Naohito Urawa

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.

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.

Upregulation of transferrin receptor 2 and ferroportin 1 mRNA in the liver of patients with chronic hepatitis C

Background:  Iron accumulation has been reported to be associated with progression of liver injury. The mechanism of iron accumulation in the liver is not known. In the present study, hepatic messenger RNA (mRNA) expression of transferrin receptor (TfR)1, TfR2, and ferroportin (FP)1 was measured in patients with chronic hepatitis (CH).

Role of transferrin receptor 2 in hepatic accumulation of iron in patients with chronic hepatitis C

Background and Aim:  Iron deposition in the liver is a common finding in patients with chronic hepatitis C (CH‐C). The mechanism of this hepatic accumulation of iron is not completely understood. This study assessed if the protein expression of transferrin receptor 2 (TfR2) is upregulated in the liver of patients with CH‐C and if TfR2 protein mediates iron accumulation during hepatitis C virus (HCV) infection.

Influence of phlebotomy on iron-related gene expression levels in the livers of patients with chronic hepatitis C

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Hepatitis C virus free-virion and immune-complex dynamics during interferon therapy with and without ribavirin in genotype-1b chronic hepatitis C patients

Summary.  The Synergistic effect of interferon (IFN) and ribavirin for patients with chronic hepatitis C has been demonstrated, but ribavirin has no apparent direct antiviral effect against hepatitis C virus (HCV) when used as monotherapy. To elucidate the mechanism of ribavirin on enhanced HCV eradication when used in combination therapy, we investigated the serum HCV dynamics of free‐virions (FV) and immune‐complexes (IC) in genotype‐1b infected patients treated with IFN‐α2b alone (n = 11) or in combination with ribavirin (n = 15). Serum FV‐ and IC‐HCV RNA were separated by immunoprecipitation using anti‐human immunoglobulin and quantified serially using real‐time detection polymerase chain reaction. At the first phase (day 0–2), the decline of FV‐ and IC‐HCV RNA was similar between the two treatment groups. At the second phase (day 2–28), the decline of IC was significantly faster in patients treated with IFN plus ribavirin compared with IFN alone [exponential decay slope = 0.079 ± 0.036 vs 0.048 ± 0.027 log10/day, P = 0.0248; half‐life = 81.1 ± 21.4 vs 135.1 ± 61.4 h, P = 0.0053], although the second phase FV‐decline was not significantly different between the two treatment groups. The fast second phase decline of IC was associated with sustained virological response to therapy. These results suggest that ribavirin may modulate the humoral immune response against HCV and trigger a favourable response to IFN. In conclusion, analysis of early IC‐HCV dynamics is useful for predicting the response to therapy and for understanding the mechanism of action of antiviral drugs in chronic hepatitis C patients.

Validity of Japanese version of SARC-F questionnaire in patients with chronic liver disease: Japanese version of SARC-F questionnaire

We aimed to examine the validity of the Japanese version of SARC‐F questionnaire (SARC‐F‐J) that employs the diagnostic criteria for sarcopenia established by the Japan Society of Hepatology in patients with chronic liver disease.

A 10-year Follow-up Study of a Japanese Family with Ferroportin Disease A: Mild Iron Overload with Mild Hyperferritinemia Co-occurring with Hyperhepcidinemia May Be Benign

This is a 10-year follow-up study of a family with ferroportin disease A. The proband, a 59-year-old man showed no noteworthy findings with the exception of an abnormal iron level. The probands 90-year-old father showed reduced abilities in gait and cognition; however, with the exception of his iron level, his biochemistry results were almost normal. Brain imaging showed age-matched atrophy and iron deposition. In both patients, the serum levels of ferritin and hepcidin25, and liver computed tomography scores declined over a 10-year period. These changes were mainly due to a habitual change to a low-iron diet. The iron disorder in this family was not associated with major organ damage.