Ryosuke Sugimoto

Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C

Background and Aims:  Liver iron accumulation in patients with chronic hepatitis C (CHC) has received increasing attention in recent years. The aim of this study was to determine the prevalence and severity of liver iron deposition in CHC, to assess its relationship with clinical, biochemical and histological characteristics, and to study its influence on the response to interferon (IFN) plus ribavirin combination therapy.

Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C

Although the oxidative stress frequently occurs in patients with chronic hepatitis C, its role in future hepatocellular carcinoma (HCC) development is unknown. Hepatic 8-hydroxydeoxyguanosine (8-OHdG) was quantified using liver biopsy samples from 118 naïve patients who underwent liver biopsy from 1995 to 2001. The predictability of 8-OHdG for future HCC development and its relations to epidemiologic, biochemical and histological baseline characteristics were evaluated. During the follow-up period (mean was 6.7±3.3 years), HCC was identified in 36 patients (30.5%). Univariate analysis revealed that 16 variables, including 8-OHdG counts (65.2±20.2 vs 40.0±23.5 cells per 105 μm2, P<0.0001), were significantly different between patients with and without HCC. Cox proportional hazard analysis showed that the hepatic 8-OHdG (P=0.0058) and fibrosis (P=0.0181) were independent predicting factors of HCC. Remarkably, 8-OHdG levels were positively correlated with body and hepatic iron storage markers (vs ferritin, P<0.0001 vs hepatic iron score, P<0.0001). This study showed that oxidative DNA damage is associated with increased risk for HCC and hepatic 8-OHdG levels are useful as markers to identify the extreme high-risk subgroup. The strong correlation between hepatic DNA damage and iron overload suggests that the iron content may be a strong mediator of oxidative stress and iron reduction may reduce HCC incidence in patients with chronic hepatitis C.

Comparison of hepatic oxidative DNA damage in patients with chronic hepatitis B and C

Summary.  8‐Hydroxydeoxyguanosine (8‐OHdG) is a promutagenic DNA lesion produced by hydroxyl radicals and is recognized as a useful marker in estimating DNA damage induced by oxidative stress. The aim of this study was to clarify the clinical significance of hepatic 8‐OHdG levels in patients with chronic viral hepatitis. Hepatic 8‐OHdG accumulation was investigated in patients with chronic hepatitis C (CH‐C) (n = 77) and chronic hepatitis B (CH‐B) (n = 34) by immunohistochemical staining of liver biopsy samples. 8‐OHdG positive hepatocytes were significantly higher in patients with CH‐C compared to CH‐B (median 55.0 vs 18.8 cells/105 μm2, P < 0.0001). The number of positive hepatocytes significantly increased with the elevation of serum aminotransferase levels, especially in CH‐C patients (8‐OHdG vs alanine aminotransferase (ALT)/aspartate aminotrasferase (AST) were r = 0.738/0.720 in CH‐C and 0.506/0.515 in CH‐B). 8‐OHdG reactivity was strongly correlated with body and hepatic iron storage markers in CH‐C (vs serum ferritin, r = 0.615; vs hepatic total iron score, r = 0.520; vs hepatic hepcidin mRNA levels, r = 0.571), although it was related to serum HBV‐DNA titers (r = 0.540) and age of patients (r = –0.559) in CH‐B. These results indicate that hepatic oxidative DNA damage is common in chronic viral hepatitis, in particular chronic HCV‐infected patients, suggesting a possible link between chronic hepatic inflammation and hepatocarcinogenesis. The strong positive correlation between hepatic DNA damage and iron overload suggests that iron content is one of the most likely mediators of hepatic oxidative stress and iron reduction may be beneficial to reduce the incidence of hepatic cancer in CH‐C patients.

Patients with chronic hepatitis C achieving a sustained virological response to peginterferon and ribavirin therapy recover from impaired hepcidin secretion

BACKGROUND/AIMS The aim of this study is to determine the clinical relevance of hepatic producing iron regulatory hormone-hepcidin, on iron overload in patients with chronic hepatitis C (CHC). METHODS Serum hepcidin was measured in 73 CHC patients by surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS), and compared to those of healthy controls and anemia of inflammation patients, and analyzed their relationship to hepatic hepcidin mRNA expression levels and clinical, hematological, and histological findings. The sequential changes of hepcidin were investigated in 27 CHC patients treated with a 48 week-course of pegylated-interferon (PEG-IFN) plus ribavirin therapy. RESULTS Serum hepcidin was positively correlated with hepatic hepcidin mRNA levels, serum ferritin and the degree of hepatic iron deposition in CHC. Serum hepcidin-to-ferritin ratios were significantly lower in HCV positive patients than in HCV negative controls in both hyper- and normal-ferritinemic conditions. This relative impairment of hepcidin production was fully reversible after successful HCV eradication by PEG-IFN plus ribavirin, concomitantly with the improvement of the iron overload condition. CONCLUSIONS The impairment of hepatic hepcidin production occurring with chronic HCV infection may enhance iron toxicity and lead to disease progression, and modulation or supplementation of hepcidin may be beneficial for these conditions in CHC.

Restriction of dietary calories, fat and iron improves non‐alcoholic fatty liver disease

Background:  The pathogenesis of non‐alcoholic steatohepatitis (NASH) is unclear. Recent studies suggested that oxidative stress plays an important role in the mechanism of NASH. Excessive accumulation of iron in the liver causes oxidative stress. The aim of the present study was to evaluate the grade of hepatic iron accumulation and the therapeutic response to restriction of calories, fat and iron in patients with non‐alcoholic fatty liver disease (NAFLD).

Value of the apparent diffusion coefficient for quantification of low-grade hepatic encephalopathy.

BACKGROUND AND AIMS:Minimal hepatic encephalopathy (HE) is associated with poorer quality of life and increased work disability. Recently, low-grade cerebral edema has been implicated in chronic liver disease.METHODS:We measured the apparent diffusion coefficient (ADC) of water in various regions of the brains of patients with cirrhosis, and elucidated the significance of the evaluation of ADC in quantifying low-grade HE and predicting overt HE and survival. Forty patients with cirrhosis and 24 controls underwent diffusion-weighted imaging, and patients were followed up every month.RESULTS:The mean ADC values were increased in cirrhotic patients with minimal HE versus no HE or controls. Minimal HE patients separated from no HE patients with a sensitivity of 70∼90% and a specificity of 85∼90%. ADC values correlated with individual neuropsychological tests. ADC values of white matter, such as the frontal (log-rank test 4.35, P < 0.05) and parietal (log-rank test 5.98, P < 0.05) white matter, was predictive of further bouts of overt HE.CONCLUSIONS:ADC is a reliable tool for quantification of low-grade HE, and could predict the development of overt HE.

Effects of bezafibrate in patients with chronic hepatitis C virus infection: combination with interferon and ribavirin.

Summary.  An association of hepatitis C virus (HCV) with low‐density lipoproteins (LDL) in serum of patients with chronic hepatitis C (CHC) has been suggested. We conducted a prospective study in CHC patients complicated with hyperlipidaemia, to examine whether bezafibrate, which is commonly used for treatment of hyperlipidaemia, reduces serum HCV‐RNA titre and improves liver dysfunction. Fifteen patients received daily oral bezafibrate treatment (400 mg/day) for 8 weeks, and its effects on serum lipids, transaminases, HCV‐RNA titres, and HCV‐RNA titres bound to LDL were evaluated. Fifteen untreated patients with CHC and hyperlipidaemia were used as controls. The mean serum alanine aminotransferase levels and HCV‐RNA titres significantly decreased at the end of bezafibrate therapy in the treated group (105 ± 34 to 80 ± 32 IU/L, P = 0.02 and 2.23 ± 2.71 to 1.78 ± 2.38 × 107 copies/mL, P < 0.01 respectively), but no changes were observed in the control group. Serum HCV‐RNA titres bound to LDL, as quantified by immunoprecipitation using anti‐LDL antibody, also decreased in all 15 treated patients [5.55 ± 6.59 to 1.07 ± 1.58 × 106 copies/ml, P < 0.01 (mean reduction rate was −78.5 ± 17.0%)]. Sucrose density‐gradient ultracentrifugation study revealed that HCV‐RNA‐decreased density fractions after the bezafibrate were identical to LDL‐density fractions (1.015–1.062 g/mL). Eight CHC patients were treated with bezafibrate, interferon, and ribavirin triple therapy for 32 weeks, and four patients achieved sustained virological response to therapy. This pilot study provides further evidence of an association between HCV and LDL in serum and suggests the potential usefulness of bezafibrate as an anti‐HCV reagent for the treatment of CHC patients.

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.

Sarcopenia and Sarcopenic Obesity Are Prognostic Factors for Overall Survival in Patients with Cirrhosis

OBJECTIVE Although the prognosis is known to be poor in cirrhosis patients associated with sarcopenia, the relationships among skeletal muscle, visceral fat, and the liver have not yet been thoroughly investigated. Therefore, the prognosis and its associations with body composition and the severity of liver disease were examined in patients with cirrhosis. METHODS The skeletal muscle mass and visceral fat area were measured in 161 patients with cirrhosis, the effects of body composition on the prognosis were analyzed, and any factors that contribute to changes in body composition were assessed. RESULTS During the mean observation period of 1,005 days, 73 patients died. Patients with sarcopenia or sarcopenic obesity had a poor prognosis, and this difference was pronounced in the subset of patients classified as Child-Pugh class A. A decreased skeletal muscle mass was strongly correlated with decreased serum albumin levels. Sarcopenia is a common feature of advanced cirrhosis, and transitions were observed from normal body composition to sarcopenia and from obese to sarcopenic obesity. CONCLUSION The body composition is a prognostic factor for cirrhosis, and a better body composition may be advantageous for obtaining a long-term survival in patients with cirrhosis.

Nutrition therapy using a multidisciplinary team improves survival rates in patients with liver cirrhosis

OBJECTIVES Very few reports thus far have clinically elucidated the advantages of a nutrition support team (NST) in the field of liver diseases. The present study retrospectively analyzed whether nutrition therapy for liver cirrhosis (LC), performed by a multidisciplinary team that includes registered dieticians, improves survival rates. METHODS In study 1, we compared survival rates between two groups of patients with LC to elucidate the effects of nutrition management by registered dieticians. The first group was comprised of 101 patients that received no dietary counseling from a dietician, and the second group was comprised of 133 patients that received nutritional counseling following nutrition assessment. In study 2, we split the patients who received nutritional counseling in study 1 into two groups and compared their survival rates with the objective of investigating the effects of a multidisciplinary team approach on survival rate. The first group was comprised of 51 patients that, in addition to regular nutritional counseling given by a dietician, regularly attended courses on liver disease given every 3 to 6 mo. The second group was comprised of 82 patients that did not attend the liver-disease courses. RESULTS During study 1, 34 patients in the first group and 20 patients in the second group died, representing a significant difference (P < 0.05). This difference was even more pronounced in the subset of patients classified as Child-Pugh class A (P < 0.01), but no differences were seen among patients in classes B and C (P = 0.378). During study 2, four patients in the first group and 15 patients in the second group died, representing a significant difference (P < 0.05). CONCLUSIONS This study showed that nutritional intervention using a multidisciplinary team during the treatment of LC improves survival rates and quality of life of the patients.