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The patient was a 62-year-old woman. She had been treated for systemic lupus erythematosus (SLE) for 15 years and had a stable clinical course with cyclosporine, prednisolone, and ticlopidine. She experienced anal pain, diarrhea, and bloody stools for four months. Colonoscopy showed scattered large and small punchedout ulcers in the colon and deep longitudinal ulcers in the sigmoid colon. Blood test results indicated low SLE activity. Culture of mucosal biopsy did not reveal any findings. Computed tomography showed intestinal membrane arteriovenous dilatation (comb sign), therefore lupus enteritis was suspected. After initiating endoxan pulse therapy, symptoms improved rapidly. Disappearance of ulcers was confirmed by endoscopic images.

ObjectiveAscites in patients with decompensated cirrhosis can lead to abdominal distention and decrease quality of life. Tolvaptan, a vasopressin V2 receptor antagonist, is an effective agent in the treatment of ascites, whereas some patients are refractory to tolvaptan. The efficacy of transjugular intrahepatic portosystemic shunt (TIPS) for these patients is not known. In this study, we performed TIPS for tolvaptan-refractory cirrhotic patients and analysed its efficacy and safety in these patients.DesignThis retrospective analysis included patients with liver cirrhosis who received TIPS for ascites or hydrothorax refractory to tolvaptan therapy along with conventional diuretics between January 2015 and May 2018 at Tokai University Hospital. We evaluated the efficacy and safety of TIPS.ResultsThis study included four patients. All patients presented with Child-Pugh class B liver cirrhosis and model for end-stage liver disease-sodium scores were 10/12/14/16. TIPS was generated successfully without any major complications in all patients. The body weight decreased by a mean of 4.7 (SD=1.0) kg and estimated glomerular filtration rate improved from a mean of 38.2 (SD=10.3) to 59.5 (SD=25.0) mL/min/1.73 m2in a month after TIPS procedure.ConclusionTIPS is an effective potential treatment for ascites in patients with tolvaptan refractory condition. In appropriate patients who can tolerate TIPS, the treatment may lead towards renal function improvement.

BACKGROUND The commonest sites of extrahepatic metastases from hepatocellular carcinoma (HCC) are the lungs, bones, adrenal glands, and regional lymph nodes. Hematogenous metastasis to the gastrointestinal (GI) tract is a rare condition in patients with HCC, and the prognosis is usually poor. We report, herein, an extremely rare case of a patient with intussusception due to hematogenous metastasis of HCC to the ileum and his long-term survival with multidisciplinary therapy. CASE SUMMARY The patient was a 71-year-old man with a history of chronic hepatitis B, who had undergone three surgeries for HCC. He was treated with sorafenib for peritoneal metastases of HCC. He was admitted to our hospital with chief complaints of abdominal pain and vomiting. Abdominal contrast-enhanced computed tomography imaging revealed a small intestinal tumor, presenting with intussusception and small bowel obstruction. Conservative treatment was started, but due to repeated exacerbation of symptoms, surgery was planned on the 28th d of hospitalization. Partial ileal resection without reducing the intussusception and end-to-end anastomosis was performed. On histological examination, tumor cells were not observed on the serosal surface, but intravascular invasion of tumor cells was seen. Immunohistochemistry was positive for immunohistochemical markers, and a diagnosis of hematogenous metastasis of HCC to the ileum was made. He remains alive 82 mo after the first surgery. CONCLUSION Prognosis of HCC patients with GI tract metastasis is usually poor, but in some cases, multidisciplinary therapy may prolong survival.

Purpose: To assess the utility of measurement of the computed tomography (CT) attenuation value (CTav) in predicting tumor necrosis in hepatocellular carcinoma (HCC) patients who achieve a complete response (CR), defined using modified Response Evaluation Criteria in Solid Tumors (mRECIST), after lenvatinib treatment. Method: We compared CTav in arterial phase CT images with postoperative histopathology in four patients who underwent HCC resection after lenvatinib treatment, to determine CTav thresholds indicative of histological necrosis (N-CTav). Next, we confirmed the accuracy of the determined N-CTav in 15 cases with histopathologically proven necrosis in surgical specimens. Furthermore, the percentage of the tumor with N-CTav, i.e. the N-CTav occupancy rate, assessed using Image J software in 30 tumors in 12 patients with CR out of 571 HCC patients treated with lenvatinib, and its correlation with local recurrence following CR were examined. Results: Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off value of CTav of 30.2 HU, with 90.0% specificity and 65.0% sensitivity in discriminating between pathologically identified necrosis and degeneration, with a CTav of less than 30.2 HU indicating necrosis after lenvatinib treatment (N30-CTav). Furthermore, the optimal cut-off value of 30.6% for the N30-CTav occupancy rate by ROC analysis was a significant indicator of local recurrence following CR with 76.9% specificity and sensitivity (area under the ROC curve; 0.939), with the CR group with high N30-CTav occupancy (>30.6%) after lenvatinib treatment showing significantly lower local recurrence (8.3% at 1 year) compared with the low (30.6% might be a predictor of maintenance of CR. Use of these indicators have the potential to impact systemic chemotherapy for HCC.

Katsuaki Ogushi,1,* Makoto Chuma,1,* Haruki Uojima,2 Hisashi Hidaka,2 Kazushi Numata,1 Satoshi Kobayashi,3 Shunji Hirose,4 Nobuhiro Hattori,5 Tomoaki Fujikawa,6 Takahide Nakazawa,2 Naohisa Wada,2 Shuitirou Iwasaki,2 Taito Fukushima,3 Yusuke Sano,3 Makoto Ueno,3 Kuniyuki Kawano,3 Kota Tsuruya,4 Masako Shomura,4 Tsunamasa Watanabe,5 Kotaro Matsunaga,5 Yosuke Kunishi,7 Yusuke Saigusa,8 Kuniyasu Irie,9 Shogo Iwabuchi,6 Makoto Kako,10 Manabu Morimoto,3 Tatehiro Kagawa,4 Katsuaki Tanaka,11 Shin Maeda9 1Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan; 2Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan; 3Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan; 4Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; 6Department of Gastroenterology, Shonan Fujisawa General Hospital, Fujisawa, Japan; 7Department of Gastroenterology, Kanagawa Prefectural Ashigarakami Hospital, Kanagawa, Japan; 8Department of Biostatistics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; 9Department of Gastroenterology, Yokohama City University Hospital, Yokohama, Japan; 10Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Japan; 11Gastroenterology Division, Hadano Red Cross Hospital, Hadano, Japan*These authors contributed equally to this workCorrespondence: Makoto Chuma Gastroenterological CenterYokohama City University Medical Center, 4-57 Urafune-Cho, Minami-Ku, Yokohama, Kanagawa 2320024, JapanTel +81 45 261 5656Fax +81 45 253 9955Email chuma@yokohama-cu.ac.jpPurpose: To assess the safety, efficacy and prognostic impact of clinical factors related to lenvatinib treatment in Child-Pugh class A (CP-A) and class B (CP-B) patients with unresectable hepatocellular carcinoma (u-HCC).Methods: Patients with u-HCC who were treated with lenvatinib at multiple centers in Japan were retrospectively analyzed for treatment outcomes according to their respective CP status. Radiological objective response (OR) was assessed using modified response evaluation criteria in solid tumors (mRECIST) guidelines.Results: Baseline demographic parameters were comparable between 126 (69.6%) patients with CP-A disease and 55 patients (30.4%) with CP-B disease. Frequency of lenvatinib-related adverse events, including decreased appetite (P=0.034), diarrhea (P=0.040), elevated serum bilirubin (P=0.016) and vomiting (P=0.009), were higher in CP-B than in CP-A patients. Relative dose intensity (RDI) was significantly higher in CP-A (0.69) than CP-B patients (0.50, P < 0.001). Furthermore, OR rate (44.0%) was markedly higher in CP-A5 patients as compared to CP-A6 (25.5%), CP-B7 (22.2%), and CP-B8 patients (5.3%), respectively (P=0.002). In multivariable analysis, performance status (0 vs 1, 2, P=0.026), CP class (A vs B, P=0.045) and RDI (≥ 0.7 vs < 0.7, P=0.034) were identified as factors associated with response to lenvatinib treatment. Overall survival (OS) at 12 months was significantly different between CP-A (66.3%) and CP-B patients (30.0%, P=0.002), and between CP 5– 7 (59.2%) and CP 8 patients (34.8%, P=0.003). In multivariable analysis, CP class (A vs B, P=0.007) and Barcelona clinic liver cancer (BCLC) stage (B vs C, P=0.002) were associated with OS following lenvatinib treatment.Conclusion: Lenvatinib treatment offers significant benefits in patients with good liver function in real-world practice. The various characteristics identified in this study might be helpful as clinical predictors of response to lenvatinib and survival in clinical practice. Further studies are required to address eligibility for lenvatinib treatment in CP 7 patients.Keywords: lenvatinib, tyrosine kinase inhibitor, hepatocellular carcinoma, Child-Pugh, adverse events, overall survival

Indocyanine green (ICG) retention test is widely used for preoperative evaluation of liver function. OATP1B3 (gene symbol: SLCO1B3) is the major transporter for hepatic ICG uptake. We previously demonstrated that the individuals with a homozygous SLCO1B3 null allele revealed markedly impaired ICG clearance. However, the effect of heterozygosity of this variant on ICG clearance remains unknown. We compared the results of ICG retention rate at 15 min (ICG-R15) and hepatic OATP1B3 expression among individuals whose SLCO1B3 genotype was determined. Although OATP1B3 expression was significantly lower in the heterozygosity than the wild-type, the ICG-R15 results were comparable; 8.4 ± 3.4 (mean ± SD) % in the heterozygosity and 8.7 ± 6.0% in the wild-type. A homozygous individual revealed markedly high ICG-R15 (79.8%) and lacked OATP1B3 expression. In conclusion, the individuals with a heterozygous SLCO1B3 null variant had similar ICG clearance capacity to those with the wild-type despite decreased hepatic OATP1B3 expression.

Background: We aimed to elucidate the characteristics and prognosis of autoimmune hepatitis (AIH) patients with immunoglobulin (Ig) G4-positive plasma cell infiltration. Methods: We enrolled 84 AIH patients. The number of IgG- and IgG4-positive plasma cells was immunohistochemically counted per high-power field in the portal area. Patients with 3 or more IgG4-positive plasma cells on average and a ratio of IgG4 to IgG-positive plasma cells ≥5% were defined as IgG4-associated AIH (IgG4-AIH), and their clinicopathological characteristics and prognosis were compared to those of the remaining classical-AIH patients. Results: Ten (11.9%) and 74 patients (88.1%) were categorized as IgG4-AIH and classical-AIH patients, respectively. The median age of the IgG4-AIH patients was 67 years, the majority was female (80.0%), and the distribution was similar to that of the classical-AIH patients. The IgG4-AIH patients exhibited significantly more severe phenotypes in portal inflammation, interface hepatitis, fibrosis, and rosette formation. All clinical laboratory data were similar except for serum IgG4 levels, which were higher in IgG4-AIH patients (168.5 vs. 22.9 mg/dL, p = 0.014). During a median follow-up period of 139 months, the relapse rate was significantly lower in the IgG4-AIH group than in the classical-AIH group (11.1 vs. 49.2%; p = 0.048). Twelve (16.2%) and 6 (8.1%) classical-AIH patients underwent liver-related events and liver-related deaths, respectively. In contrast, none of the IgG4-AIH patients progressed to severe liver disease. Conclusions: The IgG4-AIH patients had more severe inflammation and advanced fibrosis in the liver. However, their prognosis was not poor compared to that of classical-AIH patients. IgG4-AIH may have a phenotype distinct from classical-AIH.

Balloon-occluded retrograde transvenous obliteration is an effective treatment for gastric varices. In this report, we illustrate a consecutive treatment strategy via brachial vein approach and n-butyl cyanoacrylate (NBCA) packing of the gastrorenal shunt (GRS) after injecting sclerosing agent in a severely obese patient. The brachial vein approach reduced the burden on the patient, and the closure of the GRS using NBCA shortened the procedure time. These techniques may improve patient comfort as well as reduce medical costs and the risks of several complications.

Hepatitis C virus (HCV) was identified in 1989. In 2020, three decades after HCV identification, three researchers won the Nobel Prize in Physiology or Medicine for the discovery of this virus. In 1992, three years after the discovery, interferon (IFN) was launched as the first anti-HCV therapy in Japan; however, the efficacy of IFN therapy was far from acceptable due to severe adverse effects. The advent of IFN-free direct-acting antivirals (DAAs) in 2014 dramatically improved the outcomes of antiviral treatment without serious adverse effects. In this study, we aimed to summarize anti-HCV therapy at the Tokai University Hospital.We identified patients who underwent anti-HCV therapy by searching medical records from January 1992 to December 2020, analyzed their background, and compared safety and efficacy among treatments.A total of 1777 treatments were given to 1299 patients. The sustained virologic response rate has dramatically increased over the past 30 years, with only 7% for IFN monotherapy and 95% or higher for recent IFN-free DAA therapies.We documented the results of anti-HCV therapy at the Tokai University Hospital. In the 30 years since the discovery of HCV, surprisingly successful progress has been accomplished in the anti-HCV treatment.

Purpose To assess the impact of clinical factors on the safety and efficacy of atezolizumab plus bevacizumab (ATZ+BV) treatment in patients with unresectable hepatocellular carcinoma (u-HCC). Method Ninety-four u-HCC patients who were treated with ATZ+BV at multiple centers were enrolled. We defined Child-Pugh (CP)-A patients who received ATZ+BV treatment as a 1st line therapy as the 'meets the broad sense of the IMbrave150 criteria' group (B-IMbrave150-in, n=46), and patients who received ATZ+BV treatment as a later line therapy or CP-B patients (regardless of whether ATZ+BV was a 1st line or later line therapy) as the B-IMbrave150-out group (n=48). Patients were retrospectively analyzed for adverse events (AEs) and treatment outcomes according to their clinical status characteristics, including neutrophil lymphocyte ratio (NLR) at baseline. Results The overall incidence of AEs was 87.2% (82/94 patients). The frequency of interruption of ATZ+BV treatment due to fatigue was higher in CP-B than CP-A patients (P=0.030). Objective response (OR) rates of the B-IMbrave150-in group (28.3%, 39.1%) were significantly higher than those of the B-IMbrave150-out group (8.3%, 18.8%; P=0.0157, 0.0401) using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST, respectively. In multivariate analysis, neutrophil lymphocyte ratio (NLR) (hazard ratio (HR), 4.591; P=0.0160) and B-IMbrave150 criteria (HR, 4.108; P=0.0261) were independent factors associated with the OR of ATZ+BV treatment using RECIST. Conclusion In real-world practice, ATZ+BV treatment might offer significant benefits in patients who meet B-IMbrave150 criteria or have low NLR. This article is protected by copyright. All rights reserved.

A 47-year-old woman visited Tokai University Hospital complaining of left cervical lymph node swelling in 2007. The laboratory data were almost normal except for slight anemia (Hgb 10.5 g/dL), elevation of serum soluble interleukin (IL)-2 receptor levels (645 U/mL [normal range 220–530 U/mL]), and positive hepatitis C virus (HCV) antibody. Serum transaminase and lactated dehydrogenase levels were normal. Contrast-enhanced computed tomography (CT) showed lymph node swelling with a diameter of 3 cm at the left supraclavicular fossa and mild splenomegaly, and 18F-fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT) revealed abnormal uptake in the left supraclavicular fossa. The patient was diagnosed as having indolent nodal marginal zone B-cell lymphoma by lymph node biopsy. After 9 years with no progression of lymphoma, the patient received 12-week ledipasvir/sofosbuvir therapy for HCV infection and achieved sustained virologic response without any adverse effects. The left supraclavicular mass disappeared in the FDG-PET/CT performed 5 months after antiviral therapy indicating complete response. The serum soluble IL-2 receptor concentration decreased to 244 U/mL. Thereafter, her lymphoma was in remission for 3 years.

412 Background: The standard treatment for intermediate stage hepatocellular carcinoma (HCC) has been transarterial chemoembolization (TACE); however, it might not be suitable for patients (pts) beyond the up-to-7 criteria because of its insufficient efficacy and decline of liver function. Conversely, lenvatinib has shown a good response rate in the phase III trial REFLECT and was considered promising as an initial treatment for patients with BCLC stage B2 HCC. Methods: We conducted a multicenter prospective observational study to evaluate the efficacy of lenvatinib as an initial treatment for pts aged 20 years or older, diagnosed with BCLC stage B2 HCC, naive to TACE, and with preserved organ function. The primary endpoint was a 1-year survival rate, with a threshold of 60% and an expected survival rate of 78% based on previous reports of TACE. With a one-sided alpha error of 5% and a power of 70%, 25 pts were recruited over an enrollment period of 2 years and a follow-up period of 10 months. Results: Enrollment began in June 2018 and was closed with 31 eligible pts enrolled by June 2020. Data cut-off was done in April 2021. Patient characteristics are as follows: the median age was 77 years (range: 57–86); 94% of the pts were male; the etiology of chronic liver disease was hepatitis B virus, hepatitis C virus, alcohol abuse, and others in 3, 6, 9, and 10 pts, respectively; 20 and 11 pts had a Child-Pugh score of 5 and 6 points, respectively; the median maximum tumor diameter was 36 mm (range: 10–135); the number of pts with a tumor number of ≥10 was 8; and the median AFP level was 52.1 ng/mL (range: 2.4–49800). The 1-year survival rate was 71.0% (90% confidence interval [CI]: 68.4–73.6) and the primary endpoint was met. The median overall and progression-free survival was 17.0 months (95% CI, 15.3–19.2) and 10.4 months (95% CI, 6.6–13.8), respectively; the 2-year survival rate was 32.3%. The objective response rate according to RECIT1.1 and mRECIST was 22.6% and 70.0%, respectively. The common adverse events (AEs) were fatigue (68%), hypertension (65%), and anorexia (61%) in any grade, AST increased (23%), ALT increased (16%), and proteinuria (13%) in grade 3 or worse. Treatment interruption and dose reduction was required in 61% and 81% of the pts, respectively. The median relative dose intensity was 61.8% (range: 7.5–100). At the time of analysis, out of 24 pts, 17 (55%), nine (29%), and two (6%) discontinued lenvatinib due to disease progression, AEs, and conversion to curative treatments, respectively. One patient who showed partial response suddenly died during treatment due to unknown reasons. Systemic chemotherapy, TACE, and transarterial infusion therapy was administered in 11 (38%), six (21%) and one (3%) as a post study treatment, respectively. Conclusions: Our study indicates that initial treatment using lenvatinib prolongs the survival of pts with BCLC stage B2 HCC.

Simple Summary Patients with advanced hepatocellular carcinoma (HCC) undergoing molecular targeted therapy often experience non-negligible adverse events (AEs). Paradoxically, certain AEs are reportedly associated with a good prognosis. We aimed to identify factors predictive of treatment duration and overall survival (OS) in patients with HCC undergoing lenvatinib therapy. This study suggested that better baseline liver function was predictive of longer treatment duration and better prognosis in patients with advanced HCC treated with lenvatinib. Moreover, an AE of Grade 2/3 hypothyroidism was associated with a better prognosis in patients receiving lenvatinib treatment for advanced HCC. Continuing anticancer therapy with appropriate thyroid hormone replacement may contribute to longer survival. Abstract Patients with advanced hepatocellular carcinoma (HCC) undergoing molecular targeted therapy often experience non-negligible adverse events (AEs). Paradoxically, certain AEs are reportedly associated with a good prognosis. We aimed to identify factors predictive of treatment duration and overall survival (OS) in patients with HCC undergoing lenvatinib therapy. Forty-six consecutive patients with advanced HCC who received lenvatinib therapy from April 2018 to November 2019 were prospectively followed until November 2019. Treatment efficacy was assessed according to the modified Response Evaluation Criteria in Solid Tumors for 2–3 months after therapy initiation. The disease control rate (DCR) was defined as the percentage of patients with a complete response, partial response, or stable disease. The DCR was 65.2%, with a median survival of 10.2 months. Grade 2/3 hypoalbuminemia resulted in shorter treatment duration. Factors predictive of longer OS were a Child-Pugh score of 5 at baseline and the occurrence of Grade 2/3 hypothyroidism. Conversely, Grade 2/3 hypoalbuminemia was associated with a poorer prognosis. An AE of Grade 2/3 hypothyroidism was associated with a better prognosis in patients receiving lenvatinib treatment for advanced HCC. Continuing anticancer therapy with appropriate thyroid hormone replacement may contribute to longer OS.

Aims To assess the safety, efficacy, and prognostic impact of clinical factors associated with lenvatinib treatment in highly advanced hepatocellular carcinoma (HCC) with tumor thrombus in the main portal vein trunk (VP4) or tumor with more than 50% liver occupation (tm50%LO). Methods A total of 61 highly advanced HCC patients (41 patients with tm50%LO and 20 patients with VP4) who were treated with lenvatinib at multicenter were enrolled and retrospectively analyzed for treatment outcomes according to their clinical status, including tumor morphology. Results The most frequent grade ≥3 adverse event in tm50%LO HCC was elevated aspartate aminotransferase (17.1%). Objective response rates were 37.5% and 0% in tm50%LO HCC patients with Child-Pugh grade (CP)-A and CP-B, respectively, and 26.7% and 0% in VP4 HCC patients with CP-A and CP-B, respectively. Estimated median progression-free survival and overall survival were 132 days and 229 days, and 101 days and 201 days in patients with tm50%LO and VP4, respectively. In multivariate analysis, modified albumin-bilirubin grade (hazard ratio 0.372, 95% CI 0.157-0.887; p = 0.0241) and tumor morphology (hazard ratio 0.322, 95% CI 0.116-0.889; p = 0.0287) were independently associated with progression-free survival in patients with tm50%LO HCC. In VP4 HCC, median progression-free survival was worse in CP-B (57 days) than in CP-A patients (137 days, p = 0.0462). Conclusions Lenvatinib treatment offers a benefit in highly advanced HCC (tm50%LO or VP4) patients with good liver function or nodular-type tumor. The various characteristics identified in this study might be useful as indicators of lenvatinib treatment in highly advanced HCC with tm50%LO or VP4, which are considered very refractory cancers.

Predictive biomarkers of the response of hepatocellular carcinoma (HCC) to Lenvatinib therapy have not yet been clarified. The aim of this study was to identify clinically significant biomarkers of response to Lenvatinib therapy, to target strategies against HCC. Levels of circulating angiogenic factors (CAFs) were analyzed in blood samples collected at baseline and after introducing lenvatinib, from 74 Child-Pugh class A HCC patients who received lenvatinib. As CAF biomarkers, serum vascular endothelial growth factor (VEGF), fibroblast growth factor 19 (FGF19), FGF23, and angiopoietin-2 (Ang-2) were measured using enzyme-linked immunosorbent assays. Results: Significantly increased FGF19 (FGF19-i) levels and decreased Ang-2 (Ang-2-d) levels were seen in Lenvatinib responders as compared to non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004, ratio of Ang-2 level at four weeks/baseline: 0.584 vs. 0.810, respectively, p = 0.0002). Changes in FGF23 and VEGF levels at four weeks versus baseline, however, were not significantly different in responders versus non-responders. In multivariate analysis, the combination of serum FGF19-i and Ang-2-d was the most independent predictive factor for Lenvatinib response (Odds ratio, 9.143, p = 0.0012). Furthermore, this combination biomarker showed the greatest independent association with progression-free survival (Hazard ratio, 0.171, p = 0.0240). Early changes in circulating FGF19 and Ang-2 levels might be useful for predicting clinical response and progression-free survival in HCC patients on Lenvatinib therapy.

Background Many studies have investigated the prognosis of nonalcoholic fatty liver disease (NAFLD); however, most studies had a relatively short follow-up. To elucidate the long-term outcome of NAFLD, we conducted a retrospective cohort study of patients with biopsy-proven NAFLD. Methods We re-evaluated 6080 patients who underwent liver biopsy from 1975 to 2012 and identified NAFLD patients without other etiologies. With follow-up these patients, we evaluated the outcome-associated factors. Results A total of 223 patients were enrolled, 167 (74.9%) was non-alcoholic steatohepatitis (NASH). The median follow-up was 19.5 (0.5–41.0) years and 4248.3 person-years. The risk of type 2 diabetes mellitus (T2DM) and hypertension was 11.7 (95% confidence interval [CI] 8.70–15.6) and 7.99 (95% CI 6.09–10.5) times higher, respectively, in NAFLD patients than in the general population. Twenty-three patients died, 22 of whom had NASH. Major causes of death were extrahepatic malignancy and cardiovascular disease (21.7%) followed by liver-related mortality (13.0%). All-cause mortality was significantly higher in NASH patients than in nonalcoholic fatty liver patients (P = 0.041). In multivariate analysis, older age (hazard ratio [HR] 1.09 [95% CI 1.05–1.14], P Conclusions T2DM was highly prevalent in NAFLD patients and was significantly associated with both all-cause mortality and liver-related events. The lean patients’ prognosis wasn’t necessarily better than that of overweight patients.

Background and Objective Tolvaptan, an oral vasopressin V2 receptor antagonist, has been widely used for the treatment of patients with cirrhosis and ascites. However, its efficacy in patients with renal dysfunction remains unknown. The objective of this study was to investigate the efficacy and safety of tolvaptan in patients with decompensated cirrhosis and severe chronic kidney disease (s-CKD). Methods We studied 43 patients with liver cirrhosis who received tolvaptan (7.5 mg/day) for refractory ascites. s-CKD was defined as an estimated glomerular filtration rate (eGFR)

Drug-induced liver injury (DILI) is a major adverse event caused by drug treatment, which can be categorized into three types: hepatocellular, mixed, and cholestatic. Although nearly every class of drugs can cause DILI, an overall understanding of lipid profiles in DILI patients is lacking. We used lipidomics to analyze the plasma lipid profiles of patients to understand their hepatic pathophysiology and identify DILI biomarkers. We identified 463 lipids and compared their levels between the acute and recovery phases of the three types of DILI patients. Mixed and cholestatic types demonstrated specific plasma lipid alterations between the phases, but the hepatocellular type did not. Moreover, as specific indicators of mixed-type DILI, levels of several ceramides increased in the acute phase, while those of arachidonic acid-containing ether-linked phosphoglycerolipids decreased. In contrast, as specific indicators of cholestatic-type DILI, levels of palmitic acid-containing saturated or monounsaturated phosphatidylcholines increased in the acute phase, while those of arachidonic acid- or docosahexaenoic acid-containing ether-linked phosphoglycerolipids and phosphatidylinositols decreased. We also identified lipids with a relatively high capacity to discriminate the acute phase from the recovery phase and healthy subjects. These findings may help with understanding the pathophysiology of different DILI types and identify candidate biomarkers.

Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases.

We describe our initial clinical experience regarding the use of a 3D roadmap during balloon-occluded retrograde transvenous obliteration (BRTO) in three patients.Between June 2016 and July 2016, three BRTO procedures were performed in three patients with gastric varices. Preprocedural intravenous dynamic CT was performed, and portal venous phase CT images were postprocessed to obtain volume rendering (VR) images. A 3D roadmap was developed by overlaying the VR images onto the real-time X-ray fluoroscopy images. This 3D roadmap was used for interventional guidance during the BRTO procedure.Using a 3D roadmap, the catheterization of the gastrorenal shunt was successfully accomplished. In addition, in all three patients, the sclerosant could reach the gastric varices without the administration of iodinated contrast medium. Fluoroscopy time and the iodinated contrast dose administered in the present cohort were also substantially lower than in our previous cohorts that did not use a 3D roadmap.Using a 3D roadmap during BRTO enables easier and faster catheter manipulation, thereby helping to reduce both radiation exposure and the need to administer iodinated contrast medium.

Ursodeoxycholic acid (UDCA) partly exerts choleretic effects by modifying the function of the bile salt export pump (Bsep, ABCB11). UDCA induces insertion of Bsep into the canalicular membrane of hepatocytes; however, underlying mechanisms remain unknown. We aimed to elucidate molecular mechanisms behind UDCA-induced Bsep activation.We established MDCK II cells stably expressing both Bsep and Na(+)-taurocholate cotransporting polypeptide, and investigated the effect of UDCA on activity and protein expression of Bsep using these cells. We performed inhibitor study to know the molecules involved in UDCA-induced Bsep activation, and also tested the influence of UDCA on Bsep having a disease-associated mutation.UDCA activated Bsep in a dose-dependent manner. UDCA did not affect Bsep protein expression in whole cell lysates but increased its apical surface expression by extending the half-life from 2.4 to 5.0 h. This effect was specific to Bsep because UDCA did not affect other apical and basolateral proteins, and was independent of protein kinase A, adenylate cyclase, p38(MAPK), phosphatidylinositide 3-kinase, Ca(2+), and microtubules. NorUDCA activated Bsep similar to UDCA; however, cholic acid, taurocholic acid, and tauroUDCA had no effect. UDCA significantly increased the activity of Bsep with a benign recurrent intrahepatic cholestasis 2 mutation (A570T) but did not affect Bsep with a progressive familial intrahepatic cholestasis 2 mutation (G982R or D482G).We demonstrated that UDCA stabilizes Bsep protein in the apical membrane and increases its activity in MDCK II cells, presumably by retarding the endocytotic process.

Aim In this multicenter, randomized trial, we evaluated the effectiveness of meloxicam – a non-steroidal anti-inflammatory drug – as an adjuvant for enhancing antiviral efficacy and preventing neutropenia during the treatment of patients with genotype 1 chronic hepatitis C using peginterferon and ribavirin. Methods A total of 60 patients were randomly assigned, in a 1:1 ratio, to either the meloxicam or the control group after stratification by neutrophil count. Both groups received weekly peginterferon-α-2a (180 μg) and a weight-based dose of ribavirin for 48 weeks. The meloxicam group received meloxicam (10 mg/day) for the first 8 weeks after initiation of treatment. Results Through intent-to-treat analysis, we found that the sustained virological response rate in the meloxicam group (19/30, 63.3%) was significantly higher than in the control group (11/30, 36.7%, P

A 60-year-old man received interferon/ribavirin combination therapy for chronic hepatitis C in 2002 and achieved sustained virological response. In 2008, a hepatocellular carcinoma (HCC) with a diameter of 60 mm appeared and surgical resection was performed. In March 2011, the patient was referred to our hospital because of portal lymph node swelling. Abdominal ultrasonography, dynamic CT and dynamic MRI did not show any tumors in the liver, but revealed portal lymph node swelling (18 × 11 mm). Taking the elevation of serum des-γ-carboxy prothrombin and alpha-fetoprotein levels, including the lectin-bound type, into consideration, we made the diagnosis of HCC metastasis to the portal lymph node. We started sorafenib therapy at a dose of 800 mg/day, but discontinued it after 11 days due to grade 3 hand-foot skin reaction and rash. In spite of treatment termination, portal lymph node swelling disappeared and the serum des-γ-carboxy prothrombin and alpha-fetoprotein levels normalized. We considered that our patient achieved complete response to sorafenib according to the Response Evaluation Criteria in Solid Tumors (RECIST). The patient maintains remission up to June 2012, more than 1 year after the discontinuation of sorafenib therapy. Sorafenib could be a good option for unresectable or recurrent HCC.

A 47-year-old female patient with type C liver cirrhosis underwent endoscopic injection sclerotherapy for esophageal varices 13 years ago. The patient had no past history of hysterectomy or any other gynecological disorders. She was admitted to our hospital because of persistent vaginal bleeding and exacerbation of anemia. A contrast-enhanced computed tomography scan revealed marked dilation of not only the inferior mesenteric vein, but also the left ovarian vein, the uterine vein and the internal iliac vein. A celiac arteriography showed that the blood in the splenic vein was flowing almost totally hepatofugally into the dilated inferior mesenteric vein. An ovarian venography demonstrated knob-shaped dilation of the left ovarian vein draining into the left internal iliac vein. A proximally wedged left ovarian venography visualized the right ovarian vein and the right internal iliac vein with contrast medium via a palisade venous plexus from the dilated uterine and ovarian veins. Partial splenic embolization (PSE) was performed to increase platelet count and to reduce splenic venous blood flow into the ovarian vein. Following the PSE, the platelet count increased, and the blood flow in the dilated ovarian vein and uterine vein diminished. In addition, the portal blood flow became hepatopetal, and remarkably increased. There has as yet been no case report in which vaginal bleeding developed in women with liver cirrhosis without any past history of hysterectomy or other gynecological disorders. The present case report may be warranted in view of the rarity of the condition.

Aim: The optimal ribavirin dose in the treatment of patients infected with hepatitis C virus (HCV) genotype 2 remains to be elucidated. We aimed to seek the optimal ribavirin dose required for this genotype in a randomized trial. Methods: We compared the efficacy and tolerability of the 24-week peginterferon α-2b (1.5 µg/kg/week) therapy in combination with a weight-based higher dose (600–1000 mg) and lower dose (400–800 mg) of ribavirin for genotype 2 patients. Noninferior margin was set at 10%. Results: A total of 120 patients were randomized to a higher-dose or a lower-dose group. Sustained virological response (SVR) by intention-to-treat analysis was achieved in 47/58 (81.0%, 90% confidential interval [CI]: 72.6–89.5) patients in the higher-dose group and 41/60 (68.3%, 90% CI: 58.5–78.2) patients in the lower-dose group (difference, −12.7%; 90% CI, −25.7 to 0.3). Relapse rates were 10% and 21.6% in the higher-dose and the lower-dose groups, respectively. Multiple logistic regression analysis showed that ribavirin dose/kg body weight was the only significant predictor of SVR (≥9.5 mg/kg per day vs

Alcohol intake leads to the distribution of alcohol and its metabolite, acetaldehyde throughout the blood and organs. Hepatic cirrhosis is associated with abnormal red blood cell morphology and function, particularly impaired red blood cell deformability. To investigate the effect of drinking on red blood cells in patients with hepatic cirrhosis, erythrocyte deformability was evaluated in response to alcohol and acetaldehyde tolerance. Erythrocyte deformability in 10 healthy and 15 cirrhotic subjects was examined by filterability of the red blood cells. Erythrocyte deformability decreased markedly in the cirrhosis group compared with the healthy group (p0.05). No significant change in erythrocyte deformability was observed in healthy or cirrhotic subjects due to ethanol 100 mM tolerance. Acetaldehyde tolerance elicited a significant decrease in erythrocyte deformability at 2 mM in the cirrhosis group (p0.05). Alcohol consumption in cirrhotic patients was suggested to worsen erythrocyte deformability and red blood cell function. Decreased erythrocyte deformability worsens microcirculation in the liver, resulting in more severe hepatic dysfunction.

European studies have revealed that the ABCB11 c.1331T>C (V444A) polymorphism (rs2287622) C-allele frequency is higher among patients with drug-induced cholestasis. Given the low incidence of this disease, however, this association has not been sufficiently elucidated. We aimed to investigate the significance of this polymorphism in Japanese patients. We determined ABCB11 V444A polymorphism frequencies and HLA genotypes in two independent drug-induced cholestasis cohorts. Expression and taurocholate transport activity of proteins from 444A variants were analyzed using Madin-Darby canine kidney II cells. In cohort 1 (n = 40), the V444A polymorphism C-allele frequency (66%) was lower than that in controls (n = 190, 78%), but this difference was not significant (P = 0.09). In cohort 2 (n = 119), comprising patients with cholestatic (n = 19), hepatocellular (n = 74), and mixed (n = 26) liver injuries, the C-allele frequency was lower among patients with cholestatic liver injury (68%) than among those with hepatocellular (75%) or mixed liver injury (83%), although this difference was not significant. In cohort 1, HLA-A*0201 was observed more frequently in patients (22%) than in controls [11%; P = 0.003; odds ratio, 2.4 (95% confidence interval, 1.4-4.0)]. Taurocholate transport activity of 444A-encoded protein was significantly lower than that of 444V-encoded protein (81% of 444V, P < 0.05) because of the reduced protein stability. In conclusion, ABCB11 444A had slightly reduced transport activity, but it did not contribute to the occurrence of drug-induced cholestasis in Japanese patients. Therefore, genetic susceptibility to acquired cholestasis may differ considerably by ethnicity.

To study the relationship between adverse events (AEs), efficacy, and nursing intervention for sorafenib therapy in patients with hepatocellular carcinoma (HCC).We enrolled 37 consecutive patients with advanced HCC who received sorafenib therapy. Relationships among baseline characteristics as well as AE occurrence and tumor response, overall survival (OS), and treatment duration were analyzed. The nursing intervention program consisted of education regarding self-monitoring and AEs management, and telephone follow-up was provided once in 1-2 wk.A total of 37 patients were enrolled in the study, comprising 30 males (81%) with a median age of 71 years. The disease control rate at 3 mo was 41%, and the median OS and treatment duration were 259 and 108 d, respectively. Nursing intervention was given to 24 patients (65%). Every patient exhibited some kinds of AEs, but no patients experienced G4 AEs. Frequently observed AEsG2 included anorexia (57%), skin toxicity (57%), and fatigue (54%). Factors significantly associated with longer OS in multivariate analysis demonstrated that age ≤ 70 years, presence ofG2 skin toxicity, and absence ofG2 hypoalbuminemia. The disease control rate in patients withG2 skin toxicity was 13/20 (65%), which was significantly higher compared with that in patients with no or G1 skin toxicity. Multivariate analysis revealed that nursing intervention andG2 skin toxicity were independent significant predictors for longer treatment duration.Skin toxicity was associated with favorable outcomes with sorafenib therapy for advanced HCC. Nursing intervention contributed to better adherence, which may improve the efficacy of sorafenib.

In this multicenter, randomized trial, we evaluated the effectiveness of meloxicam - a non-steroidal anti-inflammatory drug - as an adjuvant for enhancing antiviral efficacy and preventing neutropenia during the treatment of patients with genotype 1 chronic hepatitis C using peginterferon and ribavirin.A total of 60 patients were randomly assigned, in a 1:1 ratio, to either the meloxicam or the control group after stratification by neutrophil count. Both groups received weekly peginterferon-α-2a (180 μg) and a weight-based dose of ribavirin for 48 weeks. The meloxicam group received meloxicam (10 mg/day) for the first 8 weeks after initiation of treatment.Through intent-to-treat analysis, we found that the sustained virological response rate in the meloxicam group (19/30, 63.3%) was significantly higher than in the control group (11/30, 36.7%, P 0.05). The relapse rate was more than twice as high (45%) in the control group than in the meloxicam group (19.0%); however, this difference was not statistically significant. The rate of neutrophil decrease, calculated by dividing the lowest value observed during the first 8 weeks by pretreatment count, was significantly smaller in the meloxicam group (55.1 ± 14.3%) than in the control group (62.3 ± 9.6%, P 0.05).Meloxicam enhanced antiviral efficacy and reduced the decline in neutrophil counts for the peginterferon and ribavirin treatment of genotype 1 chronic hepatitis C. This drug could be a reasonable adjuvant for the treatment of patients with chronic hepatitis C. The present study including a small number of patients warrants larger clinical trials.

The optimal ribavirin dose in the treatment of patients infected with hepatitis C virus (HCV) genotype 2 remains to be elucidated. We aimed to seek the optimal ribavirin dose required for this genotype in a randomized trial. We compared the efficacy and tolerability of the 24-week peginterferon α-2b (1.5 µg/kg/week) therapy in combination with a weight-based higher dose (600-1000 mg) and lower dose (400-800 mg) of ribavirin for genotype 2 patients. Noninferior margin was set at 10%. A total of 120 patients were randomized to a higher-dose or a lower-dose group. Sustained virological response (SVR) by intention-to-treat analysis was achieved in 47/58 (81.0%, 90% confidential interval [CI]: 72.6-89.5) patients in the higher-dose group and 41/60 (68.3%, 90% CI: 58.5-78.2) patients in the lower-dose group (difference, -12.7%; 90% CI, -25.7 to 0.3). Relapse rates were 10% and 21.6% in the higher-dose and the lower-dose groups, respectively. Multiple logistic regression analysis showed that ribavirin dose/kg body weight was the only significant predictor of SVR (≥9.5 mg/kg per day vs9.5 mg/kg per day; odds ratio = 3.34; 95% CI, 1.41-7.92; P = 0.006). Twenty-one (36.2%) in the higher-dose group required ribavirin dose reduction because of anemia, whereas seven patients (11.7%) did in the lower-dose group (P 0.01). Three of the higher-dose group and two of the lower-dose group required premature termination of therapy. Weight-based lower-dose ribavirin regimen was not equivalent to the higher-dose counterpart in the treatment of HCV genotype 2. We discourage treating these patients with low-dose ribavirin regimens. The peginterferon therapy in combination with ribavirin at a weight-based higher dose (600-1000 mg) remains the standard-of-care treatment for this genotype.

To clarify the impact of adherence, we treated 122 genotype 1 high viral titer chronic hepatitis C patients with pegylated interferon (peg-IFN) and ribavirin for 48 weeks at nine referral hospitals, and evaluated the prognostic factors with a focus on the adherence to the treatment. This study included 68 (55.7%) treatment-naïve patients and 54 (44.3%) patients who did not respond to the previous treatment. Multivariate analysis revealed adherence to peg-IFN and ribavirin as the only significant predictor. Sustained virological response (SVR) rate was 72.2%, 19.0%, and 27.3% in patients given ≥80%, 60%–80%, and