Evaluation for celiac disease (CD), an autoimmune enteropathy triggered by grain proteins in wheat, barley, rye, and possibly oats, is a common indication for pediatric endoscopy and biopsy. Duodenal or jejunal biopsy remains key for the initial diagnosis of CD. Small intestinal pathology may be diffuse or focal in CD, and histologic findings are nonspecific and must be interpreted in conjunction with clinical and serologic findings. A standardized grading system for CD biopsies is recommended. This review article summarizes the epidemiology, clinical manifestations, genetics, pathogenesis, and serologic and histologic findings of CD. Clinical management of CD and general handling of small intestinal biopsies are also addressed.
GodkinA, JewellD.The pathogenesis of celiac disease. Gastroenterology1998;115:206–210.
2.
TrierJS. Celiac sprue. N. Engl. J. Med.1991;325:1709–1719.
3.
VoltaU, MolinaroN, De FranchisR, Correlation between IgA antiendomysial antibodies and subtotal villous atrophy in dermatitis herpetiformis. J. Clin. Gastroenterol.1992;14:298–301.
4.
DieterichW, LaagE, Bruckner-TudermanL, Antibodies to tissue transglutaminase as serologic markers in patients with dermatitis herpetiformis. J. Invest. Dermatol.1999;113:133–136.
DieterichW, EhnisT, BauerM, Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat. Med.1997;3:797–801.
7.
SchuppanD.Current concepts of celiac disease pathogenesis. Gastroenterology2000;119:234–242.
8.
NotT, HorvathK, HillID, Celiac disease risk in the USA: high prevalence of antiendomysium antibodies in healthy blood donors. Scand. J. Gastroenterol.1998;33:494–498.
9.
VoltaU, BellentaniS, BianchiFB, High prevalence of celiac disease in Italian general population. Dig. Dis. Sci.2001;46:1500–1505.
10.
RutzR, RitzlerE, FierzW, HerzogD.Prevalence of asymptomatic celiac disease in adolescents of eastern Switzerland. Swiss. Med. Wkly.2002;132:43–48.
11.
HillI, FasanoA, SchwartzR, CountsD, GlockM, HorvathK.The prevalence of celiac disease in at-risk groups of children in the United States. J. Pediatr.2000;136:86–90.
12.
StroberW.Gluten-sensitive enteropathy In: KingR, RotterJI, MotulskyAG, editors. Genetic Basis of Common Diseases. New York: Oxford University Press, 1992:279–304.
13.
RischN.Assessing the role of HLA-linked and unlinked determinants of disease. Am. J. Hum. Genet.1987;40:1–14.
14.
BonamicoM, MarianiP, MazzilliMC, Frequency and clinical pattern of celiac disease among siblings of celiac children. J. Pediatr. Gastroenterol. Nutr.1996;23:159–163.
15.
FarreC, HumbertP, VilarP, Serological markers and HLA-DQ2 haplotype among first-degree relatives of celiac patients. Catalonian Coeliac Disease Study Group. Dig. Dis. Sci.1999;44:2344–2349.
16.
Korponay-SzaboI, KovacsJ, LorinczM, TorokE, GoraczG.Families with multiple cases of gluten-sensitive enteropathy. Z. Gastroenterol.1998;36:553–558.
17.
MurrayJA. The widening spectrum of celiac disease. Am. J. Clin. Nutr.1999;69:354–365.
18.
HolmesGK. Non-malignant complications of coeliac disease. Acta Paediatr. (Suppl)1996;412:68–75.
19.
HogganR.Considering wheat, rye, and barley proteins as aids to carcinogens. Med. Hypotheses1997;49:285–288.
20.
EganLJ, WalshSV, StevensFM, ConnollyCE, EganEL, McCarthyCF. Celiac-associated lymphoma. A single institution experience of 30 cases in the combination chemotherapy era. J. Clin. Gastroenterol.1995;21:123–129.
21.
FergusonA, KingstoneK.Coeliac disease and malignancies. Acta Paediatr. (Suppl)1996;412:78–81.
22.
BaoF, YuL, BabuS, One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. J. Autoimmun.1999;13:143–148.
VenturaA, MagazzuG, GrecoL.Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. SIGEP Study Group for Autoimmune Disorders in Celiac Disease. Gastroenterology1999;117:297–303.
27.
ZubillagaP, VitoriaJC, ArrietaA, EchanizP, Garcia-MasdevallMD. Down's syndrome and celiac disease. J. Pediatr. Gastroenterol. Nutr.1993;16:168–171.
28.
BookL, HartA, BlackJ, FeoloM, ZoneJJ, NeuhausenSL. Prevalence and clinical characteristics of celiac disease in Down's syndrome in a US study. Am. J. Med. Genet.2001;98:70–74.
29.
LewisC, BookL, BlackJ, Celiac disease and human leukocyte antigen genotype: accuracy of diagnosis in self-diagnosed individuals, dosage effect, and sibling risk. J. Pediatr. Gastroenterol. Nutr.2000;31:22–27.
30.
LiuJ, JuoSH, HolopainenP, Genomewide linkage analysis of celiac disease in Finnish families. Am. J. Hum. Genet.2002;70:51–59.
31.
BevanS, PopatS, HoulstonRS. Relative power of linkage and transmission disequilibrium test strategies to detect non-HLA linked coeliac disease susceptibility genes. Gut1999;45:668–671.
32.
PetronzelliF, BonamicoM, FerranteP, Genetic contribution of the HLA region to the familial clustering of coeliac disease. Ann. Hum. Genet. 1997;61(Pt 4):307–317.
33.
ZhongF, McCombsCC, OlsonJM, An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland. Nat. Genet.1996;14:329–333.
34.
HoulstonRS, TomlinsonIP, FordD, Linkage analysis of candidate regions for coeliac disease genes. Hum. Mol. Genet.1997;6:1335–1339.
35.
KingAL, YiannakouJY, BrettPM, A genome-wide family-based linkage study of coeliac disease. Ann. Hum. Genet. 2000;64(Pt 6):479–490.
36.
NeuhausenSl, FeoloM, CampNJ. FarnhamJ, BookL, ZoneJJ (2002) “Genome-wide linkage analysis for celiac disease in North American families”Am. J. Med. Genet.111: 1–9
37.
GrecoL, BabronMC, CorazzaGR, Existence of a genetic risk factor on chromosome 5q in Italian coeliac disease families. Ann. Hum. Genet.2001;65(Pt 1):35–41.
38.
BourgainC, GeninE, HolopainenP, Use of closely related affected individuals for the genetic study of complex diseases in founder populations. Am. J. Hum. Genet.2001;68:154–159.
39.
MolbergO, McadamSN, KornerR, Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med.1998;4:713–717.
40.
NilsenEM, JahnsenFL, LundinKE, Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology1998;115:551–563.
41.
Westerholm-OrmioM, GariochJ, KetolaI, SavilahtiE.Inflammatory cytokines in small intestinal mucosa of patients with potential coeliac disease. Clin. Exp. Immunol.2002;128:94–101.
42.
SavilahtiE, AratoA, VerkasaloM.Intestinal gamma/delta receptor-bearing T lymphocytes in celiac disease and inflammatory bowel diseases in children. Constant increase in celiac disease. Pediatr. Res.1990;28:579–581.
43.
BarshackI, GoldbergI, ChowersY, WeissB, HorowitzA, KopolovicJ.Immunohistochemical analysis of candidate gene product expression in the duodenal epithelium of children with coeliac sprue. J. Clin. Pathol.2001;54:684–688.
44.
CiccocioppoR, Di SabatinoA, ParroniR, Increased enterocyte apoptosis and Fas-Fas ligand system in celiac disease. Am. J. Clin. Pathol.2001;115:494–503.
45.
PicarelliA, MaiuriL, MazzilliMC, Gluten-sensitive disease with mild enteropathy. Gastroenterology1996;111:608–616.
46.
MurrayJA. Serodiagnosis of celiac disease. Clin. Lab. Med.1997;17:445–464.
47.
GrodzinskyE, JanssonG, SkoghT, StenhammarL, Falth-MagnussonK.Anti-endomysium and anti-gliadin antibodies as serological markers for coeliac disease in childhood: a clinical study to develop a practical routine. Acta. Paediatr.1995;84:294–298.
48.
FarrellRJ, KellyCP. Celiac sprue. N. Engl. J. Med.2002;346:180–188.
49.
WeissR.Gliadin Antibodies, IgA and IgG, ARUP's Guide to Pediatric Clinical Laboratory Testing, 2nd edition. Salt Lake City: ARUP Laboratories, Inc., 2000:192–193.
50.
JaskowskiTD, SchroderC, MartinsTB, LitwinCM, HillHR. IgA antibodies against endomysium and transglutaminase: a comparison of methods. J. Clin. Lab. Anal.2001;15:108–111.
51.
TronconeR, MauranoF, RossiM, IgA antibodies to tissue transglutaminase: an effective diagnostic test for celiac disease. J. Pediatr.1999;134:166–171.
52.
VitoriaJC, ArrietaA, ArranzC, Antibodies to gliadin, endomysium, and tissue transglutaminase for the diagnosis of celiac disease. J. Pediatr. Gastroenterol. Nutr.1999;29:571–574.
53.
HoffenbergEJ, BaoF, EisenbarthGS, Transglutaminase antibodies in children with a genetic risk for celiac disease. J. Pediatr.2000;137:356–360.
54.
RussoPA, ChartrandLJ, SeidmanE.Comparative analysis of serologic screening tests for the initial diagnosis of celiac disease. Pediatrics1999;104(1 Pt 1):75–78.
55.
TrierJS. Diagnosis of celiac sprue. Gastroenterology1998;115:211–216.
56.
ScottBB, LosowskyMS. Patchiness and duodenal-jejunal variation of the mucosal abnormality in coeliac disease and dermatitis herpetiformis. Gut1976;17:984–992.
57.
ThomsonM, KitchingP, JonesA, Walker-SmithJA, PhillipsA.Are endoscopic biopsies of small bowel as good as suction biopsies for diagnosis of enteropathy?. J. Pediatr. Gastroenterol. Nutr.1999;29:438–441.
58.
BranskiD, FaberJ, ShinerM.A comparison of small-intestinal mucosal biopsies in children obtained by blind suction capsule with those obtained by endoscopy. J. Pediatr. Gastroenterol. Nutr.1996;22:194–196.
59.
MeeAS, BurkeM, VallonAG, NewmanJ, CottonPB. Small bowel biopsy for malabsorption: comparison of the diagnostic adequacy of endoscopic forceps and capsule biopsy specimens. B.M.J.1985;291:769–772.
60.
BranskiD, FaberJ, FreierS, Gottschalk-SabagS, ShinerM.Histologic evaluation of endoscopic versus suction biopsies of small intestinal mucosae in children with and without celiac disease. J. Pediatr. Gastroenterol. Nutr.1998;27:6–11.
61.
WeizmanZ, Ben-ZionYZ, BinsztokM, MaorE, PorathA.Correlation of clinical characteristics and small bowel histopathology in celiac disease. J. Pediatr. Gastroenterol. Nutr.1997;24:555–558.
62.
Van BeersEH, EinerhandAW, TaminiauJA, HeymansHS, DekkerJ, BullerHA. Pediatric duodenal biopsies: mucosal morphology and glycohydrolase expression do not change along the duodenum. J. Pediatr. Gastroenterol. Nutr.1998;26:186–193.
63.
MarshMN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology1992;102:330–354.
64.
JeffersMD, HourihaneDO. Coeliac disease with histological features of peptic duodenitis: value of assessment of intraepithelial lymphocytes. J. Clin. Pathol.1993;46:420–424.
65.
ShinerM (1983) “Coeliac disease” In: Ultrastructure of the Small Intestinal Mucosa. Normal and Disease-related appearances, Springer-Verlag, New York, pp 61–95
66.
FergusonA, MurrayD.Quantitation of intraepithelial lymphocytes in human jejunum. Gut1971;12:988–994.
67.
PennaFJ, HillID, KingstonD, RobertsonK, SlavinG, ShinerM.Jejunal mucosal morphometry in children with and without gut symptoms and in normal adults. J. Clin. Pathol.1981;34:386–392.
68.
GoldsteinNS, UnderhillJ.Morphologic features suggestive of gluten sensitivity in architecturally normal duodenal biopsy specimens. Am. J. Clin. Pathol.2001;116:63–71.
69.
De GiacomoC, GianattiA, NegriniR, Lymphocytic gastritis: a positive relationship with celiac disease. J. Pediatr.1994;124:57–62.
70.
AlsaighN, OdzeR, GoldmanH, AntonioliD, OttMJ, LeichtnerA.Gastric and esophageal intraepithelial lymphocytes in pediatric celiac disease. Am. J. Surg. Pathol.1996;20:865–870.
71.
JevonGP, DimmickJE, DohilR, HassallEG. Spectrum of gastritis in celiac disease in childhood. Pediatr. Dev. Pathol.1999;2:221–226.
72.
OberhuberG, GranditschG, VogelsangH.The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur. J. Gastroenterol. Hepatol.1999;11:1185–1194.
73.
JosJ.La Biopsie de la Muqueuse Intestinale chez l'Enfant. Etude des Syndromes de Malabsorption. Paris: Foulon et Cie, 1962.
74.
StuartBM, GentAE. Atrophy of the coeliac mucosa. Eur. J. Gastroenterol. Hepatol.1998;10:523–525.
75.
HowdlePD, CorazzaGR, BullenAW, LosowskyMS. Gluten sensitivity of small intestinal mucosa in vitro: quantitative assessment of histologic change. Gastroenterology1981;80:442–450.
76.
BarnesGL, TownleyRR. Duodenal mucosal damage in 31 infants with gastroenteritis. Arch. Dis. Child1973;48:343–349.
77.
CamposJV, NetoUF, PatricioFR, WehbaJ, CarvalhoAA, ShinerM.Jejunal mucosa in marasmic children. Clinical, pathological, and fine structural evaluation of the effect of protein-energy malnutrition and environmental contamination. Am. J. Clin. Nutr.1979;32:1575–1591.
ShinerM, PutmanM, NicholsVN, NicholsBL. Pathogenesis of small-intestinal mucosal lesions in chronic diarrhea of infancy: I. A light microscopic study. J. Pediatr. Gastroenterol. Nutr.1990;11:455–463.
80.
CutzE, RhoadsJM, DrummB, ShermanPM, DuriePR, ForstnerGG. Microvillus inclusion disease: an inherited defect of brush-border assembly and differentiation. N. Engl. J. Med.1989;320:646–651.
81.
ReifenRM, CutzE, GriffithsAM, NganBY, ShermanPM. Tufting enteropathy: a newly recognized clinicopathological entity associated with refractory diarrhea in infants. J. Pediatr. Gastroenterol. Nutr.1994;18:379–385.
82.
LakeBD. Microvillus inclusion disease: specific diagnostic features shown by alkaline phosphatase histochemistry. J. Clin. Pathol.1988;41:880–882.
83.
KaufmanSS, VanderhoofJA, YoungR, PerryD, RaynorSC, MackDR. Gastroenteric inflammation in children with ulcerative colitis. Am. J. Gastroenterol.1997;92:1209–1212.
84.
RuuskaT, VaajalahtiP, ArajarviP, MakiM.Prospective evaluation of upper gastrointestinal mucosal lesions in children with ulcerative colitis and Crohn's disease. J. Pediatr. Gastroenterol. Nutr.1994;19:181–186.
85.
LenaertsC, RoyCC, VaillancourtM, WeberAM, MorinCL, SeidmanE.High incidence of upper gastrointestinal tract involvement in children with Crohn disease. Pediatrics1989;83:777–781.
86.
DadyIM, ThomasAG, MillerV, KelseyAJ. Inflammatory bowel disease in infancy: an increasing problem?. J. Pediatr. Gastroenterol. Nutr.1996;23:569–576.
87.
ShinerM, BallardJ, BrookCG, HermanS.Intestinal biopsy in the diagnosis of cow's milk protein intolerance without acute symptoms. Lancet1975;2:1060–1063.
88.
AmentME, RubinCE. Soy protein—another cause of the flat intestinal lesion. Gastroenterology1972;62:227–234.
