Changes in body composition and low blood urea nitrogen level related to an increase in the prevalence of fatty liver over 20 years: A cross-sectional study.

AIM: Qualitative body composition (BC) change, characterized by the combination of visceral fat gain and muscle loss, is drawing attention as a risk factor for fatty liver (FL). The present study aimed to describe trends in BC change and its association with FL in the Japanese population. METHODS: Data from medical checkups carried out on 56 639 Japanese participants every 5 years from 1997 to 2017 were analyzed. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated using body mass index and body fat percentage. Subjects were divided into two groups according to deviations from the correlation line of FMI and FFMI as the reference: FMI-predominant BC and FFM-dominant BC. Fatty liver was determined using abdominal ultrasonography. RESULTS: The prevalence of FL significantly increased from 27.3% to 42.7% in men and from 18.0% to 25.5% in women. The prevalence of FMI predominance significantly increased from 33.6% to 43.9% in men and from 29.1% to 47.0% in women. Fat mass index predominance was independently associated with FL in men and women (odds ratio: 1.96 and 1.94, respectively). Serum blood urea nitrogen level was inversely associated with FL in men and women (0.958 and 0.961, respectively) and significantly decreased from 15.8 to 14.9 mg/dl in men and from 15.1 to 14.0 mg/dl in women. CONCLUSIONS: Increasing FMI-predominant BC and decreasing serum blood urea nitrogen level could account for the increase in the prevalence of FL over 20 years. We believe that these factors stem from current lifestyle habits in Japan.

Efficacy of rifaximin, a poorly absorbed rifamycin antimicrobial agent, for hepatic encephalopathy in Japanese patients.

AIM: Rifaximin is recommended as treatment for hepatic encephalopathy (HE) that targets intestinal bacterial flora. Although combined use with synthetic disaccharides is the standard of care worldwide, the therapeutic effects of rifaximin for overt encephalopathy (OHE) in Japanese patients have not been examined sufficiently. We examined the therapeutic effects of rifaximin for OHE in Japanese patients. METHODS: A total of 76 patients who developed OHE of West Haven grade II or higher at least once within the 12 months before starting rifaximin were included. Blood ammonia levels and the incidence of OHE during the 12 months before and after starting rifaximin therapy were compared in a before-and-after study. Rifaximin efficacy and predictors of efficacy were also examined. RESULTS: Post-treatment blood ammonia levels were significantly lower than pretreatment levels. The mean annual number of OHE incidents and intravenous branched-chain amino acid preparations used per patient were significantly lower after starting rifaximin therapy (2.51 vs. 0.76 times/year, p < 0.001; and 71.9 vs. 20.7 preparations/year, p = 0.003, respectively). The cumulative incidence of hospitalizations associated with HE significantly decreased after rifaximin therapy (hazard ratio 0.187; p < 0.001). The efficacy rate, defined as the proportion of patients without OHE during the administration of rifaximin for 1 year after starting rifaximin therapy, was 65.8%. Serum albumin ≥2.7 g/dl was an independent predictor of efficacy. CONCLUSION: Rifaximin was associated with decreased blood ammonia levels, lower incidence of OHE, and fewer hospitalizations in Japanese patients with HE. In addition, serum albumin level was an important predictor on efficacy of rifaximin.

Impact of acute kidney injury on prognosis and the effect of tolvaptan in patients with hepatic ascites.

BACKGROUND: In hepatic cirrhosis, ascites and acute kidney injury (AKI) portend poor prognosis. We examined the incidence and characteristics of AKI in patients with hepatic ascites and the impact of diuretics on AKI onset. METHODS: This study included 337 patients with hepatic ascites treated with oral diuretics during September 2013-June 2019. Incidence of AKI, cumulative survival by AKI status, and prognostic factors were investigated. Patients were divided into those treated with tolvaptan (TLV) [TLV group (n = 244)] and those not treated with TLV [control group (n = 93)]. After propensity score matching, the incidence of AKI and changes in renal function and doses of diuretics were compared. RESULTS: The incidence of AKI overall was 35% (n = 118). Patients with AKI had a significantly worse survival than those without AKI (P = 0.001), indicating that AKI is an independent prognostic factor for hepatic ascites (P = 0.025). After adjustment for background factors in the two groups (n = 77 each), the TLV group had a significantly lower incidence of AKI (27.6% vs. 44.7%, P = 0.028). While renal function worsened with higher natriuretic agent doses in the control group, no significant change was observed in the TLV group, suggesting that TLV is an independent prognostic factor for AKI onset. CONCLUSIONS: Our study suggests that concomitant AKI significantly worsens survival in Japanese patients with hepatic ascites, and TLV and natriuretic agent combination therapy might lead to an excellent synergistic therapeutic effect of hepatic ascites and inhibition of AKI onset.

Effect of tolvaptan on the prognosis of patients with hepatic ascites.

AIM: Despite accumulating evidence concerning the efficacy of tolvaptan in the treatment of body fluid retention or hyponatremia, the effect of tolvaptan on the prognosis of patients with hepatic ascites has not been fully investigated. METHODS: A total of 628 patients with hepatic ascites who were treated with diuretics (furosemide, spironolactone, or tolvaptan) between 2007 and 2017 were enrolled and divided into two groups: those who received tolvaptan (original tolvaptan group, n = 278) and those who did not (original control group, n = 350). The cumulative survival rates between the groups were compared and the factors associated with survival in patients with hepatic ascites were identified using a Cox regression analysis. In addition, propensity score matching was applied in patients who started conventional diuretics for new-onset hepatic ascites after September 2013 (pre-matching tolvaptan group, n = 177; pre-matching control group, n = 63), and the cumulative survival rates were compared between the post-matching tolvaptan and control groups. RESULTS: The survival rate was significantly higher in the tolvaptan group than the control group (P = 0.005), and tolvaptan therapy was identified as an independent factor associated with survival (hazard ratio 0.721 for death relative to control, P < 0.001). The propensity score-matched comparison also showed a significantly higher survival rate in the tolvaptan group (n = 51) than in the control group (n = 51) (P = 0.009). CONCLUSIONS: This study suggests that tolvaptan might improve the prognosis of patients with hepatic ascites.

Early sorafenib induction after transarterial chemoembolization for unresectable hepatocellular carcinoma: Can sorafenib after TACE improve loco-regional control?

This prospective study aimed to estimate the efficacy of sorafenib therapy after transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC). Between July 2011 and March 2013, 17 patients were enrolled, 11 of whom received sorafenib therapy. Patients who previously received TACE for HCC and whose disease progressed within a six-month period were given 400-800 mg sorafenib orally, once or twice daily, within the 3 weeks after a second TACE (sorafenib after TACE group). The response to treatment, time to progression (TTP), overall survival (OS), and adverse events (AEs) were recorded. Of the 113 patients who underwent initial TACE for unresectable HCC between January 1995 and January 2013, 23 patients were selected who were treated with TACE alone, and for whom the interval between the second and third TACE treatments was <6 months (TACE alone group). The interval (TTP) was calculated between the third and fourth TACE treatments, then TTP was compared among the three groups: Sorafenib after TACE for > or <4 months; and TACE alone. During a median follow-up period of 34.4 months (range, 5.9-51.7 months) in both groups receiving sorafenib after TACE, sorafenib prolonged TTP (3.9 months) and OS (34.4 months). It was demonstrated that sorafenib use for >4 months prolonged TTP (5.7 months) significantly compared with use for <4 months (3.0 months) (P=0.002). The OS of patients given sorafenib for >4 months (35.9 months) was longer than that of patients who received the drug for <4 months (17.2 months), but this difference was not significant. In the TACE alone group, the median TTP between the third and fourth TACE treatments was 4.3 months. TTP decreased among the groups in the following order: Sorafenib for >4 months, TACE alone, and sorafenib for <4 months. There were three AEs of grade 3 in the present study. Two patients demonstrated a decrease in liver reserve function following sorafenib treatment, but improved immediately after sorafenib administration was stopped. Sorafenib induction early after TACE for unresectable HCC was generally well tolerated and significantly improved TTP. Further studies are required to confirm the safety and efficacy of this combination therapy.

New resistance-associated substitutions and failure of dual oral therapy with daclatasvir and asunaprevir.

BACKGROUND: Daclatasvir (DCV) and asunaprevir (ASV) combination therapy has been primarily used in patients without NS5A L31 or Y93 resistance-associated substitutions (RASs) before treatment. We examined the characteristics of patients without these baseline RASs who did not achieve hepatitis C virus eradication with DCV and ASV combination therapy and identified new baseline NS5A RASs that are closely associated with failure of combination therapy. METHODS: Three hundred thirty-five patients with hepatitis C virus genotype 1 infection with no NS5A L31, NS5A Y93, and NS3 D168 RASs before DCV and ASV combination therapy and no history of protease inhibitor therapy were enrolled. All RASs were evaluated by direct sequencing. RESULTS: Sustained virologic response at 12 weeks (SVR12) was achieved in 297 patients (89%). Patients with NS5A Q24, L28, and/or R30 RASs or concomitant NS5A F37 and Q54 RASs had a significantly lower SVR12 rate than patients without these RASs (70% vs 92%, p < 0.001 and 79% vs 92%, p = 0.002 respectively). Multivariate analysis showed that NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs were significantly associated with virologic failure. The SVR12 rate in patients without NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs was 96.2% (202/210). CONCLUSIONS: In patients without NS5A L31 or Y93 RASs, the presence of NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs at the baseline was associated with failure of DCV and ASV combination therapy. The coexistence of baseline RASs other than NS5A L31 and Y93 may affect the therapeutic effectiveness of DCV and ASV combination therapy.

Serum manganese superoxide dismutase and thioredoxin are potential prognostic markers for hepatitis C virus-related hepatocellular carcinoma.

AIM: To evaluate the clinical significance of oxidative stress markers in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODS: Sixty-four consecutive patients who were admitted to Kagoshima University Medical and Dental Hospital were enrolled in this retrospective study. All patients had chronic liver disease (CLD) due to infection with HCV. Thirty patients with HCV-related HCC, 34 with HCV-related CLD without HCC (non-HCC), and 20 healthy volunteers (HVs) were enrolled. Possible associations between serum manganese superoxide dismutase (MnSOD) and thioredoxin (TRX) levels and clinical parameters or patient prognosis were analyzed over a mean follow-up period of 31.7 mo. RESULTS: The serum MnSOD levels were significantly higher in patients with HCV-related HCC than in patients without HCC (P = 0.03) or HVs (P < 0.001). Similarly, serum TRX levels were also significantly higher in patients with HCV-related HCC than in patients without HCC (P = 0.04) or HVs (P < 0.01). However, serum levels of MnSOD and TRX were not correlated in patients with HCC. Among patients with HCC, the overall survival rate (OSR) was lower in patients with MnSOD levels ≥ 110 ng/mL than in patients with levels < 110 ng/mL (P = 0.01), and the OSR tended to be lower in patients with TRX levels < 80 ng/mL (P = 0.05). In addition, patient prognosis with HCC was poorest with serum MnSOD levels ≥ 110 ng/mL and serum TRX levels < 80 ng/mL. Furthermore, a multivariate analysis using a Cox proportional hazard model and serum levels of five factors (MnSOD, prothrombin time, serum albumin, serum α-fetoprotein (AFP), and serum des-γ-carboxy prothrombin) revealed that MnSOD levels ≥ 110 ng/mL (risk ratio: 4.12, 95% confidential interval: 1.22-13.88, P = 0.02) and AFP levels ≥ 40 ng/mL (risk ratio: 6.75; 95% confidential interval: 1.70-26.85, P < 0.01) were independent risk factors associated with a poor patient prognosis. CONCLUSION: Serum MnSOD and TRX levels are potential clinical biomarkers that predict patient prognosis in HCV-related HCC.

Highly sensitive lens culinaris agglutinin-reactive α-fetoprotein is useful for early detection of hepatocellular carcinoma in patients with chronic liver disease.

The fucosylated fraction of α-fetoprotein (AFP-L3) is a specific marker for hepatocellular carcinoma (HCC). However, conventional AFP-L3% (c-AFP-L3%) has not always been reliable in cases with low serum α-fetoprotein (AFP) levels. In this study, we evaluated the clinical utility of a newly developed assay, highly sensitive AFP-L3% (hs-AFP-L3%). Subjects included 74 patients with benign liver disease (BLD), including chronic hepatitis and cirrhosis, and 94 with HCC. Serum hs-AFP-L3% was significantly higher than c-AFP-L3% in patients with early-stage HCC (solitary or <20 mm in diameter). Additionally, hs-AFP-L3% was significantly increased in patients with well-differentiated HCC. In patients with serum AFP <20 ng/ml, the sensitivities of c-AFP-L3% and hs-AFP-L3% were 12.5 and 44.6%, respectively, at a cut-off value of 5%. In 59 BLD patients with serum AFP <20 ng/ml, the HCC-positive rate in patients with hs-AFP-L3% ≥ 5% was significantly higher compared to those with hs-AFP-L3% <5% during the follow-up period (median, 35 months; range, 5-48 months). Importantly, none of the BLD patients with both serum AFP <20 ng/ml and hs-AFP-L3% <5% developed HCC. These results indicated that hs-AFP-L3% is useful for early detection of HCC in BLD patients, even for those with serum AFP <20 ng/ml. Furthermore, since hs-AFP-L3% increases before HCC is detectable by various advanced imaging modalities, this assay may help identify BLD patients with a higher risk of HCC.