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1.
Gastroenterology ; 155(3): 752-759.e5, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29803836

RESUMO

BACKGROUND & AIMS: Dominant strictures occur in approximately 50% of patients with primary sclerosing cholangitis (PSC). Short-term stents have been reported to produce longer resolution of dominant strictures than single-balloon dilatation. We performed a prospective study to compare the efficacy and safety of balloon dilatation vs short-term stents in patients with non-end-stage PSC. METHODS: We performed an open-label trial of patients with PSC undergoing therapeutic endoscopic retrograde cholangiopancreatography (ERCP) at 9 tertiary-care centers in Europe, from July 2011 through April 2016. Patients found to have a dominant stricture during ERCP were randomly assigned to groups that underwent balloon dilatation (n = 31) or stent placement for a maximum of 2 weeks (n = 34); patients were followed for 24 months. The primary outcome was the cumulative recurrence-free patency of the primary dominant strictures. RESULTS: Study recruitment was terminated after a planned interim analysis because of futility and differences in treatment-related serious adverse events (SAEs) between groups. The cumulative recurrence-free rate did not differ significantly between groups (0.34 for the stent group and 0.30 for the balloon dilatation group at 24 months; P = 1.0). Most patients in both groups had reductions in symptoms at 3 months after the procedure. There were 17 treatment-related SAEs: post-ERCP pancreatitis in 9 patients and bacterial cholangitis in 4 patients. SAEs occurred in 15 patients in the stent group (45%) and in only 2 patients in the balloon dilatation group (6.7%) (odds ratio, 11.7; 95% confidence interval, 2.4-57.2; P = .001). CONCLUSIONS: In a multicenter randomized trial of patients with PSC and a dominant stricture, short-term stents were not superior to balloon dilatation and were associated with a significantly higher occurrence of treatment-related SAEs. Balloon dilatation should be the initial treatment of choice for dominant strictures in patients with PSC. This may be particularly relevant to patients with an intact papilla. ClinicalTrials.gov no. NCT01398917.


Assuntos
Cateterismo/métodos , Colangite Esclerosante/cirurgia , Dilatação/métodos , Stents , Adulto , Sistema Biliar/patologia , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colangite Esclerosante/patologia , Constrição Patológica/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Resultado do Tratamento , Adulto Jovem
2.
Gut ; 67(10): 1864-1869, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-28739581

RESUMO

OBJECTIVE: Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. The aim of this study was to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables. DESIGN: The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected. We derived the prognostic index from a multivariable Cox regression model in which predictors were selected and parameters were estimated using the least absolute shrinkage and selection operator. The composite end point of PSC-related death and liver transplantation was used. To quantify the models' predictive value, we calculated the C-statistic as discrimination index and established its calibration accuracy by comparing predicted curves with Kaplan-Meier estimates. RESULTS: The final model included the variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up. CONCLUSION: The Amsterdam-Oxford model for PSC showed adequate performance in estimating PSC-related death and/or liver transplant in a predominantly population-based setting. The transplant-free survival probability can be recalculated when updated biochemical values are available.


Assuntos
Colangite Esclerosante , Transplante de Fígado , Adulto , Idoso , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/mortalidade , Colangite Esclerosante/cirurgia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Transplante de Fígado/métodos , Transplante de Fígado/estatística & dados numéricos , Pessoa de Meia-Idade , Mortalidade , Países Baixos/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Reino Unido/epidemiologia
3.
Gut ; 67(8): 1517-1524, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28779025

RESUMO

OBJECTIVE: Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. DESIGN: We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. RESULTS: We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10-9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. CONCLUSION: We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.


Assuntos
Colangite Esclerosante/genética , Colangite Esclerosante/patologia , Polimorfismo de Nucleotídeo Único/genética , Trombospondinas/genética , Adulto , Colangite Esclerosante/mortalidade , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais
4.
Hepatology ; 65(3): 907-919, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27880989

RESUMO

Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC-related death and liver transplantation), 2 (liver transplantation), and 3 (liver-related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow-up was 142 months. During follow-up, 31 patients died (20 PSC-related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver-related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49-6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17-3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10-2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10-1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19-5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09-3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22-3.77). Interobserver agreement was moderate for Nakanuma stage (κ = 0.56) and substantial for Nakanuma component fibrosis (κ = 0.67), Ishak stage (κ = 0.64), and Ludwig stage (κ = 0.62). CONCLUSION: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system-incorporating features of chronic biliary disease-again showed the strongest predictive value. (Hepatology 2017;65:907-919).


Assuntos
Colangite Esclerosante/mortalidade , Colangite Esclerosante/patologia , Transplante de Fígado/mortalidade , Adulto , Biópsia por Agulha , Colangite Esclerosante/cirurgia , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Internacionalidade , Estimativa de Kaplan-Meier , Transplante de Fígado/métodos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Variações Dependentes do Observador , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
5.
Liver Int ; 37(10): 1554-1561, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28267887

RESUMO

BACKGROUND & AIMS: Biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC) have not been firmly established. Enhanced liver fibrosis (ELF) test was previously reported to predict outcome in PSC. We aimed to validate the prognostic utility of ELF test in an independent, multi-centre, retrospective PSC study population. METHODS: We collected serum samples from PSC patients from seven countries. We estimated rates of transplant-free survival by the Kaplan-Meier method, used Cox proportional hazards regression to explore the association between ELF test and clinical outcome and determined prognostic performance of ELF test by computing the area under the receiver operating characteristic (AUC-ROC) curve. RESULTS: The final analysis included 534 PSC patients (61% males). Features of autoimmune hepatitis or concomitant inflammatory bowel disease affected 44 (8%) and 379 (71%) patients respectively. ELF test levels were higher in patients reaching the combined endpoint liver transplantation or death (median 10.9 [Interquartile range (IQR): 9.8-12.1]; n=24 deaths, 79 liver transplantations) compared to those censored (8.8 [IQR: 8.0-9.8]); P<.001. ELF test expressed as mild, moderate and severe fibrosis was significantly associated with the risk of reaching the endpoint (P<.001). ELF test independently predicted clinical outcome (Hazard ratio 1.31; 95% confidence interval [1.05-1.65]; P=.018), and enabled good discrimination between PSC patients with and without endpoint (AUC-ROC: 0.79). CONCLUSION: Our retrospective data validates the predictive utility of ELF test for clinical outcomes in PSC. The clinical utility of biomarkers for fibrosis in patients with PSC should be assessed in prospective patient cohorts.


Assuntos
Colangite Esclerosante/diagnóstico , Ácido Hialurônico/sangue , Cirrose Hepática/diagnóstico , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Adulto , Área Sob a Curva , Biomarcadores/sangue , Canadá , Colangite Esclerosante/sangue , Colangite Esclerosante/mortalidade , Colangite Esclerosante/cirurgia , Progressão da Doença , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/sangue , Cirrose Hepática/mortalidade , Cirrose Hepática/cirurgia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Adulto Jovem
6.
Liver Int ; 36(12): 1867-1875, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-26945698

RESUMO

BACKGROUND: Primary sclerosing cholangitis (PSC) is a slowly progressive liver disease. Reliable biomarkers to predict outcome are urgently needed to serve as surrogate endpoints and/or stratifiers in clinical trials. Reduction in serum alkaline phosphatase (ALP) has been proposed as prognostic surrogate marker in PSC. The aim of this study was to asses if ALP at diagnosis (T0), 1 year later (T1), and percentage change between both time points hold prognostic value, and to determine the optimal threshold. METHODS: We retrospectively collected ALP levels at T0 and T1 for patients included in a large PSC cohort. The association of ALP at T0, T1, and percentage change with the combined endpoint (PSC-related death, liver transplantation) was analysed. Predictive value was determined using C-statistics. RESULTS: A total of 366 patients were included, of whom 66 (18%) reached an endpoint: 26 (7%) PSC-related death, 40 (11%) liver transplantation. At T0 and T1, 84% used ursodeoxycholic acid. A positive association was observed between level of ALP at T0 and T1 and the hazard of reaching an endpoint, up to values around 2.5 times upper limit of normal (xULN). A larger decrease in ALP between T0 and T1 decreased the event rate. A range of thresholds (0.5-3×ULN) with about similar C-statistics was found. In this cohort, the optimal threshold was 1.3×ULN at T1. CONCLUSION: ALP can be used to discriminate between PSC patients with a good and a poor prognosis. These findings indicate that ALP can serve as stratifier, and potentially as surrogate endpoint for clinical trials in PSC.


Assuntos
Fosfatase Alcalina/sangue , Colangite Esclerosante/sangue , Progressão da Doença , Adulto , Biomarcadores/sangue , Colangite Esclerosante/diagnóstico , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prognóstico , Estudos Retrospectivos , Ácido Ursodesoxicólico/uso terapêutico , Adulto Jovem
7.
Liver Int ; 36(1): 84-91, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26077553

RESUMO

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease of unknown cause, but strongly associated with inflammatory bowel disease (IBD). Potential risk factors triggering PSC have never been studied on a population level. The aim of this study was to evaluate smoking, appendectomy, family history and geographical distribution in a population-based cohort of PSC patients, as compared to IBD control patients and healthy controls (HC). METHODS: For this case-control study 343 PSC patients, 370 IBD controls and 232 HC's living in a geographically defined area in the Netherlands filled-out a questionnaire concerning smoking, appendectomy and family history of IBD and autoimmune liver diseases. RESULTS: Smoking was associated with a lower risk of developing PSC in PSC-ulcerative colitis (UC) patients (adjusted OR 0.21; 95% CI 0.12-0.34; P < 0.001). Comparable results were found for PSC-Crohn's disease (CD) patients (16% former smokers) compared to CD patients (55% former smokers) (adjusted OR 0.17; 95% CI 0.08-0.39; P < 0.001). Frequency of appendectomy did not differ between PSC and HC, but PSC-UC patients had undergone appendectomy more often than UC patients (13% vs. 6%) (adjusted OR 2.51; 95%CI 1.04-6.07; P = 0.041). We found no association between family history of IBD or autoimmune liver disease and risk of PSC. Degree of urbanization was not associated with PSC incidence. CONCLUSION: In this large population-based case-control study we confirm that smoking is associated with a lower risk of developing PSC, independent of its protective effect for developing UC. Appendectomy is not associated with the risk of developing PSC.


Assuntos
Apendicectomia/estatística & dados numéricos , Colangite Esclerosante/epidemiologia , Doenças Inflamatórias Intestinais/epidemiologia , Fumar/epidemiologia , Adulto , Estudos de Casos e Controles , Demografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fatores de Proteção , Fatores de Risco
8.
J Hepatol ; 63(5): 1212-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26095184

RESUMO

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. At present, there is no appropriate histologic scoring system available for PSC, evaluating both degree of necroinflammatory activity (grade) and fibrosis (stage). The aim of this study was to assess if three scoring systems, commonly used in different liver diseases could be applied for grading and/or staging of PSC. METHODS: Sixty-four PSC patients from a Dutch cohort, who underwent diagnostic liver biopsy, were included. Staging was scored using Ishak, Nakanuma, and Ludwig systems. Grading was scored using Ishak and Nakanuma systems. Three measures of outcome were defined; transplant-free survival, time to liver transplantation (LTx) and occurrence of cirrhosis related symptoms (CRS). Association of grade and stage with outcome was estimated using Kaplan-Meier log-rank test, and Cox regression analysis. Correlation with biochemistry was assessed by Spearman's rank test. RESULTS: There were strong associations between disease stage measured by Ishak, Nakanuma, and Ludwig staging systems with both outcome measuring transplant-free survival (Hazard ratio (HR) 2.56; 95% CI 1.11-5.89, HR 6.53; 95% CI 2.01-21.22, HR 1.94; 95% CI 1.00-3.79, respectively), and time to LTx (HR 4.18; 95%CI 1.51-11.56, HR 7.05; 95% CI 1.77-28.11, HR 3.13; 95%CI 1.42-6.87, respectively). Ishak and Nakanuma grading systems were not associated with CRS. Weak correlations between histopathology and liver biochemistry were shown. CONCLUSION: Applying the Nakanuma, Ishak, and Ludwig histopathological staging systems is feasible and clinically relevant given their association with transplant-free survival and time to LTx. This suggests that these staging systems could be likely candidates for surrogate endpoints and stratification purposes in clinical trials in PSC.


Assuntos
Colangite Esclerosante/patologia , Fígado/patologia , Biomarcadores/metabolismo , Biópsia , Colangite Esclerosante/metabolismo , Colangite Esclerosante/mortalidade , Progressão da Doença , Feminino , Seguimentos , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Taxa de Sobrevida/tendências , Fatores de Tempo
9.
Curr Opin Gastroenterol ; 31(3): 239-46, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25695934

RESUMO

PURPOSE OF REVIEW: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin. There is no medical treatment of proven benefit on survival; once patients have progressed to end-stage liver disease, the only treatment option is liver transplantation. RECENT FINDINGS: Over the last years, some progress has been made in identifying biomarkers of PSC disease progression. Categories that can be distinguished include clinical and biochemical biomarkers, histology, imaging, prognostic modelling and genetics. With this review, we summarize biomarkers for progression of PSC from these six categories, which have been studied to date. SUMMARY: Biomarkers for the progression of PSC disease course can be used for several purposes. First of all, they can be implemented as surrogate endpoints for clinical trials. Second, biomarkers of disease progression form the basis of prognostic modelling, which is needed for proper patient counselling and management. Lastly, these biomarkers may yield a better understanding of PSC pathogenesis.


Assuntos
Fosfatase Alcalina/sangue , Autoanticorpos/sangue , Bilirrubina/sangue , Colangite Esclerosante/sangue , Doença Hepática Terminal/sangue , Biomarcadores/sangue , Colangite Esclerosante/patologia , Colangite Esclerosante/fisiopatologia , Progressão da Doença , Doença Hepática Terminal/complicações , Doença Hepática Terminal/patologia , Doença Hepática Terminal/fisiopatologia , Fadiga/etiologia , Humanos , Transplante de Fígado , Prognóstico , Prurido/etiologia , Qualidade de Vida
11.
Hepatol Int ; 11(1): 132-140, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27696157

RESUMO

BACKGROUND: Bile salts likely contribute to liver injury in patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Fibroblast growth factor 19 (FGF19) is a bile salt-induced enterokine with hepatoprotective potential as it suppresses de novo bile salt synthesis. Here, we evaluated the bile salt receptor FXR/FGF19 gut-liver axis in PSC and PBC patients. METHODS: Fasted patients with PSC (n = 12) and PBC (n = 10), and healthy controls (HC; n = 10) were orally challenged with the natural FXR agonist chenodeoxycholic acid (CDCA 15 mg/kg). Blood was sampled hourly until 8 h afterwards. Serum FGF19 and bile salt excursions were determined. Serum levels of 7α-hydroxy-4-cholesten-3-one (C4), reflecting bile salt synthesis, were measured as a biomarker of FGF19 response. RESULTS: Baseline serum FGF19 levels were comparable between groups, while fasted bile salt levels in PSC patients were elevated. Upon CDCA challenge, HC and PBC patients showed a serum FGF19 peak after 4 h followed by a decline. PSC patients showed a prolonged and elevated serum FGF19 response up to 8 h, combined with a sustained serum elevation of CDCA and other bile salts. In general, C4 levels declined following FGF19 elevation. In PSC patients with less favorable prognosis, baseline C4 levels were drastically suppressed and did not further decline. CONCLUSION: Following an oral CDCA challenge, PSC patients showed an impaired clearance of CDCA and a prolonged serum FGF19 response. FXR agonist therapy in PSC could cause prolonged exposure to elevated levels of FGF19, and we propose careful monitoring for detrimental side effects in patient studies.


Assuntos
Catárticos/administração & dosagem , Ácido Quenodesoxicólico/administração & dosagem , Colangite Esclerosante/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/metabolismo , Administração Oral , Adulto , Idoso , Estudos de Casos e Controles , Colangite Esclerosante/sangue , Colangite Esclerosante/metabolismo , Colestenonas/sangue , Protocolos Clínicos , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade
12.
World J Gastroenterol ; 21(17): 5359-71, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25954111

RESUMO

AIM: To study the clinical efficacy and safety of Fecal microbiota transplantation (FMT). We systematically reviewed FMT used as clinical therapy. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library and Conference proceedings from inception to July, 2013. Treatment effect of FMT was calculated as the percentage of patients who achieved clinical improvement per patient category, on an intention-to-treat basis. RESULTS: We included 45 studies; 34 on Clostridium difficile-infection (CDI), 7 on inflammatory bowel disease, 1 on metabolic syndrome, 1 on constipation, 1 on pouchitis and 1 on irritable bowel syndrome (IBS). In CDI 90% resolution of diarrhea in 33 case series (n = 867) was reported, and 94% resolution of diarrhea after repeated FMT in a randomized controlled trial (RCT) (n = 16). In ulcerative colitis (UC) remission rates of 0% to 68% were found (n = 106). In Crohn's disease (CD) (n = 6), no benefit was observed. In IBS, 70% improvement of symptoms was found (n = 13). 100% Reversal of symptoms was observed in constipation (n = 3). In pouchitis, none of the patients (n = 8) achieved remission. One RCT showed significant improvement of insulin sensitivity in metabolic syndrome (n = 10). Serious adverse events were rare. CONCLUSION: FMT is highly effective in CDI, and holds promise in UC. As for CD, chronic constipation, pouchitis and IBS data are too limited to draw conclusions. FMT increases insulin sensitivity in metabolic syndrome.


Assuntos
Transplante de Microbiota Fecal , Gastroenteropatias/terapia , Intestinos/microbiologia , Microbiota , Distribuição de Qui-Quadrado , Transplante de Microbiota Fecal/efeitos adversos , Fezes/microbiologia , Gastroenteropatias/diagnóstico , Gastroenteropatias/microbiologia , Humanos , Fatores de Risco , Resultado do Tratamento
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