[Show abstract][Hide abstract] ABSTRACT: Dramatic improvement in first-year outcomes post-liver transplantation (LT) has shifted attention to long-term survival, where efforts are now needed to achieve improvement. Understanding the causes for premature death is a prerequisite for improving long-term outcome. Overall and cause-specific mortality of 3299 Nordic LT patients (1985-2009) having survived 1 year post-LT were divided by expected rates in the general population, adjusted for age, sex, calendar time, and country to yield standardized mortality ratios (SMRs). Data came from the Nordic Liver-Transplant Registry and WHO mortality-indicator database. Stagnant patient survival rates >1 year post-LT were 21% lower at 10 years than expected survival for the general population. Overall SMR for death before age 75 (premature mortality) was 5.8 (95%CI 5.4-6.3), with improvement from 1985-1999 to 2000-2010 in hepatitis C (HCV) (SMR change 23.1-9.2), hepatocellular carcinoma (HCC) (SMR 38.4-18.8), and primary sclerosing cholangitis (SMR 11.0-4.2), and deterioration in alcoholic liver disease (8.3-24.0) and acute liver failure (ALF) (5.9-7.6). SMRs for cancer and liver disease (recurrent or transplant-unrelated disease) were elevated in all indications except primary biliary cirrhosis (PBC). Absolute mortality rates underestimated the elevated premature mortality from infections (SMR 22-693) and kidney disease (SMR 13-45) across all indications, and from suicide in HCV and ALF. SMR for cardiovascular disease was significant only in PBC and alcoholic liver disease, owing to high mortality in the general population. Transplant-specific events caused 16% of deaths.Conclusion: standardized premature mortality provided an improved picture of long-term post-LT outcome, showing improvement over time in some indications, not revealed by overall absolute mortality rates. Causes with high premature mortality (infections, cancer, kidney and liver disease, and suicide) merit increased attention in clinical patient follow-up and future research. (Hepatology 2014;)
[Show abstract][Hide abstract] ABSTRACT: To investigate influence of human leukocyte antigen (HLA) and killer immunoglobuline-like receptor (KIR) genotypes on risks of acute rejection (AR) after liver transplantation (LTX).
In this retrospective study we included 143 adult donor-recipient pairs with a minimum of 6 mo follow-up after LTX for whom DNA was available from both donor and recipients. Clinical data, all early complications including episodes and severity of AR and graft/patient survival were registered. The diagnosis of AR was based on clinical, biochemical and histological criteria. All suspected episodes of AR were biopsy confirmed. Key classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped using Sanger sequencing. 16 KIR genes were genotyped using a novel real time PCR approach which allows for determination of the diploid copy number of each KIR gene. Immunohistochemical staining for T (CD3), B (CD20) and natural killer (NK) cells (CD56 and CD57) were performed on liver biopsies from 3 different patient groups [primary sclerosing cholangitis (PSC), primary biliary cirrhosis and non-autoimmune liver disease], 10 in each group, with similar grade of AR.
Fourty-four (31%) patients were transplanted on the basis of PSC, 40% of them had AR vs 24% in the non-PSC group (P = 0.04). No significant impact of donor-recipient matching for HLA and KIR genotypes was detected. In the overall recipient population an increased risk of AR was detected for HLA-B*08 (P = 0.002, OR = 2.5; 95%CI: 1.4-4.6), HLA-C*07 (P = 0.001, OR = 2.4; 95%CI: 1.4-4.0) and HLA-DRB1*03 (P = 0.03, OR = 1.9; 95%CI: 1.0-3.3) and a decreased risk for HLA-DRB1*04 (P = 0.001, OR = 0.2; 95%CI: 0.1-0.5). For HLA-B*08, HLA-C*07 and DRB1*04 the associations remained evident in a subgroup analysis of non-PSC recipients (P = 0.04, P = 0.003 and P = 0.02, respectively). In PSC recipients corresponding P values were 0.002, 0.17 and 0.01 for HLA-B*08, HLA-C*07 and DRB1*04, respectively. A dosage effect of AR prevalence according to the PSC associated HLA alleles was also notable in the total recipient population. For HLA-B*08 the frequency of AR was 56% in HLA-B*08 homozygous recipients, 39% in heterozygous recipients and 21% in recipients lacking HLA-B*08 (P = 0.02). The same was observed for the HLA-C*07 allele with AR in 57%, 27% and 18% in recipients being homozygous, heterozygous and lacking HLA-C*07 respectively (P = 0.003). Immunohistochemical analysis showed similar infiltration of T, B and NK cells in biopsies with AR in all three groups.
We found significant associations between the PSC-associated HLA-B*08, HLA-C*07, HLA-DRB1*03 and HLA-DRB1*04 alleles and risk of AR in liver transplant recipients.
World Journal of Gastroenterology 04/2014; 20(14):3986-4000. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Small duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the HLA complex, which represent the strongest genetic risk factors in large duct PSC.
Four classical HLA loci (HLA-A, HLA-B, HLA-C, HLA-DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions.
HLA-DRB1*13:01 (OR=2.0, 95% CI 1.2-3.4, P=0.01) and HLA-B*08 (OR=1.6, 95% CI 1.1-2.4, P=0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA-B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4%-65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA-DRB1*13:01(P=0.03) and was otherwise distinctly dissimilar from large duct PSC.
Small duct PSC with IBD resembles large duct PSC in its HLA association and may represent early stages or mild variants of large duct disease. Different HLA associations in small duct PSC without IBD could indicate that this subgroup is a different entity. HLA-DRB1*13:01 may represent a specific risk factor for inflammatory bile duct disease. This article is protected by copyright. All rights reserved.
Liver international: official journal of the International Association for the Study of the Liver 02/2014; · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel.
A total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRβ, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35×10-11).
Our study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region.
PLoS ONE 01/2014; 9(12):e114486. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite considerable advances over the last two decades in the molecular understanding of cholestasis and cholestatic liver disease, little improvement has been made in diagnostic tools and therapeutic strategies.
To critically review controversial aspects of the scientific basis for common clinical practice in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and to discuss key ongoing challenges to improve patient management.
We performed a literature search using PubMed and by examining the reference lists of relevant review articles related to the clinical management of PBC and PSC. Articles were considered on the background of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) practice guidelines and clinical experience of the authors.
Ongoing challenges in PBC mainly pertain to the improvement of medical therapy, particularly for patients with a suboptimal response to ursodeoxycholic acid. In PSC, development of medical therapies and sensitive screening protocols for cholangiocarcinoma represent areas of intense research. To rationally improve patient management, a better understanding of pathogenesis, including complications like pruritis and fatigue, is needed and there is a need to identify biomarker end-points for treatment effect and prognosis. Timing of liver transplantation and determining optimal regimens of immunosuppression post-liver transplantation will also benefit from better appreciation of pre-transplant disease mechanisms.
Controversies in the management of PBC and PSC relate to topics where evidence for current practice is weak and further research is needed.
[Show abstract][Hide abstract] ABSTRACT: Primary sclerosing cholangitis (PSC) occurs in 2%-8% of patients who suffer from ulcerative colitis (UC). For patients who require colectomy, ileal pouch-anal anastomosis (IPAA) or ileorectal anastomosis (IRA) is employed to preserve continence.We evaluated the outcomes after IPAA and IRA for patients with UC-PSC, using patients with UC but without PSC as controls (UC-only group).
In a case-control study conducted at Sahlgrenska University Hospital, Sweden, patients with UC-PSC (N=48; 31 IPAA and 17 IRA) were compared to patients with UC only (N=113; 62 IPAA and 51 IRA). Functional outcomes (Öresland score), pouchitis, surgical complications, and failure were evaluated.
For patients with IPAA, the median Öresland scores were similar for the two groups: 5 (range, 0-13) for the UC-PSC group and 5 for the UC-only group (range, 0-12; p>0.05). However, the IRA scores were significantly different at 7 (range, 2-11) and 3 (range, 0-11) for the respective groups (p=0.005). Pouchitis was more frequent in patients with UC-PSC. Complication rates did not differ. For patients with IPAA, the failure rate was 16% for those in the UC-PSC group versus 6% for those in the UC-only group (p>0.05); the corresponding results for IRA were 53% versus 22% (p=0.03).
For cases of IPAA, pouchitis seems to be more common in patients with UC-PSC. However, the functional outcomes and failure rates are unaffected by concurrent PSC. For patients with UC-PSC, functional outcome is poor and the failure rate is high after IRA.
Journal of Crohn s and Colitis 11/2013; · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Little is known about nongenetic risk factors for primary sclerosing cholangitis (PSC), except a possible protective effect of smoking. We investigated the relationship between environmental risk factors and susceptibility to PSC.
A questionnaire was distributed to patients with PSC, recruited from Oslo University Hospital Rikshospitalet in Norway through 2011, and randomly chosen individuals from the Norwegian Bone Marrow Donor Registry (controls). Data were analyzed from 240 patients with PSC and 245 controls, matched for sex and age.
A lower proportion of patients with PSC were daily coffee drinkers than controls, both currently (76% vs 86%; odds ratio [OR], 0.52; 95% confidence interval [CI], 0.32-0.82; P=.006) and at the age of 18 y (35% vs 49%; OR, 0.58; 95% CI, 0.40-0.83; P=.003). The associations were mainly attributed to differences observed in men. Twenty percent of the patients were ever (current or former) daily smokers compared with 43% of controls (OR, 0.33; 95% CI, 0.22-0.50; P<.001). Ever daily smoking before PSC diagnosis was associated with older age at diagnosis (42 y vs 32 y, P<.001). Ever daily smoking (P<.001) and being a coffee drinker at the age of 18 y (P=.048) were independently and negatively associated with PSC. Fewer female patients with PSC than controls reported ever use of hormonal contraception (51% vs 85%, P<.001). Among female patients, there was a strong correlation between increasing number of children before the diagnosis of PSC and increasing age at diagnosis (r=0.63; P<.001).
Coffee consumption and smoking might protect against development of PSC. In women, the disease might be influenced by hormonal factors.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 09/2013; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Allelic variants of fucosyltransferases 2 and 3 (FUT2/3) influence serum levels of CA19-9, a screening parameter commonly used for detection of biliary malignancy in PSC. We aimed to improve diagnostic accuracy of CA19-9 by determining the impact of FUT2/3 genotypes.
CA19-9 levels were measured in 433 PSC patients, 41 of whom had biliary malignancy. Genotypes for FUT3 and FUT2 were used to assign patients to one of three groups: A, no FUT3 activity regardless of FUT2 activity; B, both FUT2 and FUT3 activity and C, no FUT2 activity without loss of FUT3 activity. Group-specific cut-off values were determined by Youden's index.
The median CA19-9 values of cancer-free patients were significantly different (p < 0.001) in Groups A (2.0 U/mL), B (17.0 U/mL), and C (37.0 U/mL). Biliary malignancy patients in Groups B and C had significantly higher CA19-9 values than cancer-free patients (p < 0.001). The optimal cut-off, as determined by ROC analysis, for all patients was 88.5 U/mL. Optimal cut-off values in Groups A, B, and C were 4.0 U/mL, 74.5 U/mL, and 106.8 U/mL, respectively. Use of these values improved sensitivity of CA19-9 in Groups B and C. Further, use of group-dependent cut-off values with 90% sensitivity resulted in a 42.9% reduction of false positive results.
Use of FUT2/3 genotype-dependent cut-off values for CA19-9 improved sensitivity and reduced the number of false positive results.
Journal of Hepatology 08/2013; · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Long-term use of ursodeoxycholic acid (UDCA) is the recommended therapy in primary biliary cirrhosis (PBC). The lifetime effectiveness and cost-effectiveness of UDCA in PBC have, however, not been assessed.
To estimate the health outcomes and lifetime costs of a Norwegian cohort of PBC patients on UDCA.
Norwegian PBC patients (n = 182) (90% females; mean age 56.3 ± 8.9 years; Mayo risk score 4.38) who were included in a 5-year open-label study of UDCA therapy were subsequently followed up for up to 11.5 years. The lifetime survival was estimated using a Weibull survival model. The survival benefit from UDCA was based on a randomised clinical trial from Canada, comparing the effect of non-UDCA and UDCA. Survival and costs of standard care vs. standard care plus UDCA were simulated in a Markov model with death and liver transplantation as major events, invoking transition of a patient's state in the model.
The gain in life expectancy for a PBC patient on UDCA compared with standard care was 2.24 years (1.19 years discounted). The lifetime treatment costs were EUR 151 403 and EUR 157 741 (EUR 102 912 and EUR 115 031 discounted) for patients with and without UDCA respectively. A probabilistic sensitivity analysis indicated an 82% probability that UDCA entails both greater life expectancy and lower costs than standard care.
The results of this study indicate that UDCA therapy is a dominant strategy as it confers reduced morbidity and mortality, as well as cost savings, compared with standard therapy.
[Show abstract][Hide abstract] ABSTRACT: Liver abnormalities are often seen in bowel diseases. Whether these represent aspects of two separate diseases, or if one is causing the other, is not always easy to decide. Extraintestinal manifestations of inflammatory bowel disease (IBD) or coeliac disease are frequently observed. Of these extraintestinal manifestations, hepatic disorders are among the most common. Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis are the most frequent hepatic disorders in IBD and coeliac disease, respectively. Genetic studies have lately elucidated the associations between IBD and PSC, but there is still a long way until we have complete understanding of the molecular aetiology and pathophysiology of these conditions. There is no curative treatment available for PSC, besides liver transplantation. Steatosis and cholelithiasis are also common in IBD, as are signs of hepatic injury due to IBD treatment. Less common liver abnormalities include liver abscesses, hepatic thromboembolic events, granulomatous liver disease and hepatic amyloidosis.
Best practice & research. Clinical gastroenterology 08/2013; 27(4):531-542. · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE:: The objective of this pilot study was to investigate the potential for long-term overall survival (OS) after liver transplantation for colorectal liver metastases (CLMs). BACKGROUND:: Patients with nonresectable CLMs have poor prognosis, and few survive beyond 5 years. CLMs are currently considered an absolute contraindication for liver transplantation, although liver transplantation for primary and some secondary liver malignancies shows excellent outcome in selected patients. Before 1995, several liver transplantations for CLMs were performed, but outcome was poor (5-year survival rate: 18%) and liver transplantation for CLMs was abandoned. Since then, the survival rate after liver transplantation in general has improved by almost 30%. On the basis of this, a 5-year survival rate of about 50% after liver transplantation for CLMs could be anticipated. METHODS:: In a prospective pilot study, liver transplantation for nonresectable CLMs was performed (n = 21). Main inclusion criteria were liver-only CLMs, excised primary tumors, and at least 6 weeks of chemotherapy. RESULTS:: Kaplan-Meier estimates of the OS rate at 1, 3, and 5 years were 95%, 68%, and 60%, respectively. Metastatic recurrence of disease was common (mainly pulmonary). However, a significant proportion of the recurrences were accessible for surgery, and at follow-up (after median of 27 months; range, 8-60), 33% had no evidence of disease. Hepatic tumor load before liver transplantation, time from primary surgery to liver transplantation, and progressive disease on chemotherapy were identified as significant prognostic factors. CONCLUSIONS:: OS exceeds by far reported outcome for chemotherapy, which is the only treatment option available for this patient group. Furthermore, OS is comparable with liver resection for resectable CLMs and survival after repeat liver transplantation for nonmalignant diseases. Selection strategies based on prognostic factors may further improve the outcome (ClinicalTrials.gov: NCT01311453).
[Show abstract][Hide abstract] ABSTRACT: 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 to 2001 and were followed until 2010. Endpoints 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 endpoint were compared 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 endpoint. Based on ALP levels, there were 79 responders and 116 nonresponders, overall. Of patients given UDCA, significantly more biochemical responders survived for 10 y than non-responders (P =.03, log rank). However, difference 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 y. However, patients who have reduced or normal levels of ALP have longer survival times, regardless of whether they receive UDCA or placebo.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2013; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 development of IBD in patients with PSC who have undergone liver transplantation, risk factors for IBD, and the effects of treatment on 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. Data from 218 patients who had an intact colon and had undergone pre- and post-transplant colonoscopies were further characterized. RESULTS: Macroscopic colonic inflammation was more frequent after than before liver transplantation (153 vs 124 patients; P <.001). The degree of inflammation decreased in 37 patients (17%), was unchanged in 93 (43%), and increased in 88 (40%) (P <.001). The rate of relapse after transplantation was higher than that before transplantation (P <.001); overall clinical IBD activity also increased (P<.001). Young age at diagnosis of IBD and dual treatment with tacrolimus and mycophenolate mofetil (MMF) were significant risk factors for increased IBD activity after transplantation, whereas combination treatment with ciclosporine 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 MMF to ciclosporine A and azathioprine should be considered for these patients.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2013; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cholangiocarcinoma is notoriously difficult to diagnose, and the mortality rate is high due to late clinical presentation. CpG island promoter methylation is frequently seen in cancer development. In the present study, we aimed at identifying novel epigenetic biomarkers with the potential to improve the diagnostic accuracy of cholangiocarcinoma. Microarray data analyses of cholangiocarcinoma cell lines treated with epigenetic drugs and their untreated counterparts were compared with previously published gene expression profiles of primary tumors and with non-malignant controls. Genes responding to the epigenetic treatment that were simultaneously downregulated in primary cholangiocarcinoma compared with controls (n = 43) were investigated for their promoter methylation status in cancer cell lines from the gastrointestinal tract. Genes commonly methylated in cholangiocarcinoma cell lines were subjected to quantitative methylation-specific polymerase chain reaction in a total of 93 clinical samples (cholangiocarcinomas and non-malignant controls). CDO1, DCLK1, SFRP1 and ZSCAN18, displayed high methylation frequencies in primary tumors and were unmethylated in controls. At least one of these four biomarkers was positive in 87% of the tumor samples, with a specificity of 100%. In conclusion, the novel methylation-based biomarker panel showed high sensitivity and specificity for cholangiocarcinoma. The potential of these markers in early diagnosis of this cancer type should be further explored.
Epigenetics: official journal of the DNA Methylation Society 09/2012; 7(11). · 4.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Approximately 60-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the purpose of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases and 2,977 controls and followed up top association signals in additional 1,012 PSC cases, 4,444 UC cases and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at GPR35; P=3.0×10(-9) in the overall study population, combined odds ratio (OR; 95% confidence interval (CI)) of 1.39 (1.24-1.55)], and at 18q21 [rs1452787 at TCF4; P=2.61×10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, while TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (HEPATOLOGY 2012.).
[Show abstract][Hide abstract] ABSTRACT: 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.
In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis.
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.
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.
Scandinavian Journal of Gastroenterology 05/2012; 8-9(47):1021-9. · 2.33 Impact Factor