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Preventive therapy for complicated diverticular disease of the colon: Looking for a correct therapeutic approach
December 2004
non-PBC subjects and the evaluation of false positives and low specificity.7 We encourage Mason and colleagues to address the following issues. First, the design must include a larger number of blinded sera and pathologic specimens from both patients and controls. Second, to define the nature of the resulting immunoblot reactivities, the authors should rigorously study a large number of sera (including AMA-negative), include dilution analysis, and define specificities. Third, we strongly encourage the use of blinded, freshly collected samples for parallel and unbiased analysis; they should also be willing to accept blinded samples for their own analysis. They must demonstrate specific retroviral sequences integrated in the genome of cells from patients with PBC (not achieved by Southern blotting2) and subsequently study viral expression. Finally, it appears mandatory that Mason and colleagues show the capability of MMTV to infect humans, that is the presence and nature of specific membrane receptors that determine the tropism of the virus, currently not including human cells.8 The theory on retroviruses in PBC was first proposed 6 years ago and many patients have heard about it and are now requesting the use of antivirals. Thus, it is important to either prove the thesis or put it to rest. We are delighted that we have challenged the Mason group and look forward to their data. We are working together for the very same goal. CARLO SELMI, MD, PhD Division of Rheumatology Allergy and Clinical Immunology University of California at Davis School of Medicine Davis, California and the Division of Internal Medicine San Paolo School of Medicine University of Milan Milan, Italy SUSAN R. ROSS, PhD Department of Microbiology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania AFTAB A. ANSARI, PhD Department of Pathology Emory University School of Medicine Atlanta, Georgia PIETRO INVERNIZZI, MD, PhD MAURO PODDA, MD Division of Internal Medicine San Paolo School of Medicine University of Milan Milan, Italy ROSS L. COPPEL, MD, PhD Department of Microbiology Monash University Clayton, Victoria, Australia M. ERIC GERSHWIN, MD Division of Rheumatology Allergy and Clinical Immunology University of California at Davis School of Medicine Davis, California
CORRESPONDENCE
1865
1. Selmi C, Ross SR, Ansari AA, Invernizzi P, Podda M, Coppel RL, Gershwin ME. Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis. Gastroenterology 2004;127:493–501. 2. Xu L, Shen Z, Guo L, Fodera B, Keogh A, Joplin R, O’Donnell B, Aitken J, Carman W, Neuberger J, Mason A. Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci U S A 2003;100: 8454 – 8459. 3. Yanagawa T, Ito K, Kaplan EL, Ishikawa N, DeGroot LJ. Absence of association between human spumaretrovirus and Graves’ disease. Thyroid 1995;5:379 –382. 4. Lower R, Tonjes RR, Boller K, Denner J, Kaiser B, Phelps RC, Lower J, Kurth R, Badenhoop K, Donner H, Usadel KH, Miethke T, Lapatschek M, Wagner H. Development of insulin-dependent diabetes mellitus does not depend on specific expression of the human endogenous retrovirus HERV-K. Cell 1998;95:11–14;[discussion 16]. 5. Held W, Waanders GA, Acha-Orbea H, MacDonald HR. Reverse transcriptase-dependent and -independent phases of infection with mouse mammary tumor virus: implications for superantigen function. J Exp Med 1994;180:2347–2351. 6. Golovkina TV, Dudley JP, Ross SR. B and T cells are required for mouse mammary tumor virus spread within the mammary gland. J Immunol 1998;161:2375–2382. 7. Mason AL, Xu L, Guo L, Munoz S, Jaspan JB, Bryer-Ash M, Cao Y, Sander DM, Shoenfeld Y, Ahmed A, Van de Water J, Gershwin ME, Garry RF. Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders. Lancet 1998;351:1620 –1624. 8. Ross SR, Schofield JJ, Farr CJ, Bucan M. Mouse transferrin receptor 1 is the cell entry receptor for mouse mammary tumor virus. Proc Natl Acad Sci U S A 2002;99:12386 –12390. doi:10.1053/j.gastro.2004.10.025
Preventive Therapy for Complicated Diverticular Disease of the Colon: Looking for a Correct Therapeutic Approach Dear Sir: I read with great interest the comment by Mitchell and Shaheen about the preventive therapy in perforated colonic diverticular disease.1 They comment on the recent paper by Morris et al about the effectiveness of calcium channel blockers in preventing perforation in diverticular disease,2 and conclude that this therapy may be a good option in preventing diverticular perforation, especially in patients “who have had two or more episodes of inflammation.” However, I am not sure that calcium channel blockers are the best option for these patients. Although calcium blockers may be a reasonable treatment, we should not forget that these drugs may provoke several side effects (peripheral edema, symptomatic hypotension, etc),3 and they should be used carefully. There are other safe therapeutic alternatives, especially for patients with recurrent attacks of acute uncomplicated diverticulitis. The first alternative is mesalazine. The rationale for the use of mesalazine for the treatment of diverticulitis is similar to that for the use in chronic inflammatory bowel disease. Mesalazine inhibits some key factors of inflammatory cascade (cyclooxygenase, thromboxane-synthetase, and PAF-synthetase), inhibits the production of IL-1 and free radicals4,5 and has intrinsic anti-oxidant activity.6 Some inflammatory complications of diverticulits, such as edema, are generated by an heightened production of proinflammatory cytokines (IL-1, TNF-␣), reduced anti-inflammatory cytokines (IL-ra, IL-4, IL-10, IL-11),7 and enhanced intramucosal synthesis of nitric oxide.8 Our group has shown
1866
CORRESPONDENCE
this effect in 2 studies. In the first study, a group treated with rifaximin plus mesalazine showed significant improvement in symptom severity (P ⬍ .0005), bowel habits (P ⬍ .0001), and symptomatic recurrence or complications of diverticulitis (P ⬍ .005) versus a group treated with rifaximin alone during a 12-month follow-up.9 It is noteworthy that this study has been conducted on patients affected by recurrent attacks of acute diverticulitis, some of them affected by colonic stenosis. These results have been confirmed by a more recent study, which showed that a short course of rifaximin/mesalazine (10 days) followed by a longer course of mesalazine alone (8 weeks) is extremely effective in resolving symptoms in patients with acute symptomatic diverticular disease of the colon.10 I think that longterm mesalazine therapy may be a safe and tolerable approach even in older patients, since the risk of nephotoxicity is lower than previously thought.11 Another reasonable approach may be to use probiotics. Probiotics are live microbial food ingredients that alter the enteric flora and have a favorable effect on health. Probiotic activity has most commonly been associated with lactobacilli and bifidobacteria; other nonpathogenic bacterial strains, including certain Escherichia coli and enterococci, and nonbacterial organisms such as Saccaromyces boulardii have been used.12 The rationale for probiotics in diverticular disease is strictly related to pathogenesis of the disease. Stasis of luminal contents occurs in colonic diverticula, and this is supported by alterations of defecation. Stasis is probably combined with changes in the spectrum of intestinal microflora. This process may be followed by the occurrence of abnormal metabolites causing functional changes reflected in the abdominal symptoms. In light of these considerations, it appears reasonable to influence the colonic microflora by the introduction of probiotics. Moreover, probiotic action includes production of antimicrobials, competitive metabolic interactions with proinflammatory organisms, inhibition of adherence, and translocations of pathogens, which creates a trophic effect on intestinal mucosa thanks to production of butyrate. Likewise, probiotics can determine mucosal defense by changing immune and epithelial function by diminishing TNF-␣, IL-1, and IFN-␥.13 Fricˇ and Zavoral recently showed the validity of this alternative approach.14 Another point to take in consideration is that probiotic therapy is virtually free of side effects and it may be performed indefinitely without any risk. I think that the combination of probiotics and salycilates may be more effective than mesalazine alone or calcium channel blockers, even in patients with a high risk of symptomatic recurrence of diverticular disease. This combination could act in 2 different ways in decreasing inflammation: 5-ASA inhibits the inflammatory cascade (blocking cyclooxygenase, Thromboxane-synthetase and PAF-synthetase activity, the production of IL-1, and free radicals), while probiotics act on composition of fecal flora (by the production of antimicrobials, competitive metabolic interactions with proinflammatory organisms, reduction of pH and an inhibition of adherence and translocations of pathogens) and improve colonocytes metabolism by synthesis of butyrate. Further studies are needed to confirm whether this hypothesis is only speculative or if it is the best treatment in preventing complications in diverticular disease of the colon. ANTONIO TURSI, MD Digestive Endoscopy Unit “Lorenzo Bonomo” Hospital Andria, Italy 1. Mitchell K, Shaheen NJ. Preventive therapy in perforated colonic diverticular disease? Calcium channel blockers may hold the key. Gastroenterology 2004;127:680 – 682.
GASTROENTEROLOGY Vol. 127, No. 6
2. Morris CR, Harvey IM, Stebbings WSL, Speakman CTM, Kennedy HJ, Hart AR. Do calcium channel blockers and antimuscarinics protect against perforated colonic diverticular disease? Gut 2003;52:1734 –1737. 3. Eisenberg MJ, Brox A, Bastawros AN. Calcium channel blockers: an update. Am J Med 2004;116:35– 43. 4. Eliakim R, Rachmilewitz D. Potential mediators in inflammatory bowel disease. Gastroenterology Int 1992;5:48 –56. 5. Grisham MB. Oxidants and free radicals in inflammatory bowel disease. Lancet 1994;344:859 – 861. 6. Gonçalves E, Almeida LM, Dinis TC. Antioxidant activity of 5-aminosalicylic acid against peroxidation of phosphatidylcholine liposomes in the presence of alpha-tocopherol: a synergistic interaction? Free Rad Res 1998;29:53– 66. 7. Rogler G, Andus T. Cytokins in inflammatory bowel disease. World J Surg 1998;22:382–389. 8. Izzo AA, Mascolo N, Capasso F. Nitric oxide as a modulator of intestinal water and electrolyte transport. Dig Dis Sci 1998;43: 1605–1620. 9. Tursi A, Brandimarte G, Daffinà R. Long-term treatment with mesalazine and rifaximin versus rifaximin alone for the patients with recurrent attacks of acute diverticulitis of the colon. Dig Liver Dis 2002;34:510 –515. 10. Brandimarte G, Tursi A. Rifaximin plus mesalazine followed by mesalazine alone is highly effective in obtaining remission of symptomatic uncomplicated diverticular disease. Med Sci Monit 2004;10:170 –173. 11. Sandborn WJ, Hanauer SB. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment Pharmacol Ther 2003;17:29 – 42. 12. Shanahan F. Inflammatory bowel disease: immunodiagnostics, immunotherapeutics, and echotherapeutics. Gastroenterology 2001;120:622– 635. 13. Borruel N, Casellas F, Antolin M, Llopis M, Carol M, Espiin E, Naval J, Guarner F, Malagelada JR. Effects of nonpathogenic bacteria on cytokine secretion by human intestinal mucosa. Am J Gastroenterol 2003;98:865– 870. 14. Fricˇ P, Zavoral M. The effect of non-pathogenic Escherichia coli in symptomatic uncomplicated diverticular disease of the colon. Eur J Gastroenterol Hepatol 2003;15:313–315. doi:10.1053/j.gastro.2004.10.030
Leptin Reduces the Development of the Initial Precancerous Lesions Induced by Azoxymethane in the Rat Colonic Mucosa Dear Sir: We read with great interest the article by Aparicio et al1 suggesting that leptin reduces the development of chemically induced colon carcinoma, especially as there is both laboratory and epidemiologic data to the contrary.2 The authors’ methodology is sound. Although they were unable to demonstrate significant differences in the number of abnormal crypts (AC) they did find differences in AC per square centimeter. They also did not see differences in the number of crypts per foci, a measure of the virulence of the carcinogenesis.3 Perhaps if the study went longer than 23 days, significant differences in these parameters would appear. We studied the effects of azoxymethane (AOM) induced colon carcinogenesis in a Zucker rat model and demonstrated that genetic obesity (fa/fa) was more important than a high-fat diet in AOM
non-PBC subjects and the evaluation of false positives and low specificity.7 We encourage Mason and colleagues to address the following issues. First, the design must include a larger number of blinded sera and pathologic specimens from both patients and controls. Second, to define the nature of the resulting immunoblot reactivities, the authors should rigorously study a large number of sera (including AMA-negative), include dilution analysis, and define specificities. Third, we strongly encourage the use of blinded, freshly collected samples for parallel and unbiased analysis; they should also be willing to accept blinded samples for their own analysis. They must demonstrate specific retroviral sequences integrated in the genome of cells from patients with PBC (not achieved by Southern blotting2) and subsequently study viral expression. Finally, it appears mandatory that Mason and colleagues show the capability of MMTV to infect humans, that is the presence and nature of specific membrane receptors that determine the tropism of the virus, currently not including human cells.8 The theory on retroviruses in PBC was first proposed 6 years ago and many patients have heard about it and are now requesting the use of antivirals. Thus, it is important to either prove the thesis or put it to rest. We are delighted that we have challenged the Mason group and look forward to their data. We are working together for the very same goal. CARLO SELMI, MD, PhD Division of Rheumatology Allergy and Clinical Immunology University of California at Davis School of Medicine Davis, California and the Division of Internal Medicine San Paolo School of Medicine University of Milan Milan, Italy SUSAN R. ROSS, PhD Department of Microbiology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania AFTAB A. ANSARI, PhD Department of Pathology Emory University School of Medicine Atlanta, Georgia PIETRO INVERNIZZI, MD, PhD MAURO PODDA, MD Division of Internal Medicine San Paolo School of Medicine University of Milan Milan, Italy ROSS L. COPPEL, MD, PhD Department of Microbiology Monash University Clayton, Victoria, Australia M. ERIC GERSHWIN, MD Division of Rheumatology Allergy and Clinical Immunology University of California at Davis School of Medicine Davis, California
CORRESPONDENCE
1865
1. Selmi C, Ross SR, Ansari AA, Invernizzi P, Podda M, Coppel RL, Gershwin ME. Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis. Gastroenterology 2004;127:493–501. 2. Xu L, Shen Z, Guo L, Fodera B, Keogh A, Joplin R, O’Donnell B, Aitken J, Carman W, Neuberger J, Mason A. Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci U S A 2003;100: 8454 – 8459. 3. Yanagawa T, Ito K, Kaplan EL, Ishikawa N, DeGroot LJ. Absence of association between human spumaretrovirus and Graves’ disease. Thyroid 1995;5:379 –382. 4. Lower R, Tonjes RR, Boller K, Denner J, Kaiser B, Phelps RC, Lower J, Kurth R, Badenhoop K, Donner H, Usadel KH, Miethke T, Lapatschek M, Wagner H. Development of insulin-dependent diabetes mellitus does not depend on specific expression of the human endogenous retrovirus HERV-K. Cell 1998;95:11–14;[discussion 16]. 5. Held W, Waanders GA, Acha-Orbea H, MacDonald HR. Reverse transcriptase-dependent and -independent phases of infection with mouse mammary tumor virus: implications for superantigen function. J Exp Med 1994;180:2347–2351. 6. Golovkina TV, Dudley JP, Ross SR. B and T cells are required for mouse mammary tumor virus spread within the mammary gland. J Immunol 1998;161:2375–2382. 7. Mason AL, Xu L, Guo L, Munoz S, Jaspan JB, Bryer-Ash M, Cao Y, Sander DM, Shoenfeld Y, Ahmed A, Van de Water J, Gershwin ME, Garry RF. Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders. Lancet 1998;351:1620 –1624. 8. Ross SR, Schofield JJ, Farr CJ, Bucan M. Mouse transferrin receptor 1 is the cell entry receptor for mouse mammary tumor virus. Proc Natl Acad Sci U S A 2002;99:12386 –12390. doi:10.1053/j.gastro.2004.10.025
Preventive Therapy for Complicated Diverticular Disease of the Colon: Looking for a Correct Therapeutic Approach Dear Sir: I read with great interest the comment by Mitchell and Shaheen about the preventive therapy in perforated colonic diverticular disease.1 They comment on the recent paper by Morris et al about the effectiveness of calcium channel blockers in preventing perforation in diverticular disease,2 and conclude that this therapy may be a good option in preventing diverticular perforation, especially in patients “who have had two or more episodes of inflammation.” However, I am not sure that calcium channel blockers are the best option for these patients. Although calcium blockers may be a reasonable treatment, we should not forget that these drugs may provoke several side effects (peripheral edema, symptomatic hypotension, etc),3 and they should be used carefully. There are other safe therapeutic alternatives, especially for patients with recurrent attacks of acute uncomplicated diverticulitis. The first alternative is mesalazine. The rationale for the use of mesalazine for the treatment of diverticulitis is similar to that for the use in chronic inflammatory bowel disease. Mesalazine inhibits some key factors of inflammatory cascade (cyclooxygenase, thromboxane-synthetase, and PAF-synthetase), inhibits the production of IL-1 and free radicals4,5 and has intrinsic anti-oxidant activity.6 Some inflammatory complications of diverticulits, such as edema, are generated by an heightened production of proinflammatory cytokines (IL-1, TNF-␣), reduced anti-inflammatory cytokines (IL-ra, IL-4, IL-10, IL-11),7 and enhanced intramucosal synthesis of nitric oxide.8 Our group has shown
1866
CORRESPONDENCE
this effect in 2 studies. In the first study, a group treated with rifaximin plus mesalazine showed significant improvement in symptom severity (P ⬍ .0005), bowel habits (P ⬍ .0001), and symptomatic recurrence or complications of diverticulitis (P ⬍ .005) versus a group treated with rifaximin alone during a 12-month follow-up.9 It is noteworthy that this study has been conducted on patients affected by recurrent attacks of acute diverticulitis, some of them affected by colonic stenosis. These results have been confirmed by a more recent study, which showed that a short course of rifaximin/mesalazine (10 days) followed by a longer course of mesalazine alone (8 weeks) is extremely effective in resolving symptoms in patients with acute symptomatic diverticular disease of the colon.10 I think that longterm mesalazine therapy may be a safe and tolerable approach even in older patients, since the risk of nephotoxicity is lower than previously thought.11 Another reasonable approach may be to use probiotics. Probiotics are live microbial food ingredients that alter the enteric flora and have a favorable effect on health. Probiotic activity has most commonly been associated with lactobacilli and bifidobacteria; other nonpathogenic bacterial strains, including certain Escherichia coli and enterococci, and nonbacterial organisms such as Saccaromyces boulardii have been used.12 The rationale for probiotics in diverticular disease is strictly related to pathogenesis of the disease. Stasis of luminal contents occurs in colonic diverticula, and this is supported by alterations of defecation. Stasis is probably combined with changes in the spectrum of intestinal microflora. This process may be followed by the occurrence of abnormal metabolites causing functional changes reflected in the abdominal symptoms. In light of these considerations, it appears reasonable to influence the colonic microflora by the introduction of probiotics. Moreover, probiotic action includes production of antimicrobials, competitive metabolic interactions with proinflammatory organisms, inhibition of adherence, and translocations of pathogens, which creates a trophic effect on intestinal mucosa thanks to production of butyrate. Likewise, probiotics can determine mucosal defense by changing immune and epithelial function by diminishing TNF-␣, IL-1, and IFN-␥.13 Fricˇ and Zavoral recently showed the validity of this alternative approach.14 Another point to take in consideration is that probiotic therapy is virtually free of side effects and it may be performed indefinitely without any risk. I think that the combination of probiotics and salycilates may be more effective than mesalazine alone or calcium channel blockers, even in patients with a high risk of symptomatic recurrence of diverticular disease. This combination could act in 2 different ways in decreasing inflammation: 5-ASA inhibits the inflammatory cascade (blocking cyclooxygenase, Thromboxane-synthetase and PAF-synthetase activity, the production of IL-1, and free radicals), while probiotics act on composition of fecal flora (by the production of antimicrobials, competitive metabolic interactions with proinflammatory organisms, reduction of pH and an inhibition of adherence and translocations of pathogens) and improve colonocytes metabolism by synthesis of butyrate. Further studies are needed to confirm whether this hypothesis is only speculative or if it is the best treatment in preventing complications in diverticular disease of the colon. ANTONIO TURSI, MD Digestive Endoscopy Unit “Lorenzo Bonomo” Hospital Andria, Italy 1. Mitchell K, Shaheen NJ. Preventive therapy in perforated colonic diverticular disease? Calcium channel blockers may hold the key. Gastroenterology 2004;127:680 – 682.
GASTROENTEROLOGY Vol. 127, No. 6
2. Morris CR, Harvey IM, Stebbings WSL, Speakman CTM, Kennedy HJ, Hart AR. Do calcium channel blockers and antimuscarinics protect against perforated colonic diverticular disease? Gut 2003;52:1734 –1737. 3. Eisenberg MJ, Brox A, Bastawros AN. Calcium channel blockers: an update. Am J Med 2004;116:35– 43. 4. Eliakim R, Rachmilewitz D. Potential mediators in inflammatory bowel disease. Gastroenterology Int 1992;5:48 –56. 5. Grisham MB. Oxidants and free radicals in inflammatory bowel disease. Lancet 1994;344:859 – 861. 6. Gonçalves E, Almeida LM, Dinis TC. Antioxidant activity of 5-aminosalicylic acid against peroxidation of phosphatidylcholine liposomes in the presence of alpha-tocopherol: a synergistic interaction? Free Rad Res 1998;29:53– 66. 7. Rogler G, Andus T. Cytokins in inflammatory bowel disease. World J Surg 1998;22:382–389. 8. Izzo AA, Mascolo N, Capasso F. Nitric oxide as a modulator of intestinal water and electrolyte transport. Dig Dis Sci 1998;43: 1605–1620. 9. Tursi A, Brandimarte G, Daffinà R. Long-term treatment with mesalazine and rifaximin versus rifaximin alone for the patients with recurrent attacks of acute diverticulitis of the colon. Dig Liver Dis 2002;34:510 –515. 10. Brandimarte G, Tursi A. Rifaximin plus mesalazine followed by mesalazine alone is highly effective in obtaining remission of symptomatic uncomplicated diverticular disease. Med Sci Monit 2004;10:170 –173. 11. Sandborn WJ, Hanauer SB. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment Pharmacol Ther 2003;17:29 – 42. 12. Shanahan F. Inflammatory bowel disease: immunodiagnostics, immunotherapeutics, and echotherapeutics. Gastroenterology 2001;120:622– 635. 13. Borruel N, Casellas F, Antolin M, Llopis M, Carol M, Espiin E, Naval J, Guarner F, Malagelada JR. Effects of nonpathogenic bacteria on cytokine secretion by human intestinal mucosa. Am J Gastroenterol 2003;98:865– 870. 14. Fricˇ P, Zavoral M. The effect of non-pathogenic Escherichia coli in symptomatic uncomplicated diverticular disease of the colon. Eur J Gastroenterol Hepatol 2003;15:313–315. doi:10.1053/j.gastro.2004.10.030
Leptin Reduces the Development of the Initial Precancerous Lesions Induced by Azoxymethane in the Rat Colonic Mucosa Dear Sir: We read with great interest the article by Aparicio et al1 suggesting that leptin reduces the development of chemically induced colon carcinoma, especially as there is both laboratory and epidemiologic data to the contrary.2 The authors’ methodology is sound. Although they were unable to demonstrate significant differences in the number of abnormal crypts (AC) they did find differences in AC per square centimeter. They also did not see differences in the number of crypts per foci, a measure of the virulence of the carcinogenesis.3 Perhaps if the study went longer than 23 days, significant differences in these parameters would appear. We studied the effects of azoxymethane (AOM) induced colon carcinogenesis in a Zucker rat model and demonstrated that genetic obesity (fa/fa) was more important than a high-fat diet in AOM