Association between skirt size and chronic liver disease in post-menopausal women: a prospective cohort study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: We investigated the association between self-reported skirt size (SS) and change in SS, and incidence of chronic liver disease (CLD) in a prospective cohort study of women recruited to the UKCTOCS trial. METHODS: Women recruited to UKCTOCS in England without documented CLD self-reported their current UK SS during trial participation and were asked to recall their SS when aged in 20s (via completion of a questionnaire 3-5 years after recruitment). Participants were followed up via electronic health record linkage and hazard ratios (HR) calculated for incident liver-related events (LRE). RESULTS: Three hundred twenty-two (0.3%) of 94,124 women experienced a first LRE. Compared to SS ≤ 16, rates of LRE were higher in the SS ≥ 18 groups (both when aged in 20s and at questionnaire completion). Event rates were higher if there was no change in SS or an increase in SS, compared to a decrease in SS. In the models adjusted for potential confounders, HRs for LRE were higher in the groups of women reporting SS ≥ 18 both when aged in 20s (HR = 1.39 (95% CI; 0.87-2.23)) and at questionnaire completion (HR = 1.37 (95% CI; 1.07-1.75)). Compared to a decrease in SS, HRs were higher in the no change (HR = 1.78 (95% CI; 0.95-3.34)) and increase (HR = 1.80 (95% CI; 1.01-3.21)) groups. CONCLUSION: CLD is associated with high SS and an increase in SS over time. These data suggest SS can be used in simple public health messages about communicating the risk of liver disease. TRIAL REGISTRATION: UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978 . Registered 06/04/2000.

Performance of Enhanced Liver Fibrosis test and comparison with transient elastography in the identification of liver fibrosis in patients with chronic hepatitis B infection.

Assessment of liver fibrosis is important in determining prognosis, disease progression and need for treatment in patients with chronic hepatitis B (CHB). Limitations to the use of liver biopsy in assessing fibrosis are well recognized, and noninvasive tests are being increasingly evaluated including transient elastography (TE) and serum markers such as the Enhanced Liver Fibrosis (ELF) test. We assessed performance of ELF and TE in detecting liver fibrosis with reference to liver histology in a cohort of patients with CHB (n = 182), and compared the performance of these modalities. Median age was 46 and mean AST 70 IU/L. Cirrhosis was reported in 20% of liver biopsies. Both modalities performed well in assessing fibrosis at all stages. Area under receiver operator characteristic (AUROC) curves for detecting METAVIR fibrosis stages F ≥ 1, F ≥ 2, F ≥ 3 and F4 were 0.77, 0.82, 0.80 and 0.83 for ELF and 0.86, 0.86, 0.90 and 0.95 for TE. TE performed significantly better in the assessment of severe fibrosis (AUROC 0.80 for ELF and 0.90 for TE, P < 0.01) and cirrhosis (0.83 for ELF and 0.95 for TE, P < 0.01). This study demonstrates that ELF has good performance in detection of liver fibrosis in patients with CHB, and when compared, TE performs better in detection of severe fibrosis/cirrhosis.

Strategies to manage hepatitis C virus (HCV) disease burden.

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV-related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3-5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

Validity of noninvasive markers of methotrexate-induced hepatotoxicity: a retrospective cohort study.

BACKGROUND: Methotrexate is a cost-effective systemic treatment for moderate-to-severe psoriasis, but the perceived risk of associated liver fibrosis prevents optimal use. Procollagen III aminoterminal propeptide (PIIINP) is a widely adopted noninvasive biomarker of liver fibrosis; however, its clinical utility is narrow owing to limited evidence of performance and the need for serial measurement. The Enhanced Liver Fibrosis (ELF) assay is a validated biomarker of liver fibrosis. OBJECTIVES: To evaluate the diagnostic accuracy of the ELF test compared with PIIINP for the diagnosis of liver fibrosis in a cohort of patients with psoriasis treated with methotrexate. METHODS: A retrospective cohort study comparing the diagnostic accuracy of PIIINP and ELF in detecting liver fibrosis in patients treated with methotrexate. Liver biopsy was the reference standard. RESULTS: Twenty-seven patients were identified and included in the study. The diagnostic accuracies [area under the receiver operating curve (AUROC)] of serial PIIINP and serial ELF were 0·589 [95% confidence interval (CI) 0·379-0·800] and 0·643 (95% CI 0·391-0·895), respectively, for mild fibrosis; and 0·576 (95% CI 0·237-0·916) and 0·674 (95% CI 0·421-0·927) for at least moderate fibrosis. The AUROC values for single PIIINP and single ELF were 0·582 (95% CI 0·363-0·801) and 0·693 (95% CI 0·482-0·904), respectively, for mild fibrosis; and 0·667 (95% CI 0·363-0·971) and 0·806 (95% CI 0·564-1·000) for at least moderate fibrosis. CONCLUSIONS: This pilot study suggests that ELF may be at least equivalent or possibly superior to PIIINP in the detection of liver fibrosis in patients with psoriasis treated with methotrexate, and supports further investigations into the performance of ELF in this clinical setting.

A class C CpG toll-like receptor 9 agonist successfully induces robust interferon-alpha production by plasmacytoid dendritic cells from patients chronically infected with hepatitis C.

Immunomodulators that induce local endogenous interferon-alpha (IFN-alpha) production by plasmacytoid dendritic cells (pDCs) may offer new strategies for the treatment of patients chronically infected with the hepatitis C virus (HCV). However, such an approach may be compromised if reports are true that IFN-alpha production by pDCs from patients with chronic HCV (cHCV) is profoundly impaired. To address the question of pDC dysfunction in cHCV more definitively, in the present study a panel of four prototypic synthetic agonists of toll-like receptor 7 (TLR7) or TLR9 were administered in vitro to pDCs purified from cHCV patients and from normal uninfected donors and their responses compared in terms of not only IFN-alpha production but also the global expression of other cytokines and phenotypic maturation. Plasmacytoid DCs from uninfected donors produced substantial levels of IFN-alpha in response to three of the four agonists and yet only one TLR9 agonist, a class C CpG oligodeoxynucleotide (ODN), induced robust IFN-alpha production by pDCs from cHCV patients. Proinflammatory cytokine production and phenotypic maturation in response to all four agonists was equivalent in infected and uninfected pDCs. These data point to a profound but selective defect in IFN-alpha production by pDCs from cHCV donors. Nonetheless, a class C CpG ODN successfully induced robust IFN-alpha production, suggesting that this class of TLR9 agonist may have utility as a future immunotherapeutic for the treatment of chronic HCV infection.

A novel, helminth-derived immunostimulant enhances human recall responses to hepatitis C virus and tetanus toxoid and is dependent on CD56+ cells for its action.

We have described previously an immunostimulant derived from Onchocerca volvulus, the helminth parasite that causes onchocerciasis. Recombinant O. volvulus activation-associated secreted protein-1 (rOv-ASP-1) was a potent adjuvant for antibody and cellular responses to protein, polypeptide and small peptide antigens. Our aims were to determine whether rOv-ASP-1 is immunostimulatory for human peripheral blood mononuclear cells (PBMC) and, if so, whether it could augment cellular responses against human pathogen antigens in vitro. Cytokines from rOv-ASP-1-stimulated human PBMC were measured by a fluorescence activated cell sorter-based multiplex assay. Recall responses of normal healthy donor (NHD) and chronic hepatitis C virus (c-HCV)-infected patient PBMC to tetanus toxoid (TT) or HCV core (HCVco) antigen, respectively, were measured by interferon-gamma enzyme-linked immunospot assays. Interferon-gamma was the predominant cytokine induced by rOv-ASP-1. 77.3% of NHD anti-TT and 88.9% of c-HCV anti-HCVco responses were enhanced by rOv-ASP-1. The immunostimulant effect was dependent upon contact between CD56+ and CD56- fractions of PBMC. We have described a helminth-derived protein that can act as an immunostimulant for human recall responses in vitro to TT and, perhaps more importantly, HCV antigens in patients with chronic HCV infection. Our longer-term goal would be to boost anti-viral responses in chronic infections such as HCV.

Isolated HLA-DP mismatches between donors and recipients do not influence the function or outcome of renal transplants.

The matching of donors and renal graft recipients for human leukocyte antigens A, B, and DR has been shown to exert beneficial effects on the outcome of transplantation. Until the advent of polymerase chain reaction amplification-based genotyping, the effect of HLA-DP compatibility on graft survival could not be thoroughly investigated. HLA-DP compatibility has been determined in three living-related transplants and 34 cadaveric transplants for donor-recipient pairs matched for HLA-DR and -DQ. The effect of DP mismatching on graft survival and function was assessed. No clear benefit from matching donor and recipient for HLA-DP could be discerned.

Molecular aspects of autoimmunity: a review.

Molecular genetic techniques are being widely applied to the study of autoimmune diseases. Major advances have been made in diabetes, rheumatoid arthritis and coeliac disease. Work on experimental models of autoimmune uveitis suggests that similar advances will follow in this field. The application of molecular genetics to the study of immunology has lead to great advances in our understanding of the anatomy of antigen recognition. This work has lead to the identification of some of the structural determinants of antigen binding by MHC molecules and is helping to explain some MHC-disease associations. More recently, molecular studies of the T cell receptor have characterized patterns of T cell receptor expression in humans and have lead to the identification of regions of the T cell receptor critical for antigen recognition. These techniques will hopefully provide insights into the nature of autoimmunity and permit the identification of targets for disease specific immunotherapies. This review describes attempts to corelate MHC structure and function in the context of autoimmunity and discusses some of the strategies for analyzing T cell receptor usage in autoimmune disease.

The need for evidence-based medicine.

As physicians, whether serving individual patients or populations, we always have sought to base our decisions and actions on the best possible evidence. The ascendancy of the randomized trial heralded a fundamental shift in the way that we establish the clinical bases for diagnosis, prognosis, and therapeutics. The ability to track down, critically appraise (for its validity and usefulness), and incorporate this rapidly growing body of evidence into one's clinical practice has been named 'evidence-based medicine' (EBM).

On the need for evidence-based medicine.

Doctors always seek to base their decisions on the best available evidence. Often this evidence represents extrapolations of pathophysiological principles and logic rather than established facts based on data derived from patients. The advent and proliferation of randomized controlled trials have led to a rapid increase in the quantity and quality of clinically valid evidence concerning clinical history taking and physical examination, issues of diagnosis, prognosis, therapy and other important health care issues. As a result it is becoming possible to make explicit much of the implicit non-verbal reasoning of expert clinicians, making their clinical reasoning more comprehensible and accessible to trainees. The ability to track down, critically appraise and incorporate evidence into clinical practice has been named 'evidence-based medicine'. As the quantity of valid evidence increases so does the requirement for each of us to develop the skills necessary to assimilate, evaluate and make best use of that evidence for patients. Often we fail to identify or address our daily needs for clinically important knowledge, leading to a progressive decline in our clinical competency. When we do seek knowledge traditional sources of information such as journals and text-books are often either too disorganized or out of date and we often resort to asking colleagues. The need to maintain and expand clinically important knowledge has been partially addressed by increasing demands for continuing medical education but how might this be best achieved? Recent evaluations suggest that three evidence-based medicine strategies help fulfill these goals. They include; learning evidence-based medicine, seeking and applying evidence-based medical summaries generated by others, and accepting evidence-based protocols developed by others.

Complexities of HCV management in the new era of direct-acting antiviral agents.

The availability of the direct-acting antiviral agents (DAAs) boceprevir and telaprevir provides improved treatment outcomes for many patients infected with hepatitis C virus (HCV) genotype 1. However, HCV infection must first be identified before a decision on treatment can be made and currently many patients remain unaware that they have the virus. Given the lack of prompt diagnosis, disease severity should be determined as a baseline reference for treatment, and novel non-invasive techniques for evaluating fibrosis are now available. For patients receiving a DAA regimen, response-guided therapy based on the detection, absence or level of HCV RNA at specified time points is required to achieve an optimal treatment outcome. Knowledge of the test used to measure HCV RNA and its analytical sensitivity, as well as how to interpret the results correctly, are therefore required to administer therapy appropriately. Furthermore, effective treatment management includes appropriate handling of side effects. This increased complexity associated with DAA regimens has resulted in confusion over many aspects of care, including treatment monitoring, viral load result interpretation and the optimal duration of therapy. These issues are discussed here in addition to the benefits of referring patients infected with HCV to a specialist centre.

Harnessing alveolar macrophages for sustained mucosal T-cell recall confers long-term protection to mice against lethal influenza challenge without clinical disease.

Vaccines that induce T cells, which recognize conserved viral proteins, could confer universal protection against seasonal and pandemic influenza strains. An effective vaccine should generate sufficient mucosal T cells to ensure rapid viral control before clinical disease. However, T cells may also cause lung injury in influenza, so this approach carries inherent risks. Here we describe intranasal immunization of mice with a lentiviral vector expressing influenza nucleoprotein (NP), together with an NFκB activator, which transduces over 75% of alveolar macrophages (AM). This strategy recalls and expands NP-specific CD8+ T cells in the lung and airway of mice that have been immunized subcutaneously, or previously exposed to influenza. Granzyme B-high, lung-resident T-cell populations persist for at least 4 months and can control a lethal influenza challenge without harmful cytokine responses, weight loss, or lung injury. These data demonstrate that AM can be harnessed as effective antigen-presenting cells for influenza vaccination.

Noninvasive assessment of liver fibrosis: serum markers, imaging, and other modalities.

Liver fibrosis is a common pathway of injury after chronic insult to the liver. The evolution of liver fibrosis to cirrhosis has many clinical implications, including bleeding, infection, hepatocellular carcinoma, and death. The reference standard for diagnosing liver fibrosis is currently histologic assessment of tissue obtained through liver biopsy. Although this provides valuable information, it has limitations, including its invasiveness, sampling error, observer variability, and the use of categorical scoring systems. This article outlines the various noninvasive markers, including blood tests, imaging, and novel technologies. It examines the principles behind their development, their diagnostic accuracy, and their evolution.

A decision analysis model for diagnostic strategies using DNA testing for hereditary haemochromatosis in at risk populations.

BACKGROUND: New techniques for diagnosing hereditary haemochromatosis (HHC) have become available alongside traditional tests such as liver biopsy and serum iron studies. AIM: To evaluate DNA tests in people suspected of having haemochromatosis at clinical presentation compared to liver biopsy, and in family members of those diagnosed with haemochromatosis compared to phenotypic iron studies in UK. METHODS: Decision analytic models were constructed to compare the costs and consequences of the diagnostic strategies for a hypothetical cohort of people with suspected haemochromatosis. For each strategy, the number of cases of haemochromatosis identified and treated and the resources used were estimated. RESULTS: For diagnostic strategies in people suspected clinically of having haemochromatosis, the DNA strategy is cost saving compared to liver biopsy (cost saved per case detected, 123 pounds) and continues to be so across all ranges of parameters. For family testing, the DNA strategy is cost saving for the offspring of the proband but not for siblings. If the DNA test cost were to reduce by 40% to 60 pounds or, if in the phenotypic model, those with initially normal iron indices were retested twice instead of once, the DNA strategy would be the cheaper one. CONCLUSION: Diagnostic strategies involving DNA testing are likely to be cost saving in clinical cases with iron overload and in the offspring of index cases. This study supports the UK guideline recommendations for the use of DNA testing in UK.

Monocyte-derived dendritic cell function in chronic hepatitis C is impaired at physiological numbers of dendritic cells.

Monocyte-derived dendritic cells (MoDCs) are a promising cellular adjuvant for effector immune responses against tumours and chronic viral infections, including hepatitis C virus (HCV). If autologous DC therapeutic approaches are to be applied in persistent HCV infections in patients, it is important to have an unambiguous understanding of the functional status of the cell type used, namely MoDCs from patients with chronic hepatitis C (CHC) infection. Because of conflicting published reports of either impaired or normal MoDC function in CHC infection, we re-examined the ability of MoDCs from CHC and normal healthy donors (NHD) to mature to an inflammatory stimulus [tumour necrosis factor (TNF)-alpha] and their subsequent functional capabilities. Expression of maturation-associated phenotypic markers [human leucocyte antigen (HLA)-DR, CD83, CD86, CD40], allostimulatory capacity in mixed lymphocyte reactions (MLRs) and CD40-ligand-induced cytokine and chemokine generation were compared in CHC- versus NHD-MoDCs. TNF-alpha-stimulated CHC-MoDCs up-regulated phenotypic markers, but to significantly lower levels than NHD-MoDCs. At physiological ratios of DCs to T cells, CHC-MoDCs were less allostimulatory than NHD-MoDCs, but not when DC numbers were substantially increased. CHC- and NHD-MoDCs generated equivalent amounts of cytokines [TNF-alpha, interleukin (IL)-1beta, IL-6, IL-12p70, IL-15, IL-10] and chemokines [interferon-inducible protein (IP)-10, macrophage inflammatory protein (MIP)-1alpha, regulated upon activation, normal T expressed and secreted (RANTES)] after CD40 ligation. Because the functional defect was not apparent at high MoDC : T cell ratios, autologous MoDC therapy with sufficiently high numbers of DCs could, in theory, overcome any impairment of MoDC function in CHC.

Non-invasive markers associated with liver fibrosis in non-alcoholic fatty liver disease.

The diagnosis of fibrosis within liver disease is important for prognosis, stratification for treatment, and monitoring of treatment efficacy. The rising incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) has driven the search for accurate non-invasive tools of liver fibrosis within this condition. With the aid of a systematic review, we explore how the field has evolved from the discovery of simple blood parameters to panel markers of liver fibrosis. We will discuss the biological plausibility, limitations, potential uses, and emerging diagnostic techniques of non-invasive markers in this rapidly expanding field.

Variation in human T cell receptor V beta and J beta repertoire: analysis using anchor polymerase chain reaction.

Anchor polymerase chain reaction has been applied to the study of human T cell receptor beta chain repertoire in peripheral blood. The use of this technique has demonstrated that considerable variation in V beta and J beta usage exists, both within and between individuals. Particular V beta families, including V beta 6, V beta 4 and V beta 12 are commonly utilized, while families such as V beta 10, V beta 11 and V beta 15 are rare in all individuals studied. Marked interindividual variation in V beta usage was detected for V beta 12 and V beta 4. Biased usage of J beta elements is a prominent feature of peripheral repertoire, while there is no evidence for preferential V beta-J beta recombination events. Biased J beta usage in expressed V beta-D beta-J beta-C beta transcripts, subject to selection, was the same as that in aberrant, unselected D beta-J beta-C beta transcripts, implying that bias resulted from events relating to rearrangement itself, in the absence of selection. N-region diversity showed some evidence for preferential insertion of deoxyguanosine, consistent with the action of terminal deoxytransferase. No P-nucleotide incorporation was seen in association with intact J beta elements. These data provide evidence of some of the variation in human T cell receptor beta chain repertoire and provide a basis for comparisons with sequences which may be obtained in autoimmune and superantigen-mediated diseases.

The human T cell receptor in health and disease.

The T cell antigen receptor (TCR) recognizes antigen in the form of short peptides bound to a major histocompatibility (MHC) molecule. This review provides a synopsis of the current state of knowledge of the structure and function of the receptor and its possible role in human disease. Analysis of the T cell receptor usage of T-cell lines and clones recognizing the same peptide-MHC complex is beginning to shed light onto the structural basis of the TCR-peptide-MHC complex. Also, it is now apparent that there are two mechanisms by which the TCR can interact with the MHC molecule, either through classical peptide interactions or through super-antigens. Finally, we review the role of specific TCRs in human disease. Current evidence in this area is difficult to interpret; however, it is likely that TCR-mediated disease susceptibility exists, and its basis at either a germline or somatic level will soon be clarified.