Involvement of proliferation of atypical hepatocytes and CDT 1 in the liver cancer of rats administered the diethylnitrosamine.

We have reported that extent of proliferation of atypical hepatocytes (POAH) in non-cancerous liver in hepatocellular carcinoma and chromatin licensing and DNA replication factor 1 (CDT1) are associated with postoperative recurrence. Here, we investigated whether extent of POAH and expression of CDT1 in liver are also associated with chemically induced liver cancer in rats. Male Fisher strain rats were orally administered diethylnitrosamine (DEN) in their drinking water and sacrificed at 6, 8, 12, or 14 weeks after start of DEN administration. We serially monitored changes in extent of POAH, CDT1 expression by immunohistochemistry (IHC), and CDT1 mRNA expression in liver by real-time quantitative PCR. The extent of POAH in liver progressed in a time-dependent manner after start of DEN administration. CDT1 expression was higher at 8 weeks than at 6 weeks by IHC, suggesting that CDT1 expression may be a marker of POAH severity. CDT1 mRNA expression in liver was significantly higher at 12 weeks than at 6 weeks (p<0.0001). We found that extent of POAH and the expression of CDT1 are also important factors in the development of chemical carcinogen-induced hepatocarcinogenesis. Furthermore, the association with POAH and CDT1 expression in carcinogenic process is important regardless of the cause of hepatocarcinogenesis.

Proportion of subsequent clinic visits among persons without regular clinic visits who were screened as having hyperglycemia: A retrospective cohort study.

AIMS/INTRODUCTION: We aimed to examine the proportion of subsequent clinic visits for persons screened as having hyperglycemia based on glycated hemoglobin (HbA1c) levels at screening and the presence/absence of hyperglycemia at health checkups before 1 year of the screening among those without previous diabetes-related medical care and attending regular clinic visits. MATERIALS AND METHODS: This retrospective cohort study used the 2016-2020 data of Japanese health checkups and claims. The study analyzed 8,834 adult beneficiaries aged 20-59 years without regular clinic visits who had never received diabetes-related medical care and whose recent health checkups showed hyperglycemia. The rates of 6-month subsequent clinic visits after health checkups were evaluated according to HbA1c levels and the presence/absence of hyperglycemia at checkups a year before. RESULTS: The overall clinic visit rate was 21.0%. The HbA1c-specific rates were 17.0, 26.7, 25.4 and 28.4% for <7.0, 7.0-7.4, 7.5-7.9 and ≥8.0% (64 mmol/mol), respectively. Persons with hyperglycemia at a previous screening had lower clinic visit rates than those without hyperglycemia, particularly in the HbA1c category of <7.0% (14.4% vs 18.5%; P < 0.001) and 7.0-7.4% (23.6% vs 35.1%; P < 0.001). CONCLUSIONS: The overall rate of subsequent clinic visits among those without previous regular clinic visits was <30%, including for participants with HbA1c ≥8.0%. Persons with previously detected hyperglycemia had lower clinic visit rates, despite requiring more health counseling. Our findings might be useful for designing a tailored approach to encourage high-risk individuals to seek diabetes care through clinic visits.

The proliferation of atypical hepatocytes and CDT1 expression in noncancerous tissue are associated with the postoperative recurrence of hepatocellular carcinoma.

Recently, we reported that extent of proliferation of atypical hepatocytes (atypical hepatocytes) was most important histological risk factor for development of hepatocellular carcinoma (HCC) from chronic hepatitis C or liver cirrhosis. Here, we aimed to clarify whether the atypical hepatocytes in noncancerous sections is also involved in postoperative recurrence. Furthermore, we investigated significant genes involved in the atypical hepatocytes. Association between the extent of atypical hepatocytes in noncancerous tissue and postoperative recurrence was validated in 356 patients with HCC. Next, we identified putative signature genes involved in extent of atypical hepatocytes. First, atypical hepatocytes or hepatocytes other than the atypical hepatocyte in noncancerous sections of 4 HCC patients were selectively collected by laser capture microdissection (LCM). Second, the gene expression profiles of the selected hepatocyte populations were compared using Ion AmpliSeq Transcriptome Human Gene Expression Kit (Thermo Fisher SCIENTIFIC, Waltham, MA, USA) analysis. Finally, we validated the mRNA expression of the extracted genes in noncancerous frozen liver tissue from 62 patients with HCC by RT-qPCR to identify the signature genes involved in both the extent of atypical hepatocytes and postoperative recurrence. Furthermore, the extent of atypical hepatocytes and CDT1 expression in noncancerous sections from 8 patients with HCC were also validated by selectively collecting samples using LCM. The extent of atypical hepatocytes was associated with postoperative recurrence. Of the genes that showed significant differences in expression levels between two populations, the expression of the chromatin licensing and DNA replication factor 1 (CDT1) gene was most strongly associated with the extent of atypical hepatocytes and was also associated with postoperative recurrence. Furthermore, CDT1-positive cells that exhibited stronger expression resembled those morphologically considered to be atypical hepatocytes. CDT1 and Ki-67 were colocalized in the nuclei of both hepatocytes and cancer cells. The hepatocytes in noncancerous livers were not uniform in each hepatocyte population, suggesting that the accumulation of genetic abnormalities was variable. We found that the strong degree of atypical hepatocytes and high CDT1 mRNA expression represent a high carcinogenic state of the liver. Thus, we consider the evaluation of degree of these could support the personalized medicine.

Hepatocellular adenoma, approximately half and predominantly inflammatory subtype, in 38 Japanese patients with several differences in age, gender, and clinical background factors from Western populations.

AIM: Hepatocellular adenoma (HCA) has a lower prevalence in Japan than in Western countries and HCA subtypes have been reported for only a few Japanese patients. We analyzed HCA subtype data 38 patients from 23 hospitals in Japan in order to examine character and difference between Western countries. METHODS: To confirm HCA and to analyze subtypes, we performed immunohistochemical examinations. RESULTS: Thirty-eight cases were found to have HCA without cirrhosis. The male/female ratio was 18/20. Ages ranged from 15 to 79 (average, 43.2) years. Male and elder patients are not rare, furthermore, most of elder patients are male. Glycogen storage disease, past history of medicament use, hepatitis B virus surface antigen-positivity, antihepatitis C virus -positivity, diabetes mellitus, obesity, lipid metabolism disorder and alcoholism were present in of 6, 8, 1, 1, 6, 6, 4, and 6 cases, respectively. As to HCA subtypes, HNF1alpha-inactivated HCA, beta-catenin activated HCA (b-HCA), inflammatory HCA (IHCA) and unclassified HCA (U-HCA) accounted for nine (23.7%), four (10.5%), 17 (44.7%) and eight (21.1%) cases, respectively. Two cases showed coexistence of HCA and hepatocellular carcinoma (HCC) at surgery, and another had HCC which had been detected 23 years after HCA diagnosis. The HCA subtype of one of the former cases was U-HCA, while the remaining two had b-HCA and U-HCA. CONCLUSIONS: In Japanese HCA cases, the proportions of U-HCA, male and elder cases were slightly higher than in Western countries, and most of elder patients were male. IHCA was however common regardless of race, and was assumed to be the predominant subtype of HCA.

Airfreight data from Memanbetsu airport correlated to fish and scallop catch in okhotsk subprefecture, Hokkaido, Japan.

This data article features four figures showing the correlations between the biomass of fish and scallop landed in Okhotsk subprefecture (Hokkaido, Japan) and airfreights from Memanbetsu Airport, a dominant airport in the subprefecture. Total landings of fish and scallop were collected from Hokkaido government office website while the airfreight data were acquired from the Memanbetsu Airport management office. The second and third figures in this data article are in a matrix heatmap format and a line graph, representing the statistical monthly data of airfreights from the airport and fish and scallop landings in the subprefecture; data were gathered from 2009 to 2018. Data were gathered from 2009 to 2018. The airfreight data reflect the increase and decrease in the total fish or scallop landings in the subprefecture. A Pearson's correlation coefficient and cross-correlation statistics between monthly airfreight and monthly fish landings were performed to assess their correlation and annual periodic relationship. This article also provides a data figure that shows an increasing active opening ratio to secure human resources in the motor truck transportation industry in Japan. This may be due to a workforce shortage in this trade. Annual data on the active opening ratio for jobs in Japan from 2001 to 2018 were collected from the open data available on the website of the Japanese Ministry of Health, Labour and Welfare.

The relationship between cognitive distortion, depressive symptoms, and social adaptation: A survey in Japan.

BACKGROUND: In the treatment of depression, improvements in both clinical symptoms and social adaptation are important. Previous studies have shown that cognitive distortion and depressive symptoms are mutually related, and that depressive symptoms and social adaptation are related to each other. However, it is unknown how these three factors interrelate. Therefore, this study examined the relationship between cognitive distortion, depressive symptoms, and social adaptation. METHODS: The final analyzed sample consisted of 430 employees of a manufacturing company in Japan (74.2% male, 24.7% female, 1.2% unknown). Participants completed the Worker's Cognitive Distortion Scale (WCDS), Beck Depression Inventory-Second Edition (BDI-II), and Social Adaptation Self-Evaluation Scale (SASS). The WCDS was further divided into two subscales: self-contained cognitive distortion (WCDS-S) and environment-dependent cognitive distortion (WCDS-E). We used a covariance structure analysis for the main analysis and examined the relationship between these three variables' scores. RESULTS: The results revealed that both the WCDS-S and WCDS-E affected social adaptation indirectly via depressive symptoms, and that the WCDS-S additionally affected social adaptation directly. It was further revealed that the WCDS-S exerted a greater effect on depressive symptoms than the WCDS-E. LIMITATIONS: The participants were healthy cases. As such, one must be cautious about applying the results of healthy cases to clinical cases. CONCLUSIONS: This study indicates that cognitive distortion affects social adaptation directly and that it is indirectly mediated by depressive symptoms. Thus, professionals are required to attempt to treat depressive symptoms and improve social adaptation by considering that interventions in cognitive distortion may be effective.

Data on the correlations among brand value, market capitalization, and consolidated overseas sales ratios of Japanese companies.

This data article features a figure and tables that show the correlations among brand value by Brand Valuation (Interbrand Japan, Inc. Tokyo, Japan), market capitalization, and the consolidated overseas sales ratios of Japanese companies. The figure shows the scatter plot for market capitalization vs. brand value for Japanese companies. The lines in the plot show the regression fits for two groups of companies (domestic and global) with consolidated overseas sales ratios below or above 30%, respectively. The Pearson's correlation coefficients between brand value and market capitalization are calculated for global and domestic companies separately. Additionally, cross-tabulation statistics and Chi-square test of independence for brand values and consolidated overseas sales ratios were performed to assess their correlation.

G20 Okayama Health MinistersMeeting: lessons learned and way forward.

The third G20 Health Ministers' Meeting was held in Okayama, Japan on October 19-20, 2019. The authors were involved in the decision making of the substantial issues of this meeting including theme setting, schedule management, facilitating the discussion, and preparation for the ministers' meeting. Here, we summarize our lessons of experience from hosting G20 Okayama Health Ministers' Meeting as: i) Utilizing the occasion of existing major health related meeting to gain efficiency; ii) Collaboration with other G20 tracks such as finance can function as a tool to facilitate inter-sectoral collaboration within other G20 members; iii) Two-day Health Working Group before the ministerial meeting provides sufficient time for negotiation of the declaration text; and iv) Inclusion of residents and representatives of the host city provides great opportunity to create G20 legacy. Such an experience of Japanese policymaking is rarely shared in English and the lessons learned from our experience shall provide meaningful advice for Saudi Arabia colleagues who are to hold the next G20 Health Ministers' Meeting as well as for the preparation of other G20 ministerial meetings.

Comparison of prefrontal hemodynamic responses and cognitive deficits between adult patients with autism spectrum disorder and schizophrenia.

Autism spectrum disorder (ASD) and schizophrenia share many phenotypic characteristics, but their association with prefrontal function have not been directly compared. The aim of this study is to compare cognitive profiles and their association with the prefrontal function between the two groups. We explored prefrontal dysfunction among adult individuals with ASD (n = 32), schizophrenia (n = 87), and healthy controls (HCs; n = 50). We assessed cognitive function in all participants using the Brief Assessment of Cognition in Schizophrenia (BACS). The BACS data of patients with schizophrenia were entered into hierarchical cluster analyses to assign subjects to a specific subgroup based on individual profiles. Using near-infrared spectroscopy, we measured hemodynamic responses in the fronto-temporal regions during a working memory task. Among the patients with schizophrenia, we defined 4 neurocognitive subgroups, including a global impairment, a mild impairment, and 2 selective impairment groups. Compared to the HCs, the ASD and schizophrenia groups had much weaker hemodynamic responses in the left DLPFC, left frontopolar cortex (FPC), and left inferior frontal gyrus. The ASD group showed a similar level of cognitive impairment with the mild level subgroup of schizophrenia. Additionally, the two groups shared reduced activity in the left DLPFC and left FPC during the task compared to HCs. Moreover, the BACS composite scores correlated positively with hemodynamic responses in a broad area involving fronto-temporal regions in the total patient sample. This research indicates considerable similarity in the left PFC dysfunction and its association with cognitive deficits between the disorders. These findings may guide future studies that investigate pathophysiological similarities between ASD and schizophrenia.

Association of mRNA expression of iron metabolism-associated genes and progression of non-alcoholic steatohepatitis in rats.

BACKGROUND: Excess iron is associated with non-alcoholic steatohepatitis (NASH). RESULTS: mRNA expression of duodenal cytochrome b, divalent metal transporter 1, ferroportin 1, hepcidin, hephaestin and transferrin receptor 1 in liver were higher in high fat, high cholesterol-containing diet (HFCD) group than in normal diet (ND) group. mRNA levels of divalent metal transporter 1 and transferrin receptor 1, which stimulate iron absorption and excretion, were enhanced in small intestine. Epithelial mucosa of small intestine in HFCD group was characterized by plasma cell and eosinophil infiltration and increased vacuoles. Iron absorption was enhanced in this NASH model in the context of chronic inflammation of small intestinal epithelial cells, consequences of intestinal epithelial cell impairment caused by HFCD. Iron is transported to hepatocytes via portal blood, and abnormalities in iron absorption and excretion occur in small intestine from changes in iron transporter expression, which also occurs in NASH liver. Knockdown of hepcidin antimicrobial peptide led to enhanced heavy chain of ferritin expression in human hepatocytes, indicating association between hepcidin production and iron storage in hepatocytes. CONCLUSIONS: Iron-related transporters in liver and lower/upper portions of small intestine play critical roles in NASH development. METHODS: Expression of iron metabolism-related genes in liver and small intestine was analyzed in stroke-prone spontaneously hypertensive rats (SHR-SP), which develop NASH. Five-week-old SHR-SP fed ND or HFCD were examined. mRNA and protein levels of iron metabolism-related genes in liver and small intestine from 12- and 19-week-old rats were evaluated by real-time RT-PCR and immunohistochemistry or Western blot.

Involvement of Ornithine Carbamoyltransferase in the Progression of Chronic Hepatitis C and Liver Cirrhosis.

Background: The involvement of serum ornithine carbamoyltransferase (OCT) in the progression of chronic hepatitis and liver cirrhosis is unclear. Methods: A total 256 patients with chronic hepatitis C and 5 healthy controls were examined. Serum OCT concentrations were measured by enzyme-linked immunosorbent assay. Serum OCT concentrations were compared with serum cytokine and chemokine levels, and with disease severity and development of hepatocellular carcinoma (HCC). Results: The median OCT concentrations were 21.8 ng/ml for healthy controls, 36.7 ng/ml for F0 stage disease, 48.7 ng/ml for F1 stage, 77.9 ng/ml for F2 stage, 104.8 ng/ml for F3 stage, and 121.4 ng/ml for F4 stage. OCT concentrations were correlated with aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, platelet counts, indocyanine green retention rate at 15 min, prothrombin times, the molar ratio of branched chain amino acids to tyrosine, and tyrosine. Furthermore, there were significant correlations among OCT concentrations and IP10 and IL18 levels. There were weak correlations between serum OCT concentrations and liver histology. The cumulative incidence of HCC in the high-OCT concentration group (≥75.3 ng/ml) was higher than that in the low-OCT concentration group. Conclusion: The measurement of serum OCT concentration may provide a useful marker of disease severity, and thus could be a useful marker for a high risk of HCC occurrence.

Association between social functioning and prefrontal cortex function during a verbal fluency task in schizophrenia: A near-infrared spectroscopic study.

AIM: Impaired social functioning is a common characteristic of patients with schizophrenia. Social functioning requires the complex operation of various executive functions. Deficits in the prefrontal cortex (PFC) have been implicated in executive dysfunction. Here we aimed to clarify the relation between subjectively and objectively assessed social functioning, and their associations with PFC function in patients with schizophrenia. METHODS: Twenty-three patients and 22 age- and sex-matched healthy controls (HC) were assessed. In the schizophrenia group, self- and caregiver-rated social functioning were measured using the Specific Level of Functioning Assessment (SLOF). The hemodynamic responses elicited by a verbal fluency task (VFT) in three regions of interest in the frontotemporal area were measured using multi-channel near-infrared spectroscopy (NIRS). We also investigated psychiatric symptoms, neurocognition, and cognitive insight to assess possible confounding factors. RESULTS: Significant positive correlations were found between self- and caregiver-rated SLOF composite scores and three subdomain scores. Self- and caregiver-rated SLOF composite scores were significantly associated with dorsolateral PFC and frontopolar cortex (DLPFC/FPC) activation during the VFT. Psychiatric symptoms, global functioning, neurocognition, and cognitive insight were not associated with NIRS signals. General psychopathology was associated with NIRS signals in the ventrolateral PFC and the anterior temporal cortex. DLPFC and FPC activity may be associated with social functioning in patients with schizophrenia. CONCLUSION: Our results suggest that the two distinct assessments of social functioning were significantly correlated. Moreover, DLPFC and FPC function was strongly associated with social functioning and the ability to carry out daily life in patients with schizophrenia.

Comparison of neurocognitive function in major depressive disorder, bipolar disorder, and schizophrenia in later life: A cross-sectional study of euthymic or remitted, non-demented patients using the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J).

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are associated with cognitive dysfunction both in adulthood and in later life. In this study, we directly compared neurocognitive function between these three conditions in later life, employing stringent definitions of euthymia and symptomatic remission. Cognitive function in 60 elderly outpatients with MDD, BD, or SZ (20 patients per group) was assessed using the Japanese version of the Brief Assessment of Cognition in Schizophrenia. Patients with MDD had significantly higher z scores than both the other groups with large or moderately large effect sizes, for verbal fluency, attention and speed of information processing, and composite scores. In contrast, there were no significant differences in the degree of neurocognitive impairment between patients with BD and SZ. In later life, patients with BD and SZ showed a similar degree of neurocognitive impairment, while patients with MDD showed smaller impairments in several neurocognitive domains compared to patients with either of the other two disorders.

Steatosis influences the clinical profiles and long-term outcomes of interferon-treated chronic hepatitis C and liver cirrhosis patients.

Objective: This study aimed to assess the relationship between steatosis and long-term outcomes of patients with chronic hepatitis C (CH) and liver cirrhosis (LC). Patients and methods: The study population included 282 subjects with CH or LC who underwent liver biopsy at our institute. All patients achieved a sustained virological response (SVR) to interferon (IFN). Clinical characteristics, including age, gender and body mass index (BMI), were compared. The liver biopsy specimens of all patients were examined and scores were assigned to indicate the severity of each of the following features: inflammatory cell infiltration in the periportal, parenchymal and portal areas; F (fibrosis) stage; portal sclerotic change; perivenular fibrosis; pericellular fibrosis; bile duct damage; hepatic steatosis. Results: Of the 282 patients, 112 (39.7%) were free of steatosis. The other 170 patients (60.3%) had steatosis. The blood biochemical parameters of the patients with hepatic steatosis were significantly poorer than those of patients free of steatosis. Inflammatory cell infiltration and F stage were both significantly more severe in patients with than in those without steatosis. The incidences of hepatocellular carcinoma differed significantly between the two groups. However, the incidences of hepatocellular carcinoma did not differ significantly between the groups with BMI above and below 25. Conclusion: We consider hepatic steatosis to potentially affect the blood biochemical parameters and clinical profiles of Japanese patients with CH due to hepatitis virus type C. Patients with this form of CH showed favorable clinical responses to IFN. Furthermore, fibrosis and steatosis appear to affect the long-term outcomes of these patients. However, BMI alone cannot be used to predict HCC development.

Residual Symptoms Were Differentially Associated with Brain Function in Remitted Patients with Major Depressive Disorders.

BACKGROUND: The desirable goals of the treatment of major depressive disorder (MDD) are considered both to achieve symptom remission and to help the patients be restored to their premorbid levels of functioning. Remission has often been defined clinically as a threshold using standardized scales. Such a definition, however, allows several residual symptoms to be present in the remitted state. The aim of this study was to examine the relationship between the levels of residual symptoms and social functioning and also the relationship between residual symptoms and brain function. METHODS: The subjects were 21 patients with MDD in remission, defined operationally using clinician-rated 17-item Hamilton Depression Scale. Depressive symptoms and social functioning were self-assessed with the Japanese versions of the Center for Epidemiologic Studies Depression Scale (CES-D) and the Social Adaptation Self-evaluation Scale (SASS), respectively. Brain function was measured by the changes in concentration of oxy-hemoglobin ([oxy-Hb]) in the prefrontal and temporal cortices during verbal fluency task using near-infrared spectroscopy (NIRS). RESULTS: The mean CES-D total score was 18.0, s = 13.2, indicating that they have on average mild depression. Scores of CES-D total and those of its four factors showed a significantly negative correlation with the SASS total score. Among the four factors, "Interpersonal problems" factor showed the strongest correlation with it. CES-D total score and those of its three factors, "Depressed affect", "Somatic and retarded activity" and "Positive affect", showed significantly negative correlations with the mean [oxy-Hb] changes mainly in the left hemisphere, whereas "Interpersonal problems" factor showed a significantly positive correlation with the size of NIRS activation predominantly in right prefrontal regions. CONCLUSION: Our results indicate that remitted patients with MDD possibly have residual symptoms which are most likely to impair their social functioning and that these symptoms are differentially associated with brain function measured with NIRS.

Suicidal ideation is associated with reduced prefrontal activation during a verbal fluency task in patients with major depressive disorder.

BACKGROUND: Despite the known relationship between prefrontal function and increased suicidality during major depressive episodes, the links between prefrontal function and suicidality remain unclear in major depressive disorder (MDD). Suicidal ideation usually precedes a suicide attempt. If prefrontal cortex (PFC) activity is a biomarker for suicidal ideation in depression, monitoring it could be useful for suicide prevention. Therefore, in this study, we assessed the association between prefrontal function and suicidal ideation in MDD. METHODS: Prefrontal function in 67 patients with MDD (31 with suicidal ideation and 36 without) and 67 age-, gender-, and intelligence quotient-matched healthy controls (HCs) was evaluated using near-infrared spectroscopy (NIRS) during a verbal fluency task (VFT). Suicidal ideation was assessed using item 3 of the Hamilton Depression Rating Scale (HAMD). RESULTS: Regional hemodynamic changes were significantly smaller in patients with MDD than in HCs in prefrontal and temporal regions. Hemodynamic changes in the right dorsolateral PFC (DLPFC), orbitofrontal cortex (OFC), and right frontopolar cortex (FPC) regions in patients with MDD with suicidal ideation were significantly smaller than in those without suicidal ideation. In addition, hemodynamic changes correlated negatively with the severity of suicidal ideation in the DLPFC, OFC, and FPC in patients with MDD. LIMITATIONS: Further studies with a larger sample size are required to verify our findings. CONCLUSIONS: These results suggest that the DLPFC, OFC, and FPC are brain substrates of suicidal ideation in depressive states in patients with MDD, and that NIRS data can be employed as a clinically useful biomarker for the assessment of suicide risk.

Incidence of hepatocellular carcinoma reduced by phlebotomy treatment in patients with chronic hepatitis C.

OBJECTIVE: To determine the impact of phlebotomy on the laboratory values and the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C. METHODS: Study patients with chronic hepatitis C were treated with glycyrrhizin injection and oral ursodeoxycholic acid and either with (n=52) or without (n=50) phlebotomy during the period of 2005-2012. Six phlebotomized patients had previously received interferon therapy and were subsequently excluded from the data analysis. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, lactate dehydrogenase, ferritin, iron and albumin, as well as the hemoglobin concentration, platelet count and prothrombin time, were determined. We compared the long-term outcomes based on the incidence of HCC and laboratory values, including the baseline serum ferritin levels, in patients treated with versus without phlebotomy. RESULTS: In the phlebotomy group, the mean AST and ALT levels decreased significantly at each one-year interval over five years (p<0.01), whereas the platelet counts did not. The incidence of HCC in the phlebotomized patients was significantly lower than that observed in the patients treated without phlebotomy: 10.3% vs. 43.7%, respectively, during the 8-year observation period (p=0.04). The incidence of HCC was also lower in the phlebotomized patients with a normal baseline ferritin level: 0.0% vs. 36.0% in the matched subgroup treated without phlebotomy at year 8. Phlebotomy offered a risk ratio of 0.13, thus suggesting protection against the development of HCC. CONCLUSION: The incidence of HCC can be reduced by phlebotomy treatment, which should be performed in patients with chronic hepatitis C not receiving or not responding to antiviral therapy.