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Celiac disease

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V. Villanacci, C. Catassi, K. Rostami and U. Volta Celiac disease: changing dogma on historical diagnosis
V. Villanacci, C. Catassi, K. Rostami and U. Volta, 13 January 2010
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Long ago when celiac disease was recognized as a new entity, it was known as a rare cause of severe intestinal villous atrophy with a very high mortality in absence of a gluten-free diet [1]. The incidence of this form of celiac disease was less than 1:5000.

The most prominent characteristic was histological change and histology became the gold standard for diagnosis. Despite substantial changes in the mode of presentation and diagnosis “the gold standard for the diagnosis of celiac disease remained the small-bowel mucosal biopsy” [2] reinforcing the dogma of the irreplaceable role of histology in celiac disease diagnosis.

However in recent years we have seen a progressive declining of this assumption. In 1982, Corazza et al. [3] underlined the "higher inter- and intra-observer variation in the evaluation of jejunal biopsy specimens" and in 1994 Shidrawi et al. [4] suggested that "for the correct diagnosis of celiac disease we therefore conclude that:

  • (i) a minimum of 3 biopsy specimens distal to the first part of the duodenum should be taken at the time of the initial endoscopy,
  • (ii) the biopsy specimens should be correctly oriented, be of adequate size, and be reviewed by an experienced histopathologist".
In Green and Jabri's [5] excellent seminar on celiac disease the authors emphasize that "a major pitfall in the diagnosis of celiac disease is in pathological interpretation of intestinal biopsies".

An adequate number of biopsies need to be taken because celiac disease is patchy and not all biopsy samples will be adequately oriented for the interpretation of the crypt to villous ratio. A poorly oriented biopsy, as shown by crypts cut tangentially, will falsely reduce the crypt to villous ratio. Negative serological tests or poor response to the diet should prompt review of the biopsy to ensure that the original interpretation was correct.

Over the last 30 years, simple diagnostic tools have been developed, for example, the determination of IgA class antiendomysial and anti-transglutaminase antibody and the HLA genotyping for detection of DQ2 and DQ8 predisposing haplotypes. The increasing application of these tests has shown an unsuspected frequency of "borderline" cases; potential celiac disease (celiac-type autoimmune serology with a normal small intestinal architecture) or sero-negative disease (typical celiac enteropathy and response to the gluten-free diet without serum celiac disease auto-antibodies).

The clinical behavior of cases detected because of a positive serology seems to be quite different compared to previous cases detected based on severe malabsorption and histology only (severe villous atrophy). The cases detected by positive antibodies have often non-specific histological findings that are common in other disorders as well. Despite the previously belief, symptomology in this group does not seem to be related to the degree or length of affected bowel either. With that degree of non-specificity, histology obviously fails to represent the gold standard in diagnosis of gluten sensitivity as it simply unreliable in its own. There is nothing against the fact that histology remains as an important component in diagnosis of gluten sensitivity but not as the gold standard (not even as the silver standard).

Celiac disease with flat mucosa is only a part of the spectrum. It is time to recognize that for the majority of gluten sensitive cases histology is nonspecific and hence the pathologist is only a member of the team and not the one who could make the definite diagnosis in his own. Sensitivity and specificity of serological tests are far higher than histology. At this stage clinicians need to rely on clinical symptoms, the presence of antibodies and histology should be interpreted cautiously based on these parameters only [6].

More recently, other papers have highlighted the problem of the reliability of histological findings [7-18]. There is a continuous attempt to provide new means to overcome the methodological issues and the subjectivity of interpretation related to the histology. We can summarize all these issues on the problems of histological diagnosis of celiac disease in this sentence “the greater the number of categories, the lower the inter- and intra-observer agreement, with a consequent reduction of reproducibility” [19].

For the above reasons we believe that it is the time to change the original dogma of histology as gold standard for the diagnosis of celiac disease. Today, in the light of the current knowledge and complex clinical problems, we suggest that the true gold standard is not the histology but the final diagnosis of celiac disease made by the clinician. The clinician is the only one who knows the patient, establishes the tests and their timing, and therefore is the only one who can reasonably interpret the panel of available data (clinical, serological, histological and genetic). The essential multidisciplinary team of specialists, pathologists, and laboratorists can be coordinated by the clinician.

The role of the pathologist is not diminished but rather is always an important element for celiac disease diagnosis. This is especially true today with a significant increase in borderline conditions (at least 10-20% of the present celiac disease diagnoses). In these situations an accurate assessment of the morphology of the duodenal mucosa, avoiding to draw any clinical conclusion (that are very often misleading) is crucial for the final diagnosis of celiac disease.

Our hope with these small considerations based on years of experience in the specific field and on a careful analysis of the literature is that we can start a new way based on an interactive collaboration and a proper methodology for celiac disease diagnosis, the most correct and safe as possible avoiding situations of doubt and stress for the patients.

Authors

V. Villanacci1, C. Catassi2 ,K. Rostami3, U. Volta4

1. Second Department of Pathology, Spedali Civili, University of Brescia, Italy.
2. Clinica Pediatrica, Università Politecnica delle Marche, Ancona Center for Celiac Research, University of Maryland, Baltimore MD, USA.
3. School of Medicine, University of Birmingham, United Kingdom.
4. Department of Diseases of the Digestive System and Internal Medicine, Azienda Ospedaliera-Universitaria, Policlinico S. Orsola - Malpighi, Bologna, Italy.

Corresponding author

V. Villanacci Second Department of Pathology, Spedali Civili, University of Brescia, Italy.

References

  1. Logan RF, Rifkind EA, Turner ID, et al. Mortality in celiac disease. Gastroenterol 1989; 97(2): 265-71.
  2. Antonioli DA. Celiac disease: a progress report. Mod Pathol 2003; 16(4): 342-6.
  3. Corazza GR, Bonvicini F, Frazzoni M, et al. Observer variation in assessment of jejunal biopsy specimens. A comparison between subjective criteria and morphometric measurement. Gastroenterol 1982; 83: 1217-22.
  4. Shidrawi RG, Przemioslo R, Davies DR, et al. Pitfalls in diagnosing celiac disease. J Clin Pathol 1994; 47: 693-4.
  5. Green PH, Jabri B. Coeliac Disease. Lancet 2003; 362: 383-91.
  6. Hill PG, Holmes GK. Coeliac disease: a biopsy is not always necessary for diagnosis. Aliment Pharmacol Ther 2008; 27(7): 572-7.
  7. Cammarota G, Cuoco L, Cesaro P, et al. A highly accurate method for monitoring histological recovery in patients with celiac disease on a gluten-free diet using an endoscopic approach that avoids the need for biopsy: a double-center study. Endoscopy 2007; 39(1): 46-51.
  8. Frenz MB, Mee AS. Making the diagnosis of coeliac disease: is there a role for push enteroscopy? Eur J Gastroenterol Hepatol 2004; 16(11): 1127-9.
  9. Fraquelli M, Colli A, Colucci A, et al. Bardella MT, Trovato C, Pometta R, et al. Accuracy of ultrasonography in predicting celiac disease. Arch Intern Med 2004; 164(2): 169-74.
  10. Murdock AM, Johnston SD. Diagnostic criteria for coeliac disease: time for change? Eur J Gastroenterol Hepatol 2005; 17(1): 41-3.
  11. Sempoux C. Role of the pathologist in the differential diagnosis of malabsorption. Acta Gastroenterol Belg 2006; 69(1): 49-51.
  12. Gasbarrini G, Malandrino N, Giorgio V, et al. Celiac disease: what's new about it? Dig Dis 2008; 26(2): 121-7.
  13. Vivas S, Ruiz de Morales JM, Fernandez M, et al. Age-related clinical, serological, and histopathological features of celiac disease. Am J Gastroenterol 2008; 103(9): 2360-5.
  14. Tischendorf JJ, Wopp K, Streetz KL, et al The value of duodenal biopsy within routine upper endoscopy: a prospective study in 1000 patients. Z Gastroenterol 2008; 46(8): 771-5 [German].
  15. Anderson RP. Coeliac disease: current approach and future prospects. Intern Med J 2008; 38(10): 790-9.
  16. Venkatesh K, Cohen M, Evans C, et al. Feasibility of confocal endomicroscopy in the diagnosis of pediatric gastrointestinal disorders. World J Gastroenterol 2009; 15(18): 2214-9.
  17. Dickey W. Joint BAPEN and British Society of Gastroenterology Symposium on 'Coeliac disease: basics and controversies'. Coeliac disease in the twenty-first century. Proc Nutr Soc 2009: 1-8.
  18. Rostami K, Villanacci V. Microscopic enteritis: novel prospect in coeliac disease clinical and immuno-histogenesis. Evolution in diagnostic and treatment strategies. Dig Liver Dis 2009; 41(4): 245-52.
  19. Corazza GR, Villanacci V. Coeliac disease. J Clin Pathol 2005; 58: 573-4.

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