Eiji Tsubouchi

Infection and dysfunction of circulating blood dendritic cells and their subsets in chronic hepatitis C virus infection.

BackgroundTo understand interactions between dendritic cells (DCs) and viruses, in vitro-cultured monocyte-derived DCs are usually used for functional analyses. However, several recent studies indicate that circulating blood DCs are different from monocyte-derived DCs, both phenotypically and functionally. Indeed, circulating DCs act as functional antigen-presenting cells in vivo. This study was conducted to evaluate the function of circulating blood DCs in patients with chronic hepatitis C and to examine whether circulating DCs from these patients were infected by hepatitis C virus (HCV).MethodsThe phenotypes and biological functions of circulating DCs from patients with chronic hepatitis C (n = 27), patients with non-HCV chronic liver disease (n = 7), and normal volunteers (n = 13) were analyzed. The presence of the HCV genome sequence in circulating blood DCs and in subsets of circulating DCs (myeloid DCs and plasmacytoid DCs) in patients with chronic hepatitis C was assessed.ResultsThe stimulatory capacity of circulating DCs was significantly reduced in patients with chronic hepatitis C compared to patients with non-HCV chronic liver diseases and normal controls (P < 0.01). HCV RNA was identified in the overall population of circulating DCs, and in myeloid DCs and plasmacytoid DCs. Nucleotide sequences of the 5′ non-coding region of HCV RNA showed marked differences between paired samples of circulating DCs and sera from the same patients.ConclusionsOur results indicate the dysfunction and infection of circulatory blood DCs in chronic HCV infection. This may compromise the capacity of patients with hepatitis C to induce an effective antiviral immune response.

Isolation and functional analysis of circulating dendritic cells from hepatitis C virus (HCV) RNA-positive and HCV RNA-negative patients with chronic hepatitis C: role of antiviral therapy

Hepatitis C virus (HCV) RNA has been localized in antigen‐presenting dendritic cells (DCs) from patients with chronic hepatitis C (CHC). DCs from patients with CHC also exhibit impaired functional capacities. However, HCV RNA in DCs and functional impairment of DCs in CHC might be independent or interrelated events. Moreover, the impact of antiviral therapy on the functions of DCs in CHC is not well documented. In order to address these issues, we took advantage of antiviral therapy in these patients. Ten patients with CHC, expressing HCV RNA in circulating DCs, became negative for HCV RNA in circulating DCs after therapy with interferon‐α and ribavirin for 4 weeks. The functions of DCs from HCV RNA+ patients (isolated before antiviral therapy) and HCV RNA– patients (isolated 4 weeks after antiviral therapy) were compared in allogenic mixed leucocyte reactions. In comparison to circulating DCs from normal control subjects, DCs from HCV RNA+ patients had a significantly decreased capacity to stimulate allogenic T lymphocytes (P < 0·01) and produce interleukin‐12 (P < 0·05). However, the allostimulatory capacity of circulating DCs from HCV RNA– patients was several‐fold higher compared to that of HCV RNA+ DCs from the same patient. DC from HCV RNA– patients also produced significantly higher levels of interleukin‐12 compared to HCV RNA+ DCs from the same patient (P < 0·01). Taken together, this study is the first to provide experimental evidence regarding the impact of HCV RNA and antiviral therapy on the function of DCs in patients with CHC.

Sarcopenia and two types of presarcopenia in Japanese patients with chronic liver disease.

Background/aim The frequency of sarcopenia, defined as loss of both muscle volume and strength, was analyzed in chronic liver disease (CLD). Methods and materials From April to September 2015, 807 Japanese CLD patients treated as outpatients were enrolled (67.1±10.0 years, men : women=466 : 341, hepatitis C virus : hepatitis B virus : hepatitis B and C virus : alcohol : other=511 : 134 : 3 : 45 : 114). Sarcopenia was diagnosed when the patient showed muscle volume loss and reduced handgrip strength, whereas those with only muscle volume loss were classified as ‘v-presarcopenia’ and those with only reduced handgrip strength were classified as ‘s-presarcopenia’. Muscle volume loss was determined using computed tomography findings and a previously reported index (psoas index), and cut-off values for reduced handgrip strength presented by the Asia Working Group for Sarcopenia (AWGS) (AWGS/grip criteria) and European Working Group on Sarcopenia in Older People (EWGSOP) (EWGSOP/grip criteria) (men; 26 and 30 kg, women; 18 and 20 kg, respectively) were used. Clinical features were analyzed for diagnoses of chronic hepatitis (CH, n=381), liver cirrhosis Child-Pugh A (n=330), and liver cirrhosis Child-Pugh B/C (n=96). Results When the AWGS/grip criteria were used, the frequencies of sarcopenia, v-presarcopenia, and s-presarcopenia in CH were 3.9, 7.9, and 19.4%, whereas those in Child-Pugh A were 4.8, 17.6, and 21.8% and those in Child-Pugh B/C were 16.7, 11.5, and 39.6%, respectively. When the EWGSOP/grip criteria were used, these frequencies were 7.1, 4.7, and 33.1%, in CH, 11.8, 10.6, and 32.7%, in Child-Pugh A, and 21.9, 6.3, and 49.0%, in Child-Pugh B/C, respectively. The incidence rates of sarcopenia and both types of presarcopenia increased with progression of CLD. Conclusion Evaluation of handgrip strength and psoas index is an easy and effective method for the detection of sarcopenia and presarcopenia.

Effects of antihyperlipidemic agents on hepatic insulin sensitivity in perfused Goto-Kakizaki rat liver

BackgroundWe previously reported that the Goto-Kakizaki (GK) rat, an animal model of type 2 diabetes, has hepatic insulin resistance using a perfused rat liver model. Pioglitazone, eicosapentaenoic acid (EPA), and fenofibrate are antihyperlipidemic agents and improve glucose tolerance. There have been few studies showing that these agents directly improve hepatic insulin sensitivity in type 2 diabetes mellitus. The aim of this study was to explore the effects of these agents on hepatic insulin sensitivity directly using a perfused GK rat liver model.MethodsGK rats were treated with oral pioglitazone (6 or 10 mg/kg body weight), EPA (1 or 2 g/kg body weight), or fenofibrate (30 mg/kg body weight) for 2 weeks. Livers were perfused in situ with glucagon or with glucagon and insulin, and hepatic glucose outputs were measured.ResultsIn the pioglitazone-treated GK rats, blood glucose levels were significantly decreased. In the pioglitazone- and EPA-treated GK rats, insulin infusion significantly attenuated hepatic glucose output stimulated by glucagon. In the fenofibrate-treated GK rats, fat deposits in the hepatocytes were decreased, and glucose output elicited by glucagon was significantly decreased compared with that in the untreated GK rats, whereas insulin infusion did not affect glucose output by glucagon.ConclusionsThese findings suggest that pioglitazone and EPA may improve glucose tolerance by directly increasing hepatic insulin sensitivity, while fenofibrate may improve glucose tolerance by improving hepatic glycogen metabolism in the GK rats.

Muscle volume loss as a prognostic marker in hepatocellular carcinoma patients treated with sorafenib

To elucidate the clinical significance of muscle wasting in regard to survival of hepatocellular carcinoma (HCC) patients undergoing sorafenib treatment, we evaluated prognostic factors including muscle wasting at the start of sorafenib treatment.

Efficacy of branched-chain amino acid supplementation and walking exercise for preventing sarcopenia in patients with liver cirrhosis

Background/aim Sarcopenia is recognized as a condition related to quality of life and prognosis in patients with chronic liver disease, although no useful strategy for improving muscle volume and strength has been established. Here, we evaluated the efficacy of supplementation with branched-chain amino acid (BCAA) administration and walking exercise. Patients and methods From December 2015 to July 2016, 33 Japanese outpatients with liver cirrhosis were enrolled (median: 67 years, HCV : HBV : alcohol : others=26 : 2 : 2 : 3, male : female=13 : 20, Child-Pugh A : B=30 : 3). None had a history of BCAA supplementation. After calculating the average number of daily steps using a pedometer for a 2–3-week period, BCAA supplementation (protein 13.5 g, 210 kcal/day) as a late evening snack and walking exercise (additional 2000 steps/day prescribed) were started. Body composition including muscle volume was analyzed using a bioelectrical impedance analysis method, and serological data and muscle strength (leg, handgrip) were evaluated at enrollment, and then 1, 2, and 3 months after starting the protocol. Results The median average number of daily steps was 3791 (interquartile range: 2238–5484). The average period of BCAA supplementation was 2.7±0.7 months. During the period from enrollment to 3 months after starting the protocol, HbA1c and NH3 were not significantly changed, whereas the BCAA/tyrosine ratio improved (4.3±1.35 to 5.24±2.04, P=0.001). In addition, the ratios for average daily steps (1.595, P=0.02) as well as muscle volume, leg strength, and handgrip strength (1.013, 1.110, and 1.056, respectively; all P<0.01) were increased at 3 months. Conclusion BCAA supplementation and walking exercise were found to be effective and easily implemented for improving muscle volume and strength in liver cirrhosis patients.

Impact of muscle volume and muscle function decline in patients undergoing surgical resection for hepatocellular carcinoma: Muscle volume and function in hepatoma

This study investigated the prognostic impact of muscle volume loss (MVL) and muscle function decline in patients undergoing resection for hepatocellular carcinoma (HCC).

Proposed a simple score for recommendation of scheduled ultrasonography surveillance for hepatocellular carcinoma after Direct Acting Antivirals: multicenter analysis: Predicting HCC risk after SVR24 by DAAs

To develop a scoring method using with common clinical data for predicting hepatocellular carcinoma (HCC) development after sustained virological response at 24 weeks (SVR24) after treatment with direct acting antivirals (DAAs), we retrospectively evaluated clinical features of patients who obtained SVR24.

Muscle volume loss a prognostic factor for death in liver cirrhosis patients and special relationship to portal hypertension

We examined the prognosis of liver cirrhosis (LC) patients with and without portal hypertension (PHT) and muscle volume loss (MVL).

Relative changes in handgrip strength and skeletal muscle volume in patients with chronic liver disease over a 2-year observation period: Relative muscle changes in chronic liver disease

There are few reports regarding relative changes in muscle function of patients with chronic liver disease (CLD). We examined CLD patients to evaluate relative changes in handgrip strength and muscle volume.