Predicting response to non-selective beta-blockers with liver-spleen stiffness and heart rate in patients with liver cirrhosis and high-risk varices.

INTRODUCTION: Non-selective beta-blockers (NSBB) are used for primary prophylaxis in patients with liver cirrhosis and high-risk varices (HRVs). Assessing therapeutic response is challenging due to the invasive nature of hepatic venous pressure gradient (HVPG) measurement. This study aims to define a noninvasive machine-learning based approach to determine response to NSBB in patients with liver cirrhosis and HRVs. METHODS: We conducted a prospective study on a cohort of cirrhotic patients with documented HRVs receiving NSBB treatment. Patients were followed-up with clinical and elastography appointments at 3, 6, and 12 months after NSBB treatment initiation. NSBB response was defined as stationary or downstaging variceal grading at the 12-month esophagogastroduodenoscopy (EGD). In contrast, non-response was defined as upstaging variceal grading at the 12-month EGD or at least one variceal hemorrhage episode during the 12-month follow-up. We chose cut-off values for univariate and multivariate model with 100% specificity. RESULTS: According to least absolute shrinkage and selection operator (LASSO) regression, spleen stiffness (SS) and liver stiffness (LS) percentual decrease, along with changes in heart rate (HR) at 3 months were the most significant predictors of NSBB response. A decrease > 11.5% in SS, > 16.8% in LS, and > 25.3% in HR was associated with better prediction of clinical response to NSBB. SS percentual decrease showed the highest accuracy (86.4%) with high sensitivity (78.8%) when compared to LS and HR. The multivariate model incorporating SS, LS, and HR showed the highest discrimination and calibration metrics (AUROC = 0.96), with the optimal cut-off of 0.90 (sensitivity 94.2%, specificity 100%, PPV 95.7%, NPV 100%, accuracy 97.5%).

Predictors of Hepatocellular Carcinoma Early Recurrence in Patients Treated with Surgical Resection or Ablation Treatment: A Single-Center Experience.

Introduction: Hepatocellular carcinoma (HCC) is the sixth most diagnosed malignancy and the fourth leading cause of cancer-related death worldwide, with poor overall survival despite available curative treatments. One of the most crucial factors influencing survival in HCC is recurrence. The current study aims to determine factors associated with early recurrence of HCC in patients with BCLC Stage 0 or Stage A treated with surgical resection or local ablation. Materials and Methods: We retrospectively enrolled 58 consecutive patients diagnosed with HCC within BCLC Stage 0 or Stage A and treated either by surgical resection or local ablation with maximum nodule diameter < 50 mm. In the first year of follow-up after treatment, imaging was performed regularly one month after treatment and then every three months. Each case was discussed collectively by the Liver Multidisciplinary Group to decide diagnosis, treatment, follow-up, and disease recurrence. Variables resulting in statistically significant difference were then studied by Cox regression analysis; univariately and then multivariately based on forward stepwise Cox regression. Results are represented in hazard ratio (H.R.) with 95% confidence interval (C.I.). Results: There was no statistically significant difference in recurrence rates (34.8 vs. 45.7%, log-rank test, p = 0.274) between patients undergoing surgical resection and local ablation, respectively. Early recurrence was associated with male gender (HR 2.5, 95% C.I. 1.9−3.1), nodule diameter > 20 mm (HR 4.5, 95% C.I. 3.9−5.1), platelet count < 125 × 103 cell/mm3 (HR 1.6, 95% C.I. 1.2−1.9), platelet-lymphocyte ratio < 95 (HR 2.1, 95% C.I. 1.7−2.6), lymphocyte-monocyte ratio < 2.5 (HR 1.9, 95% C.I. 1.4−2.5), and neutrophil-lymphocyte ratio > 2 (HR 2.7, 95% C.I. 2.2−3.3). Discussion and Conclusions: Our results are in line with the current literature. Male gender and tumor nodule dimension are the main risk factors associated with early HCC recurrence. Platelet count and other combined scores can be used as predictive tools for early HCC recurrence, although more studies are needed to define cut-offs.

Alanine aminotransferase and spleno-portal dynamics affect spleen stiffness measured by point shear-wave elastography in patients with chronic hepatitis C in the absence of significant liver fibrosis.

BACKGROUND: Spleen stiffness (SS) has gained a lot of interest in the context of liver cirrhosis and portal hypertension stratification. However, there is a paucity of data on confounding factors that may alter SS values. METHODS: Between January 2018 and October 2019, we enrolled 120 healthy subjects and 117 patients with hepatitis C virus (HCV) infection who did not have significant liver fibrosis (i.e., F0-1). Abdominal ultrasound evaluation was performed on each individual to measure portal vein diameter, portal flow velocity, spleen bipolar diameter, and splenic area. We also performed liver and spleen elastography. RESULTS: HCV patients had higher SS (p < 0.001), portal vein diameter (p = 0.031), portal flow velocity (p = 0.035), spleen bipolar diameter (p = 0.042) and area (p = 0.025), and ALT levels (p < 0.001). Linear regression models showed that SS increased by 3.220 kPa for each mm of portal vein diameter, by 0.7 kPa for each cm/s of portal flow velocity, by 2.239 kPa for each cm of spleen bipolar diameter, and by 0.233 kPa for each cm2 of spleen area. Patients with HCV infection were stratified according to median ALT levels (i.e. 32 IU/L). SS and spleno-portal axis parameters were significantly higher in patients with an ALT level > 32 IU/L. Besides, the relationship between SS and ALT was described by cubic polynomial regression according to the following equation: 11.735 + 0.404 (ALT)1 - 0.002 (ALT)2 + 4.26 × 10-6 (ALT)3. CONCLUSIONS: Our results bring new light to the role of inflammation as a confounding factor for SS measurement. Therefore, particular attention should be paid to serum transaminase for a correct evaluation of spleen elastography.

The role of elastography in alcoholic liver disease: fibrosis staging and confounding factors, a review of the current literature.

INTRODUCTION: Alcohol-related liver disease (ALD) was estimated to have a prevalence of 2% among the USA population. Since severe fibrosis in compensated patients is the main predictor of long-term survival, it is of utmost importance to early detect patients with severe fibrosis before decompensation occurs. Liver elastography has been used to stage liver fibrosis. However, there is a widespread lack in guidelines for the correct use of liver stiffness (LS) in ALD. EVIDENCE ACQUISITION: A structured search was carried out on MEDLINE/PubMed database. From the original 225 research articles identified, only 12 studies met the inclusion criteria, with 10 studies being eventually included. EVIDENCE SYNTHESIS: According to reported data, patients with aspartate aminotransferase (AST)>100 IU/L and 50 IU/L showed significantly higher values of LS if compared to patients with the same fibrosis stage. Also, excessive alcohol consumption greatly influences elastography, leading to false fibrosis staging. When LS values >5-6 kPa are detected, several aspects should be taken into account. First of all, the patient should be asked about the current alcohol consumption (i.e. active vs. abstinence, determination of abstinence period, and quantification of alcohol intake), and if the patient is an active drinker, liver elastography can be repeated after a complete abstinence period of at least two weeks. and if the patient is an active drinker, liver elastography can be repeated after a complete abstinence period of at least two weeks. Secondly, clinicians should check liver transaminases level, and if AST are above 100 IU/L, they should be aware of a possible overestimation of fibrosis. However, whether transaminases-adapted cut-off values should be used for ad-hoc decisions in patients with no time or option to withdraw from alcohol consumption is still a matter of debate. CONCLUSIONS: We hope that our review article may serve as a reference point in the prospect of futures guidelines.

Optimization of Point-Shear Wave Elastography by Skin-to-Liver Distance to Assess Liver Fibrosis in Patients Undergoing Bariatric Surgery.

BACKGROUND: Obesity is a primary limiting factor in liver stiffness measurement (LSM). The impact of obesity has always been evaluated in terms of body mass index (BMI), without studying the effects of skin-to-liver distance (SLD) on LSM. We studied the impact of SLD on LSM in a cohort of obese patients undergoing bariatric surgery and intra-operatory liver biopsy. MATERIALS AND METHODS: 299 patients underwent LSM by point-shear wave elastography (ElastPQ protocol), with two different ultrasound machines. SLD was measured as the distance between the skin and the liver capsule, perpendicular to where the region of interest (ROI) was positioned. We used the following arbitrary cut-offs: <5.7 kPa, F0-1; 5.7-7.99 kPa, F2; ≥8 kPa, F3-4. RESULTS: We developed two logistic regression models using elastography-histology agreement (EHA) as the dependent variable and SLD as the independent variable. The model based on the second machine showed strongly more performant discriminative and calibration metrics (AIC 38.5, BIC 44.2, Nagelkerke Pseudo-R2 0.894, AUROC 0.90). The SLD cut-off value of 34.5 mm allowed a correct EHA with a sensitivity of 100%, a specificity of 93%, negative predictive value of 100%, positive predictive value of 87%, an accuracy of 96%, and positive likelihood ratio of 3.56. CONCLUSION: The impact of SLD is machine-dependent and should be taken into consideration when interpreting LSM. We believe that our findings may serve as a reference point for appropriate fibrosis stratification by liver elastography in obese patients.

Spleen stiffness can be employed to assess the efficacy of spontaneous portosystemic shunts in relieving portal hypertension.

INTRODUCTION: Spleen stiffness (SS) has been found to mirror dynamic changes in portal pressure after transjugular intrahepatic portosystemic shunt (TIPS) placement. However, there is no data available regarding SS in patients with spontaneous portosystemic shunting (SPSS), especially in regards to prediction of hepatic decompensation. METHODS: We retrospectively selected patients with confirmed SPSS and esophageal varices (EVs) at endoscopic examination, and recorded any decompensating event (i.e., variceal hemorrhage, overt hepatic encephalopathy, refractory ascites, spontaneous bacterial peritonitis, hepatorenal syndrome) in the first twelve months following liver and spleen elastography. RESULTS: The patients who presented decompensating events showed lower platelet count (94.5 vs. 121.5 g/L, p < 0.001), higher SS (44 vs. 30 kPa, p < 0.001), higher probability of EVs according to SS (77 vs. 2 %, p < 0.001), and higher spleen diameter (14 vs. 12 cm, p = 0.043). They also showed a higher prevalence of splenorenal shunts (66.7 vs. 31.2%), and a significantly wider SPSS major diameter (14.5 vs. 8 mm, p < 0.001). CONCLUSION: SS could predict SPSS efficacy in relieving portal pressure, and could predict decompensating events in patients with SPSS.

The Importance of Transaminases Flare in Liver Elastography: Characterization of the Probability of Liver Fibrosis Overestimation by Hepatitis C Virus-Induced Cytolysis.

BACKGROUND: Liver stiffness measurement (LSM) is crucial for appropriate fibrosis staging in patients with ongoing hepatitis C virus (HCV) infection. However, there is still an ongoing debate on the impact of serum transaminases (aspartate-aminotransferase, AST; alanine-aminotransferase, ALT) on LSM. METHODS: We selected 110 patients undergoing HCV eradication therapy with LSM compatible with significant liver fibrosis. LSM was evaluated prior to therapy and one year after HCV eradication. RESULTS: LSM showed a median decrease of 35% from baseline values, and 67 (61%) patients showed posttreatment values compatible with lower fibrosis stages. We developed two logistic regression models to determine the probability of liver fibrosis overestimation according to serum transaminase. The probability of overestimation of two or more fibrosis grade is equal to (1) 50% for AST of 99 IU/L (2.2 ULN) and ALT of 90.5 IU/L (2 ULN), (2) 80% for AST of 123.5 IU/L (2.74 ULN) and ALT of 101.5 IU/L (2.25 ULN), and (3) reaches 100% for AST of 211 IU/L (4.7 ULN) and ALT of 140 IU/L (3.1 ULN). CONCLUSIONS: This study highlights the impact of serum transaminases on LSM. We believe that our findings may serve as a reference point for appropriate fibrosis stratification by liver elastography in patients with HCV infection.

Comparison between hepatocellular carcinoma prognostic scores: A 10-year single-center experience and brief review of the current literature.

BACKGROUND: Hepatocellular carcinoma (HCC) represents the most common primitive liver malignancy. A relevant concern involves the lack of agreement on staging systems, prognostic scores, and treatment allocation algorithms. AIM: To compare the survival rates among already developed prognostic scores. METHODS: We retrospectively evaluated 140 patients with HCC diagnosed between February 2006 and November 2017. Patients were categorized according to 15 prognostic scoring systems and estimated median survivals were compared with those available from the current medical literature. RESULTS: The median overall survival of the cohort of patients was 35 (17; 67) mo, and it was statistically different in relation to treatment choice, ultrasound surveillance, and serum alpha-fetoprotein. The Italian Liver Cancer (ITA.LI.CA) tumor staging system performed best in predicting survival according to stage allocation among all 15 evaluated prognostic scores. Using the ITA.LI.CA prognostic system, 28.6%, 40.7%, 22.1%, and 8.6% of patients fell within stages 0-1, 2-3, 4-5 and > 5 respectively. The median survival was 57.9 mo for stages 0-1, 43 mo for stages 2-3, 21.7 mo for stages 4-5, and 10.4 mo for stage > 5. The 1-, 3-, and 5-year survival rates were respectively 95%, 65%, and 20%, for stages 0-1; 94.7%, 43.9% and 26.3% for stages 2-3; 71%, 25.8% and 16.1% for stages 4-5; and 50%, 16.7% and 8.3% for stage > 5. At the same time, although statistically significant in prognostic stratification, the most commonly used Barcelona Clinic Liver Cancer system showed one of the most relevant differences in median survival, especially for stages A and C, when compared to the medical literature. In fact, 10.7%, 59.3%, 27.1%, 1.4%, and 0% of patients were stratified into stages 0, A, B, C, and D respectively. The median survival was > 81.1 mo for stage 0, 44.9 mo for stage A, 21.3 mo for stage B, and 3.1 mo for stage C. The 1-, 3-, and 5-year survival rates were respectively 86.7%, 60%, and 46.7% for stage 0; 91.6%, 50.6%, and 20.5% for stage A; 73.7%, 23.7% and 13.2% for stage B; and 2%, 0% and 0% for stage C. CONCLUSION: Survival analysis shows excellent prognostic ability of the ITA.LI.CA scoring system compared to other staging systems.

Spleen Stiffness Probability Index (SSPI): A simple and accurate method to detect esophageal varices in patients with compensated liver cirrhosis.

INTRODUCTION AND OBJECTIVES: Recent findings pointed out that even low-risk esophageal varices (EVs) are markers of severe prognosis. Accordingly, we analyzed spleen stiffness (SS) as a non-invasive method to predict EVs of any grade in a cohort of patients with compensated liver cirrhosis. METHOD: We measured SS and liver stiffness (LS) using point-Shear-Wave Elastography (pSWE) with Philips Affiniti 70 system in 210 cirrhotic patients who had undergone endoscopic screening for EVs. We compared SS and LS predictive capability for EVs of any grade. RESULTS: SS was higher in cirrhotic patients with EVs if compared to patients without EVs (p<0.001). The cut-off analysis detected 31kPa (100% sensitivity and negative predictive value) as the value to rule-out EVs and 69kPa (100% specificity and positive predictive value) to rule-in EVs. Besides, we developed the Spleen Stiffness Probability Index (SSPI), that can provide a probability of presence/absence of EVs. SSPI was the best model according to all discriminative and calibration metrics (AIC=120, BIC=127, AUROC=0.95, Pseudo-R2=0.74). SS demonstrated higher correlation with spleen bipolar diameter and spleen surface (r=0.52/0.55) if compared to LS (r=0.30/0.25) - and with platelet count as well (r=0.67 vs r=0.4). CONCLUSION: SS showed significantly higher performance than other parameters, proving to be the best non-invasive test in the screening of EVs: by directly applying SS cut-off of 31kPa, our department could have safely avoided endoscopy in 36% of patients. Despite cut-off analyses, it was possible to create a probability model that could further stratify low-risk from high-risk patients (for any grade of EVs).

Evaluation of spleen stiffness in healthy volunteers using point shear wave elastography.

INTRODUCTION AND OBJECTIVES: This study aims to measure the values of spleen stiffness (SS) in healthy subjects, the inter-operator agreement in SS measurement, and to detect statistically significant correlations between SS and age, sex, weight, BMI, portal vein dynamics and splenic dimensions. MATERIALS AND METHODS: The study included 100 healthy volunteers who had no substantial alcohol intake (<30g/daily for man, <20g/daily women), were negative on hepatitis B, hepatitis C, HIV blood serology, and had any history of lymphoproliferative disorders. Abdominal ultrasound, liver and spleen elastography were performed on each patient to search for focal splenic lesions, bile tract or portal vein dilatation, moderate/severe liver steatosis, and to measure liver and spleen stiffness. RESULTS: The mean value was 18.14 (±3.08) kPa. In the group of men (n=49), the mean was 17.73 (±2.91) kPa, whereas in the group of women (n=51) it was 16.72 (±3.32) kPa. Statistical analyses showed no correlation between spleen stiffness and sex, age, weight, and BMI. Regarding their splenoportal axis, statistically significant differences in SS were found in the means of the two subgroups of subjects stratified by their portal flow velocity (p=0.003) and spleen area (p<0.001). Spearman's rank showed a weak association between SS and portal flow velocty (r=0.271) and splenic area (r=-0.237). ICC showed excellent (0.96) inter-operator agreement and Bland-Altman plot demonstrated no systematic over/under-estimation of spleen stiffness values. CONCLUSIONS: Our results may serve as a reference point in the evaluation of SS especially in patients affected by advanced liver disease.

The molecular basis of jaundice: An old symptom revisited.

Increased serum bilirubin level is a widely used diagnostic marker for hepatic illnesses. Nevertheless, mild elevation of unconjugated serum bilirubin (such as in Gilbert syndrome) has been recently demonstrated to correlate with low risk of chronic inflammatory and/or oxidative stress-mediated diseases. In accord, a low serum bilirubin level has emerged as an important predisposing factor or a biomarker of these pathologic conditions including cardiovascular, tumour, and possibly neurodegenerative diseases. Bilirubin possesses multiple biological actions with interaction in a complex network of enzymatic and signalling pathways. The fact that the liver is the main organ controlling the bioavailability of bilirubin emphasizes the central role of this organ in human health.

CD209 promoter polymorphisms associate with HCV infection and pegylated-interferon plus ribavirin treatment response.

Hepatitis C is a severe liver disease caused by hepatitis C virus that could persist in the host causing progression towards chronic disease in about 80% of the cases. Pegylated-interferon plus ribavirin was the gold standard therapy, however treatment's response was quite variable among individuals and different host/viral factors may play a role in disease outcome. The cluster of differentiation 209 (CD209 antigen) is a component of the innate immune system able to recognize HCV and consequently activating the immune response. We enrolled 203 Italian HCV infected patients and 220 healthy controls investigating if five promoter polymorphisms within CD209 gene (encoding for CD209 antigen) correlated with HCV infection susceptibility, spontaneous viral clearance and interferon treatment response. CD209 -939G>A and -871A>G polymorphisms associated with HCV infection susceptibility, while, CD209 -871A>G and -336A>G polymorphisms associated with response to treatment. In conclusion, CD209 polymorphisms could play a role in the susceptibility to HCV infection as well as interferon treatment response in our study population from North-East of Italy.

Rapid identification system of frontal dysfunction in subclinical hepatic encephalopathy.

UNLABELLED:  Introduction and aim. Liver disease is associated with cognitive dysfunction also at early stages, and minimal hepatic encephalopathy, affecting 20-70% of patients, is frequently under-recognized. The main purpose of this work was to demonstrate that a substantial number of patients, enrolled due to an acute confusional state in absence of a diagnosis of liver disease, suffers of hepatic encephalopathy. MATERIAL AND METHODS: Before a diagnosis of a well-compensated liver diseases was performed, 410 patients with an acute confusional state were enrolled in this study. RESULTS: Even in the presence of minimal alterations of hepatic function, the psychometric tests applied demonstrated early signs of cerebral frontal alteration. The alteration was associated with the severity of liver disease, paralleling the progression of the patient to minimal hepatic failure or chronic liver disease. CONCLUSIONS: These psychometric tests are essential to detect early and subclinical frontal failure. Frontal dysfunction may be a useful tool in the follow-up of these patients.

Systematic review and meta-analysis on the adverse events of rimonabant treatment: considerations for its potential use in hepatology.

BACKGROUND: The cannabinoid-1 receptor blockers have been proposed in the management of obesity and obesity-related liver diseases (fatty liver as NAFLD or NASH). Due to increasing number of patients to be potentially treated and the need to assess the advantage of this treatment in terms of risk/benefit, we analyze the side events reported during the treatment with rimonabant by a systematic review and meta-analysis of all randomized controlled studies. METHODS: All published randomized controlled trials using rimonabant versus placebo in adult subjects were retrieved. Relative risks (RR) with 95% confidence interval for relevant adverse events and number needed to harm was calculated. RESULTS: Nine trials (n = 9635) were considered. Rimonabant 20 mg was associated with an increased risk of adverse event (RR 1.35; 95%CI 1.17-1.56), increased discontinuation rate (RR 1.79; 95%CI 1.35-2.38), psychiatric (RR 2.35; 95%CI 1.66-3.34), and nervous system adverse events (RR 2.35; 95%CI 1.49-3.70). The number needed to harm for psychiatric adverse events is 30. CONCLUSION: Rimonabant is associated with an increased risk of adverse events. Despite of an increasing interest for its use on fatty liver, the security profile and efficacy it is needs to be carefully assessed before its recommendation. At present the use of rimonabant on fatty liver cannot be recommended.

Natural course of chronic HCV and HBV infection and role of alcohol in the general population: the Dionysos Study.

BACKGROUND: Population-based studies of the natural course of chronic viral liver disease that consider comorbidity factors are lacking. Using data from the Dionysos Study, we quantified the burden of chronic viral liver disease and the role of alcohol intake to morbidity and mortality in a representative sample of subjects from the general population of two communities of Northern Italy. METHODS AND FINDINGS: We followed up 139 subjects with chronic hepatitis C virus (HCV) infection and 61 with chronic hepatitis B virus (HBV) infection for a median (IQR) time of 8.4 (1.0) and 8.3 (0.9) yr, respectively. Ethanol intake was evaluated using a food-frequency questionnaire, fatty liver (FL) was diagnosed by ultrasonography, and liver cirrhosis (LC) and hepatocarcinoma (HCC) were diagnosed by liver biopsy. Exact multivariable Poisson regression was performed to identify predictors of death. The incidence and remission rates of FL were 9.0 and 29.7 in the HCV cohort and 4.0 and 30.4 per 1,000 person-years (PY) in the HBV cohort. Progression to LC and HCC was more common in the HCV than in the HBV cohort (4.5 vs 2.0 and 2.7 vs 2.0 per 1,000 PY, respectively). Ethanol intake was an independent predictor of LC in the HCV cohort [rate ratio (RR) = 4.15 (95% CI 1.02-41.2) for every increase of 30 g/day of ethanol intake at baseline] and of death rate in both cohorts [RR = 8.53 (95% CI 1.40-24.61) and 3.56 (1.34 to 26.50) for every increase of 30 g/day of ethanol intake at baseline]. CONCLUSIONS: The morbidity and mortality rate of HBV and HCV infection in the general population is lower than that reported in secondary-care populations, blood donors, or clinical series. Ethanol intake is an independent predictor of LC in subjects with chronic HCV infection and an independent predictor of death in subjects with either HCV or HBV infection.

Incidence and natural course of fatty liver in the general population: the Dionysos study.

UNLABELLED: Using the general population of the Dionysos Study, we followed up 144 subjects without fatty liver (FL(-)) and 336 with fatty liver (FL(+)) for a median time of 8.5 years. All subjects had suspected liver disease (SLD) defined as altered liver enzymes, high mean corpuscular volume, or low platelet count in the absence of HBV and HCV infection. Ethanol intake was assessed using a food frequency questionnaire, and FL was diagnosed using ultrasonography. The incidence and remission rates of FL were 18.5 and 55.0 per 1,000 person-years. Progression to cirrhosis or HCC was rare in both cohorts (incidence rate: 1.7 versus 1.1 and 0.8 versus 0.4 per 1,000 person-years for FL(-) versus FL(+)). Multivariable Poisson regression was performed to identify predictors of FL incidence and remission among sex, age, body mass index, ethanol, and liver enzymes. Every increase of 20 g/day of ethanol intake at baseline was associated with a 17% increase in the rate of incident FL (P = 0.019), a 10% decrease in the rate of remitting FL and SLD (P = 0.043), a 19% decrease in the rate of remitting FL with persistent SLD (P = 0.002), and a 10% increase in mortality rate (P = 0.005) in the FL(+) cohort. CONCLUSION: In the general population of the Dionysos Study, FL regressed in nearly 1 of every 2 cases and had a substantially benign course. Ethanol intake was the most important risk factor for FL remission and incidence and a predictor of mortality in subjects with FL.

Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: Insulin resistance and response to antiviral therapy.

UNLABELLED: The response to antiviral therapy is lower in hepatitis C virus (HCV) patients with genotype 1 than in those with genotype 2. Overexpression of the suppressor of cytokine signaling 3 (SOCS3) gene in liver tissue is associated with a poorer treatment outcome in patients with chronic hepatitis C viral genotype 1. Also, insulin resistance has been implicated in nonresponse to an anti-HCV treatment. To understand why HCV genotype 1 patients respond differently, we investigated SOCS3 gene expression, metabolic syndrome (MS), and the response to therapy in a cohort of patients with HCV-related hepatitis. A total of 198 patients (108 with genotype 1 and 90 with genotype 2) treated with pegylated interferon plus ribavirin were consecutively enrolled in the study. We measured SOCS3 expression in Epstein-Barr virus-transformed lymphoblastoid cell lines derived from peripheral lymphocytes of a subset of 130 patients. MS was more frequent in genotype 1 patients than in genotype 2 patients (P < 0.01). Nonresponders (P < 0.01), MS (P < 0.001), and genotype 1 (P < 0.001) were significantly related to SOCS3 overexpression. However, SOCS3 levels were higher in nonresponders also, regardless of the genotype (P < 0.01). In a univariate analysis, the genotype (P < 0.001), age (P < 0.001), SOCS3 (P < 0.001), and MS (P < 0.001) were significantly related to the response to therapy. However, in a multivariate analysis, SOCS3 was the only independent predictor of the response (odds ratio = 6.7; P < 0.005). CONCLUSION: We speculate that SOCS3 expression per se may influence the response to antiviral therapy and that the genotype 1b virus might induce its up-regulation. This may account for the different responses to therapy between genotype 1-infected and genotype 2-infected patients.

The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population.

BACKGROUND: Fatty liver (FL) is the most frequent liver disease in Western countries. We used data from the Dionysos Nutrition & Liver Study to develop a simple algorithm for the prediction of FL in the general population. METHODS: 216 subjects with and 280 without suspected liver disease were studied. FL was diagnosed by ultrasonography and alcohol intake was assessed using a 7-day diary. Bootstrapped stepwise logistic regression was used to identify potential predictors of FL among 13 variables of interest [gender, age, ethanol intake, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase (GGT), body mass index (BMI), waist circumference, sum of 4 skinfolds, glucose, insulin, triglycerides, and cholesterol]. Potential predictors were entered into stepwise logistic regression models with the aim of obtaining the most simple and accurate algorithm for the prediction of FL. RESULTS: An algorithm based on BMI, waist circumference, triglycerides and GGT had an accuracy of 0.84 (95%CI 0.81-0.87) in detecting FL. We used this algorithm to develop the "fatty liver index" (FLI), which varies between 0 and 100. A FLI < 30 (negative likelihood ratio = 0.2) rules out and a FLI > or = 60 (positive likelihood ratio = 4.3) rules in fatty liver. CONCLUSION: FLI is simple to obtain and may help physicians select subjects for liver ultrasonography and intensified lifestyle counseling, and researchers to select patients for epidemiologic studies. Validation of FLI in external populations is needed before it can be employed for these purposes.