http://repub.eur.nl/res/aut/3070/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39556/ 2013-03-01T00:00:00Z Background and aims: It remains unclear when anticoagulant therapy should be given in patients with non-cirrhotic portal vein thrombosis (PVT). The aim of this study was to assess the effect of anticoagulation on recurrent thrombotic events and gastrointestinal bleeding in non-cirrhotic PVT patients. Methods: Retrospective study of all patients with non-cirrhotic PVT (n = 120), seen at our hospital from 1985 to 2009. Data were collected by systematic chart review. Results: Sixty-six of the 120 patients were treated with anticoagulants. Twenty-two recurrent thrombotic events occurred in 19 patients. The overall thrombotic risk at 1, 5 and 10 years was 4%, 8% and 27%, respectively. Seventy-four percent of all recurrent thrombotic events occurred in patients with a prothrombotic disorder. Anticoagulant therapy tended to lower the risk of recurrent thrombosis (hazard ratio [HR] 0.2, P = 0.1), yet the only significant predictor of recurrent thrombotic events was the presence of a prothrombotic disorder (HR 3.1, P = 0.03). In 37 patients, 83 gastrointestinal bleeding events occurred. The re-bleeding risk at 1, 5 and 10 years was 19%, 46% and 49%, respectively. Anticoagulation therapy (HR 2.0, P ≤ 0.01) was a significant predictor of (re)bleeding. Anticoagulation therapy had no effect on the severity of gastrointestinal bleeding. Poor survival was associated with recurrent thrombotic events (HR 3.1 P = 0.02), whereas bleeding (HR 1.6 P = 0.2) and anticoagulant treatment (HR 0.5 P = 0.2) had no significant effect on survival. Conclusions: In non-cirrhotic PVT patients recurrent thrombotic events are mainly observed in patients with underlying prothrombotic disorders. Anticoagulation therapy tends to prevent recurrent thrombosis but also significantly increases the risk of gastrointestinal bleeding. http://repub.eur.nl/res/pub/37725/ 2012-09-01T00:00:00Z Background: Occasionally patients undergoing resection for presumed malignancy of the pancreatic head are diagnosed postoperatively with benign disease. Autoimmune pancreatitis (AIP) is a rare disease that mimics pancreatic cancer. We aimed to determine the prevalence of benign disease and AIP in patients who underwent pancreatoduodenectomy (PD) over a 9-year period, and to explore if and how surgery could have been avoided. Methods: All patients undergoing PD between 2000 and 2009 in a tertiary referral centre were analyzed retrospectively. In cancer-negative cases, postoperative diagnosis was reassessed. Preoperative index of suspicion of malignancy was scored as non-specific, suggestive, or high. In AIP patients, diagnostic criteria systems were checked. Results: A total of 274 PDs were performed for presumed malignancy. The prevalence of benign disease was 8.4 %, overall prevalence of AIP was 2.6 %. Based on preoperative index of suspicion of malignancy, surgery could have been avoided in 3 non-AIP patients. All AIP patients had sufficient index to justify surgery. If diagnostic criteria would have been checked; however, surgery could have been avoided in one to five AIP patients. Conclusions: The prevalence of benign disease in patients who underwent PD for presumed malignancy was 8.4 %, nearly one-third attributable to AIP. Although misdiagnosis of AIP as carcinoma is a problem of limited quantitative importance, every effort to establish the correct diagnosis should be undertaken considering the major therapeutic consequences. IgG4 measurement and systematic use of diagnostic criteria systems are recommended for every candidate patient for PD when there is no histological proof of malignancy. http://repub.eur.nl/res/pub/38765/ 2012-09-01T00:00:00Z Background: Occasionally patients undergoing resection for presumed malignancy of the pancreatic head are diagnosed postoperatively with benign disease. Autoimmune pancreatitis (AIP) is a rare disease that mimics pancreatic cancer. We aimed to determine the prevalence of benign disease and AIP in patients who underwent pancreatoduodenectomy (PD) over a 9-year period, and to explore if and how surgery could have been avoided. Methods: All patients undergoing PD between 2000 and 2009 in a tertiary referral centre were analyzed retrospectively. In cancer-negative cases, postoperative diagnosis was reassessed. Preoperative index of suspicion of malignancy was scored as non-specific, suggestive, or high. In AIP patients, diagnostic criteria systems were checked. Results: A total of 274 PDs were performed for presumed malignancy. The prevalence of benign disease was 8.4 %, overall prevalence of AIP was 2.6 %. Based on preoperative index of suspicion of malignancy, surgery could have been avoided in 3 non-AIP patients. All AIP patients had sufficient index to justify surgery. If diagnostic criteria would have been checked; however, surgery could have been avoided in one to five AIP patients. Conclusions: The prevalence of benign disease in patients who underwent PD for presumed malignancy was 8.4 %, nearly one-third attributable to AIP. Although misdiagnosis of AIP as carcinoma is a problem of limited quantitative importance, every effort to establish the correct diagnosis should be undertaken considering the major therapeutic consequences. IgG4 measurement and systematic use of diagnostic criteria systems are recommended for every candidate patient for PD when there is no histological proof of malignancy. http://repub.eur.nl/res/pub/37827/ 2012-08-01T00:00:00Z We report four patients with pneumothorax as a complication of ERCP with sphincterotomy. With conservative treatment all patients recovered. Previously, 16 comparable cases have been reported in the literature. The main risk factor for this rare complication seems (pre-cut) sphincterotomy. Pneumothorax is usually right-sided or bilateral and accompanied by pneumomediastinum, pneumoretroperitoneum and subcutaneous emphysema. The prognosis seems favourable with a non-surgical approach including intravenous antibiotics, fasting and when indicated chest tube drainage. http://repub.eur.nl/res/pub/31057/ 2011-09-01T00:00:00Z http://repub.eur.nl/res/pub/26624/ 2011-07-01T00:00:00Z Background Treatment failure occurs in 20% of autoimmune hepatitis patients on prednisolone and azathioprine (AZA). There is no established second line treatment. Aim To assess the efficacy of mycophenolate mofetil as second line treatment after AZA-intolerance or AZA-nonresponse in autoimmune hepatitis and overlap syndromes. Methods Consecutive patients from the Dutch Autoimmune Hepatitis Group cohort, consisting of 661 patients, with autoimmune hepatitis or overlap syndromes, AZA-intolerance or AZA-nonresponse and past or present use of mycophenolate mofetil were included. Primary endpoint of mycophenolate mofetil treatment was biochemical remission. Secondary endpoints were biochemical response (without remission), treatment failure and prevention of disease progression. Results Forty-five patients treated with mycophenolate mofetil were included. In autoimmune hepatitis remission or response was achieved in 13% and 27% in the AZA-nonresponse group compared to 67% and 0% in the AZA-intolerance group (P = 0.008). In overlap-syndromes remission or response was reached in 57% and 14% in the AZA-nonresponse group and 63% and 25% of the AZA-intolerance group (N.S.); 33% had side effects and 13% discontinued mycophenolate mofetil. Overall 38% had treatment failure; this was 60% in the autoimmune hepatitis AZA-nonresponse group. Decompensated liver cirrhosis, liver transplantations and death were only seen in the autoimmune hepatitis AZA-nonresponse group (P < 0.001). Conclusions Mycophenolate mofetil induced response or remission in a majority of patients with autoimmune hepatitis and azathioprine-intolerance and with overlap syndromes, irrespective of intolerance or nonresponse for azathioprine. In autoimmune hepatitis with azathioprine nonresponse mycophenolate mofetil is less often effective. http://repub.eur.nl/res/pub/23584/ 2011-02-01T00:00:00Z Objective: Retrograde double balloon enteroscopy (DBE) is important for evaluating the distal small bowel, but it is more challenging compared to the oral route. Optimizing small bowel insertion may enhance the diagnostic utility of the examination. We sought to determine if insertion depths achieved with retrograde DBE when performed as an isolated procedure differed significantly from when performed immediately following anterograde DBE. Material and methods. A retrospective analysis was conducted of all retrograde DBE procedures performed at our center with comparisons made between "distal-only" DBE without preceding anterograde DBE and "combined" DBE after a prior same-day anterograde DBE. Results. Two hundred ninety retrograde DBE procedures were performed in 264 patients over 5 years. Success of terminal ileal intubation exceeded 95%. The mean insertion depth into the distal small bowel differed significantly with 112 cm (95% CI 95-129) in the "distal- only" group and 92 cm (95% CI 85-98) in the "combined" group (p = 0.01), with a trend toward a corresponding increased diagnostic yield of 48% versus 37%, respectively (p = 0.15). Multivariate regression analysis identified both insertion route strategy (distal-only > combined; p = 0.01) and type of DBE endoscope (diagnostic > therapeutic; p = 0.02) as significant predictors of retrograde insertion depth. Conclusions. The insertion depth of retrograde DBE is significantly greater when carried out as a separate distal procedure and not in combination with a preceding anterograde DBE, and when performed using a diagnostic as opposed to the therapeutic DBE endoscope. This increased retrograde depth of insertion may be associated with an increased diagnostic yield. http://repub.eur.nl/res/pub/27843/ 2010-12-30T00:00:00Z We have developed a method to longitudinally classify subjects into two or more prognostic groups using longitudinally observed values of markers related to the prognosis. We assume the availability of a training data set where the subjects' allocation into the prognostic group is known. The proposed method proceeds in two steps as described earlier in the literature. First, multivariate linear mixed models are fitted in each prognostic group from the training data set to model the dependence of markers on time and on possibly other covariates. Second, fitted mixed models are used to develop a discrimination rule for future subjects. Our method improves upon existing approaches by relaxing the normality assumption of random effects in the underlying mixed models. Namely, we assume a heteroscedastic multivariate normal mixture for random effects. Inference is performed in the Bayesian framework using the Markov chain Monte Carlo methodology. Software has been written for the proposed method and it is freely available. The methodology is applied to data from the Dutch Primary Biliary Cirrhosis Study. Copyright http://repub.eur.nl/res/pub/22960/ 2010-12-20T00:00:00Z Background: A decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX requirements in PBC over the past 20 years in the Netherlands.Methods: Analysis of PBC transplant data of the Dutch Organ Transplant Registry during the period 1988-2008, including both absolute and proportional numbers. The indication for LTX was categorized as liver failure, hepatocellular carcinoma or poor quality of life (severe fatigue or pruritus). Data were analysed for two decades: 1.1.1988-31.12.1997 (1st) and 1.1.1998-31.12.2007 (2nd). The severity of disease was quantified using MELD scores. To fit lines which show trends over time we applied a linear regression model.Results: A total of 110 patients (87% women) was placed on the waiting list. 105 patients were transplanted (1st: 61, 2nd: 44), 5 (5%) died while listed. The absolute annual number of LTX for PBC slightly decreased during the 20 year period, the proportional number decreased significantly. At the time of LTX the mean age was 53.6 yrs. (1st: 53.4, 2nd: 53.8), the mean MELD score 13.9 (1st:14.5, 2nd:13.0). The median interval from diagnosis to LTX was 90.5 months (1st:86.5, 2nd: 93.5). 69% of patients was treated with UDCA (1st38%, 2nd82%).Conclusions: Over the past 20 years the absolute number of LTX for PBC in the Netherlands showed a tendency to decrease whereas the proportional decrease was significant. There was a trend over time toward earlier transplantation. http://repub.eur.nl/res/pub/22097/ 2010-11-01T00:00:00Z Abstract: Autoimmune pancreatitis (AIP) is associated with a marked elevation of serum total IgG4. Although there is evidence of autoimmunity in AIP, there are also signs of an allergic nature of its pathogenesis. Therefore, we determined both IgE and IgG4 in 13 patients with AIP, in 12 patients with pancreatic carcinoma and in 14 patients with atopic allergy and investigated the relationship between IgE and IgG4. Total IgG4 was determined by automated nephelometry and total IgE by automated enzyme fluoroimmunoassay. Both total IgE and total IgG4 levels in patients with AIP were significantly higher than those in patients with pancreatic carcinoma (P = 0.0004 and P = 0.015, respectively). There was a significant correlation between the total IgE and total IgG4 levels in patients with AIP and patients with atopic allergy (rs = 0.82,P = 0.0006 and rs = 0.88,P < 0.0001, respectively). The IgE/ IgG4 ratio in sera from patients with atopic allergy was significantly different (P = 0.0012) from this ratio in sera from patients with AIP. These results suggest that analysis of total IgE in serum might be useful in the differentiation between autoimmune pancreatitis and pancreatic carcinoma. http://repub.eur.nl/res/pub/26063/ 2010-10-01T00:00:00Z Goals: The aim of this study was to evaluate the diagnostic and therapeutic outcome of a primary balloon-assisted enteroscopy (BAE) approach in obscure gastrointestinal bleeding (OGIB) patients. Background: In the diagnostic approach of OGIB, both wireless capsule endoscopy (WCE) and BAE are used. The advantage of the primary wireless capsule endoscopy approach is its noninvasiveness. The main advantage of the primary BAE approach is the excellent diagnostic accuracy and the possibility to perform treatment during the same procedure. Study: A retrospective analysis of our BAE database with patients evaluated for OGIB was performed. BAE data, findings, and follow-up were obtained and evaluated. Results: One hundred and thirty-two patients (81 male, mean age 62 (11-88) years) were included. In 60 (45%) patients with follow-up, a likely cause for OGIB was found in the small bowel during BAE: angiodysplasia or vascular malformations in 42 (70%), ulcerative lesions in 7 (12%), tumors in 3 (5%), and other findings in 8 (13%) patients. Follow-up was available in 118 (89%) patients; mean time of follow-up was 18 (1-47) months. Thirty-eight (76%) patients with findings at BAE received endoscopic treatment, 27 (71%) of them improved, but anemia also improved spontaneously in 34 patients (63%) with normal findings during BAE. The total number of angiodysplasia per patient was not related to the outcome after treatment. Conclusions: The primary BAE approach in OGIB patients has an acceptable diagnostic yield. Therapy seems successful at mid-term follow-up. A high frequency of spontaneous resolution of anemia in patients with normal findings during BAE was observed. http://repub.eur.nl/res/pub/20910/ 2010-09-01T00:00:00Z Objective. Gastrointestinal endoscopy databases are important for surveillance, epidemiology, quality control and research. A good quality of automatically generated databases to enable drawing justified conclusions based on the data is of key importance. The aim of this study is to validate the correctness of coding of a national automatically generated anonymous endoscopy database. Material and methods. We evaluated a total of 500 colonoscopies performed in five larger hospitals of the TRANS.IT project focusing on endoscopy reporting. Randomly 500 examinations were selected from a total of 5,000 examinations and their generated endoscopic terminology codes as well as complete reports were analysed. Indications for the examination and described findings were scored for correctness and clinical relevance of the coding that would be exported to the anonymous database. Results. Indications were correctly coded in 92% of all examinations (range 76100%) per hospital. Correct coding of findings ranged from 42% to 93% per hospital (mean 77%). Different correct coding proportions were seen varying with the diagnosis, with the highest correct coding rates in polyps, carcinoma and diverticular disease. Incorrect coded examinations were scored for clinical relevance. Overall 11% of the investigated examinations were incorrectly coded with clinical relevance. Conclusions. Accuracy of clinically relevant endoscopy data recorded in the TRANS.IT anonymous central database is high. Further improvement is desirable, which may be achieved by education of individual endoscopists and enhancement of the program. http://repub.eur.nl/res/pub/21165/ 2010-09-01T00:00:00Z Background & Aims: Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons. Methods: Cytosolic free calcium ([Ca 2+]i) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca2+]i-inducing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device. Results: Transient increases in neuronal [Ca2+]i induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca 2+]i agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls (P < .0001) and cholestatic patients with versus without pruritus (P < .0001). Autotaxin activity correlated with intensity of pruritus (P < .0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or μ-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal. Conclusions: We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions. http://repub.eur.nl/res/pub/20490/ 2010-08-01T00:00:00Z Background The clinical significance of ascites in patients with extrahepatic portal vein thrombosis (EPVT) has been poorly defined. Aims To assess the frequency, natural history and prognostic implication of ascites in patients with EPVT and to identify risk factors for this complication. Methods A single-centre retrospective study of consecutive patients diagnosed with noncirrhotic nonmalignant EPVT between 1985 and 2009. Results One hundred and three patients [35% males; median age 43 (range 16-83) years] were included and followed up for a median time of 5.2 (range 0.9-32.5) years. Twenty-nine (28%) had ascites at the time of diagnosis. Overall survival was 91% at 5 years vs. 80% at 10 years. Survival in patients presenting with and without ascites was 83% vs. 95% at 5 years and 42% vs. 87% at 10 years (P = <0.01). There was no correlation between the presence of ascites and extension of the thrombus into the large splanchnic veins, duration of thrombosis or presence of gastrointestinal bleeding. Conclusions Ascites is present in a quarter of patients presenting with noncirrhotic nonmalignant extrahepatic portal vein thrombosis. Ascites is a significant and independent prognostic factor and it is associated with a decreased long-term survival. http://repub.eur.nl/res/pub/21166/ 2010-01-01T00:00:00Z Background and aims: Ursodeoxycholic acid (UDCA) has an established effect on liver biochemistries in primary biliary cirrhosis (PBC). Few studies have evaluated long-term laboratory treatment effects and data beyond 6 years are not available. The aim of this study was to assess the long-term evolution of liver biochemistries during prolonged treatment with UDCA in biochemically non-advanced PBC. Patients and methods: Prospective multicenter cohort study of patients with PBC with pretreatment normal bilirubin and albumin, treated with UDCA 13-15 mg/kg/day. At yearly intervals, follow-up data including serum bilirubin, alkaline phosphatase (ALP), transaminases, albumin and IgM were collected. Data were analyzed with a repeated measurement model. Results: Two hundred and twenty-five patients were included and followed during a median period of 10.3 years. Following 1-year treatment with UDCA 36-100% of the total biochemical improvement was achieved, the maximum response was observed after 3 years. After initial improvements, bilirubin and AST levels increased and albumin levels significantly decreased after 6-10 years. However, these changes were of limited magnitude. The beneficial effects on ALT and ALP were maintained while IgM continued to decrease. Conclusion: In non-advanced PBC the biochemical response to UDCA is maintained up to 15 years. The long-term evolution of bilirubin, albumin and ALT differs from that of ALP and AST. The mean IgM level normalised and levels continued to decrease during the period of follow-up. http://repub.eur.nl/res/pub/24094/ 2009-11-26T00:00:00Z Background: Patients with inflammatory bowel disease (IBD) and concurrent primary sclerosing cholangitis (PSC) have a higher risk of developing colorectal cancer (CRC) than IBD patients without PSC. The aim of this study was to investigate potential clinical differences between patients with CRC in IBD and those with CRC in IBD and PSC, as this may lead to improved knowledge of underlying pathophysiological mechanisms of CRC development. Methods: The retrospective study from 1980-2006 involved 7 Dutch university medical centers. Clinical data were retrieved from cases identified using the national pathology database (PALGA). Results: In total, 27 IBD-CRC patients with PSC (70% male) and 127 IBD-CRC patients without PSC (59% male) were included. CRC-related mortality was not different between groups (30% versus 19%, P = 0.32); however, survival for cases with PSC after diagnosing CRC was lower (5-year survival: 40% versus 75% P = 0.001). Right-sided tumors were more prevalent in the PSC group (67% versus 36%, P = 0.006); adjusted for age, sex, and extent of IBD, this difference remained significant (odds ratio: 4.8, 95% confidence interval [CI] 2.0-11.8). In addition, tumors in individuals with PSC were significantly more advanced. Conclusions: The right colon is the predilection site for development of colonic malignancies in patients with PSC and IBD. When such patients are diagnosed with cancer they tend to have more advanced tumors than patients with IBD without concurrent PSC, and the overall prognosis is worse. Furthermore, the higher frequency of right-sided tumors in patients with PSC suggests a different pathogenesis between patients with PSC and IBD and those with IBD alone. Copyright http://repub.eur.nl/res/pub/16432/ 2009-04-01T00:00:00Z http://repub.eur.nl/res/pub/16575/ 2009-04-01T00:00:00Z Background & Aims: Ursodeoxycholic acid (UDCA) improves laboratory liver test results in patients with primary biliary cirrhosis (PBC). Few studies have assessed the prognostic significance of biochemical data collected following UDCA treatment. We performed a prospective multicenter study of patients with PBC treated with UDCA to compare prognosis with biochemical response. Methods: PBC was classified as early (pretreatment bilirubin and albumin levels normal), moderately advanced (one level abnormal), or advanced (both levels abnormal). Biochemical response was defined as proposed by Pares (decrease in alkaline phosphatase [ALP] level >40% of baseline level or normal level), Corpechot (ALP level <3-fold the upper limit of normal [ULN], aspartate aminotransferase level <2-fold the ULN, bilirubin level <1-fold the ULN), and our group (Rotterdam; normalization of abnormal bilirubin and/or albumin levels). Results: The study included 375 patients, and median follow-up time was 9.7 (range, 1.0-17.3) years. The prognosis for early PBC was comparable with that of the Dutch population and better than predicted by the Mayo risk score. Survival of responders was better than that of nonresponders, according to Corpechot and Rotterdam criteria (P < .001). Prognosis of early PBC was comparable for responders and nonresponders; prognosis of responders was significantly better in those with (moderately) advanced disease. Conclusions: Prognosis for UDCA-treated patients with early PBC is comparable to that of the general population. Survival of those with advanced PBC with biochemical response to UDCA is significantly better than for nonresponders. Thus, UDCA may be of benefit irrespective of the stage of disease. Prognostic information, based on bilirubin and albumin levels, is superior to that provided by ALP levels. http://repub.eur.nl/res/pub/15328/ 2009-03-09T00:00:00Z Introduction: It is estimated that 10-30% of patients with Crohn's disease (CD) have small bowel (SB) involvement, but the exact frequency and clinical relevance of these findings is unknown. Double-balloon enteroscopy (DBE) enables endoscopic visualization of the SB. In this study we evaluated whether DBE is a feasible technique for detection of CD localized in the SB in CD patients with clinical suspicion of SB lesions and whether these findings have clinical impact. Methods: Retrospectively we analyzed 52 DBE procedures in 40 CD patients (16 males, mean age 40 years, mean duration of CD 15 years). Included patients had clinical suspicion of small bowel CD activity, including persistent abdominal discomfort (n = 27), iron deficiency anemia (n = 9) and/or hypomagnesemia (n = 4). Results: Active small bowel CD was found in 24 (60%) patients, leading to a change in therapy in 18 patients (75%). After a mean follow-up of 13 months, 15 (83%) had persistent clinical improvement with a significant drop of mean CDAI from 178 to 90, after a mean follow-up of 13 months. Conclusions: DBE is a useful diagnostic tool for the evaluation of SB lesions in CD patients. The significance of these findings is emphasized by the fact that adjustment of therapy in the majority of these patients leads to significant and sustained clinical improvement. http://repub.eur.nl/res/pub/19620/ 2009-01-01T00:00:00Z In the Netherlands there are probably several thousands of patients with primary biliary cirrhosis (PBC), a slowly progressive liver disease mainly affecting middle-aged women. PBC has characteristics of an autoimmune disease but its precise aetiology remains unknown. Fatigue and pruritus are the main symptoms but patients may also be asymptomatic. The diagnosis can be established through the presence of cholestatic liver test abnormalities, antimitochondrial antibodies and diagnostic or compatible findings upon liver biopsy. Currently most patients are diagnosed with early disease. When treated with ursodeoxycholic acid these patients have a normal prognosis. http://repub.eur.nl/res/pub/25049/ 2009-01-01T00:00:00Z Background/Aims: Primary sclerosing cholangitis (PSC) patients are at risk for developing cholangiocarcinoma (CCA) and colorectal carcinoma (CRC). Our aim was to assess the risk of malignancies and their influence on survival. Methods: Data from PSC patients diagnosed between 1980 and 2006 in two university hospitals were retrieved. The Kaplan-Meier method and a time-dependent Cox regression model were used to calculate risks of malignancies and their influence on survival. Results: Two hundred and eleven patients were included, 143 (68%) were male and 126 (60%) had inflammatory bowel disease (IBD). Median transplantation-free survival was 14 years. The risk of CCA after 10 and 20 years was 9% and 9%, respectively. In patients with concomitant IBD the 10-year and 20-year risks for CRC were 14% and 31%, which was significantly higher than for patients without IBD (2% and 2% (P = 0.008)). CCA, cholangitis, and age at entry were independent risk factors for the combined endpoint death or liver transplantation. Risk factors for the endpoint death were CCA, CRC, age, and symptomatic presentation. Conclusions: Patients with PSC and IBD have a high long-term risk of developing CRC and this risk is about threefold higher than the risk for CCA. Both malignancies are associated with decreased survival. http://repub.eur.nl/res/pub/32336/ 2008-09-01T00:00:00Z http://repub.eur.nl/res/pub/29229/ 2008-05-01T00:00:00Z Background: Esophagogastric variceal bleeding is the most important complication of extrahepatic portal vein thrombosis (EPVT) and is usually treated endoscopically. Little is known about the prognosis of these patients. Objectives: To investigate the long-term clinical outcome and efficacy of endoscopic treatment in patients with esophagogastric variceal bleeding secondary to EPVT. Design: Retrospective observational study. Settings: Single university center. Patients: Twenty-seven consecutive patients with esophagogastric variceal bleeding, secondary to noncirrhotic, nonmalignant EPVT, who underwent endoscopic treatment between 1982 and 2005. Interventions: Endoscopic band ligation and/or endoscopic sclerotherapy. Main Outcome Measurements: The overall rebleeding risk, overall survival, complications of the endoscopic procedures, and predictive values of rebleeding. Analyses were performed by the Kaplan-Meier method and univariate Cox regression. Results: All patients were followed-up after the first endoscopically treated variceal bleeding. A total of 241 endoscopic procedures were performed. In all patients, initial control of bleeding was obtained. The overall rebleeding risk was 23% (95% CI, 0%-24%) at 1 year and 37% (95% CI, 43%-83%) at 5 years. Extension of thrombosis into the splenic vein and the presence of fundal varices were significant predictors of rebleeding, with a nearly 5-fold increased risk for patients with EPVT and fundal varices at the time of the first variceal hemorrhage (hazard ratio 5.07, P = .01). A portosystemic shunt procedure was performed in 5 patients: 4 for variceal bleeding and in one patient for refractory ascites. Seven patients died, none from variceal bleeding. Overall 5-year and 10-year survivals were 100% and 62% (95% CI, 38%-96%), respectively. Limitations: Retrospective design. Conclusions: In patients with variceal bleeding secondary to EPVT endoscopic treatment, in particular, band ligation appears safe and effective. EPVT-related mortality is primarily determined by other causes than variceal bleeding. http://repub.eur.nl/res/pub/30040/ 2008-02-01T00:00:00Z Liver involvement in Hodgkin's lymphoma is common and is caused by hepatic infiltration, biliary obstruction by lymphoma, hepatitis, sepsis or complications of chemotherapeutic treatment. Jaundice caused by the vanishing bile duct syndrome related to Hodgkin's lymphoma is very rare. The mechanism is poorly understood but a paraneoplastic effect seems most likely as liver biopsy samples show cholestasis in the absence of lymphoma cells. Despite adequate treatment almost all reported patients died of liver failure or disease progression. Disease progression is explained partly by the difficulties encountered in the administration of potential hepatotoxic chemotherapy in severely cholestatic patients. We describe a 17-year-old man with vanishing bile duct syndrome and Hodgkin's lymphoma who was treated successfully with chemotherapy. The markedly elevated serum bilirubin levels completely normalized. Our case demonstrates that although dosing of chemotherapy in this situation can be very difficult, a good clinical outcome is possible, which makes the attempt at curative treatment worthwhile. http://repub.eur.nl/res/pub/30313/ 2008-02-01T00:00:00Z Background: The clinical outcome of a covered vs. uncovered transjugular intrahepatic portosystemic shunt (TIPS) for patients with Budd-Chiari syndrome (BCS) is as yet largely unknown. Objectives: To compare patency rates of bare and polytetrafluoroethylene (PTFE)-covered stents, and to investigate clinical outcome using four prognostic indices [Child-Pugh score, Rotterdam BCS index, modified Clichy score and Model for End-Stage Liver Disease (MELD)]. Methods: Consecutive patients with BCS who had undergone TIPS between January 1994 and March 2006 were evaluated in a retrospective review in a single centre. Results: Twenty-three TIPS procedures were performed on 16 patients. The primary patency rate at 2 years was 12% using bare and 56% using covered stents (P = 0.09). We found marked clinical improvement at 3 months post-TIPS as determined by a drop in median Child-Pugh score (10-7, P = 0.04), Rotterdam BCS index (1.90-0.83, P = 0.02) and modified Clichy score (7.77-2.94, P = 0.003), but not in MELD (18.91-17.42, P =0.9). Survival at 1 and 3 years post-TIPS was 80% (95% CI: 59-100%) and 72% (95% CI: 48-96%). Four patients (25%) died and one required liver transplantation. Conclusions: A transjugular intrahepatic portosystemic shunt using PTFE-covered stents shows better patency rates than bare stents in BCS. Moreover, TIPS leads to an improvement in important prognostic indicators for the survival of patients with BCS. © 2008 The Authors. Journal compilation http://repub.eur.nl/res/pub/35880/ 2007-12-01T00:00:00Z Background: Extrahepatic portal vein thrombosis is an important cause of non-cirrhotic portal hypertension. Aim: To provide an update on recent advances in the aetiology and management of acute and chronic non-cirrhotic non-malignant extrahepatic portal vein thrombosis. Method: A PubMed search was performed to identify relevant literature using search terms including 'portal vein thrombosis', 'variceal bleeding' and 'portal biliopathy'. Results: Myeloproliferative disease is the most common risk factor in patients with non-cirrhotic non-malignant extrahepatic portal vein thrombosis. Anticoagulation therapy for at least 3 months is indicated in patients with acute extrahepatic portal vein thrombosis. However, in patients with extrahepatic portal vein thrombosis due to a prothrombotic disorder, permanent anticoagulation therapy can be considered. The most important complication of extrahepatic portal vein thrombosis is oesophagogastric variceal bleeding. Endoscopic treatment is the first-line treatment for variceal bleeding. In several of the patients with extrahepatic portal vein thrombosis biliopathy changes on endoscopic retrograde cholangiography (ERCP) have been reported. Dependent on the persistence of the biliary obstruction, treatment can vary from ERCP to hepaticojejunostomy. Conclusion: Prothrombotic disorders are the major causes of non-cirrhotic, non-malignant extrahepatic portal vein thrombosis and anticoagulation therapy is warranted in these patients. The prognosis of patients with non-cirrhotic, non-malignant extrahepatic portal vein thrombosis is good, and is not determined by portal hypertension complications but mainly by the underlying cause of thrombosis. http://repub.eur.nl/res/pub/35881/ 2007-12-01T00:00:00Z Background: Ascites is the most common complication of cirrhosis, associated with an expected survival below 50% after 5 years. Prognosis is particularly poor for patients with refractory ascites and for those developing complications, including spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome (HRS). Aim: To provide an evidence-based overview of the pathophysiology, diagnosis and clinical management of ascites secondary to liver cirrhosis. Methods: Review based on relevant medical literature. Results: Portal hypertension, splanchnic vasodilatation and renal sodium retention are fundamental in the pathophysiology of ascites formation. The SAAG (serum-ascites albumin gradient) allows reliable assessment of the cause of ascites. The majority of cirrhotic patients with ascites can be managed with dietary sodium restriction in combination with diuretic agents. Large volume paracentesis with albumin suppletion and TIPS are therapeutic options in patients with refractory ascites. Prophylactic antibiotics for SBP should be given in certain patient populations. Conclusions: Recent advances in the diagnosis and treatment of ascites and associated complications have improved the medical management and poor prognosis of patients with these manifestations of advanced liver disease. Early diagnosis, adequate treatment and focus on prevention of complications remain essential as well as timely referral for liver transplantation. http://repub.eur.nl/res/pub/9411/ 2007-06-01T00:00:00Z Our aim was to study the prevalence of depression in a Dutch population with PBC and PSC. In addition, to investigate the effects of using an additional diagnostic structured psychiatric interview, after screening with the Beck Depression Inventory (BDI), a self-report severity scale instrument used in former studies. Patients with PBC and PSC (n = 92)completed the BDI. Patients with scores of 10 or higher (n = 39) were interviewed using a structured psychiatric interview. Patients with scores lower than 10 were at random (30/53, 57%) also interviewed using a structured psychiatric interview. Results: Of the 92 patients that were included 42% had depressive symptoms according to the BDI. However, of these patients only 3.7% had a depressive syndrome according to the DSM-IV criteria as assessed with the structured psychiatric interview. Conclusions: The prevalence of a depressive disorder in patients with PBC and PSC is not higher than in the general population. Fatigue in patients with PBC and PSC cannot be explained by depression. http://repub.eur.nl/res/pub/13732/ 2005-03-24T00:00:00Z BACKGROUND: In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) fatigue is a major clinical problem. Abnormal amino acid (AA) patterns have been implicated in the development of fatigue in several non-hepatological conditions but for PBC and PSC no data are available. This study aimed to identify abnormalities in AA patterns and to define their relation with fatigue. METHODS: Plasma concentrations of tyrosine, tryptophan, phenylalanine, valine, leucine and isoleucine were determined in plasma of patients with PBC (n = 45), PSC (n = 27), chronic hepatitis C (n = 22) and healthy controls (n = 73). Fatigue and quality of life were quantified using the Fisk fatigue severity scale, a visual analogue scale and the SF-36. RESULTS: Valine, isoleucine, leucine were significantly decreased in PBC and PSC. Tyrosine and phenylalanine were increased (p < 0.0002) and tryptophan decreased (p < 0.0001) in PBC. In PBC, but not in PSC, a significant inverse relation between tyrosine concentrations and fatigue and quality of life was found. Patients without fatigue and with good quality of life had increased tyrosine concentrations compared to fatigued patients. Multivariate analysis indicated that this relation was independent from disease activity or severity or presence of cirrhosis. CONCLUSION: In patients with PBC and PSC, marked abnormalities in plasma AA patterns occur. Normal tyrosine concentrations, compared to increased concentrations, may be associated with fatigue and diminished quality of life. http://repub.eur.nl/res/pub/13456/ 2004-07-13T00:00:00Z BACKGROUND: Fatigue is a major clinical problem in many patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). An effective treatment has not been defined. Recently, a large proportion of patients with these diseases was found to have symptoms of depression. Because fatigue is a frequent symptom of depression and there is some evidence that treatment with an antidepressant improves fatigue in patients with fibromyalgia, we hypothesised that the antidepressant fluvoxamine might improve fatigue related to PBC and PSC. METHODS: Fatigued patients were randomised to receive fluvoxamine (75 mg BID) or placebo for a six-week period. Fatigue and quality of life were quantified using a visual analogue scale, the Fisk Fatigue Severity Scale, the Multidimensional Fatigue Inventory and the SF-36. RESULTS: Seventeen and 16 patients were allocated to fluvoxamine and placebo, respectively. There was no statistically significant beneficial effect of fluvoxamine on fatigue or quality of life. The median VAS scores in the fluvoxamine and placebo groups were 7.40 and 7.45 at day 0, 6.9 and 7.15 at day 14, 7.45 and 7.65 at day 42 and 7.8 and 8.0 four weeks after treatment discontinuation. CONCLUSION: We found no evidence for a beneficial effect of fluvoxamine on fatigue in these patients with cholestatic liver disease and severe chronic fatigue. http://repub.eur.nl/res/pub/13341/ 2004-05-01T00:00:00Z PURPOSE: To retrospectively assess the outcome of transjugular intrahepatic portosystemic shunt (TIPS) placement in a nonselected group of consecutive patients. MATERIALS AND METHODS: TIPS placement was attempted in 82 patients. Patients were followed up for at least 3 years according to a standard protocol that included repeated shunt evaluations. Fifty-four patients underwent TIPS placement for variceal bleeding, 24 for refractory ascites, and four for other indications. Recurrent bleeding, effect on ascites, long-term patency, development of encephalopathy, and survival and complication rates were evaluated with Kaplan-Meier survival analysis and Cox multivariate analysis. RESULTS: TIPS placement was successful in 75 patients (91%). Mean follow-up lasted 29.4 months. Primary patency was 22% and 12%, primary-assisted patency was 67% and 46%, and secondary patency was 91% and 91% at 1- and 5-year follow-up, respectively. Nonalcoholic liver disease (P =.007) and increasing platelet counts (P =.006) independently predicted development of shunt insufficiency. The 1- and 5-year rates of recurrent variceal bleeding were 21% and 27%, respectively. In the majority of patients with refractory ascites, a beneficial effect of TIPS placement was observed. The risk for encephalopathy was 25% at 1-month follow-up and 52% at 3-year follow-up. The risk for chronic or severe intermittent encephalopathy was 15% at 1-year follow-up and 20% at 3-year follow-up. Serum creatinine levels (P =.001) and age (P =.02) were independent risk factors. Overall survival rate was 61%, 49%, and 42% at 1-, 3-, and 5-year follow-up, respectively. Age (P =.03), serum albumin level (P =.02), and serum creatinine level (P <.001) were independently related to mortality. CONCLUSION: The risk for definitive loss of shunt function was 17% at 5-year follow-up, indicating that surveillance with shunt revision-when indicated-results in excellent long-term TIPS patency. TIPS placement effectively protects against recurrent bleeding. http://repub.eur.nl/res/pub/10371/ 2004-01-01T00:00:00Z BACKGROUND: In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) significant therapeutic effects of glucocorticoids have not been documented. The most important clinical problem in patients with these diseases is fatigue, which is occasionally invalidating. Abnormalities in the hypothalamo-pituitary-adrenal axis have been suggested as a cause of fatigue. Most effects of glucocorticoids are mediated by the glucocorticoid receptor (hGR alpha). Recently a causative role for a splicing variant of the glucocorticoid receptor (hGR beta) has been proposed in glucocorticoid resistance in asthma and ulcerative colitis, whereas another splicing variant (hGR P) might be associated with glucocorticoid-resistant haematological malignancies. The aims of the present pilot study were to assess abnormalities in glucocorticoid receptor expression and to relate these abnormalities to the development of fatigue and to disease activity and severity in autoimmune cholestatic liver disease. METHODS: Five fatigued and five nonfatigued patients with PBC or PSC were included, and the results were compared with healthy controls. RESULTS: The expression of hGR P was not different from controls, but hGR beta mRNA was significantly increased (p=0.02) and hGR alpha mRNA decreased (p=0.015). There were no significant differences between fatigued and nonfatigued patients. A significant negative correlation between the serum activity of alkaline phosphatase and hGR alpha and hGR P mRNA was found. CONCLUSION: Although there was no relation with fatigue, abnormalities in hGR expression appear to occur in patients with these diseases, and may play a role in its pathophysiology and the poor response to glucocorticoid treatment. http://repub.eur.nl/res/pub/10373/ 2004-01-01T00:00:00Z BACKGROUND: We studied whether the theoretical advantages of a spring-loaded liver biopsy needle exist in clinical practice and if so if they are dependent upon the experience of the physician performing the biopsy. METHODS: In a stratified randomised study we enrolled 215 consecutive patients to compare the safety and efficacy of a new automatic biopsy gun (Acecut) with that of a standard Tru-Cut needle. RESULTS: A total of 464 biopsies were performed. The endpoints of the study were number of needle passes needed per patient, tissue yield of each needle pass and post-biopsy complications. The performance of the automatic needle was superior and more consistent with respect to tissue yield compared with the Tru-Cut needle (median yield 100% and 80%, respectively; p < 0.001). The difference was most marked for inexperienced physicians. There was no difference between the two needles in the number of passes needed. More post-biopsy pain and post-biopsy use of analgesics were observed in the automatic needle group (p = 0.04). CONCLUSION: The automatic Tru-Cut needle offers an advantage, particularly for physicians with no or limited experience in liver biopsies. However more post-biopsy pain and post-biopsy use of analgesics were observed in the automatic needle group. http://repub.eur.nl/res/pub/13190/ 2003-08-15T00:00:00Z BACKGROUND: Since esophageal variceal bleeding is associated with a high mortality rate, prevention of bleeding might be expected to result in improved survival. The first trials to evaluate prophylactic sclerotherapy found a marked beneficial effect of prophylactic treatment. These results, however, were not generally accepted because of methodological aspects and because the reported incidence of bleeding in control subjects was considered unusually high. The objective of this study was to compare endoscopic sclerotherapy (ES) with nonactive treatment for the primary prophylaxis of esophageal variceal bleeding in patients with cirrhosis. METHODS: 166 patients with esophageal varices grade II, III of IV according to Paquet's classification, with evidence of active or progressive liver disease and without prior variceal bleeding, were randomized to groups receiving ES (n = 84) or no specific treatment (n = 82). Primary end-points were incidence of bleeding and mortality; secondary end-points were complications and costs. RESULTS: During a mean follow-up of 32 months variceal bleeding occurred in 25% of the patients of the ES group and in 28% of the control group. The incidence of variceal bleeding for the ES and control group was 16% and 16% at 1 year and 33% and 29% at 3 years, respectively. The 1-year survival rate was 87% for the ES group and 84% for the control group; the 3-year survival rate was 62% for each group. In the ES group one death occurred as a direct consequence of variceal bleeding compared to 9 in the other group (p = 0.01, log-rank test). Complications were comparable for the two groups. Health care costs for patients assigned to ES were estimated to be higher. Meta-analysis of a large number of trials showed that the effect of prophylactic sclerotherapy is significantly related to the baseline bleeding risk. CONCLUSION: In the present trial, prophylactic sclerotherapy did not reduce the incidence of bleeding from varices in patients with liver cirrhosis and a low to moderate bleeding risk. Although sclerotherapy lowered mortality attributable to variceal bleeding, overall survival was not affected. The effect of prophylactic sclerotherapy seems dependent on the underlying bleeding risk. A beneficial effect can only be expected for patients with a high risk for bleeding. http://repub.eur.nl/res/pub/10124/ 2003-01-01T00:00:00Z It is widely known that long-term use of anthranoid-containing laxatives is the cause of melanosis coli. We describe a case of melanosis coli, which occurred in a 39-year-old liver transplant patient who took an over-the-counter product containing aloe, rheum and frangula. The typical brownish pigmentation of the colonic mucosa developed in a period of ten months. The anthranoid medication was stopped and follow-up colonoscopy one year later showed normal looking mucosa once more. However, in contrast to previous examinations, a sessile polypoid lesion was found in the transverse colon. Histology showed tubulovillous adenoma with extensive low-grade dysplasia. Since there have been preliminary reports suggesting a possible role of anthranoid-containing laxatives in the development of colorectal adenomas and cancer, their use should be discouraged. http://repub.eur.nl/res/pub/31990/ 2002-10-16T00:00:00Z Our work focussed on one of the most frequent and serious complications of portal hypertension i.e. variceal bleeding. In particular, studies were initiated aimed at developing a more effective therapeutic strategy for the primary and secondary prevention of variceal bleeding. Aspects of primary prevention of variceal bleeding are discussed in Chapters 2, 3 and 4. Primary prevention implies the need to identify patients at risk. Chapter 2 discusses the feasibility of a simple radiological method to detect oesphageal varices and addresses the reliability of this approach in comparison with the more usual endoscopic diagnostic method. The majority of patients with oesphageal varices will remain free of bleeding. On the other hand, in a proportion of patients variceal haemorrhage will be a fatal event. Therefore, identification of risk factors for variceal bleeding is of paramount importance, in particular with respect to selecting patients for prophylactic therapy. In chapter 3 we report a study assessing the reliability of the NIEC risk score system and report on attempts to further improve its prognostic reliability. Chapter 4 reports the results of a multicentre randomized controlled trial assessing sclerotherapy as prophylaxis for first variceal bleeding. Variceal bleeding is a medical emergency associated with significant morbidity and mortality. In patients with active bleeding one of the medical priorities and challenges is to arrest bleeding. The results of a study on the use of thrombin as an endoscopic haemostatic agent are reported in chapter 5. A number of treatments have been proposed for the secondary prevention of variceal bleeding. Relative new therapeutic options are TIPS and endoscopic band ligation. In chapter 6 we report the results of a randomized controlled clinical trial comparing these treatment modalities, and discuss our results in the context of the cumulative results of comparable studies. http://repub.eur.nl/res/pub/9917/ 2002-01-01T00:00:00Z BACKGROUND: Although bacterial cholangitis is frequently mentioned as a cause of secondary sclerosing cholangitis, it appears to be extremely rare, with only one documented case ever reported. CASE PRESENTATION: A 48-year-old woman presented with an episode of acute biliary pancreatitis that was complicated by pancreatic abcess formation. After 3 months she had an episode of severe pyogenic (E. Coli) cholangitis that recurred over the subsequent 7 months on a further two occasions. Initially, cholangiography suggested the presence of extra-biliary intrahepatic abcesses while repeated investigations demonstrated development of multiple segmental biliary duct strictures. After maintenance antibiotic treatment was started, no episodes of cholangitis occurred over a 14-month period. CONCLUSIONS: Sclerosing cholangitis can rapidly develop after an episode of bacterial cholangitis. Extra-biliary involvement of the hepatic parenchyma with abcess formation may be a risk factor for developing this rare but particularly severe complication. http://repub.eur.nl/res/pub/9685/ 2001-01-01T00:00:00Z The clinical and pathological findings of four females with primary biliary cirrhosis (PBC) with an unusual and hitherto not well recognised course are reported. Patients suffered severe pruritus and weight loss with progressive icteric cholestasis which did not respond to such treatments as ursodeoxycholic acid and immunosuppressives. In all cases liver histology revealed marked bile duct loss without however significant fibrosis or cirrhosis. Further diagnostic studies and repeat biopsies confirmed the absence of liver cirrhosis as well as other potential causes of hyperbilirubinaemia. Comparison of the fibrosis-ductopenia relationship for our cases with that for a group of 101 non-cirrhotic PBC patients indicated that in the former the severity of bile duct loss relative to the amount of fibrosis was significantly higher. The proportion of portal triads containing an interlobular bile duct was 3%, 4%, 6%, and 10% compared with 45% (median; range 8.3--100%) for controls (p<0.001). Three patients received a liver transplant 6--7 years after the first manifestation of PBC because of progressive cholestasis, refractory pruritus, and weight loss, while the fourth patient is considering this option. In one case cirrhosis had developed at the time of transplantation while the others still had non-cirrhotic disease. These cases suggest that cholestatic jaundice in non-cirrhotic PBC may be secondary to extensive "premature" or accelerated intrahepatic bile duct loss. Although the extent of fibrosis may be limited initially, progression to cirrhosis appears to be inevitable in the long run. Despite intact protein synthesis and absence of cirrhotic complications, liver transplantation in the pre-cirrhotic stage for preventing malnutrition and to improve quality of life should be considered for these patients. http://repub.eur.nl/res/pub/8626/ 1996-01-01T00:00:00Z We reported the case of a patient in whom severe, and ultimately fatal, pulmonary hypertension developed 1.5 yrs after transjugular intrahepatic portosystemic shunt (TIPS). Pulmonary artery pressures were not affected by 100% oxygen, prostacyclin or nifedipine. Postmortem examinations showed pulmonary and vascular abnormalities typical of pulmonary hypertension. Pulmonary artery pressures should be measured in each patient with otherwise not readily explained dyspnoea following transjugular intrahepatic portosystemic shunt.