In a recent issue, Wigg and colleagues (Gut 2001;48:206–11) reported that small intestinal bacterial overgrowth (SIBO), as diagnosed by a combined 14C-d-xylose/lactulose breath test, is significantly more common in patients with non-alcoholic steatohepatitis (NASH) than in control subjects without liver disease. The authors investigated the possible pathogenic significance of this observation by examining whether intestinal permeability and circulating levels of endotoxin and tumour necrosis factor α are increased in NASH patients with SIBO compared with those without. No significant differences in any of these parameters could be demonstrated in the two groups.
An important factor influencing the validity or otherwise of these findings is the diagnostic accuracy of the 14C-d-xylose and lactulose breath tests for SIBO. Our experience, using a sterile endoscopic technique to sample small intestinal secretions under direct vision, is that these breath tests lack sensitivity and specificity for culture proven SIBO.1,2 Endogenous CO2 production and colonic metabolism of d-xylose are important factors inherently limiting the accuracy of the 14C-d-xylose breath test for SIBO.1 Furthermore, reliance on the finding of “double peaks” in serial breath hydrogen or methane levels after ingestion of lactulose to improve the accuracy of the 14C-d-xylose breath test, or as a diagnostic marker in its own right, is problematic. In a study in which a scintigraphic tracer was administered concurrently with lactulose, we found that each of the double peaks in breath hydrogen values may occur after the arrival of the test meal at the caecum, paralleling delivery patterns of fermentable substrate to caecal bacteria. A caecal source of each peak was suggested on 50% of occasions, rather than the first peak necessarily reflecting small intestinal metabolism of lactulose by overgrowth flora as purported. Conversely, a single rise in breath hydrogen levels commencing before the test meal reached the caecum was evident in 22% of subjects with culture proven SIBO. Thus both false positive and false negative diagnoses of SIBO may result.2 Indeed, as pointed out in the accompanying commentary (Gut 2001;48:148–9), the prevalence of SIBO, as diagnosed by breath testing, in control subjects in Wigg et al's study seems remarkably high.
Rather than seeking to establish the prevalence of SIBO in patients with NASH, as in the study of Wigg et al, we have investigated the prevalence of liver damage, as reflected by elevated liver enzyme levels in serum, in patients with culture proven SIBO.3 Biochemical evidence of liver injury was found in 0/11 patients with SIBO with salivary type bacteria only, 0/21 patients with SIBO with facultative anaerobic (Enterobacteriaceae) but not obligate anaerobic (Bacteroides spp) colonic type bacteria, and 1/8 patients with SIBO including Bacteroides spp. Alkaline phosphatase and gamma glutamyl transferase levels were elevated in this patient, although liver ultrasonography and cholangiography revealed no abnormality. Small intestinal permeability was increased and, together with liver enzyme abnormalities, normalised following eradication of SIBO with a metronidazole based antibiotic regimen. We concluded that liver injury, reversible with antibiotic treatment, occurs uncommonly in patients with SIBO, and only when the overgrowth flora includes obligate anaerobes such as Bacteroides spp, in keeping with earlier findings implicating such flora in the pathogenesis of liver injury associated with experimental SIBO in rodents.4 Liver injury associated with SIBO with Bacteroides spp was not a necessary consequence of increased small intestinal permeability, which was also evident in 50% of patients with SIBO with Bacteroides spp who had no evidence of liver damage.
Based on these observations, we suggest that future studies examining the prevalence of SIBO in patients with NASH and its possible pathogenic significance should use culture of small intestinal aspirate rather than breath testing as the diagnostic modality and focus on the presence or absence of overgrowth with obligate anaerobic flora such as Bacteroides spp. Such an approach would be preferable to simply assessing for any improvement in NASH following a therapeutic trial of metronidazole, as SIBO with Bacteroides spp and other obligate anaerobes is not always eradicated by a single course of antibiotic treatment. As small intestinal colonisation with Bacteroides spp depends on underlying intestinal dysmotility,5 factors other than SIBO are likely responsible for NASH in patients in whom intestinal motility is normal.
References
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