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REFERENCES by specific food proteins or other food constituents (eg, carbo-
1. Hyman PE, Milla PJ, Benninga MA, et al. Childhood functional gastro-
intestinal disorders: neonate/toddler. Gastroenterology 2006; 130:1519–
26.
2. Hassall E. Over-prescription of acid-suppressing medications in infants:
how it came about, why it’s wrong, and what to do about it. J Pediatr
2012;160:193–8.
3. Nelson SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of
gastroesophageal reflux during childhood: a pediatric practice-based
survey. Pediatric Practice Research Group. Arch Pediatr Adolesc Med
2000;154:150–4.
4. Nelson SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of
gastroesophageal reflux during infancy. A pediatric practice-based
survey. Pediatric Practice Research Group. Arch Pediatr Adolesc
Med 1997;151:569–72.
5. Hegar B, Dewanti NR, Kadim M, et al. Natural evolution of regurgita-
tion in healthy infants. Acta Paediatr 2009;98:1189–93.
6. Vandenplas Y, Rudolph CD, Di LC, et al. Pediatric gastroesophageal
Downloaded from https://journals.lww.com/jpgn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3FJPxKcC74DFrzh3ryovFL/pWPyNmGN7rUc9UXWFmLIM= on 06/11/2020
reflux clinical practice guidelines: joint recommendations of the North
American Society for Pediatric Gastroenterology, Hepatology, and
Nutrition (NASPGHAN) and the European Society for Pediatric Gas-
troenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gas-
troenterol Nutr 2009;49:498–547.
7. Moore DJ, Tao BS, Lines DR, et al. Double-blind placebo-controlled
trial of omeprazole in irritable infants with gastroesophageal reflux.
J Pediatr 2003;143:219–23.
8. Horvath A, Dziechciarz P, Szajewska H. The effect of thickened-feed
interventions on gastroesophageal reflux in infants: systematic review
and meta-analysis of randomized, controlled trials. Pediatrics 2008;
122:e1268–77.
9. Vandenplas Y. Thickened infant formula does what it has to do: decrease
regurgitation. Pediatrics 2009;123:e549–50.
10. Fleisher DR. Functional vomiting disorders in infancy: innocent vomit-
ing, nervous vomiting, and infant rumination syndrome. J Pediatr
1994;125 (6 Pt 2):S84–94.
11. Menking M, Wagnitz JG, Burton JJ, et al. Rumination—a near fatal
psychiatric disease of infancy. N Engl J Med 1969;280:802–4.
12. Luckey RE, Watson CM, Musick JK. Aversive conditioning as a means
of inhibiting vomiting and rumination. Am J Ment Defic 1968;73:139–42.
13. Whitehead WE, Drescher VM, Morrill-Corbin E, et al. Rumination
syndrome in children treated by increased holding. J Pediatr Gastro-
enterol Nutr 1985;4:550–6.
14. Sheinbein M. Treatment for the hospitalized infantle ruminator: pro-
grammed brief social behavior reinforcers. Clin Pediatr (Phila)
1975;14:719–24.
15. Cohen SA, Hendricks KM, Eastham EJ, et al. Chronic nonspecific
diarrhea. A complication of dietary fat restriction. Am J Dis Child
1979;133:490–2.
16. Fenton TR, Harries JT, Milla PJ. Disordered small intestinal motility: a
rational basis for toddlers’ diarrhoea. Gut 1983;24:897–903.
17. Kneepkens CM, Jakobs C, Douwes AC. Apple juice, fructose, and
chronic nonspecific diarrhoea. Eur J Pediatr 1989;148:571–3.
18. Tripp JH, Muller DP, Harries JT. Mucosal (Naþ-Kþ)-ATPase and
adenylate cyclase activities in children with toddler diarrhea and the
postenteritis syndrome. Pediatr Res 1980;14:1382–6.
19. Wender EH. Chronic nonspecific diarrhea. Behavioral aspects. Postgrad
Med 1977;62:83–8.
Gastrointestinal Food Allergy and
Intolerance in Infants and
Young Children
Ralf G. Heine
I nfants and young children may present with a diverse range of
gastrointestinal (GI) allergies and intolerances that are triggered
S38
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hydrates, fat). It may be clinically difficult to distinguish these
conditions because there is significant overlap in symptoms. There
are several well-characterized food allergic GI conditions that
usually manifest in the first weeks to months of life and may even
occur in exclusively breast-fed infants. GI food allergy needs to be
distinguished from nonimmunological intolerance reactions to
foods. Examples are carbohydrate or fat malabsorption, which
presents with diarrhoea and abdominal pain following ingestion
of the offending food. In addition, dietary factors may directly
influence gut functioning and motility. For example, dietary long-
chain triglycerides may delay gastric emptying, which predisposes
to vomiting or upper abdominal pain. Because of the diverse
spectrum of diseases and underlying mechanisms it may sometimes
be difficult to define an exact diagnosis, and empirical treatment of
suspected adverse reactions to foods with dietary manipulations is
common practice.
GI FOOD ALLERGY
With the rise in allergic disorders, GI food allergies have
become a relatively common problem in infants and young children
(1). Population-based studies on the epidemiology of challenge-
proven immunoglobulin E (IgE)–mediated food allergy in 1-year-
old Australian infants found a high prevalence of >10% (2).
Although non-IgE-mediated food allergy is thought to be relatively
common, its exact prevalence in infancy is not known. GI food
allergy involves non-IgE-mediated, delayed GI reactions that may
cause upper and lower GI pathologies, including mucosal inflam-
mation, ulceration, small intestinal villous damage, changes in
intestinal permeability, or motility abnormalities. Symptoms in
young children include persistent vomiting/regurgitation, chronic
diarrhoea, feeding difficulties, unsettled behaviours, and sleep
pattern disturbance.
Relatively little progress has been made in developing
diagnostic tests for cell-mediated GI food allergy. Because no
single diagnostic test for non-IgE-mediated food allergy is avail-
able, the diagnosis relies on clinical improvement after food
elimination and relapse upon challenge. GI biopsies may provide
further important diagnostic clues. The cumbersome diagnostic
process and lack of characteristic symptoms may lead to significant
diagnostic delay and may result in adverse clinical outcomes,
including growth impairment or nutritional deficiency states (eg,
iron-deficiency anaemia). Early diagnosis and appropriate treat-
ment are therefore crucial in preventing the nutritional compli-
cations of GI food allergy.
Food Protein–Induced Enteropathy
Infants and young children with food protein–induced
enteropathy typically present with chronic diarrhea and failure to
thrive. Cow’s milk and soy milk protein are considered the main
offending food allergens. The prevalence of food protein–induced
enteropathy appears to have decreased since the development
of ‘‘humanized’’ cow’s milk and soy formula. Current reliable
From the Department of Gastroenterology & Clinical Nutrition, Royal
Children’s Hospital, Melbourne, Australia.
Correspondence to Ralf G. Heine, MD, Department of Gastroenterology &
Clinical Nutrition, Royal Children’s Hospital Melbourne, Parkville
3052, Victoria, Australia (e-mail: ralf.heine@rch.org.au).
The author reports no conflicts of interest.
Copyright # 2013 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/01.mpg.0000441934.92221.ca
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 JPGN
Volume 57, Supplement 1, December 2013
prevalence figures are not available. Allergic inflammation in the
small intestine causes mucosal damage with distortion of the villous
architecture. Histological features share strong similarities with
untreated coeliac disease, which is the closest differential diagnosis.
Early studies in cow’s-milk–sensitive enteropathy demonstrated
that mucosal damage is mediated by eosinophils in the presence of
vascular cell adhesion molecule-1 (3). Cow’s-milk–specific
lymphocytes were identified in biopsies of patients with duodenal
eosinophilic gastroenteritis or food protein–induced enteropathy
(4). In addition, localised production of IgE in the mucosa of the
small intestine (in the absence of specific serum IgE) may be
implicated in the pathogenesis of food allergic enteropathies (5).
The clinical presentation of infants with cow’s-milk protein–
induced enteropathy is similar to that of coeliac disease. These
formula-fed infants present with chronic diarrhoea, vomiting, and
poor weight gain and may develop associated micronutrient
deficiencies (eg, iron deficiency, rickets). If treatment is delayed,
infants may develop protein-energy malnutrition with growth impair-
ment. Infants with cow’s-milk enteropathy develop secondary lactose
malabsorption resulting from reduced expression of brush border
lactase in the shortened intestinal villi. Lactose, therefore, needs to be
eliminated from the infant’s diet until the normal villous architecture
has been restored. Soy formula and extensively hydrolysed formulae
are commonly used in the treatment of cow’s-milk enteropathy (6).
Strict cow’s-milk protein elimination needs to be continued until
tolerance develops, usually between 12 and 24 months of age. In a
subset of patients, residual GI symptoms may persist to school age (7).
Food Protein–Induced Enterocolitis Syndrome
Food protein–induced enterocolitis syndrome (FPIES) is
characterized by potentially severe GI reactions with profuse vomit-
ing and dehydration (8). In a population-based study, FPIES reactions
occurred in 0.34% of infants (9). As with most cell-mediated food
allergic disorders, the pathological mechanisms causing FPIES are
poorly understood. The term enterocolitis may be misleading because
direct evidence for allergic inflammation in the small intestine and
colon is missing. Clinical symptoms include profuse vomiting and
diarrhoea, with onset 2 to 4 hours after a meal. Protracted vomiting
may lead to hypovolaemic shock, which is present in approximately
20% of patients with FPIES. These infants present with pallor,
lethargy, and floppiness. Cutaneous signs are absent, which, apart
from the timing of reactions, is an important distinguishing clinical
feature against anaphylaxis. No diagnostic test, other than food
challenge, is available to confirm the diagnosis. The diagnosis is
therefore often not established at first presentation, and infants may
develop recurrent FPIES reactions before this type of food allergy is
recognized (10). FPIES may be mistaken for gastroenteritis, sepsis, or
even intestinal obstruction (11). Cow’s milk and soy are considered
the main causative allergens (8). Solid foods, including rice, other
cereals, and poultry meats also may cause FPIES reactions in infancy
(12,13). FPIES to multiple food allergens is relatively common. The
condition does not appear to occur in breast-fed infants. Maternal
elimination diets in breast-fed infants are therefore not required (6).
The treatment of FPIES involves strict avoidance of the offending
food proteins. Tolerance usually is assessed by food challenge at
approximately 2 years of age. Because of the risk of significant
vomiting and dehydration during a challenge, these challenges
usually are performed in hospital.
Food Protein–Induced Proctocolitis
Food protein–induced proctocolitis is a relatively common
and benign form of GI food allergy that manifests with low-grade
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Infant Crying, Colic, and GI Discomfort in Early Childhood
diarrhoea and bright rectal bleeding in the first weeks of life (14).
Infantile proctocolitis is the most common cause of low-grade rectal
bleeding in infants younger than 3 months old (15). Exact preva-
lence figures in infancy are not available. Symptoms usually
develop between 3 and 6 weeks of age, but they may be seen
occasionally in older infants. Infantile proctocolitis occurs in both
breast- and formula-fed infants (16). The clinical presentation is
generally limited to low-grade diarrhoea containing small amounts
of fresh blood. Infants are otherwise healthy. Because blood loss is
usually minimal, clinically significant anaemia is uncommon.
Endoscopic biopsies typically demonstrate an eosinophilic procto-
colitis with the presence of >6 to 10 eosinophils per microscopic
field at high power (16). Numbers of intraepithelial lymphocytes,
predominantly CD8þ cells, also are increased (17). The differential
diagnosis of allergic proctocolitis in infants includes bacterial
gastroenteritis, anal fissures, juvenile polyps, or other nonallergic
forms of colitis, such as chronic granulomatous disease or inflam-
matory bowel disease. The treatment of infantile allergic procto-
colitis involves the dietary elimination of the offending food
protein. In the majority of cases, elimination of cow’s-milk protein
is sufficient and can be achieved by a maternal elimination diet in
breast-fed infants or the use of an extensively hydrolysed hypoal-
lergenic formula. The prognosis of infantile allergic proctocolitis is
excellent, and most infants outgrow the condition between 9 and
12 months of age (16).
FOOD INTOLERANCES AND CARBOHYDRATE
MALABSORPTION
Carbohydrate malabsorption in early childhood presents with
intermittent, food-associated diarrhea, abdominal bloating, and
pain. It is therefore one of the main differential diagnoses of GI
food allergy. The diagnostic overlap is particularly close between
non-IgE-mediated cow’s-milk allergy and lactose malabsorption.
Other forms of carbohydrate malabsorption, including congenital
sucrase-isomaltase deficiency (18), also may masquerade as food
allergy. Lactose and fructose malabsorption often are implicated in
children with recurrent abdominal pain; however, clinical trials
have demonstrated that these conditions are generally not associ-
ated with recurrent abdominal pain unless a clear history of intol-
erance to fruit or cow’s milk is evident (19).
Lactose Intolerance/Malabsorption
Lactose is a disaccharide that consists of 2 sugar molecules,
glucose and galactose, that are linked via a b-1!4 glycosidic bond.
Lactose is the main carbohydrate in human milk and occurs at a
mean concentration of 56.8 g/L (range 43–65 g/L) (20). Lactose is
converted to lactic acid by intestinal bacteria, including Strepto-
coccus lactis (21). In addition, nonabsorbed lactase is fermented by
colonic bacteria to short-chain fatty acids (eg, butyrate) and hydro-
gen (22). In breast-fed infants, low-grade lactose malabsorption is
considered physiological (23). In this age group, lactose may act as
a conditional prebiotic; however, the prebiotic effects of lactose on
faecal biodiversity and early immune modulation are still poorly
understood (22,24).
Lactose requires enzymatic hydrolysis before its subunits
D-glucose and D-galactose can be absorbed (25). Lactase is a
member of the b-galactosidase family, with a molecular weight
of 150 kDa. The enzyme is encoded by a gene located on chromo-
some 2 (26). Lactase is expressed in the brush border of mature
enterocytes’s enzyme and has its highest expression in the mid-
jejunum. Maximum lactase expression occurs during first months of
life (27). Lactase transcription is gradually downregulated after
weaning. There are significant genetic and ethnic differences in the
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 Shamir et al
rate of decline of lactase activity beyond infancy. In 65% to 70% of
the world’s population, lactase activity significantly declines by
adult life (nonpersistence). Lactase nonpersistence is linked to
2 main single nucleotide polymorphisms upstream from the lactase
gene, C/T-13910 and G/A-22018 (28,29). Heterozygotes have
intermediate lactase levels and are more susceptible to secondary
lactose intolerance during illness. Lactase persistence is more
common in people of northern European, west African or Middle
Eastern backgrounds (30).
Congenital (primary) lactose malabsorption is a rare genetic
disorder that occurs in mainly Finland and western Russia (31).
Infants present with severe diarrhoea and growth failure in the
newborn period. Lactase activity is low or completely absent from
an otherwise normal intestinal epithelium. Several mutations in the
lactase gene have been identified. Secondary lactose malabsorption
is relatively common in infancy and is the result of another
underlying disorder, including infective gastroenteritis, cow’s-milk
protein–induced enteropathy, or rare epithelial dysplasia syn-
dromes. Viral GI infection and cow’s-milk enteropathy are by
far the most common causes of secondary lactose malabsorption
in infancy.
Lactose malabsorption in infancy presents with abdominal
distension, diarrhea, and perianal excoriation caused by acidic
stools. Depending on the underlying pathology and duration of
symptoms, weight gain also may be slow (32). The treatment in
formula-fed infants consists of lactose restriction, by shifting to a
lactose-reduced, cow’s-milk–based formula. In breast-fed infants,
it is more difficult to limit the intake of lactose. Expressed breast
milk can be incubated with lactase if symptoms are severe. The need
for ongoing lactose restriction depends on the type of the underlying
process. In infants with infective gastroenteritis, adequate lactase
activity is usually restored within 2 to 4 weeks; however, in very
young infants the recovery from gastroenteritis may be delayed. If
cow’s-milk enteropathy is suspected, the infant should be started on
a hypoallergenic formula and dietary cow’s-milk protein should be
avoided. In breast-fed infants, a maternal cow’s-milk–free diet may
be beneficial.
Fructose Malabsorption
Fructose is a monosaccharide that occurs naturally in fruit,
honey, and some vegetables. Fructose is absorbed by glucose-
facilitated absorption via the intestinal transporters GLUT2 and
GLUT5 (33). Absorption is increased in the presence of equimolar
amounts (1:1) of glucose (34). Patients with fructose malabsorption
have a limited capacity to absorb fructose. Fructose malabsorption
is common in young children and generally improves with age. The
diagnosis of fructose malabsorption often can be made by taking a
careful dietary history and by assessing the response to dietary
fructose restriction. Alternatively, the diagnosis can be made objec-
tively based on breath hydrogen testing after an oral fructose dose
(35). Rates of fructose malabsorption (based on fructose breath
hydrogen testing) were 88.2% in infants younger than 1 year of age,
66.6% in 1- to 5-year-olds, 40.4% in 6- to 10-year-olds, and 27.1%
in 10- to 15-year-olds (36). These results most likely reflect the
normal maturation of fructose absorption with age, and not all
children show clinical symptoms during a positive breath hydrogen
test. Debate, therefore, continues as to whether fructose malabsorp-
tion in children is a distinct disease state or a normal variant (37).
Fermentation of nonabsorbed fructose by intestinal bacteria
causes intestinal gas production, flatulence, abdominal pain, and
diarrhoea. In young children, fructose malabsorption may present as
toddler’s diarrhoea. These young children have a long-standing
history of low-grade diarrhoea, but they generally achieve normal
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JPGN
Volume 57, Supplement 1, December 2013
weight gain and linear growth. Older children may develop irritable
bowel syndrome–like symptoms, with central abdominal pain and
bloating. The dietary treatment involves the elimination of high-
fructose foods (containing >3 g of fructose per serving). Elimin-
ation of high-fructose fruit (eg, apple, pear, watermelon, raisins,
dried fruit), fruit juice, honey, and high-fructose corn syrup often is
sufficient in young children (38,39). The role of fructans (non-
absorbable fructose polymers) in children with fructose malabsorp-
tion is less clear. There is increasing evidence that diets low in
fermentable oligosaccharides, disaccharides, monosaccharides, and
polyols are effective in the treatment of adults with irritable bowel
syndrome (40); however, the use of low–fermentable oligosaccha-
ride, disaccharide, monosaccharide, and polyol diets in young
children is still controversial. The extent of fructose and fructan
elimination needs to be individualised in children. In general, the
low-fructose diet can be relaxed over time. A paediatric dietitian
should be involved to assess the nutritional adequacy of the diet and
to monitor growth parameters.
Coeliac Disease and Noncoeliac Gluten
Sensitivity
Coeliac disease (CD) is a gluten-sensitive autoimmune dis-
ease that has returned to the scientific spotlight. CD is currently
considered a common disorder. Population-based screening in
Finland and Europe suggests a community prevalence of approxi-
mately 1% (41,42). During the past decade, there have been
significant breakthroughs in the understanding of the pathophysio-
logy of CD, particularly regarding the involvement of human
leucocyte antigens (HLA-DQ2/DQ8) and tissue transglutaminase
in the immune processing of gluten-derived peptides by antigen-
presenting cells and T lymphocytes (43,44). Highly sensitive and
specific serological markers such as serum IgA and IgG antibodies
against tissue transglutaminase and deamidated gliadin peptides
have become available in recent years (45,46). The combination of
HLA-DQ2/DQ8 screening and antibody testing has significantly
improved the diagnostic accuracy of the serological diagnosis of
CD. Despite these advances, the diagnosis of CD still requires
confirmation by small bowel biopsy (47–49).
The assessment of adverse reactions to wheat in children is
complex. Apart from CD, there is increasing recognition of non-
IgE-mediated wheat allergy (presenting with food protein–induced
proctocolitis or enterocolitis) and noncoeliac gluten sensitivity
(NCGS) (50). The pathophysiology of NCGS is still poorly under-
stood. Infants and children with non-IgE-mediated wheat allergy or
NCGS do not have evidence of CD but have reproducible GI
reactions after gluten challenge. Fructans in wheat may contribute
to GI symptoms, although children with fructose malabsorption
often tolerate small amounts of wheat. From a practical perspective,
it is important to rule out CD before wheat is eliminated from a
child’s diet. A CD serology and HLA-DQ2/DQ8 screen is a useful
diagnostic tool to assess for possible CD. Slow reintroduction of
increasing amounts of wheat into the diet, as tolerated, should be
attempted in patients with non-IgE-mediated wheat allergy or
NCGS; however, patients with CD need to remain on a lifelong,
strict gluten-free diet.
REFERENCES
1. Sicherer SH. Epidemiology of food allergy. J Allergy Clin Immunol
2011;127:594–602.
2. Osborne NJ, Koplin JJ, Martin PE, et al. Prevalence of challenge-proven
IgE-mediated food allergy using population-based sampling and pre-
determined challenge criteria in infants. J Allergy Clin Immunol
2011;127:668–76.
www.jpgn.org
 JPGN
Volume 57, Supplement 1, December 2013
3. Chung HL, Hwang JB, Kwon YD, et al. Deposition of eosinophil-
granule major basic protein and expression of intercellular adhesion
molecule-1 and vascular cell adhesion molecule-1 in the mucosa of the
small intestine in infants with cow’s milk-sensitive enteropathy.
J Allergy Clin Immunol 1999;103:1195–201.
4. Beyer K, Castro R, Birnbaum A, et al. Human milk-specific mucosal
lymphocytes of the gastrointestinal tract display a TH2 cytokine profile.
J Allergy Clin Immunol 2002;109:707–13.
5. Lin XP, Magnusson J, Ahlstedt S, et al. Local allergic reaction in food-
hypersensitive adults despite a lack of systemic food-specific IgE.
J Allergy Clin Immunol 2002;109:879–87.
6. Allen KJ, Davidson GP, Day AS, et al. Management of cow’s milk
protein allergy in infants and young children: an expert panel perspec-
tive. J Paediatr Child Health 2009;45:481–6.
7. Kokkonen J, Haapalahti M, Laurila K, et al. Cow’s milk protein-
sensitive enteropathy at school age. J Pediatr 2001;139:797–803.
8. Leonard SA, Nowak-Wegrzyn A. Clinical diagnosis and management of
food protein-induced enterocolitis syndrome. Curr Opin Pediatr 2012;
24:739–45.
9. Katz Y, Goldberg MR, Rajuan N, et al. The prevalence and natural
course of food protein-induced enterocolitis syndrome to cow’s milk: a
large-scale, prospective population-based study. J Allergy Clin Immunol
2011;127:647–53.
10. Mehr S, Kakakios A, Frith K, et al. Food protein-induced enterocolitis
syndrome: 16-year experience. Pediatrics 2009;123:e459–64.
11. Jayasooriya S, Fox AT, Murch SH. Do not laparotomize food-protein-
induced enterocolitis syndrome. Pediatr Emerg Care 2007;23:173–5.
12. Nowak-Wegrzyn A, Sampson HA, Wood RA, et al. Food protein-
induced enterocolitis syndrome caused by solid food proteins. Pedia-
trics 2003;111 (4 Pt 1):829–35.
13. Mehr SS, Kakakios AM, Kemp AS. Rice: a common and severe cause of
food protein-induced enterocolitis syndrome. Arch Dis Child 2009;94:
220–3.
14. Odze RD, Bines J, Leichtner AM, et al. Allergic proctocolitis in infants:
a prospective clinicopathologic biopsy study. Hum Pathol 1993;24:
668–74.
15. Chang JW, Wu TC, Wang KS, et al. Colon mucosal pathology in infants
under three months of age with diarrhea disorders. J Pediatr Gastro-
enterol Nutr 2002;35:387–90.
16. Lake AM. Food-induced eosinophilic proctocolitis. J Pediatr Gastro-
enterol Nutr 2000;30(Suppl):S58–60.
17. Ormala T, Rintala R, Savilahti E. T cells of the colonic mucosa in
patients with infantile colitis. J Pediatr Gastroenterol Nutr 2001;
33:133–8.
18. McMeans AR. Congenital sucrase-isomaltase deficiency: diet assess-
ment and education guidelines. J Pediatr Gastroenterol Nutr 2012;
55(Suppl 2):S37–9.
19. Gijsbers CF, Kneepkens CM, Buller HA. Lactose and fructose malab-
sorption in children with recurrent abdominal pain: results of double-
blinded testing. Acta Paediatr 2012;101:e411–5.
20. Fusch G, Choi A, Rochow N, et al. Quantification of lactose content
in human and cow’s milk using UPLC-tandem mass spectrometry.
J Chromatogr B Analyt Technol Biomed Life Sci 2011;879:3759–62.
21. Thompson J, Chassy BM, Egan W. Lactose metabolism in Streptococ-
cus lactis: studies with a mutant lacking glucokinase and mannose-
phosphotransferase activities. J Bacteriol 1985;162:217–23.
22. Francavilla R, Calasso M, Calace L, et al. Effect of lactose on gut
microbiota and metabolome of infants with cow’s milk allergy. Pediatr
Allergy Immunol 2012;23:420–7.
23. Mobassaleh M, Montgomery RK, Biller JA, et al. Development of
carbohydrate absorption in the fetus and neonate. Pediatrics 1985;75
(1 Pt 2):160–6.
24. Szilagyi A, Shrier I, Chong G, et al. Lack of effect of lactose
digestion status on baseline fecal micoflora. Can J Gastroenterol
2009;23:753–9.
25. Gupta SK, Chong SK, Fitzgerald JF. Disaccharidase activities in
children: normal values and comparison based on symptoms and
histologic changes. J Pediatr Gastroenterol Nutr 1999;28:246–51.
www.jpgn.org
Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Infant Crying, Colic, and GI Discomfort in Early Childhood
26. Kruse TA, Bolund L, Grzeschik KH, et al. The human lactase-phlorizin
hydrolase gene is located on chromosome 2. FEBS Lett 1988;240:123–
6.
27. Hamosh M. Digestion in the newborn. Clin Perinatol 1996;23:191–209.
28. Bernardes-Silva CF, Pereira AC, de Fatima Alves da Mota, et al. Lactase
persistence/non-persistence variants, C/T_13910 and G/A_22018, as a
diagnostic tool for lactose intolerance in IBS patients. Clin Chim Acta
2007;386:7–11.
29. Enattah NS, Sahi T, Savilahti E, et al. Identification of a variant
associated with adult-type hypolactasia. Nat Genet 2002;30:233–7.
30. Itan Y, Jones BL, Ingram CJ, et al. A worldwide correlation of lactase
persistence phenotype and genotypes. BMC Evol Biol 2010;10:36.
31. Savilahti E, Launiala K, Kuitunen P. Congenital lactase deficiency. A
clinical study on 16 patients. Arch Dis Child 1983;58:246–52.
32. Northrop-Clewes CA, Lunn PG, Downes RM. Lactose maldigestion in
breast-feeding Gambian infants. J Pediatr Gastroenterol Nutr 1997;
24:257–63.
33. Jones HF, Butler RN, Brooks DA. Intestinal fructose transport and
malabsorption in humans. Am J Physiol Gastrointest Liver Physiol
2011;300:G202–6.
34. Latulippe ME, Skoog SM. Fructose malabsorption and intolerance:
effects of fructose with and without simultaneous glucose ingestion. Crit
Rev Food Sci Nutr 2011;51:583–92.
35. Mann NS, Cheung EC. Fructose-induced breath hydrogen in patients
with fruit intolerance. J Clin Gastroenterol 2008;42:157–9.
36. Jones HF, Burt E, Dowling K, et al. Effect of age on fructose
malabsorption in children presenting with gastrointestinal symptoms.
J Pediatr Gastroenterol Nutr 2011;52:581–4.
37. Kyaw MH, Mayberry JF. Fructose malabsorption: true condition or a
variance from normality. J Clin Gastroenterol 2011;45:16–21.
38. Muir JG, Shepherd SJ, Rosella O, et al. Fructan and free fructose content
of common Australian vegetables and fruit. J Agric Food Chem
2007;55:6619–27.
39. Wintermeyer P, Baur M, Pilic D, et al. Fructose malabsorption in
children with recurrent abdominal pain: positive effects of dietary
treatment. Klin Padiatr 2012;224:17–21.
40. Gibson PR, Shepherd SJ. Evidence-based dietary management of
functional gastrointestinal symptoms: the FODMAP approach. J Gas-
troenterol Hepatol 2010;25:252–8.
41. Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of celiac disease
among children in Finland. N Engl J Med 2003;348:2517–24.
42. Mustalahti K, Catassi C, Reunanen A, et al. The prevalence of celiac
disease in Europe: results of a centralized, international mass screening
project. Ann Med 2010;42:587–95.
43. Sollid LM, Qiao SW, Anderson RP, et al. Nomenclature and listing of
celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ
molecules. Immunogenetics 2012;64:455–60.
44. Karell K, Louka AS, Moodie SJ, et al. HLA types in celiac disease
patients not carrying the DQA105-DQB102 (DQ2) heterodimer:
results from the European Genetics Cluster on Celiac Disease. Hum
Immunol 2003;64:469–77.
45. Alessio MG, Tonutti E, Brusca I, et al. Correlation between IgA tissue
transglutaminase antibody ratio and histological finding in celiac dis-
ease. J Pediatr Gastroenterol Nutr 2012;55:44–9.
46. Zanini B, Magni A, Caselani F, et al. High tissue-transglutaminase
antibody level predicts small intestinal villous atrophy in adult patients
at high risk of celiac disease. Dig Liver Dis 2012;44:280–5.
47. Kurppa K, Salminiemi J, Ukkola A, et al. Utility of the new ESPGHAN
criteria for the diagnosis of celiac disease in at-risk groups. J Pediatr
Gastroenterol Nutr 2012;54:387–91.
48. Marsh MN. Gluten, major histocompatibility complex, and the small
intestine. A molecular and immunobiologic approach to the spectrum of
gluten sensitivity (‘‘celiac sprue’’). Gastroenterology 1992;102:330–
54.
49. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of
coeliac disease: time for a standardized report scheme for pathologists.
Eur J Gastroenterol Hepatol 1999;11:1185–94.
50. Lundin KE, Alaedini A. Non-celiac gluten sensitivity. Gastrointest
Endosc Clin N Am 2012;22:723–34.
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