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author:("Nagao, sumiko")
1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  A retrospective case-control study of hepatitis C virus infection and oral lichen planus in Japan: association study with mutations in the core and NS5A region of hepatitis C virus 
BMC Gastroenterology  2012;12:31.
The aims of this study were to assess the prevalence of hepatitis C virus (HCV) infection in Japanese patients with oral lichen planus and identify the impact of amino acid (aa) substitutions in the HCV core region and IFN-sensitivity-determining region (ISDR) of nonstructural protein 5A (NS5A) associated with lichen planus.
In this retrospective study, 59 patients (group 1-A) with oral lichen planus among 226 consecutive patients who visited our hospital and 85 individuals (group 1-B, controls) with normal oral mucosa were investigated for the presence of liver disease and HCV infection. Risk factors for the presence of oral lichen planus were assessed by logistic regression analysis. We compared aa substitutions in the HCV core region (70 and/or 91) and ISDR of NS5A of 12 patients with oral lichen planus (group 2-A) and 7 patients who did not have oral lichen planus (group 2-B) among patients (high viral loads, genotype 1b) who received interferon (IFN) therapy in group1-A.
The prevalence of anti-HCV and HCV RNA was 67.80% (40/59) and 59.32% (35/59), respectively, in group 1-A and 31.76% (27/85) and 16.47% (14/85), respectively, in group 1-B. The prevalence of anti-HCV (P < 0.0001) and HCV RNA (P < 0.0001) in group 1-A was significantly higher than those in group 1-B. According to multivariate analysis, three factors - positivity for HCV RNA, low albumin level (< 4.0 g/dL), and history of smoking - were associated with the development of oral lichen planus. The adjusted odds ratios for these three factors were 6.58, 3.53 and 2.58, respectively, and each was statistically significant. No significant differences in viral factors, such as aa substitutions in the core region and ISDR of NS5A, were detected between the two groups (groups 2-A and -B).
We observed a high prevalence of HCV infection in patients with oral lichen planus. Longstanding HCV infection, hypoalbuminemia, and smoking were significant risk factors for the presence of oral lichen planus in patients. It is advisable for Japanese patients with lichen planus to be tested for HCV infection during medical examination.
PMCID: PMC3364160  PMID: 22490000
8.  Effect of oral care gel on the quality of life for oral lichen planus in patients with chronic HCV infection 
Virology Journal  2011;8:348.
Oral lichen planus (OLP) decreases the quality of life because it can cause spontaneous pain during eating and tooth-brushing and an uncomfortable feeling in the mouth. In addition, OLP may be associated with HCV-related liver disease.
We investigated the visual analogue scale (VAS) and effects of oral care gel, REFRECARE-H®, on patients with OLP associated with HCV infection.
Nine OLP patients (mean age 67.9 ± 7.6 years) with HCV-related liver diseases were recruited and their VAS score determined along with a biochemical examination of the blood. Types of OLP included erosive (6 patients) and reticular (3). REFRECARE-H®, an oral care gel (therapeutic dentifrice) containing hinokitiol, was applied by each patient as a thin layer on the oral membrane, after each meal and at bedtime for 30 days. Application of REFRECARE-H® improved the quality of life in all terms of dry mouth, breath odor, oral freshness, oral pain during rest, oral pain at a mealtimes, taste disorder, loss of appetite, sleep disorder, depressive mood and jitteriness. VAS scores of dry mouth, breath odor, oral freshness, and sleep disorder were significantly increased 30 days after application of REFRECARE-H® (P = 0.01, P = 0.05, P = 0.03, P = 0.04). VAS scores of oral pain at a mealtimes and taste disorder were increased 30 days after application of REFRECARE-H® (P = 0.06). There was an absence of side effects.
REFRECARE-H® improved the quality of life for OLP. It is necessary for the hepatologist to educate patients regarding oral hygiene, as well as provide treatment of liver disease.
PMCID: PMC3149004  PMID: 21749712
9.  Serum albumin and mortality risk in a hyperendemic area of HCV infection in Japan 
Virology Journal  2010;7:375.
Hypoalbuminemia has been shown to be associated with increased mortality. We reported a mass screening in 1990 of X town in Japan, which demonstrated a high prevalence of hepatitis C virus (HCV) infection. This follow-up study determined, through a period of 12 years, whether serum albumin levels impact on the life prognosis of the residents of X town.
Of the 509 subjects, 69 had died and 55 had moved to other regions by 2002. Therefore, we analyzed 454 people for whom we could confirm life and death between 1990 and 2002. Albumin levels were assigned to two groups, low (<4.0 g/L, group A) and normal (≥4.0 g/L, group B). Of the 454 subjects analyzed, 25 were in group A and 429 in group B and the mortality was 68.0% (17/25 cases, P < 0.00001 vs. group B) and 12.1% (52/429), respectively. Mortality from hepatocellular carcinoma (HCC) was 66.7% in group A (6/9 cases, P = 0.01 vs. group B) and 15.8% (3/19) in group B. According to multivariate analysis, five factors - 50 years or older, low albumin level (<4.0 g/L), abnormal AST level, history of smoking, and absence of alcohol consumption - were associated with death. The adjusted odds ratios for these five factors were 20.65, 10.79, 2.58, 2.24 and 2.08, respectively, and each was statistically significant.
We show that the serum albumin level is an independent risk factor for mortality from all causes in the residents of X town and an important prognostic indicator. Improvement of hypoalbuminaemia should be considered for improvement of prognosis.
PMCID: PMC3022684  PMID: 21194423
10.  Dental problems delaying the initiation of interferon therapy for HCV-infected patients 
Virology Journal  2010;7:192.
There has been little discussion about the importance of oral management and interferon (IFN) therapy, although management of the side effects of therapy for chronic hepatitis C has been documented. This study determined whether dental problems delayed the initiation of IFN therapy for hepatitis C virus (HCV)-infected patients.
We analyzed 570 HCV-infected patients who were admitted to our hospital from December 2003 to June 2010 for treatment consisting of pegylated IFN (Peg-IFN) monotherapy or Peg-IFN/ribavirin combination therapy. The group comprised 274 men and 296 women with a mean age 57.2 years. Of the 570 patients, six could not commence Peg-IFN therapy, despite their admission, because of dental problems such as periodontitis, pupitis, and pericoronitis. The ages of six whose dental problems delayed the initiation of Peg-IFN ranged from 25 to 67 years, with a mean age of 47.3 ± 15.2 years. IFN therapy was deferred for 61.3 ± 47.7 days. Among the six subjects for whom IFN treatment was delayed, only one had a salivary flow that was lower than the normal value.
Treatment of dental infections is required before IFN therapy for HCV infection can be started. To increase the depth of understanding of oral health care, it is hoped that dentists and medical specialists in all areas will hold discussions to generate cooperation.
PMCID: PMC2933590  PMID: 20712912

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