Risk factors and prognosis for recurrent primary sclerosing cholangitis after liver transplantation: a Nordic Multicentre Study.

OBJECTIVES: The risk for recurrent primary sclerosing cholangitis (rPSC) after liver transplantation is associated with inflammatory bowel disease (IBD). We assessed the frequency of rPSC and studied risk factors for recurrent disease with special focus on IBD. We also evaluated the importance of rPSC for prognosis. MATERIALS AND METHODS: All liver transplanted PSC patients in the Nordic countries between 1984 and 2007 (n = 440), identified by the Nordic Liver Transplant Registry, were studied. Data were retrieved from patients' chart reviews. Multivariable Cox regression models were used to calculate risk factors for rPSC and death. RESULTS: Of the 440 patients with a follow-up time after liver transplantation of 3743 patient years, rPSC was diagnosed in 19% (n = 85). Colectomy before liver transplantation was associated with a reduced risk of rPSC (HR 0.49; 95% CI, 0.26-0.94, p = 0.033). Neither high IBD activity nor presence of IBD flares before or after liver transplantation was associated with rPSC. Treatment with tacrolimus was an independent risk factor associated with increased risk for rPSC (HR, 1.81; 95% CI, 1.15-2.86, p = 0.010). The risk of dying or needing a re-transplantation after rPSC was increased in all age groups, but highest in patients transplanted before 40 years of age (HR 7.3; 95% CI, 4.1-12.8, p = 0.0001). CONCLUSIONS: This study confirms that colectomy before liver transplantation is associated with a decreased risk of rPSC. Inflammatory activity of IBD was not associated with the risk of rPSC. Tacrolimus was an independent risk factor for PSC recurrence and its use as first line immunosuppression in PSC needs further study.

Increased risk of colorectal cancer in patients diagnosed with breast cancer in women.

BACKGROUND: Epidemiological studies have shown a potential association between sex hormones and colorectal cancer. The risk of colorectal cancer in breast cancer patients who may have been exposed to increased levels of endogenous sex hormones and/or exogenous sex hormones (e.g. anti-hormonal therapy) has not been thoroughly evaluated. METHODS: Using the National Swedish Cancer Register we established a population-based prospective cohort of breast cancer patients in women diagnosed in Sweden between 1961 and 2010. Subsequent colorectal cancers were identified from the same register. Standardized incidence ratios (SIRs) and 95% confidence intervals (95%CIs) were used to estimate the risk of colorectal cancer after a diagnosis of breast cancer. The association between breast cancer therapy and risk of colorectal cancer was evaluated in a subcohort of breast cancer patients treated in Stockholm between 1977 and 2007. Hazard ratios (HRs) and 95%CIs were estimated using Cox regression models. RESULTS: In a cohort of 179,733 breast cancer patients in Sweden, 2571 incident cases of colorectal cancer (1008 adenocarcinomas in the proximal colon, 590 in the distal colon and 808 in the rectum) were identified during an average follow-up of 9.68 years. An increased risk of colorectal adenocarcinoma was observed in the breast cancer cohort compared with that in the general population (SIR=1.59, 95%CI: 1.53, 1.65). Adenocarcinoma in the proximal colon showed a non-significantly higher SIR (1.72, 95%CI: 1.61, 1.82) compared with the distal colon (1.46, 95%CI: 1.34, 1.58). In the subcohort of 20,171 breast cancers with available treatment data, 299 cases with colorectal cancers were identified. No treatment-dependent risk of colorectal cancer was observed among the breast cancer patients. CONCLUSION: An increased risk of colorectal adenocarcinoma - especially in the proximal colon - was observed in the breast cancer cohort. Breast cancer treatment did not alter this risk.

Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) has not been shown to stop progression of primary sclerosing cholangitis (PSC). However, patients with primary biliary cirrhosis treated with UDCA whose levels of alkaline phosphatase (ALP) decrease have longer survival times than patients whose levels do not decrease. We compared survival times between patients with PSC treated with UDCA or placebo, with and without decreased levels of ALP. METHODS: We collected data from patients enrolled in the Scandinavian PSC UDCA trial. Patients were randomly assigned to groups given UDCA (17-23 mg/kg/day, n = 97) or placebo (n = 101) from 1996-2001 and were followed until 2010. End points were death, liver transplantation, or cholangiocarcinoma. They were considered to be biochemical responders if they had serum levels of ALP that were normal or reduced by ≥40% after 1 year in the trial (regardless of whether they received UDCA or placebo). Numbers of patients surviving until the study end point were compared by using the Kaplan-Meier method. RESULTS: There were no differences in survival at the end of the study between patients given UDCA or placebo (P = .774, log-rank); 26 patients in the UDCA group and 29 in the placebo group reached an end point. On the basis of ALP levels, there were 79 responders and 116 nonresponders overall. Of patients given UDCA, significantly more biochemical responders survived for 10 years than nonresponders (P = .03, log-rank). However, differences remained significant regardless of group assignment; overall, patients with reductions in ALP level survived longer than patients without reductions in ALP (P = .0001, log-rank). CONCLUSIONS: There is no significant difference in long-term survival between patients with PSC given UDCA (17-23 mg/kg/day) or placebo for 5 years. However, patients who have reduced or normal levels of ALP have longer survival times, regardless of whether they receive UDCA or placebo.

Immunosuppression after liver transplantation for primary sclerosing cholangitis influences activity of inflammatory bowel disease.

BACKGROUND & AIMS: Previous studies have shown conflicting results regarding the course of inflammatory bowel disease (IBD) after liver transplantation in patients with primary sclerosing cholangitis (PSC). We studied the progression of IBD in patients with PSC who have undergone liver transplantation. We also studied risk factors, including medical therapy, that could influence on IBD disease activity. METHODS: In a longitudinal multicenter study, we analyzed data from the Nordic Liver Transplant Group on 439 patients with PSC who underwent liver transplantation from November 1984 through December 2006; 353 had IBD at the time of transplantation. We compared IBD activity before and after liver transplantation. Two hundred eighteen patients who had an intact colon and had undergone pretransplant and post-transplant colonoscopies were characterized further. RESULTS: Macroscopic colonic inflammation was more frequent after liver transplantation than before liver transplantation (153 vs 124 patients; P < .001). The degree of inflammation decreased in 37 patients (17%), was unchanged in 93 patients (43%), and increased in 88 patients (40%) (P < .001). The rate of relapse after transplantation was higher than that before transplantation (P < .001), and overall clinical IBD activity also increased (P < .001). Young age at diagnosis of IBD and dual treatment with tacrolimus and mycophenolate mofetil were significant risk factors for increased IBD activity after transplantation, whereas combination treatment with cyclosporin A and azathioprine had protective effects. CONCLUSIONS: Immunosuppression affects IBD activity after liver transplantation in patients with PSC; a shift from present standard maintenance treatment of tacrolimus and mycophenolate mofetil to cyclosporin A and azathioprine should be considered for these patients.

Colorectal neoplasia in patients with primary sclerosing cholangitis undergoing liver transplantation: a Nordic multicenter study.

OBJECTIVE: Several studies have implicated primary sclerosing cholangitis (PSC) as an additional risk factor for colorectal neoplasia in inflammatory bowel disease (IBD). Some reports have indicated that the risk is even higher in PSC-IBD patients after liver transplantation (Ltx), but this issue is controversial. We aimed to compare the risk of colorectal neoplasia in PSC-IBD patients before and after Ltx and to identify risk factors for colorectal neoplasia post-transplant. MATERIAL AND METHODS: In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis. RESULTS: Among the 439 PSC patients included, 353 (80%) had IBD at the time of Ltx and 15 (3%) patients developed de novo IBD post-Ltx. The median duration of IBD was 15 (0-50) years at the time of Ltx and follow-up after Ltx was 5 (0-20) years. Ninety-one (25%) PSC-IBD patients developed colorectal neoplasia. The cumulative risk of colorectal neoplasia was higher after than before Ltx (HR: 1.9, 95% CI: 1.3-2.9, p = 0.002). A multivariate analysis demonstrated aminosalicylates and ursodeoxycholic acid as significantly associated with an increased risk of colorectal neoplasia post-Ltx. Duration and activity of IBD did not significantly affect the risk of neoplasia. CONCLUSION: The even higher risk of colorectal neoplasia in PSC-IBD patients after when compared with that of before Ltx underscores the importance of regular surveillance colonoscopies post-Ltx. The association of aminosalicylates and ursodeoxycholic acid to the development of colorectal neoplasia after Ltx should be further investigated.

Increased risk of colorectal cancer and dysplasia in patients with Crohn's colitis and primary sclerosing cholangitis.

BACKGROUND: Almost 10% of all patients with primary sclerosing cholangitis receive a diagnosis of Crohn's disease. Clinical characteristics and the risk of colon cancer or dysplasia in Crohn's disease and primary sclerosing cholangitis are less well examined than in ulcerative colitis. OBJECTIVE: This study aimed to describe the clinical characteristics and risk of colorectal dysplasia and cancer in Crohn's disease in patients with primary sclerosing cholangitis. DESIGN: This is a cohort study of all patients diagnosed with primary sclerosing cholangitis and colorectal Crohn's disease at Karolinska University Hospital, Huddinge, 1978 to 2006. Each patient was matched for age and the onset of Crohn's disease to 2 controls with colorectal Crohn's disease without liver disease. SETTING: This study was conducted at a tertiary referral center. PATIENTS: Twenty-eight patients (61% male) with primary sclerosing cholangitis and Crohn's disease and 46 patients (50% male) with Crohn's disease alone were studied. Clinical and endoscopic data were retrieved from medical records. Colonic biopsies from patients with primary sclerosing cholangitis were re-reviewed. MAIN OUTCOME MEASURES: The primary outcome measured was the proportion of patients developing colorectal cancer. RESULTS: Colorectal cancer or dysplasia developed in 9 patients with primary sclerosing cholangitis and in 3 controls. Patients with primary sclerosing cholangitis were more likely to develop colorectal dysplasia or cancer than controls (OR 6.78; 95% CI (1.65-27.9); P = .016). In patients with primary sclerosing cholangitis compared with controls, perianal fistulas occurred in 3% vs 33% (P = .003), bowel strictures occurred in 7% vs 30% (P = .03), and bowel surgery was performed in 18% vs 46% (P = .01). Histological granulomas were seen in 29% of the patients with primary sclerosing cholangitis compared with 43% in controls (P = not significant). LIMITATIONS: This study was limited by its retrospective nature and the limited cohort. CONCLUSIONS: Primary sclerosing cholangitis is a risk factor for the development of colorectal cancer and dysplasia in Crohn's disease. Obstructing disease and perianal fistulas are rare in primary sclerosing cholangitis and less common than in colonic Crohn's disease without liver disease.

Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebo-controlled trial.

OBJECTIVES: Conflicting data exist on whether discontinuation of proton pump inhibitors (PPIs) is associated with rebound secretion of gastric acid. METHODS: A total of 48 healthy Helicobacter pylori-negative volunteers (24 females) were randomized in a double-blinded manner to treatment with either pantoprazole 40 mg or placebo once daily for 28 days. Dyspeptic symptoms were registered daily using the Glasgow dyspepsia score (GDS) 2 weeks before, during, and 6 weeks after treatment. Plasma levels of gastrin and serum levels of chromogranin-A levels were measured before, during, and after treatment. RESULTS: During the 2 weeks before treatment, the placebo group had a mean GDS of 0.20 + or - 0.7 compared with the pantoprazole group score of 0.54 + or - 1.3 (NS). No significant differences between the symptom severity scores of the two groups were shown during the treatment period. During the first week after discontinuation of treatment, the pantoprazole group had a mean symptom score of 5.7 + or - 11.7 vs. 0.74 + or - 2.6 in the placebo group (P<0.01). A total of 11 out of 25 (44%) subjects in the pantoprazole group developed dyspepsia compared with 2 out of 23 (9%) in the placebo group (P<0.01). During the second week of follow-up, the pantoprazole group had a mean symptom score of 1.6 + or - 3.4 compared with 0 + or - 0 in the placebo group (P<0.05). There were no significant differences in the mean symptom score for the pantoprazole group (1.1 + or - 0.6) compared with the placebo group (0.4 + or - 0.3) during the third week of follow-up. Symptom scores during the first week after treatment correlated with basal (P<0.01) and meal-stimulated (P<0.01) gastrin levels at the end of treatment. CONCLUSIONS: A 4-week course of pantoprazole seems to induce dyspeptic symptoms in previously asymptomatic healthy H. pylori-negative subjects. The correlation between symptom score and gastrin levels suggests that these symptoms are due to acid rebound hypersecretion and seem to be related to the degree of acid inhibition.

Altered rectal perception in irritable bowel syndrome is associated with symptom severity.

BACKGROUND & AIMS: Diverging results exist regarding the connection between altered visceral perception and gastrointestinal (GI) symptoms, as well as the effects of psychological status on visceral sensitivity. We sought to investigate different aspects of rectal perception in irritable bowel syndrome (IBS) and the association with GI and psychological symptoms. METHODS: We included 109 patients with IBS meeting Rome II criteria (77 women; age range, 20-71 years) and 29 healthy controls (21 women; age range, 20-68 years). They underwent rectal balloon distentions determining sensory thresholds for discomfort and pain, the perceived intensity of unpleasantness, and the viscerosomatic referral area. The fifth percentile (thresholds) and 95th percentile (unpleasantness and referral area) in controls were used to define altered perception. Questionnaires were used to assess severity of IBS-related GI symptoms and psychological symptoms. RESULTS: When combining the 3 aspects of perception, 67 patients (61%) had altered rectal perception. These patients, compared with normosensitive patients, more frequently reported moderate or severe pain (73% vs 44%; P < .01), bloating (73% vs 36%; P < .0001), diarrhea (47% vs 21%; P < .01), satiety (39% vs 13%; P < .01), and clinically significant anxiety (31% vs 12%; P < .05). In a multivariate analysis, only pain and bloating remained associated with altered rectal perception. CONCLUSIONS: Altered rectal perception is common in IBS and seems to be one important pathophysiologic factor associated with GI symptom severity in general and pain and bloating in particular. It is not just a reflection of the psychological state of the patient.