to increase so at this point uh Gynecology did a repeat dilation and curage um they made sure there was no evidence of metastatic disease on Imaging and they gave her methotraxate uh as chemotherapy and throughout all this her thyroid was not a problem so you could see here on this graph um the trend of her beta HCG it came down quite nicely um after uh the second treatment so some learning points to take out of this um so it&#39;s essential to recognize the link um between gestational trophoblastic disease and thyrotoxicosis and it&#39;s important to anticipate this early because thyroid toxicosis can happen especially undergoing surgery and general anesthesia um could trigger a thyroid storm and obviously severe consequences can occur um if this is left untreated so a multidisiplinary approach especially when there&#39;s no guidelines to treat such a case is very important to prevent um poor outcomes and make sure the safety of the patient so thank you if you have questions about this case you can come to the microphone and ask your questions I think this session is cursed I just about tripped over somebody um Carol weam from Spokane Washington nice presentation I was just curious as to the rationale of continuing the PTU after the evacuation of the mole so I I we got this question when we published the the paper as well um so so I it was it was just done out of preventative measures just no real no real reason that I could give you linking into this question I would like to ask you a non obgym person how long are you supposed to follow the beta ECG I saw you followed for at least n by 19 days it returned at higher levels so they were following it until it normalized so it still hadn&#39;t normalized on the graph it was still like 10,000 even though it came down significantly it kind of looked like it was normal um but it was still not yet at zero is this a common thing for a pregnan a m pregnancy to recur after DNC for or some residual tissue to be left so requiring a second D DMC like in this case I don&#39;t know the exact statistics um but I I would think it&#39;s something that&#39;s rare God it we&#39;re we&#39;re Endocrinology it&#39;s okay thank you so if there no other questions right now I&#39;d like to invite our um expert Dr another local again from Boston Dr Elizabeth Pierce from Boston University School of Medicine so thank you Laurel interesting case beautifully presented um and I think this raises a few issues that are sort of helpful to think about um that we may see in more common contexts than than the one you saw it in so anytime we see HCG mediated hyperthyroidism uh typically patients don&#39;t have a lot of hyperthyroid symptoms and that was true in the patient that you presented and that&#39;s probably because unlike Graves disease which is going to be the the other common cause of hyperthyroidism in somebody a woman of reproductive age uh the primary sort of clinical sign uh in HCG mediated hyperthyroidism is nausea and vomiting because HCG is what mediates the nausea and Pregnant and so women present with that the predominant symptom and therefore you get kind of an overlay of non-thyroidal illness so when you look at the thyroid function tests you see relatively lower t3s than you might expect uh which is effectively sort of the the body&#39;s response to starvation so she&#39;s not very thyroid toxic um and that&#39;s what I would expect we see this more frequently in women not with molar pregnancy but with gational transient thyroid toxicosis in the early pregnancy when HCG is typically not as high as you would see in AAR pregnancy like this uh but still um either very elevated as in a twin or triplet gestation or maybe women with somehow more bioactive HCG we can see patients who present with thyroid toxicosis and the challenge is often to distinguish that from graves disease in early gation uh so the TSH receptor stimulating antibody which you did eventually get in this patient uh can be very helpful in that context presence or absence of nausea presence or absence of thyroid toxic symptoms all are really helpful in making that distinction and then the challenge in this patient was to prepare her for surgery needing general anesthesia at a time when she was really pretty profoundly hyperthyroid uh you don&#39;t want to delay a surgery for a molar pregnancy women can get severe bleeding they can get preeclampsia um so there was some urgency to getting this done and you didn&#39;t have the luxury of waiting for her anti-thyroid drug to bring the thyroid hormone levels down so we have to think about rapid surgical preparation um again probably more commonly in different settings often it&#39;s the the patient with severe Graves disease who can&#39;t tolerate anti-thyroid drug where we need to get them to the O and get them through the surgery safely and we always worry about the anesthesia inducing thyroid storm so we&#39;ve got a bunch of things in the toolkit that we can use some of them were used here um in this patient she could get anti-thyroid drug PTU was selected over mimisol because of sort of the theoretic Advantage I think of blocking T4 to T3 conversion as well as decreasing thyroid hormone synthesis I&#39;m not honestly sure how much difference that makes in in most clinical contexts but it&#39;s probably the right textbook answer and the way to go um she also got glucocorticoid at high doses because that will as a potent um inhibitor of T4 to T3 conversion again and the whole goal here is to try and knock down those circulating T3 levels as quickly as possible before the operation um she got IV hydrocortisone um b 1 milligram dexamethasone actually works just fine um in in um preparing patients for for Rapid surgery when they&#39;re thyroid tox other things she could have considered um beta blocker particularly Propranolol which again decreases T4 to T3 conversion um was considered in this case but not felt to be needed and she did just fine with the surgery without it and then other possibilities and could have considered would have been um highd do iodine lugols or sski to induce the acute wolf chof effect and sort of rapidly um decrease thyroid hormone synthesis um and could have considered cholestyramine uh which will decrease circulating thyroid hormone by interrupting the enterohepatic circulation and when all else fails one can consider plasmapheresis but happily this patient did fine with glucocorticoid an anti-thyroid drug alone so with that I think we maybe got a few minutes for questions if if there are any oh and another comment about why continue the PTU um after uh the pregnancy T4 has a long halflife but the PTU obviously you know it&#39;s I as I said I don&#39;t think it&#39;s doing that much to to decrease T4 T3 circulations so I&#39;m not sure that there would have been a huge benefit thank you so much we&#39;re actually right on time but if anybody has one or two extra questions we can take them if not we thank you very much okay our next and last perer is Dr Salman bot who recently completed his ocran fellowship at John&#39;s Hopkins University in Baltimore Maryland the title of his paper is type B insulin resistance syndrome a rare cause of hypoglycemia Salon good afternoon everyone uh thank you for the opportunity and thank you for everyone for coming so um today I we going to present a interesting case of hypoglycemia that we saw in the inpatient consult service who was uh diagnosed to be uh from type B insulin resistance syndrome so um we have this 59y old black female with the history of SLE and Insulin dependent diabetes metis who presented with altered mental status she was found to have a blood glucose of uh finger stick glucose of 30 which was resolved with administration of IV dextrose um this was the first known episode of hypoglycemia she also reported 100 pound weight loss and no recent changes in her dietary patterns or insulin dosing her avany was 7.7% at the time of admission this was the medication list on admission as you can see she was on both on Long acting and short acting insulin uh none of the doses were changed and the other medication lists did not have any uh medications which with a high evidence of hypoglycemia risk um subsequently on physical examination the pertinent positives were a BMI of 29.3 she also had gingival hyperplasia with many of her teeth missing along with axillary ecosis nigricans and axillary adenopathy she had no uh significant evidence of facial uh hair or any other heroism as you can see on the left side uh she has axillary acantosis nigricans but none in the of the neck subsequently during the hospital course initial our initial thought was um exogenous insulin mediated hypoglycemia insulin use was stopped uh however Patient continued to develop multiple overnight hypoglycemic episodes which were confirmed both by finger stick testing as well as by blood glucose checks um subsequently we underwent she underwent a 72-hour fasting test to make sure all the labs were appropriately obtained as we can see here um we did the 72-hour fasting test and 12 hours into fasting she had a blood glucose of 44 with an significantly elevated insulin and pro insulin level and a detectable C you know inappropriately detectable C peptide um we also did a oral hypoglycemic agent panel and an insulin Auto anti Auto antibody testing both of which were negative um other lab evaluation also showed serum trius Rites of 71 and an high which was normal and an adonin of 28 which was high normal in a typical type 2 diabetic we would have expected a significantly higher triglyceride level and a low adiponectin level her adrenal and thyroid function was uh normal SLE antibody titer were elevated subsequently uh we she underwent Imaging of her abdomen um her CT uh abdomen pelvis showed widespread liid opathy um we also obtained an MRCP which showed an 11 mm cystic leion in the pancreas um with T2 hypointensity um which was more consistent with an intrapapillary mous neoplasm we also did uh Li um core needle biopsy of the lymphadenopathy which showed reactive lymphadenopathy at this point uh we had a wide differential diagnosis uh the initial was one was insulinoma along with these other ones which were most of which were ruled out with previous biochemical testing um at this point because of the characteristics of the tumor on the MRCP which it did not meet insulinoma it was a cystic lesion which was less likely to be an insulinoma and this patient had multiple other characteristics which are seen in this R rare case of type B insulin resistant syndrome which included her history of SLE along with uh being black subsequently we underwent she underwent further testing her blood was sent to Dr sh hur&#39;s lab in Germany which who has a validated assay for testing um this disease um and the testing was strongly positive for anti-insulin receptor antibodies which was diagnostic of type B insulin resistance syndrome as you can see here uh there was a negative control in the lab and then there was a positive control with the binding index of 38 a binding index of greater than 10 is highly positive for type B insulin resistance syndrome and as you can see in our patient it was 248 um which was sign significantly positive um our patient uh was treated by cessation of insulin therapy we provided dietary modifications with corn starch at night and continued the use of CGM um Rheumatology service was also consulted and she was continued on the hydroxy chloroquin along with addition of Bellum map 3 months after index admission uh the patient was not on any diabetic therapy uh her A1C was 5.4% and she continued to have midnight o overnight mild hypoglycemia um as you can see in the CGM tracing there was around 13.8% hypoglycemia um along with 1.6% very low hypoglycemia all of which was manageable for the patient and the graph shows this overnight hypoglycemia continuing to occur so um The Learning points um in our case uh so TYB insulin resistance syndrome is primarily um presents with uh severe insulin resistance and uh SE diabetes malius requiring a very high dose of insulin and very rarely can cause a hyperinsulinemic hypoglycemia this happens in around 20 to 40% of the patients at at some point in their clinical history diagnostic pointers towards H type B insulin resistance syndrome include black women with a history of autoimmune dis disease biochemical pointers include a normal triglyceride level and a high normal to high adiponectin levels in a typical type to diabetic patient with metabolic syndrome we would expect a normal or an elevated triglyceride level or a high adiponectin or low adipine nectin level anti-insulin receptor antibodies are diagnostic of TBS and AES are not frequently available um this was sent to Germany there are other places we can send to and I think there was a recent an paper which also discussed an aay new assay formed um which could be tested in the US and uh typically in TBS we see elevated serum insulin levels and undetectable C peptide levels our patient did have detectable C peptide levels the source of this discordance is uh the differing methods of clearance of insulin and C peptide the insulin clearance is driven by uh the receptor mediated endocytosis whe whereas C peptide is not so um in addition one point we I want to mention is the treatment protocol so NIH has a treatment protocol for this disease Which con consists of multiple imuno supressant medications um this was not followed in this patient because she had good response um to dietary modifications and you know we did not go ahead with that moreover this treatment protocol was mostly tested in hyperglycemic patients thank you [Applause] questions comments for Salon I I have one question um you know I&#39;m an adrenal guy um I I guess I don&#39;t understand why is insulin high if you have an antibody uh triggering the receptor shouldn&#39;t shouldn&#39;t insulin levels be low so the body compensates so there is significant insulin resistance um in the body so the pancreas just continues to produce insulin it&#39;s not getting the insulin does not move away because it depends on receptor mediated endocytosis which is blocked by the high receptor levels The receptors the the antibodies are binding to the receptor and preventing this breakdown of insulin that&#39;s that&#39;s the reason got it thank you Steve so is the uh black race predisposition related to the predisposition to lupus or is there something else about the black right um so good question we don&#39;t know much about what is causing that as you rightly said autoimmune disease is you know seen more slle is seen more in African-Americans that&#39;s a pretty rare disease so we really don&#39;t have much data most of the data comes from you know large case studies but we really haven&#39;t had that connection but that&#39;s a good question hi jackit are at Total Health I&#39;m lucky enough to work with Dr bot now um why did this happen now as opposed to or what triggered it as opposed to a year or two earlier that&#39;s a good question also so um it can the presence of hypoglycemia or onp of hypoglycemia can be very variable um it can be dependent on the antibody titer so high antibody tiers in this disease are linked with hypoglycemia low antibody titter are linked with hypoglycemia um so it could be very variable that her disease was going into remission a lot of patient around 20 to 30% of these patients do go into remission so that could have been a possible cause that she was slowly coming down her antibody titos were coming down and she developed this now thank you last question when there is insulin resistance generally trigly level should be high here the trigly level is normal so that&#39;s a very good question and I I did read about it so the effect of U the insulin receptor antibodies is dependent on where they act so in this case they really don&#39;t have much effect on the liver so it&#39;s not a postreceptor defect it&#39;s a you know pre-receptor defect or you know defect at the receptor itself and this does not affect the you know receptors in the liver as much and that is where the trius rides arise don&#39;t try to explain by the differential insulin resistance on the yes sir various organs in respect compared to lipo distrophy where you have a you know more generalized post receptor defect Thank You Salon thank you very much thank you so our expert discussion is Dr David delesio at Duke University School of Medicine Durham North Carolina David thanks Bill and uh thanks very much for a really nice case Dr bot I um being called an expert here it&#39;s a little euphemistic since I&#39;ve seen one case in my life and it was the year before I started my endocrine Fellowship uh I was Gunther boo I was at Temple University where Gunther Bowden was head of metabolism and he was trying to convince me to go into Endocrinology so he brought me to the Research Unit and showed me how to do a glucose clamp and the patient he didn&#39;t tell me had type B insulin resistance and he was showing me that you could give virtually infinite amounts of insulin to this patient and the blood sugar wouldn&#39;t move it did make me curious it uh uh and I did go into Endocrinology uh I I&#39;m a little nervous that somebody in the audience has seen two cases and that that they may demolish my credibility um this is a actually a a really interesting um condition historically um the first cases were described at by the NIH group in the early 70s um and it it really was led to a lot of fundamental discoveries about the insulin receptor about insulin signaling so that for for a uh cause of hypoglycemia that&#39;s very rare had a big impact scientifically and if you look at the people who reported these cases and did the evaluations flyer uh KH Taylor these were all the people that then went out and worked on insulin resistance and the the the 80s were uh a decade where insulin resistance came to the four as a pathogenic mechanism and as as essential in type two diabetes and it&#39;s this syndrome I think that drove a lot of the research put a lot of the tools in the hands of people to study the insulin receptor this particular patient is right out of Central Casting from that the cohort that the NIH assembled they they have 40 some patients and then if you look at the rest of the literature there&#39;s there&#39;s less than a hundred case reports of this so I guess my one case may not be that puny um the patients that the ni had seen were uh disproportional African-American disproportionately female and had lupus about half the time or some other autoimmune disease most of the time now that being said if you look at reports from the rest of the world in in Japan again they put together a case series that was mostly male um so I think I think making uh too many uh demographic or predisposing conclusions is probably um premature and I would say again that the the the big problem with this syndrome um is that we we don&#39;t have a great way great detection mechanism right the NIH uh people came up with an imuno precipitation assay that&#39;s very similar to what we use now clinically in Graves disease a trab mechanism where you take a recombinant protein and you use that to capture antibodies from the serum that&#39;s never been standardized and put into clinical practice so uh it ends up being a a really difficult diagnosis to make and I was really impressed that Dr bot and his colleagues were able to sort through this and come to this diagnosis because almost seemed like a madeup case with one red herring after another looking you in the face um I think a commercially available assay would be useful um you know as endocrinologists we what we when we see a case of bonafide hypoglycemia somebody that&#39;s not taking medications insulinoma is at the top of the list and you can say well the CT didn&#39;t show insulinoma that that happens about 20 or 30% of the time um so that you know the probabilities were were in this case was that even with a negative CT insulinoma might have been more common than um than type B insulin resistance although we we we don&#39;t really know what the epidemiology of the latter is um so I you know to me the things that would make me um think about something like an autoimmune mechanism would be the really high levels of of insulin and C peptide often times what we see are kind of inappropriately normal levels of insulin and C peptide and insulinoma and and in these cases where you have essentially a circulating snc of antibodies that are holding the insulin the the levels can can be really high um again just to talk about the pathogenesis again the antibodies are in high tighter whether they&#39;re true Agonist or whether they just mediate clearance of the receptor from the membrane when they bind to the receptor it&#39;s the clearance is increase so you actually have a downregulation of insulin receptors and that may be the insulin resistance they&#39;re partial agonists and the partial agonism effect seems to be present as Dr bot says at low titer so it&#39;s a it&#39;s a very confusing but again the analogy to Graves disease where you have antibodies to the TSH receptor that do different things is is not far-fetched um let me just finish by thanking Bill and Adena not only for inviting me to this really interesting session but for forwarding this journal um case reports you know oftentimes get short shrift but um if you work in a setting where you get a lot of referrals to have good case reports and a a good source for them is aen so thank you both David oh we have one question from Al but it has to be short because we&#39;re well I am short so it&#39;s EAS yeah Dave I&#39;m as expert as you are I have a series of one I was trained at the NIH uh with Ron uh in the group with Ron Khan I sat with a patient uh with this condition I gave gave her she started out with a blood sugar of 300 I gave her 50,000 units of insulin sitting by the bedside I finished her blood sugar was still 300 yeah scared the hell out of me the whole six hours I was there it when I saw my case I Didn&#39;t Know Better 10,000 units just seemed like what you gave some well I I want to thank David for the plug for the journal Aden and I encourage you all to consider submitting your interesting challenging cases to jcm case reports with that we conclude our session thank you all for coming

Transcript for:Insights from JCM Case Reports Lecture

Transcript for:
Insights from JCM Case Reports Lecture