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1.
Gastroenterology ; 163(6): 1630-1642.e3, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36150526

RESUMO

BACKGROUND & AIMS: The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA-treated external controls. METHODS: Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis. RESULTS: During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10-0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12-0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03-1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09-1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21-0.85) including hepatic decompensation. CONCLUSIONS: Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients.


Assuntos
Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Ácido Ursodesoxicólico/efeitos adversos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/cirurgia , Ácido Quenodesoxicólico/efeitos adversos , Cirrose Hepática/complicações
2.
Am J Gastroenterol ; 118(7): 1196-1203, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36621963

RESUMO

INTRODUCTION: Treatment of primary biliary cholangitis (PBC) can improve the GLOBE score. We aimed to assess the association between changes in the GLOBE score (ΔGLOBE) and liver transplantation (LT)-free survival in patients with PBC who were treated with ursodeoxycholic acid (UDCA). METHODS: Among UDCA-treated patients within the Global PBC cohort, the association between ΔGLOBE (ΔGLOBE 0-1 : during the first year of UDCA, ΔGLOBE 1-2 : during the second year) and the risk of LT or death was assessed through Cox regression analyses. RESULTS: Overall, 3,775 UDCA-treated patients were included; 3,424 (90.7%) were female, the median age was 54.0 (interquartile range [IQR] 45.9-62.4) years, and the median baseline GLOBE score was 0.25 (IQR -0.47 to 0.96). During a median follow-up of 7.2 (IQR 3.7-11.5) years, 730 patients reached the combined end point of LT or death. The median ΔGLOBE 0-1 was -0.27 (IQR -0.56 to 0.02). Cox regression analyses, adjusted for pretreatment GLOBE score and ΔGLOBE 0-12 , showed that ΔGLOBE was associated with LT or death (adjusted hazard ratio 2.28, 95% confidence interval 1.81-2.87, P < 0.001). The interaction between baseline GLOBE score and ΔGLOBE 0-1 was not statistically significant ( P = 0.296). The ΔGLOBE 1-2 was associated with LT or death (adjusted hazard ratio 2.19, 95% confidence interval 1.67-2.86, P < 0.001), independently from the baseline GLOBE score and the change in GLOBE score during the first year of UDCA. DISCUSSION: UDCA-induced changes in the GLOBE score were significantly associated with LT-free survival in patients with PBC. While the relative risk reduction of LT or death was stable, the absolute risk reduction was heavily dependent on the baseline prognosis of the patient.


Assuntos
Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/cirurgia , Colagogos e Coleréticos/uso terapêutico , Resultado do Tratamento , Estudos Retrospectivos
3.
Liver Int ; 43(7): 1497-1506, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37157905

RESUMO

BACKGROUND AND AIMS: Patients with primary biliary cholangitis (PBC) and insufficient response to ursodeoxycholic acid (UDCA), currently assessed after 1 year, are candidates for second-line therapy. The aims of this study are to assess biochemical response pattern and determine the utility of alkaline phosphatase (ALP) at six months as a predictor of insufficient response. METHODS: UDCA-treated patients in the GLOBAL PBC database with available liver biochemistries at one year were included. POISE criteria were used to assess response to treatment, defined as ALP <1.67 × upper limit of normal (ULN) and normal total bilirubin at one year. Various thresholds of ALP at six months were evaluated to predict insufficient response based on negative predictive value (NPV) and that with nearest to 90% NPV was selected. RESULTS: For the study, 1362 patients were included, 1232 (90.5%) female, mean age of 54 years. The POISE criteria were met by 56.4% (n = 768) of patients at one year. The median ALP (IQR) of those who met POISE criteria compared to those who did not was 1.05 × ULN (0.82-1.33) vs. 2.37 × ULN (1.72-3.69) at six months (p < .001). Of 235 patients with serum ALP >1.9 × ULN at six months, 89% did not achieve POISE criteria (NPV) after one year of UDCA. Of those with insufficient response by POISE criteria at one year, 210 (67%) had an ALP >1.9 × ULN at six months and thus would have been identified early. CONCLUSIONS: We can identify patients for second-line therapy at six months using an ALP threshold of 1.9 × ULN, given that approximately 90% of these patients are non-responders according to POISE criteria.


Assuntos
Cirrose Hepática Biliar , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Fosfatase Alcalina , Colagogos e Coleréticos/uso terapêutico , Bilirrubina , Ácido Ursodesoxicólico/uso terapêutico
4.
Hepatology ; 73(5): 1868-1881, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32974892

RESUMO

BACKGROUND AND AIMS: Early detection of perihilar cholangiocarcinoma (CCA) among patients with primary sclerosing cholangitis (PSC) is important to identify more people eligible for curative therapy. While many recommend CCA screening, there are divergent opinions and limited data regarding the use of ultrasound or magnetic resonance imaging (MRI) for early CCA detection, and it is unknown whether there is benefit in testing asymptomatic individuals. Our aims were to assess the diagnostic performances and prognostic implications of ultrasound and MRI-based CCA detection. APPROACH AND RESULTS: This is a multicenter review of 266 adults with PSC (CCA, n = 120) who underwent both an ultrasound and MRI within 3 months. Images were re-examined by radiologists who were blinded to the clinical information. Respectively, MRI had a higher area under the curve compared with ultrasound for CCA detection: 0.87 versus 0.70 for the entire cohort; 0.81 versus 0.59 for asymptomatic individuals; and 0.88 versus 0.71 for those listed for CCA transplant protocol. The absence of symptoms at CCA diagnosis was associated with improved 5-year outcomes including overall survival (82% vs. 46%, log-rank P < 0.01) and recurrence-free survival following liver transplant (89% vs. 65%, log-rank P = 0.04). Among those with asymptomatic CCA, MRI detection (compared with ultrasound) was associated with reduction in both mortality (hazard ratio, 0.10; 95% confidence interval, 0.01-0.96) and CCA progression after transplant listing (hazard ratio, 0.10; 95% confidence interval, 0.01-0.90). These benefits continued among patients who had annual monitoring and PSC for more than 1 year before CCA was diagnosed. CONCLUSIONS: MRI is superior to ultrasound for the detection of early-stage CCA in patients with PSC. Identification of CCA before the onset of symptoms with MRI is associated with improved outcomes.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico por imagem , Colangiocarcinoma/diagnóstico por imagem , Colangite Esclerosante/complicações , Detecção Precoce de Câncer/mortalidade , Adulto , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/etiologia , Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/etiologia , Colangiocarcinoma/mortalidade , Colangite Esclerosante/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Prognóstico , Análise de Sobrevida , Ultrassonografia
5.
Am J Ther ; 29(4): e437-e443, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31567143

RESUMO

BACKGROUND: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. AREAS OF UNCERTAINTY: The etiopathogenesis of PSC remains an enigma. DATA SOURCES: We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documented for each patient. Descriptive statistical analyses were performed. RESULTS: We identified 6 additional patients with PSC or PSC-IBD in whom there was a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. The median age of these 9 patients was 20 years, 6 were female, and 7 had ulcerative colitis. The median time from doxycycline exposure to onset of first symptoms was 3 months, and median time from doxycycline exposure to diagnosis of PSC was 15 months. THERAPEUTIC HYPOTHESIS: We describe 9 cases of PSC and PSC-IBD in which there seem to be a temporal relationship between exposure to doxycycline and onset of PSC.


Assuntos
Colangite Esclerosante , Colite Ulcerativa , Doenças Inflamatórias Intestinais , Adulto , Colangite Esclerosante/complicações , Colangite Esclerosante/diagnóstico , Doxiciclina/efeitos adversos , Feminino , Humanos , Masculino , Fatores de Risco , Adulto Jovem
6.
Clin Gastroenterol Hepatol ; 19(8): 1688-1697.e14, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32777554

RESUMO

BACKGROUND & AIMS: Gamma-glutamyltransferase (GGT) is a serum marker of cholestasis. We investigated whether serum level of GGT is a prognostic marker for patients with primary biliary cholangitis (PBC). METHODS: We analyzed data from patients with PBC from the Global PBC Study Group, comprising 14 centers in Europe and North America. We obtained measurements of serum GGT at baseline and time points after treatment. We used Cox model hazard ratios to evaluate the association between GGT and clinical outcomes, including liver transplantation and liver-related death. RESULTS: Of the 2129 patients included in our analysis, 281 (13%) had a liver-related clinical endpoint. Mean age at diagnosis was 53 years and 91% of patients were female patients. We found a correlation between serum levels of GGT and alkaline phosphatase (ALP) (r = 0.71). Based on data collected at baseline and yearly for up to 5 years, higher serum levels of GGT were associated with lower hazard for transplant-free survival. Serum level of GGT at 12 months after treatment higher than 3.2-fold the upper limit of normal (ULN) identified patients who required liver transplantation or with liver-related death at 10 years with an area under the receiver operating characteristic curve of 0.70. The risk of liver transplantation or liver-related death in patients with serum level of GGT above 3.2-fold the ULN, despite level of ALP lower than 1.5-fold the ULN, was higher compared to patients with level of GGT lower than 3.2-fold the ULN and level of ALP lower than 1.5-fold the ULN (P < .05). Including information on level of GGT increased the prognostic value of the Globe score. CONCLUSIONS: Serum level of GGT can be used to identify patients with PBC at risk for liver transplantation or death, and increase the prognostic value of ALP measurement. Our findings support the use of GGT as primary clinical endpoint in clinical trials. In patients with low serum level of ALP, a high level of GGT identifies those who might require treatment of metabolic disorders or PBC treatment escalation.


Assuntos
Colestase , Cirrose Hepática Biliar , Transplante de Fígado , Feminino , Humanos , Prognóstico , gama-Glutamiltransferase
7.
Am J Gastroenterol ; 116(7): 1514-1522, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33941746

RESUMO

INTRODUCTION: Comparative data on scores that predict outcome in primary biliary cholangitis (PBC) are scarce. We aimed to assess and compare the prognostic value of the Mayo Risk Score (MRS, 1989 and 1994), UK-PBC score, and GLOBE score in a large international cohort of patients with PBC. METHODS: Ursodeoxycholic acid-treated patients from 7 centers participating in the GLOBAL PBC Study Group were included. The discriminatory performance of the scores was assessed with concordance statistics at yearly intervals up to 5 years. Model for End-stage Liver Disease was included for comparison. Prediction accuracy was assessed by comparing predicted survival and actual survival in Kaplan-Meier analyses. RESULTS: A total of 1,100 ursodeoxycholic acid-treated patients with PBC were included, with a mean (SD) age of 53.6 (12.0) years, of whom 1,003 (91%) were female. During a median follow-up of 7.6 (interquartile range 4.1-11.7) years, 42 patients underwent liver transplantation, and 127 patients died. At 1 year, the concordance statistic for Model for End-stage Liver Disease was 0.68 (95% confidence interval [CI] 0.64-0.72), 0.74 (95% CI 0.67-0.80) for the UK-PBC score, 0.76 (95% CI 0.72-0.81) for the MRS (1989 and 1994), and 0.80 (95% CI 0.76-0.84) for the GLOBE score. The GLOBE score showed superior discriminatory performance, but differences were not statistically different. For all scores, discriminatory performance increased in those with bilirubin >0.6 × ULN and advanced fibrosis estimated with Fibrosis-4. The predicted (median) minus observed 5-year transplant-free survival was +0.4% and +2.5% for the MRS (1989) and GLOBE score, respectively. DISCUSSION: All prognostic scores developed for PBC (GLOBE, UK-PBC, and MRS) demonstrated comparable discriminating performance for liver transplantation or death as well as good prediction accuracy.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Transplante de Fígado/estatística & dados numéricos , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Idoso , Estudos de Coortes , Doença Hepática Terminal , Feminino , Humanos , Hiperbilirrubinemia , Cirrose Hepática Biliar/mortalidade , Cirrose Hepática Biliar/patologia , Cirrose Hepática Biliar/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença
8.
Liver Int ; 41(6): 1335-1343, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33751787

RESUMO

BACKGROUND AND AIM: Off-label use of fibrates in patients with cholestatic liver diseases results in improved biochemical parameters and pruritus; however, their safety in this population has been a concern. This study summarizes safety data for fibrates when used for treatment of cholestatic liver diseases. METHODS: A systematic review of published studies evaluating the use of fibrates for treatment of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) was performed. Electronic databases were searched up to December 2019 for published studies evaluating treatment outcomes associated to fibrates for these 2 diseases. RESULTS: A total of 37 studies were identified, including 31 for PBC and 6 for PSC, with a total of 1107 unique patients treated with fibrates ± ursodeoxycholic acid (UDCA). Most studies evaluated fenofibrate and bezafibrate, and only 1 study evaluated pemafibrate. There were no studies evaluating gemfibrozil or clofibrate. The most commonly reported adverse events (AEs) were gastrointestinal and musculoskeletal. Elevations of aminotransferases and serum creatinine were reported more commonly in patients treated with UDCA plus fibrates versus UDCA monotherapy. CONCLUSIONS: Fibrates appear to be safe and well tolerated in patients with PBC, with a low frequency of AEs. There are scarce data about the safety of these agents for treatment of PSC.


Assuntos
Colagogos e Coleréticos , Cirrose Hepática Biliar , Bezafibrato/efeitos adversos , Colagogos e Coleréticos/efeitos adversos , Ácidos Fíbricos/efeitos adversos , Humanos , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/efeitos adversos
9.
Liver Int ; 41(10): 2418-2426, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34224208

RESUMO

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an idiopathic, cholestatic liver disease with a diverse range of clinical manifestations. Inter-regional data on PSC are variable, but its global geoepidemiology has not been well-studied. We aimed to examine the worldwide incidence, prevalence and features of PSC and PSC-inflammatory bowel disease (PSC-IBD). METHODS: A systematic search of multiple databases was conducted to identify all original, full-text studies until December 2020 with data regarding the incidence rate (IR) and/or prevalence of PSC. Outcomes were PSC IR, prevalence, features and IBD concurrence. Additionally, a meta-analysis of PSC IR was performed. The study was registered in PROSPERO (CRD42021224550). RESULTS: Of the 1003 studies identified, 17 studies spanning three continents were included. PSC IR was 0.60 per 100 000 person-years (PY) (95% confidence interval: 0.37-0.88 per 100 000 PY). In pooled subgroup analysis for studies conducted in Europe and North America, PSC IR was 0.62 and 0.53 per 100 000 PY, respectively. PSC prevalence ranged 0-31.7 per 100 000 persons, with notable inter-regional differences. Mean age at PSC diagnosis was bimodally distributed, with relative peaks at 15 and 35 years. Mean concurrence of IBD with PSC was 50%, with 76% having ulcerative colitis, 17% Crohn's disease and 8% indeterminate/unspecified IBD. CONCLUSION: While considerable heterogeneity exists in the geoepidemiology of PSC, overall, the classical dogmata of male predilection, bimodal distribution of mean age and high PSC-IBD concurrence appear to hold true. Despite a seemingly stable IR over time, further studies are needed to better understand the geoepidemiology of PSC.


Assuntos
Colangite Esclerosante , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Colangite Esclerosante/epidemiologia , Colite Ulcerativa/epidemiologia , Humanos , Incidência , Doenças Inflamatórias Intestinais/epidemiologia , Masculino , Prevalência
10.
J Clin Gastroenterol ; 55(5): 449-457, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32976197

RESUMO

GOALS: We aimed to describe the diagnostic and prognostic performance of transient elastography (TE) and magnetic resonance elastography (MRE) in patients with primary biliary cholangitis (PBC). BACKGROUND: The diagnostic performance of TE and MRE in detecting advanced fibrosis in PBC and in predicting outcomes independent of existing serologic prognostic markers is incompletely understood. MATERIALS AND METHODS: Five hundred thirty-eight consecutive patients with PBC at 3 centers with liver stiffness (LS) measurements by TE (n=286) or MRE (n=332) were reviewed. LS cutoffs for predicting fibrosis stages were determined by receiver operating characteristic curves among those with a liver biopsy (TE, n=63; MRE, n=98). Cox proportional hazard regression modeling was used to identify associations between covariates and hepatic decompensation. RESULTS: The optimal LS thresholds for predicting histologic stage F4 were 14.40 kPa (area under the curve=0.94) for TE and 4.60 kPa (area under the curve=0.82) for MRE. Both TE and MRE outperformed biochemical markers for the prediction of histologic advanced fibrosis. Optimal LS thresholds to predict hepatic decompensation were 10.20 kPa on TE and 4.30 kPa on MRE. LS by TE and MRE (respectively) remained predictors of hepatic decompensation after adjusting for ursodeoxycholic acid responsiveness [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.24 and HR, 1.68; 95% CI, 1.28-2.19] and the GLOBE score (HR, 1.13; 95% CI, 1.07-1.19 and HR, 2.09; 95% CI, 1.57-2.78). CONCLUSION: LS measurement with either TE or MRE can accurately detect advanced fibrosis and offers additional prognostic value beyond existing serologic predictive tools.


Assuntos
Técnicas de Imagem por Elasticidade , Cirrose Hepática Biliar , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/diagnóstico por imagem , Cirrose Hepática Biliar/patologia , Espectroscopia de Ressonância Magnética , Curva ROC
11.
Gut ; 69(8): 1502-1509, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31843787

RESUMO

OBJECTIVE: The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC. METHODS: The NNT was calculated based on the untreated LT-free survival and HR of UDCA with respect to LT or death as derived from inverse probability of treatment weighting-adjusted Cox proportional hazard analyses within the Global PBC Study Group database. RESULTS: We included 3902 patients with a median follow-up of 7.8 (4.1-12.1) years. The overall HR of UDCA was 0.46 (95% CI 0.40 to 0.52) and the 5-year LT-free survival without UDCA was 81% (95% CI 79 to 82). The NNT to prevent one LT or death within 5 years (NNT5y) was 11 (95% CI 9 to 13). Although the HR of UDCA was similar for patients with and without cirrhosis (0.33 vs 0.31), the NNT5y was 4 (95% CI 3 to 5) and 20 (95% CI 14 to 34), respectively. Among patients with low alkaline phosphatase (ALP) (≤2× the upper limit of normal (ULN)), intermediate ALP (2-4× ULN) and high ALP (>4× ULN), the NNT5y to prevent one LT or death was 26 (95% CI 15 to 70), 11 (95% CI 8 to 17) and 5 (95% CI 4 to 8), respectively. CONCLUSION: The absolute clinical efficacy of UDCA with respect to LT or death varied with baseline prognostic characteristics, but was high throughout. These findings strongly emphasise the incentive to promptly initiate UDCA treatment in all patients with PBC and may improve patient compliance.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Idoso , Fosfatase Alcalina/sangue , Doença Crônica , Bases de Dados Factuais , Feminino , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/cirurgia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Números Necessários para Tratar , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Resultado do Tratamento
12.
Clin Gastroenterol Hepatol ; 18(3): 684-692.e6, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31419573

RESUMO

BACKGROUND & AIMS: Patients usually receive a diagnosis of primary biliary cholangitis (PBC) at an early stage, based on biochemical analyses. We investigated the proportion of patients who progress to moderate or advanced PBC and factors associated with progression and patient survival. METHODS: We obtained data from 1615 patients (mean age, 55.4 y) with early stage PBC (based on their normal levels of albumin and bilirubin), collected at the time of initial evaluation or treatment, from the Global PBC Study Group database (comprising patients at 19 liver centers in North American and European countries). We collected data from health care evaluations on progression to moderate PBC (abnormal level of bilirubin or albumin) or advanced-stage PBC (abnormal level of both). The median follow-up time was 7.9 years. The composite end point was decompensation, hepatocellular carcinoma, liver transplantation, or death. RESULTS: Of the 1615 patients identified with early stage PBC, 904 developed moderate PBC and 201 developed advanced disease over the study period. The proportions of patients who transitioned to moderate PBC at 1, 3, and 5 years were 12.9%, 30.2%, and 45.8%. The proportions of these patients who then transitioned to advanced PBC at 1, 3, and 5 years later were 3.4%, 12.5%, and 16.0%, respectively. During the follow-up period, 236 patients had a clinical event. The proportions of patients with moderate PBC and event-free survival were 97.9%, 95.1%, and 91.5% at 1, 3, and 5 years, respectively, and the proportions of patients with advanced PBC and event-free survival were 90.6%, 71.2%, and 58.3% at 1, 3, and 5 years later, respectively. Variables associated with transition from early to moderate PBC included baseline levels of bilirubin, albumin, and alkaline phosphatase; aspartate to alanine aminotransferase ratio; platelet count; and treatment with ursodeoxycholic acid. Transitions from early to moderate PBC and from moderate to advanced PBC were associated with higher probabilities of a clinical event (time-dependent hazard ratios, 3.0; 95% CI, 2.0-4.5; and 4.6; 95% CI, 3.5-6.2). CONCLUSIONS: Approximately half of patients with early stage PBC progress to a more severe stage within 5 years. Progression is associated with an increased risk of a clinical event, so surveillance is important for patients with early stage PBC.


Assuntos
Colangite , Cirrose Hepática Biliar , Alanina Transaminase , Bilirrubina , Colagogos e Coleréticos/uso terapêutico , Colangite/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Ácido Ursodesoxicólico/uso terapêutico
13.
Am J Gastroenterol ; 115(7): 1066-1074, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32618657

RESUMO

INTRODUCTION: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined. METHODS: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated. RESULTS: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN. DISCUSSION: Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.


Assuntos
Fosfatase Alcalina/sangue , Bilirrubina/sangue , Colagogos e Coleréticos/uso terapêutico , Colangite/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Biomarcadores/sangue , Colangite/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Valores de Referência , Taxa de Sobrevida
14.
Scand J Gastroenterol ; 55(8): 941-950, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32633158

RESUMO

BACKGROUND: Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV. METHODS: Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50 mg/kg/day in 3 divided doses if weight <30kg, and 500 mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline. RESULTS: 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total n = 59; median age was 13.5 years [range, 1.5-44 years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7 years (range, 0.2-14 years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6 months of OV treatment. One patient underwent liver transplantation 8 years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events. CONCLUSION: In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.


Assuntos
Antibacterianos , Colangite Esclerosante , Vancomicina , Adolescente , Adulto , Alanina Transaminase , Antibacterianos/uso terapêutico , Criança , Colangite Esclerosante/tratamento farmacológico , Humanos , Masculino , Estudos Prospectivos , Vancomicina/uso terapêutico , gama-Glutamiltransferase
15.
J Hepatol ; 71(2): 357-365, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30980847

RESUMO

BACKGROUND & AIMS: The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC. METHODS: This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW). RESULTS: In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1-12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1-81.2) among UDCA-treated patients and 60.7% (95% CI 58.2-63.4) among untreated patients (p <0.001). UDCA was associated with a statistically significant reduced risk of LT or death (hazard ratio 0.46, 95% CI 0.40-0.52; p <0.001). The hazard ratio remained statistically significant in all stages of disease. Patients classified as inadequate biochemical responders after 1 year of UDCA had a lower risk of LT or death than patients who were not treated (adjusted hazard ratio 0.56; 95% CI 0.45-0.69; p <0.001). CONCLUSION: The use of UDCA improves LT-free survival among patients with PBC, regardless of the disease stage and the observed biochemical response. These findings support UDCA as the current universal standard of care in PBC. LAY SUMMARY: In this international multicenter study of 3,902 patients with primary biliary cholangitis, we found that treatment with ursodeoxycholic acid is associated with prolonged liver transplant-free survival. This association was significant, irrespective of sex, age, or disease stage. The survival benefit remained statistically significant in patients with an incomplete biochemical response to ursodeoxycholic acid therapy.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Colangite/tratamento farmacológico , Colangite/mortalidade , Transplante de Fígado , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Idoso , Colangite/complicações , Colangite/cirurgia , Progressão da Doença , Feminino , Seguimentos , Humanos , Cirrose Hepática Biliar/complicações , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Risco , Taxa de Sobrevida , Resultado do Tratamento
16.
N Engl J Med ; 375(7): 631-43, 2016 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-27532829

RESUMO

BACKGROUND: Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS: In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS: Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 µmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 µmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. CONCLUSIONS: Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Cirrose Hepática Biliar/tratamento farmacológico , Adulto , Idoso , Fosfatase Alcalina/sangue , Ácidos e Sais Biliares/sangue , Densidade Óssea/efeitos dos fármacos , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/uso terapêutico , Método Duplo-Cego , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/complicações , Masculino , Pessoa de Meia-Idade , Prurido/induzido quimicamente
17.
Clin Gastroenterol Hepatol ; 17(12): 2416-2422, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31306801

RESUMO

DESCRIPTION: The purpose of this clinical practice update is to define key principles in the surveillance of hepatobiliary cancers including cholangiocarcinoma, gallbladder adenocarcinoma, and hepatocellular carcinoma in patients with primary sclerosing cholangitis (PSC). METHODS: The recommendations outlined in this expert review are based on available published evidence including observational studies and systematic reviews, and incorporates expert opinion where applicable. BEST PRACTICE ADVICE 1: Surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with PSC regardless of disease stage, especially in the first year after diagnosis and in patients with ulcerative colitis and those diagnosed at an older age. BEST PRACTICE ADVICE 2: Surveillance for cholangiocarcinoma and gallbladder cancer should include imaging by ultrasound, computed tomography, or magnetic resonance imaging, with or without serum carbohydrate antigen 19-9, every 6 to 12 months BEST PRACTICE ADVICE 3: Endoscopic retrograde cholangiopancreatography with brush cytology should not be used routinely for surveillance of cholangiocarcinomas in PSC. BEST PRACTICE ADVICE 4: Cholangiocarcinomas should be investigated by endoscopic retrograde cholangiopancreatography with brush cytology with or without fluorescence in situ hybridization analysis and/or cholangioscopy in PSC patients with worsening clinical symptoms, worsening cholestasis, or a dominant stricture. BEST PRACTICE ADVICE 5: Fine-needle aspiration of perihilar biliary strictures should be used with caution in PSC patients considered to be liver transplant candidates because of concerns for tumor seeding if the lesion is a cholangiocarcinoma. BEST PRACTICE ADVICE 6: Surveillance for cholangiocarcinoma should not be performed in PSC patients with small-duct PSCs or those younger than age 20. BEST PRACTICE ADVICE 7: The decision to perform a cholecystectomy in PSC patients with a gallbladder polyp should be based on the size and growth of the polyp, as well as the clinical status of the patient, with the knowledge of the increased risk of gallbladder cancer in polyps greater than 8 mm. BEST PRACTICE ADVICE 8: Surveillance for hepatocellular carcinoma in PSC patients with cirrhosis should include ultrasound, computed tomography, or magnetic resonance imaging, with or without α-fetoprotein every 6 months.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Colangite Esclerosante/complicações , Detecção Precoce de Câncer , Neoplasias Hepáticas/diagnóstico , Antígenos Glicosídicos Associados a Tumores/análise , Biópsia/métodos , Carcinoma Hepatocelular/diagnóstico , Colangiocarcinoma/diagnóstico , Diagnóstico por Imagem , Neoplasias da Vesícula Biliar/diagnóstico , Humanos , Transplante de Fígado , Prevalência , Fatores de Risco , Transplantados
18.
Clin Gastroenterol Hepatol ; 17(7): 1372-1378, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29705262

RESUMO

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a fibrostenosing disease of the bile ducts associated with inflammatory bowel disease (IBD), for which the only treatment is liver transplantation. PSC progression has been defined in cohorts from referral centers or single-nation population databases. However, observations made from these cohorts have limited applicability owing to referral bias and demographic confounders. We analyzed data from the worldwide PSC Partners Patient Registry, an international online database established in 2014 to obtain information from individuals with PSC or their caretakers and compare symptoms, disease progression, and treatments of PSC in the United States and other countries. METHODS: We analyzed demographic and clinical characteristics, symptoms, and clinical outcomes of patients with PSC using the PSC Partners Patient Registry. Participants completed an online standardized questionnaire and electronic case report, providing information on age, age at symptom onset, age at PSC diagnosis, methods of diagnosis, concurrent diagnoses, family history, and medication use. RESULTS: Of 873 registrants, 811 (92.9%) had completed questionnaires and 528 (65.1%) had their PSC diagnosis confirmed; we found no significant demographic or clinical differences between patients with vs without a confirmed diagnosis. In contrast to other studies, we found a higher proportion of individuals with PSC to be female (52.5%). However, the mean age at PSC diagnosis (32.4 ± 14.7 y) and the proportion of individuals with PSC and IBD (67.1%) were similar to those from prior reports. Most cases in the database were from the United States (74.9%). More than half of the participants reported having pruritus, abdominal pain, fatigue, or sleep disturbances; rates were not significantly different among participants within vs outside the United States. There was no significant difference in treatment with ursodeoxycholic acid between participants within vs outside the United States (50.0% and 57.8%; P = .07). The median time of transplant-free survival was 21 years; transplant-free survival was associated with female sex and Crohn's disease. CONCLUSIONS: Our findings from an analysis of data from the PSC Partners Patient Registry confirm those from previous studies, although we found a higher proportion of individuals with PSC to be female. In addition to allowing efficient collection of patient-reported outcomes, the patient-driven registry allows for inclusion of previously under-represented cases of PSC.


Assuntos
Colangite Esclerosante/epidemiologia , Internet , Sistema de Registros , Medição de Risco/métodos , Adulto , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colangite Esclerosante/diagnóstico , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Morbidade/tendências , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
19.
Clin Gastroenterol Hepatol ; 17(9): 1894-1901.e1, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30708109

RESUMO

BACKGROUND & AIMS: Many patients with cirrhosis who undergo esophagogastroduodenoscopy (EGD) screening for esophageal varices (EVs) are found to have no or only small EVs. Endoscopic screening for EVs is therefore a potentially deferrable procedure that increases patient risk and healthcare cost. We developed and validated a scoring system, based on readily-available data, to reliably identify patients with EVs that need treatment. METHODS: We collected data from 238 patients with cirrhosis undergoing screening EGD from January 2016 through December 2017 at 3 separate hospitals in Los Angeles (training cohort). We abstracted data on patient sex, age, race/ethnicity, platelet counts, and levels of hemoglobin, serum sodium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, international normalized ratio, albumin, urea nitrogen, and creatinine. We also included etiology of cirrhosis, presence of ascites, and presence of hepatic encephalopathy. We used a random forest algorithm to identify factors significantly associated with the presence of EVs and varices needing treatment (VNT) and calculated area under the receiver operating characteristic curve (AUROC). We called the resulting formula the EVendo score. We tested the accuracy of EVendo in a prospective study of 109 patients undergoing screening EGDs at the same medical centers from January 2018 through December 2018 (validation cohort). RESULTS: We developed an algorithm that identified patients with EVs and VNT based on international normalized ratio, level of aspartate aminotransferase, platelet counts, urea nitrogen, hemoglobin, and presence of ascites. The EVendo score identified patients with EVs in the training set with an AUROC of 0.84, patients with EVs in the validation set with and AUROC of 0.82, and EVs in patients with cirrhosis Child-Turcotte-Pugh class A (n = 235) with an AUROC of 0.81. The score identified patients with VNT in the training set with an AUROC of 0.74, VNT in the validation set with and AUROC of 0.75, and VNT in patients with cirrhosis Child-Turcotte-Pugh class A with and AUROC of 0.75. An EVendo score below 3.90 would have spared 30.5% patients from EGDs, missing only 2.8% of VNT. The same cutoff would have spared 40.0% of patients with Child-Turcotte-Pugh class A cirrhosis from EGDs, missing only 1.1% of VNT. CONCLUSIONS: We algorithmically developed a formula, called the EVendo score, that can be used to predict EVs and VNT based on readily available data in patients with cirrhosis. This score could help patients at low risk for VNT avoid unnecessary EGDs.


Assuntos
Varizes Esofágicas e Gástricas/epidemiologia , Cirrose Hepática/sangue , Aprendizado de Máquina , Idoso , Alanina Transaminase/sangue , Ascite/epidemiologia , Ascite/etiologia , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Nitrogênio da Ureia Sanguínea , Creatinina , Endoscopia do Sistema Digestório , Varizes Esofágicas e Gástricas/sangue , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/terapia , Feminino , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/prevenção & controle , Hemoglobinas/metabolismo , Encefalopatia Hepática/epidemiologia , Encefalopatia Hepática/etiologia , Hepatite C Crônica/complicações , Humanos , Coeficiente Internacional Normatizado , Cirrose Hepática/complicações , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/complicações , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Contagem de Plaquetas , Estudos Prospectivos , Medição de Risco , Albumina Sérica/metabolismo , Índice de Gravidade de Doença , Sódio/sangue , Trombocitopenia/epidemiologia , Trombocitopenia/etiologia
20.
Clin Gastroenterol Hepatol ; 17(10): 2076-2084.e2, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30616022

RESUMO

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) predominantly affects middle-aged women; there are few data on disease phenotypes and outcomes of PBC in men and younger patients. We investigated whether differences in sex and/or age at the start of ursodeoxycholic acid (UDCA) treatment are associated with response to therapy, based on biochemical markers, or differences in transplant-free survival. METHODS: We performed a longitudinal retrospective study of 4355 adults in the Global PBC Study cohort, collected from 17 centers across Europe and North America. Patients received a diagnosis of PBC from 1961 through 2014. We evaluated the effects of sex and age on response to UDCA treatment (based on GLOBE score) and transplant-free survival using logistic regression and Cox regression analyses, respectively. RESULTS: Male patients were older at the start of treatment (58.3±12.1 years vs 54.3±11.6 years for women; P<.0001) and had higher levels of bilirubin and lower circulating platelet counts (P<.0001). Younger patients (45 years or younger) had increased serum levels of transaminases than older patients (older than 45 years). Patients older than 45 years at time of treatment initiation had increased odds of a biochemical response to UDCA therapy, based on GLOBE score, compared to younger patients. The greatest odds of response to UDCA were observed in patients older than 65 years (odds ratio compared to younger patients 45 years or younger, 5.48; 95% CI, 3.92-7.67; P<.0001). Risk of liver transplant or death (compared to a general population matched for age, sex, and birth year) decreased significantly with advancing age: hazard ratio for patients 35 years or younger, 14.59 (95% CI, 9.66-22.02) vs hazard ratio for patients older than 65 years, 1.39 (95% CI, 1.23-1.57) (P<.0001). On multivariable analysis, sex was not independently associated with response or transplant-free survival. CONCLUSION: In longitudinal analysis of 4355 adults in the Global PBC Study, we associated patient age, but not sex, with response to UDCA treatment and transplant-free survival. Younger age at time of treatment initiation is associated with increased risk of treatment failure, liver transplant, and death.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Colangite/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Colangite/mortalidade , Colangite/terapia , Feminino , Humanos , Transplante de Fígado , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêutico
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