What is Glycogen Storage Disease (GSD)?

Podcast Transcript

Dr. Scott Steele: Butts & Guts, a Cleveland Clinic podcast exploring your digestive and surgical health from end to end.

Hi everybody. And welcome to another episode of Butts & Guts. I'm your host, Scott Steele, the Chair of Colorectal Surgery here at the Cleveland Clinic in beautiful Cleveland, Ohio. And today we're going to talk about something that we have not discussed on this podcast before, and that is, what is glycogen storage disease. I am absolutely pleased to have Dr. Kadakkal Radhakrishnan, who's our Director of Nutrition and Intestinal Rehabilitation here at Cleveland Clinic Children's, and super excited to have you here. Dr. Radhakrishnan, welcome to Butts & Guts.

Dr. Kadakkal Radhakrishnan: Thank you, Dr. Scott Steele. And I'm equally happy to be here with you guys.

Dr. Scott Steele: So we always like to start out here on Butts & Guts with just getting to know you a little bit better. So tell us where you're from, where'd you train, and how did it come to the point that you're here at the Cleveland Clinic?

Dr. Kadakkal Radhakrishnan: So I am originally from south of India, in a small state called Kerala. It's a kind of very tropical place. And when you look outside today, you wonder why I'm here. It's all snowy. But either ways, I had trained in England in between in pediatrics and a little bit of training prior to that in pediatrics in India. And then I came here and I've loved the Cleveland Clinic since 2000. So I trained in pediatric gastroenterology here, but I'm also a pediatric hepatologist and I have boards in pediatric transplant hepatology and my one big interest, other than nutrition, is metabolism and disorders of metabolism related to the gastrointestinal system, particularly the liver. I also had the medical side of the bowel transplant program at the Cleveland Clinic for pediatrics as well.

Dr. Scott Steele: So let's start here. So we talked about today, our topic, what is glycogen storage disease? But really, give me a bigger, broader view. What's glycogen and what is glycogen storage disease? And why are we talking about it?

Dr. Kadakkal Radhakrishnan: So glycogen basically is starch in your body. So when it's outside your body, it's starch. When it's inside your body, it's glycogen. Glycogen are chains of glucose connected by bonds with branch points. So it's a long chain of glucose if you think about it. And then it branches at sites, which again, bonds of glucose. It's kind of a, think of it like a big mesh, basically, of glucose.

Glycogen acts like a storage of energy when you're fasting or in between meals. When you eat, we need glucose for your day-to-day needs, what's happening in your body as we are going. And then whatever we don't need, we store it as a glycogen or as fat. Glycogen in your body lasts about eight to 12 hours in general. So when you have glycogen storage disease, you have problems most of the time with breaking down glycogen for your body's needs.

When I started training in medical school in 1985, there were eight different types of glycogen storage disease. Now there are 15. That is due to the advancements in testing and science, basically. Now we are going focus more on liver-related glycogen storage disease. So that'll be type I, type III, type VI, type IX, and type 0.

Dr. Scott Steele: So you mentioned these different ones. And so give us a little bit more about each of these types. And why are there different types?

Dr. Kadakkal Radhakrishnan: So the whole process of breaking down glycogen is called glycogenolysis, or breaking down glycogen. And now there is also another aspect to it, which is making glycogen, or glycogen synthesis. Due to different enzymes being involved in glycogen breakdown or glycogenolysis there are different types of disorders because of that. The most common type of glycogen storage disease of the liver is glycogen storage disease type I. There are two types: 1A and 1B. 1A is due to a mutation in an enzyme called glucose 6-phosphatase. So glycogen is broken down from glucose 6-phosphate, you got to break the phosphate from the glucose molecule to release glucose into the bloodstream. So any defect in this will cause glycogen to accumulate in the liver. And so babies come with a big liver or children come with big liver and low glucose when they fast.

Now type III glycogen storage disease, which is the other one, the severity, which is a little less than type 1A, is due to a defect enzyme called debranching enzyme. As the glycogen is broken down, the branches cannot be broken off. And they can manifest again with low glucose, large liver, and occasionally some of them may have a muscle disease as well, coexisting. And rarely, occasionally cardiomyopathy as well.

Now type VI and type IX. Now those are enzymes that [inaudible 00:04:44] in glycogenolysis. The enzyme is called hepatic phosphorylase for type VI. And that again, patients come with large liver and maybe only hypoglycemia when they fast for long hours, maybe 24 hours, or when they're sick, like for example, you have gastroenteritis. And type IX, which is an enzyme that activates the hepatic phosphorylase, which is called phosphorylase kinase. And that, again, the patients incidentally are picked up with large livers or they have hypoglycemia when they fast for long periods of time. And again, type VI in type IX are relatively milder.

Now in the past, we used to say, ignore these patients. Just don't follow them up too aggressively, but there is growing evidence that these patients can develop scarring or liver and fibrosis. So we are of the school that these patients also need close follow-up and good treatment.

Now type 0 is a disorder where patients come with no glycogen because the enzyme is glycogen synthase that is lacking. These patients come with either high sugars when they eat. And then as they fast, the sugars crash down and they have increased level levels of ketone body. So they have ketosis. Now coming back to ketosis, type III, type VI type IX also elevated ketones. In type I, you don't have any ketone elevation, which is kind of very interesting.

Now I mentioned type I, but type I has two types: type 1A and then type 1B. And type 1B is due to a mutation in a transport protein for a glucose 6-phosphate transporter defect. And these patients are interesting in the sense that they also get neutropenia and a tendency for gastrointestinal inflammation or IBD-like manifestations. And they're a very rare subtype of a type I.

Dr. Scott Steele: So you mentioned ketosis, and obviously some muscle cardiomyopathy, but on a very basic level for our patients and our patient families out there, what type of symptoms may occur with somebody with glycogen storage disease? What do they present with and what would be a red flag there?

Dr. Kadakkal Radhakrishnan: Being a pediatric doctor, most of these patients are picked up when they're young. So for example, a child would come, let's say at six months, when a parent starts to wean them off breast milk or start introducing solids and the child starts to space out their diet. So that's when they have symptoms. So when they fast, their glucose will crash down.

Now I just want to add that whenever we fast, we have a couple of defenses. One is we eat, so where glucoses go up. The second thing obviously is that you kind of break down glycogen and you increase your glucose level. The third step is gluconeogenesis. You try to make new glucose from other sources in your body, particularly proteins. And the last step is ketones or breaking down fat, and ketones are a big source of energy for your brain and for your heart, particularly when you fast.

So in glycogen storage disease type I, all these checkpoints, glycogenolysis, breaking down glycogen, glucogenesis, or forming new glucose, and ketosis, or making more ketones bodies, are all affected. So therefore they get sick very quickly when they fast. So these children, when they fast three to four hours, their glucose crashes down very quickly and they become very symptomatic. And when you examine them, they tend to have very huge liver. So for these children, their liver is below the umbilicus, almost in their right lower quadrant. And obviously because these children, for many reasons, they also deposit more fat. So they look very cute and cherubic, angelic looking children, and have big prominent bellies because of their large liver.

Now that is type I. Now type II patients, they tend to have low glucose when they fast, and a clinician feels their liver, their liver is enlarged. These children do not typically have a large spleen. So they have a pretty large liver and some elevation liver enzymes. In type VI and type IX, they come with, as I said, when they fast for long hours their glucoses drop, and they have a large liver and have elevated liver enzymes. And when the clinician thinks, why is the liver large? They could do a liver biopsy and find more glycogen in the liver. And they get picked up.

Type 0 is an interesting story. So a lot of times because the glucose go very high, to 300s when they are eating, and then the glucose crashed down. A lot of times they get misdiagnosed with diabetes because they have elevated glucose and they have ketosis as well. And then only when they're admitted and they fast, they realize glucose crashed down. And then the whole thing doesn't make sense. It doesn't fit the type I diabetes picture with ketosis. Then they get diagnosed by an astute clinician with type 0 GST.

Dr. Scott Steele: So Truth or Myth: glycogen storage diseases are only diagnosed in babies and in children.

Dr. Kadakkal Radhakrishnan: So, as I said, the types, especially type VI and type IX can be missed for years and can get picked up in older children, adolescents, and adults. Most of the type Is and type IIIs get picked when they're young kids. Now, the type 0 glycogen storage disorders could be picked up later on in childhood because children could go being missed with a diagnosis for years, and then get picked up. Now with the GST I, there is a variant we cal the Amish variant and the Hispanic variant. Those patients may get picked up by ages two, three, four, because there have some degree of enzyme activity that keeps them going.

Dr. Scott Steele: Truth or Myth: if a parent has glycogen storage diseases, their child will definitely have them.

Dr. Kadakkal Radhakrishnan: So almost all of them are autosomal recessive disorders. So you need both abnormal genes, except the GST type IX. We call it type IX A type A. So a variant of type IX, which is more common. And that is X linked. But still, it is very unlikely that if the parent has glycogen storage disease the child would develop glycogen storage disease. Unless the father or the mother is a carrier, or the father or the mother have the disease, and then the other partner is a carrier. Then you may have 50% chance of developing. That is so, so unusual. But we do see in clinical practice that some of these children may have a tendency to develop lower sugars compared to the average child in the population, tentatively called, what we call as ketotic hypoglycemia. So the answer to your question is typically not.

Dr. Scott Steele: So how is this diagnosed? Is it a blood test, a clinical diagnosis, a muscle biopsy? How do you diagnose these?

Dr. Kadakkal Radhakrishnan: That's a good question. So I think, so most of the times we make a clinical diagnosis. For example, if you see a six-month-old baby or a one-year-old child with low sugars, crashing sugars, needing sugar supplements, seizures because of low sugars. And then you examine them and find a of big liver. That is one of our big differential diagnosis for glycogen storage disease.

Now, as I said, for the type VI or type IX in a 15-year-old that is missed for years, someone does a biopsy and then you find excess glycogen in the liver. And then the pathologist will call the clinician and say, there is suspicion of glycogen storage disease. From that point, we can reach out and do genetic testing that is specific to make these diagnoses. And that can be done from blood tests or from buccal swabs. We reach out for the help from a geneticist to make the diagnosis.

Dr. Scott Steele: So I know there's different types of it. So can you walk us through just some of the overview of treatment for this disease?

Dr. Kadakkal Radhakrishnan: So basically, the toughest one to manage is type I. Now these patients need to be on a regular supplement of a low glycemic source of energy or glucose. So we resort to uncooked or raw corn starch. Why raw corn starch? Because raw corn starch, each molecule of glucose has to be broken off from the molecule and you're going to be absorbed into the blood and you don't get a big spike in glucose. And because you don't get a big spike in glucose, you are not driving more glycogen into the liver to deposit more glycogen. And you just supply enough corn starch to meet the day-to-day needs of the child or the young adult or an older patient. So we use raw corn starch on a regular dosing basis. In the beginning, it's every three hours. And as they get older, we go every three to four hours.

Now, recently in the last couple of years, there is a much more longer acting version of corn starch we call glycolate. And the effect of that could last, once you take it, for about six to eight to 10 hours sometimes, based on the patient's needs. Now we also ensure that we don't give them simple sugars. So anytime you give them simple sugars, it's going to build up in the system. And when you give excess of simple sugars, that is going be driven back into the hepatocytes form of glycogen. So we try to put them on a regular dose of corn starch to ensure that they just get their needs met. But at the same time, we try not to drive more glycogen into the hepatocytes.

And what we see over time with treatment option is that the liver shrinks down. Remember I mentioned earlier that the liver will be in the right lower quadrant, but as time goes by, with good treatment and good follow-up, we see that the liver will shrink down to a more realistic size. Maybe instead of one or two fingers below the ribcage, could be like three or four. And we also see an improvement in the metabolic profile. A lot of these patients, when they fast, we see their glucose go crash down and we see the lactates go up. That is the short term. On the long term, these patients, due to multitude of reasons, their triglycerides go very high. Their uric acid goes high and their phosphates go high. So basically we see all these long-term changes and we see improvement in all of those. The triglycerides come down with good long-term metabolic control. Uric acid comes down with good metabolic control.

Dr. Scott Steele: So I'm a family member or patient, what can I expect when I come in and see either you or one of your colleagues at Cleveland Clinic Children's department of gastrology hepatology nutrition? Walk us through that visit.

Dr. Kadakkal Radhakrishnan: We run one of the largest glycogen storage disease practices in the nation. We get patients from all over the country for that. And we are not restricted to seeing pediatric patients, we see adults too. So what happens is we have an intake process. One of our admin assistants is the coordinator for the program. And when parents call, the call gets triaged. And we look at what type of GSD it is, and they bring them in for outpatient visit in the beginning where we assess their laboratory profile. We check ultrasounds.

We have two clinics a month, usually it's the first Monday of the month and then the last Monday of the month. It's a multidisciplinary clinic. So it includes myself, a nurse practitioner, Elizabeth Robinson, and a dietitian, Christina [inaudible 00:16:08]. And we jointly manage the patients and give dietetic advices in the end.

Now to titrate the metabolic profile, we bring these patients in for a 24 hour inpatient admission. So they come in, they get IV placed and we monitor their glucose hourly. And for the ketotic type, we measure the ketotic ketone bodies every two hours. We also do a large profile of metabolic testing, including their ion levels, because a lot of these patients because of the restricted diet have a high propensity for iron deficiency anemia. And because of the restricted diet, they also have lower levels of vitamin D as well. So we also monitor their triglyceride level, their uric acid level.

I also measure alpha-fetoprotein, and why alpha-fetoprotein? Because a lot of the GSD type 1A, if the metabolic control is not good, they can develop adenomas in the liver. And over time, some of these adenomas can turn into hepatic cell carcinoma, but there is good evidence with good metabolic control that incidence can be way reduced.

Dr. Scott Steele: These kids grow up, and can they live a normal life? Can they play sports? Is it normal growth? Walk me through that a little bit.

Dr. Kadakkal Radhakrishnan: So with good metabolic control, Dr. Steele, they tend to do well. So I have patients who run three, four miles with GSD 1A. They take some extra corn starch before their physical activity. Sometimes they use an extra source of glucose while they feel their glucose is going down. And now in this age of glucose monitoring, patients have put on Dexcom or continuous glucose monitors, other forms of continuous glucose monitors, and they're trying to follow their trend.

Now there are caveats to this in the sense that when the glucose goes down, we always ask our patient to do a finger stick and measure the glucose because we really want to make sure the glucose correlates with the continuous monitor. So patients go to college, and we see that these children over time, they tend to grow much better when the metabolic control is good. And as I said, if they have adenomas in the liver, for the most part, as the metabolic control gets better, that also gets better.

Dr. Scott Steele: So what's on the horizon as far as additional research into GSD to improve treatments and quality of life?

Dr. Kadakkal Radhakrishnan: So a couple of things. Now there are gene therapies on the horizon. So there is gene therapy using adeno-associated vectors. The gene is incorporated into the vectors and then injected in, and the trials are just about to start. And we may be one of the centers for that, for gene therapy for GSD type 1A.

Now patients who have bad liver adenomas or dysplasia of the liver, we recommend that they get a liver transplant. Now, one more thing I wanted to add. Now, GSD I, particularly I in patients, other than elevated triglycerides I mentioned, and [inaudible 00:19:02] due to elevated uric acid. They can also develop kidney disease. And the kidney disease in the beginning is almost the same as type II diabetes with renal disease. So they tend to have what we call as hyperfiltration injury, then subsequently proteinuria and eventually progressive renal failure. They also have what we call is a proximal renal tubular acidosis presentation and a high propensity for renal stones, particularly if the metabolic control is bad.

Now there is good evidence that poor metabolic control has a high correlate with poor kidney function as well. So some of these patients can a kidney failure over time. So we recently had a 50-year-old man who has had GSD 1A for a long, long time and his kidney function started to worsen. So we referred him to our adult gastroenterology colleagues for a transplant evaluation as well as for renal evaluation. Why the liver transplant? Because once you do a renal transplant, it'll be very hard to manage the diet with the liver transplant and also with the poor quality of life. Managing a kidney transplant with tacrolimus and with all the secondary effects of tacrolimus, like elevated triglycerides and all that, would be a difficult thing. So there's growing evidence and growing support for this concept of doing a liver transplant first and doing a kidney transplant after.

Dr. Scott Steele: I should have asked you this at the beginning, but give me some sense for how common is this?

Dr. Kadakkal Radhakrishnan: Very good question. So the incidence of type 1a is about one in 100,000. So it's kind of a rare disorder in general. Type 0, or GSD synthase deficiency, where you don't make any glycogen is way, way rare. Like maybe about 50, 60 patients that are described in literature. Type IX and type VI are also very rare. So it's not like you walk into a clinic and you see a ton of these patients. Now in the Cleveland Clinic, we see quite a few of these kids and adult patients with this disorder. But in general, they're extremely, extremely rare. You need a high index [inaudible 00:21:06] patient to diagnose them putting the clinical picture and the laboratory profile.

Dr. Scott Steele: I want to take this moment to get to know you a little bit better. So first of all, what's your favorite sport?

Dr. Kadakkal Radhakrishnan: I'm a runner. So I just get up and run. I used to run very, very consistently for years until I avulsed my achilles and fell down. But I have done about 25 half marathons, but I used to run almost a half marathon distance every weekend for like 12 to 13 years.

Dr. Scott Steele: What's your favorite food?

Dr. Kadakkal Radhakrishnan: Sushi.

Dr. Scott Steele: You get one trip. You're going anywhere, where are you going to go?

Dr. Kadakkal Radhakrishnan: I want to see the pyramids.

Dr. Scott Steele: Been there, they're very, very impressive. And so give us a final take-home message for our listeners about GSDs.

Dr. Kadakkal Radhakrishnan: So GSD is a metabolic liver disorder and needs expertise and a team to manage. So at the Cleveland Clinic, that's what we do. We put teams together and we manage them. And we need consistency of management, good education of the parents. Now, these disorders are very rare as you asked me earlier, and there are new treatments on the horizon. So the life of these patients are going to change with the newer gene therapies. And we are very excited about the opportunity.

Dr. Scott Steele: That's fantastic. And so to learn more about treatments offered in Cleveland Clinic Children's Department of Gastroenterology, Hepatology and Nutrition please visit ClevelandClinicChildren's.org/GI. That's ClevelandClinicChildren's.org/GI. And to speak with a specialist in the department, please call 216.444.5437. That's 216.444.5437. And you hear me say it all the time. Remember, it's important for you and your family to continue to receive medical care, regular checkups and screenings. And rest assured here at the Cleveland Clinic, we're taking all the necessary precautions to sterilize our facilities and protect our patients and caregivers. Thank you so much for joining us on Butts & Guts.

Dr. Kadakkal Radhakrishnan: Thank you, Dr. Steele. It was a pleasure. Thank you for having me.

Dr. Scott Steele: That wraps things up here at Cleveland Clinic. Until next time, thanks for listening to Butts & Guts.