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1.  Association of Periodontal Diseases and Liver Fibrosis in Patients With HCV and/or HBV infection 
Hepatitis Monthly  2014;14(12):e23264.
Periodontal disease and systemic health are closely associated. However, there is no data supporting the association between periodontal disease and patients with liver diseases associated with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) infection.
The aim of this study was to evaluate the association between periodontitis and progression of liver diseases in patients with HCV and/or HBV infection.
Patients and Methods:
In this retrospective study, 351 patients with HCV- and/or HBV-related liver diseases underwent screening for periodontal disease using the Salivaster® salivary occult blood test from February 2010 to June 2014. Furthermore, we examined the prevalence of fimbrillin (fimA) genotype of Porphyromonas gingivalis (P. gingivalis) in 28 HCV-infected patients visited at our hospital between January 2013 and June 2014. P. gingivalis with fimA genotype with types I to V was further detected using a PCR method.
Of 351 patients, 76 patients (group 1) had a strong positive result for salivary occult blood test and 275 patients (group 2) had weak positive or negative test results. Significant factors between the groups were obesity, level of AST, ALT, LDH, ALP, Alb, D.Bil, T.cho, AFP, platelets (Plt), IRI, HOMA-IR, current interferon (IFN) treatment and the daily frequency of tooth brushing. Between-groups analysis indicated that total protein ( level and liver fibrosis were significant factors. According to multivariate analysis, five factors were associated with periodontal disease as Plt count below 80000, brushing teeth only once a day, current IFN treatment, aged 65 years or older and obesity. The adjusted odds ratios for these five factors were 5.80, 3.46, 2.87, 2.50 and 2.33, respectively, and each was statistically significant. Twenty-eight saliva specimens had positive results for P. gingivalis with fimA genotype types I to V. The prevalence of fimA genotype II was higher in 14 patients with liver cirrhosis or a history of hepatocellular carcinoma treatment (group B, 50.00%) than 14 patients with only hepatitis C (group A, 21.43%).
Periodontitis might be associated with progression of viral liver disease; hence, controlling oral disease is essential for the prevention and management of liver fibrosis.
PMCID: PMC4329233  PMID: 25737729
Periodontal Disease; Hepatitis C virus; Hepatitis B Virus; Interferon; Fibrosis; Porphyromonas gingivalis; Fimbrillin
2.  Effect of pioglitazone on outcome following curative treatment for hepatocellular carcinoma in patients with hepatitis C virus infection: A prospective study 
Molecular and Clinical Oncology  2014;3(1):115-120.
Pioglitazone is an insulin sensitizer used for the treatment of diabetes mellitus (DM). DM with insulin resistance is a risk factor for hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection. We aimed to investigate the effects of pioglitazone on HCC recurrence following treatment in HCV-infected patients. Between 2009 and 2011, 85 HCV-infected HCC patients who underwent curative treatment were enrolled in this prospective study. Among 45 patients with type 2 DM, 27 were administered pioglitazone (pioglitazone group) following treatment. The remaining 58 patients were assigned to the control group. The primary outcome was recurrence-free survival. Changes in insulin resistance and serum adiponectin levels resulting from pioglitazone treatment were also assessed. In the whole analysis (n=85), no significant difference in recurrence-free survival was observed between the pioglitazone and control groups. However, in a spline model analysis of DM patients, a decreased risk of HCC recurrence was associated with increased body weight in patients with a body mass index (BMI) ≥23; this association became significant at BMI ≥24 (hazard ratio=0.17; 95% confidence interval: 0.03–0.95). In addition, significantly decreased homeostasis model assessment for insulin resistance values (P=0.002) and significantly increased serum high-molecular-weight adiponectin levels (P<0.001) were observed following pioglitazone treatment. Although pioglitazone did not suppress HCC recurrence in the whole analysis, it inhibited HCC recurrence in overweight HCV-infected diabetic patients. Moreover, pioglitazone improved insulin resistance and adipocytokine levels. Thus, pioglitazone may suppress HCC recurrence, which is associated with glucose and fat metabolism disorders.
PMCID: PMC4251130  PMID: 25469280
pioglitazone; hepatocellular carcinoma; recurrence; obesity; diabetes mellitus; hepatitis C virus; insulin resistance
3.  Time trends of clinical characteristics in hepatocellular carcinoma patients with chronic hepatitis B virus infection: A field survey between 2000 and 2012 
Molecular and Clinical Oncology  2014;2(6):927-934.
The hepatitis B virus (HBV) carrier rate has decreased in Japan; however, the incidence of HBV infection among hepatocellular carcinoma (HCC) patients has not decreased accordingly. In this study, we aimed to assess the time trends of the clinical characteristics in HCC patients with chronic HBV infection. Between 2000 and 2012, we enrolled a total of 156 HCC patients with chronic HBV infection in our field survey. The HCC risk was evaluated using the HCC prediction score, which is constructed from the characteristics of age, presence of liver cirrhosis and serum levels of albumin, bilirubin and HBV DNA. Lifestyle factors and the presence of diabetes mellitus were also evaluated. The time trends of patient characteristics were analyzed using the Jonckheere-Terpstra proportion trend test. Among HCC patients with chronic HBV infection, the proportion of patients at high risk according to the HCC prediction score significantly decreased during the study period (P=0.0005). Similarly, the proportion of patients with liver cirrhosis, ≤3.5 g/dl serum albumin level, >4 log copies/ml serum HBV DNA level and ≥60 g/day alcohol intake were also significantly decreased. The proportion of male and obese patients was not significantly altered, whereas the proportion of elderly (≥65 years) and diabetic patients tended to increase during the study period (P=0.0654 and P=0.0528, respectively). In this study, we analyzed the time trends of the clinical characteristics in HCC patients with chronic HBV infection and demonstrated that aging and diabetes mellitus may be involved in the hepatocarcinogenesis in patients with chronic HBV infection.
PMCID: PMC4179821  PMID: 25279176
chronic hepatitis B; liver cancer; time trend; aging; glucose metabolism disorder
4.  Predictors of Response to 24-Week Telaprevir-Based Triple Therapy for Treatment-Naïve Genotype 1b Chronic Hepatitis C Patients 
We evaluated the genetic variation in rs8099917, substitutions in core amino acid (aa) 70, and the number of aa substitutions in the interferon sensitivity-determining region (ISDR) on the prediction of sustained virological response (SVR) in treatment-naïve hepatitis C virus (HCV) genotype 1b (G1b) patients. This multicenter study involved 150 Asian treatment-naïve patients infected with HCV G1b who received 12 weeks of telaprevir in combination with 24 weeks of peginterferon-α-2b and ribavirin. The baseline and treatment-related factors potentially associated with SVR were determined by multivariate logistic regression analysis. Virological response was analyzed on an intent-to-treat basis. Cessation of the therapy due to adverse effects occurred in only 2 patients, who discontinued the trial at 10 weeks and at 2 weeks due to cerebral infarction and renal impairment, respectively. Among the 150 patients in whom the final virological response was determined, only genotype TT in rs8099917 was identified as a pretreatment predictor (P = 7.38 × 10−4). Achievement of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 of treatment, was identified as an after-starting-treatment predictor (P = 2.47 × 10−5). However, neither a substitution in core aa 70 nor the number of substitutions in the ISDR affected treatment outcome.
PMCID: PMC4150495  PMID: 25197269
5.  Simple scoring system for predicting cirrhosis in nonalcoholic fatty liver disease 
World Journal of Gastroenterology : WJG  2014;20(29):10108-10114.
AIM: To investigate a simple noninvasive scoring system for predicting liver cirrhosis in nonalcoholic fatty liver disease (NAFLD) patients.
METHODS: A total of 1048 patients with liver-biopsy-confirmed NAFLD were enrolled from nine hepatology centers in Japan (stage 0, 216; stage 1, 334; stage 2, 270; stage 3, 190; stage 4, 38). The weight and height of the patients were measured using a calibrated scale after requesting the patients to remove their shoes and any heavy clothing. Venous blood samples were obtained in the morning after the patients had fasted overnight for 12 h. Laboratory evaluation was performed in all patients. Statistical analysis was conducted using SPSS version 12.0. Continuous variables were expressed as mean ± SD.
RESULTS: The optimal cutoff value of platelet count, serum albumin, and aminotransferase/alanine aminotransferase ratio (AAR) was set at < 15.3 104/μL, < 4.0 g/dL, and > 0.9, respectively, by the receiver operating characteristic curve. These three variables were combined in an unweighted sum (platelet count = 1 point, serum albumin = 1 point, AAR = 1 point) to form an easily calculated composite score for predicting cirrhosis in NAFLD patients, called the PLALA (platelet, albumin, AAR) score. The diagnosis of PLALA ≥ 2 had sufficient accuracy for detecting liver cirrhosis in NAFLD patients.
CONCLUSION: The PLALA score may be an ideal scoring system for detecting cirrhosis in NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use.
PMCID: PMC4123339  PMID: 25110437
Nonalcoholic fatty liver disease; Cirrhosis; Fibrosis; Platelet; Albumin; Alanine aminotransferase ratio
6.  Evaluation of endoscopic biliary stenting for obstructive jaundice caused by hepatocellular carcinoma 
AIM: To review the usefulness of endoscopic biliary stenting for obstructive jaundice caused by hepatocellular carcinoma and identify problems that may need to be addressed.
METHODS: The study population consisted of 36 patients with obstructive jaundice caused by hepatocellular carcinoma (HCC) who underwent endoscopic biliary stenting (EBS) as the initial drainage procedure at our hospital. The EBS technical success rate and drainage success rate were assessed. Drainage was considered effective when the serum total bilirubin level decreased by 50% or more following the procedure compared to the pre-drainage value. Survival time after the procedure and patient background characteristics were assessed comparatively between the successful drainage group (group A) and the non-successful drainage group (group B). The EBS stent patency duration in the successful drainage group (group A) was also assessed.
RESULTS: The technical success rate was 100% for both the initial endoscopic nasobiliary drainage and EBS in all patients. Single stenting was placed in 21 patients and multiple stenting in the remaining 15 patients. The drainage successful rate was 75% and the median interval to successful drainage was 40 d (2-295 d). The median survival time was 150 d in group A and 22 d in group B, with the difference between the two groups being statistically significant (P < 0.0001). There were no statistically significant differences between the two groups with respect to patient background characteristics, background liver condition, or tumor factors; on the other hand, the two groups showed statistically significant differences in patients without a history of hepatectomy (P = 0.009) and those that received multiple stenting (P = 0.036). The median duration of stent patency was 43 d in group A (2-757 d). No early complications related to the EBS technique were encountered. Late complications occurred in 13 patients (36.1%), including stent occlusion in 7, infection in 3, and distal migration in 3.
CONCLUSION: EBS is recommended as the initial drainage procedure for obstructive jaundice caused by HCC, as it appears to contribute to prolongation of survival time.
PMCID: PMC4051939  PMID: 24944490
Hepatocellular carcinoma; Obstructive jaundice; Biliary drainage; Percutaneous transhepatic biliary drainage; Endoscopic biliary stenting
7.  Evaluation of endoscopic cytological diagnosis of unresectable pancreatic cancer prior to and after the introduction of endoscopic ultrasound-guided fine-needle aspiration 
Molecular and Clinical Oncology  2014;2(4):599-603.
With the advances in the multidisciplinary treatment of pancreatic cancer (PC) over the last few years, it is crucial to obtain a histopathological diagnosis prior to treatment. Histopathological diagnosis for unresectable PC is currently performed with endoscopic retrograde cholangiopancreatography (ERCP) in combination with endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). We retrospectively assessed the results of these two methods and investigated diagnostic performance according to the location of the lesion and the complications. This study was conducted on a series of 263 consecutive cases of unresectable PC diagnosed with endoscopic cytology. Up to 2006, ERCP-guided cytology (group A) was performed as the first choice for the diagnosis of PC. EUS-FNA was introduced in 2007 and became the first choice thereafter (group B), except in cases with obstructive jaundice, in which ERCP-guided cytology during endoscopic biliary stenting (EBS) remains the first choice. There were statistically significant differences in the overall cancer-positive rate between groups A and B (60.4 vs. 75.3%, P=0.01). The cancer-positive rate in the pancreatic body and tail was significantly higher in group B (59.5 vs. 83.3%, P=0.005), whereas there were no significant differences regarding cancer of the pancreatic head. The complication rate was 4.95% in group A and 3.09% in group B (P=0.448). The endoscopic cytology cancer-positive rate in unresectable PC cases was increased as a result of the introduction of EUS-FNA. In conclusion, we recommend performing EUS-FNA in combination with ERCP-guided cytology in cases with a lesion in the pancreatic head that requires EBS.
PMCID: PMC4051556  PMID: 24940503
unresectable pancreatic cancer; endoscopic cytology; endoscopic retrograde cholangiopancreatography; endoscopic ultrasound-guided fine-needle aspiration
8.  Usefulness of short-term eltrombopag treatment as a supportive treatment in hepatocellular carcinoma patients with cirrhosis and severe thrombocytopenia: A report of two cases 
Oncology Letters  2014;7(6):2130-2134.
Eltrombopag is an oral thrombopoietin (TPO) receptor agonist that increases platelet counts in patients with idiopathic thrombocytopenic purpura and in patients with liver cirrhosis. When cirrhotic patients with thrombocytopenia undergo elective invasive procedures, eltrombopag treatment reduces the requirement for platelet transfusions. However, TPO is known to have proliferative effects on hepatic progenitor cells and hepatic sinusoidal endothelial cells, which indicates that eltrombopag may accelerate tumor progression. Thus, the effect of eltrombopag on hepatocellular carcinoma (HCC) progression is an important issue. The current study describes two cases of HCC with cirrhosis-related thrombocytopenia. A two-week administration of eltrombopag increased platelet counts from 4.8 to 11.3×104 /μl in case 1 and 4.5 to 23.2×104 /μl in case 2. However, no changes were identified in the serum levels of tumor markers or HCC size following eltrombopag administration in the two cases. These HCCs were curatively treated by radiofrequency ablation without platelet transfusions or serious bleeding. Thus, short-term eltrombopag administration may not accelerate HCC proliferation and may be beneficial for invasive HCC treatment in cirrhotic patients with thrombocytopenia.
PMCID: PMC4049767  PMID: 24932302
chronic liver disease; thrombopoietin receptor; hepatoma; growth; megakaryocyte growth and development factor
9.  Disappearance of Oral Lichen Planus After Liver Transplantation for Primary Biliary Cirrhosis and Immunosuppressive Therapy in a 63-year-Old Japanese Woman 
Hepatitis Monthly  2014;14(3):e16310.
There are few reports concerning association between primary biliary cirrhosis (PBC) and lichen planus. In addition, there is only one report about lichen planus after liver transplantation.
Case Presentation:
We describe a case of oral lichen planus (OLP) accompanied with PBC that resolved following liver transplantation 14 years later. This patient received immunosuppressive drugs after liver transplantation.
The disappearance of OLP might be due to immunosuppressive therapy following liver transplantation. Further observations and studies are necessary to clarify the relationship between OLP and PBC.
PMCID: PMC3984472  PMID: 24734093
Lichen Planus, Oral; Liver Cirrhosis, Biliary; Liver Transplantation
10.  Clinical characteristics and prognostic factors for advanced hepatocellular carcinoma with extrahepatic metastasis 
Molecular and Clinical Oncology  2014;2(3):393-398.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The aim of this study was to evaluate whether there are differences in the clinical characteristics and survival between patients with advanced HCC with extrahepatic metastasis who received and those who did not receive previous treatment. Between April, 1998 and April, 2012, a total of 419 HCC patients with extrahepatic metastasis (81 previously untreated and 338 previously treated) were enrolled in this study. The differences in the clinical characteristics, including metastatic sites, were compared between the two groups. In addition, the prognostic predictors among all the patients and among the 81 previously untreated patients were analyzed. The distribution of the major metastatic sites was similar in the two groups; the most frequent site of extrahepatic metastasis was the lungs, followed by the bones, lymph nodes and adrenal glands. The median survival time (MST) among the 419 patients was 6.8 months. The 1-, 2-, 3- and 5-year survival rates were 31.6, 15.3, 9.5 and 2.3%, respectively. No significant differences in survival were observed between patients who received and those who did not receive previous treatment. The multivariate analysis revealed that the Child-Pugh classification, white blood cell count, neutrophil-lymphocyte ratio (NLR) and primary tumor stage were independent predictors of survival for all the patients and for the 81 previously untreated patients. Differences in the clinical characteristics of patients with advanced HCC with extrahepatic metastasis were identified between patients who received and those who did not receive previous treatment. Furthermore, intrahepatic tumor status, Child-Pugh classification, white blood cell count and NLR were demonstrated to be independent predictors of survival in HCC patients with extrahepatic metastasis.
PMCID: PMC3999133  PMID: 24772306
hepatocellular carcinoma; extrahepatic metastasis; survival; previous treatment
11.  Contribution of diuretic therapy with human serum albumin to the management of ascites in patients with advanced liver cirrhosis: A prospective cohort study 
Molecular and Clinical Oncology  2014;2(3):349-355.
The number of available studies on the role of human serum albumin (HSA) in the treatment of cirrhotic ascites is currently limited. In this study, we aimed to investigated the parameters associated with diuretic therapy with HSA in patients with advanced cirrhotic ascites. The patient inclusion criteria were cirrhotic ascites and a serum albumin (Alb) concentration of <3.5 g/dl. A total of 49 patients registered and 38 patients were ultimately included in this study. The enrolled patients were mainly treated with oral spironolactone and furosemide, which were not specified; the HSA amount was also not specified, although the administration period was set to a maximum of 7 days. Our results demonstrated that the administration of HSA significantly increased the serum levels of Alb [0.97 g/dl; two-sided 95% confidence interval (CI): 0.83–1.11 g/dl] and decreased body weight (−2.24 kg; 95% CI: −3.06 to −1.43 kg), hematocrit ratio (0.96; 95% CI: 0.94–0.98) and plasma renin concentration (day 4; geometric mean fold change, −0.1528; 95% CI: −0.2510 to −0.0545; log-transformed data) in patients with advanced cirrhotic ascites. The observed weight loss was found to be correlated with the total amount of HSA administered (P=0.0012), as indicated by the results of the multiple linear regression analysis. In conclusion, this study confirmed the efficacy of HSA in patients with advanced cirrhotic ascites.
PMCID: PMC3999121  PMID: 24772299
human serum albumin; liver cirrhosis; ascites; diuretics
12.  Usefulness of magnifying endoscopy with narrow-band imaging for diagnosis of depressed gastric lesions 
Molecular and Clinical Oncology  2013;2(1):129-133.
The usefulness of magnifying endoscopy with narrow-band imaging (ME-NBI) for the diagnosis of early gastric cancer is well known, however, there are no evaluation criteria. The aim of this study was to devise and evaluate a novel diagnostic algorithm for ME-NBI in depressed early gastric cancer. Between August, 2007 and May, 2011, 90 patients with a total of 110 depressed gastric lesions were enrolled in the study. A diagnostic algorithm was devised based on ME-NBI microvascular findings: microvascular irregularity and abnormal microvascular patterns (fine network, corkscrew and unclassified patterns). The diagnostic efficiency of the algorithm for gastric cancer and histological grade was assessed by measuring its mean sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Furthermore, inter- and intra-observer variation were measured. In the differential diagnosis of gastric cancer from non-cancerous lesions, the mean sensitivity, specificity, PPV, NPV, and accuracy of the diagnostic algorithm were 86.7, 48.0, 94.4, 26.7, and 83.2%, respectively. Furthermore, in the differential diagnosis of undifferentiated adenocarcinoma from differentiated adenocarcinoma, the mean sensitivity, specificity, PPV, NPV, and accuracy of the diagnostic algorithm were 61.6, 86.3, 69.0, 84.8, and 79.1%, respectively. For the ME-NBI final diagnosis using this algorithm, the mean κ values for inter- and intra-observer agreement were 0.50 and 0.77, respectively. In conclusion, the diagnostic algorithm based on ME-NBI microvascular findings was convenient and had high diagnostic accuracy, reliability and reproducibility in the differential diagnosis of depressed gastric lesions.
PMCID: PMC3916206  PMID: 24649321
magnifying endoscopy; narrow-band imaging; early gastric cancer; microvascular architecture; diagnostic algorithm
13.  Metronomic Chemotherapy: Possible Clinical Application in Advanced Hepatocellular Carcinoma1 
Translational Oncology  2013;6(5):511-519.
Hepatocellular carcinoma (HCC) is a hypervascular highly angiogenic tumor usually associated with liver cirrhosis. Vascular endothelial growth factor plays a critical role in vascular development in HCC. In contrast to the treatment of early-stage HCC, the treatment options for advanced HCC are limited and prognosis is often poor, which contributes to this tumor type being the third leading cause of cancer-related deaths worldwide. Metronomic chemotherapy, which was originally designed to inhibit angiogenesis, involves low-dose chemotherapeutic agents administered in a frequent regular schedule with no prolonged breaks and minimizes severe toxicities. We reviewed the potential effects and impact of metronomic chemotherapy in preclinical studies with HCC models and in patients with advanced HCC, especially when combined with a molecular targeted agent. Metronomic chemotherapy involves multiple mechanisms that include antiangiogenesis and antivasculogenesis, immune stimulation by reducing regulatory T cells and inducing dendritic cell maturation, and possibly some direct tumor cell targeting effects, including the cancer stem cell subpopulation. The total number of preclinical studies with HCC models shows impressive results using metronomic chemotherapy-based protocols, especially in conjunction with molecular targeted agents. Four clinical trials and two case reports evaluating metronomic chemotherapy for HCC indicate it to be a safe and potentially useful treatment for HCC. Several preclinical and clinical HCC studies suggest that metronomic chemotherapy may become an alternative type of chemotherapy for advanced unresectable HCC and postsurgical adjuvant treatment of HCC.
PMCID: PMC3799193  PMID: 24151531
14.  Dipeptidyl peptidase-4: A key player in chronic liver disease 
Dipeptidyl peptidase-4 (DPP-4) is a membrane-associated peptidase, also known as CD26. DPP-4 has widespread organ distribution throughout the body and exerts pleiotropic effects via its peptidase activity. A representative target peptide is glucagon-like peptide-1, and inactivation of glucagon-like peptide-1 results in the development of glucose intolerance/diabetes mellitus and hepatic steatosis. In addition to its peptidase activity, DPP-4 is known to be associated with immune stimulation, binding to and degradation of extracellular matrix, resistance to anti-cancer agents, and lipid accumulation. The liver expresses DPP-4 to a high degree, and recent accumulating data suggest that DPP-4 is involved in the development of various chronic liver diseases such as hepatitis C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, DPP-4 occurs in hepatic stem cells and plays a crucial role in hepatic regeneration. In this review, we described the tissue distribution and various biological effects of DPP-4. Then, we discussed the impact of DPP-4 in chronic liver disease and the possible therapeutic effects of a DPP-4 inhibitor.
PMCID: PMC3631980  PMID: 23613622
Incretin; Viral hepatitis; Insulin resistance; Steatohepatitis; Cancer; Sitagliptin; Vildagliptin; Alogliptin; Teneligliptin; Linagliptin
15.  Significance of a reduction in HCV RNA levels at 4 and 12 weeks in patients infected with HCV genotype 1b for the prediction of the outcome of combination therapy with peginterferon and ribavirin 
BMC Infectious Diseases  2012;12:324.
The importance of the reduction in hepatitis C virus (HCV) RNA levels 4 and 12 weeks after starting peginterferon (PEG-IFN) and ribavirin combination therapy has been reported to predict a sustained virologic response (SVR) in patients infected with HCV genotype 1. We conducted a multicenter study to validate this importance along with baseline predictive factors in this patient subpopulation.
A total of 516 patients with HCV genotype 1 and pretreatment HCV RNA levels ≥5.0 log10 IU/mL who completed response-guided therapy according to the AASLD guidelines were enrolled. The reduction in serum HCV RNA levels 4 and 12 weeks after starting therapy was measured using real-time PCR, and its value in predicting the likelihood of SVR was evaluated.
The area under the receiver operating characteristics (ROC) curve was 0.852 for 4-week reduction and 0.826 for 12-week reduction of HCV RNA levels, respectively. When the cut-off is fixed at a 2.8-log10 reduction at 4 weeks and a 4.9-log10 reduction at 12 weeks on the basis of ROC analysis, the sensitivity and specificity for SVR were 80.9% and 77.9% at 4 weeks and were 89.0% and 67.2% at 12 weeks, respectively. These variables were independent factors associated with SVR in multivariate analysis. Among 99 patients who showed a delayed virologic response and completed 72-week extended regimen, the area under ROC curve was low: 0.516 for 4-week reduction and 0.482 for 12-week reduction of HCV RNA levels, respectively.
The reduction in HCV RNA levels 4 and 12 weeks after starting combination therapy is a strong independent predictor for SVR overall. These variables were not useful for predicting SVR in patients who showed a slow virologic response and experienced 72-week extended regimen.
PMCID: PMC3573976  PMID: 23181537
Chronic hepatitis C; Peginterferon; Ribavirin; Reduction in HCV RNA levels; Four and twelve weeks; Baseline factors; Response-guided therapy; Extended treatment
16.  Effect of branched-chain amino acid-enriched nutritional supplementation on interferon therapy in Japanese patients with chronic hepatitis C virus infection: a retrospective study 
Virology Journal  2012;9:282.
The aims of this study were to evaluate the effects of nutritional supplementation with branched-chain amino acids (BCAA) with zinc component (Aminofeel®) on adherence to and outcome of therapy in patients treated with interferon (IFN) for chronic hepatitis C and cirrhosis and to determine whether to recommend the supplement.
In this retrospective study, 51 patients who received IFN therapy were investigated among 203 consecutive patients who visited our hospital and were advised regarding the potential benefit of taking Aminofeel®. Each patient was free to choose whether to purchase and take Aminofeel®.
Twenty four patients (group 1-A) took Aminofeel® during standard IFN therapy and 13 (group 1-B) did not. Low-dose, long-term IFN (maintenance) therapy, mainly peglated (Peg)-IFN alpha 2a, was administered to 14 patients who were difficult to treat, because of no effect or harmful side effects with standard IFN therapy, and who had advanced liver fibrosis. Among the 14, 11 patients (group 2-A) took Aminofeel® and 3 (group 2-B) did not. The prevalence of obesity was significantly higher (P=0.04) in group 1-A than in group 1-B. The rate of adherence to IFN therapy was higher in group 1-A (83.3%) than in group 1-B (53.8%, P=0.05). There were no significant differences between the two groups in the rates of sustained virological response (SVR) to IFN therapy. According to multivariate analysis, two factors, SVR and intake of Aminofeel®, were associated with successful adherence to IFN therapy. The adjusted odds ratios for these two factors were 13.25 and 12.59, respectively, and each was statistically significant. The SVR rate of maintenance IFN therapy was in 18.2% group 2-A and 0% in group 2-B.
Our data show that BCAA intake is useful for adherence to and effect of IFN therapy for patients with chronic hepatitis C. Nutritional supplementation with BCAA seems to be useful for HCV-infected patients receiving IFN therapy because it is impossible to introduce standard treatment for all patients among Japan's aging population.
PMCID: PMC3545893  PMID: 23173649
Branched-chain amino acids (BCAA); Interferon (IFN); Hepatitis C virus (HCV); Standard IFN therapy; Low-dose long-term IFN therapy
17.  Candidiasis and other oral mucosal lesions during and after interferon therapy for HCV-related chronic liver diseases 
BMC Gastroenterology  2012;12:155.
Oral lichen planus (OLP) is seen frequently in patients with hepatitis C virus (HCV) infection. The aim of this study was to evaluate the occurrence of oral candidiasis, other mucosal lesions, and xerostomia during interferon (IFN) therapy for HCV infection.
Of 124 patients with HCV-infected liver diseases treated with IFN therapy in our hospital, 14 (mean age 56.00 ± 12.94 years) who attended to receive administration of IFN once a week were identified and examined for Candida infection and other oral lesions and for the measurement of salivary flow. Serological assays also were carried out.
Cultures of Candida from the tongue surfaces were positive in 7 (50.0%) of the 14 patients with HCV infection at least once during IFN therapy. C. albicans was the most common species isolated. The incidence of Candida during treatment with IFN did not increase above that before treatment. Additional oral mucosal lesions were observed in 50.0% (7/14) of patients: OLP in three (21.4%), angular cheilitis in three (21.4%) and recurrent aphthous stomatitis in one (7.1%). OLP occurred in one patient before treatment with IFN, in one during treatment and in one at the end of treatment. 85.7% of the oral lesions were treated with topical steroids. We compared the characteristics of the 7 patients in whom Candida was detected at least once during IFN therapy (group 1) and the 7 patients in whom Candida was not detected during IFN therapy (group 2). The prevalence of oral mucosal lesions (P=0.0075) and incidence of external use of steroids (P=0.0308) in group 1 were significantly higher than in group 2. The average body weight of group 1 decreased significantly compared to group 2 (P=0.0088). Salivary flow decreased in all subjects throughout the course of IFN treatment and returned at 6th months after the end of treatment. In group 1, the level of albumin at the beginning of the 6th month of IFN administration was lower than in group 2 (P=0.0550). According to multivariate analysis, one factor, the presence of oral mucosal lesions, was associated with the detection of Candida. The adjusted odds ratio for the factor was 36.00 (95% confidence interval 2.68-1485.94).
We should pay more attention to oral candidiasis as well as other oral mucosal lesions, in patients with weight loss during IFN treatment.
PMCID: PMC3503792  PMID: 23122361
18.  Valine, a Branched-Chain Amino Acid, Reduced HCV Viral Load and Led to Eradication of HCV by Interferon Therapy in a Decompensated Cirrhotic Patient 
Case Reports in Gastroenterology  2012;6(3):660-667.
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 β, 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.
PMCID: PMC3506047  PMID: 23185147
Valine; Branched-chain amino acid; Hepatitis C virus; Viral kinetics
19.  Effects and Outcomes of Interferon Treatment in Japanese Hepatitis C Patients 
BMC Gastroenterology  2012;12:139.
No study has compared the long-term prognoses of hepatitis C patients with hepatitis C virus (HCV) antibody-negative individuals and investigated the effects of interferon (IFN) treatment. To clarify the long-term prognosis of HCV-positive residents of an isolated Japanese island and prospectively investigate the effects of IFN treatment in comparison with the HCV-negative general population.
HCV antibody was positive in 1,343 (7.6%) of the 17,712 individuals screened. 792 HCV RNA-positive, HBsAg-negative subjects were enrolled. 1,584 HCV antibody-negative, HBsAg-negative general residents were sex- and age-matched to the 792 subjects. A total of 154 <70-year-old patients without liver cirrhosis (LC) or hepatocellular carcinoma (HCC) underwent IFN treatment. The survival rate with all-cause death as the endpoint was determined and causes of death were compared.
The 10- and 20-year survival rates of the hepatitis C and general resident groups were 65.4% and 87.8%, and 40.8% and 62.5%, respectively (p < 0.001; hazard risk ratio, 0.444; 95% confidence interval (CI): 0.389–0.507). There were 167 liver disease-related deaths and 223 deaths from other causes in the hepatitis C group, and 7 and 451, respectively, in the general resident group. Liver disease-related death accounted for 43.8% and 1.5% of deaths in the hepatitis C and general resident groups (p < 0.0001). The cumulative survival rate of the hepatitis C patients without IFN (n = 328) was significantly lower than the gender- and age-matched general resident group (n = 656) (p < 0.0001) but there was no significant difference between the IFN-treated (n = 154) and general resident groups (n = 308).
In the hepatitis C group, the proportion of liver disease-related death was markedly higher, and the survival rate lower, than the general resident group. Introduction of IFN treatment in <70-year-old patients with hepatitis C without LC or HCC improved the survival rate to a level comparable to that of the general residents.
PMCID: PMC3502559  PMID: 23057417
Hepatitis C virus; Hepatocellular carcinoma; Prospective cohort study; Interferon; Life expectancy
20.  Oral verrucous carcinoma arising from lichen planus and esophageal squamous cell carcinoma in a patient with hepatitis C virus-related liver cirrhosis-hyperinsulinemia and malignant transformation: A case report 
Biomedical Reports  2012;1(1):53-56.
Oral lichen planus (OLP) is a potentially malignant disorder associated with an increased risk of oral cancer. In Japan, the association of OLP with hepatitis C virus (HCV) infection is well documented. In the present study, a case of oral verrucous carcinoma arising from OLP coexisting vulvo-vaginal-gingival syndrome and esophageal squamous cell carcinoma (SCC) in a patient with HCV-related liver cirrhosis is reported. A 71-year old, non-smoking Japanese woman presented with lesions of OLP affecting the bilateral buccal mucosa, tongue, gingival, palate, oral floor and lower lip. Ten years later, an exophytic mass developed in the mandibular alveolar mucosa, the right buccal mucosa and the right lower lip. Pathological diagnosis confirmed the presence of verrucous carcinoma. However, she developed esophageal rather than oral cancer. The oral cancer was resected surgically three times and the patients underwent radiotherapy. The esophageal cancer was removed by endoscopic submucosal dissection. The risk of carcinogenesis increased as hyperinsulinemia continued. The results suggested that it is necessary to monitor for malignant changes in patients with OLP lesions and HCV infection. In addition, treatment requires the cooperation of various medical specialists, as well as an oral surgeon.
PMCID: PMC3956769  PMID: 24648893
oral lichen planus; oral verrucous carcinoma; esophageal squamous cell carcinoma; multiple primary cancers; hepatitis C virus; liver cirrhosis
21.  Analysis of the factors motivating HCV-infected patients to accept interferon therapy 
BMC Research Notes  2012;5:470.
The aims of this study were to analyze factors motivating the acceptance of interferon (IFN) therapy and to clarify the prevalence of oral mucosal diseases in hepatitis C virus (HCV)-infected Japanese patients treated with IFN.
A total of 94 HCV-infected patients who were admitted to our hospital for IFN therapy were asked questions regarding their motivation to accept IFN therapy and were investigated for the presence of oral lichen planus (OLP) before and during IFN treatment. Recommendation and encouragement from other people were the most common factors motivating the acceptance of IFN therapy (49/94, 52.13%). The other motivators were independent decision (30.85%), economic reasons (5.32%), and others. According to multivariate analysis, three factors – sex (male), retreatment after previous IFN therapy, and independent decision to accept IFN therapy - were associated with patients after curative treatment of hepatocellular carcinoma (HCC). The adjusted odds ratios for these three factors were 26.06, 14.17, and 8.72, respectively. The most common oral mucosal lesions included OLP in 11 cases (11.70%). One patient with OLP had postoperative squamous cell carcinoma of the tongue. The rate of sustained virological response (SVR) was 45.45% in cases with OLP and 54.55% in cases without OLP. There were no patients who discontinued IFN therapy because of side effects such as oral mucosal diseases.
We should give full explanation and recommend a course of treatment for a patient to accept IFN therapy. The system to support liver disease as well as oral diseases is also necessary for patient treated for IFN therapy.
PMCID: PMC3500275  PMID: 22932002
Hepatitis C virus; Interferon therapy; Chronic hepatitis C; Hepatocellular carcinoma; Oral lichen planus
22.  Dipeptidyl Peptidase IV Inhibitor Improves Insulin Resistance and Steatosis in a Refractory Nonalcoholic Fatty Liver Disease Patient: A Case Report 
Case Reports in Gastroenterology  2012;6(2):538-544.
A 67-year-old Asian woman was referred to Kurume University Hospital due to abnormal liver function tests. She was diagnosed with nonalcoholic fatty liver disease (NAFLD). NAFLD was treated by diet therapy with medication of metformin and pioglitazone; however, NAFLD did not improve. Subsequently, the patient was administered sitagliptin. Although her energy intake and physical activity did not change, her hemoglobin A1c level was decreased from 7.8 to 6.4% 3 months after treatment. Moreover, her serum insulin level and homeostasis model assessment-insulin resistance value were also improved, as was the severity of hepatic steatosis. These findings indicate that sitagliptin may improve insulin resistance and steatosis in patients with refractory NAFLD.
PMCID: PMC3432996  PMID: 22949894
Dipeptidyl peptidase IV; Incretin; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Glucose intolerance; Diabetes
24.  Efficacy and safety of eltrombopag in Japanese patients with chronic liver disease and thrombocytopenia: a randomized, open-label, phase II study 
Journal of Gastroenterology  2012;47(12):1342-1351.
Eltrombopag is an oral thrombopoietin receptor agonist that stimulates thrombopoiesis and shows higher exposure in East Asian patients than in non-Asian patients. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with thrombocytopenia associated with chronic liver disease (CLD).
Thirty-eight patients with CLD and thrombocytopenia (platelets <50,000/μL) were enrolled in this phase II, open-label, dose-ranging study that consisted of 2 parts. In the first part, 12 patients received 12.5 mg of eltrombopag once daily for 2 weeks. After the evaluation of safety, 26 patients were randomly assigned to receive either 25 or 37.5 mg of eltrombopag once daily for 2 weeks in the second part.
Pharmacokinetics showed that the geometric means of the maximum plasma concentration (Cmax) and the area under the curve (AUC) in the 12.5 mg group were 3,413 ng/mL and 65,236 ng h/mL, respectively. At week 2, the mean increases from baseline in platelet counts were 24,800, 54,000, and 60,000/μL in the 12.5, 25, and 37.5 mg groups, respectively. The median platelet counts increased within 2 weeks of the beginning of administration in all groups, and remained at the same level throughout the 2-week post-treatment period in the 12.5 mg group, whereas the platelet counts peaked a week after the last treatment in both the 25 and 37.5 mg groups. Most adverse events reported were grade 1 or 2; 2 patients in the 37.5 mg group had drug-related serious adverse events.
Eltrombopag ameliorated thrombocytopenia in Japanese patients with CLD and thrombocytopenia. The recommended dose for these patients is 25 mg daily for 2 weeks.
PMCID: PMC3523116  PMID: 22674141
Thrombopoietin receptor agonist; Pharmacokinetics; Invasive procedures; Inter-ethnic difference
25.  Motor vehicle accidents: How should cirrhotic patients be managed? 
Motor vehicle accidents (MVAs) are serious social issues worldwide and driver illness is an important cause of MVAs. Minimal hepatic encephalopathy (MHE) is a complex cognitive dysfunction with attention deficit, which frequently occurs in cirrhotic patients independent of severity of liver disease. Although MHE is known as a risk factor for MVAs, the impact of diagnosis and treatment of MHE on MVA-related societal costs is largely unknown. Recently, Bajaj et al demonstrated valuable findings that the diagnosis of MHE by rapid screening using the inhibitory control test (ICT), and subsequent treatment with lactulose could substantially reduce the societal costs by preventing MVAs. Besides the ICT and lactulose, there are various diagnostic tools and therapeutic strategies for MHE. In this commentary, we discussed a current issue of diagnostic tools for MHE, including neuropsychological tests. We also discussed the advantages of the other therapeutic strategies for MHE, such as intake of a regular breakfast and coffee, and supplementation with zinc and branched chain amino acids, on the MVA-related societal costs.
PMCID: PMC3369995  PMID: 22690067
Traffic accident; Subclinical hepatic encephalopathy; Coffee; Zinc; Branched chain amino acids

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