(Stroke. 2001;32:580-b.)
© 2001 American Heart Association, Inc.
Letters to the Editor |
High Serum Bilirubin Level Is Inversely Associated With the Presence of Carotid Plaque
Department of Cardiovascular Medicine University of Tokyo Graduate School of Medicine Tokyo, Japan
Center for Multiphasic Health Testing and Services Mitsui Memorial Hospital Mitsui, Japan
Department of Hygiene and Public Health Teikyo University School of Medicine Teikyo, Japan
To the Editor:
The antioxidant property of bilirubin, the end product of heme catabolism in mammals, was first demonstrated by Stocker et al.1 In vitro studies have demonstrated that bilirubin exerts an antioxidant effect2 in either free or albumin-bound form.3 Studies in animal models4 5 and in humans6 7 show that antioxidative agents act against formation of atheromatous lesions, which suggests that reactive oxygen species are involved in the pathogenesis of atherosclerosis. Antiatherogenic effects of bilirubin in vivo have not been well established; however, some previous reports have described the relationship between serum bilirubin levels and coronary artery disease. Schwertner et al8 have shown that a 50% decrease in total bilirubin level was associated with a 47% increase in the odds of being in the severe coronary artery category in asymptomatic US Air Force pilots and navigators, and Hopkins et al9 have reported that coronary artery disease was less marked (60% to 90%) when serum bilirubin was in the upper 2 control quintiles compared with the lowest quintile in subjects with early familial coronary artery disease.
To assess the possible association between serum bilirubin
level and lower risk of atherosclerotic disease in a larger population,
we analyzed 1741 subjects between April 1994 and February 1997
who underwent general health screening tests and high-resolution B-mode
ultrasonography (Sonolayer SSA270A, Toshiba) equipped with a 7.5-MHz
transducer (PLF-703ST, Toshiba) at Multiphasic Health Testing and
Services, Mitsui Memorial Hospital. Carotid arteries were examined
bilaterally at the levels of the common carotid, bifurcation, and
internal carotid arteries from transverse and longitudinal orientations
by trained sonographers. Results of carotid ultrasound studies were
interpreted by an observer who was blinded to the results of laboratory
tests. Plaque was defined as focal thickening of the intimal-medial
layer with an intimal-medial thickness (IMT) of 
1.3 mm at the
common or internal carotid arteries or the carotid
bulb.10
Of 1741 subjects enrolled in the present study, 330
subjects (19%) were found to have carotid plaque in either or both of
the carotid arteries. The distributions of serum bilirubin
concentration in the subjects with or without carotid plaque are shown
in the Figure
,
panel A. An unpaired t test
showed that the subjects with carotid plaque had significantly lower
serum bilirubin level than those without carotid plaque (14.4±3.8
versus 15.4±5.13 µmol/L;
P<0.05). By
univariate logistic regression analysis, the
following variables were found to have statistically significant
odds ratios for carotid plaque (odds ratio; 95% CI): male sex (2.1;
1.8 to 2.5), age >50 years (7.8; 6.0 to 10.0), systolic blood
pressure 140 mm Hg (2.1; 1.8 to 2.4), HDL
cholesterol 1.03 mmol/L (0.65; 0.56 to 0.74),
triglyceride >1.69 mmol/L (1.8; 1.6 to 2.0),
HbA1c 5.9% (2.1; 1.8 to 2.5), total bilirubin
17.1 µmol/L (0.7; 0.6 to 0.8), uric acid 416 µmol/L (1.5; 1.3
to 1.7), alanine transaminase >40 U/L (1.9; 1.6 to 2.4), and alkaline
phosphatase (1.4; 1.2 to 1.6).
|
P=0.001 compared with lowest
quartile of serum bilirubin
level.
After adjustment for sex and age, odds ratios compared with
the lowest quartile were calculated
(Figure
, panel B). A 32% and 41% reduction in risk was seen at the highest and
the second highest quartiles, respectively.
Then the multivariate logistic regression
analysis was performed with the following variables: sex,
age, status of cigarette smoking, hypertension, serum levels of total
cholesterol, HDL cholesterol,
triglyceride, HbA1c, total
bilirubin, and uric acid. An increase of 17.1 µmol/L in serum
bilirubin concentration was associated with an odds ratio of 0.37 (95%
CI, 0.28 to 0.49). The odds ratio associated with a bilirubin of 17.1
µmol/L was 0.64 (95% CI, 0.56 to 0.75) when bilirubin was entered
into the model as a continuous variable.
In the present study we demonstrated that serum
bilirubin level was inversely correlated with carotid plaque. Nieto et
al11 have reported that the
level of serum uric acid, but not serum bilirubin, was significantly
higher in cases with atherosclerotic carotid artery lesions than in
normal counterparts. Different findings between their study and ours
may be explained by differences in positive criteria of carotid
atherosclerosis (Nieto et al defined their cases by the
top decile of mean IMT in a series of 1410 participants; in the
present study, focal thickening of the intimal-medial layer with
IMT of 1.3 mm was considered to be carotid plaque) or
differences in race or age range.
In summary, we showed an odds ratio of 0.37 for carotid plaque associated with an increase of 17.1 µmol/L (ie, 1.0 mg/dL) in serum bilirubin concentration. We do not know the mechanism linking serum bilirubin to a decreased risk of carotid plaque, although it may possibly be that bilirubin exerts an antiatherogenic effect through its antioxidant property. Whether lower serum bilirubin is a cause or a result of carotid plaque formation, and thus atheromatous disease, awaits further investigation.
References
1.
Stocker
R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an
antioxidant of possible physiological importance.
Science. 1987;235:1043–1046.
2. Wu TW, Fung KP, Wu J, Yang CC, Weisel RD. Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins. Biochem Pharmacol. 1996;51:859–862.[Medline] [Order article via Infotrieve]
3.
Neuzil J,
Stocker R. Free and albumin-bound bilirubin are efficient
co-antioxidants for alpha-tocopherol, inhibiting plasma and
low density lipoprotein lipid peroxidation.
J Biol Chem. 1994;269:16712–16719.
4. Singh RB, Singh NK, Rastogi SS, Wander GS, Aslam M, Onouchi Z, Kummerow FA, Nangia S. Antioxidant effects of lovastatin and vitamin E on experimental atherosclerosis in rabbits. Cardiovasc Drugs Ther. 1997;11:575–580.[Medline] [Order article via Infotrieve]
5.
Crawford RS,
Kirk EA, Rosenfeld ME, LeBoeuf RC, Chait A. Dietary antioxidants
inhibit development of fatty streak lesions in the LDL
receptor-deficient mouse. Arterioscler
Thromb Vasc Biol. 1998;18:1506–1513.
6. Schreiner PJ. Lipoprotein(a) as a risk factor for preclinical atherosclerotic disease in a biracial cohort: the Atherosclerosis Risk in Communities (ARIC) Study. Chem Phys Lipids. 1994;67–68:405–410.
7.
Azen SP, Qian D,
Mack WJ, Sevanian A, Selzer RH, Liu CR, Liu CH, Hodis HN. Effect of
supplementary antioxidant vitamin intake on carotid
arterial wall intima-media thickness in a controlled
clinical trial of cholesterol lowering.
Circulation. 1996;94:2369–2372.
8.
Schwertner HA,
Jackson WG, Tolan G. Association of low serum concentration of
bilirubin with increased risk of coronary artery disease.
Clin Chem. 1994;40:18–23.
9.
Hopkins PN, Wu
LL, Hunt SC, James BC, Vincent GM, Williams RR. Higher serum bilirubin
is associated with decreased risk for early familial coronary
artery disease. Arterioscler Thromb Vasc
Biol. 1996;16:250–255.
10. Yamakado M, Fukuda I, Kiyose H. Ultrasonographically assessed carotid intima-media thickness and risk for asymptomatic cerebral infarction. J Med Syst. 1998;22:15–18.[Medline] [Order article via Infotrieve]
11. Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis. 2000;148:131–139.[Medline] [Order article via Infotrieve]
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