Adrenal Insufficiency - When the Adrenals go on a Strike - Dr D H Preethi Dissanayake

[00:00:07]Hi, I'm uh Dr. Priti, consultant endocrinologist from teaching hospital.

[00:00:13]So today's talk is going to be on adrenal insufficiency.

[00:00:18]uh in within the next 30 minutes or so we will talk about uh the types of adrenaline insufficiency, how to diagnose the art of replacement, crisis management and more importantly how to uh you know uh empower patient with adrenal insufficiency with education and certain other things and a little bit more about iodgenic suppression.

[00:00:44]So when it comes to introduction I first of all I have to introduce you the adunal gland. So we all know adrenal glands are a pair of glands situated on top of each kidney. The these are triangular in shape and then it has two parts adrenal medela which is the neuroendocrine uh core which is responsible for catakolamines and the outer layer is cortex. It is divided again into three zones. So the sona glaryosa which is uh situated outer most as responsible for mineralcorticoids, middle layer sona vesiculata secrete gluccocorticoids and inner layer sonar reticularis is responsible for adrenal androgens and uh this adrenal androgen and cortisol production is under hypothalmic pituitary adrenal axis. What happens is under the uh you know uh stress inputs as well as circadian rhythm the paravvententricular nucleus of the hypothalamus secrete uh corticotrophing releasing hormone and then it acts on anterior pituitary corticotroof cells to produce act. This act comes and uh stimulate the adrenal cortex for cortisol and de production.

[00:02:07]And again these gluccocorticoids have a negative feedback at the pituitary and hypothymic level. Uh the CR and act has minute stimulation for mineral or corticoid pathway but we will talk about that little later. So when we take the cortisol cortisol is the key moderator of most of the metabolic functions in the body. We know that is one of the hormones we need for survival.

[00:02:36]And um it is a it is again important in the fight and flight response as well.

[00:02:43]So more than you know mediating one particular action it has permissive action on most of the bodily function and this is under a circadian rhythm. So we know uh our metabolism is at a peak when we wake up but before we go to bed you know uh from midnight to for about 2:00 a.m. the cortisol levels are at the lowest and then it starts gradually rising from 3:00 a.m. onwards and comes to a peak just before we wake up and uh the peak value comes between 8 to 900 a.m. And this can change in a shift worker you know especially those who are working in the night and know uh like I previously mentioned aldestone production is mainly regulated by the rein andotensin aldestone system and that's a different pathway separated from the hypothermutary axis.

[00:03:44]All right let's move on to the different types of uh adrenal insufficiency. So primary adrenal insufficiency as the name denotes what happen is there is glandular failure. When there is glandular failure the cortex fails. So all the hormone secreted from the cortex fail that means uh cortisol adrenal androgen and uh mineralcorticoids.

[00:04:10]So the negative feedback won't happen and act and CR goes up and this elevated ACT and related metabolites increase the pigmentation of the patient and as we are lacking aldsterone significantly uh you know we can't uh secrete potassium out of the body then there will be hypercalemia associated with hyponetriia.

[00:04:36]When it comes to secondary adrenal insufficiency, the pathology is mostly at the pituitary level. So isolated act deficiency is rare. Most of the pathologies affecting the pituitary uh gland will affect the other pituitary hormonal axis like thyroid, growth hormone and reproductive axis. Uh but um what you have to remember is when there is pituitary failure. Okay. So what is under hypothermic pituitary uh adrenal axis is uh mainly cortisol and adrenal androgen. So those two are getting affected but alone level will be normal and it is the sim same as uh tertiary uh adrenal insufficiency but the level of damage is at hypothalamic level and the common same disease um or same pathologies affecting the pituitary can affect the hypothalamus as well. But most of the time the tertiary adal insufficiency is due to the exogenous uh use of steroids you know supraphysiological doses of steroids using over longer period of time. Again the picture is similar you have low cortisol and adrenal androgens but alone will be normal. So it is easy you know since the pathologies are also most of the time similar and the management is again similar. Secondary and tertiary adrenal insufficiency we will put together and call them secondary and primary adrenal insufficiency we take separately.

[00:06:13]Okay. So next few slides I will take you through three interesting cases. The first case you have a 61 year old female who is coming uh over period of three months with progressive fatigue, unexplained weight loss, recurrent episodes of dizziness. The patient reports waning energy levels, old cravings and intermittent abdominal pain. She notes that her skin appears tanned despite minimum sun exposure and she has a past history of hypothyroidism. An examination you can appreciate there is a significant postural drop and she has hyperpigmentation and BMI is normal.

[00:06:55]If you focus on the picture you can appreciate the patient before treatment and after treatment and how different the patient is. Look at the investigations. There is hyponetriia with hypercalemia and very low name cortisol. the normal level would be at least above 300 nanom moles per liter and plasma act is significantly elevated. Uh that is why the patient is pigmented. So the diagnosis is none other than primary adrenal insufficiency. It's an easy case.

[00:07:30]Moving on to the second case. Uh just take a bit of time to appreciate the patient's facial appearance and the skin. So this is a 55year-old uh female um post-menopausal. She's coming with a thunderclap headache associated with vomiting and visual blurring and she reports that she had recurrent episodes of headaches uh previously as well. An examination reveals pale skin and uh low mood and blood pressure. Again there is a postural drop and she maintains a good BMI and um at bedside she demonstrate by temporal hemianopia without of thermoplasia. So this pale skin appearance that happens in this sort of a situation I'll tell you later it is called alabaster skin appearance and then if you focus on the investigations you can appreciate that almost all the pituitary hormones are low including the gonadotrophins which we would expect to be very high in a post-menopausal women in a post-menopausal woman uh and there is hyponetriia but no hyperc calmia and in the CT you can appreciate a nice rounded mass with acute bleeding into it. So again the diagnosis is nothing else. It is pituitary apoplelexy with panhypopituterism.

[00:08:54]So the patient must have had a pituitary tumor. Now there is bleeding into it and patient has already developed panhypoputerism including um ACT deficiency. So patient has secondary adrenal insufficiency.

[00:09:11]The third case is a usual scenario that you will encounter. So this is a 16-year-old school girl referred by dermatologist for the evaluation of rapid weight gain and cushionid features. Upon reing inquiry, she has heretism and oliguminaria, but she generally leads a very sedentary lifestyle and she was putting on lot of weight and then she started developing white stretch marks over the arms and the abdomen and she was very much concerned about this and she wanted uh to make them disappear. So she went to the GP got a cream and started applying all over the body where she has these stretch marks. And then upon application of the cream she is telling that all these white marks started becoming purple and she started feeling very weak and unable to concentrate on the study.

[00:10:03]And this is the appearance of the patient. You know she has generally rounded face and bit of facial pora [snorts] and there was no thinning of the skin proximal muscle weakness or easy bruising but you can appreciate the white purple stri. And there was the doses cervical fat pad and uh blood pressure is little towards uh lower side. And again you can appreciate there is hyponetriia with normal potassium and very low uh name cortisol repeatedly and act is suppressed.

[00:10:38]So this diagnosis is very easy. So what she was doing is um so she started applying some strong um you know topical steroid and uh it was absorbing systematically and her adrenals are getting suppressed and on top of that she's developing iotrogenic Cushing syndrome. So she has irogenic Cushing syndrome with gluccocorticoid induced insufficiency.

[00:11:08]All right.

[00:11:10]Okay. So let's move on to primary adrenal insufficiency which we call Edison's disease. So thanks to uh Dr. Thomas Edison one of the founders in clinical endocrinology back in 1850 uh we got to know about the adrenal insufficiency. First uh we have epidemiological data from western societies. So the prevalence of adrenal insufficiency since it's a rare disease about 100 to 140 cases per million and incidence is uh four uh per million per year and we notice that there is a rising incidence due to the use of immune checkpoint inhibitors uh causing adrenalitis and hypophasitis uh you know for cancer chemotherapy.

[00:11:57]Let's take the clinical picture. So they might come with very sort of nonspecific clinical picture. They will come and tell you loss of appetite, loss of weight, nausea, vomiting, abdominal pain, diarrhea. You know they might be having fatigue, reduced lipido, depression and some might be salt having salt craving, postural dizziness, hypotension and myia joint pain and weakness and hyperpigmentation. In the case of primary adrenal insufficiency investigations, you might appreciate nomocitic normocchromic anemia, lymphocytosis andia because cortisol is important for the you know white blood cell production as well as hematopo hematopois and in uh investigations the lab investigations will show hyponetriia with hypercalemia if it is primary adrenal insufficiency and mild hypercalcemia.

[00:12:59]But one thing to remember almost all these symptoms are nonspecific and they come uh you know come to the doctors several times before we make the proper diagnosis. So you need to have a high degree of suspicion and uh you know uh you should uh prevent a life-threatening adal crisis at all. So most of the time there is delayed diagnosis. They say a phys uh you know uh the patients will go through 7 to eight physicians by the time you know they come with the diagnosis ethology uh you know I can give you an exhaustive list of causes but uh what we have to remember is out of all the patients who are having primary adrenal insufficiency the most common cause is autoimmune adrenalis. is like hypothyroidism uh and infections like tuberculosis, fungal infections, uh retroviral infections can give rise to adrenal insufficiency. Infiltrations like hemocromattosis, amoidosis, metastasis, uh again injuries like trauma or bleeding into the adrenals can give rise to adrenal insufficiency. Drug induced causes like adrenolytic uh drugs uh or uh you know uh anti-B drugs, anti-epileptics can give rise to adrenal insufficiency. Uh the rare genetic causes like congenital adrenal hypoplasia or hypoplasia uh can be found in infants and you know young children.

[00:14:40]>> [clears throat] >> So this is a very busy slide but this summarizes you know all the causes of primary adrenal insufficiency. When it comes to secondary adrenal insufficiency it is due to the pathology at the level of the pituitary and hypothermus. It can be a tumor. It can be radiation. It can be trauma. It can be uh surgery and it can be uh autoimmune hypothesis and also infiltrative disorders like sarcoidosis, hemocromattosis, amoidosis.

[00:15:12]Then again don't forget the infections tuberculosis and retroviral infections and medications like immune checkpoint inhibitors.

[00:15:21]The drug induce adrenal insufficiency if you take super physiological doses of gluccocorticoids is the main cause but opioids adrenolytic drugs like meipristone umdidate metropone ketoconosol mitoin >> [snorts] >> uh antiBB like reampin uh anti-epileptics like phenitoine pheninoarbone and then again the key uh imunotherrapeutic agents immune checkpoint inhibitors All right. So, let's move on to the diagnosis of um adrenal insufficiency.

[00:15:57]When you have a patient uh with suspected adrenal insufficiency, the first most thing that you need to do is I name cortisol. If the basel cortisol is less than 138, it is highly suggestive of ads insufficiency. And if you can couple it with an elevated plasma CTH level done at the same time.

[00:16:19]If it is more than two folds over the upper limit of the normal again you can confirm primary adrenal insufficiency.

[00:16:27]But the gold standard for confirmation of adun insufficiency is the short synactin test. 250 micrograms of synactanin will stimulate the adrenals to produce cortisol and we measure the response at 30 minutes and 60 minutes.

[00:16:42]If the co peak cortisol goes above 500, that's a normal response. If it is low, you have to uh diagnose adrenal insufficiency. But there are certain pitfalls uh because we are using serum total cortisol essay that we will discuss later. And there are other dynamic function tests that we use to diagnose adrenal insufficiency mainly when the patients are having secondary or tertiary adrenal insufficiency.

[00:17:12]Insulin tolerance test, glucagon stimulation test, metropones test uh are used mainly for the secondary adrenal insufficiency. Lowdose act stimulation.

[00:17:23]You might have heard about 1 microgram synct. This is being used when the resources are poor but you know it is not uh being recommended over short and standard short synct.

[00:17:38]Um we know that when it is primary adrenal insufficiency aldsterone axis is affected. So simultaneous measurement of rein and aldsterone will help diagnose mineral corticoid deficiency. But remember this is not available in our setup freely. Therefore uh we cannot use this uh all the time and who should be tested and how. So when there is a patient who is coming with the suspicion of adrenal insufficiency, if the patient is stable, okay, you can do all these tests that I have discussed. But if it is a crisis situation, if the patient is acutely unwell, the most important thing is you have to treat them on suspicion. Once the patient is stable, then we can consider doing short synact test.

[00:18:29]So these are the problems and limitations using cortisol assess. So we know uh cortisol is a hormone which is 90% of the time bound to cortisol binding globuline and uh albumine only 10% remains free but what we are measuring is the total cortisol level not the free cortisol. So when there are conditions like pregnancy and oral contraceptive use due to the high estrogen levels they have high cortisol binding globuline. So when the cortisol binding globulines are high although the patient has adrenal insufficiency they can have higher uh number of you know total cortisol. So when you do the cortisol essay or when you do short synact test by having a normal responseless more than 500 nanom moles per liter of cortisol we can't exclude adrenal insufficiency but if it is clearly low then you can diagnose adrenal insufficiency. This is similar in case where nephrotic syndrome and critical illness you have low cortisol binding globuline and also remember there are rare conditions like cortisol binding globuline deficiency gluccocorticoid resistant and hyper sensitivity which can give rise to uh issues with interpretation of the total cortisol level. Okay. Now you have diagnosed adrenal insufficiency. You have to find out the eeology according to the guideline. If you are dealing with an infant or uh you know certain uh children that we suspect congenital adrenal hypoplasia you have to do the 17 hydroxy progesterone but all the other adults to confirm the autoimmune eeology you have to do 21 hydroxilase antibodies. Again in our resource poor setup it is not freely available. So what we do is if it is clearly autoimmune you know we won't do any further investigations but if we have a doubt about other ethologies we go ahead with the CT adrenals. CT adrenals will show you whether there are hemorrhoages, calcifications, infections, malignant tumors. [snorts] And uh for those who have positive antibodies, think of autoimmune polylandular syndromes and look for other autoimmune disorders. And when both are negative, you have to think of adrenalucodistrophe, which is an excellent condition mainly happening in young um adolescent males. They might come with neurological symptoms, they might not. So you have to have a high degree of suspicion and arrange very long chain fatty acids for them.

[00:21:13]Okay, this is just to show you know if you can appreciate on the left hand side you have normal adrenal glands you know the thickness is similar to the cruise of the diaphragm but on the left hand side you can appreciate they are enlarged and they are calcified and that is due to the adrenal TB. If you can appreciate here, you know, you can see the adunal calcifications.

[00:21:42]Okay. So let's talk about the art of replacement. So what we are trying to do is mimic the der rhythm by replacing glucaorticoids and also we have to think of mineral corticicoid replacement and I will tell you about adrenal androgen replacement a bit as well. So when you take the first thing uh gluccocorticoid replacement happens most of the time in the form of hydrocortisone and the total daily dose would be between 15 to 25 we give it in two to three divided doses.

[00:22:16]So the standard regime is we give the highest dose upon waking up 10 mig and half a tablet 5 mg per day midday and 5 mgs uh before sleep and at least this has to be given 4 to 6 hours before sleep otherwise patients will come and complain uh to you about insomnia and for children we use much lower doses between 5 to 8 mg per square meter per day. We have to calculate the dose for each and everyone. It is not a fixed dose. For adults, we can use predicilon less than 5 mg per day which we can administer once a day especially for those who have poor compliance.

[00:23:00]But remember we do not have 1 mig tablets in Sri Lanka. So what we do is we either use 5 mig tablet or half a tablet 2.5 mg. Um, dexamethasone is a potent uh steroid which is not recommended for replacement and the monitoring is mainly clinically. We do not need cortisol assess when we are replacing gluccocorticoids. So we have to check for postural drop, weight gain, energy levels, signs of excess or under replacement.

[00:23:33]So this graph you you know shows you how we are trying to mimic the uh cortisol levels the dial rhythm of the cortisol by giving 10 five5 or 105 2.5 you know spreaded um throughout the day. Uh this is because the hydrocortisone has a very short uh halflife and it remains in the circulation for about 90 minutes.

[00:24:01]There are other preparations like I mentioned um cortisol acetate is available in other parts of the world.

[00:24:11]When it comes to mineral corticids the dose is a fixed dose flutracortisone either 50 or 100 and you have to tell the patient uh to take unrestricted salt intake and monitoring again by uh clinical assessment. You have to ask the patient about soul craving, postural hypertension. We need to check at the clinic and any uh presence of edema.

[00:24:33]Look at the electrolytes and maintain the potassium at the upper limit of the normal or within the normal range. In other parts of the world, you do rein levels and keep it in the upper normal reference range.

[00:24:47]What happens when someone develops hypertension while on flutortisone?

[00:24:52]So you have to reduce the dose. You can have the dose and see if it is still uncontrolled. You really can't take it off completely. You have to add an anti-hypertensive like AC inhibit andotensin receptor blocker or a calcium channel blocker. But try to avoid diuretics and do not use pyonolactone which is contraindicator.

[00:25:15]Okay. So there are uh a set of patients who are on optimum replacement but will come this is mainly females will come with low energy levels low libido depressive symptoms poor quality of life for them the guideline recommends 6 month trial of di 25 to 50 mig as a single oral dose in the morning while monitoring the DI levels and uh you know some people nicely respond to this and some people will not make a significant difference so that we can you know switch off the trial. Uh but again I am stressing you this is not available in Sri Lanka but in other countries this is being practiced.

[00:26:00]So few bit more about treatment during pregnancy and childhood. So during pregnancy we know there are lot of physiological changes happening. What we have to do is we have to review the patient every trimester and we need to increase the dose of hydrocortisone during the third trimester after the 24th week in order to reflect the physiology of increased free cortisol.

[00:26:26]Uh and stress dosing should be used during active phase of labor and as in the case with major surgical stress. Any other steroids are not recommended during pregnancy and flutortisone dose adjustments are not usually needed during childhood. Like I previously mentioned we use calculated dose according to the uh body surface area and this we give or you know uh divided into three or four doses. We might have to give a little late dose around 700 p.m. or so because the ch children are sometimes studying late. So they need little bit more energy to do the evening activities. Therefore you can give a little later dose for them tiny one you know something like 2.5 mg. Any other steroids are not recommended during childhood and you have to monitor the growth velocity and monitoring uh very carefully for over replacement. The flutricotortisone dose is the same as it does but for infants as the breastfeed does not contain adequate uh sodium we need to supplement them with sodium chloride tablets during the newborn period and up to the age of 12 months.

[00:27:48]All right. Uh let's move on to crisis management. So we all you know have managed an adrenal crisis, right? So this is called acute adrenal insufficiency or addisonian crisis and earlier um it is known uh with this clinical trial hypertension, hyponetriia and hypercalemia. But uh now it is found that only 50% of the cases will uh come with this full definition. But the more pragmatic definition is if there is an acute deterioration in the health status of a patient who is diagnosed with adrenal insufficiency associated with hypotension you should suspect adrenal crisis and usually if it is actual adrenal crisis within 1 to two hours of uh IV hydrocortisone the patient fully recovers. If it is not you have to think of other alternative courses.

[00:28:46]The prevalence of adrenal insuffic crisis is more with primary adrenal insufficiency probably because you know uh of the combined deficiency of mineralcorticoid and gluccocorticoids.

[00:29:01]Uh the treatment of choice is IV hydrocortisone OIM. We can give IV hydrocortisone 100 mg stat followed by 200 mg 24 hours. If we can't give over a you know as a continuous infusion we can give as small bololises 50 migram 6 hourly. But remember what is more important is uh fluid resistation because most of these patients are now uh dehydrated and they have uh you know low salt stores. Therefore [snorts] you have to resusate with normal saline and monitoring is important and tapering off of the steroids when they are stable and almost always you have to find out a precipitating event and treat that as well.

[00:29:48]Then again peroperative management is important. There is a separate guideline for this. I'm not going to discuss in detail. What you have to identify is surgery is a m significant stress for the patient. So you have to cover up with doubling of the doses or IV hydrocortisone during surgical stresses.

[00:30:08]So if it is a minor to moderate surgical stress like a cataract surgery, dental surgery, uh you can just double or triple the doses of per oral hydrocortisone. But when it comes to surgery under anesthesia or colonoscopy under sedation, trauma delivery and ICU critical illness, we have to manage the patient as with uh as for uh adrenal crisis with IV hydrocortisone uh you know bolers dose followed by infusion. So there is clearcut guideline how to tail off and what sort of doses that you have to give. I'm not going to uh go into the depth because of the time constraint [snorts] and during the management of adal insufficiency what is more important is safety netting of the patient. So safety netting of the patient involves the first thing is education of the sick day rules. So you have to tell the patient if you're unwell, if you're having fever, can't eat anything, you're on the bed and you have vomiting and diarrhea, you need to double the dose or triple the dose for uh you know probably uh 2 to 3 days or even up to a week until the recovery. But if the patient cannot keep anything down you know patient has significant vomiting and the you know patient is deteriorating they need IV hydrocortisone or IM hydrocortisone they need to go to the nearest hospital as soon as possible. You have to stress the patient with this. If you are not recovering with just doubling or tripling the doses you must immediately attend the nearest hospital.

[00:31:47]When you are using hydrocortisone more than 50 migram over 24 hours, you don't need mineralocorticids because it has adequate mineralotic effect. And above all, you have to advise the patient when you are ill. Make sure your hydration is optimized and emergency injection education is a must. In other countries, you have to provide the patients with emergency kits. The patient and one of the family members, all of the family members should be educated about the emergency injection. But this is not uh feasible in our country and this is not available in our country.

[00:32:26]The steroid alert card cards and medical alert bracelet or necklaces are again important. So we provide in our endocrine clinic almost all the patients who are diagnosed with adrenaline insufficiency with a red card to keep uh keep uh that in their pockets all the time. It mention their name, date of birth, the uh diagnosed condition and the current dose of hydrocortisone or whatever the steroid and when they go to hospital in an emergency, it's very very easy for others to notice that. [snorts] And also uh you can encourage the patient to wear a bracelet or necklace mentioning that uh they have ad insufficiency and need steroids.

[00:33:12]Okay. Uh so moving on to irogenic suppression. Um this is the most common cause of adrenal insufficiency nowadays but the exact prevalence is unclear.

[00:33:23]Patients with gluccocorticoid induced adrenal insufficiency are at a greater risk of developing Cushing syndrome concominantly as well as uh they will develop withdrawal symptoms when we are tapering off the regimes and they are at high risk of uh HP axis suppression and patients with cancer you know those who are on long-term opioids radiation exposure immune uh checkpoint inhibitor therapy and highdose gluccocorticoid are a group uh you know they are at very high risk of having irogenic suppression of the cortisol axis. [snorts] So I will focus on the gluccocorticoid induced adunal insufficiency. We know that almost all the disciplines in medicine are using gluccocorticoids for different reasons. It can be anti-inflammatory, it can be immunosuppressive or something else.

[00:34:16]>> [snorts] >> So at least 1% of the population use chronic gluccocorticoid therapy and if it is with supra physicological doses and long-term use can cause syndrome along with HP axis suppression and like I previously told you they can develop withdrawal symptoms during tapering off.

[00:34:40]So if you focus this and you can appreciate you know if you use systemic steroids compared to topical steroids the risk of adal insufficiency is more and if it is longer duration and if it is with the higher dose again the adrenal insufficiency risk is higher.

[00:35:02]This graph uh chart shows you you know higher the potency of the steroids the more systemic the steroid is and uh higher the dose and longer the duration the risk is more.

[00:35:18]So what happens uh when you're on uh superysiological doses of steroids your usual axis is suppressed and when you stop your act will start recovering gradually but we don't know the duration and the cortisol will take time to recover and then it becomes normal. So during this period of the time we have to be very careful and we might have to supplement them with uh some sort of steroids or we might have to very gradually tail off the steroids. So tapering off or withdrawal of the steroids should happen when the need for gluccocorticoid is no longer there. So you have to identify that first and then if it is a shorter course less than 1 month you can immediately stop. Do not do routine cortisol levels when you're on supraological doses of steroids. No point. So when you're on a higher dose of prediscolone you can start decreasing the dose 5 to 10 mig every week. But if you're on a medium sort of a dose try to gradually very gradually taper it off so that the withdrawal symptoms will be less.

[00:36:34]So what do you do uh when you come to the physiological dose let's say predinisolone 5 mg per day or hydrocortisone 1055. So what are you going to do before that I would tell you you know if you want texamethasone or some sort of a very potent uh steroid do not try to tail off that but switch to predniscolone or hydrocortisone which is more intermediate acting and it is easy to tail it off. So when you reach the physiological doses there are two things you can do. One thing is you can keep gradually declining the dose while monitoring for the symptoms and signs of adrenal insufficiency. And the other way the more commonly used way is you check the morning cortisol of um steroids for 24 hours and depending on the cortisol you make the decision. Routine use of short synactan test is not recommended here. So what do you do? You check the name cortisol and if it is more than 300 the likelihood of adrenal recovery is high and you can stop the gluccocorticoid safely. If it is less than 100 or 150 you know adrenals are suppressed you should continue glucocorticoids and attempt tailing off very gradually. What if it is intermediate? If it is intermediate, you have to go ahead with short synact test to demonstrate that they have adequate adrenal function.

[00:38:05][snorts] And [clears throat] almost all the patient should be educated about the sick day rules and there is no need of mineral or corticoid replacement. And in case you failing to recover the axis by the end of first year, seek specialist advice. If it is going beyond 4 years the tapering off you know we can't take off the patient from steroids usually they will need long-term um supplementation and we will have to treat them as chronic catal insufficiency because the evidence says beyond 4 years the recovery is minimum.

[00:38:43]So the take-h home messages the followup and monitoring of the patient with adrenal insufficiency is very important.

[00:38:51]You can at least annually do the full workup and education about the sick day rules are very much important and almost always check the availability of the steroid cards with the patient and they need to have sufficient supply of medication. So almost always when you're writing the prescription prescribe a stress pack each month so that patient can keep extra amount of hydrocortisone or predisolone with them and they should have an emergency contact number in case of an emergency and you need to have a high degree of suspicion for adrenal insufficiency for someone who is diagnosed with adrenal insufficiency and periodic screening at least annually uh for hypothyroidism hypoparathyroid type 1 diabetes is needed in patients with primary adrenal insufficiency.

[00:39:44]Okay. So a little bit more about before winding up uh I wanted to tell you about these new advances. So we earlier discussed the limitations about serum cortisol essay. So nowadays lot of evidence is coming up for salivory cortisol because it's not an invasive test. You can do it at home and not cumbersome and also this measures free cortisol. Therefore, it is not getting affected by the cortisol binding globuline changes. That is one thing.

[00:40:15]And since we are trying to mimic the dion rhythm by giving three times daily doses, you know, it's sometimes um not easy to take three times daily uh with the timing and patients will develop poor compliance. So there are available modified release or delayed release preparations to mimic the der rhythm like pleadron, fodi and chronoc. These are being used in other countries especially for congenital adrenal hypoplasia patients those who have adrenal insufficiency and like in uh diabetes like you know they have insulin pumps and they are now they are developing hydrocortisone pumps as well.

[00:40:58]uh and there is lot of evidence now coming up for adrenal transplantation and gene therapy but these are mostly at research level still but we have a hope in the future for everything and these are my references and I hope uh you understand you know um something about adal insufficiency and management of adal insufficiency. So since this is a recorded lecture, I will skip the uh Q&A session and thank you for uh your kind attention. Thank you very much.