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Small Intestinal Bacterial Overgrowth, Bile Acid Malabsorption and Gluten Intolerance As Possible Causes of Chronic Watery Diarrhoea X.FAN*&J.H.SELLIN

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Small Intestinal Bacterial Overgrowth, Bile Acid Malabsorption and Gluten Intolerance As Possible Causes of Chronic Watery Diarrhoea X.FAN*&J.H.SELLIN Alimentary Pharmacology & Therapeutics Review article: small intestinal bacterial overgrowth, bile acid malabsorption and gluten intolerance as possible causes of chronic watery diarrhoea X.FAN*&J.H.SELLIN *Division of Gastroenterology, Univer- SUMMARY sity of Texas Medical Branch, Galves- ton, TX, USA; Division of Background Gastroenterology, Baylor College of Chronic watery diarrhoea is one of the most common symptoms Medicine, Houston, TX, USA prompting GI evaluation. Recently, new diagnostic considerations have Correspondence to: emerged as possible factors in chronic diarrhoea. Dr J. H. Sellin, Division of Gastroenterology, Baylor College of Aim Medicine, Houston, TX 77555-0764, To review available data regarding diagnosis and treatment of chronic USA. Email: [email protected] diarrhoea with an emphasis on bacterial overgrowth and bile acid mal- absorption. Publication data Methods Submitted 2 May 2008 A systematic search of the English language literature of chronic diar- First decision 31 May 2008 Resubmitted 24 June 2008, 7 January rhoea was performed focused on three possible aetiologies of diarrhoea: 2009, 1 February 2009, 6 February small intestinal bacterial overgrowth (SIBO), idiopathic bile salt mal- 2009, 10 February 2009 absorption (IBAM), gluten responsive enteropathy. Accepted 10 February 2009 Epub Accepted Article 15 February Results 2009 Recent studies suggest that SIBO and bile acid malabsorption may have been underestimated as possible causes of chronic watery diarrhoea. Gluten intolerance with negative coeliac serology is a contentious possi- ble cause of watery diarrhoea, but requires further research before acceptance as an entity. Conclusion In patients with otherwise unexplained chronic watery diarrhoea, small intestinal bacterial overgrowth and bile salt malabsorption should be considered and investigated. Aliment Pharmacol Ther 29, 1069–1077 ª 2009 Blackwell Publishing Ltd 1069 doi:10.1111/j.1365-2036.2009.03970.x 1070 X. FAN and J. H. SELLIN also be significant causes of osmotic diarrhoea.5, 6 INTRODUCTION Identification and elimination of the offending agent This review will focus on the clinical evaluation and generally eliminates the diarrhoea. Perhaps more differential diagnosis of chronic watery diarrhoeas. important than the calculation of an osmotic gap is They commonly present considerable diagnostic chal- the stool weight itself. A stool weight of >1 kg ⁄ day lenges for clinicians. (volume>1 L ⁄ day) generally indicates secretory diar- A systematic search for relevant literature was per- rhoea, particularly if the diarrhoea continues with sim- formed through Pubmed and using as key words, ilar volume after cessation of oral intake. Intravenous chronic diarrhoea, small intestine bacterial, hydrogen fluid replacement should be provided while this is breath test, irritable bowel syndrome, bile salt induced assessed. It is our experience that approximately 20% diarrhoea, SeHCAT, coeliac disease, gluten sensitive of patients with a complaint of chronic diarrhoea will enteropathy. have normal stool weights; this finding clearly shapes further diagnostic studies. FUNDAMENTALS OF A DIARRHOEA WORK-UP TRENDS IN DIAGNOSIS OF CHRONIC WATERY DIARRHOEA Donowitz, et al. concluded that a specific diagnosis could be reached in approximately 90% of cases of Over the last several decades, novel insights into the chronic watery diarrhoea, although he estimated that possible aetiologies of chronic diarrhoea have consid- 30% of those patients would be labelled functional erably expanded our differential diagnosis. An elegant diarrhoea.1 A detailed history, physical exam and study by Fordtran’s group in 1980 in a very select appropriate work-up should be performed to search group of patients estimated that perhaps a third of for other causes of diarrhoea, i.e. ‘the rule ⁄ out work- patients with chronic diarrhoea may be laxative abus- up’ before the final diagnosis of functional diarrhoea ers.7 This then led to many work ups searching for or IBS is made. occult laxative use. Although this is always a diagnos- It is important to consider the role of diet. Poorly tic consideration, the incidence in a general GI referral absorbed carbohydrates (lactose, but also fructose and practice appears to be much less 30%. sorbitol and excessive ingestion of coffee (i.e. Star- With the advent of radioimmunoassays for a series bucks R diarrhoea) may be contributing factors.2 Medi- of neuropeptides, the consideration of a secretory diar- cations should also be considered as a possible cause.3 rhoea driven by a specific hormone such as VIP Haemoglobin A1C, thyroid function tests and coeliac became an attractive diagnosis. Although these are serology should be measured. Colonosocopy is appro- now commonly ordered tests, their utility in the initial priate to diagnose microscopic colitis, a common aeti- stages of a diarrhoea evaluation is yet to be demon- ology of chronic watery diarrhoea. A normal faecal strated. About 50% of the patients with chronic diar- calprotectin or lactoferrin makes the likelihood of an rhoea could have false positive results; in some occult inflammatory process less likely. However, patients, the abnormal value is as high as is seen with recent reports suggest that it may also be increased in peptides-secreting tumours.8 Even with tumours microscopic colitis.4 secreting these peptides, testing for VIP can probably A timed stool collection for 48–72 h may be a logis- only identify the tumours with liver metastasis.9 tic challenge for both patient and physician, but this This suggests that random testing is probably not can provide invaluable information that can guide fur- warranted. ther diagnostic studies. By measuring stool electrolytes Laxative abuse and neuroendocrine tumours will and osmolarity, one can calculate an osmotic gap i.e. account for only a small percentage of cases of osmolarity that is not accounted for by the measured chronic diarrhoea. Over the last several years, two new electrolytes. A significant gap (>50 mosm) implies an diagnostic considerations have emerged as possible osmotic diarrhoea, whereas a minimal gap is consis- factors in chronic diarrhoea: small intestinal bacterial tent with a secretory diarrhoea. Osmotic diarrhoeas are overgrowth and idiopathic bile salt malabsorption. associated with the ingestion of a poorly absorbed sol- These are not new diagnoses per se, but changing pat- ute such as sorbitol. Recent evidence suggests that die- terns of either diagnostic testing or diagnostic criteria tary fructose, fructans (fructo-oligosaccharides), may have led to more frequent identification of these as Aliment Pharmacol Ther 29, 1069–1077 ª 2009 Blackwell Publishing Ltd CHRONIC WATERY DIARRHOEA 1071 the aetiology for chronic diarrhoeas. These novel positive tests. A false negative result may also occur explanations for chronic diarrhoea are intriguing and either because of prior antibiotic treatment or because may well expand both our understanding of the path- of the lack of H2 producing bacteria. Variables in the ophysiology of diarrhoea and our therapeutic options. test protocols, such as dosage of carbohydrate admin- It is unclear how well they will stand the test of time. istered, method of collection, the amplitude of increase We will review these with a specific focus on the in H2 considered as positive test can all affect the accuracy of diagnostic tests, specificity of therapeutic results of HBT. options and plausibility of proposed pathophysiology. Rapid intestinal transit is the most important con- founding variable in applying HBTs to the diagnosis of SIBO. As lactulose is a non-absorbable disaccharide, SMALL INTESTINAL BACTERIAL it passes through the small intestine into the colon OVERGROWTH (SIBO) normally, where it is quickly metabolized. Thus, con- Small intestinal bacterial overgrowth has increasingly ventionally, an H2 signal from lactulose represents been implicated as a major aetiological factor in IBS, OCTT. A double peak pattern (early for bacterial primarily diarrhoea predominant IBS (D-IBS).10 Bacte- metabolism in the small intestine and late for OCTT) rial overgrowth in the distal small intestine may be has been proposed to be diagnostic for SIBO, but diagnosed by an abnormal hydrogen breath test (HBT) even this putatively classic pattern may not be entirely in many of patients with IBS. Normalization of breath specific.18, 21 tests and improvement of symptoms after a course of Given the uncertainties in utilizing breath tests for antibiotics tend to support the SIBO-IBS connection. the diagnosis of SIBO, it is critical to establish rigorous However, several studies failed to confirm the frequent criteria to confirm the SIBO ⁄ IBS linkage. This requires diagnosis of SIBO in IBS patients.11–13 (1) clearly distinguishing SIBO from OCTT and (2) Small intestine bacterial overgrowth (SIBO) is a con- identifying clear differences in breath tests in IBS dition generally associated with anatomic or motility compared to normals. In the absence of a double peak, abnormalities. Symptoms related to SIBO include gas a positive lactulose BT has been defined as an increase 22–24 bloating, diarrhoea, weight loss, malabsorption and in H2 within 90 to 180 min in various studies. anaemia. The diagnostic gold standard has been the However, OCTT in normals may be as short as 60 min quantitative culture of luminal fluid from small intes- or less measured by barium meal.25 Lactulose itself tine. However, this test is rarely performed in clinical may accelerate small bowel transit.26
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