RESUMEN
BACKGROUND: Activated hepatic macrophages play a key role in inflammation and fibrosis progression in chronic liver disease. AIM: To assess the prognostic value of soluble (s)CD163 and mannose receptor (sMR) in cirrhotic patients and explore associations with markers of intestinal permeability (lactulose-mannitol ratio, diamine oxidase), bacterial translocation (endotoxin, lipopolysaccharide-binding protein) and markers of systemic immune activation (interleukin-6, interleukin-8, sCD14). METHODS: We prospectively investigated 101 cirrhotic patients (Child-Pugh class A: n = 72, Child-Pugh classes B and C: n = 29) and 31 healthy controls. Patients were observed for a median follow-up of 37 months. RESULTS: Median plasma levels of sCD163 and soluble mannose receptor were significantly elevated in cirrhotic patients (P < .001) and increased with disease severity (sCD163 in healthy controls = 1.3, Child-Pugh class A = 4.2, Child-Pugh classes B and C = 8.4 mg/L; sMR in healthy controls = 15.8, Child-Pugh class A = 36.5, Child-Pugh classes B and C = 66.3 µg/dL). A total of 21 patients died during the observation period. Patients with sCD163 levels above 5.9 mg/L showed significantly reduced survival (survival rate after 36 months: 71% versus 98%, P < .001). Patients with soluble mannose receptor levels above 45.5 µg/dL developed significantly more complications of cirrhosis within 12 months (73% versus 9%, P < .001). Furthermore, both variables correlated with the lactulose-mannitol ratio, diamine oxidase, lipopolysaccharide and interleukin-8. CONCLUSION: Our data demonstrate the prognostic value of sCD163 in predicting long-term survival in patients with liver cirrhosis and identify soluble mannose receptor as a prognostic marker for occurrence of cirrhosis-associated complications. The correlation between gut barrier dysfunction and activation of macrophages points towards a link between them.
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Antígenos CD/sangre , Antígenos de Diferenciación Mielomonocítica/sangre , Mucosa Intestinal , Lectinas Tipo C/sangre , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/mortalidad , Fallo Hepático/diagnóstico , Fallo Hepático/mortalidad , Lectinas de Unión a Manosa/sangre , Receptores de Superficie Celular/sangre , Anciano , Traslocación Bacteriana/fisiología , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Intestinos/microbiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/metabolismo , Fallo Hepático/etiología , Fallo Hepático/microbiología , Masculino , Receptor de Manosa , Persona de Mediana Edad , Permeabilidad , PronósticoRESUMEN
BACKGROUND: Probiotics may correct intestinal dysbiosis and proinflammatory conditions in patients with liver cirrhosis. AIM: To test the effects of a multispecies probiotic on innate immune function, bacterial translocation and gut permeability. METHODS: In a randomised, double blind, placebo-controlled study, stable cirrhotic out-patients either received a daily dose of a probiotic powder containing eight different bacterial strains (Ecologic Barrier, Winclove, Amsterdam, The Netherlands) (n = 44) or a placebo (n = 36) for 6 months and were followed up for another 6 months. RESULTS: We found a significant but subclinical increase in neutrophil resting burst (2.6-3.2%, P = 0.0134) and neopterin levels (7.7-8.4 nmol/L, P = 0.001) with probiotics but not with placebo. Probiotic supplementation did not have a significant influence on neutrophil phagocytosis, endotoxin load, gut permeability or inflammatory markers. Ten severe infections occurred in total; one during intervention in the placebo group, and five and four after the intervention has ended in the probiotic and placebo group, respectively. Liver function showed some improvement with probiotics but not with placebo. CONCLUSIONS: Probiotic supplementation significantly increased serum neopterin levels and the production of reactive oxygen species by neutrophils. These findings might explain the beneficial effects of probiotics on immune function. Furthermore, probiotic supplementation may be a well-tolerated method to maintain or even improve liver function in stable cirrhosis. However, its influence on gut barrier function and bacterial translocation in cirrhotic patients is minimal.
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Traslocación Bacteriana/fisiología , Absorción Gastrointestinal/fisiología , Inmunidad Innata/fisiología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/inmunología , Probióticos/administración & dosificación , Adulto , Traslocación Bacteriana/efectos de los fármacos , Suplementos Dietéticos , Método Doble Ciego , Femenino , Absorción Gastrointestinal/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/fisiología , Humanos , Inmunidad Innata/efectos de los fármacos , Cirrosis Hepática/microbiología , Masculino , Persona de Mediana Edad , Permeabilidad/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Bile acid induced apoptosis in hepatocytes can be antagonised by nuclear factor kappaB (NFkappaB) dependent survival pathways. Sulfasalazine modulates NFkappaB in different cell types. We aimed to determine the effects of sulfasalazine and its metabolites sulfapyridine and 5-aminosalicylic acid (5-ASA) on bile acid induced apoptosis in hepatocytes. METHODS: Apoptosis was determined by caspase assays and immunoblotting, NFkappaB activation by electrophoretic mobility shift assay and reporter gene assays, generation of reactive oxygen species (ROS) fluorometrically, bile secretion gravimetrically, and bile acid uptake radiochemically and by gas chromatography in HepG2-Ntcp cells and isolated perfused rat livers. RESULTS: Glycochenodeoxycholic acid (GCDCA 75 micromol/l) induced apoptosis was reduced by sulfasalazine dose dependently (1-1000 micromol/l) in HepG2-Ntcp cells whereas its metabolites 5-ASA and sulfapyridine had no effect. Sulfasalazine significantly reduced GCDCA induced activation of caspases 9 and 3. In addition, sulfasalazine activated NFkappaB and decreased GCDCA induced generation of ROS. Bile acid uptake was competitively inhibited by sulfasalazine. In perfused rat livers, GCDCA (25 micromol/l) induced liver injury and extensive hepatocyte apoptosis were significantly reduced by simultaneous administration of 100 micromol/l sulfasalazine: lactate dehydrogenase and glutamate-pyruvate transaminase activities were reduced by 82% and 87%, respectively, and apoptotic hepatocytes were observed only occasionally. GCDCA uptake was reduced by 45 (5)% when sulfasalazine was coadministered. However, when 50% of GCDCA (12.5 micromol/l) was administered alone, marked hepatocyte apoptosis and liver injury were again observed, questioning the impact of reduced GCDCA uptake for the antiapoptotic effect of sulfasalazine. CONCLUSION: Sulfasalazine is a potent inhibitor of GCDCA induced hepatocyte apoptosis in vitro and in the intact liver.
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Antiinflamatorios no Esteroideos/farmacología , Ácido Glicoquenodesoxicólico/farmacología , Hepatocitos/patología , Sulfasalazina/farmacología , Animales , Antiinflamatorios no Esteroideos/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3 , Caspasa 9 , Caspasas/metabolismo , Línea Celular Tumoral , Depresión Química , Relación Dosis-Respuesta a Droga , Técnica del Anticuerpo Fluorescente , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Mesalamina/farmacología , FN-kappa B/metabolismo , Perfusión , Ratas , Ratas Sprague-Dawley , Sulfapiridina/farmacología , Sulfasalazina/metabolismoRESUMEN
AIM: To assess the long-term efficacy of the antimetabolite agent mycophenolate mofetil in patients with Crohn's disease. METHODS: Twenty patients with complicated Crohn's disease were treated with mycophenolate mofetil, 1 g b.d., for up to 7 years. Twelve patients were intolerant to azathioprine, seven were resistant to azathioprine and one had a history of mesalazine-induced pancreatitis. The response to mycophenolate mofetil was determined by calculation of the Harvey-Bradshaw index, the ability to taper steroids and the grading of fistula activity. RESULTS: After 6 months, 11 of the 20 patients had responded. Seven of the 11 responders relapsed after a median of 18 months, three have an ongoing response at month 17, 19 and 82, and one discontinued mycophenolate mofetil owing to toxicity. After initial treatment failure, mycophenolate mofetil was continued in 12 of 17 patients for a further 2-41 months without inducing a stable remission. Mycophenolate mofetil was of benefit in nine of the 12 patients intolerant to azathioprine and in two of the seven patients resistant to azathioprine. Perianal fistulas improved in seven of eight patients; five of the seven subsequently deteriorated, but only one due to reactivated perianal disease. CONCLUSIONS: Mycophenolate mofetil was initially effective in a sizeable fraction of patients with complicated Crohn's disease, but relapse within 18 months was common. Nevertheless, mycophenolate mofetil could be a useful alternative in patients intolerant to azathioprine.
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Antiinflamatorios no Esteroideos/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Adolescente , Adulto , Femenino , Estudios de Seguimiento , Humanos , Fístula Intestinal/etiología , Masculino , Persona de Mediana Edad , Recurrencia , Análisis de Supervivencia , Resultado del TratamientoAsunto(s)
Anticoagulantes/administración & dosificación , Fibrinolíticos/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Vena Porta , Trombosis de la Vena/tratamiento farmacológico , Enfermedad Aguda , Administración Oral , Adulto , Anticoagulantes/uso terapéutico , Femenino , Humanos , Resultado del TratamientoAsunto(s)
Antimetabolitos/efectos adversos , Feto/efectos de los fármacos , Resultado del Embarazo , Ribavirina/efectos adversos , Adulto , Femenino , Fertilización , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Masculino , Mutagénesis , Exposición Paterna , Embarazo , Proteínas RecombinantesRESUMEN
OBJECTIVE: To investigate the efficacy of high-dose interferon alpha (IFN-alpha) with or without ribavirin in interferon (IFN) non-responders. STUDY DESIGN: 304 chronic hepatitis C patients received 5 MU IFN-alpha2b (IntronA, Schering-Plough, Kenilworth, NJ, USA) three times a week for 3 months. Non-responders were randomized either to continue with IFN (IFN 5 MU/TIW followed by 10 MU/TIW, each for 3 months) alone (group A: n = 76, m: f = 54: 22, age 45.7 +/- 12 years, 16% cirrhosis, alanine aminotransferase [ALT] 66 +/- 35 U/l) or in combination with ribavirin (approximately 14 mg/kg/day) (group B: n = 81, m: f = 57: 24, age 48.2 +/- 12 years, 17% cirrhosis, ALT 71 +/- 40 U/l). At the end of treatment, patients were followed for 6 months. MAIN OUTCOME MEASURES: Virological response at end of treatment and 6 months thereafter. SETTING: University hospitals and tertiary referral centres. RESULTS: At the end of treatment, eight (10.8%) and 25 (31.3%, P= 0.0066) patients were HCV-RNA negative, and 51 and 39 were HCV-RNA positive, in groups A and B, respectively. There were 17 drop-outs in each group. Six months after treatment, only one patient in group A (1.3%) and seven patients (8.6%, P= 0.06) in group B had normal ALT and undetectable serum HCV-RNA. CONCLUSIONS: A combination of high-dose IFN with ribavirin induces a short-lasting complete response in about one-third of IFN-non-responders.
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Antivirales/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , ARN Viral/análisis , Ribavirina/administración & dosificación , Adulto , Anciano , Secuencia de Bases , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Hepatitis C Crónica/diagnóstico , Humanos , Interferones/administración & dosificación , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Organización y Administración , Reacción en Cadena de la Polimerasa , Probabilidad , Estudios Prospectivos , Valores de Referencia , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Cholestasis is associated with retention of potentially toxic bile acids and alterations in hepatocellular transporter expression. Conversely, nontoxic ursodeoxycholic acid (UDCA) stimulates bile secretion and counteracts cholestasis. This study aimed to determine the effects of UDCA and cholic acid (CA) on the expression of hepatocellular transporters for bile acids (Ntcp, Bsep), organic anions (Oatp1, Mrp2), organic cations (Mdr1a/b), and phospholipids (Mdr2) in mouse liver. METHODS: Bile flow/composition was analyzed in UDCA- or CA-fed mice. Transporter expression was studied by reverse-transcription polymerase chain reaction, Western blotting, and immunofluorescence microscopy. RESULTS: UDCA had no effect on basolateral Ntcp and down-regulated Oatp1, whereas canalicular Bsep and Mrp2 were up-regulated. CA down-regulated basolateral Ntcp and Oatp1, whereas canalicular Bsep, Mrp2, and Mdr1a/b were up-regulated. Neither UDCA nor CA affected Mdr2 expression. Both UDCA and CA stimulated biliary bile acid and glutathione excretion, although only CA increased phospholipid and cholesterol excretion. CONCLUSIONS: Down-regulation of basolateral and up-regulation of canalicular transporters in response to CA may represent a defense mechanism, in an attempt to prevent hepatocellular accumulation of potentially toxic bile acids. The therapeutic effects of UDCA may be caused in part by stimulation of canalicular transporter expression in the absence of hepatocellular toxicity.
Asunto(s)
Conductos Biliares/metabolismo , Ácido Cólico/farmacología , Hígado/efectos de los fármacos , Ácido Ursodesoxicólico/farmacología , Administración Oral , Animales , Ácidos y Sales Biliares/metabolismo , Transporte Biológico/efectos de los fármacos , Ácido Cólico/administración & dosificación , Regulación hacia Abajo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba/efectos de los fármacos , Ácido Ursodesoxicólico/administración & dosificaciónRESUMEN
Cholestasis may result from genetic or acquired defects in bile secretion. Cloning of hepatobiliary transporter genes has advanced our understanding of the molecular basis of bile formation and cholestasis. Hereditary mutations of transporter genes, exposure to cholestatic injury (eg, drugs, hormones, cytokines), or the combination of both can result in reduced expression and function of hepatobiliary transport systems. These molecular changes impair hepatic uptake and excretion of bile salts and other organic anions (eg, bilirubin). Other molecular changes contibuting to cholestasis include alterations of membrane fluidity, cytoskeleton, vesicle movement, and cell contacts. Transporter mutations can be diagnosed at the molecular genetic level. Gene therapy and hepatocyte transplantation could be used in the future to correct hereditary transport defects. Drugs used to treat cholestatic liver diseases (eg, ursodeoxycholic acid) stimulate and partially restore defective transporter expression and function. New information on the molecular mechanisms of cholestasis should lead to the development of novel drugs for cholestatic liver diseases.
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Colestasis/etiología , Endocarditis Bacteriana/diagnóstico , Infecciones Estafilocócicas/diagnóstico , Síndrome de Alagille/genética , Animales , Colestasis/genética , Fibrosis Quística/genética , Modelos Animales de Enfermedad , Endocarditis Bacteriana/complicaciones , Humanos , Ictericia Idiopática Crónica/genética , Masculino , Persona de Mediana Edad , Infecciones Estafilocócicas/complicacionesRESUMEN
Reduced hepatobiliary transporter expression could explain impaired hepatic uptake and excretion of bile salts and other biliary constituents resulting in cholestasis and jaundice. Because little is known about alterations of hepatobiliary transport systems in human cholestatic liver diseases, it was the aim of this study to investigate such potential changes. Hepatic mRNA levels in hepatobiliary transport systems for bile salts (NTCP, BSEP), organic anions (OATP2, MRP2, MRP3), organic cations (MDR1), phospholipids (MDR3), and aminophospholipids (FIC1) were determined in 37 human liver biopsies and control livers by competitive reverse-transcription polymerase chain reaction (RT-PCR). Transporter tissue distribution was investigated by immunofluorescence microscopy. In patients with inflammation-induced icteric cholestasis (mainly cholestatic alcoholic hepatitis), mRNA levels of NTCP, OATP2, and BSEP were reduced by 41% (P <.001), 49% (P <.005), and 34% (P <.05) compared with controls, respectively. In addition, NTCP and BSEP immunostaining was reduced. MRP2 mRNA levels remained unchanged, but canalicular immunolabeling for MRP2 was also decreased. mRNA expression of MRP3, MDR1, MDR3, and FIC1 remained unchanged. In contrast to the alterations of transporter expression in inflammation-induced icteric cholestasis, transporter expression did not change in anicteric cholestasis caused by primary biliary cirrhosis (PBC) stages I and II. In conclusion, reduced expression of hepatobiliary transport systems for bile salts and other organic anions may contribute to inflammation-induced cholestasis in humans. Reduction of transporter gene expression can occur at the mRNA level as observed for NTCP, OATP2, and BSEP. However, reduced MRP2 immunostaining in the presence of conserved MRP2 mRNA levels suggests an additional role for posttranscriptional/posttranslational mechanisms.
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Conductos Biliares/metabolismo , Proteínas Portadoras/metabolismo , Colestasis/metabolismo , Hígado/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfatasas/genética , Adulto , Aniones/metabolismo , Ácidos y Sales Biliares/metabolismo , Biopsia , Proteínas Portadoras/genética , Colestasis/patología , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Valores de ReferenciaRESUMEN
Hepatic uptake and excretion of bile salts and several nonbile salt organic anions (eg, bilirubin) are mediated by a distinct set of polarized transport systems at the basolateral and apical plasma membrane domains of hepatocytes and bile duct epithelial cells (cholangiocytes). With the increasing availability of molecular probes for these transporters, evidence now exists that decreased or even absent expression of hepatobiliary transport proteins in hepatocytes or cholangiocytes may explain impaired transport function that results in hyperbilirubinemia and cholestasis. This review summarizes the molecular defects in hepatocellular membrane transporters that are associated with hereditary and acquired forms of cholestatic liver disease.
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Ácidos y Sales Biliares/metabolismo , Proteínas Portadoras/fisiología , Colestasis/metabolismo , Hepatocitos/fisiología , Hígado/metabolismo , Bilis/metabolismo , Colestasis/genética , Colestasis/fisiopatología , HumanosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Pólipos del Colon/diagnóstico , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Anciano , Biopsia , Neoplasias del Colon/patología , Pólipos del Colon/complicaciones , Colonoscopía , Diagnóstico Diferencial , Humanos , Linfoma de Células B de la Zona Marginal/patología , MasculinoRESUMEN
Portal venous decompression with transjugular intra-hepatic portosystemic shunt (TIPS) is a new approach in the treatment of Budd-Chiari syndrome. We report on a 31-year-old female with Budd-Chiari syndrome due to anti-phospholipid antibodies with compression of the inferior vena cava treated with TIPS and stenting of the inferior vena cava. TIPS was complicated by massive intra-hepatic haematoma which was managed conservatively. Treatment options and pathogenic mechanisms of Budd-Chiari syndrome under the rare coincidence of aplastic anaemia and anti-phospholipid syndrome are discussed. TIPS may be considered for venous decompression in Budd-Chiari syndrome, but physicians should be aware of potential TIPS' complications in these patients.
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Síndrome de Budd-Chiari/cirugía , Hematoma/etiología , Hepatopatías/etiología , Derivación Portosistémica Intrahepática Transyugular/efectos adversos , Adulto , Anemia Aplásica/complicaciones , Anemia Aplásica/diagnóstico , Angiografía , Anticuerpos Antifosfolípidos/sangre , Anticoagulantes/administración & dosificación , Síndrome de Budd-Chiari/complicaciones , Síndrome de Budd-Chiari/diagnóstico , Femenino , Estudios de Seguimiento , Hematoma/diagnóstico por imagen , Hematoma/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico , Humanos , Hepatopatías/diagnóstico por imagen , Hepatopatías/tratamiento farmacológico , Pruebas de Función Hepática , Derivación Portosistémica Intrahepática Transyugular/métodos , Resultado del Tratamiento , UltrasonografíaRESUMEN
Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies, termed Mallory bodies (MBs). Studies with MB mouse models and cultured hepatocytes suggested that CK8/18 hyperphosphorylation might be involved in MB formation. However, no data exist on phosphorylation of CK8/18 in human AH. In this study, antibodies that selectively recognize phosphorylated epitopes of CK8 or CK18 were used to analyze CK8/18 phosphorylation states in normal human and murine livers, human AH biopsies, and livers of 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC)-intoxicated mice, the last serving as model for MB induction. Hepatocyte cytokeratins become hyperphosphorylated at multiple sites in AH and in DDC-intoxicated mice. Hyperphosphorylation of CK8/18 occurred rapidly, after 1 day of DDC intoxication and preceded architectural changes of the cytoskeleton. In long-term DDC-intoxicated mice as well as in human AH, MBs preferentially contain hyperphosphorylated CK8/18 as compared with the cytoplasmic cytokeratin intermediate filament network suggesting that CK8/18 hyperphosphorylation may play a contributing role in MB pathogenesis. Furthermore, the site-specific phosphorylation of cytokeratin in different stages of MB induction provides indirect evidence for the involvement of a variety of protein kinases known to be activated in stress responses, mitosis, and apoptosis.
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Hepatitis Alcohólica/metabolismo , Cuerpos de Inclusión/metabolismo , Queratinas/metabolismo , Hígado/metabolismo , Animales , Dicarbetoxidihidrocolidina/envenenamiento , Hepatitis Alcohólica/patología , Humanos , Hígado/patología , Masculino , Ratones , FosforilaciónRESUMEN
Inflammatory cytokines produced in response to various infectious and non-infectious stimuli are potent inducers of intrahepatic cholestasis (inflammation-induced cholestasis). The cholestatic effect of cytokines results mainly from inhibition of expression and function of hepatocellular transport systems which normally mediate hepatic uptake and biliary excretion of bile salts and various non-bile salt organic anions (e.g. bilirubin). These cytokine effects are reversible and bile secretory function is restored upon disappearance of the inflammatory injury. This review summarizes the clinical, pathophysiological and molecular aspects of inflammation-induced cholestasis.
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Colestasis/etiología , Inflamación/complicaciones , Adulto , Transporte Biológico/efectos de los fármacos , Niño , Colestasis/sangre , Citocinas/sangre , Citocinas/toxicidad , Endotoxinas/sangre , Endotoxinas/toxicidad , Hepatitis/sangre , Hepatitis/complicaciones , Humanos , Infecciones/sangre , Infecciones/complicaciones , Síndromes Paraneoplásicos/complicaciones , Nutrición Parenteral Total/efectos adversos , Complicaciones PosoperatoriasRESUMEN
Hepatic uptake and biliary excretion of bile salts and non-bile salt organic anions (e.g., bilirubin) is mediated by specific transport proteins located at the basolateral and canalicular membranes of hepatocytes. Several hepatobiliary transport systems have been identified and cloned over the past years. This development has facilitated molecular biological and genetic analyses of these transporters in experimental cholestasis and human cholestatic liver diseases. Evidence now exists that decreased or even absent expression of hepatobiliary transport systems may explain impaired transport function resulting in hyperbilirubinemia and cholestasis. This review summarizes the molecular defects in hepatocellular membrane transporters associated with hereditary and acquired forms of cholestatic liver diseases. The increasing information on the molecular regulation of hepatobiliary transport systems should bring new insights into the pathophysiology and treatment of human cholestatic liver diseases.
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Ácidos y Sales Biliares/metabolismo , Bilirrubina/metabolismo , Proteínas Portadoras/genética , Colestasis/genética , Cirrosis Hepática Biliar/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/genética , Colestasis/diagnóstico , Humanos , Cirrosis Hepática Biliar/diagnóstico , Mutación PuntualRESUMEN
UNLABELLED: This trial investigated the efficacy of a combination of high-dose interferon-alpha (IFN-alpha) with ribavirin in IFN nonresponders. STUDY PROTOCOL: 304 patients with chronic hepatitis C were treated with 5 MU IFN-alpha2b (IntronA(R), Schering-Plough) per TIW for 3 months. Nonresponders (defined by HCV-RNA positivity in serum after the 3 months of therapy) were randomized either to continue with IFN (5 MU IFN per TIW followed by 10 MU per TIW for each 3 months) alone (group A) or in combination with ribavirin (1-1.2 g per day) (group B). ALT was measured in monthly intervals, HCV-RNA in 3 monthly intervals. Pretreatment characteristics of the randomized patients were as follows: group A, n = 76; m/f, 54/22; 16% cirrhosis, age, 45. 7 +/- 12 years; ALT (U per litre), 66 +/- 35; group B, n = 81; m/f, 57/24; 17% cirrhosis, age, 48.2 +/- 12; ALT, 71 +/- 40. After 9 months of treatment, nine (11.6%) and 27 (32.5%, P = 0.0066) patients were HCV-RNA negative and 51 and 39 were HCV-RNA positive, in groups A and B, respectively. There were 17 drop-outs in group A and 15 in group B. Six months after treatment only two patients in group A (2.5%) and five (6%, P = 0.06) in group B had normal ALT and no detectable HCV-RNA in serum. In addition to the well-known side-effects of IFN the mean haemoglobin concentration dropped by 2 g per litre in group B. These data indicate that a combination of high-dose IFN with ribavirin is effective in inducing a short-lasting complete response in one-third of IFN nonresponders. Prolonged treatment with IFN/ribavirin may be necessary to obtain a sustained response.
Asunto(s)
Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Ribavirina/administración & dosificación , Adulto , Anciano , Alanina Transaminasa/sangre , Quimioterapia Combinada , Hepatitis C Crónica/virología , Humanos , Persona de Mediana Edad , ARN Viral/sangreRESUMEN
OBJECTIVE: Intolerance to azathioprine is a rare but important problem in treating chronically active Crohn's disease. We performed this study to evaluate mycophenolate mofetil as an alternative immunosuppressive therapy for patients with Crohn's disease who did not tolerate azathioprine. METHODS: Four patients with highly active perianal Crohn's disease and two patients with chronically active, steroid-dependent Crohn's disease were included. All patients consumed 2 g/day of mycophenolate mofetil for a median of 8 months (range, 6-12 months). Disease activity was measured by the Perianal Crohn's Disease Activity Index in patients with perianal disease and by the Crohn's Disease Activity Index in patients with chronically active Crohn's disease. RESULTS: Azathioprine-induced side effects disappeared after the drug was discontinued. All patients improved during treatment with mycophenolate mofetil, as shown by a remarkable reduction in the respective clinical scores. Five patients showed no side effects during treatment with mycophenolate mofetil. After 4 months' treatment one patient developed diarrhea that was probably not due to mycophenolate mofetil. CONCLUSION: Mycophenolate mofetil could be an alternative therapy to azathioprine in patients with Crohn's disease.
Asunto(s)
Enfermedad de Crohn/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Ácido Micofenólico/análogos & derivados , Adulto , Azatioprina/efectos adversos , Azatioprina/uso terapéutico , Enfermedad de Crohn/fisiopatología , Femenino , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Retratamiento , Resultado del TratamientoRESUMEN
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver frequently associated with extrahepatic autoimmune phenomena. Specific antibodies against platelet glycoproteins may play an important role in the pathogenesis of thrombocytopenia associated with PBC. This is the first report of life-threatening idiopathic thrombocytopenic purpura successfully treated with steroids in a 62-yr-old woman 2 yr after liver transplantation for PBC.