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Like esophageal varices, cardiac varices are often treated with endoscopic variceal ligation (EVL). However, we previously reported that EVL for cardiac varices may be associated with a high risk of rebleeding from the ulcer if the O-ring spontaneously drops off early. The efficacy and safety of para-variceal endoscopic injection sclerotherapy (EIS) with polidocanol for the treatment of cardiac varices in children and adolescents were evaluated.Eleven patients under 18 years of age with portal hypertension who underwent para-variceal EIS with polidocanol for cardiac varices with red signs, which were considered to be at high risk of bleeding, were retrospectively reviewed.One session of para-variceal polidocanol-EIS was performed for each of the 11 patients. One patient experienced temporary hypoxia due to aspiration of saliva when the tracheal intubation tube was removed after the procedure but recovered by endotracheal suctioning; there were no other adverse events. In six of the eight cases in which efficacy could be evaluated, eradication of cardiac varices was achieved.Para-variceal polidocanol-EIS may be considered instead of EVL for small cardiac varices with red signs in pediatric patients with cardiac varices.

Endoscopic injection sclerotherapy (EIS) for esophagogastric varices (EGV) was attempted for a 29-year-old man with extrahepatic portal vein obstruction. However, pipeline varices characterized by a large blood flow volume were present, and the sclerosant did not accumulate sufficiently in them. Transileocolic obliteration (TIO) using coils was performed, but some EGVs and palisading veins remained. Thus, EIS was performed once again immediately after TIO. Since a reduction in the intravariceal blood flow was achieved by preceding TIO, effective injection of sclerosant into the vessels was possible. For pipeline varices difficult to treat endoscopically, combination therapy with TIO may be effective.

Immune-related liver injury (liver-irAE) is a clinical problem with a potentially poor prognosis.We retrospectively collected clinical data from patients treated with immune checkpoint inhibitors between September 2014 and December 2021 at the Nagoya University Hospital. Using an unsupervised machine learning method, the Gaussian mixture model, to divide the cohort into clusters based on inflammatory markers, we investigated the cumulative incidence of liver-irAEs in these clusters.This study included a total of 702 patients. Among them, 492 (70.1%) patients were male, and the mean age was 66.6 years. During the mean follow-up period of 423 days, severe liver-irAEs (Common Terminology Criteria for Adverse Events grade ≥ 3) occurred in 43 patients. Patients were divided into five clusters (a, b, c, d, and e). The cumulative incidence of liver-irAE was higher in cluster c than in cluster a (hazard ratio [HR]: 13.59, 95% confidence interval [CI]: 1.70-108.76, P = 0.014), and overall survival was worse in clusters c and d than in cluster a (HR: 2.83, 95% CI: 1.77-4.50, P 0.001; HR: 2.87, 95% CI: 1.47-5.60, P = 0.002, respectively). Clusters c and d were characterized by high temperature, C-reactive protein, platelets, and low albumin. However, there were differences in the prevalence of neutrophil count, neutrophil-to-lymphocyte ratio, and liver metastases between both clusters.The combined assessment of multiple markers and body temperature may help stratify high-risk groups for developing liver-irAE.

Aim: Conventionally, the skeletal muscle area with computed tomography (CT) attenuation ranging from −29 to +150 Hounsfield unit (HU) divided by height squared (the conventional skeletal muscle index [SMI]) was used as an index of skeletal muscle mass. However, it includes fat-infiltrated skeletal muscle, which is known to have poor function. This study aims to determine whether the low-fat SMI, which uses skeletal muscle mass with CT attenuation ranging from +30 to +150 HU, or conventional SMI appropriately reflects the function of skeletal muscle. Methods: We retrospectively analyzed 120 patients with cirrhosis whose handgrip strength was measured. Among them, 48 patients underwent a physical performance assessment such as liver frailty index (LFI) and short physical performance battery (SPPB), and 80 underwent quality of life (QOL) assessment. The relationships between each SMI and handgrip strength, LFI, SPPB, and QOL were evaluated. Results: Low-fat SMI was significantly correlated with handgrip strength (males, R=0.393, p=0.002; females, R=0.423, p

A porous glass membrane-pumping emulsification device (GMD) enables the formation of a high-percentage water-in-oil emulsion with homogeneous and stable droplets. Although GMD is expected to improve the locoregional therapeutic effects of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC), its effectiveness in the management of solitary HCC remains unclear.Patients treated for solitary HCCs (5 cm) were retrospectively reviewed. A total of 46 patients who could not undergo liver resection and were unsuitable for radiofrequency ablation were included in this study. Among these, 22 patients underwent TACE using a GMD (GMD-TACE group) and 24 underwent stereotactic body radiotherapy (SBRT) using a robotic radiosurgery system (SBRT group). Local control rates were compared between the two groups.The median HCC tumour size was 24 mm (range=12-50 mm) and 22 mm (range=8-39 mm) in the GMD-TACE and SBRT groups, respectively; however, the difference between the groups was not significant. Age, liver function test results, or Child-Pugh scores were not significantly different between the two groups. The rate of local control at 6 months after treatment was 100% in both groups. Although the 1-year local control rate was higher in the SBRT group (92.3%) than in the GMD-TACE group (81.8%), there was no significant difference in the log-rank test (p=0.654). No major treatment-related complications occurred in either group during the observation period.TACE with GMD could be considered an effective treatment option for the management of solitary HCC.

Background Elevated bile acid levels have been associated with liver tumors in fatty liver. Ileal bile acid transporter inhibitors may inhibit bile acid absorption in the distal ileum and increase bile acid levels in the colon, potentially decreasing serum and hepatic bile acids. This study investigated the impact of these factors on tumors. Methods C57BL/6J mice received a one-time intraperitoneal injection of 25 mg/kg of diethylnitrosamine. They were fed a choline-deficient high-fat diet for 20 weeks starting from 8 weeks of age, with or without elobixibat (EA Pharma, Tokyo, Japan). Results Both groups showed liver fat accumulation and fibrosis, with no significant differences between the two groups. However, mice treated with elobixibat showed fewer liver tumors. The total serum bile acid levels, including free-/tauro-/gly- conjugated bile acids and tauro-α/β-muricholic acids in the liver, were noticeably reduced with elobixibat. The proportion of gram-positive bacteria in feces was significantly lower in the group treated with elobixibat (5.4%) than in the group without elobixibat (33.7%). Conclusion Elobixibat suppressed tumor growth by inhibiting bile acid reabsorption and decreasing total bile acid and primary bile acid levels in the serum and liver. Additionally, the presence of bile acids in the colon may have led to a significant reduction in the proportion of gram-positive bacteria, potentially resulting in decreased secondary bile acid synthesis.

Background: Immune-related sclerosing cholangitis (irSC) is relatively rare and its clinical characteristics are not well known. In this study, we aimed to summarize the clinical features of irSC. Methods: Clinical data were collected retrospectively from 1,393 patients with advanced malignancy treated with immune-checkpoint inhibitors (ICIs) between August 2014 and October 2021. We analyzed patients with immune-related adverse events of liver injury (liver-irAEs) and compared irSC and non-irSC groups. Results: Sixty-seven patients (4.8%) had a liver-irAE (≥ grade 3) during the follow-up period (median, 262 days). Among these, irSC was observed in eight patients (11.9%). All patients in the irSC group were treated with anti-PD-1/PD-L1 antibodies. Compared with the non-irSC group, the irSC group showed mainly non-hepatocellular liver injury (87.5 % vs 50.8 %, P = 0.065), and had elevated serum inflammatory markers (e.g., CRP and NLR) and biliary enzymes (e.g., GGTP and ALP) at the onset of liver-irAEs. Furthermore, most patients with irSC had abdominal pain. In the non-irSC group, the liver injury of 23 patients improved only with the discontinuation of ICIs, and 22 patients improved with medication including prednisolone (PSL). Conversely, almost all patients (n=7) in the irSC group were treated with PSL, but only two patients experienced an improvement in liver injury. Conclusion: We found that irSC is characterized by a non-hepatocellular type of liver injury with abdominal pain and a high inflammatory response and is refractory to treatment. Further examination by imaging is recommended to detect intractable irSC in cases with these characteristics.

The impact of a high-fat diet (HFD) on intestinal permeability has been well established. When bacteria and their metabolites from the intestinal tract flow into the portal vein, inflammation in the liver is triggered. However, the exact mechanism behind the development of a leaky gut caused by an HFD is unclear. In this study, we investigated the mechanism underlying the leaky gut related to an HFD. C57BL/6J mice were fed an HFD or control diet for 24 weeks, and their small intestine epithelial cells (IECs) were analyzed using deep quantitative proteomics. A significant increase in fat accumulation in the liver and a trend toward increased intestinal permeability were observed in the HFD group compared to the control group. Proteomics analysis of the upper small intestine epithelial cells identified 3684 proteins, of which 1032 were differentially expressed proteins (DEPs). Functional analysis of DEPs showed significant enrichment of proteins related to endocytosis, protein transport, and tight junctions (TJ). Expression of Cldn7 was inversely correlated with intestinal barrier function and strongly correlated with that of Epcam. This study will make important foundational contributions by providing a comprehensive depiction of protein expression in IECs affected by HFD, including an indication that the Epcam/Cldn7 complex plays a role in leaky gut.

The gut microbiota interacts with infectious diseases and affects host immunity. Liver disease is also reportedly associated with changes in the gut microbiota. To elucidate the changes in the gut microbiota before and after hepatitis C virus (HCV) eradication through direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C (CHC), we investigated 42 samples from 14 patients who received DAA therapy for HCV. Fecal samples were obtained before treatment (Pre), when treatment ended (EOT), and 24 weeks after treatment ended (Post24). The target V3–4 region of the 16S rRNA gene from fecal samples was amplified using the Illumina Miseq sequencing platform. The diversity of the gut microbiota did not significantly differ between Pre, EOT, and Post24. Principal coordinates analysis showed that for each patient, the values at Pre, EOT, and Post24 were concentrated within a small area. The linear discriminant analysis of effect size showed that the relative abundances of Faecalibacterium and Bacillus increased at EOT, further increased at Post24, and were significantly increased at Post24 compared to Pre. These suggest that changes in the gut microbiota should be considered as among the various effects observed on living organisms after HCV eradication.

Objective: In patients with liver cirrhosis, the clinical characteristics of dynapenia, a condition in which skeletal muscle mass is maintained but muscle strength is reduced, are not yet known. This study aimed to clarify the characteristics of dynapenia and its impact on quality of life (QOL) in patients with liver cirrhosis. Methods: We retrospectively analyzed 116 patients with cirrhosis. Based on grip strength and skeletal muscle mass measured by the bioelectrical impedance analysis method, patients were divided into four groups: normal muscle status, dynapenia, pre-sarcopenia (a condition involving only low muscle mass), and sarcopenia. The characteristics of dynapenia and its influence on QOL were examined. Results: Fourteen patients had dynapenia. Liver function did not differ among the four groups. In patients with dynapenia, BMI was highest and computed tomography attenuation of skeletal muscle at the third lumbar spine vertebra was lowest among the four groups. The percentage of patients with both BMI ≥25 kg/m2 and myosteatosis was significantly higher in patients with dynapenia [9/14 (64.3%)] than in those with sarcopenia [2/23 (8.7%), P = 0.004] and pre-sarcopenia [0/18 (0%), P < 0.001] and tended to be higher than those with normal muscle status [16/61 (26.2%), P = 0.065]. The physical QOL in patients with dynapenia was as low as that in those with sarcopenia and significantly lower than that in those with normal muscle status. Conclusion: Cirrhotic patients with dynapenia had high BMI and myosteatosis, and impaired physical QOL.

Background & aims Hepatocellular carcinoma in nonalcoholic steatohepatitis is caused by the complex factors of inflammation, fibrosis and microbiomes. We used network analysis to examine the interrelationships of these factors. Methods C57Bl/6 mice were categorized into groups: choline-sufficient high-fat (CSHF, n = 8), choline-deficient high-fat (CDHF, n = 9), and CDHF+ diethylnitrosamine (DEN, n = 8). All mice were fed CSHF or CDHF for 20 weeks starting at week 8, and mice in the CDHF + DEN group received one injection of DEN at 3 weeks of age. Bacterial gene was isolated from feces and analyzed using Miseq. Results The CSHF group had less fibrosis than the other groups. Tumors were found in 22.2% and 87.5% of the CDHF group and CDHF + DEN groups, respectively. Gene expression in the liver of Cdkn1a (p21: tumor-suppressor) and c-jun was highest in the CDHF group. Bacteroides, Roseburia, Odoribacter, and Clostridium correlated with fibrosis. Streptococcus and Dorea correlated with inflammation and tumors. Akkermansia and Bilophila were inversely correlated with fibrosis and Bifidobacterium was inversely correlated with tumors. Conclusions DEN suppressed the overexpression of p21 caused by CDHF. Some bacteria formed a relationship networking associated with their progression and inhibition for tumors and fibrosis.

Background Endoscopic variceal ligation (EVL) is a widely accepted treatment for esophagogastric varices in patients with portal hypertension. It is used for urgent treatment and prophylactic treatment of esophagogastric varices not only in adults, but also in pediatric patients. However, major life-threatening adverse events such as early rebleeding can occur. Although early rebleeding after EVL among children and adolescents has been reported, the risk factors remain obscure. This study evaluated the risk factors for early rebleeding after EVL in children and adolescents. Methods Subjects were children and adolescents with portal hypertension aged less than 18 years who underwent EVL for esophagogastric varices. Early rebleeding was defined as hematemesis, active bleeding or blood retention in the stomach, confirmed by esophagogastroduodenoscopy from 2 hours to 5 days after EVL. Results A total of 50 EVL sessions on 22 patients were eligible for this study. There were 4 episodes of early rebleeding. No other major adverse events have occurred. Multivariate analysis showed that EVL implemented at cardiac varices just below the esophagogastric junction (EGJ); within 5mm from the EGJ, is the independent factor of higher risk of early rebleeding: odds ratio 18.2 (95% Confidence interval: 1.40-237.0), p=0.02. Conclusions Children and adolescents who undergo EVL for cardiac varices just below the EGJ have a higher risk of early rebleeding than those who do not.

Aim Lipid droplets have been found in the nuclei of hepatocytes, however, their role in liver is not clearly understood. The purpose of this study was to explore the pathophysiological roles of intranuclear lipid droplets in liver diseases. Method This study included 80 patients who underwent liver biopsies. A part of the liver biopsy specimen was dissected and fixed for electron microscopic observation. Lipid droplets in the nuclei were distinguished into two types based on the presence of adjacent cytoplasmic invagination of the nuclear membrane: nuclear lipid droplet (nLD) and cytoplasmic lipid droplet invagination with nucleoplasmic reticulum (cLD in NR). Results nLDs were found in 69% of the liver biopsy samples, and cLDs in NR were found in 32%. A significant positive correlation was observed between the frequencies of nLD and cLD in NR. Although nLD was frequently found in hepatocytes of patients with nonalcoholic steatohepatitis, there was no correlation between the frequency of nLD and hepatic steatosis, indicating that nLD does not directly reflect cytoplasmic lipid accumulation. Significant positive correlations were found between the frequencies of nLD and endoplasmic reticulum (ER) expansion or liver enzymes, suggesting that nLD is formed in the nucleus under ER stress. Conversely, cLD in NR showed a significant negative correlation with hepatic steatosis, implying that cLD in NR is formed in lipid-restricted hepatocytes. Moreover, no correlations were observed between the frequency of cLD in NR and ER expansion. Conclusion This study revealed two distinct pathophysiological roles of lipid droplets in liver diseases.

Esophagogastric varices (EGVs) may develop as a result of portal hypertension in children with biliary atresia (BA). Although endoscopic injection sclerotherapy (EIS) with ethanolamine oleate (EO) is reported useful for children, risk factors associated with the presence of high-risk EGVs after treatment remain unknown.The subjects were BA patients under 15 years of age who underwent EO-EIS. We retrospectively reviewed a total of 28 treatment sessions of EGVs with red signs and those larger than F2, which were considered to be at high risk of bleeding. Survival analysis was performed for the presence of high-risk EGVs at the time of follow-up endoscopy as the occurrence of an event.Univariate analysis showed a significantly increased risk of the presence of high-risk EGVs post-EO-EIS in patients with increased liver stiffness (LS) and Mac-2 binding protein glycan isomer (M2BPGi), with hazard ratios of 1.48 and 1.15, respectively. The median presence-free period was significantly shorter in the LS ≥ 2.8 m/sec patients than in those with LS 2.8 m/sec (189 vs. 266 days). Similarly, the median presence-free period was significantly shorter in patients with M2BPGi ≥ 4.0 than in those with M2BPGi 4.0 (182 vs. 203 days). The results of multivariate analysis revealed that the risk of the presence of high-risk EGVs was significantly higher only in the high-LS group, with a hazard ratio of 2.76.Increased LS is associated with risk of the presence of high-risk EGVs following EO-EIS in children with BA. (246 words).

Objectives In this study, we revisited the reasons for poorer prognosis afterlivertransplantin patients with hepatitis C virus, whose main causes of death were generally known to be recurrent disease. Materials and methods Between April 2003 and March 2017, among 132 patients who underwent liver transplantbecause ofliver cirrhosis at ourinstitution, 40 patients (30.3%) were positive for hepatis C virus. We retrospectively compared the overall survival afterliver transplantin patients with and without hepatitis C virus infection. Furthermore, we investigated the causes of death in transplant recipients with hepatitis C virus infections. Results In patients with hepatitis C virus infection, overall survivalwas 82.2%, 75.2%, and50.8% at 1, 5, and 10 years,respectively, afterlivertransplant;these results were lower than those in patients without infection (94.5%, 87.0%, and 87.0% at 1, 5, and 10 years, respectively; P = .001). Among 40 patients with positive infection, 14 patients died after liver transplant. A main reason for death was hepatocellular carcinoma recurrence (3 patients). Surprisingly, only 1 patient died from hepatitis C virus-related complication (fibrosing cholestatic hepatitis); the remaining 10 patients died from reasons other than hepatitis C virus disease progression. Conclusions Our results suggest that clinicians should not only be aware of hepatitis C virus recurrence but should also be aware of other unrelated complications in transplant recipients who are positive for this virus.

Background & Aims To provide an adequate treatment strategy for chronic hepatitis B, it is essential to know which patients are expected to have a good prognosis and which patients do not require therapeutic intervention. Previously, we identified the substitution of isoleucine to leucine at amino acid 97 (I97L) in the hepatitis B core region as a key predictor among patients with stable hepatitis. In this study, we attempted to identify the point at which I97L affects the hepatitis B virus (HBV) life cycle and to elucidate the underlying mechanisms governing the stabilization of hepatitis. Methods To confirm the clinical features of I97L, we used a cohort of hepatitis B e antigen–negative patients with chronic hepatitis B infected with HBV-I97 wild-type (wt) or HBV-I97L. The effects of I97L on viral characteristics were evaluated by in vitro HBV production and infection systems with the HBV reporter virus and cell culture-generated HBV. Results The ratios of reduction in hepatitis B surface antigen and HBV DNA were higher in patients with HBV-I97L than in those with HBV-I97wt. HBV-I97L exhibited lower infectivity than HBV-I97wt in both infection systems with reporter HBV and cell culture-generated HBV. HBV-I97L virions exhibiting low infectivity primarily contained a single-stranded HBV genome. The lower efficiency of cccDNA synthesis was demonstrated after infection of HBV-I97L or transfection of the molecular clone of HBV-I97L. Conclusions The I97L substitution reduces the level of cccDNA through the generation of immature virions with single-stranded genomes. This I97L-associated low efficiency of cccDNA synthesis may be involved in the stabilization of hepatitis., Graphical abstract

Purpose Gastrointestinal bleeding (GIB) due to esophageal varices (EV) is one of the factors that negatively impacts native liver survival of patients with biliary atresia (BA). Gastrointestinal fibroscopy (GIF) is usually used to determine the presence of EVs; however, it require general anesthesia. The aim of this study is to search for markers in blood tests obtained during routine check-ups that can predict the development of GIB. Methods Data of patients with BA who underwent portoenterostomy at our hospital from 2014 to 2020 were retrospectively reviewed. The patients’ data were assigned to three groups according to specific time points: Group B, which included data at GIB; Group NB-T, which included data at GIF and EV treatment; and Group NB-NT, which included data at GIF without treatment. The data in Group B were compared to those of other groups. Results In our study, GIB occurred in 11 patients, and 12 cases, and 8 cases were classified into Groups NB-NT and NB-T, respectively. Compared with the other groups, only ChE and M2BPGi in Group B showed statistically significant differences. Conclusions ChE and M2BPGi are useful for predicting GIB.

Summary Background & aims The impact of obesity, evaluated using body mass index (BMI), on mortality in patients with cirrhosis is controversial. The prognostic impact of visceral fat accumulation, which is recommended as an indicator of obesity-related mortality, is still unknown. This study aimed to clarify the impact of visceral fat accumulation on mortality in patients with cirrhosis. Methods A total of 335 cirrhotic patients without hepatocellular carcinoma were retrospectively evaluated. The impact of obesity, defined as a visceral fat area ≥100 cm2 at the umbilical level or BMI ≥25 kg/m2 on mortality, was evaluated using competing risk analysis. Results Of 355 patients, visceral fat accumulation was seen in 147 patients. During the observation period (1340 ± 980 days), 84 patients died, and 17 received liver transplantation. Visceral fat accumulation was not found to be associated with mortality (hazard ratio [HR] 1.423, P = 0.180) in any of the patients. After stratification of the patients, visceral fat accumulation was observed to be associated with a poor prognosis in patients with skeletal muscle depletion (HR 3.804, P = 0.003), but not in those without (HR 1.147, P = 0.660). On the other hand, obesity defined by BMI ≥25 kg/m2 was not found to be associated with mortality in patients with (HR 0.341, P = 0.390) or without skeletal muscle depletion (HR 1.227, P = 0.500). Conclusions Visceral fat accumulation is a useful index for evaluating obesity and aggravates mortality in cirrhotic patients with skeletal muscle depletion, but not in those without.

Background: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. Method: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. Results: In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. Conclusion: Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib.

Diagnosis and severity assessments of portosystemic shunts (PSSs) are important because the pathology sometimes results in severe hepatic encephalopathy, which can be treated almost completely by shunt embolization. At present, morphological assessment of PSS is performed mainly by computed tomography, and ultrasound is used for blood flow assessment. In two cases of PSS-related hepatic encephalopathy, we used time-resolved 3D cine phase-contrast (4D-flow) magnetic resonance imaging (MRI) to assess blood flow before and after shunt embolization. Before the intervention, blood flow in the main trunk of the superior mesenteric vein was mostly hepatofugal. However, post-interventional 4D-flow MRI revealed hepatopetal superior mesenteric vein flow with significantly increased portal vein blood flow. 4D-flow MRI is an ideal adjunct to Doppler ultrasonography, allowing for objective and visual assessment of morphology and blood flow of the portal venous system, including PSSs, and is useful in determining the indications for, and outcome of, PSS embolization.

Background/aim The purpose of this study was to determine changes in the hepatic arteries after treatment with a molecular targeted agent (MTA), and evaluate the safety and efficacy of transarterial chemoembolization (TACE) as a post-MTA treatment in patients with hepatocellular carcinoma (HCC). Patients and methods The cases of 33 patients with intermediate HCC treated with MTA and TACE were studied retrospectively. The hepatic arteries, and the safety and efficacy of TACE were evaluated before and after MTA treatment. Results Following long-term MTA treatment, the diameters of hepatic arteries decreased significantly, while there was no difference in the diameters of the splenic artery or the portal vein. No significant adverse events were observed due to TACE after MTA; however, the therapeutic effect of TACE was limited after MTA treatment. Conclusion This study demonstrated that the diameters of hepatic arteries were significantly smaller than those before MTA induction, suggesting ischemic effects and tumor vessel "normalization" by MTA treatment. Although TACE can be performed as a post-MTA treatment without lowering the hepatic reserve or causing serious complications, its therapeutic effect is limited.

This study aimed to evaluate the usefulness of a coaxial double balloon catheter for simplification of the balloon-occluded retrograde transcatheter obliteration (BRTO) procedure compared with a single-balloon catheter. Thirty-three patients who underwent BRTO with a single-balloon catheter (Single-balloon group, n = 15) or a coaxial double balloon catheter (Coaxial group, n = 18) were included, retrospectively. The frequency of additional procedures for stagnation of sclerosant including ethanol injection, coil embolization, and additional balloon occlusion for collateral draining veins; the dose of ethanolamine oleate (EO); and the complication rate and the success rate of sclerosant stagnation were evaluated. Additional procedures were needed in four patients in the Coaxial group, which was significantly lower than that in the Single-balloon group (nine patients, P = 0.038). The dose of EO in the Coaxial group (11.2 ± 6.6 g) was lower, but not significantly different than that in the Single-balloon group (14.4 g ± 6.1 g, P = 0.184). The complication rate and the success rate of sclerosant stagnation were not different between the two groups. The use of a coaxial double balloon catheter can simplify the BRTO procedure compared with a single-balloon catheter.

The albumin–bilirubin (ALBI) score is calculated using only serum albumin and bilirubin levels, and was developed as a simple method to assess hepatic function. In this study, a total of 409 patients with primary biliary cholangitis (PBC) were enrolled between March 1990 and October 2018. The predictive performances of the ALBI score and other well-established prognostic scores were compared using time-dependent receiver operating characteristic (ROC) analysis. During the follow-up period, 60 patients died, 45 due to liver-related diseases and 15 due to non-liver-related diseases, and 16 patients underwent liver transplantation. Time-dependent ROC analysis showed that the ALBI score has higher the areas under the ROC curves (AUROCs) than the Child–Pugh (C–P) score at each time point; AUROCs at 3, 5, and 10 years after the start of follow-up were 0.94, 0.91, and 0.90 for the ALBI score, and 0.89, 0.88, and 0.82 for the C–P score, respectively. The ALBI score showed the highest AUROCs within 2 years after the start of observation; beyond 2 years, however, the Mayo score had better prognostic ability for mortality and liver transplantation. The ALBI score/grade, derived from objective blood tests, and the Mayo score were superior prognostic tools in PBC patients.

OBJECTIVE Chronic liver diseases are associated with zinc (Zn) deficiency. However, no previous studies have examined the relationship between serum Zn levels and hepatic pathological findings in patients with nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the serum Zn levels in NAFLD patients based on pathological/laboratory findings. METHODS We evaluated a total of 191 NAFLD patients who underwent liver biopsy with the goal of identifying laboratory markers and pathological findings associated with serum Zn levels. RESULTS Zn levels significantly decreased along with progression of hepatic fibrosis (P = 0.039), but there were no significant differences among inflammatory grades. Zn levels were most strongly correlated with albumin levels (r = 0.410, P

Background/aim We aimed to compare the outcomes between sorafenib and lenvatinib as first-line therapy for advanced hepatocellular carcinoma (HCC) with major portal vein tumor thrombosis (Vp3/4). Patients and methods This retrospective study enrolled 41 HCC patients with Vp3/4 and Child-Pugh A. Results The outcomes in the lenvatinib group (n=13) were significantly better than those in the sorafenib group (n=28) [best objective response rate according to the modified Response Evaluation Criteria in Solid Tumors: 53.8% vs. 14.3%; p=0.0193, best disease control rate: 92.3% vs. 35.7%; p=0.0008, median overall survival (OS): not reached vs. 187 days; p=0.0040, respectively]. Lenvatinib treatment was the only significant predictor of better OS and time to tumor progression. No patient needed to discontinue lenvatinib treatment due to drug-related adverse events. Conclusion Compared with sorafenib, lenvatinib treatment for advanced HCC with Vp3/4 may lead to more favorable outcomes.

Background/aim The outcomes of ramucirumab after lenvatinib failure for hepatocellular carcinoma (HCC) patients with alpha fetoprotein (AFP) levels of ≥400 ng/ml are unknown. Patients and methods Of 12 patients treated with ramucirumab after lenvatinib failure, 10 patients were enrolled in this retrospective study. Results The disease control rate of 80% at 6 weeks and the median time to progression of 3.1 months were the same by both the Response Evaluation Criteria in Solid Tumors (RECIST) and the modified RECIST. AFP reduction was seen in 5 patients at 2 weeks and in 3 patients at 6 weeks. The incidence of grade 3 adverse events was low at 10%. The albumin-bilirubin scores within 6 weeks did not worsen. Conclusion Ramucirumab might have potential therapeutic efficacy and safety in advanced HCC patients after lenvatinib failure. Further studies are needed to confirm the outcomes of ramucirumab after lenvatinib failure.

Liver injury induced by immune checkpoint inhibitors (ICIs) is an immune-related adverse event (irAE) whose incidence has increased with the broader use of ICIs in clinical practice. However, the incidental risk factors of immune-related liver injury are unknown. We investigated the clinical characteristics of immune-related liver injury. A total of 546 patients treated with ICIs for advanced malignancies between September 2014 and February 2019 were included retrospectively. Factors associated with immune-related liver injury were determined. Immune-related liver injury (≥ Grade 3) occurred in 29 (5.3%) patients (Grade 3, n = 20; Grade 4, n = 8; Grade 5, n = 1) during the follow-up period (median 153 days). The patterns of liver injuries were hepatocellular, n = 6 (20.7%); cholestatic, n = 17 (58.6%); and mixed, n = 6 (20.7%). The median period between the initial administration of ICIs and the incidence of irAEs was 52 days. Of 29 patients with immune-related liver injury (≥ Grade 3), four showed immune-related cholangitis with non-obstructive dilation of the bile ducts. Factors that were significantly associated with the incidence of immune-related liver injury in multivariate analysis were use of ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agent [hazard ratio [HR] 4.22, 95% confidence interval (CI) 1.65–10.80, P = 0.003], and fever over 38 °C within 24 h of initial ICI administration (HR 6.21, 95% CI 2.68–14.40, P

Background/aim Sorafenib results in several adverse events, the mechanism and predictors of which are unknown. Recently, it was reported that metabolism by microbiome changes the structure and effects of drugs. The blood levels of sorafenib may be affected by enterohepatic recycling of sorafenib due to microbial enzymes in the gut. We evaluated the relationship between adverse events caused by sorafenib treatment and microbiome in patients with advanced hepatocellular carcinoma. Materials and methods Twenty-five patients were classified into two groups based on the presence of hand-foot syndrome (HFS) or diarrhea within 12 weeks post-sorafenib treatment. Before sorafenib treatment, the fecal samples were analyzed targeting the V3-V4 region of 16s ribosomal RNA. Microbiome and predicted functional gene were compared between two groups. Results The non-HFS group had a richer abundance of Veillonella, Bacillus, Enterobacter, Faecalibacterium, Lachnospira, Dialister, and Anaerostipes than the HFS group at genus level. Carotenoid biosynthesis and bacterial invasion of epithelial cells were enriched in the HFS group. The former three bacteria are classified as oral-origin bacteria, and the two predicted functions are associated with dysbiosis. The non-diarrhea group had a higher abundance of Butyricimonas and a lower abundance of Citrobacter, Peptostreptococcus, and Staphylococcaceae than the diarrhea group. Eight categories of predicted functional genes were detected with differences between the two groups. Conclusion The non-HFS group had a higher relative abundance of oral-origin bacteria, which likely led to more robust dysbiosis in the gut. This dysbiosis may affect enterohepatic recycling. Additionally, the metabolism of these short-chain fatty acids in the gut may be different between the diarrhea and non-diarrhea groups.

Changes in body composition parameters are important prognostic factors in hepatocellular carcinoma (HCC) treatment. This study aimed to assess the clinical impact of early changes in body composition during lenvatinib (LEN) treatment on its time to treatment failure (TTF) for patients with advanced HCC.In this retrospective study, we enrolled 65 patients who were administered LEN as the first-line treatment for unresectable HCC and evaluated the body composition change using computed tomography. We focused on the body composition change after 2 weeks of LEN treatment and assessed its impact on TTF and prognosis.Significant changes in body composition were observed during 14 weeks of LEN treatment. Among these changes, mean-skeletal muscle attenuation (SMA) decreased significantly within 2 weeks (This study revealed that LEN treatment induces a change in the skeletal muscle asymptomatically for a short period, and evaluation of this change may help to predict the TTF of LEN treatment in patients with HCC.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2022.2049322 .

Background: Rifaximin is commonly used for hepatic encephalopathy (HE). However, the effects of long-term treatment for Japanese people are limited. Therefore, this study aimed to investigate the effects and safety of long-term treatment with rifaximin on HE. Methods: A total of 215 patients with cirrhosis administered with rifaximin developed overt or covert HE, which was diagnosed by an attending physician for >12 months. Laboratory data were extracted at pretreatment and 3, 6, and 12 months after rifaximin administration. The long-term effect of rifaximin was evaluated, and the incidence of overt HE during 12 months and adverse events was extracted. Results: Ammonia levels were significantly improved after 3 months of rifaximin administration and were continued until 12 months. There were no serious adverse events after rifaximin administration. The number of overt HE incidents was 9, 14, and 27 patients within 3, 6, and 12 months, respectively. Liver enzymes, renal function, and electrolytes did not change after rifaximin administration. Prothrombin activity is a significant risk factor for the occurrence of overt HE. The serum albumin, prothrombin activity, and albumin–bilirubin (ALBI) scores were statistically improved after 3 and 6 months of rifaximin administration. Moreover, the same results were obtained in patients with Child–Pugh C. Conclusions: The long-term rifaximin treatment was effective and safe for patients with HE, including Child–Pugh C.

Introduction and objectives Hepatitis C virus (HCV) infections in patients with hemophilia lead to the development of hepatocellular carcinoma (HCC) at a relatively younger age than that in patients without hemophilia. Although recent progress in direct-acting-antivirals has facilitated a high rate of sustained virological response (SVR), the clinical influence of HCV eradication in hemophilia patients remains unclear. This study aimed to compare the clinical outcomes of SVR against HCV in patients with and without hemophilia. Patients and methods The study enrolled 699 patients who achieved SVR after HCV antiviral treatment. Patients were divided into two groups: 78 patients with hemophilia (H group) and 621 patients without hemophilia (NH group). We evaluated patient characteristics, clinical outcomes, and the cumulative incidence of HCC after SVR. Results Compared with the NH group, patients in the H-group were significantly younger and had a lower hepatic fibrosis score. No difference was found in the incidence of liver-related disease or overall death between the two groups over a mean follow-up period of 7 years. Four patients in the H group and 36 patients in the NH group were diagnosed with HCC after SVR. Multivariate analysis showed that male sex, age, and cirrhosis were significant risk factors for HCC incidence. There was no significant difference in the cumulative incidence of HCC after propensity-score matching adjusting for the risk factors of HCC between the two groups. Conclusion Hemophilia is not a significant risk factor for hepatocarcinogenesis after SVR against HCV.

A man in his 50s with Budd-Chiari syndrome diagnosed with the suprahepatic inferior vena cava (IVC) obstruction on CT was assessed using 4D Flow MRI before and after balloon angioplasty. 4D Flow MRI acquired in two respiratory phases, depicted complex hemodynamic and respiratory variability, and a jet stream at the narrowed channel of the membranous IVC. Post-interventional 4D Flow MRI showed that the IVC blood flow increased with corrected flow directions in the infrarenal IVC.

Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma.This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH.Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2.The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells.Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH.

Introduction: Lenvatinib has been widely used for the treatment of advanced hepatocellular carcinoma (HCC). Some adverse events, including diarrhea, have been reported for lenvatinib. Diarrhea may be associated with the changes in the intestinal microbiome; however, the underlying mechanism has not been elucidated. Aim: In this study, we aimed to investigate the relationship between the intestinal microbiome and diarrhea caused by lenvatinib via analysis of fecal samples collected before treatment. Methods: A total of 21 patients with advanced HCC who were treated with lenvatinib were enrolled. Fecal samples were collected from patients. The patients were divided into diarrhea (n = 8) and nondiarrhea groups (n = 12). We compared the characteristics of patients, incidence of adverse events, composition of the intestinal microbiome, and enrichment of functional pathways between both groups using QIIME2 and PICRUSt2. Results: The median age of the two groups was 73 years. The nondiarrhea group comprised a relatively higher number of male patients than the diarrhea group; however, there were no significant differences in patient characteristics between both groups. The proportion of the microbiome was similar, and alpha and beta diversities were not significantly different between both groups. The relative abundance of order Bacteroidales, including Parabacteroides and Prevotella, was higher in the diarrhea group than in the nondiarrhea group. PICRUSt2 analysis showed some metabolic pathways, including butanoate (butyrate) metabolism, were enriched in the nondiarrhea group when compared with those in the diarrhea group. Conclusion: Differences in the intestinal microbiomes and their functions may influence the incidence of diarrhea during lenvatinib treatment.

It remains unclear whether severe liver immune-related adverse events (liver-irAEs) can affect the prognosis in non-small cell lung carcinoma (NSCLC) patients. Of the 365 NSCLC patients treated with immune checkpoint inhibitors (ICIs), 19 suffered from severe liver-irAEs (grade ≥3). The median time-to-onset of liver-irAEs was 53 days post-injection of the first ICI. The progression-free survival and overall survival of the liver-irAEs group (median 69 and 262 days, respectively) were significantly worse than the non-liver-irAEs group (128 and 722 days; P = 0.010 and P = 0.007; respectively). In conclusion, liver-irAEs were associated with poor prognosis in NSCLC patients.