© 1996 American Heart Association, Inc.
Articles |
Higher Serum Bilirubin Is Associated With Decreased Risk for Early Familial Coronary Artery Disease
From Cardiovascular Genetics, Department of Internal Medicine, Cardiology Division, University of Utah School of Medicine (P.N.H., L.L.W., S.C.H., R.R.W.); Department of Pathology, University of Utah School of Medicine, Associated Regional and University Pathologists (ARUP) (L.L.W.); Intermountain Health Care and University of Utah School of Medicine (B.C.J.); and Cardiology Division, LDS Hospital, and University of Utah School of Medicine (G.M.V.), Salt Lake City.
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Abstract |
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Abstract Mildly increased serum bilirubin has recently been suggested as a protective factor, possibly reducing the risk of coronary artery disease (CAD) by acting as an antioxidant. We tested this hypothesis by examining serum bilirubin concentrations and other coronary risk factors in 120 men and 41 women with early familial CAD and 155 control subjects. At screening, both cases and control subjects were 38 to 68 years old. Early familial CAD patients had experienced myocardial infarction, coronary artery bypass grafting, or coronary angioplasty by age 55 years for men and 65 for women and had another sibling similarly affected. The average total serum bilirubin concentration was 8.9±6.1 µmol/L in cases and 12.4±8.1 µmol/L in control subjects (P=.0001 for difference). In univariate analysis stratified by sex, serum bilirubin was strongly and inversely related to CAD risk, with relative odds of 0.4 to 0.1 (relative to the lowest quintile, P=.04 to .00001) in both men and women as bilirubin increased into the upper two quintiles. Multiple logistic regression analysis was performed including age, sex, smoking, body mass index, diabetes, hypertension, plasma measured LDL cholesterol, HDL cholesterol, triglycerides, and serum bilirubin as potential risk factors. Bilirubin entered as an independent protective factor with an odds ratio of 0.25 (P=.0015) for an increase of 17 µmol/L (1 mg/dL). The standardized logistic regression coefficient for bilirubin was -.33 compared with -.34 for HDL, suggesting that the protective effect of bilirubin on CAD risk in the population is comparable to that of HDL cholesterol. A history of cigarette smoking was associated with significantly lower serum bilirubin concentration and appeared to attenuate the protective effect of bilirubin.
Key Words: serum bilirubin • coronary artery disease • risk factors • case-control studies • genetics
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Introduction |
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Serum bilirubin acts as a natural antioxidant in several in vitro systems.1 2 3 4 5 6 Furthermore, bilirubin, especially with albumin, appears to be cytoprotective.7 8 9 Recent in vitro evidence suggests that LDL is protected from oxidation by bilirubin,10 possibly acting with vitamin E as a co-antioxidant.11 Although there is growing epidemiological evidence that other antioxidants, particularly vitamin E12 13 and some flavonols,14 15 16 17 protect against coronary artery disease (CAD), similar evidence that serum bilirubin may be protective is much more limited. The only epidemiological study to examine CAD risks associated with bilirubin was conducted among male Air Force pilots referred for coronary angiography. Stenoses of 50% or more were significantly associated with lower serum bilirubin concentrations independent of other CAD risk factors.18
We have been examining potential coronary risk factors in men and women with early familial CAD. Such patients tend to have a high prevalence of recognized coronary risk factors. They may be a particularly suitable group for examining the effects of novel risk factors because the high risk associated with a positive family history of CAD is not adequately explained by standard coronary risk factors.19 20 21 22 23 24 Accordingly, we have examined the CAD risks associated with graded levels of serum bilirubin in a representative group of early familial CAD cases and control subjects. This is the first study to examine this issue in women as well as in men.
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Methods |
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Early familial CAD patients included 120 men and 41 women who had survived a myocardial infarction, percutaneous transluminal angioplasty, or coronary artery bypass grafting before age 55 years for men and 65 for women. Each of these cases had a sibling confirmed to have early CAD by the same definition. Only unrelated CAD cases were used in the present study. These were selected as the sibling with the earliest onset of CAD in families with multiple screened siblings. More than 90% of patients with early familial CAD who were invited to our clinic were screened. Given this high recruitment rate, the sample is probably quite representative of families with multiple cases of early CAD.
Control subjects comprised 85 men and 70 women who were ascertained from a random population sampling or who were spouses of hypertensive siblings who had participated in previous studies in our clinic. Both groups may be considered representative of a general population of adults with children in high school as they were selected from family health questionnaires filled out by high school students with the help of their parents as part of an ongoing program supported in part by the Utah Department of Health. Control subjects from the two sources were confirmed to have comparable risk factor distributions before they were combined into one group. Further details of the ascertainment methods have been published.25 Nearly all cases and control subjects were white, reflecting the diverse and representative northern European ancestry of most Utah residents, in whom inbreeding is minimal.26 27
Ages for both cases and control subjects were restricted to 38 to 68 years, but control subjects were not individually matched for age or sex. This study was approved by the Institutional Review Board of the University of Utah Medical Center. All subjects signed informed consent before participating.
We defined early familial CAD as the presence of two or more first-degree relatives with onset of CAD by age 55 years in men and 65 in women. CAD included prior diagnosis of myocardial infarction, percutaneous transluminal angioplasty, or coronary artery bypass graft. We considered hypertension to be present if a patient was taking antihypertensive medication with a prior physician diagnosis of hypertension or if the mean of two supine diastolic pressures taken with an automated blood pressure machine (Dynamap, Critikon) was greater than 95 mm Hg. Diabetes was considered present if a prior physician diagnosis had been made or if the fasting serum glucose on screening was greater than 7.77 mmol/L (140 mg/dL). For most analyses cigarette smoking was dichotomized into "ever" or "never" (since many patients quit after their first episode of CAD), with ever smoking defined as having smoked daily for 1 year or more.
Blood samples were collected in the morning after 12 to 16 hours of fasting and were prepared according to guidelines of the Lipid Research Clinics Program Manual of Laboratory Operations.28 Lipids were measured by a microscale procedure developed in our laboratory.29 Our lipid laboratory is certified by the Centers for Disease Control and Prevention in Atlanta, Ga. Total serum bilirubin was analyzed with a diazotized sulfanilic acid reagent and a commercial colorimetric method on a FARA II autoanalyzer (Roche).30
Statistical Analyses
The SAS statistical software package was
used for data
analysis (SAS Institute, Inc). Statistical analyses on
triglycerides (which were significantly skewed to the
right) were done after logarithmic transformation to normalize the
distribution. After transformation, the distribution was normally
distributed as shown by the Kolmogorov D statistic. Analyses
with bilirubin were performed both with and without log transformation.
Univariate comparisons between cases and control subjects
of qualitative variables (such as cigarette smoking, hypertension,
or diabetes) were performed with the 
2 test and
Fisher's exact test. For univariate comparisons of
continuous quantitative variables, we used Student's t
test. To evaluate potential confounding or interrelations between
bilirubin and other variables, we used Pearson's correlation and
ANCOVA (with the SAS GLM procedure). Unconditional stepwise multiple
logistic regression was used to estimate risk associated with changes
in bilirubin after correction for other recognized risk factors.
We did not select individually matched control subjects for several reasons. Of primary importance in a case-control design is that control subjects be representative of the general population from which the cases were selected and that the cases be representative of all similar cases. Age range should be comparable (since prevalence of several risk factors is age dependent). Given these prerequisites, individual matching is not necessary to control for confounding. An analysis stratified by the confounding factor (sex, for example) will provide equally valid results whether applied to matched or unmatched data. In fact, counter to intuitive expectation, matching can introduce confounding where none previously existed if the exposure variable to be tested is associated with the matching variable.31 To avoid this bias, matched data can be analyzed only after stratifying by the matching variable or variables. In multiple logistic regression, because the prevalence of the matched variable among control subjects becomes "conditioned" on the distribution in the cases, a "conditional" analysis must be applied rather than "unconditional" regression. Furthermore, variables used for matching cannot be evaluated for associated risks. For example, if cases and control subjects had been matched by sex, the relative risk associated with male sex could not be calculated. Nevertheless, only after we found a similar pattern of risk association in each sex analyzed separately did we combine them for a grouped analysis. Finally, while matching can lead to improved statistical efficiency (not greater validity) in data analysis (by ensuring that different strata have sufficient numbers for meaningful comparisons), matching can add considerable cost if new control subjects must be recruited; it is usually not necessary when adequate numbers of cases and control subjects are available.31
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Results |
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Clinical characteristics of cases and control subjects are given in Table 1
. Although our patients with CAD were
significantly older than control subjects at the time of screening,
their mean age at clinical onset of CAD was 46.5±6.6 years, 2 years
younger than the control subjects (P=.0036). There were
fewer women among the cases compared with control subjects. In
addition, hypertension and diabetes were much more prevalent among the
cases. This remained true even when only diagnoses made by the age of
onset of CAD among the cases were included (42.2% prevalence of
hypertension by age at CAD diagnosis, 13.0% for diabetes, both
P<.00001 compared with control subjects). Cases had
significantly greater body mass index (kilograms per meter squared);
blood pressures; and levels of serum glucose, plasma total
cholesterol, triglycerides, and VLDL
cholesterol. Plasma HDL cholesterol was lower
among cases. Surprisingly, measured plasma LDL cholesterol
levels were not different in cases versus control subjects. However,
more than half (52%) of the cases were being treated for high
cholesterol (34% were taking drugs), whereas only 6% of
the control subjects were on a diet and none were taking
lipid-lowering medication. These results were essentially the same
for women and men considered separately, as reported
previously.32
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The distributions of serum bilirubin concentration in cases and control
subjects are shown separately for men and women in Fig 1. Among
cases, the bilirubin distributions appeared to
be shifted to lower levels compared with control subjects. Furthermore,
there were no cases with a serum bilirubin concentration higher than 31
µmol/L (1.8 mg/dL), whereas six control subjects had levels in this
range. The highest level seen in control subjects was 54.5 µmol/L
(3.2 mg/dL). None of these higher bilirubin levels were associated with
abnormal liver function tests.
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To estimate the effect of different bilirubin levels on risk, we
categorized cases and control subjects by quintile of serum bilirubin
concentration (as determined among control subjects). Relative odds
compared with the lowest quintile were calculated, as shown in Fig
2. There was a striking and progressive decrease in risk
among both men and women as serum bilirubin levels increased. A 60% to
90% reduction in risk was apparent at higher quintiles. The
Mantel-Haenszel test for trend was highly significant in men
(P=.00003) and women (P=.00002).
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Multiple stepwise logistic regression was then performed with the
following variables tested in the model, with presence of early CAD
(case versus control) as the dependent variable: age, sex, body
mass index, cigarette smoking, hypertension, diabetes, plasma total
cholesterol, measured LDL cholesterol,
triglycerides (natural log transformed), HDL
cholesterol, and serum bilirubin concentration.
Systolic and diastolic pressures were also tested
in a separate model (data not shown), but the diagnosis of hypertension
was associated with greater risk and precluded the entry of blood
pressures into the model. Results of the multiple logistic regression
are shown in Table 2. For bilirubin, a relative odds of
0.25 (95% confidence interval, 0.11-0.59; P=.0015) was
associated with an increase of 17 µmol/L (1 mg/dL) in serum bilirubin
concentration, a result remarkably consistent with the
univariate calculation above. Results using log transformed
bilirubin were virtually identical (not shown). Thus, the reduction in
risk associated with increasing serum bilirubin appeared to be
independent of other recognized coronary risk factors. The
standardized regression coefficient for bilirubin (calculated by
multiplying the nonstandardized coefficient by the SD of bilirubin) was
similar to that for HDL cholesterol, suggesting that a 1 SD
increase in either variable was associated with a similar degree of
risk reduction.
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Because the patients with CAD were actually slightly younger than the
control subjects at the time of their first diagnosis of CAD and many
were being treated with lipid-lowering drugs, an analysis
was performed without age as a variable and with the use of
historical information. In this multiple logistic regression
analysis, diabetes and hypertension were considered present
only if diagnosed by the time of CAD onset, and lifetime maximum
reported total cholesterol (from questionnaires) was
substituted for total measured cholesterol if it was higher
than the measured total cholesterol at screening. Lifetime
maximum total cholesterol entered first into this model
(relative odds, 1.23; 95% confidence interval, 1.15 to 1.32;
P<.0001), followed by HDL cholesterol and the
other factors shown in Table 2
. Risk estimates for these
factors,
including bilirubin, were essentially unchanged from values given in
Table 2. In both models, sex was not a significant factor when
HDL
cholesterol and smoking entered into the equation. Logistic
regressions performed separately for men and women showed virtually
identical results for men (with bilirubin entering as a significant
factor, P=.0008), whereas in the model for women, bilirubin
was of marginal significance (P=.051) in all women but was
highly significant when tested in nonsmoking women separately
(P<.01). These results suggest that age differences in the
cases and control subjects had little influence on the risk estimate
for serum bilirubin. Among women, smoking appeared to modify the risks
associated with serum bilirubin.
To further evaluate possible confounding, we examined
univariate correlations between serum bilirubin and other
variables. Although bilirubin did not correlate with age, body mass
index, serum total cholesterol, LDL
cholesterol, triglycerides, or blood pressure,
there were significant correlations with HDL cholesterol
(r=-.18, P=.02 in control subjects;
r=-.27, P=.0005 in cases), albumin
(r=.28, P=.0004 in control subjects;
r=.24, P=.003 in cases), and
creatinine (r=.15, P=.06 in control
subjects; r=.34, P=.0001 in cases). In
addition,
cigarette smoking was associated with significantly lower serum
bilirubin concentrations. Including these variables in a multiple
logistic regression did not alter the strength of association between
serum bilirubin and coronary risk (data not shown).
Furthermore, in ANCOVA, the difference in mean serum bilirubin
concentration comparing all cases with all control subjects remained
highly significant after adjustment for sex, HDL
cholesterol, albumin, creatinine, and
cigarette smoking. Nevertheless, as shown in Fig 3,
bilirubin levels in either former or current cigarette smokers (after
adjustment for sex, albumin, creatinine, and HDL
cholesterol) were not significantly different in cases and
control subjects. Thus, most of the bilirubin effect was due to the
striking differences seen between cases and control subjects who had
never smoked.
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In Fig 4, relative odds are shown separately for never-
and ever-smokers. The protective effect of higher bilirubin levels
remained clearly evident in the larger group of never-smokers.
Although numbers are sparse for ever-smoking control subjects,
there appeared to be some reversal of the protective effect of
bilirubin among people with a positive smoking history.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In this investigation we have confirmed and extended a previous observation that increases in serum bilirubin concentration within the normal range are associated with a significant and marked reduction in CAD risk. We observed a 60% to 90% reduction in risk when serum bilirubin was in the upper two control quintiles compared with the lowest quintile for both men and women. This risk reduction was independent of other known CAD risk factors and covariates. The apparent protective effects of bilirubin were of a similar magnitude as HDL cholesterol in this population. Much of this effect appeared to be restricted to nonsmokers, with reduced serum bilirubin found among smokers.
The single previously available epidemiological study of serum bilirubin in relation to CAD involved male Air Force pilots who had been referred for angiography because of positive or equivocal results in noninvasive testing. Those having angiographically defined coronary artery stenoses of 50% or greater had lower bilirubin levels than those who had normal coronary arteries (stenosis <10%). Furthermore, in multiple logistic regression after adjustment for other cardiovascular risk factors, a 50% decrease in total bilirubin was associated with a 47% increased risk of having more severe CAD (P=.02).18 This predicted effect of serum bilirubin on CAD risk is somewhat less than our own. Differences in study design may in part account for the steeper risk gradient seen in our study. Our ascertainment of early familial CAD cases may select for those who are most vulnerable, and hence, those with the fewest natural defenses against disease. If a higher serum bilirubin level is indeed a natural protective factor, then average levels would be expected to be more markedly decreased in a group with generally higher risk.
Several laboratory investigations have provided some biological
plausibility for bilirubin acting as an antiatherogenic factor. Stocker
et al1 were the first to demonstrate antioxidant
properties that may have physiological
significance. Bilirubin and biliverdin at concentrations of 10 to 50
µmol/L were found to prevent formation of linoleic acid peroxides on
exposure to a radical initiator in a homogeneous chloroform
solution or in phospholipid liposomes. Bilirubin was more effective as
an antioxidant at low oxygen tensions; at 2% oxygen, bilirubin
suppressed oxidation more effectively than
-tocopherol. In a subsequent study,
albumin-bound bilirubin was found to effectively inhibit
peroxidation of albumin-bound fatty acids and inhibited
oxidation of albumin itself. Albumin-bound
bilirubin was converted to biliverdin on oxidation, quenching 2 mol of
peroxyl radicals for each mole of bilirubin consumed.2
Bilirubin and more especially albumin-bound bilirubin were
found to be cytoprotective to rat hepatocytes, human
erythrocytes, and human myocytes when these cells were exposed to
oxyradicals.4 8 9 Importantly, the
ability of bilirubin at
physiological concentration to effectively prevent
oxidation of LDL lipids was recently demonstrated.10 In
another study, peroxidation of LDL lipids and vitamin E in fresh human
plasma incubated with a constant source of peroxyl radicals occurred
only after ubiquinol-10, vitamin C, and bilirubin were initially
consumed. Furthermore, continued peroxidation of LDL lipid and vitamin
E was strongly inhibited when exogenous bilirubin was added back into
the oxidizing mixture. However, bilirubin no longer inhibited oxidation
of LDL lipids once the LDL vitamin E was completely
depleted.11
Our current findings and those of Schwertner et al18 represent retrospective analyses of coronary cases and control subjects. In any case-control study it is not possible to be certain that the disease itself does not alter the risk factor in question. In two investigations of serum enzymes and bilirubin after acute myocardial infarction, there was a slight initial rise in serum bilirubin followed by a return to normal within 10 days.33 34 No long-term studies were found in a literature search. We cannot exclude the possibility that serum bilirubin declines after onset of CAD. Among a select group of neonates in whom enteral feeding had been withheld, babies with illnesses expected to cause increased oxidative stress had smaller increments of serum bilirubin than similarly treated infants without such diseases.35 If CAD were similarly associated with a higher production of free radicals, increased consumption of bilirubin might occur as a secondary result of the CAD. Certainly, a number of well-conducted prospective investigations of CAD have included serum bilirubin among their baseline blood measurements. These data will be of great interest in analyses examining the important issue of time sequence and will provide confirmation of the retrospective analyses performed to date.
Cigarette smoking increases oxidative stress, as manifested by increased levels of a marker of lipid peroxidation in plasma of cigarette smokers.36 Exposure of LDL to cigarette smoke results in oxidation of lipids and greater uptake of modified LDL by macrophages.37 38 The lower serum bilirubin levels associated with cigarette smoking in our study may be due to oxidation of bilirubin by reactive species generated in cigarette smoke. Several other large population surveys have reported mildly reduced bilirubin levels in the serum of cigarette smokers.39 40 41 These findings suggest that a possible additional mechanism whereby cigarette smoking increases the risk of CAD is by decreasing serum bilirubin. We cannot explain our observation that serum bilirubin was similarly reduced in former as well as current cigarette smokers. Perhaps an examination of prospective data could provide further insights regarding this question.
Interestingly, serum bilirubin levels were found to be higher in vegans than nonvegetarians.42 Possibly the vegans' lower caloric intake may have resulted in higher bilirubin levels because fasting is well known to result in higher bilirubin levels.43 Higher altitudes have also been associated with increased bilirubin levels apparently because of increased bilirubin production in association with the expected hematopoietic response.44
In conclusion, we have confirmed a strong inverse association between serum bilirubin and risk for early familial CAD. The reduction in benefit among current or former cigarette smokers may be consistent with an antioxidant role for bilirubin. These retrospective findings urgently need confirmation by prospective analyses.
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Acknowledgments |
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This work was supported by grants HL-47651, HL-21088, and HL-47466 from the National Heart, Lung, and Blood Institute, Bethesda, Md.
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Footnotes |
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Reprint requests to Dr Paul N. Hopkins, Cardiovascular Genetics Research Clinic, 410 Chipeta Way, Room 161, Salt Lake City, UT 84108.
Received May 19, 1995; accepted October 16, 1995.
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 Y.-H. Chen, L.-Y. Chau, J.-W. Chen, and S.-J. Lin Serum Bilirubin and Ferritin Levels Link Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients Diabetes Care, August 1, 2008; 31(8): 1615 - 1620. [Abstract] [Full Text] [PDF]
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 J. M. van der Bol, R. H.J. Mathijssen, W. J. Loos, L. E. Friberg, R. H.N. van Schaik, M. J.A. de Jonge, A. S.Th. Planting, J. Verweij, A. Sparreboom, and F. A. de Jong Cigarette Smoking and Irinotecan Treatment: Pharmacokinetic Interaction and Effects on Neutropenia J. Clin. Oncol., July 1, 2007; 25(19): 2719 - 2726. [Abstract] [Full Text] [PDF]
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H. Gullu, D. Erdogan, D. Tok, S. Topcu, M. Caliskan, T. Ulus, and H. Muderrisoglu High Serum Bilirubin Concentrations Preserve Coronary Flow Reserve and Coronary Microvascular Functions Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2289 - 2294. [Abstract] [Full Text] [PDF]
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T. Morita Heme Oxygenase and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1786 - 1795. [Abstract] [Full Text] [PDF]
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P. N. Hopkins, L. L. Wu, S. C. Hunt, and E. A. Brinton Plasma triglycerides and type III hyperlipidemia are independently associated with premature familial coronary artery disease J. Am. Coll. Cardiol., April 5, 2005; 45(7): 1003 - 1012. [Abstract] [Full Text] [PDF]
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C.-M. Hu, Y.-H. Chen, M.-T. Chiang, and L.-Y. Chau Heme Oxygenase-1 Inhibits Angiotensin II-Induced Cardiac Hypertrophy In Vitro and In Vivo Circulation, July 20, 2004; 110(3): 309 - 316. [Abstract] [Full Text] [PDF]
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 T. W. Sedlak and S. H. Snyder Bilirubin Benefits: Cellular Protection by a Biliverdin Reductase Antioxidant Cycle Pediatrics, June 1, 2004; 113(6): 1776 - 1782. [Full Text] [PDF]
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J. Hokamaki, H. Kawano, M. Yoshimura, H. Soejima, S. Miyamoto, I. Kajiwara, S. Kojima, T. Sakamoto, S. Sugiyama, N. Hirai, et al. Urinary biopyrrins levels are elevated in relation to severity of heart failure J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1880 - 1885. [Abstract] [Full Text] [PDF]
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H. A. Schwertner Bilirubin Concentration, UGT1A1*28 Polymorphism, and Coronary Artery Disease Clin. Chem., July 1, 2003; 49(7): 1039 - 1040. [Full Text] [PDF]
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