28. Myers A, Clark J, Foster H. Tuberculosis and treatment withinfliximab. N Engl J Med 2002;346:623–6.

Reprint requests and correspondence: Marsha Kay, M.D., TheDepartment of Pediatric Gastroenterology and Nutrition, TheCleveland Clinic Foundation, Desk A111, 9500 Euclid Avenue,Cleveland, OH 44195.

Received Jan. 7, 2003; accepted Jan. 8, 2003.

Small Bowel Bacterial Overgrowth,Celiac Disease, and IBS: What Are theReal Associations?A potential association between celiac disease and irritablebowel syndrome (IBS) remains as yet poorly defined. Sev-eral reports have described either a significant prevalence ofceliac disease among those presenting with apparent IBS, ora striking frequency of IBS-type symptoms among thosewith diagnosed celiac disease (1–3).

These associations prompt several questions: Firstly, doesthis merely represent a failure to recognize the contempo-rary clinical spectrum of celiac disease? Secondly, is thisapparent concurrence merely a reflection of the nonspeci-ficity of the symptom repertoire? Thirdly, could the inflam-mation intrinsic to celiac disease trigger the neuromuscularchange associated with IBS in a manner analogous to an-other proposed immune-mediated mechanism for IBS,namely postinfectious IBS? Finally, if this is indeed a trueassociation, are there other potential mechanisms?

Let us address the first two of these questions together.The rise in prevalence of celiac disease has paralleled thedevelopment of sensitive and specific screening serologicaltests. This has been reflected clinically in a broadening ofthe spectrum of symptoms that we now recognize as beingconsistent with gluten intolerance. These changes notwith-standing, typical pathological changes on small intestinalbiopsy and a favorable response to a gluten-free diet are stillrequired for definitive diagnosis of celiac disease.

IBS, on the other hand, remains a clinical diagnosis,based on the presence of a cluster of symptoms. In theabsence of diagnostic tests, various attempts have beenmade to formalize this symptom-based diagnosis, the mostwidely employed being those developed by the Rome com-mittees and recently updated as the Rome II criteria.

According to these criteria, organic disease precludes thediagnosis of IBS; there are, however, no established rulesregarding the extent of the workup, which should precedediagnosis. Thus, although on the face of it IBS and celiacdisease should not be confused, the situation, in practice, ismuch more problematic. In The Lancet, November, 2001,Sanders et al. reported a prevalence of celiac disease of 5%among a population of 300 patients with newly diagnosedIBS (1). This study used endomysial antibodies (EMA) andIgG/IgA antigliadin antibodies to screen for celiac diseaseand the Rome II criteria to diagnose IBS (1). Wahnschaffe

et al. published an interesting report in the December, 2001issue of Gastroenterology (2). In a group of 102 patientswith diarrhea-predominant IBS, the expression of HLADQ2and increased antibodies against gliadin and/or tissue trans-glutaminase in duodenal aspirate identified those with latentor potential celiac disease. The subgroup of these IBS pa-tients subsequently treated with a gluten-free diet had asignificant reduction in stool frequency and succus antibodytiters (2). The authors concluded that latent or potentialceliac disease may be responsible for symptoms in a pro-portion of patients otherwise categorized as having IBS. Inthe June, 2002 issue of this journal, O’Leary et al. reportedon a group of 150 celiac patients screened for IBS-typesymptoms using the modified Rome I criteria (3). Theyfound a prevalence of 20% in celiac patients, compared with5% of controls (3). These studies have not only highlightedthe prevalence of celiac disease among IBS patients, buthave also emphasized the importance of its active exclusion.This creates somewhat of a dilemma: How far should one goin the search for celiac disease?

Wahnschaffe et al. found that antibodies in duodenalaspirate were more accurate in the diagnosis of latent andpotential celiac disease than serology (2). However, thisidentifies a subgroup of patients on whom we have limitedknowledge regarding optimal management at present.

A reasonable approach, at least until further data becomeavailable, is to perform a serological screen using the EMAand IgA/IgG antigliadin antibody in those in whom there isa low index of suspicion. A high clinical suspicion or anyfactor associated with increased risk (for example, a positivefamily history/celiac disease-associated disorders/connec-tive tissue disease, particularly Sjogren’s disease/immunethyroid or liver disease/Down’s or Turner’s syndrome, andselective IgA deficiency) for celiac disease should promptperformance of duodenal biopsy even in the absence ofpositive serology (4).

The association of celiac disease and IBS is also impor-tant from a pathogenetic perspective. At the outset, one mustquestion whether this may be related to undiagnosed (latentor potential) or partially treated celiac disease rather thantrue IBS. The potential for diagnostic confusion related tothe nonspecificity of the Rome criteria is self-evident.

If real, one might speculate that gluten-induced mucosalinflammation is the mediator. Inflammation is known topredispose to altered gut motility, which in turn can precip-itate IBS-type symptoms. Postinfectious IBS is an excellentexample of this, being associated with both altered gutfunction (25% at 6 months) and IBS itself (7%) (5). Tofurther support this argument, Simren et al. have reported atwo-to-three times increased prevalence of IBS-like symp-toms in inflammatory bowel disease patients in long-stand-ing remission when compared with the normal population(6). Psychological factors seem to play a role in the devel-opment and perpetuation of IBS-type symptoms in bothinflammatory bowel disease patients (6) and in the postin-

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fective enterocolitides (7); whether this role is primary orsecondary remains to be determined.

The other potential explanation for the high prevalence ofIBS-type symptoms among celiac patients is small intestinalbacterial overgrowth (SIBO). Pimental et al. have reporteda prevalence of SIBO of almost 80% in IBS patients (8). Inthis month’s issue of the Journal, Tursi et al. report SIBO intwo thirds of a group of celiac patients studied (9). Bothgroups used the lactose breath hydrogen test (LBHT) fordiagnosis, and both also demonstrated significant clinicalimprovement with effective eradication. Despite the poten-tial inaccuracies associated with this diagnostic technique, itis difficult to ignore the data, and it certainly provokes thehypothesis that SIBO may be a common link between IBSand celiac disease. This concept is supported by other data.

Tursi et al. (9) reported on a group of 15 patients withconfirmed celiac disease, who experienced persistent GIsymptoms (diarrhea, abdominal pain/discomfort/slow gas-tric emptying) 6–8 months after introduction of a GFD.Dietary compliance was established at the outset; the groupwere then screened for SIBO using the LBHT. SIBO wasdiagnosed in two thirds of the group studied. Treatment withrifaximin resolved the symptoms in all patients. The LBHTalso became negative (9). This is an extremely interestingstudy with considerable potential clinical implications; itprovokes a number of issues worthy of further discussion.

Firstly, opinions regarding the preferred diagnostic tech-nique for SIBO are conflicting. In this study, a diagnosis ofSIBO was based on a positive LBHT. After the administra-tion of a test dose of lactulose, expiratory samples werecollected every 30 min for 4 h. A test was consideredpositive if there was a peak �20 ppm occurring �15 minbefore the colonic peak, or an elevated fasting histamine-2combined with an early increase in histamine-2 after lactu-lose ingestion.

The reliability of this diagnostic technique has been crit-icized, particularly when used alone, and reported sensitiv-ity ranges from 16.7% (10) to 68% (11), with an estimatedspecificity of 70% (10). The LBHT also appears to performsuboptimally when used to assess response to treatment.Double peaks in serial breath hydrogen concentrations,which previously defined an abnormal LBHT, are nowrecognized to sometimes represent rapid orocecal transittime or delivery of fermentable substrate to cecal bacteria.The performance of the test in conjunction with scintigraphyto monitor transit renders the LBHT somewhat more im-pressive, with a specificity of 100%, though sensitivityremains low at 38.9% (10).

Aspiration and direct culture of jejunal contents is re-garded by many as the gold standard for the diagnosis ofSIBO. The main difficulty with direct culture is the high riskof contamination by microflora in the oropharynx, givingrise to inaccurate results. Furthermore, sampling is restrictedto the proximal small bowel, i.e., the limit of the upperendoscope.

This diagnostic dilemma already provoked criticism afterPimental et al.’s publication in the December, 2000 issue ofthis journal (8). The main concern among correspondentswas the poor reliability of the LBTH. The high prevalencein this group of celiac patients, who again are without apredisposing anatomical abnormality, must raise similarquestions regarding the accuracy of the breath test.

The 100% effective eradication rate (i.e., symptom reso-lution and conversion of LBHT from positive to negative) ofa single course of treatment with a single antibiotic in thesesubjects is impressive and supports a correct initial diagno-sis.

Secondly, SIBO is most common among those with pre-disposing motility or structural disorders. In this study, theauthors propose that disturbed intestinal motility secondaryto celiac disease may account in part for the unexpectedlyhigh proportion of celiac patients with SIBO. Althoughprolonged orocecal transit is a recognized phenomenon inuntreated celiac patients with active mucosal lesions, thisreverts to normal within 6–8 months of a satisfactory glu-ten-free diet (12). It is, therefore, unlikely to be a majoretiological factor in this subgroup.

Thirdly, the high proportion of patients with negativeEMA deserves further comment. The anti-EMA has anapproximate sensitivity and specificity of 95–98% and 94–95%, respectively. It is recognized that in subjects withMarsh III lesions (partial or subtotal villous atrophy), thesensitivity falls, and may be as low as 31% (13). In thisgroup, five of 15 patients had negative EMA at diagnosis.IgA deficiency had been excluded. Each of these individualshad Marsh IIIa and IIIb lesions, which provides the mostlikely explanation for this finding.

The final issue that arises is whether sufficient time wasallowed to elapse before reassessment after introduction ofthe GFD. It is known that seroconversion is not a reliableindicator of histological recovery (14); in fact, completehistological recovery may take up to 2 yr (15). The persis-tent mucosal lesions, which incidentally, were improving at6 months, may have simply reflected the natural history oftreated disease.

In conclusion, this is a novel study, which provides apotential explanation for one of the causes of persistent GIsymptoms among compliant celiac patients. To define thetrue prevalence of SIBO and to make sound recommenda-tions regarding the timing of testing, reproduction of theseresults in the setting of a controlled study, ideally usingjejunal culture for diagnosis, is necessary. Until then, thequestion regarding the true association between SIBO, ce-liac disease, and IBS will remain unanswered.

Clare O’Leary, M.D.Eamonn M. M. Quigley, M.D., F.A.C.G.

Department of MedicineCork University Hospital

Cork, Ireland

721AJG – April, 2003 Editorials

REFERENCES

1. Sanders DS, Carter MJ, Hurlstone DP, et al. Association ofadult celiac disease with irritable bowel syndrome: A casecontrol study in patients fulfilling Rome II criteria referred tosecondary care. Lancet 2001;358:1504–8.

2. Wahnschaffe U, Ullrich R, Riecken O, et al. Celiac disease-like abnormalities in a subgroup of patients with irritablebowel syndrome. Gastroenterology 2001;121:1329–38.

3. O’Leary C, Wieneke P, Buckley S, et al. Celiac disease andirritable bowel-type symptoms. Am J Gastroenterol 2002;97:1463–7.

4. Fasano A, Catassi C. Current approaches to diagnosis andtreatment of celiac disease: An evolving spectrum. Gastroen-terology 2001;120:636–51.

5. Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinalsymptoms six months after bacterial gastroenteritis and riskfactors for development of the irritable bowel syndrome:Postal survey of patients. BMJ 1997;314:779–82.

6. Simren M, Axelsson J, Gillberg R, et al. Quality of life ininflammatory bowel disease in remission: The impact of IBS-like symptoms and associated psychological factors. Am JGastroenterol 2002;97:389–96.

7. Gwee KA, Leong YL, Graham C, et al. The role of psycho-logical and biological factors in post-infective gut dysfunction.Gut 1999;44:400–6.

8. Pimental M, Chow E, Lin H. Eradication of small intestinalbacterial overgrowth reduces symptoms of irritable bowelsyndrome. Am J Gastroenterol 2000;95:3503–6.

9. Tursi A, Brandimarte G, Giorgetti GM. High prevalence ofsmall intestinal bacterial overgrowth in celiac patients withpersistence of gastrointestinal symptoms after gluten with-drawal. Am J Gastroenterol 2003;98:839–43.

10. Riordan S, McIver C, Walker B, et al. The lactulose breathhydrogen test and small intestinal bacterial overgrowth. Am JGastroenterol 1996;9:1795–803.

11. Corazza G, Menozzi M, Strocchi L, et al. The diagnosis of smallbowel bacterial overgrowth. Gastroenterology 1990;98:362–9.

12. Bassotti G, Castellucci G, Betti C, et al. Abnormal gastroin-testinal motility in patients with celiac sprue. Dig Dis Sci1994;39:1947–54.

13. Rostami K, Kerckhaert J, Tiemessen R, Von Blomberg M.Sensitivity of antiendomysium and antigliadin antibodies: Dis-appointing in clinical practice. Am J Gastroenterol 1999;94:888–94.

14. Dickey W, Hughes D, McMillan S. Disappearance of en-domysial antibodies in treated celiac disease does not in-dicate histological recovery. Am J Gastroenterol 2000;95:712–4.

15. Grefte J, Bouman J, Grond J, et al. Slow and incompletehistological and functional recovery in adult gluten sensitiveenteropathy. J Clin Pathol 1988;41:886–91.

Reprint requests and correspondence: Eamonn M. M. Quigley,M.D., F.A.C.G., National University of Ireland, Cork UniversityHospital, Clinical Sciences Building, Cork, Ireland.

Received Sep. 4, 2002; accepted Jan. 2, 2003.

IBD: The Drugs Work. . .But Do thePatients?Imagine, if you will, a set of mysterious diseases that strikeat a young age, follow a chronic and often relentless course,

target patients who are predominantly white, living in in-dustrialized countries, with a trend toward the higher socio-economic classes. Then try to calculate the impact of diseaseupon the patients’ professional lives, starting not at the firstjob, but often back in school, and then extending throughouttheir years of employment, to either retirement or disability.Multiply that disability by the lifetime earning potential ofthat patient, and voila, you have finally solved the equationof lifetime impact of inflammatory bowel disease (IBD)upon work losses. Let me know when you are done.

Patients with IBD (Crohn’s disease [CD] or ulcerativecolitis [UC]) are faced with many obvious physical andemotional challenges, but the impact upon their professionallife is often ignored by health care professionals and plan-ners. A steady stream of research over the years suggeststhat it is time to wake up to the reality of the cripplingimpact upon school and work-related issues, which in them-selves should be the targets of treatment goals in the ap-proach to the “whole patient.”

Young IBD patients miss school. Absences of 2 monthsor greater were reported in 57% of Scottish juvenile pa-tients, with an average of 6.5 hospital admissions (93–102days) (1). British CD juveniles were more likely than buddyand community controls to require hospitalization for atleast 2 wk (42% vs 4%), and because of their disease, wereunable to sit for exams (17%), whereas 12–14% believedthat their disease prevented the education that they wouldhave liked, calling for special schools for children with CD(2).

In this issue of the Journal, the next chronological stepsof employment and disability were studied in nearly 11,000adult respondents to the Canadian National PopulationHealth Survey (3). The 1.7% of respondents who stated thatthey had been diagnosed by a health care professional tohave “a bowel disorder such as CD or colitis” were 20%more likely to be out of the work force. This was mostapparent in sicker patients (i.e., those reporting hospitaliza-tion or high levels of pain). However, for those who wereemployed, there was no difference in consecutive monthsworked before a break in employment.

These findings were similar to an earlier Swedish study,where IBD sick leave from work was uncommon (86 epi-sodes/100,000) but of long duration (mean 45 days), with anaverage early retirement duration of 14 yr (4). Comparablework capacity between UC patients and controls was alsofound in a British study, whereas disability rates were higherin CD patients (15–24%) than in controls (4.4%) (5). Theresults were somewhat different in a Swedish study of IBDpatients with ileostomies, where 19% of UC and 13% of CDpatients missed �1 month of work within a 2-yr period oftime, and 19% had full- or part-time disability because oftheir condition (6).

The concern of loss of productive work years was high-lighted in a West German study, where the age distributionat time of granting disability pensions was shifted 20 yrearlier in CD (with a peak at ages �40 yr) than in pensioners

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