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Endocrine Hypertension

Feb 01 | 3:30 PM

Primary aldosteronism, glucocorticoid excess, and pheochromocytoma-paraganglioma syndromes cause adrenal-gland-related endocrine hypertension. Rare diseases in patients with congenital adrenal hyperplasia and glucocorticoid resistance are also leading causes of hypertension. To discuss the reasons underlying endocrine hypertension and treatments for the same, Medflix is hosting Dr. Nihal Thomas for a fascinating discussion on the topic!

[Music] good evening everyone i am dr i welcome you all uh in this interesting session on endocrine hypertension we have one eminent faculty with us today dr nihal thomas who is professor and head of department of endocrinology unit 1 at cmc wellner uh so we'll be covering lot of interesting aspects of endocrine hypertension and we have one interesting quiz at the end of the session so uh stay and enjoy this session ah thank you thank you for that introduction it's real pleasure to be here with all of you uh richard would do my slides appear over here yeah yeah yeah thank you once again for the invitation and it's uh i'm gonna cover a topic which is i suppose important to all physicians right across the board it's an area which encompasses a large spectrum of clinical medicine basic science biochemistry genetics and radiology so endocrine hypertension is a disorder which is something which is more common that one would envisage i'll cover in this talk an introduction and a broad differential diagnosis uh i'll talk about theochromocyatomas and paragongliomas hyper aldosteronism cushing syndrome and then a broad clinical approach to the problems so secondary hypertension comprises about one to five percent of patients with hypertension and uh it approaches about seven to fifteen percent in a tertiary care center uh pheochromocytomas which are exciting clinical disorders comprise only about 0.1 percent of individuals with hypertension and this is probably however an underestimate so when we look at the etiology of secondary hypertension we have categories which involve endocrine which include the fears hypoaldostomism cushing's syndrome and then we have the rarer conditions like 11 beta hydroxylase deficiency 17 alpha hydroxy deficiency which are congenital disorders of enzyme defects in the adrenal gland and of course we have disorders which present by their clinical uh features which are much more prominent in the hypertension itself so as i was saying secondary hypertension comprises about one to five percent of patients with hypertension approaches um about seven to five percent in a tertiary care center and fear cross cytomas about point one percent of individuals with hypertension which is probably an underestimate when we look at the etiology we have endocrine disorders which include cytomas and hyperaldosteronism and cushing syndrome and then we have the rarer disorders like 11 beta hydroxylase deficiency 17 alpha hydroxylase deficiency which are rare disorders congenital enzyme defects which are generally seen in the pediatric age group and then we have acromegaly hypothyroidism and hypothyroidism wherein the clinical endocrine conditions are more prominent and these disorders the hypertension is just something which is a bystander more than anything else but let me remind you that the commoner causes for high secondary hypertension are indeed chronic kidney failure glomerulonephritis recycle urethral reflux and relative psoriasis these are these disorders as a whole the renal causes are more common than the endocrine disorders per se and the other conditions uh which include cooperation of iota raised ict and off area are disorders which are largely medical but may be also associated with sudden episodic episodes of hypertension right so when we look at endocrine hypertension one of the most important things that we image is the ct of the abdomen and a ct of the abdomen has its normative dimensions when we look at the adrenal glands and we did a study just last year when we looked at a number of patients and the normal adrenal gland is a little thicker on the left side than the right side they're slightly larger in males than in females i need to be aware of the differences between the two sides when you look at the adrenal glands so let's first talk about pheochromocytomas and paragon gliomas three chromosomes as when we first looked at them way back around 25 years ago in our institution we looked at a series of cases around 35 of them and we also measured the metadifference more lately now when we look at the spectrum of cases over the last 25 years the entire spectrum has in fact changed largely we had patients who were with severe episodic episodes of hypertension the classical examples of palpitations wetting and tremors and weight reduction which was seen in these cases nowadays we move to a spectrum where about 25 to 30 percent of patients just present with severe hypertension and do not have associated uh episodic hypertension so it may mimic ordinary systemic hypertension without associated episodes which we commonly associate with viochromocytomas so in our publications we have looked at patients who have mutations seen among patients with viochromocytos and paragraphyomas and this is a fairly large population which i would advise you to read at some point of time and we have looked particularly at a common disorder of one hippolympus syndrome which is indeed the commonest cause for familial hypertension in any part of the world my presentation is going to be largely case-based and i'm going to be focusing on the familial forms of your chromocytoma in particular because now it is believed that almost 40 to 50 percent of patients with vio will have a mutation and a cause and you can look for a family member who may have the problem either parallel or later on in life so we have the men2 syndrome which has fios melary thyroid cancers and parathyroid adenomas we have one hippolynda syndrome which has chromocytomas with little angiomas as the common surrogate presentation at the same time and they also have hemangioblastomas in the neuraxis renal cell carcinomas in some patients and pancreatic isle tumors and then we have the sdh mutations particularly the dramatic sdhb mutations which present with a metastatic disease in a large number of patients now genetics plays a very important role in fear chromositomas paraganglumas are patient our patients who have the neuroendocrine tumors which are outside the adrenal axis and then we have bilateral adrenal fiochromocytomas in bilateral disease we should always think about associated familial causes for female theochromocytomas unilateral pheochromocytomas when there's a family history uh there's a strong family history then we think about doing genetic testing and then we have union natural adrenal fuel chromositomas at a young age of onset less than 45 please do genetic testing in all these cases other clinical findings suggested for one of the associated syndromic disorders uh uh like patients who have middle ear thyroid cancer obviously don't need to have a verbal screening or they have a pancreatic tumor okay so let's go to our first case and the rest of the presentation is going to be largely case based this is a 44 year old gentleman came with a history of severe hypertension of two years and a recent onset of diabetes and you can see over here the standard test that we do when we measure it with high performance liquid chromatography is the urinary meta difference and the normative difference and over here you can see it's just a borderline value normally patients who have an obvious viogramacitoma the values are more than 600 micrograms in 24 hours over here it says 400 but at the same time the serum calcium is elevated and the phosphate is also in the middle level but the parathyroid hormone is also inappropriately elevated so when you see a patient like this with the episodic and severe hypertension along with the parent with hypercalcemia and elevated pth you should think of a syndrome so you can see over here this is a isotope scan which we use for patients who have underlying geographic homocytomas and the ct scan showed a three centimeter to 1.4 centimeter lesion of a right adrenal mass and a left adrenal mass which is even larger so we had performed an isotope scan and this is called an mibg scan now a methylened benzylic uranine scan is used in patients who have these catecholamine secreting tumors especially if you're not sure if the ct shows you a fear or not particularly in those who have normal catecholamine measurements so you can see over here there's an uptake in the liver and that's a normal uptake but you can see also in the right bed of the adriani an enlarged lesion it's bright the anterior and the posterior and this is indeed of your chromosytoma so with clinical symptoms or incidentally discovered two centimeter vascular adrenal mass a fear should be suspected even if the measurements of fractionated metadata and catecholamines are normal so you can have normal catecholamines in patients like this all fears and paragraph tumors are pre-biochemical in the early stages so you can have patients with episodic hypertension where the biochemistry is not elevated you can see over here now that this ultrasound of the neck shows evidence of a parathyroid adenoma in addition so this patient underwent a bilateral adrenalectomy he had underwent excision of the right parathyroid adenoma along with the right hemithyrictomy as the thyroid gland appeared bulky on the right side a biopsy was performed as a parathyroid adenoma with a medullary thyroid carcinoma he then underwent a thyroidectomy and the final diagnosis therefore if you have a feo along with leary thyroid cancer with the parathyroid adenoma you should think about 2a he has remained asymptomatic on follow-up so this is our published series on medullary thyroid cancer and there are several germline activating point mutations which are seen with this gene and these are associated with men type 2 and familial medullary thyroid cancer so why is it important to do these mutational testing in patients who have fears with medullary thyroid cancer number one if you have a person who has a few and the son of the daughter has a screening test and it's positive you can do a prophylactic thyroidity and adrenalectomy before the child turns five years of age you can do a prophylactic pyro addiction screening of siblings and children should be performed of all patients who have medullary thyroid cancer and theo the presence of men2 when non-syndromic can also be picked up so you may have patients who have only a only a medullary thyroid cancer but if the mutation is positive then you might suspect that they also have a fear which might come up later on in life and these mutations also predict the severity of disease for example cordon 918 in malaria thyroid cancer indicates a more severe malignant medullary thyroid cancer here is an 18 year old lady who presented with severe hypertension for three months the urine meta nephrons were 100 but urine our meta nephrons are sky high 5700 and the ct scan shows an extremely large vision in fact it's probably outgrown its blood supply and therefore it has underground necrosis looks like a cyst seven into six into seven point five centimeters on the right hand side and there is also a small lesion on the left hand side which you can't see on this part of the ct scan which is 21.5 centimeters now another cut in the ct scan by accident shows a vascular lesion in the tail of the pancreas so what should you think about when you have a bacterial articulation and a bilateral fear bromocytoma this is one hypo lindo syndrome so when you would like to ensure that you're seeing all your lesions like i mentioned we do a meta i don't benzyl uranus scan an mibg scan is done in these patients and you can see over here the large region on the left side shows an uptake she underwent the right adrenalectomy and a cortical sparing left editing why did we do that now if i take off both the adrenal glands the patient will be lifelong dependent on steroids glucocorticoids i'll have to give him prednisone hydrocortisone as well as well as neurological supplements protocol so if i do a take off the right adrenal which had a huge tumor and then strip off the left-sided tumor and leave behind a bit of the cortex the patient does not need glucocorticoid or metallocoicoid replacement and because the lesion was large there was a necessity for a distilled pancreatic and the spleen ectomy in addition and the distribution was also done because this pancreatic tumor might become large and could become functional future in future and this could actually cause problems with the patient the histopathology of patients with theo essentially are not a predictor of malignancy you may see a lot of nuclear play morphism we may say mitotic figures as you can see on the sister pathology but be remember few chromosomals are very vascular and they're highly mitotic lesions and so therefore this does not mean it's malignant how do you make sure a patient has a malignant fear well only if there's vascular invasion or capsule invasion or metastasis in rare cases then you should think about a metastatic a a malignant pheochromocytoma the post-operative phase in this patient was uneventful and the patient uh does not require steroid supplement and the cortisol when we checked to be really sure that the adrenals the left adrenal was functioning was normal but we still give hydrocortisone intravenously in stress situations when they have vomiting diarrhea or fever now this patient did not have retinal angiomas but yet has a one hippolynda syndrome which tells you that the phenotypic presentation of these disorders can be very varied this is the basic pathophysiology of a one-hip belinder syndrome basically this is a tumor suppressor gene and if there's a mutation what happens is the specific protein which is produced we it basically induces vegf which causes angiogenesis vascular lesions increased glucose transport which makes the tumors bigger and autocrine growth stimulation because of tgf which subsequently makes the tumor potentially hormone producing in addition so while hippolyndo syndrome what we do is we measure metanephrines and non-normative difference every year we do a periodic mra of the brain spinal cord and the ct of the abdomen initially annually and then followed by once in three years we also do an optic fundoscopy because sometimes these retinal angiomas can bleed and the patients may in fact develop a large vicious hemorrhage which can cause blindness so therefore if you have retinal elangiomas sometimes we do prophylactic uh laser treatment for them so what is the algorithm for management of fears and paragraph humans what we do we measure 24-hour urine metanephrines and normative reference and then we do a ct abdomen and an mra the abdomen and adrenals and basically this ct abdomen is all that you really require unless you're thinking of lesions which are very close to the liver or a suspicious pancreatic lesion you really don't need to do an mri and then we do mibg or dota pet scans dota pet scans are now the more state-of-the-art tests to look at into consumers they're more specific than fdg pet scans and they can basically can locate extraordinary lesions and lesions which are undiscernable or metastatic as well preoperatively pheochromocytomas and paragraph levels are the only cause of hypertension where you give a lot of salt you load them with salt and why do you load them with salt because when you have catecholamine production there is vasoconstriction and if you take off this tumor after surgery what will happen if there's vasoconstriction there will be a total collapse of the blood pressure so to prevent this from happening what you do is you load them with lots of fluid four to five liters per day for 14 days and give them salt 8 to 12 grams of salt per day which you don't want any other cause of hypertension what is the drug of choice for treating them preoperatively you give them alpha blockade phenoxybenzamine is a competitive alpha blocker and therefore may be a more ideal drug but it's very very expensive nowadays so we use prasas in practice in excel and you have to give it for at least 10 days and you start the beta blockade only in the last few days before the surgery if you give it too early you may have a paradoxical vasoconstriction and you can cause a catecholamine crisis so you start the beta blocker later but you do need to start it to lower the heart rate which right frightens the anaesthetist at times therefore you need to lower the heart rate to prevent arrhythmias occurring in the perioperative phase calcium channel blockers have been used by some investigators but we don't believe that they are as effective if you have a very refractory hypertension prior to surgery what we do is we infuse them with sodium nitro precide or nitro crystalline infusion bring the blood pressure down surgery under general anesthesia with the uh when we of course nowadays these are the commonly used anaesthetic agents in the olden days papers use nitrous oxide and halothane which used to provoke catecholamine production laparoscopic surgery is generally now preferred and endocrine surgeons are pretty good they remove these adrenal tumors even if they are 10 centimeters and in size through the laparoscopic approach if they are multiple of course you might do an open surgery here is a 35 year old female who presented with diabetes hypertension and progress of weight loss and you look at the pedigree chart there are a lot of people in the family who have a lot of problems some died of hepatic metastasis some had sudden cardiac death so here the urinary metanephrine uh normative nephrons are elevated and you can see a large extra adrenal tumor over there behind the head of the pancreas abutting the iota and this is a retroperitoneal tumor so it's a paraganguloma that we're dealing with in this particular case and this patient also has a mat in the pelvis which we picked up incidentally on the ct scan so these paragamus and fuse they can last for many many years they can even be metastatic and you may not know about it patient could be living with metastasis for four or five years as well but the bad news is when we did an mibg scan we found metastasis all over the place in the in the spine in the pelvis and in multiple bones in the ribs etc so when you see this kind of metastatic disease it means it's a bad disease and that's an easy way to remember this mutation because the mutation which causes this bad disease is the sustanyl dehydrogenase b b for bad mutation which can cause extensiveness so over here our endocrine surgeons are pretty ex are pretty expeditious and adventurous what they do is they remove the large malignant tumor because you debulk as much a visceral tumor the blood pressure will go down and then you can think of adjuvant tumor once you remove as much tumor as possible so here once again the mutation has been shown to be an sdhb exon mutation and the patient is currently on chemotherapy 70 to 80 percent of patients with sthb related metastatic paragangliomas respond to cbd chemotherapy and these are the various forms of chemotherapy which are used uh rapamycin and evalnimus more recently galdomycin and gamma trillium and also the hiv inhibitors and the akt and emitters have been tried out in these patients but generally when you have extensive metastatic disease you may need to think about using uh associated isotope therapy so here is our algorithm if you're using the standard sanger sequencing because now we use next generation sequencing for the genetic testing and the standard sanger sequencing use this kind of an algorithm to diagnose these patients with the mutation screening 31 year old gentleman the eldest sibling presented four months history of record episodes of palpitations flushing and headache one episode was associated with giddiness and vomiting high blood pressure of 160 to 120 millimeters of mercury and he noticed two swellings on either side of the neck for the last five years which was of insidious onset the urinary metanephrine's normative difference was elevated and his urinary metanephrine was normal over here you can see a large highly vascular lesion just below the liver on the right hand side and this was enhancing on the arterial phase this is typical of a few very very vascular issues now this patient also had vascular lesions in the neck on palpation of the neck and you can see over here the mri shows large character now body tumors on both sides so after adequate blood pressure control we first attacked the little laparotomy and attacked the the lesions of the abdomen and the histopathology confirmed the diagnosis and mibt scan was done and did not show evidence of any residual lesions the lesions of the neck walls operated by a head and neck surgeons and this is a dota pet scan which basically shows evidence of residual lesions two years after the initial surgery the patient had a peptide radioreceptor therapy this is basically an isotope treatment you do about dota pet scan and then you give lutetium to these patients after lutetium there is a small regression of the tumor you can try this about two or three times but sometimes it may be still residue left and you just keep the patients on alpha blockade with the processing and the patients can do pretty well so the dota pet scan is actually more specific as i mentioned for these tumors we don't use the ftg pet in these patients here is the rest of the family history as you can see in this patient this patient had another second sibling there was a lady who presented was initially normal to the age of 21 years and had several episodes of hypertensive crisis and also bled into the brain on one particular occasion she survived this massive cerebral hemorrhage and she also had excision of tumors and went into remission thereafter so this is our series of patients with the familial keratin body tumors uh which sdhd mutations they have a better prognosis than the sch b mutations so about four to twelve percent of sporadic viochromocytomas and up to fifty percent of familial feuchromocitomas have sdhd or sdhd mutations xthb mutation speed results to mainly extra adrenal geochromocytomas with a highly malignant potential and the sdhd mutations are associated with multifocal parasympathetic head and neck paragangliomas that's the character body tumors with benign extra adrenal fair chromosome to us so what's the protocol for screening these patients we do an mri skull base and neck ct thorax and retroperitoneum and pelvis on a annual basis once we are sure that this total clearance we do a screening gadolinium dota to pet scan once in a couple of years 25 year old lady comes with a history of right hemi parasites falling into a bleed got married conceived and had an unusual pregnancy the baby was born by lscs then she started complaining of headache and was found to have high blood pressure she was noticed to have profuse sweating and worsening our symptoms after using the toilet so basically she had a micturition syncope her blood pressure was 130 by 100 on routine checking and 180 by 110 after passing urine the optic finder showed hypertensive changes and she had left ventricular hypertrophy and a normative difference elevated so here is the imaging on this lady and you can see over here that the mri of the abdomen and the pelvis shows a large lesion which is adjacent to the urinary bladder she underwent a partial cystectomy and removal of the lesion and you can also see the mibg scan over here what we do in these mibg scans because the mibg can collect in the bladder we do the scan after four or five days to make sure that it's not urine containing a maybe in the bladder but it's a tumor which is actually taken now after this lady had a cystectomy dude she did perfectly well and she still comes to us for follow-up almost 12 to 13 years later this is the biopsy and you can see over here the spindle cell tumor inside the urinary bladder and the neuroendocrine marker that is chromogranin is positive in the histology of this tumor and the follow-up neuro meta-nephrons and normative reference are normal this is our publication in the british journal of urology on patients with blood of your chromosomes rare disorders but in fact truly speaking they are not blood of yours they occur outside the urinary bladder and with nutrition copay is in fact a less common presentation so what are the differential diagnosis of your chromositomas if you see somebody in your clinic as a physician think of anxiety or panic attacks hyperthyroidism paroxysmal atrial tachycardia and even menopause and hot flushes can be pretty nasty and can mimic of your chromocytominous up ladies think of a severe vasodilatory headache someone with migraine can in fact have an elevated systolic or diastolic hypertension so think of all these commoner disorders as physicians do not think of pure chromositomas as your first diagnosis when you see such patients and of course even hypoglycemia has all the features of a fuel if you have a patient who has diabetes or has a hypo you have a catecholamine surge it can cause palpitations tremors sweating and even a flush on the face in summary attempt to look for syndromic associations and fears and paragraph humors genetic testing is essential for these patients and determines the etiology of these disorders and identifies the risks in siblings it can predict those in future generations so it's very very important in geochromocytomas isotope scans ranging for mig to denote a pet scans are mandated and supportive of isotope application may be required in patients who have malignant disease or residual or very large patients and of course we all work together to handle these humors the endocrinologists the endosurgeons nuclear medicine and medical oncologists so i'll talk about my second theme over here and that is hyper aldosterone and this is far far more common than feochromocytomas let me get back to the physiology over here i'm not a great artist but actually through this little cartoon for you and you can see over here that kidney as you know produces renin from the juxtaglobular cells and this of course leads to the production of angiotensin or adjutants in one in the liver and antigens in two in the lung and this might stimulate the adrenal gland to produce aldosterone now in patients who have excessive production of aldosterone you may have in fact increased potassium product excretion which leads to hypokalemia and metabolic alkalosis in addition so here is a 32 year old lady who came of recurrent episodes of flaccid quadriplegics over six years and a known hypertensive for three years the blood pressure was elevated and the patient was treated elsewhere with the calcium channel blockers and bacterial showed severe hypertension and she also had left ventricular hypertrophy with allowed a2 she also had difficulty in getting up from the squat a biochemistry showed a borderline high sodium and a potassium which was low so you have a hypokalemic calculosis now remember hypokalemia per se which is severe and persistent can also cause ankylosis also remember that the commonest cause for hypokalemic calculus is not one syndrome but is a diuretic but if you have ruled out a diuretic and a patient has recommended episodes of periodic paralysis please think of corn syndrome as a most common potential cause when you have hypertension at the same time the sodium is normal or borderline height it is never elevated in spite of aldosterone production and you go back to your old physiology days you'll remember you have a phenomena called the aldosterone escape and why does this happen because aldosterone stimulates the production of atrial nutritic peptide from the heart and that causes a loss of sodium in the urine so you never have a high sodium you have a high normal or a normal sodium as well so here you can see the ct scan which shows a lipoid rich tumor and does not take up contrast in co which is in stark difference to what you see in fears and fears your vascular lesion ganglion is your vascular lesion and the contrast scan is red hot whereas in these patients you give contrast and nothing is taken up so alkaloid levels are elevated related levels are suppressed in these patients you have hypo renin and hyper aldosteronism periodic paralysis is seen in almost 50 percent of cases in the past nowadays many patients with hypertension are treated with ace or arbs and the diagnosis may be made late because the potassium is normalized and some of these patients inadequate inadvertently the end organ damage is less severe than geochromocytomas and the treatment of choice medically of course is fibrinolactone and then you can add on ace inhibitors arbs and even calcium channel blockers the dye hydropyridine calcium channel blockers act by blocking the effect on aldosterone on the receptors as well the surgery is far more simple than feochromocytomas and the laparoscopic positive approach is almost always done in these patients so here you can see the histopathology of the tumor it is a typical yellow looking tumor because it contains a lot of fat and it is small it's generally less than three centimeters usually in the range of 1.5 to 2.5 centimeters unlike the fuels i showed you and look at the histopathology a typical clear cell tumor why is it clear cell because when you fix the tumor the fat basically is removed and it doesn't take up any stain and the most important thing which i'd like to highlight is that most patients with hypo aldosteronism in fact have what is called idiopathic hypoallergenism they do not have tumors and the adrenal glands can be normal in size in fact this very visionary paper published by jerome khan whom of course constant rome is named after described that primary hypoallergenism may exist for many years before clinical potassium deficiency is absolutely correct thirty percent of patients with hypoallergenicism have a normal potassium or a low normal potassium between three point five to four a large proportion of patients with essential hypertension have primary hypoallergenism so called essential hypertension probably have and that's also true 10 of your patients with a with systemic hypertension below the age of 40 are probably walking around with private primary hyper analysis if they are of course severe and they need more than three medications please think about that incidental cortical adenomas without hypertension physically appear the same appear the same so patients who have cortical adenomas without hypertension uh may in fact have incident lomas which are fat containing so there are types of hypotheticism and as i mentioned bilateral idiopathic hypoallergenicism is the most common cause sixty to seventy percent of cases of primary hypoallergenism urinary latinomas uh basically are seen in 30 to 40 percent of cases and they are basically due to a somatic mutation a somatic mutation so you don't do a blood test you will find this mutation only in the adrenal tissue so therefore a genetic testing does not really help in these cases the other rare causes include unilateral adrenal hyperplasia which has a similar outcome to adrenal adenomas familial hypoallergenism type one two and three where you have germline mutation so you can do a blood test in these patients and you may have a family member who have an aldosterone producing adenoma and really you may have alderstone producing cortical adrenocortical carcinomas uh they are ectopic aldosterone secreting tumors in the ovary and the kidney but these are extremely rare so the prevalence of these conditions is pretty common five to thirteen percent and point six percent of adrenal incident low mass the prevalence of this condition is apparently increasing and 39 percent of resistance patients resistant hypertension patients on three or four drugs maximal doses you should think about this condition with aldosterone ratio being used as a screening tool the prevalence of primary hyper aldosteronism averages about six percent of patients with hypertension hypertension usually is substantially elevated in both systolic and diastolic pressures without malignant hypertension in these patients hypokalemia is present in 40 to 60 percent of cases and there is a lack of edema so despite the aldosterone being elevated you don't have a fluid retention and this is due to the aldosterone escape phenomena metabolic alkalosis hypomagnesiuma and mild hypernatremia also seen so you may have a low magnesium in these patients in addition which is also due to the effect of the aldosterone itself now can we use this as a screening tool the aldosterone rendering ratio you can have a false positive in 50 percent and this is a real headache because this is the biochemical test of choice in these patients plasmarin levels can be low in 30 of those patients with hypertension and a low limit of pra changes from 0.6 nanogram per ml per hour to as low as 0.1 nanogram per ml per hour and this of course indicates variability so sometimes we do this ratio on a second location to double check okay i'll finally turn to cushing syndrome and i always say cushing keeps us blushing because it is a condition which has a vast and varied presentation and perhaps one day i'll do a test talk to you on pushing syndrome percy here is a 30 year old lady at 18 weeks of gestation and she presented with headache dizziness and left loin pain for two months hypertension and detection really severe through 10 by 130. no palpitations visual disturbances in copay no proximal myopathy or easy bruisability so the features of cushing's were subtle on examination she had no over cushing height features but she had edema and the blood pressure was elevated she also had great hypertensive changes in the fundus but no viralization on investigation a potassium is low so this is much the opposite to the other patient i told you about she does not have my body but her potassium is really low magnesium is borderline low and she has alkalosis in addition with detection of newly diagnosed diabetes the cortisol is massively elevated the normal cortisol at atm is around 21 and of course make sure the patient does not have obstructive sleep apnea or has come from a different time zone from another country because all these things can falsely elevate the atm cortisol the post-age 8mg dexa suppression cortisol is also non-suppressed it should normally be less than 2 microgram per deciliter the catecholamines are normal and the patient has a hypertrophic lv or an echo now because she was pregnant of course she only had an ultrasound of the abdomen done and this fortunately showed well unfortunately for the patient showed a large 12 centimeter diameter tumor so we need to reconfirm and we do the ct scan and you can see this massive 12 centimeter tumor on the left side and the tumor also has some heterogeneity as you can see over here uh if you look closely so when you see such a big tumor in the adrenal gland what you think about you should think about a malignancy and it's a cortisol producing adrenal tumor you think of an adrenal cortical carcinoma and of course the differential of a few is there but why should a feo produce cortisol it doesn't a fuel could produce acth very rarely and stimulate the adrenal cortex to produce cortisol that's extremely rare the blood pressure was very difficult to control the patient needed five medications and then the patient had a spontaneous miscarriage after the miscarriage the cortisol was still elevated just remember if you check cortisol in pregnancy it will be elevated so that's a catch but here the cortisol was elevated even after the miscarriage so the patient was operated and had a very large tumor bigger than what looked at the ct no adenopathy no hypertensive crisis during surgery and the histopathology shows this variegated mitotic tumor and this basically is an adenocortical carcinoma now adrenocortical carcinomas uh even if you take the whole tumor off we have histopathological staging which can tell us the prognosis and this patient's prognosis was intermediate i'm not going to talk about the staging over here but the post-operative period was uh uneventful the number of antioxidants were reduced and probably due to chronic hypertension there must have been some hypertensive global sclerosis which caused residual hypertension but because of capsular invasion which was detected by the pathologist the patient was advised radiotherapy followed by mitotine patient had radiotherapy and could not afford mitori mitrine is an extremely expensive medication extremely meaning it costs something like about 400 to 500 rupees per day i know there are people who could afford it but this lady was the wife of a farmer she could not afford it and the good news is that seven years later she's doing pretty well after radiotherapy 19 year old medical student came to us with hypertension during screening for medical admission in well not in our medical college but elsewhere borderline blood pressure and the medical check-up doctor said this is white collar hypertension he's scared of getting into medical college but then after that he developed weight gain high blood pressure as well swelling of the lower limbs with facial puffiness increase skin pigmentation stretch marks acne and of course i'm sure even a medical student would make this diagnosis of cushing syndrome progressive weakness of the lower limbs wet bound and severe hypokalemia low back pain and then develop psychosis also polyuria with polydipsia and find found to have a high glucose and the potassium level was also lowered severe hypokalemia with alkalosis so my question to you is what kind of cushing's does this patient have well young male hypertension diabetes rapidly progressive symptoms over a few months gross hyperpigmentation and severe hyperkalemia young male think about ectopic ecth remember the communist course for androgenous cushing's is an acth producing lesion but it's usually in the pituitary but pituitary lesions can be more insidious in onset don't have such severe hyperkalemic calculus and they are more common in females about 80 percent and females so you can see over here he's developed grossly cushioning idle look with acne and pigmentation is uh basically quite dull and apathetic uh he was an antioperances when he came to us and this was his appearance and he had a lot of vacuums at the blood drawing site so we investigated him in detail his baseline cortisol is but through the roof 60 remember the normal is more than 21 are less than 21 the midnight cortisol was elevated and then we did a low dose hexamethazone separation test overnight 1mg that was also not suppressed and the high dose is also not suppressed so if the low dose is not suppressed and the high dose is suppressed you're thinking of a pituitary tumor here both the low dose and the high dose were not suppressed next mothers and separation and the urine free cortisol was really really high patients with pituitary dependent cushing's have urinary cortisols which are usually less than two thousand or three thousand here it was in tens of thousands and the acth pituitary tumors usually have ach levels less than hundred was very high once again more than six hundred so here is the pituitary gland on the mri it looks a little bulky it would come into what we call esters grade 3 flat topped pituitary but there's no definite tumor we did what we call dynamic imaging that means you take an mri in the fourth dimension that means you give a contrast and then you take time dependent sequences uh with dynamic dynamic imaging and that also did not show a tumor this is the ct of the abdomen and you can see huge large adrenal glands they are not tumors but they are hypertrophic hyperplastic lesions non-contrast enhancing uh they do not take up contrast and they're hypoplastic and they're bilateral indicating that eth is stimulating both the adrenal glands and over here this is the ct of the thorax which shows an anterior medicine lesion what does that make you think about what is an anterior medial stimulation which can produce acth and the answer is well thymus so when you think about acth producing cushing syndrome the communist is a pituitary and then you think of medullary thyroid cancer very rare and then you think of intrathoracic lesions like thymus bronchial carcinoids bronchogenic carcinoma and then you can think of pancreatic tumors which can produce acth but the more common ones are above the diaphragm and that intrathoracic acth ectopic is reducing tumors include bronchial adenomas thymomas and broccogenic asthma and this is a time of anterior medicine lesion we did a dotenox scan and this showed uptake as well which indicates that this is a thymoma a neuroendocrine tumor these dota pet scans and dotonoc scans are specific neuroendocrine tumors patient underwent surgery thymic thymus was excised but there was also a lot of adhesions to the nominate vein indicating local metastasis and after the initial post-op improvement he had persistent hypokalemia which indicates bad news there is local disease there is local metastasis so he did not uh have a full remission so we did a bilateral activity to help him resolve his questions now postoperatively he developed a pneumonia now when you have a pneumonia post-operatively after the adrenalectomy what might be happening is that this may be a pyogenic pneumonia and basically that's one possibility but you should also think of opportunistic infections even after the adrenal have been removed no cardia hemocystis karani and these are the possibilities that i would think in this particular patient so what you can see over here is pneumonia and you should think about an opportunistic infection in these patients not necessarily an ordinary pyogenic and you should hit them very hard so what are the opportunistic infections that you should think about of these patients all of them will indeed uh no cardio and pneumocystia both respond to meropenem and you should also use uh high dose spec bacterium dears or ceptran in these patients which will hit them you can't wait for the microbial biological diagnosis in these patients okay so with the clock strong clinical suspicion was started on meropenem amicayson and uh septrandias and uh he was followed up in the intensive initial intensive phase for three drugs six weeks and september was continued for a year after that so this is the histopathology showing uh branched filamentous organisms and this is a partial acid fast staining bacteria and basically this responds very well to the combination that we gave him two months later his x-ray looks good and he's doing well he had chemotherapy for the rest uh residual action producing tumor with diazolamide and capacitor bin for the residual tumor and he's doing pretty well for the last uh seven years that's your patient pre-med after becoming a medical student with cushing's and then after surgery you started to resolve so let me summarize over here a broad clinical approach when you have a patient to have severe hypertension when you investigate for secondary hypertension difficult to control with maximal doses of more than three medications early age or presentation less than 30 years western textbooks will tell you less than 35 bch less than 30 because you can get a fair amount of systemic hypertension more than 30 patients in the metabolic syndrome in india atypical signs and symptoms recurrent palpitations market weight loss catecholamine tube producing tumors are catabolic and they can cause a lot of weight loss periodic paralysis uh which happens in hypokalemia polyuria why does polyolio happen in patients with chronic hyperkalemia you have macular tubular changes in the kidney you can have polyurea recurrent urinary attack infections in recyclable reflux fever arthritis and hematuria in patients with sleep poly arthritis nodosa cuteness lesions in those conditions as well uh family history of severe hypertension and rainy failure uh think about adult polycystic kidney disease severe presentations of encephalopathy papilloedema and left ventricular failure any of the causes for accelerated hypertension and secondary hypertension causes and then your examination checklist cushing height features and acromegaly features look for them in these patients severe hypertensive retinopathy investigative detail features of men2 like uh marfanoid features an mem2b turner syndrome well of course they're short statured and they could have cooperation of the ayatta so your radio femoral building skin lesions in polyurethane dosa palpitable kidneys and adult polycystic kidney disease and of course adrenal tumors which are very large and an abdominal brew and renal artery stimulus so these are your baseline tests which you would do even in a primary healthcare center which are easily available now in most parts of the country and of course when you go tertiary for proper investigations you know your urinary metanephrons plasma metal nephrons are very expensive catecholamine levels in the plasma we don't do it in ourselves because it would be very expensive for our patients aldosterone and related reverse remember very useful in many patients with so-called accelerated hypertension or what has been misdiagnosed as a systemic hypertension for many years cct of the abdomen in patients with paragangiomas and remember in cushing's ectopic cushing's the ct thorax will pick up some tumor in at least 70 of cases mibg and dota pet scans for our neuroendocrine tumors digital subtraction and angiography for vasolitic lesions such as disease vasolitic workup and renal biopsies of course when you're thinking about a nephritic or nephrotic cause for hypertension so i'd like to thank a number of people who have contributed towards the diagnosis and treatment of these conditions uh it's all teamwork when it comes to treatment of endocrine hypertension uh uh endocrinologist my team a lot of the residents who worked with us whose names i can't mention over the years surgical endocrinology nuclear medicine radiology pathology and our biochemistry department as well thank you for your patient listening i'd be very happy to answer any questions of yours uh thanks a lot for beautifully summarizing it and i'll just talk presentation here so i'll just take a few relevant questions uh which we have so dr thawker has asked what replacement is given after total adrenalectomy so uh so could you please just say you are on new type i guess uh thank you good question if you're doing a bilateral me you need to replace glucocorticoids and mineralocorticoids so how do you replace leukocorticoids uh much more easily available of course you have a prednisone and you the standard dosage is about 5mg in the morning and 2.5 mg in the evening but you can get patients who get away with this 5mp once a day so you might find people turning even pushing out on a tiny dose of 5 and 2.5 you need to give neutral cortisol in many patients because they also understand deficient so the dosage could vary as low as 50 micrograms per day up to 100 or even 200 micrograms per day in some patients if you're doing a cortical sparing adrenalectomy on one side uh uh if you're doing a bi instead of doing a bilateral disease and in some patients with bilateral fuels you can do a cortical sparing adrenectomy you don't need to replace anything but in case of stress be more vomiting diarrhea or any surgery all these patients should have intravenous hydrocortisone just to make sure that they don't have a collapse at that point right uh so there is one more interesting question or dr priya pattak has asked in a hyper aldosteronism it is it not necessary to have edema uh due to solid sodium water retention mechanism is it like necessary symptom or we might not see that it almost never happens if you have edema in a patient who has hyperkalemia and alkalosis you should think of cushing syndrome maybe even ectopic acts producing cushing's might be the cause not uh concentrate so they normally never have it unless they have some other comorbidity or you know some other illness which is causing hypoallernia or if they have very severe hypertension they could have cardiac failure that could cause edema but usually hypoallergenism does not cause it and i told you the mechanism aldosterone stimulates the heart to produce eat related peptide and this acts as a diuretic it also acts as a meteoritic and that is why they do not have elevated sodium the total body sodium may not be as high enough to cause interstitial edema right dr priya i hope this answers your question uh so we can quickly take the quiz before uh everyone actually will everyone will actually get some time to put their questions and they can actually raise hand and come on stage and ask us directly if you have anything in mind so uh sir has actually authored two interesting books uh let me know when the slide is so i'll just put up three quiz questions here uh whenever uh the question is announced you can put your answer in the comment section you can just mark uh it as abc or even the options will do yeah so these are the clinical class give these as gifts to people to answer the questions accurately maybe the first ten people yeah yeah yeah post correct one so uh sir sir will be sending all the copies to the winners of this quiz uh we have these two books authored by sir clinica class in endocrinology and diabetes and diabetes bullet has practical guide so uh i'll just go to question is it okay or you want to explain a bit about this and then please please go ahead yeah so here is uh the first quiz question are you ready for the quiz the least common cause for a few chromocytoma amongst the following is here are the options sdhb mutation max mutation okay do you want me to give the correct answer richard oh yeah so if you want to explain a bit about it so the correct answer is actually max mutation e one hippo linda syndrome is the commonest i think i've highlighted that in my talk amongst the familiar future homozygous um if you look at prevalence files men2 ma and 2b would probably be the next and then sdhv mutations mac mutations are much rarer and are tend to occur in older people but they are much later okay perfect so we'll announce uh winners in the comment box uh till then i'll go to second part of the quiz uh here is it uh in kerner syndrome which of the following is false a renin is suppressed and aldosterone is elevated b acdh is suppressed c potassium may be normal d malignancy is less than 10 percent and e is the adenomas do not enhance contrast on cd scan we can give them correct answers for many doctors have already okay interestingly has gone in contrast to the last one i think too many didn't get this right so but anyway the correct answer is actually d so i'll go through this red is suppressed and understand is elevating that's the basic physiology aldison is elevated therefore unsuppressed that is correct act as suppressed because you have hypokalemic calculus because you already have hypertension there could be a tendency towards a slightly lower act potassium may be normal which i told you corn himself described that almost 75 years ago now malignancy is actually extremely rare aldosteronomus very rare i think i've seen only three in the last 25 years so uh it's a very bad malignancy to have it's worse than the adenocortical carcinomas per se even though they are not that large so it's fortunately very very rare maybe less than 0.5 of all understood producing as you can see so that is uh that's actually that's false male malignancy is seen and only less than point one percent and adenomas don't take up contrast on on ct scan because they're fat containing they're not vascular they do not take contrast we'll move to the last part of the quest this is the question which of the following are false myotannin is a adrenolitic asian ketoconazole works on enzyme involved in the synthesis of cortisol ecth levels are generally more than 100 nanogram per dl in ectopic ecth secreting uh gushing syndrome fdh pet scan gives specific uptake in patients with neuroendocrinicity or screening tumors and last is 24 hour urine free cortisol level are usually very high in ectopic acidity secreting again not you know ddt right so this is very similar to ddt in fact mitotine was discovered when rats started dying of adrenal failure due to ddt so they invented ddd opd uh so it's an activating agent it is an act that's correct ketoconazole works on several enzymes in the cortisol production pathway in the adrenal gland which is correct acth levels are generally more than hundred in ectopic activity segregating cushing's this is also correct because in pituitary cushing's uh the acth reduction is usually less than 100 but in ectopic it's usually more than 100. ftg pet scans give specific uptake in patients with neuroendocrine acetate cyclicals it doesn't give specific uptake if you don't fdg pet in any neoplastic lesion you can have an uptake uh and of course if you have metastatic lesions which are more aggressive you can have an update but in acth producing neuroendocrine tumors like timic or bronchogenic carcinoma or pancreatic tumors it is the dota pet scan which is more specific it is sensitive as well as is more specific than fdg pet scans so that is false 24 urine free cortisol levels as i shown you are usually very high in ectopic aches sacred youtubers congratulations to the winners who managed to get all three correct so we have list of winners dr narayanan tavkar has won this quilt uh we'll definitely get in touch with you and we'll send the book office really soon uh so thanks a lot sir uh it was really interesting and we hope to have you again with us

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