RESUMO
BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) has shown efficacy in primary biliary cirrhosis (PBC), a chronic, slowly progressive disease. We hypothesized that UDCA use would reduce the need for liver transplantation in PBC. Our study's aim was to assess liver transplantation requirements in PBC over a 12-year period. For comparison, we studied patients with primary sclerosing cholangitis (PSC) because it shares similar characteristics to PBC, but with a decreased response to UDCA. METHODS: PBC and PSC transplant data of first-time liver recipients from the United Network for Organ Sharing database were collected from 1995 to 2006. RESULTS: The absolute number of liver transplantations in the United States increased an average of 249 transplants per year (P < .001). The absolute number of transplants performed for PBC decreased an average of 5.4 cases per year (P = .004). The absolute number of transplantations for PSC showed no statistical change (P = .621). The trends for the absolute number of individuals added to the transplant waitlist showed a similar pattern: (1) an increase in total listings for transplants of all diagnoses (beta = 265; P = .001); (2) a decrease in PBC (beta = -12.1; P < .001); (3) and no change for PSC (beta = -5.434; P = .083). CONCLUSIONS: The liver transplantation burden of PBC in the United States decreased between 1995 and 2006. This is despite an increase in total liver transplants and no change in transplant rates for PSC.
Assuntos
Cirrose Hepática Biliar/terapia , Transplante de Fígado/tendências , Colagogos e Coleréticos/uso terapêutico , Colangite Esclerosante/epidemiologia , Colangite Esclerosante/terapia , Humanos , Cirrose Hepática Biliar/epidemiologia , Estudos Retrospectivos , Estados Unidos , Ácido Ursodesoxicólico/uso terapêutico , Listas de EsperaRESUMO
AIM: To assess the real-world effectiveness and cost of simeprevir (SMV), and/or sofosbuvir (SOF)-based therapy for chronic hepatitis C virus (HCV) infection. METHODS: The real-world performance of patients treated with SMV/SOF ± ribavirin (RBV), SOF/RBV, and SOF/RBV with pegylated-interferon (PEG) were analyzed in a consecutive series of 508 patients with chronic HCV infection treated at a single academic medical center. Patients with genotypes 1 through 4 were included. Rates of sustained virological response - the absence of a detectable serum HCV RNA 12 wk after the end of treatment [sustained virological response (SVR) 12] - were calculated on an intention-to-treat basis. Costs were calculated from the payer's perspective using Medicare/Medicaid fees and Redbook Wholesale Acquisition Costs. Patient-related factors associated with SVR12 were identified using multivariable logistic regression. RESULTS: SVR12 rates were as follows: 86% (95%CI: 80%-91%) among 178 patients on SMV/SOF ± RBV; 62% (95%CI: 55%-68%) among 234 patients on SOF/RBV; and 78% (95%CI: 68%-86%) among 96 patients on SOF/PEG/RBV. Mean costs-per-SVR12 were $174442 (standard deviation: ± $18588) for SMV/SOF ± RBV; $223003 (± $77946) for SOF/RBV; and $126496 (± $31052) for SOF/PEG/RBV. Among patients on SMV/SOF ± RBV, SVR12 was less likely in patients previously treated with a protease inhibitor [odds ratio (OR): 0.20, 95%CI: 0.06-0.56]. Higher bilirubin (OR: 0.47, 95%CI: 0.30-0.69) reduced the likelihood of SVR12 among patients on SOF/RBV, while FIB-4 score ≥ 3.25 reduced the likelihood of SVR12 (OR: 0.18, 95%CI: 0.05-0.59) among those on SOF/PEG/RBV. CONCLUSION: SVR12 rates for SMV and/or SOF-based regimens in a diverse real-world population are comparable to those in clinical trials. Treatment failure accounts for 27% of costs.
RESUMO
AIM: To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection. METHODS: Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite outcome. RESULTS: Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre-treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P < 0.01), estimated glomerular filtration rate (OR = 0.95 per mL/min per 1.73 m(2), 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P < 0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for cases. CONCLUSION: Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge.
Assuntos
Antivirais/efeitos adversos , Doença Hepática Terminal/cirurgia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Falência Hepática/induzido quimicamente , Transplante de Fígado/efeitos adversos , Sofosbuvir/efeitos adversos , Adulto , Idoso , Anemia/induzido quimicamente , Quimioterapia Combinada , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/virologia , Feminino , Hepacivirus/patogenicidade , Hepatite C/diagnóstico , Hepatite C/virologia , Humanos , Estimativa de Kaplan-Meier , Falência Hepática/diagnóstico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Recidiva , Ribavirina/efeitos adversos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ativação Viral/efeitos dos fármacosRESUMO
AIM: To describe our experience using a low-accelerating-dose regimen (LADR) with pegylated interferon alpha-2a and ribavirin in treatment of hepatitis C virus (HCV) recurrence. METHODS: From 2003, a protocolized LADR strategy was employed to treat liver transplant (LT) recipients with recurrent HCV at our institution. Medical records of 182 adult patients with recurrent HCV treated with LADR between 1/2003 and 1/2011 were reviewed. Histopathology from all post-LT liver biopsies were reviewed in a blinded fashion. Paired recipient and donor IL28B status were assessed. A novel technique was employed to ascertain recipient and donor IL28B (rs12979860) Gt data using DNA extracted from archival FFPE tissue from explanted native livers and donor gallbladders respectively. The primary endpoint was SVR; secondary endpoints examined include (1) patient and graft survival; (2) effect of anti-viral therapy on liver histology (fibrosis and inflammation); (3) incidence of on-treatment development of ACR, CDR, or PCH; (4) association of recipient and donor IL28B genotype with SVR; and (5) incidence of anti-viral therapy-associated adverse events (anemia, leukopenia, thrombocytopenia, depression) and hepatic decompensation. RESULTS: The overall SVR rate was 38% (29% Gt1, 67% Gt2, 86% Gt3 and 58% Gt4). HCV Gt (P < 0.0001), donor age (P = 0.003), cytomegalovirus mismatch (P = 0.001), baseline serum bilirubin (P = 0.002), and baseline viral load (P = 0.04) were independent predictors for SVR. SVR rates were significantly higher in the recipient-CC/donor-non CC pairs (P = 0.007). Neither baseline fibrosis nor change in fibrosis stage after anti-viral therapy were associated with SVR. Fibrosis progressed in 72% of patients despite SVR. Median graft survival was 91 mo. Five-year patient survival was superior in patients who achieved SVR (97% vs 82%, P = 0.001). Pre-treatment ALP ≥ 150 U/L (P = 0.01), total bilirubin ≥ 1.5 mg/dL (P = 0.001) and creatinine ≥ 2 mg/dL (P = 0.001) were independently associated with patient survival. Only 13% of patients achieving SVR died during the follow-up period. Treatment discontinuation and treatment-related mortality occurred in 35% and 2.2% of patients, respectively. EPO, G-CSF and blood transfusion were needed in 89%, 40% and 23% of patients, respectively. Overall hospitalization rate for treatment-related serious adverse events was 21%. Forty-six (25%) of the patients were deceased; among those who died, 25 (54%) were due to liver-related complications, and 4 deaths (9%) occurred while receiving therapy (2 patients experienced hepatic decompensation and 2 sepsis). CONCLUSION: LADR strategy remains relevant in managing post-LT recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs.
Assuntos
Antivirais/administração & dosagem , Doença Hepática Terminal/cirurgia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Interferon-alfa/administração & dosagem , Transplante de Fígado/efeitos adversos , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Antivirais/efeitos adversos , Biópsia , Progressão da Doença , Quimioterapia Combinada , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/virologia , Feminino , Genótipo , Sobrevivência de Enxerto , Hepacivirus/genética , Hepacivirus/crescimento & desenvolvimento , Hepatite C/complicações , Hepatite C/diagnóstico , Hepatite C/genética , Hepatite C/mortalidade , Humanos , Interferon-alfa/efeitos adversos , Interferons , Interleucinas/genética , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque , Polietilenoglicóis/efeitos adversos , Modelos de Riscos Proporcionais , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Recidiva , Estudos Retrospectivos , Ribavirina/efeitos adversos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Ativação Viral/efeitos dos fármacosRESUMO
Individuals afflicted with primary biliary cirrhosis (PBC) first undergo chronic, nonsuppurative destruction of their intrahepatic bile ducts, eventually leading to cirrhosis. Over nearly 50 years, many faculty members at the Mount Sinai School of Medicine, including Dr. Hans Popper and Dr. Fenton Schaffner, have made important contributions to our understanding of the natural history and histopathologic evolution of PBC. And today, many patients with PBC continue to be cared for at Mount Sinai. In the absence of a cure for the disease, these patients continue to be enrolled in clinical trials and, when necessary, in the Mount Sinai liver transplant program. The establishment of the Center for the Study of Primary Biliary Cirrhosis at Mount Sinai, supported by the Artzt Family Foundation Trust, has enabled the faculty to expand both clinical and basic science initiatives related to primary biliary cirrhosis. Several of these new initiatives are described below and placed in the context of our current understanding of the immunopathogenesis of PBC.
Assuntos
Cirrose Hepática Biliar/imunologia , Antígenos/sangue , Apoptose , Autoanticorpos/sangue , Doenças Autoimunes/complicações , Humanos , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/terapiaRESUMO
Primary biliary cirrhosis (PBC) is an uncommon autoimmune disease with a homogeneous clinical phenotype that reflects incomplete disease concordance in monozygotic (MZ) twins. We have taken advantage of a unique collection consisting of genomic DNA and mRNA from peripheral blood cells of female MZ twins (n = 3 sets) and sisters of similar age (n = 8 pairs) discordant for disease. We performed a genome-wide study to investigate differences in (i) DNA methylation (using a custom tiled four-plex array containing tiled 50-mers 19,084 randomly chosen methylation sites), (ii) copy number variation (CNV) (with a chip including markers derived from the 1000 Genomes Project, all three HapMap phases, and recently published studies), and/or (iii) gene expression (by whole-genome expression arrays). Based on the results obtained from these three approaches we utilized quantitative PCR to compare the expression of candidate genes. Importantly, our data support consistent differences in discordant twins and siblings for the (i) methylation profiles of 60 gene regions, (ii) CNV of 10 genes, and (iii) the expression of 2 interferon-dependent genes. Quantitative PCR analysis showed that 17 of these genes are differentially expressed in discordant sibling pairs. In conclusion, we report that MZ twins and sisters discordant for PBC manifest particular epigenetic differences and highlight the value of the epigenetic study of twins.
RESUMO
Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease with a strong genetic susceptibility due to the high concordance in monozygotic (MZ) twins and a striking female predominance. Women with PBC manifest an enhanced X monosomy rate in peripheral lymphocytes and we thus hypothesized an X chromosome epigenetic component to explain PBC female prevalence. While most genes on the female inactive X chromosome are silenced by promoter methylation following X chromosome inactivation (XCI), approximately 10% of X- linked genes exhibit variable escape from XCI in healthy females. This study was designed to test the hypothesis that susceptibility to PBC is modified by one or more X-linked gene with variable XCI status. Peripheral blood mRNA and DNA samples were obtained from a unique cohort of MZ twin sets discordant and concordant for PBC. Transcript levels of the 125 variable XCI status genes was determined by quantitative RT-PCR analysis and two genes (CLIC2 and PIN4) were identified as consistently downregulated in the affected twin of discordant pairs. Both CLIC2 and PIN4 demonstrated partial and variable methylation of CpG sites within 300 bp of the transcription start site that did not predict the XCI status. Promoter methylation of CLIC2 manifested no significant difference between samples and no significant correlation with transcript levels. PIN4 methylation showed a positive trend with transcription in all samples but no differential methylation was observed between discordant twins. A genetic polymorphism affecting the number of CpG sites in the PIN4 promoter did not impact methylation or transcript levels in a heterozygous twin pair and showed a similar frequency in independent series of unrelated PBC cases and controls. Our results suggest that epigenetic factors influencing PBC onset are more complex than methylation differences at X-linked promoters and variably 3 inactivated X-linked genes may be characterized by partial promoter methylation and biallelic transcription.
Assuntos
Cromossomos Humanos X/metabolismo , Metilação de DNA , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Cirrose Hepática Biliar/metabolismo , Gêmeos Monozigóticos/metabolismo , Inativação do Cromossomo X , Canais de Cloreto/biossíntese , Canais de Cloreto/genética , Cromossomos Humanos X/genética , Estudos de Coortes , Ilhas de CpG/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Cirrose Hepática Biliar/genética , Linfócitos/metabolismo , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase/biossíntese , Peptidilprolil Isomerase/genética , Polimorfismo Genético , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Transcrição Gênica/genética , Gêmeos Monozigóticos/genéticaRESUMO
Primary biliary cirrhosis (PBC) is an autoimmune disease of unclear etiology. It is a chronic, progressive condition that causes intrahepatic ductal destruction ultimately leading to symptoms of cholestasis, cirrhosis and liver failure. The disease predominantly affects middle aged Caucasian women. It has a predilection to certain regions and is found in higher incidences in North America and Northern Europe. It also has a genetic predisposition with a concordance rate of 60% among monozygotic twins. Combinations of genetic and environmental factors are proposed in the pathogenesis of this disease with a compelling body of evidence that suggests a role for both these factors. This review will elucidate data on the proposed environmental agents involved the disease's pathogenesis including xenobiotic and microbial exposure and present some of the supporting epidemiologic data.
Assuntos
Exposição Ambiental/efeitos adversos , Cirrose Hepática Biliar/etiologia , Animais , Predisposição Genética para Doença , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Positivas/complicações , Humanos , Cirrose Hepática Biliar/epidemiologia , Cirrose Hepática Biliar/genética , Fatores de Risco , Xenobióticos/efeitos adversosRESUMO
BACKGROUND: To lessen the severity of recurrent hepatitis C virus (HCV) postliver transplantation (post-LT) by treating HCV patients with cirrhosis, we assessed the safety and efficacy of an escalating dose pegylated interferon (PEG-IFN)/ribavirin protocol in pre-LT patients. METHODS: Ninety patients were treated with 90 microg PEG-IFN alpha-2a and 400 mg ribavirin and advanced to 180 microg and 800 to 1200 mg, respectively, over 8 weeks. RESULTS: Mean age was 55.3 years. Thirty-four percent of patients received prior interferon treatment, 77% had genotype 1 or 4. Mean Child's score was 6.7 and model for end-stage liver disease 11.2; 49% reached full-dose PEG-IFN and 85% ribavirin, 18% required dose reduction, 33% stopped treatment because of adverse effects, 9% had deterioration of liver function, and 7% died. Follow-up of 9.6 months showed sustained virological response in 13% of patients. The rate of serious complications was 16.3% in Child's class A, 48% in B, and 100% in C (P=0.005). Serum albumin was a significant predictor for worsening liver function (P=0.007). CONCLUSIONS: Using an escalating dose regimen of PEG-IFN alpha-2a and ribavirin, we achieved only a 13% sustained virological response in HCV cirrhotic pre-LT patients with an accompanying 9% risk of worsening liver function and 7% risk of death.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/metabolismo , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Interferon-alfa/uso terapêutico , Cirrose Hepática/terapia , Transplante de Fígado/métodos , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Idoso , Esquema de Medicação , Feminino , Genótipo , Humanos , Interferon alfa-2 , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Resultado do TratamentoRESUMO
Primary biliary cirrhosis is characterized by chronic hepatic inflammation and immune mediated apoptosis of bile duct epithelial cells. Delayed macrophage phagocytosis of opsonized apoptotic cells, noted in other autoimmune diseases, may promote inflammation. Recent studies suggest serum anti-CD16 autoantibodies contribute to impaired macrophage phagocytosis by blocking complement receptor 3 (CR3) signaling via CD16. Therefore, serum anti-CD16 levels and the ability of monocyte derived macrophages from individuals with PBC to phagocytosis apoptotic cells were compared to controls. The mean level of anti-CD16 IgM autoantibodies (0.86+/-0.62 v. 0.35+/-0.22, respectively, p=0.031) was increased in PBC compared to control sera, and mean PBC phagocytosis of opsonized apoptotic cells was significantly decreased compared to controls (23.9+/-12.2% v. 43.9+/-14.4%, respectively, p=0.020). However, PBC phagocytosis of opsonized apoptotic cells was not significantly affected by the presence or absence of autologous serum (20.8+/-13.5% v. 23.9+/-12.2%, respectively, p=0.560). PBC phagocytosis of opsonized apoptotic cells inversely correlated with CD16 (and CR3) expression levels on Day 5 after culture in the presence or absence of autologous serum (r=-0.546, p=0.033 and r=-0.519, p=0.042, respectively). Phagocytosis of non-opsonized apoptotic cells did not correlate with CD16 or CR3 expression (p>0.050). In conclusion, PBC macrophage phagocytosis of opsonized apoptotic cells is impaired, irrespective of serum factors and may increase hepatic inflammation.
Assuntos
Apoptose/imunologia , Autoanticorpos/sangue , Cirrose Hepática Biliar/imunologia , Fagocitose/imunologia , Receptores de IgG/imunologia , Autoantígenos/imunologia , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/patologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Opsonizantes/imunologiaRESUMO
Statin treatment reduces hypercholesterolemia and may be anti-inflammatory. Case reports noted decreased alkaline phosphatase and histological improvement following statin treatment in primary biliary cirrhosis. The objective of this study was to assess the long-term effects of statin treatment in primary biliary cirrhosis. A retrospective analysis compared clinical and biochemical data from 15 hypercholesterolemic individuals with primary biliary cirrhosis who were treated long-term with atorvastatin with an age and gender matched, primary biliary cirrhosis control group. A significant decrease in total cholesterol and low-density lipoprotein (LDL)-cholesterol (p < or = 0.002) was observed throughout atorvastatin treatment (median time 2.5 years). LDL-cholesterol levels in the control group were not significantly changed after 2 years (p > 0.050). No significant changes were noted in alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin and Mayo Risk Score in either group (p > 0.05). Long-term atorvastatin treatment reduced LDL-cholesterol in primary biliary cirrhosis, but there was no evidence of any anti-inflammatory effect.
Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Cirrose Hepática Biliar/tratamento farmacológico , Pirróis/uso terapêutico , Idoso , Atorvastatina , Feminino , Humanos , Hipercolesterolemia/complicações , Lipídeos/sangue , Cirrose Hepática Biliar/complicações , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are uncommon liver diseases of unknown etiology. Reported clustering of PBC cases may be due to environmental factors. Individuals with PBC have a high prevalence of thyroid disease and thyroid disease is reportedly more prevalent near Superfund toxic waste sites (SFS). The objective of this study was to examine the prevalence and potential clustering of individuals with PBC and PSC near SFS. De-identified clinical and demographic data were used to determine the observed prevalence for each New York City zip code (n = 174) and borough (n = 5) of patients with PBC (PBC-OLT) or PSC (PSC-OLT) who were listed for liver transplantation. The expected prevalence was calculated using Organ Procurement and Transfer Network (OPTN) and U.S. Census data. Both PBC-OLT patients and patients not listed for liver transplantation (PBC-MSSM) were included in the cluster analysis. Prevalence ratios of PBC-OLT and PSC-OLT cases were compared for each zip code and for each borough with regard to the proximity or density of SFS, respectively. SaTScan software was used to identify clusters of PBC-OLT cases and PBC-MSSM cases. Prevalence ratio of PBC-OLT, not PSC-OLT, was significantly higher in zip codes containing or adjacent to SFS (1.225 vs. 0.670, respectively, P = .025). The borough of Staten Island had the highest prevalence ratio of PBC-OLT cases and density of SFS. Significant clusters of both PBC-OLT and PBC-MSSM were identified surrounding SFS. In conclusion, toxin exposure may be a risk factor influencing the clustering of PBC cases.
Assuntos
Resíduos Perigosos/efeitos adversos , Cirrose Hepática Biliar/epidemiologia , Análise por Conglomerados , Resíduos Perigosos/estatística & dados numéricos , Humanos , Cirrose Hepática Biliar/etiologia , Cidade de Nova Iorque/epidemiologia , Prevalência , Fatores de RiscoRESUMO
OBJECTIVES: Fatigue, which may have a significant impact on quality of life, is the most common reported symptom in primary biliary cirrhosis (PBC). Multiple instruments to quantify fatigue and quality of life in liver disease have been validated, but have not been broadly applied to U.S. PBC patients. This study examines the extent of fatigue and its effect on quality of life in U.S. PBC patients. METHODS: Seventy patients with PBC were administered two validated questionnaires about quality of life (the Mayo version of the NIDDK-QA) and fatigue (the Fisk Fatigue Impact Score) and a proposed physical measure of fatigue in PBC (the grip strength test) on the day of routine physician visit. Nonparametric methods were employed. RESULTS: The fatigue and quality of life domain scores (physical functioning, liver symptoms, health satisfaction, Karnofsky index) discriminated between patients with and without self-reported fatigue (p < 0.05), as opposed to the grip strength results. Fatigue and quality of life domains correlated strongly with each other (r between 0.33 and 0.74, p= 0.006) and not with the grip strength results. Neither quality of life nor fatigue scores correlated with age. CONCLUSIONS: The correlation between fatigue and quality of life scores suggests fatigue has an impact on quality of life in U.S. primary biliary cirrhosis patients. However, our fatigue scores suggest U.S. PBC patients have less fatigue than non-U.S. PBC patients. The grip strength is an insensitive measure of fatigue in U.S. PBC patients.
Assuntos
Fadiga/classificação , Cirrose Hepática Biliar/fisiopatologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Atitude Frente a Saúde , Cognição/fisiologia , Depressão/fisiopatologia , Depressão/psicologia , Fadiga/fisiopatologia , Fadiga/psicologia , Feminino , Força da Mão/fisiologia , Humanos , Avaliação de Estado de Karnofsky , Cirrose Hepática Biliar/psicologia , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Satisfação Pessoal , Prurido/fisiopatologia , Prurido/psicologia , Qualidade de Vida , Comportamento Social , Inquéritos e Questionários , Estados UnidosRESUMO
OBJECTIVE: Preliminary data suggested possible benefits of methotrexate in primary biliary cirrhosis. We assessed the effectiveness of methotrexate use in primary biliary cirrhosis and its tolerance in patients with this disease. METHODS: A total of 110 primary biliary cirrhosis patients began methotrexate 15 mg/wk; for most, ursodeoxycholic acid was added during the study. We analyzed data from patients completing 5 yr of treatment with methotrexate to assess its effect on biochemical and histologic parameters after 5 yr of therapy. Based on an intent to treat analysis, we also compared survival of our patients (n = 110) with that of patients in a previously published, placebo-controlled trial of ursodeoxycholic acid (n = 180). RESULTS: Only half of the study group completed 5 yr of methotrexate therapy. Therapy did not prevent progression of disease, as indicated by a rising Mayo risk score. Portal fibrosis tended to remain the same. Methotrexate did not diminish the risk of death or liver transplantation when compared with ursodeoxycholic acid or placebo; however, ursodeoxycholic acid use decreased the risk of death or transplant (p = 0.006). CONCLUSIONS: Methotrexate is not well tolerated in primary biliary cirrhosis. The toxicity of methotrexate and its inability to prevent complications of progressive liver disease or improve survival and the need for liver transplantation limits its utility. The benefits of ursodeoxycholic acid were again confirmed.
Assuntos
Imunossupressores/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Metotrexato/uso terapêutico , Adulto , Idoso , Estudos de Coortes , Humanos , Cirrose Hepática Biliar/mortalidade , Pessoa de Meia-Idade , Taxa de Sobrevida , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
BACKGROUND & AIMS: There is growing evidence that the interplay of genetic susceptibility and environmental factors leads to primary biliary cirrhosis (PBC). In particular, family members of an infected individual have up to a 100-fold higher risk of developing PBC. Although concordant rates for identical twins in other autoimmune diseases range between 25% and 50%, there are no such data on PBC. Accordingly, we evaluated the concordance of PBC in a genetically defined population of twin sets and evaluated the clinical characteristics between concordant subjects. METHODS: We identified 16 pairs of twins within a 1400-family cohort followed up by several centers worldwide, evaluated the diagnosis of PBC in all individuals, and determined the zygosity of sets reported as identical by the analysis of 2 highly variable HLA class II regions and 5 short tandem repeats. RESULTS: Eight of 16 sets of twins were monozygotic. In 5 of 8 monozygotic twin sets, both individuals had PBC (pairwise concordance rate, 0.63). Among the dizygotic twins (n = 8), no set was found to be concordant for PBC. Interestingly, the age at onset of disease was similar in 4 of 5 concordant sets of monozygotic pairs; however, there were differences in natural history and disease severity. CONCLUSIONS: The concordance rate of PBC in identical twins is among the highest reported in autoimmunity. However, discordant pairs were identified. The data show not only the role of genetics but also emphasize that either epigenetic factors and/or environment play a critical role.
Assuntos
Meio Ambiente , Epigênese Genética , Cirrose Hepática Biliar/genética , Adulto , Feminino , Humanos , Cirrose Hepática Biliar/diagnóstico , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Sequências de Repetição em Tandem , Gêmeos Dizigóticos , Gêmeos MonozigóticosRESUMO
OBJECTIVES: Most studies establishing the role of antiviral therapy in patients with chronic hepatitis C (CHC) excluded the patients with normal ALT levels. Small trials with interferon monotherapy suggested a limited efficacy and/or de novo ALT elevations. We sought to evaluate the efficacy of two doses of interferon alfa-2b (IFN) with ribavirin (RBV) in patients with normal ALT [correction]. METHODS: Patients with biopsy-proven CHC with detectable HCV RNA and at least two normal ALT levels three or more months apart were randomized to receive either 3 or 5 million units of IFN thrice a week plus RBV 1,000-1,200 mg. Therapy was stopped at 24 wk if HCV RNA remained detectable and continued for an additional 24 wk if HCV RNA was undetectable. A final HCV RNA level was obtained 24 wk after discontinuation of therapy. RESULTS: Fifty-six patients were randomized and received at least one dose of treatment. The overall rate of sustained virologic response (SVR) was 32%. SVR rates were higher in genotype 2 and 3 patients (80%) than in genotype 1 patients (24%, p = 0.002). There was a tendency toward higher SVR in genotype 1 patients treated with the higher IFN dose (36%vs 10%, p = 0.07). Five patients had mild, transient ALT elevations. No sustained ALT elevations were noted. CONCLUSIONS: Patients with normal ALT had a rate of SVR comparable to that reported in patients with elevated ALT. Higher dose of interferon tended to be more effective in genotype 1 infected patients. De novo ALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of ALT alone. Combination therapy with pegylated interferon and ribavirin should be evaluated in these patients.