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Editorial
10.1517/14728220802655321 © 2009 Informa UK Ltd ISSN 1472-8222 139All rights reserved: reproduction in whole or in part not permitted
Bilirubin and peripheral arterial disease: 15 years later Lars H Breimer † & Dimitri P Mikhailidis † Örebro University Hospital, Department of Laboratory Medicine, SE-701 85 Örebro, Sweden
The past year has seen renewed interest in the link between peripheral arterial disease and plasma bilirubin. Two important studies that evaluate this relationship have been published: Perlstein et al ., in a cross-sectional cohort study, and Kronenberg’s group, in a retrospective case control study, provide substantial evidence that serum bilirubin may play a protective role in peripheral arterial disease as well as ischaemic heart disease, as suggested almost 15 years ago in a small retrospective analysis. Briefly, that study found that serum bilirubin concentrations in peripheral arterial disease patients were significantly (p < 0.001) lower than those in a healthy reference population. This editorial discusses the new data in a historical context.
Keywords: bilirubin , free radicals , Innsbruck , NHANES , PAD (peripheral arterial disease) , smoking
Expert Opin. Ther. Targets (2009) 13 (2):139-140
In the past year, there has been renewed interest in the link between peripheral arterial disease (PAD) and plasma bilirubin. Two important studies evaluating this relationship have been published. Perlstein et al ., in a cross-sectional cohort study, and Kronenberg’s group, in a retrospective case control study, provide substantial evidence that serum bilirubin may play a protective role in PAD as well as in ischaemic heart disease (IHD) [1,2] , as suggested almost 15 years ago in a small retrospective analysis that found that serum bilirubin concentrations in PAD patients were significantly (p < 0.001) lower than those in a healthy reference population.
The strength of Perlstein et al .’s work is that it is part of a large (7075 adults) study (National Health and Nutrition Examination Survey, NHANES) that included both sexes and various racial groups [1] . They found that for each 1.7 µmol/l (0.1 mg/dl) increase in bilirubin, there was a 6% reduction in the odds of having PAD. The Innsbruck team retrospectively compared 255 men with intermittent claudication with 255 matched controls [2] . Plasma bilirubin was lower in patients with PAD and they estimated a protective effect of 11.5% per 1.7 µmol/l (0.1 mg/dl) of bilirubin. By comparison, the protective effect of bilirubin was estimated at 3.7% per 1.7 µmol/l (0.1 mg/dl) of bilirubin on the presence of carotid artery plaque in a Japanese study of 1741 subjects [4] , while a 9% reduction in the odds of a stroke per 1.7 µmol/l (0.1 mg/dl) of bilirubin was found by a separate analysis of the NHANES database [5] .
As Perlstein et al . point out, it is difficult to isolate the effect of bilirubin owing to confounding variables, which require the large number of subjects in their study (more than 7000 subjects) to dissect out. This is illustrated by our follow-up work [6-8] . Serum bilirubin and albumin were measured in 456 patients classified in three groups: i) no clinically evident cardiovascular disease (CVD); ii) IHD present; and iii) PAD present [6] . Smoking status and gender (which affect bilirubin and albumin levels in healthy individuals) were considered separately. Serum bilirubin was lower in smoking men than in non-smokers, and non-smoking women had significantly (p = 0.004) lower bilirubin levels than the
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Bilirubin and peripheral arterial disease: 15 years later
140 Expert Opin. Ther. Targets (2009) 13(2)
corresponding group of men. Frequency analysis of male non-smokers revealed significantly (p = 0.04) more patients with a lower bilirubin (< 6.5 µmol/l; 0.38 mg/dl) in the PAD compared with the no CVD group.
A survey of 376 patients with primary dyslipidaemia (209 men) to determine correlations between CVD risk calculated using the Framingham equation and the circulating levels of four emerging vascular risk predictors (fibrinogen, lipoprotein (a), albumin and bilirubin) found that smokers, when compared with non-smokers, had significantly higher median fibrinogen levels (p < 0.0001) – a well-established phenomenon – and lower median bilirubin levels (8 (3 – 17) vs 10 (1 – 28) µmol/l; 0.47 (0.17 – 1.0) vs 0.58 (0.06 – 1.64) mg/dl; p = 0.016). In smokers, the only significant correlation was a negative one between bilirubin and CVD risk [7,8] .
It is reassuring that, following Schwertner’s seminal paper, the observations on a possible protective role of plasma bilirubin in arterial disease remain consistent, including all racial groups studied, and that the initial observations in PAD have now been confirmed [3,9] . Probably, this effect is related to bilirubin acting as an intrinsic anti-oxidant system [10] . This consistency is particularly remarkable given the well-recognized problems associated with measuring
bilirubin. For example, different analytical methods, photo-oxidation of bilirubin by sunlight (or even bright light) and biological variation (e.g., fasting vs fed state) [11] . In our work, and that of Kronenberg’s group, these variables were controlled for by blood sampling after an overnight fast and immediate processing of samples. Kronenberg also avoided the sex difference (women have lower bilirubin levels than men) by studying only males. In the NHANES protocol, subjects were instructed to fast overnight or for 6 h before the afternoon or evening examination, but the instructions were not followed uniformly.
Studying the role of bilirubin in vascular disease is frustrated by the impracticality of raising circulating levels. Pharmacological interventions to raise plasma bilirubin are likely to impact on the liver and be associated with unacceptable side effects. It is also possible that bilirubin is a surrogate biomarker of an unidentified process. Nevertheless, a better understanding of any protective effect of bilirubin may lead to new treatments for all types of arteriosclerosis, although the most obvious (but not the easiest to achieve) remains smoking cessation. The future of bilirubin as a therapeutic target may rest with its use as a potential predictor of vascular risk and/or with finding a safe analogue.
Bibliography 1. Perlstein TS, Pande RL, Beckman JA,
Creager MA. Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease. Arterioscl Thromb Vascul Biol 2008 ; 28 : 166 -72
2. Rantner B, Kollertis B, Anderwald-Stadler M, et al. Association between the UGT1A1 TA-repeat polymorphism and bilirubin concentration in patients with intermittent claudication: results from the CAVASIC study. Clin Chem 2008 ; 54 : 851 -7
3. Breimer LH, Spyropolous KA, Winder AF, et al. Is bilirubin protective against coronary artery disease? Clin Chem 1994 ; 40 : 1987 -8
4. Ishizaka N, Ishizaka Y, Takahashi E, et al. High serum bilirubin level is inversely associated with the presence of carotid plaque. Stroke 2001 ; 32 : 580 -3
5. Perlstein TS, Pande RL, Creager MA, et al. Serum total bilirubin level, prevalent
stroke, and stroke outcomes: NHANES 1999 – 2004. Am J Med 2008 ; 121 : 781 -8
6. Krijgsman B, Papadakis JA, Ganotakis ES, et al. The effect of peripheral vascular disease on the serum levels of natural anti-oxidants: bilirubin and albumin. Int Angiol 2002 ; 21 : 44 -52
7. Papadakis JA, Ganotakis ES, Jagroop IA, et al. Effect of hypertension and its treatment on lipid, lipoprotein (a), fi brinogen, and bilirubin levels in patients referred for dyslipidemia. Am J Hypertens 1999 ; 12 : 673 -81
8. Ganotakis ES, Vrentzos GE, Gazi IF, et al. Fibrinogen, lipoprotein (a), albumin and bilirubin (F-L-A-B) levels and cardiovascular risk calculated using the Framingham equation. In Vivo 2007 ; 2 : 685 -94
9. 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
10. Vitek L, Schwertner HA. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem 2007 ; 43 : 1 -57
11. Burtis CA, Ashwood ER, editors, Tietz Textbook of Clinical Chemistry, 3rd edition. WB Saunders & Co; Philadelphia, PA, USA; 1999
Affi liation Lars H Breimer † 1 BM BCh MA PhD MFPM FRCPath & Dimitri P Mikhailidis 2 MD FCP FFPM FRCP FRCPath † Author for correspondence 1 Örebro University Hospital, Department of Laboratory Medicine, SE-701 85 Örebro, Sweden Tel: +46 19 602 78 17 ; Fax: +46 19 602 37 85 ; E-mail: [email protected] 2 University College London, University College Medical School, Royal Free Hospital Campus, Department of Clinical Biochemistry, NW3 2QG, London, UK
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