Markers Of Hepatic Fibrosis Research Articles

Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, ameliorates the development of liver fibrosis in diabetic Otsuka Long-Evans Tokushima fatty rats.

It is widely understood that insulin resistance (IR) critically correlates with the development of liver fibrosis in several types of chronic liver injuries. Several experiments have proved that anti-IR treatment can alleviate liver fibrosis. Sodium-glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules, improving IR. The aim of this study was to elucidate the effect of an SGLT2 inhibitor on the development of liver fibrosis using obese diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and their littermate nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. Male OLETF and LETO rats were intraperitoneally injected with porcine serum twice a week for 12weeks to augment liver fibrogenesis. Different concentrations of ipragliflozin (3 and 6mg/kg) were orally administered during the experimental period. Serological and histological data were examined at the end of the experimental period. The direct effect of ipragliflozin on the proliferation of a human hepatic stellate cell (HSC) line, LX-2, was also evaluated in vitro. OLETF rats, but not LETO rats, received 12weeks of porcine serum injection to induce severe fibrosis. Treatment with ipragliflozin markedly attenuated the development of liver fibrosis and expression of hepatic fibrosis markers, such as alpha smooth muscle actin, collagen 1A1, and transforming growth factor beta (TGF-β), and improved IR in a dose-dependent manner in OLETF rats. In contrast, the proliferation of LX-2 in vitro was not affected, suggesting that ipragliflozin had no significant direct effect on the proliferation of HSCs. In conclusion, our dataset suggests that an SGLT2 inhibitor could alleviate the development of liver fibrosis by improving IR in naturally diabetic rats. This may provide the basis for creating new therapeutic strategies for chronic liver injuries with IR.

Circulating miR-21 and miR-29a as Markers of Disease Severity and Etiology in Cholestatic Pediatric Liver Disease.

Circulating microRNAs have been investigated as markers of disease severity in a variety of conditions. We examined whether circulating miR-21 and miR-29a could serve as markers of hepatic fibrosis and disease etiology in children with various liver diseases. Circulating miR-21 and miR-29a were determined in 58 children (21 female, age 0.1–17.8 (median 9.8) years)) with chronic liver disease and compared to histological grading of hepatic fibrosis. 22 healthy children served as controls for circulating miRNAs. Levels of circulating miR-21 appeared to be age-dependent in healthy children. Children with biliary atresia had significantly higher levels of miR-21 compared both to healthy controls and to age-matched children with other cholestatic liver disease. Circulating miR-29a levels in biliary atresia children did not differ from healthy controls, but tended to be higher than in age-matched children with other cholestatic liver disease. Neither miR-21 nor miR-29a correlated well with hepatic fibrosis. Circulating miR-21 and miR-29a levels can potentially serve as non-invasive diagnostic markers to differentiate biliary atresia from other cholestatic disease in infancy. They do not appear suitable as non-invasive markers for the degree of hepatic fibrosis in an unselected cohort of children with various liver diseases. The discriminating effect regarding neonatal cholestasis should be followed up in a prospective longitudinal study.

New advances in the diagnosis of canine and feline liver and pancreatic disease

The diagnosis of liver and pancreatic disorders in dogs and cats present their own set of challenges. However, as new diagnostic tests are developed and the optimal ways in which to use existing tests are determined, the ability of the veterinary profession to make these diagnoses continues to improve. Histopathological assessment is considered to be the reference standard for the diagnosis of many hepatic and pancreatic diseases, but it has some inherent limitations.New classes of diagnostic tests for liver disease that are currently being studied include direct and indirect serum markers of hepatic fibrosis, such as hyaluronic acid; novel markers of hepatocellular injury, such as circulating microRNAs; and quantitative tests of hepatic microsomal function. Assays for pancreas-specific lipase have greatly improved the ability of practitioners to diagnose pancreatitis in dogs and cats. However, further research is needed to fully understand the characteristics of these assays, especially in patients with concurrent non-pancreatic disease. The more common use and refinement of CT and MRI to assess the hepatobiliary system and pancreas of dogs and cats also have huge potential to improve diagnostic capabilities.

Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible?

BackgroundNonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative.MethodsWe evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice.ResultsMice fed WD for 22–24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7–8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 ≥ 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (PUFA) content.ConclusionThese studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD-induced NASH and fibrosis in Ldlr-/- mice.

Intrahepatic Fat Content and Markers of Hepatic Fibrosis in Obese Children.

Aim. We evaluated both direct and indirect hepatic fibrosis markers in obese children and their relationship with intrahepatic fat (IHF) content. We also aimed to investigate the possible roles of IHF and fibrosis markers in metabolic syndrome (MS). Methods. 189 obese children were divided into simple obese (SOB), simple steatosis (SS), and nonalcoholic steatohepatitis (NASH) groups according to their IHF and blood alanine transaminase (ALT) levels. They were also scored for the MS components. IHF was assessed as a continuous variable by proton magnetic resonance spectroscopy (1H-MRS). In addition, 30 nonobese children were enrolled as controls and their direct hepatic fibrosis markers and IHF were assessed. Results. Age was related to IHF, NFS, and FIB-4. Both NFS and APRI were related to IHF more significantly than the direct markers. In the estimation of liver function impairment, indirect markers had greater AUROC than direct markers. In MS, IHF and all the fibrosis markers showed similar AUROC. Conclusions. Both direct and indirect markers played a valuable role in evaluating MS. Indirect markers were more effective in distinguishing fatty hepatitis. Age is an important factor underlying hepatic steatosis and fibrosis even in children.

Serum hyaluronic acid as a noninvasive marker of hepatic fibrosis in chronic hepatitis c patients

Background Patients with chronic hepatitis C virus (HCV) infection are often asymptomatic with few clinical signs of liver disease. Recognition of the presence of fibrosis or cirrhosis is difficult without liver biopsy, but with the availability of effective treatments, such as interferon, and the potential for progression to hepatoma in some cases, an accurate measure of the stage of disease is important. Serum hyaluronic acid (HA) has been identified as a potential marker of fibrosis or cirrhosis. Aim of the work The aim of this study was to evaluate the serum level of HA as a noninvasive marker of hepatic fibrosis in comparison with liver biopsy and indirect serum fibrosis markers such as AST/ALT ratio and aspartate transaminase to platelet ratio index (APRI) in chronic HCV patients. Patients and methods Our patients were classified into three groups: group 1 included 20 patients with mild hepatic fibrosis (F1 stage); group 2 included 20 patients with moderate hepatic fibrosis (F2 stage); and group 3 included 20 patients with marked hepatic fibrosis and cirrhosis (F3 and F4 stages). The control group included 20 normal volunteers. Serum HA level evaluation, liver function tests, and complete blood count were carried out for all groups, whereas liver biopsy was performed only for patients to determine the stage of liver fibrosis. Results There was a highly significant increase in serum HA level in group 2 and group 3 in comparison with the control group and a significant increase in group 1 in comparison with the control group. However, there was highly significant increase in group 3 in comparison with group 1 and group 2 and a significant increase in group 2 in comparison with group 1. The cutoff point for HA level was greater than 42.18 ng/l to discriminate between the patient and the control group, with a sensitivity of 91.7% and a specificity of 95.0% for HA. The cutoff point for HA level was greater than 81.68 ng/l to discriminate between group 1 (mild fibrosis) and group 2 (moderate fibrosis), with a sensitivity of 100% and a specificity of 70%. The cutoff point for HA level to discriminate between group 2 (moderate fibrosis) and group 3 (severe fibrosis and cirrhosis) was greater than 167.98 ng/l, with a sensitivity of 90% and specificity of 80%. There was a significant positive correlation between serum HA level and APRI. Conclusion HA is a promising reliable simple noninvasive marker for assessing liver fibrosis in HCV-infected patients with high sensitivity and specificity. There was a positive correlation between serum HA level with stages of hepatic fibrosis and APRI.

High FIB-4 index as an independent risk factor of prevalent chronic kidney disease in patients with nonalcoholic fatty liver disease

Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is linked to an increased risk for chronic kidney disease (CKD); liver fibrosis with biopsy-proven NAFLD has also been shown to associate with an increased risk of CKD. This study compares the diagnostic performance of simple noninvasive tests in identifying prevalent CKD among individuals with ultrasonography-diagnosed NAFLD. A total of 755 with ultrasonography-diagnosed NAFLD were included. Estimated glomerular filtration rate and noninvasive markers for hepatic fibrosis: aspartate transaminase to alanine transaminase ratio (AAR), aspartate transaminase to platelet ratio index (APRI), FIB-4 score, NAFLD fibrosis score (NFS) and BARD score were assessed. Binary logistic regression to generate a propensity score and receiver operating characteristic curves were developed for each of the noninvasive markers for predicting CKD, and the area under the receiver operating characteristic curve was greatest for FIB-4 score (0.750), followed by NFS (0.710), AAR (0.594), APRI (0.587), and BARD score (0.561). A cut-off value of 1.100 for FIB-4 score gave a sensitivity of 68.85% and a specificity of 71.07% for predicting CKD. The positive predictive value and negative predictive value were 37.50 and 90.05%, respectively. In multiple logistic regression analysis, only FIB-4 score ≧1.100 (OR 2.660, 95% CI 1.201-5.889; p = .016), older age, higher diastolic blood pressure and higher uric acid were independent predictors of CKD. High noninvasive fibrosis score is associated with an increased risk of prevalent CKD; the FIB-4 is the better predictor. With a cut-off value of 1.100 for FIB-4, it is useful in excluding the presence of CKD in patients with NAFLD.

Mulberry leaves (Morus alba L.) ameliorate obesity-induced hepatic lipogenesis, fibrosis, and oxidative stress in high-fat diet-fed mice.

Obesity is associated with chronic diseases such as fatty liver, type 2 diabetes, cardiovascular disease, and severe metabolic syndrome. Obesity causes metabolic impairment including excessive lipid accumulation and fibrosis in the hepatic tissue as well as the increase in oxidative stress. In order to investigate the effect of mulberry leaf (Morus alba L.) extract (MLE) on obesity-induced oxidative stress, lipogenesis, and fibrosis in liver, MLE has been gavaged for 12weeks in high-fat diet (HFD)-induced obese mice. MLE treatment significantly ameliorated LXRα-mediated lipogenesis and hepatic fibrosis markers such as α-smooth muscle actin, while MLE up-regulated lipolysis-associated markers such as lipoprotein lipase in the HFD-fed mice. Moreover, MLE normalized the activities of antioxidant enzymes including heme oxygenase-1 and glutathione peroxidase in accordance with protein levels of 4-hydroxynonenal in the HFD-fed mice. MLE has beneficial effects on obesity-related fatty liver disease by regulation of hepatic lipid metabolism, fibrosis, and antioxidant defense system. MLE supplementation might be a potential therapeutic approach for obesity-related disease including non-alcoholic fatty liver disease.

Clinically significant chronic liver disease in people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

Background: Type 2 diabetes is an independent risk factor for chronic liver disease, however disease burden estimates and knowledge of prognostic indicators are lacking in community populations.Aims: To describe the prevalence and incidence of clinically significant chronic liver disease amongst community-based older people with Type 2 diabetes and to determine risk factors which might assist in discriminating patients with unknown prevalent or incident disease.Design: Prospective cohort study.Methods: Nine hundred and thirty-nine participants in the Edinburgh Type 2 Diabetes Study underwent investigation including liver ultrasound and non-invasive measures of non-alcoholic steatohepatitis (NASH), hepatic fibrosis and systemic inflammation. Over 6-years, cases of cirrhosis and hepatocellular carcinoma were collated from multiple sources.Results: Eight patients had known prevalent disease with 13 further unknown cases identified (prevalence 2.2%) and 15 incident cases (IR 2.9/1000 person-years). Higher levels of systemic inflammation, NASH and hepatic fibrosis markers were associated with both unknown prevalent and incident clinically significant chronic liver disease (all P < 0.001).Conclusions: Our study investigations increased the known prevalence of clinically significant chronic liver disease by over 150%, confirming the suspicion of a large burden of undiagnosed disease. The disease incidence rate was lower than anticipated but still much higher than the general population rate. The ability to identify patients both with and at risk of developing clinically significant chronic liver disease allows for early intervention and clinical monitoring strategies. Ongoing work, with longer follow-up, including analysis of rates of liver function decline, will be used to define optimal risk prediction tools.

Biomarcadores, índices y algoritmos para el diagnóstico de fibrosis hepática en pacientes con hepatitis crónica por virus C

Precise staging of liver fibrosis is essential in the management of liver disease activity in chronic hepatitis C patients. Liver biopsy has been considered the reference method for diagnosing disease, grading necroinflammatory activity, and staging fibrosis, but it has some technical limitations and risks. Taking into account these limitations, there is a need to introduce non-invasive serum markers for fibrosis that would be able to partially replace liver biopsy. Ideal serum markers should be specific for the liver and easy to perform. Serum markers of hepatic fibrosis are divided into direct and indirect. Direct markers reflect extracellular matrix turnover, whereas indirect markers reflect alterations in hepatic function. The degree of implementation of non-invasive diagnostic tests for liver fibrosis still remains limited. This review provides a current overview of biomarkers, indexes and algorithms for hepatic fibrosis diagnosis in chronic hepatitis C patients.

Should HFE p.C282Y homozygotes with moderately elevated serum ferritin be treated? A randomised controlled trial comparing iron reduction with sham treatment (Mi-iron)

IntroductionHFE p.C282Y homozygosity is the most common cause of hereditary haemochromatosis. There is currently insufficient evidence to assess whether non-specific symptoms or hepatic injury in homozygotes with moderately elevated iron...

Diagnostic and Prognostic Values of Noninvasive Predictors of Portal Hypertension in Patients with Alcoholic Cirrhosis.

Portal hypertension is a direct consequence of hepatic fibrosis, and several hepatic fibrosis markers have been evaluated as a noninvasive alternative to the detection of portal hypertension and esophageal varices. In the present study, we compared the diagnostic and prognostic values of the noninvasive fibrosis markers in patients with alcoholic cirrhosis. A total of 219 consecutive alcoholic cirrhosis patients were included. Biochemical scores and liver stiffness (LS) were compared with hepatic venous pressure gradient (HVPG). For the detection of clinically significant portal hypertension (CSPH; HVPG≥10 mmHg) in compensated patients, LS and LS–spleen diameter to platelet ratio score (LSPS) showed significantly better performance with area under the curves (AUCs) of 0.85 and 0.82, respectively, than aspartate aminotransferase-to-platelet ratio index, FIB-4, Forns’ index, Lok index, (platelet count)2/[monocyte fraction (%) × segmented neutrophil fraction (%)], and platelet count-to-spleen diameter ratio (all P<0.001). However, for the detection of high-risk varices, none of the non-invasive tests showed reliable performance (AUCs of all investigated tests < 0.70). During a median follow-up period of 42.6 months, 46 patients with decompensated cirrhosis died. Lok index (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.05–1.22; P = 0.001) and FIB-4 (HR, 1.06; 95% CI, 1.01–1.10; P = 0.009) were independently associated with all-cause death in decompensated patients. Among the tested noninvasive markers, only Lok index significantly improved discrimination function of MELD score in predicting overall survival. In conclusion, LS and LSPS most accurately predict CSPH in patients with compensated alcoholic cirrhosis. In the prediction of overall survival in decompensated patients, however, Lok index is an independent prognostic factor and improves the predictive performance of MELD score.

Predicting Risk of End-Stage Liver Disease in Antiretroviral-Treated Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Patients.

Background. End-stage liver disease (ESLD) is an important cause of morbidity among human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. Quantifying the risk of this outcome over time could help determine which coinfected patients should be targeted for risk factor modification and HCV treatment. We evaluated demographic, clinical, and laboratory variables to predict risk of ESLD in HIV/HCV-coinfected patients receiving antiretroviral therapy (ART).Methods. We conducted a retrospective cohort study among 6016 HIV/HCV-coinfected patients who received ART within the Veterans Health Administration between 1997 and 2010. The main outcome was incident ESLD, defined by hepatic decompensation, hepatocellular carcinoma, or liver-related death. Cox regression was used to develop prognostic models based on baseline demographic, clinical, and laboratory variables, including FIB-4 and aspartate aminotransferase-to-platelet ratio index, previously validated markers of hepatic fibrosis. Model performance was assessed by discrimination and decision curve analysis.Results. Among 6016 HIV/HCV patients, 532 (8.8%) developed ESLD over a median of 6.6 years. A model comprising FIB-4 and race had modest discrimination for ESLD (c-statistic, 0.73) and higher net benefit than alternative strategies of treating no or all coinfected patients at relevant risk thresholds. For FIB-4 >3.25, ESLD risk ranged from 7.9% at 1 year to 26.0% at 5 years among non-blacks and from 2.4% at 1 year to 14.0% at 5 years among blacks.Conclusions. Race and FIB-4 provided important predictive information on ESLD risk among HIV/HCV patients. Estimating risk of ESLD using these variables could help direct HCV treatment decisions among HIV/HCV-coinfected patients.

PWE-104 Gamma-glutamyl transferase but not markers of hepatic fibrosis is associated with cardiovascular disease in older people with type 2 diabetes mellitus: the edinburgh type 2 diabetes study

<h3>Introduction</h3> Patients with chronic liver disease (CLD) and, in particular, non-alcoholic fatty liver disease (NAFLD) are known to have both higher all-cause mortality and cardiovascular (CV) mortality rates than the general population. Beyond investigation of GGT there has been little exploration of the relationship between CV disease (CVD) and other markers of liver disease (non-specific liver injury, steatosis, steatohepatitis, liver fibrosis or portal hypertension). We examined the association of prevalent and incident CV disease with CLD in a cohort of community-based people with type 2 diabetes (T2DM) in order to determine the relationship between these two important conditions. <h3>Method</h3> 1066 participants of the Edinburgh Type 2 Diabetes Study, a large, randomly-selected population of patients with T2DM aged 60–75 years were invited for liver assessment. A range of liver disease markers (non-specific liver injury – serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT); steatosis – liver ultrasound; steatohepatitis – serum cytokeratin-18; fibrosis – serum AST to Platelet Ratio Index (APRI), AST:ALT ratio, Enhanced Liver Fibrosis (ELF) panel, Fibrosis-4 Score, NAFLD Fibrosis Score; portal hypertension – platelet count) were measured. Subjects were followed-up using patient and GP questionnaires and record linkage for incident CV events (coronary artery disease (CAD), cerebrovascular disease and peripheral vascular disease). <h3>Results</h3> At baseline there were 372/1035 patients with prevalent CVD, including 319/1035 with CAD. After mean follow-up of 4.4 years there were 121/1035 incident CVD events, including 76/121 CAD events. There were 30/82 CVD related deaths. However, risk of dying from or developing CVD was no higher in subjects with steatosis than without (HR 1.31 95% CI 0.78–2.20, p &gt; 0.05). The only significant relationship was with GGT (U/L log₂incident CVD, adjusted HR 1.18 95% CI 1.00–1.39, p = 0.045; incident CAD, adjusted HR 1.24 95% CI 1.02–2.51, p = 0.032). <h3>Conclusion</h3> We conducted the first comprehensive population-based study of older people with T2DM and found no association between non-invasive markers of hepatic steatosis, steatohepatitis, or fibrosis with the development of, or mortality from, CVD. Our finding of a significant independent association between GGT and CVD warrants further evaluation as a potentially useful addition to current CV risk prediction models in T2DM. <h3>Disclosure of interest</h3> None Declared.

Epigallocatechin gallate attenuated non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet

Nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), are the most common causes of chronic liver disease. In this study, we evaluated the effects of Epigallocatechin gallate (EGCG) on methionine- and choline-deficient (MCD) diet-induced NASH. Our data showed that EGCG significantly prevented MCD diet-induced liver and body weight loss. Histological analysis showed that EGCG inhibited MCD diet-induced steatohepatitis including fat accumulation and inflammatory cells infiltration. Biochemical analysis data showed that EGCG significantly reduced the elevation of plasma ALT and AST levels but increased plasma triglyceride and cholesterol contents. However, EGCG significantly inhibited hepatic triglyceride and cholesterol content in MCD diet fed mice. Consistent with histology results, EGCG treatment significantly inhibited MCD diet-induced IL-1β, IL-6, TNF-α and MCP-1 mRNA expression. As an antioxidant, EGCG treatment significant inhibited hepatic MDA contents and increased hepatic SOD contents. In addition, transforming growth factor (TGF)-β, collagen I-α1, tissue inhibitor of metalloproteinase 1 (TIMP-1) and α-smooth muscle actin (SMA) mRNA expression, which are markers of hepatic fibrosis, were markedly inhibited by EGCG treatment. Western blot data showed that EGCG inhibited Smad2 and Smad3 phosphorylation in the liver and LX-2 cells which were involved in TGF-β-induced pathway. Taken together, EGCG attenuated NASH induced by MCD diet associated with ameliorating fibrosis, oxidative stress, and hepatic inflammation. Our results indicate that EGCG has beneficial roles in the development of MCD diet-induced NASH.

Relationship between hepatitis B surface antigen, HBV DNA quantity and liver fibrosis severity

To explore the correlation between serum hepatitis B surface antigen (HBsAg) level and hepatic tissue pathological staging in patients with chronic hepatitis B (CHB). Clinical data was collected from our hospital's records for 302 CHB patients with HBsAg-positive status for more than 6 months and who had undergone hepatic biopsy. The HBsAg level,HBV DNA level and other clinical data were measured using commercial diagnostic assays. Liver histology was scored using the GS staging system. Correlation between serum HBsAg quantity, HBV DNA quantity, stage of inflammation and degree of fibrosis was assessed statistically. The correlation of serum HBsAg level and HBV DNA level was notable. The serum HBsAg level was a variable affecting hepatic tissue pathological stage significantly. Serum HBsAg level appeared to be a highly specific and sensitive diagnostic marker of hepatic fibrosis. As the severity of liver fibrosis increased, the quantitative levels of platelet (PLT), HBsAg and HBV DNA gradually decreased, and the APRI index gradually increased; there were significant differences between the groups (all P<0.001). Serum HBsAg and HBV DNA levels in patients with hepatitis B e antigen-positive (HBeAg(+)) status showed strong correlation (r=0.721, P<0.0001) by Spearman analysis. HBeAg(+) patients with moderate to severe fibrosis (S2-4) exhibited significantly lower serum HBsAg and HBV DNA levels compared with patients with no or mild fibrosis (S0-1; t=5.475 and 4.826, P<0.001). ROC analysis suggested that a serum HBsAg cutoff of 4.46 log 10 IU/mL (28 800 IU/mL) would provide a theoretical sensitivity of 76.3%, with theoretical specificity of 70.5% in HBeAg(+) CHB patients. A serum HBV DNA cutoff of 7.13 log 10 IU/mL (1.35*10(7) copies/mL) would provide a theoretical sensitivity of 71.1%, with theoretical specificity of 73.4% in HBeAg(+) CHB patients. Logistic regression analysis showed that the level of HBsAg was an independent prognostic factor of moderate to severe liver fibrosis, with alanine aminotransferase, aspartate aminotransferase, HBsAg, HBV DNA and PLT (P<0.001). HBsAg and HBV DNA levels decrease gradually along with aggravation of liver fibrosis. The cutoff values of 28800 IU/mL for HBsAg and 1.35*10(7) copies/mL ofHBV DNA provide higher specificity and sensitivity for predicting the degree of liver fibrosis in HBeAg-positive CHB patients, and the former is an independent predictor of severe liver fibrosis.

γ-Glutamyltransferase, but not markers of hepatic fibrosis, is associated with cardiovascular disease in older people with type 2 diabetes mellitus: the Edinburgh Type 2 Diabetes Study.

Aims/hypothesisWe examined the association of prevalent and incident cardiovascular disease (CVD) with chronic liver disease in a cohort of community-based people with type 2 diabetes, in order to clarify the relationship between these two important conditions.Methods1,066 participants with type 2 diabetes aged 60–75 years underwent assessment of a range of liver injury markers (non-specific injury, steatosis, steatohepatitis, fibrosis, portal hypertension). Individuals were followed up for incident cardiovascular events.ResultsAt baseline there were 370/1,033 patients with prevalent CVD, including 317/1,033 with coronary artery disease (CAD). After a mean follow-up of 4.4 years there were 44/663 incident CVD events, including 27/663 CAD events. There were 30/82 CVD-related deaths. Risk of dying from or developing CVD was no higher in participants with steatosis than in those without (HR 0.90; 95% CI 0.40, 2.00; p > 0.05). The only notable relationship was with γ-glutamyltransferase (GGT) (incident CVD: adjusted HR for doubling GGT 1.24 [95% CI 0.97, 1.59] p = 0.086; incident CAD: adjusted HR 1.33 [95% CI 1.00, 1.78] p = 0.053), suggesting that in our study population, chronic liver disease may have little effect on the development of, or mortality from, CVD.Conclusions/interpretationAn independent association between GGT and CVD warrants further exploration as a potentially useful addition to current cardiovascular risk prediction models in diabetes. However, overall findings failed to suggest that there is a clinical or pathophysiological association between chronic liver disease and CVD in elderly people with type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3575-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Feasibility of Different b-Values of MRI Diffusion in Quantitative Assessment of Liver Fibrosis

Purpose: We aimed to assess the accuracy of hepatic ADC and the best b-value for diffusion-weighted imaging (DWI) for quantification of liver fibrosis, aiming to improve diagnostic accuracy, in order to achieve a reliable non invasive marker of hepatic fibrosis. Materials & Methods: One hundred patients with history of chronic hepatitis C virus and twenty five healthy adult volunteers control group were investigated by diffusion MRI in the axial plane, during a single end expiratory breath-hold at different b-values of (200, 500, 700 and 1000 s/mm2) on the same day before liver biopsy. ADC maps were generated and the mean hepatic ADC was calculated as the arithmetic mean of the four hepatic ADC values calculated at each b-value. Liver ADCs were correlated with fibrosis scores using the Spearman’s rank correlation coefficient, while Receiver Operating Characteristic (ROC) curve analysis was used to determine the area under the ROC curve (AUC), and the threshold ADC was used to maximize the average of sensitivity and specificity. Results: The patient group were stratified pathologically according to modified Ishak classification as stage 1 to stage 6 (n=14, 40, 28, 5, 28, 4 and 9 patients respectively). We achieved negative correlation between the ADC values and the degree of liver fibrosis at b-values 200 and 1000 s/mm2, respectively, with P=0.000. The ROC curve analysis at b-value =1000 s∕mm 2 , revealed significant difference in ADC values between patients with early fibrosis (F≤4) and those with cirrhotic liver (F≥5) (p=0.000), where the best cut off ADC value to distinguish between these groups was 1.12 x 10 -3 mm 2 /s, with 80.5% sensitivity and 77% specificity. Conclusion: Liver ADC showed a significant difference in the ADC values of nonfibrotic and cirrhotic patients, with high sensitivity and specificity at b-value 1000 s/mm 2 with cut off value 1.12 x 10 -3 mm 2 /s.

Assessment of Serum Hydroxyproline and Osteopontin as Noninvasive Markers of Hepatic Fibrosis in Egyptian Patients with Chronic Hepatitis C Virus Infection

Background: Hepatitis C virus (HCV) infection is a progressive disease that may result in chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is an essential factor that must be considered in the management of patients with HCV. Although liver biopsy represents the gold standard for evaluating the presence, type and stage of liver fibrosis, this technique remains a costly and invasive procedure. Therefore, several diagnostic methods for determining liver fibrosis, such as the detection of serum biomarkers, have been used. Objective: To evaluate the use of serum hydroxyproline (HYP) and osteopontin (OPN) as non invasive direct markers to assess the degree of hepatic fibrosis in Egyptian patients with chronic HCV infection in comparison to indirect markers such as aspartate aminotransferase platelet ratio index (APRI) and to determine the most diagnostically accurate non invasive marker of hepatic fibrosis, hoping to replace liver biopsy in the next few years. Methodology: This study was carried out on 48 patients with chronic HCV infection who had undergone liver biopsy and scored as mild fibrosis (F1), moderate fibrosis (F2), sever fibrosis (F3) and liver cirrhosis (F4) based on Metavir scoring system, and 12 age and sex matched controls. The serum levels of HYP and OPN were measured by enzyme linked immunosorbent assay (ELISA). Results: There was a highly significant increase in HYP, OPN and APRI in all patients groups in comparison to control group and their increase was significantly associated with the degree of hepatic fibrosis. Furthermore, HYP, OPN and APRI values showed highly significant increase in significant hepatic fibrosis (F2- F4) in comparison to mild fibrosis (F1), and in hepatic cirrhosis (F4) in comparison to hepatic fibrosis (F1-F3). There was a highly significant positive correlation between serum HYP level, OPN and APRI. The receiver operating characteristic (ROC) curve analysis revealed that OPN has the highest area under the curve (AUC) value for discriminating fibrosis stages, followed by HYP and lastly APRI. Conclusion: This study demonstrated that OPN was the most diagnostically accurate marker for assessing the severity of hepatic fibrosis and served as a prognostic index towards the progression of hepatic fibrosis to cirrhosis in patients with chronic HCV infection, followed by HYP and lastly APRI. These findings indicated that OPN and HYP could be used as non invasive markers of hepatic fibrosis and cirrhosis which would help to reduce the need for liver biopsy in chronic HCV infection

びまん性肝疾患の線維化評価におけるreal-time tissue elastography

The long-term prognosis for patients with diffuse liver disease depends on an accurate diagnosis of hepatic fibrosis and assessment and prediction of improvements in this fibrosis with treatment. These assessments are vital for determining the hepatic cancer risk. A histological diagnosis of liver biopsy specimens is regarded as the gold standard for the assessment of hepatic fibrosis; however, noninvasive and accurate assessment methods for hepatic fibrosis are desired because of difficultly with repeated assessments due to the invasiveness and sampling errors encountered with biopsy. Based on platelet count and hepatic fibrosis marker measurements as well as relevant blood tests, formulas for calculating hepatic fibrosis have been tested. A method of assessing hepatic fibrosis using ultrasound was also developed, and its usefulness has been reported. Real-time tissue elastography (RTE) is a technology developed in Japan that can be loaded into commercially available diagnostic equipment. It provides a color display of information on tissue hardness in real time using a fast computation method, Combined Autocorrelation Method (CAM), for relative hardness based on tissue deformation in vivo. RTE enables measurements to be performed simply and noninvasively for the assessment of hepatic fibrosis. Relationships between the degrees or severity of features on RTE images and various stage assessment methods for hepatic fibrosis have been reported, but RTE most favorably reflects fibrosis without the effects of inflammation, cholestasis, or fatty deposition. It also enables serial assessments of improvements in hepatic fibrosis in response to treatment to be performed.