The Relationship Between Serum Bilirubin And Metabolic Syndrome:A Health Check-up Cohort Study

BackgroundMetabolic syndrome(MS)is a cluster of interrelated metabolic risk factors that include hypertension,hyperglycemia,dyslipidemia and obesity.Evidences found that MS can increase the risk of cardiovascular disease,chronic kidney disease and cancers.With the development of social economy and a dramatic lifestyle change,the prevalence of MS is increasing year by year and poses as a major public health problem worldwide.Based on the Chinese National Health and Nutrition Examination Survey from 2010 to 2012,the prevalence of MS among Chinese adults(?18 years)is 11.0%by increasing about 5 million people with MS over the 10 years.It is very important to prevent and control MS in China.Bilirubin is a product of heme catabolism.Clinical workers commonly use it in assistant diagnosis of neonatal jaundice,haemolytic and hepatobiliary diseases.Accumulating evidence suggests that bilirubin is a potent endogenous anti-oxidant and anti-inflammatory molecule.Researchers generally believe that oxidative stress and chronic inflammation are key factors in the initiation and progression of MS.In addition,studies found that low serum bilirubin levels are associated with an elevated risk of cardiovascular diseases,type 2 diabetes mellitus and cancers,which are closely related to MS.Therefore,serum bilirubin may have a protective effect on the prevention of MS.To date,several studies have explored the relationship between serum bilirubin and MS.but it is still being debated.Most of these studies are cross-sectional which can not delineate the temporal association of serum bilirubin with MS.Besides,exiting cohort studies generally ignored changes of serum bilirubin during the follow-up,which may cause bias of the results.Furthermore,the relationship may differ by demographic characteristics,such as gender,age and ethnicity.But,the longitudinal study in Chinese population is still lack.Serum total bilirubin(TBIL)is constituted of indirect bilirubin(IBIL)plus direct bilirubin(DBIL).The two forms of bilirubin have some differences in the physical property and clinical significance.The association might be different in indirect bilirubin(IBIL)and direct bilirubin(DBIL).However,most of studies on the epidemiology of MS in relation to bilirubin were limited to TBIL.In a word,the relationship between bilirubin and MS still have much unknown need to be studied.Objectives1.To explore the relationships between the three serum examination items,namely TBIL,IBIL and DBIL.and the development of MS.2.To analyze the associations between TBIL/IBIL/DBIL and components of MS.MethodsA dynamic health check-up cohort study was set up at Shengli Oilfield Central Hospital in Dongying City from January 2006 to January 2015.Participants who had at least three health examinations during the 10 years and were free of MS at the first test were involved in this study.Subjects were excluded from analysis if they had one of the following items at baseline:1)a positive test for hepatitis C virus antibody or hepatitis B virus surface antigen;2)abnormal liver functions;3)a medical history of liver diseases and some serious diseases,such as heart failure.Subjects in this study all underwent a doctor's interview,laboratory and anthropometric test.In our study.MS was defined according to the criteria proposed by China Diabetes Society in 2004.SPSS 18.0 and SAS 9.3 were applied to analyze the data.Generalized estimated equations(GEE)models were used to explored the relationship between serum bilirubin and MS.In data analysis,we firstly used simple GEE analysis to select potential factors associated with MS.Furthermore,we sufficiently considered statistical significant level(P)of 0.10 and biological vaIlues,then adjusted potential confounding factors in multiple GEE analysis.In GEE models,'Logit' was used as the link function,data distribution was set as 'binomialr distribution,the structured correlation matrix was set as 'exchangeable' structure,'follow year' was used to distinguish different items within a cluster,P<0.05 was considered significant.Serum bilirubin levels were divide into quartiles and the top quartile was used as the reference.Results1.General characteristics:This study included 9154 subjects,with 3363 females and 5791 males.The average age in the tota]population was 41.1 ± 10.8 years old(40.1 ± 10.3 years old for females and 41.7± 11.0 years old for males).During the nine-year follow-up,2126 participants developed MS,and the incidence density was 5.33 per 100 person-year.The incidence density was 7.28 per 100 person-year and higher in men(u=22.902,P<0.001),compared with women(2.39 per 100 person-year).The constituent ratio of subjects with 0,1 and 2 components of MS are as follows:42.7%,30.7%and 26.6%.2.Multiple GEE analysis for serum bilirubin levels and MS:The differences of relative risk of developing MS for the higher quartiles of IBIL were not significant,compared with the lowest quartile.Increased TBIL and DBIL levels were negatively associated with MS in a dose-response manner(P<0.05).The relative risk of developing MS in the top quartile of TBIL was 0.839(95%confident interval was 0.727-0.968)and DBIL was 0.588(95%confident interval was 0.502-0.687),compared with the bottom quartile.3.Multiple GEE analysis of serum bilirubin levels and MS in different subgroups:1)in six subgroups with different sexes and ages in baseline.IBIL was not statistically significant associated with MS,and the relationship between TBIL/DBIL and MS was different in women and men.TBIL was not related to MS among all age groups in women,but negatively related to MS under 45 years old in men.DBIL was negatively associated with MS only under 45 years old in women,while there was still a negative correlation between DBIL and MS among the middle-aged group(45-55 years old)in men.2)in three subgroups with different numbers of MS components in baseline,DBIL was negatively associated with MS,and the negative relationship will be weakened by increasing the number of components of MS in baseline.3.Multiple GEE analysis for serum bilirubin levels and components of MS in subjects without components of MS in baseline:Serum TBIL was inversely associated with dyslipidemia and overweight/obesity.Serum IBIL was negative correlation with dyslipidemia.Serum DBIL was negatively related to hypertension dyslipidemia and overweight/obesity.Conclusions1.Low serum bilirubin levels maybe a risk factor for MS.The negative relationship between serum TBIL and MS may be due to the negative association between DBIL and MS.2.The negative relationship between serum DBIL and MS will be weakened by serious dysmetabolic changes.