Soichiro Kiyono

Palmitate-induced Regulation of PPARγ via PGC1α: a Mechanism for Lipid Accumulation in the Liver in Nonalcoholic Fatty Liver Disease

The aim was to examine the effect of free fatty acids on the regulation of PPARγ-PGC1α pathway, and the effect of PPARγ/PGC1α in NAFLD. The mRNA and protein expression of PGC1α and phospho/total PPARγ were examined in Huh7 cells after the palmitate/oleate treatment with/without the transfection with siRNA against PGC1a. The palmitate content, mRNA and protein expression of PGC1α and PPARγ in the liver were examined in the control and NAFLD mice. Palmitate (500 μM), but not oleate, increased protein expression of PGC1α and phospho PPARγ (PGC1α, 1.42-fold, P=0.038; phospho PPARγ, 1.56-fold, P=0.022). The palmitate-induced PPARγ mRNA expression was reduced after the transfection (0.46‑fold), and the protein expressions of PGC1α (0.52-fold, P=0.019) and phospho PPARγ (0.43-fold, P=0.011) were suppressed in siRNA-transfected cells. The palmitate (12325.8 ± 1758.9 μg/g vs. 6245.6 ± 1182.7 μg/g, p=0.002), and mRNA expression of PGC1α (11.0 vs. 5.5, p=0.03) and PPARγ (4.3 vs. 2.2, p=0.0001) in the liver were higher in high-triglyceride liver mice (>15.2 mg/g) than in low-triglyceride liver mice (<15.2 mg/g). The protein expressions of both PGC1α and PPARγ were higher in the NAFLD group than in the controls (PGC1α, 1.41-fold, P=0.035; PPARγ, 1.39-fold, P=0.042), and were higher in the high-triglyceride liver group (PGC1α, 1.52-fold, p=0.03; PPARγ, 1.22-fold, p=0.05) than in the low-triglyceride liver group. In conclusion, palmitate appear to up-regulate PPARγ via PGC1α in Huh7 cells, and both PGC1α and PPARγ are up-regulated in the NAFLD mice liver, suggesting an effect on lipid metabolism leading to intrahepatic triglyceride accumulation.

Influence of splenorenal shunt on long-term outcomes in cirrhosis

Abstract Objective. To examine the clinical effect of splenorenal shunt (SRS) on the long-term outcomes in patients with cirrhosis. Methods. The study consisted of 162 cirrhosis patients (male 85, female 77; 62.6 ± 11.7 years). The clinical findings and prognosis were examined with respect to portal hemodynamics including collateral vessel patterns, with or without the presence of SRS or short gastric vein (SGV). Median observation period was 30 months. Results. The incidence was 18.5% for SRS and 10.5% for SGV. Decompensated cirrhosis was significantly more frequent in patients with SRS (22/30) than those with SGV (5/17, p = 0.0034), and in patients with SRS >5.5 mm (14/15) or >95 ml/min (14/15) (both, median values) than those with SRS <5.5 mm (8/15, p = 0.013) or <95 ml/min (8/15, p = 0.013). Cumulative overall survival rate was 87.4% at 1 year, 73.4% at 3 years, and 59.1% at 5 years. There was no significant difference in the cumulative survival rate according to the development of SRS: 80% at 1 year, 66.6% at 3 years, and 58.3% at 5 years in patients with SRS; 94.1% at 1 year, 87.4% at 3 years, and 72.8% at 5 years in patients with SGV; 88.3% at 1 year, 73.1% at 3 years, and 58% at 5 years in patients without SGV/SRS; 94.1% at 1 year, 87.4% at 3 years, and 72.8% at 5 years in patients with SGV (overall, p = 0.2). Conclusion. In spite of no significant effect on the prognosis in cirrhosis, careful management may be necessary for the patients with SRS because of potential poor liver function demonstrated by the close linkage between the presence of SRS and decompensation.

Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment

SummaryBackground Regorafenib has been investigated for its efficacy and safety as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC). We assessed the characteristics of patients with HCC treated with sorafenib who might be eligible for second-line treatment in general and regorafenib in particular. Methods Patients with HCC treated with sorafenib were retrospectively analyzed. We defined second-line candidate patients as maintaining Child–Pugh A and ECOG-PS ≤1 at the time of sorafenib failure. We also defined regorafenib candidate patients as follows: 1) continuing sorafenib at the time of radiological progression, 2) maintaining Child–Pugh A and ECOG-PS ≤ 1 at the time of sorafenib failure, and 3) continuing sorafenib 400 mg or more without intolerable adverse events at least 20 days of the last 28 days of treatment. Results Of 185 patients, 130 (70%) and 69 (37%) were candidates for second-line treatment and regorafenib. Child-Pugh score 6 and ECOG-PS 1 at the time of starting sorafenib were significantly lower in both second-line treatment and regorafenib candidate patients. Moreover, hand–foot skin reaction and liver failure during sorafenib treatment were associated with significantly low and high probabilities, respectively, of both Child–Pugh score > 6 and ECOG-PS > 1 at the time of sorafenib failure. Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child–Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients.

INTENSITY-BASED ASSESSMENT OF MICROBUBBLE-ENHANCED ULTRASONOGRAPHY: PHASE-RELATED DIAGNOSTIC ABILITY FOR CELLULAR DIFFERENTIATION OF HEPATOCELLULAR CARCINOMA

This prospective study aimed to elucidate the effect of phase-related quantitative parameters of contrast-enhanced ultrasound (CEUS) with perflubutane microbubble agent to assess the cellular differentiation of hepatocellular carcinoma (HCC). Intensity was analyzed in 94 lesions (19.4 ± 4.9 mm, 86 patients), 47 well-differentiated HCCs (wHCCs) and 47 moderately-differentiated HCCs (mHCCs): I(e) (early phase) = I(te) (tumor) - I(le) (liver), I(p) (post-vascular phase) = I(tp) (tumor) - I(lp) (liver), I(ep) = I(e) - I(p). The area under the receiver operating characteristic curve with the best cutoff value (I(e), 13.2, I(p), -4.5, I(ep), 21.3) for discriminating between wHCC and mHCC was 0.6922 for Ie, 0.7680 for Ip and 0.7925 for Iep, which indicated a significantly greater ability to differentiate between wHCC and mHCC compared with visual/qualitative assessment (early phase, 0.6170, p = 0.04; post-vascular phase, 0.6702, p = 0.01; both phases, 0.7021, p = 0.04). In conclusion, I(ep) was found to have the highest diagnostic ability, suggesting it is a promising parameter for the cellular differentiation of HCCs with CEUS.

Hepatic filling rate of a microbubble agent: a novel predictor of long-term outcomes in patients with cirrhosis.

The aim of the study described here was to evaluate the significance of the hepatic filling rate of a perflubutane microbubble agent in predicting long-term outcomes and prognoses in 32 patients with cirrhosis (37-76 y, 20 females, Child-Pugh A16, B16). The time from delivery of the contrast agent to the hepatic artery to maximum enhancement of the liver parenchyma on the sonogram was defined as the hepatic filling rate (mean = 18.6 s). Hepatic filling rate did not correlate significantly with the Child-Pugh score or the model for end-stage liver disease score. However, the survival rate was lower (93.3% at 1 y, 60.2% at 3 y) and the rate of occurrence of hepatocellular carcinoma (HCC) was higher (13.3% at 1 y, 33.3% at 3 y) in the group with the slow filling rate (≥18 s) than in the group with the rapid filling rate (<18 s) (93.3% at 1 and 3 y for survival, 6.3% at 1 and 3 y for HCC occurrence). Hepatic filling rate may constitute a non-invasive marker for the occurrence of HCC and prognosis of cirrhosis.

Two‐dimensional shear wave elastography with propagation‐based reliability assessment for grading hepatic fibrosis and portal hypertension

The aim of the present study was to examine the diagnostic ability of two‐dimensional shear wave elastography (2D‐SWE) with propagation‐based reliability for grading of hepatic fibrosis and portal hypertension.

Potential stagnation in the splanchnic hemodynamics demonstrated by the dynamic microbubbles in chronic liver disease

Impaired splanchnic hemodynamics are well‐documented phenomena in cirrhosis. However, comprehensive hemodynamic features from the superior mesenteric artery (SMA) to the superior mesenteric vein (SMV) via intestinal capillaries have not been studied. The aim was to examine splanchnic hemodynamics and their relationship with clinical presentations.

Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis

Background Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases. Results All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment. Conclusions Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments. Methods Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed.

Eradication of esophageal varices by sclerotherapy combined with argon plasma coagulation: Effect of portal hemodynamics and longitudinal clinical course.

To demonstrate the effect of endoscopic injection sclerotherapy (EIS) with argon plasma coagulation (APC) as a primary/secondary prophylaxis for esophageal varies (EV) on portal hemodynamics and long‐term outcomes in cirrhosis.

Liver Stiffness: A Significant Relationship with the Waveform Pattern in the Hepatic Vein

The aim of this prospective study was to assess the relationship between liver stiffness and hepatic vein waveform patterns in 42 patients with chronic hepatitis and 55 with cirrhosis. Liver stiffness measurement (LSM) values (FibroScan, Echosens, Paris, France) were significantly lower in the triphasic pattern group (11.3 ± 8.4 kPa) than in the monophasic pattern (32.5 ± 23.5 kPa, p = 0.001) and biphasic pattern (25.6 ± 18.1 kPa, p = 0.001) groups, indicating no significant relationship with portal pressure. The ability to diagnose cirrhosis represented by the highest area under the receiver operating characteristic curve was 0.921 (83.6% sensitivity, 90.5% specificity, best cutoff value: 16.9 kPa) by LSM and 1.000 (best cutoff value: 19.4 kPa) by LSM combined with the monophasic pattern. This study revealed a close linkage between liver stiffness and hepatic vein waveform findings, resulting in a better understanding of hepatic vein hemodynamics and wider application of its analysis.