The combination of fatty liver and increased gamma-glutamyl transpeptidase levels as a risk factor for atherosclerotic plaque development in apparently healthy people

Background/aim: To elucidate how the combination of fatty liver and increased serum gamma-glutamyl transpeptidase (GGT) levels influences atherosclerotic plaque development in apparently healthy people. Materials and methods: The study population included people who had received an annual health checkup for more than 7 years and had no evidence of carotid plaque at baseline. We investigated the risk factors for carotid plaque occurrence using the Cox proportional hazards model. Results: A total of 107 people (76 men and 31 women; median age, 49 years) were enrolled. At baseline, fatty liver and a serum GGT level ≥50 U/L were observed in 13 and 38 people, respectively. During a median follow-up period of 13.3 years, carotid plaques appeared in 34 people. Multivariate analysis revealed that the combination of fatty liver and a serum GGT level ≥50 U/L was the only significant risk factor for carotid plaque occurrence (age- and sex-adjusted hazard ratio: 5.55; 95% confidence interval 1.70­18.14; P = 0.005). Conclusion: The combination of fatty liver and increased serum GGT levels raises the risk for atherosclerotic plaque development in apparently healthy people.

Recombinant thrombomodulin prevented hepatic ischemia-reperfusion injury by inhibiting high-mobility group box 1 in rats.

Recombinant thrombomodulin (rTM) is a novel anticoagulant and anti-inflammatory agent that inhibits secretion of high-mobility group box 1 (HMGB1) from liver. We evaluated the protective effects of rTM on hepatic ischemia-reperfusion injury in rats. Ischemia was induced by clamping the portal vein and hepatic artery of left lateral and median lobes of the liver. At 30 min before ischemia and at 6 h after reperfusion, 0.3 ml of saline (IR group) or 0.3 ml of saline containing 6 mg/kg body weight of rTM (IR-rTM group) was injected into the liver through inferior vena cava or caudate vein. Blood flow was restored at 60 min of ischemia. Blood was collected 30 min prior to induction of ischemia and before restoration of blood flow, and at 6, 12, and 24 h after reperfusion. All the animals were euthanized at 24 h after reperfusion and the livers were harvested and subjected to biochemical and pathological evaluations. Serum levels of ALT, AST, and HMGB1 were significantly lower after reperfusion in the IR-rTM group compared to IR group. Marked hepatic necrosis was present in the IR group, while necrosis was almost absent in IR-rTM group. Treatment with rTM significantly reduced the expression of TNF-α and formation of 4-hydroxynonenal in the IR-rTM group compared to IR group. The results of the present study indicate that rTM could be used as a potent therapeutic agent to prevent IR-induced hepatic injury and the related adverse events.

Associations of Fatty Liver Disease with Hypertension, Diabetes, and Dyslipidemia: Comparison between Alcoholic and Nonalcoholic Steatohepatitis.

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are representative types of fatty liver disease (FLD) and have similar histologic features. In this study, we aimed to compare the associations of the two FLD types with hypertension (HT), diabetes mellitus (DM), and dyslipidemia (DL). A nationwide survey investigating FLD status included 753 Japanese subjects (median age 55 years; male 440, female 313) with biopsy-proven ASH (n = 172) or NASH (n = 581). We performed a multiple logistic regression analysis to identify the factors associated with HT, DM, or DL. Older age and a higher body mass index were significant factors associated with HT. Older age, female sex, a higher body mass index, advanced liver fibrosis, and the NASH type of FLD (odds ratio 2.77; 95% confidence interval 1.78-4.31; P < 0.0001) were significant factors associated with DM. Finally, the NASH type of FLD (odds ratio 4.05; 95% confidence interval 2.63-6.24; P < 0.0001) was the only significant factor associated with DL. Thus, the associations of NASH with DM and DL were stronger than those of ASH with DM and DL. In the management of FLD subjects, controlling DM and DL is particularly important for NASH subjects.

An Image Fusion System for Estimating the Therapeutic Effects of Radiofrequency Ablation on Hepatocellular Carcinoma.

BACKGROUND: During ultrasound-guided radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC), high echoic areas due to RFA-induced microbubbles can help calculate the extent of ablation. However, these areas also decrease visualization of target tumors, making it difficult to assess whether they completely cover the tumors. To estimate the effects of RFA more precisely, we used an image fusion system (IFS). PATIENTS AND METHODS: We enrolled patients with a single HCC who received RFA with or without the IFS. In the IFS group, we drew a spherical marker along the contour of a target tumor on reference images immediately after administering RFA so that the synchronized spherical marker represented the contour of the target tumor on real-time ultrasound images. When the high echoic area completely covered the marker, we considered the ablation to be complete. We compared outcomes between the IFS and control groups. RESULTS: We enrolled 25 patients and 20 controls, and the baseline characteristics were similar between the two groups. The complete ablation rates during the first RFA session were significantly higher in the IFS group compared with those in the control group (88.0% vs. 60.0%, P = 0.041). The number of RFA sessions was significantly smaller in the IFS group compared with that in the control group (1.1 ± 0.3 vs. 1.5 ± 0.7, P = 0.016). CONCLUSIONS: The study suggested that the IFS enables a more precise estimation of the effects of RFA on HCC, contributing to enhanced treatment efficacy and minimized patient burden.

Measurement of Spleen Stiffness With Acoustic Radiation Force Impulse Imaging Predicts Mortality and Hepatic Decompensation in Patients With Liver Cirrhosis.

BACKGROUND & AIMS: Hepatic venous pressure gradient can predict mortality and hepatic decompensation in patients with cirrhosis. Measurement of hepatic venous pressure gradient requires an invasive procedure; therefore, prognostic markers are needed that do not require invasive procedures. We investigated whether measurements of spleen stiffness, made by acoustic radiation force impulse (ARFI) imaging, associated with mortality and decompensation in patients with cirrhosis, compared with liver stiffness and other markers. METHODS: We measured spleen stiffness in 393 patients diagnosed with cirrhosis (based on histologic or physical, laboratory, and radiologic findings) at a hospital in Japan from September 2010 through August 2013 (280 patients with compensated and 113 patients with decompensated cirrhosis). Patients underwent biochemical, ARFI, ultrasonography, and endoscopy evaluations every 3 or 6 months to screen for liver-related complications until their death, liver transplantation, or the end of the study period (October 2015). The primary outcome was the accuracy of spleen stiffness in predicting mortality and decompensation, measured by Cox proportional hazards model analysis. We compared spleen stiffness with other noninvasive parameters using the Harrell's C-index analysis. RESULTS: During a median follow-up period of 44.6 months, 67 patients died and 35 patients developed hepatic decompensation. In the multivariate analysis, spleen stiffness was an independent parameter associated with mortality, after adjustment for levels of alanine aminotransferase and serum sodium, and the model for end-stage liver disease score (P < .001). Spleen stiffness was associated independently with decompensation after adjustment for Child-Pugh score and model for end-stage liver disease score (P < .001). Spleen stiffness predicted mortality and decompensation with greater accuracy than other parameters (C-indexes for predicting mortality and decompensation were 0.824 and 0.843, respectively). A spleen stiffness cut-off value of 3.43 m/s identified the death of patients with a 95.3% negative predictive value and 75.8% accuracy. A spleen stiffness cut-off value of 3.25 m/s identified patients with decompensation with a 98.8% negative predictive value and 68.9% accuracy. CONCLUSIONS: Spleen stiffness, measured by ARFI imaging, can predict death of patients with cirrhosis with almost 76% accuracy and hepatic decompensation with almost 70% accuracy. It might be a useful noninvasive test to predict patient outcome. UMIN Clinical Trials Registry no. UMIN000004363.

Therapy with Direct-Acting Antiviral Agents for Hepatitis C-Related Liver Cirrhosis.

Chronic hepatitis C virus (HCV) infection may eventually lead to liver cirrhosis (LC), a condition associated with a high risk of liver failure and hepatocellular carcinoma. Although interferon (IFN)-based therapy has made substantial contributions to the management of HCV-infected patients, this therapy has limitations for LC patients in terms of eligibility, tolerability, relatively low and high rates of sustained virological response (SVR), and serious adverse events. Therapy with newly developed direct-acting antiviral agents (DAAs) can overcome these limitations in IFN-based therapy. Recent phase 3 trials have demonstrated that DAA therapy achieved high SVR rates (more than 90% for genotype 1; 80% to 90% for genotype 2; 60% to 70% for genotype 3) for compensated LC patients, with high tolerability and relatively low rates of serious adverse events. Furthermore, trials have suggested that DAA therapy can be used for the treatment of decompensated LC patients as well as pretransplant and posttransplant LC patients. In this article, we review the current status of DAA therapy for HCV-related LC patients.

GGsTop, a novel and specific γ-glutamyl transpeptidase inhibitor, protects hepatic ischemia-reperfusion injury in rats.

Ischemia-reperfusion (IR) injury is a major clinical problem and is associated with numerous adverse effects. GGsTop [2-amino-4{[3-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid] is a highly specific and irreversible γ-glutamyl transpeptidase (γ-GT) inhibitor. We studied the protective effects of GGsTop on IR-induced hepatic injury in rats. Ischemia was induced by clamping the portal vein and hepatic artery of left lateral and median lobes of the liver. Before clamping, saline (IR group) or saline containing 1 mg/kg body wt of GGsTop (IR-GGsTop group) was injected into the liver through the inferior vena cava. At 90 min of ischemia, blood flow was restored. Blood was collected before induction of ischemia and prior to restoration of blood flow and at 12, 24, and 48 h after reperfusion. All the animals were euthanized at 48 h after reperfusion and the livers were harvested. Serum levels of alanine transaminase, aspartate transaminase, and γ-GT were significantly lower after reperfusion in the IR-GGsTop group compared with the IR group. Massive hepatic necrosis was present in the IR group, while only few necroses were present in the IR-GGsTop group. Treatment with GGsTop increased hepatic GSH content, which was significantly reduced in the IR group. Furthermore, GGsTop prevented increase of hepatic γ-GT, malondialdehyde, 4-hydroxynonenal, and TNF-α while all these molecules significantly increased in the IR group. In conclusion, treatment with GGsTop increased glutathione levels and prevented formation of free radicals in the hepatic tissue that led to decreased IR-induced liver injury. GGsTop could be used as a pharmacological agent to prevent IR-induced liver injury and the related adverse events.

Management of gastroesophageal varices in cirrhotic patients: current status and future directions.

Bleeding from gastroesophageal varices (GEV) is a serious event in cirrhotic patients and can cause death. According to the explosion theory, progressive portal hypertension is the primary mechanism underlying variceal bleeding. There are two approaches for treating GEV: primary prophylaxis to manage bleeding or emergency treatment for bleeding followed by secondary prophylaxis. Treatment methods can be classified into two categories: 1) Those used to decrease portal pressure, such as medication (i.e., nonselective ß-blockers), radiological intervention [transjugular intrahepatic portosystemic shunt (TIPS)] or a surgical approach (i.e., portacaval shunt), and 2) Those used to obstruct GEV, such as endoscopy [endoscopic variceal ligation (EVL), endoscopic injection sclerotherapy (EIS), and tissue adhesive injection] or radiological intervention [balloon-occluded retrograde transvenous obliteration (BRTO)]. Clinicians should choose a treatment method based on an understanding of its efficacy and limitations. Furthermore, elastography techniques and serum biomarkers are noninvasive methods for estimating portal pressure and may be helpful in managing GEV. The impact of these advances in cirrhosis therapy should be evaluated for their effectiveness in treating GEV.

The superficial elevated and depressed lesion type is an independent factor associated with non-curative endoscopic submucosal dissection for early gastric cancer.

BACKGROUND: The expanded criteria for endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) have led to an increase in the number of EGC patients who receive curative treatment involving endoscopic techniques. Identifying the factors that are associated with treatment outcomes would be helpful in the application of ESD for EGC. METHODS: Potential factors associated with incomplete ESD and with non-curative ESD were investigated using a multiple logistic regression model in EGC patients who consecutively underwent ESD according to the expanded criteria. RESULTS: A total of 363 patients with 398 EGC lesions were enrolled. The rates of complete ESD and curative ESD were 96.2 % (383/398) and 85.7 % (341/398), respectively. No significant factors associated with incomplete ESD were identified. In contrast, a tumor size >20 mm [odds ratio (OR) 3.31; 95 % confidence interval (CI) 1.74-6.29], the superficial elevated and depressed type (0-IIa + IIc or IIc + IIa) (OR 4.37; 95 % CI 1.88-9.88), and the undifferentiated type (OR 5.93; 95 % CI 1.65-19.41) were identified as independent factors associated with non-curative ESD. The superficial elevated and depressed type in particular was found to be highly related to submucosal and lymphovascular invasion. The rate of non-curative ESD in cases of this macroscopic type occurring together with a tumor size >20 mm was 58.3 %, and the adjusted OR was 16.48 (95 % CI 4.69-62.09). CONCLUSION: The results suggest that the superficial elevated and depressed type is an independent factor associated with non-curative ESD and that the risk of non-curative ESD is increased when this macroscopic type is present along with a large tumor size.

Serum endocan as a survival predictor for patients with liver cirrhosis.

BACKGROUND: The relationship between endocan expression and outcome in patients with chronic liver disease is not fully understood. OBJECTIVE: To examine whether serum endocan level is predictive of outcome in patients with liver cirrhosis. METHODS: A total of 68 patients with liver cirrhosis were enrolled. Outcome predictors were analyzed using the Cox proportional hazards model. The overall survival rates were calculated using the Kaplan-Meier method, and differences were evaluated using the log-rank test. RESULTS: During the median follow-up period (7.1 years), nine patients had hepatocellular carcinoma (HCC) and 10 patients died. Of the deceased patients, nine died due to hepatic decompensation or associated conditions. No significant factors were found to be predictive of the occurrence of HCC. In contrast, an elevated serum endocan level (≥2.0 ng/mL; HR 2.34 [95% CI 1.05 to 7.03]; P=0.037) and high Child-Pugh grade B/C (HR 2.65 [95% CI 1.30 to 6.89; P=0.006) were predictive of poor survival. Kaplan-Meier analysis revealed that the respective cumulative survival rates at five and 10 years were 97.1% and 87.4% in patients with serum endocan levels <2.0 ng/mL and 85.8% and 64.4% in patients with levels ≥2.0 ng/mL (P=0.009), respectively. Moreover, the cumulative survival rates were significantly different among the patient groups divided according to serum endocan level and Child-Pugh grade (P=0.002). CONCLUSION: These findings suggest that serum endocan level may be a survival predictor for patients with liver cirrhosis.

Elevated Serum Gamma-glutamyl Transpeptidase Levels and Fatty Liver Strongly Predict the Presence of Carotid Plaque.

AIM: There is a strong relationship between carotid atherosclerosis and future cardiovascular disease (CVD). This study sought to clarify the association of fatty liver and an elevated serum gamma-glutamyl transpeptidase (GGT) level with carotid atherosclerosis. METHODS: We reviewed the medical records of subjects who underwent medical checkups at our institute. Carotid atherosclerosis and fatty liver were assessed using ultrasound (US), and predictors of increased carotid intima-media thickness (IMT) and carotid plaque were identified using a logistic regression model. RESULTS: In total, 958 subjects (564 men, 394 women; median age, 59 years) were enrolled. The median value of the mean carotid IMT was 0.713 mm, and the frequency of carotid plaque was 19.5%. For the highest quartile of the mean carotid IMT (≥ 0.863 mm), a male sex, older age, hypertension (HT), dyslipidemia (DL) and type 2 diabetes mellitus (DM) were identified as independent predictors. A male sex, older age, HT and elevated serum GGT level were found to be significant predictors of the presence of carotid plaque. In addition, fatty liver correlated with the existence of carotid plaque. When the combination of the serum GGT level and presence or absence of fatty liver was included as a variable in the analysis, a male sex, older age, HT and fatty liver with a serum GGT level of ≥ 83 IU/L (90th percentile) (odds ratio 3.21, 95% confidence interval 1.27-8.12, p=0.014)were identified to be significantly associated with carotid plaque. CONCLUSIONS: This study suggests that the simultaneous presence of an elevated serum GGT level and fatty liver is highly predictive of carotid plaque.

Serum osteopontin predicts degree of hepatic fibrosis and serves as a biomarker in patients with hepatitis C virus infection.

BACKGROUND & AIMS: Osteopontin (OPN) is a matricellular protein that upregulates during pathogenesis of hepatic fibrosis. The present study was aimed to evaluate whether serum OPN could be used as a biomarker to assess the degree of hepatic fibrosis in patients with hepatitis C virus (HCV) infection. METHODS: Needle biopsy was performed on HCV patients and scored as zero fibrosis (F0), mild fibrosis (F1), moderate fibrosis (F2), severe fibrosis (F3) and liver cirrhosis (F4) based on Masson's trichrome and α-smooth muscle actin (α-SMA) staining. Serum OPN levels were measured using ELISA and correlated with the degree of fibrosis. Furthermore, the OPN values were correlated and evaluated with platelets count, serum hyaluronic acid (HA), and collagen type IV and subjected to receiver operating characteristic (ROC) curve analysis. RESULTS: Serum OPN levels were remarkably increased from F0 through F4 in a progressive manner and the differences were significant (P < 0.001) between each group. The data were highly correlated with the degree of hepatic fibrosis. The ROC curve analysis depicted that serum OPN is an independent risk factor and an excellent biomarker and a prognostic index in HCV patients. CONCLUSIONS: The results of the present study indicate that serum OPN levels reflect the degree of hepatic fibrosis and could be used as a biomarker to assess the stage of fibrosis in HCV patients which would help to reduce the number of liver biopsies. Furthermore, serum OPN serves as a prognostic index towards the progression of hepatic fibrosis to cirrhosis and hepatocellular carcinoma.

Planning Sonography Using Real-time Virtual Sonography and Contrast-enhanced Sonography for Radiofrequency Ablation of Inconspicuous Hepatocellular Carcinoma Nodules.

BACKGROUND/AIMS: Determining whether planning sonography, using real-time virtual sonography (RVS) and contrast-enhanced sonography (CEUS), enables the identification of inconspicuous HCC nodules on conventional sonography (US), during percutaneous radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODOLOGY: We examined the factors associated with poor conspicuity, identification rate of inconspicuous HCC nodules in planning US using RVS and CEUS, the success rate of RFA for such nodules and local recurrence rates. RESULTS: Sixty inconspicuous HCC nodules were analyzed. Factors associated with poor conspicuity included location of the nodules for 34 nodules, US findings of HCC nodules for 24 nodules, US findings of surrounding hepatic parenchyma for 26 nodules and local recurrence for 18 nodules. Fifty-five (90.0%) HCC nodules were identified with RVS. Of the remaining five HCC nodules, three were visualized with CEUS. Thus, 96.7% (58/60) of the inconspicuous HCC nodules were identified. Forty-six (79.3%) identified HCC nodules, were treated with RFA; the success rate was 95.7% (44/46). The cumulative local recurrence rates were 0%, 2.7% and 9.4% at 12, 24 and 36 months, respectively. CONCLUSIONS: This study suggested that planning US using RVS and CEUS permits the identification of most inconspicuous HCC nodules, thereby improving the success rate of RFA.

Real-time image fusion for successful percutaneous radiofrequency ablation of hepatocellular carcinoma.

Percutaneous radiofrequency ablation (RFA) is an established nonsurgical curative treatment for hepatocellular carcinoma (HCC). Because of its efficiency and safety, sonography is the most commonly used imaging modality when performing RFA. However, the presence of HCC nodules that are inconspicuous when using conventional sonography is a major drawback of RFA and limits its feasibility as a treatment for HCC. However, a new technology has been developed that synthesizes high-resolution multiplanar reconstruction images using 3-dimensional data and is combined with a position-tracking system using magnetic navigation. With this technology, real-time sonograms can be fused with corresponding computed tomographic, magnetic resonance imaging, or even sonographic volume data; this process is known as real-time image fusion. In this article, we describe this novel imaging method as a useful tool for successful RFA treatment of HCC.

Binge alcohol consumption aggravates oxidative stress and promotes pathogenesis of NASH from obesity-induced simple steatosis.

The pathogenesis of nonalcoholic steatohepatitis (NASH) is a two-stage process in which steatosis is the "first hit" and an unknown "second hit." We hypothesized that "a binge" could be a "second hit" to develop NASH from obesity-induced simple steatosis. Thirty-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) rats were administered 10 mL of 10% ethanol orally for 5, 3, 2, and 1 d/wk for 3 consecutive weeks. As control, male Otsuka Long-Evans Tokushima (OLET) rats were administered the same amount of alcohol. Various biochemical parameters of obesity, steatosis and NASH were monitored in serum and liver specimens in untreated and ethanol-treated rats. The liver sections were evaluated for histopathological alterations of NASH and stained for cytochrome P-4502E1 (CYP2E1) and 4-hydroxy-nonenal (4-HNE). Simple steatosis, hyperinsulinemia, hyperglycemia, insulin resistance, hypertriglycemia and marked increases in hepatic CYP2E1 and 4-HNE were present in 30-wk-old untreated OLETF rats. Massive steatohepatitis with hepatocyte ballooning was observed in the livers of all OLETF rats treated with ethanol. Serum and hepatic triglyceride levels as well as tumor necrosis factor (TNF)-α mRNA were markedly increased in all ethanol-treated OLETF rats. Staining for CYP2E1 and 4-NHE demonstrated marked increases in the hepatic tissue of all the groups of OLETF rats treated with ethanol compared with OLET rats. Our data demonstrated that "a binge" serves as a "second hit" for development of NASH from obesity-induced simple steatosis through aggravation of oxidative stress. The enhanced levels of CYP2E1 and increased oxidative stress in obesity play a significant role in this process.

Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease.

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Although most subjects with excessive alcohol or food intake experience simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease. Notably, both ALD and NAFLD are frequently accompanied by extrahepatic complications, including cardiovascular disease and malignancy. The survival of patients with ALD and NAFLD depends on various disease-associated conditions. This review delineates the clinical characteristics and outcomes of patients with ALD and NAFLD by comparing their epidemiology, the factors associated with disease susceptibility and progression, and the predictors and characteristics of outcomes. A comprehensive understanding of the characteristics and outcomes of ALD and NAFLD is imperative in the management of these chronic liver diseases.

Nutrition and exercise in the management of liver cirrhosis.

Liver cirrhosis (LC) patients often have protein-energy malnutrition (PEM) and decreased physical activity. These conditions often lead to sarcopenia, which is the loss of skeletal muscle volume and increased muscle weakness. Recent studies have demonstrated that PEM and sarcopenia are predictors for poor survival in LC patients. Nutrition and exercise management can improve PEM and sarcopenia in those patients. Nutrition management includes sufficient dietary intake and improved nutrient metabolism. With the current high prevalence of obesity, the number of obese LC patients has increased, and restriction of excessive caloric intake without the exacerbation of impaired nutrient metabolism is required for such patients. Branched chain amino acids are good candidates for supplemental nutrients for both obese and non-obese LC patients. Exercise management can increase skeletal muscle volume and strength and improve insulin resistance; however, nutritional status and LC complications should be assessed before an exercise management regimen is implemented in LC patients. The establishment of optimal exercise regimens for LC patients is currently required. In this review, we describe nutritional status and its clinical impact on the outcomes of LC patients and discuss general nutrition and exercise management in LC patients.

Hepatitis C-related liver cirrhosis - strategies for the prevention of hepatic decompensation, hepatocarcinogenesis, and mortality.

Liver cirrhosis (LC) is a critical stage of chronic liver disease, including that caused by hepatitis C virus (HCV). In the absence of antiviral therapy, 67%-91% of patients with HCV-related LC patients die of liver-related causes, including hepatocellular carcinoma (HCC) and liver failure. Among the therapeutic strategies used to prevent liver-related complications in these patients is standard therapy with pegylated interferon and ribavirin, which induces a sustained virological response (SVR) in 25% of HCV genotype 1-infected patients and in 69% of patients infected with genotypes 2 and 3. SVR in patients with HCV-related LC has been associated with reduced rates of hepatic decompensation, HCC, and mortality. More recently developed direct-acting antiviral agents have shown excellent antiviral efficacy, with preliminary data demonstrating that an interferon-free regimen that includes these direct-acting antiviral agents achieved SVR in more than 50% of patients with HCV genotype 1 LC. Branched-chain amino acid supplementation, improvement of insulin resistance, and the use of ß-blockers for portal hypertension may also reduce liver-related complications. Here, we review advances in antiviral and adjunctive therapies for improved outcomes in patients with HCV-associated LC.

Serum endocan as a novel prognostic biomarker in patients with hepatocellular carcinoma.

Endocan is a vascular endothelium-derived factor regulated by angiogenic factors. The aim of this study was to determine whether serum endocan levels are prognostic for survival in patients with hepatocellular carcinoma (HCC). Serum endocan levels were measured in 64 HCC patients who were naïve to treatment, eight apparently healthy subjects, and 68 patients with liver cirrhosis; the latter two groups served as controls. Prognostic factors for the survival of HCC patients were examined using a Cox proportional hazards model. The median serum endocan levels were 1.145 ng/mL (range, 0.93-1.68 ng/mL) in healthy subjects, 1.93 ng/mL (range, 0.45-8.47 ng/mL) in liver cirrhosis patients, and 3.73 ng/mL (range, 0.74-10.95 ng/mL) in HCC patients (P = 0.0001). In HCC patients, elevated serum endocan levels were significantly associated with poor hepatic function (P = 0.015), a greater number of tumors (P = 0.034), and vascular invasion (P = 0.043). The median follow-up period was 23.0 months, and 33 HCC patients died during follow up. Multivariate analysis showed that serum endocan levels ≥ 2.20 ng/mL (hazard ratio 2.36, 95% confidence interval 1.22-5.36, P = 0.008) as well as elevated serum α-fetoprotein and des-γ-carboxy prothrombin levels were independent prognostic biomarkers for poor survival. The combination of serum endocan and these two additional markers was significantly predictive of worse survival (P < 0.0001). Thus, serum endocan may be a prognostic biomarker for survival in HCC patients, and the combination of serum endocan, α-fetoprotein, and des-γ-carboxy prothrombin levels can result in better prognostic stratification of these patients.