Shiro Takami

Characteristics of Patients With Nonalcoholic Steatohepatitis Who Develop Hepatocellular Carcinoma

BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to characterize the clinical features of NASH patients with HCC. METHODS In a cross-sectional multicenter study in Japan, we examined 87 patients (median age, 72 years; 62% male) with histologically proven NASH who developed HCC. The clinical data were collected at the time HCC was diagnosed. RESULTS Obesity (body mass index ≥25 kg/m(2)), diabetes, dyslipidemia, and hypertension were present in 54 (62%), 51 (59%), 24 (28%), and 47 (55%) patients, respectively. In nontumor liver tissues, the degree of fibrosis was stage 1 in 10 patients (11%), stage 2 in 15 (17%), stage 3 in 18 (21%), and stage 4 (ie, liver cirrhosis) in 44 (51%). The prevalence of cirrhosis was significantly lower among male patients (21 of 54, 39%) compared with female patients (23 of 33, 70%) (P = .008). CONCLUSIONS Most patients with NASH who develop HCC are men; the patients have high rates of obesity, diabetes, and hypertension. Male patients appear to develop HCC at a less advanced stage of liver fibrosis than female patients.

Clinical and pathological progression of non-alcoholic steatohepatitis to hepatocellular carcinoma

Aim:  Non‐alcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to examine the clinical and pathological course of how NASH progresses to HCC.

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

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.

AUGMENTED ENDOGENOUS NITRIC OXIDE PRODUCTION IN PARTIAL PORTAL VEIN-LIGATED RATS

1. Endothelium‐derived nitric oxide (NO) is a potent vasodilator. Because the body oxidizes it to nitrate ions, NO3‐, measurement of the serum concentration and the urinary excretion of NO3‐ may be an index for endogenous NO. We investigated the role of NO on hyperdynamic circulation in cirrhotic and partial portal vein‐ligated rats by measuring NO3.

Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers

The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7,672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67–2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25–1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23–1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84–4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63–0.67)]. Conclusions: We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients.

Real-world efficacy of daclatasvir and asunaprevir with respect to resistance-associated substitutions

AIM To investigate daclatasvir (DCV) and asunaprevir (ASV) efficacy in hepatitis C (HCV) patients, with respect to resistance-associated substitutions (RASs). METHODS A total of 392 HCV-infected patients from multiple centers were included in this study. We evaluated their clinical courses and sustained virologic responses (SVR) according to pretreatment factors (gender, age, history of interferon-based regimens, platelet counts, level of viremia, pretreatment NA5A:L31, and Y93 substitutions). We also analyzed the pretreatment and post-treatment major RASs of NS3:D168, NS5A:L31 and Y93 substitutions using a direct-sequencing method in 17 patients who were unable to achieve SVR at 12 wk after treatment completion (SVR12). RESULTS The overall SVR12 rate was 88.3%. Thirty-one patients discontinued treatment before 24 wk because of adverse events, 23 of whom achieved SVR12. There were no significant differences in SVR12 rates with respect to gender, age, history of interferon-based regimens, and platelet counts. The SVR12 rate in patients with viral loads of ≥ 6.0 log IU/mL was significantly lower than those with viral loads of < 6.0 log IU/mL (P < 0.001). The SVR12 rate in patients with Y93 substitution-positive was significantly lower than those with Y93 substitution-negative (P < 0.001). The L31 substitution-positive group showed a lower SVR12 rate than the L31 substitution-negative group, but the difference was not statistically significant. Seventeen patients who did not achieve SVR12 and had available pretreatment and post-treatment sera had additional RASs in NS3:D168, NS5:L31, and Y93 substitution at treatment failure. CONCLUSION Combination of DCV and ASV is associated with a high SVR rate. Baseline RASs should be thoroughly assessed to avoid additional RASs after treatment failure.

Comparison of peg-interferon, ribavirin plus telaprevir vs simeprevir by propensity score matching.

AIM To compare efficacy of telaprevir (TVR) and simeprevir (SMV) combined with pegylated interferon (PEG-IFN) and ribavirin (RBV) while treating chronic hepatitis C (CHC). METHODS In all, 306 CHC patients were included in this study. There were 159 patients in the TVR combination therapy group and 147 patients in the SMV combination therapy group. To evaluate pretreatment factors contributing to sustained virological response at 12 wk (SVR12), univariate and multivariate analyses were performed in TVR and SMV groups. To adjust for patient background between TVR and SMV groups, propensity score matching was performed. Virological response during treatment and SVR12 were evaluated. RESULTS Overall rates of SVR12 [undetectable serum hepatitis C virus (HCV) RNA levels] were 79.2% and 69.4% in TVR and SMV groups, respectively. Patients in the SMV group were older, had higher serum HCV RNA levels, lower hemoglobin, higher prevalence of unfavorable interleukin-28B (IL28B) genotype (rs8099917), and poorer response to previous PEG-IFN and RBV treatment. Propensity score matching was performed to adjust for backgrounds (n = 104) and demonstrated SVR12 rates of 74.0% and 73.1% in the TVR and SMV groups, respectively. In the TVR group, discontinuation rates were higher because of adverse events; however, breakthrough and nonresponse was more frequent in the in SMV group. Multivariate analysis revealed IL28B genotype (rs8099917) as the only independent predictive factor of SVR12 in both groups. CONCLUSION SVR12 rates were almost identical following propensity score matching.