Rapid Responses to:

CLINICAL REVIEW: David S Sanders, David P Hurlstone, Mark E McAlindon, Marios Hadjivassiliou, Simon S Cross, Graeme Wild, and Christopher J Atkins Antibody negative coeliac disease presenting in elderly people—an easily missed diagnosis BMJ 2005; 330: 775-776 [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Seronegative coeliac disease - a clinical challenge

Antonio Tursi   (26 April 2005)

Unforgiving Master of Non-Specificity And Disguise

Kamran Rostami, Chris Mulder, Professor in Gastroenterology   (27 April 2005)

Seronegative coeliac disease - a clinical challenge 26 April 2005
Antonio Tursi, consultant gastroenterologist Digestive Endoscopy Unit, Send response to journal: Re: Seronegative coeliac disease - a clinical challenge	Antonio TURSI,M.D. Consultant Gastroenterologist Digestive Endoscopy Unit, “Lorenzo Bonomo” Hospital, Andria (BA) - Italy Sir, I read with extreme interest the recent case report by David Sanders and collegues about the uncommon case of a 79-year old man in whom celiac disease was diagnosed despite antibodies negativity (1). This case confirms several other recent reports, which showed that in some celiac patients antibodies may be negative. In particular, seronegative celiac disease seems to be quite frequent in patients with Marsh I-IIIa lesions (2-6). This is a very important challenge in clinical practice, since most of general pratictioners (and most of gastroenterologists) advice and carry out gastroscopy in suspected coeliac disease only after a positive antibodies assessment. On the other hand, it is not easy to obtain patients’ consent to gastroscopy in presence of mild gastrointestinal symptoms (as dyspepsia) or in absence of them but suspected for celiac disease (as patients complaining for iron-deficiency anaemia or osteoporosis), and negative for serological searching. How we can overcome this problem? In their recent excellent review, Armin Alaedini and Peter Green underline the concept of intestinal biopsy in high clinical suspicion of celiac disease and irrespective of serological results (7). However, I think that other non-invasive methods should be carried out to select patients to undergo gastroscopy. In particular, I think that tests evaluating small bowel absorption should be performed in every case of suspicious celiac disease and irrespective of serological searching, since they may supply more information about small bowel function. In fact we cannot forget that coeliac disease is a malapsorptive syndrome, and that it affect always small bowel function. We performed a sorbitol H2 breath test in every patient suspected for celiac disease as adjunctive non invasive method assessing small bowel function. Sorbitol, a hexahydroxy alcohol used as a sugar substitute in many dietetic foods and as a drug vehicle, has been recently used to diagnose celiac patients, since its supply at low dose and concentration to patients with celiac disease resulted in an increased excretion of H2 with respect to healthy controls (8). At the same time, it has been showed that this test may be useful as a screening tool in patients with celiac disease (9), as well as we demonstrate more recently its effectiveness both in detecting histological lesions in patients affected by subclinical/silent form of celiac disease (10) and in detecting histological damage in first-degree seronegative relatives (11). Sorbitol H2 breath test is useful even in borderline gluten-sensitive enteropathy, in whom histology is often confounding or misleading or inconsistent for coeliac disease but clinical features are consistency for celiac disease (as iron deficiency anaemia not responding to oral iron supplementation): in these cases sorbitol H2 breath test- positivity before gluten-free diet and sorbitol H2 breath test- negativity after gluten-free diet showed a small bowel restoration after gluten withdrawal and permitted to made a definitive diagnosis of celiac disease (12). Unfortunately, this test shows high sensitivity but low specificity in detecting small bowel histological damage, since also diseases involving small bowel (as Crohn’s disease) may show abnormal sorbitol H2 breath test (13). So, I don’t think that sorbitol H2 breath test may replace serological tests nor intestinal biopsy. However, Sorbitol H2 breath test is a cheap, easy and non-invasive method to assess small bowel function, and I think that it may supply a valid contribution in detecting intestinal damage even in seronegative patients and in selecting patients to undergo small intestinal biopsy. REFERENCES 1) Sanders DS; Hurlstone DP, McAlindon ME, Hadjuvassiliou M, Cross SS, Wild G, Atkins CJ. Antibody negative celiac disease presenting in elderly people – an easily missed diagnosis. BMJ 2005;330: 775-6 2) Rostami K, Kerckhaert J, Tiemessen R, von Blomberg ME, Meijer JWR, Mulder CJJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol 1999;94: 888-94 3) Dickey W, Hughes DF, McMillan SA. Reliance on serum endomysial antibody testing underestimates the true prevalence of coeliac disease by one fifth. Scand J Gastroenterol 2000;35: 181-3 4) Tursi A, Brandimarte G, Giorgetti G, Gigliobianco A, Lombardi D, Gasbarrini G. Low prevalence of antigliadin and anti-endomysium antibodies in subclinical/silent coeliac disease. Am J Gastroenterol 2001; 96: 1507- 10 5) Tursi A, Brandimarte G, Giorgetti G. Prevalence of anti-tissue transglutaminase antibodies in different degrees of intestinal damage in celiac disease. J Clin Gastroenterol 2003; 36: 219-221 6) Abrams JA, Diamone B, Rotterdam H, Green PHR. Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy. Dig Dis Sci 2004;49: 546-50 7) Alaedini A, Green PHR. Narrative review. Celiac disease: understanding a complex autoimmune disordes. Ann Intern Med 2005;142: 289-98 8) Corazza GR, Strocchi A, Rossi R, Sirola D , Gasbarrini G. Sorbitol malabsorption in normal volunteers and in patients with coeliac disease. Gut 1988;29: 44-8 9) Pelli MA, Capodicasa E, De Angelis V, Morelli A, Bassotti G. Sorbitol H2-breath test in celiac disease. Importance of early positivity. Gastroenterol Int 1998;11: 65-8 10) Tursi A, Brandimarte G, Giorgetti GM. Sorbitol H2-Breath test versus anti-endomysium (EMA) antibodies for the diagnosis of subclinical/silent coeliac disese. Scand J Gastroenterol 2001;36: 1170-2 11) Tursi A, Brandimarte G, Giorgetti GM, Inchingolo CD. Effectiveness of sorbitol H2 breath test in detecting histological damage among relatives of coeliacs. Scand J Gastroenterol 2003;38: 727-731 12) Tursi A, Brandimarte G. The symptomatic and histological response to a gluten-free diet in patients with borderline enteropathy. J Clin Gastroenterol 2003;36(1): 13-17 13) Tursi A, Giorgetti GM, Brandimarte G, Elisei W. High prevalence of celiac disease among patients affected by Crohn’s disease. Inflamm Bowel Dis 2005; (in press) Competing interests: None declared
Unforgiving Master of Non-Specificity And Disguise 27 April 2005
Kamran Rostami, MD., PhD. Coeliac Disease Research Centre, Free University Amsterdam, The Netherlands, Chris Mulder, Professor in Gastroenterology Send response to journal: Re: Unforgiving Master of Non-Specificity And Disguise	The review by Sander’s et al. [1] shares insights from seronegative subgroup of coelics showing us another feature of non-specificity of gluten-sensitive enteropathy spectrum. Their report reminds us how coeliac disease’s (CD) behaviour could simply be beyond clinician’s expectations, the reason for which most sufferers remain under and/or undiagnosed. Despite many published reports on seronegative coeliacs since we first characterised their clinical presentation in 1998-99, this subgroup understandably continues to be forgotten or not included in diagnostic workup, unless presenting with coeliac crisis. Why? Because, we know that non-elucidated tricks and non-specificities in the nature of this common and tricky disorder including atypical clinical symptoms, atypical serology and histology, makes the diagnostic pathway extremely difficult. We have still no clue as to how high the prevalence of sero-negative cases might be as this has not been investigated or even estimated. Do the clinicians know that excluding IgA-deficient cases, ± 40% of coeliac patients could present with negative serology [2-3]? If yes we should clearly expect a higher prevalence for CD, as epidemiological studies are obviously based on serological tests. A significant number of patients seen in Gastroenterology clinics are presenting with IBS and atypical symptoms but again, who knows how many of them could be seronegative coeliacs? How could we find them? It’s time to forget the classical presentation and focus on non-specific specificities of CD spectrum. As Peter Watson highlighted in the same issue, we may improve the detection rate by a combination of serological tests instead of using only one antibody test. Biopsies taken from only 2nd part of duodenum seems to be inefficient, as CD could affect any part of small bowels from bulb to terminal ileum [4-5]. Very often symptomatic cases present with negative serology and/or normal biopsy. Bear in mind that the same cases might present with positive results later in life like in Sander’s et al. case. Therefore, CD cannot be excluded based on one serology and biopsy attempt. Repeating the tests, i.e. after a few months to 2 years, would be the key steps in detecting sufferers in disguise. 1.Sanders DS, Hurlstone DP, McAlindon ME, Hadjivassiliou M, Cross SS, Atkins CJ.Antibody negative coeliac disease presenting in elderly people--an easily missed diagnosis. BMJ. 2005;2;330:775-6. 2.Abrams JA, Diamond B, Rotterdam H, Green PH. Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy. Dig Dis Sci. 2004;49:546-50. 3. Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BM, Meijer JW, Mulder CJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol. 1999;94:888-94 4. Meijer JW, Wahab PJ, Mulder CJ. Small intestinal biopsies in celiac disease: duodenal or jejunal? Virchows Arch. 2003;442:124-8. 5. Dickey W, Hughes DF. Histology of the terminal ileum in coeliac disease. Scand J Gastroenterol. 2004;39:665-7. Competing interests: Associate, Medical Advisory Council, Coeliac UK