Intestinal motility and bacterial overgrowth in patients with gallstones

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adjuvant chemotherapy to MSI+ CRC based on the presently available evidence only. In most studies, 12%-15% of stage C CRCs are MSI+, I and the proportIOn of MSI+ CRC was 9% m the senes of Elsaleh et al. Because prospective randomized trials have found a survival difference of 25%-30% m favor of patients treated with adjuvant chemotherapy m Dukes C colon cancer,4 the proportion of MSI+ CRC appears to be too small to account for the chemotherapy etfect. Unequal dlstnbutlOn of prognostiC factots between the chemotherapy and nonchemotherapy groups m nonrandomlzed senes may also explam some of the observed lack of effect of adjuvant chemotherapy m the MSI- group. Further studies assessmg the relative benefit of adjuvant chemotherapy are partIcularly mtetestmg in the MSI- subgroup of CRe. Ideally, this question could be answeted usmg paraffin-embedded tissue of parients who have partICipated m a tandomlzed controlled trial m whlCh a sutgety-only arm IS available. Regardmg MSI+ CRC, both our results and those of Elsaleh et al. suggest that adjuvant 5-FU-based chemotherapy benefits these patients. (Supported by Damon Runyon-Walter Winchell FoundatIOn, the PalVlkb and Sakan Sohlberg FoundatIOn, The Fmnish Cultural Fund, the Ida Montln FoundatIOn, the Maud KUlstlla Foundation, the Fmnlsh SCience Academy, the Emil Aaltonen FoundatIOn, and the Slgnd Juselllls FoundatIOn.) AKSELI HEMMINKI, M.D., Ph.D. Gene Therapy Center, DIVISIOn of Human Gene Therapy University of Alabama at Blrmmgham and Department of Medical GenetiCS, Haartman Institute Unwerstty of Helsmkl, Fmland HEIKKI JOENSUU, M.D, Ph.D Department of Oncology, Helsmkl University Central Hospital Helsmkl, Fmland 1. Hemminkl A, Mecklin JP, Jarvinen H, et al. Microsatellite Instability IS a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology 2000;119:921-928, 2. Wright CM, Dent OF, Barker M, et al. Prognostic significance of extensive microsateilite Instability In sporadiC clinicopathological stage C colorectal cancer, Br J Surg 2000;87:1197-1202. 3. Elsaleh H, Joseph D, Grieu F, et al. Association of tumour site and sex with survival benefit from adjuvant chemotherapy In colorectal cancer. Lancet 2000;355:1745-1750. 4. Stewart JM, Zalcberg JR. Update on adjuvant treatment of colorectal cancer. Curr Opln Oncol 1998;10:367-374,

Intestinal Motility and Bacterial Overgrowth in Patients With Gallstones Dear Sir: We tead With a great mterest the artIcle of Thomas et al.I who reported that patients With cholesterol-nch gallbladder stones have slow colOniC transit times, mcreased numbers of gram-pOSitive anaerobes, and greater 7a-dehydroxylase activity and that all 3 favor enhanced deoxychollC aCid (DCA) formatIOn and ItS passive absorption from the large mtestme. These observations are very mterestmg because both intestmal hypomotility and bacterial overgrowth may also faCilitate enhanced unconJugated bilirubin (UCB) formation, ItS passive absorptIOn, and mcreased levels of bilirubm conjugates m bile, Therefore, we believe that mcreased DCA formatIOn IS Important m the pathogeneSIs of cholesterol and pigment gallstones, and It raises the pOSSibility that the ongms of cholesterol gallstones and pigment gallstone disease are

GASTROENTEROLOGY Vol. 120, No, 5

lmked through thiS secondary bile aCid. There IS published eVidence to support thiS hypotheSIS. First, billrubm pigments are part of the composltlon of both cholesterol and pigment gallstones. Second, cholesterol gallstone charactenstlcally contams a central pigmented nidus With elthet radial or lamellar pigmented bands alternatmg With nonpigmented areas. Third, analYSIS of the matrix associated with the pigment area m the cholesterol stones mdlCates that 83% IS UCB, 15% billrubm monoglucuronIdes, and traces of dlConJugates 2 all apparenrly as calcIUm salts. There IS also some eVidence that argues In favor to the role of the mtestinal hypomotlltty m an mcreasmg absorption of UCB; thiS m turn may contrIbute m the pathogenesis of hyperbilirubmemia and pigment gallstones. Kotal et a1.3 observed m rats that fastmg decreases mtestmal motility and fecal elimination of bile pigments; thiS alteration m turn enhanced enterohepatlC circulatIOn of UCB and resulted m an mcreased reflux to plasma because of the low first-pass clearance of UCB by the liver. Furthermore, the ratio of biliary bllirubm to bile aCids doubled dUrIng fastmg. If thiS also happens m humans, such changes could contnbute to bile pigment sludge and stone formatIOn observed dUrIng, for example, prolonged parenteral nutritIOn. In recent studies we found that Ileal resection m rats leads to a doublmg of conjugated blltrubm secretIOn rates m bile, compared With proXimal Intestmal resectIOn or sham-operated controls." We hypotheSized that thiS IS a result of the enterohepatlc cyclmg of UCB induced by small mtestinal bile salt loss. Some pOSSible conSiderations that support thiS hypotheSIS are that UCB IS known to be absorbed by passive diffUSIOn from the mtestme, whereas ItS conjugated form IS not, and at the Intestinal level, both UBC solubiltty and absorptIOn are bile salt dependent. Interestmgly, thiS observation has been confirmed m patients With mflammatory (Crohn's) bowel disease.> One would thmk that in patients With anaerobIC bactenal overgrowth m the small mtestme, bIlirubm deconJugation and enterohepatlc cyclmg would also occur. There are some cltnIcal condltlons aSSOCiated with bactenal overgrowth such as hypochlorhydna, or achlohydna Afferent loop of Billroth II, duodenal-Jejunal divertIculosis, surgical bltnd loop (end-to-side anastomOSIS), obstruction (StriCture, adheSIOn), mfiammatlOn, neoplasm, scleroderma, diabetiC autonomlC neuropathy, resectIOn of diseased Ileocecal valve, chroniC panCreatitiS, ImmunodefiCiency syndromes, and Cirrhosis may potentially mduce bactenal overgrowth. In addltlon, Berr et al. 6 have proposed thar DCA excess m patients With cholesterol-rIch gallbladder stones could be caused by one or more of the followmg mechanisms. (1) decreased absorptIOn of choltc aCid m the ileum attnbutable to Impairment of ileal bile aCid transport or bmding of choltc aCid to lummal contents, (2) enhanced colOnization of the large and pOSSibly the small mtestme With anaerobIC bactena capable of CA-7a-dehydroxylatlOn, and (3) mcreased absorptIOn of DCA from the colon pOSSibly caused by some alteratIOn in the phYSICal state of DCA m the colon or by slow colonIC transit Fmally, according to our hypotheSIS, deconJugation of DCA contemporaneously With billrubm conjugates probably faCiltrares rhe UCB mresrmal absorption, and rhereby enterohepatic cyclmg of billrubm could occur ThiS question could be answered wherher Thomas er al I have measured rhe molecular blltrubm speCies m bIle of patients with cholesterol-nch gallbladder stones. NAHUM MENDEZ-sANCHEZ, M.D., Ph.D. MISAEL URIBE, M.D. Departments of BIOmedical Research and Gastroenterology Medica Sur Clmlc & FoundatIOn MixlCO City, Mixlco

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April 2001

1. Thomas LA, Veysey MJ, Bathgate T, et al. Mechanism for the transit-induced increase in colonic deoxycholic acid formation in cholesterol cholelithiasis. Gastroenterology 2000;119:806-815. 2. Smith B, LaMont JT. Identification of gallstone mucin-bilirubin complex in human cholesterol gallstone matrix. J Clin Invest 1985;76: 439-445. 3. Kotal P, Vitek L, Fevery J. Fasting-related hyperbilirubinemia in rats: the effect of decreased intestinal motility. Gastroenterology 1996;111:217-223. 4. Brink AM, Mendez-Sanchez N, Carey MC. Bilirubin cycles enterohepatically after ileal resection in the rat. Gastroenterology 1996; 110:1945-1957. 5. Brink MA, Siors JF, Keulemans YC, et al. Enterohepatic cycling of bilirubin: a putative mechanism for pigment gallstone formation in ileal Crohn's disease. Gastroenterology 1999;116:1420-1427. 6. Berr F, Kullack-Ublick GA, Paumgartner G, et al. 7a-Dehydroxylating bactena enhance deoxycholic acid input and cholesterol saturation of bile in patients with gallstones. Gastroenterology 1996; 111:1611-1620. doi:10.1053/gast.2001.23648

Reply. We thank Dts. Mendez-Sanchez and Uribe for theit Interest in OUt article. The first paragraph of theIr letter accurately summanzes our findings, although it fails to mention the transit-related changes In colOnIC luminal pH,'-3 which are also important In solubIlizing nascent DCA and in promoting its passive absorption from the latge bowel. We too believe that Increased colonic DCA formation and absorption are important in the pathogenesIs of cholesterol-nch gallbladder stones, although thIS concept is controversial, as indicated in our article. The suggestion that DCA 1S also Involved In the development of pigment gallstones is interesting, but largely unrelated to the alms and objectives of our study. We agree that pure cholesterol gallstones are rare and that most cholesterol-nch stones are mixed in composition, containIng bJie pigments and calcium salts, In additIOn to crystalline cholesterol. Howevet, we question whethet this constitutes "published eVIdence" to support the hypothesis that the origins of cholesterol and pigment gallstones are linked, through the secondary bile acid, DCA. We accept that many (but not all) cholesterol-rich gallstones have a central pIgmented nidus, a phenomenon first descnbed more than 100 years ago by Naunyn. 4 We are aware that the bJiirubin content of the pigment matrix in the center of cholesterol gallstones IS mainly the calcIUm salt of UCB. However, this often coprecipitates WIth polymerized bJiirubin and other calcium salts such as calcIUm carbonate. Even if calcium bilirublnate nucleus is invanably present In cholesterol-rich stones, and responsible for inItiating the subsequent precipItation of cholesterol crystals, it IS far from proven that the "central pIgmented nidus" is due to altered DCA metabolIsm, as opposed to alternative mechanisms such as the defective hydrogen ion secretIOn by the gallbladder mucosa. 5 ,6 We are, of course, familIar with the interesting observation that Ileal resection In the rat leads to increased enterohepatic cycling of UCB. We also suPPOtt the suggestion that UCB solubilIty and absorption are "bile salt dependent," but we know of no evidence that these phenomena are speCIfically dependent on DCA. Mendez-Sanchez and Uribe cite the important article by Berr et aU However, thIS study was based on analyses of feces rathet than on aspIrates from the cecum/proxImal colon, where DCA formation and absorption are thought to occur. Furthermore, Berr's observations were made on 2 preselected groups of gallstone patients: those with Increased DCA pool sizes and/or high DCA-cholIc acid molar ratios

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vs. those with normal DCA metabolism. Of the various hypotheses proposed by Berr et al. to explain the altered DCA metabolism in patients with gallstones, we have no evidence of impaIred ileal bile acid transport, of cholic acid binding to luminal contents, or of "enhanced colOnIzation" (bacterial overgrowth) of the small intestine in our patients. To answer the specific question raised by Drs. Mendez-Sanchez and Unbe, we sampled neither bile nor bile-rich duodenal fluid and, thetefore, did not measure molecular bilIrubin speCIes in our patient's bile. However, we question the final hypotheses in Mendez-Sanchez and Unbe's letter for 2 reasons. First, our observations do not depend so much on the deconjugation of DCA, but more on the deconjugatlon and 7a-dehydroxylatlOn of ItS "parem" or substrate bJie aCId, cholic acid. Second, weB and others 9 belIeve that cholic aCId 7adehydroxylation IS probably rate-lImiting In DCA formation. That being the case, the enzyme systems responsible for DCA formatIOn (cholylglyclne hydrolase and cholIc acid 7a-dehydroxylase) and bilIrubin deconjugation are quite different. Therefore, if the bIOmass and/or specific activity of these different enzyme pathways were to increase "contemporaneously," we would suggest that this is likely to be fortuitous, rather than necessarily linked. R. HERMON DOWLING LINZI A.THOMAS Gastroenterology Unit, Diviszon of Medlczne GKT School of Medlczne, St. Thomas' HospItal London, England 1. EI Oufir L, Flourie B, Bruley des Varannes S, et al. Relations between transit time, fermentation products, and hydrogen consuming flora in healthy humans. Gut 1996;38:870-877. 2. Lewis SJ, Heaton KW. Increasing butyrate concentration in the distal colon by accelerating intestinal transit. Gut 1997;41:245251. 3. Thomas LA, Veysey MJ, Murphy GM, et al. Influence of pH on the phase distribution of nascent deoxycholic aCid in fresh human cecal aspirates. Am J Physiol (submitted). 4. Naunyn. Ueber cholecystitis und cholangitis calculosa. Zeitschrift fur Prakt Aerzte Frankf 1898;7:637-643. 5. Schiffman ML, Sugerman HJ, Moore EW. Human gallbladder mucosal function. Effect of concentration and acidification of bile on cholesterol and calcium solubility. Gastroenterology 1990;99:1452-1459. 6. Gleeson 0, Hood KA, Murphy GM, et al. Calcium and carbonate Ion concentrations in gallbladder and hepatic bile. Gastroenterology 1992;102:1707-1716. 7. Berr F, Kullak-Ublick GA, Paumgartner G, et al. 7a-Dehydroxylating bacteria enhance deoxycholic acid input and cholesterol saturation of bile in patients with gallstones. Gastroenterology 1996; 111:1611-1620. 8. Sarsam RP, Shannon KP, Bathgate T, et al. Identification of cholic acid 7a-dehydroxylatlng bacteria using Bai gene probes (abstr). Gastroenterology 2000;118:A10. 9. Stellwag EJ, Hylemon PB. 7a dehydroxylation of cholic acid and chenodeoxycholic acid by Clostridiumleptum. J Lipid Res 1979; 20:325-333.

Hepatitis B Infection in Heart Transplant Recipients Dear Sir: The natural course of hepatitis B VIruS (HBV) Infection in Immunosuppressed Individuals is still a matter of debate. Knowledge on mechanisms and speed of disease progressIOn mlghr have Important consequences for rhe treatment of hepatlrls B surface antigen