RESUMEN
OBJECTIVES: Liver transplantation remains the only curative therapy for decompensated liver cirrhosis. However, it has several limitations, and not all patients can receive liver transplants. Therefore, liver regenerative therapy without liver transplantation is considered necessary. In this study, we attempted minimally invasive liver regenerative therapy by peripheral vein infusion of bone marrow-derived mesenchymal stem cells (BMSCs) cultured from a small amount of autologous bone marrow fluid and evaluated the effects of BMSCs on hepatocarcinogenesis in a mouse model. METHODS: C57BL/6 male mice were injected intraperitoneally with N-nitrosodiethylamine once at 2 weeks of age, followed by carbon tetrachloride twice a week from 6 weeks of age onwards, to create a mouse model of highly oncogenic liver cirrhosis. From 10 weeks of age, mouse isogenic green fluorescent protein-positive BMSCs (1.0 × 106/body weight) were infused once every 2 weeks, for a total of 5 times, and the effects of frequent BMSC infusion on hepatocarcinogenesis were evaluated. RESULTS: In the histologic evaluation, no significant differences were observed between the controls and BMSC-administered mice in terms of incidence rate, number, or average size of foci and tumors. However, significant suppression of fibrosis and liver injury was confirmed in the group that received BMSC infusions. DISCUSSION: Considering that BMSC infusion did not promote carcinogenesis, even in the state of highly oncogenic liver cirrhosis, autologous BMSC infusion might be a safe and effective therapy for human decompensated liver cirrhosis.
Asunto(s)
Trasplante de Médula Ósea/métodos , Cirrosis Hepática/cirugía , Neoplasias Hepáticas Experimentales/prevención & control , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Animales , Carcinogénesis , Células Cultivadas , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Neoplasias Hepáticas Experimentales/etiología , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various noninvasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 to January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.(AU)
Asunto(s)
Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Vitamina E/uso terapéutico , Trasplante de Hígado , Tiazolidinedionas/uso terapéutico , Cirugía BariátricaRESUMEN
OBJECTIVE: To evaluate the CT enteroclysis (CTE)/enterography findings of patients with small-bowel mucosal damage induced by aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) and to compare these findings with the duration of drug use and endoscopic findings. METHODS: CTE findings of 11 patients (22 lesions) with drug-induced small-bowel damage were reviewed, including 8 NSAID users and 3 aspirin users. Three patients were short-term users (6 months or shorter) and eight were long-term users (3 years or longer). Nine patients also underwent videocapsule endoscopy (VCE) or double-balloon enteroscopy (DBE). RESULTS: Small-bowel abnormalities were visible in 8 of 11 patients (73%) on CTE. Multiple lesions were seen in five patients, including all short-term users. Lesions were classified into three types. Type 1 (mucosal patchy enhancement) was found in four of eight patients (50%, 12 lesions) all were short-term users. Small erosions with mild oedema/redness were shown by DBE. Type 2 (homogeneous hyperenhancement) was found in two of eight patients (25%, four lesions) who were long-term users. Large ulcers with marked oedema/redness were shown by DBE. Type 3 (stratification enhancement) was found in four of eight patients (50%, six lesions), both short-term and long-term users. Annular or large ulcers with strictures were shown by VCE or DBE. CONCLUSION: On CTE, Type 1 lesions in patients with mostly short-term aspirin or NSAID use, Type 2 lesions in patients with long-term use and Type 3 lesions in both types of patients were detected. CTE may have usefulness for the detection of mild damage. ADVANCES IN KNOWLEDGE: Small-bowel abnormalities owing to aspirin or NSAID present with three different patterns on CTE.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Endoscopía Capsular/métodos , Enfermedades Intestinales/diagnóstico por imagen , Intestino Delgado/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Femenino , Humanos , Enfermedades Intestinales/inducido químicamente , Intestino Delgado/efectos de los fármacos , Masculino , Persona de Mediana Edad , Radiografía , Estudios RetrospectivosRESUMEN
OBJECTIVES: This study investigated the pharmacokinetic and pharmacodynamic profile of tolvaptan, and verified its efficacy and safety in patients with liver cirrhosis-associated ascites, with insufficient response to conventional diuretic treatment. METHODS: This multicentre, double-blind, parallel-group study allocated patients with cirrhosis to receive either 3.75 or 7.5 mg/day tolvaptan orally, once daily, for 7 days. Pharmacokinetic, pharmacodynamic and efficacy variables were measured. RESULTS: Tolvaptan was shown to have high plasma concentrations, and prolonged duration of maximum concentration and half life, in these patients with impaired hepatic function. Tolvaptan resulted in dose-dependent decreases in body weight and ascites volume, and increases in urine output. There were no effects on urinary or serum electrolytes. Tolvaptan was well tolerated, with a good safety profile. CONCLUSIONS: Tolvaptan at 3.75 mg/day exerts some effects due to the pharmacokinetic profile in patients with liver cirrhosis. Tolvaptan at 7.5 mg/day is a clinically useful option for treating patients who do not respond well to conventional diuretics.
Asunto(s)
Benzazepinas/farmacocinética , Benzazepinas/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de los Receptores de Hormonas Antidiuréticas , Ascitis/tratamiento farmacológico , Benzazepinas/farmacología , Diuréticos/uso terapéutico , Método Doble Ciego , Electrólitos/sangre , Electrólitos/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , TolvaptánRESUMEN
BACKGROUND/AIMS: Vascular endothelial growth factor plays an important role in angiogenesis and vascular endothelial growth factor-C is concerned with lymphangiogenesis. METHODOLOGY: The present study employed immunostaining to investigate the relationship between expression of these factors and clinicopathologic findings in 100 patients with esophageal cancer. RESULTS: Fifty-six of the 100 tumors (56%) showed expressed vascular endothelial growth factor and 43 tumors (43%) expressed of vascular endothelial growth factor-C. Expression of the latter was correlated with the depth of tumor invasion (p=0.0095), lymphatic invasion (p=0.0065), lymph node metastasis (p=0.0l34). The prognosis was significantly worse for patients with tumors positive for vascular endothelial growth factor-C than for those with negative tumors (p=0.036). In contrast, expression of vascular endothelial growth factor was not correlated with the prognosis. Microvessel density was significantly higher in tumors expressing vascular endothelial growth factor-C compared with negative tumors (p=0.0014). Stepwise multivariate analysis with Cox's proportional hazards model identified gender (p=0.0420), age (p=0.0192), vascular endothelial growth factor-C expression (p=0.0286), and lymphatic invasion (p=0.0030) as prognostic determinants. CONCLUSIONS: Expression of vascular endothelial growth factor-C is related to lymphatic invasion and is a prognostic indicator for esophageal cancer.
Asunto(s)
Neoplasias Esofágicas/química , Factor C de Crecimiento Endotelial Vascular/análisis , Anciano , Anciano de 80 o más Años , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
OBJECTIVE: We created and validated a Markov model to simulate the prognosis with treatment for HCV-related hepatocellular carcinoma (HCC) for assessment of cost-effectiveness for alternative treatments of HCC. METHOD: Markov state incorporated into the model consisted of the treatment as a surrogate for HCC stage and underlying liver function. Retrospective data of 793 patients from three university hospitals were used to determine Kaplan-Meier survival curves for each treatment and transition probabilities were derived from them. RESULTS: There was substantial overlap in the 95% CIs of the Markov model predicted and the Kaplan-Meier survival curves for each therapy. The predicted survival curves were also similar with those from the nationwide survey data supporting the external validity of our model. CONCLUSIONS: Our Markov model estimates for prognosis with HCC have both internal and external validity and should be considered applicable for estimating cost-effectiveness related to HCC.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Anciano , Carcinoma Hepatocelular/economía , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/fisiopatología , Intervalos de Confianza , Análisis Costo-Beneficio , Progresión de la Enfermedad , Femenino , Hepatitis C/complicaciones , Hepatitis C/economía , Hepatitis C/mortalidad , Humanos , Masculino , Cadenas de Markov , Persona de Mediana Edad , Modelos Estadísticos , Probabilidad , Pronóstico , Estudios Retrospectivos , SobrevidaRESUMEN
In a previous study, we showed that levels of cell-free DNA (cfDNA) were significantly higher in sera of patients with hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) than in sera of non-HCC patients with HCV. To confirm this finding, we analysed serum cfDNA levels in a cohort of 96 patients with HCV-related HCC and in 100 HCV carriers without known HCC. Again we found that serum cfDNA levels were significantly higher in HCC patients than in HCV carriers (115.9+/-98.3 vs 34.4+/-40.4 ng ml(-1) (mean+/-s.d.), P<0.0001). Of 87 eligible patients who underwent curative hepatectomy, those with a high cfDNA level had a significantly shorter overall survival (OS) time than those in whom the cfDNA level was not high. Cox proportional hazards model showed the cfDNA level to be an independent prognostic factor for OS and cancer recurrence in distant organs. Our results suggest that the serum cfDNA level reflects the metastatic potential of HCV-related HCC and that it can be a useful predictive biomarker for distant metastasis after curative surgery.
Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/secundario , ADN de Neoplasias/sangre , Hepatitis C/sangre , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/secundario , Anciano , Carcinoma Hepatocelular/virología , Femenino , Estudios de Seguimiento , Hepacivirus/aislamiento & purificación , Hepatitis C/complicaciones , Humanos , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Recurrencia , Tasa de SupervivenciaRESUMEN
BACKGROUND: With the development of endoscopic submucosal dissection, an expansion of the criteria for local treatment was suggested for lesions with ulcerous changes or undifferentiated-type adenocarcinoma. AIM OF THE STUDY: To determine the efficacy of endoscopic ultrasonography for such lesions, we retrospectively analyzed factors that influenced accurate diagnosis by endoscopic ultrasonography of the depth of tumor invasion. METHODS: We investigated 267 gastric adenocarcinomas for which histopathological results were obtained by endoscopic mucosal resection or gastrectomy. The lesions were divided into four groups by histological type and the presence of ulcerous changes. Five clinicopathological factors were assessed for their possible associations with incorrect diagnosis. RESULTS: The positive predictive value (PPV) for cancer limited within the mucosa (endoscopic ultrasonography, EUS-M) and cancer invaded into the submucosal layer (EUS-SM) were 88.0% (125 of 142 lesions) and 60.0% (30 of 50 lesions), respectively. The lesions diagnosed as EUS-M/SM borderline (37 lesions) included 19 lesions (51.4%) of M cancer and 17 lesions (45.9%) of SM cancer. In logistic analysis, ulcerous changes (p < 0.0001) and macroscopic classification (p = 0.0284) were factors that caused incorrect diagnosis by endoscopic ultrasonography. In the group having differentiated-type adenocarcinoma with ulcerous changes, the PPV of EUS-SM was 25% (3 of 12), and there was a significant difference (p < 0.05) between the EUS-SM of this group and that of the differentiated-type adenocarcinoma without ulcerous changes. CONCLUSION: The accuracy of endoscopic ultrasonography tumor staging was not sufficient for the lesions with ulcerous changes in our study. Therefore, we should be careful to perform endoscopic submucosal dissection for lesions with ulcerous changes.
Asunto(s)
Adenocarcinoma/diagnóstico por imagen , Diagnóstico Diferencial , Endosonografía , Neoplasias Gástricas/diagnóstico por imagen , Úlcera Gástrica/diagnóstico por imagen , Adenocarcinoma/patología , Mucosa Gástrica/diagnóstico por imagen , Mucosa Gástrica/patología , Humanos , Invasividad Neoplásica , Estadificación de Neoplasias , Estudios Retrospectivos , Estómago/diagnóstico por imagen , Estómago/patología , Estómago/cirugía , Neoplasias Gástricas/patología , Úlcera Gástrica/complicacionesRESUMEN
The mechanism by which Hepatitis C virus(HCV) infection promotes the development of hepatocellular carcinoma(HCC) is not known exactly. HCV related HCC occurs frequency in the patients with cirrhosis. There have been reports indicating that Th2-type cytokines down-regulated antitumor immunity, and the activation of type 1 T cell responses produced antitumor immunity. We thought Th1/Th2 imbalance in HCV-related liver cirrhosis might be closely related to the development of HCC. In this study, therefore, we investigated the Th1/Th2 balance at the single lymphocyte level of the patients with HCV-related liver cirrhosis and compared with normal controls by using flow cytometry. Th1-type cytokines(IFN-gamma, IL-2) production was significantly decreased in patients with cirrhosis, whereas Th2-type cytokine production(IL-10) was increased. These suggest Th1/Th2 imbalance in HCV-related cirrhosis would decrease the antitumor immunity and its improvement might present the protective effect from HCC.
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Carcinoma Hepatocelular/inmunología , Hepacivirus , Cirrosis Hepática/inmunología , Cirrosis Hepática/virología , Neoplasias Hepáticas/inmunología , Células TH1/inmunología , Células Th2/inmunología , Carcinoma Hepatocelular/virología , Citocinas/metabolismo , Humanos , Neoplasias Hepáticas/virologíaRESUMEN
PURPOSE: Alterations in the kinetics of hepatic stellate cells (HSCs) after the cells are activated once have not been well documented. We investigated the characteristic profiles of cell proliferation of once-activated HSCs in contrast to the in fibrogenesis activity. METHODS: HSCs from male Wistar rats were submitted to primary culture for 14 days and to secondary culture for 7 days. The potential for cell proliferation was evaluated by the number of the cells in G2/M phase, based on flow cytometric analysis of the cell cycle. The fibrogenesis activity was assessed by Northern blot analysis of the expression of type I and type III procollagen mRNA. RESULTS: The number of HSCs in G2/M phase was maintained at a low level in primary culture after 6 days, while a significantly (P < 0.05) elevated number of HSCs in G2/M phase was observed on days 3 to 4. In secondary culture, the number of HSCs in G2/M phase was also consecutively maintained at a decreased level. By contrast, HSCs showed progressively increased type I and type III procollagen mRNA expression during the experimental periods of primary culture. CONCLUSIONS: These results clearly demonstrated consecutively decreased proliferative activity, evaluated by the potential for cell mitogenesis, in once-activated HSCs, in contrast to their progressively increased fibrogenesis activity.
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Hepatocitos/citología , Interfase/fisiología , Animales , División Celular/genética , ADN/análisis , Citometría de Flujo , Japón , Cirrosis Hepática/patología , Masculino , Procolágeno/análisis , ARN Mensajero/análisis , Ratas , Ratas Wistar , Fase S/fisiologíaRESUMEN
Fulminant hepatic failure (FHF) usually has a fatal prognosis without liver transplantation. We describe the case of a woman who developed FHF, and was evaluated as a candidate for liver transplantation, but who was cured without transplantation through intensive medical care that included glucagon-insulin therapy, methylprednisolone pulse therapy, interferon beta and lamivudine administration, cyclosporine administration, and high-volume hemodiafiltration and plasma exchange. In a patient with FHF who is a candidate for liver transplantation but for whom the transplantation cannot be performed for some reason, intensive medical therapy, including regeneration-promoting therapy, immunosuppressive therapy, antiviral therapy, and vigorous hepatic support, should be carried out.
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Antivirales/uso terapéutico , Hepatitis B/complicaciones , Fallo Hepático/terapia , Ciclosporina/uso terapéutico , Femenino , Hemodiafiltración/métodos , Humanos , Interferón beta/uso terapéutico , Fallo Hepático/diagnóstico , Fallo Hepático/virología , Trasplante de Hígado , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Intercambio Plasmático/métodosRESUMEN
The aim of this study was to investigate the association of stellate cell activation with serum fibrosis markers in a rat model of hepatic fibrosis prepared using a choline-deficient L-amino acid (CDAA) defined diet. CDAA diet administration resulted in increased liver hydroxyproline contents in a time-dependent manner with activated stellate cells, expressing alpha-smooth muscle actin (alpha-SMA) as well as increased serum concentrations of amino-terminal procollagen type III peptide (PIIIP) and the 7S fragment of type IV collagen. Hydroxyproline content of the liver showed a closer correlation with the serum 7S (r = 0.75, P < 0.01) concentration than with the serum PIIIP (r = 0.51, P < 0.01) concentration. The percent area of alpha-SMA-positive cells showed stronger correlation with the serum PIIIP concentration (r = 0.85, P < 0.01) than with the 7S concentration (r = 0.50, P < 0.01). These results indicate that the serum PIIIP concentration reflects the activity of fibrogenesis, while the serum 7S concentration reflects the accumulation of collagen fibers in the liver.
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Deficiencia de Colina/patología , Colágeno/sangre , Cirrosis Hepática Experimental/patología , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Animales , Hígado/patología , Masculino , Ratas , Ratas WistarRESUMEN
The aim of the study was to investigate the effect of the immunosuppressant FK 506 (tacrolimus hydrate) on acute liver injury induced by Propionibacterium acnes and lipopolysaccharide (LPS). Acute liver injury was induced in male Wistar rats by injecting the animals with P. acnes (10 mg/rat), and administering LPS (10 microg/rat) seven days later. One group was given FK 506 (1 mg/kg) 24 and 2 hr before administration of LPS, and the other group was given the same dose of saline. The 24-hr survival rate, serum alanine aminotransferase (ALT) concentration, and tumor necrosis factor (TNF) -alpha mRNA and protein concentrations in the liver and spleen were then compared. Hepatic macrophages were also isolated from rats seven days after P. acnes injection, LPS, and FK 506 or saline were added to the culture supernatant, and TNF-alpha production was studied. The 24-hr survival rate was 100% in the FK 506-treated group, in contrast with 16.6% in the saline group. Four hours after LPS injection, the serum ALT concentration was 755 +/- 401 in the saline group versus 119 +/- 42 units/ml (P < 0.01) in the FK 506-treated group. The serum TNF-alpha concentration was lower in the FK 506-treated group (1,419 +/- 957 pg/ml) than in the saline group (9205 +/- 2215) (P < 0.01). The mRNA and protein concentrations in the liver and spleen in the two groups did not differ significantly 1 hr after LPS injection but were significantly lower in the FK 506-treated group after 4 hr. FK 506 did not directly inhibit TNF-alpha production by isolated cultured hepatic macrophages. FK 506 is unable to inhibit initial TNF-alpha production by hepatic macrophages (or probably that by splenic macrophages either) stimulated by injection of LPS in P. acnes + LPS-induced acute liver injury. However, the immunosuppressant does limit hepatic damage by inhibiting subsequent aggravation of inflammation by the cytokine network.
Asunto(s)
Hepatitis Autoinmune/inmunología , Inmunosupresores/farmacología , Fallo Hepático Agudo/inmunología , Tacrolimus/farmacología , Alanina Transaminasa/sangre , Animales , Hepatitis Autoinmune/patología , Lipopolisacáridos/inmunología , Hígado/inmunología , Hígado/patología , Fallo Hepático Agudo/patología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Propionibacterium acnes/inmunología , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Injection of pig serum into rats twice a week for eight weeks induced transforming growth factor-beta1 (TGF-beta1) mRNA expression and protein production resulting in liver fibrosis without parenchymal cell injury. Eight-week treatment with pig serum reduced bromodeoxyuridine (BrdU) -positive hepatocytes 24 hr after 70% partial hepatectomy compared to that in the livers of rats treated with saline for eight weeks. Administration of a choline-deficient L-amino acid-defined (CDAA) diet for six weeks with pig serum coadministration, after pretreatment with pig serum for eight weeks, led to the development of preneoplastic lesions that were positive for the placental form of glutathione S-transferase (GSTP). Eight-week pretreatment with pig serum induced more GSTP-positive lesions and TGF-beta1 mRNA expression and protein concentration in the livers of rats subsequently fed a CDAA diet for six weeks than in rats fed the CDAA diet with saline treatment. These results indicate that TGF-beta1 induced by pig serum treatment inhibited hepatocyte proliferation but failed to prevent the development of preneoplastic lesions in a CDAA diet model.