RESUMO
Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.
Assuntos
Ácidos Cólicos/administração & dosagem , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estearoil-CoA Dessaturase/genética , Alanina Transaminase , Biópsia , Ácidos Cólicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismoRESUMO
Serum bile acids (SBAs) are commonly elevated in cholestatic liver diseases, but it is unclear if SBA levels are also elevated in noncholestatic chronic liver diseases and whether those levels correlate with disease severity. We analysed SBA levels of 135 consecutive patients with chronic hepatitis C virus infection and correlated these levels with the degree of liver fibrosis as determined by liver biopsy. In addition, we assessed the accuracy of SBA levels as a noninvasive predictor for liver fibrosis by its comparison to the patients' FibroTest scores. Two-thirds (90/135 patients, 67%) of the study patients had nonsevere liver fibrosis (Metavir F0-F2), and the others (45/135, 33%) had severe fibrosis or cirrhosis (Metavir F3-F4). The SBA levels were significantly higher in patients with severe fibrosis as compared to nonsevere fibrosis (11.46 ± 10.01 vs 6.37 ± 4.69, P < 0.0001). Furthermore, a receiver operator characteristics curve based on a model that included serum bile acids, age, body mass index, serum AST, glucose and cholesterol levels suggested that this combination reliably predicts the degree of liver fibrosis and is not inferior to the current noninvasive FibroTest score (areas under the curve of 0.837 vs 0.83, respectively, P = 0.87). We conclude that measurement of SBA levels may have a clinical role as a simple noninvasive tool to assess the severity of HCV-induced liver disease. Combined with widely available laboratory parameters, SBA levels can predict disease severity with a high degree of accuracy.
Assuntos
Ácidos e Sais Biliares/sangue , Hepatite C Crônica/sangue , Cirrose Hepática/sangue , Adulto , Algoritmos , Biomarcadores/sangue , Feminino , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Curva ROC , Índice de Gravidade de DoençaRESUMO
Skin cancer incidence has been shown to be increased in the context of transplant-associated immunosuppression. There is, however, limited information specifically about the incidence of skin cancer after cardiac transplantation in the United States. A 10-year retrospective cohort study of 6271 heart transplants at 32 US transplant centers revealed increased postprocedure incidence of nonmelanoma and melanoma skin cancers, especially cutaneous squamous cell carcinoma, for which the incidence increased from 4- to 30-fold compared to the age and gender equivalent general population. Incidence of skin cancer in this study was consistent with prior single-center data regarding cardiac transplant patients. Comparison of all-cause mortality statistics for patients with basal cell carcinoma, squamous cell carcinoma and melanoma, respectively, demonstrated increased mortality associated with melanoma. Skin cancer screening and prophylaxis may be of some utility in reducing morbidity and mortality in cardiac transplant patients.
Assuntos
Transplante de Coração/efeitos adversos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/epidemiologia , Carcinoma Basocelular/mortalidade , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/mortalidade , Estudos de Coortes , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Melanoma/epidemiologia , Melanoma/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Non-invasive modalities to estimate fibrosis stage are desirable in hepatitis C-infected haemophilia patients. Previous studies found a high rate of significant fibrosis both by Fibrotest (FT) and Fibroscan (FS) in these patients. To estimate liver fibrosis and to assess the concordance between FT and FS in hepatitis C-infected haemophilia patients. FT and FS were performed at different laboratories and were unaware of the results of the alternative test. Three successive liver stiffness measurements (LSM) were performed at different sites on the liver. Two-validated algorithms were used to improve evaluation of fibrosis by non-invasive methods. Fifty-seven hepatitis C-infected haemophilia patients were evaluated by FT and FS. Acquisition of LSMs was not feasible in two patients: obesity--one, surgical scars--one. Fibrosis stage > or=F2, > or =F3 or =F4 were estimated in about a half, about a third and in 15-20% of the evaluated patients by FS and FT respectively. The corresponding concordance rates and kappa score for fibrosis stage > or =F2, > or =F3 or =F4 between FT and FS were 62%, 69%, 85% and 0.24, 0.32, 0.44 respectively. Using the two aforementioned algorithms, additional 14 patients could be reliably estimated for fibrosis stage > or =F2. High proportion hepatitis C-infected haemophilia patients were estimated with significant or advanced stages of liver fibrosis using both tests. Nevertheless, the agreement between modalities was only fair and improved with more advanced stages of fibrosis. Practical algorithms for the accuracy of FT and FS may improve reliable evaluation of fibrosis in this population.
Assuntos
Hemofilia A/complicações , Hepatite C/complicações , Cirrose Hepática/diagnóstico , Adolescente , Adulto , Idoso , Algoritmos , Biópsia , Elasticidade , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND/AIMS: Despite its being considered a primary mitogen for hepatocytes, triiodothyronine (T3) has no effect on the proliferation of hepatocytes in vitro, and in our studies, induces significant in vivo hepatocyte proliferation only during liver injury. We hypothesized that T3 may affect hepatocytes proliferation indirectly, by inducing other cells in the liver to secrete hepatic mitogens. METHODS: In vivo studies: Lipopolysaccharide, T3 and a combination of the two were injected into rats, and hepatocyte proliferation was determined by PCNA staining and mitotic index. IN VITRO STUDIES: a rat hepatic stellate cell line (HSC-6T) was cultured with T3, IL-6 and a combination of the two, and we assessed the effect of these cytokine/hormone combinations on the cell proliferation and on secretion of IL-6 and HGF, measured by ELISA. Expression of thyroid hormone receptors was assessed by RT-PCR. RESULTS: In vivo: T3, together with lipopolysaccharide, enhances PCNA staining and the mitotic index of hepatocytes in the treated rats. In vitro: the hepatic stellate cell line expresses thyroid hormone receptor alpha 1, but not beta 1. Proliferation of stellate cells is not affected by T3, with or without IL-6. T3 has no effect on secreted levels of IL-6 in the stellate cell line. Hepatic stellate cells cultured with T3 and IL-6 show significantly increased amounts of secreted HGF after 48 h in culture. CONCLUSION: T3 may induce hepatocyte proliferation in vivo during injury by turning on expression of HGF in stellate cells and acting together with IL-6.
Assuntos
Divisão Celular/genética , Substâncias de Crescimento/metabolismo , Fator de Crescimento de Hepatócito/biossíntese , Hepatócitos/efeitos dos fármacos , Interleucina-6/metabolismo , Regeneração Hepática/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Tri-Iodotironina/metabolismo , Animais , Linhagem Celular , Fígado/citologia , Masculino , Mitógenos/biossíntese , Índice Mitótico , Antígeno Nuclear de Célula em Proliferação , Ratos , Ratos Endogâmicos F344 , Receptores dos Hormônios TireóideosRESUMO
We have shown, in animal models as well as in retrospective human study, that some degree of decreased thyroid function is beneficial for subjects with liver damage of various etiologies. Therefore, we herein present the results of a cohort population study. Between 1991 and 1994, 18 patients (12 women and 6 men; mean age, 59 +/- 24 years) with both biopsy-proven active cirrhosis (5 hepatitis C virus, 4 hepatitis B virus, 1 immunocompromised host, 2 primary biliary cirrhosis, 1 alcoholic, and 5 cryptogenic; Child's-Pugh criteria: A-8, B-8, C-2) and primary or induced (by either drug or surgery) thyroxine-treated hypothyroidism were prospectively followed. Each patient was examined at least twice yearly and served as their own control. The thyroid of the profiled patients ranged between euthyroidism and subclinical hypothyroidism. Liver function tests were evaluated and compared in states of normal versus increased thyroid-stimulating hormone (TSH) blood levels. A significant improvement in alanine aminotransferase (p < 0.001), alkaline phosphatase (p < 0.0001), albumin (p < 0.001), and bilirubin (p < 0.01) was found in the increased TSH group. Prothrombin time was also found to be significantly better (p < 0.001). We conclude that euthyroid patients with liver cirrhosis might benefit from a controlled hypothyroidism.
Assuntos
Hipotireoidismo/fisiopatologia , Cirrose Hepática/fisiopatologia , Fígado/fisiopatologia , Tireotropina/sangue , Idoso , Estudos de Coortes , Interpretação Estatística de Dados , Feminino , Seguimentos , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/tratamento farmacológico , Cirrose Hepática/sangue , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , Testes de Função Tireóidea , Tiroxina/uso terapêutico , Fatores de TempoRESUMO
To identify cells that have the ability to proliferate and differentiate into all epithelial components of the liver lobule, we isolated fetal liver epithelial cells (FLEC) from ED 14 Fischer (F) 344 rats and transplanted these cells in conjunction with two-thirds partial hepatectomy into the liver of normal and retrorsine (Rs) treated syngeneic dipeptidyl peptidase IV mutant (DPPIV(-)) F344 rats. Using dual label immunohistochemistry/in situ hybridization, three subpopulations of FLEC were identified: cells expressing both alpha-fetoprotein (AFP) and albumin, but not CK-19; cells expressing CK-19, but not AFP or albumin, and cells expressing AFP, albumin, and cytokeratins-19 (CK-19). Proliferation, differentiation, and expansion of transplanted FLEC differed significantly in the two models. In normal liver, 1 to 2 weeks after transplantation, mainly cells with a single phenotype, hepatocytic (expressing AFP and albumin) or bile ductular (expressing only CK-19), had proliferated. In Rs-treated rats, in which the proliferative capacity of endogenous hepatocytes is impaired, transplanted cells showed mainly a dual phenotype (expressing both AFP/albumin and CK-19). One month after transplantation, DPPIV(+) FLEC engrafted into the parenchyma exhibited an hepatocytic phenotype and generated new hepatic cord structures. FLEC, localized in the vicinity of bile ducts, exhibited a biliary epithelial phenotype and formed new bile duct structures or were incorporated into pre-existing bile ducts. In the absence of a proliferative stimulus, ED 14 FLEC did not proliferate or differentiate. Our results demonstrate that 14-day fetal liver contains lineage committed (unipotential) and uncommitted (bipotential) progenitor cells exerting different repopulating capacities, which are affected by the proliferative status of the recipient liver and the host site within the liver where the transplanted cells become engrafted. These findings have important implications in future studies directed toward liver repopulation and ex vivo gene therapy.
Assuntos
Transplante de Células , Transplante de Tecido Fetal , Fígado/citologia , Fígado/cirurgia , Células-Tronco/citologia , Animais , Ductos Biliares/citologia , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/citologia , Hepatectomia/métodos , Fígado/embriologia , Mitógenos/farmacologia , Período Pós-Operatório , Alcaloides de Pirrolizidina/farmacologia , Ratos , Ratos Endogâmicos F344 , Transplante Isogênico , Tri-Iodotironina/farmacologiaRESUMO
It has been suggested that the increase in C3 and C4 levels in jejunal perfusates of patients with Crohn's disease (CD) results from local intestinal synthesis of complement. The present study evaluated the expression of these complement genes in inflamed tissues from patients with CD. Surgically resected specimens from patients with CD and control tissue obtained from subjects with adenocarcinoma of the colon were evaluated for C3 and C4 gene expression by the use of 35S-labelled anti-sense RNA probes. All tissue samples, diseased and normal tissue, expressed C4 mRNA throughout in the intestinal epithelium. C3 mRNA was not detected in epithelial cells in histologically normal tissue, but in diseased specimens there was a focal distribution of C3 mRNA in epithelial cells of the crypts, but not in villous epithelium. Focal C3 gene expression correlated with crypt abscess formation and the presence of polymorphonuclear leucocytes in the lumen of the crypts. In addition, C3 mRNA was also found in macrophages of the submucosa. These macrophages were CD68+, fusiform with faint cytoplasm and morphologically different from the large rounded lamina propria macrophages, which do not express C3 mRNA. Multinucleated giant cells did not express either C3 or C4 genes. In addition to its presence in intestinal epithelium, C4 mRNA was also expressed in mast cells, which however did not express C3 mRNA. These observations identify cells in the intestinal wall expressing complement genes and support the hypothesis that there is local regulated production of complement in the intestine of patients with CD, and subsequent complement activation may contribute to the inflammatory process.
Assuntos
Complemento C3/metabolismo , Complemento C4/metabolismo , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Transcrição Gênica/imunologia , Corticosteroides/uso terapêutico , Adulto , Idoso , Complemento C3/genética , Complemento C4/genética , Doença de Crohn/tratamento farmacológico , Doença de Crohn/patologia , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , Transcrição Gênica/efeitos dos fármacosRESUMO
Elevation of serum iron is frequently observed in patients' with chronic Hepatitis C virus infection and was found to be a negative predictive factor for treatment response. We prospectively evaluated the iron status of 112 patients with acute viral infection not due to hepatitis viruses. The virus infections included Epstein-Barr virus (57%), cytomegalovirus (22.3%) and others (20.7%). Increased serum iron was documented in two patients only. Out of nine patients who were evaluated twice, seven had increased serum iron but the level remained well within the normal range. Transferrin saturation was normal in all patients. Disturbed liver function tests were documented in 30-40% of patients. We conclude that serum iron is not significantly increased during acute non (A-E) hepatitis viral infections with or without liver involvement.
Assuntos
Ferro/sangue , Transferrina/análise , Viroses/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Viroses/enzimologiaRESUMO
Complement components in breast milk may enhance the local immune response in the gut of infants. In this study, we investigated the expression of complement genes in the mammary gland and attempted to determine possible regulatory mechanisms. We have studied the expression of C3, C4, factor B, and HLA-DRalpha mRNA by in situ hybridization in gestational mammary gland specimens and compared these findings to those in breast tissue affected with an inflammatory process, lactating adenoma or idiopathic gynecomastia. In normal resting breast, only C4 mRNA was noted in some ductal epithelium. In gestational mammary gland, there was a diffuse expression of C4, C3, and factor B mRNA in the epithelial cells of the acini. A similar pattern of complement gene expression was found in localized areas of an infectious inflammatory process. In addition, in the inflammatory specimens, there was also expression of C3 mRNA in infiltrating macrophages (CD 68 positive cells). In gynecomastia, C4 mRNA was noted in ductal epithelium, and there was a marked increased expression of C3 mRNA in the proliferating epithelium of the lactating adenoma. HLA-DRalpha was observed only in macrophages involved in the inflammatory response. Our findings, which reflect the hormonal and inflammatory events in vivo, provide new insights as to in situ complement gene expression.
Assuntos
Mama/metabolismo , Proteínas do Sistema Complemento/genética , Mastite/metabolismo , Complicações na Gravidez , Adenoma/metabolismo , Adenoma/patologia , Adulto , Biópsia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Complemento C3/genética , Complemento C4/genética , Fator B do Complemento/genética , Feminino , Expressão Gênica , Ginecomastia/metabolismo , Ginecomastia/patologia , Humanos , Lactação/metabolismo , Masculino , Pessoa de Meia-Idade , Gravidez , Complicações Neoplásicas na GravidezRESUMO
Recently, we described a new strategy for hepatocyte transplantation, using retrorsine/partial hepatectomy (PH) in a DPPIV- mutant Fischer rat model. Treatment of rats with retrorsine, a pyrrolizidine alkaloid, blocks endogenous hepatocytes from proliferating, so that after exposure to this agent coupled with PH and hepatocyte transplantation, transplanted hepatocytes selectively repopulate the liver. In the present study, we determined whether this method of cell transplantation can restore biosynthetic and physiological function in the liver by transplanting normal hepatocytes into rats genetically deficient in albumin synthesis, the Nagase analbuminic rat (NAR). After hepatocyte transplantation, albumin mRNA and protein were identified in the liver by in situ hybridization and immunohistochemistry, respectively, and serum albumin levels were determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, and enzyme-linked immunosorbent assay (ELISA) methods. At 1 month posttransplantation, large clusters of cells expressing albumin mRNA and protein were identified in the liver, representing approximately 50% of hepatocytes for albumin mRNA and approximately 61% for protein. At 2 months' posttransplantation, cells expressing albumin mRNA represented approximately 77% of hepatocyte mass, and cells expressing albumin protein represented approximately 81% of total hepatocyte mass. Hepatocyte-transplanted NAR also exhibited normal or near-normal serum albumin levels (3.0 +/- 0.2 g/dL). High levels of serum albumin were sustained for the 2-month duration of experiments. These results demonstrate the ability of this protocol for hepatocyte transplantation to restore a major biosynthetic and physiological function of the liver, and suggest its potential use as a method to treat genetic-based or acquired liver diseases.
Assuntos
Acetilglucosaminidase/deficiência , Transplante de Células , Fígado/metabolismo , Albumina Sérica/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Separação Celular , Dieta , Hibridização In Situ , Fígado/patologia , Masculino , Alcaloides de Pirrolizidina/farmacologia , RNA Mensageiro/biossíntese , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Albumina Sérica/biossíntese , Albumina Sérica/deficiênciaRESUMO
Recently, we described a new model for hepatocyte transplantation with nearly total replacement of the liver by exogenous hepatocytes (E. Laconi et al., Am. J. Pathol., 153: 319-329, 1998). The model is based on the mitoinhibitory effect of the pyrrolizidine alkaloid retrorsine on hepatocytes in the resident liver while transplanted hepatocytes proliferate. In this study, we exploit this novel approach to address the important and controversial issue of whether hepatocytes, when proliferating extensively, undergo dedifferentiation and give rise to foci of undifferentiated hepatocytes. Genetically marked hepatocytes (isolated from normal Dipeptidyl peptidase IV+ Fischer 344 rats) were delivered intraportally (2 x 10(6) cells) into the liver of retrorsine-treated Dipeptidyl peptidase IV- mutant Fischer 344 rats in conjunction with partial hepatectomy. Transplanted hepatocytes were detected histochemically or immunohistochemically, and cell proliferation was studied by in situ hybridization for histone-3 mRNA. Expression of alpha-fetoprotein (AFP) mRNA, a marker of hepatocyte dedifferentiation, was also revealed by in situ hybridization. One day after partial hepatectomy and hepatocyte transplantation, endogenous hepatocytes and oval cells expanding in the liver expressed histone-3 mRNA (cells had entered S phase); 2 days later, transplanted hepatocytes and nonparenchymal cells also expressed histone-3 mRNA. Although the majority of endogenous hepatocytes did not divide and became arrested as quiescent megalocytes, the exogenous hepatocytes, as well as newly formed small hepatocytes, most probably derived from liver progenitor cells, underwent extensive proliferation. After 7-14 days, the nonparenchymal cells stopped proliferating, but transplanted hepatocytes and small endogenous hepatocytes continued to proliferate for 1 month, forming foci of dividing parenchymal cells. Although many of the hepatocytes in clusters were in S phase (histone-3 mRNA positive), none expressed AFP mRNA. In contrast, high expression of AFP mRNA was observed in proliferating oval and transitional cells, forming duct-like structures of cytokeratin-19-positive cells. From these studies, we conclude that hepatocyte proliferation in the adult liver is not associated with dedifferentiation.
Assuntos
Transplante de Células , Regeneração Hepática , Transplante de Fígado , Alcaloides de Pirrolizidina/farmacologia , alfa-Fetoproteínas/metabolismo , Animais , Diferenciação Celular , Divisão Celular , Dipeptidil Peptidase 4/genética , Hepatectomia , Histonas/metabolismo , Filamentos Intermediários/metabolismo , Mutação , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , alfa-Fetoproteínas/análiseRESUMO
We recently showed that some decrease in thyroid hormone blood levels can effectively and significantly prevent the development of cirrhosis and fulminant hepatic failure and decrease portal pressure in three different rat models. This study was conducted to determine whether hypothyroidism has a beneficial effect over euthyroidism on patients with active liver cirrhosis of different etiologies. The medical files of hypothyroid patients with cirrhosis who were referred to the Tel-Aviv Medical Center between the years 1980 and 1995 were retrospectively evaluated. Of 3,528 patients with biopsy-proven cirrhosis and 4,738 hypothyroid patients who were identified, only 46 (25 female, 54%; mean age, 52.3 +/- 9.1) met the eligibility criteria. The patients suffered from cirrhosis (mean, 9.5 +/- 4.3 years; range, 4-23) and had hypothyroidism (mean, 12 +/- 6 years; range, 4-31). Most patients suffered from hypothyroidism of unknown etiology (85%), whereas the rest had hypothyroidism after surgical/iodine ablation of the gland. In the hypothyroid versus the euthyroid state, a significant negative correlation was found between thyroid-stimulating hormone blood levels and both functional and synthetic liver function tests (p < 0.001). A significant negative correlation was also found between thyroid-stimulating hormone blood levels and clinical deterioration manifested as bleeding varices, the development of ascites, and episodes of encephalopathy. We conclude that in patients with liver cirrhosis, the liver function in the hypothyroid state tend to be better than in the euthyroid state. A mild controlled decreased thyroid function may be beneficial for euthyroid cirrhotic patients.
Assuntos
Hipotireoidismo/sangue , Hipotireoidismo/complicações , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Doença Aguda , Adulto , Feminino , Humanos , Cirrose Hepática/etiologia , Testes de Função Hepática , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND/AIMS: Long-term gene transfer into hepatocytes requires DNA synthesis. Although this can be achieved in vitro, using various hepatic mitogens, marked proliferative response is not seen in vivo in the quiescent liver. We have speculated that controlled reversible liver damage might change the steady state of the liver, and thus render it susceptible to manipulations by growth factors and cytokines. Therefore, the influence of thyroxine on proliferation of hepatocytes and of bile duct epithelial cells was investigated, using an in vivo model of thioacetamide-induced liver insult. METHODS: Five groups of ten rats each were studied: normal rats, thioacetamide-treated, thyroxine-treated, both thioacetamide and thyroxine-treated, and a 70% partial hepatectomy group. DNA synthesis was looked at by PCNA labeling. RESULTS: The PCNA labeling indexes of hepatocytes and of bile duct epithelial cells in rats treated with both thioacetamide and thyroxine (9.5+/-1.2 and 33.8+/-5.7% respectively) were significantly (p<0.0002) higher than those of the normal (0.84+/-0.2 and 4.4+/-0.50%), thioacetamide-treated (2.1+/-0.3 and 7.1+/-2.3%) and thyroxine-treated animals (0.6+/-0.3 and 11+/-5.6%). The labeling index in the hepatectomized animals was significantly higher for hepatocytes (18.3+/-1.2%, p<0.003), but lower for biliary cells (15+/-2.6, p<0.05) than that observed in thioacetamide and thyroxine-treated rats. Hypothyroid rats had significantly lower PCNA labeling index, as compared to the thioacetamide-thyroxine-treated group or the partial hepatectomy group. CONCLUSIONS: Following controlled liver damage, thyroxine is a potent mitogen for both hepatocytes and bile duct epithelial cells.
Assuntos
Divisão Celular/efeitos dos fármacos , Terapia Genética , Fígado/efeitos dos fármacos , Tiroxina/farmacologia , Animais , Ductos Biliares/citologia , Células Epiteliais/efeitos dos fármacos , Feminino , Fígado/citologia , Antígeno Nuclear de Célula em Proliferação/análise , Ratos , Ratos WistarRESUMO
Genetically marked hepatocytes from dipeptidyl peptidase (DPP) IV+ Fischer 344 rats were transplanted into the liver of DPPIV- mutant Fischer 344 rats after a combined treatment with retrorsine, a pyrrolizidine alkaloid that blocks the hepatocyte cell cycle, and two-thirds partial hepatectomy. In female rats, clusters of proliferated DPPIV+ hepatocytes containing 20 to 50 cells/cluster, mostly derived from single transplanted cells, were evident at 2 weeks, increasing in size to hundreds of cells per cluster at 1 month and 1000 to several thousand cells per cluster at 2 months, representing 40 to 60% of total hepatocyte mass. This level of hepatocyte replacement remained constant for up to 1 year, the duration of experiments conducted. In male rats, liver replacement occurred more rapidly and was more extensive, with transplanted hepatocytes representing 10 to 15% of hepatocyte mass at 2 weeks, 40 to 50% at 1 month, 90 to 95% at 2 months, 98% at 4 months, and 99% at 9 months. Transplanted hepatocytes were integrated into the parenchymal plates, exhibited unique hepatic biochemical functions, and fully reconstituted a normal hepatic lobular structure. The extensive proliferation of transplanted cells in this setting of persistent inhibition of resident hepatocytes represents a new general model to study basic aspects of liver repopulation with potential applications in chronic liver disease and ex vivo gene therapy.
Assuntos
Transplante de Células/métodos , Transplante de Fígado/métodos , Fígado/citologia , Alcaloides de Pirrolizidina/farmacologia , Adenosina Trifosfatases/metabolismo , Animais , Divisão Celular , Dipeptidil Peptidase 4/metabolismo , Feminino , Glucose-6-Fosfato/metabolismo , Glicogênio/metabolismo , Hepatectomia , Queratinas/metabolismo , Fígado/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos Mutantes , Albumina Sérica/metabolismo , Fatores Sexuais , Fatores de TempoRESUMO
Recent data from animal studies suggest that induced hypothyroidism prevents the hyperdynamic circulation in portal vein ligated rats, liver cirrhosis in rats chronically treated with thioacetamide (TAA), and immune-mediated acute liver injury induced in mice by concanavalin A. Therefore, the aim of this present study is to determine whether hypothyroidism would likewise prevent fulminant hepatic failure (FHF) in rats. FHF was induced by 3 consecutive ip injections of TAA (400 mg/kg) at 24-hour intervals. Hypothyroidism was induced in rats by either methimazole (MMI) or propylthiouracil (PTU) and surgical thyroidectomy and was confirmed by elevated serum thyroid stimulating hormone levels. Serum levels of liver enzymes, blood ammonia, and prothrombin time were significantly lower in all 3 groups of hypothyroid rats. The stage of hepatic encephalopathy (HE) and the survival rates were significantly improved in the hypothyroid rats (P < .01); the histologic examination of their livers showed less necrosis and inflammation (P < .01). In the hypothyroid rats, the serum levels of malondialdehyde 48 hours after thioacetamide (TAA) administration were lower than in control rats (P < .01). Exogenous supplementation of hypothyroid rats with L-thyroxine started 48 hours before TAA administration abrogated the protective effects of hypothyroidism. The serum levels of tumor necrosis factor alfa (TNF-alpha), interleukin (IL) 2 and IL-6 after 24 hours were slightly lower in the hypothyroid rats, but the administration of soluble receptor of TNF (10-1,000 microg/rat) did not prevent the induction of fulminant liver failure by TAA. Oxygen extraction, studied in isolated perfused liver preparation, was significantly lower in livers of hypothyroid rats (P < .01). These results suggest that induced hypothyroidism decreases the development of liver injury in a rat model of FHF. The mechanism may involve diminished oxidative cell injury caused by decreased oxygen utilization and hypometabolism associated with hypothyroidism.
Assuntos
Encefalopatia Hepática/prevenção & controle , Hipotireoidismo/fisiopatologia , Fígado/efeitos dos fármacos , Tioacetamida/toxicidade , Amônia/sangue , Animais , Citocinas/sangue , Encefalopatia Hepática/induzido quimicamente , Hipotireoidismo/patologia , Fígado/enzimologia , Fígado/patologia , Masculino , Malondialdeído/análise , Ratos , Ratos Wistar , Receptores do Fator de Necrose Tumoral/análise , Tiroxina/farmacologiaRESUMO
BACKGROUND: At present only one large controlled study has indicated that parenteral methotrexate may be effective in chronic active Crohn's disease (CD). AIM: To evaluate the effectiveness of oral methotrexate in chronic steroid-dependent CD. PATIENTS: Patients with active CD, who have received steroids and/or immunosuppressives for at least 4 months during the preceding 12 months and with a current Harvey-Bradshaw index of > or = 7 were studied. METHODS: Methotrexate (12.5 mg weekly) or 6-mercaptopurine (50 mg daily), or placebo were given during the 9 months of the trial in addition to steroids and 5-aminosalicylic acid as clinically indicated. RESULTS: Eighty-four patients were included (methotrexate, 26 patients; 6-mercaptopurine, 32 patients; placebo, 26 patients). The proportion of patients entering first remission as well as the proportions of patients relapsing after first remission were not significantly different between the groups. The mean Harvey-Bradshaw index and the mean monthly steroid dose were also similar. However, when each patient was evaluated as his or her own control, the reduction in steroid dose, the general well being, and the reduction in abdominal pain were significantly better in the methotrexate treated patients. CONCLUSIONS: Methotrexate at a weekly oral dose of 12.5 mg was found to be moderately better than 6-mercaptopurine and placebo in patients with chronic active CD.
Assuntos
Antirreumáticos/uso terapêutico , Doença de Crohn/tratamento farmacológico , Metotrexato/uso terapêutico , Dor Abdominal/prevenção & controle , Administração Oral , Adolescente , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/administração & dosagem , Doença Crônica , Método Duplo-Cego , Estudos de Avaliação como Assunto , Feminino , Seguimentos , Nível de Saúde , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Israel , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/uso terapêutico , Mesalamina/administração & dosagem , Mesalamina/uso terapêutico , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Placebos , Recidiva , Indução de Remissão , Resultado do TratamentoRESUMO
From 1988 to 1995, 30 patients (16 men) with malignant bone (n 23) and soft tissue (n 7) tumors of the shoulder girdle underwent surgery in our department. The mean age was 34 (6-80) years. 26 patients had primary and 4 had metastatic lesions. The average follow-up period was 3 (2-8) years, at the end of which 18 patients showed no evidence of disease, 2 were alive with disease, and 10 had died (9 because of tumor). 25 of the operations were limb-sparing procedures, while the other 5 were major amputations. Radical resection was performed in 4 patients, wide resection in 25 and marginal resection in 1. Local recurrence was observed in 2 patients. 10 patients with stage IIB tumors of the proximal humerus underwent extraarticular humeral and glenoid resection. Reconstruction was performed with either a modular or an improvised implant. Following surgery, those patients had a concave contour of the shoulder and poor abduction ability. Overall functional outcome was good in 18 patients, moderate in 11 and poor in 1. No correlation was found between functional outcome and reconstruction technique.