Ryuta Shigefuku

Metabolic dysfunction‐associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disease worldwide, with an increasing number of patients progressing to cirrhosis and hepatocellular carcinoma (HCC). Early identification of individuals at high risk for advanced fibrosis is essential for preventing liver‐related events and improving long‐term outcomes. This guideline summarizes current evidence and provides practical recommendations for the diagnosis, risk stratification, and management of MASLD in clinical practice. These recommendations were developed through systematic evaluation of the literature and expert consensus. Diagnostic approaches, including noninvasive fibrosis assessment tools, imaging, biochemical testing, and indications for referral to gastroenterology/hepatology specialists, were reviewed. Advanced fibrosis is the major determinant of liver‐related morbidity and mortality in MASLD. The Fibrosis‐4 (FIB‐4) index is a widely accessible and reliable first‐line noninvasive tool for fibrosis risk stratification. Patients with elevated FIB‐4 values or clinical features suggestive of progressive liver injury should undergo secondary assessment with elastography and be referred to a specialist when appropriate. Liver biopsy is not routinely required for the diagnosis of MASLD but remains essential for establishing a definitive diagnosis of at‐risk metabolic dysfunction–associated steatohepatitis (MASH), assessing inflammatory activity, resolving discrepancies between noninvasive tests, and differentiating MASLD from other chronic liver diseases. Lifestyle modification remains the foundation of management, with pharmacological therapy considered for patients with a high likelihood of at‐risk MASH. MASLD represents a heterogeneous disease spectrum in which advanced fibrosis is the key prognostic factor. These guideline recommendations aim to standardize clinical practice and support evidence‐based management of MASLD in Japan.

Background: Hepatocellular carcinoma (HCC) with Vp4 portal vein tumor thrombosis (PVTT) has an extremely poor prognosis, and evidence for effective systemic therapy is limited. Preclinical studies suggest that hypofractionated radiation therapy (HFRT) may enhance immune checkpoint inhibitor (ICI) efficacy through immunogenic cell death and modulation of the tumor microenvironment. Methods: We conducted a retrospective feasibility study of HFRT combined with ICIs for unresectable HCC. Patients receiving atezolizumab plus bevacizumab (Atz/Bev) or durvalumab plus tremelimumab (Dur/Tre) as first‐line therapy between October 2020 and March 2025 were analyzed. Since July 2022, those with Vp4 PVTT received HFRT (5 Gy × 5) targeting PVTT with ICIs. Outcomes were compared among Vp4 patients with HFRT, Vp4 patients without HFRT, and patients without Vp4 invasion (non‐Vp4). Results: Eight Vp4 patients received HFRT plus ICIs (Atz/Bev, n = 5; Dur/Tre, n = 3). The best responses of the main intrahepatic lesions by RECIST 1.1 were complete response (CR) in 1 (12.5%), partial response (PR) in 6 (75%), and stable disease in 1 (12.5%), yielding a high objective response rate (ORR) of 87.5%. By mRECIST, CR was achieved in 3 patients (37.5%). Overall survival in Vp4 patients with HFRT was comparable to non‐Vp4 patients and significantly better than Vp4 patients without HFRT. No gastrointestinal bleeding or perforation occurred, and ALBI scores were preserved at 12 weeks. Conclusions: HFRT combined with ICIs is feasible, well tolerated, and may improve outcomes in HCC with Vp4 PVTT. Prospective studies are warranted to confirm efficacy and determine optimal treatment protocols.

A 22-year-old female was referred to our hospital due to thrombocytopenia and esophagogastric varices (EGV) [LmF2CbRC1, Lg-c,F1RC0], therefore we performed endoscopic variceal ligation. Dynamic abdominal computed tomography showed giant portosystemic shunts (PSSs) from the left gastric vein to the superior vena cava and splenomegaly despite normal hepatic contour. Blood tests showed thrombocytopenia and hypoalbuminemia, but there were no abnormalities in hepatic function. Retrograde hepatic venography and transjugular liver biopsy were subsequently performed in order to further examine liver pathology. These examinations revealed anastomosis between the right and middle hepatic veins, with no features to suggest cirrhosis, therefore diagnosed as idiopathic portal hypertension. Splenectomy was performed for the treatment of hypersplenism with thrombocytopenia. Nine months after undergoing a splenectomy, the patient consulted a cardiologist due to exertional dyspnea with WHO functional class II. Echocardiography revealed a mild dilatated right ventricle (RV) with an estimated systolic pressure of 55 mmHg, consistent with pulmonary hypertension. Right heart catheterization determined an increased mean pulmonary arterial pressure of 40 mmHg and pulmonary vascular resistance of 7.5 wood units, but a normal pulmonary capillary wedge pressure value of 7 mmHg, resulting in the diagnosis of portopulmonary hypertension (PoPH). Administration of oral macitentan 5 mg/day was initiated. Exertional dyspnea and the findings from right heart catheterization were improved with macitentan 10 mg/day. No report exists of PoPH occurring within one year after splenectomy, however we report here a very rare case in which a splenectomy brought about the onset of PoPH.

Introduction Non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated steatotic liver disease (MASLD), is a phenotype of the metabolic syndrome in the liver and is clearly associated with metabolic abnormalities such as hyperglycaemia and dyslipidaemia. Although the prevalence of MASLD is increasing worldwide, there is currently no consensus on the efficacy and safety of the drugs used to treat MASLD/metabolic dysfunction-associated steatohepatitis (MASH). Pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was designed to have higher peroxisome proliferator-activated receptor alfa (PPARα) agonist activity and selectivity than existing PPARα agonists, and in development trials, without increasing creatinine levels, lipid parameters and alanine aminotransferase (ALT) were significantly improved. Thus, pemafibrate may effectively ameliorate the pathogenesis and metabolic abnormalities in MASLD/MASH. In this trial, we evaluated the efficacy and safety of pemafibrate in patients with MASLD/MASH. Methods and analysis This trial was designed as an open-label, three-arm, randomised controlled study. After obtaining informed consent, patients aged 20–80 years who met the selection criteria were enrolled. Patients were randomised to receive pemafibrate 0.4 mg/day, 0.2 mg/day or fenofibrate (n=120 per group). The duration of treatment was 48 weeks. The primary endpoint was a change in ALT levels after 24 weeks of administration. Secondary endpoints included changes from baseline in liver fibrosis markers (fibrosis-4 index, type IV collagen 7s, enhanced liver fibrosis and Mac-2 binding protein glycosylation isomer) at 48 weeks as well as changes in liver fat mass and liver stiffness measured by MRI and ultrasound (US) at centres equipped with MRI and US capabilities. Ethics and dissemination Ethical approval was obtained from the Yokohama City University Certified Institutional Review Board before participant enrolment (CRB20-014). The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. Participants wishing to understand the results of this study will be contacted directly on data publication. Trial registration number This trial was registered in the Japan Registry of Clinical Trials (number: jRCTs031200280). Protocol version V.1.9, 23 November 2023

Background and Aims: Skeletal muscle loss has been identified as a prognostic factor in patients with unresectable hepatocellular carcinoma (uHCC) undergoing treatment with lenvatinib (LEN). While atezolizumab plus bevacizumab (ATZ-BEV) is recommended as first-line therapy for uHCC, the impact of skeletal muscle loss in these patients remains unclear. Methods: We enrolled 97 patients treated with either LEN or ATZ-BEV as their first-line therapy and divided them into two groups based on the presence or absence of a low psoas muscle index (low PMI) before treatment. We compared patient characteristics and overall survival (OS) between the groups. Additionally, we investigated the transition of the PMI during drug therapy, specifically before treatment, at the initial evaluation, and after the end of treatment. Results: Seventy percent of patients in the LEN group and seventy-one percent in the ATZ-BEV group had a low PMI. Multivariate analysis across all patients revealed a low PMI (hazard ratio [HR] 3.25, p = 0.0004) as a prognostic factor for OS. The PMI decreased more in the LEN group compared to the ATZ-BEV group. In the Barcelona Clinic Liver Cancer—C group, the OS of ATZ-BEV therapy was significantly better than that of LEN therapy when a low PMI was present (p = 0.046). Conclusions: A low PMI emerges as a significant prognostic factor in uHCC patients undergoing drug therapy, not only in LEN therapy but also in ATZ-BEV therapy. Additionally, ATZ-BEV therapy may be more favorable for sarcopenic patients with advanced HCC stages.

Hereditary hemochromatosis (HH) is recognized as a progressive iron‐storage disorder, and leading to severe organ impairments, including liver cirrhosis. Hereditary hemochromatosis type 3 arises from mutations in the transferrin receptor 2 (TFR2) gene. However, HH type 3 is rare in Asia, and information regarding genetic mutations and associated phenotypes remains limited. Here, we reported the case of a Japanese patient with HH type 3, with a novel homozygous mutation of the TFR2 gene. A 69‐year‐old woman presented to our hospital with hand joint pain and was referred due to liver impairment. Viral hepatitis and autoimmune liver diseases were ruled out. However, the transferrin saturation was 92.2%, and the serum ferritin level was 1611.8 ng/mL. Additionally, abdominal computed tomography showed diffuse increased density of the liver parenchyma. Abdominal magnetic resonance imaging also suggested iron deposition. There is no history of prior treatments involving blood transfusions or iron agents. Her parents were involved in a consanguineous marriage, prompting genetic testing. She had a homozygous novel mutation, c.1337G>A (p.G446E), in the TFR2 gene. Serum hepcidin‐25 level was decreased to 2.9 ng/mL. According to the American Society of Medical Genetics and Genomics guideline, the mutation was classified as likely pathogenic, leading to the diagnosis of HH type 3. Following phlebotomy, her arthritis resolved, and serum transaminase levels were normalized. This case marks the first demonstration of homozygous mutation, c.1337G>A (p.G446E), in the TFR2 gene in patients with HH type 3.

Background Zinc-α2-glycoprotein (ZAG) is secreted by various organs, such as liver, kidney and adipose tissue; is involved in lipolysis; and may contribute to the pathogenesis of chronic liver disease (CLD). We therefore assessed whether or not ZAG is a surrogate marker for the hepatorenal function, body composition and all causes of mortality, as well as complications, including ascites, hepatic encephalopathy (HE) and portosystemic shunts (PSS) in CLD. Methods Serum ZAG levels were measured in 180 CLD patients upon hospital admission. The associations of ZAG levels with the liver functional reserve and clinical parameters were investigated using a multiple regression analysis. Kaplan-Meier analyses were performed to evaluate the associations of the ZAG/creatinine ratio (ZAG/Cr) and prognostic factors with mortality. Results High serum ZAG levels were associated with preserving the liver function and renal insufficiency. A multiple regression analysis showed that the estimated glomerular filtration rate (p<0.0001), albumin-bilirubin (ALBI) score (p=0.0018) and subcutaneous fat area (p=0.0023) had a significant independent correlation with serum ZAG levels. Serum ZAG levels were elevated in the absence of HE (p=0.0023) and PSS (p=0.0003). In all patients and those without hepatocellular carcinoma (HCC), the cumulative mortality rate was significantly decreased in patients with a high ZAG/Cr compared with those with a low ZAG/Cr (p=0.0018 and p=0.0002, respectively). The ZAG/Cr, presence of HCC, ALBI score and psoas muscle index were independent predictors of the prognosis in CLD patients. Conclusion Serum ZAG levels are associated with the hepatorenal function and can be used to predict the survival in CLD patients.

To identify patients suitable for endoscopic injection sclerotherapy (EIS) by evaluating their portal hemodynamics and liver function. We selected 58 patients with esophagogastric varices (EGV) and liver cirrhosis (LC) related to either hepatitis C virus (C) (n = 19), hepatitis B virus (n = 2), alcohol (AL) (n = 20), C + AL (n = 6), non-alcoholic steatohepatitis (n = 6), others (n = 3), or non-LC (n = 2). All patients underwent EIS. We measured their portal venous tissue blood flow (PVTBF) and hepatic arterial tissue blood flow (HATBF) using xenon computed tomography before and after EIS. We classified them into increased group and decreased group according to the PVTBF to identify the predictors that contribute to PVTBF increase post-EIS. Low value of indocyanine green retention at 15 min (ICG-R₁₅), the absence of paraesophageal veins, and low baseline PVTBF/HATBF (P/A) ratio predicted increased PVTBF in the multivariate logistic analysis (odds ratio (OR) 10.46, p = 0.0391; OR 12.45, p = 0.0088; OR 13.57, p = 0.0073). The protein synthetic ability improved 1 year post-EIS in increased group. Cox proportional hazards regression identified alcohol drinking (hazard ratio; 3.67, p = 0.0261) as an independent predictor of EGV recurrence. Patients with low ICG-R₁₅, low P/A ratio, and the absence of paraesophageal veins were probable predictors of PVTBF improvement post-EIS. In addition, the improvement of hepatic hemodynamics likely enhanced liver function following EIS.

Background: Oxaliplatin is a key drug for the chemotherapy of colorectal cancer; however, it is also known to cause non-cirrhotic portal hypertension. We aimed to identify the characteristics of patients who developed esophagogastric varices (EGVs) after treatment with oxaliplatin. Methods: This study retrospectively analyzed patients with colorectal cancer who were treated with chemotherapy including oxaliplatin between 2010 and 2016. All patients were evaluated by contrast-enhanced computed tomography (CE-CT) every 3 months both during and after treatment; and endoscopy was performed when appearance of portal hypertension was suspected. Results: A total of 106 patients were divided into two groups: EGV formation (n = 6) and EGV non-formation (n = 100). In the EGV group, platelet counts decreased and the size of the spleen calculated by CT (CT spleen index; CT-SI) increased markedly. The highest area under the receiver operating characteristic curve (AUC) for the change in platelet counts was 0.81 (80% sensitivity and 83% specificity) at 3 months post treatment, and the maximum AUC for CT-SI was 0.89 (79% sensitivity and 83% specificity) at 6 months post treatment. Conclusions: EGV formation could be predicted by the assessment of platelet counts and spleen size. If progressive splenomegaly and thrombocytopenia are observed not only during but also after completion of the oxaliplatin-containing chemotherapy, EGVs should be confirmed by endoscopy for avoiding subsequent rupture.