Chronic liver disease detection and quantification

Chronic liver disease (CLD) is a major cause of death in the UK. The major contributors are alcohol, fat and viral hepatitis. The common pathway towards cirrhosis is progressive liver fibrosis. The utility of the traditional method of evaluating fibrosis, liver biopsy, is limited by procedural risk, sampling error and variability in histological analysis. This has driven exploration of non-invasive markers of liver fibrosis. I evaluated the performance of the Enhanced Liver Fibrosis (ELF) test to detect liver fibrosis in chronic hepatitis B and compared it to an alternative modality, transient elastography (TE), demonstrating good diagnostic performance in fibrosis assessment, with comparable performance to TE. Further, liver biopsy is not feasible in community settings, and although the role of non-invasive markers of fibrosis is expanding, they have not been widely evaluated in community settings. I estimated the incidence of CLD in a large cohort of community-based postmenopausal women and investigated the contribution of alcohol and overweight / obesity to risk of CLD, observing more clinical events attributable to cirrhosis among those who were overweight or obese, with the highest risk in those who were overweight or obese consuming the most alcohol. I estimated the association between skirt size, as a surrogate for overweight / obesity, and CLD, finding significantly increased risk in those with larger or increasing skirt size. I demonstrated that the ELF test predicts CLD in women with risk factors comprising alcohol excess and / or overweight or obesity. In addition to contributing to the epidemiological data in postmenopausal women, an important but under-evaluated group in terms of liver disease, I have provided data that could be used to design pathways for the early detection and stratification of CLD in the community

The fate of indeterminate liver lesions: What proportion are precursors of hepatocellular carcinoma?

BACKGROUND: The natural history and incidence of hepatocellular carcinoma (HCC) arising from indeterminate liver lesions are not well described. We aimed to define the incidence of HCC in a cohort of patients undergoing surveillance by magnetic resonance imaging (MRI) and estimate any associations with incident HCC. METHODS: We performed a retrospective follow-up study, identifying MRI scans in which indeterminate lesions had been reported between January 2006 and January 2017. Subsequent MRI scan reports were reviewed for incident HCC arising from indeterminate lesions, data were extracted from electronic patient records and survival analysis performed to estimate associations with baseline factors. RESULTS: One hundred and nine patients with indeterminate lesions on MRI were identified. HCC developed in 19 (17%) patients over mean follow up of 4.6 years. Univariate Cox proportional hazards analysis found incident HCC to be significantly associated with baseline low platelet count (hazard ratio (HR) = 7.3 (95% confidence intervals (CI) 2.1-24.9), high serum alpha-fetoprotein level (HR = 2.7 (95% CI 1.0-7.1)) and alcohol consumption above fourteen units weekly (HR = 3.1 (95% CI 1.1-8.7)). Multivariate analysis, however, found that only low platelet count was independently associated with HCC (HR = 5.5 (95% CI 0.6-5.1)). CONCLUSIONS: HCC arises in approximately one fifth of indeterminate liver lesions over 4.6 years and is associated with a low platelet count at the time of first diagnosis of an indeterminate lesion. Incidence of HCC was more common in people with viral hepatitis and in those consuming > 14 units of alcohol per week. Our data may be used to support a strategy of enhanced surveillance in patients with indeterminate lesions

The Enhanced Liver Fibrosis test is associated with liver-related outcomes in postmenopausal women with risk factors for liver disease

BACKGROUND: Chronic liver disease (CLD) is usually asymptomatic but earlier detection is critical to permit life-saving interventions for those at risk due to high alcohol consumption and increased body mass index (BMI). The aim of this study was to estimate the association between the Enhanced Liver Fibrosis (ELF) test and liver-related events (LRE) and its performance in predicting LRE in postmenopausal women with risk factors in a nested case-control study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS).METHODS: In a cohort of 95,126 we performed a case-control study measuring ELF in blinded samples from 173 participants with self-reported high alcohol use and / or BMI ≥25 kg/m2 comprising all 58 cases who developed LRE and 115 controls matched for age, alcohol and BMI who did not develop LRE during median follow-up of 8.5 years.RESULTS: Using Cox regression at an ELF threshold of 10.51 hazard ratios (HR) for LRE were 4.88 (95% confidence interval (CI) 2.37-10.03) (unadjusted model) and 4.62 (95% CI 2.12-10.08) (adjusted for deprivation and self-reported hypertension, heart disease, hypercholesterolaemia and diabetes). At a threshold of 9.8 HR for LRE were 2.21 (95% CI 1.22-3.97) (unadjusted model) and 2.18 (95% CI 1.19-4.01) (adjusted). ELF was evaluated as a time dependent variable by generating time-dependent Cox models; HRs at an ELF threshold of 10.51 were 1.94 (95% CI 1.10-3.39) (unadjusted) and 2.05 (95% CI 1.16-3.64) (adjusted) and at a threshold of 9.8 HRs were 1.85 (95% CI 1.09-3.15) (unadjusted) and 1.80 (95% CI 1.04-3.13) (adjusted). Area under the receiver operating characteristic curve for recruitment ELF predicting LRE was 0.58 (95% CI 0.49-0.68), and for second subsequent ELF 0.61 (95% CI 0.52-0.71).CONCLUSION: This study demonstrates the association between ELF and CLD in postmenopausal women with risk factors for liver disease, creating the opportunity to intervene to reduce liver-related mortality and morbidity. Although larger studies are required, these results demonstrate the potential of ELF as a prognostic tool in health checks in primary care.TRIAL REGISTRATION: This study is nested in UKCTOCS. UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Registered 06/04/2000.</p

Telaprevir or boceprevir based therapy for chronic hepatitis C infection: development of resistance-associated variants in treatment failure.

The use of triple-therapy, pegylated-interferon, ribavirin and either of the first generation hepatitis C virus (HCV) protease inhibitors telaprevir or boceprevir, is the new standard of care for treating genotype 1 chronic HCV. Clinical trials have shown response rates of around 70-80%, but there is limited data from the use of this combination outside this setting. Through an expanded access programme, we treated 59 patients, treatment naïve and experienced, with triple therapy. Baseline factors predicting treatment response or failure during triple therapy phase were identified in 58 patients. Thirty seven (63.8%) of 58 patients had undetectable HCV RNA 12weeks after the end of treatment. Genotype 1a (p=0.053), null-response to previous treatment (p=0.034), the rate of viral load decline after 12weeks of previous interferon-based treatment (p=0.033) were all associated with triple-therapy failure. The most common cause of on-treatment failure for telaprevir-based regimens was the development of resistance-associated variants (RAVs) at amino acids 36 and/or 155 of HCV protease (p=0.027) whereas in boceprevir-based regimens mutations at amino acid 54 were significant (p=0.015). SVR12 rates approaching 64% were achieved using triple therapy outside the clinical trial setting, in a patient cohort that included cirrhotics

Additional file 1: Figure S1. of Risk of chronic liver disease in post-menopausal women due to body mass index, alcohol and their interaction: a prospective nested cohort study within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Crude rates of first liver-related events (per 1000 person years) according to a) BMI category and b) alcohol consumption category over mean follow-up of 5.1 years. Table S1. ICD-10 codes and death certificate text of first LREs. (DOCX 120 kb

Timing and Characteristics of Drug Resistance Mutations (DRMs) in Chronic Hepatitis C Patients During and After Treatment with Protease Inhibitor Therapy at a Single Centre

Introduction: We report the prevalence and characteristics of DRMs associated with virological failure (VF) in a prospective cohort of 59 patients with chronic HCV infection treated with telaprevir (TVR) or boceprevir (BOC) combined with pegylated interferon-alfa and ribavirin (PEG/R). Methods: All patients had baseline HCV RNA levels >10,000 IU/ml and evidence of at least bridging fibrosis. VF was defined as HCV RNA >1000 IU/ml at week 4 or 12 for TVR, or HCV RNA >100IU/ml at week 12 for BOC, or an increase of >1log10 VL from nadir. Genotypic resistance was detected using nested RT-PCR to amplify viral RNA and the first 181 amino acids of the NS3 protease were sequenced by population sequencing. Results: Forty seven patients (80%) were treated with TVR and 12 (20%) with BOC. Nineteen patients (32%) had VF (18 TVR, 1 BOC) of which DRMs were detected in 16 (84%). All patients who developed VF with DRMs had HCV genotype 1a and were treated with TVR. Mutations evolved at NS3 positions 155 and 36; Arginine to Lysine at 155 and/or Valine to Methionine, Leucine, Alanine or Valine/Methionine at 36, none of which were detected at baseline. Eight of fifteen DRMs were detected during TVR therapy, the remainder during PEG/R ‘tail’ of therapy (4 at week 4; 2 at week 8; 2 at week 12; 1 at week 15; 3 at week 24; 1 at week 36; 1 at week 48 and 1 at week 60). Those patients with VF without identifiable DRMs had breakthrough after week 12 with TVR (1 at week 22; 1 at week 24) and at week 8 with BOC. Of the VF/no DRM patients, all TVR patients had subtype 1b and severe fibrosis. The BOC treated patient had subtype 1a with moderate fibrosis. Conclusion: In this cohort treated with TVR, VF was associated with development of DRMs which were identified both before and during the PEG/R tail of therapy. Given the potential impact of DRMs on success of future therapy with protease inhibitors we suggest HCV protease sequencing for DRMs for all patients presenting with VF

The UK-PBC risk scores:Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis

The biochemical response to ursodeoxycholic acid (UDCA)--so-called "treatment response"--strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: &gt;0.90).Conclusions: the prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care.</p