Search

Introduction In PSC it has been believed that staging fibrosis is unhelpful due to the patchy nature of the condition, hence liver biopsy is rarely performed. Emerging data indicates that TE correlates well with fibrosis stage on liver histology and that both TE and the ELF test provide prognostic information in PSC. Thus far there has been no direct comparison of ELF testing and TE. Here we present a comparison of clinical scores, TE and the ELF test in patients with PSC. Method Patients with large-duct PSC had TE [Fibroscan® (Echosens): 10 valid measurements and a success rate >60% after 3 hrs fasting] and serum stored at the same visit to the Royal Free, London and the Hospital Clinic, Barcelona (Jun 2010–Feb 2015). Full patient demographics and clinical outcomes were recorded. Clinical scores of disease severity (APRI and Mayo risk score) were obtained on the day of assessment. Stored sera were tested for ELF [ADVIA Centauro® XP system (Siemens Diagnostics). Spearman–s rank correlation was used due to the non-normal distribution of measures. Results 39 [1 autoimmune overlap, 28(72%) male] PSC patients [mean (±SD): age 50(±14) yrs; age at diagnosis 42(±14) yrs; time from diagnosis of 7.8(±7.1) yrs] were evaluated. 28 patients (80%) were diagnosed with IBD: 21 ulcerative colitis, 6 Crohn’s disease, 1 indeterminate colitis. There were no significant differences in ELF, TE or age between UK and Barcelona patients. Fibroscan correlated with ELF with a Spearman–s rho 0.676 p Conclusion A significant correlation between liver stiffness measured by TE, ELF test, APRI and Mayo risk score is here demonstrated for the first time in patients with PSC. Our results suggest that while the process of fibrosis progression in PSC is poorly understood, non-invasive tests validated in other chronic liver diseases perform consistently in patients affected and should be further evaluated as tools for staging the disease, monitoring disease progression and prognosis and may provide much needed surrogate end points for clinical trials in PSC. Disclosure of interest F. Saffioti: None Declared, M. Vesterhus: None Declared, A. Telese: None Declared, G. Mazza: None Declared, D. Roccarina: None Declared, M. Rosselli: None Declared, W. Jonasson: None Declared, A. Pares: None Declared, T. Karlsen: None Declared, W. Rosenberg: None Declared, M. Pinzani: None Declared, A. Marshall: None Declared, D. Thorburn Grant/Research Support from: Boston Scientific to fund a clinical research fellow.

increased synthesis of extracellular matrix components is a major hallmark of SSc. Focal adhesion kinase (FAK), an essential component in the extracellular matrix-mediated adhesive signalling, was found to be hyperactivated in lesional scleroderma fibroblasts, and therefore this kinase has been hypothesized to be a key mediator of this disease. The present study was undertaken to investigate the role of FAK signalling in SSc and to evaluate the therapeutic potential of FAK inhibition for the treatment of lung fibrosis. FAK activity and expression is up-regulated in lungs of mice subjected to non-infectious injury and in human idiopathic pulmonary fibrosis (IPF) or scleroderma (SSc) patients as investigated by immunohistochemistry (IHC). Genetic or pharmacological targeting of FAK abrogates fibrogenesis in the bleomycin-induced lung fibrosis model as quantitated by IHC and collagen content. In vitro, FAK activation is required for endothelin-1induced myofibroblast differentiation, extracellular matrix (ECM) production and contractility as tested by western blot, real-time PCR and gel contraction assay. These results implicate FAK as a central mediator of fibrogenesis, and highlight this kinase as a potential therapeutic target in fibrotic diseases. These findings might have direct translational implications because different inhibitors of FAK are available and have yielded promising results in cancer trials.

Introduction The enhanced liver fibrosis (ELF) test comprises a panel of biomarkers of liver fibrosis shown to accurately assess fibrosis and predict clinical outcomes in a range of chronic liver diseases. This is the first study of performance of ELF in patients with chronic hepatitis B (CHB) using a single aetiology cohort, and we compare its performance with an alternative method of assessing fibrosis, transient elastography (TE). Aim We aimed to compare the performance of ELF with transient elastography (TE) in a cohort of patients with CHB, in the identification of liver fibrosis using liver biopsy as the reference standard. Method 188 patients with CHB were recruited consecutively at a single Italian centre. TE, serum sampling and liver biopsy were performed on the same day. ELF tests were performed in one batch at a central laboratory using thawed samples previously stored at −20°C. Biopsies were assessed by one pathologist using the Ishak staging system. Diagnostic performance of ELF and TE for detection of histological stages of liver fibrosis was assessed and area under receiver operator characteristic curves (AUROC) calculated. Only those in whom TE was successfully performed were included. Different fibrosis levels were assessed, from any fibrosis (0 vs 1–6) to cirrhosis (0–4 vs 5, 6 and 0–5 vs 6). Results Patients were treatment-naive, median age was 47 years. 78% were e-antigen negative. Biopsies reported mild/moderate fibrosis (Ishak 0–1) in 21%, moderate fibrosis (2–3) 41% and severe fibrosis/cirrhosis (4–6) 38%. ELF and TE demonstrated good performance in identifying fibrosis (Abstract P23 table 1—representative fibrosis stages are shown, further data available). Both modalities showed similar performance in identifying any fibrosis and minimal fibrosis, with TE performing better in identifying moderate and severe fibrosis, and cirrhosis. Conclusion In untreated patients with CHB with moderate and severe fibrosis or cirrhosis, TE correlated more closely with histological staging than ELF. The relatively modest performance of ELF in detecting severe fibrosis compared to previous studies may be attributable to disease aetiology or prolonged sample storage at −20°C. Further validation of TE and ELF in CHB should include analysis at the time of sampling and evaluation of the prognostic performance for clinical outcomes as well as histology.

Introduction The detection of non-alcoholic steatohepatitis (NASH) within non-alcoholic fatty liver disease (NAFLD) is important both for ascertaining prognosis and the stratification of patients for existing interventions and emerging therapies. Liver biopsy is considered the reference standard for assessing NASH. The aim of this study was to develop a biomarker of NASH which would be able to detect NASH prior to the development of significant hepatic fibrosis. Candidate biomarkers of hepatic inflammation, apoptosis and liver fibrosis were selected on the basis of biological plausibility and previous association with NAFLD. Method 172 patients with NAFLD and no evidence of other liver disease were consecutively recruited from two centres. 84 patients from the first centre were included as a training cohort and 88 patients from the second centre as a validation cohort. Liver biopsies were performed on all patients and scored using the NAFLD activity score (NAS). 36 patients with advanced fibrosis were excluded from the analysis. Serum samples were taken on all patients and tested for five matrix proteins (HA, P3NP, TIMP-1, Procollagen 4 and YKL-40) and 19 haematological and biochemical parameters including HOMA-IR. Stepwise multiple linear regression was used to determine the relationship of the multiple variables to the NAS score. Results A model combining terminal peptide of pro-collagen III (P3NP) and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) was found to significantly correlate with the NAS score in the training cohort (R=0.643, R2=0.413, p Conclusion This model appears to have good diagnostic performance for the detection of NASH in both the training and validation cohorts. Our results appear promising and if confirmed in further studies this model will be of clinical utility in detecting the minority of patients with NAFLD who have NASH and are at risk of developing progressive liver disease.

To evaluate the effect of a three-hour training session in formulating questions and searching databases.A randomised controlled trial and before and after study, with blinded outcome assessment.Oxford University Medical School, first clinical year.Altogether 108 medical students were randomly assigned to an experimental group (54) or a control group (54), and all were given the task of searching for evidence around an ulcer related problem or a cardiac problem. Students in the experimental group were randomly allocated to research one of the two problems before training and the remaining problem afterwards. Control students received no training and were randomly allocated to search for evidence around either of these problems.Searching performance; the quality of evidence retrieved; student satisfaction.Training improved the students' search performance and the quality of evidence retrieved. Students' satisfaction with the training was high.A three-hour interactive training session improved the students' ability to search databases and retrieve evidence and was well received by the students.

Primary biliary cirrhosis is a chronic cholestatic disease, thought to be immune-mediated with genetic susceptibility encoded in the major histocompatibility complex. In northern Europeans, the best established associations are with HLA-DR8 and the complement allele, C4B2. These associations could be due to a single susceptibility locus on an extended haplotype linking HLA-DR8 and C4B2 or to both HLA-DR8 and C4B2 independently conferring disease susceptibility. C4B2 genotyping was performed on 64 patients with primary biliary cirrhosis and 61 controls matched for ethnic background and frequency of HLA-DR8. C4B2 was associated with HLA-DR8 (p0.05) in PBC. No difference in the frequency of C4B2 was detected between control and disease populations, suggesting that HLA-DR8 and C4B2 are in linkage disequilibrium and that C4B2 is not a susceptibility locus for PBC. Taq I polymorphisms were screened in the disease and control populations with the cosmid probe G91, located midway between the HLA-DR and complement loci. One G91 restriction fragment (G91A) was found to be associated with both HLA-DR8 and C4B2, at equal frequency in health and disease, providing evidence of an HLA-DR8-G91A-C4B2 extended haplotype. The frequency of G91A was the same in the disease and control populations, suggesting that G91A does not confer disease susceptibility. These findings establish G91 as the telomeric boundary for disease susceptibility associated with HLA-DR8, encoded on chromosome six. These studies help define the immunogenetic susceptibility locus for primary biliary cirrhosis.

Most patients with rheumatoid arthritis (RA) exhibit an HLA class II epitope found on most DR4 and DR1 molecules. We have investigated the possibility of other associations being present in the minority of patients lacking these antigens. One hundred and eighty patients with classical or definite RA and 100 controls were assigned HLA-DR, DQ and DP types by a DNA-based system using sequence-specific oligonucleotides to probe amplified class II alleles amplified by the polymerase chain reaction. The expected associations with DR4 (relative risk 10, P less than 0.0001) and DR1 (relative risk 2.3, P less than 0.001) were observed and only 13% of individuals lacked both of these alleles compared with 54% of age- and race-matched controls. A significant association with DRw10 (P = 0.02) was also observed in the DR4/DR1-negative RA group (3/23 patients compared with 0/54 DR4/DR1-negative controls). No novel associations with other DR, DQ, or DP alleles were evident in contrast to some previous studies. The third allelic hypervariable region of the DR beta chain of DRw10 contains a similar amino acid sequence to that found in many DR4 and DR1 molecules. These results extend this correlation and suggest that this susceptibility determinant may account for the HLA-linked susceptibility in 89% of our cases of RA.