Characteristics Of Lipid Metabolism In Primary Biliary Cholangitis And Its Effect On Prognosis Of Patients

【Background】 Primary biliary cholangitis(PBC)is a chronic cholestatic disease that is characterized by immune-mediated,progressive damage of intrahepatic bile ducts,which eventually leads to cirrhosis and life-threatening complications if undertreated or incomplete biochemical response.Presently,ursodeoxycholic acid(UDCA)is widely accepted as the first line of therapy for patients with PBC.And it has been confirmed that UDCA could significantly improve liver functiong and survival rates without liver transplant in PBC patients.However,an incomplete biochemical response has been reported in 30%~40% of UDCA-treated patients,which can lead to significantly worse outcomes.Progressive damage of intrahepatic bile ducts and chronic cholestasis result in not only alterations of serum and fecal bile acid profiles,but also hypercholesterolemia in patients with PBC,which has been frequently observed in clinical practice.Several studies have shown that an increase in cholesterol in PBC poses a low risk for patients with atherosclerosis and cardiovascular disease.Cholesterol and its metabolites play a crucial role in energy supply,the regulation of inter-organ communication,metabolism,and immune responses.Experimental evidence has indicated that hypercholesterolemia and consequent accumulation of excess cholesterol in immune cells play a causal role in the development of autoimmune disease.A moderate increase in plasma cholesterol can disrupt the homeostasis of human immune cells in vivo,which can contribute to immune cellmediated inflammatory disease in patients with hypercholesterolemia.These results suggest that hypercholesterolemia may play a critical role in the development of PBC.However,there is no study on the effect of dysregulated lipids on biochemical response to UDCA and clinical prognosis in PBC patients.And there is no lipid metabolomics analysis of PBC,which may provide a new research perspective for PBC with incomplete response to UDCA treatment and poor prognosis and provide a new treatment direction for those patients.【Aims】1.To analyze the characteristics of biochemical blood lipid in patients with PBC using clinical data,and to explore the potential relationship between dysregulated lipids and clinical prognosis of patients;2.To further analyze and verify the predictive ability of dyregulated lipids for the longterm clinical prognosis of patients with PBC;3.To comprehensively analyze the characteristics of lipid metabolism and their possible relationship with the clinical prognosis of patients with PBC.【Methods】1.Analysis of biochemical blood lipid characteristics in PBC patients.Retrospectively collected treated-na(?)ve PBC patients without decompensated cirrhosis.Clinical and laboratory data were collected during the start of UDCA treatment and follow-up from medical records.The Globe score was calculated and biochemical response to UDCA treatment was defined as ALP<1.67 times the upper limit of normal(ULN)level after 12 months of treatment(ALP1.67 criteria).The primary endpoint of the study was defined as the occurrence of at least one of the following adverse events: liver-associated death,liver transplantation(LT),or complications due to cirrhosis(e.g.variceal bleeding,ascites,hepatic encephalopathy,or hepatocellular carcinoma).Endpoints were evaluated using univariate and multivariable-adjusted Cox proportional-hazards models adjusted for baseline covariates(including age,sex,BMI,TBIL,albumin,AST,ALP,platelet count,and histological stage)in the total cohort;2.To analyze the predictive ability of dysregulated lipids for poor clinical outcomes.Enrolled patients with UDCA treatment-naive PBC without prior cirrhosis-related complications were randomly divided into derivation and validation cohorts at a ratio of 7:3.The prognostic value of baseline disorderd lipids was compared with the explanatory variables that were previously reported to predict survival outcomes in PBC,including Globe score and ALP1.67 criteria.The predictive performance of disordered lipids was evaluated using The Harrell’s C-index and time-dependent receiveroperating-characteristic area under the curve(AUC)analyses.The cut-offs of lipids were based on the standard of borderline high for Chinese adults;3.To characterize the serum bile acid and lipidomic profiles in patients with PBC using UPLC-MS.Their relationships with clinical data and prognosis of patients were analized by bioinformatics technology.【Results】1.Baseline characteristics of lipids of the patients with PBC.531 patients with UDCA treatment-naive PBC without prior cirrhosis-related complications were enrolled,among which 205(38.6%)patients had total cholesterol(TC)levels above 5.2 mmol/L.The baseline TC level of patients was positively correlated with the cholestasis index,Globe score and ALP1.67 criteria.Multivariable-adjusted Cox model adjusted for baseline covariates in the total cohort showed that baseline TC level,but not triglyceride(TG),was an independent predictor of poor clinical outcomes(HR=1.189,95% CI:1.103–1.281,p<0.001);2.The overall predictive ability of baseline TC for poor clinical outcomes.TC levels at baseline in PBC patients was a valuable predictive criterion of the likelihood of a poor prognosis,including liver-related death,LT,or complications.The prognostic value of baseline TC levels as an individual and readily available parameter was comparable to that of the composite Globe score in both derivation and validation cohorts.Patients with baseline TC below 5.2 mmol/L exhibited a significantly better outcome compared with those with baseline TC above 5.2 mmol/L.Notably,a combination of baseline TC and Globe score thresholds provided a more accurate stratification of patients into risk subgroups,that is patients with baseline TC below 5.2 mmol/L exhibited a significantly better outcome compared with Globe score-matched patients with baseline TC above 5.2 mmol/L in both derivation and validation cohorts;3.Bile acid compositions in serum significantly differed between treatment-naive PBC and HC.Particularly,PBC was associated with decreased conversions of conjugated to unconjugated and secondary/primary ratio.The increased ratio of conjugated/unconjugated bile acids and decreased secondary/primary bile acids were associated with the levels of TBIL,ALP,and TC.Blood lipid disorder was found in patients with PBC and hypercholesterolemia.A significant increase in lipid families was observed in high-TC patients(baseline TC≥5.2 mmol/L),whereas similar lipid components were found in low-TC patients(baseline TC<5.2 mmol/L)and HC.And 66 species were significantly increased in high-TC patients when compared with those in low-TC patients.A KEGG pathway analysis of the 66 differential lipids was performed to determine the changes in lipid metabolism associated with hypercholesterolemia,it was found that the glycerophospholipid metabolism and the sphingolipid metabolism were profoundly affected.Furthermore,the levels of the hits of lipids were significantly higher in patients with poor clinical outcomes than in those without poor clinical outcomes.【Conclusion】The present study showed that hypercholesterolemia at baseline in patients with PBC is a valuable predictive criterion of the likelihood of a poor prognosis,including liver-related death,LT,or complications.The prognostic value of baseline TC levels as an individual and readily available parameter was comparable to that of the composite Globe score.Furthermore,based on the 5.2 mmol/L cut-off criterion for baseline TC,patients could be optimally divided into low-and high-TC groups.Additionally,this study provides a comprehensive review of lipidomics in PBC and reveals a general increase in lipids,especially dysregulated glycerophospholipid and sphingolipid metabolisms,as a characteristic feature of high-TC group.