Hirotaka Hirano

Quantification of Pregenomic RNA and Covalently Closed Circular DNA in Hepatitis B Virus-Related Hepatocellular Carcinoma

Pregenomic RNA (pgRNA) is generated from covalently closed circular DNA (cccDNA) and plays important roles in viral genome amplification and replication. Hepatic pgRNA and cccDNA expression levels indicate viral persistence and replication activity. This study was aimed to measure hepatic pgRNA and cccDNA expression levels in various states of hepatitis B virus (HBV) infection. Thirty-eight hepatocellular carcinoma (HCC) patients, including 14 positive for hepatitis B surface antigen (HBsAg) and 24 negative for HBsAg but positive for anti-hepatitis B core (anti-HBc) antibody, were enrolled in this study. In HBsAg-negative but anti-HBc-positive group, HBV-DNA was detected in 20 of 24 (83%) noncancerous liver tissues for at least two genomic regions based on polymerase chain reaction (PCR) analysis. pgRNA and cccDNA expression levels in occult HBV-infected patients were significantly lower than those in HBsAg-positive patients (P < 0.001). pgRNA and cccDNA in cancerous tissues were also detected without significant difference from those in noncancerous tissues. In conclusion, cccDNA and pgRNA are detected and represented HBV replication not only in noncancerous but also in cancerous liver tissues. In addition, the replication is shown in not only patients with HBsAg-positive but also occult HBV-infected patients, suggesting the contribution to HCC development.

Chronic Liver Disease Questionnaire would be a primary screening tool of neuropsychiatric test detecting minimal hepatic encephalopathy of cirrhotic patients

The neuropsychiatric test (NP test) is a clinically available modality to confirm minimal hepatic encephalopathy (MHE), but it takes at least 30 min for outpatients to complete. An easier primary screening tool of the NP test would be helpful to predict MHE in routine testing on the public.

Serum level of taurine would be associated with the amelioration of minimal hepatic encephalopathy in cirrhotic patients

A variety of treatment modalities including L‐carnitine have been tried for cirrhotic patients with minimal hepatic encephalopathy (MHE), which improved MHE for some patients, but were not effective for the other patients. We aimed to identify pre‐therapeutic independent factors to predict the amelioration of MHE after L‐carnitine treatment.

A case of intravascular lymphoma diagnosed in an explanted liver after liver transplantation.

Intravascular lymphoma (IVL) is a rare form of B‐cell lymphoma. We encountered a rare case of IVL diagnosed in an explanted liver. A 49‐year‐old man visited a clinic with high fever. Because of elevated liver function, he was diagnosed with acute liver failure. Deceased donor liver transplantation (LT) was performed 16 days after admission. The post‐transplantation course was uneventful until IVL was reported in the explanted liver on postoperative day (POD) 21. Rituximab was administered on POD 27, and rituximab–cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (R‐CHOP) treatment administered on POD 38. The R‐CHOP treatment was repeated for eight cycles, and the patient remains free of recurrence 1 year post‐transplantation. Although systemic lymphoma is a contraindication to transplantation, our experience indicates that IVL can be successfully treated by the administration of prompt chemotherapy after LT for fulminant hepatitis.

Serum albumin and prothrombin time before entecavir treatment in chronic hepatitis B or cirrhosis are related to amelioration of liver function after treatment.

Objectives Nucleotide analogs such as entecavir (ETV) ameliorate liver function in chronic hepatitis B or cirrhotic patients, but we cannot predict in which patients this will occur before ETV treatment. We aimed to develop a new pretherapeutic predictive model for the amelioration of liver function after treatment. Patients and methods We carried out a case–control study involving 88 chronic hepatitis B or cirrhotic patients who underwent ETV treatment at Kobe University Hospital. Blood biochemical and virological examinations were performed before and 1 year after ETV treatment. Child’s score as an indicator of liver function was also evaluated at the same time. Factors associated with amelioration of Child’s score 1 year after ETV treatment were assessed by multivariate analyses. A predictive model of Child’s score amelioration was established. Results Multivariate analyses showed that albumin (Alb) and prothrombin time (PT) before ETV treatment were independent factors for Child’s score amelioration after the treatment (P=0.001 and 0.030, respectively). The decreases in Alb and PT before the treatment were significantly related to the decrease in Child’s score 1 year after the treatment (P=0.001 and 0.006, respectively). The following predictive model of Child’s score amelioration was developed: P=1−(1/(1+Exp(−2.215×Alb−0.058×PT+12.543))). The model could well discriminate area under ROC at 0.819 (95% confidence interval: 0.707–0.932). The optimal cutoff point was 0.185, and sensitivity and specificity were 83.3 and 73.9%, respectively. Conclusion Alb and PT before ETV treatment were related to amelioration of liver function after treatment. With our model, the probability of amelioration of liver function after treatment could be better estimated.

Serum NX-DCP as a New Noninvasive Model to Predict Significant Liver Fibrosis in Chronic Hepatitis C

Background: Finding a noninvasive method to predict liver fibrosis using inexpensive and easy-to-use markers is important. Objectives: We aimed to clarify whether NX-des-γ-carboxyprothrombin (NX-DCP) could become a new noninvasive model to predict liver fibrosis in hepatitis C virus (HCV) related liver disease. Patients and Methods: We performed a prospective cohort study on a consecutive group of 101 patients who underwent liver biopsy for HCV-related liver disease at Kobe University Hospital. Laboratory measurements were performed on the same day as the biopsy. Factors associated with significant fibrosis (F3-4) were assessed by multivariate analyses. A comparison of predictive ability between multivariate factors and abovementioned noninvasive models was also performed. Results: Increase in serum NX-DCP was significantly related to increase in fibrosis stage (P = 0.006). Moreover, NX-DCP was a multivariate factor associated with the presence of significant fibrosis F 3-4 (median 21 of F0-2 group vs. median 22 of F3-4 group with P = 0.002). The AUC of NX-DCP showed no significant differences compared with those of the AST-to-platelet ratio index (APRI), modified-APRI, the Göteborg University Cirrhosis Index (GUCI), the Lok index, the Hui score, cirrhosis discriminating score (CDS) and the Pohl score (P > 0.05). Conclusions: NX-DCP correlated positively with fibrosis stage and could discriminate well between HCV-related patients with or without significant fibrosis. Moreover, NX-DCP had a similar predictive ability to the abovementioned models, and thereby could be a new noninvasive prediction tool for fibrosis.

Reduction in Non-Protein Respiratory Quotient Is Related to Overall Survival after Hepatocellular Carcinoma Treatment

Background Transcatheter arterial chemoembolization (TACE) is an effective treatment for hepatocellular carcinoma (HCC) that can occasionally lead to the shortening of life expectancy. We aimed to make a new and more accurate prognostic model taking into account the course of disease after TACE. Methodology/Principal Findings We performed a prospective cohort study involving 100 HCC patients who underwent TACE at Kobe University Hospital. Indirect calorimetry and blood biochemical examinations were performed before and 7 days after TACE. Time-dependent and time-fixed factors associated with 1-year mortality after TACE were assessed by multivariate analyses. A predictive model of 1-year mortality was established by the combination of odds ratios of these factors. Multivariate analyses showed that the ratio of non-protein respiratory quotient (npRQ) (7 days after/before TACE) and Cancer of Liver Italian Program (CLIP) score were independent factors of 1-year mortality after TACE (p = 0.014 and 0.013, respectively). Patient-specific 1-year mortality risk scores can be calculated by summarizing the individual risk scores and looking up the patient-specific risk on the graph. Conclusions The short-term reduction of npRQ was a time-dependent prognostic factor associated with overall survival in HCC patients undergoing TACE. CLIP score was a time-fixed prognostic factor associated with overall survival. Using the prediction model, which consists of the combination of time-dependent (npRQ ratio) and time-fixed (CLIP score) prognostic factors, 1-year mortality risk after TACE would be better estimated by taking into account changes during the course of disease.

Letter: liver dysfunction and survival in hepatocellular carcinoma treated by transarterial chemoembolisation

A.Miki*, K.Momose*, H. Hirano*, M. Yoshida* & T. Azuma* *Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan. Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan. Division of Metabolomics Research, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan. E-mail: azumat@med.kobe-u.ac.jp

The serum level of NX-DCP-R, but not DCP, is not increased in alcoholic liver disease without hepatocellular carcinoma

BACKGROUND AND AIM Alcoholic liver disease (ALD) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Des-gamma-carboxy prothrombin (DCP) is elevated in many patients with HCC, but also in severe alcoholics without HCC. We aimed to clarify whether the DCP/NX-DCP ratio (NX-DCP-R) could have a high specificity in ALD patients without HCC. METHODS We performed a prospective cohort study on a total of 703 consecutive outpatients of liver diseases including severe alcoholics and healthy volunteers, who underwent blood biochemical examinations at Kobe University Hospital. Serum DCP was measured by electrochemiluminescence immunoassay (ECLIA) using a monoclonal antibody, MU-3. A novel parameter, serum NX-DCP, which represents predominantly DCP caused by reduced vitamin K availability, was also measured by ECLIA using monoclonal antibodies P-16 and P-11. The diagnostic accuracy of DCP and NX-DCP-R in patients with and without excessive alcohol intake was statistically examined. RESULTS DCP was significantly higher in alcoholics than in non-alcoholics (p= 0.005), whereas the NX-DCP-R did not differ between alcoholics and non-alcoholics (p= 0.375). DCP was significantly increased in the serum of each patient with alcoholic hepatitis and alcoholic cirrhosis (p< 0.05), whereas the NX-DCP-R was not increased (p> 0.05). CONCLUSIONS NX-DCP-R, but not DCP, was not increased in alcoholics without HCC. As for negative screening for HCC, the specificity of the NX-DCP-R in alcoholics without HCC was better than that of DCP in alcoholics without HCC, and so could be a useful negative screening tool for HCC in millions of alcoholics worldwide.

NX-DCP as a novel biomarker would be related to liver function in cirrhotic patients with hepatocellular carcinoma.

The treatment for hepatocellular carcinoma (HCC) is decided by the tumor staging and liver function because HCC generally develops against a background of liver cirrhosis. Therefore, it is necessary to consider HCC treatment carefully from the viewpoint of liver function in addition to the tumor stage. In this paper, we first report that novel des-g-carboxy prothrombin (DCP) would be much more related to liver function.