Episode Transcript
00:00:04
Host: Hello and welcome to Cook Children's Doc Talk. Today we're talking about hyperinsulinism with pediatric endocrinologist Dr. Paul Thornton, pediatric surgeon Dr. John Uffman and neonatologist Dr. Jonathan Nedrelow. All three have very distinguished careers. And we could probably spend 30 minutes just going through their backgrounds. But here's the abbreviated introduction. Dr. Thornton hails from Dublin, Ireland, where he received his medical degree from University College Dublin, Ireland medicine. He completed his pediatric residency at Temple Street Children's Hospital, the National Maternity Hospital, Guy's Hospital, the Hospital for Sick Children and the Children's Hospital of Philadelphia, where his work with the world's experts in children with hypoglycemic disorders began and led him to where he is today as the medical director of Cook Children's endocrinology department. He is recognized the world over for his work in hyperinsulinism, serves on many national and international boards and committees and is a much sought after speaker and teacher. He was recognized as a Rare Disease Hero for his work in hyperinsulinism.
00:01:13
Dr. Uffman earned his degree and completed his residency at Louisiana State University Health Sciences Center and fellowship in pediatric surgery in Memphis, Tennessee, at Le Bonheure and St. Jude Children's Research Hospital. He's board certified by the American Board of Surgery in both pediatric and general surgery. He is also a member of the American Pediatric Surgery Association, American College of Surgeons, Children's Oncology Group, Texas Medical Association, Tarrant County Medical Society, Fort Worth surgical society, Fort Worth Pediatric Society and Cook Children's Physician Network. Dr. Uffman is also very active with the medical staff at Cook Children's. He serves on many committees and boards and is the past medical staff president. Dr. Uffman has received many honors and awards throughout his career for his esprit de corps and for his involvement and talent as an excellent teacher. Dr. Nedrelow is board certified in neonatal perinatal medicine. He earned his medical degree from the University of Minnesota Medical School and completed his pediatric residency at Duke University Medical Center and neonatal perinatal fellowship at Yale New Haven Children's Hospital. Dr. Nedrelow currently serves as medical director of neonatology at Cook Children's Medical Center. He's given numerous lectures throughout Texas on subjects such as cardiopulmonary development, management of bilirubin in term and near-term infants, delivery room emergencies, pain management in the newborn and the use of hyperthermia for the treatment of birth asphyxia. Welcome and thank you for being here.
00:02:49
Dr. Nedrelow: Nice to be here.
00:02:50
Dr. Uffman: Happy to be here.
00:02:51
Host: So for physicians who may not be familiar with hyperinsulinism, and its risk, can you give us a little background on what it is and who it affects?
00:03:01
Dr. Thornton: Congenital hyperinsulinism is a condition in which the beta cells of the pancreas make too much insulin, and more importantly, have lost the ability to regulate insulin based on the plasma glucose levels. As a result, the excess secretion of insulin causes hypoglycemia. And in addition, the excess secretion of insulin suppresses lactate and beta hydroxy butyrate levels. And so the real danger about this condition is that the brain needs glucose lactate and ketones for energy. And in congenital hyperinsulinism, none of those fuels are available, and hence a very high risk of 20 to 40% of brain damage that can occur in this condition. And this condition primarily affects newborn babies, but also some children in their first year of life. And very rarely we see children presenting after one year of life. And then, of course, there are acquired forms that are not genetically inherited, that are indeed much more common, happening to about one in 1,200 babies. And these conditions typically occur because of stresses in utero in the mom, such as hypertension, or preeclampsia. So there are both congenital forms due to genetic conditions and acquired forms due to different conditions in the mom that make this such a difficult condition to treat overall.
00:04:29
Host: So Dr. Thornton, you started the hyperinsulinism program here at Cook Children's in 2010. What motivated you?
00:04:37
Dr. Thornton: Well, I was very fortunate that I trained with some of the world's leading experts, Dr. Charlie Stanley and Dr. Lester Baker. And for a short while I trained with Dr. Al Aynsley-Green and these were the top three people in hyperinsulinism at the time, and so basically, they piqued my interest and I realized that this was a rare but niche condition, and that would be very interesting to get involved. And so I started in my fellowship to focus primarily in my clinical years on congenital hyperinsulinism. And then when I stayed on in the Children's Hospital of Philadelphia, I was a clinical director of the Hyperinsulinism Center there. And so when I came to Fort Worth, it was natural to continue the work here. And initially, there was a lot of things to be done in the endocrine department. But by 2010, seven years after I got here, I realized that I had a skill set that we needed to utilize fully because there just aren't a lot of people trained in hypoglycemia. So we set up the center, and in 2012, I got an endowed chair that allowed me to do some research with hyperinsulinism. And then we subsequently got an 18 F-DOPA investigational new drug license to enable to image the pancreas. We formed a big multidisciplinary team with my colleagues here, Dr. Nedrelow and Dr. Uffman and also with our radiologists, Dr. Putegnat. And we involved neurology and gastroenterology and really put together a full multidisciplinary team to manage children with this rare condition.
00:06:15
Host: So there are several healthcare systems that have hyperinsulinism programs, but only a few who actually do what we do here. In fact, in June of 2021, the hyperinsulinism program here at Cook Children's was among the first and only six worldwide to be named a designated Hyperinsulinism Center of Excellence. What are the protocols or requirements for earning this designation? And how does this separate these programs from others in terms of treating patients with this diagnosis?
00:06:45
Dr. Thornton: First, let me say, Jan, that we gained the designation as a Center of Excellence because of the tremendous work of all the team. It was not one person. It was the whole team from the doctors, nurse practitioners, nutritionists, psychologists, clinical therapists, it takes a whole village to manage these children. The second thing is that the designation comes from an organization called Congenital Hyperinsulinism International. And this is a family organization that offers family support for children with hyperinsulinism. And they decided about three to four years ago that they wanted to recognize that some centers have everything it takes to take care of these children. And so they developed a 70 question questionnaire that really addressed you know, our history of quality outcomes. What sort of outcomes did we have with our patients? Were we seeing a lot of patients? Was our surgeon performing lots of operations? Were are we doing research and were are we publishing? What sort of care did we provide to our families? And they were very interested in family centered care. And so we filled in the application and scored really highly and we're able to get recognized as a Center of Excellence.
00:08:02
Host: You noted that a key component of the Center of Excellence designation is research. You serve as a member of the scientific advisory group for Congenital Hyperinsulinism International. Your cohorts are among the foremost congenital hyperinsulinism specialists, including researchers and clinicians at leading hospitals, research centers and clinics from around the world. What are you working on?
00:08:25
Dr. Thornton: Working with Congenital Hyperinsulinism International has been very exciting, especially to watch them from when they started out in the early 2000s As a small family organization supporting the patients in the Philadelphia area, and then subsequently nationally, and now internationally. Recently, congenital hyperinsulinism international applied for a grant from the Chan Zuckerberg Initiative, which has set as a lofty goal to cure all rare diseases by the end of this century. And this grant was to enable the organization, which we call CHI, to perform patient driven research. So for the last two years, our focus working with CHI has been to identify gaps in current knowledge, and to identify a research agenda that we're now going to work off over the next couple of years. And this all came to a climax in Lisbon two weeks ago, where all of the experts in hyperinsulinism from around the world, all of the leaders in drug development from the pharmaceutical companies and the family representatives got together and hammered out this research agenda and have set aside some big projects that we're going to look into in the next couple of years.
00:09:43
Host: So what types of research are you and your team currently involved in here at Cook Children's? And in what capacity?
00:09:50
Dr. Thornton: Probably our biggest project at the moment is looking at imaging of the pancreas to identify patients who have focal and diffuse disease. And to help the surgeon know where to look to find the focal lesion so he can cure the patient and get rid of the hyperinsulinism. And this has been a big project that we started in 2014. We have an investigational new drug license to make and use 18 fluorodopa, which is taken up by the pancreas, and it seems to function best by demonstrating those areas of the pancreas that secrete the most insulin. And so when Dr. Uffman takes a patient to surgery, he does biopsies and if those biopsies look normal, and the PET scan suggests that there's a focal lesion, for example, in the head of the pancreas, he will then go in and resect out the head until he finds the lesion and we can cure the patients. So that's a big thing that we're doing now. Other projects are related to drug development. So currently, we've been involved in phase two and phase three studies looking at novel drugs to treat hyperinsulinism. The first drug we did was a form of liquid glucagon, which we infused into newborn babies with subcutaneous insulin pump. So this is an off-label use of an established drug using equipment that was not designed to do this. And we found that it was very effective when we were able to reduce the amount of glucose that a baby needed by 40 to 50%. Recently, we've done some phase two studies looking at antibodies to the insulin receptor. And we just published those results at the Pediatric Endocrine Society meetings this year, and show that you can get a 60 to 70% reduction in time below range when monitoring glucose is by continuous glucose monitoring. So this is a very promising drug. And we are currently designing a couple of phase three studies with some other pharmaceutical companies. Now, what makes this most exciting is there have been no new drugs for the treatment of hyperinsulinism since 1967, when diazoxide was first approved. So we've been going for close to 50 years with no new drugs. And we're hoping that in the next three to five years, we will have three or four new drugs available to us, which will really help our children and, most importantly, should be able to avoid near total pancreatectomy is which we sometimes have to do to treat the really severe children. And this, of course, prevents the long term development of diabetes. So this is a very exciting advancement.
00:12:32
Host It's such a rare disease and difficult to diagnose, you helped write the global guidelines for diagnosing and treating hyperinsulinism. Those guidelines are a real game changer, especially for neonatologists and getting an earlier diagnosis, correct? And why is an early diagnosis so important for patient outcomes?
00:12:52
Dr. Thornton: Back in 2015, we published a guideline for the diagnosis and management of hypoglycemia. And the purpose of that guideline was to help physicians who care for newborn babies to be able to recognize the difference between the very common and most likely benign forms of hypoglycemia that occur during transition from injury uterine to extra uterine life, from the more serious pathological conditions, which happen probably overall, when you take into account all of those conditions, about one in a thousand babies. So that was the first step to help early diagnosis of hyperinsulinism. This year, we've just completed, but not yet published, guidelines on the management of hyperinsulinism. Because what we've come to realize is that we are very fortunate in the United States to have every tool available to us to treat our babies, but throughout the world, some things are lacking. For example, in South America, it's very difficult to get the only FDA approved drug to treat hyperinsulinism. And so these guidelines really help physicians around the world, not just in the developed countries, determine the best approach to diagnose and treat patients with hyperinsulinism. And our goal with both of these projects, is to try and reduce the frequency of brain damage from 20 to 40%, down to, obviously, zero, but certainly to make a significant impact so that the lives of our families, even after we cure them from their hypoglycemia are not devastated by the effects of long term neurological brain damage.
00:14:33
Host: So Dr. Nedrelow, neonatologists are often the first to recognize or suspect that a baby has hyperinsulinism. What are the initial challenges you face in diagnosing such a rare disease and how do these guidelines help?
00:14:46
Dr. Nedrelow: Well, the challenge is that this disease is hidden amongst the common symptom of hypoglycemia in the newborn. It's the proverbial needle in the haystack. The incidence of true genetic hyperinsulinism is estimated to be somewhere between one in 25,000 to one in 30,000 births. Yet, many, many, many babies have a transitional form of hypoglycemia that's very benign. It's actually, probably a normal part of the transition from in utero life to postnatal life. It's up to a third to 40% of the babies will have some degree of hypoglycemia after they're born. And so how do you weed out, or how do you screen for the kids who ultimately have this rare genetic condition? And that's where the guidelines come in. So you have to have a systematic programmatic way to think about screening these kids. It's really all about how long the baby, newborn, stays hypoglycemic and to what degree they are hypoglycemic. And if you're systematic about that, and the guidelines highlight that, then you can literally find the needle in the haystack, which is very rewarding. I spend a lot of my time teaching other frontline providers about the value of having this kind of protocol, about having a screening program. And ultimately, the screening that we do is a physiologic based screening. It's not a bunch of expensive lab tests, it's not a bunch of imaging, we are literally looking for babies that have an extended period of hypoglycemia. They have deeper hypoglycemia than expected, a quote unquote, doesn't make sense. And we simply fast these babies for a period of time to either prove they have normal glucose metabolism and normal use of insulin, or they fail this fast. And that's where we really dive into the workup and find these kids with this rare condition.
00:16:35
Dr. Thornton: If I could add to that, Jan, you know, the hypoglycemia guidelines are helping the neonatologist not just find the severe genetic forms of hyperinsulinism. But also the more common acquired forms of hyperinsulinism like perinatal stress hyperinsulinism, which is far more common. And it also helps them identify kids with hypopituitarism that causes hypoglycemia, and the glycogen storage diseases, so all of these together are very, very rare. But when you look at the frequencies of everything, it turns out that about one and 1,000 babies will have significant hypoglycemia that needs to be treated, and maybe not necessarily for life, and it's from that group that we find all the rare causes.
00:17:21
Host: As we talked about 18 F-DOPA research, how has 18 F-DOPA PET scan created a crucial shift in the diagnosis, and especially treatment of children with focal hyperinsulinism, Dr. Uffman
00:17:34
Dr. Uffman: I would say that 18 F-DOPA has been a real game changer, and a really important imaging tool for me as the surgeon going in. Sometimes when you operate on these babies, even knowing where it is, is like finding a needle in a haystack. And so it looks very subtly different from the remainder of the pancreas. Sometimes it barely looks different at all. And so having a tool that directs me where to focus my search really helps cut down on the time that the baby has to be in the operating room, and the amount of kind of random sampling that you would end up doing to try and find this needle in the haystack.
00:18:07
Host: So we've talked about focal hyperinsulinism, which is curable. There are other types of hyperinsulinism we can't currently cure. What about these patients? Why can't we cure them? And what options for treatment are available? Dr. Thornton?
00:18:22
Dr. Thornton: Well, I think it's almost easier to say, Why can we cure the patients with focal? And the reason is because in these children an unusual thing happens in that they inherit an autosomal recessive mutation from their father, but they lose a part of chromosome 11 where this gene is located on their mom's copy. So in a small part of the pancreas, the second event occurs and it creates what would have been a carrier for an autosomal recessive disease into someone who has a area of the pancreas in which there's a loss of tumor suppressor genes and an expression of overgrowth genes. So you get an overgrowth of the small area of the pancreas that secretes insulin inappropriately, and when the 18 F-DOPA PET scan identifies that area, and Dr. Uffman is able to remove it, you've removed all of the bad tissue. Now, all of the other forms of hyperinsulinism involve every beta cell in the pancreas. And so if you take out 50% of the pancreas, the 50% you will leave behind is affected. The same for 95%. The 5% you leave behind, and it only takes one or 2% of the pancreas to be making insulin in an abnormal fashion to cause a severe hypoglycemia. So the other 13 genetic types of hyperinsulinism, the forms that are associated with the syndromes, the transient forms, all of those forms of hyperinsulinism affect all the cells. And as I mentioned earlier, we only have one treatment, diazoxide. And we're blessed in that it works in all of the transient forms. But for most of the genetic forms, about 50% of them will have ongoing hypoglycemia. And so right now we have no treatment, which is why there's such a focus on developing new treatments.
00:20:19
Host: So let's go a little deeper into what makes this team really unique in terms of training and care. Dr. Thornton, I guess we can start with you, radiologists and pathologists?
00:20:30
Dr. Thornton: The team is made up of many, many members. And each one is really important because without any single member of the team, the whole team can't do its job. So it's critical that we have a multidisciplinary team with people from all specialties. Radiologists are critically important in the interpretation of the 18 F-DOPA scans and guiding us to finding the focal lesion. But at the surgery, the pathologists are very important because Dr. Uffman has to start off and take biopsies and we look at those and if they are normal, then we know that there must be a focal lesion because in diffuse disease, the biopsies are always abnormal. So to interpret a frozen section biopsy and in order to prevent the patient from losing too much pancreas, Dr. Offman sends us really tiny pieces of pancreas, so it's tough to interpret them. So the pathologist has to decide is this focal or diffuse? If it's focal, they have to decide when the surgeon has removed everything. And so without both the radiologist and the pathologist, Dr. Uffman and I can't do our job. So this is a nice disease example of how everyone is critically important. You know, I may get all the glory and go give all the talks. But the reality is, is that without everyone on the team, we can't do this.
00:21:57
Host: So Dr. Uffman, specialized expertise is required for curative surgery. And you do that and also train other surgeons, correct, to develop this expertise?
00:22:07
Dr. Uffman: Yes, that's correct. I probably started doing this about seven years ago. And I learned from my mentor, Dr. Miller, that was retiring. I agree with Dr. Thornton, the team is what really makes me as the surgeon very successful and I have to be able to communicate real-time with the pathologist and frequently Dr. Thornton during surgery that helps guide my decision making as we're deciding how much pancreas to take or what to do surgically. It does take doing this type of surgery multiple times. You gain more experience each time you do it. In terms of trying to identify where the lesion is and learning the, you know, the subtleties of how much pancreas do you remove in order to cure the patient and preserve as much normal pancreas as you can. And I think you have to be ready to deal with, you know the other complications that occur just by the nature of pancreatic surgery, which in a small neonate is a very delicate small organ with a lot of other important things like the bile duct and the splenic structures that live nearby.
00:23:07
Host: And Dr. Nedrelow, you have a specialized NICU for hyperinsulinism babies correct? And specially trained NICU and endo nurses?
00:23:17
Dr. Nedrelow: Yes. So you know, the ICU is the concentration of human expertise. People often confabulate and say it's all about the technology. And it's important. But what we've done for many different diseases and also for HI, for hyperinsulinism, is we have a core group of nurses that know all the particulars of taking care of these babies. There's a long period of hospitalization. They often need long-term, central venous access. So we have a very protocolized way to help minimize complications of central lines such as infection. And then importantly, the nurses know exactly how to do all the diagnostic blood draws. They know how to do the therapy. These patients are rare, but we see enough of them, where we can garner expertise amongst this core group of nursing staff to help care for these babies to minimize their length of hospitalization and minimizing the complications related to their ICU stay.
00:24:12
Dr. Thornton: If I can add to that, Jonathan, over the years, the feedback we've gotten from all our families is how amazing it is that our nurses know so much. And so the role of the nurses as part of the team is really very important because these families come from institutions where they may have never seen a baby with hyperinsulinism, or they've seen one. And because the nurses are not experienced, they haven't been able to answer questions. And when our families arrive and they roll into NICU B where we cohort all of our hyperinsulinism patients, they come across a cadre of nurses who are very experienced and who are able to put the families at ease. So that cannot be overstated how important they are. And likewise the nurses on our 3 North endocrine floor, where all of the children, once they get past the neonatal stage, are admitted and treated, for families to come and undergo fasting studies with a cohort of nurses who know exactly what they're doing, has made a huge difference. And so part of the success of this team has been the development of a wonderful group of nurses and nurse practitioners who really know what they're doing, and are probably could manage these kids without us in a way, because they're so knowledgeable and experienced.
00:25:31
Host: I think that ties nicely into what Dr. Nedrelow said, too, about this being a human expertise. It's not just the technology
00:25:38
Dr. Nedrelow: That's right.
00:25:39
Host: Speaking of training, it's important for a broader group of physicians to know what to do when these kids present. We know the majority of these children present in the neonatal period, Dr. Nedrelow, what should OB Gyns, primary care physicians and neonatologists be looking for?
00:25:54
Dr. Nedrelow: For the OB GYN. I think it's important. Obviously, if there's a family history, super important you pick it up on the front end during the pregnancy. And it's one of those things that you can see could be easily missed, potentially. So it's so important for the obstetrician to understand the family history, and then call the endocrinologist, call Dr. Thornton or myself and we'll get you talking to the right people. Pediatricians and primary care doc's who deal with newborns, similar to bilirubin, there's a spectrum of that outcome, which is to say oftentimes, it's physiologic like a lot of babies have low blood sugar in the first hours after life. And there are many causes for exaggerated hyperbilirubinemia. And the worst form of it is very dangerous and toxic to the brain. Hypoglycemia is the same there. Paul alluded to it earlier. There are many reasons for hyperglycemia. Few of them are due to genetic hyperinsulinism. There's a bunch of intermediate reasons that will go away but still need treatment. And then there are some babies with hypoglycemia that no treatment's required. Having a very systematic way to screen for and understand that spectrum, it is important. And pediatricians know this. This is how they think about hyperbilirubinemia, a common thing they understand and start to know in their training and through their practice. Okay, that's jaundice that's not going to harm this baby. This might be jaundice, that's going to be an issue, you have to have that same programmatic thought process for looking at hypoglycemia. And figuring out who has what version of hypoglycemia.
00:27:29
Host: So for kids who have hypoglycemia longer than just during their baby years, but as they continue to grow, how do you work with their primary care physicians?
00:27:39
Dr. Nedrelow: Well, this is really a in hospital right after birth hours, not days or years that that you live with this. We've got a time limited opportunity. You know, newborns are a captive audience. They don't have long hospitalizations. But if there is a protocol in place and a screening mindset in place, you'll be able to pick up on the kids that are outliers, and work them up further. And so this literally these happen during the initial hospitalization after these babies are born. Not dissimilar once again to hyperbilirubinemia. That's a good analogy for the pediatricians listening. It was a new concept for me, I did not have that until I started hanging around with Dr. Thornton. And it's almost dismissed as, Oh, yeah, hypoglycemia, that's common, and it'll just go away. That's the wrong mindset. You have to have a different mindset when it comes to hypoglycemia. And pediatricians understand that mindset in regards to jaundice. And so I think it's a good analogy.
00:28:33
Dr. Thornton: Yeah. Another thing about that is that, although the vast majority of children who have genetic forms of hyperinsulinism present in the first week of life, before they get out of the newborn period in the hospital, there still are about 30% to 40% of kids who present after that. So from a pediatrician perspective, you know, if moms are reporting that their kids are very irritable and wanting to feed all the time, of course, the most common thing is probably going to be colic. But this is something you need to keep in the back of your mind. If the moms say that the child is very lethargic and sleeping, then you know, there are many reasons for that. But again, hypoglycemia is something that needs to be kept in the back of the mind. And then, particularly if parents are concerned about seizures, or about development that was progressing nicely and then regresses or stops progressing, these are things that among many other things that they have to think about, they have to think about hypoglycemia. So in a way, I sort of think about my job as the easiest because they come to me with a diagnosis. The neonatologist and the pediatrician has to be able to look at it, you know, maybe for some pediatricians 20,000, 30,000 children before they'll ever see one with this condition. So how do you keep that to the forefront of their mind and that's very tough. So it can be a tough job trying to look at children who are almost never going to have this condition, but try and keep it in the back of your mind.
00:28:52
Dr. Thornton: So that leads nicely into my next question, which is what are the signs you see initially missed most often? And how do you any one of you think that this can be better addressed?
00:30:17
Dr. Nedrelow: In my world, which is roughly two thirds of the babies diagnosed in the newborn population, it's really a persistence of hypoglycemia beyond an age that you would usually expect resolution, right? So most babies resolve, anybody who works with newborns kind of understands, Oh, yeah, that blood glucose now is it much closer to the normal range or in the normal range after a certain period of time. It's that sweeping it under the carpet or persistence of hypoglycemia. Oh, it'll be okay. Tomorrow, it'll get better. And now we're beyond that first week of life. And there's still persistent hypoglycemia. That's probably the most common symptom that I see. And it's always easy to retrospectively go back and say, Oh, yeah, that child had exaggerated hypoglycemia, or extended hypoglycemia, beyond the age at which I would expect resolution. And so that's where the protocol is so important. It eliminates in some ways, or standardizes, and drives patient-driven variation in addressing patient driven variation. You don't want provider-driven variation. So you don't want to have each doctor's understanding or notion of how to what is too long, or how long is too long for hypoglycemia. You all get together as a group, and you agree, okay, this is too long. And this is when we start screening, or these are the issues that prompt us to screen for this. And I think that's the take home for all these cases that we see that did have a delay in diagnosis.
00:31:43
Dr. Thornton: It's very interesting, because the study has just been published where a group of physicians in Germany video recorded a series of babies who were having normal blood sugars and a series of babies who were in the middle of having low blood sugars. And they then presented all that data to the neonatologists. I mean, not at the time, but they stored up all this data. And then they got 10 neonatologists, 10 neonatal nurse practitioners, 10 pediatricians, 10 endocrinologists, and they said, Okay, tell me from looking at this video, which baby is hypoglycemic. And they showed very nicely that you can't tell from looking. And that's why what Dr. Nedrelow says is so important is that the issue really is whether babies have very severe low blood sugars, whether they need intravenous glucose to treat them. And anyone that has, you know, blood sugar's below 50, persisting after 48 to 72 hours of life, or below 60, after 72 hours of life, or who needs intravenous glucose to treat their low blood sugar, one has to seriously consider that there's a pathological cause of that hypoglycemia, and that this is not transitional, neonatal glucose dysregulation. So the reliance on signs and symptoms is very difficult, and has been shown not to be sufficient to be able to pick up these kids. And that's why these protocols are so important.
00:33:11
Host: So another area is emergency rooms, what should ER physicians be looking for? How do they confirm and when do they refer?
00:33:20
Dr. Thornton: Well, that's very interesting. We actually did a study a few years ago, looking at over 225,000 children who presented to the emergency room here at Cook Children's, and we were able to look at every single glucose level that was measured. Now, many children come to the emergency room for many, many reasons. And out of that 225,000 children, about 19,000 children had a glucose level measured. And out of that 19,000 Children 160 had a low glucose that was not explainable by their current disease. So for example, a child with diabetes could come into the emergency room with a low glucose. So this was 160 children out of 225,000 children who had an unexplained low glucose, and that's one in 1,400 children. So that's quite rare. However, of those 160 children 17, or approximately 10%, had a serious underlying problem. So the message here for the emergency room is that when you check a blood glucose, if it is low, there is a 10% chance that there's a serious problem that could cause this child brain damage. Now, there are very few things that if we had a 10% chance of a serious disease that we wouldn't further investigate. So one of the important messages that has gone out over the years is that children presenting to an emergency room with previously undiagnosed hypoglycemia need to have a very careful consideration of the underlying causes, and that's been very important. And the amount of diagnoses that are made in our emergency room is really dramatic. And because physicians will get a screening glucose that'll be low, they'll draw a critical sample. And they'll be able to make a diagnosis of the cause of the hypoglycemia. So it is really important to under that circumstance, that people don't just say, well, the kid had diarrhea and gastroenteritis, that's why they're low, one needs to consider more than that.
00:35:23
Host: What about geneticists? Since this is a genetic disease? Do you foresee a time in the future when genetic testing may play a role in the treatment and even prevention of hyperinsulinism?
00:35:33
Dr. Thornton: That's a really interesting question because, as Dr. Nedrelow knows, there are some institutions now where they can do ultra-rapid whole-exome sequencing, and get the results in 18 to 24 hours. And so there are some hospitals that have started doing this in the neonatal units, and screening all of the babies to get an early identification. For hyperinsulinism, for the 60% of babies who present in the immediate newborn period, that's probably not going to work, and which is why it's so important to focus on identifying those patients based on, you know, glucose levels and the duration of hypoglycemia. But for the kids who present later with the milder forms, this would actually be a very effective way. And so I do see a future where everyone will have their genes tested at birth, we'll identify, you know, people who are carriers. And so there'll be a higher suspicion that when they have children, that there could be an affected child. And we'll identify some of the milder forms of hyperinsulinism, that if not treated adequately, can still cause harm. So I think in the long term, that's a very exciting area and that we will be moving forward to, and I think they're starting to do this and other conditions. And this is something that's not too far fetched an idea.
00:36:56
Dr. Uffman: And I would think you would agree with me, too, that when we know the genetics ahead of time going into surgery, that we have much more confidence as a team that what we're going to be looking for is what we're actually going to find and it really helps drive the interop decision too.
00:37:09
Dr. Thornton: Yeah, absolutely. And the other thing, Dr. Nedrelow, you might remember some of the cases we've had where we knew the genetics before birth. So this was a second child for a family. And we knew that the baby was going to have diffuse disease. And rather than have the baby deliver in a small neonatal unit that doesn't have all the facilities, the mom comes to Cook Children's and has her baby here in the maternity hospital next door, and we transfer them straight over here. And that's been something that we've started doing more recently and has been very effective.
00:37:44
Dr. Nedrelow: I agree back to your idea of using these high throughput genetic tests to balance against cost, but there is a foreseeable future where the speed and the quantity of genetic information, at a price that's affordable, will happen such that rare diseases in general will be screened for very early in life for the human population. I think that's not a far fetched idea. And one of those diseases, of course, that will fall out in this analysis will be hyperinsulinism.
00:38:17
Host: Speaking of the future, what breakthroughs are you currently working on? And what do you see in the future for patients, families and a cure for all types of hyperinsulinism?
00:38:27
Dr. Thornton: Well, I think the exciting work I'm doing with the Chan Zuckerberg Initiative really has this as a goal. Specifically, our team is focused on curing hyperinsulinism. So you know, the one area we're doing a lot of work in is in developing new drugs, and they're not going to cure but at least treat. Another big thing we'd like to do is to try and have a better understanding of the mechanism of hypoglycemic brain damage. And more specifically, what degree of hypoglycemia causes harm, in order for us to better identify to what degree of treatment we have to achieve to prevent the hypoglycemia. And so we're probably going to work with some different groups, and some different diseases that have hypoglycemia as a significant component, to try and understand this a little bit better. And then of course, getting the genetics testing to a point where it can be done really quickly and very cheaply, will be a cost-effective way of at least diagnosing these kids and preventing the long term complications while we wait for a cure which may be you know, by gene therapy or different things like that.
00:39:39
Dr. Uffman: From a surgical perspective, I think anything that can help us to positively identify the lesion for, particularly for focal disease interoperatively rapidly and quickly would be a real nice breakthrough. And so we've been looking lately at the use of ICG green dye to see if we can help localize these lesions a little bit more efficiently and potentially save the baby from unnecessary pancreatic resection.
00:40:06
Dr. Nedrelow: Lastly, I'll piggyback on the idea of ounce of prevention is worth a pound of cure. So, right now, the state-of-the-art is astute clinicians who have a protocolized way to search for these babies, not by signs and symptoms, as Dr. Thornton laid out, but by degree and persistence of hypoglycemia. But someday there will be a more elegant screening tool that's molecular genetic based, and that will be a game changer. Maybe the cure won't be here yet. But prevention will happen because you'll identify these children really with high-fidelity prior to them having any kind of injury. So treatment can ensue and to mitigate the risk of injury.
00:40:50
Host: Thank you guys all for being here. Appreciate it.
00:40:53
Doctors: Thank you. Thanks for having us. Wonderful,
00:40:56
Host: We're so glad you could join us today. If you'd like to learn more about this program or any program at Cook Children's, please visit us at Cook Children's dot org
