Tanaz Danialifar, MD Presents the Changing Face of CSID

Tanaz Danialifar, MD discusses the clinical presentation and prevalence of Congenital Sucrase-Isomaltase Deficiency (CSID). She explains the available testing options that aid in the diagnosis of CSID and reviews the relationship between CSID and patients previously diagnosed with IBS.

Video Transcript

Dr. Danialifar:
Good evening. So, I just wanna’ share with you guys, um, a little bit of my experience with what I think is the changing face of Congenital Sucrase-Isomaltase Deficiency or CSID. These are my disclosures, a little bit of the overview for tonight. We’ll talk about the clinical presentation and the different phenotypes of sucrase deficiency. We’ll review a little bit about the enzyme, available diagnostic testing methods, and touch on the relationship between CSID and patients diagnosed with IBS, and then I’ll share with you a couple of case presentations from patients in my clinic.

Just to review, sucrase-isomaltase is an enzyme that digests dietary carbohydrates. It’s responsible for the digestion of sucrose into glucose and fructose. Those are then absorbed into the bloodstream, also responsible for the, uh, release of glucose from starch, which is important because of the role that starches play in symptoms for many of these patients as well. A schematic of the enzyme…you can bind the disaccharidase, you convert it into individual sugars, those are released and absorbed, then the enzyme is available to take up substrate again.

To review the altered gut physiology that we see in sucrose malabsorption, you have two distinct things that are happening. The first is the sugars that are staying within the intestinal lumen cause an increased osmotic load, a subsequent influx of fluids and electrolytes into the lumen, which results in increased intestinal transit time, and that gives you the symptom of diarrhea. Additionally, bacterial fermentation of the undigested sugars results in gas production and those common symptoms of bloating, cramping, abdominal, um, distension, and overall abdominal pain.

Going back to medical school, many of us learned the classic CSID patient. Upon introduction of solid foods to the diet, there was, um, there was diarrhea, irritability, vomiting, failure to thrive, often a very classic diaper rash which results from the, uh, undigested sugars and the high, the acidity of the stool. What we don’t often think about is this patient which we probably see multiple times every day: bloating, cramping, diarrhea, generalized abdominal pain, nausea or vomiting, dyspepsia, some of them failure to thrive, some of them just generalized irritability. And these could…these patients could have any one of a number of diagnoses, and many of them fall into a category that we often will then call functional. Are we missing something that could be going on?

Just to review, historically, the prevalence of CSID has been about 0.2 to 0.4% in the North American and European populations, much higher in some specific populations: Greenland Eskimos and Canadian natives. Looking at the prevalence in a more specific population. So, this is some work from Khalil El-Chammas; he looked at 203 patients with chronic abdominal pain and looked at disaccharidase done on endoscopy for those patients. 21% of those patients had sucrase deficiency, a large number of them also have lactase deficiency.

We just are closing out a study where we looked at patients referred for lactulose hydrogen breath testing, for small intestinal bacteria overgrowth, and they got a C13 sucrose breath test. 23% of those patients actually had abnormal sucrase activity on breath test. So if you look at a select population of abdominal pain or bloating, you may find a much higher prevalence.

To review the diagnostic tests that are available, um, disaccharidases are gonna’ be the gold standard, and we’ll talk through many of these. Um, we may also start to talk about, is there another more noninvasive way? Um, is a sugar load or a sugar challenge gonna’ be of value to us? Disaccharidase analysis, how many people are doing this at their institution? Okay. It’s good to see. Some places were limited by availability, um, by skills and handling the specimens, and some places by coverage as well.

So here, you’re taking duodenal tissue, it’s homogenized, incubated with disaccharide substrate, and we look for, um, glucose formation. It gives us a very nice quantitative measure of enzyme activity, and the reference ranges are up there. Limitations…invasive, poor handling of the specimen, and variability in terms of, um, how easy it is to access.

Hydrogen breath testing, I won’t spend a lot of time on, because I think it’s really gonna’ go out of favor for, um, sucrase malabsorption. The main limitations are that there’s so much confounding factor from what’s going on in terms of intestinal bacteria, in terms of gut transit as well. But really what you’re looking for is a rise in your breath hydrogen, which results from, uh, bacterial fermentation of undigested sugars.

C13 breath test…show of hands, who’s been using these in their clinical practice? So, I’m gonna’ go through a little bit of what’s behind the test, um, and then we can talk about actually how easy it is to get. Um, so you give them a sucrose load with a labeled carbon. If they have appropriate sucrase activity, they digest it, the individual sugars are absorbed, and then through the systemic circulation, you have carbon dioxide gas tagged with the 13 that’s then released, and you’re looking for normative values at 90 minutes. This test is easy to administer at home actually, um, and QOL will provide test kits that you can send your patients home with.

What’s nice is, as compared to the lact … the hydrogen methane breath test, you don’t need any dietary change the day before, you just need a fasting period. It’s a 90-minute study the parents and patients can collect at home, and then the samples are analyzed, they send them through the mail. Um, one of the downfalls is, because you’re giving a sucrose load, although not a very high sucrose load, patients who really do have CSID may become symptomatic during the study, and it’s always something I like to tell them before they leave. It’s not well validated to, to differentiate, um, Congenital Sucrase-Isomaltase Deficiency from a secondary sucrase deficiency.

The other thing is, a lot of these normative values are based on true, true CSID patients who have little to no enzyme activity. So, could we be missing a population of patients in there?

The sucrase-isomaltase gene is a heterodimer, you have sucrase and isomaltase, it’s on chromosome 3, and it’s a very large gene. And I stress that, just to show that there are a lot of opportunities for mutation. There are over 2000 rare variants, of those, um, over 800 of them can be pathogenic variants. We know that in, uh, patients already diagnosed on biopsy with Congenital Sucrase-Isomaltase Deficiency, we find at least one of the four most common variants in 60% of those patients. And we’re learning now that they can have all different genotypes, ranging from homozygous, compound, heterozygotes, and simple heterozygotes.

So the question is, is there a relationship between all those variants and unexplained abdominal symptoms? So, in this study, they found that hetero … heterozygous SI gene variants can be symptomatic, and those patients may have postprandial diarrhea, pain, and bloating. And they also may actually demonstrate reduced, but not entirely abnormal, sucrase activity. These were family members of known biopsy proven CSID patients that they did the studies on. They’ve also done in vitro models, where they characterized the polymorphisms, and they show 20% to 35% reduction in enzyme activity. So, the question is, is that reduction in enzyme activity clinically significant? And that goes back to what’s in the diet, how much are they eating, when are they eating?

In another study, they looked at the incidence of sucrase-isomaltase pathogenic variants in patients with two specific GI symptoms: chronic diarrhea, or those characterized as IBS with diarrhea, and they found an incidence of about 4% in that subset of patients. There’s more data that suggests maybe there’s a relationship between abnormal sucrose metabolism or digestion and patients with IBS. Um, for those who were at the post-graduate course, Dr. Schulman touched on the study as well. They randomized IBS patients to a low-starch and sucrose diet for two weeks of ordinary eating habits, and they saw a significant improvement in their IBS symptoms severity scores…about 66% of the patients. And that’s actually similar to what we see with the low-FODMAP diet, which is already very well accepted in the treatment of irritable bowel syndrome.

Just to touch on overlaps and the FODMAP foods and the sucrose foods, those circled are high-sucrose foods. So, there’s a pretty significant overlap, and it may be that some patients we’re diagnosing as IBS who may have some abnormal sucrose, uh, digestion, may also be improving because you’re removing a lot of the high-sucrose foods from their diet. This is looking at, um, FODMAP and CSID and those that are still left in the diet.

We ask the question, is there clinical significance to intermediate levels of sucrase activity? So, if you look at the reference ranges, the normal is about 50 plus or minus 25. And a specimen for abnormal sucrose won’t be labeled as abnormal unless it’s less than 25. And often we see them way, way lower in those patients with a very classical presentation.

So we looked at about 460 patients who had endoscopy and disaccharidases done at our institution, and we added this label of intermediate sucrase activity for those who were in the 25 to 54 range. Just taking a look at the prevalence of overall disaccharidase abnormalities, um, a lot of this is similar to other studies or our prevalence of sucrase, um, deficiency was a little bit lower than what’s been found in other studies, but intermediate sucrase patients were 41% of the patients. Of those patients who had intermediate sucrase activity, more than half of them, about 75% of them had normal duodenal histology, which tells us this is unlikely to be a secondary issue.

Just to take a look at the distribution of sucrase activity, many of them are in that third quartile, between the zero to 50 range. Most common symptoms, abdominal pain, diarrhea are gonna’ be the most common on there, but it was also the most common symptoms for patients coming in, uh, getting endoscopies for a variety of reasons. It also shows that you can have intermediate sucrase activity along with another deficiency. And I bring this up because a lot of times when people get pan-disaccharidase deficiencies, and they throw those away, we don’t know what to make of them. So, you can have, in and of itself, a high prevalence of lactase deficiency. And so, we end up seeing a lot of overlap between those two things.

I’m gonna’ transition and share with you two cases in which this diagnosis, I think, was helpful for my patients. So, the first is an 11-year-old boy; he came in with, um, a history of borderline autism spectrum disorder and significant anxiety. His GI symptoms were alternating diarrhea constipation, stooling urgency resulting in fecal incontinence, uh, prolonged stooling despite no straining, symptoms of bloating, abdominal pain, and nocturnal stooling. And his symptoms were becoming progressive to the fact that it was affecting school attendance and all of those things. He was already getting psychology support services. He had minimal improvement on a strict, lactose-free diet, unremarkable laboratory testing, he had an EGD and colonoscopy because of the nocturnal stooling, and some weight loss he had along with this.

So the histology on all his tissue was normal, he does have a lactase deficiency, he also ended up in this very borderline sucrase. And I saw this patient around when I first really started learning more about Congenital Sucrase-Isomaltase Deficiency, and this mother was desperate for something to help her son. And so, I said, “You know, I don’t know, maybe 35 is not enough for his diet.” So we put him on enzyme replacement and we got him approved for a two-week trial enzyme replacement.

He had immediate resolution of his symptoms, significant improvement across the board, and I just saw him for, I think, 18-month follow-up from when we originally started therapy. He continues on therapy, he adjusts his diet somewhat, and he knows when he’s eaten a meal and forgotten to take his Sucraid®, because those days he becomes very, very symptomatic.

Second patient is one we all see commonly. 13-year-old female, no real family…no real history, having abdominal pain exacerbated by meals, and bloating, stooling is okay, she’s done a lactose-free diet; she thinks refined sugars and in her mind, sweets or candy make symptoms worse, but hasn’t really made other significant dietary modifications. Unremarkable laboratory testing, she had a lactulose breath test that was positive, got a course of antibiotics, and had minimal response to that. And on her C13 sucrose breath test, which I gave her because it’s so easy and so accessible, and she had these sugar-related symptoms, she had abnormal sucrose digestion.

She ended up going on a low-sucrose diet, um, and she had a lot of improvement in her symptoms. Um, I just wanna’ highlight that QOL makes their dietitian available to your patients if they need dietary counseling, which has been really helpful. And it’s … the handout is a lot of foods, and so learning how to implement that can be really helpful for them as well.

Okay, well thank you so much for your time, everyone. Enjoy the rest of your evening.