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Aim: Patients with chronic hepatitis B virus (HBV) infection experiencing viral breakthrough (BTH) or partial response (PR) during lamivudine (LAM) or entecavir hydrate (ETV) administration often took ETV plus tenofovir alafenamide fumarate (TAF) due to the emergence of a drug‐resistance mutation. However, in patients lacking drug‐resistance mutation against TAF, sufficient antiviral effects may be achievable with TAF monotherapy. We assessed the drug‐resistance profile through nucleotide sequences of HBV pregenome RNA, and subsequently changed to TAF monotherapy from ETV plus TAF. Methods: This prospective study included 25 patients with serum HBV‐DNA below 20 IU/mL under ETV plus TAF administration. Pregenome RNA nucleotide sequences of HBV in the sera were analyzed using direct sequencing and deep sequencing. ETV was discontinued in patients without rtA194T and rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutations in direct sequencing. Results: LAM‐PR, LAM‐BTH, ETV‐PR, and ETV‐BTH were observed in 1, 16, 7, and 1 patient(s), respectively. Pregenome RNA nucleotide sequences were analyzable in 20 patients. Among the 12 patients classified as LAM‐BTH, six patients showed rtL180M + rtM204V/I in direct sequencing, and one patient showed minor clones containing rtL180M + rtM204V + A194T in deep sequencing at a frequency of 0.3%. In the six patients classified as ETV‐PR, one patient harbored rtM204I. No clones showing rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutation were detected in deep sequencing. Subsequently, ETV was discontinued, and serum HBV‐DNA remained undetectable up to 48 weeks in all patients. Conclusion: Patients receiving ETV plus TAF due to partial response or BTH during initial LAM or ETV administration were able to safely transition to TAF monotherapy based on nucleotide sequences of HBV pregenome RNA in the sera. [ABSTRACT FROM AUTHOR]

Aim: To determine the outcomes concerning portal venous blood flow and portosystemic shunts in patients with decompensated cirrhosis due to hepatitis C virus (HCV) infection who achieved sustained viral response (SVR) following antiviral therapy. Methods: Portal hypertension‐related events and liver function were evaluated in 24 patients achieving SVR following sofosbuvir plus velpatasvir therapy. Results: Serum albumin level (median; g/dL) increased from 2.9 at baseline to 3.5 at 12 weeks after the end of treatment (EOT) (p = 0.005), while liver volumes (cm3) decreased from 1260 to 1150 (p = 0.0002). Portal hypertension‐related events developed in 10 patients (41.7%), and the cumulative occurrence rates after the EOT were 29.2%, 33.3%, and 46.1% at 24, 48, and 96 weeks, respectively. Multivariate logistic regression analysis revealed that the maximal diameter of the shunts (p = 0.0235) was associated with the development of the events, with a cut‐off value of 8.3 mm (p = 0.0105). Meanwhile, multiple linear regression analysis revealed that portal venous blood flow, liver volume, serum albumin, and bilirubin levels at baseline were associated with serum albumin levels at 12 weeks after EOT (p = 0.0019, p = 0.0154, p = 0.0010, and p = 0.0350, respectively). Conclusion: In patients with decompensated cirrhosis due to HCV infection, the baseline portal venous blood flow and liver volume and function were predictive of liver function following SVR, while the maximal diameter of portosystemic shunts predicted the occurrence of portal hypertension‐related events. [ABSTRACT FROM AUTHOR]

Background: The Japanese guidelines for the treatment of cirrhosis suggest zinc supplementation to prevent hepatic encephalopathy in patients with cirrhosis and zinc deficiency, although the factors that are associated with therapeutic efficacy remain unknown. Method: A total of 159 patients with chronic liver diseases but without previous zinc supplementation were analyzed. Factors associated with serum zinc levels as well as the therapeutic efficacy of zinc supplementation were evaluated. Result: Serum zinc levels decreased with the progression of liver diseases. A multiple linear regression analysis revealed that the serum levels of albumin and cholinesterase and the daily furosemide dose were independently associated with the serum zinc levels. The optimal furosemide cut‐off dosage for patients with zinc deficiency (<60 μg/dl) was 5 mg/day. Among 34 patients receiving zinc acetate hydrate, overt hepatic encephalopathy occurred in 12 patients (35.4%). A multivariate analysis identified a minimal serum zinc level of 50 μg/dl after more than 12 weeks of zinc supplementation as a factor associated with overt encephalopathy development, while furosemide use was not associated. The Child‐Pugh score at baseline was the only factor associated with the maintenance of sufficient serum zinc levels. Conclusion: Although the furosemide dose was negatively correlated with the serum zinc level in patients with chronic liver diseases, furosemide use was not associated with the occurrence of overt encephalopathy in those receiving zinc supplementation. Serum zinc levels of ≥50 μg/dl were required to prevent overt encephalopathy development during zinc supplementation in both patients with and those without furosemide administration. [ABSTRACT FROM AUTHOR]

A protective effect of Rho-kinase inhibitor on various organ injuries is gaining attention. Regarding liver injury, Rho-kinase inhibitor is reported to prevent carbon tetrachloride ([CCl.sub.4])- or dimethylnitrosamine-induced liver fibrosis and hepatic ischemia-reperfusion injury in rats. Because Rho-kinase inhibitor not only improved liver fibrosis but also reduced serum alanine aminotransferase (ALT) level in [CCl.sub.4]-induced liver fibrosis, we wondered whether Rho-kinase inhibitor might exert a direct hepatocyte-protective effect. We examined this possibility in acute [CCl.sub.4] intoxication in rats. Rho-kinase inhibitor, HA-1077, reduced serum alanine ALT level in rats with acute liver injury induced by [CCl.sub.4] with the improvement of histological damage and the reduction of the number of apoptotic cells. In cultured rat hepatocytes in serum-free condition, HA-1077 reduced apoptosis evaluated by quantitative determination of cytoplasmic histone-associated DNA oligonucleosome fragments with the reduction of caspase-3 activity and the enhancement of Bcl-2 expression. HA-1077 stimulated phosphorylation of Akt, and wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway, abrogated the reduction of hepatocyte apoptosis by HA-1077 in vitro. Furthermore, wortmannin abrogated the reduction of serum ALT level by HA-1077 in rats with acute liver injury induced by [CCl.sub.4], suggesting that the activation of PI3-kinase/Akt pathway may be involved in the hepatocyte-protective effect by Rho-kinase inhibitor in vivo. In conclusion, Rho-kinase inhibitor prevented hepatocyte damage in acute liver injury induced by [CCl.sub.4] in rats and merits consideration as a hepatocyte-protective agent in liver injury, considering its direct antiapoptotic effect on hepatocytes in vitro. HA-1077; fasudil; Y-27632; Rho

Ikeda, Hitoshi, Kayo Nagashima, Mikio Yanase, Tomoaki Tomiya, Masahiro Arai, Yukiko Inoue, Kazuaki Tejima, Takako Nishikawa, Masao Omata, Satoshi Kimura, and Kenji Fujiwara. Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 285: G880-G886, 2003. First published June 26, 2003; 10.1152/ ajpgi.00039.2003.--Hepatic stellate cells (HSCs) play a central role in the development of hepatic fibrosis. Recent evidence has revealed that HSCs also play a role in its resolution, where HSC apoptosis was determined. Moreover, induction of HSC apoptosis caused a reduction of experimental hepatic fibrosis in rats. Thus knowing the mechanism of HSC apoptosis might be important to clarify the pathophysiology and: establish the therapeutic strategy for hepatic fibrosis. In HSCs, Rho and Rho kinase are known to regulate contraction, migration, and proliferation with modulation of 'cell morphology. Controversy exists as to the participation of Rho and Rho kinase on cell survival, and little is known regarding this matter in HSCs. In this study, we directed our focus on the role of the Rho pathway in the regulation of HSC survival. C3, an inhibitor of Rho, increased histone-associated DNA fragmentation and caspase 3 activity with enhanced condensation of nuclear chromatin in rat cultured HSCs. Moreover, Y-27632, an inhibitor of Rho kinase, had the same effects, suggesting that inhibition of the Rho/Rho kinase pathway causes HSC apoptosis. On the other hand, lysophosphatidic acid, which stimulates the Rho/Rho kinase pathway, decreased histone-associated DNA fragmentation in HSCs. Inhibition of the Rho/Rho kinase pathway did not affect p53, Bcl-2, or Bax levels in HSCs. Thus we concluded that the Rho/Rho kinase pathway may play a role in the regulation of HSC survival. lysophosphatidic acid; C3 exoenzyme; Y-27632

Aim: To establish a therapeutic strategy for cirrhosis patients with gastric variceal bleeding. Methods: The outcomes of 137 patients with bleeding gastric varices were evaluated. Results: The bleeding source was gastroesophageal varices (GOV) in 86 patients, and gastric fundal varices (FV) in 51 patients. The Child-Turcotte-Pugh classes were A, B, and C in 26, 79, and 32 patients, respectively; 34 patients (24.8%) had hepatocellular carcinoma (HCC), of which 11 also had complicating portal venous tumor thrombosis (PVTT). Patients with GOV were treated by endoscopic variceal ligation or endoscopic injection sclerotherapy (EIS) with ethanolamine oleate, while those with FV were treated by EIS with cyanoacrylate; 29 patients with FV also underwent additional balloon-occluded retrograde transvenous obliteration (BRTO). Hemostasis was successfully achieved in 136 patients (99.3%), and the cumulative 1-year, 3-year, and 5-year rebleeding rates were 18.1%, 30.8%, and 30.8%, respectively, in the patients with GOV, and 2.2%, 12.5% and 12.5%, respectively, in the patients with FV. The overall 1-year, 3-year, and 5-year survival rates were 79.7%, 71.5% and 64.4%, respectively, in the patients with GOV, and 91.0%, 76.9% and 59.5%, respectively, in the patients with FV. Multivariable analysis identified PVTT and alcoholic cirrhosis as a significant risk factor associated with rebleeding, model for end-stage liver disease (MELD) score and PVTT as significant factors associated with survival. Conclusions: Endoscopic therapies with or without BRTO appeared to be useful therapeutic strategies to prevent rebleeding in patients with gastric variceal bleeding, and favorable outcomes were obtained, except in patients with underlying HCC associated with PVTT and/or severe liver damage. [ABSTRACT FROM AUTHOR]

Background: To evaluate the long-term efficacy of switching of the nucleos(t)ide analog used for treatment from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in patients with chronic HBV infection. Methods: A total of 103 patients with serum HBsAg levels of ≥100 IU/mL who had received ETV were enrolled. The nucleos(t)ide analog used for the treatment was switched from ETV to TAF, and the changes in serum HBsAg levels during the 144-week period before and after the drug switching were compared in 74 patients who had received ETV at least for 192 weeks. Results: Significant decreases of serum HBsAg levels were observed during both the ETV and the TAF administration period, although the degree of reduction was greater during the latter period than during the former period (P<0.001). Significant decreases of serum HBsAg levels were seen in both patients with genotype B HBV infection and genotype C HBV infection, irrespective of the serum HBsAg and HBcrAg levels at the time of the drug switching. Conclusion: Switching of the nucleos(t)ide analog used for treatment from ETV to TAF merits consideration in patients with chronic HBV infection, since the extent of reduction of the serum HBsAg level was greater during the TAF treatment period than during the ETV treatment period. [ABSTRACT FROM AUTHOR]

Aim: To optimize the therapeutic strategy for patients with decompensated cirrhosis manifesting hepatic ascites and/or edema, factors affecting the outcome of patients receiving tolvaptan were evaluated. Methods: The subjects were 165 patients receiving tolvaptan including 116 patients (70%) also treated with furosemide. The therapeutic efficacy of tolvaptan was defined as "effective" when a body weight reduction of 1.5 kg or more was obtained within 1 week. The long‐term outcome was defined as "favorable" when the ascites‐related events‐free duration was prolonged following tolvaptan treatment, compared with that before treatment, or ascites‐related events were absent for at least 120 days during treatment based on the hazard function analysis. Results: Tolvaptan was effective in 115 patients (70%). Among them, the long‐term outcome was evaluated in 99 patients and was favorable in 70 patients (71%). A multivariate analysis revealed that the serum blood urea nitrogen levels at baseline (odds ratio 0.960 per +1 mg/dL, P = 0.021) and the type of tolvaptan initiation (planned vs. emergent; 3.695, P < 0.001) were associated with therapeutic efficacy, while the furosemide dose (0.280 per +20 mg/day, P = 0.014) and previous ascites‐related events (0.074, P < 0.001) were associated with the long‐term outcome. Receiver operating curve analyses identified the optimal cut‐off values for the furosemide dose as 15 mg/day (P < 0.001). Furthermore, the cumulative survival rates in patients receiving furosemide at 15 mg/day or less were significantly higher than those in the remaining patients (P = 0.048). Conclusion: Furosemide given at baseline contributed to an unfavorable outcome in patients receiving tolvaptan; consequently, tolvaptan should be given before increasing the furosemide dose. [ABSTRACT FROM AUTHOR]

Aim: To optimize the therapeutic strategy for cirrhotic patients manifesting hepatic encephalopathy, factors affecting the outcome of patients receiving rifaximin were evaluated. Methods: The subjects were 95 patients receiving rifaximin. Serum ammonia levels were measured serially during rifaximin treatment. Factors associated with long‐term outcomes and cumulative survival rates were evaluated. Results: Serum ammonia levels were decreased at 4 weeks after rifaximin treatment compared to the levels at baseline even in patients receiving rifaximin as an add‐on therapy with lactitol hydrate (P < 0.001) and reduction values were negatively correlated with the maximal diameter of portosystemic shunts (r = −0.275, P = 0.009). Overt encephalopathy occurred in 37 patients (38.9%) during rifaximin treatment, and the hazard function analysis identified 90 days as a high‐risk term for developing the first‐time overt encephalopathy. Thus, the long‐term outcome was judged as favorable in 77 patients (81.1%) in whom overt encephalopathy was absent for at least 90 days during rifaximin initiation. A multivariate analysis revealed that furosemide, especially at daily doses of ≥20 mg both at baseline and during rifaximin treatment, was a significant factor associated with unfavorable outcome (P = 0.009 and P = 0.022, respectively) as well as occurrence and recurrence of overt encephalopathy (P = 0.012). Moreover, furosemide treatment significantly deteriorated the cumulative survival rate of patients receiving rifaximin (P = 0.026). Conclusion: Furosemide contributed to the deteriorated outcome of patients receiving rifaximin. Consequently, rifaximin should be given before increasing the furosemide dose, and the furosemide dose should not be increased during rifaximin treatment. [ABSTRACT FROM AUTHOR]

Aim: This study sought to clarify the usefulness of lenvatinib for patients with unresectable hepatocellular carcinoma (HCC). Methods: The subjects were 69 patients with HCC receiving lenvatinib; the median age was 73 years, and 14 and 67 patients had been previously treated with regorafenib and/or sorafenib and therapies without molecular-targeted agents, respectively. Therapeutic efficacy was evaluated using contrast-enhanced CT images obtained 4–8 weeks after the start of lenvatinib and the middle-term outcome using Kaplan-Meier method. Results: The baseline Child-Pugh scores were 5, 6 and 7 in 31, 32 and 6 patients, respectively, and the modified albumin-bilirubin (mALBI) grades were 1, 2a and 2b in 20, 20 and 29 patients, respectively. The Barcelona Clinic Liver Cancer (BCLC) stages following downsizing after prior treatment were A, B and C in 17, 22 and 30 patients, respectively. The therapeutic efficacy was evaluated in 54 patients, and the percentages of patients achieving CR, PR, SD and PD were 3.7%, 44.4%, 37.0%, and 14.8%, respectively. The ALBI scores deteriorated significantly between 4 and 12 weeks after the start of therapy, compared with the baseline. The cumulative survival rates at 48 weeks were significantly higher among patients achieving CR/PR (95.5%) than among those showing no response (54.3%). Multivariate analyses revealed that the BCLC stages and the serum AFP levels were significantly associated with therapeutic efficacy, while the mALBI grade was associated with the middle-term outcome. Conclusions: A favorable middle-term outcome was obtained in patients with HCC receiving lenvatinib, especially in those manifesting grades 1/2a mALBI at baseline, despite the deterioration in ALBI scores during treatment. [ABSTRACT FROM AUTHOR]

Aim: Factors responsible for impaired improvement of liver function despite sustained viral response after direct‐acting antiviral agents therapies in cirrhotic patients with hepatitis C virus need to be elucidated. Methods: Liver function and the extent of portosystemic shunting were evaluated for 79 patients with compensated cirrhosis, in whom sustained viral response had been achieved after direct‐acting antiviral agents therapies for hepatitis C virus at least 3 years earlier. Results: Portosystemic shunts were observed in 63 patients (80%). Improvement and worsening, as compared with the baseline, of esophageal/gastric varices after direct‐acting antiviral agents therapies was seen in three patients (4%) and 10 patients (13%), respectively. Portal hypertension‐related events, such as varices and ascites requiring treatment, were observed in six patients (8%), in whom three patients showing worsening of Child–Pugh scores were included. Multivariate analysis showed that maximal diameter of the shunts (P = 0.012) and serum Mac‐2 binding protein glycosylation isomer levels at the end of treatment (P = 0.005) were associated with the development of portal hypertension‐related events, with cut‐off values of 5.25 mm (P = 0.001) and 6.84 cut‐off index (P < 0.001), respectively. The increase of serum albumin levels at 3 years, as compared with the baseline, was smaller in 22 patients having shunts with maximal diameters of ≥5 mm than in the remaining 57 patients (P = 0.034), whereas no such difference was seen between the patients with and without elevation of serum Mac‐2 binding protein glycosylation isomer level of ≥6.8 cut‐off index. Conclusions: A large size of portosystemic shunts was found to be a crucial determinant of impaired improvement of liver function, as well as of the development of portal hypertension‐related events, even after sustained viral response in patients with compensated cirrhosis. [ABSTRACT FROM AUTHOR]

The significance of switching of the nucleos(t)ide analog used to treat patients with hepatitis B virus (HBV) from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) is uncertain. The subjects of this study were 159 patients with HBV who received treatment with ETV followed by TAF. Among these patients, serial changes in the HBV marker levels were monitored in 92 patients in whom the serum HBsAg levels were ≥100 IU/mL during the 48‐week period immediately before and after the switching. A questionnaire survey for medication compliance was performed in 127 patients. The serum HBsAg levels (log IU/mL) decreased by 0.041 during the ETV treatment period and by 0.068 during the TAF administration period. The degree of reduction was higher during the TAF administration period than during the ETV administration period in patients without cirrhosis (P =.030), patients with genotype B HBV (P =.014), and patients with undetectable serum HBcrAg (P =.038). Multivariate analysis revealed the HBV genotype (B vs C; odds ratio, 3.400; P =.025) and serum aspartate aminotransferase level (every 1+; 1.111; P =.015) at the time of switching as factors influencing the treatment efficacy. Thirty‐six patients (28%) responded that the number of days that they forgot to take the drug decreased after the drug switching, and 77 patients (61%) reported feeling satisfied with the drug switching. Switching of the nucleos(t)ide analog used from ETV to TAF may be useful in the treatment of patients with HBV infection, as it is associated with both a decrease in the serum HBsAg level and improvement of the medication compliance. [ABSTRACT FROM AUTHOR]

A 42‐year‐old Chinese man with chronic hepatitis C virus (HCV) infection visited our hospital for antiviral therapy. The subgenotype could not be determined using the HCV GENOTYPE Primer Kit (Institute of Immunology, Tokyo, Japan), which can identify genotype 3a HCV exclusively among genotype 3 HCV. Thus, the whole‐genome sequence of HCV was analyzed using the MinION nanopore sequencer (Oxford Nanopore Technologies, Oxford, UK), a third‐generation single‐molecule sequencing platform. Consequently, a total of 9442 bases with a 73.6 mean depth, corresponding to the sequences between nt25 and PolyU/UC were determined (LC414155.2). The similarity analysis revealed that the obtained sequence was classified into genotype 3b HCV and showed nucleotide identities from 87.6% to 93.9% with those of 12 previously reported strains. Furthermore, possible resistance‐associated substitutions in non‐structural protein (NS)3, NS5A, and NS5B based on consensus sequences of 12 genotype 3b HCV strains, including NS5A‐Y93H and NS5B‐S282 T substitutions, were absent. In conclusion, the MinION nanopore sequencer is useful for analyzing the HCV genome, especially the genomes of genotype 3 HCV strains for which standardized real‐ time PCR methods for all subgenotypes have not been established. [ABSTRACT FROM AUTHOR]

Aim: A nationwide survey of acute liver failure (ALF) and late‐onset hepatic failure (LOHF) has revealed that the outcomes of recent patients whose diseases were caused by infection with hepatitis A virus (HAV) have worsened, compared with those of previously reported patients. The factors associated with this deterioration were evaluated. Methods: A total of 83 patients with HAV infection seen between 1998 and 2015 were enrolled. All the patients had a prothrombin time–international normalized ratio of 1.5 or more and hepatic encephalopathy of grade 2 or more severe. The demographic and clinical features of 45 patients seen prior to 2003 (cohort 1) and 38 patients seen during 2004 and thereafter (cohort 2) were compared. Results: Three and four patients in cohort 1 and cohort 2, respectively, received liver transplantations; the survival rates among the remaining patients were 56% for cohort 2 and 79% for cohort 1 (P < 0.05). The mean age (±standard deviation) of the patients was higher in cohort 2 than in cohort 1 (58 ± 11 vs. 48 ± 13 years; P < 0.01). The percentages of patients with underlying metabolic diseases were 22% in cohort 1 and 61% in cohort 2 (P < 0.01). Diabetic mellitus was more common among deceased patients than among rescued patients (29% vs. 8%; P < 0.05) among patients who did not receive liver transplantations, and a multivariate analysis revealed that patient age and disease type were significantly and independently associated with the outcome. Conclusion: The outcomes of recent patients with ALF or LOHF caused by HAV infection have recently worsened mainly because of an increase in underlying metabolic diseases as a consequence of aging. [ABSTRACT FROM AUTHOR]

Aims: Liver injury can occur during antiviral therapies with direct-acting antivirals (DAAs), potentially necessitating discontinuation of the therapies, with consequent worsening of the sustained viral response (SVR) rates, in patients with hepatitis C virus (HCV). To clarify the mechanisms involved in serum transaminase level elevation, we performed a retrospective evaluation of the serum concentrations of daclatasvir and asunaprevir, both classified as DAAs, in patients receiving treatment with a combination of the two drugs. Methods: Subjects were 278 Japanese patients with genotype-1b HCV who received daclatasvir plus asunaprevir therapy for more than 4 weeks. Serum concentrations of both the DAAs were measured at 4 weeks after the initiation of therapy. Result: Liver injuries including serum AST and/or ALT level elevation to 150 U/L or over were found in 34 patients (12.2%). Multivariate logistic regression analysis identified serum asunaprevir concentrations as being significantly associated with developing liver injury, with an odds ratio of 1.046 (95% confidence interval 1.011–1.082, p<0.05). Serum asunaprevir concentrations showed correlation with the extent of liver fibrosis, estimated by peripheral platelets counts and serum albumin levels and baseline and FIB4 index and serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at 4 weeks of the therapy; the concentrations were significantly higher among patients showing 3.0 or more of M2BPGi levels than among those with the levels less than 3.0; on the other hand, no such correlation/difference was found in serum daclatasvir concentrations. Conclusion: High serum concentrations of serum asunaprevir, which were associated with the extent of liver fibrosis, appear to provoke the occurrence of liver injury in patients with genotype-1b HCV receiving combined daclatasvir plus asunaprevir therapy. [ABSTRACT FROM AUTHOR]

Background: A nationwide survey was performed to clarify the recent status of acute liver failure (ALF) and late-onset hepatic failure (LOHF) in Japan.Methods: Two-step surveys for patients with ALF and LOHF meeting the Japanese diagnostic criteria were performed annually in 782 hospitals. The clinical features of the patients were then compared to those reported in previous surveys.Results: In total, 1554 and 49 patients with ALF and LOHF, respectively, who were seen between 2010 and 2015 were enrolled. The subjects were classified into 1280 patients with hepatitis (642 non-comatose and 638 comatose) and 323 patients without hepatitis (190 non-comatose and 133 comatose). Compared with patients seen between 1998 and 2009, an older patient age and a higher percentage of underlying extrahepatic disease were observed. Although hepatitis virus infection was the most frequent etiology, the percentage of patients with this etiology had decreased, compared with previous cohorts, while the percentages of patients with drug-induced liver injuries, autoimmune hepatitis, and an indeterminate etiology had increased. Liver transplantation was performed in 170 patients (10.6%), whereas artificial liver support with plasmapheresis and/or hemodiafiltration were performed for most of the comatose patients. The outcomes of comatose patients were unfavorable, similar to previous surveys, especially the outcomes of hepatitis B virus carriers, including those with de novo hepatitis B (survival rate of 5.4% without liver transplantation).Conclusion: Although the clinical features, including the etiologies, of patients with ALF and LOHF have changed, the outcomes of patients have not improved in recent years. [ABSTRACT FROM AUTHOR]

Aim: To establish diagnostic criteria for acute‐on‐chronic liver failure (ACLF) in Japan, a multicenter pilot survey was carried out to examine the usefulness of overseas criteria in patients with chronic liver diseases manifesting acute decompensation. Methods: Patients fulfilling the Asian‐Pacific Association for the Study of the Liver (APASL), European Association for the Study of the Liver (EASL), or Chinese Medical Association (CMA) criteria for decompensation were enrolled from eight institutions in Japan, and the clinical features were evaluated. Results: Among 112 patients, 109 patients (97.3%) fulfilled the APASL criteria for decompensation; 7 patients were excluded because the decompensation had been provoked by gastrointestinal bleeding. Consequently, 102 patients (91.1%) were diagnosed as having ACLF according to the APASL definition. Among the patients who fulfilled the APASL criteria for decompensation, the etiologies of the underlying liver diseases were alcohol abuse in 59 cases (54.1%) and hepatitis B or hepatitis C virus infection in 24 (22.0%). The acute insults were alcohol abuse in 50 (45.9%), bacterial infection in 26 (23.9%), and exacerbation of underlying liver disease in 14 (12.8%). Fifty‐four patients (49.5%) satisfied the CMA criteria, but the survival rates were similar between patients who did and those who did not meet the criteria. When 84 patients with underlying cirrhosis were classified according to the EASL–Chronic Liver Failure (Clif) Consortium criteria, the survival rates differed according to grade: 67.6% (23/34) for patients without ACLF, and 41.2% (14/34) and 18.8% (3/16) for those with grade 1/2 and grade 3 ACLF, respectively. Conclusion: The APASL definition was suitable for screening Japanese patients with ACLF, including those whose conditions were triggered by gastrointestinal bleeding, and the EASL‐Clif Consortium criteria were useful for predicting outcome. [ABSTRACT FROM AUTHOR]

Aim: To improve the therapeutic efficacy of sofosbuvir/ledipasvir (SOF/LDV) for the retreatment of patients after daclatasvir/asunaprevir (DCV/ASV), a customized therapy with or without lead‐in interferon (IFN)‐β injections was formulated according to the types of resistance‐associated substitutions (RAS) in the non‐structural protein (NS)5A region of genotype 1b hepatitis C virus (HCV). Methods: Thirty‐three patients failing prior DCV/ASV received SOF/LDV for 12 weeks. Patients with HCV carrying unfavorable NS5A‐RAS and/or those previously treated with simeprevir were given lead‐in IFN‐β injections twice a day for 2 weeks; sequential changes in the NS5A‐RAS during the injection period were evaluated using deep sequencing. Results: Lead‐in injections were not undertaken in 27 patients; a sustained viral response (SVR) was achieved in 26 patients, while viral relapse occurred in 1 patient with HCV carrying NS5A‐L28M/R30H/Y93H mutations. Among the 6 patients receiving lead‐in injections, viral relapse occurred in 2 patients who had an unfavorable IFN‐λ3‐related gene single nucleotide polymorphism allele; both patients had been previously treated with simeprevir, and HCV carrying NS5A‐L31V/Y93H mutations had emerged after DCV/ASV. Deep sequencing revealed no changes in the NS5A‐RAS profiles during the lead‐in injection period in either patient. In contrast, in a patient with a favorable allele who was infected with similar unfavorable HCV strains, NS5A‐L31/Y93 wild‐type strains appeared during the injection period, enabling an SVR. Conclusion: Using customized therapies based on the NS5A‐RAS profiles, a high SVR rate was obtained after SOF/LDV in patients failing prior DCV/ASV. Lead‐in IFN‐β injections did not improve the efficacy in patients with HCV carrying unfavorable NS5A‐RAS except in those with a favorable IFN‐λ3‐related gene allele. [ABSTRACT FROM AUTHOR]

Aim: Portosystemic shunts aggravate liver function by decreasing portal blood flow. The usefulness of balloon‐occluded retrograde transvenous obliteration (B‐RTO), a standardized therapeutic procedure for gastric fundal varices (GFV), for the improvement of liver function was evaluated in cirrhotic patients with or without varices. Methods: The subjects were 161 patients with portosystemic shunts. A balloon catheter was inserted into the shunts, followed by the injection of 5% ethanolamine oleate through the catheter under balloon inflation. The balloon was kept inflated for 6 to 48 h. Results: B‐RTO was performed as a therapy for GFV in 112 patients and for the improvement of liver function in 49 patients. The targets were splenorenal shunts in 104 patients (93.6%) in the former group and 33 patients (67.3%) in the latter group, and the procedures were successfully completed in 109 (97.3%) and 39 (79.6%) patients, respectively. In both groups, the serum albumin levels were increased and the serum ammonia levels were decreased at more than 1 month after the procedures, compared with the baseline levels, whereas significant improvements in the Child–Pugh scores and prothrombin times were only seen in the latter group. In these patients, the portal blood flows evaluated using Doppler ultrasound were increased at 1 week after the procedures, compared with the baseline levels. Conclusions: B‐RTO is a useful therapeutic procedure for improving liver function even in patients without GFV by increasing the portal venous flow with successfully targeted, uncommon portosystemic shunts. [ABSTRACT FROM AUTHOR]

Background: Hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, enhances hepatocyte function without stimulating proliferation, depending on the physiological conditions. p53, a transcription factor, suppresses the cell proliferation by expressing p21WAF1/CIP1 in various tissues. Aim: To investigate the mechanism through which the hepatocytes maintain mitotically quiescent even in the presence of HGF. Methods: We studied the relationship between p53 and p21 expression and the effect of p53-p21 axis on hepatocyte proliferation in primary cultured rat hepatocytes stimulated by HGF. Hepatic p21 levels are determined serially after partial hepatectomy or sham operation in rats. Results: DNA synthesis was markedly increased by HGF addition in rat hepatocytes cultured at low density but not at high density. Cellular p53 levels increased in the hepatocytes cultured at both the densities. p21 levels were increased and correlated with cellular p53 levels in hepatocytes cultured at high density but not at low density. When the activity of p53 was suppressed by a chemical inhibitor for p53, cellular p21 levels were reduced, and DNA synthesis was increased. Similarly, p21 antisense oligonucleotide increased the DNA synthesis. In rats after partial hepatectomy, transient elevation of hepatic p21 levels was observed. In contrast, in sham-operated rats, hepatic p21 levels were increased on sustained time scales. Conclusion: p53-related induction of p21 may suppress hepatocyte proliferation in the presence of HGF in the setting that mitogenic activity of HGF is not elicitable. [ABSTRACT FROM AUTHOR]

The article discusses a research study on predicting the development of hepatocellular carcinoma (HCC) through the activity of a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13). Patients who have chronic hepatitis B or C with HCC or without were evaluated for plasma ADAMTS13. Conclusions indicated the risk of developing HCC in chronic liver disease with higher activity of plasma ADAMTS13.

Abstract: Amino acids regulate cellular functions in a variety of cell types. Most notably, leucine stimulates protein production through the mammalian target of rapamycin (mTOR)-dependent signaling pathway. We investigated the effect of amino acids on hepatocyte growth factor (HGF) production. Treatment with glutamine and proline, as well as leucine, increased HGF levels in the culture medium of a rat hepatic stellate cell clone in a dose-dependent manner. Up-regulation of phosphorylation of 70kDa ribosomal protein S6 kinase and eukaryotic initiation factor 4E-binding protein 1 was not apparent in the cells after treatment with glutamine or proline. When rats received injections of glutamine or proline, hepatic and circulating HGF levels increased and peaked around 12h after treatment. Glutamine and proline may have the potential to stimulate HGF production but the mechanism underlying this stimulation seems not to be through the mTOR-dependent signaling pathway. [Copyright &y& Elsevier]