A Prediction Model for Successful Increase of Adalimumab Dose Intervals in Patients with Crohn's Disease: Secondary Analysis of the Pragmatic Open-Label Randomised Controlled Non-inferiority LADI Trial.

BACKGROUND: In the pragmatic open-label randomised controlled non-inferiority LADI trial we showed that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in patients with Crohn's disease (CD) in clinical and biochemical remission. AIMS: To develop a prediction model to identify patients who can successfully increase their ADA dose interval based on secondary analysis of trial data. METHODS: Patients in the intervention group of the LADI trial increased ADA intervals to 3 and then to 4 weeks. The dose interval increase was defined as successful when patients had no persistent flare (> 8 weeks), no intervention-related severe adverse events, no rescue medication use during the study, and were on an increased dose interval while in clinical and biochemical remission at week 48. Prediction models were based on logistic regression with relaxed LASSO. Models were internally validated using bootstrap optimism correction. RESULTS: We included 109 patients, of which 60.6% successfully increased their dose interval. Patients that were active smokers (odds ratio [OR] 0.90), had previous CD-related intra-abdominal surgeries (OR 0.85), proximal small bowel disease (OR 0.92), an increased Harvey-Bradshaw Index (OR 0.99) or increased faecal calprotectin (OR 0.997) were less likely to successfully increase their dose interval. The model had fair discriminative ability (AUC = 0.63) and net benefit analysis showed that the model could be used to select patients who could increase their dose interval. CONCLUSION: The final prediction model seems promising to select patients who could successfully increase their ADA dose interval. The model should be validated externally before it may be applied in clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Cost-Effectiveness Analysis of Increased Adalimumab Dose Intervals in Crohn's Disease Patients in Stable Remission: The Randomized Controlled LADI Trial.

BACKGROUND AND AIMS: We aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn's disease [CD] in stable clinical and biochemical remission. DESIGN: We conducted a pragmatic, open-label, randomized controlled non-inferiority trial, comparing increased adalimumab intervals with the 2-weekly interval in adult CD patients in clinical remission. Quality of life was measured with the EQ-5D-5L. Costs were measured from a societal perspective. Results are shown as differences and incremental net monetary benefit [iNMB] at relevant willingness to accept [WTA] levels. RESULTS: We randomized 174 patients to the intervention [n = 113] and control [n = 61] groups. No difference was found in utility (difference: -0.017, 95% confidence interval [-0.044; 0.004]) and total costs (-€943, [-€2226; €1367]) over the 48-week study period between the two groups. Medication costs per patient were lower (-€2545, [-€2780; -€2192]) in the intervention group, but non-medication healthcare (+€474, [+€149; +€952]) and patient costs (+€365 [+€92; €1058]) were higher. Cost-utility analysis showed that the iNMB was €594 [-€2099; €2050], €69 [-€2908; €1965] and -€455 [-€4,096; €1984] at WTA levels of €20 000, €50 000 and €80 000, respectively. Increasing adalimumab dose intervals was more likely to be cost-effective at WTA levels below €53 960 per quality-adjusted life year. Above €53 960 continuing the conventional dose interval was more likely to be cost-effective. CONCLUSION: When the loss of a quality-adjusted life year is valued at less than €53 960, increasing the adalimumab dose interval is a cost-effective strategy in CD patients in stable clinical and biochemical remission. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Efficacy of different bowel preparation regimen volumes for colorectal cancer screening and compliance with European Society of Gastrointestinal Endoscopy performance measures.

BACKGROUND: Various volumes of bowel preparation are used in clinical practice. There is conflicting data on the effectiveness of individual regimens. This study aims to evaluate the efficacy and compliance of currently used bowel preparations with the European Society of Gastrointestinal Endoscopy (ESGE) performance measures using data of the Dutch nationwide colorectal cancer screening (CRC) program. METHODS: In a prospective, multicenter endoscopy database, we identified all CRC screening colonoscopies performed in 15 Dutch endoscopy centers from 2016 to 2020. We excluded procedures without documented bowel preparation or the Boston Bowel Preparation Scale (BBPS) score. Bowel preparation regimens were categorized into three groups, that is, 4-L (polyethylene glycol (PEG)), 2-L (2-L PEG with ascorbic acid) and ≤1-L volumes (sodium picosulfate with magnesium citrate, 1L-PEG with sodium sulfate and ascorbic acid or oral sulfate solution). European Society of Gastrointestinal Endoscopy performance measures included adequate BBPS score (≥6) (>90%), cecal intubation rate (CIR, >90%), adenoma detection rate (ADR, >25%) and polyp detection rate (PDR, >40%). Logistic regression was performed to identify predictive factors for adequate BBPS and patient discomfort. RESULTS: A total of 39,042 CRC screening colonoscopies were included. Boston Bowel Preparation Scale scores, CIR, ADR and PDR for 4L, 2L and ≤1L regimens all met the minimum ESGE performance measures standards. However, an adequate BBPS score was more frequently seen with 2L regimens (98.0%) as compared to 4L (97.1%) and ≤1L regimens (97.0%) (p < 0.001), respectively. In addition, CIR was higher for ≤1L (98.4%) versus 4L (97.7%) and 2L (97.9%) regimens (p = 0.001), ADR higher for lower volume (≤1L (60.0%) and 2L (61.2)) versus higher volume (4L (58.6%)) regimens (p < 0.001), and PDR higher for ≤1L (70.0%) and 2L (70.8%) versus 4L (67.2%) regimens (p < 0.001). Boston Bowel Preparation Scale for ≤1L regimens was higher when combined with bisacodyl (97.3%) than without (95.6%) (p < 0.001). Overall, bisacodyl use was independently associated with higher patient discomfort (odds ratios = 1.47, confidence intervals = 1.26-1.72). CONCLUSIONS: Despite variations in bowel preparation volumes, all regimens meet the minimum ESGE performance measures for bowel preparation and other quality parameters. Boston Bowel Preparation Scale can be further improved if ultra low volume regimens are combined with bisacodyl. The choice for either bowel preparation volume can therefore be based on volume-tolerance and patient preference.

Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Despite its effectiveness in treating Crohn's disease, adalimumab is associated with an increased risk of infections and high health-care costs. We aimed to assess clinical outcomes of increased adalimumab dose intervals versus conventional dosing in patients with Crohn's disease in stable remission. METHODS: The LADI study was a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial, done in six academic hospitals and 14 general hospitals in the Netherlands. Adults (aged ≥18 years) diagnosed with luminal Crohn's disease (with or without concomitant perianal disease) were eligible when in steroid-free clinical and biochemical remission (defined as Harvey-Bradshaw Index [HBI] score <5, faecal calprotectin <150 µg/g, and C-reactive protein <10 mg/L) for at least 9 months on a stable dose of 40 mg subcutaneous adalimumab every 2 weeks. Patients were randomly assigned (2:1) to the intervention group or control group by the coordinating investigator using a secure web-based system with variable block randomisation (block sizes of 6, 9, and 12). Randomisation was stratified on concomitant use of thiopurines and methotrexate. Patients and health-care providers were not masked to group assignment. Patients allocated to the intervention group increased adalimumab dose intervals to 40 mg every 3 weeks at baseline and further to every 4 weeks if they remained in clinical and biochemical remission at week 24. Patients in the control group continued their 2-weekly dose interval. The primary outcome was the cumulative incidence of persistent flares at week 48 defined as the presence of at least two of the following criteria: HBI score of 5 or more, C-reactive protein 10 mg/L or more, and faecal calprotectin more than 250 µg/g for more than 8 weeks and a concurrent decrease in the adalimumab dose interval or start of escape medication. The non-inferiority margin was 15% on a risk difference scale. All analyses were done in the intention-to-treat and per-protocol populations. This trial was registered at ClinicalTrials.gov, NCT03172377, and is not recruiting. FINDINGS: Between May 3, 2017, and July 6, 2020, 174 patients were randomly assigned to the intervention group (n=113) or the control group (n=61). Four patients from the intervention group and one patient from the control group were excluded from the analysis for not meeting inclusion criteria. 85 (50%) of 169 participants were female and 84 (50%) were male. At week 48, the cumulative incidence of persistent flares in the intervention group (three [3%] of 109) was non-inferior compared with the control group (zero; pooled adjusted risk difference 1·86% [90% CI -0·35 to 4·07). Seven serious adverse events occurred, all in the intervention group, of which two (both patients with intestinal obstruction) were possibly related to the intervention. Per 100 person-years, 168·35 total adverse events, 59·99 infection-related adverse events, and 42·57 gastrointestinal adverse events occurred in the intervention group versus 134·67, 75·03, and 5·77 in the control group, respectively. INTERPRETATION: The individual benefit of increasing adalimumab dose intervals versus the risk of disease recurrence is a trade-off that should take patient preferences regarding medication and the risk of a flare into account. FUNDING: Netherlands Organisation for Health Research and Development.

Sex Differences in Neoplastic Progression in Barrett's Esophagus: A Multicenter Prospective Cohort Study.

Recommendations in Barrett's esophagus (BE) guidelines are mainly based on male patients. We aimed to evaluate sex differences in BE patients in (1) probability of and (2) time to neoplastic progression, and (3) differences in the stage distribution of neoplasia. We conducted a multicenter prospective cohort study including 868 BE patients. Cox regression modeling and accelerated failure time modeling were used to estimate the sex differences. Neoplastic progression was defined as high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Among the 639 (74%) males and 229 females that were included (median follow-up 7.1 years), 61 (7.0%) developed HGD/EAC. Neoplastic progression risk was estimated to be twice as high among males (HR 2.26, 95% CI 1.11-4.62) than females. The risk of HGD was found to be higher in males (HR 3.76, 95% CI 1.33-10.6). Time to HGD/EAC (AR 0.52, 95% CI 0.29-0.95) and HGD (AR 0.40, 95% CI 0.19-0.86) was shorter in males. Females had proportionally more EAC than HGD and tended to have higher stages of neoplasia at diagnosis. In conclusion, both the risk of and time to neoplastic progression were higher in males. However, females were proportionally more often diagnosed with (advanced) EAC. We should strive for improved neoplastic risk stratification per individual BE patient, incorporating sex disparities into new prediction models.

Implementation of mandatory ERCP registration in The Netherlands and compliance with European Society of Gastrointestinal Endoscopy performance measures: a multicenter database study.

BACKGROUND: In 2018, the European Society of Gastrointestinal Endoscopy (ESGE) and United European Gastroenterology (UEG) published quality performance measures for endoscopic retrograde cholangiopancreatography (ERCP). Since January 2016, all endoscopists in the Netherlands have been required to register all ERCP procedures in a nationwide quality registry. This study aimed to evaluate the procedural success rates of ERCP after the implementation of mandatory national registration and to compare these with the ESGE quality performance measures. METHODS: This study was conducted with data from a multicenter endoscopy database. Data from 2019 and 2020 were analyzed. The primary outcome was ERCP procedural outcome. ESGE performance measures that could be evaluated were the percentage of successful bile duct cannulations in patients with virgin papillary anatomy; successful stent placement for a biliary obstruction located below the liver hilum; and complete removal of bile duct stones (< 10 mm). RESULT: In total, 5295 ERCPs performed in 11 centers were included for analysis. The overall procedural success rate was 89.1 %. Successful biliary cannulation in patients with a virgin papilla was 90.3 % in nonacademic and 92.4 % in academic centers. The rates of successful stent placement in patients with a biliary obstruction located below the liver hilum were 97.0 % in nonacademic and 98.2 % in academic centers, and of successful bile duct stone extraction were 97.9 % in both nonacademic and academic centers. CONCLUSIONS: The quality of ERCPs performed met five of the six evaluated ESGE performance measures. The 95 % target for successful biliary cannulation in patients with virgin papillary anatomy in academic centers was not met. Mandatory registration provides valuable insight into ERCP performance rates.

Health outcomes of 1000 children born to mothers with inflammatory bowel disease in their first 5 years of life.

OBJECTIVE: The aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes. DESIGN: We performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies. RESULTS: We included 1000 children born to 626 mothers (381 (61%) Crohn's disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population. CONCLUSION: In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies.

Impact of the COVID-19 pandemic on gastrointestinal endoscopy in the Netherlands: analysis of a prospective endoscopy database.

BACKGROUND: COVID-19 has dramatically affected gastrointestinal endoscopy practice. We aimed to investigate its impact on procedure types, indications, and findings. METHODS: We retrospectively analyzed endoscopies performed in 15 Dutch hospitals by comparing periods 15 March to 25 June of 2019 and 2020 using the prospective Trans.IT database. RESULTS: During lockdown in 2020, 9776 patients underwent endoscopy compared with 19 296 in 2019. Gastroscopies decreased by 57 % (from 7846 to 4467) and colonoscopies by 45 % (from 12219 to 5609), whereas endoscopic retrograde cholangiopancreatography volumes remained comparable (from 578 to 522). Although endoscopy results indicative of cancer decreased (from 524 to 340), the likelihood of detecting cancer during endoscopy increased (2.7 % [95 % confidence interval (CI) 2.5 - 3.0] in 2019 versus 3.5 % [95 %CI 3.1 - 3.9] in 2020; P < 0.001). After lifting of lockdown, endoscopy volumes started to return to normal, except for colorectal cancer screening. CONCLUSIONS: Fewer endoscopies were performed during the COVID-19 lockdown, leading to a significant reduction in the absolute detection of cancer. Endoscopies increased rapidly after lockdown, except for colorectal cancer screening.

Fully vs. partially covered selfexpandable metal stent for palliation of malignant esophageal strictures: a randomized trial (the COPAC study).

BACKGROUND: Covered esophageal self-expandable metal stents (SEMSs) are currently used for palliation of malignant dysphagia. The optimal extent of the covering to prevent recurrent obstruction is unknown. Therefore, we aimed to compare fully covered (FC) versus partially covered (PC) SEMSs in patients with incurable malignant esophageal stenosis. METHODS: In this multicenter randomized controlled trial, 98 incurable patients with dysphagia caused by a malignant stricture of the esophagus or cardia were randomized 1:1 to an FC-SEMS or PC-SEMS. The primary outcome was recurrent obstruction after endoscopic SEMS placement. Secondary outcomes were technical and clinical success, adverse events, and health-related quality of life (HRQoL). Patients were followed until 6 months after SEMS placement or to SEMS removal, second SEMS insertion, or death, whichever came first. RESULTS: Recurrent obstruction after SEMS placement was similar for both types of stents: 19 % for FC-SEMSs and 22 % for PC-SEMSs (P = 0.65). The times to recurrent obstruction did not differ. The frequency of adverse events was similar between the two groups, with major adverse events occurring in 38 % and 47 % of patients for FC-SEMSs and PC-SEMSs, respectively (P = 0.34). No significant differences were seen in technical success, improvement of dysphagia, and HRQoL. Proximal esophageal stenosis and female sex were independently associated with recurrent obstruction and/or major adverse events. CONCLUSIONS: Esophageal FC-SEMSs did not reveal a lower recurrent obstruction rate compared with PC-SEMSs in the palliative management of malignant dysphagia.

The Polyp Manager: a new tool for optimal polyp documentation during colonoscopy. A pilot study.

BACKGROUND AND STUDY AIMS: Conventional reporting of polyps is often incomplete. We tested the Polyp Manager (PM), a new software application permitting the endoscopist to document polyps in real time during colonoscopy. We studied completeness of polyp descriptions, user-friendliness and the potential time benefit. PATIENTS AND METHODS: In two Dutch hospitals colonoscopies were performed with PM (as a touchscreen endoscopist-operated device or nurse-operated desktop application). Completeness of polyp descriptions was compared to a historical group with conventional reporting (CRH). Prospectively, we compared user-friendliness (VAS-scores) and time benefit of the endoscopist-operated PM to conventional reporting (CR) in one hospital. Duration of colonoscopy and time needed to report polyps and provide a pathology request were measured. Provided that using PM does not prolong colonoscopy, the sum of the latter two was considered as a potential time-benefit if the PM were fully integrated into a digital reporting system. RESULTS: A total of 144 regular colonoscopies were included in the study. Both groups were comparable with regard to patient characteristics, duration of colonoscopy and number of polyps. Using the PM did reduce incomplete documentation of the following items in CRH-reports: location (96 % vs 82 %, P = 0.01), size (95 % vs 89 %, P = 0.03), aspect (71 % vs 36 %, P < 0.001) and completeness of removal (61 % vs 37 %, P < 0.001). In the prospective study 23 PM-colonoscopies where compared to 28 CR-colonoscopies. VAS-scores were significantly higher in the endoscopist-operated PM group. Time to report was 01:27 ± 01:43 minutes (median + interquartile range) in the entire group (PM as CR), reflecting potential time benefit per colonoscopy. CONCLUSIONS: The PM is a user-friendly tool that seems to improve completeness of polyp reporting. Once integrated with digital reporting systems, it is probably time saving as well.

Comparison of cecal intubation and adenoma detection between hospitals can provide incentives to improve quality of colonoscopy.

BACKGROUND AND STUDY AIMS: Cecal intubation rate (CIR) and adenoma detection rate (ADR) have been found to be inversely associated with the occurrence of post-colonoscopy colorectal cancer. Depicting differences in CIR and ADR between hospitals could provide incentives for quality improvement. The aim of this study was to compare quality parameters of routine colonoscopies between seven hospitals in The Netherlands in order to determine the extent to which possible differences were attributable to procedural and institutional factors. PATIENTS AND METHODS: Consecutive patients undergoing colonoscopy were prospectively included between November 2012 and January 2013 at two academic and five nonacademic hospitals. Patients with inflammatory bowel disease or hereditary colorectal cancer syndromes were excluded. Main outcome measures were CIR and ADR. RESULTS: A total of 3129 patients were included (mean age 59 ±â€Š15 years; 45.5 % male). The majority of patients (86.2 %) had a Boston Bowel Preparation Scale (BBPS) score ≥ 6. Overall CIR was 94.8 %, ranging from 89.4 % to 99.2 % between hospitals. After adjustment for case mix (age, sex, American Society of Anesthesiologists score, and indication for colonoscopy), factors associated with CIR were hospital and a BBPS score ≥ 6. Overall ADR was 31.8 % and varied between hospitals, ranging from 24.8 % to 46.8 %. Independent predictors for ADR were hospital, BBPS score ≥ 6, and cecal intubation. By combining CIR and ADR for each hospital, a colonoscopy quality indicator (CQI) was developed, which can be used by hospitals to stimulate quality improvement. CONCLUSION: Differences in the quality of colonoscopy between hospitals can be demonstrated using CIR and ADR. As both indicators are affected by institution and bowel preparation, a comparison between hospitals based on the newly developed CQI could assist in further improving the quality of colonoscopy.

Predicting inadequate bowel preparation for colonoscopy in participants receiving split-dose bowel preparation: development and validation of a prediction score.

BACKGROUND: Adequate bowel preparation is important for optimal colonoscopy. It is important to identify patients at risk for inadequate bowel preparation because this allows taking precautions in this specific group. OBJECTIVE: To develop a prediction score to identify patients at risk for inadequate bowel preparation who may benefit from an intensified bowel cleansing regimen. DESIGN: Patient and colonoscopy data were prospectively collected, whereas clinical data were retrospectively collected for a total of 1996 colonoscopies in participants who received split-dose bowel preparation. Multivariate logistic regression analyses were conducted in a random two-thirds of the cohort to develop a prediction model. Validation and evaluation of the discriminative power of the prediction model were performed within the remaining one-third of the cohort. SETTING: Four centers, including one academic and three medium-to-large size nonacademic centers. PATIENTS: Consecutive colonoscopies in November and December 2012. Mean age was 57.3 ± 15.9 years, 45.8% were male and indications for colonoscopy were screening and/or surveillance (27%), abdominal symptoms and/or blood loss and/or anemia (60%), inflammatory bowel disease (9%), and others (4%). INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Inadequate bowel preparation defined as Boston Bowel Preparation Scale score <6. RESULTS: A total of 1331 colonoscopies were included in the development cohort, of which 172 (12.9%) had an inadequate bowel preparation. Independent factors included in the prediction model were American Society of Anesthesiologists Physical Status Classification System score ≥3, use of tricyclic antidepressants, use of opioids, diabetes, chronic constipation, history of abdominal and/or pelvic surgery, history of inadequate bowel preparation, and current hospitalization. The discriminative ability of the scale was good, with an area under the curve of 0.77 in the validation cohort. LIMITATIONS: Study design partially retrospective, no data on patient compliance. CONCLUSION: We developed a validated, easy-to-use prediction scale that can be used to identify subjects with an increased risk of inadequate bowel preparation with good accuracy.

Pregnancy and ABCB4 gene mutation: risk of recurrent cholelithiasis.

Cholelithiasis is a common problem in the Western world. Recurrent gallstones after cholecystectomy, however, are rare. We describe a case of a young woman with recurrent gallstones after a laparoscopic cholecystectomy leading to cholangitis during pregnancy. Additional testing revealed an ATP-binding cassette B4 (ABCB4) gene mutation. ABCB4 gene mutations leading to a multidrug resistance (MDR)3-P-glycoprotein deficiency are related to, among other diseases, recurrent cholelithiasis. Medical treatment consists of administering oral ursodeoxycholic acid. If untreated, MDR3 deficiency can lead to progressive liver failure requiring liver transplantation.

[A patient with an alpha-foetoprotein producing tumour]. / Een patiënt met een alfafoetoproteïneproducerende tumor.

A 45-year-old Turkish man presented with a chronic hepatitis B virus infection, a nodular lesion in the liver and a highly elevated serum alpha-foetoprotein (AFP) concentration. Ultrasound and MRI showed multiple focal liver lesions and a thickened wall of the gastro-oesophageal junction. Biopsies taken from both sites showed stomach type mucosa with a poorly differentiated adenocarcinoma and AFP positive tumour cells. The diagnosis was hepatoid adenocarcinoma of the stomach. The authors' conclusion is that an elevated serum AFP concentration in a patient with chronic hepatitis B and a nodular lesion in the liver is not diagnostic for a hepatocellular carcinoma. AFP measurement should not be used as a screening method for this type of cancer.

Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis.

BACKGROUND/AIMS: Former studies reported a high prevalence of depression in patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). These studies hypothesized that the presence of depression could explain the fatigue experienced by these patients. METHODS: Our aim was to study the prevalence of depression in a Dutch population with PBC and PSC. In addition, to investigating 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.

Prognosis of ursodeoxycholic Acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients.

BACKGROUND AND AIMS: The therapeutic potential of ursodeoxycholic acid (UDCA) treatment in primary biliary cirrhosis (PBC) remains controversial. In addition, relatively few data have been reported on the outcome of patients who have been treated long term. The aim of the present study was to document long-term survival of a prospectively followed large cohort of UDCA treated patients in comparison to that predicted by the Mayo model and of a matched control cohort of the Dutch population. METHODS: Two hundred ninety-seven patients were included and followed during a median period of 68 (range 3-126) months until death or the end of the study. RESULTS: Survival free of transplantation (1 yr 99.7%, 5 yr 87%, and 10 yr 71%) was significantly better than predicted by the Mayo model (p= 0.01). However, for patients with abnormal serum bilirubin and/or albumin concentrations at entry, observed and predicted survival did not significantly differ. Compared with survival for a standardized cohort of the Dutch population, observed survival for the total group was significantly decreased (p= 0.0003); for noncirrhotic patients and patients with normal entry bilirubin and albumin concentrations survival was comparable. Serum bilirubin and albumin concentrations were the prognostic factors most consistently associated with survival. CONCLUSIONS: A 10-year prognosis for most UDCA-treated patients with PBC, i.e., those with a normal bilirubin and albumin concentration, is comparable to that of a matched general population. Our finding that observed survival was significantly better than predicted by the Mayo model may suggest that this model did not accurately predict prognosis in our cohort. Alternatively, this finding indicates an important therapeutic effect of long-term UDCA treatment in PBC, particularly in patients with noncirrhotic, nonadvanced disease.

The relation between plasma tyrosine concentration and fatigue in primary biliary cirrhosis and primary sclerosing cholangitis.

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.

Fluvoxamine for fatigue in primary biliary cirrhosis and primary sclerosing cholangitis: a randomised controlled trial [ISRCTN88246634].

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.

Transjugular intrahepatic portosystemic shunts: long-term patency and clinical results in a patient cohort observed for 3-9 years.

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.