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Background & Aims: Primary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life expectancy and impaired quality of life is ill-described. The aim of this study was to assess long-term disease burden in a large population-based registry with regard to survival, clinical course, quality adjusted life years (QALYs), medical consumption and work productivity loss., Methods: All PSC patients living in a geographically defined area covering ~50% of the Netherlands were included, together with patients from the three liver transplant centres. Survival was estimated by competing risk analysis. Proportional shortfall of QALYs during disease course was measured relative to a matched reference cohort using validated questionnaires. Work productivity loss and medical consumption were evaluated over time., Results: A total of 1208 patients were included with a median follow-up of 11.2 year. Median liver transplant-free survival was 21.0 years. Proportional shortfall of QALYs increased to 48% >25 years after diagnosis. Patients had on average 12.4 hospital contact days among which 3.17 admission days per year, annual medical costs were €12 169 and mean work productivity loss was 25%., Conclusions: Our data quantify for the first time disease burden in terms of QALYs lost, clinical events, medical consumption, costs as well as work productivity loss, and show that all these are substantial and increase over time., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: The Netherlands has a low hepatitis C virus (HCV) prevalence, estimated at 0.16%. Previous studies have shown that up to 30% of the diagnosed HCV population in the Netherlands has been lost to follow-up (LTFU). Retrieval of these patients could halt progression of liver disease in infected patients, reduce the number of infected individuals and limit HCV transmission. Several regional Dutch retrieval projects have already been executed, which demonstrated that retrieval is feasible. Therefore, we initiated a nationwide retrieval project, aiming to achieve microelimination in previously diagnosed but LTFU patients with chronic HCV through retrieval., Methods: Laboratory records will be used to identify possible patients with chronic hepatitis C, defined as either a positive most recent HCV RNA or positive HCV antibodies without known RNA result. Reviewing patient records and obtaining current contact information from municipality databases will identify LTFU patients who are eligible for retrieval. These patients will be invited for outpatient clinic care. The primary outcome of the study is the total number of LTFU patients who have been successfully linked to care., Discussion: Hepatitis C ELimination In the NEtherlands (CELINE) is within the remit of WHO elimination targets and the Dutch National Hepatitis Plan. The methodology of CELINE is based on previously conducted regional retrieval projects and is designed to overcome some of their limitations. After ethical approval was obtained in 2018, the first centre initiated retrieval in 2018 and the project is expected to finish in 2021., Trial Registration Number: NCT04208035., Competing Interests: Competing interests: CJI, SMB and MvD have no conflicts of interest. MvdV declares that the Amsterdam Infection & Immunity Institute Amsterdam UMC, on behalf of MvdV, received fees for participation in advisory boards of Abbvie, Gilead, Johnson & Johnson, Merck Sharp & Dohme (MSD), and ViiV and received independent research grants from Abbvie, Johnson & Johnson, Gilead, and MSD. RJdK declares that the Erasmus University Medical Centre, on behalf of RJdK, received honoraria for consulting/speaking from Gilead, Janssen-Cilag, Bristol-Myers Squibb (BMS), Abbvie, MSD, Roche, and Norgine and received research grants from Gilead, Janssen-Cilag, BMS, and Roche. JEA declares that the University Medical Centre Utrecht, on behalf of JEA, received honoraria for participation in advisory boards of Gilead, Janssen-Cilag, BMS, Abbvie, MSD, and ViiV and received research grants from BMS, Abbvie, and ViiV. JPHD declares that the Radboudumc, on behalf of JPHD, received honoraria or research grants from Novartis, Ipsen, Otsuka, Abbvie, and Gilead. JPHD served as consultant for Gilead and Abbvie, and in the last two years has been member of advisory boards of Otsuka, Norgine Gilead, BMS, Janssen, and Abbvie. JS participated in advisory boards of Gilead and received research grants from Gilead and Abbvie. SW has received honoraria for consulting/speaking from Gilead, Janssen-Cilag, BMS, and Roche, participated in advisory boards of Gilead, BMS, and Abbvie and received research grants from Gilead, Janssen-Cilag BMS, Abbvie, MSD, and Roche. BvH participated in advisory boards of Janssen-Cilag, BMS, Abbvie, MSD, and Norgine and received a research grant from Zambon Pharma. DP has no conflicts of interest to declare. DB has received honoraria for consulting/speaking from MSD, participated in advisory boards of MSD and received research grants from Gilead, Janssen-Cilag, BMS, MSD, and Roche. HB has participated in advisory boards of Gilead. KvE participated in advisory boards of Gilead, Janssen-Cilag, BMS, Abbvie, and MSD and received research grants from Gilead and Janssen-Cilag., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: In low-endemic countries it is debated whether first-generation migrants should be screened for chronic hepatitis B infection. We describe the clinical impact of five large-scale Dutch screening projects for hepatitis B in first-generation Chinese migrants., Methods: Between 2009 and 2013 five independent outreach screening projects for hepatitis B targeting first-generation Chinese migrants were conducted in five main Dutch regions. To explore the relevance of our screening we defined clinical impact as the presence of an indication for: (i) antiviral therapy, (ii) strict follow-up because of high hepatitis B DNA levels and/or (iii) surveillance for hepatocellular carcinoma., Results: In total, 4423 persons participated in the projects of whom 6.0% (n = 264) were HBsAg positive. One hundred and twenty-nine newly diagnosed HBsAg-positive patients were analysed in specialist care. Among these patients prevalence of cirrhosis was 6.9% and antiviral therapy for hepatitis B was started in 32 patients (25%). In patients without a treatment indication, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma was considered indicated in 64 patients (50%)., Conclusions: In our screening project in first-generation Chinese migrants, antiviral treatment, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma were considered indicated in three of four analysed HBsAg-positive patients. These data show that detection of hepatitis B in Chinese migrants can have considerable impact on patient care., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Immunosuppressive therapy may impact cancer risk in inflammatory bowel disease (IBD). Cancer specific data regarding risk and outcome are scarce and data for renal cell carcinoma (RCC) are lacking. We aimed(1) to identify risk factors for RCC development in IBD patients (2) to compare RCC characteristics, outcome and survival between IBD patients and the general population., Methods: A PALGA (Dutch Pathology Registry) search was performed to establish a case group consisting of all IBD patients with incident RCC in The Netherlands (1991-2013). Cases were compared with two separate control groups: (A) with a population-based IBD cohort for identification of risk factors (B) with a RCC cohort from the general population to compare RCC characteristics and outcomes., Results: 180 IBD patients with RCC were identified. Pancolitis (OR 1.8-2.5), penetrating Crohn's disease (OR 2.8), IBD related surgery (OR 3.7-4.5), male gender (OR 3.2-5.0) and older age at IBD onset (OR 1.0-1.1) were identified as independent risk factors for RCC development. IBD patients had a significantly lower age at RCC diagnosis (p < 0.001), lower N-stage (p = 0.025), lower M-stage (p = 0.020) and underwent more frequently surgical treatment for RCC (p < 0.001) compared to the general population. This translated into a better survival (p = 0.026; HR 0.7) independent of immunosuppression., Conclusions: IBD patients with a complex phenotype are at increased risk to develop RCC. They are diagnosed with RCC at a younger age and at an earlier disease stage compared to the general population. This translates into a better survival independent of immunosuppressive or anti-TNFα therapy.

Background: Aspiration sclerotherapy is an effective therapeutic option for large symptomatic hepatic cysts. However, incomplete cyst reduction following aspiration sclerotherapy is frequently reported. Strong post-procedural cyst fluid secretion by cholangiocytes, which line the epithelium of the hepatic cyst, seems to be associated with lower reduction rates. Previous studies showed that somatostatin analogues curtail hepatic cyst fluid production. This trial will evaluate the effect of aspiration sclerotherapy combined with the somatostatin analogue pasireotide on cyst reduction. By combining treatment modalities we aim to improve cyst reduction leading to greater symptomatic relief and reduced rates of cyst recurrence., Methods/design: This single center, randomized, double-blind, placebo-controlled clinical trial evaluates the additional effect of pasireotide when combined with aspiration sclerotherapy in patients with a large (>5 cm) symptomatic hepatic cyst. A total of 34 participants will be randomized in a 1:1 ratio. In the active arm, patients will receive pasireotide (long-acting release, 60 mg injection) two weeks prior to and two weeks following aspiration sclerotherapy. Patients in the control arm will receive placebo injections at corresponding intervals. The primary outcome is proportional cyst diameter reduction four weeks after aspiration sclerotherapy compared to baseline measurements, obtained by ultrasonography. As secondary outcomes, proportional volume reduction, recurrence, symptomatic relief and improvement of health-related quality of life will be assessed. Furthermore, safety and tolerability of the combination of pasireotide and aspiration sclerotherapy will be evaluated., Discussion: This trial aims to improve efficacy of aspiration sclerotherapy by a combined approach of two treatment modalities. We hypothesize that pasireotide will decrease fluid re-accumulation after aspiration sclerotherapy, leading to effective hepatic cyst reduction and symptomatic relief., Trials Registration: This trial is registered with ClinicalTrials.gov (identifier: NCT02048319 ; registered on 6 January 2014) and EudraCT (identifier: 2013-003168-29; registered on 16 August 2013).

Background: Chronic pancreatitis is a complex disease with many unanswered questions regarding the natural history and therapy. Prospective longitudinal studies with long-term follow-up are warranted., Methods: The Dutch Chronic Pancreatitis Registry (CARE) is a nationwide registry aimed at prospective evaluation and follow-up of patients with chronic pancreatitis. All patients with (suspected) chronic or recurrent pancreatitis are eligible for CARE. Patients are followed-up by yearly questionnaires and review of medical records. Study outcomes are pain, disease complications, quality of life, and pancreatic function. The target sample size was set at 500 for the first year and 1000 patients within 3 years., Results: A total of 1218 patients were included from February 2010 until June 2013 by 76 participating surgeons and gastroenterologist from 33 hospitals. Participation rate was 90% of eligible patients. Eight academic centers included 761 (62%) patients, while 25 community hospitals included 457 (38%). Patient centered outcomes were assessed by yearly questionnaires, which had a response rate of 85 and 82% for year 1 and 2, respectively. The median age of patients was 58 years, 814 (67%) were male, and 38% had symptoms for less than 5 years., Discussion: The CARE registry has successfully recruited over 1200 patients with chronic and recurrent pancreatitis in about 3 years. The defined inclusion criteria ensure patients are included at an early disease stage. Participation and compliance rates are high. CARE offers a unique opportunity with sufficient power to investigate many clinical questions regarding natural course, complications, and efficacy and timing of treatment strategies., (Copyright © 2014 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Myosin IXb (MYO9B) is involved in the regulation of epithelial barrier function. We hypothesized that MYO9B variants are associated with increased intestinal permeability measured in patients with Crohn's disease (CD), where barrier dysfunction is crucially involved in disease development., Methods: We sequenced MYO9B and genotyped five MYO9B variants (rs1545620, rs1457092, rs2279003, rs2305764 and rs2279002) and correlated these data to measurement of intestinal permeability in German CD patients (n = 122) obtained by standard oral sugar test using the lactulose/mannitol ratio after measurement of urinary excretion. We furthermore studied MYO9B variants in three European cohorts with inflammatory bowel disease (IBD) and healthy controls : Germany (CD = 264; ulcerative colitis = 143 [UC]; HC = 372); Hungary (CD = 147; UC = 117; HC = 195), the Netherlands (CD = 157; HC = 219)., Results: We found an association for four studied MYO9B variants to an increased intestinal permeability in CD patients (rs1545620, p = 0.010; rs1457092, p = 0.024; rs2279003, p = 0.003; rs2305764, p = 0.015). Furthermore, we observed significantly higher absolute values of intestinal permeability for individuals carrying risk alleles within MYO9B. Looking for an overall disease association, only the rs2305764 variant was associated with CD in the Dutch cohort (p = 0.004), but not in the German or Hungarian cohort. No association to UC or a distinct phenotype in both CD and UC patients was observed for all studied MYO9B variants., Conclusion: Our data suggest a link between MYO9B variants to an increased intestinal permeability in CD patients. This supports the influence of Myosin IXb on the integrity of the epithelial barrier. The role of MYO9B variants in the overall susceptibility to IBD, however, remains to be elucidated.

Background and Aims: Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants)., Methods: Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire., Results: The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3-19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5-2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1-44 years). Familial occurrence was reported in three cases., Conclusion: This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH.

Objective: According to screening studies, celiac disease (CD) is prevalent in Western Europe. Actual prevalence tends to be much lower. The width of this actual gap is determined by the balance between disease symptoms and the "case-finding" capabilities of the healthcare system. Therefore, we conducted a nationwide study to determine the temporal trends in the incidence in the Netherlands including a focus on demographic aspects., Materials and Methods: We performed a nationwide search in the Dutch Pathology Registry (PALGA) to identify all biopsy-proven cases of CD in five different years between 1995 and 2010. Furthermore, demographic profiles and socioeconomic status (SES) of patients were studied., Results: The overall incidence of CD increased from 2.72 (confidence interval [CI] 2.46-2.99) in 1995 to 6.65 (CI 6.27-7.06) per 100,000 inhabitants in 2010. No significant regional differences were noticed. In men, rates increased from 2.28 (CI 1.95-2.65) to 4.71 (CI 4.25-5.20) per 100,000 in 2010. In women, the increase was from 3.27 (CI 2.88-3.70) to 8.66 (CI 8.04-9.31) per 100,000 in 2010. A trend toward leveling of incidence was observed from 2008 to 2010. Patients diagnosed during childhood live in areas with a higher SES compared with patients diagnosed at adult age., Conclusion: The incidence of biopsy-proven CD in the Netherlands increased almost threefold between 1995 and 2010. In areas with a higher SES, relatively more children were diagnosed.

Background & Aims: Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH., Methods: We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region., Results: We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits., Conclusions: In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Although restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) substantially reduces the risk of colorectal cancer in patients with inflammatory bowel disease (IBD), subsequent pouch neoplasia can develop. There are few data on the incidence of and risk factors for neoplasia, so there is no consensus on the need for pouch surveillance. We aimed to determine the cumulative incidence of pouch neoplasia in patients with IBD and identify risk factors for developing pouch neoplasia., Methods: We searched the Dutch Pathology Registry (PALGA) to identify all patients with IBD and IPAA in The Netherlands from January 1991 to May 2012. We calculated the cumulative incidence of pouch neoplasia and performed a case-control study to identify risk factors. Demographic and clinical variables were analyzed with univariable and multivariable Cox regression analyses., Results: We identified 1200 patients with IBD and IPAA; 25 (1.83%) developed pouch neoplasia, including 16 adenocarcinomas. Respective cumulative incidences at 5, 10, 15, and 20 years were 1.0%, 2.0%, 3.7%, and 6.9% for pouch neoplasia and 0.6%, 1.4%, 2.1%, and 3.3% for pouch carcinoma. A history of colorectal neoplasia was the only risk factor associated with pouch neoplasia. Hazard ratios were 3.76 (95% confidence interval, 1.39-10.19) for prior dysplasia and 24.69 (95% confidence interval, 9.61-63.42) for prior carcinoma., Conclusions: The incidence of pouch neoplasia in patients with IBD without a history of colorectal neoplasia is relatively low. Prior dysplasia or colon cancer is associated with an approximate 4- and 25-fold increase in risk, respectively, of developing pouch neoplasia., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Extensive population-based studies are much needed to accurately establish epidemiology and disease course in patients with primary sclerosing cholangitis (PSC). We aimed to obtain population-based prevalence and incidence figures, insight in disease course with regard to survival, liver transplantation (LT), and occurrence of malignancies, as well as risk factors thereof. Four independent hospital databases were searched in 44 hospitals in a large geographically defined area of the Netherlands, comprising 50% of the population. In addition, all PSC patients in the three Dutch liver transplant centers and all inflammatory bowel disease (IBD) patients in the adherence area of a large district hospital were identified. All medical records were reviewed on-site, verifying diagnosis. Five hundred and ninety PSC patients were identified, resulting in an incidence of 0.5 and a point prevalence of 6.0 per 100,000. Median follow up was 92 months. Estimated median survival from diagnosis until LT or PSC-related death in the entire cohort was 21.3 years, as opposed to 13.2 years in the combined transplant centers cohort (n = 422; P < 0.0001). Colorectal carcinoma (CRC) risk was 10-fold increased, as compared to ulcerative colitis controls, and developed at a much younger age (39 years; range, 26-64), compared to IBD controls (59 years; range, 34-73; P = 0.019). Colonoscopic surveillance was associated with significantly better outcome., Conclusion: This study exemplifies that, for relatively rare diseases, it is paramount to collect observational data from large, population-based cohorts, because incidence and prevalence rates of PSC are markedly lower and survival much longer than previously reported. The selection of a bias-free, population-based cohort showed a significantly longer survival, compared to the tertiary referral cohort. CRC can develop at an early age, warranting surveillance from time of PSC diagnosis., (© 2013 by the American Association for the Study of Liver Diseases.)

Esophageal cancer (EC), mainly consisting of squamous cell carcinoma (ESCC) in the Eastern world and adenocarcinoma (EAC) in the Western world, is strongly associated with dietary factors such as alcohol use. We aimed to clarify the modifying role in EC etiology in Caucasians of functional genotypes in alcohol-metabolizing enzymes. In all, 351 Caucasian patients with EC and 430 matched controls were included and polymorphisms in CYP2E1, ADH and near ALDH2 genes were determined. In contrast to the results on ESCC in mainly Asian studies, we found that functional genotypes of alcohol-metabolizing enzymes were not significantly associated with EAC or ESCC in an European population.

Susceptibility to esophageal carcinoma (EC) is influenced by the interaction between genetic and environmental factors. To clarify the etiology of EC, several genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in PCLE1 and RFT2 genes as esophageal squamous cell carcinoma (ESCC) susceptibility loci in Asian populations. This study aimed to determine whether these SNPs also modify the risk of esophageal adenocarcinoma (EAC) and ESCC in western populations of Caucasian ethnicity. A European case-control study including 349 EC patients and 580 controls matched for age, sex, geographical location, and race was carried out. The SNPs rs2274223 in the PCLE1 gene at chromosome 10q23 and rs13042395 in the RFT2 gene at chromosome 20p13 were determined using PCR. Genotype distributions were compared between patients and controls, and odds ratios with 95% confidence intervals were calculated. The total EC group included 86 patients with ESCC and 258 patients with EAC. The distribution of PLCE1 and RFT2 genotypes did not differ between patients with EAC or ESSC, and the controls. In contrast to the modulation of the risk of ESCC in Asians, it is unlikely that the PLCE1 rs2274223 and RFT2 13042395 SNPs play a role in EAC or ESCC susceptibility in Dutch Caucasians.

Background & Aims: Single nucleotide polymorphisms (SNP) in the Cytotoxic T lymphocyte antigen-4 gene (CTLA-4) have been associated with several autoimmune diseases including autoimmune Hepatitis (AIH). In this chronic idiopathic inflammatory liver disease, conflicting results have been reported on the association with a SNP at position +49 in the CTLA-4 gene in small patient cohorts. Here, we established the role of this SNP in a sufficiently large cohort of AIH patients., Methods: The study population consisted of 672 AIH patients derived from academic and regional hospitals in the Netherlands and was compared with 500 controls selected from the 'Genome of the Netherlands' project cohort. Genotype frequencies were assessed by PCR for patients and by whole genome sequencing for controls., Results: No significant differences in allele frequencies were found between patients and controls (G Allele: 40% vs 39%, P = 0.7). Similarly, no significant differences in genotype frequencies between patients and controls were found. Finally, there was no relation between disease activity and the G allele or AG and GG genotypes., Conclusion: The Cytotoxic T Lymphocyte Antigen-4 +49 A/G polymorphism does not represent a major susceptibility risk allele for AIH in Caucasians and is not associated with disease severity at presentation., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Identifying and monitoring high-risk patients can aid the prevention of esophageal cancer (EC). The interaction of environmental risk factor exposure and genetic susceptibility may contribute to the etiology of EC. Biotransformation enzymes such as Glutathione S-Transferases (GSTs ) detoxify mutagenic and genotoxic compounds and therefore control the rate of detoxification of carcinogens. Functional polymorphisms in the genes coding for GSTs alter their enzyme activity in vitro, and were reported to modify EC risk in Asians. We hypothesized that altered enzyme activity GST genotypes influence the susceptibility for esophageal adeno- (EAC) and squamous cell carcinoma (ESCC) in Caucasians., Methods: We performed a case-control study including 440 Caucasian patients with EC and 592 healthy Caucasian controls matched for age and sex. Functional polymorphisms were selected and genotypes were determined in GST classes Alpha, Mu, Theta and Pi by means of polymerase chain reaction. Genotypes were classified into predicted high, intermediate and low enzyme activity categories based on in vitro activity data. The distribution of the activity genotypes were compared between patients with EAC or ESCC, and controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated by logistic regression analyses. Gene-gene interactions were tested and for comparison purposes, the predicted low and intermediate activity genotypes were combined. Genotypes with similar risks for EAC or ESCC were combined and analyzed for multiplicative effects., Results: Our analyses includes 327 patients with EAC and 106 patients with ESCC. Low or intermediate activity enzyme genotypes for GSTM1, GSTA1, GSTP1 I105V and A114V as well as for GSTT1, did not significantly modify the risk for ESCC or EAC in our Dutch population., Conclusion: Functional genotypes in GST genes are not involved in EAC or ESCC susceptibility in Caucasians, in contrast to results on ESCC from Asia or Africa.

The frequency of certain medical procedures and their results vary strongly between countries, and also between regions within one country. These variations in clinical practice mean the quality of healthcare is suboptimal, result in unnecessary expense and patients are at risk of complications caused by unnecessary interventions. Patient Reported Outcome Measures (PROMs) are an instrument to clarify if a patient has benefited from a certain treatment. Systematic measurement of PROMs is necessary to show relevant differences in the effect of a therapy. If data of differences in results are combined with those of regional variations in clinical practice, it will become clear where too much or too less is treated. We expect that the systematic measurement of PROMs will make a valuable contribution to improving the quality of Dutch healthcare.

Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Crucial risk factors are exposure to toxins or carcinogens. Microsomal epoxide hydrolase (mEH) is a biotransformation enzyme essential for the detoxification of xenobiotics. Polymorphisms in exon 3 and exon 4 of the microsomal epoxide hydrolase gene (EPHX1) modify catalytic activity of this enzyme and subsequently may play a role in EC etiology. This case-control study investigated whether these polymorphisms in the EPHX1 gene influence esophageal cancer susceptibility in a Dutch Caucasian population. A case-control study including 349 Caucasian EC patients and 581 Caucasian healthy controls was conducted and the polymorphisms Tyr113His (exon 3) and His139Arg (exon 4) in the EPHX1 gene were determined, using polymerase chain reaction. The distribution of exon 3 and exon 4 genotypes were compared between cases and controls. Analyses included a stratification according to tumor histology; esophageal adenocarcinoma (EAC) or squamous cell carcinoma (ESCC). Furthermore, on the basis of allelic in vitro enzyme activity assays, exon 3 and 4 genotypes were combined and categorized according to their predicted high, medium or low enzyme activity. Homozygosity and heterozygosity for both exon 3 and 4 polymorphisms were correlated with a decreased esophageal squamous cell carcinoma risk. Heterozygosity and homozygosity for both polymorphisms correlated with an increased and a decreased esophageal adenocarcinoma risk, respectively. Predicted intermediate and high activity genotypes were risk and protective factors for esophageal squamous cell carcinoma and esophageal adenocarcinoma, respectively. However, none of these associations were statistically significant. In conclusion, the polymorphisms in exon 3 and exon 4 of the EPHX1 gene do not seem to be modifiers of esophageal squamous cell carcinoma or esophageal adenocarcinoma risk in Dutch Caucasians.

Background: Pain is the major symptom of chronic pancreatitis. The role of genetics in pancreatic pain is unclear. Catechol-O-methyltransferase (COMT) regulates enkephalin levels and influences pain perception. The COMT gene contains functional polymorphisms that have been found to influence human pain perception. The aim of our study was to investigate COMT single-nucleotide polymorphisms (SNP s) and diplotypes in chronic pancreatitis patients and healthy controls., Methods: We genotyped four COMT gene SNP s: c.1-98A>G (rs6269), c.186C>T (p.=) (rs4633), c.408C>G (p.=) (rs4818) and c.472G>A (p.Val158Met) (rs4680) using a dual-colour discrimination assay in 240 chronic pancreatitis patients and 445 controls. We generated five diplotypes with a frequency >0.5% and compared prevalence between patients and controls., Results: There was no significant association between the SNPs in the COMT gene and chronic pancreatitis. The diplotype ATCA÷ACCG was more prevalent in controls compared with patients (OR 0.48, 95% CI 0.24 to 0.93, p=0.03) where the most common diplotype GCGG ÷ATCA served as reference. However, after correction for multiple testing, this is not a significant difference. The distribution of other diplotypes was not significantly different between patients and controls., Conclusion: COMT SNP s and diplotypes are not associated with chronic pancreatitis. As a consequence, our results do not support a significant role for the COMT gene in chronic pancreatitis.

Background and Aim: Isolated polycystic liver disease (PCLD) is characterized by the presence of multiple cysts in the liver in the absence of polycystic kidneys. The clinical profile of PCLD is poorly defined and we set up a study for the clinical characteristics of PCLD., Methods: We collected clinical data on 188 PCLD patients (defined as >10 liver cysts) from five tertiary referral centres, and 137 patients were selected for the purpose of this study. We performed molecular analysis of the PCLD associated genes PRKCSH and SEC63 in 91 patients., Results: A total of 118 (86%) patients were female. The majority of patients (88%) had >20 cysts. The median age at diagnosis was 47 years (range 23-84). 37 (41%) patients carried a mutation. Clinical symptoms at presentation were present in 111 (84%) patients. γ-glutamyl transferase was elevated to 1.4 times upper limit of normal (interquartile range 1.0-2.7). The presence of a mutation and female gender predicted a more severe course: female patients were 9 years younger at the time of diagnosis (47 years; range 23-84) and 91% had symptoms (P<0.01); likewise, mutation carriers were younger at presentation (39 years; range 35-48) and 95% of this cohort had symptoms (P<0.01). During follow-up [median 8.2 years (range 0-35)], 10% of untreated and 51% of treated patients developed complications. Mortality in this cohort was 8%, but only 2% died of PCLD-related causes. 58% of patients were treated a median of 2 years (range 0-25) after diagnosis., Conclusion: Symptomatic PCLD patients are mainly females. Females and mutation carriers were younger at diagnosis and had a more severe course of disease., (© 2010 John Wiley & Sons A/S.)

Background: The reported incidence of hepatocellular carcinoma (HCC) among patients with primary biliary cirrhosis (PBC) varies from 0.7-3.8%, whereas in cirrhotic patients the risk is considerably higher. Age, male sex, cirrhosis, and portal hypertension are reported risk factors. It has been suggested that ursodeoxycholic acid (UDCA) may protect against HCC. We aimed to define risk factors for the development of HCC at the time of PBC diagnosis and to identify, among patients treated with UDCA for a long term, a subgroup that could benefit from screening., Methods: Prospective multicenter cohort study of patients with established PBC treated with 13-15 mg/kg/day UDCA. Age, sex, antimitochondrial antibodies, bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, aspartate amino transferase, cirrhosis, portal hypertension, Mayo Risk Score, prognostic class (based on bilirubin and albumin levels), and response to UDCA (normalization of bilirubin and/or albumin levels) were analyzed as potential risk factors in Cox regression analysis., Results: Three hundred and seventy-five patients were included, median follow-up was 9.7 years. HCC occurred in nine patients, corresponding with an annual incidence of 0.2%. The factor significantly associated with the development of HCC was the response to UDCA (P<0.001). The risk for HCC was highest in the group of nonresponders to UDCA: the 10 years incidence of HCC was 9% and the 15 years incidence was 20%. The number needed to screen in this subgroup was 11., Conclusion: In UDCA treated PBC patients the risk of HCC is relatively low. The main risk factor for HCC in this study was the absence of biochemical response to UDCA after 1-year treatment.

Objectives: Premature activation of pancreatic digestive enzymes is considered as a major factor in the pathogenesis of pancreatitis. Genetic alterations of different pancreatic zymogens or their inhibitors have been associated with chronic pancreatitis (CP)., Methods: We sequenced all 12 GP2 exons in 380 German CP patients and in 182 German control subjects. In addition, we analyzed exon 3 of GP2 in 803 further CP patients and 1780 controls originating from Germany, the Netherlands, and India by targeted DNA sequencing., Results: We detected 12 nonsynonymous and 6 synonymous exonic variants. All nonsynonymous changes with exception of c.220C>T (p.R74X) and c.502&#95;503delG (p.G168fsX174) in exon 3 and c.541C>T (p.R181X) in exon 4 were missense mutations and predominantly located in exon 3. All nonsynonymous variants were found in single cases only, with exception of 2 alterations, c.355A>G (p.M119V) and c.409G>A (p. A137T), both located in exon 3. To elucidate the role of these 2 exon 3 variants, we investigated additional patients and controls. The frequency of these variants was similar between patients and controls regardless of ethnic background or cause of CP., Conclusions: Our data suggest that GP2 alterations do not alter the risk for the development of CP.

Background: The major clinical feature in chronic pancreatitis is pain, but the genetic basis of pancreatic pain in chronic pancreatitis is poorly understood. The transient receptor potential vanilloid receptor 1 (TRPV1) gene has been associated with pain perception, and genetic variations in TRPV1 may modify the presence and phenotype of chronic pancreatitis. The aim of our study was to investigate the genetic variation of TRPV1 in Dutch patients with chronic pancreatitis and healthy controls., Methods: We genotyped 4 SNPs (rs222749, rs222747, rs224534 and rs8065080) in 228 chronic pancreatitis-patients and 207 healthy controls by PCR, followed by restriction-fragment-length-polymorphism analysis and DNA sequencing. We generated 27 diplotypes and compared prevalence between patients and controls., Results: There was no significant difference in allele frequency of the 4 TRPV1 gene SNPs in patients with chronic pancreatitis and healthy controls. Distribution of diplotypes was not statistically significantly different between patients and controls., Conclusion: TRPV1 diplotypes are not associated with chronic pancreatitis.

Objectives: Chronic pancreatitis (CP) and pancreatic adenocarcinoma (pCA) are associated with risk factors such as alcohol intake and tobacco smoking. Microsomal epoxide hydrolase (EPHX1) is a phase II detoxifying enzyme capable of tobacco-borne toxicant inactivation. We studied the role of the EPHX1 c.337T>C (p.Y113H) variant, whichleads to altered enzyme activity, in pancreatic diseases., Methods: We genotyped 2391 patients by melting curve analysis. We enrolled 367 patients with pCA, 341 patients with alcoholic CP (aCP), 431 patients with idiopathic CP or hereditary pancreatitis, 192 patients with acute pancreatitis, and 679 controls of German descent. We replicated data in 77 patients with aCP and 304 controls from The Netherlands., Results: In German patients with aCP, Y113 was more common than in controls (allele frequencies, 0.73 vs 0.68; risk ratio, 1.21 [95% confidence interval, 1.05-1.39]). However, we could not confirm this association in the Dutch population (allele frequencies, 0.62 vs 0.68, P=not significant). In total, Y113 frequency was 0.71 in aCP and 0.68 in controls (P = not significant). Allele frequencies did not differ in the other disease groups (acute pancreatitis, 0.69; idiopathic CP or hereditary pancreatitis, 0.68; pCA, 0.68; and control, 0.68)., Conclusions: The EPHX1 Y113H variant is not associated with pancreatic diseases indicating that EPHX1 does not play a significant role in the initiation of pancreatic inflammation or cancer.

Background: Recently, the Dutch Association of Gastroenterology and Hepatology issued new guidelines for the treatment of chronic hepatitis C virus (HCV). These guidelines reflect the current standard of care. Before these guidelines were published and implemented we (1) studied the current clinical care of HCV patients among Dutch physicians, and (2) identified areas for future refinement in the current treatment., Methods: We conducted a non-targeted survey among Dutch medical specialists in Gastroenterology, Hepatology and Internal Medicine who actively treat HCV patients. The questionnaire contained items about facility, duration and dosing of treatment, and side effect management using clinical vignettes followed by short questions., Results: We received 49 questionnaires from treating HCV specialists. The majority (65%) of respondents treat HCV patients during regular outpatient clinics, while 35% treat these patients in a separate setting dedicated to the care of HCV patients. The majority of physicians follow the stipulated dosage regimens of pegylated interferon (88%) and ribavirin (83%). A minority (13%) exceed the advised dosage of ribavirin. Side effects such as neutropenia are mostly managed by decreasing the interferon dosage (42%). Some 35% of physicians reduce ribavirin if haemoglobin levels drop below 5.4 mmol/l, and 41% initiate erythropoietin treatment., Conclusion: Dutch clinical practice reflects the recently issued HCV guidelines. An important area of refinement in treatment of HCV is the management of side effects.

Objective: To assess genetic, clinical and morphological characteristics of hereditary pancreatitis, a rare type of chronic pancreatitis with an early onset of symptoms, which is, among others, caused by mutations in the PRSS1 gene., Design: Observational cohort study., Method: The study population consisted of 496 patients (27,375 person-years) who were referred to Radboud University Nijmegen Medical Centre for molecular diagnosis of hereditary pancreatitis during period 2000 to 2007. 61 patients with a positive family history of hereditary pancreatitis were selected. Analysis for PRSS1 gene mutations was performed by complete sequence analysis of the exons. All patients received a structured questionnaire., Results: From 25 families 61 patients were included (2,047 person-years). PRSS1 mutations were detected in 52 patients (85.2%): p.R122H (67.2%), p.N29I (14.8%), p.E79K (1.6%), p.N29T (1.6%). In the 40 patients whose clinical data were known the median age at diagnosis was 10.5 years (range: 0-42 years). Pain was reported in 28 (70% of 40 patients in whom all information was complete). 27 patients (67.5%) were admitted to the hospital once or more due to the attacks of pancreatitis. Exocrine and endocrine dysfunction was seen in 6 patients (15%). 24 patients (60%) had undergone a surgical intervention, 10 of whom had undergone a pancreaticojejunostomy. A family history of pancreatic carcinoma was found in 5 patients (12.5%)., Conclusion: The percentage of PRSS1 mutation was high (85.2%) among this Dutch population that was selected on basis of a positive family history of hereditary pancreatitis. Most patients had no chronic pain.

The main options for secondary prevention of gastrooesophageal variceal bleeding are endoscopic therapy and treatment with propranolol. Creation ofa transjugular intrahepatic portosystemic shunt (TIPS) is currently considered a valuable secondary 'rescue' treatment when other therapies fail. Recent data suggest that the use of covered stents markedly increases the efficacy of TIPS, compared with conventional uncovered stents. Therefore, a multicentre randomised trial was designed to compare the effects of TIPS using covered stents with those of endoscopic therapy plus propranolol in patients with a first or second episode ofgastro-oesophageal variceal bleeding. TIPS will be performed in 4 university centres with relevant expertise. The trial will hopefully gain nationwide support, and all centres in The Netherlands are cordially invited to participate.

Objectives: To elucidate the rate of missense mutations in the SCN9A gene (which encodes sodium channel Na(v)1.7) (OMIM 603415) among patients with primary erythermalgia and to examine the possibility that other sodium channels can cause the disease., Design: Case series., Setting: Department of Medicine, Radboud University Nijmegen, the Netherlands., Participants: Six patients with sporadic and 9 with unique familial primary erythermalgia. Interventions Questionnaire to determine clinical profile and sequencing of all coding exons from SCN9A and those of SCN10A (OMIM 604427) and SCN11A (OMIM 604385) in 2 selected cases with a clear family history of the disease., Main Outcome Measures: Detection of SCN9A mutation., Results: We identified 1 patient with an SCN9A mutation. This mutation (I848T) has been associated with primary erythermalgia. Sequencing of 2 other candidate genes did not show mutations in 2 patients with familial primary erythermalgia., Conclusions: The Na(v)1.7 voltage-gated sodium channels are related to syndromes of altered nociception. We detected a low SCN9A mutation rate in patients with primary erythermalgia, suggesting that pain syndromes in the skin may have a polygenic basis.

Background: A recent study reported that the c.30T>A (p.Cys10Ter; rs2043211) variant, in the CARD8 (TUCAN) gene, is associated with Crohn's disease (CD). The aim of this study was to analyze the frequency of p.C10X in 3 independent European (IBD) cohorts from Germany, Hungary, and the Netherlands., Methods: We included a European IBD cohort of 921 patients and compared the p.C10X genotype frequency to 832 healthy controls. The 3 study populations analyzed were: (1) Germany [CD, n = 317; ulcerative colitis (UC), n = 180], (2) Hungary (CD, n = 149; UC, n = 119), and (3) the Netherlands (CD, n = 156). Subtyping analysis was performed in respect to NOD2 variants (p.Arg702Trp, p.Gly908Arg, c.3020insC) and to clinical characteristics. Ethnically matched controls were included (German, n = 413; Hungarian, n = 202; Dutch, n = 217)., Results: We observed no significant difference in p.C10X genotype frequency in either patients with CD or patients with UC compared with controls in all 3 cohorts. Conversely to the initial association study, we found a trend toward lower frequencies of the suggestive risk wild type in CD from the Netherlands compared with controls (P = 0.14). We found neither evidence for genetic interactions between p.C10X and NOD2 nor the C10X variant to be associated with a CD or UC phenotype., Conclusions: Analyzing 3 independent European IBD cohorts, we found no evidence that the C10X variant in CARD8 confers susceptibility for CD.

Background: Chronic hepatitis C virus (HCV) is transmitted by blood-blood contact and this leads to high HCV prevalence in risk populations such as haemophilia patients and intravenous drug users. The prevalence in the general Dutch population is unknown, although it appears to be very low in screened blood donors (0.0169%)., Aim: The objective of this study is to estimate the prevalence of HCV in a general population sample living in an urbanized region in the Netherlands., Methods: We randomly selected 2200 EDTA blood samples that had been submitted for analysis of biochemical parameters to a regional servicing laboratory for general practitioners (SHO, Arnhem/Nijmegen, the Netherlands). HCV antibody testing was performed using a three-step approach. For initial screening, an enzyme immunoassay (Bioelisa HCV 4.0, Biokit, Spain) was used. Positive samples were subjected to a second, microparticle enzyme-linked immunoassay (AxSYM HCV version 3.0, Abbott laboratories, IL , USA). Genotypes were determined by Line Probe Assay., Results: A total of four persons (two females, two males) (0.2%) tested positive for HCV antibodies. The average OD/cut-off ratio of the screening assay was 2.9 (range 1.0 to 7.3) and serological findings were confirmed using a specific second immunoassay. HCV RNA (genotype 1b) was found in the sera of two persons., Conclusion: The HCV prevalence in our sample of the Dutch population was 0.2% which accords with earlier estimates from prevalence studies in the Netherlands.

Background: Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated the relation of Caspase-Activation Recruitment Domain containing protein 15 with inflammatory bowel disease and Crohn's disease phenotypic characteristics in a large Dutch cohort and performed a pooled analysis on inflammatory bowel disease patients and Crohn's disease phenotypic characteristics reported in association studies., Methods: We genotyped 781 cases and 315 controls for the R702W, G908R and 1007fsinsC variants and for six microsatellite markers in and close to Caspase-Activation Recruitment Domain containing protein 15. In the pooled analysis data of 7201 inflammatory bowel disease patients and 3720 controls from 20 studies were included., Results: Association was found for Crohn's disease with R702W and 1007fsinsC, including several disease characteristics, and not for ulcerative colitis. In the pooled analysis all three common Caspase-Activation Recruitment Domain containing protein 15 variants showed strong association with Crohn's disease (p<0.00001; odds ratio varying from 3.0 for single heterozygotes to 14.7 for compound heterozygotes) and not with ulcerative colitis. Phenotype analysis showed association with small bowel involvement, stricturing and penetrating disease., Conclusion: Caspase-Activation Recruitment Domain containing protein 15 is associated with Crohn's disease and not with ulcerative colitis. All three common Crohn's disease-associated variants are associated with small bowel involvement, the G908R and 1007fsinsC alleles also being associated with a complicated disease course.

Objective: To evaluate the risk factors for the development of acute renal failure (ARF) in severe rhabdomyolysis., Design: Observational historical cohort study., Setting: General intensive care unit of a university hospital., Patients: Twenty-six patients with severe rhabdomyolysis, who were admitted between July 1996 and July 2001., Measurements and Results: Clinical and laboratory data were reviewed and groups were stratified according to presence or absence of acute renal failure. The underlying cause of rhabdomyolysis was ischemia by vascular obstruction (50%), crush injury by trauma (23%), sepsis (11.5%), heatstroke/hyperthermia (11.5%) and hyponatremia in a single patient. Mean creatine kinase (CK) level was 38,351+/-35,354 U/l on admission and rose further in all patients (mean: 59,747+/-67,514 U/l). Renal failure developed in 17 patients (65%). Serum CK levels correlated with onset of ARF, as these patients had significantly higher admission and peak serum CK concentrations. Patients with ARF had a higher mortality (59% vs 22%)., Conclusion: In our cohort of patients with severe rhabdomyolysis the level of serum CK predicted the development of ARF. Although our results suggest that series of CK determination might be beneficial for the evaluation of the effect of therapy, the value of CK determination as a prognostic tool is limited, given the wide range of CK levels.

Polycystic liver disease (PCLD, OMIM 174050) is a dominantly inherited condition characterized by the presence of multiple liver cysts of biliary epithelial origin. Fine mapping established linkage to marker D19S581 (Z(max) = 9.65; theta = 0.01) in four large Dutch families with PCLD. We identified a splice-acceptor site mutation (1138-2A-->G) in PRKCSH in three families, and a splice-donor site mutation (292+1G-->C) in PRKCSH segregated completely with PCLD in another family. The protein encoded by PRKCSH, here named hepatocystin, is predicted to localize to the endoplasmic reticulum. These findings establish germline mutations in PRKCSH as the probable cause of PCLD.

Hereditary pancreatitis is an autosomal dominant form of chronic pancreatitis. It presents with recurrent attacks of acute pancreatitis, usually starting in early childhood. The attacks may vary from mild abdominal pain to pancreatic necrosis, splenic vein thrombosis, pseudocysts and death. Ultimately chronic pancreatitis ensues with unrelenting pain, calcifications, endocrine and exocrine dysfunction. The penetrance is estimated at 80%. With the use of genetic linkage analysis the gene for hereditary pancreatitis was placed on the long arm of chromosome 7 (7q35). Mutational analysis identified cationic trypsinogen as the disease gene. Cationic trypsinogen mutations are thought to result in resistance of this molecule to autolysis.