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1.
Frontline Gastroenterol ; 10(4): 364-371, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31656561

RESUMO

Objective: Immune checkpoint inhibitors like anti-programmed cell death protein 1 (PD-1) drugs Nivolumab and Pembrolizumab and anti-cytotoxic T-lymphocyte associated (CTLA-4) drug Ipilimumab have become standard of care in many metastatic cancers. Immunotherapy-related hepatitis and cholangitis present a diagnostic and management challenge, being rare and incompletely characterised. We aim to report the incidence, features and treatments used for this in a real-world setting and to identify useful biomarkers, which can be used to predict effective use of steroids. Design: Retrospective review of 453 patients started on immunotherapy over 7 years. Setting: Tertiary hepatology and oncology centre. Patients: 21 patients identified with immunotherapy-related hepatotoxicity. Results: Hepatitis was most common in those receiving dual therapy (incidence 20%), with 75% of Grade 4 hepatitis cases occurring with ipilimumab-containing regimens. Corticosteroid monotherapy is first line treatment, but doses above 60 mg OD prednisolone do not demonstrate any additional benefit in time to hepatitis resolution. The alanine transaminase (ALT) reduction in steroid-responsive hepatitis is typically rapid (with a halving of ALT within 11 days). The commencement of additional immunosuppression (typically mycophenolate) appears safe and prompts a more rapid fall in ALT than corticosteroid use alone. Infliximab was safely used twice as hepatitis treatment. We also describe one patient with rare immunotherapy-induced biliary disease. Conclusions: Vigilance is required for detection of immunotherapy-associated liver disease as, other than dual immunotherapy, we can identify no predictive factors for its development. Our data suggest that corticosteroid response is not dependent on the higher dosing regimens. Early escalation of immunosuppression may be of benefit in the absence of a rapid response to corticosteroids.

2.
PLoS One ; 14(8): e0221066, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430314

RESUMO

BACKGROUND AND AIMS: Non-invasive assessment of portal hypertension is an area of unmet need. This proof of concept study aimed to evaluate the diagnostic accuracy of a multi-parametric magnetic resonance technique in the assessment of portal hypertension. Comparison to other non-invasive technologies was a secondary aim. METHODS: T1 and T2* maps through the liver and spleen were acquired prior to trans-jugular liver biopsy and hepatic vein pressure gradient (HVPG) measurement. T1 measurements reflect changes in tissue water content, but this relationship is confounded by the presence of iron, which in turn can be quantified accurately from T2* maps. Data were analysed using LiverMultiScan (Perspectum Diagnostics, Oxford, UK) which applies an algorithm to remove the confounding effect of iron, yielding the "iron corrected T1" (cT1). Sensitivity, specificity, diagnostic values and area under the curve were derived for spleen cT1, liver cT1, transient elastography, and serum fibrosis scores. HVPG was the reference standard. RESULTS: Nineteen patients (15 men) with median age 57 years were included. Liver disease aetiologies included non-alcoholic fatty liver disease (n = 9; 47%) and viral hepatitis (n = 4; 21%). There was strong correlation between spleen cT1 and HVPG (r = 0.69; p = 0.001). Other non-invasive biomarkers did not correlate with HVPG. Spleen cT1 had excellent diagnostic accuracy for portal hypertension (HVPG >5 mmHg) and clinically significant portal hypertension (HVPG ≥10 mmHg) with an area under the receiver operating characteristic curve of 0.92 for both. CONCLUSION: Spleen cT1 is a promising biomarker of portal pressure that outperforms other non-invasive scores and should be explored further.

3.
mBio ; 10(3)2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239374

RESUMO

HBsAg and HBeAg have gained traction as biomarkers of control and clearance during chronic hepatitis B virus infection (CHB). Improved understanding of the clearance correlates of these proteins could help inform improvements in patient-stratified care and advance insights into the underlying mechanisms of disease control, thus underpinning new cure strategies. We collected electronic clinical data via an electronic pipeline supported by the National Institute for Health Research Health Informatics Collaborative (NIHR HIC), adopting an unbiased approach to the generation of a robust longitudinal data set for adults testing HBsAg positive from a large UK teaching hospital over a 6-year period (2011 to 2016 inclusive). Of 553 individuals with CHB, longitudinal data were available for 319, representing >107,000 weeks of clinical follow-up. Among these 319 individuals, 13 (4%) cleared HBsAg completely. Among these 13, the HBsAg clearance rate in individuals on nucleos(t)ide analogue (NA) therapy (n = 4 [31%]; median clearance time,150 weeks) was similar to that in individuals not on NA therapy (n = 9 [69%]; median clearance time, 157 weeks). Those who cleared HBsAg were significantly older and less likely to be on NA therapy than nonclearers (P = 0.003 and P = 0.001, respectively). Chinese ethnicity was associated with HBeAg positivity (P = 0.025). HBeAg clearance occurred in individuals both on NA therapy (n = 24; median time, 49 weeks) and off NA therapy (n = 19; median time, 52 weeks). Improved insights into the dynamics of these biomarkers can underpin better prognostication and patient-stratified care. Our systematized approach to data collection paves the way for scaling up efforts to harness clinical data to address research questions and support improvements in clinical care.IMPORTANCE Advances in the diagnosis, monitoring, and treatment of hepatitis B virus (HBV) infection are urgently required if we are to meet international targets for elimination by the year 2030. Here we demonstrate how routine clinical data can be harnessed through an unbiased electronic pipeline, showcasing the significant potential for amassing large clinical data sets that can help to inform advances in patient care and provide insights that may help to inform new cure strategies. Our cohort from a large UK hospital includes adults from diverse ethnic groups that have previously been underrepresented in the literature. By tracking two protein biomarkers that are used to monitor chronic HBV infection, we provide new insights into the timelines of HBV clearance, both on and off treatment. These results contribute to improvements in individualized clinical care and may provide important clues into the immune events that underpin disease control.


Assuntos
Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/sangue , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , Biomarcadores/sangue , Criança , Estudos de Coortes , Feminino , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Hospitais/estatística & dados numéricos , Humanos , Estudos Longitudinais , Masculino , Informática Médica , Pessoa de Meia-Idade , Reino Unido , Adulto Jovem
4.
Gut ; 68(8): 1356-1378, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31154395

RESUMO

These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.


Assuntos
Neoplasias do Sistema Biliar , Colangite Esclerosante , Técnicas de Diagnóstico do Sistema Digestório , Doença Relacionada a Imunoglobulina G4/diagnóstico , Administração dos Cuidados ao Paciente/métodos , Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/etiologia , Colangite Esclerosante/complicações , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/etiologia , Diagnóstico Diferencial , Humanos , Prognóstico , Reino Unido
5.
Open Forum Infect Dis ; 6(3): ofz076, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30949527

RESUMO

Background: Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome. Methods: Full-genome sequencing was performed on HCV plasma samples with <85% sequence homology of NS3, NS5A, and/or NS5B to HCV genotype (GT) 1-8 reference strains. Results: A total of 14 653 patients with GT1-6 HCV infection were enrolled in clinical studies of sofosbuvir-based regimens. For the majority of the patients, a specific subtype could be assigned based on a close genetic relationship to previously described subtypes. However, for 19 patients, novel subtypes were identified with <85% homology compared with previously described subtypes. These novel subtypes had the following genotypes: 9 in GT2, 5 in GT4, 2 in GT6, and 1 each in GT1, GT3, and GT5. Despite the presence of polymorphisms at resistance-associated substitution positions, 18 of the 19 patients treated with sofosbuvir-containing therapy achieved SVR12. Conclusions: Nineteen novel HCV subtypes were identified, suggesting an even greater genetic diversity of HCV subtypes than previously recognized.

6.
BMC Infect Dis ; 18(1): 461, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30217169

RESUMO

BACKGROUND: As direct acting antiviral (DAA) therapy is progressively rolled out for patients with hepatitis C virus (HCV) infection, careful scrutiny of HCV epidemiology, diagnostic testing, and access to care is crucial to underpin improvements in delivery of treatment, with the ultimate goal of elimination. METHODS: We retrospectively studied microbiology records from a large UK teaching hospital in order to compare the performance of HCV screening and diagnostic tests (antibody, antigen and HCV RNA detection). Having described a local cohort of adults with active HCV infection, we investigated the proportion who attended hospital appointments, were prescribed direct acting antiviral (DAA) therapy, and cleared HCV RNA following treatment. RESULTS: Over a total time period of 33 months between 2013 and 2016, we tested 38,509 individuals for HCV infection and confirmed a new diagnosis of active HCV infection (HCV-Ag + and/or HCV RNA+) in 353 (positive rate 0.9%). Our in-house HCV-Ab screening test had a positive predictive value of 87% compared to repeat HCV-Ab testing in a reference laboratory, highlighting the potential for false positives to arise using this test. HCV-Ag had 100% positive predictive value compared to detection of HCV RNA. There was a strong correlation between quantitative HCV-Ag and HCV RNA viral load (p < 0.0001). Among the cases of infection, genotype-1 and genotype-3 predominated, the median age was 37 years, 84% were male, and 36% were in prison. Hepatology review was provided in 39%, and 22% received treatment. Among those who received DAA therapy with 12 weeks of follow-up, 93% achieved a sustained virologic response (SVR12). CONCLUSIONS: HCV-Ag performs well as a diagnostic test compared to PCR for HCV RNA. Active HCV infection is over-represented among men and in the prison population. DAA therapy is successful in those who receive it, but a minority of patients with a diagnosis of HCV infection access clinical care. Enhanced efforts are required to provide linkage to clinical care within high risk populations.


Assuntos
Hepatite C/diagnóstico , Adulto , Antivirais/uso terapêutico , Estudos de Coortes , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C/virologia , Anticorpos Anti-Hepatite C/sangue , Hospitais de Ensino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Estudos Retrospectivos , Resposta Viral Sustentada , Reino Unido/epidemiologia
7.
Confl Health ; 12: 27, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30026794

RESUMO

Background: Non-communicable diseases (NCDs) - including cardiovascular disease (CVD), cancer and diabetes - have become a significant global burden on health. Particularly concerning are CVD rates, causing approximately 18 million deaths worldwide every year. The statistics show that the disease is no longer a predominantly high-income country phenomenon, but affects, increasingly, countries in both developing regions and conflict-affected areas. In the occupied Palestinian territory (oPt), the focus of this article, CVD ranks top of ten NCD killers, accounting for approximately 37.6% of deaths. Key risk factors discerned in primary care settings have been related to both structural determinants (i.e. the Israeli occupation) and individual behavioural factors. Unfortunately, no data are available for secondary care settings in the region and, consequently, little is known about patients and their capacity for risk factor behaviour change to manage their CVD.To begin closing this gap in knowledge, our study provides insight into cardiovascular disease secondary prevention care with the overall aim to enhance the understanding of the complexities of managing NCDs like CVD in conflict-affected settings. Specifically, research was carried out among Palestinian health professionals who specialise in coronary artery disease in the West Bank to elicit their views on (a) how socio-political, health system and individual behavioural factors might hinder patients to change their health behaviour and impact on the provision of healthcare and (b) possible solutions for overcoming identified barriers to behaviour change on societal as well as individual-patient levels within secondary care provision in a context of protracted conflict. Methods: This study is based on a qualitative approach in order to provide more in-depth information about health beliefs and behaviours, experiences and views of health professionals with regards to CVD secondary care. In total, 12 semi-structured interviews were conducted among doctors providing treatment to patients with CVD in secondary care settings. Interviews focused on health professionals' perspectives on risk factors and perceived barriers to behaviour change among known CVD patients receiving secondary care. Interviewees were also asked to propose possible actions that could be taken to overcome the identified barriers at both societal and individual patient levels. All interviews were digitally recorded, transcribed and analysed using thematic analysis. Results: Study results confirmed our prior theory of the complex entanglement of socio-political, health system and individual-level factors with regards to CVD experience, health-seeking and treatment. Also confirmed was our assumption that it is crucial to understand experts' definitions and approaches to treatment in order to grasp their visions for appropriate and improved prevention and treatment options. In particular, study participants highlighted how political determinants, notably the detrimental impact of the Israeli occupation, and social determinants, directly and indirectly influence behavioural determinants due to physical and bureaucratic barriers to accessing health facilities, economic hardship and chronic stress. These stressors, in turn, were perceived as having a negative effect on individual behavioural risk factors including smoking, unhealthy diet and an increasingly sedentary lifestyle. Proposed solutions included more focused interventions from the Ministry of Health as well as surveillance, primary prevention and health promotion, and management to positively effect behaviour change in order to address the growing burden of CVD in the region. Conclusions: The study has highlighted medical professionals' perceptions of how structural and individual behavioural determinants influence their own and individual patient's abilities to manage cardiovascular risk factors in a setting affected by chronic conflict. Consequently, we propose that medical and social intervention strategies generally used to address CVD risk, be strategically adapted in order to be useful and effective in contexts of armed conflict. Specifically, we call for a solid understanding of the socio-political context and existing health services as well as health providers' and patients' health beliefs and related behaviours when developing future health options aimed at addressing CVD in the region. Moreover, for health provision to be effective as well as sustainable, attention needs to be given above all towards a solution for political change.

8.
Gut ; 67(9): 1568-1594, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29593060

RESUMO

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Colagogos e Coleréticos/uso terapêutico , Colangite/diagnóstico , Colangite/terapia , Gastroenterologia , Ácido Ursodesoxicólico/uso terapêutico , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Autoanticorpos/sangue , Bilirrubina/sangue , Biomarcadores/sangue , Ácido Quenodesoxicólico/uso terapêutico , Colangite/sangue , Progressão da Doença , Humanos , Cirrose Hepática Biliar , Mitocôndrias/imunologia , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Sociedades Médicas , Resultado do Tratamento , Reino Unido
9.
Hepatology ; 67(6): 2113-2126, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29473975

RESUMO

Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. CONCLUSION: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126).


Assuntos
Antivirais/uso terapêutico , Benzofuranos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Adulto , Idoso , Combinação de Medicamentos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade
10.
Liver Int ; 38(1): 164-173, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28679028

RESUMO

BACKGROUND AND AIMS: Elevated serum ferritin is common in NAFLD, and is associated with more advanced disease and increased mortality. Hyperferritinaemia in NAFLD is often attributed to inflammation, while in other conditions ferritin closely reflects body iron stores. The aim of this study was to clarify the underlying cause of hyperferritinaemia in NAFLD. METHODS: Ferritin levels were examined with markers of iron status, inflammation and liver injury across the clinical spectrum of NAFLD using blood, tissue and magnetic resonance (MR) imaging. A separate larger group of NAFLD patients with hepatic iron staining and quantification were used for validation. RESULTS: Serum ferritin correlated closely with the iron regulatory hormone hepcidin, and liver iron levels determined by MR. Furthermore, ferritin levels reflected lower serum adiponectin, a marker of insulin resistance, and liver fat, but not cytokine or CRP levels. Ferritin levels differed according to fibrosis stage, increasing from early to moderate disease, and declining in cirrhosis. A similar pattern was found in the validation cohort of NAFLD patients, where ferritin levels were highest in those with macrophage iron deposition. Multivariate analysis revealed liver iron and hepcidin levels as the major determinants of serum ferritin. CONCLUSIONS: While hyperferritinaemia is associated with markers of liver injury and insulin resistance, serum hepcidin and hepatic iron are the strongest predictors of ferritin levels. These findings highlight the role of disordered iron homeostasis in the pathogenesis of NAFLD, suggesting that therapies aimed at correcting iron metabolism may be beneficial.


Assuntos
Ferritinas/sangue , Distúrbios do Metabolismo do Ferro/sangue , Ferro/análise , Fígado/química , Hepatopatia Gordurosa não Alcoólica/sangue , Adiponectina/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Hepcidinas/análise , Humanos , Resistência à Insulina , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/etiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Estudos Prospectivos , Regulação para Cima
11.
J Am Soc Nephrol ; 28(9): 2738-2748, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28465378

RESUMO

Polycystic liver disease is a well described manifestation of autosomal dominant polycystic kidney disease (ADPKD). Biliary tract complications are less well recognized. We report a 50-year single-center experience of 1007 patients, which raised a hypothesis that ADPKD is associated with biliary tract disease. We tested this hypothesis using all England Hospital Episode Statistics data (1998-2012), within which we identified 23,454 people with ADPKD and 6,412,754 hospital controls. Hospitalization rates for biliary tract disease, serious liver complications, and a range of other known ADPKD manifestations were adjusted for potential confounders. Compared with non-ADPKD hospital controls, those with ADPKD had higher rates of admission for biliary tract disease (rate ratio [RR], 2.24; 95% confidence interval [95% CI], 2.16 to 2.33) and serious liver complications (RR, 4.67; 95% CI, 4.35 to 5.02). In analyses restricted to those on maintenance dialysis or with a kidney transplant, RRs attenuated substantially, but ADPKD remained associated with biliary tract disease (RR, 1.19; 95% CI, 1.08 to 1.31) and perhaps with serious liver complications (RR, 1.15; 95% CI, 0.98 to 1.33). The ADPKD versus non-ADPKD RRs for biliary tract disease were larger for men than women (heterogeneity P<0.001), but RRs for serious liver complications appeared higher in women (heterogeneity P<0.001). Absolute excess risk of biliary tract disease associated with ADPKD was larger than that for serious liver disease, cerebral aneurysms, and inguinal hernias but less than that for urinary tract infections. Overall, biliary tract disease seems to be a distinct and important extrarenal complication of ADPKD.


Assuntos
Doenças Biliares/epidemiologia , Hospitalização/estatística & dados numéricos , Hepatopatias/epidemiologia , Rim Policístico Autossômico Dominante/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Biliares/etiologia , Estudos de Casos e Controles , Inglaterra/epidemiologia , Feminino , Hérnia Inguinal/epidemiologia , Humanos , Aneurisma Intracraniano/epidemiologia , Transplante de Rim , Hepatopatias/etiologia , Masculino , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/complicações , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/terapia , Diálise Renal , Fatores Sexuais , Infecções Urinárias/epidemiologia , Adulto Jovem
12.
Liver Int ; 37(7): 1065-1073, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27778429

RESUMO

BACKGROUND & AIMS: The diagnosis of non-alcoholic steatohepatitis and fibrosis staging are central to non-alcoholic fatty liver disease assessment. We evaluated multiparametric magnetic resonance in the assessment of non-alcoholic steatohepatitis and fibrosis using histology as standard in non-alcoholic fatty liver disease. METHODS: Seventy-one patients with suspected non-alcoholic fatty liver disease were recruited within 1 month of liver biopsy. Magnetic resonance data were used to define the liver inflammation and fibrosis score (LIF 0-4). Biopsies were assessed for steatosis, lobular inflammation, ballooning and fibrosis and classified as non-alcoholic steatohepatitis or simple steatosis, and mild or significant (Activity ≥2 and/or Fibrosis ≥2 as defined by the Fatty Liver Inhibition of Progression consortium) non-alcoholic fatty liver disease. Transient elastography was also performed. RESULTS: Magnetic resonance success rate was 95% vs 59% for transient elastography (P<.0001). Fibrosis stage on biopsy correlated with liver inflammation and fibrosis (rs =.51, P<.0001). The area under the receiver operating curve using liver inflammation and fibrosis for the diagnosis of cirrhosis was 0.85. Liver inflammation and fibrosis score for ballooning grades 0, 1 and 2 was 1.2, 2.7 and 3.5 respectively (P<.05) with an area under the receiver operating characteristic curve of 0.83 for the diagnosis of ballooning. Patients with steatosis had lower liver inflammation and fibrosis (1.3) compared to patients with non-alcoholic steatohepatitis (3.0) (P<.0001); area under the receiver operating characteristic curve for the diagnosis of non-alcoholic steatohepatitis was 0.80. Liver inflammation and fibrosis scores for patients with mild and significant non-alcoholic fatty liver disease were 1.2 and 2.9 respectively (P<.0001). The area under the receiver operating characteristic curve of liver inflammation and fibrosis for the diagnosis of significant non-alcoholic fatty liver disease was 0.89. CONCLUSIONS: Multiparametric magnetic resonance is a promising technique with good diagnostic accuracy for non-alcoholic fatty liver disease histological parameters, and can potentially identify patients with non-alcoholic steatohepatitis and cirrhosis.


Assuntos
Cirrose Hepática/diagnóstico por imagem , Fígado/diagnóstico por imagem , Imagem por Ressonância Magnética , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Adulto , Idoso , Algoritmos , Área Sob a Curva , Biópsia , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Projetos Piloto , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes , Índice de Gravidade de Doença
13.
Hepatology ; 64(6): 1934-1950, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27631819

RESUMO

The interplay between host antiviral immunity and immunopathology during hepatitis E virus (HEV) infection determines important clinical outcomes. We characterized the specificity, functionality, and durability of host T-cell responses against the full-length HEV virus and assessed a novel "Quantiferon" assay for the rapid diagnosis of HEV infection. Eighty-nine volunteers were recruited from Oxford, Truro (UK), and Toulouse (France), including 44 immune-competent patients with acute HEV infection, 18 HEV-exposed immunosuppressed organ-transplant recipients (8 with chronic HEV), and 27 healthy volunteers. A genotype 3a peptide library (616 overlapping peptides spanning open reading frames [ORFs] 1-3) was used in interferon-gamma (IFN-γ) T-cell ELISpot assays. CD4+ /CD8+ T-cell subsets and polyfunctionality were defined using ICCS and SPICE analysis. Quantification of IFN-γ used whole-blood stimulation with recombinant HEV-capsid protein in the QuantiFERON kit. HEV-specific T-cell responses were detected in 41/44 immune-competent HEV exposed volunteers (median magnitude: 397 spot-forming units/106 peripheral blood mononuclear cells), most frequently targeting ORF2. High-magnitude, polyfunctional CD4 and CD8+ T cells were detected during acute disease and maintained to 12 years, but these declined over time, with CD8+ responses becoming more monofunctional. Low-level responses were detectable in immunosuppressed patients. Twenty-three novel HEV CD4+ and CD8+ T-cell targets were mapped predominantly to conserved genomic regions. QuantiFERON testing demonstrated an inverse correlation between IFN-γ production and the time from clinical presentation, providing 100% specificity, and 71% sensitivity (area under the receiver operator characteristic curve of 0.86) for HEV exposure at 0.3 IU/mL. CONCLUSION: Robust HEV-specific T-cell responses generated during acute disease predominantly target ORF2, but decline in magnitude and polyfunctionality over time. Defining HEV T-cell targets will be important for the investigation of HEV-associated autoimmune disease. (Hepatology 2016;64:1934-1950).


Assuntos
Vírus da Hepatite E/imunologia , Hepatite E/imunologia , Hepatite E/virologia , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T/imunologia , Linfócitos T/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hepatite E/sangue , Hepatite E/diagnóstico , Humanos , Interferon gama/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
14.
Vaccines (Basel) ; 4(3)2016 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-27490575

RESUMO

An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection, would significantly reduce the global burden of disease associated with chronic HCV infection. A recombinant chimpanzee adenoviral (ChAd3) vector and a modified vaccinia Ankara (MVA), encoding the non-structural proteins of HCV (NSmut), used in a heterologous prime/boost regimen induced multi-specific, high-magnitude, durable HCV-specific CD4+ and CD8+ T-cell responses in healthy volunteers, and was more immunogenic than a heterologous Ad regimen. We now assess the immunogenicity of this vaccine regimen in HCV infected patients (including patients with a low viral load suppressed with interferon/ribavirin therapy), determine T-cell cross-reactivity to endogenous virus, and compare immunogenicity with that observed previously in both healthy volunteers and in HCV infected patients vaccinated with the heterologous Ad regimen. Vaccination of HCV infected patients with ChAd3-NSmut/MVA-NSmut was well tolerated. Vaccine-induced HCV-specific T-cell responses were detected in 8/12 patients; however, CD4+ T-cell responses were rarely detected, and the overall magnitude of HCV-specific T-cell responses was markedly reduced when compared to vaccinated healthy volunteers. Furthermore, HCV-specific cells had a distinct partially-functional phenotype (lower expression of activation markers, granzyme B, and TNFα production, weaker in vitro proliferation, and higher Tim3 expression, with comparable Tbet and Eomes expression) compared to healthy volunteers. Robust anti-vector T-cells and antibodies were induced, showing that there is no global defect in immunity. The level of viremia at the time of vaccination did not correlate with the magnitude of the vaccine-induced T-cell response. Full-length, next-generation sequencing of the circulating virus demonstrated that T-cells were only induced by vaccination when there was a sequence mismatch between the autologous virus and the vaccine immunogen. However, these T-cells were not cross-reactive with the endogenous viral variant epitopes. Conversely, when there was complete homology between the immunogen and circulating virus at a given epitope T-cells were not induced. T-cell induction following vaccination had no significant impact on HCV viral load. In vitro T-cell culture experiments identified the presence of T-cells at baseline that could be expanded by vaccination; thus, HCV-specific T-cells may have been expanded from pre-existing low-level memory T-cell populations that had been exposed to HCV antigens during natural infection, explaining the partial T-cell dysfunction. In conclusion, vaccination with ChAd3-NSmut and MVA-NSmut prime/boost, a potent vaccine regimen previously optimized in healthy volunteers was unable to reconstitute HCV-specific T-cell immunity in HCV infected patients. This highlights the major challenge of overcoming T-cell exhaustion in the context of persistent antigen exposure.

16.
Am J Gastroenterol ; 111(5): 733-43, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27091321

RESUMO

OBJECTIVES: Elevated serum immunoglobulin G4 (IgG4) levels have been associated with autoimmune pancreatitis and IgG4-related disease (IgG4-RD) for over a decade. However, an elevated serum IgG4 is not specific for the disease. There have been inconsistent reports of its use in diagnosis, as a marker of disease relapse, and its relationship to organ involvement in retrospective cohorts. The aims of this study were to ascertain conditions that are associated with an elevated serum IgG4 and to investigate the role of IgG4 in diagnosis, relapse, and organ involvement in a prospective cohort of patients with IgG4-RD. METHODS: We evaluated serum IgG4 measurements in the Oxford Immunology Laboratory over 6 years. Patients in whom serum IgG4 was requested to differentiate IgG4-RD from other diseases were recruited into a longitudinal follow-up study to determine final diagnosis. In a prospective cohort of IgG4-RD patients, organ involvement, response to therapy, and disease relapse were determined. RESULTS: Two thousand and sixty-seven samples from 1,510 patients had serum IgG4 measured. Of these, IgG4 was elevated (≥1.4 g l(-1)) in 243 (16.1%) patients. The main indication (85.6%) was to distinguish between IgG4-RD and non-IgG4-RD conditions. Only 5.1% of patients who had serum IgG4 measured for this purpose had a final diagnosis of IgG4-RD. Of those with an elevated serum IgG4, 22.4% met IgG4-RD diagnostic criteria. Serum IgG4 was elevated in 48 (82.8%) of IgG4-RD patients. An IgG4 cutoff of 1.4 g l(-1) gave a sensitivity of 82.8% and specificity of 84.7% to diagnose IgG4-RD. Increasing this to 2.8 g l(-1) increased specificity to 96.2% and negative predictive value to 97.7%, with a lower sensitivity of 56.9% and positive predictive value of 44.5%. Serum IgG4 levels fell with corticosteroid therapy, but this was not disease-specific. A serum IgG4 of ≥2.8 g l(-1) at diagnosis was associated with multi-organ involvement and risk of relapse. CONCLUSIONS: Serum IgG4 levels are elevated in multiple non-IgG4-RD inflammatory and malignant conditions, with less than one-quarter of those with an elevated IgG4 meeting IgG4-RD diagnostic criteria. A serum IgG4 of ≥2.8 g l(-1) is useful in distinguishing between IgG4-RD and non-IgG4-RD diagnoses, predicting multiple-organ involvement and risk of relapse in IgG4-RD.


Assuntos
Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Imunoglobulina G/sangue , Pancreatite/diagnóstico , Paraproteinemias/sangue , Paraproteinemias/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/etiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Pancreatite/sangue , Pancreatite/etiologia , Paraproteinemias/etiologia , Valor Preditivo dos Testes , Recidiva , Reino Unido , Adulto Jovem
17.
Hepatology ; 63(5): 1455-70, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26474390

RESUMO

UNLABELLED: Adenoviral vectors encoding hepatitis C virus (HCV) nonstructural (NS) proteins induce multispecific, high-magnitude, durable CD4(+) and CD8(+) T-cell responses in healthy volunteers. We assessed the capacity of these vaccines to induce functional HCV-specific immune responses and determine T-cell cross-reactivity to endogenous virus in patients with chronic HCV infection. HCV genotype 1-infected patients were vaccinated using heterologous adenoviral vectors (ChAd3-NSmut and Ad6-NSmut) encoding HCV NS proteins in a dose escalation, prime-boost regimen, with and without concomitant pegylated interferon-α/ribavirin therapy. Analysis of immune responses ex vivo used human leukocyte antigen class I pentamers, intracellular cytokine staining, and fine mapping in interferon-γ enzyme-linked immunospot assays. Cross-reactivity of T cells with population and endogenous viral variants was determined following viral sequence analysis. Compared to healthy volunteers, the magnitude of HCV-specific T-cell responses following vaccination was markedly reduced. CD8(+) HCV-specific T-cell responses were detected in 15/24 patients at the highest dose, whereas CD4(+) T-cell responses were rarely detectable. Analysis of the host circulating viral sequence showed that T-cell responses were rarely elicited when there was sequence homology between vaccine immunogen and endogenous virus. In contrast, T cells were induced in the context of genetic mismatch between vaccine immunogen and endogenous virus; however, these commonly failed to recognize circulating epitope variants and had a distinct partially functional phenotype. Vaccination was well tolerated but had no significant effect on HCV viral load. CONCLUSION: Vaccination with potent HCV adenoviral vectored vaccines fails to restore T-cell immunity except where there is genetic mismatch between vaccine immunogen and endogenous virus; this highlights the major challenge of overcoming T-cell exhaustion in the context of persistent antigen exposure with implications for cancer and other persistent infections.


Assuntos
Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Linfócitos T/imunologia , Vacinas contra Hepatite Viral/imunologia , Adenoviridae/genética , Adulto , Idoso , Sequência de Aminoácidos , Epitopos de Linfócito T , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Riboflavina/administração & dosagem , Vacinação
18.
J Hepatol ; 64(2): 308-315, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26471505

RESUMO

BACKGROUND & AIMS: Multiparametric magnetic resonance (MR) imaging has been demonstrated to quantify hepatic fibrosis, iron, and steatosis. The aim of this study was to determine if MR can be used to predict negative clinical outcomes in liver disease patients. METHODS: Patients with chronic liver disease (n=112) were recruited for MR imaging and data on the development of liver related clinical events were collected by medical records review. The median follow-up was 27months. MR data were analysed blinded for the Liver Inflammation and Fibrosis score (LIF; <1, 1-1.99, 2-2.99, and ⩾3 representing normal, mild, moderate, and severe liver disease, respectively), T2∗ for liver iron content and proportion of liver fat. Baseline liver biopsy was performed in 102 patients. RESULTS: Liver disease aetiologies included non-alcoholic fatty liver disease (35%) and chronic viral hepatitis (30%). Histologically, fibrosis was mild in 54 (48%), moderate in 17 (15%), and severe in 31 (28%) patients. Overall mortality was 5%. Ten patients (11%) developed at least one liver related clinical event. The negative predictive value of LIF<2 was 100%. Two patients with LIF 2-2.99 and eight with LIF⩾3 had a clinical event. Patients with LIF⩾3 had a higher cumulative risk for developing clinical events, compared to those with LIF<1 (p=0.02) and LIF 1-1.99 (p=0.03). Cox regression analysis including all 3 variables (fat, iron, LIF) resulted in an enhanced LIF predictive value. CONCLUSIONS: Non-invasive standardised multiparametric MR technology may be used to predict clinical outcomes in patients with chronic liver disease.


Assuntos
Hepatite Crônica , Fígado , Imagem por Ressonância Magnética/métodos , Hepatopatia Gordurosa não Alcoólica , Adulto , Biópsia , Feminino , Fibrose/diagnóstico por imagem , Fibrose/patologia , Hepatite Crônica/diagnóstico por imagem , Hepatite Crônica/mortalidade , Hepatite Crônica/patologia , Hepatite Crônica/virologia , Humanos , Inflamação/diagnóstico por imagem , Inflamação/patologia , Estimativa de Kaplan-Meier , Fígado/diagnóstico por imagem , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/mortalidade , Hepatopatia Gordurosa não Alcoólica/patologia , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Índice de Gravidade de Doença , Reino Unido/epidemiologia
19.
J Clin Pathol ; 68(11): 935-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26216906

RESUMO

AIMS: With changing indications for performing medical liver biopsies, we aimed to develop a tool to allow pathologists to evaluate the current usefulness, value and impact of their medical liver biopsy service. METHODS: We designed and piloted a questionnaire-based clinico-pathological audit for medical liver biopsies. RESULTS: The audit tool was simple to implement and provided useful information about our service. Hepatologists felt that 96% of reports were clinically useful. 56% of biopsies confirmed clinical diagnoses, 46% helped differentiate between diagnoses and 42% were able to exclude possible diagnoses. 74% resulted in a change of management and 27% of liver biopsies resulted in a diagnosis which was not clinically suspected. CONCLUSIONS: We demonstrate the usefulness of an audit tool in providing evidence of the value of the liver pathology service in a large UK regional centre.


Assuntos
Biópsia , Hepatopatias/diagnóstico , Fígado/patologia , Auditoria Médica/métodos , Auditoria Médica/normas , Humanos , Inquéritos e Questionários
20.
BMJ Case Rep ; 20152015 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-25827915

RESUMO

Primary sclerosing cholangitis is associated with an increased risk of cholangiocarcinoma; appropriate surveillance should be undertaken for this. Our case illustrates an unexpected liver lesion in such a patient, which would not have been detected with imaging alone. In suspected cancer, if a patient is not a candidate for liver resection, liver biopsy should be considered in case there is a treatment option for an alternative cause of the liver lesion. This is a careful decision to be made due to the risk of tumour seeding compromising cure and needs to be discussed via the hepatobiliary multidisciplinary team.


Assuntos
Colangiocarcinoma/diagnóstico , Colangite Esclerosante/complicações , Neoplasias Hepáticas/diagnóstico , Colangiocarcinoma/etiologia , Diagnóstico Diferencial , Humanos , Neoplasias Hepáticas/etiologia , Masculino , Melanoma/diagnóstico , Pessoa de Meia-Idade , Resultado do Tratamento
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