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Celiac disease or Sprue Celiac disease (CD) is a malabsorption syndrome characterized by villous atrophy and crypt hyperplasia of the small intestinal mucosa. In genetically susceptible individuals, there is a T-cell response to a new epitope generated by the transglutaminase-mediated deamidization of dietary gliadin.


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Gluten sensitive enteropathy
INCIDENCE 1:200-300 of people in Western countries


Severe Malabsorption due to Refractory Celiac Disease Complicated by Extensive Gastric Heterotopia of the Jejunum

Tribl, Barbara MD*; Aschl, Gerhard MD†; Mitterbauer, Gerlinde MD‡; Novacek, Gottfried MD*; Vogelsang, Harald MD, PHD*; Chott, Andreas MD§

From the *Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, the §Department of Pathology, the ‡Department of Laboratory Medicine, Vienna General Hospital, Vienna, and the †Krankenhaus der Barmherzigen Schwestern, Wels, Austria.

The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 262-265 Abstract quote

Refractory celiac disease denotes that patients considered to have celiac disease fail to respond histologically to treatment with a gluten-free diet. Among several causes of nonresponsiveness, enteropathy-type T-cell lymphoma is most important because of its almost invariably rapid lethal outcome.

We present the case of a 44-year-old patient with refractory celiac disease complicated by unusually severe malabsorption. Repeated duodenal biopsies disclosed normal and slightly shortened villi, focal crypt hypertrophy, and a moderate increase of intraepithelial lymphocytes consistent with celiac disease, but unable to explain the severe malabsorption. To rule out cryptic lymphoma, push enteroscopy was done providing 21 biopsies taken along the entire jejunum. Surprisingly, about 70% of the biopsies were composed of gastric glands covered by nonabsorptive-type, strongly periodic acid-Schiff-positive surface epithelium and showed a villous architecture. Alternating with the gastric mucosa, there were areas of flat mucosa with elongated crypts and occasional erosions. Irrespective of the type of surface epithelium, intraepithelial lymphocytes were increased with counts up to 80/100 epithelial cells.

Despite harboring an aberrant immunophenotype, overt T-cell lymphoma was ruled out histologically and by lack of monoclonality, as tested by polymerase chain reaction. To the best of our knowledge, this is the first case of refractory celiac disease complicated by extensive jejunal gastric heterotopia, which might have contributed to the severe malabsorption.


Celiac disease associated with autoimmune myocarditis.

Frustaci A, Cuoco L, Chimenti C, Pieroni M, Fioravanti G, Gentiloni N, Maseri A, Gasbarrini G.

Department of Cardiology, Catholic University, Rome, Italy.

Circulation 2002 Jun 4;105(22):2611-8 Abstract quote

BACKGROUND: Both celiac disease (CD) and myocarditis can be associated with systemic autoimmune disorders; however, the coexistence of the 2 entities has never been investigated, although its identification may have a clinical impact.

METHODS AND RESULTS: We screened the serum of 187 consecutive patients with myocarditis (118 males and 69 females, mean age 41.7+/-14.3 years) for the presence of cardiac autoantibodies, anti-tissue transglutaminase (IgA-tTG), and anti-endomysial antibodies (AEAs). IgA-tTG-positive and AEA-positive patients underwent duodenal endoscopy and biopsy and HLA analysis. Thirteen of the 187 patients were positive for IgA-tTG, and 9 (4.4%) of them were positive for AEA. These 9 patients had iron-deficient anemia and exhibited duodenal endoscopic and histological evidence of CD. CD was observed in 1 (0.3%) of 306 normal controls (P<0.003). In CD patients, myocarditis was associated with heart failure in 5 patients and with ventricular arrhythmias (Lown class III-IVa) in 4 patients. From histological examination, a lymphocytic infiltrate was determined to be present in 8 patients, and giant cell myocarditis was found in 1 patient; circulating cardiac autoantibodies were positive and myocardial viral genomes were negative in all patients. HLA of the patients with CD and myocarditis was DQ2-DR3 in 8 patients and DQ2-DR5(11)/DR7 in 1 patient. The 5 patients with myocarditis and heart failure received immunosuppression and a gluten-free diet, which elicited recovery of cardiac volumes and function. The 4 patients with arrhythmia, after being put on a gluten-free diet alone, showed improvement in the arrhythmia (Lown class I).

CONCLUSIONS: A common autoimmune process toward antigenic components of the myocardium and small bowel can be found in >4% of the patients with myocarditis. In these patients, immunosuppression and a gluten-free diet can be effective therapeutic options.


Prevalence of undiagnosed coeliac syndrome in osteoporotic women.

Nuti R, Martini G, Valenti R, Giovani S, Salvadori S, Avanzati A.

Institute of Internal Medicine, Metabolic Disease Unit, University of Siena, Siena, Italy.

J Intern Med 2001 Oct;250(4):361-6 Abstract quote

OBJECTIVES: The aims of the study were to quantify the prevalence of asymptomatic coeliac disease (CD) in a cohort of osteoporotic females, and to investigate the features of bone loss. Design and subjects. We studied 255 women (mean age 66.6 +/- 8.5 SD) with primary osteoporosis (WHO diagnostic criteria). After the first CD screening with the measure of serum IgG antigliadin antibodies (IgG-AGA), 53 women showed a positive test: antibodies to tissue transglutaminase (TG-ab) were subsequently determined to confirm the diagnosis of CD. Bone metabolism was evaluated by: serum and urinary calcium, serum and urinary phosphate, serum alkaline phosphatase, urinary crosslaps, serum 25(OH)D and serum parathyroid hormone.

RESULTS: High levels of IgG-AGA and TG-ab were observed in 24 patients with a prevalence of serological disease of 9.4%. These women were characterized, in comparison with the other patients, by a statistically significant reduction in serum 25(OH)D (17.8 +/- 7.2 vs. 55.1 +/- 20.3 nmol L-1, P < 0.01) together with a significant increase of iPTH (65.1 +/- 29.7 vs. 35.1 +/- 20.0 pg mL-1; P < 0.01). Patients with high TG-ab levels showed also slightly raised values of urinary crosslaps (288 +/- 88 vs. 270 +/- 90 &mgr;m mol-1 Cr). In IgG-AG positive patients a statistically significant inverse correlation was found between 25(OH)D serum levels and log-transformed TG-ab values (r: -0.95, P < 0.001). Intestinal biopsies were obtained in 10 TG-ab positive women and verified CD in six patients.

CONCLUSIONS: These data support the hypothesis that patients with undiagnosed celiac disease develop high remodelling processes related to calcium malabsorption, secondary hyperparathyroidism and unavailability of vitamin D with a consequent more marked bone loss.

Selective IgA deficiency  
Insulin dependent diabetes mellitus  
Sjogren's syndrome  
Autoimmune thyroiditis  



Predominance of HLA DQ2 and/or DQ8

Genomewide Linkage Analysis of Celiac Disease in Finnish Families.

Liu J, Juo SH, Holopainen P, Terwilliger J, Tong X, Grunn A, Brito M, Green P, Mustalahti K, Maki M, Gilliam TC, Partanen J.

Columbia Genome Center, Columbia University, New York, New York, USA

Am J Hum Genet 2001 Nov 19;70(1) Abstract quote

Celiac disease (CD), or gluten-sensitive enteropathy, is a common multifactorial disorder resulting from intolerance to cereal prolamins. The only established genetic susceptibility factor is HLA-DQ, which appears to explain only part of the overall genetic risk.

We performed a genomewide scan of CD in 60 Finnish families. In addition to strong evidence for linkage to the HLA region at 6p21.3 (Zmax>5), suggestive evidence for linkage was found for six other chromosomal regions-1p36, 4p15, 5q31, 7q21, 9p21-23, and 16q12. We further analyzed the three most convincing regions-4p15, 5q31, and 7q21-by evaluation of dense marker arrays across each region and by analysis of an additional 38 families. Although multipoint analysis with dense markers provided supportive evidence (multipoint LOD scores 3.25 at 4p15, 1.49 at 5q31, and 1.04 at 7q21) for the initial findings, the additional 38 families did not strengthen evidence for linkage. The role that HLA-DQ plays was studied in more detail by analysis of DQB1 alleles in all 98 families. All but one patient carried one or two HLA-DQ risk alleles, and 65% of HLA-DQ2 carriers were affected.

Our study indicates that the HLA region harbors a predominant CD-susceptibility locus in these Finnish families.

Tissue trans-glutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease.

Molberg Ø, Mcadam SN, Korner R, et al.

Nat Med. 1998;4:713-717.

Increased Enterocyte Apoptosis and Fas-Fas Ligand System in Celiac Disease

Rachele Ciccocioppo, etal.

Am J Clin Pathol 2001;115:494-503 Abstract quote

Our aim was to evaluate whether increased enterocyte apoptosis was responsible for mucosal flattening in celiac disease (CD), and, since the mechanisms responsible for tissue injury in this condition are unknown, we studied the possibility that the Fas-Fas ligand (FasL) system may be involved.

Endoscopic duodenal biopsy specimens from 12 patients with untreated and 12 with treated CD and 12 control subjects were evaluated for enterocyte apoptosis by the terminal deoxynucleotidyl transferase–mediated digoxigenin-deoxyuridine triphosphate nick-end labeling assay and for Fas and FasL expression by immunohistochemistry. A coculture of isolated enterocytes (targets) and purified lamina propria mononuclear cells (LPMCs) (effectors) was performed in the absence or presence of an antagonistic ZB4 anti-Fas antibody.

We found a significant correlation between the degree of villous atrophy, morphometrically evaluated, and the level of enterocyte apoptosis, suggesting that mucosal flattening is a consequence of exaggerated epithelial cell death. Most celiac enterocytes express Fas, and LPMCs express FasL. The abolishment of enterocyte apoptosis observed in the presence of ZB4 antibody suggests that enterocytes are potential targets of lymphocyte infiltrate.

These results directly demonstrate that FasL-mediated apoptosis is a major mechanism responsible for enterocyte death in CD.

Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue.

Daum S, Weiss D, Hummel M, Ullrich R, Heise W, Stein H, Riecken EO, Foss HD.

Medical Clinic I, Gastroenterology and Infectious Diseases, Universitatsklinikum Benjamin Franklin, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.

Gut 2001 Dec;49(6):804-12 Abstract quote

BACKGROUND: Clonal T cell receptor (TCR) gene rearrangements and loss of T cell antigens such as CD8 and TCR-beta in intraepithelial lymphocytes (IELs) may indicate the development of an enteropathy-type intestinal T cell lymphoma (EITCL) in patients with refractory sprue.

AIMS: To define the diagnostic value of these markers in duodenal biopsies from patients with villous atrophy as a result of various underlying disorders. PATIENTS AND

METHODS: Duodenal biopsies from eight patients with coeliac disease and five patients with villous atrophy caused by defined disorders were compared with three patients with refractory sprue evolving into overt EITCL, two patients with ulcerative jejunitis, and with eight patients with overt EITCL, for expression of CD3, CD4, CD8, and TCR-beta in IELs using immunohistochemistry and for clonal TCR-gamma gene rearrangements using polymerase chain reaction. In addition, biopsies from six consecutive patients with refractory sprue of uncertain cause were examined.

RESULTS: Clonal TCR-gamma gene rearrangements were found in all resected tumours of patients with EITCL, in 3/8 duodenal biopsies of patients with EITCL, in 2/2 patients with ulcerative jejunitis, in 2/3 patients with refractory sprue evolving into overt EITCL, and in 1/6 patients with refractory sprue. No rearrangements were found in biopsies from patients with refractory sprue caused by defined disorders or those with coeliac disease. Clonality in duodenal biopsies was associated with an abnormal phenotype of IELs in all cases and in all but one case in patients with evidence of underlying coeliac disease. Specificity for detection of an EITCL using immunohistology was 77% for CD8 and for TCR-beta staining, and 100% for detection of a clonal TCR-gamma gene rearrangement. Sensitivity was 62% for staining with CD8 and clonality investigation, while sensitivity reached 100% for TCR-beta staining in all investigated patients with EITCL.

CONCLUSIONS: Clonal proliferations of phenotypically abnormal IELs in refractory sprue represent an early manifestation of EITCL, for which the term "sprue-like intestinal T cell lymphoma" is proposed. This constellation is also found in duodenal biopsies from patients with an overt EITCL and is not related to other sprue syndromes, resulting in a high specificity for detection of an EITCL or refractory sprue evolving into EITCL. Overt EITCL may develop directly from coeliac disease without a precursor lesion (refractory sprue with clonal IELs) being demonstrable in duodenal biopsies or via a "sprue-like intestinal T cell lymphoma". This latter entity is a complication of coeliac disease.

Altered Expression, Localization, and Phosphorylation of Epithelial Junctional Proteins in Celiac Disease

Rachele Ciccocioppo, MD, etal..
Am J Clin Pathol 2006;125:502-511
Abstract quote

We aimed to study the expression and localization of the molecular components of enterocyte junctions in celiac disease together with the level of tyrosine phosphorylation, a phenomenon known to affect their cellular distribution and function, and to explore the influence of proinflammatory cytokines.

Duodenal biopsy specimens from patients with celiac disease and control subjects were used for immunoprecipitation, immunoblotting, and immunolocalization by using antioccludin, anti–zonula occludens (ZO)-1, anti– E-cadherin, anti–b-catenin, and antiphosphotyrosine antibodies. The same procedures were carried out on filter-grown Caco-2 cells incubated in the absence or presence of interferon g and tumor necrosis factor a. In active celiac disease, the absence of a phosphorylated ZO-1 and the extensive phosphorylation of b-catenin might be responsible for the absence of membranous localization of occludin and E-cadherin, respectively.

The in vitro system showed an influence of the cytokines on the assembly of these complexes that proved the opposite to celiac samples as far as tight junctions were concerned because the presence of a phosphorylated ZO-1 enables occludin to localize in the membrane.



Antibodies against human tissue transglutaminase and endomysium in diagnosing and monitoring coeliac disease.

Burgin-Wolff A, Dahlbom I, Hadziselimovic F, Petersson CJ.

Institute for Coeliac Disease, Liestal, Switzerland. a.buergin-

Scand J Gastroenterol. 2002 Jun;37(6):685-91 Abstract quote

BACKGROUND: Coeliac disease (CD) patients often present a variety of uncharacteristic symptoms and therefore sensitive and specific screening tests are needed as an aid in making an accurate diagnosis. A recently developed ELISA, using human recombinant tissue transglutaminase (tTG) as antigen, was evaluated for its significance in the diagnosis of CD. The patient's compliance to a gluten-free diet and the serological reaction during gluten challenge were also monitored. The results were compared with IgA-endomysium antibody (EMA) results.

METHODS: Sera previously collected from 365 patients (0.4-76 years) with jejunal biopsy on a gluten-containing diet and from 41 patients on a gluten-free diet or challenge were tested for IgA anti-human tTG antibodies (IgA tTG ab) with Celikey (Pharmacia Diagnostics). The study population comprised 208 CD patients and 157 controls. The diagnostic performance and cut-off for the assay were estimated with ROC analysis. EMA was analysed by indirect immunofluorescence microscopy on cryostat sections of monkey oesophagus.

RESULTS: 200/208 patients with CD had positive IgA tTG ab (median >100 U/ml), while only 1/157 of the control patients were positive (median 1.67 U/ml). The area under the ROC curve was 98.3% and the sensitivity and specificity of the test were 96% and 99% for the study population. Only 4/365 patients (1%) presented discordant IgA tTG ab and EMA results, 2 of them had only IgA tTG ab and 2 only EMA. The IgA tTG ab levels and the EMA titres were closely correlated to the duration of gluten-free diet and gluten challenge, respectively.

CONCLUSION: IgA tTG ab can be used as an accurate observer-independent alternative to EMA in diagnosing or monitoring CD.

Comparative evaluation of serologic tests for celiac disease: a European initiative toward standardization.

Stern M; Working Group on Serologic Screening for Celiac Disease.

University Children's Hospital, Tubingen, Germany

J Pediatr Gastroenterol Nutr 2000 Nov;31(5):513-9 Abstract quote

BACKGROUND: Serologic methods have been used widely to test for celiac disease and have gained importance in diagnostic definition and in new epidemiologic findings. However, there is no standardization, and there are no reference protocols and materials.

METHODS: The European working group on Serological Screening for Celiac Disease has defined robust noncommercial test protocols for immunoglobulin (Ig)G and IgA gliadin antibodies and for IgA autoantibodies against endomysium and tissue transglutaminase. Standard curves were linear in the decisive range, and intra-assay variation coefficients were less than 5% to 10%. Calibration was performed with a group reference serum. Joint cutoff limits were used. Seven laboratories took part in the final collaborative study on 252 randomized sera classified by histology (103 pediatric and adult patients with active celiac disease, 89 disease control subjects, and 60 blood donors).

RESULTS: IgA autoantibodies against endomysium and tissue transglutaminase rendered superior sensitivity (90% and 93%, respectively) and specificity (99% and 95%, respectively) over IgA and IgG gliadin antibodies. Tissue transglutaminase antibody testing showed superior receiver operating characteristic performance compared with gliadin antibodies. The K values for interlaboratory reproducibility showed superiority for IgA endomysium (0.93) in comparison with tissue transglutaminase antibodies (0.83) and gliadin antibodies (0.82 for IgG, 0.62 for IgA).

CONCLUSIONS: Basic criteria of standardization and quality assessment must be fulfilled by any given test protocol proposed for serologic investigation of celiac disease. The working group has produced robust test protocols and reference materials available for standardization to further improve reliability of serologic testing for celiac disease.


Comparison of IgA endomysium antibody and IgA tissue transglutaminase antibody in celiac disease.

Gillett HR, Freeman HJ.

Department of Medicine, University of British Columbia, Vancouver.

Can J Gastroenterol. 2000 Sep;14(8):668-71 Abstract quote

The antigen for immunoglobulin (Ig) A endomysium antibody (EmA), a sensitive and specific serological marker for celiac disease, has recently been described as tissue transglutaminase (tTG).

The aim of this study was to compare the assays used to measure IgA EmA and IgA tTG antibody in patients with celiac disease and disease control subjects. Sera from 21 patients with untreated celiac disease, 48 patients with treated celiac disease and 128 disease control subjects were tested both for IgA EmA with the use of indirect immunofluorescence against human umbilical cord and for IgA tTG antibody with the use of ELISA.

Titres of IgA tTG antibody were significantly higher in both the untreated and treated celiac groups than in the disease control group. Titres in the treated group were, however, significantly lower than in the untreated group. A reference range was calculated to include 99.8% of the disease control group in whom small bowel biopsy showed no evidence of celiac disease. One patient from the disease control group with raised IgA tTG antibody titres and positive IgA EmA was found to have celiac disease on small bowel biopsy.

The sensitivity, specificity, and positive and negative predictive values of the IgA EmA assay were all 100%. The sensitivity of the IgA tTG antibody assay was 95%, specificity 100%, positive predictive value 100% and negative predictive value 97.7%. An ELISA used to measure IgA tTG antibody is an excellent tool to screen for celiac disease and may prove useful for monitoring response to treatment.


J Pediatr Gastroenterol Nutr 1998;27:191-195

More specific than antigliadin titers

However, may not be optimally sensitive in patients with architecturally normal villi since it is present only with villus injury or flat mucosa

Antiendomysial antibody test reliability in children with frequent diarrhea and malnutrition: is it celiac disease?

Gandolfi L, Catassi C, Garcia S, Modelli IC, Campos Jr D, Pratesi R.

Departments of Pediatrics, University of Brasilia School of Medicine, Brasilia, Brazil, and Department of Pediatrics, University of Ancona, Italy.

J Pediatr Gastroenterol Nutr 2001 Oct;33(4):483-7 Abstract quote

BACKGROUND: The aim of this study was to evaluate the specificity of the immunoglobulin A (IgA) antiendomysial antibody test in the diagnosis of celiac disease in a group of malnourished children with acute diarrhea, chronic diarrhea, or parasitosis, because the reliability of this test has been questioned when applied to this specific group of patients.

METHODS: Serum IgA level, IgA antiendomysial antibody (EMA) test, and stool examination were performed in 315 children, ranging in age 6 months to 13 years (range, 41 +/- 2.9 months), affected by malnutrition, isolated or in association with diarrhea or parasitosis. Independent of results, 33 children with a strong suspicion of celiac disease, also underwent IgA antitransglutaminase antibody test and jejunal biopsy.

RESULTS: The EMA test was negative in 313 children, including the 43 with parasitosis, being positive in two patients in whom biopsy disclosed typical celiac mucosal abnormalities (1:157). The 31 children with negative EMA test who underwent biopsy also showed negative antitransglutaminase antibody results. Their biopsies disclosed normal mucosa in 1 patient, variable degree of jejunal atrophy (grade 1 and 2) in 27 patients, and grade 3 abnormalities in 3 patients. One of these three children, showing severe jejunal atrophy, died. The diagnosis of celiac disease was apparently not confirmed by a protracted gluten challenge in the other two children.

CONCLUSIONS: The specificity of the EMA test seems to be high also in children with chronic malnutrition and diarrhea. However, the possibility of false-negative tests among immunologically compromised children cannot be excluded. In doubtful cases, the gluten challenge is required in malnourished children with clinical picture, biopsy finding, and evolution suggestive of celiac disease.


The role of antitissue transglutaminase assay for the diagnosis and monitoring of coeliac disease: a French-Italian multicentre study.

Tonutti E, Visentini D, Bizzaro N, Caradonna M, Cerni L, Villalta D, Tozzoli R; French-Italian Laboratory Study Group on Coeliac Disease.

Istituto di Chimica Clinica, Azienda Ospedaliera S. Maria della Misericordia, 33100 Udine, Italy.

J Clin Pathol. 2003 May;56(5):389-93 Abstract quote

AIMS: Tissue transglutaminase (tTG) was recently identified as the major autoantigen in coeliac disease. The aim of this multicentre study was to evaluate the impact of a new immunoenzymatic assay for the detection of IgA anti-tGT antibodies.

METHODS: Seventy four Italian and French clinical laboratories participated in this study; anti-tTG IgA with an enzyme linked immunosorbent assay (ELISA) method using guinea pig liver extract as the coating antigen, anti-endomysium IgA autoantibodies (EMA), and total serum IgA were determined in 7948 patients, 1162 of whom had coeliac disease (737 untreated cases and 425 on a gluten free diet). A proportion of the sera were then sent to a reference laboratory for anti-tTG retesting with an ELISA method using recombinant human tTG antigen.

RESULTS: Seven thousand four hundred and fifty eight (93.8%) sera were EMA/antiguinea pig tTG concordant (positive or negative); 490 (6.2%) were non-concordant. The sensitivity of EMA and antiguinea pig tTG in the 737 untreated patients with coeliac disease was 92.1% and 94.8%, respectively, and the specificity was 99.8% and 99.2%, respectively. Retesting of the discordant sera showed that of the 162 sera classified as EMA negative/antiguinea pig tTG positive, only 49 were positive for human recombinant anti-tTG, and that 39 of these were also EMA positive. Furthermore, of the 36 sera classified as EMA positive/antiguinea pig tTG negative, only two were confirmed as EMA positive.

CONCLUSIONS: The antiguinea pig tTG assay is more sensitive but less specific than EMA, whereas the antihuman recombinant tTG assay is far more specific and just as sensitive as antiguinea pig tTG. Testing for EMA presents considerable interpretative problems and is difficult to standardise.

Antibodies to human recombinant tissue transglutaminase may detect coeliac disease patients undiagnosed by endomysial antibodies.

Tesei N, Sugai E, Vazquez H, Smecuol E, Niveloni S, Mazure R, Moreno ML, Gomez JC, Maurino E, Bai JC.

'Dr Carlos Bonorino Udaondo' Gastroenterology Hospital, Del Salvador University, Buenos Aires, Argentina; USNMA, San Martin Hospital, La Plata, Argentina.

Aliment Pharmacol Ther. 2003 Jun 1;17(11):1415-23 Abstract quote

BACKGROUND: The screening and diagnosis of coeliac disease have been simplified by the advent of new serological tools. AIM: To assess the clinical utility of a newly developed kit for antibodies to human recombinant tissue transglutaminase (hu-anti-tTG) in a large population of patients undergoing intestinal biopsy for suspected intestinal disorders.

METHODS: We evaluated 426 serum samples from consecutive adult patients (250 from untreated coeliac disease patients and 176 from individuals in whom a diagnosis of coeliac disease had been excluded), obtained at the time of intestinal biopsy. Samples were tested for immunoglobulin A (IgA) hu-anti-tTG by enzyme-linked immunoabsorbent assay, IgA endomysial antibodies (EmA) by indirect immunofluorescence and IgA and IgG antigliadin antibodies by enzyme-linked immunoabsorbent assay. A sub-group of samples was also assessed for a guinea-pig-based anti-tissue transglutaminase.

RESULTS: According to the cut-off for hu-anti-tTG, the sensitivity, specificity and positive and negative predictive values were 91%, 96%, 97% and 87%, respectively. Simultaneous determination of EmA showed values of 86%, 100%, 100% and 83% for the same parameters. Although 19 coeliac disease patients (7.6%) were negative for EmA and hu-anti-tTG, both tests rendered superior statistical values to antigliadin antibody tests. At diagnosis, IgA deficiency was detected in 11 patients, but both assays were able to detect samples with mild to moderate deficiency. The comparison of hu-anti-tTG with EmA showed excellent concordance between the tests (kappa statistic, 0.85). Discordance was observed in 20 samples from coeliac disease patients (8%) and in nine samples from controls (5%). Fifteen samples had an EmA-negative but hu-anti-tTG-positive serology, and five showed the converse pattern. Comparison of human recombinant and guinea-pig tests showed concordant results in 96% of cases.

CONCLUSIONS: The quantitative determination of hu-anti-tTG type IgA using a commercial enzyme-linked immunoabsorbent assay kit was highly sensitive and specific for the detection of coeliac disease. Our results in a large population of patients with a clinical condition suggestive of the disorder demonstrated that the test can be used to detect a substantial number of patients otherwise unrecognized by IgA EmA.

Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease.

Sulkanen S, Halttunen T, Laurila K, Kolho KL, Korponay-Szabo IR, Sarnesto A, Savilahti E, Collin P, Maki M.

Institute of Medical Technology, University of Tampere, Tampere, Finland.

Gastroenterology 1998 Dec;115(6):1322-8 Abstract quote

AIMS: Tissue transglutaminase has been reported to be the target for endomysial antibodies in celiac disease. We sought to establish whether immunoglobulin (Ig) A class tissue transglutaminase autoantibodies can be considered specific for celiac disease.

METHODS: Serum samples from 136 patients with untreated celiac disease (diagnosed according to the criteria of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition) and 207 disease controls were studied. Enzyme-linked immunosorbent assay (ELISA) and Western blots were performed using calcium-treated and untreated tissue transglutaminase as antigen. Reticulin, endomysial, and mouse monoclonal tissue transglutaminase antibodies were studied by an indirect immunofluorescence method and gliadin antibodies with ELISA.

RESULTS: The calcium-activated tissue transglutaminase autoantibody ELISA was highly sensitive (129 of 136) and specific (194 of 207) in detecting celiac disease. The new autoantibody ELISA test correlated well with the endomysial antibody test. Tissue transglutaminase autoantibody ELISA showed a clearly better predictive potential than the IgA class gliadin antibody ELISA. Immunoblots and ELISA blocking studies showed that calcium is needed for the specific antigen-antibody reaction to occur. Double immunofluorescence staining in human umbilical cord with sera from patients with celiac disease and with monoclonal tissue transglutaminase antibodies showed complete overlap.

CONCLUSIONS: Calcium-activated tissue transglutaminase autoantibody ELISA is highly accurate in detecting untreated celiac disease. Tissue transglutaminase seems to be the target self-antigen for endomysial antibodies.


Late onset disease

May account for up to 25% of patients
Diagnosed after age 45-50 years
Short stature, infertility, peripheral neuropathies, iron and/or folate deficiency, osteoporosis, recurrent abdominal pain (usually children), indigestion (adults), dental enamel defects

Minimal to absent diarrhea
Malabsorption detected by testing only

Refractory disease

Celiac disease patients who do not respond or stop responding clinically and histologically to a gluten-free diet

May be secondary to:
Unrecognized intake of gluten
Development of lymphoma



Morphologic Features Suggestive of Gluten Sensitivity in Architecturally Normal Duodenal Biopsy Specimens

Neal S. Goldstein, MD, and Jeanette Underhill, MD

Am J Clin Pathol 2001;116:63-71 Abstract quote

We studied small bowel biopsy specimens with architecturally normal villi from 78 adult patients with potential gluten sensitivity (GS) and correlated them with outcome to characterize morphologic features that would allow a pathologist to suggest GS.

No patient had a previous GS diagnosis. Twelve study patients had GS. The mean number of intraepithelial lymphocytes (IELs) per 20 enterocytes from the tips of 5 random villi was significantly greater in GS than non-GS biopsy samples, but the groups overlapped significantly, making the number diagnostically useful only when markedly increased. Crypt mitoses counts had similar relationships. Twelve patients had an even distribution of IELs along villus sides and over tips (3/66 [5%] non-GS patients, 9/12 [75%] GS patients). Non-GS patients had a decrescendo pattern of IELs along the sides of villi. Architecturally normal small bowel biopsy specimens with an appreciable, continuous, even distribution of IELs along the sides and tips of villi and a mean of 12 or more IELs in the tips of several villi are suggestive of GS. Pathologists should be watchful for these morphologic features in small bowel biopsy specimens to suggest GS.

The Histologic Spectrum and Clinical Outcome of Refractory and Unclassified Sprue

Marie E. Robert, M.D.; Marvin E. Ament, M.D.; Wilfred M. Weinstein, M.D.

Department of Pathology (M.E.R), Yale University School of Medicine, New Haven, Connecticut, U.S.A.; Departments of Pediatrics (M.E.A.) and Medicine (W.M.W.), University of California, Los Angeles, Center for Health Sciences, Los Angeles, California, U.S.A.

Am J Surg Pathol 2000;24:676-687 Abstract quote

The vast majority of patients with celiac disease respond to a gluten-free diet; yet, a small number of refractory patients do not respond and have persistent malabsorption and residual mucosal abnormalities of the small intestine. The histologic features of refractory/unclassified sprue have been published as case reports, often without long-term follow up, and no clear histologic picture has emerged.

We present the results of a long-term study of the clinical and histologic features of 10 patients with refractory/unclassified sprue.

The histologic features of small bowel biopsies in this group of patients were compared with those of 10 patients with responsive celiac disease and with 10 patients without malabsorption who had normal duodenal biopsies. Five of the 10 refractory patients ultimately developed collagenous sprue as a distinct histologic marker of refractory disease. Additional distinctive findings found in small bowel biopsies in the refractory group were subcryptal chronic inflammation (10 of 10) and marked mucosal thinning in three patients. Other nonspecific findings included acute inflammation and gastric metaplasia. One patient with collagenous sprue developed a B-cell lymphoma of the ileum, and in general collagenous sprue was associated with a poor prognosis. Two of five patients died whereas two others require total parenteral nutrition for survival.

Pathologists evaluating small bowel biopsies in the setting of malabsorption should be aware of the subtle histologic changes described here that may portend a refractory course.


Histologic follow-up of people with celiac disease on a gluten-free diet: slow and incomplete recovery.

Wahab PJ, Meijer JW, Mulder CJ.

Department of Gastroenterology and Hepatology, Rijnstate Hospital Arnhem, The Netherlands.

Am J Clin Pathol 2002 Sep;118(3):459-63 Abstract quote

To assess histologic recovery in response to gluten withdrawal in celiac disease, 158 patients seen in our hospital during a 15-year period underwent follow-up small intestine biopsies (SIBs) within 2 years after starting a gluten-free diet; further SIBs were done if villous atrophy was present.

A modified Marsh classification was used (IIIA, partial villous atrophy; IIIB, subtotal villous atrophy; IIIC, total villous atrophy). Of patients with Marsh IIIA, IIIB, or IIIC lesions, histologic remission was seen in 65.0% within 2 years, 85.3% within 5 years, and 89.9% in long-term follow-up. Eleven patients (7.0%) with persisting (partial) villous atrophy had symptoms and signs of malabsorption and were considered to have refractory celiac disease; 5 of them developed an enteropathy-associated T-cell lymphoma. Children recovered up to 95% within 2 years and 100% in the long-term.

Histologic recovery in celiac disease after starting a gluten-free diet takes time and is incomplete or absent in a substantial subgroup of patients (10.1% villous atrophy after 5 years). Systematic follow-up of patients with celiac disease and the malabsorption syndrome and secondary complications is needed.


Characterization of gastric mucosal lesions in patients with celiac disease: a prospective controlled study.

Diamanti A, Maino C, Niveloni S, Pedreira S, Vazquez H, Smecuol E, Fiorini A, Cabanne A, Bartellini MA, Kogan Z, Valero J, Maurino E, Bai JC.

Small Bowel Section, Clinical Service, Hospital de Gastroenterologia, Dr. Carlos Bonorino Udaondo, Universidad del Salvador, Buenos Aires, Argentina.


Am J Gastroenterol 1999 May;94(5):1313-9 Abstract quote

OBJECTIVE: Several studies have demonstrated that chronic exposure to gluten may damage the structure and function of the gastric mucosa in gluten-sensitive patients. However, until now, these abnormalities have been incompletely studied. Our purpose in the present study was to characterize, in a prospective controlled study, the endoscopic and histological appearance of the gastric mucosa in a large cohort of patients with celiac disease with and without Helicobacter pylori (H. pylori) infection.

METHODS: We evaluated biopsy specimens taken from the gastric body and antrum of 218 individuals who underwent upper endoscopy for small bowel biopsy. One hundred-four patients had celiac disease (80 of them at the time of diagnosis-untreated). In 114 subjects celiac disease was excluded.

RESULTS: Endoscopic findings did not show a difference between the groups. The prevalence of cases with normal gastric mucosa, chronic superficial gastritis, and atrophic gastritis was similar in patients and controls. Similarly, presence of metaplasia, inflammatory activity, and lymphoid follicles and aggregates did not show differences between the groups. Histological or serological evidence of H. pylori infection was detected in 86% of patients (82% of untreated celiacs and 95% of those on those taking treatment). The infection was highly prevalent in patients (89%) and controls (97%) diagnosed with chronic gastritis. Untreated patients had a significant greater IEL count in the antrum and corpus than controls (p < 0.0001 and p < 0.001, respectively). A global analysis of the data on intraepithelial lymphocyte (IEL) counts in the different populations suggest that the inflammatory state may represent the cumulative effect of H. pylori infection and gluten sensitivity. Only three patients had IEL infiltration compatible with diagnosis of lymphocytic gastritis (count >25%) and three other patients had borderline counts.

CONCLUSIONS: According to our results, celiac disease patients presented a similar prevalence of gastric mucosal abnormalities compared with the control population. Evidence of H. pylori infection was very high compared with the prevalence in the general Argentine population. As a particular observation in our celiac population, the disease was rarely associated with lymphocytic gastritis. We suggest that the chronic inflammatory state evidenced by a gastric mucosal lymphocyte infiltration may be secondary to the combination of H. pylori infection and chronic gluten ingestion in gluten-sensitive subjects.



Role of lymphocytic immunophenotyping in the diagnosis of gluten-sensitive enteropathy with preserved villous architecture.

Mino M, Lauwers GY.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114-2696, USA.
Am J Surg Pathol. 2003 Sep;27(9):1237-42. Abstract quote  

Clinically significant gluten-sensitive enteropathy (GSE) can be associated with architecturally normal small bowel villi and evenly distributed increased intraepithelial T lymphocytes (IELs).

This distribution pattern of IELs has been shown to be a sensitive feature of GSE but to be of relatively low specificity, thus limiting its usage as a diagnostic marker. We demonstrate herein the potential diagnostic role of IEL immunophenotyping. We show that a top-heavy distribution pattern of CD3+ IELs is a sensitive diagnostic feature of GSE. Despite overlap between GSE and non-GSE patients, the difference is underscored when using a tip-to-base ratio. Of the GSE patients, 87.5% showed a tip-to-base ratio >1.7 compared with only 12.5% of non-GSE patients and none in controls. This pattern was retained in 50% of treated GSE patients, although the CD3+ tip-IEL scores were significantly smaller. Conversely, CD8 immunostaining appears of limited diagnostic value.

The discrepancy in distribution of CD3+ and CD8+ IELs between GSE and non-GSE patients can be explained by the presence of CD4- CD8- TCR-gamma delta+ IELs which, have been reported in GSE. Since the immunophenotyping of T- IELs is feasible with readily available antibodies, and given the clinical benefits for patients with 'latent' GSE, we advocate using CD3 immunostaining to triage patients with normal villi and increased IELs.


Intraepithelial lymphocytosis in architecturally preserved proximal small intestinal mucosa: an increasing diagnostic problem with a wide differential diagnosis.

Brown I, Mino-Kenudson M,Deshpande V, Lauwers GY.

Sullivan Nicolaides Pathology, Taringa, Queensland, Australia.

Arch Pathol Lab Med. 2006 Jul;130(7):1020-5 Abstract quote.

CONTEXT: An increased intraepithelial lymphocyte density in an architecturally normal proximal small intestinal mucosal biopsy is a common finding facing surgical pathologists dealing with gastrointestinal biopsy specimens. Approximately 1% to 2% of all proximal small intestinal biopsies will show this change. It is increasingly recognized by surgical pathologists that gluten-sensitive enteropathy is an important cause of this pattern; however, gluten-sensitive enteropathy accounts for the minority of all cases. A wide variety of immunologic stimuli can raise intraepithelial lymphocyte numbers. Among the other common associations are enteric infection, autoimmune disease, drugs, and gastric Helicobacter infection.

OBJECTIVE: To outline the causes of intraepithelial lymphocytosis, to highlight the importance and the difficulties faced in establishing gluten-sensitive enteropathy as the cause, and to aid the surgical pathologist in the routine sign out of these cases.

DATA SOURCES: A review of the literature detailing the causes or associations of proximal small intestinal intraepithelial lymphocytosis is presented.

CONCLUSIONS: Increased lymphocyte numbers in the epithelium of architecturally preserved proximal small intestinal biopsies is a morphologic feature associated with a broad differential diagnosis.

Non–Gluten Sensitivity–Related Small Bowel Villous Flattening With Increased Intraepithelial Lymphocytes

Not All That Flattens Is Celiac Sprue

Neal S. Goldstein, MD
Am J Clin Pathol 2004;121:546-550 Abstract quote

Seven patients (mean age, 37.6 years; 5 women) had several weeks of gluten sensitivity (GS)-like symptoms; 2 had flu-like symptom prodromes.

The 7 cases had morphologically similar biopsy specimens; all tissue fragments had uniform injury—increased lymphoplasmacytic lamina propria inflammation, moderate to complete villous flattening, numerous crypt mitoses, and markedly increased villous intraepithelial lymphocytes (IELs).

All patients were diagnosed with GS and prescribed a gluten-free diet; all returned 9 to 38 weeks later questioning their diagnosis because symptoms had resolved substantially or completely. Clinical improvement was unrelated to gluten abstinence or ingestion. Repeated endoscopy and colonoscopy performed 4.1 to 16 months later showed normal mucosa in all 7 patients.

Diseases other than GS can cause marked villous flattening and increased villous IELs in adults. The cause of small bowel mucosal injury is unknown. A similar non-GS–associated clinicopathologic complex, assumed to be due to a protracted viral enteritis or slow regression of a virus-induced immune reaction, occurs in children.

The temporal aspects of symptom improvement and mucosal restitution in these 7 patients are similar to "acute self-limited colitis." An overly exuberant immune response to an infectious agent is possible.
Autoimmune enteropathy Crypt injury and destruction
Anti-enterocyte antibodies
Tropical sprue No anti-endomysial antibodies
Response to antibiotic and folate therapy
Common variable immunodeficiency Paucity or absence of plasma cells
Marked lymphoid nodular hyperplasia
Giardia infection common
Duodenal intraepithelial lymphocytosis with normal villous architecture: common occurrence in H. pylori gastritis.

Memeo L, Jhang J, Hibshoosh H, Green PH, Rotterdam H, Bhagat G.

1Department of Pathology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.

Mod Pathol. 2005 Aug;18(8):1134-44. Abstract quote  

We have observed expansions of intraepithelial lymphocytes in duodenal biopsies from patients with Helicobacter pylori gastritis.

This study was undertaken to prospectively evaluate, unselected, paired gastric and duodenal biopsies from 50 patients with H. pylori gastritis and a comparison group of 30 patients with other types of gastritis (10 autoimmune and 20 reactive) to: (1) quantify duodenal intraepithelial lymphocytes, determine their distribution patterns, epithelial location, and phenotype, and (2) correlate the intraepithelial lymphocyte elevations with various features of gastric and duodenal pathology.

Intraepithelial lymphocytes were analyzed with antibodies including CD3, CD8, and TIA-1. A stain for H. pylori was performed on all gastric and duodenal biopsies. Duodenal intraepithelial lymphocytes from patients with H. pylori gastritis (using CD3) ranged from 3 to 42 lymphocytes/100 epithelial cells (mean 18.5) compared to 3 to 18 lymphocytes/100 epithelial cells (mean 6.6) in the comparison group.

Intraepithelial lymphocyte elevations were seen in 44% of the duodenal biopsies from patients with H. pylori gastritis (using CD3). Significant differences in the intraepithelial lymphocyte counts between patients with H. pylori gastritis and the comparison group were seen for all three T-cell antigens (P<0.001 for CD3 and CD8 and P<0.002 for TIA-1). Duodenal intraepithelial lymphocytes in the H. pylori+ cases had a latent cytotoxic phenotype, H. pylori was not visualized in any of the duodenal biopsies from patients with H. pylori gastritis, and no patient had clinical evidence of celiac disease.

Our study highlights frequent duodenal intraepithelial lymphocytosis in individuals with H. pylori gastritis and the lymphocyte distribution patterns (and numbers) overlapped with those described for celiac disease patients. H. pylori gastritis must be considered as a possible explanation for duodenal intraepithelial lymphocytosis with normal villous architecture, especially when lymphocytosis is patchy, intraepithelial lymphocytes display a 'latent' cytotoxic phenotype, and the clinical findings and serologic profile does not fit celiac disease.
Infectious enteritis-usually viral Normal IEL counts
Food protein intolerance (eggs, cow milk) Increased eosinophils
Allergic manifestations like atopy
Response to elimination diets


Modified Marsh Classification See below
Increased risk of esophageal squamous cell carcinoma
Increased risk of small bowel adenocarcinoma

Refractory sprue syndrome with clonal intraepithelial lymphocytes evolving into overt enteropathy-type intestinal T-cell lymphoma.

Daum S, Hummel M, Weiss D, Peters M, Wiedenmann B, Schaper F, Stein H, Riecken EO, Foss H.

Department of Gastroenterology and Infectious Diseases, Klinikum Benjamin Franklin, Free University of Berlin, Berlin, Germany.

Digestion 2000;62(1):60-5 Abstract quote

INTRODUCTION: Recently, patients with refractory sprue have been shown to contain a clonal proliferation of phenotypically abnormal intraepithelial lymphocytes in their intestine. Whether this signifies early enteropathy-type intestinal T-cell lymphoma (EITCL) or a reactive condition is not clear. We report on a patient presenting with the findings of refractory sprue who subsequently developed overt EITCL.

MATERIAL AND METHODS: Duodenal biopsies from 1997 (refractory sprue) and duodenal and jejunal biopsies from 1998 (intestinal T-cell lymphoma) were compared by immunohistochemistry and PCR for the detection of T-cell receptor (TCR)-gamma gene rearrangements. Clonal PCR products were sequenced.

RESULTS: The duodenal biopsies from both 1997 and 1998 and the jejunal tumor biopsy showed villus atrophy and an increase of intraepithelial lymphocytes with an abnormal immunophenotype (CD3+, CD4-, CD8- and TCR-beta-). In all duodenal specimens including the one from 1997, and the jenunal tumor biopsy, an identical clonal amplificate was detected by enzymatic amplification of the TCR-gamma gene.

CONCLUSION: These data suggest that refractory sprue containing a clonal proliferation of phenotypically abnormal intraepithelial lymphocytes may represent an early manifestation of EITCL. The detection of immunohistochemical negativity for several antigens normally found on intraepithelial lymphocytes such as CD8 or the TCR-beta chain in combination with clonal T-cell populations by PCR may be helpful in identifying refractory sprue with a malignant transformation.

Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group.

Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, Macintyre E, Cerf-Bensussan N, Brousse N.

Department of Gastroenterology, Hopital Laennec, INSERM E9925, Paris, France.

Lancet 2000 Jul 15;356(9225):203-8 Abstract quote

BACKGROUND: Adult refractory sprue is a poorly defined disorder. We did a multicentre national study of patients with refractory sprue to characterise their clinical and pathological profile and outcome, and to assess the frequency and prognostic significance of phenotypic and molecular abnormalities in the intraepithelial T-cell population.

METHODS: Patients with severe symptomatic villous atrophy mimicking coeliac disease but refractory to a strict gluten-free diet, and with no initial evidence of overt lymphoma, were diagnosed at gastrointestinal referral centres between 1974 and 1998. Fixed and/or frozen duodenojejunal biopsy samples were reanalysed and immunostained with CD3 and CD8 monoclonal antibodies to find out the phenotype of intraepithelial lymphocytes (IEL). TCRgamma gene rearrangements were assessed on frozen biopsy samples by multiplex fluorescent PCR.

FINDINGS: There were 21 patients with refractory sprue and 20 controls with coeliacs disease. 16 (84%) of 19 assessed patients had an aberrant intraepithelial lymphoid intestinal population expressing intracytoplasmic CD3 but not surface CD8. Clonal intestinal TCRgamma gene rearrangements were found in 13 (76%) of 17 patients assessed; four (out of 12 assessed) had clonal dissemination to the blood. The 16 patients with an aberrant phenotype all had uncontrolled malabsorption; three subsequently developed overt T-cell lymphoma, and eight died. The three (16%) patients without aberrant clonal IEL made a complete clinical and histological recovery with steroid therapy plus a gluten-free diet.

INTERPRETATION: An immunophenotypically aberrant clonal intraepithelial T-cell population (similar to that of most cases of enteropathy-associated T-cell lymphoma) can be found in up to 75% of patients with refractory coeliac sprue; its identification by simple diagnostic techniques represents a marker of poor outcome (including occurrence of overt T-cell lymphoma). We suggest that refractory sprue associated with an aberrant clonal IEL may be the missing link between coeliac disease and T-cell lymphoma and may be classified as cryptic enteropathy-associated T-cell lymphoma.

Risk of Non-Hodgkin Lymphoma in Celiac Disease

Carlo Catassi, MD; Elisabetta Fabiani, MD; Giovanni Corrao, PhD; Maria Barbato, MD; Amalia De Renzo, MD; Angelo M. Carella, MD; Armando Gabrielli, MD; Pietro Leoni, MD; Antonio Carroccio, MD; Mariella Baldassarre, MD; Paolo Bertolani, MD; Paola Caramaschi, MD; Michele Sozzi, MD; Graziella Guariso, MD; Umberto Volta, MD; Gino R. Corazza, MD; for the Italian Working Group on Coeliac Disease and Non–Hodgkin's-Lymphoma

JAMA. 2002;287:1413-1419 Abstract quote

Celiac disease is one of the most common lifelong disorders. Non-Hodgkin lymphoma is a possible complication of celiac disease and may lead to a large portion of lymphoma cases.

To quantify the risk for developing non-Hodgkin lymphoma of any primary site associated with celiac disease.

Design and Setting
Multicenter, case-control study conducted between January 1996 and December 1999 throughout Italy.

Cases were older than 20 years (median, 57; range, 20-92 years) with non-Hodgkin lymphoma of any primary site and histological type and were recruited at the time of the diagnosis. Controls were healthy adults (2739 men and 2981 women) from the general population.

Main Outcome Measure
Positive test result for class A serum antiendomysial antibody.

Celiac disease was diagnosed in 6 (0.92%) of 653 patients with lymphoma. Of the 6 cases, 3 were of B-cell and 3 were of T-cell origin. Four of 6 cases had lymphoma primarily located in the gut. In the control group, 24 (0.42%) had celiac disease. The odds ratio (adjusted for age and sex) for non-Hodgkin lymphoma of any primary site associated with celiac disease was 3.1 (95% confidence interval [CI], 1.3-7.6), 16.9 (95% CI, 7.4-38.7) for gut lymphoma, and 19.2 (95% CI, 7.9-46.6) for T-cell lymphoma, respectively. The risk for non-Hodgkin lymphoma for the overall population, which was adjusted for age and sex, was 0.63% (95% CI, - 0.12% to 1.37%).

Celiac disease is associated with an increased risk for non-Hodgkin lymphoma, especially of T-cell type and primarily localized in the gut. However, the association does not represent a great enough risk to justify early mass screening for celiac disease.

TREATMENT Gluten free diet
Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease.

Norris JM, Barriga K, Hoffenberg EJ, Taki I, Miao D, Haas JE, Emery LM, Sokol RJ, Erlich HA, Eisenbarth GS, Rewers M.

Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA.
JAMA. 2005 May 18;293(19):2343-51. Abstract quote  

CONTEXT: While gluten ingestion is responsible for the signs and symptoms of celiac disease, it is not known what factors are associated with initial appearance of the disease.

OBJECTIVE: To examine whether the timing of gluten exposure in the infant diet was associated with the development of celiac disease autoimmunity (CDA).

DESIGN, SETTING, AND PATIENTS: Prospective observational study conducted in Denver, Colo, from 1994-2004 of 1560 children at increased risk for celiac disease or type 1 diabetes, as defined by possession of either HLA-DR3 or DR4 alleles, or having a first-degree relative with type 1 diabetes. The mean follow-up was 4.8 years.

MAIN OUTCOME MEASURE: Risk of CDA defined as being positive for tissue transglutaminase (tTG) autoantibody on 2 or more consecutive visits or being positive for tTG once and having a positive small bowel biopsy for celiac disease, by timing of introduction of gluten-containing foods into the diet.

RESULTS: Fifty-one children developed CDA. Findings adjusted for HLA-DR3 status indicated that children exposed to foods containing wheat, barley, or rye (gluten-containing foods) in the first 3 months of life (3 [6%] CDA positive vs 40 [3%] CDA negative) had a 5-fold increased risk of CDA compared with children exposed to gluten-containing foods at 4 to 6 months (12 [23%] CDA positive vs 574 [38%] CDA negative) (hazard ratio [HR], 5.17; 95% confidence interval [CI], 1.44-18.57). Children not exposed to gluten until the seventh month or later (36 [71%] CDA positive vs 895 [59%] CDA negative) had a marginally increased risk of CDA compared with those exposed at 4 to 6 months (HR, 1.87; 95% CI, 0.97-3.60). After restricting our case group to only the 25 CDA-positive children who had biopsy-diagnosed celiac disease, initial exposure to wheat, barley, or rye in the first 3 months (3 [12%] CDA positive vs 40 [3%] CDA negative) or in the seventh month or later (19 [76%] CDA positive vs 912 [59%] CDA negative) significantly increased risk of CDA compared with exposure at 4 to 6 months (3 [12%] CDA positive vs 583 [38%] CDA negative) (HR, 22.97; 95% CI, 4.55-115.93; P = .001; and HR, 3.98; 95% CI, 1.18-13.46; P = .04, respectively).

CONCLUSION: Timing of introduction of gluten into the infant diet is associated with the appearance of CDA in children at increased risk for the disease.

Refractory coeliac disease: a window between coeliac disease and enteropathy associated T cell lymphoma.

Mulder CJ, Wahab PJ, Moshaver B, Meijer JW.

Depts. of Gastroenterology and Pathology, Rijnstate Hospital, P.O. Box 5555, 6800 TA Arnhem, The Netherlands

Scand J Gastroenterol Suppl 2000;(232):32-7 Abstract quote

The treatment of coeliac disease (CD) is straightforward and simple: life-long adherence to a gluten-free diet. However, in a small subgroup of patients, the clinical and histological abnormalities persist or recur. This non-responsiveness leaves a poorly understood syndrome known as refractory coeliac disease (RCD). A specific definition of RCD is lacking in the literature.

We speculate that RCD may appear in a subgroup of coeliacs with persisting histologic abnormalities. In all patients screened for RCD we look for DQ2 and DQ8. In non-DQ2/DQ8 patients we reconsider the diagnosis of CD and of auto-immune enteropathy. Most of the patients referred to us because of suspicion of RCD are affected by other diseases. Probably the commonest cause of non-responsiveness is continued gluten intake. Exocrine pancreas insufficiency, hyperthyroid disease, collagenous colitis are other common explanations. RCD and enteropathy-associated T cell lymphomas (EATL) can be distinguished by intra-epithelial lymphocyte phenotyping and TCR-gamma gene rearrangements.

In RCD, an unexplained sustained stimulation of T cell cytotoxic activity is present. Immunosuppressive treatment might moderate this. Cyclosporine has been reported as a resounding success in case reports; however, our results were disappointing. We suggest azathioprine and steroids in RCD without aberrant T-lymphocytes in their mucosa. However, in RCD with aberrant T-lymphocytes we suggest chemotherapy. As the prognosis of EATLs is extremely poor the early detection of RCD with aberrant T cells is crucial.

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Commonly Used Terms


Lymphoma-Enteropathy Type

Modified Marsh Classification (Baillieres Clin Gastroenterol 1995;9:273-293)

Marsh Type IEL per 100 enterocytes Crypts Villi
0 <40 Normal Normal
1 >40 Normal Normal
2 >40 Normal Normal
3a >40 Increased Normal
3b >40 Increased Mild atrophy
3c >40 Increased Absent


0 Normal mucosa
1 (Infiltrative lesion)

Seen in patiens on a gluten-free diet (suggesting minimal amounts of gliadin being ingested)
Patients with dermatitis herpetiformis
Family members of patients with Celiac disease

Patients need to be followed since many convert to Type 3

2 (Hyperplastic type) Very rare
Occasionally seen in dermatitis herpetiformis
3 (Destructive lesion) Spectrum of changes seen in symptomatic Celiac disease

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