So, it's always a challenge to do a talk with a very mixed audience because there are endocrinologists in the audience and also generalists and everything. So, I'm going to try to keep it engaging for everyone, but please feel free, and I don't mind being interrupted in the middle, although probably for time's sake, we're going to do question and answers at the end, I believe, so I'm happy to take questions at the end. So, you know, no disclosures from my end, and I wanted to begin with the scope of the problem. As you can see, that in the MENA region, thalassemia is the most prevalent, so this is a carrier rate for thalassemia compared to the rest of the world, and you can see that we are colored blue or dark blue, and that's where our carrier rate is the highest in the world. In Pakistan, it is estimated to be about, you know, one in 17 to one in 18 individuals being a carrier. In addition to that, so the disease burden is high, but the availability of monitoring for iron overload, which is the main pathophysiology of endocrinopathy, is the poorest in our country. So, apart from a few dark spots that you can see in affluent countries like Saudi and some emirate countries, it is quite poor in the region, so it's a double problem. Incidence is high. Resources are low, so it really becomes quite a significant problem, and this was a problem I was not prepared to when I trained, you know, in the U.S. for 13 years, where we saw maybe one or two people very, very young and, you know, very well-chelated, no endocrinopathy, so to me, the patient with thalassemia actually holds the textbook of endocrinology in their hand because all of their endocrine glands are affected, and it is quite a significant problem. Also, you know, the people have studied the effectiveness of monitoring, so if the resources are there, how effectively are they used, and you can see that we don't score very well also in our region about how effectively we can actually provide care. So that becomes a huge problem, and as I mentioned, that all of the endocrine glands can be involved, and I'll try to show you based on evidence and experience what is the sort of the higher versus lower incidence endocrinopathy that can come, although any one of these can come. So in terms of the sort of the bigger picture as to what is the reason, so it's actually a combination of the anemia, the iron overload that comes with not only the ineffective erythropoiesis and the natural iron load coming from your bone marrow, but also the transfusion load that you're giving every few weeks to those patients because you do need to maintain the hemoglobin above a certain level. Is everything okay with the AV? Okay, I'm sorry, I'm not noticing that, so I hope it's okay. So anyway, so you've got the blood-related problems, the anemia and the iron overload, and in addition, you have liver disease, right, and the liver disease is also multifactorial because not only does it stem from the actual metabolic effects of the anemia and the iron overload, but also, at least in our part of the world, yeah, I can wait, yeah, sorry. I don't need the slides, so maybe I'll just continue talking. So it's also the infectious diseases that come with the repeated blood transfusions, so for example, hepatitis C and hepatitis B are a huge, huge problem in Pakistan, and unfortunately, when these kids get multiple transfusions, they get infections, and so they're co-infected, and in fact, we've seen kids who have hepatitis C, HIV, and thalassemia and all the stuff that comes with it, so it's really, really an unfortunate mixture of pathology that these kids have to deal with, and then when they become adults, a lot of problems show up. So this is the prevalence, and this is according to the Thalassemia International Foundation data internationally, right, and as you can see, the hypogonadism, delayed puberty seems to be quite high, almost 100% in some studies, but then stunting, bone disease, impaired glucose tolerance and diabetes, I mean, at least half the patients will get all of these, and then you go down, and then you've got, apart from adrenal insufficiency, which is relatively rare, others are quite common, and I've seen very, very bad complications with hypoparathyroidism as well. And we did our own study in Pakistan where we created a thalassemia registry within Karachi, which is the largest city, and we, a lot of what the international data said was mirrored over here, but the only thing was our incidence rates were much higher, so we had a 92% incidence rate for hypogonadism, for example, stunting was unusually high, hypopara was almost 50%, which was very much so, so it's really significant. And we were able to correlate almost a prediction that if you had myocardial siderosis, which is basically a marker of how much iron overload you have, you could actually look at the endocrinopathy and predict how bad your heart would be, and the heart is actually the reason why kids die, they die of arrhythmias and heart failure, so if you had hypogonadism, you had a four times more likelihood of having cardiac siderosis and so forth. So we were actually able to come up with some predictive markers because, in general, cardiac MRI is expensive in Pakistan and it's hard to do, but we did it in our study to prove that you need to do that, and simply measuring ferritin levels was not adequate. So if you come to the endocrine glands and what's affected, I'll just begin one at a time to see if there's a response, and if there isn't, that's when you then would begin the replacement therapy, et cetera, and so forth. It used to be that people would give 200 to 250 milligrams once monthly, but that peak and trough really doesn't do well and it's not physiological, so if you're having to use intramuscular, then using it every 10 days, 75 to 100 milligrams is what's recommended by the Thalassemia International Foundation, and you can achieve the same effects by doing bi-topical, and if you're in a country where topical is easily available and affordable, that actually is the preferred way. Unfortunately, again, in Pakistan, it is extremely expensive, so we're not able to give that to our patients, but that's an easy way to do it. With the females, again, I put that age somewhat reluctantly because, again, it has to be personalized for the family history, et cetera, and so forth, and where the girl is. Do the bone age, obviously, and again, a low dose of ethanol estradiol for six months to see, give a six-month gap, see if there's spontaneous puberty, and if there isn't, then slowly reintroduce it and then build the dose up until you can give a combination pill after about 12 to 24 months, and sometimes you have to, you know, the sign is the breakthrough bleeding, you know, it doesn't happen, then you can basically start the low-dose combination pill, and then you start it long-term. In our replacement regimens like that, I think that the most emotionally challenging thing for the parents is to realize that this is not going to attain fertility because they're expecting their kids to attain fertility, and that counseling has to, so you have to take care of everything, and you have to take care of the patient together. So this is a typical growth chart that seems to evolve that slowly, you know, initially they might even have a normal growth velocity, and this is, again, well-chelated patients who will do this. In our setup, we're actually showing them dropping off the curve much, much earlier, but initially, the growth failure is due to hypoxia and anemia. That's kind of the main driver, and then later on, the iron overload starts happening and starts affecting the growth hormone IGF1 axis, and then by that time, when they're ready for puberty, the gonadal axis is completely overwhelmed with the iron overload, and it doesn't wake up, doesn't respond, so you get this triple hit, and it's quite chronic, and that's why it's so resistant to any intervention that we can do. Yeah. Okay. Yeah. Great. Great. So when you're assessing growth, it's very important to understand that with thalassemia, you'll do your standard height and weight, but you have to do a sitting height, because what happens with the bone disease, and I'll mention the bone disease in just a second, you actually get vertebral compression, so you will, you know, get longer limbs and a shorter torso, so you want to make sure you do a sitting height as well, and if you don't have a stadiometer in your clinic, just developing a standardized box where the child can sit, which is a standard height, you can actually minus that from the regular stadiometer that you use. It's pretty easy to do, and it must be documented if you're going to then follow the child long term, because this is what the x-rays end up looking like. You get vertebral compression fractures, and again, your best efforts to try to intervene with increasing growth may not be very effective. With regards to the growth axis, again, it's not easy. It's not just growth hormone deficiency, it's actually growth hormone resistance as well, and then post, you know, IGF1, you know, downstream pathway problems as well, so you have to kind of take care of the entire picture. So the main thing that people recommend really is prevention. You know, if you can try to take care of the anemia and the iron overload early, you'll actually have a better growth outcome. So if you're seeing the child at 13 or 14 when they've had, you know, 7, 8, 10 years of this cycle already ongoing, you're going to have very little to offer to them, even with the, you know, higher doses of growth hormone that you will use. You know, the nutrition and all the other stuff that comes with it, all, you know, it's really important, and then inducing puberty at the right time, inducing it gently rather than with higher doses, all those kind of things will actually affect your final outcome. And then paying attention to bone health also, important because, again, the vertebral compression fractures will shorten height anyways. So the recommendations really are, and this is, again, they've put levels of evidence to what they recommend, is that, you know, there's this balance between using aggressive chelation to bring the iron down, but it turns out that iron chelators themselves actually can cause, you know, risk of short stature as well. So you want to find that balance where they're chelated well but not over-chelated or not having side effects from the medications. It seems to be that there's really no consensus on the universal use of growth hormone. People understand that IGF-1 axis will be affected, but should you treat in every case, and also, again, in our part of the world, expense becomes a huge consideration, but it turns out that even in well-resourced settings, the linear growth effect isn't as good as what you typically see with growth hormone deficiency and possibly due to growth hormone resistance. So I think people can certainly give it a try, and again, standard doses are used as far as most people are concerned, but it really isn't as efficacious, so I think that has to be expected and people have to be counseled accordingly. And it seems that it may actually have some potential benefits for the heart. So maybe some patients with cardiac failure may benefit from growth hormone replacement. In terms of bone disease, again, the pathophysiology, as I mentioned, is, you know, quite diverse. And here, specific to the bones, you have the marrow expansion that is, you know, thinning out the bones. You have direct ion toxicity to the bone cells themselves. The chelation therapy that's toxic to the bones, the hypogonadism that is making the bones weaker, liver disease, and then these kids are not very physically active, they're not very energetic, so they're not going to have the bone load, the mechanical loading on the bone that will help them. So all of those things lead to osteoporosis, fracture risk, bone pain and discomfort, and spinal deformity. So it's a pretty bad mix in terms of the bone. So how do you do the assessment? So obviously, you begin at an age where you're quite confident with the dexa levels being good, you know, in setups where they don't have a lot of pediatric patients, make sure you're using the right standards and everything that goes without saying. These are the standard biochemical markers for bone health, as you can see over here. And then you can use the more advanced bone markers, bone formation, or resorption markers if you have them, get a baseline and then follow up over time to see what happens. Again, like with the other problems, prevention is really going to be what really, really saves these patients and gives them a better long-term outlook. So you assess annually and you try to encourage physical activity. Smoking is a very, very bad idea in thalassemia, which is obvious. You can optimize calcium and vitamin D intake. In fact, as I'll show you with the hypoparathyroidism, you actually need to give active vitamin D because they'll have hypopara. Early management of diabetes as it comes, because that affects the bones as well. And then really optimization of the chelation and the hormonal replacement. The bisphosphonates are now being used more and more, and they seem to definitely improve the bone pain that they get, especially with the vertebral compression that they get. But it's not a given that every child with thalassemia should get it, and you shouldn't just use bone mineral density as your reason to use bisphosphonates. So it's something that has to be done very prudently and individualized. These are the bisphosphonates that have been used in thalassemia, and the general recommendation right now is to not use them long-term, and to kind of use something that you can monitor and that you can see having a positive benefit, at least with dexine, with bone pain and with fracture incidence, et cetera. With the hypoparathyroidism, it is, again, related to the fact that you've got iron overload within the parathyroid glands that'll cause all the problems. You all know what the parathyroid hormone does and how the axis works. So the clinical features you will be looking out for when you're monitoring these kids will be obviously either a low calcium, you might even have a normal calcium initially with a high phosphorus, and a normal PTH in the face of low calcium is inappropriately normal as you all know. And so in these patients, replacing them with standard vitamin D will not work. You'll have to give them either 125 D or 1 alpha, hydroxyvitamin D, both will work okay. You have to be cognizant of liver disease, obviously, so if you've got liver disease and you want to use 125. The goal is to keep the calcium to a low normal range, just kind of you do with any hypopara, you don't want to put it in the higher range and you want to normalize the phosphorus and you want to look out for nephrocalcinosis and all the other complications that come with this. If you need phosphate binders, do not use aluminum because that's toxic. In thalassemia, you don't want to do that. And again, use bisphosphonates carefully. I've had patients who've had acute hypocalcemia because of inappropriate use of bisphosphonates and adult doses being given in children. No real evidence for any of the newer drugs or recombinant PTH in thalassemia, so use carefully and again, not approved, at least in growing kids for sure. The thyroid hormone also gets affected, again, as you know, thyroid gland affects many, many different body systems, so you need good thyroid health. And it seems to be that it could be both central or primary hypothyroidism. You'll get the classic hormonal pattern that you typically see with this easy to recognize. In either case, all are treated with oral levothyroxine replacement. You do the standard monitoring, et cetera. So this gets forgotten in all the long cycle of transfusions and other things that the kids are happening. So we always keep reminding people, don't forget about the thyroid and you don't want to just blindly just take a TSH because you might have central hypothyroidism, so always do a free T4 with a TSH or don't screen with just a TSH alone. So this is kind of the management algorithm suggested by the TIF with regards to how you look at the patterns of TSH and free T4 and what you do. It's always important to look at the adrenal function before you replace. In the overt hypothyroidism cases, their hearts are quite fragile, especially with long years of ion toxicity, so do a cardiac assessment and so forth. If you're assuming central, you can actually do a pituitary MRI and get a sense of the ion overload in the pituitary as well. So it's always good to do that and take it accordingly. Diabetes is a real problem and as some of our patients are surviving longer, we're seeing this. Kind of like with the CFRD thing that the CF patients survive longer, now diabetes becomes a much bigger problem. And here, the classic bronze diabetes is clearly there and we see it. And the pathophysiology is actually, again, quite complex because it relates to the liver disease, the ion overload, and it's basically not only a beta cell dysfunction and insulin deficiency, but also at the cellular level, insulin resistance as well. So you kind of have to keep that in mind. Although with treatments, I'll show you, it's probably better to have insulin early on on board and it's going to be hard to just manage with oral medications. So again, preventing is good chelation, keeping a healthy liver, preventing the liver disease that comes with it. If those two are there, you'll have a much easier time managing your diabetes. With regards to the screening and the numbers, they're exactly the same. So you don't have to learn new numbers for screening for type 2 diabetes. For diabetes, they're exactly the same for fasting as well as for a two-hour postprandial post-glucose load test. A1c is not useful because these individuals will not be having red blood cells that live for 120 days. So where fructosamine is available, it is a good test to look for a marker of glycemic control. Otherwise, we're really having to just look at the numbers themselves and making decisions based on just their daily charts, et cetera. People are using pancreatic MRI to look at the iron load, but it's very hard to make clinical decisions just on the imaging or even the quantification. So you really have to go for the screening tests and if they are overtly diabetic, then you treat them. People have used these oral drugs in the past, as you can see, but the general recommendation is have a low threshold to begin insulin because these patients will ultimately need it and they have a level of insulin resistance as well. People have used metformin in combination with insulin too, but you have to be cognizant of liver disease, et cetera, and so forth. So be careful there. Adrenal insufficiency is overall quite rare. Biochemically, it's quite common, 45% of patients will have it, but actually clinically having adrenal insufficiency is quite rare. So in general, what people say is that when the kids are old enough, and this is somewhere in the teenage years, 12 or 13, start doing your screening with both basal and stimulated cortisol levels. We end up seeing a lot of patients who end up in ICU with cardiac problems, so we always do a level over there, and we have a low threshold to give them at least a short-term steroid replacement there because you don't want to be suffering from adrenal insufficiency in an ICU setting. So you can see the numbers over here. If you need to do a stimulated test, do it, and then we do the standard replacement like you would do, and sometimes we counsel families to, in terms of physiologic stress, et cetera, give stress doses, although thankfully, clinically, it seems to be rare. So in terms of overall, there's actually a group called the ICET, which was established in 2013, and they actually are the ones that give recommendations, so most of what I've discussed based under the umbrella of the Thalassemia International Foundation comes out of the evidence from this group. And they have not updated their guidelines from 2013, but it looks like the evidence still continues, and that's what they recommend, and it's a good group of scientists, and they're very easily available. You can email Dr. DeSantis, et cetera, and so forth, and they'll give you, if you have a personal question, they're happy to answer. And they've kind of come up with this standard endocrine evaluation and the timing, and I find this table quite useful. So in Pakistan, we have a number of charity-based thalassemia centers that actually patients go to, because it's chronic care. So we've circulated this protocol, and they're, you know, doctors, either hematologists or general physicians who are taking care of these individuals follow these protocols, and they'll do the screening, and then they'll send the patients to us once, if anything comes back abnormal. So it's good to kind of give them these tools, because these are things that can be done at the primary center. They don't have to necessarily come to an endocrinologist to get all of this, but certainly the interpretation of the test requires endocrine expertise. This is the TIF guideline. It's excellent resource, so most of what I presented today comes from here, and they updated their guidelines in 2021. Previously it was 2013. So it's good to keep up to date. And they have a, this is the longer version. They have a handbook version of this, too, so every subject is two pages each. So it's a very, very good resource, and it's freely available on their websites. If you just go to the Thalassenia International Foundation website, you can see it, and it's really, really a great resource. So like I mentioned, the ISET resource is certainly there, and you guys can all rely on it. And if there is a need to update it, then it certainly will be updated, but like I said, this is from 2013. So in summary, you know, endocrine complications I've shown you are actually very common. And when I'm teaching medical students, I say, if you want to learn endocrinology, just take one patient who's an adolescent or, you know, older individual with thalassemia. They will teach you everything you need to know about, you know, all the endocrine glands that could be affected. The liver disease is a huge issue, and the concomitant problems that come with it. So be cognizant of those as you're treating your patients. We need regular monitoring, regular screening, and prevention. Prevention really is the key. So the good news is that even if you have historically poorly chelated patients, if they now adopt an aggressive chelation regimen, you can actually have reversal of some of these endocrinopathies. So the diabetes seems to be a good one. The bone disease may be much, much harder because it's much more chronic, but the diabetes seems to be reversed. And hypogonadism is probably extremely hard to reverse. So it seems that the gonadotrophs in the pituitary are uniquely susceptible to ion toxicity, much more so than some of the other cells. So it seems to be something, you know, harder to do. But if you see well-chelated patients from the beginning, those are the ones who will naturally be undergoing puberty, will have good stature, will have good bone health, et cetera. So it is possible to prevent all of that from happening. So with that, I will end, and I think we'll take questions at the end. So thank you very much for your attention.

thalassemia

iron overload

endocrinopathy

Pakistan

chelation therapy

Thalassemia International Foundation