佐久間 康成

While endogenous cortisol secretion rises in the early morning, the number of lymphocytes in the blood is higher at night, thus exhibiting an antiphase pattern to cortisol secretion. Therefore, compared with the daytime, the infiltration of lymphocytes into immune-reactive tissues is enhanced at night. This study aimed to determine whether the administration of methylprednisolone (mPSL) in the evening is more effective against T cell-mediated rejection (TCMR) after liver transplantation compared with morning administration. This study used a randomized, open-label, parallel-group comparison design. Pediatric patients scheduled to undergo living-donor liver transplantation were randomly divided into morning (8:00 a.m.) and evening (8:00 p.m.) mPSL administration groups. The primary endpoint was the occurrence of TCMR within 14 days of surgery. Sixty-two patients were enrolled between 2014 and 2023, and six patients were excluded from the analysis as their dose of mPSL deviated from the protocol within 14 days after surgery. Of the 56 subjects analyzed, TCMR was detected in 10 of the morning group (n = 29) and three of the evening group (n = 27) within 14 days after surgery. Stratified analysis of patients who did not receive preoperative rituximab treatment showed that none of the evening group and 36.4% of the morning group developed TCMR within 14 days after surgery (P < 0.01, 95% confidence interval; 2.00-infinity). Safety evaluation results were comparable between the two groups. This study shows that the evening administration of mPSL is an effective approach for suppressing TCMR. This study is hypothesis generating, and replication in further studies is needed.

BACKGROUND: Cytomegalovirus (CMV) is a major infectious complication in solid-organ transplant recipients, particularly in the context of pediatric liver transplantation. CMV serostatus is a well-established risk factor for postoperative CMV infection, with CMV seronegative recipients who receive organs from seropositive donors (D+/R-) being at the highest risk. Our previous research indicated a higher incidence of CMV infection in recipients with inherited metabolic diseases (IMDs) compared with those with biliary atresia (BA). This study aimed to determine whether IMDs constitute an independent risk factor for postoperative CMV infection. METHODS: We retrospectively analyzed data from 45 IMD and 230 BA recipients. We collected information on the occurrence and timing of episodes of CMV infections, methylprednisolone (mPSL) pulse therapy, patient characteristics, and peri- and postoperative data. RESULTS: Multivariable analysis identified mPSL pulse therapy (Odds Ratio (OR): 4.43), CMV serostatus (D+/R-) (OR: 6.03), and underlying IMDs (OR: 3.28) as independent risk factors for CMV infection. Further stratified analysis, which considered the timing of CMV infection diagnosis relative to mPSL pulse therapy, confirmed that CMV serostatus with (D+/R-) (OR: 5.61) and underlying IMDs (OR: 2.83) remained independent predictors of CMV infection, even when excluding the influence of mPSL pulse therapy. CONCLUSIONS: This study demonstrates that IMDs are a potent independent risk factor for CMV infection following pediatric liver transplantation. CLINICAL TRIAL NUMBER: Not applicable.

Background: Even though many metabolic liver diseases can now be diagnosed using blood tests and diagnostic imaging, early diagnosis remains difficult. Understanding mechanisms contributing to the progression from Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Alcoholic Hepatitis (AH) to cirrhosis is critical to reduce the burden of end-stage liver disease. Monitoring individual bile acids has been proposed as a way to distinguish various liver disorders. Methods: This study explored bile acid profiles in patients with MASH and AH. Plasma samples from patients with MASH, AH, and a control group were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify bile acid concentrations. Targeted metabolomic analysis was performed to compare bile acid levels between the hepatitis and control groups. Results: Concentrations of ursodeoxycholic acid (UDCA), chenodeoxycholic acid (CDCA), taurocholic acid (TCA), tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid (TCDCA), glycoursodeoxycholic acid (GUDCA), glycochenodeoxycholic acid (GCDCA), and glycocholic acid (GCA) were significantly elevated in the hepatitis group. Correlation analysis revealed strong positive relationships between the total and direct bilirubin levels and TUDCA and GCDCA. Aspartate aminotransferase (AST) showed strong positive correlations with TCDCA and GCDCA. Child-Pugh score, Fibrosis-4 index, and non-alcoholic fatty liver disease fibrosis score were positively correlated with GCA, whereas the aspartate aminotransferase-to-platelet ratio correlated with TCA, TCDCA, and GCA. The model for end-stage liver disease (MELD) score showed a strong positive correlation with GCDCA. Implications: GCDCA may serve as a predictive biomarker for liver damage, potentially enabling early diagnosis and targeted intervention in patients with MASH and AH.

Portal cavernoma cholangiopathy (PCC) is a complex condition associated with portal hypertension, particularly in patients with extrahepatic portal vein obstruction (EHPVO). Herein, we present a case of liver failure with PCC in a 55-year-old male successfully treated with living-donor liver transplantation (LDLT). The patient had a history of gastrointestinal bleeding and recurrence of cholangitis. Imaging studies confirmed cavernous transformation and pericholedochal varices. Preoperative angiography verified hepatopetal flow in the pericholedochal varix, which facilitated successful anastomosis with the donor's portal vein during LDLT. Histological examination of the explanted liver confirmed vanishing bile duct syndrome (VBDS) and secondary bile stasis was considered to have caused liver failure. No postoperative complications were observed within 13 months of LDLT. We report the first case of VBDS in the PCC resulting from EHPVO that was successfully managed with LDLT. Careful management of similar cases should involve angiography and long-term postoperative monitoring of portal vein complications.

BACKGROUND: Globally, prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing, and there is an urgent need to develop innovative therapies that promote liver regeneration following hepatectomy for this disease. Surgical excision is a key therapeutic approach with curative potential for liver tumors. However, hepatic steatosis can lead to delayed liver regeneration and higher post-operative complication risk. Mesenchymal stem cells-conditioned medium (MSC-CM) is considered a rich source of paracrine factors that can repair tissues and restore function of damaged organs. Meanwhile, hydrogels have been widely recognized to load MSC secretome and achieve sustained release. This study aimed to evaluate the therapeutic effect of hydrogel-encapsulated MSC-CM on liver regeneration following partial hepatectomy (PHx) in a rodent model of diet-induced hepatic steatosis. METHODS: Male Lewis rats were fed with a methionine and choline-deficient diet. After 3 weeks of feeding, PHx was performed and rats were randomly allocated into two groups that received hydrogel-encapsulated MSC-CM or vehicle via the intra-mesenteric space of the superior mesenteric vein (SMV). RESULTS: The regeneration of the remnant liver at 30 and 168 h after PHx was significantly accelerated, and the expressions of proliferating cell nuclear antigen were significantly enhanced in the MSC-CM group. MSC-CM treatment significantly increased hepatic ATP and β-hydroxybutyrate content at 168 h after PHx, indicating that MSC-CM fosters regeneration not only in volume but also in functionality. The number of each TUNEL- and cleaved caspase-3 positive nuclei in hepatocytes at 9 h after PHx were significantly decreased in the MSC-CM group, suggesting that MSC-CM suppressed apoptosis. MSC-CM increased serum immunoregulatory cytokine interleukin-10 and interleukin-13 at 30 h after PHx. Additionally, mitotic figures and cyclin D1 expression decreased and hepatocyte size increased in the MSC-CM group, implying that this mode of regeneration was mainly through cell hypertrophy rather than cell division. CONCLUSIONS: MSC-CM represents a novel therapeutic approach for patients with MASLD requiring PHx.