RESUMEN
Early data regarding the "real-world" experience with novel therapies for hepatitis C (HCV) are encouraging. Data are still limited, however, regarding real-world rates of sustained virologic response (SVR) for ledipasvir-sofosbuvir (LDV-SOF), particularly for patients with prior treatment failure. We performed a retrospective cohort study of 1597 patients with chronic genotype 1 HCV who were treated using 12 weeks of the following regimens LDV-SOF±ribavirin (RBV) (n=1521 without RBV, n=76 with RBV). The primary outcome was SVR-determined at 12 weeks in an intention-to-treat design. Prescription according to Food and Drug Administration (FDA) approved labelling (adding RBV for patients with cirrhosis and treatment failure) was assessed in multivariate models. The study population was aged 60 years on average (range 19-89), 60% male, 50% Caucasian, 43% cared for at an academic centre and 30% cirrhotic. Overall, LDV-SOF resulted in a 94% SVR rate. Only 44 (2.9%) patients relapsed. LDV-SOF+RBV yielded SVR in 97% with 0 viral relapses. While cirrhosis and thrombocytopenia were associated with lower odds of SVR, in a multivariable regression model, only treatment at an academic centre and prescriptions contrary to FDA labelling were significantly associated with lower SVR-odds ratios, 0.56 95% CI (0.35-0.87) and 0.29 95% CI(0.12-0.68), respectively. The real-world experience with LDV-SOF mirrors the SVR rates observed in clinical trials. Efforts to promote prescription within FDA recommendations are warranted.
Asunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Genotipo , Hepacivirus/clasificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Uridina Monofosfato/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Hepacivirus/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Ribavirina/uso terapéutico , Sofosbuvir , Respuesta Virológica Sostenida , Resultado del Tratamiento , Uridina Monofosfato/uso terapéutico , Adulto JovenRESUMEN
Despite the clinical success in the real-world of all oral hepatitis C virus (HCV) therapy with response rates approaching that seen in the clinical trials, access has been limited by many payers with discussion of prioritization of treatment based upon AASLD guidelines. We evaluated patients in the TRIO network who were prescribed sofosbuvir (SOF)-based regimens to determine reasons for not starting treatment. Trio Health is a disease management company that works in partnership with academic medical centres, community physicians and specialty pharmacies in the United States to optimize care for HCV. Data for 3841 patients prescribed a sofosbuvir-containing regimen between December 2013 and September 2014 were obtained through this programme. Of the entire group, 315 (8%) patients did not start the prescribed sofosbuvir-containing therapy. A total of 141 (45%) of the nonstart patients had a commercial plan as their primary insurance, 137 (44%) were primarily covered by Medicaid, 17 (5%) were primarily covered by Medicare, and 20 (6%) were either without coverage or coverage was not specified. Reasons for nonstarts were varied and overlapping. Only 15 patients (5% of nonstarts) did not start because they were unreachable or failed to complete required testing. Another 39 patients who did not start (12%) were following their physicians' direction to either wait for new treatment options or to hold treatment for an unspecified reason. Insurance-related processes and financial reasons accounted for 254 (81%) of the 315 nonstarts. The remaining 7 (2%) patients did not have a specified reason for not starting treatment. Nonstart rates were highest in the Medicaid-covered population at 35%. Medicare and Commercial nonstart rates were 2% and 6%, respectively. In a matched comparison, patients with commercial coverage were 6.5 times as likely to start SOF-based therapy compared to patients with Medicaid. Despite high SVR rates of SOF-based regimens in clinical practice, there are still barriers to access to care. In fact, almost half of the nonstart patients had advanced fibrosis scores (F3 or F4) and should have been prioritized to start treatment. As better treatment for HCV with high efficacy and low side effect rates become available, the disparity in access to treatment, as evidenced by the high nonstart rate in the Medicaid-covered group, must be resolved.
Asunto(s)
Antivirales/administración & dosificación , Accesibilidad a los Servicios de Salud , Hepatitis C Crónica/tratamiento farmacológico , Sofosbuvir/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Adherence to therapeutic regimens affects the efficacy of peginterferon alfa (P) and ribavirin (R) therapy in patients with chronic hepatitis C virus genotype 1. AIM: To determine if medication adherence impacts efficacy [sustained virological response (SVR)] with triple therapy that includes boceprevir (BOC) plus P/R. METHODS: Adherence was determined in two Phase 3 clinical studies with BOC: SPRINT-2 (previously untreated patients) and RESPOND-2 (patients who failed previous therapy with P/R). Adherence to the assigned duration of the dosing regimen and adherence to the three times a day (t.d.s.) dosing interval of 7-9 h for BOC were assessed by the recording of data from patients' dosing diaries and by the amount of study drug dispensed and returned. RESULTS: Most patients (63-71%) adhered to ≥80% of their assigned treatment duration and achieved SVR rates of 86-90%. In contrast, patients who adhered to <80% of their assigned treatment duration achieved SVR rates of 8-32% (P < 0.0001), particularly low in patients who failed previous therapy (SVR = 8-15%). Different rates of adherence (<60% to >80%) to the t.d.s. dosing interval (7-9 h) with BOC did not influence the SVR rates (SVR = 60-83%) with the exception of patients who failed previous treatment and adhered to <60% of the t.d.s. dosing interval with BOC (SVR = 48-50%; P = 0.005). CONCLUSIONS: The achievement of an SVR is more dependent on adherence to the assigned duration of treatment than adherence to the t.d.s. dosing interval with boceprevir. Adherence to >60% of t.d.s. dosing with boceprevir is important in patients who failed previous therapy.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Cumplimiento de la Medicación , Polietilenglicoles/uso terapéutico , Prolina/análogos & derivados , Ribavirina/uso terapéutico , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Genotipo , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Prolina/uso terapéutico , ARN Viral/genética , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: The efficacy of re-treating genotype I hepatitis C virus (HCV) patients who failed combination therapy with interferon/pegylated interferon (PEG-IFN) and ribavirin remains unclear. AIMS: To quantify sustained virological response (SVR) rates with different re-treatment regimens through meta-analysis of randomized controlled trials (RCTs). METHODS: Randomized controlled trials of genotype I HCV treatment failure patients that compared currently available re-treatment regimens were selected. Two investigators independently extracted data on patient population, methods and results. The pooled relative risk of SVR for treatment regimens was computed using a random effects model. RESULTS: Eighteen RCTs were included. In nonresponders to standard interferon/ribavirin, re-treatment with high-dose PEG-IFN combination therapy improved SVR compared with standard PEG-IFN combination therapy (RR=1.49; 95% CI: 1.09-2.04), but SVR rates did not exceed 18% in most studies. In relapsers to standard interferon/ribavirin, re-treatment with high-dose PEG-IFN or prolonged CIFN improved SVR (RR=1.57; 95% CI: 1.16-2.14) and achieved SVR rates of 43-69%. CONCLUSIONS: In genotype I HCV treatment failure patients who received combination therapy, re-treatment with high-dose PEG-IFN combination therapy is superior to re-treatment with standard combination therapy, although SVR rates are variable for nonresponders (≤18%) and relapsers (43-69%). Re-treatment may be appropriate for select patients, especially relapsers and individuals with bridging fibrosis or compensated cirrhosis.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Interferones/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepatitis C/virología , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/uso terapéutico , Interferones/administración & dosificación , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes , Retratamiento , Insuficiencia del Tratamiento , Carga ViralRESUMEN
BACKGROUND: A human betaretrovirus has been characterized in patients with primary biliary cirrhosis (PBC). Uncontrolled studies using combination anti-retroviral therapy have reported significant biochemical and histological improvement. AIM: To conduct a double blind, randomized controlled trial as a proof of principal to link infection with PBC. METHODS: Fifty-nine patients with an alkaline phosphatase level>1.5 upper limits of normal stabilized on ursodeoxycholic acid therapy were randomized to either 300 mg zidovudine and 150 mg lamivudine B.I.D. or placebo for 6 months. RESULTS: None of the patients normalized alkaline phosphatase and no significant differences were observed in normalizing serum aminotransferase levels. Significant differences were observed in the antiviral versus placebo arms with improvements in serial alkaline phosphatase (p<0.04), ALT (p<0.03) and AST (p<0.04) as well as clinical score (p<0.02). After 6 months, 25% of patients in the placebo arm and 4% in the antiviral arm had evidence of virus in serum. CONCLUSIONS: The study endpoints for normalizing hepatic biochemistry were too stringent to show efficacy for zidovudine and lamivudine therapy despite the demonstrable impact on clinical and biochemical improvement. Accordingly, more potent anti-viral regimens will be required to confirm the efficacy of antiviral therapy in PBC patients with human betaretrovirus infection.
Asunto(s)
Antivirales/uso terapéutico , Lamivudine/uso terapéutico , Cirrosis Hepática Biliar/tratamiento farmacológico , Infecciones por Retroviridae/tratamiento farmacológico , Infecciones Tumorales por Virus/tratamiento farmacológico , Ácido Ursodesoxicólico/uso terapéutico , Zidovudina/uso terapéutico , Adulto , Anciano , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Antivirales/efectos adversos , Aspartato Aminotransferasas/sangre , Betaretrovirus/efectos de los fármacos , Colagogos y Coleréticos/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Lamivudine/efectos adversos , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/complicaciones , Masculino , Persona de Mediana Edad , Infecciones por Retroviridae/sangre , Infecciones por Retroviridae/complicaciones , Resultado del Tratamiento , Zidovudina/efectos adversosRESUMEN
Hereditary hemochromatosis type 3 is an iron (Fe)-overload disorder caused by mutations in transferrin receptor 2 (TfR2). TfR2 is expressed highly in the liver and regulates Fe metabolism. The aim of this study was to investigate duodenal Fe absorption and hepatic Fe uptake in a TfR2 (Y245X) mutant mouse model of hereditary hemochromatosis type 3. Duodenal Fe absorption and hepatic Fe uptake were measured in vivo by 59Fe-labeled ascorbate in TfR2 mutant mice, wild-type mice, and Fe-loaded wild-type mice (2% dietary carbonyl Fe). Gene expression was measured by real-time RT-PCR. Liver nonheme Fe concentration increased progressively with age in TfR2 mutant mice compared with wild-type mice. Fe absorption (both duodenal Fe uptake and transfer) was increased in TfR2 mutant mice compared with wild-type mice. Likewise, expression of genes participating in duodenal Fe uptake (Dcytb, DMT1) and transfer (ferroportin) were increased in TfR2 mutant mice. Nearly all of the absorbed Fe was taken up rapidly by the liver. Despite hepatic Fe loading, hepcidin expression was decreased in TfR2 mutant mice compared with wild-type mice. Even when compared with Fe-loaded wild-type mice, TfR2 mutant mice had increased Fe absorption, increased duodenal Fe transport gene expression, increased liver Fe uptake, and decreased liver hepcidin expression. In conclusion, despite systemic Fe loading, Fe absorption and liver Fe uptake were increased in TfR2 mutant mice in association with decreased expression of hepcidin. These findings support a model in which TfR2 is a sensor of Fe status and regulates duodenal Fe absorption and liver Fe uptake.
Asunto(s)
Duodeno/metabolismo , Hemocromatosis/genética , Absorción Intestinal , Hierro/metabolismo , Hígado/metabolismo , Receptores de Transferrina/genética , Animales , Secuencia de Bases , Transporte Biológico , Cruzamientos Genéticos , Cartilla de ADN , Modelos Animales de Enfermedad , Femenino , Ferritinas/metabolismo , Tamización de Portadores Genéticos , Hemocromatosis/metabolismo , Hierro/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones MutantesRESUMEN
Hepatitis C is a global problem with significantly associated morbidity and mortality. Although some recent therapeutic advances have shown rates of sustained virologic remission of 50% or higher, combination therapy with interferon and ribavirin is often not well tolerated and is giving rise to a growing number of nonresponders. As a result, a large number of experimental drugs for the treatment of chronic hepatitis C are in development. As the clinical trial reports are made available, physicians need to become familiar with issues related to the design of these studies and to develop strategies to interpret the evidence they yield. The articles in this supplement describe the issues in clinical trial design and the evaluation of evidence from clinical trials in patients with chronic hepatitis C.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/crecimiento & desarrollo , Hepatitis C Crónica/tratamiento farmacológico , Ensayos Clínicos como Asunto , Quimioterapia Combinada , Humanos , Interferones/uso terapéutico , Ribavirina/uso terapéuticoRESUMEN
Hereditary hemochromatosis, a disease of iron overload, occurs in about 1 in 200-400 Caucasians. The gene mutated in this disorder is termed HFE. The product of this gene, HFE protein, is homologous to major histocompatibility complex class I proteins, but HFE does not present peptides to T cells. Based on recent structural, biochemical, and cell biological studies, transferrin receptor (TfR) is a ligand for HFE. This association directly links HFE protein to the TfR-mediated regulation of iron homeostasis. Although evidence is accumulating that binding of HFE to TfR is critical for the effects of HFE, the final pieces in the HFE puzzle have not been established. This review focuses on recent advances in HFE research and presents a hypothetical model of HFE function.
Asunto(s)
Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase I/genética , Hierro/farmacocinética , Proteínas de la Membrana , Mutación/fisiología , Absorción , Animales , Antígenos HLA/fisiología , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/fisiología , Homeostasis , Humanos , Hierro/metabolismo , Sobrecarga de Hierro/genéticaAsunto(s)
Terapias Complementarias , Hepatopatías/terapia , Adyuvantes Inmunológicos/uso terapéutico , Antioxidantes/uso terapéutico , Enfermedad Crónica , Terapias Complementarias/estadística & datos numéricos , Hepatitis C/terapia , Humanos , Fitoterapia , Extractos Vegetales/uso terapéutico , Seguridad , Vitaminas/uso terapéuticoRESUMEN
OBJECTIVES: Therapy with a interferon is associated with a rise in serum triglyceride levels, although this effect has not been well studied with newer forms of interferon or interferon in combination with ribavirin. METHODS: Review of combined data obtained from several prospective, randomized controlled clinical trials conducted in the clinical studies unit of a tertiary care referral center among patients with chronic hepatitis C undergoing treatment with various forms of a interferon, with or without the addition of ribavirin. Serum levels of triglycerides and cholesterol were measured before and during therapy. Changes in these levels were correlated with baseline characteristics. RESULTS: At baseline, the mean serum triglyceride level among 152 patients studied was 130 mg/dL (range 32-620) and was elevated above normal in three patients (2%). During therapy, triglyceride levels rose significantly early on and began to decline spontaneously after 12 wk, returning to baseline after stopping treatment. Triglyceride levels rose above 500 mg/dL in 18 patients (12%) and above 1000 mg/dL in two patients (1.3%) although none experienced acute complications or clinical symptoms. Serum cholesterol levels did not change significantly during therapy (mean at baseline 172 vs 168 mg/dL at 24 wk). Factors correlated with the rise in triglycerides included baseline triglyceride levels, HCV genotype, and the type of interferon used. CONCLUSIONS: Serum triglyceride levels increase consistently in patients with chronic hepatitis C treated with all forms of a interferon, often to very high levels. These changes do not seem to be associated with clinical signs or complications and triglyceride levels decline while patients are still on therapy and return to normal after stopping.
Asunto(s)
Antivirales/uso terapéutico , Colesterol/sangre , Hepatitis C Crónica/sangre , Hepatitis C Crónica/tratamiento farmacológico , Interferones/uso terapéutico , Triglicéridos/sangre , Adulto , Anciano , Distribución de Chi-Cuadrado , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Ribavirina/uso terapéuticoRESUMEN
The gene for hemochromatosis (HFE) was recently identified and contains two missense mutations: C282Y and H63D. The C282Y mutation is found homozygous in approximately 85% to 90% of patients of Northern European ancestry with hereditary hemochromatosis. There are no previous reports with results of genetic testing in Chinese patients with regard to iron overload. In this case report, we describe a Chinese woman with marked hepatic iron overload that was nonfamilial, with unusual biopsy findings, in whom neither the C282Y nor the H63D mutations in HFE were found.
Asunto(s)
Antígenos HLA/genética , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana , Anciano , Biopsia , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Hemocromatosis/patología , Proteína de la Hemocromatosis , Hong Kong , Humanos , Hígado/patologíaRESUMEN
Hereditary hemochromatosis (HH) is a common chronic human genetic disorder whose hallmark is systemic iron overload. Homozygosity for a mutation in the MHC class I heavy chain paralogue gene HFE has been found to be a primary cause of HH. However, many individuals homozygous for the defective allele of HFE do not develop iron overload, raising the possibility that genetic variation in modifier loci contributes to the HH phenotype. Mice deficient in the product of the beta(2)-microglobulin (beta(2)M) class I light chain fail to express HFE and other MHC class I family proteins, and they have been found to manifest many characteristics of the HH phenotype. To determine whether natural genetic variation plays a role in controlling iron overload, we performed classical genetic analysis of the iron-loading phenotype in beta(2)M-deficient mice in the context of different genetic backgrounds. Strain background was found to be a major determinant in iron loading. Sex played a role that was less than that of strain background but still significant. Resistance and susceptibility to iron overload segregated as complex genetic traits in F(1) and back-cross progeny. These results suggest the existence of naturally variant autosomal and Y chromosome-linked modifier loci that, in the context of mice genetically predisposed by virtue of a beta(2)M deficiency, can profoundly influence the severity of iron loading. These results thus provide a genetic explanation for some of the variability of the HH phenotype.
Asunto(s)
Ligamiento Genético/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/patología , Proteínas de la Membrana , Microglobulina beta-2/deficiencia , Envejecimiento , Animales , Cruzamientos Genéticos , Femenino , Antígenos HLA/genética , Hemo/metabolismo , Hemocromatosis/genética , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/genética , Hierro/metabolismo , Sobrecarga de Hierro/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos , Fenotipo , Caracteres Sexuales , Cromosomas Sexuales/genética , Microglobulina beta-2/genéticaRESUMEN
BACKGROUND/AIMS: The mechanism of hepatic fibrogenesis with chronic viral hepatitis is not well understood. Persistent activation of hepatic stellate cells is felt to play a role in the development of fibrogenesis and progression to cirrhosis. METHODOLOGY: We determined the expression of hepatic alpha-smooth muscle actin, a marker of hepatic stellate cell activation, in 29 patients with chronic hepatitis C and varying degrees of liver injury and fibrosis. In addition to a baseline evaluation, we assessed the effect of interferon therapy on alpha-smooth muscle actin expression in 11 patients, including 6 with a sustained response to therapy. Specimens were evaluated by light microscopy for grade of inflammation and stage of fibrosis. Expression of alpha-smooth muscle actin was assessed semiquantitatively by immunohistochemical staining. RESULTS: At baseline, all patients had alpha-smooth muscle actin expressed within the liver without an obvious correlation with the severity of liver injury. However, among sustained responders, a reduction in hepatic necroinflammatory activity was associated with a trend towards a decrease in alpha-smooth muscle actin expression. This however did not reach statistical significance. CONCLUSIONS: Hepatic alpha-smooth muscle actin expression, as a marker of hepatic stellate cell activation appears reversible and tends to correlate with necroinflammatory activity.
Asunto(s)
Actinas/análisis , Antivirales/uso terapéutico , Hepatitis C Crónica/metabolismo , Interferón-alfa/uso terapéutico , Hígado/química , Músculo Liso/metabolismo , Biomarcadores/análisis , Femenino , Fibrosis , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/patología , Hepatocitos/química , Humanos , Inmunohistoquímica , Inflamación , Hígado/patología , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
Chronic infection with hepatitis C virus (HCV) may result in cirrhosis, liver failure, and hepatocellular carcinoma. A minority of patients have a sustained response to antiviral therapy, and nonresponders remain at risk of developing progressive liver disease. We conducted a randomized, controlled trial of therapy with the combination of interferon (IFN) and ribavirin in patients with chronic hepatitis C who had not responded to an initial course of therapy with IFN alone. A total of 124 patients were randomized to receive the combination of IFN and ribavirin for either 24 or 48 weeks and followed for an additional 24 weeks after stopping therapy. Thirty-eight treated patients (30.6%) achieved a sustained virologic response (undetectable HCV RNA at the 24-week follow-up point). This was associated with significant improvement in necroinflammatory activity noted on liver biopsy. Interestingly, there was not a statistically significant difference in response rates based on the duration of treatment; HCV genotype was the strongest predictor of a sustained response. Sustained responses were noted even in patients with poor predictive factors, including those with advanced hepatic fibrosis or cirrhosis, high levels of HCV RNA in serum, and those infected with HCV genotype 1. The study included 24 patients with normal serum alanine transaminase (ALT) values before therapy who had similar responses to those with initially elevated transaminase values. This study suggests that the combination of IFN and ribavirin is a useful modality of therapy in patients with chronic hepatitis C who did not respond to IFN alone.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferones/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Anciano , Alanina Transaminasa/sangre , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Hepacivirus/genética , Hepatitis C Crónica/sangre , Hepatitis C Crónica/patología , Hepatitis C Crónica/virología , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , ARN Viral/análisis , Recurrencia , RetratamientoRESUMEN
HH should be distinguished from the other syndromes of iron overload. Many patients with HH have abnormal serum iron values before the development of any significant symptoms or clinical findings, and liver biopsy is less important in these patients. HFE mutation analysis has strengthened our ability to diagnose HH accurately and is useful in family studies. HFE mutations may play a contributory role in some patients with PCT, NASH, or chronic HCV. Generalized population screening for HH may someday become a reality and lead to the identification and treatment of more patients before they have tissue damage or increased morbidity. With the identification of the HFE gene, we are beginning to unravel many of the mysteries of both normal iron absorption and the disorder of iron metabolism found in patients with HH.
Asunto(s)
Hemocromatosis/diagnóstico , Proteínas de la Membrana , Antígenos HLA/genética , Hemocromatosis/genética , Hemocromatosis/terapia , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Sobrecarga de Hierro/clasificación , Hepatopatías/genética , MutaciónRESUMEN
Hereditary hemochromatosis (HH) is a common disorder of iron metabolism caused by mutation in HFE, a gene encoding an MHC class I-like protein. Clinical studies demonstrate that the severity of iron loading is highly variable among individuals with identical HFE genotypes. To determine whether genetic factors other than Hfe genotype influence the severity of iron loading in the murine model of HH, we bred the disrupted murine Hfe allele onto three different genetically defined mouse strains (AKR, C57BL/6, and C3H), which differ in basal iron status and sensitivity to dietary iron loading. Serum transferrin saturations (percent saturation of serum transferrin with iron), hepatic and splenic iron concentrations, and hepatocellular iron distribution patterns were compared for wild-type (Hfe +/+), heterozygote (Hfe +/-), and knockout (Hfe -/-) mice from each strain. Although the Hfe -/- mice from all three strains demonstrated increased transferrin saturations and liver iron concentrations compared with Hfe +/+ mice, strain differences in severity of iron accumulation were striking. Targeted disruption of the Hfe gene led to hepatic iron levels in Hfe -/- AKR mice that were 2.5 or 3.6 times higher than those of Hfe -/- C3H or Hfe -/- C57BL/6 mice, respectively. The Hfe -/- mice also demonstrated strain-dependent differences in transferrin saturation, with the highest values in AKR mice and the lowest values in C3H mice. These observations demonstrate that heritable factors markedly influence iron homeostasis in response to Hfe disruption. Analysis of mice from crosses between C57BL/6 and AKR mice should allow the mapping and subsequent identification of genes modifying the severity of iron loading in this murine model of HH.
Asunto(s)
Hemocromatosis/metabolismo , Hierro/metabolismo , Animales , Modelos Animales de Enfermedad , Hemocromatosis/genética , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad de la Especie , Bazo/metabolismo , Bazo/patología , Transferrina/metabolismoAsunto(s)
Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles , Ribavirina/uso terapéutico , Aprobación de Drogas , Quimioterapia Combinada , Humanos , Interferón alfa-2 , Proteínas Recombinantes , Estados Unidos , United States Food and Drug AdministrationRESUMEN
BACKGROUND/AIMS: Myofibroblasts are the primary cells responsible for increased matrix deposition in hepatic fibrosis. Activation of hepatic stellate cells and portal fibroblasts to myofibroblasts during cholestatic liver injury is accompanied by increased expression of the activation marker, alpha-smooth muscle actin (SMA), and collagen genes. In contrast to our understanding of injury, the cellular mechanisms of liver repair are not well defined. This study was designed to examine the morphological relationship between bile duct hyperplasia, matrix deposition and myofibroblast phenotype in a model of chronic cholestatic liver injury and repair. METHODS: Reversible extrahepatic obstruction was accomplished in rats using a soft vessel loop suspended from the anterior abdominal wall: duct manipulation alone was performed in sham-operated controls. After 7 days, rats were either sacrificed or decompressed by release of the loop and subsequently sacrificed 2-10 days after reversal. Liver sections were obtained for in situ hybridization for procollagen alpha1(I) mRNA, immunohistochemical staining for SMA and cytokeratin 19, and histochemical staining for reticulin. RESULTS: Cholestatic livers demonstrated bile duct hyperplasia, which reversed to normal within 10 days after decompression. Fibrosis was also substantially reduced during this period. SMA-positive myofibroblasts were abundant and localized to regions adjacent to proliferating ducts and excess matrix in the obstructed animals. Decompressed livers showed a dramatic time-dependent reduction in the number of SMA-positive cells and in the expression of procollagen I mRNA. CONCLUSIONS: Our results show that the disappearance of bile duct hyperplasia after biliary decompression is accompanied by a similarly rapid loss of SMA-positive myofibroblasts. Both cellular events may abrogate enhanced matrix synthesis and allow repair to occur.
Asunto(s)
Conductos Biliares/patología , Colestasis Extrahepática/patología , Matriz Extracelular/metabolismo , Fibroblastos/fisiología , Hiperplasia/patología , Regeneración Hepática , Hígado/metabolismo , Actinas/metabolismo , Alanina Transaminasa/sangre , Animales , Conductos Biliares/metabolismo , Bilirrubina/sangre , Colestasis Extrahepática/complicaciones , Colestasis Extrahepática/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Fibroblastos/citología , Histocitoquímica , Hiperplasia/complicaciones , Hiperplasia/metabolismo , Queratinas/metabolismo , Hígado/patología , Cirrosis Hepática Experimental/complicaciones , Cirrosis Hepática Experimental/metabolismo , Cirrosis Hepática Experimental/patología , Masculino , Procolágeno/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reticulina/metabolismo , gamma-Glutamiltransferasa/sangreRESUMEN
Lamivudine is effective in inhibiting hepatitis B virus (HBV) replication, and its clinical use in patients with chronic hepatitis B is associated with improvements in serum aminotransferase levels and liver histopathologic characteristics. Few data are available on its use in patients with advanced liver disease. We report on the outcomes of 5 patients with hepatic decompensation caused by chronic hepatitis B treated long term with lamivudine. All patients were adult white men seropositive for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) before therapy. All 5 patients had biopsy-proven cirrhosis with clinical and biochemical evidence of hepatic decompensation. Two patients had Child's class C cirrhosis; 2 patients, class B; and 1 patient, class A (although this patient had persistent portasystemic encephalopathy and developed variceal bleeding). HBV DNA became undetectable in all patients and remained so throughout the study. Both patients with Child's class C and 1 patient with class B cirrhosis had significant clinical improvement. Child-Pugh scores improved from 12 to 7 and 11 to 7 in the 2 patients with Child's class C cirrhosis, and the patient with class B cirrhosis had complete resolution of troublesome encephalopathy. Serum aminotransferase, albumin, and total bilirubin levels improved significantly in 3 of 5 patients. One patient with Child's class B cirrhosis underwent orthotopic liver transplantation at week 13 after dramatic increases in liver tests and clinical worsening. The patient subsequently cleared HBeAg and HBsAg from serum posttransplantation. In conclusion, prolonged therapy with lamivudine resulted in improved serum biochemical values and loss of HBV DNA in patients with decompensated cirrhosis. Clinical improvements, reflected in Child-Pugh classification and functional status, may also occur, particularly among those with Child's class C disease initially.