Motoh Iwasa

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.

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)

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.

Increased lipid peroxidation in patients with non-alcoholic fatty liver disease and chronic hepatitis C as measured by the plasma level of 8-isoprostane.

Background:  Oxidative stress plays an important role in the pathogenesis of chronic liver diseases. The plasma level of 8‐isoprostane, a product of lipid peroxidation, is a marker of oxidative stress in vivo. The aim of the present study was to clarify whether the degree of lipid peroxidation, as measured by the plasma level of 8‐isoprostane, influences the progression of chronic liver diseases and hepatocarcinogenesis.

Lactoferrin inhibits hepatitis C virus viremia in chronic hepatitis C patients with high viral loads and HCV genotype 1b

carcinoma have been reported during the past 16 yr. The time interval between fine-needle aspiration/biopsy and recurrence has varied from as early as 3 wk to as late as 4 yr. Needle diameter, number of passes, and the surrounding liver parenchyma are the factors influencing the rate of recurrence (2). The risk of needle tract recurrence of liver tumor should be regarded as significant, especially in patients with small hepatocellular carcinoma for whom long term survival is expected after surgical resection or orthotopic liver transplantation (3). Hence, the role of needle biopsy in confirming hepatocellular carcinoma needs critical evaluation. It should possibly be reserved for cases not amenable to surgical resection or where hepatocellular carcinoma cannot be diagnosed with noninvasive imaging modalities and -fetoprotein levels.

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.

Spirulina-associated hepatotoxicity

of the population have a clinically silent abnormality of intestinal rotation. Discovery of anomalous intestinal rotation in an asymptomatic adult does not warrant any surgical intervention (7). However, both patient and physician should be aware of the abnormality so that abdominal symptoms are interpreted correctly and managed properly. If our patient’s intestinal rotation abnormality were known, cecal volvulus might have been suspected earlier. Although abdominal discomfort after colonoscopy is common, pain that is severe or increasing several hours after the procedure should not be dismissed. Complications such as perforation, ileus, splenic injury, hematoma, and incarceration of an inguinal hernia should be considered. Although rare, cecal volvulus should also be considered, especially if the patient is known to have an intestinal rotation abnormality or other risk factors for cecal volvulus.