Differential Effects of Genetic Polymorphism on Comorbid Disease in Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND & AIMS: PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 have been associated with an increased risk of liver-related events (LREs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we investigated the combined effects of these variants on LREs. METHODS: The longitudinal multicenter cohort study enrolled 1178 patients with biopsy-proven MASLD. We calculated the genetic risk of hepatic fibrosis and LRE according to the impact of these variants. RESULTS: Patients with genetic fibrosis scores of 2, 3, and 4 or 5 were at greater risk than patients with scores of 0 or 1, with odds ratios of 2.45 (95% CI, 1.27-4.74), 2.14 (95% CI, 1.17-3.94), and 2.54 (95% CI, 1.35-4.77), respectively. Multivariate analysis revealed that PNPLA3 and TM6SF2, but not HSD17B13, were associated significantly with LRE development. The hazard ratio of the genetic high-risk group for LRE was 1.91 (95% CI, 1.20-3.04). The higher risk of LRE development in the genetic high-risk group also was seen in patients with F ≥ 3 or Fibrosis-4 index > 2.67. The hazard ratios of the genetic high-risk group for LRE were greater in patients without obesity, without diabetes, and of younger age compared with patients with obesity, with diabetes, or of older age, respectively. CONCLUSIONS: This combination of MASLD-related genetic variants is useful for predicting LREs in Japanese patients with MASLD. The genetic risk according to these variants is useful for LRE risk assessment, especially in patients without metabolic risk factors or in younger patients in Japan.

Safety/efficacy of atezolizumab + bevacizumab during anti-platelet/anticoagulation therapy in unresectable hepatocellular carcinoma.

BACKGROUND AND AIMS: This study aimed to determine the safety and efficacy of atezolizumab + bevacizumab therapy in hepatocellular carcinoma patients receiving anti-platelet agents or anticoagulants. METHODS: Patients were divided into those using (IM out) and those not using (IM in) anti-platelet agents or anticoagulants, who violated the exclusion criteria of the IMbrave150 trial, and were retrospectively examined. RESULTS: The study included 185 patients (IM in: 157; IM out: 28). For first-line treatment, progression-free survival was 184 days for IM in and 266 days for IM out (p = .136). Overall survival was 603 days for IM in and not reached for IM out (p = .265), with no significant between-group difference. Similarly, there were no significant between-group differences in progression-free survival or overall survival for later-line treatment. Haemorrhagic adverse events of ≥grade 3 were observed in 11 IM in patients and 3 IM out patients. No significant factors associated with haemorrhagic adverse events of ≥grade 3 were identified in the multivariate analysis including IM out classification, whose p value was .547. Regarding thrombotic/embolic adverse events in the IM out group, one case of exacerbation of portal vein thrombosis was observed. No deaths were directly attributable to bleeding events or exacerbations of thrombosis. CONCLUSION: Atezolizumab + bevacizumab therapy shows similar safety and efficacy in patients receiving and those not receiving anti-platelet agents or anticoagulants; therefore, it can be considered for patients with hepatocellular carcinoma receiving anti-platelet agents or anticoagulants.

The greater impact of PNPLA3 polymorphism on liver-related events in Japanese non-alcoholic fatty liver disease patients: A multicentre cohort study.

BACKGROUND & AIMS: PNPLA3 rs738409 has been associated with an increased risk of liver-related events in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the epidemiology of NAFLD and the impact of PNPLA3 on prognosis in Japan. METHODS: A longitudinal multicentre cohort study, the JAGUAR study, includes 1550 patients with biopsy-proven NAFLD in Japan. We performed genetic testing and evaluated outcomes from this cohort. Liver-related events were defined as hepatocellular carcinoma (HCC) and decompensated liver cirrhosis events. RESULTS: During follow-up (median [range], 7.1 [1.0-24.0] years), 80 patients developed HCC, 104 developed liver-related events, and 59 died of any cause. The 5-year rate of liver-related events for each single-nucleotide polymorphism was 0.5% for CC, 3.8% for CG, and 5.8% for GG. Liver-related deaths were the most common (n = 28); only three deaths were due to cardiovascular disease. Multivariate analysis identified carriage of PNPLA3 CG/GG (hazard ratio [HR] 16.04, p = .006) and FIB-4 index >2.67 (HR 10.70, p < .01) as predictors of liver-related event development. No HCC or liver-related death was found among patients with PNPLA3 CC. There was a significantly increased risk of HCC, liver-related events, and mortality for CG/GG versus CC, but no difference between the CG and GG genotypes. CONCLUSIONS: In Japanese individuals, the main cause of death from NAFLD is liver-related death. The greater risk of liver-related events incurred by PNPLA3 G allele was shown in Japan. Risk stratification for NAFLD in Japan is best accomplished by integrating PNPLA3 with the FIB-4 index.

Artificial intelligence/neural network system that accurately diagnoses hepatocellular carcinoma in nonalcoholic steatohepatitis.

BACKGROUND AND AIM: The aim of this study was to develop a novel noninvasive test using an artificial intelligence/neural network system (called HCC-Scope) to diagnose early-stage hepatocellular carcinoma (HCC) on the background of nonalcoholic steatohepatitis (NASH). METHODS: In total, 175 patients with histologically proven nonalcoholic fatty liver disease and 55 patients with NASH-HCC were enrolled for training and validation studies. Of the 55 patients with NASH-HCC, 27 (49.1%) had very early-stage HCC, and six (10.9%) had early-stage HCC based on the Barcelona Clinic Liver Cancer staging system. Diagnosis with HCC-Scope was performed based on 12 items: age, sex, height, weight, AST level, ALT level, gamma-glutamyl transferase level, cholesterol level, triglyceride level, platelet count, diabetes status, and IgM-free apoptosis inhibitor of macrophage level. The FMVWG2U47 hardware (Fujitsu Co. Ltd, Tokyo, Japan) and the originally developed software were used. RESULTS: HCC-Scope had sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 100% for the differential diagnosis between non-HCC and HCC in a training study with gray zone analysis. It was also excellent in the validation study (95.0% sensitivity, 100% specificity, 100% PPV, and 97.1% NPV with gray zone analysis and 95.2% sensitivity, 100% specificity, 100% PPV, and 97.1% NPV without gray zone analysis). HCC-Scope had a significantly higher sensitivity (85.3%) and specificity (85.1%) than alpha-fetoprotein (AFP) level, AFP-L3 level, des-gamma-carboxy prothrombin (DCP) level, and the gender-age-AFP-L3-AFP-DCP (GALAD) score. CONCLUSIONS: HCC-Scope can accurately differentially diagnose between non-HCC NASH and NASH-HCC, including very early-stage NASH-HCC.

Serum levels of immunoglobulin M-free inhibitors of macrophage/CD5L as a predictive and early diagnostic marker for nonalcoholic steatohepatitis-associated hepatocellular carcinoma.

BACKGROUND: The apoptosis inhibitor of macrophage (AIM) is usually associated with the immunoglobulin M (IgM) pentamer in the blood and is dissociated from IgM in various diseases, including hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH). We aimed to elucidate whether IgM-free AIM (fAIM) is useful for detecting latent HCC in NASH. METHODS: This research consisted of two cohort studies. The levels of serum fAIM, alpha-fetoprotein (AFP), and des-gamma carboxy prothrombin (DCP) of 18 NASH patients who developed HCC were measured during the follow-up period before HCC diagnosis (median, 4.7 years). In total, 199 patients with nonalcoholic fatty liver disease (NAFLD) were included in the HCC survey. The serum fAIM levels were analyzed using enzyme-linked immunosorbent assays. RESULTS: In the cohort of 18 patients with HCC, 12 had high fAIM at the time of the initial blood sample, three had normal fAIM levels throughout the follow-up period, and three had fAIM elevated from normal to positive. The positive ratio of fAIM prior to HCC diagnosis remained significantly higher than that of AFP and DCP, and the fAIM ratio gradually increased. In a survey of 199 non-HCC NAFLD patients, a Cox regression analysis using independent variables, such as AFP, fAIM, age, albumin, bilirubin, and fibrosis stage, revealed that fAIM and AFP were significantly associated with the incidence of HCC. CONCLUSIONS: During the development of NASH-HCC, AIM activation in blood appears to start even before HCC is diagnostically detectable. Thus, the serum IgM-free AIM levels could be a new, sensitive biomarker for latent NASH-HCC.

Comparison of thrombocytopenia between patients with non-alcoholic fatty liver disease and those with hepatitis C virus-related chronic liver disease.

AIM: Thrombocytopenia is widely recognized as a simple surrogate marker of liver fibrosis in non-alcoholic fatty liver disease (NAFLD). Thrombocytopenia of NAFLD has not been compared with that of hepatitis C virus-related chronic liver disease (CLD-C). Here, we examined whether there is any difference in the platelet counts between patients with NAFLD and CLD-C and investigated the underlying mechanisms. METHODS: A total of 760 biopsy-confirmed NAFLD and 1171 CLD-C patients were enrolled. After stratification according to the liver fibrosis stage, platelet counts between NAFLD and CLD-C patients were compared. The platelet count, spleen size, serum albumin level, serum thrombopoietin level, and immature platelet fraction (IPF) value were also compared after covariate adjustment using propensity score (PS) matching. RESULTS: The median platelet counts (×104 /µL) of NAFLD and CLD-C patients were 20.2 and 18.7 (p = 2.4 × 10-5 ) in F1; 20.0 and 14.5 (p = 2.1 × 10-12 ) in F2; 16.9 and 12.3 (p = 8.1 × 10-10 ) in F3; and 11.1 and 8.1 (p = 0.02) in F4, respectively. In the F3 group, NAFLD patients had a significantly higher platelet count and significantly smaller spleen volume than CLD-C patients. Although the serum thrombopoietin levels were comparable between NAFLD and CLD-C patients, the IPF value of NAFLD patients was significantly higher than that of CLD-C patients. CONCLUSIONS: NAFLD patients had a significantly higher platelet count than CLD-C patients following stratification according to the liver fibrosis stage. The milder hypersplenism and higher platelet production in NAFLD than CLD-C may have contributed to this difference.

Novel artificial intelligent/neural network system for staging of nonalcoholic steatohepatitis.

AIM: To develop a novel noninvasive test using an artificial intelligence (AI)/neural network (NN) system (named Fibro-Scope) to determine the fibrosis stage in nonalcoholic steatohepatitis (NASH). METHODS: Three hundred twenty-four and 110 patients with histologically diagnosed nonalcoholic fatty liver disease (NAFLD) were enrolled for training and validation studies, respectively. Two independent pathologists histologically diagnosed patients with NAFLD for the validation study. Fibro-Scope was undertaken using 12 items: age, sex, height, weight, waist circumference, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, cholesterol, triglyceride, platelet count, and type 4 collagen 7s. RESULTS: Differentiation of F0 versus F1-4 using the Fibro-Scope revealed 99.5% sensitivity, 90.9% specificity, 97.4% positive predictive value, and 98.0% negative predictive value in a training study with gray zone analysis, which was also effective in the analysis without gray zone. Discrimination was also excellent when comparing F0-1 versus F2-4 and F0-2 versus F3-4. In a validation study with gray zone analysis, differentiation of F0 from F1-4 using Fibro-Scope was also excellent. The discrimination of F0-1 from F2-4 using Fibro-Scope with gray zone analysis showed over 80% sensitivity and specificity in the histological diagnosis of both pathologists, but was lower without the gray zone analysis. The discrimination of F0-2 from F3-4 was effective in the analysis with gray zone; however, their sensitivity and specificity were slightly inferior in the analysis without gray zone. CONCLUSIONS: Artificial intelligence/neural network algorithms termed Fibro-Scope are easy to use and can accurately differentially diagnose minimal, moderate, and advanced fibrosis. Fibro-Scope will promote rapid NASH diagnosis and facilitate diagnosing the fibrosis stage in NASH.

Artificial intelligence/neural network system for the screening of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

AIM: We aimed to develop a novel noninvasive test using an artificial intelligence (AI)/neural network (NN) system (named nonalcoholic steatohepatitis [NASH]-Scope) to screen nonalcoholic fatty liver disease (NAFLD) and NASH. METHODS: We enrolled 324 and 74 patients histologically diagnosed with NAFLD for training and validation studies, respectively. Two independent pathologists histologically diagnosed patients with NAFLD for validation study. Additionally, 48 subjects who underwent a medical health checkup and did not show fatty liver ultrasonographically and had normal serum aminotransferase levels were categorized as the non-NAFLD group. NASH-Scope was based on 11 clinical values: age, sex, height, weight, waist circumference, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, cholesterol, triglyceride, and platelet count. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operator characteristic curve of NASH-Scope for distinguishing NAFLD from non-NAFLD in the training study and validation study were 99.7% versus 97.2%, 97.8% versus 97.8%, 99.7% versus 98.6%, 97.8% versus 95.7%, and 0.999 versus 0.950, respectively. Those for distinguishing NASH with fibrosis from NAFLD without fibrosis were 99.5% versus 90.7%, 84.3% versus 93.3%, 94.2% versus 98.0%, 98.6% versus 73.7%, and 0.960 versus 0.950. These results were excellent, even when the output data were divided into two categories without any gray zone. CONCLUSIONS: The AI/NN system, termed as NASH-Scope, is practical and can accurately differentially diagnose between NAFLD and non-NAFLD and between NAFLD without fibrosis and NASH with fibrosis. Thus, NASH-Scope is useful for screening nonalcoholic fatty liver and NASH.

A novel rapid immunoassay of serum type IV collagen 7S for the diagnosis of fibrosis stage of nonalcoholic fatty liver diseases.

AIM: Type IV collagen 7S (T4C7S) is a valuable biomarker for detecting liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). The conventional T4C7S measurement via radioimmunoassay (T4C7S RIA) has shortcomings of radioisotope usage and longer assay periods. We compared T4C7S RIA with a newly developed, fast T4C7S chemiluminescent enzyme immunoassay (T4C7S CLEIA) and examined the diagnostic accuracies of and correlation between the two techniques. METHODS: We evaluated 170 biopsy-confirmed patients with NAFLD. T4C7S was measured via both T4C7S RIA and T4C7S CLEIA. The correlation between T4C7S RIA and T4C7S CLEIA was analyzed in 305 total serum samples via exploratory research and 47 validation samples. The diagnostic accuracies of T4C7S CLEIA and T4C7S RIA were compared in the sera of patients with NAFLD and test samples. RESULTS: Sera T4C7S levels of T4C7S CLEIA and T4C7S RIA significantly correlated in patients' samples via exploratory (r = 0.914, P = 0.000) and validation (r = 0.929, P = 0.000) research. At a 10% coefficient, T4C7S CLEIA concentration was 0.26 ng/ml in the serum samples, indicating high accuracy at even low concentrations. T4C7S CLEIA revealed distinct changes between each stage and high sensitivity in detecting the F2 stage, indicating a higher sensitivity in detecting low fibrosis stages than T4C7S RIA in patients with NAFLD. CONCLUSIONS: The T4C7S CLEIA correlated well with the T4C7S RIA. Favorably, the T4C7S CLEIA has a higher sensitivity and rapid measurement time and requires a small sample volume; thus, it is a promising and popular biomarker for fibrosis stage diagnosis in NAFLD.

Epidemiology: Pathogenesis, and Diagnostic Strategy of Diabetic Liver Disease in Japan.

Type 2 diabetes (T2D) is closely associated with nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to cirrhosis, hepatocellular carcinoma (HCC), and hepatic decompensation. Patients with T2D have twice the risk of HCC incidence compared with those without T2D. Because the hepatic fibrosis grade is the main determinant of mortality in patients with NAFLD, identifying patients with advanced fibrosis using non-invasive tests (NITs) or imaging modalities is crucial. Globally, the fibrosis-4 index (FIB-4 index), NAFLD fibrosis score, and enhanced liver fibrosis test have been established to evaluate hepatic fibrosis. Two-step algorithms using FIB-4 index as first triaging tool are globally accepted. It remains unknown which kinds of NITs or elastography are best as the second step tool. In Japan, type IV collagen 7s or the CA-fibrosis index (comprising type IV collagen 7s and aspartate aminotransferase (AST)) is believed to precisely predict advanced fibrosis in NAFLD. Patients with NAFLD who have high non-invasive test results should be screened for HCC or esophageal varices. Risk factors of rapid fibrosis progression in NAFLD includes age, severe obesity, presence of T2D, menopause in women, and a patatin-like phospholipase domain containing the 3 GG genotype. Patients with NAFLD who have these risk factors should be intensively treated with lifestyle modification or pharmacotherapies for preventing liver-related mortality.

[The impact of direct-acting antiviral therapy on the diagnosis of hepatitis-C virus-associated hepatocellular carcinoma].

Since the introduction of direct-acting antiviral (DAA)-based combination therapies in September 2014 for patients with chronic hepatitis-C (CH-C), numerous patients have been diagnosed with hepatitis-C virus (HCV)-associated hepatocellular carcinomas (HCCs) during the screening performed prior to DAA therapy. The present study was conducted on the antiviral therapy for CH-C in two phases:i) the interferon (IFN) phase between January 2011 and August 2014 and ii) the DAA phase between September 2014 and September 2016. During the DAA phase, HCCs were detected in eight patients who were referred to our hospital for anti-HCV therapy. In contrast, HCCs were detected in only two patients during the IFN phase. The number of patients with newly detected HCC in the DAA phase (20.5%) who were referred for the anti-HCV therapy was significantly higher than that in the IFN phase (1.7%). Owing to the high efficacy and safety of the DAA therapy, the number of patients referred to our hospital for anti-HCV therapy increased from 40.5 persons/year in the IFN phase to 80.3 persons/year in the DAA phase. The average ages of patients in the DAA and IFN phases were 68 and 61 years, respectively. The increase in the number of patients with newly detected HCC referred for the anti-HCV therapy in the DAA phase could be attributed to the increase in the number of referred patients for anti-HCV therapy and the aging of these patients in the DAA phase. All the eight patients with newly detected HCC who were referred for anti-HCV therapy in the DAA phase received curative treatments. The median age, rate of liver cirrhosis, and median tumor size of the patients were 69 years, 13%, and 16mm. Therefore, the findings of this study indicate that DAA therapies not only eradicate HCV infection but also contribute to the early diagnosis of HCC by encouraging the HCV-infected patients to visit hospitals and by promoting active network between hepatologists and family physicians.

Assessment of transient elastography in Japanese patients with non-alcoholic fatty liver disease.

AIM: Transient elastography (TE) is a non-invasive method for predicting liver fibrosis. However, there are limited data regarding the performance of TE in Japanese patients with non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate the association between liver stiffness measurement (LSM) by TE and liver fibrosis stage, and define a cut-off value for predicting liver fibrosis. METHODS: A total of 171 Japanese patients with biopsy-proven NAFLD underwent LSM using TE with FibroScan. The area under the receiver operating characteristic curve of LSM and other non-invasive markers of liver fibrosis were compared to determine the most accurate method of predicting liver fibrosis. RESULTS: Liver stiffness measurement significantly correlated with fibrosis stage (P < 0.001). The areas under the receiver operating characteristic curve of LSM for fibrosis stage ≥1 and ≥3 was 0.85 and 0.91, respectively and were higher than those of the aspartate aminotransferase/alanine aminotransferase ratio, aspartate aminotransferase to platelet ratio index, fibrosis-4 index, and NAFLD fibrosis score. The best cut-off values of LSM fibrosis stage ≥1 and ≥3 were 7.2 kPa (sensitivity 78.5%, specificity 78.3%) and 10.0 kPa (sensitivity 89.5%, specificity 87.6%), respectively. The combination of LSM (≥10 kPa) and type IV collagen 7 s (≥6.0 ng/mL) had a specificity of 97.6% for advanced fibrosis. The LSM in patients with high alanine aminotransferase levels or high body mass index was associated with false positive results regarding advanced fibrosis. CONCLUSIONS: In NAFLD patients, TE has excellent utility for the assessment of liver fibrosis, particularly for advanced stage cases. The cut-off value of LSM by TE for predicting liver fibrosis stage ≥3 is 10.0 kPa in Japanese NAFLD patients.

Classification of patients with non-alcoholic fatty liver disease using rapid immunoassay of serum type IV collagen compared with liver histology and other fibrosis markers.

AIM: Non-alcoholic fatty liver disease (NAFLD) can progress to non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). We investigated the association among serum type IV collagen level, liver histology, and other fibrosis markers in NAFLD progression. METHODS: We evaluated 184 patients diagnosed with NAFLD following biopsy, including 89 males and 95 females with an average age of 52.6 and 62.6 years, respectively. Non-alcoholic fatty liver disease was classified as NAFL or NASH using Matteoni's classification, and the grade and stage of NASH were assessed using Brunt's classification. Serum type IV collagen was measured by a rapid and sensitive latex particle-enhanced turbidimetric immunoassay. RESULTS: Forty-two patients with NAFL and 142 patients with NASH were included in this study. Compared with patients with NAFL, patients with NASH showed more significant liver function disorder and increased expression of fibrosis markers including type IV collagen, collagen 7S, Mac2-binding protein (M2BP), and hyaluronic acid (HA). Expression of type IV collagen and collagen 7S, but not M2BP and HA, was more significantly elevated in patients with stage 1 NASH than in patients with NAFL, indicating that type IV collagen and collagen 7S may be better discriminators of NASH and NAFL than M2BP and HA at an early stage of fibrosis. When patients were stratified by NAFLD activity score, type IV collagen and collagen 7S were significantly elevated as NAFLD activity score progressed, whereas M2BP and HA expression were not significantly elevated. CONCLUSION: Type IV collagen may be a useful measure of NASH severity as latex particle-enhanced turbidimetric immunoassay-based rapid type IV collagen assay can be carried out routinely.

Genetic influence of dopamine receptor, dopamine transporter, and nicotine metabolism on smoking cessation and nicotine dependence in a Japanese population.

BACKGROUND: This study investigated whether polymorphisms of the ankyrin repeat and kinase domain containing 1 gene (ANKK1), which is adjacent to the dopamine D2 receptor gene (DRD2), and the dopamine transporter (SLC6A3) and cytochrome P450 2A6 (CYP2A6) genes influence smoking cessation and nicotine dependence in a Japanese population. In 96 current and former smokers, genotyping frequencies for the ANKK1/DRD2 TaqIA, SLC6A3 VNTR, and CYP2A6 polymorphisms were subjected to chi-square analysis, and regression analyses were used to determine the association of the genotypes of current smokers with a Heavy Smoking Index, in addition to evaluating the effect of the subjects' smoking history on the association. RESULTS: Genotyping results suggested that nicotine dependence among current smokers homozygous for the SLC6A3 10r allele was lower than that of smokers carrying the minor alleles, and that the CYP2A6 polymorphism might mediate this association. Furthermore, the age at which current smokers began smoking might moderate the association between their genetic polymorphisms and nicotine dependence. CONCLUSIONS: This study provides preliminary findings on the influence of genetic variants on the smoking phenotypes in a Japanese population.

Efficacy and safety of sorafenib in very elderly patients aged 80 years and older with advanced hepatocellular carcinoma.

AIM: Sorafenib is the standard systemic therapy for patients with advanced hepatocellular carcinoma (HCC). We aimed to assess the efficacy and safety of sorafenib therapy in very elderly patients aged 80 years and older with advanced HCC. METHODS: In a retrospective multicenter study in Japan, we reviewed 185 patients (median age, 71 years; 82% male; 95% Child-Pugh class A) with advanced HCC who received sorafenib therapy. Data were compared between 24 (13%) patients aged 80 years and older and 161 (87%) patients aged less than 80 years. We used propensity score matching to adjust for differences between the two groups. RESULTS: Median overall survival was 10.6 months in all patients: 11.7 months in patients aged 80 years and older and 10.5 months in those aged less than 80 years. There were no significant differences in overall survival, tumor response, and frequency and severity of drug-related adverse events between patients aged 80 years and older and those aged less than 80 years in both the entire study cohort and the propensity-matched cohort. CONCLUSION: Sorafenib may be effective and well tolerated, even in patients with advanced HCC who are aged 80 years and older, as well as those aged less than 80 years.

Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats.

BACKGROUND/AIMS: Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibit endogenous cholesterol synthesis, possess pleiotropic activities, such as anti-inflammatory, anti-oxidative and antifibrotic effects. Here, we investigated whether statins ameliorate steatohepatitis using a high-fat and high-cholesterol (HFHC) diet-induced rat model. METHODS: Eight-week-old male Sprague-Dawley rats were fed control chow or HFHC diet. Half of the HFHC diet-fed rats were orally administered 2 mg/kg/day rosuvastatin for 12 weeks. Hepatic injury, steatosis, fibrosis and markers of lipid peroxidation/oxidant stress were evaluated. RESULTS: As previously reported, HFHC diet induced steatohepatitis in rat livers with hypercholesterolaemia. Rosuvastatin decreased Oil Red O stained-positive areas, liver/body weight ratio, serum total cholesterol levels and hepatic free fatty acid contents in HFHC diet-fed rats. Further study revealed that rosuvastatin significantly decreased hepatic mRNA expression of tumour necrosis factor-α and interleukin-6, serum alanine aminotransferase levels and hepatic lobular inflammation grade. Hepatic fibrosis was also ameliorated by rosuvastatin with decreases in hepatic mRNA expression of transforming growth factor-ß, connective tissue growth factor and type-1 procollagen. Similarly, hepatic Sirius red stained or α-smooth muscle actin stained-positive areas and expression of markers of lipid peroxidation/oxidant stress [hepatic 8-hydroxy-oxyguanosine and hepatic 4-hydroxy-2-nonenal] were decreased. Interestingly, whereas the expression of carnitine palmitoyltransferase-1 and long-chain acyl-CoA dehydrogenase was not affected, that of catalase and acyl-coA oxidase was restored. CONCLUSIONS: These data suggest that rosuvastatin improved not only hepatic steatosis but also hepatic injury and fibrosis via improved peroxisomal ß-oxidation in this rat HFHC model.

Effects of moderating factors including serotonin transporter polymorphisms on smoking behavior: a systematic review and meta-analysis update.

INTRODUCTION: The aim of this review was to report an update of a previous meta-analysis (by another group) of a possible relationship between serotonin transporter (5-HTTLPR) genotype and smoking behavior, and extend previous work by factoring in some demographic parameters (age, gender, and ethnicity) in a multiple regression model to examine the relationship between these demographic factors and the effect of 5-HTTLPR polymorphism on smoking behavior. METHODS: Effect sizes were calculated for each study selected for meta-analysis and were pooled using the random-effects model, which assumes within-study sampling and between-study variance and provides wider confidence intervals. Effect sizes calculated in each study were used to evaluate the correlations with participant data for age, gender, and ethnicity (moderating variable) by multiple regression analysis. RESULTS: Meta-analysis indicated a relationship between smoking rate and the 5-HTTLPR genotype, but not smoking initiation and persistence, which was consistent with that of the previous review. Publication bias was not indicated for smoking initiation or persistence. Multiple regression analysis revealed that mean participant age significantly affected effect sizes for smoking initiation and persistence of each study. The proportion of Caucasians may have been partially influenced by the difference in effect sizes for smoking persistence among the studies. CONCLUSION: A significant relationship stratified by ancestry was observed between the 5-HTTLPR genotype and smoking rate, but not between the 5-HTTLPR genotype and smoking initiation and persistence. Regression analysis detected effects of age and/or ethnicity as moderating factors on smoking initiation and persistence.

Association between dopamine receptor 2 TaqIA polymorphisms and smoking behavior with an influence of ethnicity: a systematic review and meta-analysis update.

INTRODUCTION: The relationship between dopamine receptor D2 (DRD2) gene TaqIA polymorphisms and smoking behavior remains controversial. The aim of this review was to update a previous meta-analysis on the effect of DRD2 polymorphisms on smoking behavior by considering the influence of ethnicity. METHODS: This review presents analyses stratified by ancestry, as the samples included individuals of different ethnicities. Pooled effect sizes were calculated using fixed- and random-effects models to verify heterogeneity. We investigated the association for the proportion of men and Caucasians by regression analysis using the effect sizes calculated by each meta-analysis. RESULTS: Analysis of smoking cessation revealed a significant effect, which suggested that ethnic differences between Caucasians and Asians moderate the effect of DRD2 polymorphisms. Smoking initiation and rate exhibited no relationship with DRD2 polymorphisms; furthermore, we detected heterogeneity. Although the analysis of smoking persistence indicated significant effects, heterogeneity was detected. The finding of heterogeneity for smoking persistence and rate suggests the possibility of gene-gene interactions arising from ethnic differences between the samples. We found a significant inverse relationship between the proportion of men and effect sizes among Caucasians for smoking persistence and rate. Gender differences between Caucasian samples may moderate the effect of DRD2 polymorphisms on smoking persistence and rate. CONCLUSIONS: Our findings indicate that the ethnicity of the participants alters the effect of DRD2 polymorphisms on smoking behavior. The observed heterogeneity may be associated with participant gender as a moderating factor, and the association may be specific to Caucasians.

Fibro-Scope V1.0.1: an artificial intelligence/neural network system for staging of nonalcoholic steatohepatitis.

BACKGROUND: Fibro-Scope is an artificial intelligence/neural network system to determine the fibrosis stage in nonalcoholic steatohepatitis (NASH) using 12 parameters of the patient: age, sex, height, weight, waist circumference (WC), platelet count, and the levels of aspartate and alanine aminotransferase, gamma-glutamyltransferase, cholesterol, triglycerides, and type IV collagen 7S. However, measurement of WC is unstable and often missing from patient databases. Herein, we created Fibro-Scope V1.0.1 that has the same detection power as its predecessor, without the need to consider WC. METHODS: To build a new AI diagnostic system available for the global needs, data from 764 patients with NASH and bridging fibrosis (STELLAR-3) or compensated cirrhosis (STELLAR-4) that participated in two phase III trials were added to the Japanese data. Finally, the data of a total of 898 patients in the training and of 300 patients in the validation studies were analyzed, respectively. RESULTS: The discrimination of F0-2 from F3,4 through Fibro-Scope V1.0.1 was characterized by a 99.8% sensitivity, a 99.6% specificity, a 99.8% positive predictive value, and a 99.6% negative predictive value in a training study with gray zone analysis; similar effectiveness was also revealed in the analysis without a gray zone. In the validation studies with and without gray zone analysis, high sensitivity and specificity were also identified. Fibro-Scope V1.0.1 exerted a diagnostic accuracy for F3,4 advanced fibrosis that was comparable to that of the original Fibro-Scope and delivered high (> 92%) sensitivity and specificity. CONCLUSION: Fibro-Scope V1.0.1 can accurately diagnose F3,4 fibrosis without the need of WC.