Speak 1:
Please welcome Dr. William Chey.

Dr. Chey:
Hi, everybody. Thanks. Thanks for coming. This is quite a venue, huh? Beats the lecture hall back at the convention center.

So, you might wonder, how is it that I’m standing here tonight talking about CSID, and I was actually thinking about that as we were getting ready to put this whole thing together tonight. And you know, realize that what Derick said is true, which is that I’ve been working in irritable bowel syndrome now for a long, long time. And I must say that it was with a lot of hesitation that I responded to an inquiry from somebody that used to work for Derick. And she contacted me and said, “You know, I’d really like to talk to you about sucrase-isomaltase deficiency.” And you know, I had been taught that sucrase-isomaltase deficiency was so rare that it was unimportant. You know? So, it was with a lot of trepidation that I finally decided to go talk to Derick, actually. And Derick talked to me with the same level of enthusiasm as he just did with you tonight. And he kind of convinced me to at least start to read about this problem and also start to do some studies in this area to better understand whether this is a real issue or not. And I must say that we were surprised by the results of a preliminary study that I’ll show you as we get into the talk. In fact, so surprised and so intrigued that it’s really led to us developing a number of studies around this particular topic, which I think you’ll find interesting. The story is really evolving. I’m really thrilled that I’m part of driving this evolution, and I’m not sure exactly where it’s going to end, but I do think that at the end of the journey, we will be talking about this issue.

I don’t know, are there any pediatric gastroenterologists in the audience? Yeah. So you guys already know this, right? It’s preaching to the choir. One of the things that I found most fascinating when I started this whole journey was the fact that you guys had already been testing for this, and thinking about this, and treating this for years. You realize, in an adult gastroenterology, we literally, this is not even on our radar screens, not even part of our GI training. So you’re way ahead of us.

All right, so let’s start with some basics.

So obviously, carbohydrates constitute a very large proportion of the Western diet. Clearly there are other components, as you can see on this slide. But what you can also appreciate on the bottom of this slide is that the majority, well actually not the majority, but almost half of our diet is really carbohydrates.

So almost all dietary carbs become FODMAPs. We’re all very familiar with that term now, right? Fermentable oligo, di-, mono-saccharides, and polyols. And of course, we have a lot of dietitians here, so they know more about this than I do. But we think about those five traditional groups of FODMAPs as being the collective wisdom in terms of all the FODMAPs. But what’s interesting to consider is there may be… individual patients may have other FODMAPs based upon the integrity of their brush border enzymes, for example. And I’ll actually show you an example of what I’m talking about in that regard in just a moment.

So you’re very familiar with this term, I don’t think we need to spend a lot of time on this, but there are short chain carbohydrates that your small intestine either has difficulty digesting, absorbing, or just simply can’t digest and absorb. And collectively, we refer to this group of carbohydrates or sugars as FODMAPs.

Normal carbohydrate absorption, digestion and absorption requires that disaccharides, or long chain sugars, be broken down to monosaccharides before they can be absorbed by the small bowel epithelium. And if you go back to your physiology and recall, we’re all very familiar with lactase, right? And the absence of lactase leads to lactose maldigestion; the lactose maldigestion with symptoms leads to lactose intolerance.

Well, it turns out the same can be true for the other disaccharides. So, for example, sucrose, remember, which is composed of a glucose and fructose molecule, needs to be broken down by sucrase to be able… so that those monomers can be absorbed. Similarly, maltose, a disaccharide composed of glucose, needs to be broken down by maltase to be able to be absorbed. Now these other enzyme deficiencies, outside of lactase, are clearly not as common as lactase deficiency, but I think we’re starting to learn that they’re underappreciated as a potential cause of unexplained GI symptoms, particularly in patients with diarrhea.

So just thinking about the physiology here, this should be intuitively obvious based on the comments that I said. If you are missing lactase, sucrase, maltase, and you can’t absorb, you can’t break down those disaccharides, and you can’t absorb the monosaccharides, all of them will reach the distal, small bowel, and colon, where they’re potentially fermentable by the constituent bacteria. Okay? So just like everybody knows about lactose intolerance, the exact same logic holds for these other disaccharides in the face of disaccharidase deficiency.

So what do we know about carbohydrates and IBS? Well, for years and years, we tried lactose reduction as a primary treatment for patients with IBS. And let me just say, that occasionally it works, right? There’s the occasional patient where reducing lactose consumption makes their symptoms better. But there are many circumstances in which simply reducing lactose is not enough to significantly improve a patient’s symptoms. And this really goes back to that concept of FODMAPs, which is it’s probably the cumulative effect of those short chain, poorly absorbed carbohydrates as a whole. But again, overlooked in this whole thing, may be some patients with other disaccharidase deficiencies. Remember that around 46% of carbohydrate, or of caloric consumption, in the United States is attributable to carbohydrates. So almost half of your diet is attributable to carbohydrates. And actually, in some parts of the country, it’s actually more than half, significantly more than half of your calories on a daily basis are composed of carbohydrates and sugars. And this issue about sucrase-isomaltase deficiency is really flown under the radar. You know, I don’t think, again, like for the pediatric gastroenterologists, I think you guys have been thinking about this for a long time. For adult gastroenterologists, I literally never even considered this until that conversation, those sets of conversations that I had four or five years ago. And by the way, think of it, raise your hand if you’ve gone to a lecture other than a lecture I’ve given, and anybody’s talked about sucrase-isomaltase deficiency at DDW. Good, that’s great, but hardly anybody, which tells you something, and that says, again, it really hasn’t penetrated into the consciousness of adult gastroenterologists at the current time.

All right, so when should we think about CSID? Well, patients with frequent multiple episodes of bowel movements, particularly diarrhea, but also bloating and abdominal pain or discomfort. Sounds really familiar, kind of like IBS, doesn’t it? And I think a couple things can clue you into thinking about this.

First thing is lifelong history of symptoms. If a patient described symptoms dating back to childhood, think about this as a possibility. Of course, it’s helpful if the patient describes postprandial symptoms. It makes sense that the symptoms would tend to occur after eating in the face of this particular problem. Also, don’t forget to ask about a family history. There is an occasional patient where maybe a sibling, for example, had problems as a child and was diagnosed with this problem. So asking about family history can be very helpful. Also, I think it’s even helpful if you ask about that and a person says, “Oh yeah, well everybody on my mother’s side of the family has problems with abdominal pain, bloating, and diarrhea.” You know, that should raise flags for a whole bunch of congenital abnormalities: celiac disease, lactose intolerance, sucrase-isomaltase deficiency.

So this is a study to give you some idea about how commonly this condition has been reported by a small number of studies. Realize we really don’t have much data on the background prevalence of sucrase-isomaltase deficiency in patients with GI symptoms. We have almost nothing in the general population. Almost all of the data that we have is from kids. And in fact, most of the samples from this particular study is from children. So based on disaccharidase assay, which you can see here, is that of children and adults that underwent upper endoscopy and small bowel biopsy for disaccharidase assay, 45% of the samples demonstrated at least one disaccharidase deficiency. I was really shocked about this when I saw it, and I’m still not sure I completely believe that, but this is what’s available at the current time. Now of those individuals that had evidence of a disaccharidase deficiency, you can see that the vast majority, more than three quarters, were actually lactase deficiency. But look down at the bottom, 21% of that 40%, or 9% of this cohort with GI symptoms had sucrase-isomaltase deficiency. That’s really interesting. Again, if you had asked me before you showed me these results what the prevalence would’ve been, I would’ve said like one or 2%. Now, this requires validation, particularly requires validation in a large adult cohort, but this is the data as it exists at the current time. This is data from another study which looked at genetic variance diagnostic of congenital sucrase-isomaltase deficiency. Look at the prevalence of congenital variance, which would be consistent with this deficiency. Around 4.5% in patients with chronic diarrhea, 4.2% in patients that fulfilled criteria or had been diagnosed with IBS-D.

Think about this. Raise your hand if you do celiac testing in every patient with diarrhea or IBS-D that you see. We all do. Every guideline tells us to do that. What’s the prevalence of celiac disease in IBS patients in the United States? So in other words, if you have a patient that fulfills the Rome III or Rome IV criteria, they have IBS-D, and you order celiac testing, what is the prevalence of finding celiac disease? Any idea? 0.7%. That’s what’s so interesting about this, is we test everybody for… and by the way, do I think it’s important to test for… yeah, I do, because celiac disease is a clearly definable genetic disorder with a very effective treatment that prevents downstream complications of the disease if left undiagnosed, so it’s very important to test for celiac disease. But we test everybody for a disease that has a prevalence of less than 1%.

This is the study that I alluded to that we conducted with the assistance of GI Health Foundation and QOL. We actually amalgamated several practices, some academic, some private practice, and we asked them to phenotype patients with either abdominal pain, bloating, or diarrhea, so we gave them standardized questionnaires collecting the frequency and severity of their symptoms.

Then we did a sucrose breath test on all of them, so a surrogate for a sucrase-isomaltase deficiency. If you look here, for individuals with bloating, abdominal pain, gas, and diarrhea, you’ll see, first of all, on the top, 22% had a positive breath test. Of those individuals with a positive breath test, you can see the prevalence of the symptoms they reported on the bottom. The point being, again, these patients really looked like IBS patients. Almost all of them had some combination of abdominal pain, bloating, and diarrhea.

Now, let me just take a step back and say I’m not saying that 20% of patients with these symptoms have sucrase-isomaltase deficiency. What I am saying is 20% had a positive sucrose breath test. Here’s the issue with the sucrose breath test to remember is that sucrase-isomaltase can lead to a positive sucrose breath test, but so can bacterial overgrowth. Bacterial overgrowth will cause a sucrose breath test to be positive.

We didn’t have any way to cull those patients out of this dataset, so some of these patients probably have SIBO, but it’s very interesting and provocative, isn’t it, that 22% of these patients ended up having a positive sucrose hydrogen breath test.

There’s this bit of data that we presented. Some of you came to the presentation today, but this is a bit of data that we presented at DDW yesterday. So as most of you know, our center did the only US randomized, controlled trial evaluating the low-FODMAP diet versus usual dietary recommendations in US adults. Our study found that around half of the patients got better, got adequate relief of their IBS symptoms with the low-FODMAP diet and that the diet was particularly effective for pain and bloating. Well, that’s great. Half of the patients got better with a low-FODMAP diet. If you told me that half the patients would get better with any diet 10 years ago, I would have been jumping up and down for joy and saying, “That’s absolutely fantastic.” But here’s the flip side of that. What that means is in our study, half of the patients did not get better.

So a fundamental and interesting question is why didn’t they get better? Our hypothesis was maybe one of the reasons why these patients didn’t get better is because they were more likely to have sucrase-isomaltase deficiency. Think about this for a minute. Low-FODMAP diet does not exclude sucrose or starch; therefore, if you’re sucrase-isomaltase deficient, you would not expect that you’d get better with a low-FODMAP diet.

What we did is we elicited the help of a colleague of ours, Mauro D’Amato at Karolinska Institute, who was kind enough to help to run all of the genetic snips that are commonly identified in patients with CSID, congenital sucrase-isomaltase deficiency. And guess what we found? What we found was that individuals with two mutated alleles of the sucrase-isomaltase gene were substantially less likely to get better with low-FODMAP than individuals with no-risk alleles. In fact, you can see that 61% of the patients that had no genetic evidence of CSID got better with the low-FODMAP diet, so a substantially higher proportion than we otherwise saw. So we proved our hypothesis, and also, this should be making us think about, again, is this something that we may be missing in a small but potentially substantial proportion of our patients?

By the way, this raises the question of a couple of things. One is, should we be doing genetic testing as we start diet therapies to decide whether we need to exclude sucrose in addition to the other FODMAPs? Should we wait and maybe think about doing testing for sucrase-isomaltase deficiency in patients who don’t respond to the low-FODMAP diet? I can tell you that in our practice, that’s what we’re starting to do. We’re starting to think about that. All right, so diagnosis. Well, there are tests that allow you to assess the actual enzyme activity, so disaccharidase assays, and we’ll talk about that in a moment. There are breath tests, and there are actually several different types of breath tests. We’ll touch on that. And then there’s just the old-fashioned sucrose challenge. You know, you’re suspicious. You give somebody a couple, four tablespoons of, or tablespoons of sugar, and you see if they develop problems. Signs and symptoms can be helpful as we already reviewed. I think there might be a slide or two on that as well. And then, of course, rule out other diseases, so other diseases that could mimic or actually lead to acquired sucrase-isomaltase deficiency.

So we talked about celiac disease. Well, celiac disease is commonly associated with SID. Crohn’s disease, commonly associated with SID. By the way, do you think about sucrase-isomaltase deficiency as a cause of persistent symptoms in patients who are on a gluten-free diet, celiacs who are on a gluten-free diet, patients with IBD who are on a biologic with no evidence of inflammation? Maybe we should be thinking about this. I mean, we clearly need more data, but it’s a tantalizing hypothesis. All right, so enzyme deficiency or disaccharidase assay. This slide gives you an idea of how to do it. Literally collect about two to three biopsy samples, and there are standardized assays that one can perform to quantitate the amount of the various disaccharides in the brush border epithelium. So you can look at lactase, you can look at sucrase, you can look at maltase and palatinase. Doing this actually gives you a comprehensive view of the disaccharidase concentrations in the brush border epithelium. There’s also the C-13 sucrose breath test. This is different than the standard sucrose breath test.

The standard sucrose breath test, let me see if I got a picture, remember, relies upon fermentation. This is the notion that in individuals with sucrase-isomaltase deficiency, the absence of the enzyme is associated with maldigestion, malabsorption of the sucrose, which then gets to the colon where it’s fermented, releasing hydrogen and methane, which you can measure in the breath. So it requires fermentation. There are also all sorts of issues in regards to being confounded by bacterial overgrowth like I told you about, and also the right timing for when the breath hydrogen or methane goes up. So there’s a lot of imprecision to the standard sucrose breath test that we did for the purpose of this study.

The C-13 sucrose breath test is a bit different. So this is a direct measure of proximal small bowel sucrase activity over 90 minutes. The reason for that is because sucrose contains naturally C-13, so the level of C-13 measured in the breath gives you an idea about whether the sucrose is absorbed in the small bowel, and then metabolized in the liver and the circulation leading to the increased excretion of the C-13 in the breath.

This is different than the standard sucrose breath test. It’s purported to potentially be more accurate, although we’ll see. We’re literally doing a study as we speak where we’re doing disaccharidase assay in adults that fulfill Rome criteria for IBS. We’ll be using that as a gold standard, and we’ll be doing C-13 sucrose breath testing as a comparator to that gold standard so that hopefully by next year, or soon thereafter, I’ll be able to tell you whether this test is really accurate and reliable or not, and I’ll be able to tell you what the background prevalence of sucrase-isomaltase deficiency is in adults with IBS-D symptoms. Another way to go is this simple 4-4-4 sucrose challenge. This is something that any of us can do. It requires absolutely no technology. Four tablespoons of table sugar and four ounces of water, and simply assessing symptoms after one consumes the water and table sugar solution.

Another thing just to think about is, again, I think thinking through this issue about whether this is congenital sucrase-isomaltase deficiency or acquired sucrase-isomaltase deficiency. In the setting of acquired sucrase-isomaltase deficiency, what’s the explanation for this SID? Like in other words, what has led to the acquired sucrase-isomaltase deficiency? Maybe as we see in some IBS patients, it’s post infection. Maybe it’s celiac disease, inflammatory bowel disease, bacterial overgrowth. The point is that there’s usually a reason for somebody to have acquired sucrase-isomaltase deficiency. If it’s lifelong and you have evidence of genetic mutations, that’s a different animal. That’s congenital sucrase-isomaltase deficiency.

So let’s finish up with a few slides on treatment.

So all CSID patients are sucrose intolerant. Some may be starch intolerant. Okay, so in other words, right now the dogma is that if you really are sucrase-isomaltase deficient, and particularly let’s say CSID homozygous, 100% of those patients are symptomatic to some degree. Treat sugar intolerance first. Okay, so the idea here is that you always start in the setting where you’re worried about SID, you always start by treating the sucrase deficiency first. Okay? So you can do that with diet. You can do that with sucrase supplement, or optimally both. Restricting dietary sucrose and also using the dietary supplement.

So start with sucrose. There are sucrose-reduced, even sucrose-free diets. They’re difficult; of course the low-FODMAP diet’s also difficult.

You can imagine adding this onto a low-FODMAP diet; that would be very challenging. Then reduce dietary starch, if the patient is starch intolerant. So in other words, if you do an adequate job of reducing sucrose intake, and/or use the dietary supplement, and the patient is still symptomatic, now you should start thinking about the possibility of starch intolerance.

This is when you’d restrict starch. I mean the obvious issue here is you don’t want to over restrict the patient, and you don’t want to doom the patient to not being adherent by putting them on a million different restrictions coming out of the shoot.

Limit or avoid high carbohydrate ingredients. So eliminate sugar first, and you can see a list of different food items here. If they’re still symptomatic, that’s when you try to eliminate starch. And you can see some different food items here.

Sacrosidase oral solution or sucrase replacement is very simple to use. Literally it’s putting a small volume in milk or water and taking that around meal time.

And the data that’s available suggests that this is very effective in patients with sucrase deficiency; 97% of patients surveyed in this open-label survey study reported significant symptom improvement with Sucraid^®, 81% over a more prolonged period of time. So pretty good results with this enzyme deficiency.

All right, so a case study, 21-year-old male is referred to address chronic diarrhea.

The patient reports loose stools three or four times per day forever, so lifelong. He also reports intermittent abdominal cramping and bloating. All of his symptoms are worse after eating. He was diagnosed with IBS in the past and treated with fiber and antidiarrheals, really with no success. He has also been treated with an antidepressant as well as a very expensive antibiotic.

I suspect you can guess which one that is. Which also didn’t help. He’s tried a gluten-free diet and a low-FODMAP diet without much benefit. Over the past two to three years, his problems have grown worse with more frequent, loose, watery stools; laboratory and stool studies have been normal. What would be your greatest concern in this patient, remembering why you’re all here tonight?

So choice A: sucrase-isomaltase deficiency. Raise your hand if you think of that. Okay. Choice B: celiac disease. Anybody? Okay. Very good. Microscopic colitis and bile acid diarrhea? You know, you’d think about all these things actually. You would definitely think about all these things. But the point is, maybe that first thing should be on our list. And part of the reason that we’re doing this program tonight is just to sort of inject this possibility into your thinking as you’re seeing patients, particularly the more difficult ones like this, where you’re really scratching your head and clawing for potential solutions to try to help this patient who’s clearly suffering. Maybe this should be on our radar screens.

So to conclude, why is this condition overlooked? Well, it’s really thought to be a pediatric problem. In fact, again, that’s what I thought. When they first approached me with this, I said “That’s a kid’s problem. That’s not something we ever see in adults.” What I came to realize is one of the reasons we never see it in adults is because we never look.

Thought to be rare, and it might still turn out that it is rare. We don’t know that yet, but boy, the data that we have suggested it’s not as rare as we thought. Probably somewhere in the neighborhood of around 4%, 5% at least.

No education regarding CSID for GI fellowship. I actually received no education about sucrase-isomaltase deficiency during my fellowship training. And I dare say, well actually I talk about it a fair amount now, but my suspicion is there’s very little formal education of any kind on this topic outside of lactase deficiency in most adult GI fellowship training programs. Poor awareness on the part of dietitians. I hope I’m not being offensive, but I think that my suspicion is that this is not widely disseminated amongst the dietitian community either. Poor awareness of the treatment options. Again, I think, since nobody gets any training, surprise, surprise, they don’t know how to treat it. And enzyme supplements. The enzyme supplement is expensive and can be difficult to get through insurance. So a really elegant, effective solution that’s really hard to get. So sucrase-isomaltase deficiency is an important and under-recognized cause of carbohydrate maldigestion malabsorption, inherited and acquired forms exist.

Genetic tests, disaccharidase assays, and breath tests can be used to establish a diagnosis. Treatment includes dietary modification and/or enzyme supplementation. CSID has been associated with IBS symptoms. I actually didn’t show you that, but there are two studies now, both from Karolinska, reporting an increased rate of CSID mutations in IBS patients in general. So, which again, I think is brand new information, literally published within the last two years. CSID has been associated maybe more likely in IBS patients who are low-FODMAP non-responders. Again, something else to think about. Another potential option to test for and to potentially offer therapy for in the patients that have clear postprandial symptoms but don’t get better with low-FODMAP.

So, thank you very much.