Disaccharidase Deficiency: An Overview for Gastroenterologists Focusing on CSID
Overview of Carbohydrate Metabolism
Nearly half of the average Western diet is composed of carbohydrates,1 which are made up of simple and complex sugars. Simple sugars are monosaccharides (eg, glucose, fructose) or disaccharides (eg, sucrose, maltose, lactose), whereas complex sugars include starches, glycogen, and fibers, which are composed of multiple glucose molecules with varying structures and bonds.2,3 Because relevant transporters in the small intestine can only transport monosaccharides, disaccharides and polysaccharides must be hydrolyzed to monosaccharides for absorption to occur (Figure 1).2 The digestion of starch is initiated by salivary and later pancreatic a-amylases that hydrolyze it into smaller sugar residues, maltose and sucrose.2 In the final step of starch digestion, enzymes in the brush border of the small intestine hydrolyze disaccharides into monosaccharides such as glucose and fructose, which are then transported across the epithelial brush border for absorption and metabolism.2,4 Isomaltase hydrolyzes branched a-linked dextrins into 2 glucose molecules, while sucrase hydrolyzes sucrose to fructose and glucose.4,5 Given its abundance and substrate specificity, the sucrase-isomaltase enzyme complex is responsible for nearly all sucrase activity and approximately 60% to 80% of maltase activity in the intestine.4,6 Disaccharidase activities vary throughout the small intestine, with lower values in the proximal duodenum, peak activities in the mid-
jejunum, and decreasing activities in the ileum.7
What Is CSID?
First described in 1960,9 congenital sucrase-isomaltase deficiency (CSID) is an inherited primary defect of sucrase-isomaltase caused by variants in the sucrase-isomaltase (SI) gene.6,10 Patients with CSID harbor 2 defective copies of the SI gene due to recessive homozygous or compound heterozygous mutations, leading to the absence or diminished activity of sucrase-isomaltase at the brush border and the clinical symptoms of carbohydrate maldigestion.10,11 At least 37 pathogenic mutations in the SI gene have been described that affect various aspects of gene function, resulting in multiple phenotypes with a broad range of enzymatic activity and clinical presentations (Table 1).5,12,13 Sucrase activity in patients with CSID can range from completely absent to low residual activity, while isomaltase activity can range from absent to normal.6 Maltase activity is also reduced significantly in most patients with CSID.6
When sucrase-isomaltase is absent or deficient, nonabsorbed carbohydrates enter the distal small intestine and colon where they are fermented, leading to the excessive production of short-chain fatty acids and gases such as hydrogen, methane, and hydrogen sulfide.6,10 This in turn can lead to abdominal distension, cramping, pain, excessive flatulence, and osmotic diarrhea (Figure 2).6,10 If left untreated, significant sucrase-
isomaltase deficiency (SID) can result in inadequate growth and failure to thrive in children as well as weight loss in adults.10,14-16
Other Causes of SID
In addition to the congenital forms of the disorder, acquired or secondary forms of SID have been observed in patients with chronic diarrhea.4 Decreased enzyme activity can result from generalized intestinal damage related to various etiologies involving villous atrophy, infection, and/or rapid transit (Table 2).4,17 The clinical impact of SID on these disorders may be transient, with enzymatic activity returning to normal as the underlying disorder resolves.4
Epidemiology and Clinical Presentation of CSID/SID
Reassessing the Prevalence of CSID
CSID has been historically considered a rare disease, with an estimated 0.2% prevalence in North American and European populations18 and an even lower prevalence in African Americans and whites of Hispanic descent.6,19 Higher estimates have been reported among certain populations,20,21 with one study reporting a 10% prevalence among Inuit communities in Greenland.21
In contrast to these earlier reports, more recent studies demonstrating that heterozygous carriers of SI variants also experience symptoms suggest that CSID may be more common than once believed.4-6,22,23 The true prevalence of CSID is likely underestimated due to a number of factors, including inconsistencies in nomenclature of the condition, diverse testing methodologies with unclear performance characteristics, the existence of multiple genomic abnormalities with broad phenotypic variability, symptom overlap with other gastrointestinal (GI) disorders, and lack of high-quality epidemiologic data in adults.5,11,22 In a 6-year retrospective study involving disaccharidase assay of 27,875 mucosal biopsy tissue samples in symptomatic children, at least 1 disaccharidase deficiency was present in 45% of samples, with 9.3% deficient in sucrase and maltase.22 A subsequent systematic review of 30 observational studies in children undergoing esophagogastroduodenoscopy (EGD) found similar results, with an overall prevalence of lactase, sucrase, and maltase deficiencies noted to be 39.2%, 9.0%, and 9.1%, respectively.24
Clinical Features
CSID has classically been thought to present with severe watery diarrhea, failure to gain weight, irritability, and diaper rash in infants who have been exposed to sucrose and starch in baby juices, baby food, fruits, teething biscuits, crackers, and other starches.6,25 In a case series of 65 patients with CSID, diarrhea was the most frequently described symptom, followed by bloating/gas, abdominal pain, and irritability.6 However, the clinical presentation and severity vary considerably depending on the nature and type of the SI gene mutations, as well as their homozygous or heterozygous combinations.11,26 Other factors that can influence clinical presentation include the amount of sugar and starch being consumed and patient age, as children may be more susceptible to symptoms due to the shorter length of their small intestine and reduced reserve capacity of the colon to absorb excess luminal fluid.4,6
Although symptoms usually appear early in life, increasing reports demonstrate that CSID can present later in life, either in children with diagnoses of nonspecific diarrhea of childhood or in adolescents or adults often carrying diagnoses of diarrhea-predominant irritable bowel syndrome (IBS-D).5,6,26 In either case, clinical features characteristic of CSID include symptoms that are lifelong, frequent (typically multiple events per day and multiple days per week), and occur postprandially (Table 3).3-6,27,28 In a study involving 17 adults with a positive sucrose breath test suggestive of SID, more than 75% of patients reported experiencing abdominal pain, bloating, and gas, and over half had experienced symptoms for more than 2 years.3 These symptoms had considerable impact on patients’ quality of life, with over half of patients reporting that their symptoms led to food avoidance and emotional distress often to always (Figure 3).
Exploring the Connection Between CSID/SID and FGIDs
Several studies have investigated the potential association between SI polymorphisms and irritable bowel syndrome (IBS), including the generation of symptoms in this disorder. To that end, several studies have identified SI variants that are linked with an increased risk of IBS.11,26 In a study involving 1031 IBS cases from around the world, patients with IBS had a 1.84 odds ratio (OR) of having a genetic SI mutation compared with controls.11 In a larger study involving 2207 patients with IBS, 4.2% of patients with IBS-D were found to carry SI pathogenic variants, a higher frequency relative to a large matched reference population.26 Most recently, a study involving pediatric and young adult patients with symptoms of functional gastrointestinal disorders (FGIDs) found a higher prevalence of 13 known pathogenic SI variants in patients with abnormal sucrase activity via disaccharidase assay compared with those with moderate-normal or high-normal sucrase activity (29.0% vs 6.4% and 2.0%, respectively; P<.001).28
In addition to an increased risk of FGID symptoms and diagnoses, SI polymorphisms have been linked to nonresponse to common dietary approaches to IBS.29 In an analysis of data from 46 patients with IBS-D in a previous randomized, controlled trial,30 patient response to a low–fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet was stratified by SI genotype data.29 Patients who carried hypomorphic (pathogenic) SI variants were significantly less likely to experience adequate symptom relief from the low-FODMAP diet compared with noncarriers (43.5% vs 60.9%; P=.031; OR, 4.66) (Figure 4). Although preliminary, data such as these characterizing the association of SI pathogenic variants with the risk of IBS and likelihood of response to various therapies may eventually pave the way for routine screening for SI genetic defects among patients with IBS-like symptoms to allow for more personalized diet management.
Diagnosing CSID/SID
A diagnosis of CSID/SID is usually suggested by the patient’s clinical history, paying particular attention to the pattern of symptoms in relation to meals.7 As mentioned, symptoms can range from severe diarrhea in infancy to chronic, nonspecific diarrhea; gas; and bloating in adolescents to adults reporting dyspeptic or IBS symptoms.5,7,25 A number of diagnostic tests are available to support the diagnosis of disaccharidase deficiency, with disaccharidase assay of duodenal biopsy specimens considered the gold standard.6,17,24 However, a number of noninvasive diagnostic tests can help establish the diagnosis. Despite the availability of multiple testing options, the optimal diagnostic strategy for CSID/SID remains unclear, as each option carries its own advantages and limitations (Table 4).
Disaccharidase Assays
The gold standard for diagnosing intestinal disorders associated with carbohydrate metabolism is endoscopic small bowel biopsies assayed for disaccharidase activities (Table 5).2,6 Given the distribution of sucrase-isomaltase, 2 to 4 biopsies should be obtained distal to the ampulla of Vater and placed into a container without formalin (Eppendorf tube). The Eppendorf tube with collected samples should be placed on ice immediately and stored at -20° C to -70° C within 2 hours of collection until disaccharidase assay is performed. The general diagnostic criteria for CSID/SID include normal small bowel morphology in the presence of absent or markedly reduced sucrase activity, isomaltase activity varying from no to full activity, and reduced maltase activity.6 Lactase activity can be normal or reduced in children, in which case the sucrase:lactase ratio should be less than 1 to support a diagnosis of CSID. Histologic examination of the intestinal biopsy specimen can help differentiate secondary cases of SID from congenital deficiencies.2 Clinical features can also help distinguish secondary deficiencies, with the recent onset of symptoms more typical in these patients compared with the frequent, lifelong, and postprandial symptoms experienced by patients with CSID.
Although disaccharidase assay remains the standard for diagnosing CSID/SID, the most widely used method (the Dahlqvist method) requires properly trained staff and typically requires resources of a specialty laboratory.17 Additionally, the assay is limited by considerable variability, with a demonstrated 27% coefficient of variation, and potential for false-positive results due to mishandled biopsy specimens, samples from the proximal rather than more distal duodenum, and/or patchy distribution of enzymes in the brush border.6,31,32
Breath Testing
The hydrogen-methane breath test has been used in the evaluation of carbohydrate maldigestion for decades.7,33 This test is based on the premise that when patients fail to digest carbohydrates in the small intestine, malabsorbed carbohydrates will be fermented by the intestinal flora and produce hydrogen and/or methane that diffuse into the circulation and are ultimately expired in the breath.7 According to the North American Consensus Guidelines, a rise of at least 20 ppm from baseline in hydrogen is considered positive for carbohydrate maldigestion, while a rise of at least 10 ppm is positive for methane.33 Although this test is safe and noninvasive, it is not specific for CSID/SID, and results can be compromised by contamination from a number of factors (eg, dumping syndrome, bacterial overgrowth, recent antibiotic use) that can produce either false-positive or false-negative results.6,34 Further, given that patients must ingest a 2 g/kg sucrose load, the test can cause severe symptoms in patients with CSID/SID.6
The use of isotope-labeled carbohydrates for breath testing was introduced in the 1970s and is a more specific methodology than the hydrogen-methane breath test.7,34 Carbon-13 (13C) is a stable isotope of carbon that occurs naturally in sucrose, making it possible to track an individual’s ability to digest and absorb sucrose by measuring the amount of 13CO2 exhaled after drinking a sucrose solution. The utility of the 13C-sucrose breath test was prospectively evaluated in a case-control study involving 10 patients with confirmed CSID based on mucosal tissue biopsy samples and 10 controls with normal sucrase levels and histology.34 Subjects received oral 13C-glucose and 13C-sucrose loads on consecutive study days, followed by breath collection and measurement of 13CO2 enrichment. The results of sucrose digestion and oxidation were expressed as the mean percentage of glucose oxidation (% CGO), which was found to correlate with biopsy-determined duodenal sucrase activity with 100% sensitivity and 100% specificity. Additionally, 13C-sucrose breath test mean % CGO corrected to control levels in CSID patients after supplementation with sacrosidase enzyme. Given the low dose of sucrose solution required (0.02 g/kg), patients with CSID tolerated the test well, without the symptoms of diarrhea, bloating, or cramping typically observed with the hydrogen-methane breath test.7,34 Despite these encouraging results, more data are needed to validate the use of the 13C-sucrose breath test and inform how and when it should be used in clinical practice.
Other Strategies
A sucrose 4-4-4 challenge is a simple test that consists of monitoring for the presence of symptoms (bloating, gas, diarrhea) for a 4- to 8-hour period after the patient drinks 4 ounces of water with 4 tablespoons of dissolved table sugar.4 Although theoretically sensitive, this method has not been validated and is likely to cause significant symptoms in patients with severe CSID/SID. Other approaches that may be helpful in supporting a diagnosis of CSID/SID but have yet to be validated include a short (2-week) trial of enzyme (sacrosidase) replacement therapy, an empiric trial of a low-
sucrose diet, and measurement of urinary disaccharides.4,6,35,36 Although SI exome genetic sequencing can identify homozygous and compound heterozygous mutations responsible for CSID, a normal test does not exclude CSID, as all mutations have not yet been identified.4,13,37
Is It CSID or IBS?
The diagnosis of CSID/SID can be delayed or even missed because the symptoms are incorrectly attributed to other causes of recurrent diarrhea.12 Given the overlapping symptoms with IBS, it has been speculated that CSID/SID may be frequently misdiagnosed as IBS in clinical practice, particularly in patients with meal-related symptoms.3,5 To explore this possibility, the prevalence of SID was investigated in 132 patients with chronic (>6 months) symptoms suggestive of the disorder (ie, diarrhea, bloating, nausea, early satiety, and/or abdominal pain).3 Of these patients, 17% (n=22) had a positive sucrose breath test suggestive of SID, and more than half of patients (65%) had been diagnosed previously with IBS-D. In a subsequent pilot study, SID was found by disaccharidase testing in 11 of 31 (35%) patients undergoing EGD for presumed IBS-D or mixed IBS (IBS-M).5 The higher-than-expected prevalence of SID in this study may have been related to selection and referral bias inherent to this population of patients with IBS undergoing EGD at a tertiary referral motility center. Taken collectively, however, these findings suggest that sucrose maldigestion may contribute to symptoms in patients with presumed IBS-D/M and should be considered in the differential diagnosis of such patients.5
Managing CSID
Dietary Management
Historically, the primary treatment option for CSID/SID has been implementing lifelong sucrose- and starch-
restricted diets adapted to the requirements of the patient.2,6 Given that all patients with CSID/SID are sucrose-intolerant, a sucrose-free diet should be implemented before starch intake is modified.38 Common foods rich in sucrose include table sugar, brown sugar, and certain fruits, vegetables, and sweets/convenience foods (Table 6).39 If symptoms persist after institution of a sucrose-free diet, starch consumption may need to be reduced. Starch tolerance may become more important in patients with severe symptoms and/or patients with low maltase activity.38 Starch-rich foods include potatoes, rice, bread, pasta, dextrins, maltodextrins, and glucose polymers (Table 7).39 Strategies for improving starch tolerance include chewing foods slowly to maximize salivary amylase exposure and eating starches with greater fiber content (eg, oats, barley, brown rice, whole grain flour) to prolong exposure to amylase throughout the GI tract.
Although dietary restriction alone should be theoretically effective, only a minority of patients remain consistently asymptomatic with this approach, with up to 75% of patients continuing to experience diarrhea, gas, and/or abdominal pain. Compliance even among younger patients can be suboptimal, with several studies suggesting that only half of children are typically compliant with the prescribed diet.6,14,40
Access to a registered dietitian who is knowledgeable about CSID/SID and maintaining a food diary are essential for guiding patients and their families in implementing dietary restrictions, ensuring adequate nutritional status, and introducing appropriate foods (Table 8)39 safely in combination with sacrosidase to find tolerance levels.38 Additionally, dietitians are instrumental in teaching patients and their families to understand food labels and recognize sucrose and starch in foods. Importantly, the amount of starch is not listed on food labels, but can be calculated by subtracting the amount of fiber and sugar from the total carbohydrates.
Enzyme Replacement Therapy
Treatment of CSID/SID has improved considerably with the availability of enzyme replacement therapy (sacrosidase), which allows liberalization of the sucrose-restrictive diet.6 Derived from baker’s yeast (Saccharomyces cerevisiae), sacrosidase is available as a solution containing 8500 IU of the enzyme/mL.41 The efficacy of sacrosidase was demonstrated in a randomized, double-blind trial involving 28 children with confirmed CSID who received various concentrations of the enzyme following a baseline period of maintaining a sucrose-free, low-starch diet.42 At the end of the 10-day treatment period, 81% of patients using full-strength sacrosidase were able to remain asymptomatic while consuming an unrestricted diet, which compared favorably with the experience of patients during the diet-restricted phase, during which 78% of patients were asymptomatic.42 However, because sacrosidase does not replace deficient isomaltase, restricting starch in the diet may still be necessary in some patients.41
Sacrosidase is usually taken with each meal or snack, mixed with 2 to 4 ounces of milk, water, or formula.41 Dosing is weight-based, with 1 mL recommended in children of no more than 15 kg and 2 mL in patients over 15 kg (ie, older children and adults). In order to maintain enzyme viability, the solution should be refrigerated and should not be mixed in hot or acidic beverages, nor should it be heated after mixing. Because sacrosidase is derived from baker’s yeast, it should not be given to people with a known hypersensitivity to yeast or yeast products. In addition, sacrosidase should be avoided or utilized with extreme caution in people with poorly controlled diabetes, as it can raise blood glucose levels through sucrose hydrolysis.
Conclusion
Increasing clinical and genetic evidence indicates that CSID/SID, once believed to be rare, are more common than previously appreciated.4-6,22,23 Given its broad phenotypic variability and shared symptoms with other causes of chronic diarrhea, it is likely that many patients with CSID/SID have been misdiagnosed with other GI conditions. This may be particularly true of patients diagnosed with IBS-D/M, in whom a high prevalence of SI mutations and sucrase deficiency has been reported.3,5,26,28 Accordingly, clinicians should be alert to the possibility of CSID in patients of all ages who experience lifelong, frequent, and postprandial GI symptoms, particularly patients who carry a diagnosis of IBS-D/M. While duodenal biopsy and disaccharidase assay remain the gold standard for diagnosis of CSID/SID, the diagnosis can be supported by less-invasive methods such as breath testing, sucrose challenge, and a trial of enzyme replacement therapy.4,6,35 Once diagnosed, the symptoms of CSID/SID can be improved through maintaining a low-sucrose, low-starch diet, although it is difficult for patients to comply with the restrictiveness of such a diet.6,14,40 Fortunately, the treatment of CSID/SID has improved considerably with the availability of enzyme replacement therapy, which allows patients to control their symptoms with less-restrictive dietary regimens.6,42 The key points of CSID/SID are summarized in Table 9.
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