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Rostom A, Dubé C, Cranney A, et al. Celiac Disease. Rockville (MD): Agency for Healthcare Research and Quality (US); 2004 Sep. (Evidence Reports/Technology Assessments, No. 104.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Celiac Disease.

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Appendix H. Biopsy Results

Relationship of Serology to Histology

CD clearly exists in patients with histological grades milder than Marsh IIIa, and given that the sensitivity of biopsy is improved by using a lower grade as a cut-off, an important question arises—what test is most sensitive for detecting CD with mild histologic changes, biopsy or serology?

Fasano,1 in a large American prevalence study of CD in at risk and not at risk populations, found that only 34% of biopsied EMA-positive subjects had subtotal or total VA (modified Marsh IIIb or IIIc). In this study, no EMA-positive patient had a Marsh 1 lesion, 26% of EMA-positive patients had a Marsh II lesion, and 40% had a Marsh IIIa lesion. All newly-diagnosed, EMA-positive CD patients with (n=98) or without (n=114) biopsy had HLA DQ2, DQ8 or both, as apposed to 59% of EMA-negative subjects (n=92). The results of this study once again suggest that applying a criterion of subtotal or total VA would miss 66% of CD patients. The absence of Marsh I lesions in EMA-screened subjects is not surprising (discussed below), given the lower sensitivity of this test in lower-grade histologic lesions of CD, suggesting that the CD may have been unrecognized in some EMA-negative subjects. Unfortunately, HLA was not evaluated in all subjects and assessment of the correlation with serology in the population at large or systematically with biopsy grade was not reported.

Rostami et al.2 evaluated the diagnostic value of IgA EMA and AGA in 101 untreated CD patients. The diagnosis of CD was made on the basis of “appropriate histopathological features” (Marsh IIIa or greater) and clinical improvement on a gluten-free diet (GFD). Sixteen first-degree relatives with minor histologic abnormalities (Marsh I–II) were used as controls. Sixteen patients were excluded for not meeting diagnostic criteria, IgA deficiency, or undergoing serology while on GFD.

Rostami et al.2 Marsh I–II (controls)Marsh IIIaMarsh IIIbMarsh IIIc
Biopsy1629 (%)23 (%)17 (%)
AGA3 (21%)9 (31%)16 (70%)14 (82%)
EMA09 (31%)16 (70%)17 (100%)

The combination of the two tests showed an overall sensitivity of 76%. Unfortunately, the authors, as is commonly done, considered Marsh I–II as controls; it is unclear if any of these, particularly those who were AGA positive, actually have CD. As will be described below, there is a subset of patients with Marsh I–II who are serology negative who have CD. In any case, this study demonstrates an important finding, i.e., that the sensitivity of the studied serological markers varies with the severity of the histologic grade. Alarmingly, the sensitivity even for CD patients with Marsh IIIa lesions is close to 30%. This is partially at odds with the results of the Fasano study1 where only 34% of the identified patients were found to have Marsh IIIb or greater grade lesions, with the rest having grade II to IIIa lesions. In both studies, no EMA-positive Marsh I lesions were found. The Fasano study, being a population-based screening study, obviously did not biopsy all screened patients. This begs the question of how many grade IIIb or less patients with CD were missed based on the findings of Rostami and Tursi (detailed below).

Tursi et al.3 assessed the relationship of the histologic grade of 119 consecutive adult patients with CD defined by characteristic duodenal biopsy and “permanent gluten-sensitive enteropathy.” The following table summarizes the main findings.

Tursi et al.3 Marsh IMarsh IIMarsh IIIaMarsh IIIbMarsh IIIc
Biopsy13 (11%)24 (20%)27 (23%)31 (26%)24 (20%)
tTG positive1 (8%)8 (33%)15 (56%)26 (84%)23 (96%)
Mean tTG level UA/mL7.318.5n/a3674.95

In this study, 69% of CD patients had VA (Marsh IIIa or greater). The frequency of tTG-positivity (sensitivity) and mean tTG levels were greatest with the highest Marsh grade and dropped steadily with milder histologic grades, reaching a low of only 8%-positivity in CD patients with Marsh I lesions. Since these patients all have “permanent gluten-sensitive enteropathy,” it is clear that tTG would have missed 76% of this cohort of CD patients with Marsh I or II lesions who were picked up by biopsy.

Tursi et al.,4 also assessed 123 adult patients (possibly the same patients cohort from the above study) with either subclinical (equivalent to atypical in this review) or silent CD. All patients were biopsied and CD was diagnosed on the basis of “permanent-gluten sensitive enteropathy”, and histology was classified with the modified Marsh criteria. The subclinical group included patients with associated CD conditions such as iron deficiency but without GI symptoms, while silent CD patients were asymptomatic patients screened in at risk groups such as first-degree relatives or type 1 diabetes. EMA was positive in 77/96 (80.8%) of subclinical CD cases and 17/27 (63.0%) of silent CD cases. EMA was negative in patients with Marsh I lesions. Once again, assuming that all these patients with “permanent gluten-sensitive enteropathy” are truly CD patients, then EMA would miss 19% of subclinical CD patients, and 37% of silent CD that were picked-up by biopsy.

In what appears to be a partial duplicate publication, Tursi et al.5 demonstrated similar results with AGA, and EMA in 115 patients with subclinical or silent CD.

Patients with subclinical CD

Tursi et al5 Marsh IMarsh IIMarsh IIIaMarsh IIIbMarsh IIIc
Biopsy210182530
AGA pos.03 (30%)14 (77%)21 (84%)27 (90%)
EMA pos04 (40%)16 (88.9%)23 (92%)29 (96.7%)

Patients with silent CD

Tursi et al5 Marsh IMarsh IIMarsh IIIaMarsh IIIbMarsh IIIc
Biopsy22569
AGA pos.003 (60%)4 (66.7%)7 (77.8%)
EMA pos004 (80.0%)5 (83.3%)8 (88.9%)

As before, in this group of CD patients, serology would miss patients that would be picked up by biopsy.

Demir et al.6 (Celiac 4) studied the presentation and clinical features of 104 newly diagnosed Turkish children. EMA and biopsy correlation was available for 72 children. Similar to what was described above, EMA was positive in 92% of children with Marsh III compared with 66.6% of children with Marsh I–II.

Kotze et al.7, 8 assessed 47 symptomatic subjects with CD with intestinal biopsy, tTG and EMA antibodies. Forty were suspected of having CD (9 were children) and the investigations were performed together, while seven were biopsy-diagnosed CD who were already on a GFD. Both EMA and tTG antibodies were negative in these seven patients. The findings of the 40 suspected CD patients are presented in the following table.

Kotze et al7, 8
Normal biopsy7821 (child)
Partial VA11
Total VA1378 (child)8
Mean tTG titer8.1411.8741.5181.7356.3307.4432.8
Mean EMA titerneg1/2.51/51/101/201/401/80

Titers of EMA and tTg antibodies of 1/2.5 and 20 U, respectively

VA= VA

The authors used an older histology grading system, and did not systematically report on the overall number of “normal biopsies” with raised IELs. They also did not report on the number of subjects with the Marsh II hyperplastic lesion, nor did they distinguish between Marsh IIIa and IIIb (lumped as “partial VA”). Nonetheless, the authors report that in the eight subjects with positive-EMA antibodies (>1/2.5) yet negative for tTG antibodies (<20), the mucosa showed normal villous structure but raised levels of IELs. These eight subjects responded to a GFD and were considered to have CD. The correlation between the two serological tests was high (Pearson's Chi square [the large R is ‘accountable’ variance]; r=0.797). However, the same finding as in the previous studies is repeated again. CD occurred in eight patients with negative tTG antibodies, and the titres of both EMA and tTG antibodies correlated with histologic grade, once again suggesting that serology alone would miss CD patients who would be picked-up by biopsy. This is a very recent study and it would shed a great deal of light on the false-positive and negative-rate of biopsy if the authors would publish a follow-up study on: (1) the status of the three subjects who were positive for EMA and tTG antibodies yet had “normal” biopsies (IEL status not reported); (2) the seven subjects who were negative for all tests; and (3) the histologic and clinical response to GFD in those who were diagnosed with CD.

Hoffenberg et al.9 studied a group of children at risk of CD who were part of a large prospective study of the genetic and environmental factors associated with autoimmune diseases. For the CD portion, newborns were screened for the presence of HLA DR3/3, DR3/4, or DR3/x as markers for DQ2. In another group, at risk children with type I diabetes, first-degree relatives of type 1 diabetics, and first-degree relatives of CD patients, were studied. Thirty anti-tTG positive subjects among these screened patients were enrolled in the study (14 diabetics, 11 first-degree relatives, and five HLA DR3). All 30 children underwent Marsh biopsy grading. No relationship was found between Marsh grade and the genetic risk factor leading to screening. A significant correlation was found between Marsh grade and anti-tTG (r=0.57, p<0.01). The calculated mean anti-tTG titers are presented in parentheses in the table below.

Biopsy results of 30 tTG-positive children

Hoffenberg et al9 Marsh 0Marsh IMarsh IIMarsh III
Biopsy5 (16.7%)4 (13.3%)2 (6.7%)19 (63%)
Mean tTG level UA/mL< 0.6< 0.6< 0.6> 0.6 (0.70)

Unlike the other studies presented in this series, this study selected patients at risk of CD who were anti-tTG positive. Unfortunately, this makes direct comparisons difficult, but in essence this study supports the notion of a greater sensitivity of tTG in high-grade histologic lesions through the finding that high-grade lesions are associated with higher anti-tTG titres.

In a small case control study assessing the diagnostic value of EMA, Sategna-Guidetti,10 also found that in patients with documented CD, EMA positivity correlated with the severity of the histologic grade. In this study, EMA was falsely negative in 50% of CD patients without VA.

Other Histological Features

Several other histological features have been studied in an attempt to improve the accuracy of biopsy in the diagnosis of CD. Some of these features include: assessment of small bowel mucosal mast cells,11–14 mucosal fat,15 and endocrine cell hyperplasia.16 Discussion of these features is beyond the scope of this review.

Appendix H References

1.
Fasano A, Berti I, Gerarduzzi T, Not T, Colletti R B, Drago S. et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Archives of Internal Medicine. 2003;163(3):286–92. [PubMed: 12578508]
2.
Rostami K, Kerckhaert J, Tiemessen R, von Blomberg B M, Meijer J W, Mulder C J. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. American Journal of Gastroenterology. 1999;94(4):888–94. [PubMed: 10201452]
3.
Tursi A, Brandimarte G, Giorgetti G M. Prevalence of antitissue transglutaminase antibodies in different degrees of intestinal damage in celiac disease. Journal of Clinical Gastroenterology. 2003;36(3):219–21. [PubMed: 12590232]
4.
Tursi A, Brandimarte G, Giorgetti G M. Sorbitol H2-breath test versus anti-endomysium antibodies for the diagnosis of subclinical/silent coeliac disease. Scand J Gastroenterol. 2001;36(11):1170–2. [PubMed: 11686216]
5.
Tursi A, Brandimarte G, Giorgetti G, Gigliobianco A, Lombardi D, Gasbarrini G. Low prevalence of antigliadin and anti-endomysium antibodies in subclinical/silent celiac disease. American Journal of Gastroenterology. 2001;96(5):1507–10. [PubMed: 11374690]
6.
Demir H, Yuce A, Kocak N, Ozen H, Gurakan F. Celiac disease in Turkish children: presentation of 104 cases. Pediatrics International - Official Journal of the Japan Pediatric Society. 2000;42(5):483–7. [PubMed: 11059535]
7.
Kvedar J C, Pion I A, Bilodeau E B, Baden H P, Greco M A. Detection of substrates of keratinocyte transglutaminase in vitro and in vivo using a monoclonal antibody to dansylcadaverine. Biochemistry. 1992;31(1):49–56. [PubMed: 1370626]
8.
Kotze Lorete Maria da Silva, Utiyama Shirley Ramos da Rosa, Nisihara R M, de C V, Ioshii S O. IgA class anti-endomysial and anti-tissue transglutaminase antibodies in relation to duodenal mucosa changes in coeliac disease. Pathology. 2003;35(1):56–60. [PubMed: 12701686]
9.
Hoffenberg E J, Bao F, Eisenbarth G S, Uhlhorn C, Haas J E, Sokol R J. et al. Transglutaminase antibodies in children with a genetic risk for celiac disease. Journal of Pediatrics. 2000;137(3):356–60. [PubMed: 10969260]
10.
Sategna-Guidetti C, Bruno M, Pulitano R, Ferfoglia G. Disease specificity of IgA class anti-endomysium antibodies (IgA-EmA) in adult coeliac disease. Eur J Gastroenterol Hepatol. 1991;3(3):251–4.
11.
Kosnai I, Kuitunen P, Savilahti E, Sipponen P. Mast cells and eosinophils in the jejunal mucosa of patients with intestinal cow's milk allergy and celiac disease of childhood. Journal of Pediatric Gastroenterology and Nutrition. 1984;3(3):368–72. [PubMed: 6737181]
12.
Strobel S, Busuttil A, Ferguson A. Human intestinal mucosal mast cells: expanded population in untreated coeliac disease. Gut. 1983;24(3):222–7. [PMC free article: PMC1419930] [PubMed: 6826106]
13.
Suranyi Y, Freier S, Faber J, Dollberg L. Intestinal mast cells in different stages of celiac disease. Israel Journal of Medical Sciences. 1986;22(5):370–5. [PubMed: 3744785]
14.
Dollberg L, Gurevitz M, Freier S. Gastrointestinal mast cells in health, and in coeliac disease and other conditions. Arch Dis Child. 1980;55(9):702–5. [PMC free article: PMC1626996] [PubMed: 7436534]
15.
Variend S, Placzek M, Raafat F, Walker-Smith J A. Small intestinal mucosal fat in childhood enteropathies. Journal of Clinical Pathology. 1984;37(4):373–7. [PMC free article: PMC498736] [PubMed: 6707223]
16.
Johnston C F, Bell P M, Collins B J, Shaw C, Love A H, Buchanan K D. Reassessment of enteric endocrine cell hyperplasia in celiac disease. Hepato-Gastroenterology. 1988;35(6):285–8. [PubMed: 3215624]

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