Masakatsu Uchihara

Incidence and clinical course of major depression in patients with chronic hepatitis type C undergoing interferon-alpha therapy: a prospective study.

This study examined the incidence, clinical course and its risk factors for major depression in patients with chronic hepatitis type C undergoing interferon-alpha therapy. Ninety-nine subjects underwent the psychiatric interviews for diagnosis of major depressive episode according to the DSM-IV criteria before the start of interferon therapy, and once every 4 weeks during both the 24-week treatment period and 12 weeks after the end of therapy. Depressive symptoms were also evaluated using the Hamilton Rating Scale for Depression. Major depression occurred during interferon therapy in 23 patients (23.2%). In 73.9% of them depression occurred within 8 weeks after the start of therapy. Twenty-two patients with depression completed the therapy and 59.1% of them achieved remission by the end of therapy with a mean duration of 11.6 weeks. Although the other 40.9% were not in remission at the end of therapy, they achieved remission within 12 weeks thereafter. The only risk factor for depression was advanced age. Depression occurs frequently among patients with hepatitis type C undergoing interferon-alpha therapy. Such patients require careful observation, and psychiatrists should be sufficiently aware of this significant psychiatric complication of interferon therapy.

Interferon Therapy for Chronic Hepatitis C in Hemodialysis Patients: Increased Serum Levels of Interferon

Background/Aims: The efficacy and side effects of interferon (IFN) therapy have not been well clarified in hemodialysis patients with chronic hepatitis C. Methods: In 6 of 9 hemodialysis patients with chronic hepatitis C, 3 million units (MU) or 6 MU of recombinant IFN-α2b or natural IFN-α were administered intramuscularly daily for the first 2 weeks, followed by three times a week for 22 weeks. In the remaining 3 patients, 3 MU of IFN-α2b were given three times a week for 24 weeks. Serum concentrations of IFN-α2b were measured sequentially after the injection of interferon. Responders were defined as the patients with normal serum aminotransferase and negative serum HCV RNA 6 months after the cessation of IFN therapy. Results: Three of the 6 patients who were administered IFN daily in the first 2 weeks were responders, while the other 3 withdrew from the therapy due to serious adverse events such as depression, loss of consciousness and persistence of high-grade fever. Serious adverse events were not observed in the 3 patients without daily administration. Half-lives of IFN-α2b in hemodialysis patients were significantly longer than those in nonuremic patients (10.0 vs. 6.0 h, p < 0.05). Moreover, the areas under the serum concentration curve of the hemodialysis patients were significantly larger than those of nonuremic patients (756 ± 223 vs. 324 ± 223 IU·h/ml, p < 0.05), despite the fact that the dose of IFN-α administered to hemodialysis patients was half that administered to nonuremic patients. Conclusions: In hemodialysis patients with chronic hepatitis C, pharmacokinetic parameters of IFN may be different from those in nonuremic patients, and daily or high-dose administration of IFN may lead to serious adverse events in those patients.

Assessment of Kupffer cells by ferumoxides-enhanced MR imaging is beneficial for diagnosis of hepatocellular carcinoma: comparison of pathological diagnosis and perfusion patterns assessed by CT hepatic arteriography and CT arterioportography

To investigate the clinical significance of the radiographic assessment of Kupffer cells and hemodynamics in the diagnosis of hepatocellular nodules, both magnetic resonance (MR) imaging enhanced by ferumoxides and CT hepatic arteriography (CTHA)/CT arterioportography (CTAP) were undertaken for 118 patients with 158 primary nodular hepatocellular lesions. The radiographic findings were analyzed in the context of the pathological diagnosis. Among nodules presumed to be pre- or early HCC by CTHA/CTAP, all 13 hyperintense nodules identified by MR imaging (MRI) were found pathologically to be hepatocellular carcinoma (HCC). In contrast, in 14 hypointense nodules, no advanced (moderately or poorly differentiated) HCC was pathologically identified and none of these progressed to advanced HCC during the follow up period (mean: 24 months). Instead, 78% of these cases were pathologically confirmed as dysplastic nodules. For the 16 lesions undetectable by CTHA/CTAP, four of eight (50%) hypointense nodules turned out to be dysplastic nodules and one hyperintense lesion was HCC. Signal intensity by ferumoxides-enhanced MRI showed a strong correlation with the increase or decrease of Kupffer cells assessed by immunohistochemistry. Assessment of Kupffer cells by ferumoxides-enhanced MRI is beneficial for the accurate diagnosis of primary hepatocellular nodules that are considered borderline or early stage HCC by their hemodynamic profile.

Interferon-stimulated gene expression and hepatitis C viral dynamics during different interferon regimens

BACKGROUND/AIMS To address the molecular mechanism for enhanced antiviral efficacy associated with a frequent dosing of interferon (IFN)-beta. METHODS Serum hepatitis C viral (HCV) dynamics, double-stranded RNA-activated protein kinase (PKR) mRNA and MxA mRNA levels in peripheral blood mononuclear cells (PBMC) were analyzed serially in 140 patients who were randomly assigned to a twice daily (3 MU bid) or once daily (6 MU qd) administration group. RESULTS In twice daily group, the rate of HCV decline during the second phase was 2-fold greater than in the once daily group (P=0.04). Peak PKR and MxA gene expression levels in the first phase (observed 4 h after a single administration) were 2-fold higher in the once daily group. However, the expression in the second phase was maintained at a significantly higher level in the twice daily group. Initial and peak expression levels were related to initial viral load. Basal expressions in PBMC were significantly correlated with those in the liver tissue (PKR, r=0.81; MxA, r=0.75, respectively, P<0.0001). CONCLUSIONS Our data suggest that elimination of HCV-infected cells is enhanced by twice daily dosing of IFN-beta, and that this enhanced effect is associated with a higher intracellular expression of PKR and MxA during the second phase.

Core promoter/pre-core mutations are associated with lamivudine-induced HBeAg loss in chronic hepatitis B with genotype C

BACKGROUND/AIMS To clarify the factors associated with the efficacy of lamivudine. METHODS Variables including basic core promoter (BCP) and pre-core (PreC) mutations were evaluated in 60 chronic hepatitis B e antigen (HBeAg)-positive patients with genotype C. Thirty patients were treated with lamivudine and the remaining 30 patients were age- and sex-matched controls. RESULTS Severe fibrosis was significantly more frequent in patients with the BCP-mutant/PreC-wild (MW) and BCP-mutant/PreC-mutant (MM) patterns compared to BCP-wild/PreC-wild (WW) pattern (P=0.02). The cumulative rates of HBeAg loss at 6, 12 and 18 months were significantly higher in the lamivudine group (14.2, 36.3, and 60.9%) compared with the control group (17.6, 17.6, and 24.5%, P=0.03), and was especially pronounced in patients with the MW pattern (P=0.04). The rate of lamivudine-related HBeAg loss was significantly lower in patients with the WW pattern (P=0.03). Factors correlating with HBeAg loss were histological fibrosis and activity, hepatitis B virus-DNA levels, BCP/PreC mutation and lamivudine therapy. Multivariate analysis revealed BCP/PreC mutations and fibrosis were independent factors for HBeAg loss. CONCLUSIONS With specific reference to the genotype C, we found earlier HBeAg loss was expected in patients carrying MM and MW patterns, while the efficacy of lamivudine was limited in patients with the WW pattern.

A Comparison of the Exponential Decay Slope between PEG-IFN alfa-2b/Ribavirin and IFN alfa-2b/Ribavirin Combination Therapy in Patients with Chronic Hepatitis C Genotype 1b Infection and a High Viral Load

Objectives: A high virological response rate can often be shown to be obtained with PEG-IFN α-2b and ribavirin combination therapy in chronic hepatitis C patients. Viral dynamics have been utilized for the evaluation of antiviral effects, especially the exponential second decay slope, which represents the elimination of infected cells. Methods: Forty-nine patients were randomly assigned to the IFN α-2b group (n = 26) or the PEG-IFN α-2b group (n = 23). Ribavirin was administered equally to both groups. Measuring the serum concentration of HCVRNA, the exponential viral decay during phase 1 and 2 was calculated. Results: The exponential decay slope in phase 2 during the first 2 weeks was greater in the IFN α-2b group than in the PEG-IFN α-2b group; however, from weeks 3 to 4, it was greater in the PEG-IFN α-2b group than in the IFN α-2b group. Interestingly, in the PEG-IFN α-2b group, the exponential decay slope was greater from weeks 3 to 4 after initiating combination therapy than during the weeks 1–2 (p < 0.01), despite administration of the same PEG-IFN α-2b dose (1.5 µg/kg once weekly). Conclusions: In PEG-IFN α-2b and ribavirin combination therapy, elimination of infected cells may be pronounced following an increase in serum ribavirin concentration in chronic hepatitis C patients with genotype 1b infection and a high viral load.

Polymerase domain B mutation is associated with hepatitis relapse during long-term lamivudine therapy for chronic hepatitis B.

Breakthrough hepatitis remains the major issue in long-term lamivudine therapy for chronic hepatitis B. However, the emergence of drug-resistant hepatitis B virus (HBV) is not always accompanied by a relapse of hepatitis. To elucidate factors predictive of breakthrough hepatitis, 53 patients with genotype C of HBV on long-term lamivudine therapy were analyzed. HBV reappeared during therapy in 19 patients with a cumulative incidence of 15% at 1 year, 34% at 2 years, and 60% at 3 years. Within this group, breakthrough hepatitis developed in 12 patients (63%). A polymerase gene domain B mutation (rt180M) emerged in 13 patients, and domain C mutations (rt204I, rt204V) were found in 19 patients. The rt180M mutation was associated with breakthrough hepatitis (p < 0.05) with a positive predictive value of 85% and a negative predictive value of 83%. Patients with the rt180M mutation had higher HBV-DNA levels during viral breakthrough compared to patients with rt180wt (p < 0.05). The mutational pattern of rt204 was not associated with breakthrough hepatitis. In conclusion, genotypic assays for the rt180M mutation after viral breakthrough may be useful in predicting the risk of breakthrough hepatitis and in deciding when to initiate alternative or additive nucleoside analogue therapy.

A case of primary leiomyoma of the liver in a patient without evidence of immunosuppression.

A 31-year-old Japanese male was admitted to our hospital for investigation of an asymptomatic nodular lesion of the liver detected by abdominal ultrasonography (US) during a routine medical examination. Computed tomography (CT) revealed a single, hypovascular mass 35 mm in diameter, within the left lobe of the liver. The tumor demonstrated hypointensity on T1-weighted, and hyperintensity on T2-weighted magnetic resonance (MR) imaging. Hematological and biochemical investigations were normal. There were no abnormalities of the gastrointestinal or urinary tracts. A left lateral segmentectomy of the liver was performed. Pathological examination of the nodule revealed a primary leiomyoma of the liver, with positive immunohistochemical staining for vimentin and desmin antigens. Primary leiomyoma of the liver is rare, with the majority of cases associated with immunodeficiency disorders. This patient had no evidence of any underlying disease. Primary leiomyoma of the liver should be considered when a nodular lesion is found in a patient without evidence of viral hepatitis.

Development of Hepatocellular Carcinoma after Interferon Therapy in Chronic Hepatitis C

Objectives: Although the incidence of hepatocellular carcinoma (HCC) has been shown to be reduced after interferon (IFN) monotherapy in chronic hepatitis C, the risk factors for the development of HCC have not been fully understood. The aim of this study is to investigate the risk factors for the development of HCC after IFN in chronic hepatitis C as well as whether the incidence of HCC will be reduced by ribavirin and IFN combination therapy or not. Methods: 495 patients with chronic hepatitis C and which received IFN monotherapy were followed and the incidence and risk factors for the development of HCC were examined. On the other hand, in the patients which received ribavirin and IFN combination therapy, the sustained response rate was assessed and the reduction rate of HCC development was predicted. Results: Multivariate analysis by the Cox proportional hazard model revealed that the risk factors for HCC development were age, male gender, severe fibrosis and outcome of IFN therapy. On ribavirin and IFN combination therapy, the sustained response rate reached 17.3% in genotype 1b and 74% in genotypes 2a and 2b infection, thus reducing 20% of the estimated incidence of HCC. Conclusion: To reduce the incidence of HCC in chronic hepatitis C, improvement of the sustained response rate is an essential issue, and ribavirin and IFN combination therapy shows to be promising.

Laparoscopic ablation therapy for hepatocellular carcinoma. Clinical significance of a newly developed laparoscopic sector ultrasonic probe

Background:  Although a laparoscopic approach for local ablation plays an important role in treating hepatocellular carcinoma (HCC) near the liver surface, precise targeting ablation has been difficult using a conventional linear ultrasonic probe. We have recently developed a sector ultrasonic probe with a guiding tract for precisely targeting tumors.