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.

Brief intervention for chronic liver disease patients with alcohol use disorder in a hepatology outpatient unit: Effects and limitations.

AIM: It is not uncommon to encounter outpatients in the hepatology department with harmful alcohol habits. When treating such chronic liver disease (CLD) patients, an adequate intervention method for harm reduction of alcohol use, such as brief intervention (BI) or BI and nalmefene, should be considered. This study aimed to elucidate the clinical effectiveness of BI for CLD patients affected by harmful alcohol use. METHODS: From June 2021 to 2023, 123 Japanese CLD outpatients (hepatitis B virus : hepatitis C virus : alcoholic liver disease : others = 32:18:42:31) with an Alcohol Use Disorders Identification Test (AUDIT) score of ≥8 at the initial interview and a repeat interview with AUDIT 9 months later were enrolled. Clinical features related to patient behavior following the initial AUDIT interview were retrospectively evaluated, and compared between patients without and with BI treatment. RESULTS: For the non-BI and BI groups, baseline AUDIT score (median 10 [interquartile range (IQR) 9-13] vs. 12 [IQR 10-17], p = 0.016) and relative change in AUDIT score (median 0 [IQR -3 to 2] vs. -3 [IQR -7 to 0], p < 0.01) showed significant differences, whereas there was no significant difference between the groups for AUDIT score at the time of the second interview (p = 0.156). Following BI, significant improvements were observed for items 1, 2, 3, 4, 5, 8, and 10 of AUDIT (each p < 0.05). CONCLUSION: Patients with an alcohol use disorder as well as those with alcohol dependency who received BI showed a significant decline in AUDIT score, although the score of the follow-up AUDIT indicated continued alcohol use disorder. In addition to BI, medication with nalmefene should be considered, based on individual factors.

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.

Liver fibrosis analysis using digital pathology.

Digital pathology has enabled the noninvasive quantification of pathological parameters. In addition, the combination of digital pathology and artificial intelligence has enabled the analysis of a vast amount of information, leading to the sharing of much information and the elimination of knowledge gaps. Fibrosis, which reflects chronic inflammation, is the most important pathological parameter in chronic liver diseases, such as viral hepatitis and metabolic dysfunction-associated steatotic liver disease. It has been reported that the quantitative evaluation of various fibrotic parameters by digital pathology can predict the prognosis of liver disease and hepatocarcinogenesis. Liver fibrosis evaluation methods include 1 fiber quantification, 2 elastin and collagen quantification, 3 s harmonic generation/two photon excitation fluorescence (SHG/TPE) microscopy, and 4 Fibronest™..　In this review, we provide an overview of role of digital pathology on the evaluation of fibrosis in liver disease and the characteristics of recent methods to assess liver fibrosis.

EUS-guided fine-needle biopsy sampling of solid pancreatic tumors with 3 versus 12 to-and-fro movements: a multicenter prospective randomized controlled study.

BACKGROUND AND AIMS: A novel EUS-guided fine-needle biopsy sampling (EUS-FNB) needle enabled physicians to obtain sufficient pathologic samples with fewer to-and-fro movements (TAFs) within the lesion. We compared the diagnostic yields of EUS-FNB with 3 and 12 TAFs at each puncture pass. METHODS: The primary endpoint of this multicenter, noninferiority, crossover, randomized controlled trial involving 6 centers was diagnostic sensitivity. Secondary endpoints were diagnostic accuracy and quantity and quality evaluation of EUS-FNB specimens. Length of the macroscopically visible core (MVC) and microscopic histologic quantity were used for quantitative evaluation. Macroscopic visual and microscopic histologic evaluations were performed for qualitative evaluation. RESULTS: Among 110 patients (220 punctures, 110 for 3 TAFs and 12 TAFs each), 105 (210 punctures) had malignant histology. Diagnostic sensitivity for malignancy of 3 TAFs (88.6%) was not inferior to that of 12 TAFs (89.5%; difference, -.9%; 95% confidence interval, -9.81 to 7.86). Diagnostic accuracy for malignancy was 92.7% for 3 TAFs and 94.6% for 12 TAFs. Overall median MVC length was 13.5 mm in both groups. The 3-TAF group had a significantly higher rate of score ≥3 on macroscopic visual quality evaluation than the 12-TAF group (71.8% vs 52.7%, P = .009). No significant intergroup differences existed in microscopic histologic quantity and quality evaluations (quantity evaluation, 88.2% for 3 TAFs vs 83.6% for 12 TAFs; quality evaluation, 90.0% for 3 TAFs vs 89.1% for 12 TAFs). CONCLUSIONS: Diagnostic sensitivity and accuracy of EUS-FNB with 3 TAFs were not inferior to those with 12 TAFs for solid pancreatic lesions. The 3-TAF group showed significantly less blood contamination in sampled tissues than the 12-TAF group. (Clinical trial registration number: UMIN000037309.).

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.

Clinical features of patients with chronic liver disease in Japan related to alcohol use: Nationwide examination using alcohol use disorders identification test.

AIM: Patients often do not respond truthfully to physicians' interviews concerning alcohol. Few reports regarding the level of alcohol dependence in patients with chronic liver disease (CLD) have been presented. This study aimed to elucidate severity distribution in patients with CLD using the alcohol use disorders identification test (AUDIT). METHODS: From March to June 2022, 2034 Japanese outpatients with CLD, including 415 cases associated with hepatitis C virus, 436 with hepatitis B virus, 173 with alcohol-related liver disease (ARLD), and 1010 with other factors, were interviewed using AUDIT. Clinical features related to alcohol use in these patients were then retrospectively evaluated. RESULTS: In all patients, an AUDIT score 8-14 (harmful use) was noted in 5.8% of hepatitis C virus, 8.9% of hepatitis B virus, 24.3% of ARLD, and 4.4% of other groups, respectively (P < 0.001), while a score ≥15 (dependency) was noted in 3.4%, 3.0%, 27.7%, and 1.9%, respectively (P < 0.001). When the country was divided into regions, the percentages remained similar. Comparisons between patients with and without an AUDIT score ≥8 (n = 1412), performed after exclusion of those without related data (n = 622), showed no significant differences for hepatic reserve function, while those with harmful alcohol use were significantly younger (66 vs. 70 years, P = 0.006) and had a larger percentage of men (80.4% vs. 45.1%, P < 0.001). CONCLUSION: Harmful alcohol and alcohol dependency were observed in approximately 10% of patients with viral or non-viral CLD, after excluding patients with ARLD. Assessment of alcohol intake by use of the AUDIT questionnaire as well as adequate intervention should be considered necessary.

Respiratory support with nasal high flow without supplemental oxygen in patients undergoing endoscopic retrograde cholangiopancreatography under moderate sedation: a prospective, randomized, single-center clinical trial.

BACKGROUND: Nasal high flow (NHF) may reduce hypoxia and hypercapnia during an endoscopic retrograde cholangiopancreatography (ERCP) procedure under sedation. The authors tested a hypothesis that NHF with room air during ERCP may prevent intraoperative hypercapnia and hypoxemia. METHODS: In the prospective, open-label, single-center, clinical trial, 75 patients undergoing ERCP performed with moderate sedation were randomized to receive NHF with room air (40 to 60 L/min, n = 37) or low-flow O2 via a nasal cannula (1 to 2 L/min, n = 38) during the procedure. Transcutaneous CO2, peripheral arterial O2 saturation, a dose of administered sedative and analgesics were measured. RESULTS: The primary outcome was the incidence of marked hypercapnia during an ERCP procedure under sedation observed in 1 patient (2.7%) in the NHF group and in 7 patients (18.4%) in the LFO group; statistical significance was found in the risk difference (-15.7%, 95% CI -29.1 - -2.4, p = 0.021) but not in the risk ratio (0.15, 95% CI 0.02 - 1.13, p = 0.066). In secondary outcome analysis, the mean time-weighted total PtcCO2 was 47.2 mmHg in the NHF group and 48.2 mmHg in the LFO group, with no significant difference (-0.97, 95% CI -3.35 - 1.41, p = 0.421). The duration of hypercapnia did not differ markedly between the two groups either [median (range) in the NHF group: 7 (0 - 99); median (range) in the LFO group: 14.5 (0 - 206); p = 0.313] and the occurrence of hypoxemia during an ERCP procedure under sedation was observed in 3 patients (8.1%) in the NHF group and 2 patients (5.3%) in the LFO group, with no significant difference (p = 0.674). CONCLUSIONS: Respiratory support by NHF with room air did not reduce marked hypercapnia during ERCP under sedation relative to LFO. There was no significant difference in the occurrence of hypoxemia between the groups that may indicate an improvement of gas exchanges by NHF. TRIAL REGISTRATION: jRCTs072190021 . The full date of first registration on jRCT: August 26, 2019.

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.

The Usefulness of the Athens Insomnia Scale for Evaluating Sleep Disturbance in Patients with Chronic Liver Disease Comparing with Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale.

Background and Objectives: Sleep disturbance due to muscle cramps or hepatic encephalopathy in patients with chronic liver disease (CLD) can lead to a reduced quality of life. The Pittsburgh sleep quality index (PSQI) is commonly used for evaluating sleep disturbance; however, this questionnaire is time-consuming owing to the large number of questions. As the usefulness of the Athens insomnia scale (AIS) in patients with CLD is not sufficiently known, the present study aimed to determine whether the AIS and Epworth sleepiness scale (ESS) could be used as simple alternative questionnaires for evaluating sleep disturbances in patients with CLD. Materials and Methods: A total of 117 patients with CLD were retrospectively evaluated. Patients with overt hepatic encephalopathy were excluded. All patients were examined using the AIS, PSQI, and ESS, and their responses to these questionnaires were statistically analyzed. Results: The number of patients diagnosed with sleep disturbance using the AIS, PSQI, and ESS were 39 (33.3%), 37 (31.6%), and 9 (7.7%), respectively. There was no correlation between PSQI and ESS scores (r = 0.011, p = 0.910); in contrast, the AIS scores showed a significant correlation with the PSQI scores (r = 0.689, p < 0.001). When the PSQI was considered as the standard for evaluating sleep disturbance, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the AIS were 76.9%, 91.0%, 81.1%, and 88.8%, respectively. In the sleep medication group, the sensitivity, specificity, PPV, and NPV of the AIS were 100%, 70%, 78.6%, and 100%, respectively. Conclusions: This is the first report to indicate that the AIS is an alternative questionnaire to the PSQI and that it can be a useful tool for detecting cirrhosis-related complications in patients with CLD.

Serum Mac-2 binding protein glycosylation isomer as a biomarker of fibrosis in living donor liver transplant graft.

INTRODUCTION: Non-invasive assessment of graft fibrosis is important in liver transplantation. Mac-2 binding protein glycosylation isomer (M2BPGi) has been reported as a diagnostic marker for this purpose, and thus, this predictive ability of M2BPGi was assessed in this study. PATIENTS AND METHODS: In this retrospective study, 236 patients who received living donor liver transplantation (LDLT) from August 1997 to March 2017 were enrolled. Among them, 94 biopsy patients were analyzed. Further, the predictive ability of fibrotic biopsy using M2BPGi, Fibroscan, and Fib-4 index was compared. RESULTS: Of 94 LDLT patients (53 men, 41 women), the median ages of recipients and donors were 57.5 and 33.0 years, respectively. The median M2BPGi values in patients with F0 (n = 11), F1 (n = 38), F2 (n = 35), and F3/4 (n = 10) were 0.680, 0.760, 1.240, and 4.110 COI, respectively. There were significant correlations between the fibrotic stage and M2BPGi levels (Kruskal-Wallis test, P < .0001). The area under the ROC curve for the diagnosis of F ≥ 2 in M2BPGi was 0.778, which was superior to Fibroscan (0.701) and Fib-4 index (0.639). CONCLUSION: M2BPGi is an accurate, non-invasive detection method for significant fibrosis after LDLT.

Proposal of Stroop test cut-off values as screening for neuropsychological impairments in cirrhosis: A Japanese multicenter study.

AIM: Despite its relevant clinical impact and high prevalence, covert hepatic encephalopathy (HE) still remains underdiagnosed. As patients with liver cirrhosis tend to be older in Japan, more suitable tests for the elderly and cut-off values based on this attribute are needed. Recently, a Stroop test has been developed and validated for the screening and diagnosis of covert HE in the United States. The present study aims to establish the cut-off values of the Stroop test to screen covert HE. METHODS: This study was a prospective multicenter cross-sectional endeavor. We undertook a survey of 311 cirrhotic patients, administering the number connection test (NCT)-A and -B and the Stroop-off and -on test. RESULTS: We determined the cut-off values of Stroop test results for cirrhotic patients in a variety of age ranges. The cut-off value of the Stroop test was strongly correlated with age. There was a significant correlation between the results of NCT-B and age, and Stroop-on test results showed a correlation with serum albumin (Alb) levels. Serum Alb ≤3.2 g/dl could have the potential to be an objective biomarker of covert HE. In addition, stepwise logistic regression analysis revealed a relationship between the results of the Stroop-on test and plasma ammonia levels. CONCLUSIONS: We established the cut-off values of Stroop test results and confirmed the efficacy of the Stroop test as a simple tool for assessing cognitive alterations. The Stroop test could be suitable as a necessary minimum for the diagnosis of covert HE.

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.

Blood carnitine profiling on tandem mass spectrometry in liver cirrhotic patients.

BACKGROUND: The level and profiles of blood free carnitine and acylcarnitines, obtained by acylcarnitine analysis using tandem mass spectrometry, reflect various metabolic conditions. We aimed to examine the level of free carnitine and acylcarnitines in liver cirrhosis patients by acylcarnitine analysis and determine the clinical and subjective factors associated with blood carnitine fraction levels in liver cirrhosis. METHODS: We compared blood carnitine fractions in 54 liver cirrhotic patients to other laboratory test results and questionnaire answers. RESULTS: In almost all patients, the blood levels of free carnitine (C0) and acetylcarnitine (C2) were within the normal reference range. However, in some patients, the levels of long-chain acylcarnitines, such as C16 and C18:1-acylcarnitine, were higher than the normal reference range. Liver function, assessed by Child-Pugh score, was significantly correlated with the blood level of each carnitine fraction measured (C0, C2, C3, C4, C6, C10, C12, C12:1, C14:1, C16, C18:1, and C18:2-acylcarnitine). Cirrhotic symptom score was significantly correlated with C0, C2, C3, C16, and C18-1-acylcarnitine blood levels. Among the 36-item short-form health survey (SF-36) items, the physical component summary was significantly associated with C0, C2, and C18-1-acylcarnitine blood levels. CONCLUSIONS: Carnitine fraction levels were positively correlated with liver cirrhosis stage, particularly, long-chain acylcarnitines. Moreover, carnitine fraction levels were associated with various subjective physical symptoms in liver cirrhosis patients.

Calculated body muscle mass as a useful screening marker for low skeletal muscle mass and sarcopenia in chronic liver disease.

AIM: Sarcopenia is a harmful condition in patients with chronic liver disease. However, the evaluation of body muscle mass requires expensive instrumentation. The sarcopenia index (SI): (creatinine / cystatin C × 100) has been reported to correlate with muscle volume. A calculated body muscle mass (CBMM) using creatinine, cystatin C, and bodyweight also correlates with muscle mass. We evaluated the applicability of using SIs and CBMMs as screening methods for sarcopenia. METHODS: Patients (n = 303) with liver damage were evaluated for creatinine, cystatin C, and grip strength (GS). All patients were evaluated using cross-sectional computed tomography images of the third lumbar vertebrae to determine their skeletal muscle (SM) mass. CBMMs and SIs were compared with SMs, GSs, and sarcopenia. RESULTS: Correlation coefficients (R) between SMI (SM / height2 [m2 ]) and CBMM, and between GS and CBMM were 0.643 and 0.723, respectively. Factors contributing to low GSs; low SM indices; and sarcopenia were age and SM; sex, age, GS, SI, and CBMM indices; and sex, bodyweight, and CBMM, respectively, in the multivariate logistic analyses. Receiver operating characteristic curve analysis between sarcopenia and CBMM showed an area under the receiver operating characteristic curve of 0.78504 in women and 0.86067 in men. Cut-off CBMM values for sarcopenia were 27.903 (sensitivity 0.73958) in women and 39.731 (sensitivity 0.7941) in men. CONCLUSIONS: CBMMs and SIs are simple and minimally invasive screening methods in which low levels are indicative of sarcopenia in patients with liver disease.

Procedure-Related Complications and Survival after Gastrostomy: Results from a Japanese Cohort.

INTRODUCTION: In 2010, a large-scale multi-institutional study in Japan showed a good prognosis for percutaneous endoscopic gastrostomy (PEG). However, the function and efficacy of PEG are not fully understood by patients, families, and health-care professionals; thus, the number of PEG treatments in Japan has declined. Therefore, we aimed to investigate the safety of the PEG procedure and subsequent survival after PEG. METHODS: In total, 249 PEGs were performed at Juzenkai Hospital from 2005 to 2017. PEG was originally performed using the pull method and then by a modified introducer method from mid-2011. We examined procedure-related complications and survival rates after PEG. RESULTS: Fifty-one (20.5%) procedure-related complications occurred; emergency surgery was required in 4 cases. Infections accounted for 76.5% (39/51) of complications. More infections occurred with the pull method than with the modified introducer method. The 1-year survival rate was 66.8%; the median survival time was 678 days. Nine patients (3.6%) died within 30 days; no deaths were directly related to PEG. Sex, age, and albumin level before surgery significantly influenced the prognosis. CONCLUSION: Due to changes in the PEG insertion method and other factors, PEG has become a safer treatment method. Additionally, PEG-based nutritional supplementation is associated with adequate survival.

Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression.

Nonalcoholic fatty liver disease is a major liver disease that leads to cirrhosis and/or hepatocellular carcinoma in a subset of patients. The mechanism underlying disease progression is largely unknown. p53-binding protein 1 (53BP1) is a DNA damage response protein that rapidly localizes at the site of DNA double-strand breaks. In this study, we investigated nuclear 53BP1-positive foci formation as an indicator of DNA double-strand breaks in human nonalcoholic fatty liver disease liver tissues by immunofluorescence microscopy. A total of 52 liver tissue samples, including 43 nonalcoholic fatty liver disease samples and 9 controls, were studied. Our results show that the number of abnormal 53BP1-positive foci in hepatocytes (defined as three or more discrete nuclear foci and/or large foci greater than 1 µM) was significantly increased in nonalcoholic fatty liver disease patients compared to that in controls, both in nonalcoholic fatty liver (p < 0.01) and nonalcoholic steatohepatitis patients (p < 0.01). The number of large foci was significantly increased in the nonalcoholic steatohepatitis cases compared to that in the nonalcoholic fatty liver cases (p < 0.05) and correlated with increased stage of fibrosis. The number of large-foci-expressing hepatocytes was positively correlated with increased age (p < 0.01) and negatively correlated with serum platelet count (p < 0.05). In addition, we performed an in vitro assay using rat hepatocytes treated with the saturated free fatty acid palmitate. Treatment appeared to augment the number of abnormal foci, indicating an induction of double-strand breaks in the hepatocytes through free fatty acid treatment in a caspase-dependent manner. This study demonstrates that 53BP1-positive nuclear foci formation is associated with disease progression in nonalcoholic fatty liver disease patients. Analysis of 53BP1 expression might be a feasible technique to estimate genomic instability in nonalcoholic fatty liver disease.

Sevoflurane has postconditioning as well as preconditioning properties against hepatic warm ischemia-reperfusion injury in rats.

PURPOSE: Ischemia-reperfusion (IR) injury is inevitable after liver transplantation and liver resection with inflow occlusion. Sevoflurane has been widely used during hepatobiliary surgery and was reported to exhibit preconditioning (PreC) properties against hepatic IR injury; however, its postconditioning (PostC) properties remain unknown. This study examined whether a clinically applicable dose of sevoflurane has PostC and PreC properties against hepatic IR injury and roles of heme oxygenase-1 (HO-1). METHODS: Warm ischemia was induced in male Wistar rats, excluding the sham group, for 1 h, followed by 3 h of reperfusion. Group C received propofol from 60 min before ischemia until the end of the experimental procedure. In the SPreC and SPostC groups, propofol was replaced by 2.5% sevoflurane for 30 min from 35 min before ischemia in the SPreC group and for 30 min from 5 min before reperfusion in the SPostC group. The SPreC+Z and SPostC+Z groups received a HO-1 inhibitor, zinc protoporphyrin (Znpp), 60 min before ischemia, and sevoflurane PreC and PostC were induced. RESULTS: Serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels, and histological damage scores in the SPreC and SPostC groups were significantly lower than those in group C. Inhibiting HO-1 with Znpp partially blocked these protective effects of sevoflurane. Sevoflurane PreC and PostC significantly increased the number of HO-1-positive Kupffer cells in comparison with group C, and Znpp prevented sevoflurane-induced HO-1 expression. CONCLUSION: PostC and PreC by sevoflurane at a clinically applicable dose have equally protective effects against hepatic IR injury by increasing HO-1 expression.

Relationship of muscle cramps to quality of life and sleep disturbance in patients with chronic liver diseases: A nationwide study.

BACKGROUND & AIMS: Although muscle cramps frequently occur in patients with cirrhosis, the importance of muscle cramps remains unclear. The aims of this study were to investigate the relationship of muscle cramps with quality of life (QOL) and sleep disturbance. In addition, this multi-institutional collaborative study in Japan investigated factors associated with muscle cramps in patients with cirrhosis. METHODS: A total of 1788 patients with chronic liver diseases including both non-cirrhosis and cirrhosis completed a questionnaire survey investigating: (i) frequency of muscle cramps, (ii) relationship of muscle cramps to poor QOL and sleep disturbance, (iii) characteristics of patients who require therapeutic intervention and (iv) characteristics of patients prone to experiencing muscle cramps. RESULTS: This study revealed that 51.8% of patients with cirrhosis have experienced muscle cramps. People who experienced muscle cramps were more likely to have reduced QOL and sleep disturbance if muscle cramps had (i) high frequency (occurring daily to a few times per week, P < .01); (ii) long duration (between a few minutes and a few hours, P < .01) and (iii) intense severity (visual analogue scale ≥4, P < .01). Age, female sex, positive results for hepatitis C virus, low serum albumin concentration, and cirrhosis were independent factors related to the severity of muscle cramps. CONCLUSION: Muscle cramps occurred with great frequency and were associated with various factors such as age, sex, hepatitis C virus and liver function. Many patients experience poor QOL (26.3%) due to muscle cramps, and therapeutic interventions are therefore needed.

Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice.

BACKGROUND: Geranylgeranylacetone (GGA), an anti-ulcer drug widely used in Japan, has attracted interest because of its various therapeutic effects. Therefore, we investigated the effects of GGA on human hepatic stellate cells (HSCs) in vitro and in a mouse model of liver fibrosis. METHODS: LX2, an immortalized human HSC line, was cultured and treated with GGA at concentrations up to 0.5 mM. After GGA treatment, changes in cellular morphology, apoptosis, and fibrosis-related gene expression were assessed. Male C57BL/6 J mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis was treated with GGA. Liver fibrosis was evaluated using Sirius red staining and immunohistochemistry for α-smooth muscle actin (SMA). RESULTS: GGA decreased the density of LX2 and primary human hepatic stellate cells but not that of HepG2 cells (a human hepatoma cell line), which was employed as control. In addition, GGA decreased the expression of fibrogenic genes and increased that of C/EBP homologous protein (CHOP). It also induced endoplasmic reticulum (ER) stress and increased apoptosis. CHOP knockdown, however, failed to suppress the GGA-induced decrease in LX2 cell density, suggesting the involvement of additional molecules in ER stress-associated apoptosis. Expression of death receptor 5, mitogen-activated protein kinase, heat shock protein 70, and Akt, all of which affect the activity of stellate cells, was unchanged in relation to LX2 cell fibrogenic activity. In the mouse model of liver fibrosis, GGA decreased the extent of Sirius red staining and SMA expression. CONCLUSIONS: GGA attenuated fibrogenic activity and induced apoptosis in cultured human HSCs, and suppressed liver fibrosis in mice, suggesting its potential as an agent for treating liver fibrosis.