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Glucocorticoid Induced Adrenal Insufficiency
Glucocorticoid Induced Adrenal Insufficiency
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So I have no disclosures for this talk, so we'll just get in. And some of the references I used for this talk, and most of us know now that the combined endocrine society and the European guidelines are out on this topic, and we'll definitely look at some of the areas they did discuss. So how big is this problem? We know that pretty much all the medical subspecialties use steroids, high-dose steroids, or prolonged-dose steroids for immunosuppression or for anti-inflammatory purposes, and once the dose is high or the duration is high, a lot of these patients will have suppression of HPXs. Now, we can call it glucocorticoid-induced adrenal insufficiency. Sometimes we use the term adrenal suppression, but I think what it encompasses, the main term is that we have patients who have suppression of the HPXs, they have symptoms, and they are inadequately treated with steroids when they are under major stress. So we have to look at it in a more comprehensive way, and across different forms, different doses, the prevalence is around 37%, but we'll look at the breakdown of some of the major steroids used. And luckily, it's just the zona fasciculata and reticularis that get affected, and the ROS is spared in this scenario. Looking at U.S. and U.K. populations, around 1% of the adult population have used chronic oral glucocorticoids at any given time in their life, and this number goes up to 3% to 10% in elderly people where they have more risk of complications. And what are the risks? When we are using high dose, like around prednisone six milligram per day or more, we can have diabetes, sacropenia, demineralization, worsening of hypertension, venous thromboembolism, especially when compared with people not using these steroids. And even, I would like to say, for the lower dose, especially at the lower spectrum of prednisone 2.5 milligram per day also have increased risk of these complications. Now, the absolute risk with the lower dose is not very high, but when we look at the population number, this becomes a serious problem because a lot of people do get smaller doses for some time extended period of times. Who can get it? I mean, the summary is anybody who is using hydrocortisone 15 to 25 milligram per day or equivalent of prednisone of four to six milligram or methylprednisolone of three to five milligram or dexamethasone of quarter to a half milligram over three to four weeks or more. And what happens? Either you're using the oral steroids, they go directly get absorbed, they go through the fast metabolism, or we use the non-oral like intramuscular, inhaled, topical, or intra-articular. They all get have access to the systemic circulation. And what they do is they go and they suppress the hypothalamic and the pituitary and you have decreased CRH and ACTH. And what we know from the rodent models is that these steroids have pro-apoptotic effect. And we also know this thing from the Crookes Hyland deposits in the cell that protein degradation happens. And then that translates into adrenal atrophy, especially the cortisol and the androgens. And as we said that the ROS is spared. So looking at the route and the dose and the duration, we can see that nasal administration has a lower risk of 4.2% causing HP axis suppression to the intra-articular administration up to 52%. And we know this thing that these patients, they get one shot and then for several months that HP axis is suppressed. Now, looking at the dose on the lower spectrum for the low dose, we can have 2.4%. To the high dose, we have 21% risk of HP axis suppression. And then medium dose is somewhere in between around 11%. Also, duration matters. Less than one month is 1.4%. And more than one year, it can get as high as 27%. Now, one thing about the duration and less than 28 days, generally what we say that if you're using steroids for less than four weeks, you can abruptly stop them. But some data from the one microgram test has shown that these patients do have some biochemical suppression. Now, but I think we all know that there is no clinically relevant clinical suppression. So we do afford to stop them abruptly if it's less than one month. Maybe on the shelf. Now, this, the first numbers, they look at self-reported data about the risk of adrenal crisis. And now we also have this realization that not all the biochemical suppression translates into clinical suppression, clinically relevant suppression. Only 10% of the patients who have HP axis suppression will have clinical symptoms and 90% won't. So in this self-reported health reporting, the adrenal crisis was just 0% for glucocorticoid-induced adrenal insufficiency. But then one Dutch group did report around 15% adrenal crisis with glucocorticoid-induced adrenal insufficiency. So I think the real number is somewhere between zero and 15%. And some we can look at indirectly that they have seen a very sharp increase in mortality in the first two months after the high-dose steroids are stopped, which number goes down at three months. So there is a possibility that some of these high mortality is related to adrenal crisis. So there's a good chance that adrenal crisis is under-reported. And then also the risk is higher if we are using higher dose, like pregnisone, more than five milligram. Who has the highest risk? Some people have very high risk, especially if they have adrenal crisis in the past or they have iatrogenic Cushing syndrome because that means that they have much higher exployer or they have secondary reasons where the adrenal crisis are precipitated even if we follow the general guidelines to taper the steroid and get them off the steroids. Then high-risk categories, more than five milligram pregnisone for more than four weeks, or two to three milligram per meter square for the children. Again, same duration. And the moderate risk is lesser use of the five milligram dose, especially in post-liver transplant cases sometime, which do come off steroids eventually. And then also in kids, if they also use half month of higher than five, higher than two to three milligram per meter square steroids. And then if the steroid dose is less than five milligram for a lesser period of time or multiple courses for COPD exacerbations or long-term treatment on alternate days, especially this last point. I think this last point is important because what we'll see that even if the higher doses are used but not used on daily basis, then these patients have lesser chance or better recovery from glucocorticoid-induced adrenal insufficiency. Looking back for inhaled steroids, we did earlier report that the risk is 4% for a shorter duration, but if inhaled steroids are used for a long time, more than one year, the risk can go as high as 20%. And then if you are using spacer devices, then you're delivering a bigger load or you have higher lung volumes or you are also using concurrent oral steroids too for these cases, then the risk goes high. Topical steroids, again, larger surface area where the application is done, higher doses, longer durations. We do see dermal atrophy and we do see a very potent suppression of the HPX. We just have one case recently in the hospital. She's been recovering, it's almost eight months because she was using high-dose baclomethasone for a long time on a bigger surface area presented with recurrent severe hypoglycemia to the hospital. Very high risk from epidural and intra-articular steroids, around 50%. Again, longer durations, multiple joints, potent steroids like methylprednisolone have higher risk. Now, again, many time patients forget that they are getting these things. They get a shot in the steroids a few months back and they'll not remember that. So I think in those cases, we can do the serum and the urine testing for the synthetic steroids to get with the mass spec assays and then we can see that the prednisone can be detected up to 40 days from the epidural injection and up to 60 days from the triamcinolone epidural injection. So some patients who we have no good explanation for HPX suppression, urine can be tested for these synthetic steroids. Again, formulations, some are more potent, we know that. Dexamethasone, much potent than 25 times than hydrocortisone and prednisone four times because they have longer effects. They keep the excess suppressed for a long time. Now, there are no good studies about head-to-head between like looking at each steroid. I think many factors go in. So dose is just, the potency alone is probably not the only factor. Duration, method of application, they also count in. Again, as I mentioned earlier, that if the pulse therapy is used with high-dose glucocorticoid on alternate dose, they have less likely to get long-term suppression as opposed to a daily bedtime dosing. Or again, for COPD exacerbations, this is our experience. If they use seven to 14 days of these short bursts, they do recover pretty fast. So I think this is important that alternate day dosing does help in this situation. This list does not include every medicine, but what I wanna say here is that P450 is the main pathway for inactivation of glucocorticoids. And if you have inhibitors, then obviously the effect will be more lasting and more risk for suppression. But also the reverse is true for inducers because when inducers are used and we are tapering the steroids, then these patients could have higher risk to go into adrenal crisis on the doses we don't expect. Or withdrawal syndrome, which we will talk. And again, the use of concomitant drugs can also contribute the risk. Now in summary, we have many factors here. One is the potency for hydrocortisone, low potency or cortisone, nasal, topical, or ophthalmic routes, low dose, low duration, and then patients have lower BMI indexes and they're young people. But then the risk keeps on getting higher and higher with prednisone and dexamethasone, or higher doses of the potent steroids, longer durations from one to three months or more than three months, and if the patients are obese or overweight or older patients, they have higher risk for, they have higher risk for not only severe suppression and taking longer time to recover. We'll see that they have higher risk to develop glucocorticoid withdrawal syndrome, which has a lot of overlap with the adrenal crisis or very significant adrenal insufficiency. So Xs do recover. This first line looks at using the ACTS stimulation test at the end of the withdrawal period and at one month, and definitely we can see that the numbers drop from 40% to 15% if the use was less than one month. But then if the steroid use was used for a bigger duration, like say one year, in these cases, they take six months and only half of them have recovery of the HPXs, and some of these cases, it can take up to six to 12 months to recover. And the cutoff they used are, in these studies, was less than 18 microgram per DL with the standard-dose ACTS stimulation test. Looking at, like, in another way about the long-term recovery of the adrenal function, it can be 60% at 16 months, and sometime can take as high as 24 months that some of these cases don't even recover, 40% might not even recover, because some cases, though there's a minority, can have persistent suppression of the HPXs. They will never go to complete recovery and they might benefit from using PRN steroids under stressful conditions, not daily steroid replacements. There are no studies to look at the clinical characteristics that can help us, but then we know that higher doses, women, and patients who have severe hydrogenic cushing have slower recoveries, and then if you use a smaller period, like, say, less than one month of exployer, you'll have faster recovery. Now, predictors of recovery, clinical studies are not there for the clinical parameters, but we can look at either the random cortisol levels or we can look at the cortisol response to ACTS stimulation. I tried to have both units available, but the conversion factor between the SI unit and the conventional unit is 27, in case I didn't mention it, but if you have a better increment on ACTS stimulation test of 219 nanomole per liter versus a smaller increment, that suggests that for a bigger increment, you have a better chance that adrenals are recovering now and you have a higher chance to recover from the HP axis suppression. Now, looking at the random cortisol only, a random change between the two ACTS stimulation tests done a month apart, if the number was 7.2 microgram per dl for the cortisol at baseline, they have a better chance for recovery. Recovery, when it's happening, you have first the ACTH starts going up, so you have less suppression of the hypothalamic pituitary functions, and then the cortisol follows that, and after some time, they do match then at the end, but you will see that some of our patients post-transplant, some of the time we are seeing that the ACTH recoveries are very fast. You can see very higher ACTH numbers for these cases. Now, how to taper? We'll talk a little bit more in detail about it, but many factors, smaller studies, there is no head-to-head trial, and then, again, for some physicians, they use a quick, so one general theme is that above supraphysiological dose, until then, you can do a quick taper, and when you reach the physiological dose range, then you slow it down. What can guide us to see that the recovery is happening? We can use, now, some experts are not doing ACTH stimulation tests, and I was talking to my mentor, Dr. Richard Aukas, who's not a very big fan of ACTH stimulation in this scenario, and just relies a lot on the basal testing because it also gives us a very good information, and looking at these numbers, if you have morning cortisol less than 3.6 microgram per DL, you have almost 100% risk of failing the ACTH stimulation test, and if the number goes above 12.6 microgram per DL, you have 100% pass rate. Same, again, looking another way that for specificity, cortisol morning, more than 336 nanomole per liter, 100% specificity, and same as 100% sensitivity for lower number. Now, all these assays are the immunoassays for the cortisol. Now, it's important that we are familiar with our own institutional assays because even among the immunoassays, the range to predict success or failure is somewhere, for the number can be from 350 nanomole per liter to up to 500 nanomole per liter, so, and for mass spec assays and the newer assays, the absolute number for the random morning cortisol is lower than what we know from the immunoassay. Taper plan is above 40 milligram. We go by five to 10 milligram per week. Once we reach 40 milligram, we can go five milligram per week. At 20 milligram, we can do half milligram per week or even we can extend that period. So, one important thing here is when we reach the prednisone 7.5 milligram per week, at this stage, there are two ways. Either we do a very slow taper and not do HPA-access biochemical testing or we do the test to guidance and do abrupt taper. And now there is a randomized control trial happening to look at two strategies that when we reach 7.5, what's the best way going forward? So, I think we can skip this one for the sake of time and go here, that if we use the help of HPA-access, then we can use these two numbers. Less than 150 nanomole per liter, we keep the replacement, check back in a month. Above 300, we can stop it and in between, we can either keep the same dose, check back in a few weeks later or do the dynamic testing. But what I wanna tell here is that these numbers are just a guide because what can happen is at 300, these patients can have relative insufficiency, meaning that they look good on the number of 300 but then if they see a major stress, their adrenal might not rise up to the occasion. And so, maybe doing a TH stimulation test might be useful here or at least tell the patients that if you have a major stress, you might need stress, though even we have decided to stop your hydrocortisone replacement. Again, at the time when we are getting to prednisone 7.5, it's better if you have lower doses of prednisone available like say one or two milligram. But if you don't have available, then you can transition them to hydrocortisone and that helps the recovery. Now, this slide, what I wanna say here is that this is a big issue that not all the endocrinologists will be able to help our medicine colleagues with all this journey. So, from a medicine perspective, what we wanna say to our subspecialties in our institutions, we can talk to them, we can guide them that when they start these steroids, they need to tell the patients about the side effects and what would be the taper plan when these steroids are not needed and how the taper plan will happen, the risk of glucocorticoid withdrawal syndrome and the risk of adrenal crisis. They all need to be educated from their primary teams and not necessarily consultant endocrinologists for that because we'll not be able to see everybody because we all have big practices with the transplant programs and a lot of these patients will be on high-dose steroids or oncology where they use this immune checkpoint and they'll get a lot of steroids with that or the chemo. So, one quick thing on the glucocorticoid withdrawal syndrome, the overlap between the risk of adrenal crisis and the glucocorticoid withdrawal syndrome. Now, one thing which is very important that above 7.5 milligram prednisone, the risk of adrenal crisis is very low but the risk of withdrawal syndrome is very high at that range, especially between 7.5 prednisone and 30 prednisone, especially if the patients have used steroids for a long time, they can have a lot of these symptoms of withdrawal. We can reassure our colleagues in other medical subspecialties or our ER colleagues because when these patients come to ED with the glucocorticoid withdrawal, what happens is they are given stress dose steroids or their primary teams go back up on the steroids for another several months, not realizing that. So, for the glucocorticoid withdrawal syndrome, the best remedy is going back to the last dose where they did not have symptoms and then taper slowly. These are the two interventions that will help them when they get the glucocorticoid withdrawal syndrome. Quick comparisons, I think one thing we all know from endocrinology that hyponatremia, hypoglycemia, hypotension, these signs are not there in the glucocorticoid withdrawal syndrome. It will be more of a symptom complex, myalgias, arthralgias, mood changes, sleep problem, and the etiology seems to be increased in the inflammatory cytokines because when the dose is being decreased, the inflammatory cytokines go up and they kind of precipitate the withdrawal syndrome here. So, on adrenal crisis, we all know what are the guidelines on giving stress dose steroids, and the take-home message is that primary care physicians or primary teams should be aware of the high incidence of glucocorticoid-induced adrenal insufficiency when they are treated with different formulations other than oral formulation, inhale, intra-articular. Withdrawal syndrome needs to be differentiated from the adrenal insufficiency, adrenal crisis, and the best remedy is to slow the taper, not necessarily bump the dose too much. And then primary teams are also encouraged to taper the steroids and have programs in their own clinics. Not everybody will be able to be seen by an endocrinologist, but we definitely guide our teams. We can do education sessions with them. And if patient does develop these symptoms, as I said, we just kind of go a little slow on the taper. Yeah, thank you. Thank you so much, Dr. Rajmal. Thank you so much, Dr. Rajmal, for an excellent talk.
Video Summary
The talk primarily discusses the challenges and intricacies associated with glucocorticoid-induced adrenal insufficiency. It highlights the significant use of steroids across various medical specialties for immunosuppression or anti-inflammatory purposes, leading to suppression of the hypothalamic-pituitary-adrenal (HP) axis. The prevalence of such suppression ranges around 37%, with increased risk in the elderly. High doses or prolonged use of steroids like prednisone can result in complications such as diabetes and hypertension. The talk underscores the importance of comprehensive assessment and tapering of steroid use, considering factors like dosage forms, BMI, and patient age. It also distinguishes between adrenal crisis and glucocorticoid withdrawal syndrome, suggesting slower tapering as an effective remedy for withdrawal. Emphasis is placed on educating healthcare professionals about managing long-term steroid use and ensuring patients are informed about potential side effects, highlighting the necessity for collaborative care and better management strategies to mitigate risks.
Asset Subtitle
Dr. Adnan Ajmal
Keywords
glucocorticoid-induced adrenal insufficiency
steroid use
hypothalamic-pituitary-adrenal axis
adrenal crisis
glucocorticoid withdrawal syndrome
collaborative care
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