Lower Serum Bilirubin Concentrations Research Articles

Association of Low Serum Bilirubin Concentrations and Promoter Variations in the UGT1A1 and HMOX1 Genes with Type 2 Diabetes Mellitus in the Czech Population.

Bilirubin has potent biological beneficial effects, protecting against atherosclerosis, obesity, and metabolic syndrome. The aim of this study was to assess serum bilirubin concentrations and (TA)n and (GT)n microsatellite variations in the promoter regions of the UGT1A1 and HMOX1 genes, respectively, in patients with type 2 diabetes mellitus (T2DM). The study was carried out in 220 patients with T2DM and 231 healthy control subjects, in whom standard biochemical tests were performed. The (TA)n and (GT)n dinucleotide variations were determined by means of fragment (size-based) analysis using an automated capillary DNA sequencer. Compared to controls, both male and female patients with T2DM had lower serum bilirubin concentrations (9.9 vs. 12.9 μmol/L, and 9.0 vs. 10.6 μmol/L, in men and women, respectively, p < 0.001). Phenotypic Gilbert syndrome was much less prevalent in T2DM patients, as was the frequency of the (TA)7/7UGT1A1 genotype in male T2DM patients. (GT)nHMOX1 genetic variations did not differ between diabetic patients and controls. Our results demonstrate that the manifestation of T2DM is associated with lower serum bilirubin concentrations. Consumption of bilirubin due to increased oxidative stress associated with T2DM seems to be the main explanation, although (TA)n repeat variations in UGT1A1 partially contribute to this phenomenon.

Bilirubin levels and kidney function decline: An analysis of clinical trial and real world data.

ObjectiveTo evaluate if previously found associations between low serum bilirubin concentration and kidney function decline is independent of hemoglobin and other key confounders.Research design and methodsClinical trial data from the SAVOR-TIMI 53 trial as well as the UK primary care electronic healthcare records, Clinical Practice Research Datalink (CPRD), were used to construct three cohorts of patients at risk of chronic kidney disease (CKD). The randomized clinical trial (RCT) cohort from the subset of SAVOR-TIMI 53 trial consisted of 10,555 type-2 diabetic patients with increased risk of cardiovascular disease. The two observational data cohorts from CPRD consisted of 71,104 newly diagnosed type-2 diabetes (CPRD-DM2) and 82,065 newly diagnosed hypertensive (CPRD-HT) patients without diabetes. Cohorts were stratified according to baseline circulating total bilirubin levels to determine association on the primary end point of a 30% reduction from baseline in estimated glomerular filtration rate (eGFR) and the secondary end point of albuminuria.ResultsThe confounder adjusted hazard ratios of the subpopulation with lower than median bilirubin levels compared to above median bilirubin levels for the primary end point were 1.18 (1.02–1.37), 1.12 (1.05–1.19) and 1.09 (1.01–1.17), for the secondary end point were 1.26 (1.06–1.52), 1.11 (1.01–1.21) and 1.18 (1.01–1.39) for SAVOR-TIMI 53, CPRD-DM2, CPRD-HT, respectively.ConclusionOur findings are consistent across all cohorts and endpoints: lower serum bilirubin levels are associated with a greater kidney function decline independent of hemoglobin and other key confounders. This suggests that increased monitoring of kidney health in patients with lower bilirubin levels may be considered, especially for diabetic patients.

Serum Bilirubin in the Czech Population - Relationship to the Risk of Myocardial Infarction in Males.

The potential antiatherogenic role of bilirubin is generally acknowledged, so the aim of this study was to determine serum bilirubin concentrations and the prevalence of Gilbert syndrome (GS) in the Czech general population with particular reference to its relationship to the risk of myocardial infarction (MI).Methods and Results:Biochemical markers were analyzed in 2 independent Czech post-MONICA studies (in total, n=3,311), and in 741 male MI patients. TheUGT1A1promoter gene variant (rs81753472) was analyzed in these MI patients and in the first control population cohort (n=717). Medians of serum bilirubin concentrations in the 2 Czech general population cohorts were 9.6 and 9.8 μmol/L (10.7 and 11.3 μmol/L in males, and 8.3 and 8.8 μmol/L in females; P<0.01). The prevalence of GS was 8.9%, twice as high in males compared with females (11.6 vs. 6.1%; P<0.01). TheUGT1A1(TA)7/7promoter repeats significantly influenced serum bilirubin concentrations in the controls, but not in the MI patients. Serum bilirubin concentrations were significantly lower in MI patients (7.7 vs. 10.7 μmol/L; P<0.01), with almost 5-fold lower prevalence of GS. Serum bilirubin concentrations and the prevalence of GS were determined in the Czech general population. Significantly lower serum bilirubin concentrations were observed in male MI patients.

Bilirubin concentration is positively associated with haemoglobin concentration and inversely associated with albumin to creatinine ratio among Indigenous Australians: eGFR Study

Low serum bilirubin concentrations are reported to be strongly associated with cardio-metabolic disease, but this relationship has not been reported among Indigenous Australian people who are known to be at high risk for diabetes and chronic kidney disease (CKD).Hypothesis: serum bilirubin will be negatively associated with markers of chronic disease, including CKD and anaemia among Indigenous Australians.Method: A cross-sectional analysis of 594 adult Aboriginal and Torres Strait Islander (TSI) people in good health or with diabetes and markers of CKD. Measures included urine albumin: creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), haemoglobin (Hb) and glycated haemoglobin (HbA1c). Diabetes was defined by medical history, medications or HbA1c≥6.5% or ≥48mmol/mol. Anaemia was defined as Hb<130g/L or <120g/L in males and females respectively. A multivariate regression analysis examining factors independently associated with log-bilirubin was performed.Results: Participants mean (SD) age was 45.1 (14.5) years, and included 62.5% females, 71.7% Aboriginal, 41.1% with diabetes, 16.7% with anaemia, 41% with ACR>3mg/mmol and 18.2% with eGFR<60mL/min/1.73m2. Median bilirubin concentration was lower in females than males (6 v 8μmol/L, p<0.001) and in Aboriginal than TSI participants (6 v 9.5μmol/L, p<0.001). Six factors explained 35% of the variance of log-bilirubin; Hb and cholesterol (both positively related) and ACR, triglycerides, Aboriginal ethnicity and female gender (all inversely related).Conclusion: Serum bilirubin concentrations were positively associated with Hb and total cholesterol, and inversely associated with ACR. Further research to determine reasons explaining lower bilirubin concentrations among Aboriginal compared with TSI participants are needed.

Update on Phototherapy in Jaundiced Neonates.

Even relatively low serum bilirubin concentrations can cause neurodevelopmental impairment in extremely low birth weight (EBWL) infants, while sequelae from hyperbilirubinemia in late preterm and term infants are rare and occur only at very high serum bilirubin levels. Phototherapy is the current treatment of choice. To present an update on the most important issues involved in phototherapy for jaundiced infants. Light absorption by bilirubin in the skin transforms the native Z,Z-bilirubin to conformational photoisomers Z,E-bilirubin and E,Z-bilirubin and structural photoisomers E,Z-lumirubin and E,E-lumirubin. Formation and excretion of Z,E-bilirubin and E,Z-lumirubin are both important routes of elimination of bilirubin through bile and urine, although the precise contributions of the various photoisomers to the overall elimination of bilirubin are unknown. It appears that the photoisomers of bilirubin are predominantly formed in the plasma, and the rate of formation is affected by the hemoglobin concentration. Phototherapy lights with an emission spectrum of 460-490 nm provide the most efficient bilirubin-reducing light. LEDs should replace fluorescent tubes and halogen spotlights as the preferred light sources. Recent data raise concerns that sick ELBW infants under prolonged phototherapy may have an increased risk of death, though survivors may benefit from reduced rates of neurodevelopmental impairment. Comparison of the efficacy of cycled vs. continuous phototherapy has given divergent results. Changing the infant's position does not increase the efficacy of phototherapy. During the last decade, we have made progress in our understanding of how and where phototherapy works and in its practical applications.

Associations between serum bilirubin levels and essential trace elements status in an adult population.

ObjectiveThis paper aims to evaluate the relations between serum bilirubin and essential trace elements in an adult population.ResultsDemographic and clinical data were stratified according to the median of serum bilirubin concentrations (50th percentiles). There were statistical differences in regarding with age, body mass index, white blood count, hemoglobin, mean corpuscular hemoglobin, alanine aminotransferase, creatinine, high-sensitivity C-reactive protein, iron, zinc and copper. Studying the correlation of serum bilirubin levels with iron, zinc, copper and high-sensitivity C-reactive protein, we found positive correlations for iron and zinc, and negative correlations for high-sensitivity C-reactive protein and copper in whole participants. Similar results of correlation analysis were repeated when the further analyses were performed separately for subjects with high and low serum bilirubin concentrations. Similar results were also observed in gender-based stratified analysis. Multiple linear regression analysis revealed that serum bilirubin levels were independently correlated with serum iron, zinc and copper.Materials and MethodsThe cross-sectional study involved 264 healthy subjects.ConclusionsThe current study demonstrated that serum bilirubin within the reference range is correlated with iron, zinc and copper in an adult population, regardless of potential confounders.

Role of Bilirubin in Diabetic Vascular Complications: Can Bilirubin Predict More than Just Liver Disease?

Role of Bilirubin in Diabetic Vascular Complications: Can Bilirubin Predict More than Just Liver Disease?

Low serum bilirubin concentration is a predictor of chronic kidney disease

ObjectiveChronic kidney disease (CKD) is a worldwide public health problem. It is very important to identify the factors that affect CKD. Previous studies have reported that serum bilirubin concentration was positively correlated with renal function in a cross-sectional study. The aim of this study was to investigate the relationship between serum bilirubin concentration and the progression of CKD. MethodsA cohort study was performed on a consecutive series of 2784 subjects without CKD, defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, at baseline. We analyzed the relationship between serum total bilirubin concentration at baseline and new-onset CKD in the general population. ResultsWe followed the subjects for a median period of 7.7 years. There were 1157 females and 1627 males, and 231 females and 370 males developed CKD during this period. Multiple Cox regression analyses revealed that serum total bilirubin concentration (hazard ratio (HR) per 1.0 μmol/L increase 0.97 (95% CI 0.95–0.99), P = 0.0084) in addition to age, gamma-glutamyl transpeptidase (GGT), uric acid (UA), creatinine and medication for hypertension in men and serum total bilirubin concentration (HR per 1.0 μmol/L increase 0.96 (95% CI 0.93–1.00), P = 0.0309) in addition to age, GGT, alanine aminotransferase, UA, creatinine and medication for dyslipidemia in women were independent predictors of new-onset CKD, after adjusting for confounders. ConclusionOur study demonstrated that serum total bilirubin concentration could be a novel risk factor for the progression of CKD, defined as eGFR <60 ml/min/1.73 m2, in the general population.

Low serum bilirubin concentration is a novel risk factor for the development of albuminuria in patients with type 2 diabetes

ObjectiveBilirubin has been recognized as an important endogeneous antioxidant. Previous studies reported that bilirubin could prevent atherosclerosis. The aim of this study was to investigate if serum bilirubin concentration could be a predictor for the development of albuminuria in patients with type 2 diabetes. Materials and MethodsWe measured serum bilirubin in 320 consecutive patients with normoalbuminuria. We performed follow-up study to assess the development of albuminuria, mean interval of which was 3.2±0.9years. Cox proportional hazards regression was used to examine the relationship between serum bilirubin concentration and the development of albuminuria. ResultsDuring follow-up duration, 43 patients have developed albuminuria. In multivariate analysis, after adjusting for comprehensive risk factors, the risk of developing albuminuria was higher in the lowest quartile of serum bilirubin concentrations than that in the highest quartile of serum bilirubin concentrations (Hazard ratio, 5.76; 95% CI, 1.65 to 24.93). ConclusionsLow serum bilirubin concentration could be a novel risk factor for the development of albuminuria in patients with type 2 diabetes.

Serum total bilirubin levels and prevalence of diabetic retinopathy in a Chinese population (中国人群血清总胆红素水平与糖尿病视网膜病变相关性的研究)

Patients with type 2 diabetes (T2D) are at a high risk of developing microvascular complications, such as diabetic retinopathy (DR). Previous studies have shown that low serum bilirubin concentrations in T2D patients may increase the risk of diabetic complications. Thus, the aim of the present was to investigate the association between the prevalence of DR and serum concentrations of total bilirubin in a Chinese population. The present study was a population-based cross-sectional study on 1761 T2D patients aged ≥40 years from the Jiading district of Shanghai, China. Fundus photographs were taken to confirm the presence and severity of DR. Subjects were assigned to quartiles based on serum total bilirubin concentrations (Quartile (Q) 1 <0.60 mg/dL; Q2 0.60-0.76 mg/dL; Q3 0.77-0.99 mg/dL; Q4 >0.99 mg/dL). Logistic regression models were used to explore the association between bilirubin concentrations and the prevalence of DR. The prevalence of DR in the entire study population was 9.6%. The prevalence of DR was significantly lower in Q4 compared with the other three quartiles (Ptrend = 0.004). After adjustment for multiple confounding factors, T2D patients in Q4 (i.e. serum bilirubin >0.99 mg/dL) were less likely (odds ratio 0.55; 95% confidence interval 0.33-0.91) to suffer from DR than patients in Q1 (i.e. serum bilirubin <0.60 mg/dL). Serum bilirubin concentrations were inversely associated with DR in an elderly Chinese population, independent of traditional risk factors for microvascular complications.

Cochrane Review: Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants

Low birth weight and premature infants are at major risk for exaggerated hyperbilirubinaemia and jaundice that can lead to bilirubin encephalopathy. Phototherapy is the most common treatment for neonatal hyperbilirubinaemia and could be most effective in preventing the sequelae of hyperbilirubinaemia if initiated prophylactically. To evaluate the efficacy and safety of prophylactic phototherapy for preterm (< 37 weeks gestational age) or low birth weight infants (birth weight < 2500 g). We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3) on 31 March 2011, MEDLINE (1950 to 31 March 2011), EMBASE (1980 to 31 March 2011) and CINAHL (1982 to 31 March 2011). Randomised controlled trials or quasi-randomised controlled studies evaluating the effects of prophylactic phototherapy for preterm or low birth weight infants. Two authors independently obtained data from published articles. We performed fixed-effect meta-analysis for the outcomes: rate of exchange transfusion, cerebral palsy or other neurodevelopmental impairment, peak serum bilirubin level and all-cause mortality. Nine studies of 3449 participants were included. The rate of exchange transfusion was reduced in one study with liberal transfusion criteria (risk ratio (RR) 0.20; 95% confidence interval (CI) 0.13 to 0.31) but not in the other two more recent studies with stringent criteria (typical RR 0.66; 95% CI 0.19 to 2.28). There was no statistically significant difference in the rate of cerebral palsy (typical RR 0.96; 95% CI 0.50 to 1.85; two studies, 756 participants). However, one large study that reported on neurodevelopmental impairment (a composite outcome including cerebral palsy) found a slightly lower rate of neurodevelopmental impairment with prophylactic phototherapy (RR 0.85; 95% CI 0.74 to 0.99; 1804 participants). The prophylactic phototherapy group had lower peak bilirubin levels (mean difference (MD) -2.73; 95% CI -2.89 to -2.57; six studies, 2319 participants) and had fewer neonates with peak unconjugated serum bilirubin levels > 10 mg/dl (typical RR 0.27; 95% CI 0.22 to 0.33; three studies, 1090 participants) or peak unconjugated serum bilirubin levels > 15 mg/dl (typical RR 0.13; 95% CI 0.07 to 0.23; four studies, 1116 participants). There was no statistically significant difference in the rate of all-cause mortality between the two groups (typical RR 1.08; 95% CI 0.93 to 1.26; four studies, 3044 participants). Prophylactic phototherapy helps to maintain a lower serum bilirubin concentration and may have an effect on the rate of exchange transfusion and the risk of neurodevelopmental impairment. However, further well-designed studies are needed to determine the efficacy and safety of prophylactic phototherapy on long-term outcomes including neurodevelopmental outcomes.

Inverse Relation of Total Serum Bilirubin to Coronary Artery Calcification Score Detected by Multidetector Computed Tomography in Males

Serum total bilirubin has been suggested to have potential anti-inflammatory and antioxidant effects on the vasculature, acting against plaque formation and subsequent atherosclerosis. This study was designed to assess the association of serum total bilirubin with coronary artery calcification (CAC). Individuals with higher bilirubin level would be less likely to develop CAC. Male subjects (N = 3408) underwent evaluation of CAC by cardiac computed tomography. Correlation and logistic regression analysis were performed to assess the relationships between CAC score and other variables. Subjects with a higher CAC score had significantly lower total bilirubin level (P = 0.001). Total bilirubin level was negatively correlated with CAC score (r = -0.052, P = 0.002). A 0.1-mg/dL increase in bilirubin was associated with a reduced odds ratio (OR) of the risk by 29.2% for a CAC score above 100 (OR: 0.708, 95% confidence interval: 0.542-0.927, P = 0.012) after adjustment for several variables. Bilirubin was inversely correlated with high-sensitivity C-reactive protein (hsCRP) (r = -0.117, P < 0.001). This study demonstrated an independent inverse association between serum total bilirubin and CAC score in males. Low serum bilirubin concentration would be useful as a potential risk factor for CAC in males. Additionally, reduced hsCRP may be 1 of the mechanisms for how bilirubin reduces CAC.

Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants

Low birth weight and premature infants are at major risk for exaggerated hyperbilirubinaemia and jaundice that can lead to bilirubin encephalopathy. Phototherapy is the most common treatment for neonatal hyperbilirubinaemia and could be most effective in preventing the sequelae of hyperbilirubinaemia if initiated prophylactically. To evaluate the efficacy and safety of prophylactic phototherapy for preterm (< 37 weeks gestational age) or low birth weight infants (birth weight < 2500 g). We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3) on 31 March 2011,MEDLINE (1950 to 31 March 2011), EMBASE (1980 to 31 March 2011) and CINAHL (1982 to 31 March 2011). Randomised controlled trials or quasi-randomised controlled studiesevaluating the effects of prophylactic phototherapy for preterm or low birth weight infants. Two authors independently obtained data from published articles. We performed fixed-effect meta-analysis for the outcomes: rate of exchange transfusion, cerebral palsy or other neurodevelopmental impairment, peak serum bilirubin level and all-cause mortality. Nine studies of 3449 participants were included. The rate of exchange transfusion was reduced in one study with liberal transfusion criteria (risk ratio (RR) 0.20; 95% confidence interval (CI) 0.13 to 0.31) but not in the other two more recent studies with stringent criteria (typical RR 0.66; 95% CI 0.19 to 2.28). There was no statistically significant difference in the rate of cerebral palsy (typical RR 0.96; 95% CI 0.50 to 1.85; two studies, 756 participants). However, one large study that reported on neurodevelopmental impairment (a composite outcome including cerebral palsy) found a slightly lower rate of neurodevelopmental impairment with prophylactic phototherapy (RR 0.85; 95% CI 0.74 to 0.99; 1804 participants). The prophylactic phototherapy group had lower peak bilirubin levels (mean difference (MD) -2.73; 95% CI -2.89 to -2.57; six studies, 2319 participants) and had fewer neonates with peak unconjugated serum bilirubin levels > 10 mg/dl (typical RR 0.27; 95% CI 0.22 to 0.33; three studies, 1090 participants) or peak unconjugated serum bilirubin levels > 15 mg/dl (typical RR 0.13; 95% CI 0.07 to 0.23; four studies, 1116 participants). There was no statistically significant difference in the rate of all-cause mortality between the two groups (typical RR 1.08; 95% CI 0.93 to 1.26; four studies, 3044 participants). Prophylactic phototherapy helps to maintain a lower serum bilirubin concentration and may have an effect on the rate of exchange transfusion and the risk of neurodevelopmental impairment. However, further well-designed studies are needed to determine the efficacy and safety of prophylactic phototherapy on long-term outcomes including neurodevelopmental outcomes.

Association of serum bilirubin levels with albuminuria in patients with essential hypertension

Objectives This study was undertaken to evaluate the relationship between serum bilirubin concentrations and the degree of urinary albumin excretion in hypertensive patients. Design and methods A total of 120 hypertensive subjects were enrolled, in which 80 (67%) with normoalbuminuria (albumin excretion rate [AER] of < 20 μg/min), 30 (25%) with microalbuminuria (AER of 20–200 μg/min) and 10 (8%) with macroalbuminuria (AER > 200 μg/min). Logarithmic (log) transformation of urinary albumin excretion was carried out before performing correlation and regression analysis. Results Patients with micro- or macroalbuminuria had significantly lower serum bilirubin concentrations ( P = 0.004). By multivariate regression analysis, serum bilirubin concentration was an independent determinant of albuminuria and had an inverse correlation with log (urinary albumin excretion) in hypertensive patients ( β = − 0.189, P = 0.023). Conclusions These findings may partly explain the pathogenetic processes that link microalbuminuria and enhanced cardiovascular risk in hypertensive patients.

Low serum bilirubin concentration in haemodialysis patients with Type 2 diabetes

Previous studies have implicated reduced serum bilirubin concentrations in the development of cardiovascular disease. The aim of this study was to examine whether bilirubin may explain the high incidence of vascular complications in haemodialysis patients with Type 2 diabetes. We compared serum bilirubin concentrations, as well as other known aetiological risk factors for cardiovascular disease, in 206 Type 2 diabetes patients on haemodialysis with those in 741 Type 2 diabetes patients not receiving haemodialysis, and evaluated the association between serum bilirubin concentration and cardiovascular disease incidence. Incidences of cardiovascular disease and systolic blood pressure were higher; however, BMI and serum total cholesterol were lower in haemodialysis patients compared with those in patients without haemodialysis. Serum total (0.30 ± 0.10 vs. 0.74 ± 0.26 mg/dl, 0.005 ± 0.002 vs. 0.013 ± 0.004 mmol/l, P < 0.0001) and indirect (0.17 ± 0.08 vs. 0.70 ± 0.23 mg/dl, 0.003 ± 0.001 vs. 0.012 ± 0.004 mmol/l, P < 0.0001) bilirubin were lower in haemodialysis patients compared with those in patients without haemodialysis. Stepwise regression analysis demonstrated that age (β = 0.109, F = 5.959, P < 0.05), duration of diabetes (β = -0.112, F = 6.048, P < 0.05), sex (β = -0.123, F = 8.623, P < 0.05), cardiovascular disease events (β = -0.099, F = 5.131, P < 0.05) and presence of haemodialysis (β = -0.626, F = 201.727, P < 0.01) were independent factors for serum total bilirubin. Logistic regression demonstrated that age (OR 1.089, 95% CI 1.044-1.136; P < 0.0001), duration of diabetes (OR 1.029, 95% CI 1.001-1.059; P = 0.0423), body mass index (OR 1.115, 95% CI 1.001-1.242; P = 0.0487), habit of smoking (OR 2.445, 95% CI 1.046-5.716; P = 0.0391) and serum total bilirubin (OR 0.192, 95% CI 0.037-0.989; P = 0.0484) were independent factors for cardiovascular disease events. Low serum bilirubin concentration could be one of the important factors for the high incidence of cardiovascular disease in Type 2 diabetes patients receiving haemodialysis.

Citrus Fruit Intake Is Associated with Lower Serum Bilirubin Concentration among Women with the UGT1A1*28 Polymorphism

UDP-glucuronosyltransferase (UGT) 1A1 glucuronidates bilirubin, estrogens, and xenobiotic compounds. The UGT1A1*28 polymorphism results in lower promoter activity due to 7 thymine-adenine (TA) repeats rather than the more common 6 TA repeats. Previously, we showed that serum bilirubin, a marker of UGT1A1 activity, was lower among individuals homozygous for the UGT1A1*28 polymorphism (7/7) when randomized to a high fruit and vegetable (F&V) diet, whereas there was no effect in individuals with the wild-type (6/6) and heterozygous (6/7) genotypes. Our objective here was to determine if we could detect genotype × diet interactions on bilirubin concentrations in an observational study. Healthy nonsmoking men (n = 146) and women (n = 147), recruited from the Seattle area, provided blood samples for genotyping and bilirubin measurements. We used multiple linear regression to assess the relationships among UGT1A1 genotype, bilirubin concentrations, and consumption of specific F&V [cruciferous vegetables, citrus fruits, and soy foods (n = 268)] based on FFQ and F&V from 6 botanical families [Cruciferae, Rosaceae, Rutaceae, Umbelliferae, Solanaceae, and Leguminosae (n = 261)] based on 3-d food records. We observed a significant interaction of UGT1A1 genotype and citrus consumption among women. Women with the 7/7 genotype who consumed ≥0.5 daily servings of citrus fruit or foods from the Rutaceae botanical family had ∼30% lower serum bilirubin than those with the same genotype who consumed less, whereas 6/6 and 6/7 genotypes did not differ by consumption (P for interaction = 0.006 and 0.03, respectively). These results suggest that citrus consumption may increase UGT1A1 activity among women with the 7/7 genotype.

Low serum bilirubin concentration is associated with coronary artery calcification (CAC)

BackgroundBilirubin is a potent antioxidant and previous studies have reported the relationship between low serum bilirubin concentration and atherosclerosis. The purpose of this study was to assess the correlation between serum bilirubin concentration and coronary artery calcification (CAC). MethodsThis study consisted of 637 participants and we evaluated the relationship between CAC score determined by multislice computed tomography and serum bilirubin concentration. ResultsAn inverse correlation was found between serum bilirubin concentration and log(CAC+1) (r=−0.361, P<0.0001). Multiple regression analysis also demonstrated that age (β=0.261, P=0.0125), systolic blood pressure (β=0.153, P=0.0237), uric acid (β=0.126, P=0.0441), estimated glomerular filtration rate (β=−0.139, P=0.0416) and serum bilirubin concentration (β=−0.281, P<0.0001) were independent determinants of log(CAC+1). An increment of 1μmol/L in serum bilirubin concentration was associated with 14% decrease in the odds for CAC score ≥400 after adjustment for several risk factors. Both age and SBP were also positively associated with CAC score ≥400, but the odds ratio for CAC score ≥400 was greater for every 1μmol/L increment in serum bilirubin concentration than for every 1-year increment in age and 1-mmHg increment in SBP. ConclusionsLow serum bilirubin concentration is associated with coronary artery calcification. Serum bilirubin concentration can be measured easily in the clinical laboratory and applied in medical practice, and low serum bilirubin concentration would be useful as a provisional new risk factor of CAC.

Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes

Previous studies showed that low serum bilirubin concentrations are associated with increased risk of cardiovascular disease. To explore this further, we evaluated the relationships between serum bilirubin concentrations and the degree of urinary albumin excretion and other markers of subclinical atherosclerosis in 633 consecutive patients with type 2 diabetes. Multiple regression analysis showed that the serum bilirubin concentration was an independent determinant of and had a significant inverse correlation to the log urinary albumin excretion. Serum bilirubin concentrations were significantly lower in patients with than in those without cardiovascular disease. A significant inverse correlation was found between the serum bilirubin concentration and pulse wave velocity, while a significant positive correlation was found to the ankle-brachial index in a subgroup of 386 patients. Our study shows that the serum bilirubin level is associated with microalbuminuria and subclinical atherosclerosis in patients with type 2 diabetes.

Response to Low serum bilirubin concentrations are associated with impaired aortic elastic properties, but not impaired left ventricular diastolic function

Summary Elevated serum bilirubin concentrations protect from atherosclerotic diseases; however, it is not clear whether higher serum bilirubin concentrations in physiological ranges do the same. To investigate the association of high and low serum bilirubin concentrations with left ventricular diastolic function and aortic elastic properties. We evaluated left ventricular diastolic function and aortic elastic properties of 42 healthy subjects with hypobilirubinemia (total bilirubin 0.40 ± 0.08 mg/dl; mean age 37.0 ± 3.9) and 40 healthy subjects with hyperbilirubinemia (total bilirubin 1.56 ± 0.49 mg/dl; mean age 36.2 ± 6.0) using transthoracic second harmonic Doppler echocardiography. Age, gender, body mass index and coronary risk factors were similar between the groups, except high-sensitivity C-reactive protein (hsCRP). Left ventricular diastolic parameters were similar between the two groups. Aortic distensibility (AoD) was found to be significantly lower (11.1 ± 3.9 vs. 13.2 ± 4.9, p = 0.03) and aortic stiffness index (AoSI) (1.99 ± 0.30 vs. 1.85 ± 0.26, p = 0.02) and elastic modulus (AoEM) (2.06 ± 0.83 vs. 1.73 ± 0.68, p = 0.03; the low and high bilirubin groups, respectively) higher in the low bilirubin group. Serum total bilirubin concentration correlated with hsCRP levels, AoD, AoSI and AoEM. In conclusion, left ventricular systolic and diastolic functions were similar between hypo- and hyperbilirubinemic subjects, but aortic elastic properties were impaired in subjects with lower serum bilirubin concentrations.

Response to Low serum bilirubin concentrations are associated with impaired aortic elastic properties, but not impaired left ventricular diastolic function

To the Editor: We thank Dr Paraskevas and colleagues for their interest in our work (1). They have pointed out the additional limitations of our work. However, I have noticed that some of their comments rather focus on the language of the manuscript than on its scientific content. Indeed, a U-shaped relationship is suggested by a few studies. In our study, exclusion of the subjects with bilirubin values above the normal range might have blunted the possible U-shaped relationship. Their caution is reasonable as regards the smoking status of the subjects. However, the discrepancy regarding the smoking status of the subjects results from inadequate expression of the data of the study subjects, that is to say, some ex-smokers included in the study have not been mentioned in the study population segment. Although there is nothing to get excited about the presentation, we might be excused for the same. The subject numbers are relatively small; however, statistically adequate.