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Introduction Arthralgia and MRI-detected subclinical inflammation can precede the development of clinically evident rheumatoid arthritis (RA). However, part of the patients presenting with clinically suspect arthralgia (CSA) do not progress to RA. In these ‘non-progressors’, we aimed to study the frequencies of spontaneous improvement of arthralgia and its relation with the course of subclinical inflammation. Methods Between April 2012 and April 2015, 241 patients were considered at risk for RA based on the clinical presentation and included in the CSA cohort. One hundred fifty-two patients with complete data on clinical follow-up did not develop clinical arthritis, of which 98 underwent serial 1.5T MRI scans (wrist, MCP2–5, and MTP1–5 joints) at baseline and after 2 years. MRI scans were scored for synovitis, tenosynovitis, and bone marrow oedema (summed: MRI inflammation score). MRI scores were compared to scores of symptom-free persons. Results After a 2-year follow-up, 33% of the ‘non-progressors’ had complete resolution of symptoms; 67% had no symptom resolution and were diagnosed as persistent CSA (44%), osteoarthritis (10%), and tendinomuscular complaints (13%). With symptom-free controls as a reference, patients without resolution did not have increased MRI scores at any time point. However, patients achieving resolution of symptoms had increased MRI inflammation scores at baseline (4.0 vs. 2.6, p = 0.037), but not after 2 years (3.0 vs. 2.6; p = 0.57), and during follow-up, their MRI inflammation score decreased significantly (p = 0.036). Conclusions A subgroup of CSA patients that did not progress to RA had spontaneous improvement of symptoms and resolution of subclinical joint inflammation. This time relationship suggests that symptoms and inflammation were causally related in these patients. Further research is needed to identify the mechanisms underlying the resolution of inflammation.

Recently a EULAR-taskforce defined arthralgia suspicious for progression to RA, in order to allow inclusion of homogeneous sets of arthralgia patients in clinical studies. This longitudinal study aimed (i) to validate this definition in arthralgia patients in whom rheumatologists felt that imminent RA was more likely than other arthralgias [clinically suspect arthralgia (CSA)], that is, the target population fulfilling the entry criterion, and (ii) to explore the performance in arthralgia patients who were referred to secondary care prior to rheumatological evaluation, hence ignoring the entry criterion. The definition was assessed in 241 Dutch patients identified with CSA by rheumatologists and 113 patients referred to the Umeå university hospital with recent-onset arthralgia in small joints. The external reference was arthritis development

ObjectivesNational and international guidelines recommend prompt referral of patients presenting with inflammatory arthritis (IA), but general practitioners (GPs) feel uncertain in their proficiency to detect synovitis through joint examination, the method of choice to identify IA. Our objective was to develop and validate a rule composed of clinical characteristics to assist GPs and other physicians in identifying IA when in doubt.DesignSplit-sample derivation and validation study.SettingThe Leiden Early Arthritis Recognition Clinic (EARC), a screening clinic for patients in whom GPs suspected but were unsure of the presence of IA.Participants1288 consecutive patients visiting the EARC.Primary and secondary outcome measuresAssociations of clinical characteristics with presence of IA were determined using logistic regression in 644 patients, while validating the results in the other 644 patients (split-sample validation). To facilitate application in clinical practice, a simplified rule (with scores ranging from 0 to 7.5) was derived and validated.ResultsIA was identified by a rheumatologist in 41% of patients. In univariable analysis, male gender, age ≥60 years, symptom duration 60 min, a low number of painful joints (1–3 joints), presence of patient-reported joint swelling and difficulty with making a fist were associated with IA in the derivation data set. Using multivariable analysis, a simplified rule consisting of these seven items was derived and validated, yielding an area under the receiver operator characteristic curve (AUC) of 0.74 (95% CI 0.70 to 0.78) in the derivation data set. Validation yielded an AUC of 0.71 (95% CI 0.67 to 0.75). Finally, the model was repeated to study predicted probabilities with a lower prevalence of inflammatory arthritis to simulate performance in primary care settings.ConclusionsOur rule, composed of clinical parameters, had reasonable discriminative ability for IA and could assist physicians in decision-making in patients with suspected IA, increasing appropriateness of healthcare utilisation.

Objective Subclinical joint inflammation in patients with arthralgia is predictive for progression to rheumatoid arthritis (RA). However, the time course of progression for bone marrow edema (osteitis), synovitis, and/or tenosynovitis is unsettled. This longitudinal study assessed the course of magnetic resonance imaging (MRI)-detected subclinical joint inflammation during progression to RA. Methods Patients that progressed from clinically suspect arthralgia (CSA) to RA underwent 1.5-T MRI of the metacarpophalangeal (MCP), wrist, and metatarsophalangeal (MTP) joints at presentation with arthralgia and at first identification of synovitis assessed through physical examination (n = 31). MRIs were evaluated for osteitis, synovitis, tenosynovitis, and erosions by two readers, blinded for clinical data and order in time. To estimate changes in MRI scores between the asymptomatic state and CSA onset, scores of MRI features at CSA baseline were compared with scores from age-matched symptom-free persons. Results At presentation with CSA, synovitis and tenosynovitis scores were higher than scores from age-matched symptom-free persons (p = 0.004 and p = 0.001, respectively). Anti-citrullinated protein antibody (ACPA)-positive arthralgia patients also had increased osteitis scores (p = 0.04). Median duration between presentation with arthralgia and RA development was 17 weeks. During progression to RA, synovitis and osteitis increased significantly (p = 0.001 and p = 0.036, respectively) in contrast to tenosynovitis and erosion scores. This pattern was similar in both ACPA subsets, although statistical significance was reached for synovitis and osteitis in ACPA-negative but not ACPA-positive RA. Conclusion Increased tenosynovitis and synovitis scores at CSA onset and the increase in synovitis and osteitis during progression to RA suggest an ‘outside-in’ temporal relationship of arthritis development, in particular for ACPA-negative RA. For ACPA-positive RA, further studies are needed. Electronic supplementary material The online version of this article (10.1186/s13075-018-1756-z) contains supplementary material, which is available to authorized users.

Background The presence of autoantibodies is considered an important characteristic of rheumatoid arthritis (RA); therefore, both anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are included in the 2010 classification criteria for rheumatoid arthritis (RA). However, a considerable number of RA patients lack both these autoantibodies. Recently, several novel autoantibodies have been identified but their value for the classification of RA patients is unclear. Therefore, we studied the value of novel autoantibodies using the presence of anticarbamylated protein (anti-CarP) antibodies as an example for predicting RA development in patients with undifferentiated arthritis (UA). Methods There were 1352 UA patients included in the Leiden Early Arthritis Clinic (EAC) cohort according to the 1987 criteria. When the 2010 criteria were used, there were 838 UA patients. Of these, we evaluated whether they fulfilled the 1987 or 2010 criteria after 1 year, respectively. Logistic regression analyses were performed with RA as outcome and ACPA, RF, and anti-CarP antibodies as predictors. Analyses were repeated after stratification for ACPA and RF. Results Thirty-three percent of the 1987-UA patients and 6% of the 2010-UA patients progressed to RA during the first year of follow-up. For the 1987-UA patients, anti-CarP antibodies were associated with progression to RA, an association which remained when a correction was made for the presence of ACPA and RF (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.2–2.4). After stratification for ACPA and RF, anti-CarP antibodies were associated with progression to RA only for ACPA- and RF-negative patients (OR 2.1, 95% CI 1.3–3.7). For the 2010-UA patients, anti-CarP antibodies were associated with progression to RA; however, they were not when a correction was made for the presence of ACPA and RF (OR 0.8, 95% CI 0.3–2.1). Conclusions Our finding that anti-CarP antibodies have no additional value when RA is defined according to the 2010 criteria might be inherent to the composition of the 2010 criteria and therefore might also apply to other novel autoantibodies. Potentially it would be interesting to evaluate other, non-autoantibody biomarkers.

Pregnant women with bleeding disorders require specialised peripartum care to prevent postpartum haemorrhage (PPH). If third trimester coagulation factor levels are = 500 mL within 24h postpartum and severe PPH as blood loss >= 1000 mL. Primary PPH was observed in 62 deliveries (34%), 14 (8%) of which resulted in severe PPH. In 26 deliveries prophylactic treatment was administered due to factor levels below the 0.50 IU mL(-1) cut-off in the third trimester, 14 of which (54%) were complicated by PPH. We found an increased PPH risk in deliveries given prophylactic treatment compared with deliveries without (OR 2.7, 95% CI 1.2-6.3). In conclusion, PPH incidence was highest in deliveries with the lowest factor levels in the third trimester. Currently, delivery outcome in women with bleeding disorders is unsatisfactory, given the high PPH incidence despite specialised care. Future studies are required to optimise management of deliveries in this patient population.

INTRODUCTION: Autoantibody testing is helpful to predict the risk of progression to clinical arthritis in subjects at risk. Previous longitudinal studies have mainly selected autoantibody-positive arthralgia patients and, consequently, the predictive values of autoantibodies were evaluated relative to each other. This study assessed risks for arthritis development of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF) and/or anti-carbamylated protein antibodies (anti-CarP) in arthralgia patients considered at risk for RA by rheumatologists based on clinical characteristics (Clinically Suspect Arthralgia, CSA). METHODS: Baseline ACPA, RF and anti-CarP autoantibody-status of 241 patients, consecutively included in the CSA-cohort, was studied for risk of developing clinical arthritis during a median follow-up of 103 (IQR 81-114) weeks. RESULTS: Univariable associations for arthritis development were observed for ACPA, RF and anti-CarP antibodies; Hazard Ratios (95%CI) were 8.5 (4.7-15.5), 5.1 (2.8-9.3) and 3.9 (1.9-7.7) respectively. In multivariable analysis, only ACPA was independently associated (HR 5.1; 2.0-13.2). Relative to autoantibody-negative CSA-patients, ACPA-negative/RF-positive patients had HRs of 2.6 (1.04-6.6), ACPA-positive/RF-negative patients 8.0 (2.4-27.4), and ACPA-positive/RF-positive patients 10.5 (5.4-20.6). Positive predictive values (PPV) for development of clinical arthritis within two years were: 38% for ACPA-negative/RF-positive, 50% for ACPA-positive/RF-negative and 67% for ACPA-positive/RF-positive patients. Higher ACPA-levels were not significantly associated with increased progression to clinical arthritis, in contrast to higher RF-levels. Autoantibody levels were stable during follow-up. CONCLUSION: ACPA conferred the highest risk for arthritis development and had an additive value to RF. However, >30% of ACPA-positive/RF-positive CSA-patients did not develop arthritis during two-year follow-up. Thus, CSA and information on autoantibodies is insufficient to accurately identify imminent autoantibody-positive RA.

Objectives The use of hand and foot MRI in the diagnostic process of RA has been advocated. Recent studies showed that MRI is helpful in predicting progression from clinically suspect arthralgia (CSA) to clinical arthritis, and from undifferentiated arthritis (UA) to RA. Symptom-free persons can also show inflammation on MRI. This study aimed to evaluate if MRI findings in symptom-free volunteers are relevant when defining a positive MRI. Methods Two hundred and twenty-five CSA patients and two hundred and one UA patients underwent MRI of MCP, wrist and MTP joints at baseline and were followed for 1 year on progression to arthritis and RA, respectively, as reported previously. MRI was considered positive if ⩾ 1 joint showed inflammation (called uncorrected definition), or if ⩾ 1 joint had inflammation that was present in < 5% of persons of the same age category at the same location (called 5% corrected definition). Test characteristics were compared for both definitions. Results By using MRI data of symptom-free volunteers as reference, specificity of MRI-detected inflammation increased from 22 to 56% in CSA patients, and from 10 to 36% in UA patients. The sensitivity was not affected; it was 88 and 85% in CSA patients and 93 and 93% in UA patients. The accuracy also increased, from 32 to 60% in CSA patients and 22 to 44% in UA patients. Conclusion The use of a reference population resulted in a substantial reduction of false-positive results, without influencing the sensitivity. Although common for other tests in medicine, this phenomenon is novel for MRI in the early detection of RA.

OBJECTIVES: Magnetic resonance imaging (MRI) is recommended in the diagnostic process of rheumatoid arthritis (RA), to detect joint damage early. MRI-detected erosions are also present in symptom-free controls, especially at older age. It is unclear if RA-specific MRI-detected erosions can be distinguished from ‘physiological’ erosions in symptom-free individuals. This study compared MRI-detected erosions of RA-patients with healthy controls and with other arthritides. METHODS: 589 newly-presenting early arthritis patients (238 RA, 351 other arthritides) and 193 symptom-free controls underwent contrast-enhanced 1.5T MRI of unilateral metacarpophalangeal- and metatarsophalangeal(MTP)-joints. Total erosion score (according to RAMRIS), number, severity, location of erosions and simultaneous presence of MRI-detected inflammation (synovitis and/or bone marrow edema) were compared; participants were categorized in three age-groups (

BackgroundThe phase of arthralgia is the earliest moment to clinically recognize patients who may develop Rheumatoid Arthritis (RA). Previous imaging studies in the arthralgia phase have shown that inflammation precedes RA development. It is unknown which symptoms/characteristics relate to subclinical joint inflammation as measured by MRI. Among all patients with arthralgia, those with clinically suspect arthralgia (CSA) are suspected to progress to arthritis according to the clinical judgement of their rheumatologists. We determined the symptoms/characteristics of patients with CSA who had inflammation on MRI.Methods102 patients with CSA and without clinical arthritis were included. They completed questionnaires, underwent joint counts and unilateral 1.5 T MRI of MCP joints 2–4, wrist and MTP joints 1–5. Synovitis, bone marrow oedema (BME) and tenosynovitis were scored according to the OMERACT rheumatoid arthritis MRI scoring system. Symptoms and signs were related to MRI inflammation (based on MRI scores in symptom-free controls; a sum of synovitis, BME and tenosynovitis scores ≥3 was considered positive). Whether certain clinical characteristics frequently occurred together with MRI inflammation was studied by partial least squares analysis.ResultsMRI was performed in 93 patients with CSA, 44% of whom had subclinical MRI inflammation. Synovitis was the most prevalent inflammatory feature on MRI (20%). Patients with MRI inflammation were older and were more frequently positive for anti-citrullinated peptide antibodies than patients without MRI inflammation (pConclusionsSubclinical inflammation as measured by MRI is present in 44% of patients with CSA. A combination of symptoms/characteristics incompletely differentiated patients with and without MRI inflammation.

Human leucocyte antigen (HLA)-DRB1*13 alleles are associated with protection from anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). It is, however, unknown at which phase of disease development (seroconversion, ACPA maturation, disease onset or outcome) these alleles are most important. We therefore examined the effect of HLA-DRB1*13 on: ACPA presence (systemic autoimmunity associated with RA) in individuals with and without RA, on ACPA characteristics and on clinical outcome measures.The effect of HLA-DRB1*13 on ACPA presence in subjects with or without RA (non-RA) was assessed in the Swedish twin registry (n=10 748). ACPA characteristics were studied in patients with ACPA-positive RA from the Swedish Epidemiological Investigation of RA (EIRA, n=1224) and the Dutch Leiden Early Arthritis Clinic (EAC, n=441). Disease activity at inclusion and disease outcome (disease-modifying antirheumatic drugs (DMARD)-free sustained remission and radiographic progression) was assessed in patients with RA from the EAC.HLA-DRB1*13 is associated with protection from ACPA-positive RA (prevalence 16% vs 28% in ACPA-negative non-RA), but not with significant protection from ACPA in individuals without RA (prevalence: 22%, p value 0.09). HLA-DRB1*13 is associated with lower ACPA-levels (EIRA: 447 U/ml versus 691 U/ml, p value= 0.0002) and decreased citrullinated epitope recognition (EIRA: p0.0001). No association between HLA-DRB1*13 and disease activity or outcome was found.These data indicate that HLA-DRB1*13 mainly affects the onset of ACPA-positive RA in ACPA-positive non-RA individuals. In RA, HLA-DRB1*13 influences ACPA characteristics but not the disease course. This implies that therapeutic strategies aimed at emulating the HLA-DBR1*13 protective effect may be most effective in ACPA-positive healthy individuals at risk for RA.

Patients with clinically suspect arthralgia (CSA) have, according to their rheumatologists, an increased risk of rheumatoid arthritis (RA), but their actual outcome is unexplored. This longitudinal study investigated (1) progression from CSA to clinically detectable arthritis and (2) associations of clinical factors, serological factors (among which are anticitrullinated peptide antibodies (ACPAs)) and MRI-detected subclinical inflammation with arthritis development.150 patients with CSA were followed for ≥6 months. At baseline, clinical and serological data were collected and unilateral 1.5 T-MRI of metacarpophalangeal (MCP), wrist and metatarsophalangeal (MTP) joints was made. MRI scoring was done according to the RA MRI scoring system. Subclinical MRI inflammation was defined based on MRI results of 193 symptom-free persons.During follow-up (median=75 weeks, IQR=41-106 weeks), 30 patients developed clinical arthritis; 87% did so20 weeks after inclusion. In multivariable analyses, age, localisation of initial symptoms in small and large joints (compared with small joints only), C-reactive protein level, ACPA-positivity and subclinical MRI inflammation significantly associated with arthritis development; ACPA and MRI inflammation were most strongly associated (HR (95% CI) respectively, 6.43 (2.57 to 16.05) and 5.07 (1.77 to 14.50)). After 1-year follow-up, 31% of the patients with MRI inflammation and 71% of the ACPA-positive patients with MRI inflammation had progressed to arthritis. Forty-three per cent of the patients that developed arthritis within 1 year were ACPA-negative; 78% of them had subclinical MRI inflammation at baseline. When MRI inflammation was absent arthritis development was infrequent (6% in all patients with CSA and 3% in ACPA-negative patients with CSA).Subclinical MRI inflammation precedes clinical arthritis with a few months. Subclinical MRI inflammation is, independent of other factors such as ACPA, associated with arthritis development.

Objectives. Despite recent progress in biomarker discovery for RA diagnostics, still over one-third of RA patients-and even more in early disease-present without RF or ACPA. The aim of this study was to confirm the presence of previously identified autoantibodies to novel Hasselt University (UH) peptides in early and seronegative RA. Methods. Screening for antibodies against novel UH peptides UH-RA.1, UH-RA.9, UH-RA.14 and UH-RA.21, was performed in two large independent cohorts. Peptide ELISAs were developed to screen for the presence of antibodies to UH-RA peptides. First, 292 RA patients (including 39 early patients), 90 rheumatic and 97 healthy controls from UH were studied. Antibody reactivity to two peptides (UH-RA. 1 and UH-RA. 21) was also evaluated in 600 RA patients, 309 patients with undifferentiated arthritis and 157 rheumatic controls from the Leiden Early Arthritis Clinic cohort. Results. In both cohorts, 38% of RA patients were seronegative for RF and ACPA. Testing for autoantibodies to UH-RA. 1 and UH-RA. 21 reduced the serological gap from 38% to 29% in the UH cohort (P = 0.03) and from 38% to 32% in the Leiden Early Arthritis Clinic cohort (P = 0.01). Furthermore, 19-33% of early RA patients carried antibodies to these peptides. Specificities in rheumatic controls ranged from 82 to 96%. Whereas antibodies against UH-RA. 1 were related to remission, anti-UH-RA. 21 antibodies were associated with inflammation, joint erosion and higher tender and swollen joint counts. Conclusion. This study validates the presence of antibody reactivity to novel UH-RA peptides in seronegative and early RA. This might reinforce current diagnostics and improve early diagnosis and intervention in RA.

Objectives To assess the diagnostic value of MRI for early RA. In some RA patients, a classifiable diagnosis cannot be made at first presentation; these patients present with unclassified arthritis (UA). The use of MRI for early diagnosis of RA is recommended, yet the evidence for its reliability is limited. Methods MRI of hand and foot was performed in 589 early arthritis patients included in the Leiden Early Arthritis Clinic (229 presented with RA, 159 with other arthritides and 201 with UA). Symptom-free controls provided a reference for defining an abnormal MRI. In preliminary investigations, MRI of patients who presented with RA was compared with MRI of symptom-free controls and of patients with other arthritides. Thereafter, the value of MRI in early RA diagnosis was determined in UA patients using the 1-year follow-up on fulfilling the 1987 RA criteria and start of disease-modifying drugs as outcomes. Results Preliminary investigations were promising. Of the UA patients, 14% developed RA and 37% started disease-modifying treatment. MRI-detected tenosynovitis was associated with RA development independent of other types of MRI-detected inflammation [odds ratio (OR) = 7.5, 95% CI: 2.4, 23] and also independent of age and other inflammatory measures (swollen joints, CRP) (OR = 4.2, 95% CI: 1.4, 12.9). Within UA patients, the negative predictive value of abnormal tenosynovitis was 95% (95% CI: 89%, 98%) and the positive predictive value 25% (95% CI: 17%, 35%). The performance was best in the subgroup of UA patients presenting with oligoarthritis (18% developed RA): the positive predictive value was 36% (95% CI: 23%, 52%), the negative predictive value was 98% (95% CI: 88%, 100%), the sensitivity was 93% (95% CI: 70%, 99%) and the specificity was 63% (95% CI: 51%, 74%). Conclusion MRI contributes to the identification of UA patients who will develop RA, mostly in UA patients presenting with oligoarthritis.

The use of magnetic resonance imaging (MRI)-detected inflammation and joint damage in the diagnosis of rheumatoid arthritis is recommended by a European League Against Rheumatism imaging task force. This recommendation is based on the sensitivity of MRI and not on specificity. Knowledge of the prevalence of MRI-detected features in symptom-free persons, however, is pivotal when considering MRI for diagnostic purposes.From November 2013 to December 2014, 196 symptom-free persons of different ages were recruited from the general population. Inclusion criteria were no history of inflammatory arthritis, no joint symptoms during the previous month, and no clinically detectable arthritis on physical examination. Contrast-enhanced MRIs of the dominant metacarpophalangeal (MCP), wrist, and metatarsophalangeal (MTP) joints were obtained using a 1.5T scanner and scored by 2 readers for synovitis, bone marrow edema, tenosynovitis, and erosions. For analyses at the joint level, MRI-detected inflammation was considered present if both readers scored the image as positive.Of 193 persons scanned (ages 19-89 years), only 28% had no single inflammatory feature and 22% had no erosions. Primarily low-grade features were observed. All MRI features were positively correlated with age (P 0.001). Preferential locations for synovitis were MCP2, MCP3, the wrists, and MTP1. Bone marrow edema was frequently present in MCP3, the scaphoid, and MTP1. Tenosynovitis was infrequent, except for in the extensor carpi ulnaris. Preferential locations for erosions were MCP2, MCP3, MCP5, the distal ulna, MTP1, and MTP5. Tables with age-, location-, and inflammation type-dependent frequencies were constructed. Simultaneous colocalized presence of synovitis, bone marrow edema, tenosynovitis, or erosions occurred.MRI-detected inflammation and erosions are prevalent in symptom-free persons from the general population, especially at older ages and at preferential locations.

Background: Wider utilization of liver grafts from donors

Orthotopic liver transplantation (OLT) (LTx) using donation after circulatory death (DCD) donors is increasingly performed, but still considered to risk of poorer outcomes compared with standard donations after brain death (DBD)-OLT. Therefore we reviewed our results of DCD-OLT.Between 2003 and 2010, we performed 30 DCD-OLT (6% of all OLT). We retrospectively reviewed medical records of donors and recipients after DCD versus DBD-OLT to analyze biliary complications, retransplantation rates, and patient/graft survivals.Median donor age was similar for DCD and DBD-OLT: 51 versus 53 years (P = .244). Median donor warm ischemia time (stop ventilation to cold perfusion in DCD donors) was 24 minutes. Median cold ischemia time was shorter for DCD (6 hours 54 minutes) compared with DBD-OLT (8 hours 36 minutes; P.0001). Median laboratory model of end-stage liver disease score was 15 for DCD, and 16 for DBD-OLT (P = .59). Median post-OLT Aspartate Aminotransferase (AST) peak was higher after DCD: 1178 versus DBD-OLT 651 IU/L (P = .005). The incidence of nonanastomotic strictures was different: 33.3% for DCD versus 12.5% for DBD-OLT (P = .001). The overall retransplantation rate was 3% after both DCD and DBD-OLT. After DCD-LTx actuarial 1, 3- and 5-year patient survivals were 93, 85 and 85%, and corresponding graft survivals, 90%, 82%, and 82% respectively, and not different compared with DBD-OLT: 88%, 78%, and 72% (P = .348) and 85%, 74%, and 68% (P = .524) respectively.Despite substantial ischemic injury (high peak AST and biliary strictures) short- and long-term survival after DCD-OLT was comparable to DBD-OLT. Rapid donor surgery, careful donor and recipient selection, as well as short warm and cold ischemia times are key factors to optimize outcomes after DCD-OLT. However, strategies to reduce biliary complications remain warranted.

Biliary strictures (BS), a major complication after orthotopic liver transplantation (OLT), cause morbidity, mortality, graft loss, and increased costs. The virtually unchanged incidence of BS (approximately 10%-25%) suggests that they are not simply "technical" in origin, but probably represent a mucosa ischemic injury inherent in the transplantation procedure. To study risk factors for BS, we analyzed 403 OLTs performed between January 1, 1997 and December 31, 2006, at a single center, excluding cases of regraft or death within 1 month. The average time to the diagnosis of the BS was 253 days (range, 7-1002 days). Upon univariate analysis, the absence of flushing of donor bile ducts, an imported versus a locally procured liver, and rejection were risk factors for BS. In contrast, the following factors were protective: donor cardiac arrest followed by resuscitation (suggesting an ischemic preconditioning effect) as well as addition of epoprostenol to and pressurization of the preservation solution. Patients with higher postoperative peak values of transaminases, bilirubin, alkaline phosphatase, and gamma glutamyl transpeptidase were at greater risk for later development of BS. Donor hypotension, donor age, donor intensive care unit (ICU) stay, type of preservation, positive cross-match, cold and warm ischemia times, sequential versus simultaneous portal/arterial reperfusion, as well as cytomegalovirus (CMV) infection were not risk factors for BS. Upon multivariate analysis, only epoprostenol and pressurization offered protection from BS. In conclusion, this study 2 novel points: (1) patients with high(er) transaminase values and cholestasis early postoperatively are at greater risk to develop later BS and require close monitoring and (2) donor maneuvers for better flushing and preserving peribiliary vascular plexus and biliary mucosa (epoprostenol and pressurization of preservation solution) offer protection from BS.

The probability that a patient has common bile duct stones (CBDS) is a key factor in determining diagnostic and treatment strategies. This prospective cohort study evaluated the accuracy of clinical models in predicting CBDS for patients who will undergo cholecystectomy for lithiasis.From October 2005 until September 2006, 335 consecutive patients with symptoms of gallstone disease underwent cholecystectomy. Statistical analysis was performed on prospective patient data obtained at the time of first presentation to the hospital. Demonstrable CBDS at the time of endoscopic retrograde cholangiopancreatography (ERCP) or intraoperative cholangiography (IOC) was considered the gold standard for the presence of CBDS.Common bile duct stones were demonstrated in 53 patients. For 35 patients, ERCP was performed, with successful stone clearance in 24 of 30 patients who had proven CBDS. In 29 patients, IOC showed CBDS, which were managed successfully via laparoscopic common bile duct exploration, with stone extraction at the time of cholecystectomy. Prospective validation of the existing model for CBDS resulted in a predictive accuracy rate of 73%. The new model showed a predictive accuracy rate of 79%.Clinical models are inaccurate in predicting CBDS in patients with cholelithiasis. Management strategies should be based on the local availability of therapeutic expertise.

Introduction The western population is ageing. It is unknown whether age at diagnosis affects the severity of Rheumatoid Arthritis (RA), we therefore performed the present study. Method 1,875 RA-patients (7,219 radiographs) included in five European and North-American cohorts (Leiden-EAC, Wichita, Umeå, Groningen and Lund) were studied on associations between age at diagnosis and joint damage severity. In 698 Leiden RA-patients with 7-years follow-up it was explored if symptom duration, anti-citrullinated-peptide-antibodies (ACPA), swollen joint count (SJC) and C-reactive-protein (CRP) mediated the association of age with joint damage. Fifty-six other RA-patients of the EAC-cohort underwent baseline MRIs of wrist, MCP and MTP-joints; MRI-inflammation (RAMRIS-synovitis plus bone marrow edema) was also evaluated in mediation analyses. Linear regression and multivariate normal regression models were used. Results Analysis on the five cohorts and the Leiden-EAC separately revealed 1.026-fold and 1.034-fold increase of radiographic joint damage per year increase in age (β=1.026, 1.034, both p

The role of mid-cingulate cortex (MCC), also referred to as dorsal anterior cingulate cortex, in regulating cognitive control is a topic of primary importance in cognitive neuroscience. Although many studies have shown that MCC responds to cognitive demands, lesion studies in humans are inconclusive concerning the causal role of the MCC in the adaptation to these demands. By elegantly combining single-cell recordings with behavioural methods, Sheth et al. [Sheth, S. et al. Human dorsal anterior cingulate cortex neurons mediate ongoing behavioural adaptation. Nature 488, 218–22 (2012).] recently were able to show that neurons in MCC encode cognitive demand. Importantly, this study also claimed that focal lesions of the MCC abolished behavioural adaptation to cognitive demands. Here we show that the absence of post-cingulotomy behavioural adaptation reported in this study may have been due to practice effects. We run a control condition where we tested subjects before and after a dummy treatment, which substituted cingulotomy with a filler task (presentation of a documentary). The results revealed abolished behavioural adaptation following the dummy treatment. Our findings suggest that future work using proper experimental designs is needed to advance the understanding of the causal role of the MCC in behavioural adaptation.

Summary Background Approximately 20% of primary sclerosing cholangitis (PSC) patients with concomitant inflammatory bowel disease (IBD) have Crohn's disease (CD). Aim To compare PSC/CD with other PSC patients. Methods Retrospective study of 240 PSC patients diagnosed between 1975 and 2012 (median follow-up 12 years). Activity of PSC at diagnosis was assessed by liver biopsy, Mayo risk and ERC scores. Survival without liver transplantation, number of transplantations and liver-related death were endpoints. Results Sixty-three per cent of patients had IBD: 105 UC, 32 CD and 14 IBD unclassified (IBDu). IBD was diagnosed before PSC in 50%. The yearly development of PSC after diagnosing IBD was similar in UC, CD or IBDu. Small-duct PSC was present in 28% of PSC/CD compared to 3% of PSC/UC. Small-duct PSC had a markedly better survival than large-duct PSC: no patient developed cholangiocarcinoma or liver-related death, but colorectal cancer occurred in three patients. In large-duct PSC, a more favourable outcome was evident in patients with CD. The liver disease was less progressive: one patient underwent liver transplantation compared to 28% and liver-related deaths were absent compared to 7% in the other PSC groups. Conclusions The prevalence of PSC with concomitant Crohn's disease is relatively rare, but the outcome is more benign than PSC with UC or without IBD. Approximately one-fourth has small-duct PSC. In large-duct PSC/CD, liver disease is less aggressive and the outcome is much better. The outcome of PSC patients with UC resembled that of PSC without IBD.

In patients with rheumatoid arthritis (RA), bone marrow edema (BME) scores are associated with development of erosions. However, little is known about the course and outcome of BME at bone level. We undertook this study to determine the association of BME and synovitis with the development of erosions in the same bone longitudinally.Using 1.5T magnetic resonance imaging at baseline and at 4- and 12-month follow-up, we studied 1,947 bones of the metacarpophalangeal, wrist, and metatarsophalangeal joints in 59 patients presenting with RA or undifferentiated arthritis. Scanning and scoring of BME, synovitis, and erosions were performed according to the Outcome Measures in Rheumatology Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system. We evaluated the relationship of the course of BME and synovitis with erosive progression at bone level during 1 year.Of the bones showing BME at baseline (n = 203), BME persisted in 56%, disappeared in 39%, and disappeared and then reappeared in 5%. Stratified analyses at baseline revealed that BME was associated with erosive progression both in the presence and in the absence of local synovitis, with odds ratios (ORs) of 7.5 (95% confidence interval [95% CI] 3.8-14.9) and 6.9 (95% CI 1.9-25.6), respectively. However, local synovitis was not associated with erosive progression in the presence or in the absence of BME (ORs of 2.0 [95% CI 0.6-7.0] and 1.9 [95% CI 0.8-4.1], respectively). In multivariable generalized estimating equation analyses, persistent BME was strongly associated with erosive progression (OR 60.5 [95% CI 16.8-218.1]) in contrast to persistent synovitis (OR 1.3 [95% CI 0.4-4.4]).BME frequently persists during the first year. Persistent BME was strongly associated with erosive progression in the same bone, independently of local synovitis. No independent association was observed for persistent synovitis. These findings are relevant for comprehending the development of erosions in RA.

Introduction The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts. Methods In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients. Results No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10−7); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10−8. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5. Conclusion Variants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA. Electronic supplementary material The online version of this article (doi:10.1186/s13075-014-0514-0) contains supplementary material, which is available to authorized users.

The discovery of the gene responsible for most cases of hereditary haemochromatosis has made it possible to evaluate the role of this gene in iron accumulation in other conditions. Previous observations in patients with various inherited anaemias are suggestive of a role of the haemochromatosis gene in the noniatrogenic form of iron overload that may occur in these conditions.We studied two brothers with congenital dyserythropoietic anaemia type II, presenting with marked noniatrogenic iron overload. Young age, familial occurrence, concordance of iron overload, and histology were all suggestive of a genetic basis for the iron overload. A search for C282Y, H63D, S65C, and IVS3 + 1G?T mutations was performed by polymerase chain reaction after extraction of genomic DNA from whole blood.A search for the C282Y, H63D, S65C, and IVS3 + 1G?T mutations in the HFE gene proved to be negative. Despite the existence of ineffective erythropoiesis with mild anaemia, both patients were treated with regular phlebotomies in order to prevent long-term complications of their iron-overload. This treatment was well tolerated.1. C282Y, H63D, S65C, and IVS3 + 1G?T mutations were negative in two brothers with congenital dyserythropoietic anaemia, in whom young age, familial occurrence, concordance of iron overload, and the histological pattern were all suggestive of hereditary haemochromatosis. 2. Treatment with regular phlebotomies, in order to prevent complications of iron overload, was well tolerated despite the existence of mild haemolytic anaemia.

We describe the case of a 26-year-old man with acute liver failure secondary to ingestion of khat (Catha edulis) leaves. In fact, this is the first case of acute liver failure due to khat reported outside the United Kingdom. The combination of specific epidemiologic data (young man of East African origin) and clinical features (central nervous system stimulation, withdrawal reactions, toxic autoimmune-like hepatitis) led to the diagnosis. Mechanisms of action and potential side effects of khat are elaborated on.

For decades it has been known that the HLA-DRB1 shared epitope (SE) alleles are associated with an increased risk of development and progression of rheumatoid arthritis (RA). Recently, the following variations in the peptide-binding grooves of HLA molecules that predispose to RA development have been identified: Val and Leu at HLA-DRB1 position 11, Asp at HLA-B position 9, and Phe at HLA-DPB1 position 9. This study was undertaken to investigate whether these variants are also associated with radiographic progression in RA, independent of SE and anti-citrullinated protein antibody (ACPA) status.A total of 4,911 radiograph sets from 1,878 RA patients included in the Leiden Early Arthritis Clinic (The Netherlands), Umeå (Sweden), Hospital Clinico San Carlos-Rheumatoid Arthritis (Spain), and National Data Bank for Rheumatic Diseases (US) cohorts were studied. HLA was imputed using single-nucleotide polymorphism data from an Immunochip, and the amino acids listed above were tested in relation to radiographic progression per cohort using an additive model. Results from the 4 cohorts were combined in inverse-variance weighted meta-analyses using a fixed-effects model. Analyses were conditioned on SE and ACPA status.Val and Leu at HLA-DRB1 position 11 were associated with more radiographic progression (meta-analysis P = 5.11 × 10(-7)); this effect was independent of SE status (meta-analysis P = 0.022) but not independent of ACPA status. Phe at HLA-DPB1 position 9 was associated with more severe radiographic progression (meta-analysis P = 0.024), though not independent of SE status. Asp at HLA-B position 9 was not associated with radiographic progression.Val and Leu at HLA-DRB1 position 11 conferred a risk of a higher rate of radiographic progression independent of SE status but not independent of ACPA status. These findings support the relevance of these amino acids at position 11.

Baseline erosions are characteristic for rheumatoid arthritis (RA) and predictive for a severe disease course. The mechanisms leading to baseline erosions being a strong predictor for radiological progression are unknown. We aimed to increase this understanding by mediation analyses in an observational cohort and a cross-sectional MRI study.3256 hands and feet radiographs of 653 early RA patients assessed during 7 years of disease were scored using the Sharp-van der Heijde method. Mediation models and multivariate regression analyses were used to explore the association between baseline erosions, other predictors and radiological damage over time. 603 joints (MCP2-5 and MTP1-5) of 67 RA patients underwent 1.5 T MRI at baseline. Data on MRI inflammation were compared with clinical inflammation and baseline radiological erosions.Patients with baseline erosions had, at any point in time during 7 years, 3.45 times more joint damage than patients without erosions (p0.001, 95% CI 3.00 to 3.98). Baseline erosions were an independent predictor and not a mediator between symptom duration, systemic or local clinical inflammation (erythrocyte sedimentation rate (ESR), swollen joint count (SJC)) or autoantibodies (anti-citrullinated-peptide antibodies, rheumatoid factor) and radiological damage. Subclinical MRI inflammation was studied in relation to erosions, revealing that 83% of the non-swollen joints with baseline erosions had subclinical MRI inflammation compared with 25% of the non-swollen joints without baseline erosions (OR 15.2 95% CI 3.1 to 102.1). The association between MRI inflammation and baseline erosions was independent of symptom duration, ESR, SJC and autoantibodies.Baseline erosions are a predictor for future joint damage, independent of known predictors as time, autoantibodies or clinical measurable inflammation. Subclinical inflammation is suggested as an underlying mechanism.

Objective We recently reported an association of the SPP1 rs9138 and rs11439060 functional variants with the risk of rheumatoid arthritis (RA), the association being greater in anti-citrullinated protein autoantibody (ACPA)-negative patients. We hypothesised that SPP1 may contribute to the severity of joint destruction in RA, specifically in the ACPA-negative population. Methods Patients with RA in the ESPOIR cohort underwent genotyping for SPP1 rs9138 and rs11439060. Radiographs of the hands and feet were obtained at the first visit and at 1- and 2-year follow-up. Association analyses were performed by ACPA status. A replication study of the relevant subset of the Leiden Early Arthritis Clinic (EAC) cohort was performed. Results In the ESPOIR cohort (652 patients), rs9138 was significantly associated with radiological progression of joint destruction at 2 years, the association being restricted to 358 ACPA-negative patients (p=0.034). In the replication study with the Leiden EAC cohort (273 ACPA-negative patients), rs4754, which is in complete linkage disequilibrium with rs9138, was significantly associated with joint damage progression in ACPA-negative patients at 2- and 7-year follow-up (p=0.019 and p=0.005, respectively). Combined analysis of the two cohorts revealed a 0.95-fold rate of joint destruction per year per minor allele (p=0.022). Conclusions The SPP1 rs9138 variant contributes to joint damage progression in ACPA-negative RA.

Purpose: To compare the value of ’push-button' singe-shot non-contrast-enhanced MRI and contrast-enhanced helical CT for detection of upper abdominal disease. Methods: In 120 patients, images obtained with non contrast-enhanced single-shot MRI (T2: double echo HASTE, and T1: turbo FLASH) and contrast-enhanced helical CT were compared. Lesions or abnormalities were divided in 8 anatomical categories (1: liver; 2: pancreatobiliary; 3: kidney/adrenal gland; 4: retroperitoneum; 5: vascular; 6: spleen; 7: gastrointestinal tract and peritoneum; 8: base of thorax) and classified as follows: 2: seen at MRI only; 1: better seen at MRI; 0: no difference; −1: better seen at CT; −2: seen at CT only. Also recorded were the 'door-to-door’ examination times. Results: Of a total of 629 abnormalities, 594 were detected at MRI (94 %) and 536 at CT (85 %). CT offered better results in two categories only: retroperitoneum (mean score: −0.68) and vascular (mean score −0.87). Mean examination times were 19 min for CT and 14.8 min for MRI. Conclusion: Unenhanced single-shot MRI is a valuable first step of a comprehensive upper abdominal MR exam and may even be the final step in many patients.

OBJECTIVE: Nonalcoholic duct-destructive chronic pancreatitis is a new entity that should be distinguished from alcoholic chronic pancreatitis. The purpose of this study was to assess the imaging features of nonalcoholic duct-destructive chronic pancreatitis. CONCLUSION: Nonalcoholic duct-destructive chronic pancreatitis has characteristic CT and MR imaging features that include the presence of a focal or more diffuse mass causing either regular or irregular narrowing of the main pancreatic duct, the absence of parenchymal atrophy and significant ductal dilatation proximal to the site of stenosis, and the absence of extrapancreatic spread.

Contrast-enhanced helical CT images of the liver are usually obtained during the portal vein phase (PVP), during which the parenchyma achieves peak enhancement. The purpose of this study was to determine whether the addition of arterial-phase (AP) scans would lead to improved characterization of focal lesions.We reviewed the CT appearance of 102 focal lesions with a proven diagnosis. In the first part of the study, we assessed whether the addition of AP scans influenced the diagnostic performance of the three observers. In the second part of the study, we analyzed the morphologic appearance revealed on CT scans of the different types of lesions in the AP and PVP.The addition of AP scans led to a significant increase in the number of correct diagnoses: 71 lesions (70%) were correctly diagnosed with CT scans in both the AP and the PVP, compared with 54 lesions (53%) correctly diagnosed with CT scans in the PVP alone (p.01). The largest difference was observed in the diagnosis of focal nodular hyperplasia (FNH) and adenoma (16/24 correct diagnoses instead of 6/24) (p.005). Conversely, AP images did not significantly contribute to the diagnosis of hemangiomas and metastases. The following morphologic features were seen much more often on AP scans than on PVP scans and had a high positive predictive value (PPV): spoke-wheel pattern (FNH; PPV, 100%), central feeding vessel (FNH; PPV, 100%), and heterogeneous appearance with hyperdense components (hepatocellular carcinoma; PPV, 75%).Our data show that the radiologists' evaluation of CT scans in both the AP and the PVP improves the differentiation of hepatocellular carcinoma and FNH from other types of hepatic neoplasms.

Background The severity of radiologic progression is variable between rheumatoid arthritis (RA) patients. Recently, several genetic severity variants have been identified and were replicated, these belong to 12 loci. This study determined the contribution of the identified genetic factors to the explained variance in radiologic progression and whether genetic factors, in addition to traditional risk factors, improve the accuracy of predicting the severity of radiologic progression. Methods 426 early RA patients with yearly radiologic follow-up were studied. The main outcome measure was the progression in Sharp-van der Heijde score (SHS) over 6 years, assessed as continuous outcome or categorised in no/little, moderate or severe progression. Assessed were improved fit of a linear mixed model analysis on serial radiographs, R 2 using linear regression analyses, C-statistic and the net proportion of patients that was additionally correctly classified when adding genetic risk factors to a model consisting of traditional risk factors. Results The genetic factors together explained 12–18%. When added to a model including traditional factors and treatment effects, the genetic factors additionally explained 3–7% of the variance (p value R 2 change =0.056). The percentage of patients that was correctly classified increased from 56% to 62%; the net proportion of correct reclassifications 6% (95% CI 3 to 10%). The C-statistic increased from 0.78 to 0.82. Sensitivity analyses using imputation of missing radiographs yielded comparable results. Conclusions Genetic risk factors together explained 12–18% of the variance in radiologic progression. Adding genetic factors improved the predictive accuracy, but 38% of the patients were still incorrectly classified, limiting the value for use in clinical practice.

Advanced liver disease is characterized by prolonged global coagulation tests such as prothrombin time (PT). Using Model of End-stage Liver Disease (MELD) score-based allocation, many current transplant recipients show advanced end-stage liver disease with an elevated international normalized ratio (INR). The relationship between abnormalities in coagulation tests and the risk of bleeding has been recently challenged among liver disease patients. In this study we reassessed risk factors for bleeding and the clinical implications for patients who underwent orthotopic liver transplantation (OLT).We studied OLT patients between 2005 and 2011 excluding combined transplantations, retransplantations, or cases due to acute liver failure. We collected prospectively pre-OLT, during OLT, and post-OLT clinical and biochemical data to assess the risk for bleeding using linear regression models.The strongest predictor of overall survival among 286 patients with a mean follow-up of 32 months was the number of blood transfusions (P = .005). The risk factor for bleeding during surgery investigated by multivariate analysis only showed the INR (P.001) and the presence of ascites (P = .003) to independently correlate with the amount of blood transfusion. Receiver operation characteristics (ROC) analysis performed to determine the risk for massive blood transfusion (more than 6 units) revealed a cut-off value for INR ≥ 1.6. Appreciation of the operative field by the surgeon during the intervention as "wet" versus "dry", amounts of blood transfusion and fresh frozen plasma, and stay in the intensive care unit (ICU) and in the hospital were all significantly different (P.001) for patients with INR1.6 versus INR ≥ 1.6.Bleeding during OLT affects the outcome. The risk is independently influenced by the presence of ascites (probably reflecting the degree portal hypertension) and an INR ≥ 1.6. To improve survival after OLT therapeutic interventions should be further explored to reduce the need for blood transfusions.

We review the sensitivity of different diagnostic tests for breast cancer management based on recent experience in a 34-year-old patient. False-negative tests at diagnosis of early disease and of relapse resulted in diagnostic and therapeutic delays. Initial mammography and breast ultrasonography were falsely negative despite a palpable breast lump. Clinical examination and axillary ultrasound missed macroscopically involved lymph nodes. At relapse, metastatic lesions were missed despite symptoms, three years after primary treatment. CA 15-3 was normalsemi; bone and liver metastases were missed by standard and more advanced imaging techniques including liver ultrasonography, nuclear bone scan and PET -CT scan. Worsening of clinical symptoms, lab results and abnormal tissue biopsies finally led to the diagnosis of extensive metastatic disease. Genetic screening showed an abnormality within the BRCA-1 region of unknown clinical importance. This review highlights 1) that diagnostic tests managing symptomatic breast cancer patients may have a low sensitivity, 2) the importance of clinical findings and other markers for disease, such as lactate dehydrogenase and 3) the need for diagnostic biopsies for clinically suspect symptoms despite normal imaging and biochemistry.

Non-alcoholic Fatty Liver Disease (NAFLD) is increasingly recognised as a source of liver related morbidity and mortality. Hard data on epidemiology and natural history are scarce.To study demographic and metabolic characteristics of the NAFLD patients seen by Belgian hepatologists.Belgian hepatologists filled in a questionnaire for every newly diagnosed NAFLD patient between January 1st and December 31st 2004. Liver biopsy was advised if ALT1.5 x ULN and if 3/5 of the criteria for the metabolic syndrome (MS) (ATPI-II) were present, but was not mandatory. Biopsy was scored using the Brunt classification.230 patients were prospectively included in 9 centres; 54% were males; mean age was 49.4 +/- 13.9 y; mean BMI was 30.6 +/- 4.6 kg/m2. The MS was present in 53%. In 16% formerly undiagnosed diabetes was discovered. 51% had a liver biopsy: 25% met the criteria, 26% did not. Grading did not differ between patients with or without MS. Staging was significantly more severe in patients with MS (2.43 +/- 1.25 vs. 1.73 +/- 1.18, p0.001). A subgroup of patients with GGT5 x ULN were significantly older (55.9 vs. 47.64 y, p = 0.02), more frequently diabetic (53% vs. 23%, p = 0.01) and had more advanced fibrosis (3.42 vs. 1.08, p = 0.008). ALT levels were variable.The MS is highly prevalent in Belgian NAFLD patients and is associated with more severe disease. Mild to moderate fibrosis is frequent, and the proposed criteria for liver biopsy are not accurate in selecting these patients. Patients with elevated GGT constitute a subgroup with more advanced disease.

Purpose The aim of this study was to investigate the safety and efficacy of lifelong therapy with intravenous hepatitis B immunoglobulins (IV HBIg) to prevent recurrence of hepatitis B after orthotopic liver transplantation (OLT). Methods This was a single-center retrospective study of the long-term outcome of 56 patients who were transplanted for active hepatitis B–related liver disease. In addition to IV HBIg, patients received antiviral therapy for at least 1 year. Results 1-, 5-, and 10-year survival rates were 95%, 82%, and 80%, respectively. None of the patients died due to hepatitis B virus (HBV)–related complications. In 3 patients (5%), a hepatitis B surface antigen (HBsAg)–negative status was not reached. All of these patients had a very high viral load at the time of OLT. HBsAg and HBV DNA reappeared in 6 patients (11%): In 1 patient, recurrence occurred 9 months after OLT while still under combination treatment with lamivudine, and 2 patients were temporarily treated abroad with intramuscular HBIg. Only 3 patients suffered from HBV recurrence while under monotherapy with IV HBIg. No serious side effects to IV HBIg were reported during this long-term follow-up. Conclusion Lifelong administration of IV HBIg is safe, and recurrence of HBV disease occurred only in a minority of the patients during long-term follow-up. Prognosis of HBV-related OLT with this therapy is excellent.

Endoscopic insertion of a biliary stent is standard practice in the palliative treatment of malignant biliary obstructions. Experience with the new ePTFE-covered Viabil stent is mainly limited to the percutaneous approach. We report our experience with its endoscopic application in patients with distal malignant biliary obstructions.Eleven patients with an inoperable tumour, without apparent metastatic disease, and with an ECOG score of 0 to 1, were included. All patients received an ePTFE-covered Viabil stent of 10 mm diameter, with transmural side-holes. Primary endpoints were stent patency and patient survival.Overall median patient survival was 220 days; 10 patients died free of jaundice from non-stent related causes. Due to malfunction of the prototype stents at insertion, the introduction of 2 Viabils was required in 3 patients to acquire complete bile duct drainage. Thus, a total of 14 stents was needed in 11 patients. Stent dysfunction occurred in 3/11 patients. It always resulted from massive stone impaction needing stone removal with additional stenting in two out of 3 patients. Stent patency was 80% at 3 and 6 months, and 63% at 9 and 12 months. Lifetime palliation was 73%.Although the biliary Viabil device has been developed to minimize bacterial adherence and sludge formation, stent dysfunctions in this series always resulted from stone impaction. Moreover, malfunction of the prototype stents needed the insertion of a second stent in 3 patients. Overall life time palliation was 73%. Further experience with newer versions of the device as well as comparative studies versus other metallic stents are needed.

The value of ultrasound (US) in determining the cause and site of biliary obstruction was critically evaluated and compared to endoscopic retrograde cholangiography (ERCP), in a prospective study performed on 120 consecutive patients. The final diagnosis was based on surgery, endoscopic retrograde cholangiography or a combination of other examinations. Ultrasound successfully differentiated obstructive from non obstructive jaundice in 96% of the patients, comparing well with the results ERCP. US correctly defined the cause of obstruction in 71% of the patients with ductal stones, in 90% of the patients with tumoural bile duct obstruction, but only in 59% of the patients with chronic pancreatitis.

In the era of cost-conscious healthcare, hospitals are focusing on costs. Analysis of hospital costs per cost category may provide indications for potential cost-saving measures in the management of common bile duct stones (CBDS) with gallbladder in situ.Between October 2005 and September 2006, 53 consecutive patients suffering from CBDS underwent either a one-stage procedure [laparoscopic common bile duct exploration (LCBDE) with stone clearance and cholecystectomy (LCCE)] or a two-stage procedure [endoscopic retrograde cholangiopancreatography with sphincterotomy and stone clearance (ERCP/ERS) followed by LCCE]. Costs were defined in different cost categories for each activity centre and were linked to the individual patient via the "bill of activities". Only patients (n = 38) with an uneventful post-procedural course and with available cost data were considered for cost analysis. Total length of hospital stay (LOS) was 2 (0-6) days after one-stage and 8 (3-18) days after two-stage procedure (p0.0001).Costs per patient were significantly (p0.0001) less after one-stage versus two-stage management, i.e. total hospital costs (euro2,636 versus euro4,608), hospitalisation costs (euro701 versus euro2,190), consumables/pharmacy (euro645 versus euro1,476) and para-medical personnel (euro1,035 versus euro1,860; p = 0.0002). Operation room (OR) costs were comparable for one-stage and two-stage management (euro1,278 versus euro1,232; p = 0.280). Total hospital costs during ERCP were euro2,648 (euro729-4,544), during LCCE without LCBDE were euro2,101 (euro1,033-4,269), and during LCCE with LCBDE were euro2,636 (euro1,176-4,235).In the management of patients with CBDS and gallbladder in situ a one-stage procedure is associated with significantly less costs as compared with a two-stage procedure. From the economical point of view these patients should preferably be treated via a one-stage procedure as long as safety and efficacy of this approach are provided.

Aims Despite curative surgery for pancreatic ductal adenocarcinoma (PDAC), most patients develop cancer recurrence and die from metastatic disease. Understanding of the patterns of failure after surgery can lead to new insights for novel therapeutic modalities. The aim of the present study is to describe the patterns of recurrence after curative resection of PDAC. Methods A retrospective analysis was performed of 145 consecutive resections for PDAC between 1998 and 2005 (M/F 75/70; median (range) age 67 years (32–85 y)). The location of the first and consecutive recurrences, and the time interval to cancer recurrence after surgical resection was studied. The magnitude of tumour-free margin was less than a millimetre in 48 patients, whereas a positive surgical margin was observed in 27 patients. The median duration of follow-up was 18.5 (range 0.3–116.8) months. Results Cancer recurrence was observed in 110 patients. The first location of recurrence was locoregional in 19, extra-pancreatic in 66, and combined locoregional and extra-pancreatic in 25 patients. Extra-pancreatic recurrence developed in the liver in 57, peritoneal in 35, pulmonary in 15, and retroperitoneal in 5 patients. The median (95% CI) overall (OS) and disease-free (DFS) survival was 18.7 (15.7–23.5) and 9.8 (7.5–12.4) months, respectively. The type of cancer recurrence did not significantly influence OS, while the resection margin status had a prognostic effect. Conclusion The vast majority of patients who undergo potentially curative surgery for PDAC develop cancer recurrence located in the abdominal cavity. Surgical resection margins with tumour involvement and tumour-free margins of less then 1 mm are negative prognostic factors. Further research on better local surgical control, peri-operative locoregional treatment, and more effective adjuvant systemic therapy is necessary to improve long-term survival of patients with curable PDAC.

We report a 25-year-old man who presented with congenital absence of the portal vein, or Abernethy malformation, a rare congenital disorder in which the mesenteric and splenic venous drainages bypass the liver and directly drain into the inferior vena cava through an extrahepatic portosystemic shunt. Magnetic resonance imaging, which showed multiple nodular lesions in both liver lobes that were associated with an absence of intrahepatic portal venous branches, strongly suggested the diagnosis of the Abernethy malformation. Carbon dioxide wedged venography and transvenous liver biopsy, which were performed in the same session by a right jugular approach, confirmed these findings. This technique can be considered a valuable alternative diagnostic tool to catheter arteriography and percutaneous transhepatic liver biopsy.

Primary lymphoma of the liver is a very rare malignancy. Most often, these lesions consist of diffuse large B-cell non-Hodgkin's lymphoma that occurs mostly in immunodeficient patients. To prove the primary nature of a hepatic lesion, a systemic lymphoproliferative disease should be ruled out. Secondary liver involvement during Hodgkin's and non-Hodgkin's lymphoma is frequent. In advanced cases the incidence varies from 25% to 50%. The present case describes the MRI features of a primary lymphoma of the liver presenting as a solitary nodule. The primary lymphoma presents as a T2-hyperintense homogeneous nodule, with a signal intensity comparable with the signal intensity of the spleen. Signal intensity is comparable on in and out of phase imaging. The nodule is slightly T1-hypointense and doesn't show any arterial contrast uptake. In the late venous phase a slight increase in signal intensity is noted. Two and a half minutes after the administration of contrast agent, the lesion is iso-attenuating with the liver parenchyma. This case is rare because of the concomitant presence of heterozygous sickle cell anaemia and the presence of Gamna-Gandy bodies in the splenic parenchyma. It remains uncertain whether the presence of the Gamna-Gandy bodies is associated with the liver lymphoma or with the underlying sickle cell anaemia, or with a combination of both.

Background The application of available predictive scoring systems for the detection of common bile duct (CBD) stones has not reduced the number of patients who undergo unnecessary endoscopic retrograde cholangiopancreatography. The aim of this study was to create a predictive model for CBD stones and to assess the value of magnetic resonance cholangiopancreatography (MRCP) in prediction. Methods In 1998, 366 patients with gallstone disease (118 males, 248 females; mean age 57 (range 8–84) years) underwent cholecystectomy. Statistical analysis was performed on patient data obtained at the time of first presentation. Results CBD stones were demonstrated in 43 (12 per cent) of 366 patients. The predictive model for common duct stones included ultrasonography showing CBD stones or bile duct dilatation, age greater than 60 years, fever, serum alkaline phosphatase level above 670 units/l and serum amylase level above 95 units/l. In patients with a predicted probability greater than 5 per cent, CBD stones were present in 11 per cent, compared with 1 per cent in patients with a probability of 5 per cent or less. MRCP had an observed sensitivity of 95 per cent, specificity of 100 per cent, positive predictive value of 100 per cent and negative predictive value of 98 per cent. Conclusion In patients with a predicted probability for CBD stones of more than 5 per cent, MRCP is recommended in order to confirm the presence or absence of stones and as guidance in further management.

BACKGROUND The differential diagnosis of hepatic fibrin-ring granulomas includes infective agents (Coxiella burneti, CMV, EBV,....), hypersensitivity to medication (allopurinol) and malignancy. METHODS During a period of 6 months, four patients presented at our university hospital with a similar clinical picture of fever and abnormal liver tests, and fibrin-ring granulomas on liver biopsy. Clinical course, laboratory and imaging findings, and histopathological features were compared. RESULTS Clinical manifestations, and laboratory and imaging findings were similar. Histopathological assessment of the hepatic fibrin-ring granulomas appeared not to be helpful in identifying the causative agent. Other histopathological features (e.g. sinusoidal rows of lymphocytes, eosinophilic polymorphonuclear infiltrate) were suggestive for the causative agent, yet conclusive identification was obtained by either serology (Q fever, CMV, EBV), or by exclusion with concomitant stop of medication (allopurinol). CONCLUSIONS In the differential diagnosis of hepatic fibrin-ring granulomas, serologic titers remain the determining factor, since an infective agent is the most common cause. When hepatic fibrin-ring granulomas are present, other histopathological features may be helpful in making the differential diagnosis.

Introduction It is known that anticitrullinated peptide antibody (ACPA)–positive rheumatoid arthritis (RA) has a preclinical phase. Whether this phase is also present in ACPA-negative RA is unknown. To determine this, we studied ACPA-negative arthralgia patients who were considered prone to progress to RA for local subclinical inflammation observed on hand and foot magnetic resonance imaging (MRI) scans. Methods We studied a total of 64 ACPA-negative patients without clinically detectable arthritis and with arthralgia of the small joints within the previous 1 year. Because of the character of the patients’ symptoms, the rheumatologists considered these patients to be prone to progress to RA. For comparisons, we evaluated 19 healthy, symptom-free controls and 20 ACPA-negative RA patients, who were identified according to the 1987 American Rheumatism Association criteria. All participants underwent MRI of unilateral wrist, metacarpophalangeal and metatarsophalangeal joints. Synovitis and bone marrow oedema (BME) were scored according to the OMERACT rheumatoid arthritis magnetic resonance imaging scoring system, and the scores were summed to yield the ‘MRI inflammation score’. Scores were compared between groups. Among the ACPA-negative arthralgia patients, MRI inflammation scores were related to C-reactive protein (CRP) levels and the tenderness of scanned joints. Results MRI inflammation scores increased progressively among the groups of controls and ACPA-negative arthralgia and RA patients (median scores = 0, 1 and 10, respectively; P

Previous reports on endoscopic retrograde brush cytology (ERBC) of bile ducts and of the main pancreatic duct have reached widely varying sensitivity levels of 33 up to 85%.To report our experience with ERBC in a series of biliary strictures (n = 98) and pancreatic duct strictures (n = 8). For the purpose of our study, that was mainly directed to the value of the cytologic examination as such, only those specimens that were considered satisfactory for cytological interpretation were studied.From October 1988 until August 1994, 154 cytologic brushings were performed at ERCP in 132 patients. In 132 brushings obtained from 115 patients (86%), cell yield was satisfactory for cytologic interpretation. Nine patients lacked adequate follow-up. Hence, 123 brushings from 106 patients were included in this study. A final diagnosis of malignancy was obtained in 62 patients.Cytological changes were described as 'benign', 'columnar cell intraepithelial neoplasia', 'inconclusive' by the presence of atypical cells, or 'malignant'.For a positive diagnosis of the malignant nature of a stenosis, ERBC had an overall sensitivity of 63% with a specificity of 96%. One false positive result was obtained in a patient with a biliary infection by Fasciola Hepatica. Sensitivity was highest in malignant ampullary strictures (91%). Sensitivity was 60% for cholangiocarcinomas, and 65% for pancreatic cancer. The finding of 'columnar cell intra-epithelial neoplasia' in the ampullary region led to a Whipple resection and diagnosis of invasive carcinoma in one patient. Atypical cells were found in 4 brush specimens: in three of these 4 cases, a malignant lesion proved to be present.Brush cytology is a simple technique with a high specificity and should be performed in biliary and pancreatic duct strictures of unknown etiology. Categorizing the smears according to cytomorphology may improve diagnostic accuracy.

PSC has characteristics of an (auto)immune-mediated disease: however, few studies have evaluated corticosteroid therapy for this disorder.We performed an 8-wk double-blind randomized pilot study to assess the effects of additional treatment with 9 mg budesonide (n = 6) versus 3 mg budesonide (n = 6) versus 10 mg prednisone (n = 6) in patients who had been treated with UDCA (mean dose, 12 mg/kg/day) for at least 5 months without achieving biochemical remission. Pruritus and fatigue were evaluated using visual analog scales. Serum liver biochemistry was measured every 4 wk. At entry and at the end of the trial, adrenocorticotrophic hormone (ACTH) and dehydroepiandrosterone (DHEA) were measured to assess effects on the pituitary-adrenal axis. Duodenal bile was collected for assessment of biliary corticosteroid activity.Pruritus decreased significantly more in the prednisone group compared to both the 3-mg and the 9-mg budesonide groups (p0.05). Alkaline phosphatase (mean: -23.4%; p = 0.03) and IgG (mean: -16.2%; p = 0.04) decreased in the prednisone group, whereas bilirubin, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase did not change significantly. No significant clinical or liver biochemical changes were observed in the 3-mg and 9-mg budesonide groups. Significantly larger drops in serum ACTH were found in the 10-mg prednisone group (-40.7%; p = 0.04) and 9-mg budesonide group (-36.6%; p = 0.02) compared to the 3-mg budesonide group (+ 19.0%). No significant differences in percentage change in baseline values for DHEA between the three treatment arms were found. Mononuclear cell proliferation assays did not demonstrate corticosteroid activity in bile. Autoimmune hepatitis was observed in one case (9 mg budesonide) when corticosteroids were tapered off.The results of this pilot study suggest only minor beneficial short-term effects of prednisone but not budesonide on symptoms and serum liver tests in UDCA-treated PSC patients.

Bowel rest during treatment of acute pancreatitis deprives the gut of nutrients and affects its structure and function. Enteral feeding is usually performed late in the course of acute pancreatitis and therefore cannot prevent intestinal barrier dysfunction and possible bacterial translocation. To assess the effect of early enteral nutrition we performed a prospective study on 21 patients (11 males/10 females) presenting with severe acute pancreatitis (13 biliary, 6 alcoholic, and 2 miscellaneous). Severity was established by a mean Ranson score of 3.57. All but one patient could be fed through a double-lumen nasogastrojejunal tube within 60 h after admission. No significant complication of the technique was observed. We conclude that early jejunal feeding can be used safely in severe acute pancreatitis. Further comparative studies are necessary to demonstrate any superiority to total parenteral nutrition.