Hyperinsulinism Diagnosis, Treatment, Outcomes and Research

What is Hyperinsulinism (HI)?

Diva D. De León-Crutchlow, MD: Hyperinsulinism is a congenital disorder of regulation of insulin secretion.

Andrew Palladino, MD: The cells in the pancreas that make insulin can't turn that insulin off, and when that happens, the blood sugar becomes dangerously low.

Diva D. De León-Crutchlow, MD: Basically it's the opposite to diabetes. Children that have hyperinsulinism produce too much insulin and that causes severe low blood glucose.

Andrew Palladino, MD: Blood sugar feeds the brain. And it's what our body uses for energy as a whole.

Lisa J. States, MD: So when you feel low blood sugar you may feel weak, you may feel confused and disoriented, or you may have seizures.

Andrew Palladino, MD: So that puts the brain at higher risk for suffering damage.

Diva D. De León-Crutchlow, MD: That's why it's so important to detect when infants have a low level of blood sugar to be able to correct it as soon as possible.

N. Scott Adzick, MD: The longer it takes until diagnosis and referral, the higher likelihood that the child will have catastrophic consequences, including severe brain injury.

Diva D. De León-Crutchlow, MD: At The Children's Hospital of Philadelphia Hyperinsulinism Center, we see approximately two-thirds of all the cases that are born in this country with hyperinsulinism.

Andrew Palladino, MD: Once a diagnosis of hyperinsulinism is made, we need to educate families, to what is hyperinsulinism? What can be causing the hyperinsulinism? And how can we treat the hyperinsulinism?

Diva D. De León-Crutchlow, MD: There are two types of hyperinsulinism. There's a diffuse form and there's the focal form.

Charles A. Stanley, MD: When there's diffuse disease, all of the insulin-secreting cells in the pancreas are abnormal, but when it's focal disease, a very small cluster of cells measuring perhaps less than one-quarter of an inch in diameter are abnormal.

Enyo Dzata, MSN: So focal form really means just part of the pancreas is affected and once that part that's affected is taken out, it's curable. The disease is curable. For diffuse, typically the whole pancreas is affected. All the beta cells are not functioning properly and the babies need a near total pancreatectomy or 95 - 98 percent of their pancreas removed.

Diva D. De León-Crutchlow, MD: By doing genetic screening and finding out what gene is defective in these children we can very–with high accuracy–determine who has focal hyperinsulinism and who would have diffuse hyperinsulinism.

Andrew Palladino, MD: When we start thinking about medical management versus surgical management the genetics play an important role.

Treating Hyperinsulinism with Medicine

Diva D. De León-Crutchlow, MD: We have different treatment options for children with hyperinsulinism. About half of these children are treated medically with a combination of drugs that suppress insulin secretion and other medical management. For these children that respond to medical therapy we have only two medications that are used. The first line of therapy is Diazoxide, a medication that is used in an oral preparation is very effective in suppressing insulin secretion in milder forms of hyperinsulinism. Some require treatment with a second medication that is called Octreotide. Octreotide is an injectable drug that again suppresses insulin secretion.

Enyo Dzata, MSN: There are several tools that we have to medically manage patients. Some are oral medication, injectable medication, and the third is sugar water through a feeding tube.

Andrew Palladino, MD: They can't just drink formula or juice or something once every two hours to keep their blood sugars up. They need a continuous rate of sugar to prevent them from having severe hypoglycemia.

Diva D. De León-Crutchlow, MD: We work together with the families to make the decisions that would allow us to establish the best medical management for their children.

Andrew Palladino, MD: The patients that are relatively easily medically managed and don't need surgery, we'll see those children probably twice a year. They'll come back for outpatient follow-up in six months and every year we'll admit them to evaluate them to make sure that their blood sugars are as stable as we think they are on their current management.

Enyo Dzata, MSN: And typically those kids we anticipate will improve over time. But sometimes they may need life-long therapy for medication.

Candy Sanchez, Parent: He is 6 years old with hyperinsulinism. And he's been on the same treatment for years. Endocrinologists didn't know where to go next and how to treat Dale and she referred us here to the endocrinology team here.

Leroy Martinez, Parent: They took down a couple shots and eliminated a couple shots, but I just want him to be just a normal little boy. That's my greatest joy right there. You know, just that I can see him actually out there playing with everybody and enjoying himself. Enjoying life.

Diva D. De León-Crutchlow, MD: In half of our patients the hyperinsulinism can be treated medically. And those children will require medical therapy for most of their lives, but that controls the hypoglycemia. In the other half of the patients, the hyperinsulinism cannot be treated medically. And surgery is the only option for ameliorating the hypoglycemia.

PET/CT Scan Before Surgery for Hyperinsulinism

Charles A. Stanley, MD: What's really been exciting the last few years is the realization that there are a large number of babies with focal disease that can be cured by surgery.

N. Scott Adzick, MD: The breakthrough diagnostically has been the development of a PET scan technique which can precisely tell us whether the baby has diffuse disease or focal disease and then, with a great deal of accuracy for those babies with focal lesions, tell us where in the pancreas the focal lesion is.

Enyo Dzata, MSN: The PET scanner is a special camera that detects radioactivity. So we use radiopharmaceuticals that are injected into the body to study different body parts.

Lisa J. States, MD: Not every family is eligible for a PET scan. This is a research study. So if the genetics are consistent with diffuse disease, we do not do a PET scan.

Enyo Dzata, MSN: Failing medical therapy and having genetics that are unclear, or suggestive of focal disease, that is what will make them eligible.

Charles A. Stanley, MD: So we currently have to do the PET scans under Food and Drug Administration IND protocol.

Andrew Palladino, MD: In terms of how much radiation there is, it is the equivalent of flying cross country. It's really a minimal amount of exposure.

N. Scott Adzick, MD: The substance, 18 Fluorodopa, which is used to do this PET scan is actually prepared in the Penn Cyclotron.

Diva D. De León-Crutchlow, MD: The Cyclotron facility prepares the 18 Fluorodopa just the morning of this study.

Andrew Palladino, MD: It's not sitting on a shelf ready for use whenever. It needs to be made the day that we're going to use it, and it has to be used within hours, otherwise, it will stop working.

Lisa J. States, MD: Every 110 minutes half the dose is gone. So we have to make it on the day, get it over to the scanner, and inject it within a few hours.

Andrew Palladino, MD: The child goes downstairs to our Radiology suite and the PET scan and the CAT scan are together.

Lisa J. States, MD: Once the baby comes down to PET, the anesthesiologist will sedate the patient. During this time our technologist is getting the dose ready which is a weight-based dose. Before we start the PET scan, we position the patient to make sure we can do the PET and the CAT scan without moving the patient. The F-DOPA radiopharmaceutical is injected into the venous system and travels to the pancreas. It will travel to the beta cells and when there is a focal lesion we will see a hot spot where the focal lesion is.

Andrew Palladino, MD: It's just really the overactive nature of these cells that you're seeing a high level of activity in this focal area.

Lisa J. States, MD: This hot spot is detected by the camera. There is more radioactivity in the focal lesion than in the rest of the pancreas.

N. Scott Adzick, MD: It's a very intuitive thing. You see a beacon, quite bright, that localizes a focal lesion.

Charles A. Stanley, MD: So it tells a surgeon exactly where to go to look for the focal lesion.

Lisa J. States, MD: The PET CT machine allows us to do a PET scan and a CAT scan at the same time, on the same table, with the baby in the same position. This allows us to look at the PET scan and the CAT scan together and create a three-dimensional image. And it really lays a road map for the surgeon.

Surgery for Hyperinsulinism

Lisa Maas, Mother: Our daughter Caroline was born on June 13th, at Central Baptist Hospital in Lexington, Kentucky. She was pronounced healthy and we were discharged from the hospital and getting ready to go home when a very astute nurse noticed and thought that Caroline seemed cold and a little bit lethargic.

Michael Maas, Father: We were worried about the usual things that you worry about, you know, you want them to be healthy and you want them to have 10 fingers and 10 toes, but we had never heard about hyperinsulinism. We had been very well prepared and well briefed the day of the surgery. Dr. Adzick had talked with us the day before. We felt like we understood what was going to be happening.

N. Scott Adzick, MD: A surgical approach at the beginning is the same with either focal disease or diffuse disease. A laparotomy is performed in a baby who's under general anesthesia by one of our expert pediatric anesthesiologists. A sideways wound is made above the level of the belly button and the pancreas is exposed. The pancreas has a head, a neck, a body and a tail. I examine the pancreas using magnifying glasses that magnify things by factor of four. And sometimes there are little visual hints as to where a focal lesion might be. I also palpate the pancreas because focal lesions tend to be a bit firmer than surrounding normal pancreatic tissue. If there are no abnormal findings on inspection or palpation, I do three biopsies. One from the head, one from the body and one from the tail of the pancreas.

Lisa J. States, MD: When you have a focal lesion, the rest of your pancreas is normal. When there's diffuse disease, all the cells, all the beta cells in the pancreas are abnormal. So there will be multiple biopsies taken just to be sure.

Pierre Russo, Pathologist: It's only by pathological examination we can recognize what portion of the pancreas is exactly abnormal. And the surgeon will, in turn, be able to remove the abnormality.

Where the arrow is, these are the islets, OK. So this is normal. And this is abnormal.

N. Scott Adzick, MD: The interaction between the surgeon and the pathologist in the operating room is crucial. Because one wants accurate information given to the pathologist. One wants the frozen section diagnoses to be prompt because the baby is anesthetized. And actually we have things arranged in the operating room such that there's a large screen onto which the pathologic sections can be projected from pathology an entire floor away so that we can, in real time, discuss what the findings are. For babies with focal disease if there is not a visible or palpable hint as to where the focal lesion is, now with preoperative PET scanning, I know where to zero in. Focal lesions can be as small as two or three millimeters in size so sometimes it can be tricky, even with the preoperative information, to find it. A focal lesion in the tail or the body or the neck of the pancreas is straight forward to excise and may involve taking off the end of the pancreas along with the focal lesion or just the focal lesion itself if it's not close to the main pancreatic duct which is sort of the pipeline through which pancreatic secretions run. And we don't want to cause an injury to that during the operation. Focal lesions in the head of the pancreas are more complex because there's all this important traffic that goes through or around the pancreatic head. The portal vein is behind it. The superior mesenteric artery is behind it. The common bile duct passes through it. The arterial blood supply to the duodenum is shared. So it's a very delicate, very fine dissection and the way things work, all the drainage of the pancreatic secretion and enzymes occurs from the tail toward the head and to the duodenum. So if you take a focal lesion of the head out and have to take out the pancreatic duct in that portion, then we've learned that it's important to save the body and the tail of the pancreas. Bring up a loop of bowel, the medical term is Roux-en-y loop, so that those pancreatic secretions can drain into the intestine where they belong. And so we preserve the normal islet cells and that normal portion of the pancreas.

Lisa J. States, MD: Our surgeon has done over 400 pancreatectomies so he has the most experience in the world.

N. Scott Adzick, MD: It's a wonderful feeling to leave the operating room having done something that will have a huge impact on a child's life and on that family. You ready for some good news?

Lisa Maas, Mother: I'm ready for some good news. She had indeed had a focal lesion that was in the tail of her pancreas, which was the most unlikely place for it to be, and it's the best place to have a lesion because it's not attached to anything else. I remember him saying that there was every reason to believe that Caroline would be cured.

Diva D. De León-Crutchlow, MD: Approximately half of the children that require surgery have this focal form of hyperinsulinism. The other half have diffuse hyperinsulinism.

Charles A. Stanley, MD: Those that have diffuse disease, we can reduce the amount of pancreas by surgery, but we can't cure it completely.

N. Scott Adzick, MD: If there are abnormal findings consistent with diffuse disease on each of the three biopsies, then a near total pancreatectomy is done, saving only a tiny nub in the pancreas between the duodenum and the common bile duct. This hopefully will help in the management of the disease in terms of prevention of brain threatening hypoglycemia, but it's really not a cure. Some babies do quite well and don't need much in the way of additional medical therapy. Others can have recurrent hypoglycemia and need additional medical therapy and there's a third group that develops insulin-dependent diabetes.

After Hyperinsulinism Surgery

Andrew Palladino, MD: As it stands now, about 50 percent of our babies that have the near total pancreatectomy for diffuse disease, still have hypoglycemia after the surgery. They still need some form of medical management to keep their blood sugars from being too low. The other outcomes would be instead of needing sugar they would have too high of a sugar and have more like diabetes and need insulin, and then there's a small percentage that kind of find a balance and they don't need anything.

Diva D. De León-Crutchlow, MD: We have this multidisciplinary team that can provide ongoing care for these children even if their hyperinsulinism is not cured after surgery.

Andrew Palladino, MD: Follow-up is really going to be determined by what their continuing needs are. As these babies gain weight, their support needs to increase with that weight gain. So it's not like we put them on a regimen and send them home, then it's never going to have to change. HI is a dynamic disease. So you need to adjust with the child's growth.

Enyo Dzata, MSN: People around the world know our center and they want to refer to us and oftentimes they'll go through our International Medicine Program.

Diva D. De León-Crutchlow, MD: Because our patients come from overseas and from all over the United States, we work very hard at establishing collaboration with the local physicians that are going to be following these families long-term.

Enyo Dzata, MSN: It's really important for families to feel that they have a team that they know, a team that they've been able to build rapport with, a team that will listen to them. It really is a collaboration between the referring hospital, the family once they get to us, and then our team as a whole.

Why Choose CHOP for Hyperinsulinism Surgery?

Diva D. De León-Crutchlow, MD: We have seen cases in the past that have undergone multiple surgeries elsewhere without having the possibility of doing the imaging that would localize those lesions.

N. Scott Adzick, MD: The worst case scenario is to do a near total pancreatectomy on a child, leave a portion of the head of the pancreas and have focal lesion prove to be within that residual pancreas. 

Amy Tran, Mother: The doctor told us that she would get better in three or five days. After two weeks, the first surgery was scheduled so then I started to look all over the Internet to see if there's another place that could help her. And I found CHOP the day of the surgery. I told her the situation that my daughter is going into the OR in about half an hour and she's like, no, don't let that happen. We can help you over here and there's different tests that we can do that can help your daughter. So we canceled the operation. The PET scan was considered experimental so the State denied us to come. We went with the first surgery, it didn't go well. A week later we went with a second surgery, and that didn't go well either.

Diva D. De León-Crutchlow, MD: If the lesions are in the head of the pancreas doing a 98 percent pancreatectomy would not achieve any good results because those children will continue to have severe hypoglycemia and now you have removed pancreas that was normal.

Amy Tran, Mother: She had these seizures, and she will have disabilities. We don't know what level of disabilities she'll fall in. But, for our case if we were here earlier, I think my daughter would have had a much, much better life.

Diva D. De León-Crutchlow, MD: The best case scenario for a baby that is born with hyperinsulinism is that the diagnosis is made as early as possible.

Andrew Palladino, MD: We've had the experience of having a family deliver here at our Special Delivery Unit, and we knew ahead of time that the baby had hyperinsulinism.

Diva D. De León-Crutchlow, MD: In most circumstances that's not the case. In most cases the diagnosis is made after birth. Because sometimes in populations such as the Ashkenazic Jews, we know exactly what mutations are more common in that population so prenatal testing is something that could be done.

Rebecca Abramson, Parent: My husband and I both are of Eastern European Jewish heritage, and so my regular OB practice just offered us the standard genetic testing panel which we accepted. Really didn't think anything of it. And a couple of weeks later it came back that I was a carrier for this thing called congenital hyperinsulinism. We were referred immediately to CHOP. And pretty quickly we met with Dr. Stanley and Dr. Adzick and genetic counselors and maternal fetal medicine people and they sort of explained to us step-by-step exactly what we could expect to happen.

Andrew Palladino, MD: As soon as the baby was born we had an IV in the baby, we were giving the baby sugar through the IV. So that baby never experienced low blood sugar. And that's really, if you knew you were going to have a baby with HI, your goal is for them never to have experienced the low blood sugar. Whether they have focal disease or diffuse disease doesn't matter. The goal is the same.

Rebecca Abramson, Parent: Early treatment was key because she never had a seizure; because she never had brain damage as a result of the seizure. She has developed normally. Sheira is an amazingly fun and sweet and incredibly affectionate kid. She's really very, very special.

Hyperinsulinism Research at The Children's Hospital of Philadelphia

Diva D. De León-Crutchlow, MD: The outcomes of children affected by hyperinsulinism have really improved with the understanding of the different genetic causes of hyperinsulinism.

Enyo Dzata, MSN: With the research that's being done and the availability of the PET scan and the experience that we have with the number of patients that we've seen.

Andrew Palladino, MD: When you're dealing with an incredibly rare disease, there aren't many places that are doing research that involves that disease. And we are.

Enyo Dzata, MSN: I don't know of any other place in the country that's doing what we're doing with hyperinsulinism.

Diva D. De León-Crutchlow, MD: We have developed the technologies that allows to identify children with the focal form of hyperinsulinism that can be cured.

Andrew Palladino, MD: Just in the last, I'd say six years, four new genetic causes of hyperinsulinism have been identified. And I think that is going to grow exponentially.

Lisa J. States, MD: We have an investigational drug office in order to make the F-DOPA. And that is a huge sign of commitment to research here.

Charles A. Stanley, MD: We've opened up the possibility of being able to do laparoscopic surgery for focal disease.

N. Scott Adzick, MD: We can do that because we have the PET scan technology.

Enyo Dzata, MSN: That's what CHOP is about is– it's a Center of Excellence. It wants to make a difference in patient's lives. And research is definitely a part of that.

N. Scott Adzick, MD: If you can definitively cure a child with hyperinsulinism by what your team can do, I mean, that's incredibly gratifying.

Diva D. De León-Crutchlow, MD: Most of the time these are families that are very excited to be part of new research to take an active role in moving the field forward.

Rebecca Abramson, Parent: If there is anything that we can do to help further the treatment and therapies for this, it's unbelievably important.

Diva D. De León-Crutchlow, MD: I find that very inspiring. It makes me want to improve our understanding to develop new therapies to really make that possible.