Aki Hasebe

Glycyrrhizin enhances interleukin-10 production by liver dendritic cells in mice with hepatitis.

BackgroundGlycyrrhizin (GL), an aqueous extract of licorice root, is known to have various immune-modulating and biological response-modifier activities. GL is used in patients with hepatitis to reduce the activity of liver inflammation; however, the mechanism underlying the anti-inflammatory activity of GL is poorly understood. As antigen-presenting dendritic cells (DC) in the tissue play a major role in the regulation of the inflammatory mucosal milieu during tissue inflammation, we studied whether the function of liver DC was altered by GL therapy in a murine model of concanavalin-A (Con A)-induced hepatitis.MethodsLiver DC were propagated from control mice or mice with Con-A-induced hepatitis, and the effect of GL on liver DC was evaluated in vivo and in vitro.ResultsThe levels of interleukin (IL)-10 produced by liver DC were significantly lower in mice with Con-A-induced hepatitis compared with control mice. However, treatment with GL caused increased production of IL-10 in mice with Con A-induced hepatitis. The increased production of IL-10 by mice with Con A-induced hepatitis was also confirmed in vitro by culturing liver DC with GL.ConclusionsThis study indicates that increased production of IL-10 by liver DC due to GL administration may be involved in downregulation of the levels of liver inflammation in mice with Con A-induced hepatitis.

Recent clinical features of Wilson’s disease with hepatic presentation

BackgroundWe carried out this study to evaluate recent clinical features of Wilson’s disease (WD) with hepatic presentation, especially in terms of age, degree of liver injury, and association with hepatocellular carcinoma (HCC).MethodsSixteen patients with hepatic manifestations were diagnosed with WD in the period 1976–2003. We divided this period into two periods, “past” and “recent”. The diagnosis was based on the presence of Kayser-Fleisher rings, low serum copper levels, low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge, and increased hepatic copper concentrations. This retrospective study was done at Ehime University Hospital.ResultsFour patients, including a pair of siblings, had a family history of WD. Four patients had parental consanguinity. There were 6 patients aged over 40 years in the recent period, whereas no patients in the past period were over 40. Four patients had neurological manifestations. Ten patients had liver cirrhosis and 5 had chronic hepatitis. Two had fatty liver without obesity. All patients in the past period had liver cirrhosis. Three patients with liver cirrhosis were found to have HCC during the follow up. All patients were treated with either D-penicillamine or trientine chloride, or both. However, four patients had to discontinue these agents due to the side effects.ConclusionsRecently, the number of patients diagnosed with WD has been increasing, not only in terms of those with classical-type WD but also in terms of elderly patients or patients with non-cirrhotic liver injury such as fatty liver and chronic hepatitis. The various clinical features of WD should be recognized and particular attention should focus on HCC as a complication.

Radiofrequency ablation therapy for hepatocellular carcinoma in elderly patients

Background and Aim:  With the aging of society, the number of elderly patients with hepatocellular carcinoma (HCC) has been increasing in Japan. The Government of Japan defines elderly as being over 65 and has divided the elderly into two stages: the first elderly stage (< 75 years old) and the second elderly stage (≥ 75). We investigated the efficacy and safety of radiofrequency ablation therapy (RFA) in patients in the second elderly stage in comparison with other HCC patients, retrospectively.

Impaired functional capacities of liver dendritic cells from murine hepatitis B virus (HBV) carriers: relevance to low HBV-specific immune responses

The chronic hepatitis B virus (HBV) carrier exhibits ongoing replication of HBV and expresses abundant amounts of HBV‐related antigens in the liver. However, HBV‐specific immune responses are either absent or narrowly focused in these subjects. With the postulation that impaired functional abilities of liver dendritic cells (DCs) might be responsible for this, we assessed the functions of liver DCs in HBV transgenic mice (HBV‐TM), an animal model of the HBV carrier state. Liver DCs were isolated from normal C57BL/6 mice and HBV‐TM without the use of cytokines or growth factors. Lymphoproliferative assays were conducted to evaluate the ability of liver DCs to induce the proliferation of allogenic T lymphocytes and hepatitis B surface antigen (HBsAg)‐enriched T lymphocytes. Liver DCs were stimulated with viral and bacterial products to assess their cytokine‐producing capacities. In comparison to liver DCs from normal C57BL/6 mice, liver DCs from HBV‐TM exhibited significantly decreased T cell proliferation‐inducing capacities in allogenic mixed leucocyte reaction (P < 0·05) and HBsAg‐enriched T lymphocytes proliferation assays (P < 0·05). Liver DCs from HBV‐TM produced significantly lower levels of interleukin‐12p70, tumour necrosis factor‐alpha, interferon‐gamma, and interleukin‐6 (P < 0·05) compared to liver DCs from normal C57BL/6 mice. This study provides evidence that liver DCs from HBV‐TM had impaired ability to induce both innate and adaptive immune responses. This might account for a weak and almost undetectable HBV‐specific immune response in chronic HBV carriers. This inspires hope that up‐regulation of the functions of liver DCs in situ may have therapeutic implications in chronic HBV carriers.

Amino acid imbalance in patients with chronic liver diseases.

Aim:  The aim of this study is to clarify the amino acid imbalance in patients with chronic hepatitis (CH) as well as those with liver cirrhosis (LC).

Change of acute hepatitis B transmission routes in Japan.

Background. Many years have passed since various prophylactic policies for preventing hepatitis B virus (HBV) transmission were begun. We studied the chronological alterations in HBV infectious routes in patients with acute hepatitis B in the past 27 years. Methods. Seventy-two patients with acute HBV infection who were admitted to our hospital during the period 1976 to 2002 were enrolled in this study. This study was divided into two periods (first period, 1976–1990; and second period, 1991–2002), and the HBV infectious routes were studied. Results. Infectious routes have been changing. Posttransfusion hepatitis was seen only in the first period. In the second period, sexual transmission was the major infectious route (68%), followed by infection at a medical facility or occupational exposure such as needlestick injury (8%). Conclusions. Transmission from sexual contact has become the main infectious route of HBV in Japan.

Recent trends of Japanese hepatocellular carcinoma due to HCV in aging society.

BACKGROUND/AIMS The mean age of hepatocellular carcinoma (HCC) patients has increased (=65 years old). We want to identify the recent trend of the clinical features of HCC patients due to hepatitis C virus (HCV) (HCV-HCC). METHODOLOGY From 2000 to 2009, 855 naive HCC patients were admitted. HCV-HCC patients were divided into two groups, first period group (2000-04, n=270) and second period group (2005-09, n=343) and the clinical features of HCV-HCC were investigated. RESULTS There was no difference in gender, TNM stage and percentages of HCV-HCC between the periods. On the other hand, the ratio of HCV-HCC patients with worse liver function (Child-Pugh B or C), elderly (=75 years old) and the population of patients treated with low invasive radiofrequency ablation were increased (30.0% to 42.0%, 17.2% to 35.8% and 25.1% to 36.2%, respectively; p<0.01). The 1y-, 3y- and 5y-survival rate of HCV-HCC did not show differences (82.1%, 60.5% and 44.7% vs. 81.8%, 56.9% and 37.7%, respectively; p=0.219). CONCLUSIONS The ratio of aged HCV-HCC as well as HCV-HCC patients with worse liver function was increased. The less invasive treatment for HCC in these patients and the quick anti-viral treatment for HCV patients should be considered to avoid occurrence of HCC in Japan.

Hepatitis B Virus Reactivation Induced by Infliximab Administration in a Patient with Crohn’s Disease

A 47-year-old man diagnosed with Crohns disease was treated with infliximab. He tested negative for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) but positive for anti-HB core antibody (anti-HBc). He tested positive for hepatitis B virus (HBV-) DNA 3 months after treatment and was administered entecavir. HBV-DNA test showed negative results 1 month later. ALT was persistently within the normal range, and HBV-DNA was persistently negative thereafter despite the continuation of infliximab every 8 weeks. In our hospital, 14 patients with inflammatory bowel disease, who tested negative for HBsAg, were treated with infliximab; 2 of them tested positive for anti-HBs and/or anti-HBc, and HBV reactivation was observed in 1 patient (the present patient). The present case and these findings highlight that careful follow-up is needed in patients with inflammatory bowel disease treated with infliximab who test positive for anti-HBc and/or anti-HBs.

Induction and maintenance of anti-HBs in immunosuppressed murine hepatitis B virus carriers by a novel vaccination approach: implications for use in hepatitis B virus-infected subjects with liver transplantation.

BackgroundOne of the major problems with orthotopic liver transplantation (OLT) in patients with endstage liver diseases due to hepatitis B virus (HBV) is to maintain sustained high levels of antibody to hepatitis B surface antigen (anti-HBs) to block reactivation of HBV infection and allograft rejection. The aim of this study was to induce anti-HBs by a unique vaccination protocol, using hepatitis B surface antigen (HBsAg)-pulsed dendritic cells (DCs) in immunosuppressed murine HBV carriers.MethodsImmunosuppressed murine HBV carriers were produced by injecting FK-506 (2 mg/kg), intraperitoneally, daily for 15 days in HBV-transgenic mice (Tg) expressing HBV-related mRNAs and proteins. HBsAg-pulsed DCs were prepared by culturing murine spleen DCs with HBsAg (100 µg) for 24 h. HBsAg-pulsed DCs were injected twice, at an interval of 2 weeks, to immunosuppressed HBV-Tg and the levels of anti-HBs were measured periodically for 4 months.ResultsInjection with FK-506 resulted in the production of immunosuppressed HBV-Tg, as evident by their low production of cytokine mRNAs and proteins. Two injections of HBsAg-pulsed DCs from immunosuppressed HBV-Tg induced anti-HBs in all immunosuppressed HBV-Tg within 4–8 weeks after the second injection. More than 10 IU/l of anti-HBs was detected in the sera in all but one immunosuppressed HBV-Tg for more than 4 months, although all immunosuppressed HBV-Tg were continuously provided with FK-506 on a daily basis for the entire duration of the study.ConclusionsThe capacity of HBsAg-pulsed DCs to induce anti-HBs in immunosuppressed HBV-Tg inspires optimism for the possible use of this therapeutic regimen for HBV-infected OLT patients.

Mo1144 Efficacy of Diagnosis for Acute Cholecystitis With Contrast Enhanced Ultrasonography: Evaluation for Blood Flow of the Gall Bladder Wall

Aim/background: In early phase of acute cholecystitis (AC), ultrasonography (US) or enhanced computed tomography (CECT) sometimes do not show the typical findings. Therefore, its diagnosis is difficult in many patients. We evaluated the efficacy for diagnosis of AC with contrast enhanced US (CEUS). Methods: Subjects were 21 patients who were suspected for AC and 13 controls. B-mode US, CECT, and CEUS were performed in all of them. The symptoms of 21 patients, who were suspected for AC, were any one of upper abdominal pain and/or an attack of fever with elevation of the levels of white blood cell and/or C-reactive protein. B-mode US and CECT were reviewed for distension of GB, GB wall thickness, existence of debris in GB, pericholecystic fluid, subserosal edema, pericholecystic stranding. For diagnosis of AC by B-mode US, more than two findings of the three typical findings (distension of GB, GB wall thickness, existence of debris in GB) were necessary and distension of GB was an indispensable finding. Definitive diagnosis of AC was done by histopathological examination, the result of culture of bile juice from GB, and/or the typical finding of CECT including pericholecystic stranding. CEUS was performed with Perfulbutane (Sonazoid®). Movie video was recorded during the procedure and analysis was done with Receiver Operating Characteristic (ROC), that was focused on the GB wall in arterial phase of CEUS (20-60 seconds after injection of Sonazoid®). The results of analysis for ROC and clinical results were evaluated. Results: Nineteen of 21 patients, who were suspected for AC, were diagnosed as AC. Time intensity curve (TIC) was higher and acceleration time (ACT) was shorter in patients with AC than those without AC (4.50±2.31 vs. 2.34±1.26, P<0.01, and 8.2±2.4 vs. 15.8±7.1 seconds, P<0.01, respectively). These findings indicated the increase of the blood flow and the acceleration of the flow speed, respectively. Cut off values of TIC and ACT for diagnosis in ROC analysis were settled as >1.34, and as <15.8 respectively. With the cut off values of both TIC and ACT, seventeen patients were diagnosed as AC (17/19, 89.5%). Diagnostic value for AC with CEUS using above cut off values was equal to that of CECT (sensitivity and specificity: 89.5% and 100% vs. 73.7% and 100%, respectively). On the other hand, diagnostic value for AC of B-mode was worse (sensitivity and specificity: 21.1% and 100%). In five cases that could not be diagnosed by CECT, CEUS could diagnose them as AC. Conclusion: TIC was high and ACT was shortened in patients with AC. CEUS enabled the accurate diagnosis of AC in majority of patients whose findings of CECT or B-mode US were not typical with AC. CEUS was useful for the diagnosis of AC by analyzing TIC and ACT.