Background: Cigarette smoking has been associated with liver fibrosis in the setting of hepatitis C virus (HCV) infection but has not been studied among people with HIV (PWH) who consume alcohol. Methods: This is a cross-sectional study of PWH with heavy drinking and daily smoking in St. Petersburg, Russia. The primary independent variable was past 30-day cigarettes per day (cpd), and the secondary independent variable was pack-years at study entry. Advanced liver fibrosis was defined as FIB-4 > 3.25. Analyses were adjusted for gender, body mass index (BMI), past 30-day number of heavy drinking days, HCV and CD4 count. Results: Participants (n = 400) were two-thirds male (67.3%), young (median age 38 years), lean (median BMI 22), HCV antibody positive (84.5%) and not severely immune suppressed (median CD4 count 351). The median number of past-month cpd was 20 (IQR: 15-25), and the median pack-years was 24 (IQR: 17-31.8). The prevalence of advanced liver fibrosis was 11.3% (45/400). In the adjusted logistic regression analyses, we did not observe a significant association between cpd [middle (10.1-20 cigarettes) vs. lowest (5-10 cigarettes) category (adjusted odds ratio [aOR] (95% confidence interval [CI]): 1.06 (0.40-2.83), highest (>20.0 cigarettes) vs. lowest category aOR (95% CI): 0.65 (0.21-1.99), global p-value = 0.62]. The secondary analysis with pack-years yielded similar results [middle (20.1-30 pack-years) vs. lowest category (≤20 pack-years) aOR (95% CI): 0.81 (0.33-1.99), highest category (>30 pack-years) vs. lowest category aOR (95% CI): 0.91 (0.38-2.19); global p-value = 0.58]. Conclusions: In this Russian cohort of PWH, we did not detect an association between recent cigarette use or mean pack-years and advanced liver fibrosis.

Fibrosis is a significant indication of chronic liver diseases often due to hepatitis C Virus. It is becoming a global concern as a result of the rapid increase in the number of HCV infected patients, the high cost and flaws associated with the assessment process of liver fibrosis. This study aims to determine the features that significantly contribute to the identification of the stages of liver fibrosis and to generate rules to assist physicians during the treatment of the patients as a clinically non-invasive approach. Also, the performance of different Multi-layered Perceptron (MLP), Random Forest, and Logistic Regression classifiers are estimated and compared for the full and reduced feature sets. Decision Tree produced 28 rules in contrast with previous research work where 98002 rules had been generated from the same dataset with an accuracy rate of approximately 99.97%. The resulting rules of this study achieved a prediction accuracy for the histological staging of liver fibrosis of 97.45%. Among all the machine learning methods, MLP achieved the highest accuracy rate.

Hepatic fibrosis is a common middle stage of the pathological processes of chronic liver diseases. Clinical intervention during the early stages of hepatic fibrosis can slow the development of liver cirrhosis and reduce the risk of developing liver cancer. Performing a liver biopsy, the gold standard for viral liver disease management, has drawbacks such as invasiveness and a relatively high sampling error rate. Real-time tissue elastography (RTE), one of the most recently developed technologies, might be promising imaging technology because it is both noninvasive and provides accurate assessments of hepatic fibrosis. However, determining the stage of liver fibrosis from RTE images in a clinic is a challenging task. In this study, in contrast to the previous liver fibrosis index (LFI) method, which predicts the stage of diagnosis using RTE images and multiple regression analysis, we employed four classical classifiers (i.e., Support Vector Machine, Naïve Bayes, Random Forest and K-Nearest Neighbor) to build a decision-support system to improve the hepatitis B stage diagnosis performance. Eleven RTE image features were obtained from 513 subjects who underwent liver biopsies in this multicenter collaborative research. The experimental results showed that the adopted classifiers significantly outperformed the LFI method and that the Random Forest(RF) classifier provided the highest average accuracy among the four machine algorithms. This result suggests that sophisticated machine-learning methods can be powerful tools for evaluating the stage of hepatic fibrosis and show promise for clinical applications.

MRI has emerged as the most comprehensive noninvasive diagnostic tool for focal liver lesions and diffuse hepatobiliary disorders. The introduction of hepatobiliary contrast agents, most notably gadoxetic acid (GA), has expanded the role of MRI, particularly in the functional imaging of chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD). GA-enhanced MRI (GA-MRI) may help to distinguish between the two subgroups of NAFLD, simple steatosis and nonalcoholic steatohepatitis. Furthermore, GA-MRI can be used to stage fibrosis and cirrhosis, predict liver transplant graft survival, and preoperatively estimate the risk of liver failure should major resection be undertaken. The amount of GA uptake can be estimated, using static images, by the relative liver enhancement, hepatic uptake index, and relaxometry of T1-mapping during the hepatobiliary phase. On the contrary, the hepatic extraction fraction and liver perfusion can be measured on dynamic imaging. Importantly, there is currently no clear consensus as to which of these MR-derived parameters is the most suitable for assessing liver dysfunction. This review article aims to describe the current role of GA-enhanced MRI in quantifying liver function, primarily in diffuse hepatobiliary disorders.

3 J. Magn. Reson. Imaging 2017;45:646-659.

Blood tests and transient elastography (TE), proposed as alternatives to biopsy for identifying advanced fibrosis (METAVIR-stage-F2 or greater) or cirrhosis, have never been compared using an intention to diagnose approach, with direct comparisons only, and Bayesian approach.

To permit more appropriate comparisons.

From an overview of articles (2002-2014), we selected studies that directly compared the diagnostic accuracy of FibroTest, aspartate aminotransferase-platelet ratio index (APRI), FIB4 or TE, with biopsy as a reference, in patients with chronic hepatitis C (CHC) or B (CHB). Investigators abstracted and checked study details and quality by using pre-defined criteria. Bayesian method in intention to diagnose was the primary outcome.

Of 1321 articles identified, 71 studies including 77 groups according to aetiology (All-CB) were eligible: 37 Only-C, 28 Only-B and 12 Mixed-C-B. There were 185 direct comparisons between the area under the ROC curves (AUROCs), 99 for the diagnosis of advanced fibrosis and 86 for cirrhosis. In All-CB, Bayesian analyses revealed significant AUROCs differences in identifying advanced fibrosis in favour of FibroTest vs. TE [credibility interval: 0.06(0.02-0.09)], FibroTest vs. APRI [0.05 (0.03-0.07)] and for identifying cirrhosis TE vs. APRI [0.07 (0.02-0.13)] and FIB4 vs. APRI [0.04(0.02-0.05)]. No differences were observed between TE and FibroTest, for identifying cirrhosis in All-CB, and in sub-groups (Only-C, Only-B, Mixed-CB) for both cirrhosis and fibrosis.

In CHC and CHB, APRI had lower performances than FIB-4, TE and FibroTest. TE had lower performance than FibroTest for identifying advanced fibrosis in All-CB, without significant difference for identifying cirrhosis in all groups.

Biliary atresia is a rapidly progressive liver disease necessitating prompt diagnosis and surgical intervention, so it must be promptly distinguished from other neonatal/infantile liver diseases.

To determine whether US shear wave elastography (SWE) can differentiate biliary atresia from other neonatal/infantile liver diseases based on liver hardness.

Eleven children younger than 1 year who had suspected liver disease underwent anatomically and temporally-related hepatic shear wave elastography and clinically indicated percutaneous core needle biopsy. Shear wave elastography was performed immediately prior to liver biopsy at the targeted biopsy site using an Acuson S3000 US system/9L4 transducer (Siemens Medical Solutions USA, Malvern, PA). Shear wave elastography was performed using Virtual Touch Quantification (VTQ) and Virtual Touch IQ (VTIQ) modes, and six shear wave speed measurements were acquired from each subject for each mode. Children were placed in two groups based on histology, biliary atresia (n = 6) vs. non-biliary atresia (other neonatal/infantile liver diseases) (n = 5), and mean shear wave speed measurements were compared using the unpaired student's t-test (two-tailed). A P-value <0.05 was considered significant.

Using the VTQ mode, mean liver shear wave speed was 2.08 ± 0.17 m/s for the biliary atresia group and 1.28 ± 0.13 m/s for the non-biliary atresia group (P < 0.0001). Using the VTIQ mode, mean liver shear wave speed was 3.14 ± 0.73 m/s for the biliary atresia group and 1.61 ± 0.23 m/s for the non-biliary atresia group (P = 0.003). Ishak liver fibrosis scores ranged from 3 to 6 for the biliary atresia group and from 0 to 1 for the non-biliary atresia group.

Liver shear wave speed is abnormally increased in neonates and infants with biliary atresia.

To evaluate whether a hepatic fibrosis index (HFI), quantified on the basis of hepatic contour abnormality, is a risk factor for the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C.

Our institutional review board approved this retrospective study and written informed consent was waved. During a 14-month period, consecutive 98 patients with chronic hepatitis C who had no medical history of HCC treatment (56 men and 42 women; mean age, 70.7 years; range, 48-91 years) were included in this study. Gadoxetic acid-enhanced hepatocyte specific phase was used to detect and analyze hepatic contour abnormality. Hepatic contour abnormality was quantified and converted to HFI using in-house proto-type software. We compared HFI between patients with (n=54) and without HCC (n=44). Serum levels of albumin, total bilirubin, aspartate transferase, alanine transferase, percent prothrombin time, platelet count, alpha-fetoprotein, protein induced by vitamin K absence-II, and HFI were tested as possible risk factors for the development of HCC by determining the odds ratio with logistic regression analysis.

HFIs were significantly higher in patients with HCC (0.58±0.86) than those without (0.36±0.11) (P<0.001). Logistic analysis revealed that only HFI was a significant risk factor for HCC development with an odds ratio (95% confidence interval) of 26.4 (9.0-77.8) using a cutoff value of 0.395.

The hepatic fibrosis index, generated using a computer-aided assessment of hepatic contour abnormality, may be a useful imaging biomarker for the prediction of HCC development in patients with chronic hepatitis C.

Real-time tissue elastography (RTE) is a non-invasive method for the measurement of tissue elasticity using ultrasonography. Liver fibrosis (LF) index is a quantitative method for evaluation of liver fibrosis calculated by RTE image features. This study aimed to investigate the significance of LF index for predicting liver fibrosis in chronic hepatitis C patients.

In this prospective study, 115 patients with chronic hepatitis C who underwent liver biopsy were included, and the diagnostic accuracy of LF index and serum fibrosis markers was evaluated.

RTE imaging was successfully performed on all patients. Median LF index in patients with F0-1, F2, F3 and F4 were 2.61, 3.07, 3.54 and 4.25, respectively, demonstrating a stepwise increase with liver fibrosis progression (P < 0.001). LF index (odds ratio [OR] = 5.3, 95% confidence interval [CI] = 2.2-13.0) and platelet count (OR = 0.78, 95% CI = 0.68-0.89) were independently associated with the presence of advanced fibrosis (F3-4). Further, LF index was independently associated with the presence of minimal fibrosis (F0-1) (OR = 0.25, 95% CI = 0.11-0.55). The area under the receiver-operator curve (AUROC) of LF index for predicting advanced fibrosis (0.84) was superior to platelets (0.82), FIB-4 index (0.80) and aspartate aminotransferase/platelet ratio index (APRI) (0.76). AUROC of LF index (0.81) was superior to platelets (0.73), FIB-4 index (0.79) and APRI (0.78) in predicting minimal fibrosis.

LF index calculated by RTE is useful for predicting liver fibrosis, and diagnostic accuracy of LF index is superior to serum fibrosis markers.

Among the noninvasive alternatives to liver biopsy, several studies have demonstrated the predictive value and superior benefit/risk ratio to biopsy of two combinations of simple serum biochemical markers in patients infected with hepatitis B and C virus. These include FibroTest (BioPredictive) for the quantitative assessment of fibrosis, and ActiTest (BioPredictive) for the quantitative assessment of necroinflammatory activity (HCV-FibroSURE, LabCorp). The possible causes of false negatives and positives are also better identified. These tests, which are now available in 12 countries, can facilitate the screening and management of the most frequent liver diseases.

Progressive fibrosis is a major cause of morbidity and mortality in chronic liver disease. To replace liver biopsy for disease staging, multiple serum markers are under evaluation with multiparametric panels yielding the most promising results. The Enhanced Liver Fibrosis (ELF) score is an ECM marker set consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA) showing good correlations with fibrosis stages in chronic liver disease.

The ELF score was measured in 400 healthy controls and 79 chronic hepatitis C patients using an ADVIA Centaur automated system. The ELF score was calculated using the published algorithm combining TIMP-1, PIIINP and HA values. Patients' fibrosis stage was defined histologically. ROC analyses were performed to study marker validity. Reference values and influence factors for the ELF score were validated.

ELF score reference values ranged from 6.7 to 9.8 and were significantly higher for men vs. women (7.0-9.9 vs. 6.6-9.3, respectively). Afternoon values were slightly higher than morning values (6.7-9.9 vs. 6.6-9.5, respectively). Age was a notable influence factor. We identified three cut-off values: 7.7 for a high sensitivity exclusion of fibrosis, 9.8 for a high specificity identification of fibrosis (sensitivity 69%, specificity 98% for moderate fibrosis), and 11.3 to discriminate cirrhosis (sensitivity 83%, specificity 97%). ELF score validity was superior to the results of the single tests.

The ELF score can predict moderate fibrosis and cirrhosis. However, influence factors such as gender and age need to be taken into account.

The effect of alcohol on liver disease in HIV infection has not been well characterized.

We performed a cross-sectional multivariable analysis of the association between lifetime alcohol use and liver fibrosis in a longitudinal cohort of HIV-infected patients with alcohol problems. Liver fibrosis was estimated with 2 noninvasive indices, "FIB-4," which includes platelets, liver enzymes, and age; and aspartate aminotransferase/platelet ratio index ("APRI"), which includes platelets and liver enzymes. FIB-4 <1.45 and APRI <0.5 defined the absence of liver fibrosis. FIB-4 >3.25 and APRI >1.5 defined advanced liver fibrosis. The main independent variable was lifetime alcohol consumption (<150 kg, 150 to 600 kg, >600 kg).

Subjects (n = 308) were 73% men, mean age 43 years, 49% with hepatitis C virus (HCV) infection, 60% on antiretroviral therapy, 49% with an HIV RNA load <1,000 copies/ml, and 18.7% with a CD4 count <200 cells/mm(3) . Forty-five percent had lifetime alcohol consumption >600 kg, 32.7% 150 to 600 kg, and 22.3% <150 kg; 33% had current heavy alcohol use, and 69% had >9 years of heavy episodic drinking. Sixty-one percent had absence of liver fibrosis and 10% had advanced liver fibrosis based on FIB-4. In logistic regression analyses, controlling for age, gender, HCV infection, and CD4 count, no association was detected between lifetime alcohol consumption and the absence of liver fibrosis (FIB-4 <1.45) (adjusted odds ratio [AOR] = 1.12 [95% CI: 0.25 to 2.52] for 150 to 600 kg vs. <150 kg; AOR = 1.11 [95% CI: 0.52 to 2.36] for >600 kg vs. <150 kg; global p = 0.95). Additionally, no association was detected between lifetime alcohol use and advanced liver fibrosis (FIB-4 >3.25). Results were similar using APRI, and among those with and without HCV infection.

In this cohort of HIV-infected patients with alcohol problems, we found no significant association between lifetime alcohol consumption and the absence of liver fibrosis or the presence of advanced liver fibrosis, suggesting that alcohol may be less important than other known factors that promote liver fibrosis in this population.

Liver fatty acid-binding protein (L-FABP) is a small molecule. The aim of this study was to examine L-FABP levels and to detect its diagnostic value in chronic hepatitis C (CHC).

We studied 22 patients with CHC and 20 healthy control subjects. Patients with persistently elevated serum aminotransferases and positive HCV RNA were included in the study. Patients with CHC underwent percutaneous liver biopsy. Serum level of L-FABP was determined by ELISA method.

Patients with CHC had significantly increased levels of L-FABP compared to controls. A strong correlation between serum L-FABP concentrations and aspartate aminotransferases, alanine aminotransferases, HCV RNA levels and hepatic inflammation was found. When a cut-off value was 29,000 pg/mL for L-FABP, sensitivity and specificity were 75 and 100%, respectively. Positive and negative predictive values for L-FABP were 100 and 78%, respectively.

Serum L-FABP is used as a new diagnostic marker to detect liver injury.

The FIB-4 index is a simple formula to predict liver fibrosis based on the standard biochemical values (AST, ALT and platelet count) and age. We here investigated the utility of the index for noninvasive prediction of progression in liver fibrosis. The time-course alteration in the liver fibrosis stage between paired liver biopsies and the FIB-4 index was examined in 314 patients with chronic hepatitis C. The average interval between liver biopsies was 4.9 years. The cases that showed a time-course improvement in the fibrosis stage exhibited a decrease in the FIB-4 index, and those that showed deterioration in the fibrosis stage exhibited an increase in the FIB-4 index with a significant correlation (P < 0.001). Increase in the ΔFIB-4 index per year was an independent predictive factor for the progression in liver fibrosis with an odds ratio of 3.90 (P = 0.03). The area under the receiver operating characteristic curve of the ΔFIB-4 index/year for the prediction of advancement to cirrhosis was 0.910. Using a cut-off value of the ΔFIB-4 index/year <0.4 or ≥ 0.4, the cumulative incidence of fibrosis progression to cirrhosis at 5 and 10 years was 34% and 59%, respectively in patients with the ΔFIB-4 index/year ≥0.4, whereas it was 0% and 3% in those with the ΔFIB-4 index/year <0.4 (P < 0.001). In conclusion, measurement of the time-course changes in the FIB-4 index is useful for the noninvasive and real-time estimation of the progression in liver fibrosis.

Alcoholic liver disease (ALD) is a significant cause of death and morbidity. Detection of liver fibrosis at an early stage could provide opportunities for more optimal management. Serum markers of liver fibrosis offer an alternative to biopsy. Evidence of the performance of biomarkers in ALD is needed and a systematic review to evaluate available studies was conducted.

Electronic databases were searched. Studies were included if they evaluated paired samples of biopsy and serum, and presented data as sensitivity, specificity, or ROC curves.

15 studies were included- median participant number = 146 (range 44-1034). Studies differed with respect to patient populations. 6 single markers were evaluated (mostly Hyaluronic Acid), and ten combined panels. Biomarkers could discriminate between people with severe fibrosis/cirrhosis with high diagnostic accuracy- HA (median AUROC 0.79 range 0.69-0.93), panels (median AUROC 0.83 range 0.38-0.95). Significant heterogeneity precluded pooling. Performance was poorer for detecting less severe fibrosis.

There are limited numbers of small studies evaluating the accuracy of biomarkers in identifying fibrosis on biopsy in ALD. Some showed promise (both HA alone and some panels) in the identification of cirrhosis/severe fibrosis and could be used to rule it out in heavy drinkers. Biomarkers less accurate with less severe fibrosis.

Liver biopsy (LB) is still considered the "gold standard" for hepatological evaluation, but recently noninvasive methods have attempted to replace this invasive procedure. Recently, acoustic radiation force impulse (ARFI) imaging has been developed as a noninvasive modality to evaluate the stiffness of tissues. ARFI imaging theoretically measures liver stiffness of all the segments independently. The aim of this study was to determine whether ARFI elastography is a reliable method for predicting the severity of fibrosis in the post-operative patients with biliary atresia.

ARFI elastography was performed 21 times in eight patients with biliary atresia over the last 2 years. At the same time, we measured serum hyaluronic acid (H value), which is one of the serum elastic makers, to compare ARFI versus values in these patients. We obtained ARFI versus values as the median of S2 to S8 by three consecutive measurements acquired with a Siemens Acuson S2000 (Siemens Medical Systems, Germany).

Histological evaluation of fibrosis is graded from F0 (normal) to F4. The normal H value is under 50 mg/dl. One patient had F0 (H value 29.2 mg/dl), four had F1 (H value 11.5-18.1 mg/dl), one had F3 (H value 61.3 mg/dl), two had F4 (H value 29.2, 112 mg/dl). One patient with F4 whose ARFI versus value (3.56 m/s) was the highest, needed liver transplantation and her liver was cirrhotic.

These findings suggest that ARFI measurement may be a reliable method for predicting the severity of fibrosis after a Kasai operation.

Hepatitis C is the most frequently encountered hepatic disease in dialysis patients. Data related to pegylated interferon alfa-2a (Peg-IFN-α-2a) use in hemodialysis patients with hepatitis C virus (HCV) are limited. The aim of this study was to evaluate the efficacy of Peg-IFN-α-2a among these patients.

Forty-one IFN-naive hemodialysis patients infected by HCV were assessed. All patients had positive anti-HCV antibody and positive HCV-RNA. Peg-IFN-α-2a 135 mcg/week was given for 48 weeks. Biochemical and virological responses were evaluated at treatment weeks 12, 24, 48, and 72.

Thirty-eight of the 41 patients who completed the treatment enrolled in the study. Mean age of the 38 patients was 38.1 (range 23-65) years, and the study group was predominantly male (65.8 %). There was no statistically significant difference in mean age, gender, mean duration of hemodialysis, HCV infection, patient numbers with normal alanine aminotransferase (ALT) values and mean ALT, platelet, and HCV-RNA values between patients who achieved sustained virological response (SVR) and those who did not. Only the Knodell histology activity index correlated with SVR (P = 0.048). Biochemical and virological response rates at the 12th week (early response) were 94.7 % and 60.5 %, respectively. The 34 (89.5 %) patients achieved biochemical response at the end of therapy (48th week); 24 (63.2 %) remained HCV-RNA negative. At the 72nd week, biochemical and virological response rates were 84.2 % and 50 %, respectively.

According to results of this study, patients achieved good sustained viral and biochemical response rates with Peg-IFN-α-2a treatment. Histology activity index may be a predictor for SVR; but large randomized controlled trials are needed. Weekly 135 mcg dose of Peg-IFN-α-2a for 48 weeks is an effective treatment in HCV-infected hemodialysis patients.

Predicting significant fibrosis or cirrhosis in patients with hepatitis C virus has persistently preoccupied the research agenda of many specialized research centers. Many studies have been conducted to evaluate the use of readily available laboratory tests to predict significant fibrosis or cirrhosis with the purpose to substantially reduce the number of biopsies performed. Although many of them reported significant predictive values of several serum markers for the diagnosis of cirrhosis, none of these diagnostic techniques was successful in accurately predicting early stages of liver fibrosis. Therefore, in this study a single stage classification model and a multistage stepwise classification model based on Neural Network, Decision Tree, Logistic Regression, and Nearest Neighborhood clustering, have been developed to predict individual's liver fibrosis degree. Results showed that the area under the receiver operator curve (AUROC) values of the multistage model ranged from 0.874 to 0.974 which is a higher range than what is reported in current researches with similar conditions.

To analyze the relationship between the glycated albumin (GA) to glycated hemoglobin (HbA1c) ratio and the histological grading of liver fibrosis.

The study retrospectively included consecutive hepatitis C virus positive chronic liver disease patients (n = 142) who had undergone percutaneous liver biopsy between January 2008 and March 2010 at our institution. The ratios of GA/HbA1c were calculated in all patients to investigate the relationship with the degree of the liver fibrosis. The values of the aspartate aminotransferase-to-platelet ratio index (APRI), an excellent marker for the evaluation of liver fibrosis, were also calculated. In addition, we combined the ratio of GA/HbA1c and the APRI in order to improve our ability to detect the presence of significant liver fibrosis.

Sixty-one (43%) patients had either no fibrosis or minimal fibrosis (METAVIR score: F0-F1), while 25 (17%) had intermediate fibrosis (F2). Fifty-six (39%) patients had severe fibrosis (F3-F4) and 27 of them had cirrhosis (F4). The mean values of the GA/HbA1c increased with the progression of the fibrosis (F0-1: 2.83 ± 0.24, F2: 2.85 ± 0.24, F3: 2.92 ± 0.35, F4: 3.14 ± 0.54). There was a significant difference between the F0-F1 vs F4, F2 vs F4, and F3 vs F4 groups (P < 0.01, P < 0.01, P < 0.01 and P < 0.05, respectively). The GA/HbA1c ratio was significantly higher in the patients with cirrhosis (F4) than in those without cirrhosis (F0-F3) (3.14 ± 0.54 vs 2.85 ± 0.28, P < 0.0001). The GA/HbA1c ratio was also significantly higher in the patients with severe fibrosis (F3-F4) than in those without severe liver fibrosis (F0-F2) (3.03 ± 0.41 vs 2.84 ± 0.24, P < 0.001). Furthermore, the GA/HbA1c ratio was also significantly higher in the patients with significant fibrosis (F2-F4) than in those without significant liver fibrosis (F0-F1) (2.98 ± 0.41 vs 2.83 ± 0.24, P < 0.001). The diagnostic performance of the increased GA/HbA1c ratio (> 3.0) was as follows: its sensitivity and specificity for the detection of liver cirrhosis (F4) were 59.3% and 70.4%, respectively and its sensitivity and specificity for the detection of severe liver fibrosis (F3-F4) were 50.0% and 74.4%, respectively. With regard to the detection of significant fibrosis (F2-F4), its sensitivity was 44.4% and its specificity was 77.0%. Although even the excellent marker APRI shows low sensitivity (25.9%) for distinguishing patients with or without significant fibrosis, the combination of the APRI and GA/HbA1c ratio increased the sensitivity up to 42.0%, with only a modest decrease in the specificity (from 90.2% to 83.6%).

The GA/HbA1c ratio increased in line with the histological severity of liver fibrosis, thus suggesting that this ratio is useful as a supportive index of liver fibrosis.

To determine the sensitivity and specificity of MR elastography (MRE) in the staging of hepatic fibrosis (HF) using histopathology as the reference standard in an Asian population.

MRE was performed on 55 patients with chronic liver diseases or biliary diseases and on 5 living related liver donors (48 men and 12 women; mean age, 55.7 years). MRE was performed with modified, phase-contrast, gradient-echo sequences, and the mean stiffness values were measured on the elastograms in kilopascals(kPa). Receiver operating characteristic curve analysis was performed to determine the cutoff value and accuracy of MRE for staging HF. Histopathologic staging of HF according to the METAVIR scoring system served as the reference.

Liver stiffness increased systematically along with the fibrosis stage. With a shear stiffness cutoff value of 3.05 kPa, the predicted sensitivity and specificity for differentiating significant liver fibrosis (≥ F2) from mild fibrosis (F1) were 89.7% and 87.1%, respectively. In addition, MRE was able to discriminate between patients with severe fibrosis (F3) and those with liver cirrhosis (sensitivity, 100%; specificity, 92.2%), with a shear stiffness cutoff value of 5.32 kPa.

MRE could be a promising, noninvasive technique with excellent diagnostic accuracy for detecting significant HF and liver cirrhosis.

Recent genome-wide association studies have identified the variant p.I148M of the adiponutrin gene PNPLA3 as a risk factor for developing severe forms of non-alcoholic and alcoholic liver diseases. The risk allele confers an increased risk for fatty liver disease and elevated serum aminotransferase activities reflecting liver injury. In the current elastography-based study, we investigate variant adiponutrin as genetic determinant of liver fibrosis, the hallmark of all chronic liver diseases.

In this observational cross-sectional study, we staged 899 patients with different chronic liver diseases non-invasively by transient elastography (Fibroscan) and genotyped them for variant adiponutrin (rs738409) by PCR-based assays. A subgroup of 229 patients consented to percutaneous liver biopsy, validating the accuracy of elastography in staging fibrosis (ρ=0.743, p<0.01).

Carriers of distinct p.I148M adiponutrin genotypes display significant (p=0.017) differences in liver stiffness determined by elastography. In particular, individuals carrying the allele [G] are at higher risk of developing liver cirrhosis defined by stiffness values ≥13.0kPa (OR=1.56, p=0.005). Of note, the PNPLA3 risk variant advances fibrosis in the total cohort as well as in the subgroups of patients with viral hepatitis and non-viral liver diseases and contributes 16% of the total cirrhosis risk.

The adiponutrin risk variant is a common genetic determinant of progressive liver fibrosis. Our results underpin non-invasive follow-up for individuals with chronic liver disease at-risk for developing advanced fibrosis and cirrhosis.

A serum biomarker (FibroTest; Biopredictive, Paris, France; FibroSure; LabCorp, Burlington, USA) and liver stiffness measurement (LSM) by Fibroscan (Echosens, Paris, France) have been extensively validated in chronic hepatitis C. This review updates the clinical validation of serum biomarkers and LSM in patients with chronic hepatitis B (CHB). One meta-analysis combined all published studies and another used a database combining FibroTest individual data. Sensitivity analysis assessed the impact of several factors, including authors' independence, length of biopsy, ethnicity, hepatitis B early antigen status, viral load, and alanine aminotransferase value. Only two biomarkers had several validations: FibroTest (8 studies, 1,842 patients), and Fibroscan (5 studies, 618 patients). For the diagnosis of advanced fibrosis, the standardized area under the receiver operating curve was 0.84 (0.79-0.86) for FibroTest and 0.89 (0.83-0.96) for LSM, without significant difference. No significant factors of variability were identified for FibroTest's performance. In conclusion, FibroTest and LSM were the most validated biomarkers of fibrosis in CHB. However, the reliability of Fibroscan must be better assessed.

The clinician expects from the pathologist a clinically relevant diagnosis on the basis of liver biopsy interpretation. Today, a liver biopsy, as invasive procedure, is only justified when a significant benefit for the patient can be expected particularly with respect to the clinical management. Consequently, liver biopsy is usually not required in uncomplicated acute viral hepatitis. It is, however, an important diagnostic tool in chronic hepatitis and in transplanted liver to confirm the clinical diagnosis and to assess stage and grade of necroinflammation, treatment efficiency, and concurrent diseases. The diagnosis of liver disease is based on teamwork between clinician and pathologist. Evaluation of the biopsy in the clinical context requires clinical information and appropriate size and handling of the biopsy specimen. Aim of this review is the discussion of morphologic features of acute and chronic viral hepatitis with regard to their clinical relevance.

To evaluate the utility of hepatocyte-phase gadoxetate disodium-enhanced magnetic resonance (MR) imaging in staging hepatic fibrosis and to compare it with diffusion-weighted imaging.

This retrospective study had institutional review board approval, and the requirement for informed consent was waived. Gadoxetate disodium-enhanced and diffusion-weighted MR images obtained in 114 consecutive patients (70 men, 44 women; age range, 37-91 years) were evaluated. Liver-to-muscle signal intensity (SI) ratio on hepatocyte-phase images (SI(post)), contrast enhancement index calculated as SI(post) /SI(pre), where SI(pre) is liver-to-muscle SI ratio on nonenhanced images, and apparent diffusion coefficient (ADC) of the liver were measured. Necroinflammatory activity grades and hepatic fibrosis stages were histopathologically determined in 99 patients. Multiple regressions of SI(post), contrast enhancement index, ADC, serum albumin concentration, serum total bilirubin level, prothrombin time, and Child-Pugh score were examined to determine correlation with hepatic necroinflammatory activity grades and fibrosis stages.

Among the MR, hematologic, and clinical parameters, contrast enhancement index was most strongly correlated with fibrosis stage (r = -0.79, P < .001). Multiple regression analysis showed that the contrast enhancement index, ADC, and prothrombin time were significantly correlated (r(2) = 0.66, P < .05) with fibrosis stage and that the contrast enhancement index and serum total bilirubin level were weakly correlated (r(2) = 0.24, P < .05) with the necroinflammatory activity grade.

Gadoxetate disodium-enhanced MR imaging is more reliable for staging hepatic fibrosis than are diffusion-weighted MR imaging, hematologic, and clinical parameters.

Noninvasive risk factors are required for predicting the development of hepatocellular carcinoma (HCC) not only in patients with cirrhosis but also in those with chronic hepatitis who are infected with hepatitis C virus (HCV).

A total of 707 patients with chronic HCV infection without other risks were evaluated for the predictive value of noninvasive risk factors for HCC, including age, sex, viral load, genotype, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, and alpha-fetoprotein (AFP) at entry to the study, as well as interferon (IFN) therapy they received.

The ten-year cumulative incidence rates of HCC for patients with fibrosis stages F0/F1, F2, F3, and F4 were 2.5, 12.8, 19.3, and 55.9%, respectively. Multivariate analysis identified age ≥57 years [hazard ratio (HR) 2.026, P = 0.004], fibrosis stage F4 (HR 3.957, P < 0.001), and AFP 6-20 ng/mL (HR 1.942, P = 0.030) and ≥20 ng/mL (HR 3.884, P < 0.001), as well as the response to IFN [relative risk (RR) 0.099, P < 0.001], as independent risk factors for the development of HCC. The ten-year cumulative incidence rates of HCC in the patients with AFP levels of <6, 6-20, and ≥20 ng/mL at entry were 6.0, 24.6, and 47.3%, respectively.

Not only high (>20 ng/mL), but also even slightly elevated (6-20 ng/mL) AFP levels, could serve as a risk factor for HCC to complement the fibrosis stage. In contrast, AFP levels <6 ng/mL indicate a low risk of HCC development in patients infected with HCV, irrespective of the fibrosis stage.

Experts in psoriasis, hepatology, pharmacokinetics and pharmacogenetics convened to discuss the safety and monitoring of methotrexate with respect to hepatotoxicity when used in the treatment of psoriasis. Methotrexate is an efficacious and cost-effective treatment for psoriasis, but is associated with significant safety issues, particularly relating to hepatotoxicity. Current British, Dutch, German, EU and US guidelines for baseline evaluations, monitoring and prevention of hepatotoxicity in patients with psoriasis receiving methotrexate were evaluated. Liver safety monitoring is currently reliant upon multiple methods, including biopsy, serological tests for biomarkers such as type III procollagen amino terminal propeptide (PIIINP), and liver function tests based on liver enzymes. Monitoring of patients receiving long-term therapy is expected to be improved by the utilization of serum biomarkers currently in development such as the Enhanced Liver Fibrosis (ELF) panel and other non-invasive tests of hepatic architecture, such as fibroelastography, microbubbles and magnetic resonance imaging. Appropriate studies to determine optimal dosing to maximize efficacy and minimize toxicity, potentially utilizing pharmacogenetic principles, are clearly needed. Key questions for future research are identified including needs for optimal screening and monitoring, identification of appropriate biomarkers, assessment of relationships between dosing and safety, utility of liver biopsy, optimal dosing regimens (including route of administration), methods to measure methotrexate levels in blood, and use of methotrexate as a standardized active comparator in trials of experimental drugs used to treat psoriasis.

We compared three hyaluronic acid (HA) assays and analyzed the impact of their variations on FibroMeter scores.

In a test group of 165 patients, HA levels were assessed with the commonly used ELISA assay from Corgenix, a new ELISA assay from Teco and an immunoturbidimetry assay from Wako, this latter tested across three different instruments. Five different FibroMeter scores were calculated.

Correlation across the three assays (r(s) between 0.969 and 0.995) was very good. Means of differences (d) were lower when the immunoturbidimetry assay was compared on different instruments: d between -3.4 and 2.0 μg/L. However, a higher value for HA measurement was observed with Corgenix assay, compared to the other two assays (Teco and Wako): d between 27.1 and 36.4 μg/L. The assessment also demonstrated that HA variations had very little impact on FibroMeter scores: 0.0117 for virus and 0.0416 for alcoholic fibrosis scores, and between 0.58 and 1.71 for the area of fibrosis (expressed in percentage).

The two new assays found lower values of HA, as compared to the Corgenix assay. However, these differences had very little impact on FibroMeter scores and had no impact on clinical evaluation of liver fibrosis.

ActiTest (AT) is a biomarker of liver necro-inflammatory histological activity validated in patients with chronic hepatitis C (HCV).

The aim was to assess the accuracy of AT in comparison with alanine aminotransferase (ALT) the standard of care.

Methods used an integrated database of individual data and the new recommended Obuchowski measures. An updated "classical" meta-analysis of AT validation studies was also performed. The main end points were the area under the ROC curves (AUROCs) for the diagnosis of each histological activity grade defined using METAVIR scoring system. To avoid repeated tests and the spectrum effect of activity grades prevalence, the comparison of AT and ALT accuracies used the Obuchowski method.

For the individual analysis, a total of 1250 patients were included and for the meta-analysis six studies (2017 patients) were included. The overall accuracy of AT for the diagnosis of any activity grade (Obuchowski measure=0.850) was significantly higher than the accuracy of ALT (Obuchowski measure=0.837; P=0.009). The updated standard meta-analysis confirmed the accuracy of AT (p<0.0001) both in independent AUROC=0.79 (95% CI, 0.73-0.85) and in non independent studies AUROC=0.74 (95% CI, 0.67-0.81).

The accuracy of AT for grading the necro-inflammatory activity of patients with HCV was significantly higher than ALT serum activity alone, the standard biomarker.

This review summarizes the methodological aspects of the interpretation of non-invasive biomarkers in liver fibrosis. A scoring system has been updated to better compare the quality of fibrosis biomarkers. Several methodological issues are related to the classical methodology using biopsy, as this is considered the gold standard. However, from evidence-based data, it appears that the methodology needs to change to prevent flawed conclusions among key opinion leaders as well as in obsolete guidelines. As waiting for the perfect biomarker for the diagnosis of advanced fibrosis to come along is probably a waste of time, in the meantime, methods can be improved. The main proposals for improving the methodology are, to take into account the spectrum bias, to assess accuracy between adjacent stages, to compare biomarkers in the same patient, to assess the cause of failure among discordant cases and to use specific statistical methods adapted for imperfect gold standards.

FibroTest (FT) is a biomarker of liver fibrosis initially validated in patients with chronic hepatitis C (CHC) and subsequently assessed in other frequent liver diseases, including chronic hepatitis B (CHB), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). The primary aim of the present study was to update a previous meta-analysis of FT diagnostic value, and to summarize its advantages and limitations. The secondary aim was to provide an overview of the prognostic value of FT in CHC, CHB and ALD. For diagnostic value, the main endpoint was the FT area under the ROC curves (AUROCs) for the diagnosis of bridging fibrosis (F2/F3/F4 vs F0/F1), standardized for the spectrum of fibrosis. Sensitivity analysis integrated the non-standardized observed AUROCs, the independency of authors, size (length) of biopsy, prospective design, correctness of procedures, co-morbidities, and timelag between biopsy and serum sampling. For prognostic value, the main endpoint was the FT AUROC for the prognostic value of liver complications or death related to liver disease. A total of 38 diagnostic studies were included, which pooled 7985 subjects who had undergone both FT and biopsy (4600 HCV, 1580 HBV, 267 NAFLD, 524 ALD and 1014 mixed). The mean standardized AUROC was 0.84 (95% CI, 0.83-0.86), with no differences in terms of causes of liver disease: HCV 0.84 (0.82-0.87); HBV 0.81 (0.78-0.83); NAFLD 0.84 (0.76-0.92); ALD 0.87 (0.82-0.92); and mixed 0.85 (0.81-0.89). Three prognostic studies were also included. FT was found to have higher or similar prognostic value compared with biopsy in patients with CHC, CHB or ALD. FibroTest is an effective alternative to biopsy in patients with chronic hepatitis C or B, ALD or NAFLD. Indeed, the prognostic performance of FibroTest was at least as accurate as that of biopsy in patients with chronic hepatitis C or B, or ALD.

Liver biopsy, due to its limitations and risks, is an imperfect gold standard for assessing the severity of the most frequent chronic liver diseases. This chapter summarized the advantages and the limits of the available biomarkers of liver fibrosis. Among a total of 2237 references, a total of 14 validated biomarkers have been identified between 1991 and 2007. Nine were not patented and five were patented. FibroTest (FT) was the most studied test with 33 different populations including 6549 patients and 925 controls. The mean diagnostic value for the diagnosis of advanced fibrosis assessed using standardized area under the receiver operating characteristics (ROC) curves was 0.84 [95% confidence interval (CI), 0.83-0.86], without significant difference between the causes of liver disease, hepatitis C, hepatitis B, alcoholic or nonalcoholic fatty liver disease. High-risk profiles of false negative/positive of FT are present in 3% of populations, mainly Gilbert syndrome, hemolysis, and acute inflammation. FT has higher accuracy than aspartate aminotransferase/platelets ratio index (APRI), the most used nonpatented test. No significant difference has been observed between the five patented tests. A quality score has been assessed in order to compare the quality of fibrosis biomarkers. Neither biomarkers nor biopsy are sufficient alone to take definitive decision in a given patient and all the clinical and biological data must be taken into account. Due to the evidence-based data, health authorities in some countries have already approved validated biomarkers as first-line procedure for the staging of liver fibrosis. This overview of evidence-based data suggests that biomarkers could be used as an alternative to liver biopsy for the assessment of fibrosis stage in the four more common chronic liver diseases: C virus (HCV), hepatitis B virus (HBV), hepatitis nonalcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). Neither biomarkers nor biopsy are sufficient alone to take definitive decision in a given patient and all the clinical and biological data must be taken into account.

Liver fibrosis is a common pathway of injury after chronic insult to the liver. The evolution of liver fibrosis to cirrhosis has many clinical implications, including bleeding, infection, hepatocellular carcinoma, and death. The reference standard for diagnosing liver fibrosis is currently histologic assessment of tissue obtained through liver biopsy. Although this provides valuable information, it has limitations, including its invasiveness, sampling error, observer variability, and the use of categorical scoring systems. This article outlines the various noninvasive markers, including blood tests, imaging, and novel technologies. It examines the principles behind their development, their diagnostic accuracy, and their evolution.

Biochemical tests and ultrasonography (US) are useful in the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C (CH-C); however histology remains the reference standard. This multicenter, cross-sectional cohort study evaluated the accuracy of APRI (AST-to-platelet-ratio-index) and liver surface ultrasound nodularity (LSN), singularly and sequentially combined in an algorithm, in diagnosing advanced fibrosis (i.e. METAVIR F3,F4), to derive a prediction rule to confirm or exclude F3,F4.

Four hundred and thirty consecutive CH-C patients with elevated ALT, grouped into a first cohort (training set), and an internal and an external validation cohort, were studied. APRI and LSN were compared to liver biopsy and sequentially combined in order to obtain a predictive rule for advanced fibrosis METAVIR F3,F4.

LSN was negative and APRI < or = 1 in 185/430 patients, whereas LSN was positive and APRI>2 in 46/430 cases, with a 94% diagnostic accuracy for presence/absence of F3, F4, respectively. In a further 60/430 patients, F3,F4 was detected with an accuracy of 83%. In the remaining cases no classification was possible.

An algorithm based on APRI and LSN confirms or excludes F3,F4 in 54% of CH-C patients with elevated ALT and suggests a highly probable diagnosis in a further one-sixth of patients, thus rendering liver biopsy unnecessary in these patients.

FibroTest (FT) is a biomarker of liver fibrosis initially validated in patients with chronic hepatitis C (CHC). The aim was to test two hypotheses, one, that the FT diagnostic value was similar in the three other frequent fibrotic diseases: chronic hepatitis B (CHB), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD); and the other, that the FT diagnostic value was similar for intermediate and extreme fibrosis stages.

The main end points were the FT area under the ROC curves (AUROCs) for the diagnosis of bridging fibrosis (F2F3F4 vs. F0F1), standardized for the spectrum of fibrosis stages, and the comparison of FT AUROCs between adjacent stages. Two meta-analyses were performed: one combining all the published studies (random model), and one of an integrated data base combining individual data. Sensitivity analysis integrated the independency of authors, lenght of biopsy, prospective design, respect of procedures, comorbidities, and duration between biopsy and serum sampling.

A total of 30 studies were included which pooled 6,378 subjects with both FT and biopsy (3,501 HCV, 1,457 HBV, 267 NAFLD, 429 ALD, and 724 mixed). Individual data were analyzed in 3,282 patients. The mean standardized AUROC was 0.84 (95% CI, 0.83-0.86), without differences between causes of liver disease: HCV 0.85 (0.82-0.87), HBV 0.80 (0.77-0.84), NAFLD 0.84 (0.76-0.92), ALD 0.86 (0.80-0.92), mixed 0.85 (0.80-0.93). The AUROC for the diagnosis of the intermediate adjacent stages F2 vs. F1 (0.66; 0.63-0.68, n = 2,055) did not differ from that of the extreme stages F3 vs. F4 (0.69; 0.65-0.72, n = 817) or F1 vs. F0 (0.62; 0.59-0.65, n = 1788).

FibroTest is an effective alternative to biopsy in patients with chronic hepatitis C and B, ALD and NAFLD. The FT diagnostic value is similar for the diagnosis of intermediate and extreme fibrosis stages.

Among the noninvasive alternatives to liver biopsy, several studies have demonstrated the predictive value and a better benefit-to-risk ratio than biopsy of five combinations of simple serum biochemical markers (the super combination being FibroMAX (BioPredictive, Paris, France) in patients at risk of chronic liver diseases: FibroTest (BioPredictive) for the quantitative assessment of fibrosis; SteatoTest (BioPredictive) for the quantitative assessment of steatosis; ActiTest (BioPredictive) for the quantitative assessment of necroinflammatory activity in chronic viral hepatitis C and B; NashTest (BioPredictive) for the categorical diagnosis of nonalcoholic steatohepatitis; and AshTest for the quantitative assessment of alcoholic steatohepatitis (also known in the USA as HCV-FibroSURE, HBV-FibroSURE, ASH-FibroSURE and NASH-FibroSURE; LabCorp, NC, USA). The possible causes of false-negative and false-positive results are also better identified. These tests, which are now available in 50 countries, can facilitate the screening and management of the most frequent liver diseases.

The liver biopsy is still regarded as the gold standard for the assessment of liver disease. However, there is a growing demand for non-invasive assessment of liver fibrosis, which is the most important prognostic factor in chronic liver disease, in particular in viral hepatitis. Transient elastography is a novel, non-invasive and rapid bedside method for assessing liver fibrosis by measuring liver stiffness. Some recent extensive studies, mainly from France, have demonstrated that measurement with the FibroScan is a good alternative for the liver biopsy. The amount of fibrosis can be quantified very easily and reliably. In this review, we describe the technique and discuss the available studies in order to establish applicability and to provide points for discussion.

Both HCV and HIV are common in haemophiliacs previously treated with non-viral-inactivated clotting factor concentrates. Because of increased bleeding risks, little data are available on the safety of percutaneous outpatient liver biopsy (LBx) and impact of HIV coinfection in this population. This study aims at reporting our experience with percutaneous LBx in a cohort of haemophiliacs infected with HCV and describe the spectrum of disease and impact of HIV coinfection. A retrospective review of consecutive patients with haemophilia and HCV who underwent percutaneous LBx was performed. All patients were positive for HCV RNA by commercial assay and received factor concentrate prior to biopsy. A total of 29 male patients (mean age 36, 24 haemophilia A, five haemophilia B, and 44% coinfected with HIV) underwent successful outpatient percutaneous LBx without bleeding complication. Histologic activity index was 6.44 with advanced fibrosis (bridging fibrosis/cirrhosis) in 31%. When patients were stratified by HIV positive (n = 13) vs. HIV negative (n = 16), coinfected patients had higher fibrosis scores and higher proportion advanced fibrosis (54% vs. 12%; P = 0.0167) with no differences in age, demographic or other laboratory parameters. Multivariate logistic regression found that HIV positivity was independently associated with advanced fibrosis (OR = 3.7; 95% CI: 1.17-11.8; P = 0.026). Outpatient percutaneous LBx can be safely performed in patients with haemophilia. Despite similar age, HIV coinfection was an independent predictor of advanced fibrosis. These data support the hypothesis that HIV accelerates fibrosis progression in those coinfected with HCV and highlights the importance of liver histology in this population.

Development of liver fibrosis, which leads to cirrhosis, is the principal complication of all chronic liver diseases, regardless of their cause. Knowledge of the existence and severity of fibrosis is important from diagnostic and prognostic viewpoints. Its assessment plays an essential role in the treatment decision and makes it possible to assess the risk of progression to cirrhosis and the onset of its complications. Histologic examination of the liver remains the reference examination for assessing the extent of fibrosis during chronic liver disease. Nonetheless, the number of patients needing assessment, the risks of the punch-biopsy and the cost of this invasive examination have led many to propose other tools to assess fibrosis. Some standard indicators (transaminases, platelets, prothrombin time) have long been recognized as indirect markers of extensive fibrosis. More recently, progress in our knowledge of the mechanisms of liver fibrogenesis have made it possible to identify different peripheral blood components that may be of clinical interest. Thus serum assays of elements of the extracellular matrix, their decay products, or enzymes involved in their metabolism have been proposed as noninvasive indicators. Among these, hyaluronic acid appears the most interesting. For several years, scores have been calculated with algorithms that combine several indicators determined simultaneously to assess fibrosis in patients with hepatitis C and sometimes other chronic liver diseases. The Fibrotest is the best validated and most widely used of these. Finally, Fibroscan is a device for the diagnosis and quantification of hepatic fibrosis, based on the technique of transient elastography. The relative roles of these noninvasive markers and the value of their combinations must still be determined.

Liver fibrosis and its end-stage disease cirrhosis are a major cause of mortality and morbidity throughout the world. Fibrosis is a response to chronic liver injury or infection that if unabated leads to the replacement of normal functional liver tissue with scar tissue. Basic research over the past decade has generated a vastly improved knowledge of the cell and molecular biology of liver fibrosis that provides a framework on which to design and develop therapeutics. The field has also witnessed a genuine paradigm shift from the original dogma that liver fibrosis is only ever a progressive process, to the new understanding that liver fibrosis even in an advanced stage can be reversible. There is therefore renewed optimism that liver fibrosis may be cured providing that we develop therapies that halt the fibrogenic process and encourage the natural regenerative properties of the liver. The key to the design of effective therapeutics will be to exploit the ongoing discoveries pertaining to the biology and function of fibrogenic hepatic myofibroblasts and their interplay with other liver cells and with the hepatic extracellular matrix. This review provides a critique of those discoveries in basic research that provide the most promise for translation to the clinic. In addition, we review the latest developments in the search for minimal invasive diagnostic tests for fibrosis that will be essential for determining the efficacy of anti-fibrotic drugs.

Liver biopsy is a highly useful tool in the evaluation of patients with chronic hepatitis C. However, the technique is not free of complications and presents a series of limitations (lack of representativity and interobserver variability in sample interpretation). Due to these limitations and the development of new noninvasive techniques, the role of liver biopsy is currently being reevaluated.

We performed a descriptive retrospective study of liver biopsies performed in patients with chronic hepatitis C virus (HCV) infection from January 2002 to January 2005. Age, gender, genotype, histology of the hepatic cylinder, and the percentage of patients who received treatment after liver biopsy was analyzed. The indications for biopsy in our patients and the reasons for nontreatment after biopsy were identified. We also analyzed whether the decision to start treatment was influenced by the histological grade of the lesion and whether there is any association between histological grade and transaminase levels.

A total of 156 patients were included and 72% received treatment after biopsy. Transaminase levels were elevated in 86%. Alanine aminotransferase (ALT) levels were elevated in 92.30% of treated patients and in 66% of untreated patients. The most frequent cause of nontreatment after biopsy was fibrosis stage < 2. The histological results were as follows: G0 in 2%, G1 in 26.8%, G2 in 47.7%, G3 in 22.2% and G4 in 1.3%; stage of fibrosis was F0 in 7.2%, F1 in 30.1%, F2 in 37.9%, F3 in 19.6%, and F4 in 5.2%. Fibrosis was advanced (F >= 2) in 41% of the patients with normal ALT levels and was mild (< F2) in 33% of those with elevated ALT levels.

Liver biopsy could be useful in patients with indication for treatment but a high risk of treatment-related adverse effects, as well as in those with normal transaminase levels, in whom the degree of fibrosis observed could influence the therapeutic approach.

The aim of this study was to find a non-invasive marker, which could predict liver fibrosis without the need of liver biopsy in non-alcoholic steatohepatitis (NASH).

Fifty patients were included. All patients had one or more conditions that characterize the metabolic syndrome and histological proven NASH. Hyaluronic acid (HA), leptin (LT) and laminin (LN) were determined from serum withdrawn at the day of biopsy.

Patients were divided into two groups according to the histological findings. The first group consisted of 23 patients with NASH and fibrosis and the second group had 27 patients with NASH, ballooned cells, without fibrosis. Subjects with NASH and fibrosis had statistically significantly higher HA and LN than those with NASH without fibrosis, P<0.001, respectively. In contrast, there was no statistically significant difference between the levels of serum LT in the two groups. The stage of liver fibrosis in the 23 patients of group 1 was related only to the values of hyaluronic acid (P<0.001) and not to the ones of LT and LN.

Measurement of hyaluronic acid could be a predictive factor of the presence and stage of liver fibrosis in NASH. LN could be used to diagnose liver fibrosis but has no value in staging.

We assessed the reliability of non-invasive biological scoring indexes (Fibrotest-Actitest [FT-AT], Forns, APRI, age-platelet, platelet, hyaluronic acid) as non-invasive alternatives to liver biopsy (LB) in 138 HCV-infected patients.

Thirty-six of 138 (26%) patients had systemic vasculitis, 27% significant serum inflammation, 47% fibrosis (F2F3F4) on LB. The diagnostic value of FT (F2F3F4 vs. F0F1) was assessed by an AUC of 0.83, without difference regarding to systemic vasculitis or serum inflammation. A discordance between FT-AT and the Metavir scoring indexes, present in 29% of patients, was associated with serum hemolysis and male but not with systemic vasculitis or serum inflammation. The other non-invasive biological tests were not influenced by serum inflammation or systemic vasculitis but were less reliable than FT (P <or= 0.05).

The FT-AT is a reliable non-invasive biochemical alternative to LB in HCV-infected patients with systemic vasculitis and is more reliable than other non-invasive biological indexes.

Liver biopsy has been in use for more than a century for diagnosis and staging of acute and chronic liver diseases. Several serum markers and panels offer the opportunity to assess the extent of liver disease noninvasively and spare some patients the risks associated with percutaneous liver biopsy, but only a few of the noninvasive serum markers allow the determination of different stages of fibrosis on a continuum similar to that achieved with liver biopsy. This article reviews the results of recent published and preliminary studies on serum markers, focusing on their comparison with liver biopsy and their clinical utility.