Response to Dr. Parisi et al.

TO THE EDITOR: Dr. Parisi and others have prepared aNovartis-sponsored letter addressing their concerns aboutour recent articles evaluating the relationship between thelactulose breath test, antibiotic treatment, and symptoms ofirritable bowel syndrome (IBS) (1, 2). In our most recentarticle, we found that 84% of IBS subjects had an abnormallactulose breath test (2). Dr. Parisi and his colleagues de-scribe data from their center in Italy, where none of theirIBS subjects were positive on the glucose breath test. Theysuggest that the glucose breath test has greater sensitivityand specificity than lactulose and, based on this, they “cau-tion against antibiotic treatment for IBS patients” whenfindings of small intestinal bacterial overgrowth are basedon lactulose breath testing. These criticisms warrant someresponse.

From the conclusion of their letter, it is clear that Dr.Parisi and his colleagues did not appreciate the full breadthof our article and its implications. The focus of our recentlypublished double-blind study was not just how many IBSsubjects had an abnormality on lactulose breath testing (2).Rather, it was the dramatic clinical response seen in theirsymptoms after treatment with antibiotics compared withplacebo. The most important point of the recent article wasthat the degree of clinical improvement with antibiotics wasintimately related to the breath test outcome after treatment.Among subjects receiving antibiotics, the best clinical re-sponse was seen in those subjects whose breath test wasnormalized after antibiotic treatment, and only incrementalimprovement was seen in those with a persistently abnormalbreath test. This finding suggests that the abnormal breathtest results represent an aberration in enteric flora, so thatcorrection of this aberration is beneficial in IBS. What thataberration is remains unclear.

As for the role of bacterial overgrowth in IBS, this rela-tionship has been highly debated. Studies are now suggest-ing that subjects with IBS have excessive gas production (3)and that this gas accumulation might be in the small intes-tine (4), which intuitively implies a role of small intestinalbacteria. These studies are consistent with our observations.The problem is how to diagnose bacterial overgrowth. Aswith any infectious disease, culture is the gold standard.However, the rules for a gold standard begin to fall apartwhen it comes to culture of enteric bacteria in small intes-tinal bacterial overgrowth. The first problem is the culturetechnique itself, whereby fluid is aspirated through a naso-or orogastric tube that is passed into the small intestine.Frequently, small bowel fluid is minimal and difficult toaspirate. The second problem is that bacterial overgrowthcan be patchy (5). It is therefore inadequate to prejudiciallyaspirate from a highly focal point in the proximal jejunumand extrapolate a negative culture result to the whole 15 feetof small intestine. In fact, one would expect the most likelylocation for bacterial overgrowth to be in the distal jejunumand ileum, given their proximity to the colon, and this is the

most challenging site to access. The final problem withculture of the digestive tract is that there are estimated to bebetween 300 and 500 different species of bacteria in thedigestive tract, with only 20% thus far identified (6). Withsuch poor yield, what conclusion can be made on whether ornot overgrowth is present based on culture? Moreover, withall the difficulties with culture, how can breath testing everbe validated against this “ far from gold standard” technique,as has also been pointed out by Tillman et al. (7)?

In contrast, lactulose breath testing is not similarly limitedbecause lactulose, as a poorly digestible starch, traverses thewhole length of gut to permit access to bacterial floraanywhere in the small and large intestine. Dr. Parisi et al.,however, refer to two articles in which it was reported thatlactulose breath testing was insensitive against culture (8)and that glucose breath testing had greater sensitivity (9).Article selectivity might be an issue here, because highersensitivity can been seen in other work (10). This publica-tion variability is due, in part, to patient selection. In the caseof the article by Riordan et al., I refer Dr. Parisi to anotherletter to Dr. Riordan (11), in which arguments were madethat virtually all the patients in the referenced study hadsurgically altered anatomy. These anatomic derangementscould account for the proximally located bacterial flora, andthese subjects were not a surgically naı̈ve IBS population.As for using glucose on breath testing, the main problem isavailability. Glucose is readily absorbed by the digestivetract and should have virtually no lumenal presence beyond3 feet into the small intestine. Bacterial overgrowth in thedistal 12 feet of small intestine would not be detected withthis test, and so the results from Dr. Parisi would not besurprising.

On the issue of antibiotics in IBS, we agree that thewidespread prescription of antibiotics to these patientswould be premature. The basis for this relates to the lowefficacy of antibiotics in bacterial overgrowth (2), leading totreatment failures and multiple courses, all of which wouldresult in bacterial resistance. In their letter, Parisi et al.allude to an article that implies that antibiotic treatmentmight increase functional symptoms (12). What Parisi andmany others might have missed in the article relates to thetiming of evaluation. In this article by Maxwell et al.,subjects with and without IBS were followed after antibioticuse. The major problem was that the baseline symptomswere determined immediately at the conclusion or duringantibiotic use and subsequently 4 months later. Because theydid not have an evaluation of symptoms before the antibiotictreatment, the only conclusion should be that functionalsymptoms are better immediately after antibiotics comparedwith 4 months later.

Simren et al. recently published an abstract (13) reportingthat out of 33 IBS subjects, four (12%) were positive byjejunal culture. All four subjects received a course of anti-biotics, with one demonstrating a substantial clinical im-provement. These four subjects also had a reduction in

2573AJG – November, 2003 Letters to the Editor

phase III of interdigestive motility believed to account forthe bacterial overgrowth. Although superficially it mightseem that this study argues against bacterial overgrowth inIBS, the data actually support the notion. Even if Simren etal. are correct and only 12% of IBS subjects have upper gutbacterial overgrowth, this warrants attention. There is moreattention to ruling out celiac disease in IBS sufferers, witha reported prevalence of only 4.6% (14). Given their singlelocation sampling for bacteria, it is also likely that if moreof the small bowel were cultured more cases would havebeen detected. Furthermore, the low eradication rate withantibiotics was identical to our study (2), and the groupconfirmed our recent finding that the lack of phase III mightplay a role in these IBS cases (15).

With all the difficulties mentioned above, whether bacte-rial overgrowth or some enteric bacterial aberration is con-tributing to IBS symptoms is likely to be debated for sometime. However, in the examination of IBS and the possiblerole of enteric bacteria, the clinical response and depen-dence on the lactulose breath test after antibiotic treatmentneeds to be the focus. With the lack of better tests or evena reliable gold standard, no test can be accurately trusted,only the clinical response. What Dr. Parisi fails to explain isthe 75% clinical improvement seen in IBS subjects withnormalization of lactulose breath test after antibiotics in acontrolled, published, peer-reviewed study (2).

Dr. Parisi and colleagues might want to consider a fol-low-up study with adequate controls. Subsequently, theyshould submit any new data as an original research submis-sion for peer review and publication rather than in a letter inwhich the methodologic details leading to their results andconclusions cannot be evaluated.

Mark Pimentel, M.D.Henry C. Lin, M.D.

GI Motility ProgramDepartment of Medicine

Cedars-Sinai Medical CenterCSMC Burns & Allen Research Institute

Los Angeles, California

REFERENCES

1. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinalbacterial overgrowth reduces symptoms of irritable bowelsyndrome. Am J Gastroenterol 2000;95:3503–6.

2. Pimentel M, Chow EJ, Lin HC. Normalization of lactulosebreath testing correlates with symptom improvement in irrita-ble bowel syndrome: A double-blind, randomized, placebocontrolled study. Am J Gastroenterol 2003;98:412–9.

3. King TS, Elia M, Hunter JO. Abnormal colonic fermentationin irritable bowel syndrome. Lancet 1998;352:1187–9.

4. Koide A, Yamaguchi T, Odaka T, et al. Quantitative analysisof bowel gas using plain abdominal radiograph in patients withirritable bowel syndrome. Am J Gastroenterol 2000;95:1735–41.

5. Toskes PP, Donaldson RM Jr. Enteric bacterial flora and

bacterial overgrowth syndrome. In: Feldman M, ScharschmidtBF, Sleisenger MH, eds. Sleisinger & Fordtran’s gastrointes-tinal disease. 5th edition. 1106–1117.

6. Hart AL, Stagg AJ, Graffner H, et al., eds. Gut ecology.London: Martin Dunitz, 2002.

7. Tillman R, King C, Toskes P. Continued experience with thexylose breath test: Evidence that the small bowel culture as thegold standard for bacterial overgrowth may be tarnished. Gas-troenterol 1981;80:1304.

8. Riordan SM, McIver CJ, Walker BM, et al. The lactulosebreath hydrogen test and small intestinal bacterial overgrowth.Am J Gastroenterol 1996;91:1795–803.

9. Kerlin P, Wong L. Breath hydrogen testing in bacterial over-growth of the small intestine. Gastroenterol 1988;95:982–8.

10. Corazza G, Strocchi A, Sorge M, et al. Prevalence and con-sistency of low breath H2 excretion following lactulose inges-tion: Possible implications for the clinical use of the H2 breathtest. Dig Dis Sci 1993;38:2010–6.

11. Pimentel M, Lin HC. Response to Dr. Riordan. Am J Gastro-enterol 2001;96:2506.

12. Maxwell PR, Rink E, Kumar D, et al. Antibiotics increasefunctional abdominal symptoms. Am J Gastroenterol 2002;97:104–8.

13. Simren M, Ringstrom G, Agerforz P, et al. Small intestinal13Simren M, Ringstrom G, Agerforz P, et al. Small intestinalbacterial overgrowth is not of major importance in the irritablebowel syndrome. Gastroenterology 2003;124:A163(abstract).14Wahnschaffe U, Ullrich R, Riecken EO, SchulzkeJD. Celiac disease-like abnormalities in a subgroup of patientswith irritable bowel syndrome. Gastroenterology 2001;121:1329–38.15Pimentel M, Soffer EE, Chow EJ, Lin HC. Lowerfrequency of MMC is found in IBS subjects with abnormalbreath test suggesting bacterial overgrowth. Dig Dis Sci 2002;47:2639–43.

Reprint requests and correspondence: Mark Pimentel, M.D.,Cedars-Sinai Medical Center, 8635 W. 3rd Street, Suite 770, GIMotility Laboratory, Los Angeles, CA 90048.

Received July 8, 2003; accepted July 10, 2003.

High Prevalence of Celiac Disease inPsoriasisTO THE EDITOR: Celiac disease (CD) is an immunome-diated enteropathy caused by permanent intolerance to di-etary wheat gliadin in predisposed individuals. It is charac-terized clinically by malabsorption and histologically byvillous atrophy and crypt hyperplasia. The true prevalenceof CD is difficult to ascertain, and the diagnosis might bedelayed because its clinical presentation is often oligosymp-tomatic. Epidemiological studies in which serological testshave been used show the disease to be much more commonthan previously realized. Many autoimmune disorders, suchas dermatitis herpetiformis, thyroiditis, and diabetes melli-tus, are associated with CD.

Psoriasis is a common skin disease, characterized byerythrosquamous cutaneous lesions involving the entirebody and a chronic relapsing nature, because trigger factorscan provoke clinical manifestations. Its etiology remains

2574 Letters to the Editor AJG – Vol. 98, No. 11, 2003