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Abstract Background Circulating autotaxin (ATX) levels have been reported to correlate with liver inflammation activity and liver fibrosis severity in patients with non-alcoholic fatty liver disease (NAFLD). The objective of this study is to investigate whether serum ATX could predict liver-related events (LRE) in NAFLD patients. Methods This retrospective investigation includes 309 biopsy-proven NAFLD patients registered at Shinshu University Hospital. All patients are followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, hepatic encephalopathy, ascites, and esophagogastric varices, is investigated in relation to ATX levels at the time of liver biopsy. Results During the median follow-up period of 7.0 years, LRE are observed in 20 patients (6.5%). The area under the receiver operating characteristic curve and cut-off value of serum ATX for predicting LRE are 0.81 and 1.227 mg/l, respectively. Multivariate Cox proportional hazards models for LRE determine ATX and advanced fibrosis as independently associated factors. Furthermore, in a competing risk analysis that considered non-liver-related death as a competing event, ATX (HR 2.29, 95% CI 1.22–4.30, p = 0.010) is identified as an independent factor associated with LRE, along with advanced fibrosis (HR 8.01, 95% CI 2.10–30.60, p = 0.002). The predictive utility of ATX for LRE is validated in an independent cohort. Conclusions Serum ATX may serve as a predictive marker for LRE in patients with NAFLD.

AimShort-term use of pemafibrate (PEM), a selective modulator of peroxisome proliferator-activated receptor alpha, has been reported to improve abnormal liver function in patients with nonalcoholic fatty liver disease with hypertriglyceridemia (HTG-NAFLD). This study aimed to clarify the effects and predictive factors of long-term 72-week PEM administration on body composition, and laboratory tests in HTG-NAFLD patients.MethodsFifty-three HTG-NAFLD patients receiving a 72-week PEM regimen were retrospectively enrolled. Routine blood and body composition results were analyzed immediately before and at the end of the study period.ResultsPEM treatment significantly improved liver enzyme levels such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and gamma-glutamyl transferase, along with lipid profiles including triglyceride, total cholesterol, and low-density lipoprotein cholesterol. PEM did not have any detectable impact on body composition parameters. The factors of female, higher AST (≥ 46 U/L) and fat mass (≥ 31.9%), as well as lower soft lean mass (< 61.6%), skeletal muscle mass (< 36%), and skeletal muscle mass index (< 6.9 kg/m2) were significantly associated with the treatment response status of a > 30% decrease in ALT. All patients completed the treatment without any adverse effects.ConclusionsLong-term PEM treatment had a positive impact on liver enzymes and lipid profiles, but it did not result in significant changes in body composition among HTG-NAFLD patients. In predicting the response to PEM treatment, the evaluation of AST and body composition may be useful.

Abstract Background and Aim As the exact prevalence of portopulmonary hypertension (PoPH) and the etiology of chronic liver disease (CLD) remain unknown, the present study aimed to clarify these points in Japanese patients with CLD using symptom‐based questionnaire screening. Methods Patients with CLD were asked to complete an eight‐item written questionnaire on pulmonary hypertension (PH) symptoms. If at least one item response was “yes,” the patient was offered ultrasonic echocardiography (UCG). Patients identified as having an intermediate or high risk of PH by UCG were referred to a cardiologist for further evaluation, whereby a definitive diagnosis of PoPH was made using right heart catheterization (RHC) findings. Results A total of 1111 patients with CLD completed the survey. Of the 566 symptomatic patients with at least one question answered as “yes,” approximately half agreed to undergo UCG (n = 267). Compared with asymptomatic patients, symptomatic patients were significantly older, predominantly female, and more frequently exhibited cirrhosis. Based on UCG findings, 228, 12, and 8 patients had a low, intermediate, or high risk for PH, respectively. Intermediate‐/high‐risk patients showed significantly more advanced disease progression status than low‐risk patients. The frequencies of answer to the eight questions were comparable. Ultimately, three patients were diagnosed as having PoPH (1.1% of UCG cases), one with underlying hepatitis C virus (HCV) infection and two with primary biliary cholangitis (PBC). Conclusion This symptom‐based PoPH screening study clarified the prevalence of PoPH in CLD patients according to a PH symptom questionnaire, UCG, and RHC. Patients with HCV and PBC may have a higher risk of PoPH.

A pyogenic liver abscess (PLA) is a space-occupying lesion in the liver that is associated with significant morbidity and mortality. We herein present the case of a Japanese 76-year-old man who visited our hospital with fever and back pain lasting 3 weeks after endoscopic treatment for common bile duct stones. He was accompanied by poorly controlled diabetes mellitus (DM) with an HbA1c of 9.7 %. Laboratory tests disclosed elevated C-reactive protein level (22.1 mg/dL) and white cell count (11,910/μL). Abdominal computed tomography (CT) revealed hypodense lesions in the right liver lobe, with abdominal ultrasonography showing an echogenicity-mixed hypoechoic lesion. Percutaneous needle aspiration of a liver lesion was performed under suspicion of a PLA. Subsequent enhanced CT and magnetic resonance imaging confirmed the hepatic lesions in the right lobe as well as a septic pulmonary embolism, right hepatic vein thrombosis, spondylodiscitis, and a retroperitoneal abscess. Gram staining of the abscess drainage revealed gram-negative bacteria. The above findings indicated invasive liver abscess syndrome (ILAS) caused by Klebsiella pneumoniae. However, further examination of blood, urine, and abscess drainage cultures revealed positivity for Klebsiella oxytoca. This case illustrates that K. oxytoca may cause ILAS-like symptoms. Screening for systemic metastatic infection should be considered in patients with PLA due to K. oxytoca in whom therapeutic intervention has been delayed, especially in patients with poorly controlled DM.

Abstract Among several secreted glycoproteins belonging to the thrombospondin family, thrombospondin 2 (TSP2) is involved in various functions, including collagen/fibrin formation. Liver/serum TSP2 levels have been correlated to liver fibrosis stage and disease activity in nonalcoholic fatty liver disease. This study investigated whether serum TSP2 was associated with clinicopathological features in hepatitis C virus (HCV)-infected patients as well. A total of 350 patients with HCV who had undergone liver biopsy were retrospectively enrolled and divided into a discovery cohort (n = 270) and a validation cohort (n = 80). In the discovery cohort, serum TSP2 levels were moderately correlated with both liver fibrosis stage (r = 0.426, P

Background: Serum C-reactive protein (CRP) is an established biomarker for acute inflammation and has been identified as a prognostic indicator for hepatocellular carcinoma (HCC). However, the significance of the serum CRP level, specifically in HCC patients treated with lenvatinib, remains unclear. Methods: We retrospectively analyzed 125 HCC patients who received lenvatinib treatment at six centers. Clinical characteristics were assessed to identify clinical associations between serum CRP and HCC prognosis. Results: The median overall serum CRP level was 0.29 mg/dL. The cohort was divided into two groups: the low-CRP group with a serum CRP < 0.5 mg/dL and the high-CRP group with a serum CRP ≥ 0.5 mg/dL. The low-CRP group exhibited significantly longer overall survival (OS) than the high-CRP group (22.9 vs. 7.8 months, p < 0.001). No significant difference was observed for progression-free survival (PFS) between the high- and low-CRP groups (9.8 vs. 8.4 months, p = 0.411), while time-to-treatment failure (TTF) was significantly longer in the low-CRP group (8.5 vs. 4.4 months, p = 0.007). The discontinuation rate due to poor performance status was significantly higher in the high-CRP group (p < 0.001). Conclusion: A baseline serum CRP level exceeding 0.5 mg/dL was identified as an unfavorable prognostic factor in HCC patients receiving lenvatinib treatment.

Abstract Natural killer cells are modulated through the binding of killer cell immunoglobulin-like receptors (KIRs) with human leukocyte antigen (HLA) class I ligands. This study investigated the association of KIR/HLA pairs with progression to liver cirrhosis, hepatocellular carcinoma (HCC) development, and nucleot(s)ide (NUC) treatment freedom in hepatitis B virus (HBV) infection. KIR, HLA-Bw, and HLA-C were genotyped in 280 Japanese HBV patients for clinical comparisons. No significant associations of KIR/HLA pairs were detected in terms of liver cirrhosis development. The KIR2DS3 positive rate was significantly higher in patients with HCC (n = 39) than in those without (n = 241) [30.8% vs. 14.9%, odds ratio (OR) 2.53, P = 0.015]. The KIR3DL1/HLA-Bw4 pair rate was significantly lower in the NUC freedom group (n = 20) than in the NUC continue group (n = 114) (25.0% vs. 52.6%, OR 0.30, P = 0.042). In conclusion, this study indicated remarkable associations of KIR/HLA with HCC development (KIR2DS3) and freedom from NUC therapy (KIR3DL1/HLA-Bw4) in HBV patients, although the number of cases was insufficient for statistical purposes. Additional multi-center analyses of larger groups are needed to clarify whether KIR/HLA pairs play a role in HBV patient status.

Aim: Pemafibrate (PEM) is a novel selective peroxisome proliferator-activated receptor alpha modulator that is effective for hypertriglyceridemia accompanying non-alcoholic fatty liver disease (HTG-NAFLD). This study aimed to identify the predictors of PEM efficacy for HTG-NAFLD in clinical practice. Methods: We retrospectively enrolled 88 HTG-NAFLD patients treated with PEM for 6 months for the analysis of routine blood and body composition testing. A PEM response was defined as a decrease in serum alanine aminotransferase (ALT) of >30% compared with pre-treatment level. The clinical features related to PEM responsiveness were statistically tested between responders and non-responders. Results: All 88 patients completed the 6 month drug regimen without any adverse effects. PEM treatment significantly decreased liver enzymes, triglycerides, and total cholesterol levels, without any detectable impact on body weight or body composition. Comparisons of baseline clinical features revealed female and greater aspartate aminotransferase (AST), ALT, and fat mass % levels to be significantly associated with a PEM response. The optimal cut-off values to predict responders as determined by receiver operating characteristic analysis were AST 45 U/L, ALT 60 U/L, and fat mass 37%. Conclusions: Female HTG-NAFLD patients with higher transaminase and fat mass % levels may be preferentially indicated for PEM treatment. Additional large-scale prospective studies are warranted to verify our results.

BackgroundPortopulmonary hypertension (PoPH) is a subtype of the pulmonary arterial hypertension (PAH) associated with portal hypertension. There is a dissociation between the proportion of PoPH in PAH and that of PoPH in patients with liver cirrhosis, suggesting PoPH underdiagnosis and an incomplete understanding of this entity in the clinical setting. Specifically, real-world data in Japan is largely unknown as compared with in Europe and the United States. The present study aims to elucidate the prevalence and etiology of PoPH in Japanese patients with chronic liver disease.Methods and designIn this prospective, single-center, observational investigation of PoPH patients with chronic liver disease, a targeted 2,500 Japanese adult patients regularly visiting Shinshu University Hospital in Matsumoto, Japan, for chronic liver disease will complete a standardized questionnaire on the presence of PoPH symptoms. If the respondent has signs of possible PoPH, ultrasound echocardiography (UCG) will be performed as a primary screening. In the case that UCG findings indicate pulmonary hypertension, the patient will be referred to a cardiologist for further evaluation, whereby a definitive diagnosis PoPH can be made. PoPH prevalence and etiology will be investigated at the time of diagnosis. Afterwards, patients with PoPH will be followed for five years for determination of survival rate.DiscussionThis study will reveal the prevalence, etiology, and 5-year survival rate of PoPH in Japanese patients with chronic liver disease.Trial registrationThis study is being performed at Shinshu University following registration as UMIN 000042287 on October 29, 2020.

BackgroundThe World Health Organization has set a goal of hepatitis C virus (HCV) elimination by the year 2030. However, no regions in Japan have succeeded in eradicating HCV. Micro-elimination is an approach to attain hepatitis C eradication in which national eradication goals are applied to specific populations so that viral treatment and control efforts can move forward quickly and efficiently. In order to eradicate HCV from Japan, this study aims to achieve HCV micro-elimination in the town of Nagawa.Methods and designThe Nagawa Project is an ongoing, prospective, multiple-institution, observational study running from April 1, 2021, to March 31, 2024. All residents of Nagawa town, excluding those under 20 years of age, not consenting to the study, or unable to undergo health check-ups due to nursing care needs, will be included. If found to be HCV antibody-positive, the participant will be recommended to see a doctor in consideration of MAC-2 binding protein glycosylation isomer values. Then, the participant will undergo serum HCV RNA measurement with the real-time polymerase chain reaction by an attending physician. If the participant is HCV RNA-positive, he or she will be referred to a hepatologist for further evaluation. In the case of a definitive diagnosis of chronic hepatitis C, direct acting antiviral treatment will be initiated. Through this process, HCV will be systematically micro-eliminated from the region.DiscussionThe Nagawa Project will reveal the prevalence of chronic HCV in addition to the HCV eradication rate in Nagawa town towards achieving HCV micro-elimination.Trial registrationThis study is performed by Shinshu University School of Medicine and was registered as UMIN 000044114 on May 6, 2021.

Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset.

Background: The incidence of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is low, at 7–8% of all non-Hodgkin lymphoma cases. The most common site of MALT lymphoma occurrence is the stomach. Primary hepatic extranodal marginal zone lymphoma of MALT is classified as a type of non-gastric MALT lymphoma and is considered extremely rare, with no consensus on imaging study findings or treatment due to a limited number of reports. We herein describe a rare case of primary hepatic extranodal marginal zone lymphoma of MALT with underlying hepatitis B infection (HBV) and present useful diagnostic findings of various imaging modalities, including contrast-enhanced ultrasonography (CEUS) with Sonazoid. Case presentation: A 66-year-old woman was diagnosed as being a non-active carrier of HBV at 51 years of age at the time of total hysterectomy and bilateral adnexectomy for uterine cervical cancer. She was admitted to our hospital following the incidental detection of two focal liver lesions on computed tomography. The lesions were considered malignant based on clinical and other radiologic imaging findings. Her CEUS results of hypo-enhancement in the portal and late phases were consistent with those of previously reported cases of hepatic extranodal marginal zone lymphoma of MALT, and histological liver biopsy findings were compatible with the diagnosis. Conclusions: Primary hepatic extranodal marginal zone lymphoma of MALT is a rare condition that can appear in HBV carriers. Characteristic CEUS findings may help in disease diagnosis. Clinicians should bear primary hepatic extranodal marginal zone lymphoma of MALT in mind when encountering patients with focal liver lesions which exhibit image findings different from those of typical hepatocellular carcinoma.

Objective: Hepatic overexpression of the thrombospondin 2 gene (THBS2) and elevated levels of circulating thrombospondin 2 (TSP2) have been observed in patients with chronic liver disease. This study aimed to identify the specific cells expressing THBS2/TSP2 in non-alcoholic fatty liver disease (NAFLD) and investigate the underlying mechanism behind THBS2/TSP2 upregulation. Design: Comprehensive NAFLD liver gene datasets, including single-cell RNA sequencing (scRNA-seq), in-house NAFLD liver tissue, and LX-2 cells derived from human hepatic stellate cells (HSCs), were analysed using a combination of computational biology, genetic, immunological, and pharmacological approaches. Results: Analysis of the genetic dataset revealed the presence of 1433 variable genes in patients with advanced fibrosis NAFLD, with THBS2 ranked among the top 2 genes. Quantitative polymerase chain reaction (qPCR) examination of NAFLD livers showed a significant correlation between THBS2 expression and fibrosis stage (r = .349, p < .001). In support of this, scRNA-seq data and in situ hybridization demonstrated that the THBS2 gene was highly expressed in HSCs of NAFLD patients with advanced fibrosis. Pathway analysis of the gene dataset revealed THBS2 expression to be associated with the transforming growth factor beta (TGFβ) pathway and collagen gene activation. Moreover, the activation of LX-2 cells with TGFβ increased THBS2/TSP2 and collagen expression independently of the TGFβ-SMAD2/3 pathway. THBS2 gene knockdown significantly decreased collagen expression in LX-2 cells. Conclusions: THBS2/TSP2 is highly expressed in HSCs and plays a role in regulating fibrogenesis in NAFLD patients. THBS2/TSP2 may therefore represent a potential target for anti-fibrotic therapy in NAFLD. [ABSTRACT FROM AUTHOR]