Objective To investigate the impacts of wogonin (WG) on Th17/Treg cell balance in autoimmune hepatitis (AIH) rats. Methods A total of 10 rats were randomly selected as the control group. The ...remaining rats were injected with concanavalin A (ConA, 12.5 mg/kg) solution via tail vein to construct AIH model rat, which were randomly divided into AIH group, L-WG group (10 mg/kg), M-WG group (20 mg/kg), H-WG group (30 mg/kg), H-WG+VPA group (30 mg/kg WG+300 mg/kg Notch signal pathway activator VPA), 10 rats in each group and administered once a day for 10 days. Serum inflammatory factors and liver function indexes were detected by ELISA; HE staining was used to observe the pathological morphology of liver tissue; the level of spleen Th17/Treg cells was detected by flow cytometry; Western blot was used to detect the expression of spleen retinoid acid related orphan receptor γ t (RORγt), fork head box protein P3 (Foxp3) and liver Notch signal pathway proteins. Results The liver tissue structure of control group was no
Background and aims
Current treatment guidelines recommend ursodeoxycholic acid (UDCA) as the first-line treatment for new-diagnosed primary biliary cholangitis (PBC) patients. However, up to 40% ...patients are insensitive to UDCA monotherapy, and evaluation of UDCA response at 12 months may result in long period of ineffective treatment. We aimed to develop a new criterion to reliably identify non-response patients much earlier.
Methods
Five hundred sixty-nine patients with an average of 59 months (Median: 53; IQR:32–79) follow-up periods were randomly divided into either the training (70%) or the validation cohort (30%). The efficiency of different combinations of total bilirubin (TBIL), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcomes was assessed at 1, 3 or 6 month after the initiation of UDCA therapy. The endpoints were defined as adverse outcomes, including liver-related death, liver transplantation and complications of cirrhosis. Adverse outcome-free survival was compared using various published criteria and a proposed new criterion.
Results
A new criterion of evaluating UDCA responses at 1 month was established as: ALP ≤ 2.5 × upper limit of normal (ULN) and AST ≤ 2 × ULN, and TBIL ≤ 1 × ULN (Xi’an criterion). The 5 year adverse outcome-free survival rate of UDCA responders, defined by Xi’an criterion, was 97%, which was significantly higher than that of those non-responders (64%). An accurate distinguishing high-risk patients’ capacity of Xi’an criterion was confirmed in both early and late-stage PBC.
Conclusions
Xi’an criterion has a similar or even higher ability to distinguish high-risk PBC patients than other published criteria. Xi’an criterion can facilitate early identification of patients requiring new therapeutic approaches.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
The role of liver stiffness measurements (LSM) in patients with primary biliary cholangitis (PBC) remains to be further elucidated.
Aims
To clarify the prognostic role of LSM and to ...validate the “novel concepts” proposed by the Baveno VII Working Group.
Methods
An analysis of the prognostic significance of LSM was performed involving 672 patients.
Results
LSM and ΔLSM/ΔT were independent risk factors for liver decompensation, liver transplantation, or liver-related death (primary outcomes,
p
< 0.001, both). A rule of 5 kPa for LSM (10–15–20 kPa) could be used to denote progressively higher relative risks of primary outcomes. Patients with LSM < 10 kPa have a negligible 3-year risk of primary outcomes (< 1%). Cut-off values of 10 and 15 kPa can be used to classify PBC patients into low-, medium-, and high-risk groups. A clinically significant decrease in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially reduced risk of primary outcomes (
p
< 0.05, all), which can be defined as a decrease in LSM of > − 20% associated with LSM < 20 kPa or any decrease to LSM < 10 kPa. A clinically significant increase in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially raised risk of primary outcomes (
p
< 0.05, all), which can be defined as an increase in LSM of ≥ + 20% or any increase to LSM ≥ 15 kPa.
Conclusions
LSM can be used to monitor disease progression and predict long-term prognosis in patients with PBC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Fenofibrate (FF) has shown potential benefits in patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid (UDCA). However, the efficacy and safety of FF ...in patients with cirrhosis remain unclear. To evaluate the efficacy and safety of additional FF therapy in patients with PBC‐related cirrhosis with an incomplete response to UDCA, we conducted a retrospective analysis comparing the clinical results of additional FF therapy and continued UDCA monotherapy. A total of 59 patients were included; 27 cases underwent UDCA monotherapy and 32 cases underwent UDCA combined with FF therapy. A significant difference in alkaline phosphatase (ALP) normalization was achieved in the FF group compared to the UDCA group (37% vs. 11%, respectively; p = 0.020). Additional FF therapy was an independent risk factor for ALP normalization (hazard ratio, 7.679; 95% confidence interval, 2.059–28.633; p = 0.003). Hepatic deterioration was experienced by 40% versus 48% (p = 0.562) while 11% vs. 37% (p = 0.111) experienced liver‐related mortality or liver transplantation in the FF and UDCA groups, respectively. Compared to UDCA monotherapy, additional FF therapy was associated with lower United Kingdom (UK)‐PBC risk score and surrogate serum indices of liver fibrosis. After 12 months of add‐on FF therapy, median ALP level and UK‐PBC risk score decreased 35% and 52% from baseline (p = 0.001 and 0.210, respectively). Serum aminotransferase, triglyceride, and cholesterol decreased progressively, while total bilirubin, serum creatinine, blood urea, estimated glomerular filtration rate, aspartate aminotransferase‐to‐platelet ratio index, and fibrosis‐4 index remained stable in FF‐treated cirrhotic cases during follow‐up. No significant adverse effects associated with additional FF therapy were observed in our cohort. Conclusion: Additional FF therapy was associated with higher ALP normalization rates and lower UK‐PBC risk scores in patients with cirrhotic PBC with an incomplete response to UDCA. In addition, FF therapy seemed safe and well tolerated with a low frequency of adverse effects in patients with cirrhosis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease, and patients with inadequate response to ursodeoxycholic acid (UDCA) treatment show reduced long-term survival. Recent ...studies have shown that fenofibrate is an effective off-label therapy for PBC. However, prospective studies on biochemical response including the timing of fenofibrate administration are lacking. This study is aimed to evaluate the efficacy and safety of fenofibrate in UDCA treatment-naive patients with PBC.
A total of 117 treatment-naive patients with PBC were recruited from the Xijing Hospital for a 12-month randomized, parallel, and open-label clinical trial. Study participants were assigned to receive either UDCA standard dose (UDCA-only group) or fenofibrate at a daily dose of 200 mg in addition to UDCA (UDCA-Fenofibrate group).
The primary outcome was biochemical response percentage in patients according to the Barcelona criterion at 12 months. In the UDCA-Fenofibrate group, 81.4% (69.9%-92.9%) of patients achieved the primary outcome and 64.3% (51.9%-76.8%) in the UDCA-only group achieved the primary outcome ( P = 0.048). There was no difference between the 2 groups in noninvasive measures of liver fibrosis and biochemical markers other than alkaline phosphatase at 12 months. Creatinine and transaminases levels in the UDCA-Fenofibrate group increased within the first month, then returned to normal, and remained stable thereafter until the end of the study, even in patients with cirrhosis.
In this randomized clinical trial in treatment-naive patients with PBC, the combination of fenofibrate and UDCA resulted in a significantly higher biochemical response rate. Fenofibrate seemed to be well-tolerated in patients.
Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed ...to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the associated lipid metabolism.
Five hundred and thirty-one patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation, and cirrhosis-related complications. Lipidomics was performed in 89 patients and 28 healthy controls.
Baseline TC was independently associated with poor liver-related outcomes, and adjusted C-statistics were 0.80 (95% confidence interval CI: 0.74–0.85) and 0.88 (95% CI: 0.78–0.91) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over time and comparable with the Globe score. The 200 mg/dL cut-off optimally divided patients into low- and high-TC groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Lipidomics indicated an up-regulation of lipid families in high-TC patients. Pathway analysis of 66 up-regulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-TC patients, which were associated with poor liver-related outcomes.
Our results indicate that patients with PBC having baseline TC levels above 200 mg/dL have unique lipidome characteristics and are at a higher risk of poor liver-related outcomes.
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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.
to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC.
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).
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. During the follow-up period, serum levels of ALP and aminotransferase decreased significantly, while total bilirubin, albumin, platelet, serum creatinine, and estimated glomerular filtration rate remained stable in fenofibrate-treated participants. No fenofibrate-related significant adverse events were observed in our cohort.
Additional fenofibrate therapy significantly improved LT-free survival and ALP normalization in patients with advanced and UDCA-refractory PBC. Furthermore, adding-on fenofibrate therapy appeared to be safe and well tolerated in this population.
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.
Evaluar la eficacia y la seguridad del tratamiento adicional con fenofibrato en pacientes con colangitis biliar primaria avanzada y refractaria al ácido ursodesoxicólico.
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.
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). Estos efectos se vieron respaldados por cambios paralelos en las tasas de descompensación hepática y de progresión histológica, y por las puntuaciones de riesgo de colangitis biliar primaria del Reino Unido y de Globe. Durante el periodo de seguimiento, los niveles séricos de fosfatasa alcalina y aminotransferasa disminuyeron significativamente, mientras que la bilirrubina total, la albúmina, las plaquetas, la creatinina sérica y la tasa de filtración glomerular estimada permanecieron estables en los participantes tratados con fenofibrato. No se observaron acontecimientos adversos significativos relacionados con el fenofibrato en nuestra cohorte.
El tratamiento adicional con fenofibrato mejoró significativamente la supervivencia libre de trasplante hepático y la normalización de la fosfatasa alcalina en pacientes con colangitis biliar primaria avanzada y refractaria al ácido ursodesoxicólico. Además, el tratamiento adicional con fenofibrato parece ser seguro y bien tolerado en esta población.
