nutrients Review Diagnosing and Treating Intolerance to Carbohydrates in Children Roberto Berni Canani 1,2,3,*, Vincenza Pezzella 1, Antonio Amoroso 1, Tommaso Cozzolino 1, Carmen Di Scala 1 and Annalisa Passariello 1 1 Department of Translational Medical Science, University of Naples “Federico II”, 80131 Naples, Italy; [email protected] (V.P.); [email protected] (A.A.); [email protected] (T.C.); [email protected] (C.D.S.); [email protected] (A.P.) 2 European Laboratory for the Investigation of Food Induced Diseases, University of Naples “Federico II”, 80131 Naples, Italy 3 CEINGE Advanced Biotechnologies, University of Naples “Federico II”, 80131 Naples, Italy * Correspondence: [email protected]; Tel.: +39-081-746-2680 Received: 27 October 2015; Accepted: 25 February 2016; Published: 10 March 2016 Abstract: Intolerance to carbohydrates is relatively common in childhood, but still poorly recognized and managed. Over recent years it has come to the forefront because of progresses in our knowledge on the mechanisms and treatment of these conditions. Children with intolerance to carbohydrates often present with unexplained signs and symptoms. Here, we examine the most up-to-date research on these intolerances, discuss controversies relating to the diagnostic approach, including the role of molecular analysis, and provide new insights into modern management in the pediatric age, including the most recent evidence for correct dietary treatment. Keywords: lactose intolerance; fructose malabsorption; sucrase-isomaltase deficiency; glucose-galactose malabsorption; sorbitol intolerance; trehalose intolerance; FODMAPs intolerance; breath test; molecular analysis 1. Introduction Adverse food reactions (AFR) represent a relevant problem in daily clinical practice, but are poorly recognized and managed. They are common in industrialized countries, where, depending on data collection methods and definitions, they affect up to 20% of the general population [1]. The prevalence increases significantly in patients with irritable bowel syndrome (IBS). It has been described that up to 80% of IBS patients believe that their symptoms are diet-related, of which three quarters are possibly related to intolerance to carbohydrates [2,3]. According to the main pathophysiologic mechanism, AFRs are commonly classified into different groups (Figure1)[4–8]. Nutrients 2016, 8, 157; doi:10.3390/nu8030157 www.mdpi.com/journal/nutrients Nutrients 2016, 8, 157 2 of 16 Nutrients 20162016,, 88,, 157157 22 ofof 1616 Adverse Food Reactions ImmuneImmune mediated mediated Non‐‐ImmuneImmune mediated: mediated: Food Food Intolerances Intolerances Other EnzymaticEnzymatic TransporterTransporter Food Allergy Celiac Disease Pharmacological unknownunknown Food Allergy Celiac Disease defectsdefects defectsdefects Pharmacological triggerstriggers FigureFigure 1.1. ClassificationClassification of of adverseadverse foodfood reactions reactions (AFR). (AFR). IntoleranceIntolerance toto carbohydratescarbohydrates isis thethe most commoncommon typetype of non‐‐immuneimmune‐‐mediated AFR (Figure(Figure Intolerance to carbohydrates is the most common type of non-immune-mediated AFR (Figure2). 2). The prevalence of thisthis conditioncondition has seemedseemed toto increaseincrease during thethe lastlast fewfew decades as a The prevalence of this condition has seemed to increase during the last few decades as a consequence consequenceconsequence of thethe growing raterate of carbohydratecarbohydrate consumptionconsumption inin thethe diet. National surveysurvey data inin of the growing rate of carbohydrate consumption in the diet. National survey data in the United States thethe United States have indicatedindicated that,that, over thethe past fewfew decades, consumptionconsumption of selectedselected have indicated that, over the past few decades, consumption of selected carbohydrates, largely in the carbohydrates,carbohydrates, largelylargely inin thethe formform of added sugars,sugars, has increasedincreased by up toto 900% [9].[9]. form of added sugars, has increased by up to 900% [9]. FigureFigure 2.2.2.Classification Classification of carbohydrateof carbohydratecarbohydrate intolerances. intolerances.intolerances. CSID: CongenitalCSID: Congenital Sucrase-Isomaltase Sucrase‐‐Isomaltase Deficiency;Isomaltase Deficiency;GGM: Glucose-Galactose GGM: Glucose Malabsorption;‐‐Galactose Malabsorption; CLD: Congenital CLD: LactaseCongenital Deficiency. Lactase Deficiency. Symptoms of intoleranceintolerance toto carbohydratescarbohydrates are primarily due toto deficiency of enzymes or Symptoms of intolerance to carbohydrates are primarily due to deficiency of enzymes or transporterstransporters or overloading of a transporttransport systemsystem locatedlocated on thethe brush border of thethe epithelium transporters or overloading of a transport system located on the brush border of the epithelium lininglining thethe smallsmall intestineintestine (Figure(Figure 3). Non‐‐absorbed carbohydratescarbohydrates inin thethe intestinalintestinal tracttract drive fluidsfluids lining the small intestine (Figure3). Non-absorbed carbohydrates in the intestinal tract drive fluids into intointo thethe lumenlumen throughthrough an osmotic force,force, causingcausing osmotic diarrhea. Moreover, non‐‐absorbed the lumen through an osmotic force, causing osmotic diarrhea. Moreover, non-absorbed carbohydrates carbohydratescarbohydrates are fermentedfermented by gut microbiota toto gas. are fermented by gut microbiota to gas. Nutrients 2016, 8, 157 3 of 16 Nutrients 2016, 8, 157 3 of 16 FigureFigure 3. 3.Mechanisms Mechanisms involved involved in in main main carbohydratecarbohydrate intolerances. (A (A) )Lactose Lactose intolerance intolerance due due to to deficiencydeficiency of of lactase lactase enzyme; enzyme; ( B(B)) glucose-galactose glucose‐galactose malabsorption malabsorption due due to to a agenetic genetic defect defect in inSGLT1 SGLT1 expression; (C) fructose malabsorption due to dose‐dependent transporters overloading; (D) sucrase expression; (C) fructose malabsorption due to dose-dependent transporters overloading; (D) sucrase malabsorption due to a genetic defect in sucrase‐isomaltase activity. malabsorption due to a genetic defect in sucrase-isomaltase activity. All these events are responsible for the clinical symptoms, such as distension of the small bowel,All these non‐ eventsfocal abdominal are responsible pain associated for the clinical with symptoms,bloating and such flatulence, as distension nausea, of theincreased small bowel,gut non-focalmotility, abdominal and diarrhea pain [2,10–14]. associated Extraintestinal with bloating symptoms, and flatulence, such as nausea, headache, increased vertigo, gut memory motility, andimpairment, diarrhea [ 2and,10– 14lethargy]. Extraintestinal have been symptoms,described in such less as than headache, 20% of vertigo,subjects memorywith carbohydrate impairment, andintolerance lethargy have[15,16]. been These described systemic in symptoms less than 20%could of be subjects the result with of carbohydratetoxic metabolites, intolerance produced [15 by,16 ]. Thesesugar systemic fermentation symptoms of colonic could bacteria, be the resultthat can of alter toxic cell metabolites, signalling produced mechanisms by (Figure sugar fermentation 4). of colonic bacteria, that can alter cell signalling mechanisms (Figure4). These manifestations frequently lead to investigations to rule out other organic disorders at intestinal and extra-intestinal levels, including invasive procedures. Thus, there is a large unmet need for a clear diagnosis as well as consistent and effective advice on dietary treatments for these conditions. There have been significant advances in understanding the scientific basis of carbohydrate intolerances, and new forms (e.g., Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols intolerance, and non-celiac gluten sensitivity) have been identified [1,14]. Intolerance to carbohydrates often begins in childhood. Here, we examine the most up-to-date research on childhood intolerance to carbohydrates, discuss controversies relating to the diagnostic approach, including the role of molecular analysis, and provide new insights into the modern management of these conditions. Nutrients 2016, 8, 157 4 of 16 Nutrients 2016, 8, 157 4 of 16 Figure 4. Pathogenesis of gut and brain symptoms in patients with intolerance to carbohydrates. 2. GeneticThese manifestations Etiology with Early frequently Onset lead Carbohydrate to investigations Intolerances to rule out other organic disorders at intestinal and extra‐intestinal levels, including invasive procedures. Thus, there is a large unmet 2.1.need Congenital for a clear Sucrase-Isomaltase diagnosis as well Deficiency as consistent (CSID) and effective advice on dietary treatments for these conditions. There have been significant advances in understanding the scientific basis of Congenital sucrose-isomaltase deficiency (CSID, OMIM #222900) is a rare autosomal recessive carbohydrate intolerances, and new forms (e.g., Fermentable Oligosaccharides, Disaccharides, inherited disease of the small intestine resulting from genetic mutations in sucrase-isomaltase, an Monosaccharides, and Polyols intolerance, and non‐celiac gluten sensitivity) have been identified enzyme complex responsible for catalyzing the hydrolysis of dietary sucrose and starch [17]. Decreased [1,14]. Intolerance to carbohydrates often begins in childhood. Here, we examine the most up‐to‐