Immune-mediated Drug-induced Liver Injury Caused by Laninamivir Octanoate Hydrate.

We herein report the first case of immune-mediated drug-induced liver injury that may have been caused by laninamivir. A 15-year-old girl was diagnosed with influenza and prescribed 40 mg laninamivir. Six weeks later, she was admitted to our hospital because of jaundice and fatigue. Laboratory examinations revealed elevated levels of hepatobiliary enzymes, and acute liver injury was suspected. Laboratory examinations and histological findings were characteristic of autoimmune hepatitis. Steroid treatment was ineffective, and azathioprine was added to the treatment. Twenty-two months after the onset, a second biopsy revealed the absence of inflammatory infiltrations, and the drugs were withdrawn. Liver function tests remained normal nine months after withdrawal.

Serum albumin level is a notable profiling factor for non-B, non-C hepatitis virus-related hepatocellular carcinoma: A data-mining analysis.

AIM: Various factors are underlying for the onset of non-B, non-C hepatitis virus-related hepatocellular carcinoma (NBNC-HCC). We aimed to investigate the independent risk factors and profiles associated with NBNC-HCC using a data-mining technique. METHODS: We conducted a case-control study and enrolled 223 NBNC-HCC patients and 669 controls from a health checkup database (n = 176 886). Multivariate analysis, random forest analysis and a decision-tree algorithm were employed to examine the independent risk factors, factors distinguishing between the case and control groups, and to identify profiles for the incidence of NBNC-HCC, respectively. RESULTS: In multivariate analysis, besides γ-glutamyltransferase (GGT) levels and the Brinkman index, albumin level was an independent negative risk factor for the incidence of NBNC-HCC (odds ratio = 0.67; 95% confidence interval = 0.60-0.70; P < 0.0001). In random forest analysis, serum albumin level was the highest-ranked variable for distinguishing between the case and control groups (98 variable importance). A decision-tree algorithm was created for albumin and GGT levels, the aspartate aminotransferase-to-platelet ratio index (APRI) and the Brinkman index. The serum albumin level was selected as the initial split variable, and 82.5% of the subjects with albumin levels of less than 4.01 g/dL were found to have NBNC-HCC. CONCLUSION: Data-mining analysis revealed that serum albumin level is an independent risk factor and the most distinguishable factor associated with the incidence of NBNC-HCC. Furthermore, we created an NBNC-HCC profile consisting of albumin and GGT levels, the APRI and the Brinkman index. This profile could be used in the screening strategy for NBNC-HCC.

Efficacy, safety, and survival factors for sorafenib treatment in Japanese patients with advanced hepatocellular carcinoma.

BACKGROUND: Sorafenib, an oral multikinase inhibitor, was approved for the treatment of advanced hepatocellular carcinoma (HCC), but has not been adequately evaluated for safety and effectiveness in Japanese patients with advanced HCC. AIMS: The purpose of this study was to prospectively assess the efficacy, safety, and risk factors for survival in patients with advanced HCC treated with sorafenib. METHODS: Between May 2009 and December 2010, 96 Japanese patients with advanced HCC (76 male, 20 female, mean age: 70.4 years) were treated with sorafenib. Eighty-eight patients had Child-Pugh class A, and 8 patients had Child-Pugh class B liver cirrhosis. Barcelona Clinic Liver Cancer stage B and C were found in 64 and 32 patients, respectively. RESULTS: Twelve patients demonstrated partial response to sorafenib therapy, 43 patients had stable disease, and 33 patients had progressive disease at the first radiologic assessment. The most frequent adverse events leading to discontinuation of sorafenib treatment were liver dysfunction (n = 8), hand-foot skin reaction (n = 7), and diarrhea (n = 4). The median survival time and time to progression were 11.6 and 3.2 months, respectively. By multivariate analysis, des-γ-carboxy prothrombin serum levels and duration of treatment were identified as independent risk factors for survival. CONCLUSIONS: This study showed that sorafenib was safe and useful in Japanese patients with advanced HCC. In addition, this study demonstrated that sorafenib should be administered as a long-term treatment for advanced HCC regardless of therapeutic effect and dosage.

Valine, a branched-chain amino Acid, reduced HCV viral load and led to eradication of HCV by interferon therapy in a decompensated cirrhotic patient.

A decreased serum level of branched-chain amino acid (BCAA) is a distinctive metabolic disorder in patients with liver cirrhosis. Recently, BCAA has been reported to exert various pharmacological activities, and valine, which is a BCAA, has been shown to affect lipid metabolism and the immune system in in vivo experiments. However, the clinical impact of valine supplementation on viral hepatitis C virus (HCV) load has never been reported. Here, we first describe a case of HCV-related advanced liver cirrhosis that was treated by an oral valine agent. The administration of valine resulted in an improvement of fatigue and a reduction in hepatic fibrosis indexes as well as serum α-fetoprotein level. Furthermore, a marked reduction in HCV RNA levels was seen after valine treatment. The patient was then treated by interferon ß, resulting in the successful eradication of chronic HCV infection. Thus, valine may be involved in the reduction of HCV viral load and could support a sustained virologic response to interferon therapy.

Total and high molecular weight adiponectin and hepatocellular carcinoma with HCV infection.

BACKGROUND: Adiponectin is shown to be inversely associated with development and progression of various cancers. We evaluated whether adiponectin level was associated with the prevalence and histological grade of hepatocellular carcinoma (HCC), and liver fibrosis in patients with hepatitis C virus (HCV) infection. METHODS: A case-control study was conducted on 97 HCC patients (cases) and 97 patients (controls) matched for sex, Child-Pugh grade and platelet count in patients with HCV infection. The serum total and high molecular weight (HMW) adiponectin levels were measured by enzyme-linked immunosorbent assays and examined in their association with the prevalence of HCC. In addition, the relationship between these adiponectin levels and body mass index (BMI), progression of liver fibrosis, and histological grade of HCC was also evaluated. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI). RESULTS: There were no significant differences in the serum total and HMW adiponectin levels between cases and controls. Moreover, there were no inverse associations between serum total and HMW adiponectin levels and BMI in both cases and controls. On the other hand, serum total and HMW adiponectin levels are positively correlated with APRI in both cases (r = 0.491, P<0.001 and r = 0.485, P<0.001, respectively) and controls (r = 0.482, P<0.001 and r = 0.476, P<0.001, respectively). Interestingly, lower serum total (OR 11.76, 95% CI: 2.97-46.66 [P<0.001]) and HMW (OR 10.24, CI: 2.80-37.40 [P<0.001] adiponectin levels were independent risk factors of worse histological grade of HCC. CONCLUSIONS: Our results suggested that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low these adiponectin levels were significantly associated with worse histological grades.

Recent progress in the management of hepatocellular carcinoma detected during a surveillance program in Japan.

AIM: This study explored recent improvements in the management of hepatocellular carcinoma (HCC) diagnosed during surveillance. METHODS: The subjects were 1074 patients with HCC, subdivided into three groups. Group A comprised 211 patients for whom HCC was detected during periodic follow-up examinations at Kurume University School of Medicine, Group B comprised 544 patients diagnosed with HCC during periodic follow-up examinations at other institutions, and, Group C comprised 319 patients with HCC detected incidentally or because of symptoms. RESULTS: In 1995-2000 and 2001-2006, 91% and 91% of group A, 68% and 70% of group B, and 27% and 26% of group C patients with HCC, respectively, met the Milan criteria. For groups A and B, the proportions of patients with Child-Pugh class A and use of promising treatment increased in the later periods compared to those diagnosed during the earlier periods (group A, Child-Pugh class A, 72% vs 58% [P = 0.040], receiving treatment, 90% vs 70% [P < 0.0001]; group B, Child-Pugh class A, 71% vs 62% [P = 0.031]; receiving treatment, 72% vs 52% [P < 0.0001], respectively). The cumulative survival rates of the 405 patients with HCC detected in the latter 6 years tended to be better than those for patients diagnosed in the former 6 years (350 patients) (4 years, 58% vs 50% [P = 0.0349]). CONCLUSION: The use of promising treatment and prognosis have improved in the last 6 years for patients with HCC diagnosed through surveillance relative to those identified in 1995-2000.

Adipocytokine involvement in hepatocellular carcinoma after sustained response to interferon for chronic hepatitis C.

AIM: Interferon (IFN) dramatically reduces the risk of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) to chronic hepatitis C (CH-C). However, HCC still develops in some patients after SVR. To evaluate metabolic factors in patients with HCC occurring after SVR and to determine whether insulin resistance and adipocytokines were involved in this etiology. METHODS: We examined clinical and biochemical features, histological findings and serum levels of adipocytokine prior to IFN therapy and at the detection of HCC in nine patients who were diagnosed with HCC. As controls, 27 patients were included who showed SVR but had not been diagnosed with HCC for at least 5 years after SVR. RESULTS: Three of four patients who developed HCC within 5 years after SVR showed liver cirrhosis when HCC was diagnosed. Prior to IFN therapy, four of nine HCC patients were diagnosed as having type 2 diabetes mellitus. Serum levels of leptin and insulin, Homeostatic Model of Assessment of Insulin Resistance and body mass index (BMI) were significantly higher and serum adiponectin was significantly lower in HCC patients at the time of HCC detection than in control patients more than 5 years after SVR. Six HCC patients had increased BMI and one HCC patient had a decreased BMI during the observation period. CONCLUSION: Hepatic fibrosis may be tightly related to the emergence of HCC after SVR. Insulin resistance and adipocytokine disorders may be implicated in hepatocarcinogenesis after SVR, in part by promoting hepatic fibrosis.

HCC develops even in the early stage of chronic liver disease in elderly patients with HCV infection.

In recent years, the number of elderly patients with hepatocellular carcinoma (HCC) has been increasing. The aim of this study was to compare the liver function and the background factors of HCC patients with hepatitis C virus (HCV) infection by generation and to examine the characteristics of this disease in the elderly. A total of 1096 patients (776 men and 320 women) diagnosed with HCV-related HCC at our institution from 1995 to 2006 were divided into 4 groups as follows: D group, 75 years of age or older; C group, 65-74 years of age; B group, 55-64 years of age; A group, 54 years of age or younger, and the liver function and other clinical characteristics were compared among these 4 groups. The average age at initial diagnosis of HCV-related HCC was 66.9 years of age. The A, B, C and D groups were comprised of 87, 363, 514 and 132 patients, respectively. The rate of Child-Pugh class A patients in the D group was significantly higher than that of the other groups (P<0.05). The average levels of ALT, TB and PT-INR in the D group were significantly lower than the levels in the other groups (P<0.05). The average Alb level in the D group was significantly higher than that in the other groups (P<0.05). In conclusion, we found that HCV-related HCC in the elderly occurred against a background of chronic liver disease with mild inflammation and fibrosis.

Characteristic expression pattern of oxidative stress in livers with cryptogenic hepatocellular carcinoma.

The mechanism responsible for the development of hepatocellular carcinoma (HCC) in the setting of oxidative stress has yet to be clearly defined. We studied the role of oxidative stress in hepatocarcinogenesis in subjects without underlying chronic viral hepatitis. The subjects were 24 patients negative for serum hepatitis B surface antigen and hepatitis C antibody tests, who underwent hepatic resection for HCC (Group N). Subjects were excluded if diagnosed with liver disease predisposing to HCC. Immunohistochemical staining for oxidative stress-related markers was performed on non-cancerous liver regions. Resected liver tissues adjacent to HCC from 24 patients with chronic hepatitis B (Group B) and 21 patients with chronic hepatitis C (Group C) were also examined. The percentage of 8-hydroxydeoxyguanosine-positive hepatocytes in Group N was significantly lower than that in Group B and that in the combined population of Groups B and C. The percentage of the area positive for 4-hydroxynonenal in Group N was significantly higher than that in Groups B or C. Meanwhile, the percentage of the area positive for manganese superoxide dismutase in Group N was not different from that in Groups B and C. In conclusion, the mechanism of hepatocarcinogenesis through oxidative stress for patients without known liver disease predisposing to HCC may differ from that for patients with chronic viral hepatitis.

Microvascular invasion in patients with hepatocellular carcinoma and its predictable clinicopathological factors.

BACKGROUND: Macroscopic vascular invasion is known to be a poor prognostic factor in hepatocellular carcinoma (HCC). The aim of this study was to determine the outcomes and predictive factors after hepatic resection for HCC with microvascular invasion (MVI). METHODS: One hundred ten patients who underwent curative resection for HCC without macroscopic vascular invasion were included in this retrospective study. The risk factors of these patients for recurrence-free and disease-specific survival were investigated, and the clinicopathological factors predicting the presence of MVI were also determined. RESULTS: Of the 110 resected specimens, 49 (45%) had evidence of MVI. By univariate analysis, MVI was found to be statistically significantly associated with greater tumor size, gross classification, histological grade, and intrahepatic micrometastasis. Gross classification proved to be the only independent predictive factor for MVI by multiple logistic regression analysis. By multivariate analysis, cirrhosis and MVI were identified as independent risk factors for recurrence-free survival. The 5-year recurrence-free survival rates for patients with and without MVI were 20.8% and 52.6%, respectively. By multivariate analysis, the number of tumors, presence of MVI, and intrahepatic micrometastasis were identified as independent predictors of disease-specific survival. The 5-year disease-specific survival rates for patients with and without MVI were 59.3% and 92.0%, respectively. CONCLUSIONS: The presence of MVI was the most important risk factor affecting recurrence and survival in HCC patients after curative resection. Furthermore, this study showed that gross classification of HCC can be very helpful in predicting the presence of MVI.

Significance of glucose intolerance and SHIP2 expression in hepatocellular carcinoma patients with HCV infection.

Glucose intolerance frequently is found in hepatocellular carcinoma (HCC) patients with hepatitis C virus (HCV) infection; however, the significance of glucose intolerance remains unclear. In addition, SH2 domain-containing inositol phosphatase (SHIP) 2 is a negative regulator of intracellular insulin signaling; however, changes in SHIP2 expression have not been investigated in HCC. To assess the significance of glucose intolerance, we analyzed 118 HCC patients with HCV infection. Twenty HCC specimens were used for immunoblotting and immunostaining for SHIP2. Patients were classified into two groups: a glucose intolerance group (n=39) and a normal glucose tolerance group (n=79). There was no significant difference in the disease-free survival (P=0.838) or long-term survival (P=0.091) between the groups. However, for males, the cumulative survival rate was significantly lower in the glucose intolerance group (n=22) than that in the normal glucose tolerance group (n=52) (P=0.036). In multivariate analysis, Child-Pugh class (P=0.0003) and glucose intolerance (P=0.036) were identified as statistically significant and independent prognostic factors in males. SHIP2 expression level decreased in HCC compared to that in nontumor tissues. In conclusion, this study is the first to demonstrate the significance of glucose intolerance in prognosis of male HCC patients and down-regulation of SHIP2 expression in HCC.

Hyperplastic nodular hepatic lesions following end-to-side portacaval shunting in childhood.

We describe a 48-year-old man with nodular intrahepatic lesions accompanied by communication between the inferior vena cava and portal systems as well as absence of intrahepatic portal veins. After infection with malaria in childhood, end-to-side portacaval shunting had been performed to treat upper gastrointestinal bleeding at the age of 15 years. A biopsy specimen obtained under ultrasonographic guidance showed hyperplastic nodules suggestive of focal nodular hyperplasia. The estradiol concentration in the blood was elevated (55 pg/ml). This case suggests that portacaval shunting may be associated with hyperplastic liver nodules through hyperestrogenemia and abnormal hepatic hemodynamics.