At present chronic liver disease (CLD), the third commonest cause of premature death in the United Kingdom is detected late, when interventions are ineffective, resulting in considerable morbidity ...and mortality. Injury to the liver, the largest solid organ in the body, leads to a cascade of inflammatory events. Chronic inflammation leads to the activation of hepatic stellate cells that undergo trans-differentiation to become myofibroblasts, the main extra-cellular matrix producing cells in the liver; over time increased extra-cellular matrix production results in the formation of liver fibrosis. Although fibrogenesis may be viewed as having evolved as a "wound healing" process that preserves tissue integrity, sustained chronic fibrosis can become pathogenic culminating in CLD, cirrhosis and its associated complications. As the reference standard for detecting liver fibrosis, liver biopsy, is invasive and has an associated morbidity, the diagnostic assessment of CLD by non-invasive testing is attractive. Accordingly, in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice. Due to differing disease prevalence and treatment efficacy, disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection. To facilitate this, a review of the pathogenesis of both conditions is also conducted. Finally, the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed, including the current use of antifibrotic therapy.
Liver biopsy is the reference standard for the detection of nonalcoholic steatohepatitis (NASH) within nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify a biomarker of ...NASH in patients without significant fibrosis. In all, 172 patients from two centers with biopsy‐proven NAFLD were included in this study. Eighty‐four patients from a single center were included as a derivation cohort and 88 patients from a second center were included as a validation cohort. Serum samples were tested for candidate markers of fibrosis and inflammation alongside hematological and biochemical markers. Among patients without advanced fibrosis, terminal peptide of procollagen III (PIIINP) was the only marker found to be associated with a histological diagnosis of NASH in both cohorts. PIIINP also correlated with the total NAFLD activity score (NAS) and its constituent components (P < 0.001). Area under receiver operating characteristic curve (AUROC) for PIIINP in discriminating between NASH and simple steatosis (SS) was 0.77‐0.82 in patients with F0‐2 fibrosis and 0.82‐0.84 in patients with F0‐3 fibrosis. PIIINP was elevated in patients with advanced fibrosis, the overwhelming majority of whom had NASH. When incorporating patients with all degrees of fibrosis from both cohorts, PIIINP was able to discriminate between patients with SS and those with NASH or advanced fibrosis with AUROC 0.85‐0.87. Conclusion: PIIINP discriminates between SS and NASH or advanced fibrosis. The use of a single biomarker in this context will be of clinical utility in detecting the minority of patients with NAFLD who have NASH or advanced fibrosis related to NASH. (HEPATOLOGY 2013)
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.
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.
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)).
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.
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).
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/m
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.
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).
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.
This study is nested in UKCTOCS. UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Registered 06/04/2000.
We investigated the risk of chronic liver disease (CLD) due to alcohol consumption and body mass index (BMI) and the effects of their interaction in a prospective cohort study of women recruited to ...the UKCTOCS trial.
95,126 post-menopausal women without documented CLD were stratified into 12 groups defined by combinations of BMI (normal, overweight, obese) and alcohol consumption (none, <1-15, 16-20 and ≥21 units/week), and followed for an average of 5.1 years. Hazard ratios (HR) were calculated for incident liver-related events (LRE).
First LREs were reported in 325 (0.34%) participants. Compared to women with normal BMI, HR = 1.44 (95% CI; 1.10-1.87) in the overweight group and HR = 2.25 (95% CI; 1.70-2.97) in the obese group, adjusted for alcohol and potential confounders. Compared to those abstinent from alcohol, HR = 0.70 (95% CI; 0.55-0.88) for <1-15 units/week, 0.93 (95% CI; 0.50-1.73) for 16-20 units/week and 1.82 (95% CI; 0.97-3.39) for ≥21 units/week adjusted for BMI and potential confounders. Compared to women with normal BMI drinking no alcohol, HR for LRE in obese women consuming ≥21 units/week was 2.86 (95% CI; 0.67-12.42), 1.58 (95% CI; 0.96-2.61) for obese women drinking <1-15 units/week and 1.93 (95% CI; 0.66-5.62) in those with normal BMI consuming ≥21 units/week after adjustment for potential confounders. We found no significant interaction between BMI and alcohol.
High BMI and alcohol consumption and abstinence are risk factors for CLD in post-menopausal women. However, BMI and alcohol do not demonstrate significant interaction in this group.
UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978 . Registered 06/04/2000.
The human insulin-resistance syndromes, type 2 diabetes, obesity, combined hyperlipidaemia and essential hypertension, are complex disorders whose genetic basis is unknown. The spontaneously ...hypertensive rat (SHR) is insulin resistant and a model of these human syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a single locus on rat chromosome 4. Here we combine use of cDNA microarrays, congenic mapping and radiation hybrid (RH) mapping to identify a defective SHR gene, Cd36 (also known as Fat, as it encodes fatty acid translocase), at the peak of linkage to these QTLs. SHR Cd36 cDNA contains multiple sequence variants, caused by unequal genomic recombination of a duplicated ancestral gene. The encoded protein product is undetectable in SHR adipocyte plasma membrane. Transgenic mice overexpressing Cd36 have reduced blood lipids. We conclude that Cd36 deficiency underlies insulin resistance, defective fatty acid metabolism and hypertriglyceridaemia in SHR and may be important in the pathogenesis of human insulin-resistance syndromes.
Advancing fibrosis is regarded as the most important factor when stratifying patients with chronic hepatitis C for retreatment.
(1) To compare the performance of 10 biomarkers of fibrosis, including ...patented tests, among patients with chronic hepatitis C and treatment failure; and (2) to assess the impact on biomarker performance of using 2 different assays of hyaluronic acid (HA).
For 80 patients, liver histology (Metavir) was compared with biomarker scores using sera obtained within 6 months of liver biopsy (indirect biomarkers: AST:ALT ratio, APRI, Forns index, FIB-4, Fibrometer V3G; direct biomarkers: ELF, Fibrospect II, Hyaluronic acid-HA, Fibrometer V2G, Hepascore). Direct biomarker scores were calculated using 2 validated assays for HA (ELISA and radiometric).
Using the ELISA assay for HA to calculate the direct panels, all 10 of the biomarkers exhibited comparable overall discriminatory performance (unweighted Obuchowski measure, ordROC 0.92-0.94, P-value>0.05) except AST:ALT ratio and APRI (ordROC 0.86-0.88, P-value<0.05). For the detection of moderate (F2-4) and advanced (F3-4) fibrosis, the AUROC of Fibrometer 2G were significantly higher than AST:ALT ratio and APRI but none of the other biomarkers. Good correlation was observed between the 2 HA assays (intraclass correlation coefficient=0.873) with the ELISA assay exhibiting superior diagnostic performance (ordROC 0.92 vs. 0.88, P-value=0.003). Importantly, the performance of many of the direct biomarkers at their diagnostic thresholds was heavily influenced by the choice of HA assay.
Although many biomarkers exhibited good diagnostic performance for the detection of advancing fibrosis, our results indicate that diagnostic performance may be significantly affected by the selection of individual component assays.
Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to effect sustained elimination of the virus (a sustained virological response, ...SVR). Prior to the development of direct-acting antiviral (DAA) agents, the standard of care (SOC) for CHC comprised combined treatment with pegylated interferon (PegIFN) and ribavirin (RBV).
TMC435 (Tibotec pharmaceuticals) is a macrocyclic non-covalent NS3/NS4A protease inhibitor (DAA) that is currently in Phase III clinical development. TMC435 is being developed in treatment regimens both with and without PegIFN and RBV. In Phase IIb clinical trials, the addition of TMC435 to current SOC significantly increased the SVR rate in both treatment-naive and experienced patients with CHC. It differs, however, from the other first-generation protease inhibitors in that it is administered once daily, has a different tolerability and resistance profile and has activity against CHC genotypes 1 - 6 with the exception of genotype 3. Furthermore, the addition of TMC435 to PegIFN/RBV appears to be able to significantly shorten treatment duration in the majority of patients. This article will review the pharmacology, pharmacodynamics, safety and efficacy of TMC435 by evaluating the preclinical and clinical studies to date.
TMC435 is a 'second-wave' protease inhibitor that has the potential to play a pivotal role in the next phase of CHC treatment. The forthcoming results of Phase III trials involving TMC435 are awaited with interest.
The utility of noninvasive serum markers to longitudinally monitor liver fibrosis is not established.
A total of 70 patients with chronic hepatitis C who had previously failed antiviral therapy were ...randomized to receive pegylated interferon with or without silymarin for 24 months. Enhanced Liver Fibrosis (ELF) tests (hyularonic acid, terminal peptide of procollagen III, tissue inhibitor of matrix metaloproteinase-1) were performed on patient sera obtained before, during and at the end of the study (0, 12, 24 months) and liver histology obtained before and at the end of the study.
At 24 months, absolute changes in Ishak fibrosis stage and ELF ranged from -4 to +4 and from -2.41 to +2.68, respectively. Absolute changes in ELF at 12 months were significantly associated with changes in both ELF and histology at 24 months. A model combining both baseline ELF and change of ELF at 12 months could predict the 24-month ELF (R=0.609, P<1×10), a decrease in ELF at 24 months area under the curve (AUC): 0.80-0.85 and an increase in ELF at 24 months (AUC: 0.81-0.85). Furthermore, a model combining both baseline histologic stage and ELF together with the change of ELF at 12 months could predict 24-month histology (R=0.601, P<1×10, AUC: 0.88-0.92), histologic fibrosis regression (AUC: 0.81-0.84) and progression (AUC: 0.86-0.91).
Our observations suggest that a change in the serum marker ELF predicts changes in liver fibrosis over a longer period. These data support the use of ELF as a surrogate marker of liver fibrosis evolution in monitoring antifibrotic treatments, thus permitting 'response-guided' therapy by the early identification of patients who will benefit from prolonged treatment.
The primary aim of antiviral therapy for chronic hepatitis C (CHC) is the prevention of progressive disease. A response to interferon (IFN) treatment is associated with an improvement in all-cause ...mortality and liver-related mortality from hepatitis C. Unless contraindicated, patients with CHC are thus potential candidates for treatment. Improved response rates are observed in patients with HCV genotype 1 infection treated with first-generation protease inhibitors. However, treatment with current first-generation protease inhibitors and IFN is complex and can result in appreciable adverse effects. The advent of potent, pan-genotypic all-oral direct-acting antiviral (DAA) regimens necessitates a critical examination of the immediate application of PEG-IFN, ribavirin and DAA regimens in patients with CHC. Current guidelines and position statements do not make clear recommendations, and are behind the emerging data. Some aspects of the conundrums facing physicians and patients are summarized in this Review. Cirrhosis presents an immediate threat of disease, and ideally treatment should be targeted at those patients who have advancing or advanced disease; unfortunately, a disparity exists, as response rates are reduced in patients with cirrhosis and the risks of adverse events are increased. On balance, patients with mild disease could consider deferring treatment.
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