Shinichi Kiso

Plasma transforming growth factor-β1 in patients with hepatocellular carcinoma. Comparison with chronic liver diseases

Background. Many kinds of human malignant tissue, including hepatocellular carcinoma (HCC), were reported to overexpress transforming growth factor‐β1 (TGF‐β1) gene. However, little work has been done on the circulating TGF‐β1 in patients with malignant tumors.

Reduced plasma transforming growth factor-β1 levels in patients with chronic hepatitis C after interferon-α therapy: association with regression of hepatic fibrosis

BACKGROUND/AIM Transforming growth factor-beta1 is involved in liver fibrosis. Our aim was to examine the association of plasma transforming growth factor-beta1 levels with the degree of liver fibrosis. METHODS We analyzed plasma transforming growth factor-beta1 levels in 43 patients with chronic hepatitis C treated with interferon-alpha using a transforming growth factor-beta1 ELISA. The content of transforming growth factor-beta1 in liver tissue obtained by needle biopsy (n=13) was also analyzed. The degree of liver fibrosis was assessed histologically and morphometrically. RESULTS Plasma transforming growth factor-beta1 levels were significantly correlated with transforming growth factor-beta1 content in liver tissue (r=0.83, p<0.001), indicating that plasma levels correspond with tissue cytokine. Plasma transforming growth factor-beta1 levels in patients (8.1+/-1.1 ng/ml) before interferon-a therapy were significantly higher than in controls (1.9+/-0.3 ng/ml) (p<0.01). Plasma levels were significantly correlated with the degree of fibrosis (p<0.01). Plasma transforming growth factor-beta1 levels were significantly decreased in sustained responders (from 5.2+/-1.0 ng/ml to 2.9+/-0.7 ng/ml), relapsed patients (from 9.8+/-2.0 ng/ml to 3.4+/-0.6 ng/ml), and nonresponders (from 9.3+/-2.1 ng/ml to 3.9+/-0.9 ng/ml) at the end of therapy (p<0.05 for all comparisons). Significant regression of liver fibrosis after therapy was observed in both sustained responders and nonresponders (p<0.05 for both). CONCLUSIONS These observations suggest that plasma transforming growth factor-beta1 levels appear to be associated with the degree of liver fibrosis.

Positive correlation of plasma transforming growth factor-β1 levels with tumor vascularity in hepatocellular carcinoma

Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in tumor progression by promoting angiogenesis or suppressing immune system. We reported previously that transforming growth factor-beta 1 (TGF-beta 1) is overproduced by human hepatocellular carcinoma (HCC) tissues and that plasma TGF-beta 1 levels are elevated in patients with HCC. In the present study, we investigated the relationship between plasma TGF-beta 1 levels and tumor vascularity as assessed by conventional celiac angiography in 17 patients with HCC. The plasma TGF-beta 1 level did not correlate with tumor size or underlying liver disease. However, we found that plasma TGF-beta 1 levels correlated positively with the tumor vascularity. These results suggest that excessive TGF-beta 1 production may contribute to tumor angiogenesis in HCC.

Possible contribution of circulating transforming growth factor-beta1 to immunity and prognosis in unresectable hepatocellular carcinoma.

Transforming growth factor‐β1 (TGF‐β1) has been implicated in tumor progression. The relationship of this cytokine as measured in plasma to anti‐tumor immunity and prognosis was investigated.

Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin

Summary.  The impact of ribavirin exposure on virologic relapse remains controversial in combination therapy with pegylated interferon (Peg‐IFN) and ribavirin for patients with chronic hepatitis C (CH‐C) genotype 1. The present study was conducted to investigate this. Nine hundred and eighty‐four patients with CH‐C genotype 1 were enrolled. The drug exposure of each medication was calculated by averaging the dose actually taken. For the 472 patients who were HCV RNA negative at week 24 and week 48, multivariate logistic regression analysis showed that the degree of fibrosis (P = 0.002), the timing of HCV RNA negativiation (P < 0.001) and the mean doses of ribavirin (P < 0.001) were significantly associated with relapse, but those of Peg‐IFN were not. Stepwise reduction of the ribavirin dose was associated with a stepwise increase in relapse rate from 11% to 60%. For patients with complete early virologic response (c‐EVR) defined as HCV RNA negativity at week 12, only 4% relapse was found in patients given ≥12 mg/kg/day of ribavirin and ribavirin exposure affected the relapse even after treatment week 12, while Peg‐IFN could be reduced to 0.6 μg/kg/week after week 12 without the increase of relapse rate. Ribavirin showed dose‐dependent correlation with the relapse. Maintaining as high a ribavirin dose as possible (≥12 mg/kg/day) during the full treatment period can lead to suppression of the relapse in HCV genotype 1 patients responding to Peg‐IFN alpha‐2b plus ribavirin, especially in c‐EVR patients.

Vascular endothelial dysfunction resulting from l-arginine deficiency in a patient with lysinuric protein intolerance

Although L-arginine is the only substrate for nitric oxide (NO) production, no studies have yet been reported on the effect of an L-arginine deficiency on vascular function in humans. Lysinuric protein intolerance (LPI) is a rare autosomal recessive defect of dibasic amino acid transport caused by mutations in the SLC7A7 gene, resulting in an L-arginine deficiency. Vascular endothelial function was examined in an LPI patient who was shown to be a compound heterozygote for two mutations in the gene (5.3-kbp Alu-mediated deletion, IVS3+1G-->A). The lumen diameter of the brachial artery was measured in this patient and in healthy controls at rest, during reactive hyperemia (endothelium-dependent vasodilation [EDV]), and after sublingual nitroglycerin administration (endothelium-independent vasodilation [EIV]) using ultrasonography. Both EDV and NO(x) concentrations were markedly reduced in the patient compared with those for the controls. They became normal after an L-arginine infusion. EIV was not significantly different between the patient and controls. Positron emission tomography of the heart and a treadmill test revealed ischemic changes in the patient, which were improved by the L-arginine infusion. Thus, in the LPI patient, L-arginine deficiency caused vascular endothelial dysfunction via a decrease in NO production.

Adiponectin prevents progression of steatohepatitis in mice by regulating oxidative stress and Kupffer cell phenotype polarization.

Aim:  We reported previously that hypoadiponectinemia enhances hepatic oxidative stress and accelerates progression of nonalcoholic steatohepatitis (NASH) in mice. However, the precise mechanism and preventive effects of adiponectin on NASH remain unclear. The aim of this study was to examine the effects of adiponectin on steatohepatitis using adiponectin‐knockout (KO) mice and adenovirus‐mediated adiponectin expression system.

Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet.

Recent studies indicate an accelerated progression of nonalcoholic steatohepatitis (NASH) in postmenopausal women. Hypercholesterolemia, an important risk factor for NASH progression, is often observed after menopause. This study examined the effects of estrogen on NASH in ovariectomized (OVX) mice fed a high-fat and high-cholesterol (HFHC) diet. To investigate the effects of estrogen deficiency, OVX mice and sham-operated (SO) mice were fed normal chow or HFHC diet for 6 wk. Next, to investigate the effects of exogenous estrogen replenishment, OVX mice fed with HFHC diet were treated with implanted hormone release pellets (containing 17β-estradiol or placebo vehicle) for 6 wk. OVX mice on the HFHC diet showed enhanced liver injury with increased liver macrophage infiltration and elevated serum cholesterol levels compared with SO-HFHC mice. Hepatocyte monocyte chemoattractant protein-1 (MCP1) protein expression in OVX-HFHC mice was also enhanced compared with SO-HFHC mice. In addition, hepatic inflammatory gene expressions, including monocytes chemokine (C-C motif) receptor 2 (CCR2), were significantly elevated in OVX-HFHC mice. Estrogen treatment improved serum cholesterol levels, liver injury, macrophage infiltration, and inflammatory gene expressions in OVX-HFHC mice. Moreover, the elevated expression of liver CCR2 and MCP1 were decreased by estrogen treatment in OVX-HFHC mice, whereas low-density lipoprotein dose dependently enhanced CCR2 expression in THP1 monocytes. Our study demonstrated that estrogen deficiency accelerated NASH progression in OVX mice fed HFHC diet and that this effect was improved by estrogen therapy. Hypercholesterolemia in postmenopausal women would be a potential risk factor for NASH progression.

Expression of Rab5a in hepatocellular carcinoma: Possible involvement in epidermal growth factor signaling

Aim:  The Rab subfamily plays a role in intracellular transport. Rab5a is, in particular, involved in receptor‐mediated endocytosis. Epidermal growth factor (EGF) is known to induce cell migration and promote invasion and angiogenesis. The EGF receptor (EGFR) is actively internalized upon the addition of EGF. The aim of the present study was to clarify the expression of Rab5a in hepatocellular carcinomas (HCC) and to examine its effect on EGF signaling.

Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy

BACKGROUND & AIMS This study investigated the efficacy and adverse effects of pegylated interferon (Peg-IFN) plus ribavirin therapy in aged patients with chronic hepatitis C (CH-C). METHODS A total of 1040 naïve patients with CH-C (genotype 1, n=759; genotype 2, n=281), of whom 240 (23%) over 65 years old (y.o.), were treated with Peg-IFN alfa-2b plus ribavirin and assessed after being classified into five categories, according to age. RESULTS The discontinuance rate was higher for patients over 70 y.o. (36%), the most common reason being anemia. In the presence of genotype 1, the SVR rate was similar (42-46%) among patients under 65 y.o. and declined (26-29%) among patients over 65 y.o. For patients over 65 y.o., being male (Odds ratio, OR, 3.5, p=0.035) and EVR (OR, 83.3, p<0.001) were significant factors for SVR, in multivariate analysis. The Peg-IFN dose was related to EVR, and when EVR was attained, 76-86% of patients over 65 y.o. achieved SVR. SVR was not achieved (0/35, 0/38, respectively) if a 1-log decrease and a 2-log decrease were not attained at week 4 and week 8, respectively. In the presence of genotype 2, the SVR rate was similar (70-71%) among patients under 70 y.o. and declined among patients over 70 y.o. (43%). CONCLUSIONS Aged patients up to 65 y.o. with genotype 1 and 70 y.o. with genotype 2 can be candidates for Peg-IFN plus ribavirin therapy. The response-guided therapy can be applied for aged patients with genotype 1.