17 research outputs found
International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.
Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist
International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways
Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581]
Lessons to be learned from an on-going Trust-wide audit of the malnutrition universal screening tool (MUST)
Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score
Background Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin
treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after
12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk
can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted
using pretreatment clinical parameters.
Methods We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with
primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less
than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated
the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy.
Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury
and fibrosis, on liver biopsy samples.
Findings 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were
included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with
lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin
concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval
from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase
concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response.
In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with
follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for
the score was 0·83 (95% CI 0·79–0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the
UDCA response score was associated with ductular reaction (r=–0·556, p=0·0130) and intermediate hepatocytes
(probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present).
Interpretation We have derived and externally validated a model based on pretreatment variables that accurately
predicts UDCA response. Association with histological features provides face validity. This model provides a basis to
explore alternative approaches to treatment stratification in patients with primary biliary cholangitis
Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score
Background Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin
treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after
12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk
can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted
using pretreatment clinical parameters.
Methods We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with
primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less
than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated
the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy.
Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury
and fibrosis, on liver biopsy samples.
Findings 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were
included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with
lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin
concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval
from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase
concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response.
In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with
follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for
the score was 0·83 (95% CI 0·79–0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the
UDCA response score was associated with ductular reaction (r=–0·556, p=0·0130) and intermediate hepatocytes
(probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present).
Interpretation We have derived and externally validated a model based on pretreatment variables that accurately
predicts UDCA response. Association with histological features provides face validity. This model provides a basis to
explore alternative approaches to treatment stratification in patients with primary biliary cholangitis
Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score
Background Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin
treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after
12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk
can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted
using pretreatment clinical parameters.
Methods We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with
primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less
than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated
the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy.
Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury
and fibrosis, on liver biopsy samples.
Findings 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were
included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with
lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin
concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval
from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase
concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response.
In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with
follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for
the score was 0·83 (95% CI 0·79–0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the
UDCA response score was associated with ductular reaction (r=–0·556, p=0·0130) and intermediate hepatocytes
(probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present).
Interpretation We have derived and externally validated a model based on pretreatment variables that accurately
predicts UDCA response. Association with histological features provides face validity. This model provides a basis to
explore alternative approaches to treatment stratification in patients with primary biliary cholangitis
Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581] (Journal of Hepatology (2021) 75(3) (572–581), (S0168827821003342), (10.1016/j.jhep.2021.04.055))
It has come to our attention that the name of one of the authors in our manuscript was incorrectly spelled ‘Jinyoung Byan’; the correct spelling is ‘Jinyoung Byun’ as in the author list above. In addition, the excel files of the supplementary tables were not included during the online publication of our article. These have now been made available online. We apologize for any inconvenience caused