Biochemical criteria at 1 year are not robust indicators of response to ursodeoxycholic acid in early primary biliary cirrhosis: results from a 29-year cohort study.
ABSTRACT: In primary biliary cirrhosis (PBC), biochemical criteria at 1 year are considered surrogates of response to ursodeoxycholic acid (UDCA). However, due to the slow natural history of PBC, evaluation at 1 year may be suboptimal to assess the therapeutic response, particularly in early disease.To determine whether evaluation of biochemical criteria at 1 year is a reliable surrogate of UDCA response in early PBC.We analysed the prospectively collected data of 215 patients (untreated = 129; UDCA-treated = 86) with early PBC (normal baseline bilirubin/albumin) and a median follow-up of 8 years (range: 1-29.1). The 1-year attainment rates of the Barcelona, Paris-I, Paris-II and Toronto definitions, and their predictive relevance for a poor outcome (death, transplantation, complications of cirrhosis), were assessed either as a result of UDCA or no treatment. Independent associations with attaining each UDCA response definition were identified by multivariate analysis.Untreated patients displayed 1-year biochemical features compatible with 'treatment response' at rates (Barcelona: 36.4%, Paris-I: 66.7%, Toronto: 59.7%, Paris-II: 40.3%) similar to those obtained under UDCA. Depending on the definition, baseline ALP?3xULN (OR: 4.80-35.90), AST?2xULN (OR: 5.63-9.34) and early histological stage (OR: 3.67-3.87) were the stronger predictors for attaining the criteria. UDCA treatment was associated with attaining Barcelona (OR = 2.16) and Paris-II (OR = 2.84), but not Paris-I, and not Toronto definition when excluding late histological cases. Paris-I criteria were significantly predictive of long-term outcomes (HR = 2.83) in untreated patients.In early PBC, biochemical criteria at 1 year reflect severity of the disease rather than the therapeutic response to UDCA.
Project description:Biochemical response to ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) is variable. We have previously reported that augmented expression of lysosome-associated membrane protein 2 (LAMP-2) was correlated with the severity of PBC. This study aimed to determine whether serum LAMP-2 could serve as a predictor of biochemical response to UDCA. The efficiency of serum LAMP-2 to predict biochemical response was assessed after 1 year of UDCA treatment in PBC patients by a retrospective analysis. We found that the basal serum LAMP-2 level was increased in PBC, especially in patients with stage III-IV (p = 0.010) or TBIL > 1 mg/dL (p = 0.014). Baseline serum LAMP-2 was higher in non-responders than that in responders, but the difference was statistically insignificant. However, after UDCA treatment, serum LAMP-2 level decreased prominently in the first 3 months, which was more obvious in responders. Further studies showed that the 35% decline of LAMP-2 after treatment for 3 months could be stated as an indicator of UDCA response with the sensitivity of 62.9% and specificity of 75.0% by Paris criteria. Meanwhile the specificity and sensitivity were identified as 63.5% and 64.1% by Barcelona criteria. Together, a decline in LAMP-2 might help to predict the response to UDCA.
Project description:Primary biliary cirrhosis (PBC) is a chronic and progressive cholestasis liver disease. Bile salt export pump (BSEP) is the predominant bile salt efflux system of hepatocytes. BSEP gene has been attached great importance in the susceptibility of PBC and the response rate of ursodeoxycholic acid (UDCA) treatment of PBC patients.In this study, TaqMan assay was used to genotype four variants of BSEP, and the Barcelona criteria were used for evaluating the response rate of UDCA treatment.Variant A allele of BSEP rs473351 (dominant model, OR = 2.063; 95% CI, 1.254-3.393; P = 0.004) was highly associated with PBC susceptibility. On the contrary, variant A allele of BSEP rs2287618 (dominant model, OR = 0.617; 95% CI, 0.411-0.928; P = 0.020) provided a protective role and Barcelona evaluation criterion indicated that the frequency of variant allele at BSEP rs2287618 was significantly decreased in UDCA-responsive PBC patients (P = 0.021).These results suggested that BSEP rs473351 was closely associated with the susceptibility of PBC and if people with BSEP rs2287618 were diagnosed as PBC, the UDCA treatment was not satisfactory. Larger studies with mixed ethnicity subjects and stratified by clinical and subclinical characteristics are needed to validate our findings.
Project description:<h4>Aim</h4>To compare the response between the current recommended dosage 13-15?mg/kg/d and 20?mg/kg/d dose of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) patients who do not respond completely to a standard dose of UDCA.<h4>Methods</h4>We included 73 patients with poor response and randomized them into two groups to investigate whether increasing the dosage of UDCA was beneficial to nonresponders. Patients assigned to the 13-15?mg/kg/d group continued with standard therapy, and participants in the 18-22?mg/kg/d group switched to the higher dosage (18-22?mg/kg/d), with a follow-up of 12?months for both groups. The primary endpoints were the rate of response at 6 months and drug side effects.<h4>Results</h4>According to the Paris 2 criteria, patients receiving 18-22?mg/kg/d UDCA achieved a response rate of 59.4% compared with 36.1% in the standard dosage group (<i>P</i>=0.046) at 6 months, respectively. At 12 months, the high-UDCA-dosage group achieved a response rate of 59.4% compared with 47.2% in the standard dosage group (<i>P</i>=0.295), respectively. Additionally, the risk score predicted by the UK-PBC model was lower in high-dosage UDCA-treated patients than in the standard dosage group (all <i>P</i> < 0.05). Side effects include diarrhea, nausea and vomiting, rash, and newly developed high blood pressure, which were mild and tolerated.<h4>Conclusions</h4>Patients treated with the high UDCA dosage showed some advantages over those who continued the standard dosage in terms of biochemical remission and disease progression, indicating that standard therapy with UDCA for 6 months and then another 1 year with high UDCA dosage for nonresponders could be a treatment option before second-line therapy is recommended.
Project description:Aim:Patients with primary biliary cholangitis (PBC) have at least 60% probability of having an autoimmune extrahepatic condition, with the most common being Sjögren's syndrome (SS). The impacts of SS on the response and outcomes in ursodeoxycholic acid (UDCA)-treated patients with PBC, however, remain unclear. The aim of this study was to document the biochemical responses and clinical outcomes of UDCA-treated patients with concomitant SS and to compare the findings to those of patients with PBC alone. Methods:Data from consecutive patients with PBC who visited West China Hospital affiliated with Sichuan University between October 2013 and October 2017 were reviewed retrospectively. Results:The study populations consisted of 226 patients with PBC alone and 56 with PBC/SS. The median ages, proportions of female patients, Fib-4 scores, and aspartate aminotransferase (AST)/platelet ratio index (APRI) at baseline in the two cohorts were similar. At presentation, patients with PBC/SS had higher serum IgG levels and positive rates for serum antinuclear antibody (ANA) than patients with PBC alone (all P < 0.05). There was no statistically significant difference between the rate of biochemical response to UDCA at 1 year in the PBC/SS and PBC alone groups. The UK-PBC risk scores and GLOBE scores in UDCA-treated patients in the two cohorts were also similar. During the follow-up period, the differences in the liver enzyme levels, Fib-4 scores, APRI, and incidence of liver-related adverse events were not significant. Conclusions:The results of this retrospective, single-center study suggest that the response and clinical outcomes of UDCA-treated patients with PBC are not adversely affected by concomitant SS.
Project description:Background/Aims:Recently reported prognostic models for primary biliary cholangitis (PBC) have been shown to be effective in Western populations but have not been well-validated in Asian patients. This study aimed to compare the performance of prognostic models in Korean patients and to investigate whether inflammation-based scores can further help in prognosis prediction. Methods:This study included 271 consecutive patients diagnosed with PBC in Korea. The following prognostic models were evaluated: the Barcelona model, the Paris-I/II model, the Rotterdam criteria, the GLOBE score and the UK-PBC score. The neutrophil-to-lymphocyte ratio (NLR) was analyzed with reference to its association with prognosis. Results:For predicting liver transplant or death at the 5-year and 10-year follow-up examinations, the UK-PBC score (areas under the receiver operating characteristic curve [AUCs], 0.88 and 0.82) and GLOBE score (AUCs, 0.85 and 0.83) were significantly more accurate in predicting prognosis than the other scoring systems (all p?0.05). There was no significant difference between the performance of the UK-PBC and GLOBE scores. In addition to the prognostic models, a high NLR (?2.46) at baseline was an independent predictor of reduced transplant-free survival in the multivariate analysis (adjusted hazard ratio, 3.74; p?0.01). When the NLR was applied to the prognostic models, it significantly differentiated the prognosis of patients. Conclusions:The UK-PBC and GLOBE scores showed good prognostic performance in Korean patients with PBC. In addition, a high NLR was associated with a poorer prognosis. Including the NLR in prognostic models may further help to stratify patients with PBC.
Project description:UNLABELLED:The biochemical response to ursodeoxycholic acid (UDCA)--so-called "treatment response"--strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90). CONCLUSIONS:The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care.
Project description:BACKGROUND:Health care costs are growing faster than the rest of the global economy, according to the World Health Organization (WHO). Countries' health expenditures include paying for general medicine, diagnostic procedures, hospitalizations and surgeries, as well as medications and prescribed treatment. Primary biliary cholangitis (PBC) is a rare autoimmune liver disease and the first line available treatment is ursodeoxycholic acid (UDCA), however, direct and indirect treatment costs are expensive. Main aim of this trial was to assess if the therapeutic efficacy of UDCA manufactured by the university hospital is equivalent to that of standard UDCA and treatment cost reduction in patients with PBC. METHODS:It is a prospective, interventional, randomized, and crossover study in patients diagnosed with PBC. UDCA 300?mg tablets and capsules were developed and manufactured by the university hospital. Thirty patients under treatment with standard UDCA, in stable doses were randomized in sequence A and B, 15 patients in each arm. The groups were treated for 12?weeks and after, the UDCA formulation was changed, following for another 12?weeks of continuous therapy (tablets and capsules / capsules and tablets). Laboratory tests were performed at time T0 (beginning of treatment), T1 (at the 12?week-therapy, before the crossing-over) and T2 (end of treatment). The evaluation was done by comparing the hepatic parameters ALP, GGT, ALT, AST and total bilirubin, also considering the adverse events. The comparison of costs was based on price of the manufactured UDCA and standard UDCA price of the hospital. RESULTS:Hospital reduced 66.1% the PBC treatment costs using manufactured UDCA. There were no differences in the biochemical parameters between sequence (A and B) and tablets or capsules of UDCA formulations applied in the treatment of PBC. CONCLUSIONS:The study showed that there was no significant difference between manufactured UDCA (capsule and tablet) and standard UDCA. Hospital reduced the PBC treatment costs using the manufactured UDCA by the university hospital. TRIAL REGISTRATION:ClinicalTrials.gov: NCT03489889 retrospectively registered on January 12th, 2018; Ethics Committee approved the study (ID: 1.790.088) on October 25th, 2016.
Project description:The extrahepatic complications of primary biliary cholangitis (PBC) in Asian patients remain elusive. A 30-year cohort study of 150 Taiwanese PBC patients treated with ursodeoxycholic acid (UDCA) was conducted. Patients with alkaline phosphatase levels >1.67?×?ULN after 1-year treatment were considered suboptimal responders. At baseline, of 150 patients (mean age: 53.75 years), 128 (85.3%) were females, and 34 (22.8%) had cirrhosis. The cumulative incidences of various incident events were all-cause mortality or liver transplantation: 46.7%; extrahepatic mortality: 24.5%; extrahepatic malignancies: 8.1%; hypertension: 46.2%; dyslipidemia: 44.1%; diabetes: 30.6%; hyperuricemia: 11.2%; acute coronary syndrome: 3.1%; cerebral vascular accident (CVA): 8.9%; autoimmune diseases: 16%; and osteoporosis: 20.9%. The 5- to 20-year cumulative incidences for all-cause mortality or liver transplantation and extrahepatic mortality were 16.2-41.3% and 3.1-11.9%, respectively. Baseline associations were age and alpha-fetoprotein levels with extrahepatic mortality, 80% due to sepsis; age with extrahepatic malignancies and hypertension; gender and hyperuricemia with CVA; and UDCA response with autoimmune disease. Conclusions: Sepsis accounted for most extrahepatic mortality in PBC patients, and the longer the follow-up was, the higher the extrahepatic/all-cause mortality ratio. Baseline age is crucial for incident extrahepatic events and only CVA shows gender-dimorphism; the association between UDCA response and autoimmune disease requires further investigation.
Project description:Fatigue, itch, depressed mood, and cognitive impairment significantly impact the quality of life of many patients with primary biliary cholangitis (PBC). Previous neuroimaging studies of non-hepatic diseases suggest that these symptoms are often associated with dysfunction of deep gray matter brain regions. We used resting-state functional magnetic resonance imaging (rsfMRI) to determine whether PBC patients exhibit altered functional connections of deep gray matter.Twenty female non-cirrhotic PBC patients and 21 age/gender-matched controls underwent rsfMRI. Resting-state functional connectivity (rsFC) of deep gray matter brain structures (putamen, thalamus, amygdala, hippocampus) was compared between groups. Fatigue, itch, mood, cognitive performance, and clinical response to ursodeoxycholic acid (UDCA) were assessed, and their association with rsFC was determined.Relative to controls, PBC patients exhibited significantly increased rsFC between the putamen, thalamus, amygdala, and hippocampus, as well as with frontal and parietal regions. Reduced rsFC of the putamen and hippocampus with motor and sensory regions of the brain were also observed. Fatigue, itch, complete response to UDCA, and verbal working memory performance were also associated with altered rsFC of deep gray matter. These rsFC changes were independent of biochemical disease severity.PBC patients have objective evidence of altered rsFC of the brain's deep gray matter that is in part linked to fatigue severity, itch, response to UDCA therapy, and cognitive performance. These results may guide future approaches to define how PBC leads to altered brain connectivity and provide insight into novel targets for treating PBC-associated brain dysfunction and behavioral symptoms.
Project description:Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic, cholestatic diseases of the liver with common clinical manifestations. Early diagnosis and treatment of PBC slows progression and decreases the need for transplant. However, one-third of patients will progress regardless of treatment. Bilirubin <1.0 and alkaline phosphatase <2.0 x the upper limit of normal at 1 year after treatment appear to predict 10-year survival. Ursodeoxycholic acid (UDCA) is the recommended treatment for PBC, and recent studies with obeticholic acid showed promising results for UDCA non-responders. Unlike PBC, no therapy has been shown to alter the natural history of PSC. The recommended initial diagnostic test for PSC is magnetic resonance cholangiopancreatography, typically showing bile duct wall thickening, focal bile duct dilatation, and saccular dilatation of the intra- and/or extrahepatic bile ducts. Immunoglobulin 4-associated cholangitis must be excluded when considering the diagnosis of PSC, to allow for proper treatment, and monitoring of disease progression. In addition to the lack of therapy, PSC is a pre-malignant condition and close surveillance is indicated.