sign in sign up
<<
Home , Isomaltase, Sucrase

October 2020 Volume 16, Issue 10, Supplement 5

Congenital - Deficiency: What, When, and How?

William D. Chey, MD, AGAF, FACG, FACP Professor of Medicine University of Michigan Health System Ann Arbor, Michigan

Brooks Cash, MD Dan and Lille Sterling Professor of Gastroenterology Chief, Division of Gastroenterology, Hepatology, and Nutrition University of Texas Health Science Center at Houston Houston, Texas

Anthony Lembo, MD Professor of Medicine Harvard Medical School Boston, Massachusetts

Daksesh B. Patel, DO Illinois Gastroenterology Group/GI Alliance Chief, Division of Gastroenterology and Hepatology AMITA St Francis Hospital Evanston, Illinois Accredited by Rehoboth McKinley Christian Health Care Services Kate Scarlata, RDN, LDN Owner, For a Digestive Peace of Mind, LLC Digestive Health Nutrition Consulting Medway, Massachusetts A CME Activity Approved for 1.0 AMA PRA Category 1 CreditTM Provided by the Gi Health Foundation Release Date: October 2020

ON THE WEB: Expiration Date: gastroenterologyandhepatology.net October 31, 2021

Supported by an Estimated time to educational grant from Indexed through the National Library of Medicine complete activity: QOL Medical, LLC (PubMed/Medline), PubMed Central (PMC), and EMBASE 1.0 hour Congenital Sucrase-Isomaltase Deficiency: What, When, and How?

To claim 1.0 AMA PRA Category 1 CreditTM for this activity, please visit: gihealthfoundation.org/CSIDMONOGRAPH

Target Audience Disclosures This CME monograph will target gastroenterologists, primary care physi- Faculty members are required to inform the audience when they are dis- cians, nurse practitioners, physician assistants, and nurses. cussing off-label, unapproved uses of devices and drugs. Physicians should consult full prescribing information before using any product mentioned Goal Statement during this educational activity. The goal of this journal supplement is to deliver focused, educational William D. Chey, MD, AGAF, FACG, FACP updates highlighting clinically relevant advances in the management of Stock Options: GI OnDemand, Ritter, and ModifyHealth; Research patients with CSID/SID. Grant: Commonwealth Diagnostics, QOL Medical, Salix, Urovant, and Vibrant; Consultant: AbbVie/Allergan, Biomerica, IM Health, Ironwood, Educational Objectives QOL Medical, RedHill, Ritter, Salix/Valeant, Urovant, Vibrant, Pha- After completing this activity, participants should be better able to: thom, Gemelli, and Progenity • Describe the role of intestinal in health and disease • Summarize recent evidence regarding the epidemiology, presentation, and Brooks Cash, MD natural history of patients with CSID/SID Speaker: Salix, Allergan, Takeda, QOL Medical, RedHill, and Alfasigma; • Summarize the benefits and limitations of current diagnostic tests for Consultant: Salix/Valeant, AbbVie/Allergan, Shire, Takeda, Phathom, and CSID/SID Ironwood • Incorporate practical screening/diagnostic strategies to identify appropri- ate patients for screening, interpret test results accurately, and effectively Anthony Lembo, MD differentiate CSID/SID from other common GI disorders seen in clinical Honorarium: Biomerica, IM Health, Ironwood, QOL Medical, RedHill, practice Ritter, Salix/Valeant, Vibrant, Bayer, and Mylan • Describe the role of dietary modification and supplementation in the management of patients with CSID/SID Daksesh B. Patel, DO Speaker: QOL Medical, LLC, and Allergan Accreditation Statement and Credit Designation Kate Scarlata, RDN, LDN Consultant Fee: The a2 Milk Company, Green Valley Creamery, Enjoy This activity has been planned and implemented in accordance with the Life Foods, Salix, Monash University, and FODY Foods; Equity: Epicured accreditation requirements and policies of the New Mexico Medical Society and FODY Foods; Employee: Epicured (NMMS) through the joint providership of Rehoboth McKinley Chris- tian Health Care Services (RMCHCS) and the Gi Health Foundation. Julianne Messick, PharmD, Medical Writer No real or apparent conflict RMCHCS is accredited by the NMMS to provide continuing medical of interest education for physicians.

RMCHCS designates this activity for a maximum of 1.0 AMA PRA Cate- gory 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Supported by an educational grant from QOL Medical, LLC

Provided by the

Accredited by

Indexed through the National Library of Medicine (PubMed/Medline), PubMed Central (PMC), and EMBASE

Disclaimer This supplement is supported by an educational grant from QOL Medical, LLC. Support of this supplement does not imply the supporter’s agreement with the views expressed herein. Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Gastro-Hep Communications, Inc., the supporter, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.

©2020 Gastro-Hep Communications, Inc., 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. CONGENITAL SUCRASE-ISOMALTASE DEFICIENCY: WHAT, WHEN, AND HOW?

Congenital Sucrase-Isomaltase Deficiency: What, When, and How?

William D. Chey, MD, AGAF, FACG, FACP, Brooks Cash, MD, Anthony Lembo, MD, Daksesh B. Patel, DO, and Kate Scarlata, RDN, LDN

Disaccharidase Deficiency: molecules with varying structures and border for absorption and metabo- An Overview for bonds.2,3 Because relevant transporters lism.2,4 Isomaltase hydrolyzes branched Gastroenterologists in the can only transport a-linked into 2 mole- Focusing on CSID monosaccharides, and cules, while sucrase hydrolyzes polysaccharides must be hydrolyzed to and glucose.4,5 Given its Overview of to monosaccharides for absorption abundance and substrate specific- Metabolism to occur (Figure 1).2 The of ity, the sucrase-isomaltase enzyme Nearly half of the average Western diet is initiated by salivary and later complex is responsible for nearly all is composed of ,1 which pancreatic a- that hydrolyze sucrase activity and approximately are made up of simple and complex it into smaller residues, 60% to 80% of activity in the . Simple sugars are monosac- and sucrose.2 In the final step of starch intestine.4,6 activities charides (eg, glucose, fructose) or digestion, in the brush border vary throughout the small intestine, disaccharides (eg, sucrose, maltose, lac- of the small intestine hydrolyze disac- with lower values in the proximal tose), whereas complex sugars include charides into monosaccharides such as duodenum, peak activities in the mid- , , and fibers, which glucose and fructose, which are then jejunum, and decreasing activities in are composed of multiple glucose transported across the epithelial brush the ileum.7

Starch

a- Isomaltase, maltase

Maltose

Glucose Sucrose Sucrase Fructose

Figure 1. Normal carbohydrate digestion.6,8 Starches must be hydrolyzed for absorption, a process that begins with pancreatic a-amylase and is followed by a-. Disaccharides are hydrolyzed by disaccharidases in the small intestinal brush border to monosaccharides for absorption and metabolism.

Gastroenterology & Hepatology Volume 16, Issue 10, Supplement 5 October 2020 3 CME MONOGRAPH

Table 1. Phenotypes of CSID12

Enzymatic Activity Phenotype Cellular Localization Sucrase Maltase I ER Completely inactive Completely inactive II ER, ER-Golgi intermediate compartment, Completely inactive Completely inactive and cis-Golgi

III Brush border membrane Completely inactive Completely inactive IV Random on apical and basolateral membranes Active Active V Intracellular cleavage, degradation of sucrase, isomaltase is correctly located at the apical Absent Active membrane

VI Intracellular cleavage, enzyme secreted Active Active ER, random cell surface distribution at the VII Decreased Absent apical and basolateral membranes

CSID, congenital sucrase-isomaltase deficiency; ER, endoplasmic reticulum.

What Is CSID? and hydrogen sulfide.6,10 This in turn of the disorder, acquired or second- First described in 1960,9 congenital can lead to abdominal distension, ary forms of SID have been observed sucrase-isomaltase deficiency (CSID) cramping, pain, excessive flatulence, in patients with chronic .4 is an inherited primary defect of and osmotic diarrhea (Figure 2).6,10 Decreased enzyme activity can result sucrase-isomaltase caused by variants If left untreated, significant sucrase- from generalized intestinal damage in the sucrase-isomaltase (SI) gene.6,10 isomaltase deficiency (SID) can result related to various etiologies involving Patients with CSID harbor 2 defec- in inadequate growth and failure to villous atrophy, infection, and/or tive copies of the SI gene due to thrive in children as well as weight loss rapid transit (Table 2).4,17 The clinical recessive homozygous or compound in adults.10,14-16 impact of SID on these disorders may heterozygous mutations, leading to be transient, with enzymatic activity the absence or diminished activity of Other Causes of SID returning to normal as the underlying sucrase-isomaltase at the brush border In addition to the congenital forms disorder resolves.4 and the clinical symptoms of carbo- hydrate maldigestion.10,11 At least 37 pathogenic mutations in the SI gene have been described that affect various Normal CSID aspects of gene function, resulting in multiple phenotypes with a broad Glucose range of enzymatic activity and clinical presentations (Table 1).5,12,13 Sucrase Sucrose Sucrase Fructose

activity in patients with CSID can Small intestine range from completely absent to low residual activity, while isomaltase Bacteria activity can range from absent to nor- Normal stool mal.6 Maltase activity is also reduced Gas significantly in most patients with Colon Fermentation Diarrhea 6 Bloating CSID. Gases When sucrase-isomaltase is Pain absent or deficient, nonabsorbed carbohydrates enter the distal small Figure 2. Clinical consequences of carbohydrate .6,8 When sucrase- intestine and colon where they are isomaltase is absent or deficient, nonabsorbed carbohydrates enter the distal small intestine fermented, leading to the excessive and colon causing excess bacterial fermentation and increased production of short-chain production of short-chain fatty acids fatty acids and gases, leading to abdominal distension, cramping, pain, excessive flatulence, and gases such as hydrogen, methane, and osmotic diarrhea. CSID, congenital sucrase-isomaltase deficiency.

4 Gastroenterology & Hepatology Volume 16, Issue 10, Supplement 5 October 2020 CONGENITAL SUCRASE-ISOMALTASE DEFICIENCY: WHAT, WHEN, AND HOW?

Table 2. Potential Causes of Secondary or Acquired SID4 cies noted to be 39.2%, 9.0%, and 24 Potential Cause Conditions 9.1%, respectively. Villous Atrophy or Celiac disease Clinical Features Alteration Nontropical sprue CSID has classically been thought to Chemotherapy and radiation enteropathy present with severe watery diarrhea, Crohn’s disease failure to gain weight, irritability, Allergic enteropathy and diaper rash in infants who have Immunodeficiency Malnutrition been exposed to sucrose and starch in baby juices, baby food, fruits, Infection Acute gastroenteritis teething biscuits, crackers, and other Giardiasis starches.6,25 In a case series of 65 Tropical sprue patients with CSID, diarrhea was the HIV enteropathy most frequently described symptom, SIBO/dysbiosis followed by bloating/gas, abdominal 6 Rapid Transit Rapid gastric emptying pain, and irritability. However, the Chronic nonspecific diarrhea clinical presentation and severity vary Dumping syndrome considerably depending on the nature Crohn’s disease and type of the SI gene mutations, as Ulcerative colitis, Crohn’s colitis, lymphocytic colitis, well as their homozygous or heterozy- and collagenous colitis gous combinations.11,26 Other factors Medications that can influence clinical presentation SIBO, small intestinal bacterial overgrowth; SID, sucrase-isomaltase deficiency. include the amount of sugar and starch being consumed and patient age, as children may be more susceptible to Epidemiology and Clinical disorders, and lack of high-quality symptoms due to the shorter length Presentation of CSID/SID epidemiologic data in adults.5,11,22 In of their small intestine and reduced a 6-year retrospective study involving reserve capacity of the colon to absorb Reassessing the Prevalence of CSID disaccharidase assay of 27,875 mucosal excess luminal fluid.4,6 CSID has been historically considered biopsy tissue samples in symptomatic Although symptoms usually a rare disease, with an estimated 0.2% children, at least 1 disaccharidase defi- appear early in life, increasing reports prevalence in North American and ciency was present in 45% of samples, demonstrate that CSID can present European populations18 and an even with 9.3% deficient in sucrase and later in life, either in children with lower prevalence in African Americans maltase.22 A subsequent systematic diagnoses of nonspecific diarrhea and whites of Hispanic descent.6,19 review of 30 observational studies in of childhood or in adolescents or Higher estimates have been reported children undergoing esophagogastro- adults often carrying diagnoses of among certain populations,20,21 with duodenoscopy (EGD) found similar diarrhea-predominant irritable bowel one study reporting a 10% prevalence results, with an overall prevalence of syndrome (IBS-D).5,6,26 In either case, among Inuit communities in Green- , sucrase, and maltase deficien- clinical features characteristic of CSID land.21 In contrast to these earlier reports, more recent studies demonstrating Never Rarely to sometimes Often to always that heterozygous carriers of SI vari- 100 ants also experience symptoms suggest 80 74 that CSID may be more common than once believed.4-6,22,23 The true preva- 60 50 52 lence of CSID is likely underestimated 40 36 35 due to a number of factors, including % Patients, 22 inconsistencies in nomenclature of 20 14 13 the condition, diverse testing meth- 4 odologies with unclear performance 0 Interference with Food avoidance Emotional distress characteristics, the existence of multi- daily activity ple genomic abnormalities with broad phenotypic variability, symptom over- Figure 3. Effects of symptoms on quality of life in adults with sucrase-isomaltase lap with other gastrointestinal (GI) deficiency.3

Gastroenterology & Hepatology Volume 16, Issue 10, Supplement 5 October 2020 5 CME MONOGRAPH

Table 3. CSID Signs and Symptoms3-6,27,28 controlled trial,30 patient response to a low–fermentable , Key Symptoms Frequent, lifelong, and postprandial GI symptoms , monosaccharide, and • Diarrhea polyol (FODMAP) diet was stratified • Loose stools by SI genotype data.29 Patients who • Gas carried hypomorphic (pathogenic) SI • Bloating variants were significantly less likely • Abdominal cramping to experience adequate symptom relief from the low-FODMAP diet Other Potential Family history Signs Avoidance of carbohydrates and/or sweet foods compared with noncarriers (43.5% Nausea vs 60.9%; P=.031; OR, 4.66) (Figure Dyspepsia 4). Although preliminary, data such Low BMI as these characterizing the association IBS symptoms not responding to therapy of SI pathogenic variants with the risk of IBS and likelihood of response to BMI, body mass index; CSID, congenital sucrase-isomaltase deficiency; GI, gastrointestinal; IBS, various therapies may eventually pave irritable bowel syndrome. the way for routine screening for SI genetic defects among patients with include symptoms that are lifelong, atric and young adult patients with IBS-like symptoms to allow for more frequent (typically multiple events per symptoms of functional gastrointesti- personalized diet management. day and multiple days per week), and nal disorders (FGIDs) found a higher occur postprandially (Table 3).3-6,27,28 prevalence of 13 known pathogenic Diagnosing CSID/SID In a study involving 17 adults with a SI variants in patients with abnormal positive sucrose breath test suggestive sucrase activity via disaccharidase A diagnosis of CSID/SID is usually of SID, more than 75% of patients assay compared with those with mod- suggested by the patient’s clinical reported experiencing abdominal pain, erate-normal or high-normal sucrase history, paying particular attention to bloating, and gas, and over half had activity (29.0% vs 6.4% and 2.0%, the pattern of symptoms in relation experienced symptoms for more than 2 respectively; P<.001).28 to meals.7 As mentioned, symptoms years.3 These symptoms had consider- In addition to an increased risk can range from severe diarrhea in able impact on patients’ quality of life, of FGID symptoms and diagnoses, infancy to chronic, nonspecific diar- with over half of patients reporting that SI polymorphisms have been linked rhea; gas; and bloating in adolescents their symptoms led to food avoidance to nonresponse to common dietary to adults reporting dyspeptic or IBS and emotional distress often to always approaches to IBS.29 In an analy- symptoms.5,7,25 A number of diagnos- (Figure 3). sis of data from 46 patients with tic tests are available to support the IBS-D in a previous randomized, diagnosis of disaccharidase deficiency, Exploring the Connection Between CSID/SID and FGIDs Several studies have investigated the potential association between SI P=.031 polymorphisms and irritable bowel syndrome (IBS), including the gener- 80 ation of symptoms in this disorder. To 60.9 60 52.2 that end, several studies have identified 43.5 SI variants that are linked with an 40 increased risk of IBS.11,26 In a study involving 1031 IBS cases from around 20 symptom relief, % relief, symptom the world, patients with IBS had a 1.84 achieving Patients n=46 n=23 n=23 odds ratio (OR) of having a genetic SI 0 mutation compared with controls.11 In All patients Noncarriers Carriers a larger study involving 2207 patients with IBS, 4.2% of patients with IBS-D Hypomorphic SI variants were found to carry SI pathogenic variants, a higher frequency relative to Figure 4. Adequate relief of IBS-D symptoms with a low-FODMAP diet.29 FODMAP, a large matched reference population.26 fermentable oligosaccharide, disaccharide, monosaccharide, and polyol; IBS-D, diarrhea- Most recently, a study involving pedi- predominant irritable bowel syndrome; SI, sucrase-isomaltase.

6 Gastroenterology & Hepatology Volume 16, Issue 10, Supplement 5 October 2020 CONGENITAL SUCRASE-ISOMALTASE DEFICIENCY: WHAT, WHEN, AND HOW?

Table 4. Comparison of Diagnostic Tests for CSID/SID6,7,31,33,34,36

Test Advantages Limitations Disaccharidase Assay EGD With • Ability to determine enzyme activity for all • Invasive, requires sedation Disaccharidase disaccharidases and glucoamylase • Costly and time-consuming Assay • Increasingly, insurance payors are requiring • Assay variability (27% coefficient variation) disaccharidase assay prior to covering • False-positive results due to mishandled biopsy speci- mens, biopsy samples of the proximal duodenum, and patchy distribution of disaccharides in the brush border

Breath Tests 13C-Sucrose • Noninvasive • False-positive results due to dumping syndrome Breath Test • Safe (stable isotope—13C has never been observed • False-negative results due to delayed gastric emptying to decay) • Need for further validation • Well-tolerated (requires only 0.02 g/kg sucrose solution) • More specific than hydrogen-methane breath test

Hydrogen- • Noninvasive • Influenced by diet and motility agents Methane Breath • Safe • Indirect test (not specific for sucrose) Test • Time-consuming (3 hours) • False-positive results due to SBBO, dumping syndrome • False-negative results due to nonhydrogen producers, delayed gastric emptying • Large sucrose load (2 g/kg sucrose solution) can cause severe symptoms in CSID patients

Other Tests Sucrose • Noninvasive • Lack of validation data Challenge Test • Simple and easy • Unknown NPV and PPV • Cost-effective • Severe symptoms likely in CSID patients • Theoretically sensitive, with high likelihood to cause CSID symptoms

Empiric Trial of • Noninvasive • Costly (likely not covered by insurance without CSID Sacrosidase • Simple and easy being confirmed by an approved diagnostic test) • Theoretically sensitive, with high likelihood of • Lack of validation data symptom resolution in CSID patients • Unknown NPV and PPV

Empiric Trial • Noninvasive • Difficult to maintain such a restrictive diet— of Low-Sucrose • Theoretically sensitive, with high likelihood of recommend GI dietitian to assist patient Diet symptom resolution in CSID patients • Lack of validation data • Unknown NPV and PPV

Urinary • Noninvasive • Influenced by diet Disaccharidase • Safe • Time-consuming (10-hour urine collection) Test • Lack of validation data

Genetic Testing • Noninvasive • Costly • If positive, confirms SID regardless of genotype • Lengthy turnaround time • Normal test does not rule out CSID, as not all mutations have been identified

CSID, congenital sucrase-isomaltase deficiency; EGD, esophagogastroduodenoscopy; GI, gastrointestinal; NPV, negative predictive value; PPV, positive predictive value; SBBO, small bowel bacterial overgrowth; SID, sucrase-isomaltase deficiency.

Gastroenterology & Hepatology Volume 16, Issue 10, Supplement 5 October 2020 7 CME MONOGRAPH

with disaccharidase assay of duodenal Table 5. Normal Disaccharidase Values5 biopsy specimens considered the gold Disaccharidase Normal Range standard.6,17,24 However, a number of noninvasive diagnostic tests can help Lactase 15.0-45.5 µM/min/g protein establish the diagnosis. Despite the Sucrase 25.0-69.9 µM/min/g protein availability of multiple testing options, the optimal diagnostic strategy for Maltase 100.0-224.4 µM/min/g protein CSID/SID remains unclear, as each Isomaltase 5.0-26.3 µM/min/g protein option carries its own advantages and limitations (Table 4). with a demonstrated 27% coefficient sucrose load, the test can cause severe of variation, and potential for false- symptoms in patients with CSID/ Disaccharidase Assays positive results due to mishandled SID.6 The gold standard for diagnosing intes- biopsy specimens, samples from the The use of isotope-labeled car- tinal disorders associated with carbohy- proximal rather than more distal duo- bohydrates for breath testing was drate metabolism is endoscopic small denum, and/or patchy distribution of introduced in the 1970s and is a more bowel biopsies assayed for disacchari- enzymes in the brush border.6,31,32 specific methodology than the hydro- dase activities (Table 5).2,6 Given the gen-methane breath test.7,34 Carbon-13 distribution of sucrase-isomaltase, 2 to Breath Testing (13C) is a stable isotope of carbon that 4 biopsies should be obtained distal to The hydrogen-methane breath test has occurs naturally in sucrose, making the ampulla of Vater and placed into been used in the evaluation of carbohy- it possible to track an individual’s a container without formalin (Eppen- drate maldigestion for decades.7,33 This ability to digest and absorb sucrose 13 dorf tube). The Eppendorf tube with test is based on the premise that when by measuring the amount of CO2 collected samples should be placed on patients fail to digest carbohydrates exhaled after drinking a sucrose solu- ice immediately and stored at -20° C in the small intestine, malabsorbed tion. The utility of the 13C-sucrose to -70° C within 2 hours of collection carbohydrates will be fermented by the breath test was prospectively evaluated until disaccharidase assay is performed. intestinal flora and produce hydrogen in a case-control study involving 10 The general diagnostic criteria for and/or methane that diffuse into the patients with confirmed CSID based CSID/SID include normal small circulation and are ultimately expired on mucosal tissue biopsy samples and bowel morphology in the presence of in the breath.7 According to the North 10 controls with normal sucrase levels absent or markedly reduced sucrase American Consensus Guidelines, a and histology.34 Subjects received oral activity, isomaltase activity varying rise of at least 20 ppm from baseline 13C-glucose and 13C-sucrose loads on from no to full activity, and reduced in hydrogen is considered positive for consecutive study days, followed by maltase activity.6 Lactase activity can carbohydrate maldigestion, while a rise breath collection and measurement 13 be normal or reduced in children, in of at least 10 ppm is positive for meth- of CO2 enrichment. The results of which case the sucrase:lactase ratio ane.33 Although this test is safe and sucrose digestion and oxidation were should be less than 1 to support a diag- noninvasive, it is not specific for CSID/ expressed as the mean percentage of nosis of CSID. Histologic examination SID, and results can be compromised glucose oxidation (% CGO), which of the intestinal biopsy specimen can by contamination from a number of was found to correlate with biopsy- help differentiate secondary cases of factors (eg, dumping syndrome, bacte- determined duodenal sucrase activity SID from congenital deficiencies.2 rial overgrowth, recent antibiotic use) with 100% sensitivity and 100% spec- Clinical features can also help distin- that can produce either false-positive ificity. Additionally, 13C-sucrose breath guish secondary deficiencies, with the or false-negative results.6,34 Further, test mean % CGO corrected to control recent onset of symptoms more typical given that patients must ingest a 2 g/kg levels in CSID patients after supple- in these patients compared with the frequent, lifelong, and postprandial Table 6. Sucrose-Rich Foods39 symptoms experienced by patients with CSID. Fruits Apples, apricots, cantaloupe, dates, pineapple, mango, Although disaccharidase assay nectarine remains the standard for diagnosing Vegetables Beets, carrots, chickpeas, corn, sweet potatoes CSID/SID, the most widely used method (the Dahlqvist method) Sweets/ Breakfast cereal, granola bars, pastries, muffins, requires properly trained staff and typ- Convenience Foods pudding, cookies, pies, jams, jellies ically requires resources of a specialty laboratory.17 Additionally, the assay Sugars Brown sugar, granulated sugar, maple syrup, cane juice, molasses is limited by considerable variability,

8 Gastroenterology & Hepatology Volume 16, Issue 10, Supplement 5 October 2020 CONGENITAL SUCRASE-ISOMALTASE DEFICIENCY: WHAT, WHEN, AND HOW?

Table 7. Starch-Rich Foods39 Given the overlapping symptoms with Managing CSID IBS, it has been speculated that CSID/ Potatoes SID may be frequently misdiagnosed Dietary Management Rice as IBS in clinical practice, particularly Historically, the primary treatment Bread in patients with meal-related symp- option for CSID/SID has been imple- 3,5 Pasta toms. To explore this possibility, the menting lifelong sucrose- and starch- prevalence of SID was investigated in restricted diets adapted to the Dextrins 132 patients with chronic (>6 months) requirements of the patient.2,6 Given Maltodextrins symptoms suggestive of the disorder (ie, that all patients with CSID/SID are Glucose polymers diarrhea, bloating, nausea, early satiety, sucrose-intolerant, a sucrose-free and/or abdominal pain).3 Of these diet should be implemented before mentation with sacrosidase enzyme. patients, 17% (n=22) had a positive starch intake is modified.38 Common Given the low dose of sucrose solution sucrose breath test suggestive of SID, foods rich in sucrose include table required (0.02 g/kg), patients with and more than half of patients (65%) sugar, brown sugar, and certain fruits, CSID tolerated the test well, without had been diagnosed previously with vegetables, and sweets/convenience the symptoms of diarrhea, bloating, IBS-D. In a subsequent pilot study, SID foods (Table 6).39 If symptoms persist or cramping typically observed with was found by disaccharidase testing in after institution of a sucrose-free diet, the hydrogen-methane breath test.7,34 11 of 31 (35%) patients undergoing starch consumption may need to be Despite these encouraging results, EGD for presumed IBS-D or mixed reduced. Starch tolerance may become more data are needed to validate the IBS (IBS-M).5 The higher-than-ex- more important in patients with severe use of the 13C-sucrose breath test and pected prevalence of SID in this study symptoms and/or patients with low inform how and when it should be may have been related to selection and maltase activity.38 Starch-rich foods used in clinical practice. referral bias inherent to this population include potatoes, rice, bread, pasta, of patients with IBS undergoing EGD dextrins, maltodextrins, and glucose Other Strategies at a tertiary referral motility center. polymers (Table 7).39 Strategies for A sucrose 4-4-4 challenge is a simple Taken collectively, however, these improving starch tolerance include test that consists of monitoring for findings suggest that sucrose maldiges- chewing foods slowly to maximize the presence of symptoms (bloating, tion may contribute to symptoms in salivary amylase exposure and eating gas, diarrhea) for a 4- to 8-hour period patients with presumed IBS-D/M and starches with greater fiber content (eg, after the patient drinks 4 ounces of should be considered in the differential oats, barley, brown rice, whole grain water with 4 tablespoons of dissolved diagnosis of such patients.5 flour) to prolong exposure to amylase table sugar.4 Although theoretically sensitive, this method has not been Table 8. Foods Low in Sucrose and Starch39 validated and is likely to cause signif- icant symptoms in patients with severe Dairya Cow’s milk, cream cheese, hard cheeses, plain cottage cheese, CSID/SID. Other approaches that plain yogurt, sour cream may be helpful in supporting a diag- Protein Beef, poultry, pork, lamb, firm tofu nosis of CSID/SID but have yet to be validated include a short (2-week) trial Vegetables Artichoke, asparagus, bamboo shoots, bell peppers, bok choy, of enzyme (sacrosidase) replacement broccoli, Brussels sprouts, cabbage, cauliflower, celery, collard therapy, an empiric trial of a low- greens, cucumber, eggplant, green beans, lettuce, bean sprouts, sucrose diet, and measurement of uri- mustard greens, mushrooms, radish, rutabaga, spaghetti squash, nary disaccharides.4,6,35,36 Although SI spinach, tomatoes, turnips, summer squash, zucchini exome genetic sequencing can identify Fruits Avocado, blackberries, blueberries, boysenberries, cherries, homozygous and compound heterozy- cranberries, currants, figs, grapes, kiwifruit, lemon, lime, olive, gous mutations responsible for CSID, papaya, pears, pomegranate, prunes, raspberries, rhubarb, a normal test does not exclude CSID, strawberries as all mutations have not yet been identified.4,13,37 Fats, Nuts, Olive oil, butter, other vegetable oils,b almond butter,c Brazil Seeds nuts, flax, peanuts, peanut butterc Is It CSID or IBS? Sweeteners Granulated dextrose or fructose The diagnosis of CSID/SID can be delayed or even missed because the a In patients with concomitant intolerance, lactose-free or low-lactose foods (eg, hard cheeses, symptoms are incorrectly attributed lactose-free milk, lactose-free yogurt) should be chosen as tolerated. bCaution should be used with to other causes of recurrent diarrhea.12 margarine. cWithout added sugar.

Gastroenterology & Hepatology Volume 16, Issue 10, Supplement 5 October 2020 9 CME MONOGRAPH

Table 9. Key Points replace deficient isomaltase, restricting starch in the diet may still be necessary The majority of dietary carbohydrates are digested by sucrase-isomaltase. in some patients.41 CSID/SID are likely more common than previously believed. Current literature Sacrosidase is usually taken with suggests an overall CSID prevalence of 4% to 5%, while approximately 10% of each meal or snack, mixed with 2 to 41 symptomatic children and adults have diminished sucrase-isomaltase activity 4 ounces of milk, water, or formula. (including secondary etiologies). Dosing is weight-based, with 1 mL recommended in children of no more The optimal diagnostic strategy for CSID/SID remains unclear. While disaccharidase than 15 kg and 2 mL in patients over assay is the current gold standard, the 13C-sucrose breath test offers a noninvasive, 15 kg (ie, older children and adults). practical strategy to help establish the diagnosis. However, more data are needed to In order to maintain enzyme viability, validate this test and determine how and when it is best used in clinical practice. the solution should be refrigerated and should not be mixed in hot or acidic Although current evidence is insufficient to recommend early testing, CSID/SID beverages, nor should it be heated should be included in the differential diagnosis of patients with presumed IBS who have after mixing. Because sacrosidase is unexplained, meal-related GI symptoms (diarrhea, bloating, flatulence, and abdominal derived from baker’s yeast, it should pain), particularly those not responding to symptom-directed or dietary treatment. not be given to people with a known hypersensitivity to yeast or yeast prod- Treatment of CSID/SID should be individualized based on patient preferences, using ucts. In addition, sacrosidase should be an iterative approach that incorporates dietary management and/or enzyme replace- avoided or utilized with extreme cau- ment therapy. Whenever possible, gastroenterologists should work with a registered tion in people with poorly controlled dietitian who is knowledgeable about CSID/SID when managing these patients. diabetes, as it can raise blood glucose levels through sucrose . CSID, congenital sucrase-isomaltase deficiency; GI, gastrointestinal; IBS, irritable bowel syndrome; SID, sucrase-isomaltase deficiency. Conclusion throughout the GI tract. tracting the amount of fiber and sugar Increasing clinical and genetic evi- Although dietary restriction from the total carbohydrates. dence indicates that CSID/SID, once alone should be theoretically effective, believed to be rare, are more common only a minority of patients remain Enzyme Replacement Therapy than previously appreciated.4-6,22,23 consistently asymptomatic with this Treatment of CSID/SID has improved Given its broad phenotypic variabil- approach, with up to 75% of patients considerably with the availability of ity and shared symptoms with other continuing to experience diarrhea, gas, enzyme replacement therapy (sacro- causes of chronic diarrhea, it is likely and/or abdominal pain. Compliance sidase), which allows liberalization of that many patients with CSID/SID even among younger patients can be the sucrose-restrictive diet.6 Derived have been misdiagnosed with other GI suboptimal, with several studies sug- from baker’s yeast (Saccharomyces conditions. This may be particularly gesting that only half of children are cerevisiae), sacrosidase is available as true of patients diagnosed with IBS- typically compliant with the prescribed a solution containing 8500 IU of D/M, in whom a high prevalence of diet.6,14,40 the enzyme/mL.41 The efficacy of SI mutations and sucrase deficiency Access to a registered dietitian sacrosidase was demonstrated in a ran- has been reported.3,5,26,28 Accordingly, who is knowledgeable about CSID/ domized, double-blind trial involving clinicians should be alert to the possi- SID and maintaining a food diary 28 children with confirmed CSID bility of CSID in patients of all ages are essential for guiding patients who received various concentrations who experience lifelong, frequent, and and their families in implementing of the enzyme following a baseline postprandial GI symptoms, particu- dietary restrictions, ensuring adequate period of maintaining a sucrose-free, larly patients who carry a diagnosis nutritional status, and introducing low-starch diet.42 At the end of the of IBS-D/M. While duodenal biopsy appropriate foods (Table 8)39 safely 10-day treatment period, 81% of and disaccharidase assay remain the in combination with sacrosidase to patients using full-strength sacrosidase gold standard for diagnosis of CSID/ find tolerance levels.38 Additionally, were able to remain asymptomatic SID, the diagnosis can be supported dietitians are instrumental in teaching while consuming an unrestricted by less-invasive methods such as breath patients and their families to under- diet, which compared favorably with testing, sucrose challenge, and a trial stand food labels and recognize sucrose the experience of patients during the of enzyme replacement therapy.4,6,35 and starch in foods. Importantly, the diet-restricted phase, during which Once diagnosed, the symptoms of amount of starch is not listed on food 78% of patients were asymptomatic.42 CSID/SID can be improved through labels, but can be calculated by sub- However, because sacrosidase does not maintaining a low-sucrose, low-starch

10 Gastroenterology & Hepatology Volume 16, Issue 10, Supplement 5 October 2020 CONGENITAL SUCRASE-ISOMALTASE DEFICIENCY: WHAT, WHEN, AND HOW?

diet, although it is difficult for patients complex. J Pediatr Gastroenterol Nutr. 2012;55(suppl online July 28, 2020]. J Pediatr Gastroenterol Nutr. 2):S13-S20. doi:10.1097/MPG.0000000000002852. to comply with the restrictiveness 13. Chumpitazi BP, Robayo-Torres CC, Opekun AR, 29. Zheng T, Eswaran S, Photenhauer AL, Merchant of such a diet.6,14,40 Fortunately, the Nichols BL Jr, Naim HY. Congenital sucrase-isomaltase JL, Chey WD, D’Amato M. Reduced efficacy of low treatment of CSID/SID has improved deficiency: summary of an evaluation in one family. J FODMAPs diet in patients with IBS-D carrying Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S36. sucrase-isomaltase (SI) hypomorphic variants. Gut. considerably with the availability of 14. Antonowicz I, Lloyd-Still JD, Khaw KT, Shwa- 2020;69(2):397-398. enzyme replacement therapy, which chman H. Congenital sucrase-isomaltase deficiency. 30. Eswaran SL, Chey WD, Han-Markey T, Ball S, allows patients to control their symp- Observations over a period of 6 years. Pediatrics. Jackson K. A randomized controlled trial comparing 1972;49(6):847-853. the low FODMAP diet vs. modified NICE guide- toms with less-restrictive dietary regi- 15. Belmont JW, Reid B, Taylor W, et al. Congenital lines in US adults with IBS-D. Am J Gastroenterol. mens.6,42 The key points of CSID/SID sucrase-isomaltase deficiency presenting with failure 2016;111(12):1824-1832. are summarized in Table 9. to thrive, hypercalcemia, and nephrocalcinosis. BMC 31. Maiuri L, Raia V, Potter J, et al. Mosaic pat- Pediatr. 2002;2:4. tern of lactase expression by villous enterocytes in 16. Muldoon C, Maguire P, Gleeson F. Onset of human adult-type hypolactasia. Gastroenterology. References sucrase-isomaltase deficiency in late adulthood. Am J 1991;100(2):359-369. Gastroenterol. 1999;94(8):2298-2299. 32. Smith JA, Mayberry JF, Ansell ID, Long RG. Small 1. Seidelmann SB, Claggett B, Cheng S, et al. Dietary 17. He Z, Bolling L, Tonb D, Nadal T, Mehta DI. An bowel biopsy for disaccharidase levels: evidence that carbohydrate intake and mortality: a prospective automated method for the determination of intestinal endoscopic forceps biopsy can replace the Crosby cap- cohort study and meta-analysis. Lancet Public Health. disaccharidase and glucoamylase activities. J Autom sule. Clin Chim Acta. 1989;183(3):317-321. 2018;3(9):e419-e428. Methods Manag Chem. 2006;2006:93947. 33. Rezaie A, Buresi M, Lembo A, et al. Hydrogen and 2. Gericke B, Amiri M, Naim HY. The multiple roles of 18. Peterson ML, Herber R. Intestinal sucrase defi- methane-based breath testing in gastrointestinal disor- sucrase-isomaltase in the intestinal physiology. Mol Cell ciency. Trans Assoc Am Physicians. 1967;80:275-283. ders: the North American Consensus. Am J Gastroen- Pediatr. 2016;3(1):2. 19. Welsh JD, Poley JR, Bhatia M, Stevenson DE. Intes- terol. 2017;112(5):775-784. 3. Simmer S, Chey WD, Eswaran SL, Ranagan tinal disaccharidase activities in relation to age, race, and 34. Robayo-Torres CC, Opekun AR, Quezada-Calvillo J, Petrucelli S. Is sucrase-isomaltase deficiency an mucosal damage. Gastroenterology. 1978;75(5):847-855. R, et al. 13C-breath tests for sucrose digestion in con- under-recognized cause of IBS-D symptoms [abstract 20. Ellestad-Sayed JJ, Haworth JC, Hildes JA. Disac- genital sucrase isomaltase-deficient and sacrosidase-sup- Mo1966]? Gastroenterology. 2018;154(6)(suppl 1):S- charide malabsorption and dietary patterns in two plemented patients. J Pediatr Gastroenterol Nutr. 867. Canadian Eskimo communities. Am J Clin Nutr. 2009;48(4):412-418. 4. Cohen SA. The clinical consequences of sucrase-iso- 1978;31(8):1473-1478. 35. Puntis JWL, Zamvar V. Congenital sucrase-iso- maltase deficiency. Mol Cell Pediatr. 2016;3(1):5. 21. Gudmand-Høyer E, Fenger HJ, Kern-Hansen maltase deficiency: diagnostic challenges and response 5. Kim SB, Calmet FH, Garrido J, Garcia-Buitrago MT, P, Madsen PR. Sucrase deficiency in Greenland. to enzyme replacement therapy. Arch Dis Child. Moshiree B. Sucrase-isomaltase deficiency as a potential Incidence and genetic aspects. Scand J Gastroenterol. 2015;100(9):869-871. masquerader in irritable bowel syndrome. Dig Dis Sci. 1987;22(1):24-28. 36. Bjarnason I, Batt R, Catt S, Macpherson A, Maxton 2020;65(2):534-540. 22. Nichols BL Jr, Adams B, Roach CM, Ma CX, D, Menzies IS. Evaluation of differential disaccharide 6. Treem WR. Clinical aspects and treatment of congen- Baker SS. Frequency of sucrase deficiency in mucosal excretion in urine for non-invasive investigation of ital sucrase-isomaltase deficiency. J Pediatr Gastroenterol biopsies. J Pediatr Gastroenterol Nutr. 2012;55(suppl altered intestinal disaccharidase activity caused by Nutr. 2012;55(suppl 2):S7-S13. 2):S28-S30. alpha-glucosidase inhibition, primary hypolactasia, and 7. Robayo-Torres CC, Quezada-Calvillo R, Nichols 23. Chumpitazi BP, Lewis J, Cooper D, et al. Hypomor- . Gut. 1996;39(3):374-381. BL. Disaccharide digestion: clinical and molecular phic SI genetic variants are associated with childhood 37. Alfalah M, Keiser M, Leeb T, Zimmer KP, Naim aspects. Clin Gastroenterol Hepatol. 2006;4(3):276-287. chronic loose stools. PLoS One. 2020;15(5):e0231891. HY. Compound heterozygous mutations affect pro- 8. Berni Canani R, Pezzella V, Amoroso A, Cozzolino 24. Daileda T, Baek P, Sutter ME, Thakkar K. Disaccha- tein folding and function in patients with congen- T, Di Scala C, Passariello A. Diagnosing and treating ridase activity in children undergoing esophagogastro- ital sucrase-isomaltase deficiency. Gastroenterology. intolerance to carbohydrates in children. Nutrients. duodenoscopy: a systematic review. World J Gastrointest 2009;136(3):883-892. 2016;8(3):157. Pharmacol Ther. 2016;7(2):283-293. 38. McMeans AR. Congenital sucrase-isomaltase 9. Weijers HA, Van De Kamer JH, Mossel DA, Dicke 25. Haberman Y, Di Segni A, Loberman-Nachum N, deficiency: diet assessment and education guidelines. J WK. Diarrhoea caused by deficiency of sugar-splitting et al. Congenital sucrase-isomaltase deficiency: a novel Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S37-S39. enzymes. Lancet. 1960;276(7145):296-297. compound heterozygous mutation causing aberrant 39. Choosing your foods. CSIDCares. https://www. 10. Boney A, Elser HE, Silver HJ. Relationships protein localization. J Pediatr Gastroenterol Nutr. csidcares.org/treatment/diet/. Accessed September 5, among dietary intakes and persistent gastrointestinal 2017;64(5):770-776. 2020. symptoms in patients receiving enzyme treatment for 26. Garcia-Etxebarria K, Zheng T, Bonfiglio F, et al. 40. Kilby A, Burgess EA, Wigglesworth S, Walk- genetic sucrase-isomaltase deficiency. J Acad Nutr Diet. Increased prevalence of rare sucrase-isomaltase patho- er-Smith JA. Sucrase-isomaltase deficiency. A follow-up 2018;118(3):440-447. genic variants in irritable bowel syndrome patients. Clin report. Arch Dis Child. 1978;53(8):677-679. 11. Henström M, Diekmann L, Bonfiglio F, et al. Func- Gastroenterol Hepatol. 2018;16(10):1673-1676. 41. Sucraid [prescribing information]. Vero Beach, FL: tional variants in the sucrase-isomaltase gene associate 27. Puertolas MV, Fifi AC. The role of disaccharidase QOL Medical, LLC; 2019. with increased risk of irritable bowel syndrome. Gut. deficiencies in functional abdominal pain disorders—a 42. Treem WR, McAdams L, Stanford L, Kastoff G, 2018;67(2):263-270. narrative review. Nutrients. 2018;10(12):1835. Justinich C, Hyams J. Sacrosidase therapy for congen- 12. Naim HY, Heine M, Zimmer K-P. Congenital 28. Deb C, Campion S, Derrick V, et al. Sucrase-iso- ital sucrase-isomaltase deficiency. J Pediatr Gastroenterol sucrase-isomaltase deficiency: heterogeneity of inheri- maltase gene variants in patients with abnormal Nutr. 1999;28(2):137-142. tance, trafficking, and function of an intestinal enzyme sucrase activity and functional GI disorders [published

Gastroenterology & Hepatology Volume 16, Issue 10, Supplement 5 October 2020 11