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BACKGROUND AND AIMS: The impact of hepatitis C virus (HCV) eradication via direct-acting antiviral (DAA) therapy on overall mortality, particularly non-liver-related mortality, is understudied. METHODS: We recruited 4180 patients with chronic HCV infection who achieved sustained virological response (SVR) (HCV eradication) through DAA therapy (n = 2501, SVR group) or who did not receive antiviral therapy (n = 1679, non-SVR group); 1236 from each group were chosen using propensity score matching. Causes of death and all-cause mortality, including non-liver-related diseases, were investigated. RESULTS: Of the 4180 patients, 592 died during the follow-up period. In the SVR group, the mortality rates from liver-related and non-liver-related diseases were 16.5% and 83.5%, respectively. Compared to the non-SVR group, mortality rates from liver-related and non-liver-related diseases were 50.1% and 49.9%, respectively (p < .001). In non-cirrhotic patients, multivariable analysis revealed that SVR was an independent factor associated with both liver-related (hazard ratio [HR], .251; 95% confidence interval [CI], .092-.686) and non-liver-related (HR, .641; 95% CI, .415-.990) mortalities. In cirrhotic patients, multivariable analysis revealed that SVR remained an independent factor significantly associated with liver-related mortality (HR, .151; 95% CI, .081-.279). In propensity score-matched patients, the eradication of HCV (SVR group) decreased both liver-related (p < .001) and non-liver-related mortality (p = .008) rates compared to persistent HCV infection (non-SVR group). CONCLUSIONS: The elimination of HCV via DAA therapy reduced not only liver-related mortality but also non-liver-related mortality in patients with chronic HCV.
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AIM: The present study aimed to determine the real-world efficacy and safety of the non-structural protein (NS)5A inhibitor elbasvir (EBR) combined with the NS3/4A protease inhibitor grazoprevir (GZR) in patients with hepatitis C virus (HCV) genotype 1 (GT1) infection. METHODS: This study retrospectively evaluated the rate of sustained virologic response at 12 weeks post-treatment (SVR12) and the safety of EBR/GZR treatment in 159 men and 194 women with a median age of 72 years, and it assessed factors associated with the SVR12 rate. The attending physicians were responsible for selecting candidate patients for EBR/GZR in this retrospective study. RESULTS: Treatment outcomes for EBR/GZR were good in direct-acting antiviral (DAA)-naïve patients, of whom 99.4% achieved SVR. Of 353 patients, 10 (2.9%) had treatment failure. Of these patients, eight previously underwent DAA therapy, and the remaining two had NS5A-L31/Y93 double mutation. The SVR rate was 50% (8/16 patients) in patients who previously underwent DAA therapy, and 18.2% (2/11 patients) in patients with NS5A-L31/Y93 double mutation. On multivariate logistic regression analysis, NS5A-Y31/Y93 double mutation (odds ratio 356.3; 95% confidence interval, 23.91-16 940; P < 0.0001) was identified as an independent predictor of treatment failure. No serious adverse events were observed with EBR/GZR therapy. CONCLUSIONS: The SVR rate of EBR/GZR would have been 100% in patients without either a history of DAA therapy or double mutation. This combination of drugs could be safely given and is, thus, considered a highly useful first-line treatment for DAA-naïve patients with HCV.
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AIM: This study aimed to describe the real-world efficacy and safety of sofosbuvir (SOF) + ribavirin (RBV) for chronic hepatitis C, genotype 2. METHODS: This was a retrospective analysis of a nationwide, multicenter registry including 914 hepatitis C genotype 2 Japanese patients treated with SOF + RBV for 12 weeks. The rate of sustained virologic response at 12 weeks after treatment (SVR12), incidence of adverse events, and changes in serological parameters were analyzed. RESULTS: Treatment was completed in 98.9% of patients. Ribavirin dose reduction was required in 29.7% of patients. The SVR12 rate was 96.8% in the intention-to-treat population and 97.6% in the per-protocol population. Factors associated with SVR12 were absence of advanced fibrosis (odds ratio, 5.76, P = 0.003) and interferon-treatment-naïve status (odds ratio, 4.79, P = 0.017). Dose reduction or total adherence of RBV was not associated with SVR. The resistance-associated substitution S282 T in NS5B was not detected in any patient at virologic failure. Serum albumin levels significantly increased, and the degree of increase was greater in patients with advanced fibrosis than in those without (0.21 ± 0.32 vs. 0.05 ± 0.29, P < 0.0001). Alpha-fetoprotein decreased significantly at end of treatment (P < 0.0001), and the degree of decrease was greater in patients with advanced fibrosis than in those without (21.7 ± 60.8 vs. 2.5 ± 15.5, P < 0.001). The most commonly reported adverse event was anemia (13.7%). CONCLUSIONS: Treatment with SOF + RBV was highly effective and safe in Japanese patients with HCV genotype 2 infection.
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BACKGROUND AND AIM: Because the risk of colorectal cancer has not been well examined in fecal immunochemistry test (FIT)-positive patients who previously underwent colonoscopy, this study aimed to investigate this topic. METHODS: This was a single-center, observational study of prospectively collected data in Japan. FIT-positive, average-risk patients who underwent colonoscopy were divided into groups as follows: those who never underwent colonoscopy in the past (no colonoscopy group), those with a history of colonoscopy between 6 months and 5 years (0.5- to 5-year colonoscopy group), and those with a history of colonoscopy more than 5 years ago (> 5-year colonoscopy group). We investigated the prevalence of advanced neoplasia and invasive cancer among these groups using multiple logistic regression analysis. RESULTS: Detection rates of advanced neoplasia in the no colonoscopy group, 0.5- to 5-year colonoscopy group, and > 5-year colonoscopy group were 14.8% (240/1626), 3.9% (13/330), and 6.9% (17/248), respectively. Detection rates of invasive cancer in each aforementioned group were 5.7% (92/1,626), 0.3% (1/330), and 1.2% (3/248), respectively. Odds ratios of advanced neoplasia in the 0.5- to 5-year colonoscopy group and > 5-year colonoscopy were 0.23 (95% confidence interval [CI]: 0.13-0.42) and 0.40 (95% CI: 0.24-0.68), respectively, in multivariate analysis. The odds ratios of invasive cancer in each aforementioned group were 0.05 (95% CI: 0.01-0.37) and 0.19 (95% CI: 0.06-0.61), respectively. CONCLUSION: Re-screening with the FIT should not be recommended for at least 5 years for average-risk patients after colonoscopy without high-risk neoplasms, because the risks of colorectal cancer are low in such patients.
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Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Detecção Precoce de Câncer/métodos , Fezes/química , Imunoquímica , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Japão/epidemiologia , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Estudos Prospectivos , Risco , Fatores de TempoRESUMO
AIM: To evaluate the virologic responses and clinical course of daclatasvir plus asunaprevir treatment in non-hemodialysis (non-HD) and hemodialysis (HD) patients infected with genotype 1 hepatitis C virus (HCV). METHODS: A total of 1113 non-HD patients and 67 HD patients were assessed. To evaluate pretreatment factors contributing to sustained virological response at 12 weeks (SVR12), univariate and multivariate analyses were carried out. To adjust for differences in patient background, propensity score matching was undertaken. RESULTS: The overall SVR12 rates were 91.6% in non-HD patients and 95.5% in HD patients. Compared with non-HD patients, HD patients were younger, were more likely to be male, were less likely to have received interferon-based pretreatment, had a lower viral load, and had lower levels of alanine transaminase, hemoglobin, and α-fetoprotein. Multivariate analysis revealed that viral load, α-fetoprotein, L31 substitution negative, and Y93 substitution negative were independent predictive factors for SVR12 in non-HD patients. The proportion of patients with undetectable HCV-RNA during the initial 4 weeks was significantly higher in HD patients than in non-HD patients. The SVR12 rate was clearly higher in HD patients than in non-HD patients, although the difference was not statistically significant. After propensity score matching to adjust for viral load, α-fetoprotein, L31 substitution, and Y93 substitution, these trends disappeared. CONCLUSIONS: For treatment of HCV genotype 1 infection, daclatasvir plus asunaprevir is useful not only in non-HD patients but also in HD patients. Viral load, α-fetoprotein levels, L31 substitution, and Y93 substitution influence treatment course and outcome.
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BACKGROUND AND AIM: The significance of examination time of esophagogastroduodenoscopy (EGD) for asymptomatic examinees is yet to be established. We aimed to clarify whether endoscopists who allot more examination time can detect higher numbers of neoplastic lesions among asymptomatic examinees. METHODS: We reviewed a database of consecutive examinees who underwent EGD in our hospital from April 2010 to September 2015. Staff endoscopists were classified into fast, moderate, and slow groups based on the mean examination time of EGD without a biopsy. Neoplastic lesion detection rate among these groups was compared using multiple logistic regression. RESULTS: Of the 55 786 consecutive examinees who underwent EGD, 15 763 asymptomatic examinees who were screened by staff doctors were analyzed. Mean examination time of 13 661 EGD without biopsy was 6.2 min (range, 2-18 min). When cut-off times of 5 and 7 min were used, four endoscopists were classified into the fast (mean duration, 4.4 ± 1.0 min), 12 into the moderate (6.1 ± 1.4 min), and four into the slow (7.8 ± 1.9 min) groups. Neoplastic lesion detection rates in the fast, moderate, and slow groups were 0.57% (13/2288), 0.97% (99/10 180), and 0.94% (31/3295), respectively. Compared with that in the fast group, odds ratios for the neoplastic lesion detection rate in the moderate and slow groups were 1.90 (95% confidence interval [CI], 1.06-3.40) and 1.89 (95% CI, 0.98-3.64), respectively. CONCLUSION: Endoscopists who do not allot adequate examination time may overlook neoplastic lesions in the upper gastrointestinal tract.
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Endoscopia Gastrointestinal , Neoplasias Gastrointestinais/diagnóstico por imagem , Indicadores de Qualidade em Assistência à Saúde , Trato Gastrointestinal Superior , Idoso , Doenças Assintomáticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Físico , Estudos Retrospectivos , Fatores de TempoRESUMO
A 78-year-old man with hypertension, nephrosclerosis, and angina pectoris visited his family doctor with a history of fatigue and leg edema. He had a history of percutaneous coronary intervention 5 years prior, and was taking low-dose aspirin. Blood tests revealed hypoalbuminemia, gastrointestinal 99mTc-HSA scintigraphy was positive, and alpha-1 antitrypsin clearance was high;therefore, the hypoalbuminemia was thought to be secondary to a protein-losing enteropathy. A small bowel series revealed multiple, ring-shaped, longitudinal ulcers in the ileum. Balloon-assisted enteroscopy from the anus showed severe stenosis with an ileal ulcer. Since we were not able to diagnose the ulcers, mesalazine and supplemental nutritional care were provided. Four years after the hypoalbuminemia had been diagnosed, the patient died because of pulmonary congestion secondary to renal failure. An autopsy revealed severe atherosclerosis in his aorta and multiple cholesterol embolisms in his small intestine, kidney, stomach, colon, liver, and spleen. The multiple ulcers in the small intestine were thought to be caused by cholesterol crystal embolism, which should be considered in the differential diagnosis of small intestinal ulcers in elderly men or patients after cardiovascular intervention.
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Embolia de Colesterol/etiologia , Intestino Delgado/diagnóstico por imagem , Enteropatias Perdedoras de Proteínas/complicações , Úlcera/etiologia , Idoso , Embolia de Colesterol/diagnóstico por imagem , Humanos , Masculino , Enteropatias Perdedoras de Proteínas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Úlcera/diagnóstico por imagemRESUMO
Background and aim: In patients with chronic hepatitis C, 8 weeks of glecaprevir and pibrentasvir (GLE/PIB) treatment for chronic hepatitis (non-cirrhosis) and 12 weeks for cirrhosis have been approved in Japan. However, whether 8 weeks of treatment for cirrhosis may reduce treatment efficacy has not been adequately investigated. Methods: This prospective, nationwide, multicenter cohort study enrolled 1275 patients with chronic hepatitis C who received GLE/PIB therapy. The effect of liver fibrosis and treatment periods on the efficiency of GLE/PIB therapy was investigated. The primary endpoint was the sustained virological response (SVR) rate in patients with chronic hepatitis (non-cirrhosis) and cirrhosis. The association between treatment periods and liver fibrosis on the SVR after 12 weeks of treatment rate was investigated. Results: The SVR rates in patients with chronic hepatitis with 8 weeks of treatment, chronic hepatitis with 12 weeks of treatment, cirrhosis with 8 weeks of treatment, and cirrhosis with 12 weeks of treatment were 98.9% (800/809), 100% (87/87), 100% (166/166), and 99.1% (211/213), respectively, and were was not different among these groups (P = 0.4). Conclusion: GLE/PIB therapy for chronic hepatitis C had high efficacy regardless of liver fibrosis status and treatment periods. Periods of GLE/PIB therapy could be chosen with available modalities, and high SVR rates could be achieved regardless of the decision.
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We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions' longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child-Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC.
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BACKGROUND: Factors associated with response to lenvatinib have not been clarified in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This study retrospectively analyzed 50 patients treated with lenvatinib as first-line therapy between March 2018 and March 2019. Patients were divided into two groups by the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) (responders and non-responders, whose best overall responses were complete (CR)/partial response (PR) and stable (SD)/progressive disease (PD), respectively). Factors associated with response were assessed, including the relative dose intensity 8 weeks after lenvatinib induction (8W-RDI). RESULTS: The best overall responses were 0/22/14/14 of CR/PR/SD/PD. Multivariate analysis revealed that only 8W-RDI was significantly associated with response. The receiver operating characteristic curve for 8W-RDI in differentiating responders from non-responders revealed a cut-off value of 75%. Patients with 8W-RDI ≥75% experienced a higher response rate and longer progression-free survival than patients with 8W-RDI <75%. CONCLUSION: Our results suggest that maintaining an RDI ≥75% during the initial 8 weeks of lenvatinib treatment has a favorable impact on response.
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Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Curva ROC , Estudos Retrospectivos , Resultado do TratamentoRESUMO
A 55-year-old Japanese woman was hospitalized because liver function tests showed an abnormality. Transaminases and biliary enzymes were markedly elevated with hyperferritinemia. Her imaging tests revealed no significant abnormality. She had been taking various non-prescription supplements for over approximately 6 months. After the supplements were discontinued her liver function gradually improved. This clinical course was suggestive of supplement-induced hepatitis. She had no history of taking supplements containing iron, so it was interesting that she had hyperferritinemia. We examined C282Y and H63D, which are important mutations in theiron-metabolizing gene, HFE. She was found to be heterozygous for the H63D mutation. The interaction between hyperferritinemia and supplements is unknown, but it can be speculated that some interaction between iron overload and supplements may have underlain the pathogenesis of her liver injury.
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BACKGROUND: Underwater endoscopic mucosal resection (U-EMR) has emerged as an alternative technique for the resection of colorectal lesions. This study aimed to evaluate our initial experience using U-EMR. METHODS: This is a single-center, retrospective case series study. We analyzed the clinical outcomes of consecutive patients who underwent U-EMR in our endoscopy center, from December 2015 to February 2017. RESULTS: Our analysis included 64 lesions, contributed by 38 patients, with a mean age of 68.6 years (range, 25 to 90 years). The study sample included 33 right-sided and 25 left-sided colon lesions, and seven rectal lesions, with an average size of 16.2 mm (6 - 40 mm). Of these, 46 lesions were polypoid and 18 ones non-polypoid. Histologically, 31 lesions were low-grade adenomas, eight ones were high-grade adenomas, 11 were mucosal cancers, four were submucosal cancers, and 10 were classified as "others". En bloc resection was achieved in 52 (81%) lesions, with an en bloc resection rate of 95% for lesions < 20 mm and 55% for lesions ≥ 20 mm. Complete resection of neoplastic epithelial lesions, defined by a negative pathological margin, was achieved in 32 of 59 neoplastic epithelial lesions (54%). We identified three cases (5%) of post-procedural bleeding and one case of perforation (2%). CONCLUSIONS: U-EMR can be feasibly used for resection of colonic lesions, including lesions ≥ 20 mm, although the en bloc resection rate for these lesions was lower than for lesions < 20 mm.
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During endotoxic liver injury, large numbers of neutrophils infiltrate the liver, and serum levels of tumor necrosis factor-alpha (TNF-alpha) become elevated. The object of this study was to assess the roles of TNF-alpha secreted by Kupffer cells in the interaction between neutrophils and sinusoidal endothelial cells (SECs). Rat neutrophils were perfused onto SECs that were stimulated with either TNF-alpha or supernatant from lipopolysaccharide (LPS)-stimulated Kupffer cells using an in vitro flow system. Numbers of adhered or migrated neutrophils were counted, and the effect of an antibody against intercellular adhesion molecule-1 (ICAM-1) was studied. Compared with controls (200 +/- 21 cells/mm2), neutrophil adhesion to SECs was significantly increased by both TNF-alpha (342 +/- 26 cells/mm2; P < 0.05) and LPS-stimulated Kupffer cell supernatant (331 +/- 29 cells/mm2; P < 0.05). Anti-ICAM-1 significantly inhibited neutrophil adhesion (139 +/- 10 cells/mm2; P < 0.05) and decreased the migration rate of neutrophils on SECs treated with LPS-stimulated Kupffer cell supernatant (P < 0.05). LPS-stimulated Kupffer cells secreted TNF-alpha in an LPS dose-dependent manner, and they significantly enhanced ICAM-1 expression on SECs (P < 0.05 vs. control). In addition, dexamethasone suppressed TNF-alpha production by LPS-stimulated Kupffer cells and decreased ICAM-1 expression and neutrophil adhesion on SECs. These findings suggest that Kupffer cells are involved in neutrophil adhesion and migration in hepatic sinusoids via TNF-alpha production and induction of ICAM-1 expression on SECs during liver injury associated with endotoxemia.
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Dexametasona/farmacologia , Endotoxemia/fisiopatologia , Molécula 1 de Adesão Intercelular/metabolismo , Células de Kupffer/fisiologia , Lipopolissacarídeos/farmacologia , Neutrófilos/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Adesão Celular , Células Cultivadas , Modelos Animais de Doenças , Interações Medicamentosas , Endotélio Vascular/citologia , Endotoxemia/etiologia , Ensaio de Imunoadsorção Enzimática , Molécula 1 de Adesão Intercelular/análise , Células de Kupffer/efeitos dos fármacos , Masculino , Neutrófilos/metabolismo , Probabilidade , Ratos , Ratos Wistar , Valores de Referência , Sensibilidade e Especificidade , Fator de Necrose Tumoral alfa/análiseRESUMO
BACKGROUND: This study was carried out to clarify differences in clinical characteristics between fatty liver and nonalcoholic steatohepatitis in a Japanese population, and to assess the significance of GB virus C (GBV-C) infection, SEN virus (SENV) infection, and HFE gene mutation in the pathophysiology of these conditions. METHODS: Twenty patients with nonalcoholic steatohepatitis and 18 patients with simple steatosis were enrolled, and their clinical characteristics and histological findings were compared. Detection of GBV-C RNA and SENV DNA was performed by polymerase chain reaction (PCR). Mutational analysis of the HFE gene was performed by PCR-restriction fragment length polymorphism (RFLP). RESULTS: Serum aspartate aminotransferase (AST) and ferritin were significantly higher ( P < 0.05, for both) in NASH than in simple steatosis, and serum total cholesterol (T-Chol) was significantly lower ( P < 0.05) in NASH than in simple steatosis. While GBV-C was detectable in the serum of only one patient with NASH, SENV was detected in 50% (15/30) of the patients whose sera were tested for this virus, but the prevalence was not significantly different between the two groups (42% [8/19] in simple steatosis and 64% [7/11] in NASH). The sex ratio, body mass index (BMI), and age were not significantly different between the two groups, and mutation in the HFE gene was not detected in any patient. CONCLUSIONS: Higher serum AST and ferritin, and lower serum T-Chol are distinctive features in NASH when compared with simple steatosis. GBV-C infection, SENV infection, and HFE gene mutation were not considered to influence the development of NASH from simple fatty liver.
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Vírus de DNA/isolamento & purificação , Fígado Gorduroso/virologia , Vírus GB C/isolamento & purificação , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana/genética , Mutação , Adulto , Aspartato Aminotransferases/sangue , Colesterol/sangue , Infecções por Vírus de DNA/diagnóstico , Fígado Gorduroso/sangue , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Ferritinas/sangue , Infecções por Flaviviridae/diagnóstico , Proteína da Hemocromatose , Hepatite Viral Humana/diagnóstico , Humanos , Japão , Fígado/patologia , Masculino , Pessoa de Meia-Idade , RNA Viral/análiseRESUMO
The development of hepatocellular carcinoma (HCC) was significantly reduced in both sustained responders (SR) and transient biochemical responders (TR) in chronic hepatitis C (CH-C) patients who received interferon (IFN) therapy. However, the long-term clinical outcome of TR remains unclear. One thousand three hundred and seventy CH-C Japanese patients who received IFN therapy and 54 control cirrhotic patients were enrolled. TR were defined as those patients who showed a normal serum alanine aminotransferase level (<==30 IU/l) at the end of therapy and then relapsed. Mean follow-up period was 5.6 years (6.1 years in 48 cirrhotic patients) in the IFN group and 8.3 years in the 54 control cirrhotic patients. HCC was detected in 114 patients in the IFN group among whom 4 were in the 425 SR, 21 were in the 359 TR and 89 were in the 586 non-responders (NR). The cumulative incidence of HCC was significantly (P=0.0001) inhibited in both SR and TR compared with NR. Its inhibitory effect in TR was within 5 years. Platelet count did not significantly decrease for 2-4 years after IFN therapy in TR, but it significantly decreased in NR 2 years after IFN therapy. The cumulative survival in both SR and TR was significantly higher than NR (SR vs NR; P=0.0001, TR vs NR; P=0.0305). These results indicate that IFN therapy lowers the rate of the progression of HCC and improves the long-term survival even in CH-C patients who transiently respond to IFN therapy.
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BACKGROUND/AIMS: To examine whether or not activated Kupffer cells play an important role in intra-hepatic Th1-associated necro-inflammation in Concanavalin A (Con A)-induced hepatic injury in mice. METHODS: Con A was administered to Balb/c mice pretreated with or without gadolinium chloride (GdCl(3)). Kupffer cell activation was evaluated by their ability to produce superoxide anions in situ under liver perfusion with nitro blue tetrazolium (NBT). Hepatic concentration of cytokines was measured by ELISA and the mRNA expression of CXC chemokine receptor 3 (CXCR3) was evaluated by RT-PCR. Immunohistochemical detection of CD4 positive lymphocytes in the liver was also performed. RESULTS: GdCl(3)-pretreatment significantly (P<0.01) reduced the serum levels of alanine aminotransferase (ALT) in Con A-treated mice. Formazan deposition in Kupffer cells, the hepatic concentration of tumor necrosis factor-alpha and interferon-gamma, the mRNA expression of CXCR3 and the CD4 positive lymphocytes in the liver were decreased in GdCl(3)-pretreated mice as compared with those without GdCl(3)-pretreatment (P<0.05, respectively). CONCLUSIONS: Activated Kupffer cells, which produce superoxide anions, are involved in Con A-induced hepatic necro-inflammation in mice possibly through the activation of Th1-associated immune response mediated by CD4 and/or CXCR3 positive cells recruited into the liver.
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AIM: It is reasonable to assume that microchimerism could also be involved in the induction of primary biliary cirrhosis (PBC). However, previous reports investigated only fetus-microchimerism in women patients. Maternal microchimerism has not been investigated until now. The current study aimed to clear either maternal microchimerism was involved in the pathogenesis of PBC or not. METHODS: We used fluorescence in situ hybridization on paraffin-embedded tissue (We called "Tissue-FISH".) to determine whether maternal cells infiltrated in male patients who were diagnosed as having PBC. Tissue-FISH was performed by using both X and Y specific probes on the biopsy liver sample of 3 male PBC patients. RESULTS: Infiltrating lymphocytes demonstrated both X and Y signals in all 3 male patients. CONCLUSION: Maternal microchimerism dose not play a significant role in PBC. PBC may not relate to fetus and maternal microchimerism.
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Quimera/genética , Cirrose Hepática Biliar/genética , Quimera/sangue , Cromossomos Humanos X , Cromossomos Humanos Y , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucócitos/fisiologia , Fígado/patologia , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/patologia , Linfócitos/patologia , MasculinoRESUMO
Oxidative stress is a major pathogenetic factor in hepatic fibrosis. Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor which is known to affect oxidative stress and PPARalpha ligands may have rescue effects on hepatic fibrosis. We tested this hypothesis using rat thioacetamide (TAA) models of liver cirrhosis. Rats were given intraperitoneal injection of TAA and treated with a diet containing one of the two PPARalpha ligands, Wy-14,643 (WY) or fenofibrate. WY treatment dramatically reduced hepatic fibrosis and also prevented the inhibition catalase of mRNA expression caused by TAA. Correspondingly, catalase activity increased in the TAA+WY group but decreased in the control TAA group. The antifibrotic action of fenofibrate in the TAA model was comparable with that of WY. PPARalpha ligands have an antifibrotic action in the rat TAA model of liver cirrhosis, probably due to an antioxidant effect of enhanced catalase expression and activity in the liver.
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Antioxidantes/metabolismo , Fibrose , Fígado/patologia , PPAR alfa/metabolismo , Animais , Antioxidantes/farmacologia , Northern Blotting , Catalase/metabolismo , Densitometria , Fenofibrato/farmacologia , Fibrose/patologia , Peróxido de Hidrogênio/farmacologia , Ligantes , Fígado/metabolismo , Cirrose Hepática , Masculino , Modelos Biológicos , Estresse Oxidativo , Proliferadores de Peroxissomos/farmacologia , Pirimidinas/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/metabolismo , Tioacetamida/farmacologiaRESUMO
BACKGROUND/AIMS: The emergence of lamivudine-resistant hepatitis B virus (HBV) was reported in patients with prolonged lamivudine administration. There was no report of the existence of tyrosine-methionine-aspartate-aspartate (YMDD) mutant in non-lamivudine treated chronic hepatitis B patients. In the present study, we developed a sensitive assay and applied it to the detection of YMDD mutant. METHODS: We developed peptide nucleic acid (PNA) mediated polymerase chain reaction clamping for detecting mutations in a YMDD motif of the hepatitis B virus DNA polymerase gene. We studied YMDD mutants in a patient with HBV DNA breakthrough longitudinally and in non-lamivudine treated patients (36 patients). RESULTS: We could detect as little as 0.01-0.001% of mutant viruses coexisting in 10(5)-10(9) copies of wild-type viruses using this assay. YMDD mutant was detected 7 months before clinical breakthrough, which was 6 months earlier than using the conventional restriction fragment length polymorphism assay. YMDD mutants were also detected in four of 18 anti-HBe antibody positive untreated chronic hepatitis type B: YMDD+tyrosine-valine-aspartate-aspartate (YVDD) in two patients and YMDD+tyrosine-isoleucine-aspartate-aspartate (YIDD) in two patients, however, none in HBe antigen positive patients. CONCLUSIONS: We developed a highly sensitive assay for detecting YMDD mutants. This is an effective procedure for monitoring patients during or before lamivudine treatment and can provide more insights into the therapeutic strategies for chronic hepatitis B patients.