Suppression of Local Tumor Progression in Perivascular Hepatocellular Carcinoma by Combination Therapy with Radiofrequency Ablation and Percutaneous Ethanol Injection: A Propensity Score Matching Analysis.

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) has replaced percutaneous ethanol injection (PEI) as the treatment of choice for hepatocellular carcinoma (HCC); however, control of local tumor progression (LTP) remains a challenge in perivascular HCC. The aim of this study was to determine whether PEI added to RFA can reduce the LTP rate in perivascular HCC patients. METHODS: We retrospectively analyzed 167 patients, with 197 newly diagnosed HCC nodules with peritumoral vessels, who underwent either RFA plus PEI or RFA monotherapy as the first-line treatment between June 2001 and April 2015. Ethanol was injected inside the tumor close to the peritumoral vessels in the combination therapy group. Patients were matched 1:1 according to their propensity scores to reduce selection bias; cumulative LTP was then analyzed using log-rank tests and Cox proportional hazard regression analyses. RESULTS: The two matched groups comprised 62 tumors each. The overall median follow-up period was 34 months (range, 1-140 months). In the RFA plus PEI group, the cumulative LTP rates were 5.7%, 15.5%, and 20.4% at 1, 3, and 5 years, respectively; in the RFA monotherapy group, the rates were 13.2%, 32.0%, and 40.2%, respectively. The rates were significantly lower in the RFA plus PEI group (p = 0.032). Cox proportional hazard regression analysis showed that PEI combination treatment was significantly associated with a reduced risk of local HCC recurrence (hazard ratio, 0.44; 95% confidence interval, 0.19-0.93; p = 0.031). DISCUSSION/CONCLUSION: The risk of LTP after RFA for perivascular HCC can be significantly reduced by injecting ethanol close to the peritumoral vessels.

Frequency of null genotypes of glutathione S-transferase M1 and T1 in Japanese patients with drug-induced liver injury.

AIM: Previous reports suggest that the null genotype (*0/*0) of glutathione S-transferase (GST) M1 and/or GSTT1 could be risk factors for drug-induced liver injury (DILI). However, multi-institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients. METHODS: Blood samples of 270 DILI patients from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp-2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week-Japan score, as well as genotypes of GSTM1 and GSTT1 in each patient with DILI. RESULTS: The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of the GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and Digestive Disease Week-Japan scores was not observed. CONCLUSIONS: The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients.

Multiple focal fatty changes in the liver in patients with porphyria cutanea tarda: A case series and review of the literature.

Porphyria cutanea tarda (PCT) is commonly diagnosed in cases where multiple hyperechoic nodules are observed in the liver. Pathologically, these nodules associated with PCT are focal fatty deposits. We report here, seven cases of PCT with fatty changes over multiple foci in the liver. Furthermore, the characteristics of ultrasonography (US) findings of 32 previously reported cases are summarized. The US features of these nodules showed a homogenous hyperechoic or hyperechoic rim pattern, partial confluence, and no mass effect in the vascular structures. Because multiple hyperechoic liver nodules occasionally mimic malignancies, and because their diagnosis can be challenging, clinicians should consider checking urine porphyrin levels to rule out PCT when such nodules are observed on US.

Long-Term Effects of Rifaximin on Patients with Hepatic Encephalopathy: Its Possible Effects on the Improvement in the Blood Ammonia Concentration Levels, Hepatic Spare Ability and Refractory Ascites.

Background and Objectives: To investigate the long-term efficacy of rifaximin (RFX) for hyperammonemia and efficacy for refractory ascites in patients with cirrhosis. Materials and Methods: We enrolled 112 patients with liver cirrhosis who were orally administered RFX in this study. Changes in the clinical data of patients were evaluated up to 36 months after RFX administration. The primary endpoint was a change in blood ammonia levels. Secondary endpoints included changes in clinical symptoms, Child−Pugh (CP) score, number of hospitalizations, degree of refractory ascites, adverse events, and the relationship between RFX administration and the renin-angiotensin-aldosterone system. Results: An improved rate of overt hepatic encephalopathy (HE) of 82.7% was observed 3 months after RFX administration, which significantly induced a progressive decrease in blood ammonia concentration and an improved CP score up to 36 months. No serious RFX treatment-related adverse events were observed. 36.5% in patients after RFX administration improved refractory ascites. After RFX administration, patients with satisfactory control of hepatic ascites without addition of diuretic had lower renin concentration than those with poor control (p < 0.01). At less than 41 pg/mL renin concentration, the control of refractory ascites was significantly satisfactory (p < 0.0001). Conclusions: RFX reduced blood ammonia concentration and improved hepatic spare ability and the quality of life of patients with long-term HE to up to 36 months. Our study revealed the effects of RFX against refractory ascites, suggesting that renin concentration may be a predictive marker for assessing ascites control.

Irsogladine maleate alters expression of a tight junction protein in portal hypertensive gastropathy.

BACKGROUND AND AIM: Portal hypertensive gastropathy (PHG) is characterized by noninflammatory edema and vasodilatation of the lamina propria of the mucosal epithelium. In addition, the alterations of intercellular junction proteins and dilatation of the endothelial gaps have been reported. In this study, we examined whether irsogladine maleate (IM), a gastric mucosal protective agent, has the potential to improve PHG by restoration of tight junctions (TJs). METHODS: Twenty-four patients with PHG were registered and randomly assigned into two groups: 12 patients in the IM-administration group and 12 patients in the non-administration group. In the administration group, IM (4 mg/day) was administered orally for 12 weeks. Gastric mucosa with a red color in patients with PHG were obtained endoscopically on the registration day and 12 weeks later. The endoscopic findings were evaluated, an immunohistochemical analysis of claudin-3 (a TJ protein) expression in gastric mucosal tissues by a laser microscope was performed, and claudin-3 expression was quantified by western blot analysis. RESULTS: Irsogladine maleate improved the degree of PHG in 2/12 patients endoscopically, in contrast to none of the 12 patients in the non-administration group. Immunohistochemical analysis showed that expression of claudin-3 increased in 8/12 patients in the IM-administration group and 2/12 patients in the non-administration group (P = 0.036). Western blot analysis revealed that the increase in claudin-3 after 12 weeks was significantly higher in the IM-administration group than in the non-administration group (P = 0.010). CONCLUSIONS: The present pilot study suggested that IM might improve the gastric mucosa in PHG through restoration of TJ-protein claudin-3.

Reduction in Tumor Stain at 2 Weeks after Treatment Initiation Is a Predictor of the Efficacy of Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Lenvatinib is an oral anticancer drug for patients with unresectable advanced hepatocellular carcinoma (HCC). We evaluated whether a reduction in tumor stain at 2 weeks after lenvatinib treatment in patients with unresectable HCC is a predictor of early treatment efficacy at 12 weeks. PATIENTS AND METHODS: Of the 23 patients who initiated lenvatinib treatment between April 2018 and January 2019, treatment efficacy was measured in 15 patients for more than 12 weeks after treatment. Changes in tumor stain, tumor size on contrast-enhanced computed tomography (CT), and serum levels of tumor markers were evaluated 2 weeks after lenvatinib treatment. Therapeutic efficacy was assessed by tumor stain and tumor size by contrast-enhanced CT within the first 12 weeks, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines. RESULTS: At 12 weeks, efficacy evaluation of 15 patients revealed that 11 of them experienced partial responses, for a response rate of 73.3%. In the first 2 weeks, 13 patients (86.7%) experienced a decreased tumor stain, including 10 responders (90.9%) and 3 non-responders (75.0%). All patients in the non-responder group had required a lenvatinib dose reduction due to adverse events within 12 weeks. On contrast-enhanced CT, the change rate of tumor stain to HCC at 2 weeks after treatment was <0.8 among 10 responders (90.9%) and 1 non-responder (25.0%; p = 0.033). No significant differences between responders and non-responders were observed with regard to most characteristics at baseline and at 2 weeks after treatment initiation. However, significant differences were observed between groups in the presence or absence of a dose suspension period, the presence or absence of lenvatinib dose reduction from the maximum value during the first 2 weeks, and decreased tumor stain at 2 weeks after treatment initiation. CONCLUSION: Reduction in tumor stain at 2 weeks after lenvatinib treatment may be an early biomarker of efficacy at 12 weeks in patients with unresectable HCC.

The Efficacy and Therapeutic Outcome of Bipolar Radiofrequency Ablation for the Treatment for Hepatocellular Carcinoma in the Real-World Setting, Compared with Monopolar Radiofrequency Ablation Conducted during the Same Period.

BACKGROUND: Several reports have suggested that the bipolar radiofrequency ablation (RFA) system is useful for the treatment of hepatocellular carcinoma (HCC). We evaluated the efficacy and safety of the bipolar RFA system for HCC treatment in the real-world setting. METHODS: A total of 155 patients with 224 HCC tumors were enrolled. First, we examined the characteristics and outcomes of two RFA systems, monopolar and bipolar. Second, we identified the factors associated with local tumor progression in 72 patients with 104 HCC tumors, who could be followed up for at least 3 months after treatment and had been treated with the bipolar RFA system. RESULTS: Of the baseline characteristics, tumor size and location were associated with the selection of the bipolar RFA system. A sufficient ablative zone margin (≥5 mm) was obtained by bipolar RFA in 81 of 94 (86.1%). The 1- and 2-year local tumor progression rates were 15.6 and 26.3%, respectively. An alpha-fetoprotein-L3 (AFP-L3) ratio >10% (HR: 7.64; 95% CI: 1.7-39.8, p = 0.007) and an insufficient ablative zone margin (<5 mm) (HR: 4.53; 95% CI: 1.02-20.3, p = 0.047) were related to local tumor progression in Cox regression analysis. Although severe adverse events were not observed in most cases, severe hepatic infarction occurred in 1 patient. CONCLUSIONS: The bipolar RFA system is safe and effective for HCC treatment. Tumor localization within the liver is an important factor associated with bipolar RFA. Careful follow-up or reconsideration of treatment is necessary for cases with AFP-L3 ratio >10% or insufficient ablative zone margin (<5 mm), which were associated with local tumor progression.

Outcome of patients with acute liver failure awaiting liver transplantation in Japan.

AIM: To clarify the outcome and predictive factors in patients with acute liver failure (ALF) awaiting deceased donor liver transplantation (DDLT) in Japan. METHODS: Of the DDLT candidates in Japan between 2007 and 2016, 264 adult patients with ALF were retrospectively enrolled in this study. Factors associated with DDLT and waiting-list mortality were assessed using the Cox proportional hazard model. The DDLT and transplant-free survival probabilities were evaluated using Kaplan-Meier analysis and the log-rank test. RESULTS: The waiting-list registration year after the Transplant Law revision in 2010 was a significant factor associated with DDLT. The adjusted hazard ratio indicated that DDLT probability after 2010 was four times higher than that before, and the 28-day cumulative DDLT probability was more than 35%. The median survival time of the entire cohort was 40 days. Multivariate analysis identified the following three factors associated with waiting-list mortality: age, coma grade, and international normalized ratio. The transplant-free survival probabilities were significantly stratified by the number of risks, and patients with all three risks showed extremely poor short-term prognosis (median survival time = 23 days). CONCLUSIONS: The DDLT probability of ALF patients increased after the law revision in 2010; however, patients at high risk of short-term waiting-list mortality might need emergent living donor transplantation.

Topical Therapy with Antisense Tumor Necrosis Factor Alpha Using Novel ß-Glucan-Based Drug Delivery System Ameliorates Intestinal Inflammation.

Anti-tumor necrosis factor alpha (TNF-α) antibodies are effective in patients with inflammatory bowel disease (IBD). However, the effect is not optimal because a sufficient concentration of antibodies cannot be maintained at the site of inflammation. Thus, a macromolecular complex was developed with schizophyllan (SPG) and antisense oligonucleotides. In the present study, an SPG-antisense TNF-α complex was prepared, and its therapeutic efficacy was examined using a dextran sodium sulfate (DSS)-induced colitis model. The TNF-α production in CD11b+ macrophages significantly increased in the colon of DSS-treated mice. Dectin-1, a receptor of SPG, binds with SPG and is subsequently taken into the cells via phagocytosis. The expression of dectin-1 by CD11b+ macrophages significantly increased in DSS-treated mice. Flow cytometry revealed that the uptake of SPG-antisense TNF-α in the macrophages was efficient. TNF-α production was suppressed significantly by SPG-antisense TNF-α in vitro, which was administered via enema to evaluate its efficacy. The intrarectal administration of SPG-antisense TNF-α ameliorated the intestinal inflammation. In this study, we showed that the delivery system that conjugates SPG and antisense can have higher therapeutic efficacy. Thus, the new therapeutic approach presented in this study may be used in the management of IBD.

Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population.

A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10-9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

Safety and efficacy of cold polypectomy compared to endoscopic mucosal resection and hot biopsy polypectomy.

Backgrounds: Recently, several studies have demonstrated the usefulness of cold polypectomy (CP), a safe and simple method for the removal of small polyps. We investigated the safety and efficacy of CP compared to that of endoscopic mucosal resection (EMR) and hot biopsy polypectomy (HB). Methods: We retrospectively examined 1713 colorectal polyps (size 1-9 mm) in 731 patients. CP, EMR, and HB were performed on 476, 997, and 240 lesions, respectively. We compared the region, size, morphology, the presence of delayed bleeding as overt bleeding 24 h after operation, number of clips, pathology, the presence of antithrombotic therapy, procedure time from detection of a polyp to resection and hemostasis, device cost including device and clips, and polyp remnants. Results: The delayed bleeding in the CP group (0/476) was significantly lower compared to that in the HB group (3/240) and EMR group (7/997). There were no cases of perforations. The procedure time was significantly shorter in the CP group than in the EMR group (91.3sec vs 290.1sec, p < .0001). The CP group had a significantly lower device cost than the HB and EMR groups (49.2USD vs 58.0 USD vs 91.3 USD, p < .0001) was not inferior in terms of polyp remnants to the EMR and HB groups. (1.4% vs 0.6% vs 6.1%, p = .1599) Conclusions: CP is a safe treatment that achieves less delayed bleeding. Moreover, CP is not inferior to other groups in terms of polyp remnants and offers a cost benefit. CP can be considered useful for colonic polypectomy.

Liver transplantation in Japan: Registry by the Japanese Liver Transplantation Society.

As of 31 December 2017, a total of 9242 liver transplants have been carried out in 67 institutions in Japan. There were 447 deceased donor transplants (444 from heart-beating donors and 3 from non-heart-beating donors) and 8795 living-donor transplants. The annual total of liver transplants in 2017 was 416 (69 deceased donor transplants and 347 living-donor transplants). The most frequent indication was cholestatic disease, followed by neoplastic disease and hepatocellular disease. In terms of hepatocellular disease in 2017, cirrhosis due to hepatitis C and B decreased (13 and 8, respectively), whereas alcoholic cirrhosis markedly increased (32). Patient survival following transplantation from heart-beating donor (444 transplants: 1 year, 89.1%; 3 years, 85.2%; 5 years, 82.9%; 10 years, 75.4%; 15 years, 70.7%) was similar to that from living-donor (8794 transplants: 1 year, 85.0%; 3 years, 80.9%; 5 years, 78.5%; 10 years, 73.2%; 15 years, 68.5%; 20 years, 65.7%; 25 years, 64.6%). Graft survival was very much the same as patient survival (heart-beating donor: 1 year, 88.4%; 3 years, 84.5%; 5 years, 82.2%; 10 years, 74.7%; 15 years, 70.1%; living donor: 1 year, 84.3%; 3 years, 79.9%; 5 years, 77.3%; 10 years, 71.4%; 15 years, 66.3%; 20 years, 63.3%; 25 years, 61.9%). Survival data are reported according to age and sex of recipient, indication, age and sex of donor, ABO compatibility, and other factors.

Analysis of 307 cases with drug-induced liver injury between 2010 and 2018 in Japan.

AIM: In order to know the present status of drug-induced liver injury (DILI) in Japan, we present the data of prospectively collected DILI cases between 2010 and 2018 from 27 hospitals. METHODS: Drug-induced liver injury cases diagnosed by DILI experts from 27 hospitals all over Japan have been prospectively collected since 2010. Alanine aminotransferase level ≥150 U/L and/or alkaline phosphatase ≥2× upper limit of normal were inclusion criteria. RESULTS: In total, data of 307 cases (125 male and 182 female individuals) aged between 17 and 86 years old were collected. The types of liver injury were as follows: 64% hepatocellular type, 20% mixed type, and 16% cholestatic type. A drug-induced lymphocyte stimulation test was carried out in 59% of cases, and was positive in 48% and semipositive in 3% of cases. Eosinophilia ≥6% was observed in 27% of cases. Fifty-three percent of DILI cases occurred within 30 days and 79% of DILI cases occurred within 90 days after starting drug administration. By the diagnostic scale of the Digestive Disease Week (DDW)-Japan 2004 workshop, 93.8% of cases were diagnosed as "highly probable", and 5.9% as "possible". CONCLUSIONS: Japanese DILI patients are somewhat different from those of Europe and North America. The diagnostic scale of the DDW-Japan 2004 workshop has been used in Japan. However, there are many issues to improve the causality assessment of DILI that we must investigate in the future. It is critical to elucidate the mechanisms of drug metabolism and the pathophysiology of liver injury by various drugs to prevent DILI.

IL28B gene polymorphism is correlated with changes in low-density lipoprotein cholesterol levels after clearance of hepatitis C virus using direct-acting antiviral treatment.

BACKGROUND: Direct-acting antivirals (DAAs) rapidly clear hepatitis C virus (HCV), but the lipid dynamics after DAA treatment remain unknown. Low-density lipoprotein (LDL) cholesterolemia is the predicting factor for the onset and death of atherosclerotic cardiovascular diseases. Thus, in this study, we examined the frequency and risk of hyper-LDL cholesterolemia in HCV patients who achieved sustained virologic response (SVR) with DAA treatment. METHODS: A total of 121 patients with HCV genotype 1b, who achieved SVR with DAA treatment, were examined for serum levels of total cholesterol, LDL-cholesterol (LDL-C), high-density lipoprotein, and triglycerides from the start of treatment until 2 years after SVR (SVR-2y). ΔLDL-C was defined as the change in LDL-C levels from treatment initiation to SVR-2y. Hyper-LDL cholesterolemia was defined as ≥ 140 mg/dL LDL-C at SVR-2y. Stepwise multiple regression analysis was performed to determine whether ΔLDL-C and hyper-LDL cholesterolemia are associated with other factors, including viral kinetics. RESULTS: A total of 63, 3, and 55 patients were administered daclatasvir + asunaprevir, ombitasvir + paritaprevir + ritonavir, and ledipasvir + sofosbuvir, respectively. ΔLDL-C in patients with the IL28B (rs8099917) TG/GG genotype was significantly higher than in those with IL28B TT (27.3 ± 27.0 and 9.6 ± 27.3 mg/dL; P < 0.001). In addition, IL28B TG/GG was an independent risk factor for hyper-LDL cholesterolemia (odds ratio: 8.47; P < 0.001). CONCLUSIONS: An IL28B polymorphism is associated with ΔLDL-C and hyper-LDL cholesterolemia after achieving SVR. Thus, lipid markers should be carefully monitored in patients who achieve SVR with DAA.

Living donor liver transplantation for biliary atresia: An analysis of 2085 cases in the registry of the Japanese Liver Transplantation Society.

Biliary atresia (BA) is the most common indication for liver transplantation (LT) in pediatric population. This study analyzed the comprehensive factors that might influence the outcomes of patients with BA who undergo living donor LT by evaluating the largest cohort with the longest follow-up in the world. Between November 1989 and December 2015, 2,085 BA patients underwent LDLT in Japan. There were 763 male and 1,322 female recipients with a mean age of 5.9 years and body weight of 18.6 kg. The 1-, 5-, 10-, 15-, and 20-year graft survival rates for the BA patients undergoing LDLT were 90.5%, 90.4%, 84.6%, 82.0%, and 79.9%, respectively. The donor body mass index, ABO incompatibility, graft type, recipient age, center experience, and transplant era were found to be significant predictors of the overall graft survival. Adolescent age (12 to <18 years) was associated with a significantly worse long-term graft survival rate than younger or older ages. We conclude that LDLT for BA is a safe and effective treatment modality that does not compromise living donors. The optimum timing for LT is crucial for a successful outcome, and early referral to transplantation center can improve the short-term outcomes of LT for BA. Further investigation of the major cause of death in liver transplanted recipients with BA in the long-term is essential, especially among adolescents.

Diagnostic and clinical role of serum proteinase 3 antineutrophil cytoplasmic antibodies in inflammatory bowel disease.

BACKGROUND AND AIM: Proteinase 3 antineutrophil cytoplasmic antibodies (PR3-ANCAs) are well-known serological markers for granulomatosis with polyangiitis, but their role as serological markers for inflammatory bowel disease remains uncertain. The present study aimed to evaluate the diagnostic and clinical role of PR3-ANCAs as markers for inflammatory bowel disease. METHODS: Using a new methodology with chemiluminescence enzyme immunoassay, serum PR3-ANCA titers were assessed in 102 patients with ulcerative colitis (UC), 67 patients with Crohn's disease (CD), 44 controls with other intestinal diseases, and 66 healthy controls. Associations with clinical data were investigated. The diagnostic role of PR3-ANCAs was evaluated by receiver operating characteristic analysis. RESULTS: Proteinase 3 antineutrophil cytoplasmic antibody titers were significantly higher in patients with UC than in those with CD patients, patients with intestinal diseases (intestinal controls), and healthy controls (all P < 0.001). Receiver operating characteristic analysis demonstrated an area under the curve of 0.85 (95% confidence interval: 0.83-0.87) and showed that the manufacturer's cutoff value (3.5 U/mL) had a sensitivity of 39.2% and specificity of 96.6% for UC. There was a significant difference between PR3-ANCA-positive and PR3-ANCA-negative patients with regard to disease duration (P < 0.05) and disease severity (P < 0.01). CONCLUSIONS: Proteinase 3 antineutrophil cytoplasmic antibodies were significantly more prevalent in patients with UC than in those with CD and controls. Our results suggested the role of PR3-ANCAs as serological markers for aiding in diagnosing UC and evaluating disease severity. Further prospective studies are needed across multiple populations of patients and ethnic groups.

Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn's disease in the Ryukyu Islands.

Crohn's disease (CD) involves chronic inflammation in the gastrointestinal tract due to dysregulation of the host immune response to the gut microbiome. Even though the host-microbiome interactions are likely contributors to the development of CD, a few studies have detected genetic variants that change bacterial compositions and increase CD risk. We focus on one of the well-replicated susceptible genes, tumor necrosis factor superfamily member 15 (TNFSF15), and apply statistical analyses for personal profiles of genotypes and salivary microbiota collected from CD cases and controls in the Ryukyu Islands, southernmost islands of the Japanese archipelago. Our association test confirmed the susceptibility of TNFSF15 in the Ryukyu Islands. We found that the recessive model was supported to fit the observed genotype frequency of risk alleles slightly better than the additive model, defining the genetic effect on CD if a pair of the chromosomes in an individual consists of all risk alleles. The combined analysis of haplotypes and salivary microbiome from a small set of samples showed a significant association of the genetic effect with the increase of Prevotella, which led to a significant increase of CD risk. However, the genetic effect on CD disappeared if the abundance of Prevotella was low, suggesting the genetic contribution to CD is conditionally independent given a fixed amount of Prevotella. Although our statistical power is limited due to the small sample size, these results support an idea that the genetic susceptibility of TNFSF15 to CD may be confounded, in part, by the increase of Prevotella.

Survival in patients with Child-Pugh class C cirrhosis: Analysis of the liver transplant registry in Japan.

AIM: To clarify the survival and prognostic factors in patients with Child-Turcotte-Pugh class C (CTP-C) cirrhosis. METHODS: From all candidates for deceased donor liver transplantation in Japan between 2007 and 2015, 1014 adult patients with CTP-C cirrhosis were retrospectively enrolled in this study. The hazard ratio (HR) of factors associated with mortality was estimated by the Cox proportional hazard model. The survival probabilities were evaluated by Kaplan-Meier analysis and the log-rank test. RESULTS: Median survival time of the entire cohort was 475 days. Univariate analysis identified age, CTP, Model for End-Stage Liver Disease (MELD) score, and primary biliary cholangitis (PBC) as significant variables associated with mortality and hepatitis B virus (HBV) infection as a close-to-significant variable. Multivariate analysis revealed that age-adjusted mortality risk increased by 59% and 12% per 1 score step up in CTP and MELD scores, respectively. The HRs for HBV infection and PBC were significant after adjustment for age and CTP score, and they showed a 26% lower risk and an 83% higher risk than hepatitis C virus (HCV) infection, respectively. After adjustment for age and MELD score, the HR was also significant for HBV infection, but lost statistical significance for PBC. The survival curves were well stratified by both CTP or MELD score and revealed significant difference in both HBV infection and PBC as compared to HCV infection. CONCLUSIONS: In patients with CTP-C cirrhosis, CTP and MELD scores could well stratify the patients' survival, and HBV infection and PBC as etiologies have an impact on survival.

Non-response to daclatasvir and asunaprevir therapy in patients co-infected with hepatitis C virus genotypes 1 and 2.

Direct-acting antiviral agents for hepatitis C virus (HCV) have been developed such as combined daclatasvir (DCV) and asunaprevir (ASV) treatment. This typically enables HCV serotype 1 patients to achieve a high sustained virological response rate, but a small number of such patients fail to respond to therapy. We investigated three HCV patients who showed no response to DCV and ASV therapy. Hepatitis C genotyping was undertaken in the three patients using nested polymerase chain reaction and polymerase chain reaction direct sequencing in the core region of the HCV genome. All three patients possessed HCV serotype 1, and no mutations were identified in either the non-structural protein 3 or 5A region. The three patients were shown to be co-infected with HCV genotypes 1 and 2 because genotypes 2a and 2b were also identified. This is the first report into failed response to DCV and ASV therapy in patients co-infected with HCV genotypes 1 and 2.

Increased hepatic ABCA1 transporter is associated with hypercholesterolemia in a cholestatic rat model and primary biliary cholangitis patients.

Hepatic ATP-binding cassette A1 (ABCA1) transporter is the modulator of intrahepatic cholesterol levels via the efflux of cholesterol into plasma. This study aimed to determine the expression of hepatic ABCA1 levels in a cholestatic rat model and patients with primary biliary cholangitis (PBC). A cholesterol efflux study was conducted with Abca1 knock down using siRNA in WIF9 cells. Cholesterol levels in the ABCA1 siRNA cells in the medium were significantly decreased compared with those in controls (P < 0.05). Hepatic ABCA1 mRNA levels were significantly higher in BDL rats than in control rats (P < 0.05). Furthermore, the protein expression level of hepatic ABCA1 was also significantly increased by 200% in BDL rats (P < 0.05). In PBC patients, expression of hepatic ABCA1 mRNA was 2.2-fold higher than that in controls (P < 0.05). The level of hepatic liver X receptor (LXR)ß mRNA was correlated with ABCA1 mRNA levels in PBC patients. The expression of hepatic ABCA1 transporter was upregulated in both the cholestatic rat model and PBC patients. Upregulated hepatic ABCA1 may lead to efflux of cholesterol into plasma, thus explaining the mechanism of cholestasis leading to hypercholesterolemia.