Hirohide Miyachi

Iron Overload Is Associated with Hepatic Oxidative Damage to DNA in Nonalcoholic Steatohepatitis

Several lines of evidence have suggested that oxidative stress plays an important role for the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, by using immunohistochemical staining of liver biopsy samples, we measured hepatic 7,8-dihydro-8-oxo-2′ deoxyguanosine (8-oxodG), a DNA base-modified product generated by hydroxyl radicals, of 38 NASH patients and compared with 24 simple steatosis and 10 healthy subjects. Relation of hepatic 8-oxodG with clinical, biochemical, and histologic variables and changes after iron reduction therapy (phlebotomy plus iron–restricted diet) were also examined. Hepatic 8-oxodG levels were significantly higher in NASH compared with simple steatosis (17.5 versus 2.0 8-oxodG–positive cells/105 μm2; P < 0.0001). 8-oxodG was significantly related to iron overload condition, glucose-insulin metabolic abnormality, and severities of hepatic steatosis in NASH patients. Logistic regression analysis also showed that hepatic iron deposit and insulin resistance were independent variables associated with elevated hepatic 8-oxodG. After the iron reduction therapy, hepatic 8-oxodG levels were significantly decreased (from 20.7 to 13.8 positive cells/105 μm2; P < 0.01) with concomitant reductions of serum transaminase levels in NASH patients. In conclusion, iron overload may play an important role in the pathogenesis of NASH by generating oxidative DNA damage and iron reduction therapy may reduce hepatocellular carcinoma incidence in patients with NASH. (Cancer Epidemiol Biomarkers Prev 2009;18(2):424–32)

Branched-chain amino acid supplementation reduces oxidative stress and prolongs survival in rats with advanced liver cirrhosis.

Long-term supplementation with branched-chain amino acids (BCAA) is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (P<0.05). The prolonged survival due to BCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver.

Value of the extracellular water ratio for assessment of cirrhotic patients with and without ascites

Aims:  Ascites, which often complicates liver cirrhosis, is reported to be a factor that worsens the outcome. The aims of this study were to quantify body water compartment changes in cirrhotic patients, with and without ascites, and to elucidate the value of body water analysis for predicting the development of ascites.

Impaired regulation of serum hepcidin during phlebotomy in patients with chronic hepatitis C

Aim:  This study was conducted to determine the clinical relevance of hepcidin, a recently identified key iron regulatory hormone, in patients with chronic hepatitis C virus (C‐HCV).

Patients achieving clearance of HCV with interferon therapy recover from decreased retinol-binding protein 4 levels.

Summary.  Retinol‐binding protein 4 (RBP4) is a recently identified adipokine that is elevated in the blood in several insulin‐resistant states. We investigated the association between plasma RBP4 and histological and biochemical characteristics of chronic hepatitis C (CHC), as well as changes in RBP4 levels following interferon therapy. Eighty‐one patients with CHC infected with genotype 1 received treatment with peginterferon plus ribavirin. Histological data were available for 41 out of 81 patients before treatment, and the degree of fibrosis, inflammation and steatosis was assessed. Plasma levels of RBP4 were determined in serial samples (before, at the end of treatment, and at 6 months post‐treatment). RBP4 levels were lower in CHC patients than in control subjects (34.6 ± 12.3 μg/mL vs 46.2 ± 10.5 μg/mL; P ≤ 0.001). Higher RBP4 levels were linked to lower alanine aminotransferase (ALT) (P < 0.01), higher cholinesterase (P < 0.01), hyperlipidaemia (P < 0.01), hyperglycaemia (P < 0.05), and higher platelet (P < 0.01) count in CHC patients. Plasma RBP4 levels tended to decrease concomitantly with the grade of histological fibrosis, activity, and steatosis. RBP4 levels at baseline were not a predictor of the response to antiviral therapy in CHC patients. After peginterferon plus ribavirin therapy, only patients who had achieved clearance of hepatitis C virus had higher post‐treatment RBP4 levels. This study suggests that an association between RBP4 levels and abnormal metabolic features, and that liver function may determine RBP4 levels in CHC patents. This is further supported by the observation that RBP4 levels increased significantly after treatment only in sustained virological response (SVR) patients and reached levels comparable to those of healthy subjects.

Effect of suppressor of cytokine signaling on hepcidin production in hepatitis C virus replicon cells

Aim:  Hepcidin is a key regulator of systemic iron metabolism and its expression is modulated by hepatitis C virus (HCV) infection. Suppressor of cytokine signaling 1 (SOCS‐1) and SOCS‐3 act as negative regulators of the Jak/signal transducers and activators of transcription signaling pathway. In this study, we investigated how HCV infection modulates SOCS‐1 and SOCS‐3 production and how these SOCS proteins affect hepcidin production.

Evaluation and prognosis of sarcopenia using impedance analysis in patients with liver cirrhosis

Dear Editor, We recently read an interesting article on sarcopenia in liver cirrhosis (LC) by Hayashi et al. in Hepatology Research. They evaluated sarcopenia based on skeletal muscle mass (SMM) using impedance analysis and measurement of handgrip strength, and reported that sarcopenia in LC patients was associated with physical inactivity and insufficient dietary intake. Sarcopenia has received attention as an important predictor of prognosis in LC. Evaluation of sarcopenia has included anthropometry of upper arm circumference, dual-energy X-ray absorption, and measurement of SMM using trunk computed tomography. Impedance analysis has been used more recently as a convenient modality that does not involve radiation exposure. Hayashi et al. used SMM / height as an index. Multifrequency impedance analysis enables separate calculation of SMM at different sites, such as the arms, trunk and legs. The influence of edema of the lower extremities in LC can thus be eliminated. We therefore evaluated the usefulness of measuring SMM at different sites in LC, and also examined the influence on prognosis of sarcopenia. Participants in our study comprised 137 patients with LC (80 men, 57 women; mean age, 66 1 9 years; mean Child–Pugh score, 6.7 1 3.0). SMM was measured at different sites using a body composition analyzer (InBody 720; Biospace, Seoul, Korea) and compared with SMM in 554 patients with type 2 diabetes mellitus (DM) (323 men, 231 women; mean age, 65 1 9 years). In the DM group, exclusion criteria were as follows: positive test results for hepatitis B surface antigen or hepatitis C virus RNA; significant thrombocytopenia (platelet count <10 × 10/μL); or ultrasonographic features of cirrhosis. Measurement of SMM included arm index (arm SMM / height), leg index (leg SMM / height) and appendicular index (appendicular SMM / height). The prognosis of LC with sarcopenia was then analyzed using Kaplan–Meier analysis. Appendicular SMM / height tended to be lower in LC than in DM, but the difference was not significant (men: LC, 7.37 1 1.06 kg/m; DM, 7.52 1 0.92 kg/m; women: LC, 6.31 1 0.88 kg/m; DM, 6.48 1 1.12 kg/m). In particular, arm index was significantly lower in LC (men: LC, 1.87 1 0.32 kg/m; DM, 2.00 1 0.32 kg/m; P < 0.01; women: LC, 1.50 1 0.31 kg/m; DM, 1.63 1 0.37 kg/m; P < 0.05). In this study, sarcopenia was defined based on the result of the arm index. Values less than −1 standard deviation from the mean values in the DM group, namely, less than 1.7 kg/m in men and 1.2 kg/m in women, were considered to be indicative of sarcopenia. Comparison of patient background characteristics between the groups with and without sarcopenia showed a significantly greater proportion of men in the group with sarcopenia (23 men, seven women) than in the group without sarcopenia (57 men, 50 women; P < 0.05), but no significant differences in mean age (68 1 9 vs 66 1 9 years). Child–Pugh score was higher (men, 6.9 1 1.7 vs 6.5 1 1.7; women, 8.1 1 2.7 vs 6.7 1 1.6) and hepatic functional reserve was lower in LC with than in LC without sarcopenia. In addition, analysis of prognosis with stratification for arm index showed that prognosis was significantly poorer in the arm index subgroup with lower values (Fig. 1, P < 0.05). Sarcopenia may coexist in LC, particularly in LC with decreased hepatic functional reserve, and measurement of arm SMM can be useful in evaluation. LC patients should be monitored for sarcopenia using arm SMM, because nutritional therapy can readily improve the prognosis.

Change in skeletal muscle mass after administering entecavir in patients with hepatitis B.

OBJECTIVE Cachexia, or disease-related loss of muscle mass, is a complication of chronic liver disease that modifies its clinical course. The aim of this study was to determine whether improvement in liver function and cachexia through control of the hepatitis B virus (HBV) increases skeletal muscle mass. METHODS The blood tests and cross-sectional area (mm(2)) of the psoas major muscle on computed tomography were measured before and after long-term entecavir therapy (median, 39 mo; range, 14-76 mo) in patients with hepatitis B (17 men, 13 women; mean age, 63 ± 13 y). RESULTS The anti-HBV effect was good in 30 patients given entecavir, and most patients had undetectable serum HBV-DNA levels (93%) and alanine aminotransferase normalization (83%) within a median of 32 mo. Overall, no significant change in the area of the psoas major muscle was seen in any of the patients, although a significant increase was seen when limited to cases of protein malnutrition defined as serum albumin (Alb) <4 g/dL. A positive correlation was seen for the amount of change (Δ) in the psoas major muscle and the amount of change (Δ) in Alb. CONCLUSIONS The present findings suggest that skeletal muscle mass may fluctuate in parallel with Alb levels. An improvement in low muscle mass may thus be expected from antiviral therapy for viral liver disease, especially in patients with cachexia.