My name is Paul Reynolds, and I'm thrilled to be both speaking and moderating this session entitled Endocrine Emergencies When Zebras Are Real. Although endocrine-related interventions are some of the oldest medical interventions that we have in medicine, in 1891, in fact, sheep thyroid was first utilized for human use, followed by the 1920s in the University of Toronto when insulin was first used, bovine insulin, in fact, and then in the 1950s, corticosteroids, we know that severe derangements in insulin-related systems are still associated with some of the highest morbidity and mortality in clinical practice. Joining me today are Drs. Liz Farrington and Nicole Palm, who will be discussing DKA and HHS and adrenal crises, respectively. I have a few housekeeping issues before we start our talk. We're going to reserve any questions for each of these sessions until the very end of all three sessions. You can claim your continuing education credit via the Congress app. And thank you all for coming to this talk. We know that this is the last talk, and you guys have flights to catch or a happy hour to catch, so we really, really appreciate you being here to join us today. I'm going to try to do my best to make my way through both myxedema coma and thyrotoxicosis or thyroid storm in 15 minutes. I'm going to be talking really fast, it's going to be a roller coaster ride, but be sure to bear with me. And if you need any additional clinical information, I have a lot of supplemental information in my slides. Feel free to ask, I'm happy to answer any questions. These are my learning objectives. And then I don't have any conflicts of interest related to this to disclose. As I mentioned earlier, thyroid drugs have been around a long time. There's no real industry conflicts associated with this. So as an endocrine crash course, we have the anterior and posterior pituitary. The majority of the action happens within that anterior pituitary. That's going to be our focus today. The posterior pituitary is primarily involved with oxytocin and antiduretic hormone. We're going to be focusing on both the ACTH and the TSH hormone primarily today. We know that TSH promotes organification of T4 and T3 thyroid. In terms of key hormone accesses, our focus here is going to be on the right side of the slide today. We have the thyroid secreting hormone axes. We know that thyroid secreting hormones supports the organification of iodine and tyrosine into levothyroxine or T4 and T3. We know that this controls about 25% of basal tissue metabolism. There's two primary hormones that I just mentioned before, T4 and T3. T3 is really the active form. We also have the storage form that's regulated by deiodinases to that T3 form. Half-lifes are really important to notice here as well, T4's half-life being that storage form is five to seven days, followed by T3 half-life, which is 0.75 days. Just keep that in mind as we jump into the thyroid emergencies themselves. We're going to talk about two thyroid-related emergencies, even though I have three or four up here. We're going to be talking about thyrotoxicosis or thyroid storm and myxedema coma. This has recently been re-coined as decompensated hypothyroidism to acknowledge the fact that most people that come in with a state of myxedema coma are not always myxedemdis and they're not always comatose. It's to recognize that early treatment recognition and intervention is associated with mortality benefit in this disease state. We'll talk about what meets these different clinical classifications and terminology, and then unfortunately I don't have time to talk about this today, but euthyroid illness of critical illness or euthyroid sickness of critical illness. I call this the DIC of thyroid disorders. It's enormously hard to treat. We know that the thyroid axis is normal, but peripheral inner tissue conversion can be often impaired, and oftentimes we're trying to correct the underlying disorder that's precipitating this disease. Myxedema coma is defined as an edematous state due to glycoprotein accumulation in the absence of thyroid hormone. This is an early case report of a patient with myxedema coma, and you can see the myxedematous state in this patient. Coma obviously is altered mental status. This was originally defined by the Glasgow coma score. I will provide the caveat that most people are not in the comatose state when they present with myxedema coma. And we'll be going into the scoring system itself. I don't know how to go back on these slides, but I will say that the majority of precipitants with myxedema coma are non-adherents to thyroid medication. I can maybe hit the previous. There's no back button on here. I'll be all right. A majority of patients are elderly, and they usually present in a cold weather environment. Myxedema coma versus thyroid storm or thyroxicosis is far more rare. Myxedema cases are usually 0.22 per 10 million patient cases. You'll find this far more frequent in Japan, and a lot of the literature actually comes out of Japan because Graves' disease and Hashimoto's are far more common clinical manifestations in the Japanese population. So here's the precipitating factors that I mentioned a little bit earlier. And this is a global map of iodine repletion and the level of iodine supplementation across the world. This will come into play a little bit more when I talk about amiodarone-induced thyroid disorders, but we can see that there's a difference in global prevalence of the availability of iodine depending on what country you're coming from or you're practicing from or where your patient might be coming from. This is a slide that overviews a variety of different case series related to myxedema coma. Because this disease state is relatively rare, you're not going to find large, high-quality RCTs related to myxedema coma. A lot of this is case series, case reports, and retrospective cohort studies. But you will see that as a unifying factor, hypothermia and bradycardia are relatively common, followed by laboratory parameters that indicate a hypothyroid state. The myxedema coma scoring tool was synthesized by Warchofsky and colleagues. It's different from the Warchofsky score in thyrotoxicosis, but a score of 8 or more on this scale, which is driven primarily by Glasgow coma score, TSH levels, hypothermia, and bradycardia is over 80% predictive of the diagnosis of myxedema coma. There's also prognosticators for mortality with this disease state. So patients that are mechanically ventilated or have a SOFR score of greater than 2 are more likely to die from this disease state as well. The decompensated hypothyroidism I mentioned earlier is a co-manifestation of delirium, hypothyroidism, bradycardia, or shock, and hypoglycemia. These are all kind of antecedent to myxedema coma and can be a significant independent risk factor for morbidity and mortality. I'd advise you to read this case series by Bridwell and colleagues out of the American Journal of Emergency Medicine that overviews and emphasizes an earlier diagnosis of this disease. So when it comes to therapy for myxedema coma in a myxedema state, we know that total body thyroid stores are usually depleted by anywhere from 600 to 900 micrograms of T4. Our goal of therapy, therefore, is to rapidly and safely replete thyroid levels in these patients and to prevent morbidity and mortality and end-organ dysfunction. There is data to suggest that there is a mortality benefit with providing loading doses for patients with myxedema coma. In this study that compared patients that received a loading dose of 500 micrograms followed by a standard supplementation dose, mortality retrospectively was 16% compared to a 60% plus mortality in patients that didn't receive a loading dose. And this really has to do with the pharmacokinetics of the drug. We know that T4 has a circulating half-life of four to seven days. We want to replete these patients relatively quickly. And authors such as Warchofsky and his colleagues suggest that there's a pretty good safety index with anywhere from 500 to 800 micrograms of levothyroxine. So even if you're not 100% certain about your diagnosis of myxedema coma, an empiric dose of levothyroxine a lot of times is not going to be harmful. I will say the caveat that if your patient has CAD, arrhythmias, or may be frail or more elderly to maybe be a little bit more careful with that and maybe use a four microgram per kilogram loading dose. But in the majority of these situations, you can get away with the loading dose while you're firming up the diagnosis of myxedema coma. It has been the standard of care to use IV levothyroxine. IV levothyroxine has gotten extraordinarily expensive, and it's actually hard to acquire. But the reason for that is that a lot of GI dysfunction and malabsorption of thyroid happens in the acute myxedema state. There's actually a gut wall edema that occurs, and ileus can be relatively common. So the IV route is the safest route to start with. However, I will say that in resource-limited settings, such as in Africa, there's been case series of high loading doses of PO that have been clinically successful in the management of this disease. The other clinical question that has often arised is whether we give T4, T3, or both in the management of myxedema coma. The rationale for giving T3 is that it's the active form of thyroid. It immediately takes into effect. Interconversion of T4 to T3 is often shut down in the myxedema state. And there's a little bit of data to suggest that T3 penetrates that blood-brain barrier a little bit more effectively and confers better CNS penetration. The con for giving T3 is that we know that when we give T4 hormone, the body uses what it needs. It's relatively reliant on that T4 to T3 interconversion. And so there's a wider therapeutic index when you're using T4 monotherapy. And it does give a degree of CNS penetration. It's not like there's no CNS penetration. So you do still confer CNS penetration with T4 monotherapy. So this was a case series, again, out of Japan that compared T4 and T3 therapy. This case series actually showed a much higher mortality if you use very high doses of T4 or relatively high doses of T3. This sent out a safety signal across the literature about using T3. And for a long time, clinicians were steering away from T3 because of this mortality trend. My interpretation of this study, and I quote Paracelsus, is the dose makes the poison. This was much higher dosing than is usually clinically recommended. And I usually recommend not to exceed 50 to 75 micrograms per dose. My recommended dosing follows Wachowski's recommendations and the Thyroid Association Guidelines, which is a 10 to 20 microgram bolus if I'm going to use T3, followed by 10 micrograms every 8 to 12 hours as a supplementation dose. And I'll cut this down all the way to 2 and 1 half micrograms knowing that I have T4 on hand already. In older patients, patients with CAD or arrhythmias, this may be a narrower therapeutic index. Other important elements when it comes to management of myxedema coma. I'm just going to emphasize the first part of this slide right here. Stress dose corticosteroids can be very important in this disease state, just from the standpoint that when you maintain or restore a euthyroid state, adrenal crisis can be precipitated. So if you have any degree of hypotension, or a lot of the times we'll just start hydrocortisone on these patients until you have normal tension and a normal TSH tone in T4 and T3 levels. So we're going to jump into thyroid storm real quick here and talk about thyroid 2 high. So whenever I hear thyroid storm, I think more of a heavy metal band. I actually prefer the term thyrotoxicosis when I'm thinking about thyroid storm. But it keys into the gravity of the situation here. So thyroid storm is defined as multi-organ dysfunction due to the excess of thyroid hormones. 95% to 98% of this is precipitated by Graves' disease. And a lot of times, patients similar to DKA and HHS will have a precipitating factor before developing thyroid storm. A lot of this is usually sepsis or iodine intoxication. The epidemiology of this is far more common than myxedema coma, with 0.2 cases per 100,000 population per year. The Warchowski-Birch scoring system is the standard of care for diagnosis of thyroid storm. Think of this as myxedema coma score only opposite. And so you're going to see a lot more hyperthermia, tachycardia, and then hyperactive delirium as opposed to a comatose state. But I will say a caveat that some patients develop seizures or coma with severe end stages of thyroid storm as well. The goals in the management of thyroid storm is to ideally maintain a euthymic state. There's a couple ways that we do this. This is the hypothalamic pituitary thyroid axis. The first step that we're going to use is to take is to use PTU or methimazole. These are our thionamides. These usually take weeks to work, so it doesn't make a lot of sense to do this first. But the rationale for this is this shuts down the organification of iodine to T4 and T3. This allows us then to implement iodine and lithium therapy. Iodine and lithium work through the Warchowski effect, the Wolf-Tchaikovsky effect, I should say, in which the oversupplementation of iodine actually suppresses TSH. This will buy you about two weeks until your thionamides can take effect. And then downstream is our targets of T4 to T3 interconversion. We're trying to shut down that active T3 hormone for having its effect on tissues and conferring that hypercatabolic state that you often see in thyroid storm. So the big question is we have two different agents for depleting thyroid gland. They both work fairly similarly in terms of mechanism of action. They inhibit the incorporation of iodine into thyroglobulin and the synthesis of new T4 and T3. What's unique about probothiouracil is it actually also prevents T4 to T3 interconversion. So the theory there, and in pharmacokinetic studies, they actually see T4 and T3 normalization a lot quicker with probothiouracil versus methimazole. The bad side of probothiouracil is that it has a much higher incidence of hepatotoxicity compared to methimazole, which are concerning adverse effect is far more rare, which is agranulocytosis. This was addressed recently in a 2023 study in JAMA Open Network. This was a cohort study comparing PTU and methimazole for thyroid storm in critically ill patients. What they found in this study is, though, although T4 and T3 are normalized a lot faster with PTU, there was no difference in any of the incomes, which included mortality, end organ dysfunction, discharge to hospice, or need for thyroidectomy with either of these agents. So even though PTU might work a little bit faster, there's no difference in any clinically relevant outcome. And so what you'll see is a bifurcation in the guidelines. So the US guidelines actually recommend PTU up front, whereas the Japanese guidelines, which they see a lot more thyroid storm and thyrotoxicosis, recommend methimazole up front, just from the standpoint that it's a lot less hepatotoxic. One thing that I will say with the thiamides is that with autoimmune thyroiditis, especially with high circulating levels of antibodies, these drugs are known to be a little bit less effective. I will say the caveat to this is only 1 in 700 patients in each arm of these studies actually required a thyroidectomy. So if you dose these right, a lot of times you can maintain a euthymemic state when you're using this in adjunct with potassium iodide. I will say that the dosing is much higher than standard hyperthyroidism. We're dosing this anywhere from a four to five-fold increase compared to your normal doses in hyperthyroidism. The guidelines recommend anywhere from 1,000 plus micrograms of PTU, if you look at the US guidelines. The Japanese guidelines actually recommend 40 milligrams a day of methimazole. The US guidelines are a little bit more aggressive with addressing a 25 milligram every six-hour dose of methimazole. The next step is using that iodine hormone. So although I did emphasize that PTU and methimazole should always be given first to block the utilization, this suppresses it through oversupplementation of iodine and a subsequent suppression of TSH. This works a lot faster, but it's a safety step to have that PTU and methimazole up front. Beta blockers in thyroid storm and thyrotoxicosis, there's a lot of age-old adages about using propranolol for this, because the theory is that it shuts down T4 to T3 interconversion. I looked into the mechanism of this, and it's fairly controversial. It really has to do with an active metabolite, and they believe that there may be some conference of effects through its membrane-stabilizing activity. You have to use extraordinarily high doses of propranolol to get this effect. I don't always endorse in these patients, just from the standpoint that there's a high output cardiac failure in these patients, and there's a lot of case reports of using high-dose propranolol, and then you precipitate cardiogenic shock. So I'm a little bit more cautious with this. If I have a patient with elevated heart rate despite our initial interventions, I'll often use a short-acting medication such as Esmolol. Even though I know that it doesn't help with T4 to T3 interconversion, you're still conferring that beta blockade. It's short-acting, and you can take it off if you're worried about cardiogenic shock in these patients. And then last but not least, corticosteroids are an area of controversy in thyrotoxicosis, even though it's standard of care in mixed hematoma. This is a little bit more controversial. We know that this is very potent in terms of shutting down T4 to T3 interconversion. We also know that thyroid storm often reduces sensitivity and response to ACTH, just being an autoantibody disease. And there's older data to suggest using steroids was associated with a mortality benefit. However, newer data actually shows a mortality detriment with these, again, very limited to case series and case reports. Other treatments, we know that hyperthermia is very common in this disease state. It's one of our diagnostic criteria. The only thing I would caveat there is to avoid aspirin, because that actually facilitates T4 to T3 interconversion, and to emphasize local cooling and maybe acetaminophen. And then last but not least, fluids. Glycogen is actually quickly depleted in this disease state. Hypoglycemia is relatively common, so consider using dextrose-containing fluids when clinically appropriate and relevant, especially if the patient's hypoglycemic. Monitoring of follow-up, we usually expect improvement within two to three days of our combination therapy. We're assessing T4 and T3 every 24 hours or so. And then we'll usually convert to maintenance therapy, so that lower dosing, not that two to five-fold increase in dose of your thiamides at that point to maintain that euthyroid state. There have been case reports of therapeutic plasma exchange being used for this, especially for autoimmune thyroiditis. And then ECMO has been used both in myxedema coma and thyrotoxicosis in refractory cases of shock. And that kind of makes sense just from the standpoint that both of these disease states are hopefully transient and reversible, and so it may be an alternate therapeutic modality. I just wanted to provide a brief update in thyroid-induced drug disorders. So amiodarone is our most famous one. We know that it's 37% iodine by weight. It acts similar to your potassium iodide in that Wolf-Tchaikoff effect. The drug-induced initiation of iodine suppresses thyroid. And in some patients, you'll get that escape, and their TSH will normalize. In patients where you have escape failure, you'll develop hypothyroidism. Amiodarone-induced thyrotoxicosis is a lot more common in iodine-deficient areas, whereas here in the US, that Wolf-Tchaikoff effect is more common, and you'll actually have amiodarone-induced hypothyroidism. But you can really see any of these in a patient receiving amiodarone therapy. And then last but not least, I wanted to talk a little bit about targeted immunotherapy, because thyroiditis and thyrotoxicosis is very common with our targeted immunotherapies, such as our CTLA-4 inhibitors and pembrolizumab. The management is largely the same as thyroid storm and thyrotoxicosis, with a little bit more of an emphasis on beta-blockade therapy for symptomatic management. And a lot of times, after the initial disease or the initial drug wears off, you'll actually have hypothyroidism in these patients as well. One of the key points of emphasis here is that uniformly, a majority of the guidelines that address targeted immunotherapies and hyperthyroid states emphasize the avoidance of corticosteroids, because they directly antagonize the mechanism of action of these targeted immunotherapies and may compromise the efficacy of these drugs. The only case where they emphasize the use of steroids is in hypophysitis, when you have complete destruction of the pituitary gland through autoimmune diseases as well. And so those are relatively rare cases, and we'll often have to replete many of the pituitary hormones at that point.

endocrine emergencies

myxedema coma

thyroid storm

diabetic ketoacidosis

adrenal crises

treatment strategies