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1.
Aliment Pharmacol Ther ; 59(12): 1604-1615, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38690746

RESUMO

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.


Assuntos
Fosfatase Alcalina , Ácido Quenodesoxicólico , Colagogos e Coleréticos , Quimioterapia Combinada , Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Ácido Ursodesoxicólico/uso terapêutico , Estudos Longitudinais , Cirrose Hepática Biliar/tratamento farmacológico , Idoso , Resultado do Tratamento , Fosfatase Alcalina/sangue , Colagogos e Coleréticos/uso terapêutico , Ácidos Fíbricos/uso terapêutico , Espanha , Bilirrubina/sangue , Adulto
2.
Eur J Gastroenterol Hepatol ; 36(5): 628-635, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38555601

RESUMO

BACKGROUND: Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cholangitis (PBC), but a significant proportion of patients do not respond adequately, leading to increased risk of adverse outcomes. This study aims to develop a new and straightforward predictive score to identify PBC patients likely to achieve a complete response to UDCA. METHODS: A logistic regression analysis was conducted using a derivation cohort of PBC patients to identify pre-treatment variables associated with response to UDCA. This analysis led to the development of the ALP-A score, calculated as: Age at diagnosis divided by (alkaline phosphatase at diagnosis/upper limit of normal). ALP-A score accuracy was evaluated using the area under the ROC curve, validated with a large external cohort from Brazil. Additionally, the correlation between the ALP-A score and the previously validated UDCA response score (URS) was assessed. RESULTS: ALP-A score had good predictive power for adequate (AUC 0.794; 95% CI, 0.737-0.852) and deep (0.76; 95% CI, 0.69-0.83) UDCA response at 1 year of treatment. A cutoff score of 17 and 23 points was determined to be the optimal threshold for distinguishing adequate and deep responders, respectively, from non-responders. ALP-A score demonstrated a sensitivity of 73%, specificity of 71%, positive predictive value of 65%, negative predictive value of 78%, and overall accuracy of 72% for biochemical response. The URS displayed similar discriminative ability (AUC 0.798; 95% CI, 0.741-0.855). CONCLUSION: ALP-A score performs comparably to URS but offers the great advantage of simplicity for routine clinical use. It serves as a valuable tool to identify PBC patients less likely to respond to UDCA treatment, facilitating early consideration of alternative therapeutic approaches.


Assuntos
Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Fosfatase Alcalina , Brasil , Resultado do Tratamento
3.
N Engl J Med ; 390(9): 783-794, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38381664

RESUMO

BACKGROUND: Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. METHODS: In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). RESULTS: Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. CONCLUSIONS: In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).


Assuntos
Acetatos , Fármacos Gastrointestinais , Cirrose Hepática Biliar , Humanos , Acetatos/administração & dosagem , Acetatos/efeitos adversos , Acetatos/uso terapêutico , Fosfatase Alcalina/sangue , Método Duplo-Cego , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Prurido/etiologia , Prurido/tratamento farmacológico , Resultado do Tratamento , Ácido Ursodesoxicólico/efeitos adversos , Ácido Ursodesoxicólico/uso terapêutico , PPAR delta/agonistas , Administração Oral , Bilirrubina/sangue , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/uso terapêutico , Colagogos e Coleréticos/administração & dosagem , Colagogos e Coleréticos/efeitos adversos , Colagogos e Coleréticos/uso terapêutico
4.
Eur J Intern Med ; 124: 14-21, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38307734

RESUMO

Primary biliary cholangitis (PBC) is a rare cholestatic immune-mediated liver disease. The clinical course varies from mild to severe, with a substantial group of patients developing cirrhosis within a decade. These patients are at risk of hepatocellular carcinoma, decompensation and liver failure. First line Ursodeoxycholic acid (UDCA) treatment improves the cholestatic surrogate markers, and was recently associated with a favorable survival free of liver transplantation, even in case of an incomplete biochemical response. However, despite adequate UDCA therapy, patients remain at risk of liver disease progression. Therefore, on-treatment multifactor-based risk stratification is necessary to identify patients in need of additional therapy. This requires a personalized approach; especially as recent studies suggest that complete biochemical normalization as most stringent response criterion might be preferred in selected patients to optimize their outcome. Today, stricter biochemical goals might actually be reachable with the addition of farnesoid X receptor or peroxisome proliferator-activated receptor agonists, or, in highly-selected cases, use of corticosteroids. Randomized controlled trials showed improvements in the key biochemical surrogate markers with the addition of these drugs, which have also been associated with improved clinical outcome. Considering this evolving PBC landscape, with more versatile treatment options and treatment goals, this review recapitulates the recent insight in UDCA therapy, the selection of patients with a residual risk of liver disease progression and the results of the currently available second line treatment options.


Assuntos
Colagogos e Coleréticos , Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Progressão da Doença , Receptores Citoplasmáticos e Nucleares/agonistas , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante de Fígado , Corticosteroides/uso terapêutico , Receptores Ativados por Proliferador de Peroxissomo/agonistas
5.
Ann Hepatol ; 29(3): 101490, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38403070

RESUMO

INTRODUCTION AND OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) is often accompanied by fetal and maternal complications. MATERIALS AND METHODS: Retrospective review of the clinical course of women with ICP and their neonates treated at our medical center over a 10-year period. Special attention was paid to the maternal and neonatal response to 2 different modes of ursodeoxycholic acid (UDCA) administration. RESULTS: Neonates of mothers with high total bile acid levels had a poorer composite neonatal outcome. Twenty-seven women who presented at an advanced stage of their pregnancies did not receive UDCA. UDCA was administered in 2 modes: either a full dose at admission (76 women) or a gradually increasing dose until the desired dosage was reached (25 women). The mean gestational age at delivery for the 94 neonates that were exposed to full UDCA dose was the lowest (36±2.3 weeks for the full dose, 37±1.4 weeks for the 30 neonates from the gradually increasing dose, 38±1.6 weeks for the 29 neonates from the no treatment group, p<0.001). The group of neonates that were exposed to full UDCA dose had the highest rate of unfavorable composite neonatal outcome (53% for full dose, 30% for gradually increasing dose, 24% for the no treatment group, p=0.006). CONCLUSIONS: Compared to the administration of a full UDCA dose, the administration of a gradually increasing dose of UDCA may be associated with a greater gestational age at delivery and fewer events of unfavorable composite neonatal outcomes. These novel findings should be retested prospectively in a large cohort of patients.


Assuntos
Colagogos e Coleréticos , Colestase Intra-Hepática , Idade Gestacional , Complicações na Gravidez , Ácido Ursodesoxicólico , Humanos , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/uso terapêutico , Feminino , Gravidez , Colestase Intra-Hepática/tratamento farmacológico , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/sangue , Estudos Retrospectivos , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/sangue , Recém-Nascido , Colagogos e Coleréticos/administração & dosagem , Colagogos e Coleréticos/efeitos adversos , Colagogos e Coleréticos/uso terapêutico , Adulto , Resultado do Tratamento , Resultado da Gravidez
7.
Aliment Pharmacol Ther ; 59(8): 962-972, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38409879

RESUMO

BACKGROUND: Aetiological therapy improves liver function and may enable hepatic recompensation in decompensated cirrhosis. AIMS: We explored the potential for recompensation in patients with decompensated primary biliary cholangitis (PBC) - considering a biochemical response to ursodeoxycholic acid (UDCA) according to Paris-II criteria as a surrogate for successful aetiological treatment. METHODS: Patients with PBC were retrospectively included at the time of first decompensation. Recompensation was defined as (i) resolution of ascites and hepatic encephalopathy (HE) despite discontinuation of diuretic/HE therapy, (ii) absence of variceal bleeding and (iii) sustained liver function improvement. RESULTS: In total, 42 patients with PBC with decompensated cirrhosis (age: 63.5 [IQR: 51.9-69.2] years; 88.1% female; MELD-Na: 13.5 [IQR: 11.0-15.0]) were included and followed for 41.9 (IQR: 11.0-70.9) months after decompensation. Seven patients (16.7%) achieved recompensation. Lower MELD-Na (subdistribution hazard ratio [SHR]: 0.90; p = 0.047), bilirubin (SHR per mg/dL: 0.44; p = 0.005) and alkaline phosphatase (SHR per 10 U/L: 0.67; p = 0.001) at decompensation, as well as variceal bleeding as decompensating event (SHR: 4.37; p = 0.069), were linked to a higher probability of recompensation. Overall, 33 patients were treated with UDCA for ≥1 year and 12 (36%) achieved Paris-II response criteria. Recompensation occurred in 5/12 (41.7%) and in 2/21 (9.5%) patients with vs. without UDCA response at 1 year, respectively. Recompensation was linked to a numerically improved transplant-free survival (HR: 0.46; p = 0.335). Nonetheless, 4/7 recompensated patients presented with liver-related complications after developing hepatic malignancy and/or portal vein thrombosis and 2 eventually died. CONCLUSIONS: Patients with PBC and decompensated cirrhosis may achieve hepatic recompensation under UDCA therapy. However, since liver-related complications still occur after recompensation, patients should remain under close follow-up.


Assuntos
Varizes Esofágicas e Gástricas , Encefalopatia Hepática , Cirrose Hepática Biliar , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Estudos Retrospectivos , Varizes Esofágicas e Gástricas/etiologia , Hemorragia Gastrointestinal/etiologia , Ácido Ursodesoxicólico/uso terapêutico , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/etiologia , Resultado do Tratamento
8.
J Autoimmun ; 143: 103163, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38301505

RESUMO

BACKGROUND: In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy. METHODS: We conducted a multicenter study involving PBC patients with moderate-to-severe interface hepatitis who underwent paired liver biopsies. Firstly, we compared the efficacy of the combination therapy with UDCA monotherapy on improving biochemistry, histology, survival rates, and prognosis. Subsequently we investigated the predictors of a beneficial response. RESULTS: This retrospective cohort study with prospectively collected data was conducted in China from January 2009 to April 2023. Of the 198 enrolled patients, 32 underwent UDCA monotherapy, while 166 received combination therapy, consisting of UDCA combined with prednisolone, prednisolone plus mycophenolate mofetil (MMF), or prednisolone plus azathioprine (AZA). The monotherapy group was treated for a median duration of 37.6 months (IQR 27.5-58.1), and the combination therapy group had a median treatment duration of 39.3 months (IQR 34.5-48.8). The combination therapy showed a significantly greater efficacy in reducing fibrosis compared to UDCA monotherapy, with an 8.3-fold increase in the regression rate (from 6.3% to 52.4%, P < 0.001). Other parameters, including biochemistry, survival rates, and prognosis, supported its effectiveness. Baseline IgG >1.3 × ULN and ALP <2.4 × ULN were identified as predictors of regression following the combination therapy. A predictive score named FRS, combining these variables, accurately identified individuals achieving fibrosis regression with a cut-off point of ≥ -0.163. The predictive value was validated internally and externally. CONCLUSION: Combination therapy with IS improves outcomes in PBC patients with moderate-to-severe interface hepatitis compared to UDCA monotherapy. Baseline IgG and ALP are the most significant predictors of fibrosis regression. The new predictive score, FRS, incorporating baseline IgG and ALP, can effectively identify individuals who would benefit from the combination therapy.


Assuntos
Hepatite , Cirrose Hepática Biliar , Humanos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêutico , Imunossupressores/uso terapêutico , Prednisolona/uso terapêutico , Terapia de Imunossupressão , Hepatite/complicações , Imunoglobulina G
9.
BMC Gastroenterol ; 24(1): 18, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38178006

RESUMO

BACKGROUND: Ursodeoxycholic acid is the preferred first-line therapy for primary biliary cholangitis. Alternative therapies, such as obeticholic acid, are recommended for patients who cannot tolerate ursodeoxycholic acid or who have an inadequate response to ursodeoxycholic acid monotherapy. Prior investigations have suggested that as many as 30% of patients with primary biliary cholangitis may have never received treatment with ursodeoxycholic acid. No prior investigations have examined usage rates of obeticholic acid in the treatment of primary biliary cholangitis. METHODS: All patients with an ICD-10 diagnosis of primary biliary cholangitis who had any records within the health system were included. A review of medical records was performed to confirm the diagnosis of primary biliary cholangitis and determine which medications had been prescribed for treatment, as well as candidacy for second-line therapies. RESULTS: A total of 495 patients met inclusion criteria. Notably, 95% of patients were taking ursodeoxycholic acid for treatment of their primary biliary cholangitis, with 67% of patients having disease that was well-controlled on ursodeoxycholic acid monotherapy. In total, 8% of patients were taking obeticholic acid (either as combination or monotherapy). Only 3% would benefit from the addition of a second line therapy but had not yet been offered medication. Only 3% of patients were not on any medication for management of their primary biliary cholangitis. CONCLUSIONS: Ursodeoxycholic acid is a readily available and generally well-tolerated medication that should be offered to all patients with primary biliary cholangitis as first-line therapy. While prior investigations have suggested that up to 30% of patients with primary biliary cholangitis may never have received treatment for the disorder, the present study suggests that patients are generally being managed according to guidelines. Moreover, a significant proportion of patients with primary biliary cholangitis will qualify for second line therapies and prescribers should be aware of the indications to use these medications.


Assuntos
Colangite , Cirrose Hepática Biliar , Humanos , Colagogos e Coleréticos/uso terapêutico , Colangite/tratamento farmacológico , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico
10.
Eur Radiol ; 34(2): 1268-1279, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37581659

RESUMO

OBJECTIVES: To explore the feasibility of pretreatment nonenhanced magnetic resonance imaging (MRI) in predicting insufficient biochemical response to ursodeoxycholic acid (UDCA) in patients with primary biliary cholangitis (PBC). METHODS: From January 2009 to April 2022, consecutive PBC patients who were treated with UDCA and underwent nonenhanced MRI within 30 days before treatment were retrospectively enrolled. All MR images were independently evaluated by two blinded radiologists. Uni- and multivariable logistic regression analyses were performed to develop a predictive model for 12-month insufficient biochemical response. Model performances were evaluated by computing the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. RESULTS: A total of 74 patients (50.6 ± 11.9 years; 62 females) were included. Three pretreatment MRI features, including hepatomegaly (odds ratio [OR]: 4.580; p = 0.011), periportal hyperintensity on T2-weighted imaging (T2WI) (OR: 4.795, p = 0.008), and narrowing of the bile ducts (OR: 3.491; p = 0.027) were associated with 12-month insufficient biochemical response in the multivariable analysis. A predictive model based on the above indicators had an AUC of 0.781, sensitivity of 85.4%, and specificity of 61.5% for predicting insufficient biochemical response. CONCLUSIONS: A noninvasive model based on three pretreatment MRI features could accurately predict 12-month insufficient biochemical response to UDCA in patients with PBC. Early identification of PBC patients at increased risk for insufficient response can facilitate the timely initiation of additional treatment. CLINICAL RELEVANCE STATEMENT: A noninvasive predictive model constructed by incorporating three pretreatment MRI features may help identify patients with primary biliary cholangitis at high risk of insufficient biochemical response to ursodeoxycholic acid and facilitate the timely initiation of additional treatment. KEY POINTS: • Noninvasive imaging features based on nonenhanced pretreatment MRI may predict an insufficient biochemical response to UDCA in PBC patients. • A combined model based on three MRI features (hepatomegaly, periportal hyperintensity on T2-weighted imaging, and narrowing of the bile ducts) further improved the predictive efficacy for an insufficient biochemical response to UDCA in PBC patients, with high sensitivity and specificity. • The nomogram of the combined model showed good calibration and predictive efficacy for an insufficient biochemical response to UDCA in PBC patients. In particular, the calibration curve visualised the clinical applicability of the prediction model.


Assuntos
Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Feminino , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/diagnóstico por imagem , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/farmacologia , Colagogos e Coleréticos/uso terapêutico , Estudos Retrospectivos , Hepatomegalia/induzido quimicamente , Hepatomegalia/complicações , Hepatomegalia/tratamento farmacológico
11.
N Engl J Med ; 390(9): 795-805, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-37962077

RESUMO

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).


Assuntos
Chalconas , Fármacos Gastrointestinais , Cirrose Hepática Biliar , Receptores Ativados por Proliferador de Peroxissomo , Propionatos , Humanos , Administração Oral , Fosfatase Alcalina/sangue , Bilirrubina/sangue , Chalconas/administração & dosagem , Chalconas/efeitos adversos , Chalconas/uso terapêutico , Colestase/sangue , Colestase/tratamento farmacológico , Colestase/etiologia , Método Duplo-Cego , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/uso terapêutico , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/agonistas , PPAR alfa/agonistas , PPAR delta/agonistas , Propionatos/administração & dosagem , Propionatos/efeitos adversos , Propionatos/uso terapêutico , Prurido/tratamento farmacológico , Prurido/etiologia , Resultado do Tratamento , Ácido Ursodesoxicólico/efeitos adversos , Ácido Ursodesoxicólico/uso terapêutico , Colagogos e Coleréticos/administração & dosagem , Colagogos e Coleréticos/efeitos adversos , Colagogos e Coleréticos/uso terapêutico
12.
J Gastroenterol ; 59(1): 66-74, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37845416

RESUMO

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic immune-mediated liver disease. Previous genome-wide meta-analysis has identified the association between variants in TMEM163 with PBC. Here we aimed to evaluate the association between variants near the reported risk loci of TMEM163 at 2q21.3 and prognosis of PBC patients. METHODS: We performed a retrospective analysis of 347 PBC patients treated with ursodeoxycholic acid (UDCA) for at least 1 year. We collected clinical data at diagnosis and 1 year after UDCA treatment. SNPs within 200 kb upstream and downstream of the lead variant were genotyped and screened. RESULTS: We identified that rs661899 near MGAT5 and TMEM163 showed the strongest association with prognosis in PBC patients. Patients carrying the rs661899 T allele tended to respond incompletely to UDCA treatment and had worse performances in laboratory values including aspartate aminotransferase (53.5 vs 32 vs 28.5 U/L, p = 0.001), alkaline phosphate (157.25 vs 125 vs 113 U/L, p = 0.001), albumin (41.5 vs 42.3 vs 43.7 g/L, p = 0.008) and bilirubin (19.2 vs 14.9 vs 12.85 µmol/L, p = 0.001). GLOBE scores (p = 4.8 × 10-5) and UK-PBC risk scores (p = 4.6 × 10-4) were strongly correlated with rs661899 genotype. Patients with TT genotype had a higher risk for adverse events compared with CC genotype (p = 0.039) during the 1-year follow-up. Results were also verified in an independent cohort. CONCLUSIONS: PBC patients carrying the rs661899 T allele are associated with poor prognosis and adverse outcomes after 1-year UDCA therapy.


Assuntos
Colangite , Cirrose Hepática Biliar , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/complicações , Estudos Retrospectivos , Colagogos e Coleréticos/uso terapêutico , Resultado do Tratamento , Prognóstico , Proteínas de Membrana/genética
13.
Hepatology ; 79(1): 39-48, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37399238

RESUMO

BACKGROUND AND AIMS: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. APPROACH AND RESULTS: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7-21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7-59.9, p < 0.001) when these 2 conditions were met. CONCLUSIONS: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.


Assuntos
Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Pessoa de Meia-Idade , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Fosfatase Alcalina , Colagogos e Coleréticos/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
14.
Nat Prod Res ; 38(1): 158-163, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-35921543

RESUMO

Gentianopsis is a small gentianaceous genus with a known ethnopharmacological focus as hepatoprotectors containing two underestimated species that are scientifically unexplored: Gentianopsis komarovii (Grossh.) Toyok., which is typical of the Far East, and Gentianopsis stricta (Klotzsch) Ikonn., which is grown in Central Asia. Application of the HPLC-PDA-ESI-tQ-MS/MS technique led to the identification of 28 compounds, such as iridoid glycosides, flavones and xanthones, with loganic acid, sweroside, loganin, secologanin, isoorientin-7-O-glucoside, luteolin-7-O-gentiobioside, chrysoeriol-7-O-glucoside and acacetin-7-O-glucoside being found in the genus for the first time. The extracts of G. komarovii and G. stricta demonstrated choleretic potential, strengthening the bile flow and the total content of bile acids, bilirubin and cholesterol in the bile. The most pronounced effects were observed for luteolin-7-O-glucoside and gentiabavaroside (gentiacaulein-1-O-primveroside), establishing them as the principle choleretics of both herbs. Based on the results, G. komarovii, G. stricta and some phenolic metabolites are prospective new choleretic drugs.


Assuntos
Colagogos e Coleréticos , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Glucosídeos/farmacologia , Fenóis/análise , Extratos Vegetais/farmacologia
15.
BMC Gastroenterol ; 23(1): 400, 2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-37978445

RESUMO

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by inflammation of the interlobular bile ducts. Ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to 40% of patients with PBC have an incomplete response to UDCA. Neutrophil-to-lymphocyte (NLR) has been used to predict prognosis in various liver diseases. There is limited evidence on the treatment response to UDCA in PBC patients. Our study aimed to evaluate the relationship between NRL and the response to UDCA treatment in PBC patients. METHODS: A total of 257 primary biliary cholangitis (PBC) patients treated with UDCA (13-15 mg/kg/d) were enrolled in this retrospective study. The response to treatment was evaluated based on alkaline phosphatase levels ≤1.67 times the upper limit of the normal value after 12 months of UDCA treatment. Multivariable logistic regression analysis was performed to investigate the association between NLR at baseline and the response to 12 months of UDCA treatment after adjusting for important confounding variables. The stability of the results was evaluated by unadjusted and adjusted models. RESULTS: The results of multiple regression analysis showed that NLR at baseline was positively associated with the nonresponse to UDCA treatment after adjustments for potential confounders (age, sex, BMI, hypertension, arterial plaque, thyroid disease, jaundice, albumin, globulin, total bile acid, ALP, GGT, LDLC, total cholesterol, hemoglobin, and APTT) (OR = 1.370, 95% CI 1.066-1.761). These results reveal that NLR is an independent risk factor for UDCA treatment nonresponse. CONCLUSIONS: Our results suggest that PBC patients with a high NLR had a worse response to UDCA therapy.


Assuntos
Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Ácido Ursodesoxicólico/efeitos adversos , Estudos Retrospectivos , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/complicações , Colagogos e Coleréticos/uso terapêutico , Neutrófilos , Resultado do Tratamento
16.
Gastroenterol. hepatol. (Ed. impr.) ; 46(9): 692-701, nov. 2023. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-226946

RESUMO

Background: Although patients with advanced liver disease have been included in studies evaluating fibrates for the treatment of primary biliary cholangitis (PBC), the frequency of biochemical responses and adverse effects for this group of patients was not reported separately and comprehensively. Aims: to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC. Methods: Patients were analyzed retrospectively to determine the clinical therapeutic effects of UDCA with additional fenofibrate therapy versus continued UDCA monotherapy. The liver transplantation (LT)-free survival and the alkaline phosphatase (ALP) normalization rates were estimated using Cox regression analyses and Kaplan–Meier plots with inverse probability of treatment weighting (IPTW). Results: A total of 118 patients were included: 54 received UDCA alone and 64 received UDCA in combination with fenofibrate therapy. In the fenofibrate and UDCA groups, 37% and 11% of patients with advanced and UDCA-refractory PBC, respectively, achieved ALP normalization (P=0.001). Additional fenofibrate therapy improved both LT-free survival and ALP normalization rate after IPTW (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07–0.75, P=0.015; and HR: 11.66, 95% CI: 5.02–27.06, P=0.001, respectively). These effects were supported by parallel changes in the rates of liver decompensation and histologic progression, and the United Kingdom (UK)-PBC and Globe risk scores. (AU)


Antecedentes: Aunque los pacientes con enfermedad hepática avanzada se han incluido en los estudios que evalúan los fibratos para el tratamiento de la colangitis biliar primaria, la frecuencia de las respuestas bioquímicas y los efectos adversos para este grupo de pacientes no se informó por separado y de forma exhaustiva. Objetivos: Evaluar la eficacia y la seguridad del tratamiento adicional con fenofibrato en pacientes con colangitis biliar primaria avanzada y refractaria al ácido ursodesoxicólico. Métodos: Se analizaron los pacientes de forma retrospectiva para determinar los efectos terapéuticos clínicos del ácido ursodesoxicólico con terapia adicional de fenofibrato frente a la monoterapia continuada con ácido ursodesoxicólico. La supervivencia sin trasplante de hígado y las tasas de normalización de la fosfatasa alcalina se estimaron mediante análisis de regresión de Cox y gráficos de Kaplan-Meier con ponderación de la probabilidad inversa del tratamiento. Resultados: Se incluyeron un total de 118 pacientes: 54 recibieron ácido ursodesoxicólico solo y 64 recibieron ácido ursodesoxicólico en combinación con el tratamiento con fenofibrato. En los grupos de fenofibrato y ácido ursodesoxicólico, 37 y 11% de los pacientes con colangitis biliar primaria avanzada y refractaria al ácido ursodesoxicólico, respectivamente, lograron la normalización de la fosfatasa alcalina (p=0,001). El tratamiento adicional con fenofibrato mejoró tanto la supervivencia libre de trasplante de hígado como la tasa de normalización de la fosfatasa alcalina tras la ponderación de la probabilidad inversa del tratamiento (cociente de riesgos: 0,23, intervalo de confianza del 95% [IC 95%]: 0,07-0,75, p=0,015; y cociente de riesgos: 11,66, IC 95%: 5,02–27,06, p=0,001, respectivamente). (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Cirrose Hepática Biliar , Fenofibrato/uso terapêutico , Fosfatase Alcalina , Colagogos e Coleréticos/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêutico
17.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 54(5): 930-936, 2023 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-37866948

RESUMO

Objective: To examine the influencing factors and prognostic features of poor response to ursodeoxycholic acid (UDCA) treatment in primary biliary cholangitis (PBC) patients with dyslipidemia. Methods: A retrospective study was conducted, covering 512 patients who had a confirmed diagnosis of PBC, and who received treatment at West China Hospital, Sichuan University between January 2009 and March 2022. According to their actual response to UDCA treatment, patients were divided into two groups, UDCA full-response group ( n=305) and UDCA non-responding group ( n=207). The data from the two groups were compared to predict the adverse factors influencing patient response and the area under the curve ( AUC) of the receiver operating characteristic (ROC) curve, identify the cut-off value of total cholesterol (TC), and analyze the differences in baseline laboratory test findings and the rate of responses to treatment. According to the TC cut-off value, patients were divided into a group with TC≥5.415 mmol/L and another group with TC<5.415 mmol/L. In addition, differences in the prognosis of the two groups were assessed by comparing the UK-PBC and GLOBE scores. Results: The baseline data, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), triglycerides (TG), TC, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), were significantly increased in the UDCA non-responding group compared to those in the full-response group (all P<0.005), while the albumin level of the UDCA non-responding group was decreased compared to that of the full-response group ( P=0.012). Findings of multi-factor logistic regression analysis suggested that TC (odds ratio [ OR]=1.501, 95% confidence interval [ CI]: 1.275-1.767, P<0.01) and ALP ( OR=1.005, 95% CI: 1.003-1.006, P<0.01) were independent risk factors influencing patient response. The ROC curve analysis suggested worse prognosis for patients with TC≥5.415 mmol/L ( AUC: 0.727, 95% CI: 0.680-0.775, 63.8% sensitivity, 76.4% specificity). In addition, the UK-PBC risk score at 1 year of treatment was higher in the high-TC group (TC≥5.415 mmol/L) than that in the low-TC group (TC<5.415 mmol/L) ( P<0.05). Conclusions: Hypercholesterolemia is an independent risk factor for poor response to UDCA in PBC patients. When the baseline TC is equal to or higher than 5.415 mmol/L, PBC patients have a relatively poor response to UDCA and poor prognosis.


Assuntos
Cirrose Hepática Biliar , Humanos , Cirrose Hepática Biliar/tratamento farmacológico , Estudos Retrospectivos , Colagogos e Coleréticos/uso terapêutico , Ácido Ursodesoxicólico/uso terapêutico , Prognóstico , Fosfatase Alcalina , Colesterol
18.
Medicine (Baltimore) ; 102(41): e35655, 2023 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-37832080

RESUMO

RATIONALE: A chronic autoimmune liver disease known as primary biliary cholangitis (PBC) that selectively destructs small intrahepatic biliary epithelial cells and may result in biliary cirrhosis and eventually liver transplantation or death. PBC is associated with various other extrahepatic autoimmune diseases; however, the combination of PBC with ankylosing spondylitis has been rarely reported in the literature. Here, we reported a case of PBC with ankylosing spondylitis to improve our understanding of such coexistence and provide new ideas for the treatment of such patients. PATIENT CONCERNS: A 54-year-old man was presented to the Department of Rheumatology because of an abnormal liver function test for 7 years, chest and back pain for 1 year, and low back pain for 2 months. DIAGNOSES: Primary biliary cholangitis, ankylosing spondylitis, and old pulmonary tuberculosis. INTERVENTIONS: The patient refused to use nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, and biologic disease-modifying antirheumatic drugs; thus, he was treated with methylenediphosphonate (99Tc-MDP) and ursodeoxycholic acid (UDCA). OUTCOMES: The patient achieved remission with UDCA and 99Tc-MDP therapy. LESSONS: In the treatment of PBC combined with other disorders, the characteristics of different diseases should be considered. The patient reported herein was treated with 99Tc-MDP and UDCA, and his condition improved; thus, we consider 99Tc-MDP to be an effective treatment. Furthermore, in line with the current understanding of the pathogenesis of PBC and ankylosing spondylitis, we hypothesize that interleukin-17 inhibitor is an effective treatment for such patients.


Assuntos
Antirreumáticos , Doenças Autoimunes , Colangite , Cirrose Hepática Biliar , Espondilite Anquilosante , Masculino , Humanos , Pessoa de Meia-Idade , Espondilite Anquilosante/complicações , Espondilite Anquilosante/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Antirreumáticos/uso terapêutico , Colangite/complicações , Colangite/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico
19.
J Dig Dis ; 24(6-7): 419-426, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37464723

RESUMO

OBJECTIVES: Primary biliary cholangitis (PBC) is a rare disease characterized by intrahepatic cholestasis, whereas gallstone disease (GD) is common. In this study, we aimed to investigate the prevalence and impact of GD on the prognosis of PBC in China. METHODS: Medical records of the PBC patients were retrospectively reviewed and their follow-up data were obtained via regular structured, standardized telephone interviews. GD was defined as gallstones on ultrasonography or a history of cholecystectomy for gallstones. Propensity score matching (PSM) and Cox regression analysis were performed. The primary end-point was liver-related death and/or liver transplantation. RESULTS: A total of 985 ursodeoxycholic acid (UDCA)-treated PBC patients were enrolled with a median follow-up duration of 5.3 years (range 1.0-20.9 years). Among them, 258 (26.2%) had GD, including 157 (22.9%) of non-cirrhotic and 101 (33.8%) of cirrhotic patients. Compared with PBC without GD, those with GD were older, more often had type 2 diabetes mellitus, and had a more severe liver disease at baseline. After PSM (1:2), 229 PBC patients with GD were matched with 458 PBC patients without GD based on age, sex, cirrhosis, and total bilirubin level. The transplant-free survival and incidence of hepatic events were similar between the two groups. Furthermore, multivariate Cox regression analysis showed that concomitant GD was not independently associated with a worse prognosis for PBC patients. CONCLUSION: Concomitant GD was common but was not associated with long-term outcomes in patients with UDCA-treated PBC.


Assuntos
Diabetes Mellitus Tipo 2 , Cálculos Biliares , Cirrose Hepática Biliar , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Estudos Retrospectivos , Cálculos Biliares/complicações , Colagogos e Coleréticos/uso terapêutico , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Resultado do Tratamento
20.
Eur J Gastroenterol Hepatol ; 35(8): 899-906, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37395243

RESUMO

OBJECTIVE: Primary biliary cholangitis (PBC) is a rare chronic autoimmune cholangiopathy, characterized by a variable course and response to treatment. We aimed to describe long-term outcomes of PBC patients referred to three academic centres in Northwest Italy. METHODS: This is an ambispective cohort study of PBC patients (retrospective component: diagnosis before 1 January 2019; prospective component: thereafter), including 302 patients: 101 (33%) followed up in Novara, 86 (28%) in Turin, 115 (38%) in Genoa. Clinical features at diagnosis, biochemical response to therapy and survival were analyzed. RESULTS: Among the 302 patients (88% women, median age 55 years, median follow-up 75 months), alkaline phosphatase (ALP) levels significantly decreased during treatment with ursodeoxycholic acid (UDCA, P < 0.0001) and obeticholic acid (P < 0.0001). At multivariate analysis, ALP at diagnosis was predictive of 1-year biochemical response to UDCA [odds ratio 3.57, 95% confidence interval (CI) 1.4-9, P < 0.001]. Estimated median survival free of liver transplantation and hepatic complications was 30 years (95% CI 19-41). Bilirubin level at diagnosis was the only independent risk factor for the combined outcome of death, transplantation or hepatic decompensation (hazard ratio, 1.65, 95% CI 1.66-2.56, P = 0.02). Patients presenting with total bilirubin at diagnosis ≥0.6 times the upper normal limit (ULN) had a significantly lower 10-year survival compared to those with bilirubin <0.6 times ULN (63% vs. 97%, P < 0.0001). CONCLUSION: In PBC, both short-term response to UDCA and long-term survival can be predicted by simple conventional biomarkers of disease severity, obtained at diagnosis.


Assuntos
Cirrose Hepática Biliar , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Estudos de Coortes , Colagogos e Coleréticos/uso terapêutico , Estudos Retrospectivos , Estudos Prospectivos , Ácido Ursodesoxicólico/uso terapêutico , Bilirrubina , Resultado do Tratamento
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