E.V. BOLTOVA, L.K. PAL’GOVA, N.V. SEMENOV, K.L. RAIKHELSON, A.Yu. BARANOVSKIY

North-Western State Medical University named after I.I. Mechnikov, 41 Kirochnaya str., 191015 Saint Petersburg, Russian Federation

Boltova E.V. — Senior Laboratory Assistant of the Department of Gastroenterology and Dietology, tel. +7-911-016-82-26, e-mail: kaboi@rambler.ru

Pal’govа L.K. — D. Med. Sc., Professor of the Department of Gastroenterology and Dietology, tel. +7-952-282-99-52, e-mail: l_palgova@mail.ru

Semenov N.V. — Cand. Med. Sc., Associate Professor of the Department of Gastroenterology and Dietology, tel. (812) 235-10-93, +7-981-806-02-28, e-mail: niksem1@mail.ru

Raikhelson K.L. — Cand. Med. Sc., Associate Professor of the Department of Gastroenterology and Dietology, tel. (812) 235-10-93, +7-911-911-01-43, e-mail: kraikhelson@mail.ru

Baranovskiy A.Yu. — D. Med. Sc., Professor, Head of the Department of Gastroenterology and Dietology, tel. (812) 235-10-93, +7-921-937-70-97, e-mail: baranovsky46@mail.ru 

To date, all the hypotheses of the development of primary sclerosing cholangitis (PSC) have no clear evidence. Some studies show an important and perhaps decisive role of the intestinal microflora in the etiopathogenesis of PSC. This hypothesis is based on the frequent association of PSC and inflammatory bowel disease (IBD). However, reviewing the literature about the role of microbial factor in the development of PSC and associated IBD, we are faced with ambiguity, and sometimes with the conflicting results of numerous studies: are we implementing the antibiotic treatment of PSC etiological factor or the secondary bacterial cholangitis that has developed on the PSC background? The bacterial theory does not explain the PSC monovariant, there is no correlation of IBD severity and risk of liver disease development, portal bacteremia in patients with IBD is rarely detected and there is no impact on the development and progression of PSC after proctocolectomy. These findings demonstrate the appropriateness and prospects for further scientific research in this direction.

Key words: primary sclerosing cholangitis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, microflora.

 

 

REFERENCES

1. Delbet P. Retrecissement du choledoque: cholecyst oduodenostomie. Bull. Mem. Soc. Nat. Chir., 1924, vol. 50, pp. 1144-1146.

2. Schwartz S.I., Dale W.A. Primary sclerosing cholangitis; review and report of six cases. A.M.A. Archives of Surgery, 1958, vol. 77, no. 3, rr. 439-451.

3. Olsson R., Danielsson A., Jarnerot G. et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology, 1991, vol. 100, pp. 1319-1323.

4. Rabinovitz M., Gavaler J.S., Schade R.R. et al. Does primary sclerosing cholangitis occurring in association with inflammatory bowel disease differ from that occurring in the absence of inflammatory bowel disease? A study of sixty-six subjects. Hepatology, 1990, vol. 11, no. 1, pp. 7-11.

5. Okada H., Mizuno M., Yamamoto K. et al. Primary sclerosing cholangitis in Japanese patients: association with inflammatory bowel disease. Acta Med Okayama, 1996, vol. 50, no. 5, pp. 227-235.

6. Escorsell A., Pares A., Rodes J. et al. Epidemiology of primary sclerosing cholangitis in Spain. J Hepatol., 1994, vol. 21, pp. 787-791.

7. Schrumpf E., Abdelnoor M., Fausa O. et al. Risk factors in primary sclerosing cholangitis. J Hepatol., 1994, vol. 21, pp. 1061-1066.

8. Rasmussen H.H., Fallingborg J.F., Mortensen P. B. et al. Hepatobiliary dysfunction and primary sclerosing cholangitis in patients with Crohn’s disease. Scand J Gastroenterol., 1997, vol. 32, pp. 604-610.

9. O’Mahony C.A., Vierling J.M. Etiopathogenesis of primary sclerosing cholangitis. Seminars in Liver Disease, 2006, vol. 26, no. 1, pp. 3-21.

10. Mistilis S.P., Skyring A.P., Goulston S.J. Effect of long-term tetracycline therapy, steroid therapy and colectomy in pericholangitis associated with ulcerative colitis. Australasian Annals of Medicine, 1965, vol. 14, no. 4, rr. 286-294.

11. Pohl J., Ring A., Stremmel W. et al. The role of dominant stenoses in bacterial infections of bile ducts in primary sclerosing cholangitis. European Journal of Gastroenterology and Hepatology, 2006, vol. 18, no. 1, pp. 69-74.

12. Lichtman S.N., Keku J., Clark R.L. et al. Biliary tract disease in rats with experimental small bowel bacterial overgrowth. Hepatology, 1991, vol. 13, no. 4, pp. 766-772.

13. Lichtman S. N., Wang J., Clark R.L. A microcholangiographic study of liver disease models in rats. Academic Radiology, 1995, vol. 2, no. 6, pp. 515-521.

14. Lichtman S.N., Okoruwa E.E., Keku J. et al. Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth. Journal of Clinical Investigation, 1992, vol. 90, no. 4, pp. 1313-1322.

15. Haruta I., Kikuchi K., Hashimoto E. et al. Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation. Laboratory Investigation, 2010, vol. 90 (4), pp. 577-588.

16. Pollheimer M.J., Trauner M., Fickert P. Will we ever model PSC? «It’s hard to be a PSC model!». Clinics and Research in Hepatology and Gastroenterology, 2011, vol. 35, no. 12, pp. 792-804.

17. Welcker K., Martin A., Kulle O. et al. Increased intestinal permeability in patients with inflammatory bowel disease. European Journal of Medical Research, 2004, vol. 9, no. 10, pp. 456-460.

18. Tabibian J.H., O’Hara S.P., Larusso N.F. Primary sclerosing cholangitis: the Gut-Liver axis. Clinical Gastroenterology and Hepatology, 2012, vol. 10, rr. 819-820.

19. Tabibian J.H., Masyuk A.I., Masyuk T.V. et al. Cholangiocyte physiology. Comprehensive Physiology, 2013, vol. 3, pp. 541-565.

20. O’Hara S.P., Tabibian J.H., Splinter P.L. et al. The dynamic biliary epithelia: molecules, pathways, and disease. Journal of Hepatology, 2013, vol. 58, rr. 575-582.

21. O’Hara S.P., Splinter P.L., Trussoni C.E. et al. Cholangiocyte N-Ras protein mediates lipopolysaccharide-induced interleukin 6 secretion and proliferation. Journal of Biological Chemistry, 2011, vol. 286, no. 35, rr. 30352-30360.

22. Chen X.M., O’Hara S.P., Nelson J.B. et al. Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvum via activation of NF-κB. Journal of Immunology, 2005, vol. 175, no. 11, rr. 7447-7456.

23. Yokoyama T., Komori A., Nakamura M. et al. Human intrahepatic biliary epithelial cells function in innate immunity by producing IL-6 and IL-8 via the TLR4-NF-κB and -MAPK signaling pathways. Liver International, 2006, vol. 26, no. 4, pp. 467-476.

24. Mueller T., Beutler C., Pico A.H. et al. Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis. Liver international: official journal of the International Association for the Study of the Liver, 2011, vol. 31, rr. 1574-1588.

25. Katt J., Schwinge D., Schoknecht T. et al. Increased th17 response to pathogen stimulation in patients with primary sclerosing cholangitis. Hepatology, 2013, vol. 58, no. 3, pp. 1084-1093.

26. Liu J.Z., Hov J.R., Folseraas T. et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nature Genetics, 2013, vol. 45, no. 6, rr. 670-675.

27. Terjung B., Sohne J., Lechtenberg B. et al. Spengler p-ANCAs in autoimmune liver disorders recognise human beta-tubulin isotype 5 and cross-react with microbial protein FtsZ. Gut, 2010, vol. 59, pp. 808-816.

28. Björnsson E., Cederborg A., Akvist A. et al. Intestinal permeability and bacterial growth of the small bowel in patients with primary sclerosing cholangitis. Scandinavian Journal of Gastroenterology, 2005, vol. 40, no. 9, rr. 1090-1094.

29. Palmer K.R., Duerden B.I., Holdsworth C.D. Bacteriological and endotoxin studies in cases of ulcerative colitis submitted to surgery. Gut, 1980, vol. 21, rr. 851-854.

30. Clemente J.C., Ursell L.K., Parfrey L.W. et al. The impact of the gut microbiota on human health: an integrative view. Cell, 2012, vol. 148, no. 6, rr. 1258-1270.

31. Rankin J.G., Boden R.W., Goulston S.J. et al. The liver in ulcerative colitis; treatment of pericholangitis with tetracycline. The Lancet, 1959, vol. 274, no. 7112, pp. 1110-1112.

32. Mathew K.K. Metronidazole in primary cholangitis. Journal of the Indian Medical Association, 1983, vol. 80, no. 2, pp. 31.

33. Kozaiwa K., Tajiri H., Sawada A. et al. Case report: three paediatric cases of primary sclerosing cholangitis treated with ursodeoxycholic acid and sulphasalazine. Journal of Gastroenterology and Hepatology, 1998, vol. 13, no. 8, pp. 825-829.

34. Cox K.L., Cox K.M. Oral vancomycin: treatment of primary sclerosing cholangitis in children with inflammatory bowel disease. Journal of Pediatric Gastroenterology and Nutrition, 1998, vol. 27, no. 5, pp. 580-583.

35. Broccoletti T., Ciccimarra E., Spaziano M. et al. Refractory primary sclerosing cholangitis becoming responsive after sulphasalazine treatment of an underlying silent colitis. Italian Journal of Pediatrics, 2002, vol. 28, no. 6, rr. 515-517.

36. Tada S., Ebinuma H., Saito H. et al. Therapeutic benefit of sulfasalazine for patients with primary sclerosing cholangitis. Journal of Gastroenterology, 2006, vol. 41, no. 4, rr. 388-389.

37. Boner A.L., Peroni D., Bodini A. et al. Piacentini Azithromycin may reduce cholestasis in primary sclerosing cholangitis: a case report and serendipitous observation. International Journal of Immunopathology and Pharmacology, 2007, vol. 20, no. 4, pp. 7-849.

38. Davies Y.K., Cox K.M., Abdullah B.A. et al. Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating antibiotic. Journal of Pediatric Gastroenterology and Nutrition, 2008, vol. 47, no. 1, pp. 61-67.

39. Davies Y.K., Tsay C.J., Caccamo D.V. et al.Successful treatment of recurrent primary sclerosing cholangitis after orthotopic liver transplantation with oral vancomycin. Case Rep Transplant., 2013, vol. 5, pp. 314292-314292.

40. Duboc N., Rajca S., Rainteau D. et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut, 2013, vol. 62, no. 4, rr. 531-539.

41. DuPont A.W., DuPont H.L. The intestinal microbiota and chronic disorders of the gut. Nature Reviews Gastroenterology & Hepatology, 2011, no. 8, rr. 523-531.

42. Shimizu M., Iwasaki H., Mase S. et al. Successful treatment of primary sclerosing cholangitis with a steroid and a probiotic. Case Reports in Gastroenterology, 2012, vol. 6, pp. 249-253.

43. Vleggaar F.P., Monkelbaan J.F., Van K.J. Erpecum Probiotics in primary sclerosing cholangitis: a randomized placebo-controlled crossover pilot study. European Journal of Gastroenterology and Hepatology, 2008, vol. 20, no. 7, pp. 688-692.

44. Tabibian J.H., Lindor K.D. Primary sclerosing cholangitis: a review and update on therapeutic developments. Expert Review of Gastroenterology & Hepatology, 2013, vol. 7, rr. 103-114.

45. Elfaki D.A.H., Lindor K.D. Antibiotics for the treatment of primary sclerosing cholangitis. American Journal of Therapeutics, 2011, vol. 18, no. 3, rr. 261-265.

46. Färkkilä M., Karvonen A.L., Nurmi H. et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology, 2004, vol. 40, no. 6, pp. 1379-1386.

47. Silveira M. G., Torok N. J., Gossard A.A. et al. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. American Journal of Gastroenterology, 2009, vol. 104, no. 1, pp. 83-88.

48. Tabibian J.H., Weeding E., Jorgensen R.A. et al. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis – A Pilot Study. Alimentary Pharmacology & Therapeutics, 2013, vol. 37, pp. 604-612.