William D. Chey, MD Presents Could It Be CSID?

William D. Chey, MD reveals recent data that suggests how Congenital Sucrase-Isomaltase Deficiency (CSID) may be an overlooked cause of unresolved GI symptoms in adults previously diagnosed with and treated for IBS-D.

Video Transcript

Dr. Chey:
It’s a really cool story, the QOL story. You know it’s an interesting sort of reversal in that they have a really elegant solution. The issue is finding the patients. Finding the patients that they, they can really help. And I remember when they first came to me a number of years ago. I was incredibly skeptical, I must say, because there was no information about how commonly or uncommonly these problems occur. I’d never seen a patient with sucrase-isomaltase deficiency, of course, probably related to the fact that I’d never looked for it.

In fact, I really didn’t know very much about the enzyme or the physiology. But it’s a compelling story and you know, the good news about what this talk tonight, it’s gonna’ be really short. It’s a really short talk. So hopefully it won’t take up too much of your time this evening, but I’ll just lead you through a few facts that I think you’ll find interesting that leads you through to why sucrase-isomaltase deficiency is something that you should think about in the right patient.

So remember that, you know, that this concept of FODMAPs has obviously become all the rage. This idea that certain carbohydrates are poorly digested and absorbed by the human small intestine, and for that reason become accessible to the bacteria in the colon where fermentation produces carbon dioxide in short chain fatty acids. And in patients with IBS, for example, that have underlying abnormalities in visceral sensation and motility. You know, FODMAPs are a really important potential trigger for their symptoms.

But it’s important to recognize that beyond the carbohydrates and sugars that we think of as traditional FODMAPs, that other kinds of sugars and carbohydrates that are really common in our diet for some individuals are actually also FODMAPs. If you think about a variety of different carbohydrates, let’s just think about table sugar for example, sucrose. Now, in the absence of sucrase, sucrose can’t be digested to the monosaccharides, the constituent monosaccharides, glucose and fructose…and in that way, can’t be absorbed. And, in that circumstance, sucrose actually becomes a FODMAP.

Okay, and remember that sucrose and isomalt-, sucrase and isomaltase break down a range of different disaccharides as well as starches. And so, in the absence of that enzyme, a whole bunch of things that we would otherwise overlook and not consider as potentially problematic in terms of inducing or triggering symptoms, become FODMAPs, become a problem. So, remember that in the absence of sucrase-isomaltase, several different sugars, sucrose, maltose, and a number of simple starches, won’t be broken down normally and can’t be absorbed…and in that way, become available for fermentation in the colon like any other FODMAP.

It’s also important to remember that we oftentimes think about these disaccharides in the differential diagnosis of sugars that can induce symptoms in patients with IBS. And in particular, we almost always think about lactose. We’ve all been trained to think about lactose and that’s very appropriate because it’s an important factor for many individuals who are absent of the enzyme lactase. But really, I received no training and I think even, at this time, GI Fellows receive very little information about sucrase-isomaltase deficiency.

Now remember that the typical Western diet, almost half of what we consume, is carbohydrates. In fact, on a proportion basis, carbohydrates dominate either proteins or fats individually. But yet, we really don’t think about sucrose as a potential trigger for symptoms in patients with GI symptoms. And by the way, that’s probably appropriate because the proportion of individuals with sucrase-isomaltase deficiency, although not well-defined, is probably relatively low. I’ll show you some data on that in a second. However, I will say this, the data that exists and the data that’s emerging suggests that the prevalence of sucrase-isomaltase deficiency may be higher than we have suspected.

So thinking about CSID…there’s this acronym, FLP. So, frequent multiple events per day of symptoms, including gas, bloating, diarrhea, loose stools, and pain – symptoms very similar to IBS by the way. L, standing for lifelong. So, these patients oftentimes have a long history of, and then finally, postprandial, P, postprandial symptoms. So longstanding symptoms or postprandial symptoms, a symptom profile that for all the world sounds a lot like IBS. So how common is this problem? Well, let me just say that, as Derick alluded to, we’re really still in an exploration stage in terms of understanding the prevalence of sucrase-isomaltase deficiency. For example, in the United States, we really have very little data.

This is data from a large data set collected from upper endoscopy with small bowel biopsy for all comers. So, 27,000 biopsy samples for all different indications, leading to an upper endoscopy and small bowel biopsy. And somewhat surprisingly, 45% of these individuals and underwent endoscopy for a wide range of different indications.

By the way, the other thing to realize about this study, the vast majority of these were children, but there were about 2,000 adults in this sample as well. But 45% of individuals in this, in this cohort, actually had at least one disaccharidase deficiency. So, either lactase deficiency, sucrase deficiency, or something else, palatinase, maltase. And of those individuals that had evidence of an enzyme deficiency, not surprisingly, the largest proportion had evidence of lactase deficiency. But look at the red, the red pie chart; 21% had evidence of a quantifiable deficiency in sucrase activity, on disaccharidase assay of small bowel biopsies.

In addition, if you look at populations of individuals with diarrhea and check them for well-established genetic variance which are associated with sucrase-isomaltase deficiency, you can see that those with chronic diarrhea, 4.5%, had at least one mutation associated with CSID.

In addition, for patients with IBS-D, 4.2% had a genetic variant associated with CSID. So, in these two studies, still a relatively low prevalence, less than 10%, but I bet a much higher than you would have guessed going into this. By no means is this data definitive or perfect, but it is interesting from a hypothesis-generating standpoint and should make us think about whether or not this could be an explanation for symptoms in patients with persistent symptoms.

We completed a last, actually about a year and a half ago now, a study in 102 patients from several centers across the United States. Individuals that had specific symptoms of chronic diarrhea with or without bloating, nausea, early satiety, and abdominal pain…and we performed sucrose breath testing on all these individuals. By the way, all these individuals underwent a standard battery of tests to define their underlying condition.

And bottom line here is we were really surprised to find that 22% of these individuals, with diarrhea and no other definable cause, ended up having a positive sucrose hydrogen breath test. Now, it’s really important to point out that probably some of these patients had SIBO. There was no way for us to distinguish between whether they had a positive sucrose breath test because they have SIBO or related to sucrase-isomaltase deficiency. But nonetheless, going into this, we had no idea it was going to be this high of a proportion.

In addition, if you look at the symptoms, and I remember telling this to Derick, we actually had a long, robust discussion about this. Actually, before the study. I said to him, that the most common symptoms we’re gonna find that, in patients with a positive breath test, are going to be abdominal pain and bloating.

The traditional dogma was that it was gonna’ be diarrhea. Now, realize that, and if you look at the prevalence, particularly in the patients with medium to severe symptoms, abdominal pain and bloating were actually just as important or arguably more important than diarrhea. And the reason I harp on this is because this really brings IBS into play. Remember that, for IBS patients must have some level of abdominal pain. Almost all patients with IBS have some level of bloating.

And then we presented this data at DDW this past year and just recently published it. It’s available online early at Gut. Our post hoc analysis from our US randomized controlled trial evaluating the low-FODMAP diet versus traditional dietary recommendations in patients with Rome defined IBS-D. And what we found was that 52% of a cohort of around 90 patients with IBS-D responded to the low-FODMAP diet.

And in those individuals that were randomized to a low-FODMAP diet, the presence or absence of genetic variance associated with CSID was associated with a higher or lower likelihood of response to the low-FODMAP diet. Let me just make that a little bit simpler to understand. The presence of CSID genetic variance in individuals who received the low-FODMAP diet predicted a lower likelihood of response to the diet. Proving the hypothesis of what I said at the very beginning of this talk, which is that in individuals that don’t respond to the low-FODMAP diet, they’re likely to be enriched for a sucrase-isomaltase deficiency. Because remember that the low-FODMAP diet does not exclude sucrose or many of the starches that are digested by sucrase or isomaltase. And so in that circumstance, the low-FODMAP diet would not be expected to be fully effective.

And in fact, that’s exactly what we found. By the way, the opposite was also true. If you had no genetic variants associated with CSID, you were much more likely to respond to the low-FODMAP diet. So, we’re actually starting to think about the best way to study this idea of leveraging response as a way to identify patients that we should be testing for sucrase-isomaltase deficiency.

There are a number of ways to diagnose this condition, and again, I think we’re still in an exploration phase right now. We’re actually doing a very large study right now comparing a number of different diagnostic techniques to determine what the prevalence of sucrase-isomaltase is in the United States. We’ll be doing it at, we’re already doing it at our center, Brooks Cash at UT Houston will also be joining us and starting the study very shortly.

We’re also doing breath tests as well, and comparing that to a gold standard of disaccharidase assay performed with mucosal biopsies from the duodenum. So, the gold standard right now, as I just said, is mucosal biopsy from the duodenum for disaccharidase assay. There are surrogate tests, either a sucrose hydrogen breath test or a c13 sucrose hydrogen breath test, which remain unvalidated at the current time. I showed you a little data using the traditional sucrose breath test. And there’s also a sucrose challenge; you can simply give people sucrose and see whether they develop symptoms. That’s another surrogate test to look for CSID.

As far as treatment goes, there is a sucrose-free diet. So dietitians can talk to patients about a sucrose-free diet. There’s also an enzyme supplement that’s commercially available that has actually proven…this is the sacrosidase or Sucraid® is the oral enzyme supplement that can be utilized in patients with sucrase-isomaltase deficiency, easy to use. The big barrier here that can come up in clinical practice is insurance coverage. But in open-label clinical trial, 81% of patients with documented sucrase-isomaltase deficiency actually experienced a significant improvement in their GI symptoms with this enzyme supplement.

So, in conclusion, initially CSID for many years was thought to be only a pediatric problem. In fact, you know, it’s interesting when you talk to our pediatric GI colleagues. Do we have any pediatric GIs here in the audience? Just out of curiosity. Do you guys do disaccharidase assay? Yeah. And in fact, almost all the big pediatric GI groups already do mucosal biopsy for disaccharidase assay. But raise your hand if you’re an, if you’re an adult GI and you do mucosal biopsy for disaccharidase assay. So, a couple; that’s great. But you can see only a couple; it’s really not widely available in the adult GI community. It was also thought to be rare, but I’ve showed you data to suggest that while it’s uncommon, it may not be as rare as we once thought. Again, I think our study as well as other studies that are ongoing, will shed light on what the background prevalence is in the United States. Right now, it’s a little bit of a moving target, but the data that we have suggested it’s probably somewhere between 4% and 8% in the United States. No education regarding CSID in GI Fellowships…we’ve only just recently started talking about this at Michigan. There was no education on SID, really up until very recently. By the way, do we have any GI Fellows here? Just out of curiosity. Yeah, have you gotten any education about sucrase-isomaltase deficiency?

Speaker 2:
Yes. We are working with a [inaudible].

Dr. Chey:
That’s fantastic. Great. Disaccharidase assay, we talked about, is rarely available. Poor awareness on the part of dietitians – this is another issue. I think the dietitian community is just starting to get turned on to this possible diagnosis. Poor awareness of treatment options…I think that, again, just like most fellows and gastroenterologists aren’t really aware of the condition…obviously, they’re not going to be aware of the optimal treatment options. And the enzyme supplements…there are challenges in regards to the cost. This is a rare disease treatment and also insurance, insurance coverage.

So sucrase-isomaltase deficiency is an important and under-recognized cause of carbohydrate malabsorption and maldigestion. There are both acquired and inherited forms. So, you can do genetic testing to pick up CSID, Congenital Sucrase-Isomaltase Deficiency. But remember that anything that’s significantly damages to the brush border, just like it can lead to lactase deficiency can also theoretically lead to acquired sucrase deficiency.

So that’s an important thing to remember and particularly, in your patients that have sustained some type of small bowel injury that aren’t behaving like you would normally expect with your usual interventions. Think about this condition, acquired sucrase-isomaltase deficiency, should be on your differential. Genetic tests, disaccharidase assays, and breath tests can aid the diagnosis. But again, the gold standard right now, disaccharidase assay; I think the breath test we really need a little bit more work to validate. Treatment includes dietary modification and enzyme supplements.

CSID has been associated with IBS and may be an important thing to consider in individuals who don’t respond to the low-FODMAP diet. So, with that, I’ll stop. I’m happy to answer any questions. Thanks so much for coming tonight and for your attention during this talk. Thanks.