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The colon and PSC: new liver, new danger?
  1. John Radcliffe Hospital,
  2. Headington, Oxford OX3 9DU, UK

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See article on page 639

The close relation between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) continues to provide more questions than answers. The prevalence of IBD in patients with PSC is about 55–75%, and PSC occurs in patients with ulcerative colitis at a frequency of 2.5–7.5%.1 ,2 PSC is found less often in Crohn’s disease where it is usually associated with colonic involvement. Recent studies have found an increased prevalence of colonic dysplasia and cancer in patients with PSC and ulcerative colitis compared with ulcerative colitis alone.3 ,4 The mechanism by which PSC increases the risk of colonic neoplasia is unknown. The increased long term survival of patients with both PSC and ulcerative colitis after liver transplantation may therefore put these patients at an increased risk of developing colorectal cancer in view of the increased neoplastic potential as a result of the immunosuppressive therapy required after liver transplantation. Indeed, some studies have suggested that there may be a higher incidence of colorectal cancer in the first two years after liver transplantation.5-7 This may reflect the higher doses of immunosuppression used during this time as after this period, increased rates of colonic cancer have not been reported. However, three studies, including the report by Papatheodoridis et al (see page 639), have been unable to detect higher rates of colonic cancer.8 ,9 Although the data are conflicting, colonic surveillance is mandatory in this high risk group of patients and yearly colonoscopy has been recommended.10

Despite the fact that the colitis is usually total in extent it has been a constant feature of all clinical series that the clinical course of the ulcerative colitis is mild or asymptomatic.11 It has also been established from retrospective studies that the clinical course and activity of the ulcerative colitis seems to be independent of the natural history and progress of the hepatobiliary disease.1 ,2 There is evidence from the Mayo Clinic that patients who have had an ileal reservoir created for ulcerative colitis and who also have PSC, have a higher rate of pouchitis. However, the course of pouchitis in PSC is not altered by liver transplantation.12

In view of the fact that ulcerative colitis usually has a milder asymptomatic course and that after liver transplantation most patients are treated with immunosuppressive agents, it could be expected that the course of IBD would further improve after orthotopic liver transplantation (OLT). To date, however, the published studies provide contrasting data.13 ,14 In the first report from Pittsburgh, 23 patients transplanted for PSC were treated with maintenance immunosuppression with cyclosporin and prednisolone.13 All six patients who were asymptomatic before OLT remained well. No patients worsened and 14 (82%) of 17 patients with previously active ulcerative colitis reported significant improvement. These results were confirmed at another centre in which remission was maintained with cyclosporin or tacrolimus and corticosteroids with or without the addition of azathioprine or cyclophosphamide.8 Eighteen of 27 patients with IBD showed improvement, four patients remained stable and only five had worsening IBD activity after transplantation.14 In notable contrast, two other studies have found no difference or worsening in activity after OLT.15 ,16 Shaked et alstudied 24 patients and found that 33% worsened after OLT and only 4% improved. Confirmation of these results came from another recent study where triple immunosuppression was used,17 and worsening and progression of IBD symptoms were observed in 31% of 19 patients. However, it should be noted that the course of post-transplant ulcerative colitis was compared only with the clinical status of colitis in the immediate pretransplant period.

Papatheodoridis et al have reported the results from the Royal Free Hospital, a transplant unit in which corticosteroids are withdrawn three months after transplantation and patients are then maintained with either cyclosporin or tacrolimus with or without azathioprine. They have described 30 patients who were transplanted for PSC and survived more than 12 months. The clinical course of ulcerative colitis after OLT compared with that up to five years before transplantation was the same in 50% and worse in 50%. Two thirds of patients who were quiescent beforehand remained quiescent and one third worsened, whereas all patients who had had an active pretransplant course developed significant worsening after liver transplantation. Also of interest, despite immunosuppression, three of 12 patients with PSC, without previous evidence of IBD, developed active colitis after transplantation. However, exacerbation of colitis occurred only after steroid withdrawal.

What do these results mean? Current evidence suggests that after OLT ulcerative colitis may pursue a more aggressive course or even develop for the first time in patients in whom corticosteroids are withdrawn and where other immunosuppressive drugs are used. There is no obvious explanation for these surprising findings. Papatheodoridis and coworkers suggest that the presence of normally functioning liver creates a new balance in immunoregulation, pointing out that patients with advanced liver disease often have depressed T cell function as well as other immune system disturbances. An alternative explanation may be that altered bile salt concentrations after OLT may adversely affect colonic function.

To date, the aetiology and pathogenesis of PSC and its association with IBD remain unknown. Cholangiocytes and colonocytes may share common autoantigens or bacterial products such as formyl peptides which may ascend the portal vein to excite hepatobiliary change in susceptible patients. Further insights into the disease mechanisms involved in the pathogenesis of IBD may elucidate the paradox of the mild clinical course of total colitis before liver transplantation with significant worsening after transplantation.


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