Total bile acids levels as a stratification tool for screening portopulmonary hypertension in patients with decompensated cirrhosis.

AIM: Echocardiography is necessary for portopulmonary hypertension diagnosis, and identifying patients with cirrhosis who require it is challenging. In this study, we aimed to investigate the utility of the total bile acid (TBA) levels as a screening tool for identifying patients with decompensated cirrhosis who should undergo echocardiography for portopulmonary hypertension diagnosis. METHODS: We evaluated 135 patients with decompensated cirrhosis who underwent liver transplantation. Subsequently, factors contributing to tricuspid regurgitation pressure gradient (TRPG) elevation (≥30 mmHg) were analyzed using preoperative data, including the TBA levels. RESULTS: The median age of patients was 58 years (61 women), and 45 and 90 patients had Child-Turcotte-Pugh grades of B and C, respectively. The median TRPG level was 21 mmHg, and 17 patients (12.6%) showed TRPG elevation. Multiple logistic regression analysis revealed that elevated TBA (odds ratio 4.322; p = 0.013) and main pulmonary artery diameter ≥33 mm (odds ratio 4.333; p = 0.016) were significantly associated with TRPG elevation. The TBA cut-off value (167.7 µmol/L) showed a high diagnostic performance, with 70.6% sensitivity and 64.4% specificity. Ursodeoxycholic acid (UDCA) administration increased the TBA levels dose-dependently. Analysis stratified by UDCA use revealed that in patients not taking UDCA (n = 59), elevated TBA levels and younger age significantly contributed to TRPG elevation. However, in those taking UDCA (n = 76), this contribution disappeared, suggesting that UDCA consumption reduced TBA levels' efficiency in diagnosing TRPG elevation. CONCLUSIONS: The TBA levels may be a potential screening tool for TRPG elevation; however, caution is warranted when interpreting cases treated with UDCA.

Non-liver-related mortality in the DAA era: Insights from post-SVR patients with and without previous HCC history.

BACKGROUND AND AIMS: Mortality after sustained virological response (SVR) with interferon-free direct-acting antiviral (IFN-free DAA) therapy is crucial for optimizing post-SVR patient care, but it remains unclear, especially regarding non-liver-related mortality. METHODS: Consecutive post-SVR patients from 14 institutions were stratified into three cohorts: A (without advanced fibrosis and without prior HCC), B (with advanced fibrosis and without prior HCC), and C (curative HCC treatment). We assessed mortality (per 1000 person-years [/1000PY]) post-SVR. Mortality rates were compared between cohorts A and B and the general population using age- and sex-adjusted standardized mortality ratio (SMR). Comparison of survival between each cohort was performed using propensity-score (PS) matching with sex, age, and comorbidity. RESULTS: In cohort A (n = 762; median age, 65 years), 22 patients died (median follow-up, 36 months); all-cause mortality was 10.0/1000PY, with 86.4% non-liver-related deaths. In cohort B (n = 519; median age, 73 years), 27 patients died (median follow-up, 39 months); all-cause mortality was 16.7/1000PY, with 88.9% non-liver-related deaths. In both cohorts, malignant neoplasm was the most common cause of death; all-cause mortality was comparable to that of the general population (SMR: 0.96 and 0.92). In cohort C (n = 108; median age, 75 years), 15 patients died (median follow-up, 51 months); all-cause mortality was 36.0/1000PY, with 53.3% liver-related deaths. PS matching showed no significant survival differences between cohorts A and B, both of which had better survival than cohort C. CONCLUSIONS: Mortality varies based on HCC history in the DAA era; nevertheless, attention should be paid to non-liver-related deaths in all post-SVR patients.

Impact of low pharyngeal/esophageal pressure associated with sarcopenia on postendoscopic submucosal dissection pneumonia in patients with superficial esophageal cancer.

OBJECTIVES: The aging population, including patients with superficial esophageal cancer, encounters critical dysphagia- and postoperative pneumonia-related issues. Although endoscopic submucosal dissection (ESD) provides advantages over other modalities, older patients are at higher risk of postoperative pneumonia. Furthermore, the etiologies of pneumonia are complex and include patient- (such as sarcopenia) and treatment- (including ESD) related factors. Therefore, this study evaluated swallowing function in patients with superficial esophageal cancer and identified post-ESD pneumonia-associated factors. METHODS: Comprehensive swallowing function and sarcopenia were evaluated in patients pre-ESD and 2 months post-ESD using high-resolution manometry and several swallowing studies by multiple experts. The effects of mucosal resection and sarcopenia on swallowing function changes post-ESD, the relationship between preoperative swallowing function and sarcopenia, and the factors influencing postoperative pneumonia were investigated. RESULTS: Twenty patients were included in the study. Patients with preoperative sarcopenia had significantly lower pharyngeal/upper esophageal sphincter and tongue pressures than those without sarcopenia. However, ESD did not worsen pharyngeal or upper esophageal pressure. Post-ESD pneumonia incidence tended to be higher in patients with sarcopenia than in those without sarcopenia. The lower upper esophageal sphincter-integrated relaxation pressure (UES-IRP) was a significant factor in pneumonia development. Furthermore, the receiver operating characteristic curve for UES-IRP in pneumonia yielded an area under the curve of 0.82. CONCLUSIONS: Sarcopenia is associated with preoperative dysphagia, which increases post-ESD pneumonia risk. Therefore, postoperative pneumonia incidence is expected to increase with an aging population, making preoperative sarcopenia and swallowing function evaluation crucial.

Hypoglycemia measured by flash glucose monitoring system predicts liver-related events in chronic liver disease patients.

Impaired glucose tolerance, glucose fluctuations, and hypoglycemia have been observed in patients with chronic liver disease (CLD). The flash glucose monitoring (FGM) system, which recognises continuous and dynamic glucose changes in real time, is used in daily clinical practice. This study aimed to examine the association between glucose fluctuations and hypoglycemia, as measured by the FGM system, and liver-related events. Seventy-two patients with CLD and type 2 DM who had their blood glucose measured using Freestyle Libre Pro between April 2017 and July 2018 at our institution were enrolled in this retrospective study. We assessed the results of the FGM system measurements and liver-related events, as defined by gastrointestinal bleeding, infection, ascites, encephalopathy, and liver-related death. The standard deviation (SD) of mean glucose as measured by the FGM system was 41.55 mg/dl, and hypoglycemia was observed in 48.6% (35/72) of the patients. Liver-related event-free survival was not significant when stratified based on SD; however, the event-free survival was significantly lower when stratified by hypoglycemia (p = 0.007). In a multivariate analysis using the Cox proportional hazards model, Child-Pugh class B [Hazards ratio (HR) 2.347 (95% confidence interval (CI): 1.042-5.283), p = 0.039] and hypoglycemia [HR 2.279 (95% CI: 1.064-4.881), p = 0.034] were identified as factors contributing to event-free survival. Hypoglycemia, as determined by the FGM system, was identified as a significant factor that was closely associated with liver-related events. In addition to measuring glucose levels, the FGM system is useful in predicting the occurrence of liver-related events.

Peripheral lymphocyte fluctuation as an indicator of severe immune-related adverse events in patients treated with immune checkpoint inhibitors.

AIM: Immune checkpoint inhibitors (ICIs) have proven to be effective treatments for various cancers, but can also elicit immune-related adverse events (irAEs). Given that severe irAEs can be life-threatening, biomarkers that can predict the occurrence of irAEs are of paramount importance. ICIs affect the dynamics of lymphocytes, and alterations in these dynamics may play a role in the development and severity of irAEs. The aim of this study was to investigate the correlation between irAEs and changes in lymphocyte counts. METHODS: Information on irAEs was collected from 226 ICI cases from 2014 to 2020. We compared lymphocyte counts before treatment and at the onset of irAE and investigated the association between lymphocyte count fluctuations and the presence and severity of irAE, the course after steroid treatment, and overall survival. RESULTS: Of the 226 cases, 27 patients developed grade 3 or higher irAE. Compared to the other groups, the lymphocyte count in this group was significantly decreased at the time of irAE (p < 0.01). There was a trend toward a rapid increase in lymphocyte count in the steroid responder group compared to the non-responder group. Regarding overall survival, patients with irAE had significantly longer survival than those without irAE (p = 0.0025). However, there was no association between changes in lymphocyte count and survival in patients with irAE. CONCLUSION: The percentage change in lymphocyte count was found to correlate with the incidence of severe irAEs. Close monitoring of the patient's condition is crucial when the lymphocyte count decreases during ICI treatment.

Regular protocol liver biopsy is useful to adjust immunosuppressant dose after adult liver transplantation.

INTRODUCTION: Adjusting immunosuppression to minimal levels post-adult liver transplantation (LT) is critical; however, graft rejection has been reported in LT recipients with normal liver function evaluated by liver biopsy (LBx). Continual protocol liver biopsy (PLB) is performed regularly in LT recipients with normal liver function in some centers; however, its usefulness remains inadequately evaluated. This study aimed to assess retrospectively the usefulness of late PLB after adult LT. METHODS: LBx evaluations of LT recipients with normal liver function and hepatitis B and C virus seronegativity were defined as PLB. The cases requiring immunosuppressive therapy for rejection findings based on Banff criteria were extracted from the PLBs, and pathological data collected before and after immunosuppressive dosage adjustment (based on modified histological activity index [HAI] score) were compared. RESULTS: Among 548 LBx cases, 213 LBx in 110 recipients fulfilled the inclusion criteria for PLB. Immunosuppressive therapy after PLB was intensified in 14 LBx (6.6%) recipients (12.7%); of these, nine had late-onset acute rejection, three had isolated perivenular inflammation, one had plasma cell-rich rejection, and one had early chronic rejection. Follow-up LBx after immunosuppressive dose adjustment showed improvement in the modified HAI score grading in 10 of 14 cases (71.4%). No clinical background and blood examination data, including those from the post-LT period, immunosuppressant trough level, or examination for de novo DSA, predicted rejection in PLB. Complications of PLB were found in only three cases. CONCLUSION: PLB is useful in the management of seemingly stable LT recipients, to discover subclinical rejection and allow for appropriate immunosuppressant dose adjustment.

Most Cases of Cryptogenic Cirrhosis May Be Nonobese Nonalcoholic Steatohepatitis - Risk Factors of Liver Steatosis After Liver Transplantation for Cryptogenic Cirrhosis: A Retrospective Study.

Objective The course of cryptogenic cirrhosis (CC) after liver transplantation (LT) is unknown. We therefore clarified the natural course post-LT for CC and investigated the etiology of CC. Methods Eighteen patients who underwent LT for CC were included. To rule out the possibility of nonalcoholic steatohepatitis (NASH) in patients with CC, those with a history of obesity or liver steatosis found pretransplantation were excluded. A liver biopsy was performed one year after LT and annually thereafter. Results Liver steatosis and steatohepatitis were identified in 61% and 39% of patients after LT, respectively, with a median time to the onset of 12 and 27 months, respectively. There were no other pathological findings such as liver allograft rejection, autoimmune hepatitis, or primary biliary cholangitis. The body mass index after LT (28.5 vs. 22.4 kg/m2; p=0.002) and mean muscle attenuation at the time of LT were significantly higher (33.3 vs. 25.8 Hounsfield units, p=0.03) and the postoperative hospitalization period shorter (50 vs. 102 days; p=0.02) in the steatosis group than in the non-steatosis group. Recipients were significantly younger in the steatohepatitis subgroup than in the simple steatosis subgroup (55.0 vs. 63.5 years old; p=0.04). Conclusion Despite excluding CC patients with a history of obesity, we observed that patients with CC had a high prevalence of steatosis after LT than those without CC. Young patients with a favorable postoperative course were noted to have a high risk of NASH after LT for CC. Patients with CC may represent cases of non-obese NASH.

Association between hospital acquired disability and post-discharge mortality in patients after living donor liver transplantation.

BACKGROUND: Hospital-acquired disability (HAD) in patients who undergo living donor liver transplantation (LDLT) is expected to worsen physical functions due to inactivity during hospitalization. The aim of this study was to explore whether a decline in activities of daily living from hospital admission to discharge is associated with prognosis in LDLT patients, who once discharged from a hospital. METHODS: We retrospectively examined the relationship between HAD and prognosis in 135 patients who underwent LDLT from June 2008 to June 2018, and discharged from hospital once. HAD was defined as a decline of over 5 points in the Barthel Index as an activity of daily living assessment. Additionally, LDLT patients were classified into four groups: low or high skeletal muscle index (SMI) and HAD or non-HAD. Univariate and multivariate Cox proportional hazard models were used to evaluate the association between HAD and survival. RESULTS: HAD was identified in 47 LDLT patients (34.8%). The HAD group had a significantly higher all-cause mortality than the non-HAD group (log-rank: p < 0.001), and in the HAD/low SMI group, all-cause mortality was highest between the groups (log-rank: p < 0.001). In multivariable analysis, HAD was an independent risk factor for all-cause mortality (hazard ratio [HR]: 16.54; P < 0.001) and HAD/low SMI group (HR: 16.82; P = 0.002). CONCLUSION: HAD was identified as an independent risk factor for all-cause mortality suggesting that it could be a key component in determining prognosis after LDLT. Future larger-scale studies are needed to consider the overall new strategy of perioperative rehabilitation, including enhancement of preoperative physiotherapy programs to improve physical function.

Long-term Outcomes and Prognostic Factors of Stereotactic Body Radiotherapy for Hepatocellular Carcinoma.

BACKGROUND/AIM: This study was conducted to determine the prognosis and risk factors for survival in patients treated with stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This retrospective study analyzed 73 patients who underwent SBRT for HCC at Nagasaki University Hospital from December 2012 to July 2019 and examined the relationship between baseline information and prognosis. The Kaplan-Meier analysis and log-rank test were used to estimate the survival rate. Cox regression analysis was performed to determine the factors associated with overall survival (OS) after SBRT. RESULTS: The 1- and 2-year local control rates were 98.6% and 89.9%, respectively. Survival rates at 1, 3, and 5 years were 94.5%, 63.9%, and 45.5%, respectively. In the univariate analysis, baseline modified albumin-bilirubin grade (mALBI grade) [2b/3, hazard ratio (HR)=2.762, p=0.001], tumor size (≥2 cm, HR=2.479, p=0.003), and Barcelona Clinic Liver Cancer stage (BCLC) (B/C, HR=3.284, p<0.001) were significantly associated with poor prognosis. In multivariate analysis, baseline mALBI grade (2b/3, HR=2.283, p=0.009) and BCLC stage (B/C, HR=2.330, p=0.013) were significantly associated with poor prognosis. Only three patients (4.1%) developed grade 3 adverse events related to SBRT. CONCLUSION: SBRT is effective and safe in patients with HCC. The baseline mALBI grade is useful for predicting patient prognosis after SBRT. Patients with an mALBI grade of 1/2a are expected to have a better prognosis than patients with an mALBI grade of 2b/3.

Automated fibrosis phenotyping of liver tissue from non-tumor lesions of patients with and without hepatocellular carcinoma after liver transplantation for non-alcoholic fatty liver disease.

BACKGROUND: Fibrosis is the most important pathological feature in predicting development of Hepatocellular carcinoma (HCC). However, the incidence rate of HCC in patients with non-alcoholic fatty liver disease (NAFLD) is relatively low. We evaluated phenotypic histological features to differentiate HCC from non-HCC in patients with non-tumor lesions of cirrhotic livers. METHODS: Seventeen patients with NAFLD who underwent liver transplantation were enrolled. FibroNest was used to quantify histological phenotypes of non-tumor fibrosis lesions. Quantification included collagen content and structure traits, fiber morphometric traits, and fibrosis architecture traits. Each trait was described by up to seven quantitative fibrosis traits (qFTs). Among the qFTs measured in each specimen, those that described most of the variability between consecutive groups were automatically detected and combined into a normalized Phenotypic Composite Fibrosis Score (Ph-CFS). We trained FibroNest to identify the principal traits that differentiate HCC from non-HCC. RESULTS: HCC was found in 8 cases and non-HCC in 9 cases. The Ph-CFS significantly differentiated HCC from non-HCC (4.6 vs. 5.9, p < 0.05). Individual qFTs for morphometric features including collagen fiber length, width, perimeter, and area denoted significant differences between HCC and non-HCC. The Ph-CFS could be used to distinguish HCC (Ph-FCS < 5.0) from non-HCC (Ph-FCS ≥ 5.0) with 75% sensitivity and 100% specificity. CONCLUSION: In patients who underwent liver transplantation, fibrotic histological phenotypes in non-tumor lesions appeared to be different between HCC and non-HCC. Phenotypic analysis of collagen in non-tumor lesions might be an effective and automated method to distinguish HCC from non-HCC on histopathology imaging.

Impact of lenvatinib on renal function compared to sorafenib for unresectable hepatocellular carcinoma.

ABSTRACT: Anti-VEGF drugs, such as tyrosine kinase inhibitors, play an important role in systemic therapy for unresectable hepatocellular carcinoma (uHCC). We examined the effects of sorafenib and lenvatinib on proteinuria and renal function.Patients who were administered sorafenib (n = 85) or lenvatinib (n = 52) as first line treatment for uHCC from July 2009 to October 2020, were enrolled in this retrospective observational study. A propensity score analysis including 13 baseline characteristics was performed. Eighty four patients were selected (sorafenib, n = 42; lenvatinib, n = 42) by propensity score matching (one-to-one nearest neighbor matching within a caliper of 0.2). We analyzed changes in estimated glomerular filtration rate (eGFR) during tyrosine kinase inhibitor treatment, as well as the development of proteinuria in both groups. A multivariate analysis was performed to identify predictors of a deterioration of eGFR.At 4, 8, 12, and 16 weeks, ΔeGFR was significantly lower in the lenvatinib group than in the sorafenib group (P < .05). The lenvatinib group showed a significantly higher frequency of proteinuria than the sorafenib group (30.9% vs 7.1%, P = .005) and had a higher rate of decrease in eGFR than the sorafenib group (P < .05). Multivariate analysis revealed that lenvatinib use was the only predictive factor of eGFR deterioration (odds ratio 2.547 [95% CI 1.028-6.315], P = .043). In cases of proteinuria ≤1+ during lenvatinib treatment, eGFR did not decrease. However, eGFR decreased in the long term (>24 weeks) in patients who have proteinuria ≥2+.Lenvatinib has a greater effect on proteinuria and renal function than sorafenib. In performing multi-molecular targeted agent sequential therapy for uHCC, proteinuria and renal function are important factors associated with drug selection after atezolizumab-bevacizumab combination therapy currently used as the first-line treatment.

High serum concentrations of growth differentiation factor-15 and their association with Crohn's disease and a low skeletal muscle index.

Sarcopenia comprises a low skeletal muscle index (SMI) and low muscle strength (MS) or low physical function. Many sarcopenia biomarkers have been reported. With Crohn's disease (CD), a low SMI is predictive of intestinal complications. Therefore, many CD studies have reported that sarcopenia is defined by SMI alone. This study investigated the sarcopenia frequency by assessing the SMI and MS of Japanese patients with CD and biomarkers predicting a low SMI. We evaluated the SMI using a bioelectrical impedance analysis, handgrip strength, and C-reactive protein, albumin, interleukin-6, tumor necrosis factor-α, growth differentiation factor (GDF)-8, and GDF-15 levels as biomarker candidates for 78 CD patients at our hospital. Sarcopenia and a low SMI were observed in 7.7% and 42.3% of the patients, respectively. There was a significant difference in the GDF-15 levels of the low SMI group and normal group according to the multivariate analysis (P = 0.028; odds ratio [OR], 1.001; 95% confidence interval [CI] 1.000-1.002). When evaluated by sex, males exhibited a negative correlation between the GDF-15 level and SMI (Pearson's r = - 0.414; P = 0.0031), and the multivariate analysis indicated a significant difference in the GDF-15 levels (P = 0.011; OR, 1.001; 95% CI 1.000-1.002). GDF-15 levels may indicate a low SMI with CD.

Evaluating the Role of Hepatobiliary Phase of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging in Predicting Treatment Impact of Lenvatinib and Atezolizumab plus Bevacizumab on Unresectable Hepatocellular Carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab therapy has high response rates in patients with unresectable hepatocellular carcinoma (HCC). The hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) has been reported to be useful as an imaging biomarker for detecting ß-catenin mutations. We evaluated whether the pretreatment of the hepatobiliary phase of EOB-MRI could predict the therapeutic effect of lenvatinib and atezolizumab plus bevacizumab. METHODS: This study included 68 patients (lenvatinib group (n = 33) and atezolizumab plus bevacizumab group (n = 35)). The visual assessment and relative enhancement ratio (RER) of the largest HCC lesions were evaluated using the hepatobiliary phase of EOB-MRI. RESULTS: The hyperintensity type (RER ≥ 0.9) was 18.2% in the lenvatinib group and 20.0% in the atezolizumab plus bevacizumab group. In the lenvatinib group, progression-free survival (PFS) was not different between the heterogeneous and homogenous types (p = 0.688) or between the hyperintensity and hypointensity types (p = 0.757). In the atezolizumab plus bevacizumab group, the heterogeneous type had significantly shorter PFS than the homogenous type (p = 0.007), and the hyperintensity type had significantly shorter PFS than the hypointensity type (p = 0.012). CONCLUSIONS: The hepatobiliary phase of EOB-MRI was useful for predicting the therapeutic effect of atezolizumab plus bevacizumab therapy on unresectable HCC.

The impact of single-nucleotide polymorphisms on liver stiffness and controlled attenuation parameter in patients treated with direct-acting antiviral drugs for hepatitis C infection.

Single-nucleotide polymorphisms (SNPs) of patatin-like phospholipase domain-containing 3 (PNPLA3), tolloid-like protein 1 (TLL1) and interleukin-28 (IL28) have been identified as susceptibility factors for liver steatosis, inflammation and fibrosis in patients with hepatitis C virus (HCV) infection. Here, whether these polymorphisms affected predispositions to changes in liver stiffness (LS) and controlled attenuation parameter (CAP) following direct-acting antiviral (DAA) therapy was assessed. The changes in LS and steatosis in 77 HCV-infected patients receiving DAA therapy were compared with PNPLA3, TLL1 and IL28 genotypes, using CAP, FibroScan and Virtual Touch tissue quantification (VTTQ) before treatment and 12 weeks after the end of the treatment. VTTQ results showed that LS significantly decreased in PNPLA3 CC (P=0.035), TLL1 AA (P=0.011) and IL28B TT (P=0.005) genotypes; no significant differences were observed in PNPLA3 CG/GG, TLL1 AT/TT and IL28B TG/GG. FibroScan results showed that LS significantly decreased in TLL1 AA (P=0.028) and IL28B TT (P=0.032), with no significant difference in PNPLA3 CC. No significant differences were observed in PNPLA3 CG/GG, TLL1 AT/TT and IL28B TG/GG groups. CAP was significantly increased in PNPLA3 CG/GG (P=0.039 and P<0.05) and IL28B TT (P=0.014); no significant difference was observed in PNPLA3 CC and all genotypes of TLL1 and IL28B TG/GG. Therefore, these results indicated that SNPs could predict changes in LS and steatosis after DAA therapy.

Proposal for new sleep disorder criteria in patients with chronic liver disease: Influence of liver-related complications.

AIM: Sleep disorder is common in patients with chronic liver disease (CLD). Liver-related silent complications, including muscle cramps, covert hepatic encephalopathy (HE), and sarcopenia, often reduce the quality of life of patients with CLD and have been reported to cause sleep disorders. In this study, we clarified the prevalence of liver-related complications associated with sleep disorders in patients with CLD. METHODS: We conducted a multicenter cohort study of 271 patients with CLD. The Athens Insomnia Scale, muscle cramps questionnaires, and Stroop test were used to assess insomnia, muscle cramps, and covert HE, respectively. In addition, sarcopenia, dynapenia, and myopenia were diagnosed according to the guidelines of the Japan Society of Hepatology. RESULTS: In total, 136 patients (50.2%) had sleep disorders. Serum albumin and hemoglobin levels and prothrombin time activity were significantly lower in patients with sleep disorders than in those without sleep disorders. On univariate and multivariate analyses adjusted with inverse probability weighting, muscle cramps, covert HE, and dynapenia were associated with a sleep disorder. Sleep disorder was categorized as follows: cramp, covert HE, dynapenia, multiple complications, and others. In total, 106 of 136 patients (77.9%) with sleep disorder had at least one liver-related complication, whereas 75 patients had multiple liver-related complications. CONCLUSION: Sleep disorder in patients with CLD was classified into four categories (muscle cramp, covert HE, dynapenia, and others). Questionnaire for sleep disorder might be an easy primary step for surveillance of high-risk patients with silent complications associated CLD.

Bile extracellular vesicles from end-stage liver disease patients show altered microRNA content.

BACKGROUND: Extracellular vesicles (EVs) have recently attracted attention as novel diagnostic biomarkers and therapeutic tools. Several reports have correlated blood EVs with liver diseases. However, blood EVs do not reflect the liver state as it contains other systemically circulating EVs. Therefore, we focused on bile EVs, which are secreted directly from the liver, for the identification of potential biomarkers of liver failure. METHODS: Bile samples were collected from liver transplant recipients (n = 21) diagnosed with end-stage liver disease (ESLD) and donors (normal liver, NL; n = 18) during transplantation. Bile EVs were extracted using ultracentrifugation. RESULTS: Nanoparticle tracking analysis showed that bile EV concentration was significantly higher in recipients than in donors. Among recipients, bile EV concentration was remarkably higher in those with hepatocellular carcinoma. Next-generation sequencing revealed 461 and 465 types of microRNAs (miRNAs) in donor and recipient bile EVs, respectively, with no significant difference in diversity between the groups. Among 43 high-expression miRNAs, the expression of 86.0% of the miRNAs was higher in the bile EVs of recipients than in those of donors. Quantitative PCR validation showed that the levels of miR-17, miR-92a, miR-25, miR-423, and miR-451a significantly increased in bile EVs of recipients. Levels of miR-17 were remarkably higher in recipients with alcoholic ESLD. CONCLUSIONS: Secretion of EVs into the bile and their miRNA content increase in the ESLD state. Additionally, miRNA levels in bile EVs are not correlated with those in serum EVs. Bile EVs could be promising novel biomarkers for liver diseases.

Assessment of the association between dysphagia and sarcopenia among elderly patients with cirrhosis: Usefulness of the finger-ring test.

AIM: Sarcopenic dysphagia has become an urgent matter of debate in our aging society. However, little is known about the relationship between sarcopenia and dysphagia in patients with liver cirrhosis. Our aim was to assess sarcopenia and dysphagia among elderly patients with cirrhosis using two easy-to-use screening tests, i.e., the eating assessment tool-10 and the finger-ring test. METHODS: The eating assessment tool-10, handgrip strength, skeletal muscle mass index, computed tomography, and the finger-ring test were included in our analysis. One hundred patients with cirrhosis and without a history of aspiration pneumonia were divided into the elderly (≥75 years) and non-elderly (<75 years) groups. RESULTS: In the elderly group, sarcopenia was identified in 56.5% of the patients; of these, 30.4% and 13.0% had eating assessment tool-10 scores of ≥2 and ≥3, respectively. Sarcopenia-related factors correlated significantly with the eating assessment tool-10 scores (p<0.01). Multivariate regression analysis revealed that sarcopenia was significantly associated with dysphagia (p=0.028; odds ratio, 7.27). Among the elderly patients, the calf size of the non-dominant lower limb was less than the finger-ring circumference in 37.0% of the patients. This group had a significantly higher proportion of patients with an eating assessment tool-10 score of ≥2 than those with a greater calf than finger-ring circumference (p<0.01). CONCLUSIONS: Sarcopenia, rather than the hepatic reserve function, is associated with dysphagia among elderly patients with cirrhosis. The finger-ring test might be useful in screening for dysphagia.

Liver Function in Older Patients With Unresectable Hepatocellular Carcinoma After Administration of Lenvatinib.

BACKGROUND: The age of patients with advanced hepatocellular carcinoma (HCC) eligible for molecular-targeted drug treatment is increasing. We assessed liver function after lenvatinib administration according to age in patients with advanced HCC. PATIENTS AND METHODS: In this retrospective, multicenter, observational study, we reviewed the records of patients with HCC who received lenvatinib treatment (March 2018-March 2020). Liver function was measured using the Albumin-Bilirubin Index (ALBI). RESULTS: Of 119 patients, with a median age of 72.0 years, median overall survival was 15.3 months. Overall survival was significantly better in the group which maintained liver function (p=0.02). Older age (≥72 years) was associated with liver-function deterioration within 8 weeks (odds ratio=2.47, 95% confidence interval=1.06-5.75, p=0.035). The ALBI score was significantly higher in the older group at 4 and 8 weeks after lenvatinib administration. CONCLUSION: Lenvatinib administration was more likely to adversely affect liver function in older patients; dose adjustment should be considered in such patients.

Comparative study of the effect of neuromuscular electrical stimulation and oral administration of branched-chain amino acid on preventing sarcopenia in patients after living-donor liver transplantation: study protocol for an open-label randomized controlled trial.

BACKGROUND: Liver cirrhosis is the irreversible fibrosis of the liver and causes refractory ascites and hepatic encephalopathy, which might not respond to treatment. Living donor liver transplantation (LDLT) is an effective treatment for patients with cirrhosis. However, post-LDLT patients are prone to muscle atrophy and sarcopenia. Therefore, physiotherapy of post-LDLT patients is essential for preventing the progression of sarcopenia. Recently, rehabilitation using neuromuscular electrical stimulation (NMES) has been reported to be useful for preventing the progression of sarcopenia. Similarly, nutrition therapy is essential for post-LDLT patients because these patients frequently experience malnutrition. However, the effects of combined NMES and nutrition therapy on post-LDLT patients remain unknown. METHODS/DESIGN: This open-label, randomized, parallel-group study will compare the effects of combined therapy with NMES and branched-chain amino acids (BCAA) with those of NMES alone in patients with decompensated cirrhosis after LDLT. After LDLT, 50 patients with decompensated cirrhosis will be randomly assigned to receive NMES with BCAA or NMES without BCAA. The duration of the intervention will be 3 months. To analyze the change in skeletal muscle mass, InBody 770 body composition and body water analysis and ultrasonography will be performed before LDLT and 4 weeks and 12 weeks post-LDLT. The primary endpoint is changes in the skeletal muscle mass from baseline to 3 months. Important secondary endpoints are the changes in the skeletal muscle mass from baseline to 1 month and changes in the quadriceps strength from baseline to 1 month. DISCUSSION: The results of this study are expected to provide evidence regarding the effect of NMES combined with BCAA therapy on the skeletal muscle of post-LDLT patients. TRIAL REGISTRATION: Japan Registry of Clinical Research jRCTs071190051 . Registered on February 26, 2020.

Geranylgeranylacetone decreases the production of hepatitis B virus-related antigen by comprehensive downregulation of mRNA transcription activity.

BACKGROUND AND AIM: Elimination of hepatitis B virus (HBV) is infrequently achieved with current therapies. Therefore, more effective anti-HBV therapy is needed. We previously reported that geranylgeranylacetone (GGA) showed anti-hepatitis C virus activity in human hepatoma cells. In this study, we examined the anti-HBV activity of GGA. METHODS: We used HepG2.2.15.7 cells, PXB cells infected with HBV, Huh7 cells transfected with linear HBV, and PLC/PRF/5 cells as HBV-infected hepatocyte models. After GGA treatment, HBV-related antigen was measured by chemiluminescent immunoassay. HBV-related mRNA was examined by Northern blot. cccDNA and endoplasmic reticulum stress markers were measured by real-time polymerase chain reaction. The activities of HBV promoters and enhancer regions were examined using luciferase vectors. RESULTS: After GGA treatment, hepatitis B surface antigen and hepatitis B e antigen secretion was decreased in all HBV-infected hepatocyte models. HBV-related mRNA was also decreased by GGA treatment, although cccDNA levels were not affected. Additionally, the activity of HBV S1 and S2 promoter region and Enhancer 1/Enhancer 2/core promoter region was reduced by GGA treatment. The mRNA expression of the main transcription factors, hepatocyte nuclear factor 3 and 4 and CCAAT/enhancer binding protein, was also decreased. Further, the expression levels of endoplasmic reticulum stress markers were increased by GGA treatment, which reflected the change in HBV-related antigen secretion. CONCLUSIONS: Geranylgeranylacetone treatment reduces HBV-related protein levels by suppressing comprehensive downregulation of HBV promoter and enhancer activity, which might be caused by decreased hepatic transcription factor expression. GGA treatment may enhance anti-HBV effects in combination with other therapies.