Francisco Barrera

Soluble CD163, a macrophage activation marker, is independently associated with fibrosis in patients with chronic viral hepatitis B and C

Macrophages are involved in inflammation and liver fibrosis and soluble (s)CD163 is a specific marker of activated macrophages. We investigated associations between sCD163 and biochemical and histological parameters of inflammatory activity and fibrosis in 551 patients with chronic hepatitis C virus (HCV) and 203 patients with chronic hepatitis B virus (HBV) before antiviral treatment. Scheuer histological scores of activity and fibrosis were obtained. Clinical, biochemical, and metabolic parameters were recorded. We measured sCD163 by enzyme‐linked immunosorbent assay (ELISA). Soluble CD163 was higher in patients with HCV compared to HBV (3.6 [interquartile range (IQR) 2.5‐5.4] versus 2.4 [IQR 1.8‐3.6] mg/L, P < 0.001). sCD163 was associated with fibrosis stages for both HCV (odds ratio [OR] 1.49, 95% confidence interval [CI]: 1.38‐1.61) and HBV (OR 1.32, 95% CI: 1.17‐1.49) patients, with highest levels in patients with advanced fibrosis and cirrhosis. sCD163 was a marker of fibrosis independent of other biochemical parameters and known risk factors. We created two novel sCD163‐based fibrosis scores, CD163‐HCV‐FS and CD163‐HBV‐FS, which showed areas under the receiver operating characteristics curve (AUROC) of 0.79 (95% CI: 0.74‐0.83) and 0.71 (95% CI: 0.62‐0.79), respectively, for significant fibrosis. Compared to existing fibrosis scores, CD163‐HCV‐FS was significantly superior to the aspartate aminotransferase (AST) to platelet ratio index (APRI) for all fibrosis stages and to FIB‐4 for significant fibrosis, but CD163‐HBV‐FS was not. Conclusion: sCD163 levels are increased in patients with chronic viral hepatitis, reflecting macrophage activation. Increased sCD163 is associated with the severity of disease and predicts fibrosis. A sCD163‐based fibrosis score, CD163‐HCV‐FS, is superior to APRI and FIB‐4 for the diagnosis of significant fibrosis in patients with HCV infection. (Hepatology 2014;60:521–530)

The role of diet and nutritional intervention for the management of patients with NAFLD.

During the last few decades, the prevalence of obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD) have dramatically increased. Nutrition and modern lifestyle habits are intimately involved in this epidemiological change. Although lifestyle intervention can theoretically revert the metabolic disturbances and prevent the long term complications of NAFLD, its efficacy is diminished in clinical practice by poor implementation and reduced adherence to lifestyle intervention programs. In this article we summarize the main elements of dietary interventions for NAFLD, describe practical strategies to optimize efficacy and review potential nutritional strategies under development that hopefully will improve outcomes in the future.

Markers of Collagen Remodeling Detect Clinically Significant Fibrosis in Chronic Hepatitis C Patients.

Background and Aim Detection of advanced fibrosis (Metavir F≥3) is important to identify patients with a high urgency of antiviral treatments vs. those whose treatment could be deferred (F≤2). The aim was to assess the diagnostic value of novel serological extracellular matrix protein fragments as potential biomarkers for clinically significant and advanced fibrosis. Methods Specific protein fragments of matrix metalloprotease degraded type I, III, IV and VI collagen (C1M, C3M, C4M, C6M) and type III and IV collagen formation (Pro-C3 and P4NP7S) were assessed in plasma from 403 chronic hepatitis C patients by specific ELISAs. Patients were stratified according to Metavir Fibrosis stage; F0 (n = 46), F1 (n = 161), F2 (n = 95), F3 (n = 44) and F4 (n = 33) based on liver biopsy. Results Pro-C3 was significantly elevated in patients with significant fibrosis (≥F2) compared to F0-F1 (p<0.05), while the markers C3M, C4M, C6M and P4NP7S were significantly elevated in patients with advanced fibrosis (≥F3) compared to F0-F2 (p<0.05). C1M showed no difference between fibrosis stages. Using Receiver Operating Characteristics analysis, the best marker for detecting ≥F2 and ≥F3 was Pro-C3 with AUC = 0.75 and AUC = 0.86. Combination of Pro-C3 and C4M with age, BMI and gender in a multiple ordered logistic regression model improved the diagnostic value for detecting ≥F2 and ≥F3 with AUC = 0.80 and AUC = 0.88. Conclusion The Pro-C3 protein fragment provided clinically relevant diagnostic accuracy as a single marker of liver fibrosis. A model combining Pro-C3 and C4M along with patient’s age, body mass index and gender increased the diagnostic power for identifying clinically significant fibrosis.

The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease.

Macrophage activation plays a key pathogenic role in experimental non‐alcoholic fatty liver disease (NAFLD) and contributes to the progression of steatohepatitis (NASH) and fibrosis. We studied macrophage activation in human NAFLD by measuring soluble (s)CD163, a specific macrophage activation marker, hypothesizing that sCD163 would be associated with the patients’ morphological disease grade. Furthermore, we investigated an association between sCD163 and the apoptosis marker cytokeratin‐18 (CK‐18) to explore a link between macrophage activation and apoptosis.

Prothrombotic factors and nonalcoholic fatty liver disease: An additional link to cardiovascular risk?

O ne of the vexing questions in clinical hepatology is defining the specific and independent contribution of the liver to systemic metabolic dysregulation, defined operationally by the term metabolic syndrome. The latter comprises a spectrum of disorders including obesity, insulin resistance, hypertension, and dyslipidemia. Clarifying the conundrum is difficult, as we tend to practice in silos as hepatologists or diabetic specialists, rather than as physicians. Ideally, defining the role of the liver to cardiometabolic risk requires prospective, well-defined, large patient cohorts with baseline liver histology, determinations of fat depots, an assessment of endocrine function and insulin sensitivity, together with long-term follow-up and regular liver assessments. Nevertheless, some progress has been made. Several cross-sectional studies have described an association between the presence of nonalcoholic fatty liver disease (NAFLD) and markers of atherosclerosis such as carotid artery thickness, endothelial dysfunction, coronary artery calcification, and stenosis. Epidemiological studies have also demonstrated an association between an imaging-based diagnosis of NAFLD and an increased risk of coronary, cerebrovascular and peripheral vascular disease, and mortality. While some of these associations persist after adjusting for traditional cardiovascular risk factors, in others the association is lost. The latter, however, does not negate a role for the liver since, for example, atherogenic dyslipidemia is, in large part, liver-dependent. Numerous mechanisms have been proposed to explain the contribution of NAFLD to cardiovascular risk, including hepatic insulin resistance, atherogenic dyslipidemia, hepatic inflammation, and a prothrombotic milieu. In fatty liver, the accumulation of diacylglycerol and sphingolipids enhances hepatic insulin resistance. Likewise, hepatic cholesterol synthesis and very-low-density lipoprotein (VLDL) export are increased, catabolism of triglyceride-rich HDL is augmented, and LDL receptors are reduced, favoring the presence of cholesterol-rich VLDL remnants, small atherogenic LDL, and reduced HDL. In addition, hepatocytes, macrophages, and stellate cells are sensitized to endoand exotoxins, increasing inflammatory cytokines and promoting a systemic proinflammatory atherogenic state. Since the liver is the site of production of most coagulation factors, clotting factor abnormalities are expected in liver disease. In this issue, Verrijken et al. clarify this aspect of the NAFLD-metabolic syndrome-cardiovascular risk puzzle. In a large well-characterized group of NAFLD subjects (n 5 273), serum levels of five procoagulant factors (factors VII, VIII, XI, von Willebrand, and fibrinogen), two anticoagulant factors (protein C and AT III), activated protein C resistance (APC-R) and plasminogen activator inhibitor-1 (PAI-1) were quantified and platelet function assessed. In accordance with prior data, a correlation was observed between components of the metabolic syndrome and elevated fibrinogen, factor VIII, von Willebrand factor and PAI1, and decreased ATIII. Interestingly, PAI-1 was the only factor associated with hepatic histology, namely, steatosis, inflammation, ballooning, and fibrosis. In multivariate analysis, steatosis was an independent predictor of PAI-1 levels, after adjusting for metabolic factors. However, only 12% of its variance was explained by hepatic histology, probably a consequence of the ubiquitous expression of PAI-1. These findings align with prior reports in NAFLD where PAI-1 was elevated and in which the association persisted after adjusting for metabolic factors. Importantly, in a subgroup who had available liver tissue, PAI-1 expression was higher in those with nonalcoholic steatohepatitis (NASH) than those without, suggesting that the increased PAI-1 derives, at least partially, from liver. PAI-1 is a member of the serine protease inhibitor proteins family that inhibits tissue-type plasminogen Abbreviations: ECM, extracellular matrix; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; PAI-1, plasminogen activator inhibitor-1; tPA, tissuetype plasminogen activator; uPA, urokinase plasminogen activator. Supported by a Robert W. Storr Bequest to the Sydney Medical Foundation and National Health and Medical Research Council (NHMRC 632630 and 1049857). Address reprint requests to: Professor Jacob George, Darcy Road Westmead NSW 2145, Australia. E-mail: jacob.george@sydney.edu.au; fax: 161-296357582. Copyright VC 2013 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26588 Potential conflict of interest: Nothing to report.

P824 SOLUBLE CD163, A MACROPHAGE ACTIVATION MARKER, IS INDEPENDENTLY ASSOCIATED WITH STEATOHEPATITIS IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE

Patients with NASH had higher cT1 than those with NAFLD (971±89ms versus 879±139ms; p =0.03). The three obese boys with greatest steatosis also had cT1 ≥970ms, compared to 783±25ms in lean boys, suggesting they had steatohepatitis similar to adult NASH. Conclusions: Multiparametric MR can quantify hepatic steatosis, which increases with obesity, in adults and children, and may be used to differentiate NASH from NAFLD.