Non-invasive Markers Of Liver Fibrosis Research Articles

Serum hyaluronic acid in chronic viral hepatitis B and C: a biomarker for assessing liver fibrosis in chronic hemodialysis patients.

Serum hyaluronic acid (sHA) is studied as a noninvasive marker of liver fibrosis (F) in chronic B and C viral hepatitis in general population but less in end-stage renal disease patients undergoing hemodialysis. We evaluated sHA as a noninvasive biomarker of F in a multicenter prospective, transversal, and observational study which included 52 end-stage renal disease patients with chronic B (14) and C (38) viral hepatitis (age 55.57 ± 14.46 years, dialysis vintage 132.59 ± 86.02 months). Of the noninvasive tests analyzed, only sHA, APRI, and FIB4 index were able to differentiate patients with F1 (sHA p = 0.006; APRI p = 0.031; FIB4 p = 0.016). No statistically significant differences were found between sHA and APRI, ASAT/ALAT ratio, and FIB4 index in detecting F1 a (p > 0.02). sHA seemed to be more efficient than APRI, ASAT/ALAT ratio, and FIB4 index, having the highest estimated AUC value. The sHA threshold value for F1 was equal to 33.46 ng/mL, with the following estimated values of the performance indicators: Se 88.46 % and Sp 50 %. sHA was the only noninvasive test of the studied tests that could determine F2 (p = 0.002), with a threshold value of 80.24 ng/mL (Se 63 %, Sp 88 %), and F3 (p = 0.008), with a threshold value of 88.54 ng/mL (Se 60 %, Sp 84 %). None of the studied noninvasive tests could determine F4. In patients with chronic B and C viral hepatitis undergoing hemodialysis, sHA may be a useful biomarker for the liver fibrosis grades: F1-mild, F2-moderate, and F3-severe, but it does not differentiate between chronic hepatitis (F1-F3) and liver cirrhosis (F4).

Relation of cytokeratin 18-Apoptosense M30 to activity and fibrosis in chronic HCV patients

Hepatitis C virus (HCV) is a progressive disease that may result in Chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Cytokeratin(CK)18 is an intermediary filament protein, expressed in hepatocytes, which is proteolytically cleaved during liver damage. M30 epitope of cytokeratin18(CK18-M30) is involved at different levels in apoptotic pathways. The aim of this study to investigate the diagnostic accuracy of cytokeratin 18-apoptosin M30 fragments (CK18-M30) as non-invasive method of liver fibrosis assessment and their correlation to METAVIR score. Serum concentrations of CK18-M30 were measured by ELISA in One hundred and sixty eight chronic hepatitis C patients (112 males and 56 females). Results showed that serum concentrations of CK18 were significantly increased in a stepwise fashion from A0 to A3 and from F0 to F4.There was highly significant positive correlation between CK18 and fibrosis stages (r = 0.881 & p < 0.001) and activity grades (r = 0.881 & p < 0.001). Also, serum CK18 correlated positively with serum levels of transaminases (r = 0.355 & p < 0.05). CK18 was correlated positively with viral level (r = 0.3 & p < 0.05). It was concluded that Elevated serum CK18-M30, as an indicator of enhanced apoptosis of hepatocytes, was increased and correlated significantly with inflammation severity, stages of fibrosis, transaminases (ALT) levels and viral load in chronic HCV patients. These findings may place CK18-M30 as a non-invasive marker of liver fibrosis and disease activity.

MicroRNA-122 associates with serum apolipoprotein B but not liver fibrosis markers in CHC genotype 1 infection

miR-122 is the predominant liver miRNA that regulates hepatic lipid metabolism and inflammation. Hepatitis C virus (HCV) modulates host intracellular lipid metabolism. HCV stability and propagation also depend on an interaction between virus and miR-122. Our aims were to examine the associations between miR-122, apolipoproteins, and serum makers of fibrosis in chronic hepatitis C (CHC) patients. We evaluated baseline sera from 36 CHC genotype 1 patients who completed the Phase IIa study of miravirsen (LNA oligonucleotide targeting miR-122). Samples were assessed for liver transaminases, IL 28B genotype, IP-10, and lipid profiles. The noninvasive markers of liver fibrosis, APRI, and FIB-4, were calculated using standard formulae. miR-122 levels were measured using RT-PCR and expressed as fold-change compared to normal healthy controls. CHC patients were mostly male (61%) with mean age 47.5 ± 11.6 years. Patients with higher ApoB (ApoB/ULN ≥ 0.5) has significantly lower miR-122 levels in compared to patients with lower ApoB (ApoB/ULN < 0.5). (8.28 ± 6.23 vs. 16.28 ± 13.71; P = 0.02). There were no similar associations between miR-122 and ApoA-1 or between HCV RNA and lipoproteins. There were no differences in miR-122 levels between patients with different stages of fibrosis determined by APRI or FIB-4. Patients with lower ApoB had higher serum miR-122 levels. However, we cannot identify significant association between miR-122, ApoA-1, or fibrosis markers in this small cohort of CHC genotype 1 patients. The mechanism of HCV dyslipidemia is complex and could partly relate to the effect of miR-122 on lipid metabolism which requires further evaluation in a larger study.

Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein Level Predicts Liver Fibrosis and Prognosis in Primary Biliary Cirrhosis.

Noninvasive markers of liver fibrosis in patients with primary biliary cirrhosis (PBC) are needed for predicting disease progression. As the Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA(+)-M2BP) was recently established as a liver fibrosis glycobiomarker in chronic hepatitis C, we assessed its efficacy in evaluating liver fibrosis stage and disease progression in PBC. A total of 137 patients with PBC who underwent liver biopsy and serological tests for WFA(+)-M2BP were enrolled. All patients were treated with ursodeoxycholic acid. Clinical data were compared with those for other noninvasive markers (aspartate aminotransferase-to-platelet ratio, FIB-4 index, aspartate aminotransferase/alanine aminotransferase ratio, Forn's index, and Mayo score) for estimating liver fibrosis using receiver operating characteristic analysis. The association between WFA(+)-M2BP and clinical outcome (liver decompensation, liver transplantation, or death) was evaluated using the Cox proportional hazards model with stepwise method. WFA(+)-M2BP was independently associated with liver fibrosis stage as determined by liver biopsy. The cutoff values of WFA(+)-M2BP for fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 0.7, 1.0, 1.4, and 2.0, respectively. The area under the receiver operating characteristic curve values for significant fibrosis, severe fibrosis, and cirrhosis were 0.979, 0.933, and 0.965, respectively. WFA(+)-M2BP was significantly superior to the other indices for the determination of significant and severe fibrosis stages. Furthermore, the WFA(+)-M2BP level at enrollment was strongly and independently associated with clinical outcome (hazard ratio 18.59, P=0.021). Baseline measurements of WFA(+)-M2BP represent a simple and reliable noninvasive surrogate marker of liver fibrosis and prognosis in patients with PBC.

IVER FIBROSIS EVALUATION BY ACOUSTIC RADIATION FORCE IMPULSE IMAGING AND&amp;NBSP; THE ASPARTATE AMINOTRANSFERASE TO PLATELET RATIO INDEX IN CHRONIC HEPATIC DISEASE

Background/Objectives: Acoustic radiation force impulse (ARFI) is a novel non-invasive technology for the assessment of liver fibrosis. Some studies previously reported that ARFI is a promising method for assessing liver fibrosis. Aspartaste aminotransferase (AST) to platelet ratio index (APRI) has been proposed as an easily determined and quite accurate noninvasive marker of liver fibrosis. This study aimed to explore the value of liver fibrosis assessment by ARFI, APRI and their combination in patients with chronic hepatic disease. Patients and Methods: The study was carried out on 119 patients with chronic hepatitis B, C, alcoholic liver disease and NASH. All of patients underwent a liver biopsy for histological assessment of liver fibrosis, ARFI elastography and calculate APRI. Cut-off values were determined using receiver-operating characteristic (ROC) curves. The corresponding cut-off values, sensitivities (Se), specificities (Sp), positive predict value (PPV) and negative predict value (NPV) were calculated and compared. In addition, the correlation of liver fibrosis stages with SWV and APRI were also tested to evaluate significant data. Results: Histological liver fibrosis was evaluated by Metavir scoring; F0: 9 cases, F1: 57 cases, F2: 23 cases, F3: 19 cases and F4: 11 case. SWV correlated significantly with the fibrosis stage (Spearman rho: 0.69, p = &lt;0.0001). The areas under the ROC curves (AUROC) were 0.86 (95% CI: 0.79-0.93) for ≥F2 and 0.88 (0.80-0.96) ≥ F3. The cut-off values of SWV were as follows: ≥1.29 m/s for ≥F2 (Se 79.25%, Sp 89.36%, PPV 85.7% and NPV 84.3%), ≥ 1.36 m/s for ≥F3 (Se 96.67%, Sp 86.52%, PPV 70.7%, NPV 98.7%). APRI correlated with the fibrosis stage (Spearman rho: 0.35, p = 0.0001). AUROC were 0.7 (95% CI: 0.56-0.79) for ≥F2 and 0.7 (0.85-0.81) ≥ F3. The cut-off values of APRI were as follows: ≥0.569 for ≥F2 (Se 50.94%, Sp 88.33%, PPV 71.1% and NPV 67.9%), ≥ 1.163 for ≥F3 (Se 40%, Sp 96.63%, PPV 80%, NPV 82.7%). When both methods were taken into consideration, for predicting F ≥2, we obtained 45.3% Se, 100% Sp, 100% PPV, 69.5% NPV and 0,73 AUROC, while for predicting F ≥3 we obtained 40% Se, 98.9% Sp, 92.3% PPV, 83% NPV and 0.7 AUROC. When ARFI and APRI results agreed, F ≥2 was confirmed by liver biopsy in 45% of cases and F ≥3 in 43.3% of cases. Conclusions: Increasing SWV and APRI correlate with high degree of liver fibrosis. ARFI has a good accuracy with high specificities and NPV for prediction of significant and advanced fibrosis. APRI has a quite good accuracy with high specificities for prediction of significant and advanced fibrosis and high NPV for prediction of advanced fibrosis. The specificities and PPV of the combined tests were better than ARFI or APRI alone for predicting significant and advanced liver fibrosis. When these two methods are concordant in significant or advanced fibrosis, liver biopsy can be avoided. The methods should be employed routinely in the workup of patients with chronic liver disease to evaluate the presence of significant and advanced liver fibrosis. Key words: liver fibrosis, liver stiffness, chronic hepatic disease, acoustic radiation force impulse imaging (ARFI), the aspartate aminotransferase to platelet ratio index (APRI)

Options for non-invasive assessment of liver fibrosis based on clinical data

Liver cirrhosis is one of the leading causes of death worldwide. Liver biopsy is considered as the gold standard for the diagnosis of chronic liver diseases. Studies have focused on non-invasive markers for liver fibrosis because of the dangers and complications of liver biopsy. The authors review the non-invasive direct as well as indirect methods for liver fibrosis assessment and present the positive and negative predictive value, sensitivity and specificity of those. Clinical utilities of transient elastography (Fibrsocan) is also reviewed. Non-invasive methods are useful in the assessment of liver fibrosis, monitoring disease progression and therapeutic response. Their accuracy can be increased by the combined or sequential use of non-invasive markers.

Soluble urokinase plasminogen activator receptor levels are associated with severity of fibrosis in nonalcoholic fatty liver disease

The identification of individuals with severe liver fibrosis among patients with chronic liver disease is of major importance when evaluating prognosis, potential risk for complications, and when deciding treatment strategies. Although percutaneous liver biopsy is still considered a "gold standard" for staging of liver fibrosis, attempts to find reliable noninvasive markers of liver fibrosis are frequent. Inflammation is essential for the progression of fibrosis. The urokinase plasminogen activator and its receptor have been associated with hepatic inflammation and fibrosis in mice. High serum concentrations of soluble urokinase plasminogen activator receptor (suPAR) are suggested to be involved in inflammation, tissue remodeling, and cancer metastasis. Here, we evaluated serum suPAR as a noninvasive test to detect liver fibrosis in 82 well-characterized patients with nonalcoholic fatty liver disease (NAFLD), and in 38 untreated patients with chronic hepatitis C virus (HCV) infection at the time of their first liver biopsy. suPAR levels were increased in chronic liver disease compared with blood donors (P<0.001). Patients with HCV had higher suPAR concentrations than patients with NAFLD (P<0.002). suPAR levels were associated with the severity of fibrosis, particularly in NAFLD, but did not correlate with inflammation. Regarding the performance in predicting severity of fibrosis, suPAR was essentially as good as other commonly used noninvasive fibrosis scoring systems. The results in HCV confirm previous observations. However, this is the first study to investigate suPAR as a biomarker in NAFLD, and theresults indicate that suPAR may constitute a severity marker related to fibrosis and prognosis rather than reflecting inflammation.

FibroSURE as a noninvasive marker of liver fibrosis and inflammation in chronic hepatitis B.

BackgroundNoninvasive markers of liver fibrosis have not been extensively studied in patients with chronic hepatitis B virus (HBV) infection. Our aim was to evaluate the capacity of FibroSURE, one of the two noninvasive fibrosis indices commercially available in the United States, to identify HBV infected patients with moderate to severe fibrosis.MethodsForty-five patients who underwent liver biopsy at a single tertiary care center were prospectively enrolled and had FibroSURE performed within an average interval of 11 days of the biopsy.ResultsOf the 45 patients, 40% were Asian, 40% were African American, and 13% were Caucasian; 27% were co-infected with HIV and 67% had no or mild fibrosis. We found FibroSURE to have moderate capacity to discriminate between patients with moderate to high fibrosis and those with no to mild fibrosis (area under receiver operating characteristic [AUROC] curve = 0.77; 95% confidence interval [CI] [0.61, 0.92]). When we combined the fibrosis score determined by FibroSURE with aspartate aminotransferase (AST) measurements and HIV co-infection status, the discriminatory ability significantly improved reaching an AUROC of 0.90 (95% CI [0.80, 1.00]). FibroSURE also had a good ability to differentiate patients with no or mild from those with moderate to high inflammation (AUROC = 0.83; 95% CI [0.71, 0.95]).ConclusionsFibroSURE in combination with AST levels has an excellent capacity to identify moderate to high fibrosis stages in chronic HBV-infected patients. These data suggest that FibroSURE may be a useful substitute for liver biopsy in chronic HBV infection.

Diagnostic accuracy of noninvasive markers of liver fibrosis in patients with psoriasis taking methotrexate: a systematic review and meta-analysis

People with psoriasis taking methotrexate may be at increased risk of developing liver fibrosis compared with the general population. Noninvasive methods of detecting fibrosis have been widely adopted but their clinical utility is uncertain. To evaluate the diagnostic accuracy of noninvasive methods to detect fibrosis compared with liver biopsy (reference standard) in people with psoriasis taking methotrexate. A systematic search using Ovid/Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library and Clinical Trials Register was performed. Diagnostic cohorts or case-control studies of adults taking or being considered for methotrexate therapy were considered. Study quality was evaluated using the Quality Assessment tool for Diagnostic Accuracy Studies (QUADAS-2). Pooled data analysis was performed using RevMan 5.1. Bayesian meta-analysis was conducted using Markov chain Monte Carlo simulation. Seventeen studies were included. Sensitivity and specificity were 38% and 83% for standard liver function tests (LFTs), 74% and 77% for procollagen-3N-terminal peptide (P3NP), 60% and 80% for Fibroscan(®) (Echosens, France, www.echosens.com), and 55% and 49% for ultrasound. Confidence in these results is limited owing to low-quality data; old, small studies displayed significant selection bias and significant variation in the prevalence of fibrosis. No studies were identified evaluating recently developed markers. The clinical utility of LFTs, P3NP and liver ultrasound is poor. Therefore if these tests are used in isolation, a significant proportion of patients with liver fibrosis may remain unidentified. Larger prospective studies are required in this population to validate newer non-invasive methods.

Long-term native liver fibrosis in biliary atresia: Development of a novel scoring system using histology and standard liver tests

Although liver fibrosis is an important predictor of outcomes for biliary atresia (BA), postsurgical native liver histology has not been well reported. Here, we retrospectively evaluated postsurgical native liver histology, and developed and assessed a novel scoring system - the BA liver fibrosis (BALF) score for non-invasively predicting liver fibrosis grades. We identified 259 native liver specimens from 91 BA patients. Of these, 180 specimens, obtained from 62 patients aged ≥1 year at examination, were used to develop the BALF scoring system. The BALF score equation was determined according to the prediction of histological fibrosis grades by multivariate ordered logistic regression analysis. The diagnostic powers of the BALF score and several non-invasive markers were assessed by area under the receiver operating characteristic curve (AUROC) analyses. Natural logarithms of the serum total bilirubin, γ-glutamyltransferase, and albumin levels, and age were selected as significantly independent variables for the BALF score equation. The BALF score had a good diagnostic power (AUROCs=0.86-0.94, p<0.001) and good diagnostic accuracy (79.4-93.3%) for each fibrosis grade. The BALF score revealed a strong correlation with fibrosis grade (r=0.77, p<0.001), and was the preferable non-invasive marker for diagnosing fibrosis grades ⩾F2. In a serial liver histology subgroup analysis, 7/15 patients exhibited liver fibrosis improvement with BALF scores being equivalent to histological fibrosis grades of F0-1. In postsurgical BA patients aged ⩾1year, the BALF score is a potential non-invasive marker of native liver fibrosis.

Thrombocytopenia, Liquor Use and Marijuana are Associated with Noninvasive Markers of Liver Fibrosis in People Living with HIV

Objective and aims: Liver disease is currently one of the leading causes of death among people living with HIV. Although platelets alterations are well recognized in the course of liver disease, the impact of thrombocytopenia (TCP: platelet counts <150,000 per microliter), which is highly prevalent among Hazardous Alcohol Users (HAU), is unclear. This lack of information limits the possibility to identify those at risk and to create targeted interventions. Methods: In this study, a total of 400 people living with HIV underwent laboratory assessments to determine if in addition to alcohol, TCP or its related factors (i.e., serotonin) were associated with non-invasive markers of liver fibrosis. The FIB-4 and the APRI scores were calculated using the Sterling’s and the Wai’s formulas, respectively. Results: Liver fibrosis was present in almost half of the study population (47%). As expected, APRI values of Hepatitis C co-infected subjects were higher than in HIV mono-infected patients (0.96 ± 0.18 vs. 0.5 ± 0.45, p=0.01). Notably, the risk was higher among marijuana users (OR= 9 95% CI 1.3-9.5, p=0.02). The risk of moderate fibrosis was also higher in the HAU (OR = 1.3; 95% CI, 1-2.5, p=0.04) when compared to non-HAU. Additional analyses indicated that consumption of liquor even 1-2 drinks per day, and high daily intakes of beer or wine (> 3 drinks per day) increases the risk of liver fibrosis. Thrombocytopenia, which is still prevalent (HAU=15% versus Hep C=22%) significantly increased the odds of moderate fibrosis (OR = 9; 95% CI, 3.6-23; p=0.0001). The odds of having severe fibrosis were 52% higher in the TCP group (95% CI, 13-97; p=0.0000). Serotonin, which is stored in the platelets, was also reduced among subjects with liver fibrosis levels (55.7 ± 6.7 vs. 87.3 ± 7.8 ng/mL, p=0.003). Multivariate analysis identified gender, hepatitis C, liquor use, TCP, marijuana and serotonin alterations as risk factors associated with liver fibrosis. Conclusion: Liver fibrosis is a condition that was associated with modifiable risk factors such as HAU, marijuana, TCP and viral hepatitis C. These results indicated that health care providers must be attentive for signs of these conditions to avert the risk of this terminal liver disease. From the clinical perspectives, analyses suggest that platelet-based interventions and serotonin agonist could be potential therapeutic targets.

Baseline Values and Changes in Liver Stiffness Measured by Transient Elastography Are Associated With Severity of Fibrosis and Outcomes of Patients With Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease that leads to extensive liver fibrosis and cirrhosis, which are associated with poor outcome. However, there are no validated noninvasive markers of liver fibrosis in patients with PSC. We assessed the diagnostic performance, reproducibility, longitudinal changes, and prognostic value of liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE). In a prospective study, we analyzed percutaneous liver biopsy specimens from 73 consecutive patients with PSC from January 2005 to December 2010. Patients underwent VCTE no more than 6 months after the biopsy specimens were collected. The biopsy specimens were analyzed by a pathologist blinded to the results of VCTE for the stage of fibrosis, and LSM was associated with the stage of fibrosis and other variables using the Kruskal-Wallis and Spearman correlation tests. The cutoff values of LSM were selected based on the accuracy with which they identified the stage of fibrosis on receiver-operating characteristic analysis. The rates of LSM progression were assessed using a linear mixed model, and the association between LSM values and clinical outcomes were evaluated using Cox regression analysis in 168 patients with PSC treated with ursodeoxycholic acid and followed up from November 2004 to July 2013 (mean follow-up period, 4 years). LSM was independently linked to the stage of fibrosis. Cutoff values for fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 7.4 kPa, 8.6 kPa, 9.6 kPa, and 14.4 kPa, respectively. The adjusted diagnostic accuracy values for severe fibrosis and cirrhosis were 0.83 and 0.88, respectively. The diagnostic performance of LSM was comparable to that of hyaluronic acid measurement but superior to the aspartate aminotransferase/platelet ratio index, FIB-4 score, and Mayo risk score in differentiating patients with significant or severe fibrosis from those without. LSM had a high level of reproducibility between operators for the same measurement site and for the same operator between 2 adjacent sites. LSM increased significantly and exponentially over time. Baseline measurements and rate of LSM progression were strongly and independently linked with patients' outcomes. VCTE is able to differentiate severe from nonsevere liver fibrosis with high levels of confidence in patients with PSC. Baseline measurements of LSM and longitudinal changes are prognostic factors for PSC.

Can Biomarkers Predict Significant Fibrosis In Patients With Chronic Hepatitis C (CHC)?

Purpose: CHC causes significant morbidity and mortality related to progressive fibrosis and associated complications. Histological details, including degree of fibrosis, are best described by liver biopsy; however, it is invasive, and has other limitations. Emerging blood tests target assessment of fibrosis, which is critical in making management decisions and predicting prognosis. Comprehensive prospective validation of these tests in a U.S. population is lacking. The aim of our study is to compare and validate the performance of aspartate aminotransferase/platelet ratio index (APRI), FIB4, and HCV FibroSURETM scores as predictors of significant hepatic fibrosis in HCV treatment-naive patients. Methods: One hundred ninety seven consecutive, treatment-naive patients with CHC undergoing liver biopsy were studied over a calendar year. Routine hematological, biochemical, and serological tests were performed, and demographics recorded. APRI, FIB4, and HCV FibroSURETM scores were calculated. Liver biopsy was interpreted and staged according to the Metavir system, by a pathologist blinded to other clinical information. AUROC were calculated on various parameters to determine the performance of the non-invasive scores when compared with the biopsy. Results: Only 196 patients' data could be included for the calculation of the APRI and FIB4 models. Demographics of the study cohort were: mean age 49.31 ± 9.96 years, 70% male, 79.7% Caucasians, 8.1% Hispanic, and 6.1% African Americans. The genotype distribution of study cohort was GT1-139 (70.55%), GT2-20 (10.15%), GT3-26 (13.19%), GT4-8 (4.06%), and GT6-4 (2.03%). Mean AST, ALT, and platelet counts were 61.86, 82.27, and 207.99, respectively. Significant fibrosis was defined based on histology (stage F2 and above), APRI score (>1.5), FIB4 index (>3.25), and HCV FibroSURETM (F2 and above). Based on liver histology, significant fibrosis was identified in 124 patients. The AUROC calculated for FibroSURETM was 0.712, APRI = 0.77, and FIB4 = 0.80. The PPV and NPV for FibroSURETM was 79.2% and 62.3%, respectively. The PPV/NPV for APRI and FIB4 were 100% /45.6% and 100%/ 44.5%, respectively. Additionally, the specificity for APRI and FIB4 were 100%. Conclusion: The APRI and FIB4 correlated better than FibroSURETM in identifying significant fibrosis. However, in the absence of significant fibrosis, none of these markers demonstrated satisfactory correlation, and therefore, a liver biopsy may still need to be performed. In conclusion, although non-invasive markers of liver fibrosis are easier to obtain than a biopsy, they are most useful when there is significant fibrosis, and thus cannot be used in lieu of a biopsy to accurately predict the stage of hepatic fibrosis. Further studies are needed to evaluate biomarkers that might demonstrate better correlation.

Non-invasive Liver Fibrosis Markers Are Associated with Liver-Related Death in the Multicenter AIDS Cohort Study

Non-invasive Liver Fibrosis Markers Are Associated with Liver-Related Death in the Multicenter AIDS Cohort Study

Liver biopsy for parenchymal liver disease—Is routine real time image guidance unnecessary?

Liver biopsy even today remains the standard of care for grading and staging chronic hepatitis despite advances in noninvasive markers of liver fibrosis. Literature suggests an expanding role for real-time image guided liver biopsy and declining trend for blind liver biopsies. In our center, where we perform around 400 liver biopsies per year, we performed a prospective clinical audit of our practice of blind outpatient percutaneous liver biopsies. Patients requiring histological grading and staging of chronic hepatitis routinely undergo blind outpatient percutaneous liver biopsies in our endoscopy unit unless there is a definite indication for real-time image guidance. All procedures were assessed for safety, and all specimens were evaluated by a specimen quality grading score for adequacy for grading and staging of chronic hepatitis. Of the 446 patients referred for histological grading and staging of chronic hepatitis C by liver biopsy, only 42 patients (9.5 %) required real-time ultrasound for liver biopsy. The remaining 404 patients underwent blind outpatient percutaneous liver biopsies which were found to be extremely safe with no major complications, yielding adequate liver tissue with high specimen quality score allowing optimal grading and staging of chronic hepatitis.

Interleukin-6 Is Associated with Noninvasive Markers of Liver Fibrosis in HIV-Infected Patients with Alcohol Problems

Both HIV and hepatitis C virus (HCV) cause chronic inflammation and alterations in serum inflammatory cytokines. The impact of inflammatory cytokines on liver fibrosis is not well understood. We studied the association between interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α and liver fibrosis in HIV-infected patients with current or past alcohol problems (CAGE ≥2 or physician investigator diagnosis). Liver fibrosis was estimated with FIB-4 (FIB-4 <1.45 defined the absence of liver fibrosis and FIB-4 >3.25 defined advanced fibrosis). Logistic regression was used to assess the association between cytokines and fibrosis, adjusting for age, sex, CD4, HIV RNA, current antiretroviral therapy, body mass index, and HCV. Secondary analyses explored whether the association between HCV and liver fibrosis was mediated by these cytokines. Participants (n=308) were all HIV-infected; 73% were male with a mean age of 42 years; half had detectable HCV-RNA, 60.7% had an absence of liver fibrosis, and 10.1% had advanced fibrosis. In models that adjusted for each cytokine separately, higher levels of IL-6 were significantly associated with an absence of fibrosis [adjusted OR (95% CI): 0.43 (0.19, 0.98), p=0.05] and were borderline significant for advanced fibrosis [adjusted OR (95% CI): 8.16 (0.96, 69.54), p=0.055]. In the final model, only higher levels of IL-6 remained significantly associated with advanced liver fibrosis [adjusted OR (95% CI): 11.78 (1.17, 118.19), p=0.036]. Adjustment for inflammatory cytokines attenuated the adjusted OR for the association between HCV and fibrosis in the case of IL-6 [for the absence of fibrosis from 0.32 (0.17, 0.57) p<0.01 to 0.47 (0.23, 0.96) p=0.04; and for advanced fibrosis from 7.22 (2.01, 25.96) p<0.01 to 6.62 (1.20, 36.62) p=0.03], suggesting IL-6 may be a partial mediator of the association between HCV and liver fibrosis. IL-6 was strongly and significantly associated with liver fibrosis in a cohort of HIV-infected patients with alcohol problems. IL-6 may be a useful predictive marker for liver fibrosis for HIV-infected patients.

Commentary: prognostication of chronic hepatitis B – are Fibrotest and Fibroscan the final answers? Authors' reply

We read with great interest the commentary by Wong et al.1 We completely agree that further large clinical studies with long-term follow-up should be conducted to predict the prognosis of patients with chronic liver diseases. For this reason, in France, a large cohort, named HEPATHER, started at the end of 2012. In this prospective study, 25 000 hepatitis C (HCV) or hepatitis B (HBV) patients will be followed up for 8 years. This cohort is supported by ANRS (Agence Nationale de Recherche sur le SIDA et les hépatites). Our study confirms that non-invasive markers of liver fibrosis (blood markers or liver stiffness) are excellent methods for the prognosis of HBV patients,2 as published before in HCV patients,3 or more recently in non-alcoholic fatty liver disease patients.4 The role of serial or combination of non-invasive tests should be also explored in chronic liver diseases. The authors' declarations of personal and financial interests are unchanged from those in the original article.2

Serum cystatin C: a non-invasive marker of liver fibrosis or of current liver fibrogenesis in chronic hepatitis C?

Background. Serum levels of cystatin C, an endogenous inhibitor of cysteine proteases, provide an alternative method to creatinine-based criteria for measuring glomerular filtration rate. Preliminary data suggested that serum cystatin C levels parallel with the stage of liver fibrosis in chronic liver disorders. Our aim has been to evaluate the possible role of serum cystatin C as a marker of liver fibrosis in hepatitis C virus (HCV)-induced chronic liver disease. Material and methods. 100 consecutive patients (56 men, mean age 51.2 ± 9.5 yrs) with HCV-induced chronic liver disease, scheduled for their first liver biopsy and naive for antiviral therapy were included. Liver fibrosis was evaluated with the METAVIR score. Serum cystatin C and standard laboratory tests were measured simultaneously. Patients with ethanol abuse (> 50 g/day), HBV or HIV coinfection or plasma creatinine ≥ 1.20 mg/dL were excluded. In addition, a second group of 16 patients fulfilling the same requisites and diagnosed with HCV-induced compensated cirrhosis by clinical evidence of portal hypertension was included. Results. Serum cystatin C levels significantly increase from F0 to F2 fibrosis stages, remained stable in F3 and F4 stages and increased again in the group of non-biopsied compensated cirrhosis. Serum cystatin C levels were higher in patients with moderate-advanced necroinflammation in the liver biopsy. Conclusion. Serum cystatin C level may reflect current fibrogenic and necroinflammatory activities in chronic HCV-induced liver disease with normal renal function but can not be considered as a non-invasive marker of liver fibrosis.

Course of Liver Fibrosis in HIV-Hepatitis C Virus-Coinfected Patients Depending on the Response to Hepatitis C Therapy

To evaluate the course of liver fibrosis, 328 HIV-hepatitis C virus (HCV)-coinfected patients (210 HCV treated and 118 HCV untreated) were followed-up for 38-42 months. Liver fibrosis was assessed by biopsy or elastometry at baseline and by elastometry afterward, in addition to other noninvasive indexes. A combined liver stiffness stage (LSS) was established and evaluated over time. Eighty patients had sustained virological response (SVR) and 130 had treatment failure (TF) after a standard course of peginterferon-ribavirin therapy. LSS decreased significantly in all fibrosis indexes during HCV therapy in treated patients, but the improvement persisted only in those with SVR. At the end of study, median elastometry values suffered variations of -29%, -5.0%, and +15.4% in SVR, TF, and untreated patients, respectively. Likewise, LSS worsened in 2.5%, 33.1%, and 39% of these groups, respectively: [OR (95% CI) 19.3 (4.4-119), p<0.001] for TF vs. SVR; [24.9 (5.6-154), p<0.001] for no therapy vs. SVR; and [1.29 (0.74-2.3), p=0.40] for no therapy vs. TF. LSS improved in 53.8%, 19.2%, and 5.9% of these groups, respectively: [4.88 (2.51-9.53), p<0.001] for SVR vs. TF; 18.4 (7.17-49.4), p<0.001 for SVR vs. no therapy; and 3.78 (1.47-10.1), p=0.003 for TF vs. no therapy. Independent predictive factors of LSS improvement or worsening were as follows: alcohol abuse [OR (95% CI) 0.48 (0.20-0.99), p=0.047] and [2.45 (1.19-5.03), p=0.016], respectively; SVR [27.7 (6.41-168), p<0.001] and [0.15 (0.07-0.31), p<0.001], respectively; and lower baseline CD4 counts [1.92 (1.08-3.45), p=0.026] and [0.31 (0.15-0.63), p=0.001], respectively. SVR was usually associated with regression of noninvasive liver fibrosis markers, whereas TF and HCV-untreated patients experienced poorer outcomes.

PMO-172 Direct non-invasive serum markers of liver fibrosis predict fibrosis evolution in chronic hepatitis C but are increased by interferon-based therapy

IntroductionLiver biopsy remains the reference standard for the detection of liver fibrosis. While non-invasive markers of liver fibrosis have been validated in chronic hepatitis C, their performance during interferon-based therapy...