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The enhanced liver fibrosis (ELF) test is a noninvasive method for diagnosing hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). This multicenter cohort study aimed to evaluate the accuracy of the ELF test and compare it with other noninvasive tests in Japan.We analyzed 371 Japanese patients with biopsy-proven NAFLD. We constructed area under the receiver operator characteristics curves (AUROC) to determine the diagnostic accuracies of the ELF test, the Mac-2-binding protein glycosylation isomer (M2BPGi), the FIB-4 index, and combinations of these indices.In patients with F0/F1/F2/F3/F4 fibrosis, the median respective values of the ELF test were 8.98/9.56/10.39/10.92/11.41. The AUROCs of the ELF test for patients with F0 vs F1-4, F0-1 vs F2-4, F0-2 vs F3-4, and F0-3 vs F4 fibrosis were 0.825/0.817/0.802/0.812, respectively. The AUROCs of the ELF test were greater than those of the FIB-4 index and M2BPGi at each fibrosis stage. Respective low and high cutoff values yielded sensitivities and specificities for predicting advanced fibrosis (≥F3) of 91.1% and 50.8% and 38.5% and 92.8%, respectively. For F3 or F4 fibrosis, the combined values from the ELF test and FIB-4 index showed a sensitivity of 98.5%, and the combined values from the ELF test and M2BPGi assay showed a specificity of 97.5%.In Japan, the ELF test predicts NAFLD-related fibrosis from its early stages. The diagnostic ability of the ELF test was not inferior to that of other indices, and the combined values of ELF plus other indices were more accurate. This article is protected by copyright. All rights reserved.

Dysbiosis in the intestinal microflora can affect the gut production of microbial metabolites, and toxic substances can disrupt the barrier function of the intestinal wall, leading to the development of various diseases. Decreased levels of Clostridium subcluster XIVa (XIVa) are associated with the intestinal dysbiosis found in inflammatory bowel disease (IBD) and

Taurine, the end product in the sulfur-containing amino acid pathway, is conjugated with bile acids (BAs) in the liver. The rate-limiting enzymes in both taurine synthesis and BA conjugation may be regulated by a nucleus receptor, FXR, that promotes BA homeostasis. However, it is controversial because BAs act as natural FXR agonists or antagonists in humans and mice, respectively, due to the species differences in BA synthesis. The present study evaluated the influences of different BA compositions on both pathways in the liver by comparing Cyp2a12−/−/Cyp2c70−/− mice with a human-like BA composition (DKO) and wild-type (WT) mice. The DKO liver contains abundant natural FXR agonistic BAs, and the taurine-conjugated BA proportion and the taurine concentration were significantly increased, while the total BA concentration was significantly decreased compared to those in the WT liver with natural FXR antagonistic BAs. The mRNA expression levels of the enzymes Bacs and Baat in BA aminations and Cdo and Fmo1 in the taurine synthesis, as well as Fxr and its target gene, Shp, were significantly higher in the DKO liver than in the WT liver. The present study, using a model with a human-like BA composition in the liver, confirmed, for the first time in mice, that both the taurine synthesis and BA amidation pathways are upregulated by FXR activation.

Western-style high-fat/high-sucrose diet (HFHSD) changes gut microbiota and bile acid (BA) profiles. Because gut microbiota and BAs could influence each other, the mechanism of changes in both by HFHSD is complicated and remains unclear. We first aimed to clarify the roles of BAs in the HFHSD-induced change of gut microbiota. Then, we studied the effects of the changed gut microbiota on BA composition and liver function. Male wild-type (WT) and human-like Cyp2a12/Cyp2c70 double knockout (DKO) mice derived from C57BL/6J were fed with normal chow or HFHSD for 4 weeks. Gut microbiomes were analyzed by fecal 16S ribosomal RNA gene sequencing, and BA composition was determined by liquid chromatography-tandem mass spectrometry. The DKO mice exhibited significantly reduced fecal BA concentration, lacked muricholic acids, and increased proportions of chenodeoxycholic and lithocholic acids. Despite the marked difference in the fecal BA composition, the profiles of gut microbiota in the two mouse models were quite similar. An HFHSD resulted in a significant increase in the BA pool and fecal BA excretion in WT mice but not in DKO mice. However, microbial composition in the two mouse models was drastically but similarly changed by the HFHSD. In addition, the HFHSD-induced change of gut microbiota inhibited BA deconjugation and 7α-dehydroxylation in both types of mice, which improved chronic liver injury observed in DKO mice. Conclusion: The HFHSD itself causes the change of gut microbiota due to HFHSD, and the altered composition or concentration of BAs by HFHSD is not the primary factor. On the contrary, the gut microbiota formed by HFHSD affects BA composition and ameliorates liver injury in the mouse model with human-like hydrophobic BA composition.

Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case–control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case–control study to identify the environmental factors associated with the development of PBC in Japan. From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis. The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01–2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07–1.92), ever smoking (OR, 1.70; 95% CI, 1.28–2.25), and hair dye use (OR, 1.57; 95% CI, 1.15–2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99–19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077–0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52–68.0) in the model for medical and familial factors. These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan.

Background Measurement of the tricuspid regurgitation pressure gradient (TRPG) by echocardiography is recommended as the most objective examination for the detection of portopulmonary hypertension (PoPH). This prospective study aimed to identify factors associated with a high TRPG in patients with cirrhosis and develop a screening method for identifying patients most likely to benefit from investigation with echocardiography.Results Four hundreds and eighty-six patients with cirrhosis underwent Doppler echocardiography, and were analyzed in the present study. Of the 486 patients, 51 (10.5%) had TRPG ≥35 mmHg. The median BNP was 39.5 (range, 3.3–712.0) pg/mL. Ninety-one (18.7%) patients reported shortness of breath. Multivariate analysis identified female, shortness of breath, and BNP ≥49 pg/mL as independent factors for TRPG ≥35 mmHg. The risk score for predicting TRPG ≥35 mmHg was calculated: risk score = −3.230 + 0.622 × gender (female: 1, male: 0) + 1.403 × shortness of breath (presence: 1, absence: 0) + 0.726 × BNP (≥ 49pg/mL: 1, −8).Conclusions We clarified the characteristics of patients with suspected PoPH, and developed a scoring model for identifying patients at high risk of PoPH, which may have utility in selecting patients with cirrhosis that may benefit from echocardiography.

Hiroaki Hagiwara,1 Yoshinori Kinno,1 Tadashi Ikegami2 1Department of Radiology, Yokohama Minamikyosai Hospital, Yokohama, Japan; 2Department of Diagnostic Imaging, Kanagawa Dental University, Yokosuka, JapanCorrespondence: Hiroaki Hagiwara, Department of Radiology, Yokohama Minamikyosai Hospital, 1-21-1 Mutsuura-higashi Kanazawa-ku, Yokohama, 236-0037, Japan, Tel +81-45-782-2101, Fax +81-45-701-9159, Email hhagi1936@gmail.comPurpose: Spontaneous pneumomediastinum, supposedly attributed to air leakage from the respiratory tract, is a common complication of interstitial lung disease often resulting in mediastinal widening. However, several cases of pneumomediastinum without mediastinal widening have been observed. This study aimed to investigate the cause of pneumomediastinum in patients without mediastinal widening.Patients and Methods: This study included 41 patients diagnosed with pneumomediastinum using computed tomography (CT) between July 2011 and September 2021 at Yokohama Minamikyosai Hospital; patients had undergone previous CT showing no gas density. Based on a comparison with previous CT images, the patients were classified into two groups: without mediastinal widening and with mediastinal widening.Results: Of the 41 patients, 13 and 28 had pneumomediastinum without and with mediastinal widening, respectively. There were no significant differences in the sex, age, body mass index, or pneumomediastinum distribution between the groups. However, the rate of weight loss per month was significantly greater in the group without mediastinal widening than in that with mediastinal widening. No significant differences were observed in the respiratory function test results between the two groups; that said, 10 of the 13 patients without mediastinal widening had restrictive disorders. Pulmonary disease in this group included idiopathic pulmonary fibrosis (n = 6), interstitial lung disease with collagen disease (n = 4), and other disease (n = 1). Pneumomediastinum occurred during periods of weight loss in all patients without widening, excluding two patients without data.Conclusion: Pneumomediastinum without mediastinal widening occurs during rapid weight loss and is often associated with restrictive lung disorders. The negative pressure attributed to the decreased plasticity of the lungs, which complements the space where the mediastinal fat has disappeared, is presumably the cause of pneumomediastinum. This pathophysiology is different from that of conventional pneumomediastinum attributed to increased intrapleural space pressure; thus, we propose to name the abovementioned pathophysiology “negative pressure pneumomediastinum”.Graphical Abstract: Keywords: interstitial lung disease, idiopathic lung fibrosis, restrictive lung disorder

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the prognosis of NAFLD/NASH has been reported to be dependent on liver fibrosis degree. Liver biopsy remains the gold standard, but it has several issues that must be addressed, including its invasiveness, cost, and inter-observer diagnosis variability. To solve these issues, a variety of noninvasive tests (NITs) have been in development for the assessment of NAFLD progression, including blood biomarkers and imaging methods, although the use of NITs varies around the world. The aim of the Japan NASH NIT (JANIT) Forum organized in 2020 is to advance the development of various NITs to assess disease severity and/or response to treatment in NAFLD patients from a scientific perspective through multi-stakeholder dialogue with open innovation, including clinicians with expertise in NAFLD/NASH, companies that develop medical devices and biomarkers, and professionals in the pharmaceutical industry. In addition to conventional NITs, artificial intelligence will soon be deployed in many areas of the NAFLD landscape. To discuss the characteristics of each NIT, we conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis in this study with the 36 JANIT Forum members (16 physicians and 20 company representatives). Based on this SWOT analysis, the JANIT Forum identified currently available NITs able to accurately select NAFLD patients at high risk of NASH for HCC surveillance/therapeutic intervention and evaluate the effectiveness of therapeutic interventions.

Deficiency of the functional amino acid-like compound taurine induced in cats by taurine-depleted food was previously shown to significantly decrease the levels of taurine-conjugated bile acids (BAs) and significantly increase the levels of unconjugated BAs, with a significant decrease in total BA concentration in the bile. Because the ratios of primary BAs (cholic acid [CA] and chenodeoxycholic acids [CDCA]) have also been shown to be altered in the bile, taurine has been suggested to play an important role in BA synthesis in the liver. The present study showed that in the liver of taurine-deficient cats, CYP7A1 protein expression and its metabolites (7α-hydroxycholesterol and α-hydroxy-4-cholesten-3-one) were significantly increased and, therefore, the ratio of the CA product in this pathway was decreased. On the other hand, the expression of the mitochondrial CYP27A1 protein and its metabolite 27-hydroxycholesterol (27HC) were significantly decreased in the taurine-deficient liver. Thus, a significantly decreased ratio of CDCA, which is the main product of 27HC, was found. The decreased activity of the CDCA-producing pathway might be related to mitochondrial dysfunction induced by taurine deficiency. In addition, a significant decrease in cholesterol levels in the liver was induced by a decrease in intestinal cholesterol absorption because of decreased hepatic-intestinal circulation of taurine-conjugated BAs. The results of this study showed that taurine deficiency alters both the quality and quantity of BAs through inactivity of the mitochondrial CDCA production pathway caused by impaired mitochondrial function and inhibited the absorption of cholesterol in the intestine.

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.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.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.The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients.

AIM This study aimed to evaluate the real-world efficacy and safety of 12-week sofosbuvir/velpatasvir (SOF/VEL) treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus (HCV) infection. METHODS A total 72 of patients with Child-Pugh (CP) class B or C were enrolled. We evaluated the sustained virologic response at 12 weeks after the end of treatment (SVR12), adverse events (AEs), and changes in the liver function. RESULTS All participants had genotype 1 or 2 HCV infection. At baseline, the numbers of patients with CP class B and C were 59 and 13, respectively. The overall SVR12 rate was 95.8% (69/72); 94.9% (56/59) in CP class B and 100% (13/13) in CP class C. The serum albumin level, prothrombin time and ascites were significantly improved (P

Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naive patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10–5; genotype 2 vs. 3, p = 3.28 × 10–5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1–3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4–5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512–148.550), p value (p = 4.06 × 10–5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153–13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4–5 (41.6% [79/190]) than CKD stage 1–3 (26.1% [319/1220]) patients (p = 2.00 × 10–5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10–18) patients. G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.

Non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA) are the most common causes of drug-induced gastroduodenal ulcer and We investigated preventive treatment with use of concomitant anti-ulcer drugs and the clinical features of gastroduodenal ulcer in cases treated with these drugs. Patients with gastroduodenal ulcer and patients with bleeding were classified into 3 groups: LDA, non-aspirin NSAIDs, and those taking neither aspirin nor NSAIDs. Chronological changes over the past 16 years (1st–5th period) were investigated. The status of prevention of ulcer and clinical features were examined. From January 2002 to December 2018, the ratio of all patients taking NSAIDs and LDA increased significantly until 3rd period (p

The bile acid (BA) composition in mice is substantially different from that in humans. Chenodeoxycholic acid (CDCA) is an end product in the human liver; however, mouse Cyp2c70 metabolizes CDCA to hydrophilic muricholic acids (MCAs). Moreover, in humans, the gut microbiota converts the primary BAs, cholic acid and CDCA, into deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. In contrast, the mouse Cyp2a12 reverts this action and converts these secondary BAs to primary BAs. Here, we generated Cyp2a12 KO, Cyp2c70 KO, and Cyp2a12/Cyp2c70 double KO (DKO) mice using the CRISPR-Cas9 system to study the regulation of BA metabolism under hydrophobic BA composition. Cyp2a12 KO mice showed the accumulation of DCAs, whereas Cyp2c70 KO mice lacked MCAs and exhibited markedly increased hepatobiliary proportions of CDCA. In DKO mice, not only DCAs or CDCAs but also DCAs, CDCAs, and LCAs were all elevated. In Cyp2c70 KO and DKO mice, chronic liver inflammation was observed depending on the hepatic unconjugated CDCA concentrations. The BA pool was markedly reduced in Cyp2c70 KO and DKO mice, but the FXR was not activated. It was suggested that the cytokine/c-Jun N-terminal kinase signaling pathway and the pregnane X receptor-mediated pathway are the predominant mechanisms, preferred over the FXR/small heterodimer partner and FXR/fibroblast growth factor 15 pathways, for controlling BA synthesis under hydrophobic BA composition. From our results, we hypothesize that these KO mice can be novel and useful models for investigating the roles of hydrophobic BAs in various human diseases.

BACKGROUND In clinical trials, a pangenotype direct-acting antiviral (DAA) regimen consisting of glecaprevir (GLE) and pibrentasvir (PIB) exhibited high virologic efficacy and tolerability in patients with hepatitis C virus (HCV) infection. This study sought to confirm these findings in real-world settings, focusing on patients with cirrhosis, history of DAA failure, or HCV genotype 3 who were treated with a 12-week regimen in a large multicenter study from Japan. METHODS In a nationwide multicenter prospective cohort study, we analyzed background characteristics, tolerability, and treatment outcome of patients who underwent a 12-week GLE/PIB regimen. RESULTS Of 1190 patients, 509 (42.8%) underwent the 12-week regimen, and the remaining patients underwent an 8-week regimen. The rate of sustained virologic response (SVR) of patients treated with the 12-week regimen was 99.0%, comparable with that of patients treated with the 8-week regimen. The adverse events were observed in 29.1% of patients. The main adverse event was pruritus, which was observed in 14.7%. Ten patients (2.0%) discontinued therapy during treatment period. CONCLUSION The 12-week GLE/PIB regimen was well-tolerated with high virologic efficacy in patients with cirrhosis, experience of DAA, or HCV genotype 3; tolerability and SVR rate were comparable with those of DAA-naive, non-cirrhotic, non-genotype 3 patients who underwent 8-week regimen.

Based on high efficacy and safety demonstrated in clinical trials, treatment with glecaprevir/pibrentasvir (G/P) for 8 weeks is recommended for hepatitis C virus (HCV)-infected patients who are direct-acting antiviral (DAA) naïve, genotype 1 or 2, and noncirrhotic. The aim of this study was to validate real-world experience with 8-week G/P treatment in Japan. We conducted a prospective observational cohort study in 554 patients who underwent 8-week treatment from among 1,022 patients who initiated G/P therapy. The majority (54.5%) were male, with a median age of 66 years, and HCV genotype distribution was genotype 1, 43.8%; genotype 2, 55.3%; and mixed subtype, 0.9%. Overall, the sustained virologic response rate at 12 weeks (SVR12) was 92.8% (530/571) in the intention-to-treat population and 99.3% (526/530) in the per-protocol population. The SVR12 rates by subgroups were as follows: subtype 1a, 100% (6/6); 1b, 100% (189/189); 2a, 99.3% (150/151); 2b, 99.0% (103/104); and mixed subtype, 50% (2/4). Among four patients with virologic failure following 8-week treatment with G/P, none had baseline polymorphisms or treatment-emergent amino acid substitutions in NS3. However, 2 of 4 patients with virologic failure had treatment-emergent amino acid substitutions in NS5A. Adverse events (AEs) were reported in 21.5% of patients and 1.2% of patients discontinued due to drug-related AEs. In conclusion, G/P treatment for 8 weeks was safe and effective for DAA-naïve noncirrhotic genotype 1 or 2 patients in a real-world clinical setting in Japan.

BACKGROUND Patients with chronic hepatitis C are often complicated by chronic kidney disease (CKD). AIM To evaluate the efficacy, safety and pharmacokinetics of glecaprevir/pibrentasvir in patients with severe renal impairment. METHODS In a prospective, multicentre study involving 35 medical institutions, 832 genotype 1-3 patients were treated with glecaprevir/pibrentasvir. The efficacy and safety of glecaprevir/pibrentasvir were analysed for patients with CKD stage 4 or 5. Multivariate analysis was performed to identify the factors associated with the most frequently observed adverse event. In patients undergoing haemodialysis, a pharmacokinetic study was conducted to investigate the dialysability of the drugs: plasma samples were obtained from the arterial and venous sides of a dialyser to serially measure drug concentrations. RESULTS The subjects comprised 141 patients (32 with CKD stage 4 and 109 with CKD stage 5), of whom 100 were undergoing haemodialysis. All but one stage 5 CKD patients undergoing haemodialysis achieved sustained virologic response (99.3%). Adverse events were observed in 39.7% of subjects: pruritus was the most frequent (30.5%), and was significantly associated with haemodialysis. In the pharmacokinetic study, no arterial-venous differences in the plasma concentrations of glecaprevir/pibrentasvir were detected during the haemodialysis sessions. CONCLUSIONS Glecaprevir/pibrentasvir was highly effective and safe in chronic hepatitis C patients with severe renal impairment. Haemodialysis was associated with increased incidence of pruritus, which was the most frequent adverse event, but had little or no influence on the drug concentrations, which indicated that their dialysability is very low and that no dose modification is required in patients undergoing haemodialysis. (UMIN registration no. 000032073).

Nuclear receptor farnesoid X receptor activation inhibits fatty acid synthesis through the liver X receptor-α-sterol regulatory element binding protein-1c pathway universally in animals, but also has human-specific crosstalk with the peroxisome proliferator-activated receptor-α. The effects of farnesoid X receptor-ligands on both the synthesis and degradation of fatty liver through nuclear receptor-related regulation were investigated in both human and murine hepatocytes. A fatty liver culture cell model was established using a synthetic liver X receptor-α-ligand (To901317) for both human and mouse non-neoplastic hepatocytes. The hepatocytes were exposed to natural or synthetic farnesoid X receptor-ligands (bile acids, GW4064, obeticholic acid) together with or after To901317. Cellular triglyceride accumulation was significantly inhibited by the farnesoid X receptor-ligands along with inhibition of lipogenic genes and up-regulation of farnesoid X receptor-target small heterodimer partner in both human and mouse cells. The accumulated triglyceride was significantly degraded by the farnesoid X receptor-ligands only in the human cells accompanied with the up-regulations of peroxisome proliferator-activated receptor-α and fatty acid β-oxidation. Farnesoid X receptor-ligands can be therapeutic agents for treating human fatty liver through dual effects on inhibition of lipogenesis and on enhancement of lipolysis.

BACKGROUND Sorafenib is an oral drug that prolongs overall survival (OS) in patients with hepatocellular carcinoma. Adverse events, including hand-foot skin reaction (HFSR), lead to permanent sorafenib discontinuation. AIM To clarify the association between interventions for adverse events and patient prognosis. METHODS We performed a retrospective, multicenter study of patients treated with sorafenib monotherapy between May 2009 and March 2018. We developed a mutual cooperation system that was initiated at the start of sorafenib treatment to effectively manage adverse events. The mutual cooperation system entailed patients receiving consultations during which pharmacists provided accurate information about sorafenib to alleviate the fear and anxiety related to adverse events. We stratified the patients into three groups: Group A, patients without HFSR but with pharmacist intervention; Group B, patients with HFSR and pharmacist interventions unreported to oncologists (nonmutual cooperation system); and Group C, patients with HFSR and pharmacist interventions known to oncologists (mutual cooperation system). OS and time to treatment failure (TTF) were evaluated using the Kaplan-Meier method. RESULTS We enrolled 134 patients (Group A, n = 41; Group B, n = 30; Group C, n = 63). The median OS was significantly different between Groups A and C (6.2 vs 13.9 mo, p < 0.01) but not between Groups A and B (6.2 vs 7.7 mo, P = 0.62). Group A vs Group C was an independent OS predictor (HR, 0.41; 95%CI: 0.25-0.66; P < 0.01). In Group B alone, TTF was significantly lower and the nonadherence rate was higher (P < 0.01). In addition, the Spearman’s rank correlation coefficients between OS and TTF in each group were 0.41 (Group A; P < 0.01), 0.13 (Group B; P = 0.51), and 0.58 (Group C; P < 0.01). There was a highly significant correlation between OS and TTF in Group C. However, there was no correlation between OS and TTF in Group B. CONCLUSION The mutual cooperation system increased treatment duration and improved prognosis in patients with HFSR. Future prospective studies (e.g., randomized controlled trials) and improved adherence could help prevent OS underestimation.

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called “diabetic hepatopathy or diabetic liver disease”. NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.

Background Primary malignant melanoma of the lung (PML) is extremely rare. No precursor lesions of PML have been identified, and little is known about the genetic mutations associated with the disease. Typically, 15–20% of malignant melanomas possess NRAS gene mutations, but no cases of NRAS-mutated PML have been reported in the English literature. We present a case of PML involving an NRAS mutation. Case presentation Clinical summary A 74-year-old Japanese female presented with worsening dyspnea and was admitted to hospital. Computed tomography (CT) revealed a right lung (S10) mass and pleural dissemination. Cytology of the pleural effusion in the right lung was performed, and malignant melanoma or clear cell sarcoma was suspected. A dermatological examination and gallium scintigraphy were conducted to determine the primary tumor site, but no suspicious lesions, expect for the right lung mass, were found. After admission, CT showed complicating bilateral pneumonia, and an antibiotic drug was administered, but the pleural effusion got worse. About 2 weeks later, the patient died of respiratory failure and cardiac arrest. An autopsy was performed to determine the histological diagnosis. Autopsy findings A 26x15x20-mm black and pale yellow mass was found in the right lower lobe. Many disseminated nodules were found in the right lobe. The tumor had invaded the right diaphragm. Subcarinal lymph node metastasis was also detected. Immunohistochemically, the tumor cells exhibited positivity for S-100 and HMB45 staining. The patient was diagnosed with malignant melanoma. Sanger sequencing of the tumor detected an NRAS mutation. Conclusions We found an NRAS D54N mutation in PML, which has not been reported previously anywhere in the world. Previous reports indicated that most cases of PML can be classified into the triple-wild-type, but BRAF mutation status was only analyzed in a few cases. We should analyze the mutation patterns of PML to determine whether any subtypes other than the triple-wild-type exist. PML might be a form of de novo cancer.

Aim Although the development of new direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection has markedly advanced, the effects of cirrhosis on DAA treatment remain unclear. We aimed to clarify the impact of cirrhosis on DAA treatment of patients infected with HCV. Methods This large-scale, multicenter, retrospective study consisted of 2130 HCV genotype 1b-infected patients who were treated with one of the following DAA combination therapies: asunaprevir/daclatasvir (ASV/DCV), ledipasvir/sofosbuvir (LDV/SOF), or paritaprevir/ombitasvir/ritonavir (PTV/OBV/r). Ninety-two patients (4.3%) previously received DAA-based treatment. Seven hundred and forty-five patients (34.9%) had cirrhosis. Results Overall, the sustained virologic response (SVR) rate was 93.0%. The SVR rates in patients who received ASV/DCV, LDV/SOF, or PTV/OBV/r were 90.0%, 96.9%, and 97.6%, respectively. The SVR rate in patients with cirrhosis (89.1%) was significantly lower than that in patients without cirrhosis (95.1%, P = 6.94 × 10-7 ). In the multivariate analysis for the overall cohort, absence of cirrhosis (P = 1.26 × 10-3 ), no previous DAA-based treatment (P = 2.54 × 10-14 ), low HCV-RNA levels (P = 1.64 × 10-6 ), wild-type non-structural protein 5A L31/Y93 (P = 7.33 × 10-13 ), and DAA regimen (LDV/SOF or PTV/OBV/r) (P = 1.92 × 10-14 ) were independent factors contributing to SVR. Except for patients with DAA-based treatment history, absence of cirrhosis (P = 2.15 × 10-3 ; odds ratio, 2.51) was an independent factor contributing to SVR in 2038 DAA-naive patients. Conclusion This study suggests that the presence of cirrhosis reduces the SVR rate of DAA treatment, regardless of the type of DAA treatment.

Objective Since the majority of direct-acting antivirals (DAAs) that are used in the treatment of hepatitis C virus (HCV) infection are mainly metabolized by CYP3A4, it is hypothesized that inter-individual differences in CYP3A4 activity may be associated with the bioavailability of these agents. Methods The level of serum 4β-hydroxycholesterol (4βHC), a surrogate marker of CYP3A4 activity, was determined by LC-MS/MS in samples obtained from patients with HCV infection (CHCs) as well as healthy control subjects (CTLs). Serum samples obtained from patients treated with either asunaprevir/daclatasvir (ASV/DCV) or ombitasvir/paritaprevir/ritonavir (OTV/PTV/r) were used for additional assays. Results The serum 4βHC level in CHCs was significantly higher than that in CTLs, and a gender difference was seen among CHCs. In patients treated with OTV/PTV/r, the serum 4βHC level was observed to gradually decrease during the treatment period. In the cohort treated with ASV/DCV, 4 of 83 patients showed virological treatment failure. In pretreatment testing, an Invader assay detected a low prevalence of resistance-associated variants in these four patients. The average serum concentration of DCV/ASV in the treatment-failed group tended to be lower than that in the sustained virological response (SVR) group. The pretreatment serum 4βHC level in patients with treatment failure was significantly higher than that in patients with an SVR but in whom the prevalence of resistance-associated variants was low in the pretreatment setting. Conclusion The evaluation of CYP3A4 activity by measuring 4βHC before treatment may provide additional information that can potentially be used to select cost- and efficacy-optimized treatment of HCV.

AIM The aim of this study was to clarify the effects and safety of ombitasvir/paritaprevir/ritonavir (OBT/PTV/r) therapy in genotype 1b chronic hepatitis C patients with non-dialysis chronic kidney disease (CKD). METHODS This retrospective, multicenter study of 12-week OBT/PTV/r therapy included genotype 1b patients with non-dialysis CKD. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR)

Background and aim This study aimed to clarify the factors predictive of treatment response to tolvaptan (V2-receptor antagonist) for cirrhotic patients with hepatic edema in a real-world setting. Methods In this retrospective, multicenter study, tolvaptan was orally administered at a dose of 7.5 mg once a day. Patients with a decrease in body weight of 1.5 kg or greater from baseline were characterized as responders at day 7. Results Of 229 patients, 210 were subjected to this analysis. Patients consisted of 133 men and 77 women, with the median age of 67 years (range, 40-89 years). According to the Child-Pugh classification, five patients were classified as class A, 90 as class B, and 115 as class C. The frequencies of responders and nonresponders were 55.2% and 44.8%, respectively. Blood urea nitrogen (BUN) level was significantly lower in responders compared with nonresponders (P = 3.77 × 10-3 ). Using the receiver operating characteristic curve, the cutoff value of 28.2 mg/dL was the most useful in discriminating responders from nonresponders. Among 154 patients with BUN level of less than 28.2 mg/dL, 95 (61.7%) were responders. By contrast, among 56 patients with BUN level of 28.2 mg/dL or more, 21 (37.5%) were nonresponders (P = 2.70 × 10-3 ). On multivariate analysis, BUN level of 51 mEq/day were found to be independent factors associated with the response to tolvaptan. Conclusions This study suggests that BUN level and urinary sodium excretion are closely associated with the response to tolvaptan in cirrhotic patients with hepatic edema.

The gut microbiota (GM) play a central role in their host's metabolism of bile acids (BAs) by regulating deconjugation, dehydroxylation, dehydrogenation, and epimerization reactions to generate unconjugated free BAs and secondary BAs. These BAs generated by the GM are potent signaling molecules that interact with BA receptors, such as the farnesoid X receptor and Takeda G-protein-coupled receptor 5. Each BA has a differential affinity to these receptors; therefore, alterations in BA composition by GM could modify the intensity of receptor signaling. Bile acids also act as antimicrobial agents by damaging bacterial membranes and as detergents by altering intracellular macromolecular structures. Therefore, BAs and the GM reciprocally control each other's compositions. In this review, we discuss the latest findings on the mutual effects of BAs and GM on each other; we also describe their roles in the pathophysiology of liver disease progression and potential therapeutic applications of targeting this cross-talk.