Circulating myostatin levels as a prognostic biomarker in patients with acute liver failure and late-onset hepatic failure.

AIM: Myostatin is a myokine involved in muscle mass regulation. The associations between circulating myostatin levels and clinical characteristics in patients with acute liver failure (ALF) and late-onset hepatic failure (LOHF) are unclear. METHODS: In this retrospective study, 51 patients with ALF or LOHF were included. Serum myostatin was measured using an enzyme-linked immunosorbent assay. RESULTS: Myostatin levels were significantly lower in patients with ALF and LOHF than in controls (ALF/LOHF: 2522 pg/mL, controls: 3853 pg/mL, p = 0.003). The prevalence of low myostatin in deceased patients was significantly higher than that in spontaneous survivors and patients who underwent liver transplantation. Patients with low myostatin levels had a high incidence of complications. There was a positive correlation between the psoas muscle index and serum myostatin levels. Patients with low myostatin levels had shorter 1-year transplant-free survival and shorter 1-year overall survival than patients with high myostatin levels. Low serum myostatin levels were associated with poor prognosis independent of the Japanese scoring system for ALF ≥3, King's College criteria, or model for end-stage liver disease score >30.5. The combination of serum myostatin levels and prognostic models for ALF significantly stratified patients according to 1-year prognosis. CONCLUSIONS: Low serum myostatin levels were associated with a low psoas muscle index, complication rate, and poor prognosis in patients with ALF and LOHF. Assessment of circulating myostatin levels may improve the prediction of outcomes in patients with ALF and LOHF.

Association between sleep duration and a new onset of nonalcoholic fatty liver disease.

Objective A short sleep duration is associated with non-alcoholic fatty liver disease (NAFLD). However, the causal relationship between a short sleep duration and the onset of NAFLD remains unknown because of the lack of any longitudinal studies. Therefore, we evaluated the association between sleep duration and the onset of NAFLD. Methods We evaluated health checkup data for 1,862 NAFLD-free Japanese adults aged 33-86 years at baseline and followed those individuals for a median of 41 months. Hepatic steatosis was examined using ultrasonography (US). The Cox proportional hazards model was used to evaluate the association between sleep duration and NAFLD onset. Results Among the 1,862 participants, 483 (25.9%) developed NAFLD. The proportion of women who developed NAFLD was the highest in the group with a sleep duration of <6 hours and lowest in the group with a sleep duration of 7 to <8 hours. The multivariable-adjusted hazard ratio (95% confidence interval) for the onset of NAFLD in women with a sleep duration <6 hours compared with those with a sleep duration of 7 to <8 hours was 1.55 (1.09-2.20; p=0.02). Conclusions In women, a short sleep duration was independently associated with the onset of NAFLD, thus suggesting that an adequate sleep duration can be a promising preventive factor for the onset of NAFLD in women.

Esophageal squamous cell carcinoma complicated with varices successfully treated by endoscopic injection sclerotherapy and argon plasma coagulation: A case report.

Treatment guidelines for esophageal squamous cell carcinoma (ESCC) with concomitant esophageal varices (EVs), which increase the risk of bleeding, are unavailable. A 66-year-old man with a history of total gastrectomy was admitted to the hospital owing to hematemesis. Emergency upper gastrointestinal endoscopy revealed variceal bleeding near the anastomosis between the esophagus and jejunum, and endoscopic clipping stopped the bleeding. Upper gastrointestinal endoscopy following hemostasis revealed four EVs and a two-thirds ESCC circumference. The ESCC depth was suspected to be up to the mucosa. The patient underwent intravariceal endoscopic injection sclerotherapy (EIS) for EVs, followed by paravariceal EIS. However, after these treatments, blood flow in the EVs just below the ESCC remained, and endoscopic resection of the ESCC was judged to be difficult to perform. Therefore, we prioritized EV treatment and performed a second EIS on the ESCC, followed by argon plasma coagulation (APC). APC was expected to not only solidify the EVs but also eliminate the ESCC existing in the mucosa. Finally, EVs and ESCC were treated by EIS and APC. EIS followed by APC may be useful for treating concurrent EVs and intramucosal ESCC in patients with liver cirrhosis when embolization of the EVs is ineffective.

Safety and effectiveness of SARS-CoV-2 vaccines for patients with intractable hepatobiliary diseases: A multicenter, questionnaire-based, cross-sectional study.

AIM: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease. METHODS: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected. RESULTS: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination. CONCLUSION: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases.

Characteristics of peripheral blood mononuclear cells and potential related molecular mechanisms in patients with autoimmune hepatitis: a single-cell RNA sequencing analysis.

Autoimmune hepatitis (AIH) is an immune disorder characterized by hypergammaglobulinemia, autoantibodies, and chronic active hepatitis on liver histology. However, immune cell population characteristics in AIH patients remain poorly understood. This study was designed to analyze peripheral blood mononuclear cell (PBMC) characteristics in AIH through single-cell RNA sequencing (scRNA-seq) and explore potential AIH-related molecular mechanisms. We generated 3690 and 3511 single-cell transcriptomes of PBMCs pooled from 4 healthy controls (HCs) and 4 AIH patients, respectively, by scRNA-seq. These pooled PBMC transcriptomes were used for cell cluster identification and differentially expressed gene (DEG) identification. GO functional enrichment analysis was performed on the DEGs to determine the most active AIH immune cell biological functions. Although the PCA-based uniform manifold approximation and projection (UMAP) algorithm was used to cluster cells with similar expression patterns in the two samples, 87 up- and 12 downregulated DEGs were retained in monocytes and 101 up- and 15 downregulated DEGs were retained in NK cells from AIH PBMCs. Moreover, enriched GO terms in the PBMC-derived monocyte and NK cell clusters were related mainly to antigen processing and presentation, IFN-γ-mediated signaling, and neutrophil degranulation and activation. These potential molecular mechanisms may be important targets for AIH treatment.

L-Menthol for Color Difference Change Between Early Gastric Cancer and Surrounding Mucosa: A Prospective Study.

BACKGROUND: L-Menthol sprayed on early gastric cancer (EGC) has been reported to improve the visibility of the lesion. However, its impact when used in combination with novel image-enhanced endoscopy has not been investigated. AIM: This study aimed to evaluate the visual effect of spraying L-menthol on EGC under linked color imaging (LCI). METHODS: This open-label, single-arm, prospective study investigated the color difference between EGC and the surrounding mucosa (ΔEG) before and after spraying L-menthol. The primary endpoint was the percentage of lesions with ΔEG ≥ 5 on LCI. The percentage of lesions with ΔEG ≥ 5 on white light imaging (WLI) and blue laser imaging (BLI), ΔEG before and after spraying L-menthol, and percentage of lesions with increased ΔEG after spraying L-menthol constituted the secondary endpoints. RESULTS: Sixty patients were included in the final analysis. 100% lesions had ΔEG ≥ 5, both before and after spraying L-menthol on LCI, with similar results observed in WLI as well as BLI. The median ΔEG on LCI, WLI, and BLI increased after spraying L-menthol (LCI: 16.9 vs. 21.5, p < 0.01; WLI: 10.4 vs. 13.4, p < 0.01; BLI; 12.1 vs. 15.7, before and after, respectively, p < 0.01); and LCI demonstrated the highest percentage of lesions with increased ΔEG (LCI, WLI, and BLI: 98.3%, 81.7%, and 76.7%, respectively, p < 0.01). CONCLUSION: Although spraying L-menthol did not improve the visibility of EGC under LCI observation, a significant increase in ΔEG was observed in LCI (jRCTs 021200027).

Lifestyle factors affecting new-onset nonalcoholic fatty liver disease.

Evidence for the influence of lifestyle factors on nonalcoholic fatty liver disease (NAFLD) onset is limited because the association between lifestyle factors and NAFLD has been reported mostly in cross-sectional studies. Our purpose was to elucidate which lifestyle factors are associated with NAFLD onset by performing a longitudinal study. This was a longitudinal study of 1,713 Japanese participants who underwent multiple health checkups from June 2013 to the end of March 2018 and were not diagnosed with NAFLD at the first health checkup at Watari Hospital in Fukushima, Japan. Baseline characteristics, including lifestyle factors, were compared among participants with and without NAFLD. Cox proportional hazards models were used to identify the association between lifestyle factors and NAFLD onset. Among the 1,713 participants, 420 (24.5 %) developed NAFLD during the observation period (median 47 months). There were significant differences in body mass index and hepatobiliary enzyme levels between participants with and without NAFLD. In Cox proportional hazards models, eating between meals (hazard ratio (HR): 2.08, 95 % confidence interval (CI): 1.25-3.45, p < 0.01) and eating fast (HR: 1.59, 95 % CI: 1.26-2.00, p < 0.01) were risk factors for NAFLD onset in men and women, respectively. Moreover, fast walking was a protective factor against NAFLD onset in women (HR: 0.76, 95 % CI: 0.60-0.96, p = 0.02). These findings could help to identify patients at risk and prevent future NAFLD onset.

Influence of serum Gas6 levels on prognosis in patients with hepatocellular carcinoma.

OBJECTIVE: The prediction of prognosis in hepatocellular carcinoma patients is important for switching treatment. The association between circulating growth arrest-specific 6 levels and prognosis in hepatocellular carcinoma patients is unknown. METHODS: We retrospectively analysed the association between serum growth arrest-specific 6 levels and clinical findings in 132 patients with hepatocellular carcinoma. Serum growth arrest-specific 6 levels were measured using enzyme-linked immunosorbent assay. RESULTS: Amongst 132 patients, the Barcelona Clinic Liver Cancer stage was classified as 0, A, B, C and D in 19, 48, 41, 18 and 6 patients, respectively. Serum growth arrest-specific 6 levels in hepatocellular carcinoma patients were higher than those in healthy controls (28.4 ng/mL vs. 19.6 ng/mL, P < 0.001), and growth arrest-specific 6 levels were positively correlated with soluble Axl levels. In the entire cohort, high growth arrest-specific 6 levels were associated with a shorter survival period (hazard ratio: 1.78 per 20 ng/mL, 95% confidence interval: 1.01-3.16, P = 0.045). In early and intermediate-stage hepatocellular carcinoma patients treated with transcatheter arterial chemoembolization (n = 59), we determined a cut-off value of 36.4 ng/mL based on the receiver operating characteristic curve to predict death within 3 years, and high growth arrest-specific 6 levels were associated with a high cumulative incidence of portal vein tumour thrombosis (Gray's test: P = 0.010) and shorter overall survival (log-rank: P = 0.005). CONCLUSIONS: Serum growth arrest-specific 6 levels were associated with prognosis in hepatocellular carcinoma patients. In early and intermediate-stage hepatocellular carcinoma patients who underwent transcatheter arterial chemoembolization, high growth arrest-specific 6 levels were associated with a high incidence of portal vein tumour thrombosis. Circulating growth arrest-specific 6 levels may be a useful prognostic marker in hepatocellular carcinoma patients.

A new model to estimate duration of survival in patients with hepatocellular carcinoma with BCLC intermediate stage.

It is difficult to determine whether an individual therapy contributes to the elongation of survival because of the difficulty of organizing clinical research in patients who receive multiple treatments in HCC. We aimed to establish a new model of survival prediction in patients with intermediate stage HCC to establish standards in the recent and coming multi-MTA era. This analysis was prepared using a data set of 753 patients diagnosed HCC prior to 2017. Multiple regression analysis showed age, naïve or recurrence, the size of the largest tumor nodule, the number of nodules, total bilirubin, albumin and α-fetoprotein as independent predictors of survival. A Weibull model had the best fit and, based on these predictors, we established a new predicted survival model. The survival duration can be predicted the proposed model; EXP (4.02580 + (- 0.0086253) × age + (- 0.34667) × (naïve/recurrence) + (- 0.034962) × (number of nodules) + (- 0.079447) × (the size of the largest nodule) + (- 0.21696) × (total bilirubin) + 0.27912 × (albumin) + (- 0.00014741) × (α-fetoprotein)) × (- natural logarithm(0.5))^0.67250. This model is useful for the planning and evaluating the efficacy of recent sequential therapies in multi-MTA era.

Bacillus cereus Sepsis in a Patient with Severe Alcoholic Hepatitis: A Case Report.

A 57-year-old woman with a liver injury was referred to our hospital. She had a history of heavy alcohol consumption and had developed severe alcoholic hepatitis. Blood cultures revealed bacteremia caused by Bacillus cereus. The patient was treated with short-term steroid therapy for liver injury and vancomycin administration for B. cereus sepsis, which led to recovery. The findings in the present case suggest the need for empirical therapy with vancomycin in patients with severe alcoholic hepatitis and suspected B. cereus infection.

Percutaneous endoscopic necrosectomy for walled-off necrosis in the retroperitoneal space of the elderly: A case report.

BACKGROUND: Walled-off necrosis (WON) is a late complication of acute pancreatitis possibly with a fatal outcome. Even for WON spreading to the retroperitoneal space, percutaneous endoscopic necrosectomy (PEN) can be an alternate approach to surgical necrosectomy, particularly for the older individuals or patients with poor condition because of WON. CASE SUMMARY: An 88-year-old man was admitted to our hospital with a jaundice. Endoscopic retrograde cholangiopancreatography (ERCP) was performed to improve jaundice; however, post-ERCP pancreatitis developed. The inflammation of pancreatitis spread widely from the right retroperitoneal cavity to the pelvis, and WON was formed 4 wk later. A percutaneous drainage tube was placed into the WON under computed tomography guidance. However, the drainage did not ameliorate clinical symptoms including fever, which assured less invasive necrosectomy. A metallic stent for the upper gastrointestinal (GI) tract was placed from the percutaneous drainage route. An upper GI endoscope was inserted into the inside of the WON through the metallic stent, and the necrotic tissues were bluntly removed with a snare forceps. Ten times of these necrosectomies resulted in the near-complete removal of necrotic tissues. These procedures consequently abated his fever and remarkable improvement in blood tests. CONCLUSION: PEN for WON occurring in the retroperitoneal space was safe and effective for very old individuals.

Transarterial embolization for ruptured pancreaticoduodenal artery aneurysm due to segmental arterial mediolysis combined with median arcuate ligament syndrome: a case report.

A 75-year-old female with a history of Parkinson's disease treatment and hypertension presented at the emergency section with sudden onset of right abdominal pain. Contrast-enhanced computed tomography revealed beaded irregular stenosis and dilation of the superior mesenteric artery (SMA) and an aneurysm in the branch of the pancreaticoduodenal artery (PDA) that communicates with the common hepatic artery and SMA. Additionally, a hematoma had formed in the retroperitoneal space, and extravasation of contrast medium from the pancreaticoduodenal artery aneurysm (PDAA) into the hematoma was observed. The celiac artery (CA) was compressed by the median arcuate ligament; stenosis of the CA at its origin and dilation on the distal side were observed. Based on the imaging findings, it was diagnosed that PDAA was ruptured, SMA developed segmental arterial mediolysis (SAM), and CA developed median arcuate ligament syndrome (MALS). The ruptured PDAA was thought to be caused by SAM combined with MALS. Transcatheter arterial embolization (TAE) was performed for the ruptured PDAA. To the best of our knowledge, there have been no reports of TAE for a ruptured PDAA caused by SAM and MALS. After TAE, the PDAA did not re-rupture.

Association between equol and non-alcoholic fatty liver disease in Japanese women in their 50s and 60s.

BACKGROUND AND AIM: Equol is a metabolite of soy isoflavone and has estrogenic activity. The incidence of non-alcoholic fatty liver disease (NAFLD) increases after menopause in women, which is thought to result in a decrease in estrogen. This study aimed to evaluate the association between equol and NAFLD. METHODS: We evaluated 1185 women aged 50-69 years who underwent health check-ups at four health centers in Fukushima, Japan. Equol producers were defined by a urinary equol concentration of 1.0 µM or more. In addition to comparison between equol producers and non-producers, the association between equol and NAFLD was estimated using logistic regression analysis adjusting for fast walking and eating habits. RESULTS: Of the 1185 participants, 345 (29.1%) women were equol producers. The proportions of women who had NAFLD (34.8% vs 45.2%) were significantly lower in the equol-producing group than in the non-producing group. Multivariable logistic regression analysis showed that equol production was significantly associated with NAFLD (odds ratio = 0.66, 95% confidence interval: 0.51-0.86). CONCLUSIONS: Equol production was significantly associated with NAFLD in women in their 50s and 60s.

Impact of Lifestyle and Psychosocial Factors on the Incidence of Hepatobiliary Enzyme Abnormalities After the Great East Japan Earthquake: Seven-Year Follow-up of the Fukushima Health Management Survey.

OBJECTIVE: Residents who lived near the Fukushima Power Plant accident were forced to change their lifestyle after the 2011 accident. This study aimed to elucidate the association of resident lifestyle and psychological factors with onset of hepatobiliary enzyme abnormalities (HEA) after the accident. METHODS: This longitudinal study included 15705 residents who underwent a comprehensive health check, as well as a mental health and lifestyle survey between June 2011 and March 2012. Follow-up surveys were conducted between June, 2012 and March 2018. Risk factors for new HEA onset were evaluated using the Cox proportional hazards model, moreover, population attributable risks for new HEA onset were calculated. RESULTS: HEA developed in 29.7% of subjects. In addition to metabolic factors such as overweight, hyperglycemia, and hyperlipidemia; there were differences in alcohol intake, evacuation, unemployment, educational background, and psychological distress between subjects with and without HEA onset. After we adjusted for potential confounding factors, an association of being overweight, hypertension, and dyslipidemia, as well as alcohol consumption, evacuation, and psychological distress with increased risk of HEA onset was realized. Among these identified risk factors, evacuation accounted for the greatest share. CONCLUSIONS: Metabolic characteristics and disaster-related lifestyle aspects, including mental status, were risk factors for HAE onset after the Fukushima Power Plant accident.

Novel Photodynamic Therapy for Esophageal Squamous Cell Carcinoma following Radiotherapy.

Radiotherapy (RT) or chemoradiotherapy (CRT) are frequently selected as treatments for esophageal squamous cell carcinoma (ESCC). However, salvage treatment remains challenging when endoscopic resection is not indicated for residual or recurrent ESCC following RT or CRT. Recently, owing to the emergence of second-generation photodynamic therapy (PDT) using talaporfin sodium, PDT can be performed with less phototoxicity and therefore has regained popularity in the treatment of ESCC. In this study, the effectiveness and safety of second-generation PDT in patients with residual or recurrent ESCC following RT or CRT were examined. Local complete response (L-CR) rates, procedure-related adverse events, and prognosis were evaluated. In 12 patients with 20 ESCC lesions, the L-CR rates were 95.0%. Perforation, postoperative bleeding, and photosensitivity were not observed. Esophageal stricture following PDT developed in one patient, but this could be addressed using balloon dilation. During a median follow-up period of 12 (range, 3-42) months, the 3-year cause-specific survival rate was 85.7%. Even in patients with a Charlson comorbidity index score ≥ 3, the 2-year overall survival rates were 100%. In conclusion, PDT was an efficacious and a safe salvage treatment in patients with local residual or recurrent ESCC following RT or CRT.

Factors Associated With Difficult Endoscopic Ultrasonography-guided Biliary Drainage.

BACKGROUND AND AIMS: When endoscopic retrograde cholangiopancreatography-guided biliary drainage is challenging, endoscopic ultrasound-guided biliary drainage (EUS-BD) can be used as an alternate treatment; however, this method requires operator expertise. Therefore, this study aimed to clarify the factors that are associated with a difficult EUS-BD. PATIENTS AND METHODS: Patients who successfully underwent EUS-BD were enrolled in this study. The patients were divided into the easy group and difficult group depending on whether the procedural time was more than 60 minutes, which was the cutoff value elicited from past reports. Patient characteristics and procedural factors were compared between the two groups. The factors associated with difficult procedures were also investigated. RESULTS: The patient characteristics were not significantly different between the easy group (n=22) and the difficult group (n=19). The diameter of the punctured bile duct was significantly different between the two groups. In the multivariate analysis, the diameter of the punctured bile duct was the only factor associated with a difficult EUS-BD (odds ratio 0.65, 95% confidence interval 0.46-0.91, P value=0.012). The cutoff value for the diameter of the punctured bile duct in predicting a difficult EUS-BD was 7.0 mm (area under the curve: 0.83, sensitivity 84.2%, specificity 86.4%). CONCLUSIONS: A nondilated bile duct might be a predictive factor for a difficult EUS-BD. For beginners of EUS-BD, the cutoff value for the punctured bile duct diameter found in this study, 7.0 mm, might become a barometer for puncture point selection.

Comparison of time to recurrent biliary obstruction between plastic stents and metallic stents for endoscopic ultrasound­guided biliary drainage.

Endoscopic ultrasound-guided biliary drainage (EUS-BD) may prevent stent placement at the bile duct stricture. Therefore, whether a plastic stent (PS) or metallic stent (MS) should be used for EUS-BD remains to be undetermined. The present study aimed to clarify whether a PS or MS was more efficient for EUS-BD. Patients with malignant biliary obstruction who were successfully treated with EUS-BD were enrolled in the present study. The clinical characteristics, procedural outcomes and time to recurrent biliary obstruction (TRBO) were compared between patients treated with a PS (PS group) and patients treated with an MS (MS group). Consequently, 28 patients underwent PS placement and 11 patients underwent MS placement. In the PS group, 12 patients also underwent EUS-antegrade stenting (AGS) using an MS. The TRBO was not significantly different between the two groups (P=0.25). When the patients with AGS were excluded, the TRBO was significantly longer in the MS group than in the PS group (P=0.036). However, the TRBO was not significantly different between the patients in the MS group and those in the PS group who underwent AGS (P=0.61). In EUS-BD, MS is expected to be associated with a longer TRBO than PS. However, combining EUS-BD with AGS may help overcome the shorter TRBO associated with the use of PS.