Shunichi Matsuoka

Influence of occult hepatitis B virus coinfection on the incidence of fibrosis and hepatocellular carcinoma in chronic hepatitis C.

We examined prospectively the influence of occult hepatitis B virus (HBV) infection on the histopathological features and clinical outcome of HCV RNA-positive chronic hepatitis (CH-C) and detected hepatitis B core (HBc) particles in hepatocytes. The subjects were 468 patients with CH-C or liver cirrhosis (LC) who were negative for serum hepatitis B surface antigen (HBsAg) by enzyme-linked immunosorbent assay. HBV DNA was detected in serum by nested PCR. HBsAg and HBc antigen (HBcAg) in liver were investigated using immunohistochemical techniques and light (LM) and electron microscopy (EM). Serum HBV DNA was detected in 43.6% of the patients studied. There were no significant differences between HBV DNA-positive and DNA-negative patients in terms of their clinical profiles. For HBV DNA-positive patients, the degree of inflammatory cell infiltration and irregular regeneration of hepatocytes was significantly greater than for HBV DNA-negative patients. The cumulative probability of development of hepatocellular carcinoma (HCC) was significantly higher for HBV DNA-positive patients than for HBV DNA-negative patients. HBV DNA positivity was a risk factor for the occurrence of HCC according to multivariate analysis. HBsAg and HBcAg were detected in 8.5 and 72.3%, respectively, of the livers of serum HBV DNA-positive individuals. Core particles were detected in the nuclei of the hepatocytes by IEM. The histopathological features and long-term outcome of CH-C or LC could be affected by occult HBV infection.

Isoniazid-induced Acute Liver Failure during Preventive Therapy for Latent Tuberculosis Infection

Treating latent tuberculosis infection is a strategy for eliminating tuberculosis, and isoniazid is recommended as preventive therapy. However, concerns have been raised regarding the application of isoniazid due to its toxicity, particularly hepatotoxicity; however, biochemical monitoring is not routinely performed during treatment. We herein present a case of fatal isoniazid-induced acute liver failure. The patients liver function was not periodically examined and isoniazid therapy was continued for 10 days despite the onset of symptoms associated with hepatitis. The patient died four months after hospitalization. It is essential to consider the potential toxicities of isoniazid and establish strategies to prevent acute liver failure.

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.

Prevalence and Risk Factors of Diabetes Mellitus in Patients with Autoimmune Hepatitis.

OBJECTIVE The administration of corticosteroids is a standard treatment for autoimmune hepatitis (AIH), but it can occasionally induce various adverse effects. Diabetes mellitus (DM) is a major complication of chronic liver diseases. We investigated the prevalence and risk factors of DM in patients with AIH. METHODS We retrospectively analyzed 118 Japanese patients diagnosed with AIH from 1990 to 2014 at our institution. The prognosis of patients with and without DM was also compared. RESULTS Twenty-nine (24.5%) patients had DM and 21 (72.4%) received corticosteroids. The annual cumulative incidence rate of newly diagnosed DM was 1.2%. Multivariate analysis showed that DM occurred in older patients [OR=6.290; 95% confidence interval (CI)=1.230-32.100; p=0.018] with higher serum immunoglobulin G levels (OR=12.400; 95% CI=2.560-60.400; p=0.002). A Cox hazard regression analysis revealed that predictive factors for DM were absence of other autoimmune diseases (OR=0.171; 95% CI=0.036-0.805; p=0.025), use of corticosteroids (OR=6.693; 95% CI=1.391-32.210; p=0.049) and lower platelet counts (OR=3.873; 95% CI=1.021-14.690; p=0.046). The 10 year survival rates of the DM and non-DM groups were 94.1% and 94.6%, respectively. There was no significant difference between these groups (p=0.293). CONCLUSION DM occurred in 24.5% of patients with AIH; older age, absence of other autoimmune diseases and higher serum immunoglobulin G levels are risk factors. Taking corticosteroids and a lower platelet count are risk factors for a new onset of DM. DM did not influence the prognosis of AIH patients.

Pathological evidence of the cause of spontaneous regression in a case of resected hepatocellular carcinoma.

A 67-year-old man presented for an evaluation after experiencing right hypochondrial pain lasting for two months. Abdominal ultrasonography showed a hepatic tumor in the right liver and extremely mild hepatic steatosis. The imaging findings indicated that the tumor (43 mm in size) was ischemic, and the lesion was surgically resected and examined. The histopathological findings demonstrated 95% necrosis with moderately differentiated hepatocellular carcinoma (HCC). The diagnosis was HCC with spontaneous regression. There was also pathological evidence of thrombus formation in the peripheral arteries and portal veins. In addition, the non-cancerous regions of the liver were diagnosed as exhibiting non-alcoholic steatohepatitis. The pathological findings obtained after resection of the HCC lesion showed spontaneous regression.

Early implantation of Denver shunt.

BACKGROUND/AIMS The Denver peritoneovenous shunt is useful in the resolution of refractory ascites, because it alleviates symptoms and allows effective palliation. However, this shunt did not prolong the life expectancy of patients with decompensated liver cirrhosis. Therefore, when deciding whether or not to implant a Denver shunt, it is important to determine the condition of the patient with refractory ascites. Here, we determined the appropriate time for Denver shunt implantation. METHODOLOGY We retrospectively studied 21 patients who underwent Denver shunt implantation for hepatic failure-related ascites. The patients were divided into PC and WPC groups depending on whether or not paracentesis was performed before implantation of the Denver shunt, respectively. RESULTS The mean interval from hospital admission to Denver shunt implantation was significantly shorter in the WPC group (9.0±2.2 days) than in the PC group (25.9±5.9 days) (p<0.0001). The mean survival time was significantly longer in the WPC group (8.4±2.5 months) (p<0.0071) than in the PC group (5.6±1.7 months). CONCLUSIONS Early implantation of a Denver shunt should be considered for the treatment of ascites that is resistant to conservative medical therapy.

Early occurrence and recurrence of hepatocellular carcinoma in hepatitis C virus-infected patients after sustained virological response

Chronic hepatitis C virus (HCV) infection is one of the major causes of liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the interferon-free combination of direct-acting antiviral agents (DAAs) against HCV could result in higher sustained virological response (SVR) rates (* 95%) [1]. In the interferon era, long-term eradication of HCV could lead to the reduction of liver-related complications, including HCC [2]. In the DAA era, achievement of SVR and long-term eradication of HCV can be expected to prevent liver-related complications, including HCC.

Onset of Tuberculosis from a Pulmonary Latent Tuberculosis Infection during Antiviral Triple Therapy for Chronic Hepatitis C

A 62-year-old man was diagnosed with the onset of tuberculosis (Tb) from a pulmonary latent tuberculosis infection (LTBI) during triple therapy with pegylated interferon α2a, ribavirin, and telaprevir for a chronic hepatitis C infection in 2013 before interferon (IFN)-free anti-viral therapy was introduced in Japan. A liver biopsy before IFN treatment revealed the presence of epithelioid cell granulomas (ECGs). IFN may also be employed for chronic hepatitis B infection and malignant tumors, thus, special attention must be paid to the development of Tb from a LTBI when ECGs are observed before treatment. It is also necessary to review the significance of the liver biopsy.

Expression of intercellular adhesion molecule-1 in the livers of rats treated with diethylnitrosamine.

It has been reported that levels of soluble intercellular adhesion molecule-1 (ICAM-1) in the blood are elevated in hepatocellular carcinoma patients. In the present study, serial observations of the localization of ICAM-1 in the liver were made by light and electron microscopy in rats with carcinogen-induced cancer. Male Fisher rats were given diethylnitrosamine (DEN) orally in their drinking water. Rats were sacrificed at 6, 8, 12, or 14 weeks after the start of DEN administration and the liver tissue was collected. ICAM-1 expression in liver was assessed using indirect immunoperoxidase staining with anti-rat ICAM-1 antibody. Although ICAM-1 expression by endothelial cells in livers of DEN-treated rats was lower than in the control group at 8 weeks, it was higher in the membrane and cytoplasm of hepatocytes. The expression of ICAM-1 in mesenchymal cells was decreased, paralleling development of cellular atypia, whereas in hepatocyte membranes and cytoplasm it was increased in these atypia. ICAM-1 was localized to the cytoplasm of cancer cells, but to the membrane of hepatocytes in the treated livers at 14 weeks. Furthermore, the levels of ICAM-1 in mesenchymal cells tended to be lower in the cancerous area than in the atypical hyperplastic nodule, and were reduced as the density of cell atypia increased, in comparison to cells in areas without cancerous nodules. We concluded that ICAM-1 may be influenced the development of cancer induced in the rat liver by a chemical carcinogen.

Persistent Hepatic Inflammation Plays a Role in Hepatocellular Carcinoma After Sustained Virological Response in Patients with HCV Infection

Objective: Hepatitis C virus (HCV) infection has long been treated with interferon therapy (IFN). Currently, more than 90% of IFN-treated patients show a sustained virological response (SVR) when also treated with ribavirin and/or a protease inhibitor. Histological inflammation and fibrosis improve in IFN-treated patients, which indicates HCV clearance. IFN also reduces the incidence of hepatocellular carcinoma (HCC). However, a small proportion of patients with SVR develop HCC. To investigate the causes of hepatic carcinogenesis after SVR, we compared the liver histological findings before IFN to those after the development of HCC. Patients and methods: In total, 602 patients infected with type C chronic hepatitis or with liver cirrhosis who received IFN therapy during the period from 1992 through 2015 were included in this study. We assessed 14 of the 287 patients who achieved an SVR. Results: HCC was diagnosed by computed tomography, angiography or liver biopsy. The longest time from the SVR until HCC detection was 16.5 years, and the mean was 7.2±4.6 years. Nine of the 14 patients underwent surgery and one radiofrequency ablation. The histological findings of 10 patients were available for comparison. The comparison of the histological findings before treatment with those after the HCC diagnosis revealed an amelioration of liver fibrosis and other inflammatory changes. All ten patients showed improvements in fibrosis and steatosis. However, we observed that mild inflammatory change persisted from 1.8 years to 16.5 years after the confirmation of SVR in all cases. Conclusion: We suspect that persistent histological inflammation is one of the factors contributing to hepatocarcinogenesis (i.e., HCC development) even after successful treatment.