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.

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.

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.

Public Interest and Accessibility of Telehealth in Japan: Retrospective Analysis Using Google Trends and National Surveillance.

BACKGROUND: Recently, the use of telehealth for patient treatment under the COVID-19 pandemic has gained interest around the world. As a result, many infodemiology and infoveillance studies using web-based sources such as Google Trends were reported, focusing on the first wave of the COVID-19 pandemic. Although public interest in telehealth has increased in many countries during this time, the long-term interest has remained unknown among people living in Japan. Moreover, various mobile telehealth apps have become available for remote areas in the COVID-19 era, but the accessibility of these apps in epidemic versus nonepidemic regions is unknown. OBJECTIVE: We aimed to investigate the public interest in telehealth during the first pandemic wave and after the wave in the first part of this study, and the accessibility of medical institutions using telehealth in the epidemic and nonepidemic regions, in the second part. METHODS: We examined and compared the first wave and after the wave with regards to severe cases, number of deaths, relative search volume (RSV) of telehealth and COVID-19, and the correlation between RSV and COVID-19 cases, using open sources such as Google Trends and the Japanese Ministry of Health, Labour and Welfare (JMHLW) data. The weekly mean and the week-over-week change rates of RSV and COVID-19 cases were used to examine the correlation coefficients. In the second part, the prevalence of COVID-19 cases, severe cases, number of deaths, and the telehealth accessibility rate were compared between epidemic regions and nonepidemic regions, using the JMHLW data. We also examined the regional correlation between telehealth accessibility and the prevalence of COVID-19 cases. RESULTS: Among the 83 weeks with 5 pandemic waves, the overall mean for the RSV of telehealth and COVID-19 was 11.3 (95% CI 8.0-14.6) and 30.7 (95% CI 27.2-34.2), respectively. The proportion of severe cases (26.54% vs 18.16%; P<.001), deaths (5.33% vs 0.99%; P<.001), RSV of telehealth (mean 33.1, 95% CI 16.2-50.0 vs mean 7.3, 95% CI 6.7-8.0; P<.001), and RSV of COVID-19 (mean 52.1, 95% CI 38.3-65.9 vs mean 26.3, 95% CI 24.4-29.2; P<.001) was significantly higher in the first wave compared to after the wave. In the correlation analysis, the public interest in telehealth was 0.899 in the first wave and -0.300 overall. In Japan, the accessibility of telehealth using mobile apps was significantly higher in epidemic regions compared to nonepidemic regions in both hospitals (3.8% vs 2.0%; P=.004) and general clinics (5.2% vs 3.1%; P<.001). In the regional correlation analysis, telehealth accessibility using mobile apps was 0.497 in hospitals and 0.629 in general clinics. CONCLUSIONS: Although there was no long-term correlation between the public interest in telehealth and COVID-19, there was a regional correlation between mobile telehealth app accessibility in Japan, especially for general clinics. We also revealed that epidemic regions had higher mobile telehealth app accessibility. Further studies about the actual use of telehealth and its effect after the COVID-19 pandemic are necessary.

Change in tartrate-resistant acid phosphatase isoform 5b levels, a marker of bone metabolism, in patients with chronic hepatitis B treated with tenofovir alafenamide.

Hepatitis B virus (HBV) infection is associated with the risk of osteoporosis and bone mineral density (BMD) loss. Tenofovir alafenamide (TAF) is associated with a slightly lower degree of BMD loss compared with tenofovir disoproxil, without loss of the excellent anti-HBV effects. The aim of the present study was to verify the effect of bone metabolism in patients with HBV treated with TAF. A total of 87 patients were treated with TAF. Of these, 32 patients were treatment naïve, and 55 patients were treated with entecavir (ETV) for at least 1 year, after which ETV was switched to TAF. At the start of TAF and after 1 year, BMD in the lumbar and neck of the femur, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) levels as a marker of bone metabolism and serum inorganic phosphorus (P) were compared to estimate bone metabolism. Serum creatinine (Cr), cystatin C, urine protein and ß2 microglobulin levels were evaluated to estimate kidney function. Treatment with TAF for 1 year decreased TRACP-5b levels, particularly in patients with bone disease, except for a minimal significant change (MSC; decrease of 12.4%) in TRACP-5b levels. The change in rate of TRACP-5b levels were positively associated with changes in P, Cr-estimated glomerular filtration rate and TRACP-5b levels at the start of TAF. Logistic regression analysis showed that increased BMD in the lumbar region contributed to the switch from ETV to TAF. TAF induced a decrease in TRACP-5b levels in patients with HBV. Bone disease was a contributing factor for MSC. Since TRACP-5b can be used as a marker of bone metabolism and fractures, TAF may exhibit potential in preventing fractures in patients with HBV.

Comparison of calculated body muscle mass and SARC-F as methods of screening for sarcopenia in patients with chronic liver disease.

A simple method is required to screen for sarcopenia in patients with chronic liver disease. In the present study, the value of the existing SARC-F questionnaire as well as calculated body muscle mass (CBMM) approaches were assessed for screening of sarcopenia. A total of 482 patients with chronic liver disease underwent CBMM, grip strength (GS) and SARC-F score assessments. Cross-sectional computed tomography images of the third lumbar vertebrae were analyzed to determine the skeletal muscle (SM) mass in 303 patients. Cutoff CBMM values for sarcopenia were <27.903 in females and <39.731 in males. The cutoff SARC-F score for sarcopenia was ≥4 points. Sarcopenia was diagnosed using the criteria described in the Japan Society of Hepatology. GS was moderately correlated with SARC-F score (females, R=-0.578; males, -0.453) and CBMM (females, R=0.497; males, 0.548). The SM index was moderately correlated with CBMM for both sexes (females, R=0.546; males, 0.612), but not with SARC-F score in females (females, R=-0.132; males, -0.246). The area under the curve (AUC) for CBMM against sarcopenia (0.85964) was significantly larger than that for SARC-F score (0.72013) amongst males (P=0.03577) but not females. The AUCs for a modified SARC-F questionnaire (encompassing the SARC-F questionnaire, CBMM, sex and age; mSARC-F) against sarcopenia were 0.864 in males and 0.78185 in females. As a screening method, SARC-F is less useful than CBMM. However, the AUC for mSARC-F is greater than SARC-F and CBMM.

Direct-acting Antivirals Improved the Quality of Life, Ameliorated Disease-related Symptoms, and Augmented Muscle Volume Three Years Later in Patients with Hepatitis C Virus.

Objective Patient-reported outcomes (PROs) are important measures of the quality of life (QOL) and symptoms in patients with hepatitis C virus (HCV). We evaluated the PROs at the beginning of direct-acting antiviral (DAA) treatment and three years later. A low QOL in patients with chronic liver disease suggested a low muscle mass. We compared the relationship between the QOL and muscle mass. Methods DAAs were administered to 100 patients with HCV infection. The PROs included the cirrhosis-related symptom score (CSS), presence of restless legs syndrome, Pittsburg sleep quality index (PSQI) to evaluate sleep disturbance, SF-36 to measure the QOL, and calculated body muscle mass (CBMM) measured at the beginning of treatment and three years later. Computed tomography (CT) was used to screen 82 patients for hepatocellular carcinoma at the beginning of treatment and three years later. Cross-sectional CT images of the third lumbar vertebrae were analyzed to evaluate the body composition. Results The general health perception (GHN) of SF-36 was better at three years after DAA administration than at the beginning. Changes in the GHN (dGHN) were related to an improved sleep quality on the PSQI and CSS and increased CBMM. The dGHN was positively related to changes in the skeletal muscle. The sleep quality, sleep latency, fatigue, and abdominal fullness were related to dGHN. Conclusion The QOL is related to sleep disturbance and several other symptoms. Furthermore, in patients with an increased muscle volume after DAA treatment, increased muscle mass is associated with an improvement in the QOL.

Correction: Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice.

[This corrects the article DOI: 10.1371/journal.pone.0170591.].

Influence of Interferon-free Direct-acting Antiviral Therapy on Primary Hepatocellular Carcinoma Recurrence: A Landmark Time Analysis and Time-dependent Extended Cox Proportional Hazards Model Analysis.

Objective The influence of interferon (IFN)-free direct-acting antiviral (DAA) on hepatocellular carcinoma (HCC) recurrence remains unclear. Previous retrospective analyses revealed that the time interval between HCC curative treatment and IFN-free DAA induction is the critical factor affecting HCC recurrence. Thus, this study aimed to examine the influence of DAA therapy on HCC recurrence considering this interval. Methods Factors contributing to HCC recurrence were retrospectively analyzed using a landmark time analysis and time-dependent extended Cox proportional hazards model. Patients After screening 620 patients who were diagnosed with primary HCC from January 2001 to December 2016, 76 patients with early-stage (primary and solitary) disease who received curative treatment and were positive for serum hepatitis C virus RNA were included. Results HCC recurrence was observed in 8 of 17 (47.1%) patients who had received IFN-free DAA therapy and 45 of 59 (76.3%) who had not. No significant difference was seen between the IFN-free DAA (-) and IFN-free DAA (+) groups in the landmark time and time-dependent Cox proportional hazards model analyses. However, IFN-free DAA therapy tended to decrease the HCC recurrence rate after curative treatment for primary HCC in patients with chronic hepatitis. In addition, IFN-free DAA therapy tended to decrease the second HCC recurrence rate after treatment for the first HCC recurrence. Conclusion Our results, with a consideration of the time interval between HCC curative treatment and IFN-free DAA induction, showed that IFN-free DAA therapy was not associated with early-stage HCC recurrence after curative treatment.

Extracellular vesicles from senescent hepatic stellate cells promote cell viability of hepatoma cells through increasing EGF secretion from differentiated THP-1 cells.

Since the discovery of the senescence-associated secretory phenotype, the role of senescent hepatic stellate cells (HSCs) in hepatocellular carcinoma (HCC) development has gained increasing attention. Similar to cytokines, extracellular vesicles (EVs) are essential for intercellular communication. However, the function of EVs derived from senescent HSCs in HCC progression has not been extensively studied. The aims of the present study were to characterize the EVs derived from senescent HSCs and determine their role in the tumor microenvironment. Cellular senescence was induced in human hepatic stellate cells (HHSteCs) with various concentrations of etoposide. Induction was confirmed using EdU staining and 53BP1 and p21 immunostaining. EVs were isolated by ultracentrifugation and analyzed by nanoparticle tracking analysis. Multiplex immunoassays were used to compare the levels of growth factors secreted from hepatoma cell lines and macrophage cells pretreated with EVs derived from senescent HHSteCs (senescent EVs) with those pretreated with EVs derived from normal cultured HHSteCs (normal EVs). Treatment with 25 µM etoposide for 3 days was the most effective at inducing senescence in HHSteCs. This finding was confirmed by induction of irreversible cell-cycle arrest, upregulation of 53BP1 and p21 expression, and increased SA-ß-gal staining. Senescent HHSteCs released increased quantities of EV particles compared with normally cultured HHSteCs. Multiplex analysis revealed that there was no difference between hepatoma cell lines treated with normal EVs and those treated with senescent EVs in growth factor secretion. In contrast, the secretion of epidermal growth factor (EGF) was increased by macrophage cells treated with senescent EVs compared with those treated with normal EVs. Furthermore, senescent EVs did not affect the viability of hepatoma cells but increased the viability of hepatoma cells co-cultured with macrophage cells. In conclusion, the release of EVs from senescent HSCs was higher compared with normal HSCs. Furthermore, senescent EVs promoted HCC development by upregulating EGF secretion from macrophages.

Indices calculated by serum creatinine and cystatin C as predictors of liver damage, muscle strength and sarcopenia in liver disease.

Serum creatinine (Cr)-based glomerular filtration rate (CrGFR) is overestimated in liver disease. The present study evaluated whether the difference in CrGFR and cystatin C (CysC) GFR (dGFR) is significant in liver disease. The Cr-to-CysC ratio and sarcopenia index (SI) have been reported to correlate with muscle volume. An estimated total body muscle mass with Cr, CysC and calculated body muscle mass (CBMM) has also been reported to correlate with muscle mass. The applicability of dGFR, SI and CBMM for liver disease were evaluated. A total of 313 patients with liver damage were evaluated for Child-Pugh score, albumin-bilirubin (ALBI) score, model for end-stage liver disease, fibrosis-4, Cr, CysC, Cr-based estimated GFR (CreGFR), CysCGFR and grip strength. Of the 313 patients, 199 were evaluated using cross-sectional computed tomography (CT) of the third lumbar vertebra to determine the skeletal muscle (SM) mass. dGFR, CBMM and SI were compared to liver damage, muscle strength and muscle mass. In the 313 patients, dGFR was correlated with age, ALBI and grip strength; CBMM was correlated with body mass index (BMI) and grip strength; and SI was correlated with BMI and grip strength. In patients evaluated with CT, the correlation coefficients for CBMM and SI with SM were 0.804 and 0.293, respectively. Thus, CBMM and SI were associated with sarcopenia. The relationship between dGFR and ALBI does not differ with different grades of CrGFR-based chronic kidney disease (CKD). dGFR is a marker of liver damage and muscle strength regardless of CKD. CBMM and SI are markers for sarcopenia in liver disease.

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.

The Impact for Medical Management of the Health Information Exchange Through Changes of the Number of the First Visit Patients and Admission Patients in Japan.

Recently Health Information Exchange (HIE) is gradually spreading in Japan. But there are few reports about the effect of the hospital management. So we examined the effect for hospital management through the number of the newly admitted patients from 2013 to 2017. In this study both the total number of the admitted patients who was reserved as first visit patients was higher than not reserved and the number of the admitted patients who visited with introduction letters was higher than without introduction letters. (p < 0.01) The total number of the admitted patients who had been registered to the Ajisai-net was 624 (41.2%) for the same 5 years, and was revealed to be significantly higher than the number of the admitted patients who was reserved first visit with introduction letters. (p < 0.01) In conclusion, use of the Japanese type of the HIE has a potential to increase the newly admitted patients finally.

The Evaluation of the Medical Information Exchange on 24-Hour Operation at North Kyushu Area in Japan.

We report on triage before transportation by sharing patient information between hospitals, making it possible to use the Ajisai-net for 24 hours. Fifty-six times hospital collaboration was conducted during the period from start of hospital cooperation operation until October 2018. Transportation cost reduction of 3,935,000 yen (34,620 dollars) was estimated. It is expected to contribute to improvement of efficiency of emergency medical care in North Kyushu.

Bacteroides in colonic mucosa-associated microbiota affects the development of minimal hepatic encephalopathy in patients with cirrhosis.

BACKGROUND/PURPOSE: Gut microbiota has been associated with liver cirrhosis and, possibly, hepatic encephalopathy. However, only a few studies have examined the link between mucosa-associated microbiota (MAM) and minimal hepatic encephalopathy (MHE). Our aim was to investigate this relationship. METHODS: Twenty-four patients with cirrhosis underwent colon biopsies at our institution, between January 2014 and April 2015. Patterns of microbial colonization were examined using 16S rRNA gene sequences. MHE was diagnosed using the Neuropsychological Test. RESULTS: Ten (41.7%) of the 24 patients were diagnosed as having MHE. There was no significant difference in the diversity of gut microbiota by sampling locations between those with and without MHE. However, the diversity of the gut microbiota and the proportion of the genus Bacteroides decreased as a function of declining liver function. We divided patients into those with the highest proportion of the genus Bacteroides (Bacteroides-dominant group; n = 9) and into a Bacteroides non-dominant group (n = 15). In the Bacteroides-dominant group, only 1 patient (11.1%) was diagnosed as having MHE, with the incidence rate of MHE being significantly lower in the Bacteroides-dominant group than in the non-dominant group (p = 0.019). The Child-Pugh score (p = 0.05) and use of proton-pump inhibitors (p = 0.015) were negatively correlated to the proportion of Bacteroides. Furthermore, the proportion of the family Clostridiaceae was significantly higher in the Bacteroides-dominant group than in the non-dominant group (p = 0.078). CONCLUSIONS: The decrease in microbial diversity and genus Bacteroides in MAM is a risk factor for MHE in patients with liver cirrhosis.

Changes in serum LDL, PCSK9 and microRNA-122 in patients with chronic HCV infection receiving Daclatasvir/Asunaprevir.

The present study evaluated the changes in lipid profile, and the associations between serum protein convertase subtilisin/kexin 9 (PCSK9), microRNA (miR)122 and low-density lipoprotein variation following treatment of hepatitis C virus (HCV) genotype 1b infection with Daclatasvir/Asunaprevir. A total of 39 patients with HCV genotype 1b infection with chronic hepatitis received a 24-week treatment regimen of Daclatasvir/Asunaprevir. Laboratory data were obtained for each subject every 4 weeks during treatment and every 12 weeks after treatment. Serum miR122 and PCSK9 were measured at the start of treatment (week 0), end of treatment (week 24), 4 weeks after the end of treatment (week 28), 12 weeks after the end of treatment (week 36) and 28 weeks after the end of treatment (week 52). LDL was increased at week 4 after the start of treatment to week 52. The increased LDL/HDL ratio at week 52 compared with week 4 was also associated with relative miR122 at week 52. At week 4, PCSK9-active form (A) was lower than that at other time points, and PCSK9-inactive form (I) exhibited the greatest increase. At week 52, PCSK9-A was higher than that during treatment, but PCSK9-I level at week 52 did not markedly differ from that any time point except for week 4. Relative miR122 at week 4 was associated with increased PCSK9-A at weeks 36 and 52 from the start of DAA. In summary, treatment of HCV with Daclatasvir/Asunaprevir resulted in elevated LDL, and relative miR122 and PCSK9-A levels in serum appeared to have some association with LDL increase.

Carotid Intima-media Thickness and Small Dense Low-density Lipoprotein Cholesterol Increase after One Year of Treatment with Direct-acting Antivirals in Patients with Hepatitis C Virus Infection.

Objective Direct-acting antivirals (DAAs) for treating hepatitis C virus (HCV) infection exert a significantly high sustained viral response (SVR), and patients experience a rebound increase in low-density lipoprotein cholesterol (LDL) and total cholesterol levels. Carotid intima-media thickness (IMT) is a highly reproducible and non-invasive parameter for assessing the atherosclerotic process, and the small dense (sd) LDL level is useful for clinically evaluating the atherogenic risk. Methods A total of 48 patients with chronic HCV infection were treated with DAAs. All patients exhibited an SVR 24 weeks later. We compared the metabolic profiles of the patients, including the sdLDL and IMT values, at the start of DAA treatment with those after one year of treatment. We verified whether the HCV clearance after the administration of DAAs is associated with the development of atherosclerosis. Results The sdLDL, %sdLDL (sdLDL/LDL), and LDL values were exacerbated after a year of treatment; however, the triglyceride level, glycated hemoglobin level, insulin resistance, and body weight remained unaltered. The max-IMT was increased after a year compared to that at the start of treatment. Differences in the max-IMT (dmax-IMT) were greater in men than in women; however, no correlation was observed between the dmax-IMT and genotype, fibrosis, hypertension, hyperlipidemia, diabetes, obesity, and dialysis status. The %sdLDL at the start and a year later was positively correlated with the dmax-IMT. No correlation was observed among various factors including the LDL, triglyceride, body mass index, insulin resistance and dmax-IMT. In uni- and multivariate analyses, a significant correlation was observed between %sdLDL≥16% at the start of treatment and the sex and dmax-IMT. Conclusion Because the sdLDL and IMT values were exacerbated after a year of DAA treatment, atherosclerosis must be evaluated in patients achieving an SVR.

Risk Factors and Clinical Course for Liver Steatosis or Nonalcoholic Steatohepatitis After Living Donor Liver Transplantation.

BACKGROUND: Posttransplant liver steatosis occurs frequently and can affect patient outcome. Our aim was to clarify the risk factors for steatosis or steatohepatitis after living donor liver transplantation (LT) through a retrospective examination of recent 100 living donor LT recipients and their liver donors. METHODS: Liver biopsy was performed at 1 year after LT and each year, thereafter, or as needed due to abnormal liver enzyme levels, with a median follow-up of 4 years (2-10 years). RESULTS: Liver steatosis (≥5%) was identified in 33 cases, with steatohepatitis identified in 9 of 33 patients with liver steatosis. Recipients with liver steatosis were younger than those without steatosis (53.4 ± 9.5 years vs 57.6 ± 9.9 years, respectively; P = 0.045). Of note, the prevalence of steatosis was significantly higher among LT recipients who received a graft from a donor with steatosis than without (60% vs 23%, respectively; P = 0.001). Donor steatosis was also associated with steatohepatitis in recipients after LT (steatohepatitis/simple steatosis, 88%:50%). On multivariate analysis, younger recipient age (P = 0.023) and donor steatosis (P = 0.005) were independent risk factors of liver steatosis after LT. Among the 33 recipients in our study group, 26 were assessed by serial liver biopsies, with 6 showing progression of the nonalcoholic fatty liver disease activity score. An increase in body weight was predictive of steatosis progression after LT (P = 0.005). CONCLUSIONS: Age and donor steatosis influence the risk of liver steatosis and steatohepatitis in recipients after LT. The clinical course of steatosis is relatively benign, with only 19% developing nonalcoholic fatty liver disease activity score and 7.6% significant fibrosis.

Serum exosomal microRNA-122 and microRNA-21 as predictive biomarkers in transarterial chemoembolization-treated hepatocellular carcinoma patients.

Exosomal microRNAs (miRNAs) have been investigated as potential novel biomarkers, and miR-122 and miR-21 were shown to be important in hepatocellular carcinoma (HCC). We analyzed the importance of serum exosomal miRNA expression levels in HCC patients that underwent transarterial chemoembolization (TACE). Seventy-five HCC patients who underwent TACE as the initial treatment in Nagasaki University Hospital were enrolled. Exosomal miRNAs were isolated from serum samples collected before and after TACE. Exosomal miR-122 expression levels significantly decreased after TACE (P=0.012), while the exosomal miR-21 expression levels did not significantly change. The expression levels of exosomal miR-122 before TACE were shown to correlate significantly with aspartate aminotransferase (r=0.31, P=0.004) and alanine aminotransferase (r=0.33, P=0.003) levels, tumor diameter (r=0.29, P=0.010) and Child-Pugh score (r=-0.28, P=0.013). The median survival time for all patients was 47 months, and neither of the investigated exosomal miRNAs were shown to be independent factors associated with the disease-specific survival. According to the median relative expression of miR-122 after TACE/before TACE (miR-122 ratio) in liver cirrhosis patients (n=57), the patients with a higher miR-122 ratio had significantly longer disease-specific survival, compared with that of the patients with the lower miR-122 ratio (P=0.0461). Multivariate Cox proportional hazards regression analysis of clinical parameters revealed that a lower exosomal miR-122 ratio (HR 2.720; 95% confidence interval, 1.035-8.022; P=0.042) is associated with the disease-specific survival. Taken together, our results demonstrate that the exosomal miR-122 level alterations may represent a predictive biomarker in HCC patients with liver cirrhosis treated with TACE.