Celiac disease: how many biopsies for diagnosis?

Abstract

We recommend that 4 to 6 biopsy specimens be taken from the descending duodenum, because villous atrophy in celiac disease is patchy and orientation of the specimens is variable.Celiac disease is now considered to be common, occurring in rates approaching 1% of the population worldwide.1Green P.H. Cellier C. Celiac disease.N Engl J Med. 2007; 357: 1731-1743Crossref PubMed Scopus (1470) Google Scholar, 2Fasano A. Berti I. Gerarduzzi T. et al.Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.Arch Intern Med. 2003; 163: 286-292Crossref PubMed Scopus (1431) Google Scholar However, the rate of diagnosis, while increasing in the United States,3Murray J.A. Van Dyke C. Plevak M.F. et al.Trends in the identification and clinical features of celiac disease in a North American community, 1950-2001.Clin Gastroenterol Hepatol. 2003; 1: 19-27Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar does not approach this figure. In contrast, in Finland an active program involving the education of physicians in how and when to consider the diagnosis of celiac disease has resulted in an increase in the rate of diagnosis.4Collin P. Huhtala H. Virta L. et al.Diagnosis of celiac disease in clinical practice: physician's alertness to the condition essential.J Clin Gastroenterol. 2007; 41: 152-156Crossref PubMed Scopus (72) Google Scholar The nationwide prevalence of celiac disease in Finland is now 0.45%—0.7% in the highest to 0.3% in the lowest prevalence areas of the country. In Ireland the increased rate of diagnosis has been attributed to testing and referral by primary care physicians.5Dickey W. McMillan S.A. Increasing numbers at a specialist coeliac clinic: contribution of serological testing in primary care.Dig Liver Dis. 2005; 37: 928-933Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar We recommend that 4 to 6 biopsy specimens be taken from the descending duodenum, because villous atrophy in celiac disease is patchy and orientation of the specimens is variable. In 2004, the National Institutes of Health convened a Consensus Development Conference because of the low rate of celiac disease diagnosis in the United States.6James S.P. National Institutes of Health consensus development conference statement on celiac disease, June 28-30, 2004.Gastroenterology. 2005; 128: S1-S9Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar This low rate has been attributed to failure of physicians to recognize the diverse manifestations of the disease.7Green P.H. The many faces of celiac disease: clinical presentation of celiac disease in the adult population.Gastroenterology. 2005; 128: S74-S78Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar This failure of awareness has led to failure to test the patient when indicated. This applies to both the use of serologic testing in the primary care setting,8Catassi C. Kryszak D. Louis-Jacques O. et al.Detection of celiac disease in primary care: a multicenter case-finding study in North America.Am J Gastroenterol. 2007; 102: 1454-1460Crossref PubMed Scopus (215) Google Scholar as well as the failure to perform duodenal biopsies by endoscopists, even when it would appear indicated. This failure to perform a biopsy when indicated was addressed by Harewood et al,9Harewood G.C. Holub J.L. Lieberman D.A. Variation in small bowel biopsy performance among diverse endoscopy settings: results from a national endoscopic database.Am J Gastroenterol. 2004; 99: 1790-1794Crossref PubMed Scopus (34) Google Scholar who used the large Clinical Outcomes Research Initiative (CORI) national endoscopic database to analyze the rate of small-bowel biopsy performed in patients undergoing EGD for the evaluation of anemia, iron deficiency without anemia, weight loss, and diarrhea. They found that only 10% of those with anemia, 7% with iron deficiency, 6% with weight loss, and 19% with diarrhea underwent a duodenal biopsy . In all of these conditions it would be appropriate to consider the diagnosis of celiac disease and perform duodenal biopsies, irrespective of the results of serologic tests or the endoscopic appearance of the duodenum. Biopsy is currently the criterion standard in the diagnosis of celiac disease. Serologic testing is used to screen those at risk for the disease in order to triage for endoscopy and biopsy. These serologic tests, including those for endomysial and tissue transglutaminase antibodies, have a high sensitivity and specificity,10Rostom A. Murray J.A. Kagnoff M.F. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease.Gastroenterology. 2006; 131: 1981-2002Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar although not 100%. The sensitivity of the serologic tests correlates with the degree of villous atrophy; thus, a negative serologic test does not exclude the diagnosis of celiac disease.11Abrams J.A. Brar P. Diamond B. et al.Utility in clinical practice of immunoglobulin A anti-tissue transglutaminase antibody for the diagnosis of celiac disease.Clin Gastroenterol Hepatol. 2006; 4: 726-730Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 12Abrams J.A. Diamond B. Rotterdam H. et al.Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy.Dig Dis Sci. 2004; 49: 546-550Crossref PubMed Scopus (128) Google Scholar Who should undergo a biopsy? Certainly anyone in whom there is a consideration of celiac disease, irrespective of the results of the serologic tests. This applies to those undergoing EGD for weight loss, anemia, and diarrhea, as well those with an increased risk of the disease. This includes relatives of those with celiac disease,2Fasano A. Berti I. Gerarduzzi T. et al.Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.Arch Intern Med. 2003; 163: 286-292Crossref PubMed Scopus (1431) Google Scholar patients with irritable bowel syndrome,13Sanders D.S. Carter M.J. Hurlstone D.P. et al.Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care.Lancet. 2001; 358: 1504-1508Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar inflammatory bowel disease,14Yang A. Chen Y. Scherl E. et al.Inflammatory bowel disease in patients with celiac disease.Inflamm Bowel Dis. 2005; 11: 528-532Crossref PubMed Scopus (96) Google Scholar chronic liver disease,15Rubio-Tapia A. Murray J.A. The liver in celiac disease.Hepatology. 2007; 46: 1650-1658Crossref PubMed Scopus (150) Google Scholar Down syndrome,16Mackey J. Treem W.R. Worley G. et al.Frequency of celiac disease in individuals with Down syndrome in the United States.Clin Pediatr (Phila). 2001; 40: 249-252Crossref PubMed Scopus (36) Google Scholar and various autoimmune diseases, especially type I diabetes mellitus.17Murray J.A. Celiac disease in patients with an affected member, type 1 diabetes, iron-deficiency, or osteoporosis?.Gastroenterology. 2005; 128: S52-S56Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Celiac disease is common, and the list of those who could possibly have celiac disease can be extensive. Thus, endoscopists should consider routine biopsy of the duodenum at EGD.18Green P.H. Murray J.A. Routine duodenal biopsies to exclude celiac disease?.Gastrointest Endosc. 2003; 58: 92-95PubMed Scopus (41) Google Scholar This is especially so in the era of open-access endoscopy when many of the possible disease associations are not included in the referral indication or endoscopy unit intake history sheet. Who asks patients if they carry the diagnosis of irritable bowel syndrome prior to an EGD? Pediatric gastroenterologists typically do routine biopsies of all portions of the upper GI tract, but adult endoscopists rarely do. In this issue of Gastrointestinal Endoscopy, Pais et al19Pais W.P. Duerksen D.R. Pettigrew N.M. et al.How many duodenal biopsy specimens are required to make a diagnosis of celiac disease?.Gastrointest Endosc. 2008; 67: 1082-1087Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar address the number of biopsy specimens needed for diagnosis of celiac disease, an area that has not been addressed recently. What is known about duodenal biopsies in the diagnosis of celiac disease? First, although considered the criterion standard, they are not a perfect standard. In a large multicenter study, 10.7% of biopsy procedures were inadequate for diagnosis.20Collin P. Kaukinen K. Vogelsang H. et al.Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study.Eur J Gastroenterol Hepatol. 2005; 17: 85-91Crossref PubMed Scopus (195) Google Scholar This is mainly due to inadequate orientation of the small specimens. There is no doubt that duodenal biopsy specimens are not as hardy as those from esophageal or gastric biopsy. The pieces of tissue are more readily subject to preparation artifact as well as poor orientation. Orientation of the small pieces in the endoscopy room is, to my mind, impossible. It is time consuming, requires expertise among endoscopy assistants, and is rarely worthwhile. It is a throwback to past eras when large-piece, single-capsule or suction-tube biopsy specimens were oriented by gastroenterologists and viewed under a dissecting microscope.21Brandborg L.L. Rubin G.E. Quinton W.E. A multipurpose instrument for suction biopsy of the esophagus, stomach, small bowel, and colon.Gastroenterology. 1959; 37: 1-16PubMed Google Scholar, 22McCarthy C.F. Borland Jr., J.L. Kurtz S.M. et al.The value of the dissecting microscope in the diagnosis of nontropical sprue.Am J Pathol. 1964; 44: 585-595PubMed Google Scholar Another important variable in diagnosis of celiac disease is the fact that not all endoscopic biopsy specimens are viewed and interpreted by GI pathologists. It is important to consider just who is rendering the opinion on the biopsy specimen. Not all general pathologists are aware of the spectrum of pathologic changes seen in celiac disease as originally classified by Marsh23Marsh M.N. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue').Gastroenterology. 1992; 102: 330-354Abstract PubMed Google Scholar and later by Oberhuber et al.24Oberhuber G. Granditsch G. Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists.Eur J Gastroenterol Hepatol. 1999; 11: 1185-1194Crossref PubMed Scopus (1331) Google Scholar There is information on the location, or site, of biopsies. Endoscopic biopsy specimens of the descending duodenum were originally shown to be as good as jejunal specimens taken by capsule or suction tube.25Gillberg R. Ahren C. Coeliac disease diagnosed by means of duodenoscopy and endoscopic duodenal biopsy.Scand J Gastroenterol. 1977; 12: 911-916Crossref PubMed Scopus (49) Google Scholar, 26Mee A.S. Burke M. Vallon A.G. et al.Small bowel biopsy for malabsorption: comparison of the diagnostic adequacy of endoscopic forceps and capsule biopsy specimens.Br Med J (Clin Res Ed). 1985; 291: 769-772Crossref PubMed Scopus (103) Google Scholar Usually, biopsy specimens are taken of the descending duodenum. However, contrary to common teaching and practice, duodenal bulb biopsy specimens appear adequate, and possibly should be taken as well. In 3 different studies they were adequate for diagnosis and may be the only site demonstrating villous atrophy.27Ravelli A. Bolognini S. Gambarotti M. et al.Variability of histologic lesions in relation to biopsy site in gluten-sensitive enteropathy.Am J Gastroenterol. 2005; 100: 177-185Crossref PubMed Scopus (160) Google Scholar, 28Bonamico M. Mariani P. Thanasi E. et al.Patchy villous atrophy of the duodenum in childhood celiac disease.J Pediatr Gastroenterol Nutr. 2004; 38: 204-207Crossref PubMed Scopus (160) Google Scholar, 29Vogelsang H. Hanel S. Steiner B. et al.Diagnostic duodenal bulb biopsy in celiac disease.Endoscopy. 2001; 33: 336-340Crossref PubMed Scopus (86) Google Scholar What about biopsy forceps size or type? The type of the biopsy forceps (pediatric, regular, or jumbo) has been shown to be irrelevant.26Mee A.S. Burke M. Vallon A.G. et al.Small bowel biopsy for malabsorption: comparison of the diagnostic adequacy of endoscopic forceps and capsule biopsy specimens.Br Med J (Clin Res Ed). 1985; 291: 769-772Crossref PubMed Scopus (103) Google Scholar, 30Dandalides S.M. Carey W.D. Petras R. et al.Endoscopic small bowel mucosal biopsy: a controlled trial evaluating forceps size and biopsy location in the diagnosis of normal and abnormal mucosal architecture.Gastrointest Endosc. 1989; 35: 197-200Abstract Full Text PDF PubMed Scopus (82) Google Scholar Jumbo forceps are not needed. What about the number of biopsy specimens? One frequently sees patients who undergo EGD either for diagnosis or follow-up of celiac disease, and when the slides are obtained for review, only one or two biopsy specimens are on the slide. Upon review they are either not well oriented or have some kind of preparation artifact. It seems a waste of effort to subject a patient to an EGD and take only one biopsy specimen. In a recent review we have recommended that 4 to 6 biopsy specimens be taken from the descending duodenum.1Green P.H. Cellier C. Celiac disease.N Engl J Med. 2007; 357: 1731-1743Crossref PubMed Scopus (1470) Google Scholar This is based on the fact that the villous atrophy in celiac disease is patchy, and orientation of the biopsy specimens is variable.27Ravelli A. Bolognini S. Gambarotti M. et al.Variability of histologic lesions in relation to biopsy site in gluten-sensitive enteropathy.Am J Gastroenterol. 2005; 100: 177-185Crossref PubMed Scopus (160) Google Scholar, 28Bonamico M. Mariani P. Thanasi E. et al.Patchy villous atrophy of the duodenum in childhood celiac disease.J Pediatr Gastroenterol Nutr. 2004; 38: 204-207Crossref PubMed Scopus (160) Google Scholar Patchiness of villous atrophy in celiac disease has been clearly demonstrated by magnification endoscopy,31Hurlstone D.P. Sanders D.S. High-magnification immersion chromoscopic duodenoscopy permits visualization of patchy atrophy in celiac disease: an opportunity to target biopsies of abnormal mucosa.Gastrointest Endosc. 2003; 58: 815-816Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 32Lo A. Guelrud M. Essenfeld H. et al.Classification of villous atrophy with enhanced magnification endoscopy in patients with celiac disease and tropical sprue.Gastrointest Endosc. 2007; 66: 377-382Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar especially when combined with chromoendoscopy.33Siegel L.M. Stevens P.D. Lightdale C.J. et al.Combined magnification endoscopy with chromoendoscopy in the evaluation of patients with suspected malabsorption.Gastrointest Endosc. 1997; 46: 226-230Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Pais et al,19Pais W.P. Duerksen D.R. Pettigrew N.M. et al.How many duodenal biopsy specimens are required to make a diagnosis of celiac disease?.Gastrointest Endosc. 2008; 67: 1082-1087Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar in their current retrospective study, have addressed this issue of the number of biopsy specimens necessary for diagnosis of celiac disease.19Pais W.P. Duerksen D.R. Pettigrew N.M. et al.How many duodenal biopsy specimens are required to make a diagnosis of celiac disease?.Gastrointest Endosc. 2008; 67: 1082-1087Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar They demonstrated that 4 biopsy specimens established the diagnosis in 100% of their cases. This conclusion was also reached by Mee et al.26Mee A.S. Burke M. Vallon A.G. et al.Small bowel biopsy for malabsorption: comparison of the diagnostic adequacy of endoscopic forceps and capsule biopsy specimens.Br Med J (Clin Res Ed). 1985; 291: 769-772Crossref PubMed Scopus (103) Google Scholar In addition, Pais et al confirmed that the disease is patchy, with variable degrees of atrophy within some patients, and that orientation of the biopsy specimens was not necessary, at least in their hands. In conclusion, celiac disease is common and diagnosed by duodenal biopsy. Think of it and take at least 4 biopsy specimens of the descending duodenum! Maybe we should add a biopsy of the bulb? The author reports the following conflicts: P. H. R. Green is on the Speakers' Bureau of Prometheus Labs; a consultant for Alvine Pharmaceuticals; and has received a clinical trial grant from Alba Therapeutics.