RESUMO
BACKGROUND AND AIMS: Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease linked to symptoms including fatigue and altered mood/cognition, indicating that chronic liver inflammation associated with PBC can impact brain function. We employed near-infrared spectroscopy (NIRS), a noninvasive neuroimaging technique, to determine whether patients with PBC exhibit reduced cerebral oxygen saturation (StO2 ) and altered patterns of microvascular cerebral blood perfusion and whether these alterations were associated with clinical phenotype. This observational case-control study was conducted at a tertiary hospital clinic (University of Calgary Liver Unit). APPROACH AND RESULTS: Thirteen female patients with noncirrhotic PBC, seven female patients with cirrhotic PBC, and 11 healthy female controls were recruited by physician referral and word of mouth, respectively. NIRS was used to measure cerebral hemoglobin and oxygen saturation. A wavelet phase coherence method was used to estimate the coherent frequency coupling of temporal changes in cerebral hemodynamics. The PBC group demonstrated significantly reduced cerebral StO2 (P = 0.01, d = 0.84), indicating cerebral hypoxia, significantly increased cerebral deoxygenated hemoglobin concentration (P < 0.01, d = 0.86), and significantly reduced hemodynamic coherence in the low-frequency band (0.08-0.15 Hz) for oxygenated hemoglobin concentration (P = 0.02, d = 0.99) and total hemoglobin (tHb) concentration (P = 0.02, d = 0.50), indicating alterations in cerebrovascular activity. Complete biochemical response to ursodeoxycholic acid (UDCA) therapy in early patients with PBC was associated with increased cerebral tHb concentration and decreased hemodynamic coherence. CONCLUSIONS: Using NIRS, patients with PBC were found to have hypoxia, increased cerebral hemoglobin concentration, and altered cerebrovascular activity, which were reversed in part in UDCA responders. In addition, symptoms and quality-of-life measures did not correlate with brain hypoxia or cerebrovascular dysregulation in patients with PBC.
Assuntos
Transtornos Cerebrovasculares/diagnóstico por imagem , Colangite/complicações , Hipóxia Encefálica/diagnóstico por imagem , Cirrose Hepática Biliar/complicações , Adulto , Idoso , Transtornos Cerebrovasculares/etiologia , Feminino , Humanos , Hipóxia Encefálica/etiologia , Pessoa de Meia-Idade , Espectroscopia de Luz Próxima ao InfravermelhoAssuntos
Hepatite B Crônica , Tenofovir , Adenina , Antígenos E da Hepatite B , Humanos , Lipídeos , OrganofosfonatosRESUMO
BACKGROUND: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are first-line treatments for chronic hepatitis B (CHB). Studies suggest lipid lowering effect of TDF in human immunodeficiency virus positive (HIV+) individuals, but the effect on lipids and cardiovascular disease (CVD) risk in CHB is unknown. AIM: To compare TDF vs ETV effects on lipid levels in CHB. METHODS: In this retrospective cohort study, data on serum lipids and CVD risk factors at baseline and ~1 year on TDF or ETV were collected from CHB carriers. We used propensity score matched models to assess the effect on total cholesterol (TC), LDL-C, HDL and triglycerides (TGL). RESULTS: In 348 patients, median age was 57 (IQR: 47-65 years), 63% were male, 77% were Asian, 19% were cirrhotic, 25% were HBeAg positive at baseline, and 72% received TDF vs 28% ETV. ETV-treated patients were older (median age: 60 vs 55, P<.01), had similar smoking and hypertension rates, but diabetes and dyslipidemia were more prevalent (19% vs 9%, P=.01; 14% vs 6%, P=.05, respectively). In propensity score matched models for age, gender, usage of lipid lowering agents, dyslipidemia and diabetes, TDF-treated patients were more likely to show a 20% decrease in TC (95% CI: 3%-25%), LDL-C (95% CI: 1%-25%) and HDL-C (CI: 10%-30%) levels compared with those on ETV. No change in TGL was observed in either group. CONCLUSIONS: A greater decline in TC, LDL-C and HDL was observed in CHB carriers receiving TDF compared with ETV. These data may influence anti-viral choice in CHB carriers at risk for CVD.
Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Tenofovir/uso terapêutico , Idoso , Antivirais/farmacologia , Estudos de Coortes , Feminino , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Tenofovir/farmacologia , Resultado do TratamentoRESUMO
The serotonin neurotransmitter system, including the 5-HT(3) receptor, has been implicated in the genesis of fatigue in patients with liver disease. Therefore, we examined the possible role of 5-HT(3) receptors in cholestasis-associated fatigue. Rats were either bile duct resected (BDR) or sham resected and studied 10 days postsurgery. A significant decrease in hypothalamic 5-HT(3) receptor expression was detected by immunohistochemistry and Western blot in BDR vs sham rats, coupled with increased hypothalamic serotonin turnover identified by an elevated 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT ratio in BDR vs sham rats. To examine fatigue-like behaviour, an activity meter was used. BDR rats exhibited significantly lower locomotor activity than did sham animals. Subcutaneous injection of the 5-HT(3) receptor antagonist tropisetron (0.1 mg kg(-1)) resulted in significantly increased locomotor activity in BDR rats compared to the activity in saline-treated controls, but was without effect in sham rats. However, a 10-fold higher dose of tropisetron significantly increased locomotor activity in both BDR and sham rats compared to saline-injected controls. These findings indicate that cholestasis in the rat is associated with increased hypothalamic serotonin turnover, decreased hypothalamic 5-HT(3) receptor expression, and enhanced sensitivity to locomotor activation induced by 5-HT(3) receptor antagonism, thereby implicating the 5-HT(3) receptor system in cholestasis associated fatigue.
Assuntos
Colestase/tratamento farmacológico , Colestase/psicologia , Fadiga/tratamento farmacológico , Fadiga/psicologia , Hipotálamo/metabolismo , Receptores 5-HT3 de Serotonina/biossíntese , Antagonistas da Serotonina/uso terapêutico , Alanina Transaminase/sangue , Animais , Bilirrubina/sangue , Western Blotting , Colestase/complicações , Regulação para Baixo/efeitos dos fármacos , Fadiga/etiologia , Ácido Hidroxi-Indolacético/sangue , Hipotálamo/efeitos dos fármacos , Imuno-Histoquímica , Indóis/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores 5-HT3 de Serotonina/genética , Serotonina/sangue , Antagonistas da Serotonina/farmacologia , TropizetronaRESUMO
BACKGROUND: Patients with congenital coagulation disorders and chronic hepatitis C virus (HCV) infection have multiple risk factors (ie, infection predominantly with genotype-1 HCV, long duration of the disease, HIV coinfection and male sex) for poor response to antiviral therapy. The present study compared induction therapy with interferon-alpha (IFN-alpha)-2b with standard IFN-alpha2b therapy. Pegylated IFN was not available at the time that the study was initiated. PATIENTS AND METHODS: A randomized study was performed comparing the efficacy of traditional IFN-alpha2b therapy (group A -- three million units, three times weekly for 24 to 48 weeks) and daily ribavirin (1.0 g to 1.2 g according to weight for 24 to 48 weeks), with induction IFN-alpha2b therapy (group B -- three million units, daily for eight weeks followed by the same dose administered three times a week for a further 16 to 40 weeks) and daily ribavirin (same dose as above) in IFN-naive patients with congenital coagulation disorders and chronic HCV infection. RESULTS: Between 2000 and 2003, 54 HIV-negative patients were recruited and randomly assigned to group A or B (n=27 each). Both groups were comparable in terms of age, sex, ethnicity, body mass index, baseline HCV RNA titre, viral genotype, liver fibrosis stage and type of coagulation disorder. Induction therapy did not significantly alter sustained virological response rates (group A 50%, group B 50%; P=1.0). Multiple logistic regression analysis indicated that induction therapy did not benefit individuals with difficult-to-treat infection (ie, those infected with genotypes 1 and 4, or those with high baseline viral loads). CONCLUSIONS: There was no benefit with induction antiviral therapy for HCV infection in individuals with congenital coagulation disorders.
Assuntos
Antivirais/uso terapêutico , Transtornos da Coagulação Sanguínea/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Adulto , Transtornos da Coagulação Sanguínea/congênito , Canadá , Comorbidade , Quimioterapia Combinada , Feminino , Hepacivirus/imunologia , Hepatite C Crônica/epidemiologia , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , Proteínas Recombinantes , Ribavirina/uso terapêuticoRESUMO
BACKGROUND: Ursodeoxycholic acid is widely used as the standard therapy for the treatment of primary biliary cirrhosis and other cholestatic liver diseases. Although it has been shown to improve biochemical markers and delay disease progression, its effect upon fatigue and pruritus, is at best uncertain. AIM: To assess the safety and efficacy of methotrexate for treating symptomatic primary biliary cirrhosis patients who were biochemical partial responders or non-responders to ursodeoxycholic acid therapy. METHODS: We treated eight consecutive primary biliary cirrhosis patients with methotrexate who were followed in a single hepatology clinical practice, who were symptomatic, and who had had an incomplete biochemical response to ursodeoxycholic acid therapy. Pruritus and fatigue were assessed at each clinic visit and graded from 0 (asymptomatic) to 4 (incapacitating). RESULTS: The median dose of methotrexate was 13.75 mg/week (range 7.5-15) and the mean duration of methotrexate therapy was 49 months (range 11-126). At the end of follow-up pruritus in six of seven patients had improved, and fatigue in all patients had improved with the addition of methotrexate therapy (pruritus: baseline 2.9 +/- 1.1 vs. end of treatment 0.6 +/- 1.5, P < or = 0.0175, and fatigue: baseline 3.0 +/- 0.8, vs. end of treatment 1.0 +/- 0.8, P < or = 0.0023). Improvement in symptoms was associated with a significant improvement in biochemical markers of cholestasis. No significant adverse effects of methotrexate were documented. CONCLUSIONS: Methotrexate should be considered as a potential additive treatment for symptomatic primary biliary cirrhosis patients who are incomplete biochemical responders to ursodeoxycholic acid therapy.
Assuntos
Colagogos e Coleréticos/uso terapêutico , Imunossupressores/administração & dosagem , Cirrose Hepática Biliar/tratamento farmacológico , Metotrexato/administração & dosagem , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Esquema de Medicação , Inibidores Enzimáticos/uso terapêutico , Fadiga/tratamento farmacológico , Fadiga/etiologia , Feminino , Humanos , Imunossupressores/efeitos adversos , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/complicações , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Prurido/tratamento farmacológico , Prurido/etiologia , Rifampina/uso terapêutico , Resultado do Tratamento , gama-Glutamiltransferase/sangueRESUMO
BACKGROUND: and aims: Primary sclerosing cholangitis is a Th1 cytokine driven disease with a poor clinical responsiveness to glucocorticoid therapy. We have previously documented elevated circulating glucocorticoid levels in cholestatic rats and in addition have noted increased hepatic expression of the Th1 cytokine interferon gamma (IFN-gamma) in a rat model of cholangitis. Therefore, we examined the relationship between circulating glucocorticoid levels, hepatic IFN-gamma expression, and hepatic T cell glucocorticoid receptor (GR) expression in a rat model of cholangitis to provide insight into the possible mechanism underlying hepatic T cell glucocorticoid resistance in cholangitic diseases. METHODS: Cholangitis was induced in male Sprague-Dawley rats by oral administration of low dose alpha-naphthylisothiocyanate (ANIT). On day 14, ANIT fed and control rats were sacrificed, serum collected, and hepatic, splenic, and peripheral blood T lymphocytes isolated for GR expression, as determined by reverse transcription-polymerase chain reaction and western blotting. RESULTS: Circulating glucocorticoid levels were markedly elevated in ANIT fed rats. Hepatic T lymphocyte GR mRNA and protein levels were significantly reduced in ANIT treated rats compared with controls. In contrast, GR mRNA and protein expression in splenic and circulating T lymphocytes was similar in both groups. Furthermore, reduced hepatic T cell GR expression in ANIT fed rats was associated with reduced hepatic CD4(+) T cell sensitivity to dexamethasone inhibitory effects (that is, inhibition of interleukin 2 receptor expression). CONCLUSION: We conclude that hepatic T lymphocyte resistance to elevated endogenous glucocorticoid levels in rats with experimental cholangitis appears, in part, to be mediated by decreased GR expression.
Assuntos
Colangite Esclerosante/metabolismo , Corticosterona/sangue , Desidroepiandrosterona/sangue , Receptores de Glucocorticoides/metabolismo , Linfócitos T/metabolismo , 1-Naftilisotiocianato/administração & dosagem , 1-Naftilisotiocianato/efeitos adversos , Animais , Colangite Esclerosante/induzido quimicamente , Doença Crônica , Modelos Animais de Doenças , Regulação para Baixo , Citometria de Fluxo , Interferon gama/metabolismo , Interleucina-4/metabolismo , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina-2/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
1. Cirrhosis is associated with cardiovascular and renal dysfunction including sodium retention. Many vasoactive peptides such as atrial natriuretic peptide (ANP) and endothelin-1 (ET-1) are degraded by neutral endopeptidase 24.11 (NEP). We investigated the hemodynamic and renal effects of thiorphan, a NEP inhibitor, in a rat cirrhosis model. 2. Cirrhosis was induced by chronic bile duct ligation, and controls had sham operation. Systemic and renal hemodynamics in conscious, restrained animals were determined using radiolabeled microspheres, and glomerular filtration rate (GFR) was measured by (3)H-inulin clearance. Plasma ANP and ET-1, and renal cGMP and Na(+) - K(+) ATPase activity were assayed. These variables were measured at baseline and after intravenous infusion of thiorphan (0.5 mg kg(-1) loading dose followed by 0.1 mg kg(-1) min(-1) x 30 min). 3. Thiorphan significantly decreased cardiac output, and increased systemic vascular resistance in controls, whereas in cirrhotic rats these variables were unchanged. 4. Compared to the controls, cirrhotic rats showed a decreased baseline GFR and urine sodium excretion, and the latter was significantly increased by thiorphan. 5. Thiorphan increased plasma ET-1 levels in controls, but not cirrhotic rats. ANP levels were not significantly increased in either group by thiorphan. 6. Thiorphan significantly increased cGMP concentrations and decreased Na(+) - K(+) ATPase activity of renal medulla but not cortex in cirrhotic rats; no effect was observed in the control rats. 7. We conclude that thiorphan induces natriuresis in cirrhotic rats by a direct renal medullary mechanism via cGMP and Na(+) - K(+) ATPase, without affecting systemic hemodynamics. This may potentially be useful in patients with ascites.
Assuntos
Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Rim/efeitos dos fármacos , Cirrose Hepática Experimental/fisiopatologia , Neprilisina/antagonistas & inibidores , Tiorfano/farmacologia , Animais , Fator Natriurético Atrial/sangue , GMP Cíclico/metabolismo , Endotelina-1/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Cirrose Hepática Experimental/sangue , Cirrose Hepática Experimental/metabolismo , Natriurese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Circulação Renal/efeitos dos fármacos , Sódio/urina , ATPase Trocadora de Sódio-Potássio/metabolismoAssuntos
Colestase/fisiopatologia , Citocinas/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Hormônio Adrenocorticotrópico/sangue , Colangiopancreatografia Retrógrada Endoscópica , Sulfato de Desidroepiandrosterona/sangue , Humanos , Hidrocortisona/sangueRESUMO
Reactivation of hepatitis B virus (HBV) is a recognized complication of bone marrow transplantation (BMT). Lamivudine is a nucleoside analogue with potent antiviral activity that has been used in the prophylaxis of HBV reactivation in at-risk BMT recipients. Currently, no data exist regarding the safety of nucleoside analogue withdrawal in these patients. A 32-year-old BMT recipient with hepatitis B e antigen (HBeAg)-negative, chronic HBV who developed a serious flare of hepatic inflammation due to a rebound in viral replication within 12 weeks of discontinuing lamivudine therapy is described. The patient remained HBeAg-negative despite high level viremia, suggesting the emergence of a mutant viral strain. The patient's acute hepatitis resolved promptly with the reinstitution of lamivudine therapy. Further studies are necessary to define the safety and efficacy of nucleoside analogues in the prevention of HBV reactivation in at-risk BMT recipients. Clinicians should consider the risk of inducing serious flares of hepatic inflammation due to abrupt nucleoside analogue withdrawal in these patients.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Antígenos E da Hepatite B/análise , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Lamivudina/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Transplante de Medula Óssea/imunologia , Seguimentos , Hepatite B Crônica/imunologia , Humanos , Lamivudina/efeitos adversos , Masculino , Inibidores da Transcriptase Reversa/efeitos adversos , Medição de Risco , Prevenção SecundáriaRESUMO
Although the etiology of AIH, PBC, and PSC remains unknown, it is apparent that these autoimmune liver diseases share many common features and can coexist in the same patient. Our patient had features of PBC and later clearly developed a picture of PSC. This case suggests that PBC, PSC, AIH, and autoimmune cholangitis are part of a spectrum of chronic autoimmune liver disease that develop in response to some yet unidentified antigen.
Assuntos
Doenças Autoimunes , Colangite Esclerosante/imunologia , Cirrose Hepática Biliar/imunologia , Adulto , Colangiopancreatografia Retrógrada Endoscópica , Colangite Esclerosante/complicações , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/enzimologia , Feminino , Humanos , Fígado/patologia , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/enzimologia , Testes de Função HepáticaRESUMO
Neuropeptide Y (NPY) is a key factor in the neurochemical control of food intake, and obstructive cholestasis can be associated with disturbances in food intake. Our aim in this study was to determine whether obstructive cholestasis in the rat is associated with defective central responsiveness to NPY. Cholestasis was induced in rats by surgical bile duct resection. Rats with obstructive cholestasis exhibited a 20% reduction in food intake 2 days after laparotomy (compared with sham-resected controls) that had resolved by 4 days after surgery. Responsiveness to the orexigenic action of NPY was tested by measuring food intake after intracerebroventricular injection of NPY. In sham-resected rats, NPY infusion strikingly increased food intake, whereas bile duct-resected (BDR) rats showed a consistent significantly impaired feeding response to NPY at postlaparotomy days 2, 4, and 7. Separate experiments measured specific binding of [(3)H]NPY to hypothalamic receptors. Fos protein expression was measured in the hypothalamic paraventricular nucleus (PVN) as a marker of NPY-induced neuronal activation. The decreased orexigenic responsiveness to NPY was not caused by altered NPY binding at hypothalamic receptors or its ability to activate neurons in the PVN. Therefore, cholestatic rats demonstrate an attenuated NPY-induced orexigenic drive that occurs early after biliary obstruction, when cholestatic rats exhibit reduced food intake, and persists despite the return of food intake to normal levels and the presence of intact central NPY-related neuronal pathways.
Assuntos
Colestase/tratamento farmacológico , Ingestão de Alimentos/efeitos dos fármacos , Neuropeptídeo Y/administração & dosagem , Animais , Ductos Biliares/fisiologia , Ductos Biliares/cirurgia , Ligação Competitiva/efeitos dos fármacos , Colestase/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraventriculares , Masculino , Neuropeptídeo Y/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/metabolismoRESUMO
Midbrain somatodendritic 5-HT1A autoreceptors play a central inhibitory role in the regulation of serotonergic neurotransmission. Given that serotonergic neurotransmission appears to be altered in experimental cholestatic liver disease we examined alterations in midbrain 5-HT1A autoreceptor binding and physiological responses in rats with experimental cholestatic liver disease in comparison to non-cholestatic controls. Using a standard receptor binding assay cholestatic rats exhibited an increase in midbrain 5-HT1A receptor number but no change in receptor affinity compared to controls. Midbrain 5-HT1A receptor mRNA expression as determined by semiquantitative RT-PCR was similar in cholestatic and non-cholestatic animals. In addition, cholestatic rats exhibited enhanced 5-HT1A autoreceptor-mediated hypothermic and hyperphagic responses compared to non-cholestatic controls after the administration of the highly specific 5-HT1A receptor agonist LY293284. These findings indicate that experimental cholestatic liver injury is associated with enhanced 5-HT1A autoreceptor-mediated physiological responsiveness in the setting of increased midbrain 5-HT1A receptor number but not affinity.
Assuntos
Colestase/metabolismo , Mesencéfalo/metabolismo , Receptores de Serotonina/metabolismo , Animais , Masculino , Mesencéfalo/efeitos dos fármacos , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/biossíntese , Receptores de Serotonina/genética , Receptores 5-HT1 de Serotonina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Agonistas do Receptor de Serotonina/farmacologia , Temperatura , Triptaminas/farmacologiaRESUMO
Stress is an ever-present part of modern life. The "stress response" constitutes an organism's mechanism for coping with a given stress and is mediated via the release of glucocorticoids and catecholamines. Patients often complain of stress-related worsening of their liver disease; however, the interrelationship between stress and hepatic inflammation is incompletely understood and has received little scientific attention. Considering the broad impact glucocorticoids and catecholamines have on immune cell function, it is very likely that stress has a significant impact on the hepatic inflammatory response. This themes article discusses studies of the stress response and its peripheral effectors (glucocorticoids and catecholamines) in liver disease and their impact on hepatic inflammation and outlines potential areas for future scientific investigation.
Assuntos
Sistema Digestório/fisiopatologia , Hepatite/fisiopatologia , Estresse Fisiológico/fisiopatologia , Animais , Catecolaminas/fisiologia , Modelos Animais de Doenças , Glucocorticoides/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologiaRESUMO
BACKGROUND & AIMS: Abnormal presentation of luminal constituents to the mucosal immune system, caused by dysfunction of the intestinal epithelial barrier, is a candidate theory for the cause of Crohn's disease. Increased epithelial permeability is found in subgroups of patients at high risk for the development of Crohn's disease and has been found to precede disease recurrence. Clinical observations have suggested that disease recurrence can follow times of increased psychological stress, although the underlying mechanism remains obscure. We hypothesized that environmental stress increases gastrointestinal permeability. METHODS: We evaluated site-specific gastrointestinal permeability after application of graded levels of stress in rats. RESULTS: Increased epithelial permeability after stress was shown in all regions of the gastrointestinal tract and seemed to be mediated by adrenal corticosteroids. Stress-induced increases in epithelial permeability disappeared after adrenalectomy or pharmacologic blockade of glucocorticoid receptors. Dexamethasone treatment of control animals increased gastrointestinal permeability and mimicked the effects of stress. CONCLUSIONS: Psychological stress may increase gastrointestinal permeability, allowing luminal constituents access to the mucosal immune system. This provides a potential mechanism for the observation of stress-induced disease recurrence in Crohn's disease.
Assuntos
Corticosteroides/fisiologia , Glucocorticoides/fisiologia , Absorção Intestinal/fisiologia , Intestinos/fisiopatologia , Estômago/fisiopatologia , Estresse Psicológico/fisiopatologia , Adrenalectomia , Animais , Doença de Crohn , Dexametasona/farmacologia , Modelos Animais de Doenças , Absorção Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Masculino , Permeabilidade , Ratos , Ratos Wistar , Restrição Física , Estômago/efeitos dos fármacosRESUMO
Patients with biliary tract obstruction have unexplained, inordinately high rates of perioperative morbidity and mortality, whereas cholestatic animals display abnormal hypothalamic responses to pyrogenic stimuli. We asked if obstructive cholestasis was associated with abnormal fever generation. Male Sprague-Dawley rats (250 g) underwent laparotomy for implantation of thermistors and either bile duct resection (BDR) or sham operation. After recovery, temperatures were recorded by telemetry and conscious, unrestrained rats in each group were injected intraperitoneally with either interleukin-1beta (IL-1beta;1 microg/kg) or Escherichia coli lipopolysaccharide (LPS; 50 microg/kg). Baseline temperatures in both groups were similar. Febrile responses after IL-1beta injection in BDR and sham groups were not significantly different. However, in response to LPS injection, BDR rats showed an initial hypothermia with a subsequently attenuated febrile response. Administration of anti-tumor necrosis factor-alpha (TNF-alpha) antibody 2 h before LPS injection blocked the LPS-induced hypothermia seen in BDR animals. However, serum levels of TNF-alpha were not significantly different between sham and BDR animals after LPS injection at any time point measured (0, 1.5, and 3 h).
Assuntos
Colestase/imunologia , Febre/induzido quimicamente , Febre/imunologia , Lipopolissacarídeos , Animais , Anticorpos/farmacologia , Regulação da Temperatura Corporal/efeitos dos fármacos , Regulação da Temperatura Corporal/imunologia , Interleucina-1/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND/AIMS: Recently leptin, a protein released from adipocytes, has been identified as a potent circulating satiety factor. We therefore undertook this series of experiments to examine leptin's role in the anorexia associated with biliary obstruction. METHODS: Rats underwent either surgical bile duct resection (BDR) or sham resection (sham). Body weight, and food and water intake were measured during a baseline period and for 8 days after surgery. At 4, 8 and 16 h as well as on days 2, 4, 6, and 8 postsurgery, sham and BDR rats were sacrificed and sera collected for subsequent measurement of leptin hormone concentration by RIA. White adipose tissue was collected on days 2, 4, 6 and 8 for leptin mRNA determination by Northern blot. RESULTS: Obstructive cholestasis in BDR rats caused significant anorexia for up to 7 days post-surgery, whereas in sham rats, a significant decrease in food intake was only observed in the first 24-h period following surgery. In both sham and BDR rats, water intake was significantly decreased during the first 24-h period after surgery, but had recovered to baseline levels by day 2 in both groups. Fat pad mass corrected to body weight was not significantly different between the two experimental groups. Serum leptin levels were significantly increased 4 and 8 h after surgery, had normalized by 16 h post-surgery, and were then decreased in BDR rats on days 2, 4, 6 and 8 compared with controls. Leptin mRNA levels in epididymal fat pads were decreased by approximately 2-fold in BDR rats compared with sham rats on days 2, 4, 6 and 8. Furthermore, day 5 BDR and sham rats demonstrated similar anorectic responses to centrally administered leptin. CONCLUSIONS: Leptin production is significantly increased early after biliary obstruction but is reduced after prolonged biliary obstruction. Increased circulating leptin levels may contribute to the profound anorexia observed early after biliary obstruction but appear not to mediate the anorexia observed during more chronic biliary obstruction.
Assuntos
Colestase/sangue , Leptina/sangue , Doença Aguda , Tecido Adiposo/metabolismo , Animais , Anorexia/etiologia , Anorexia/fisiopatologia , Colestase/complicações , Colestase/fisiopatologia , Doença Crônica , Ingestão de Líquidos , Ingestão de Alimentos , Epididimo , Interleucina-6/sangue , Leptina/genética , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Valores de Referência , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Fatigue is an extremely common complaint among patients with chronic disease. However, because of the subjective nature of fatigue, and the lack of effective therapeutics with which to treat fatigue, this symptom is often ignored by clinicians, who instead focus on hard, objective disease end-points. Recently, the symptom of fatigue has received greater attention as part of overall health-related quality of life assessments in patients with chronic disease. Furthermore, new methods are being developed to help quantify fatigue, and are being utilized more frequently in the clinical setting. Moreover, studies in patients and using animal models of disease have provided some insight into changes within the brain which appear to be linked to the genesis of central fatigue. This review focuses on fatigue in chronic disease and outlines possible mechanisms which may give rise to central fatigue in chronic disease. Moreover, methods for measuring fatigue and an approach to the fatigued patient are discussed. Hopefully, a broader understanding of this distressing symptom will lead to the development of specific therapies for treating fatigue in these patients.
Assuntos
Fadiga/etiologia , Atividades Cotidianas , Reação de Fase Aguda/etiologia , Reação de Fase Aguda/metabolismo , Animais , Terapia Comportamental , Doença Crônica , Hormônio Liberador da Corticotropina/biossíntese , Hormônio Liberador da Corticotropina/fisiologia , Citocinas/fisiologia , Fadiga/diagnóstico , Fadiga/terapia , Humanos , Camundongos , Transtornos do Humor/etiologia , Transtornos do Humor/metabolismo , Transtornos do Humor/terapia , Ratos , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Estresse Fisiológico/complicações , Estresse Fisiológico/fisiopatologiaRESUMO
BACKGROUND/AIMS: Idiopathic adulthood ductopenia is a cholestatic liver disease of unknown etiology. Although most cases are sporadic, familial cases do occur. METHODS: We describe a series of adult-onset bile duct depletion involving five members of an extended family spanning three generations. The proband, a 49-year-old man, presented in 1989 with asymptomatic elevation of liver enzyme tests. Investigations for chronic liver disease, including endoscopic retrograde cholangiopancreatography, were negative. Findings on liver biopsy progressed from normal in 1989 to striking loss of interlobular bile ducts in 1992. Ursodeoxycholic acid has resulted in improvement of liver enzyme tests. The proband's brother required a liver transplant at age 35 for cryptogenic cirrhosis. The proband's sister, age 42, has had intermittent jaundice and elevation of liver enzyme tests since 1971. Her liver biopsy findings progressed from normal in 1975, to striking bile duct damage by 1997. The proband's 21-year-old son has elevated liver enzyme tests and a liver biopsy consistent with idiopathic adulthood ductopenia. The proband's father had a liver biopsy at age 70 for investigation of a liver mass. It revealed extensive fibrosis and striking bile duct destruction. RESULTS/CONCLUSIONS: This is the largest series of familial idiopathic adulthood ductopenia reported, and the first with multiple generations described. Genetics appears to play a role in some cases of adulthood ductopenia. Ursodeoxycholic acid may be beneficial in the treatment of this condition.
Assuntos
Ductos Biliares Intra-Hepáticos/patologia , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/patologia , Adulto , Idoso , Colestase Intra-Hepática/tratamento farmacológico , Ensaios Enzimáticos Clínicos , Feminino , Doenças Genéticas Inatas , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Linhagem , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are presumed autoimmune chronic cholestatic liver diseases characterized by cholangitis and progressive loss of bile ducts. Cytokines have been postulated to be involved in the progression of these diseases, but their role is poorly defined. Our objectives were to characterize a rat model of cholangitis and to determine Type 1/Type 2 (Th1/Th2) cytokine profile shifts in this model. Cholangitis was induced in Sprague-Dawley rats (200 to 225 g) by low-dose oral administration of the biliary toxin alpha-naphthylisothiocyanate (ANIT) (1 g/kg powdered rat chow ad libitum) for 4, 7, and 14 days. Cholestasis was observed in ANIT-treated animals. Liver histology of ANIT-treated rats showed hepatic inflammation centered on damaged bile ducts, significant bile duct proliferation, and progressive fibrosis. Immunohistochemistry showed enhanced staining of hepatic major histocompatibility complex (MHC) II, CD4, and CD8 in portal areas of ANIT-treated animals. In addition, the hepatic cytokine profile became increasingly Th1 in nature with progressive ANIT treatment. In summary, experimental cholangitis biochemically and histologically mimics human chronic cholangitis and furthermore, is associated with a progressive shift to a more Th1-dominant hepatic cytokine profile. Therefore, this model may be useful for examining the role of cytokines in the progression of chronic cholangitic diseases.