Risk of Ischemic Stroke and Decreased Serum Bilirubin Levels: Is There a Causal Link? Giovanni Targher Arterioscler Thromb Vasc Biol. 2014;34:702-704 doi: 10.1161/ATVBAHA.114.303279 Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 1079-5642. Online ISSN: 1524-4636
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://atvb.ahajournals.org/content/34/4/702
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Arteriosclerosis, Thrombosis, and Vascular Biology can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Arteriosclerosis, Thrombosis, and Vascular Biology is online at: http://atvb.ahajournals.org//subscriptions/
Downloaded from http://atvb.ahajournals.org/ at Universitaet Duesseldorf on March 26, 2014
Editorial Risk of Ischemic Stroke and Decreased Serum Bilirubin Levels Is There a Causal Link? Giovanni Targher
B
ilirubin, often thought to be a toxic end product of heme, is a potent antioxidant compound in vivo.1,2 As shown in the schematic Figure, degraded red blood cells release heme, which is broken down by heme oxygenase to biliverdin, which is reduced by biliverdin reductase into the hydrophobic compound bilirubin. Unconjugated bilirubin is a lipid-soluble molecule that must be made water soluble to be excreted. Unconjugated bilirubin is carried by albumin to the liver, where it is conjugated into a water-soluble form by hepatic glucuronyl transferase. The hepatic enzyme UDPglucuronyl transferase 1A1 (UGT1A1) converts bilirubin to a soluble (conjugated) form suitable for renal and biliary elimination.1,2 Importantly, in healthy European populations, common genetic variation of the UGT1A1 promoter region explains ≈50% of the variability in serum total (TB) and conjugated bilirubin levels.3 UGT1A1 is also responsible for the glucuronidation of many other small lipophilic molecules, such as steroid hormones and drugs that affect the vasculature.1,2
See accompanying article on page 946 Currently, ample evidence suggests that lower levels of TB are associated with increased risk of cardiovascular disease (CVD), independently of traditional risk factors.4–9 In 2012, further evidence for a possible beneficial role of bilirubin protecting against CVD was provided from a large UK primary care database (n=130 052 patients) with the measurement of TB levels recorded 3 months before first statin treatment. After a median of ≈3.5 years of follow-up, an inverse relationship was noted between TB levels and risk of CVD events and death. After traditional risk factors were accounted for, the associations with TB levels were nonlinear (L shaped), and the models predicted that, compared with patients with a TB level of 0.6 mg/dL, those with a similar CVD risk profile but a TB level of 0.3 mg/dL had an 18% higher risk of any CVD event, a 34% higher risk of myocardial infarction, and a 33% higher risk of death resulting from any cause.10
From the Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy. Correspondence to Giovanni Targher, MD, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale A. Stefani 1, 37126 Verona, Italy. E-mail [email protected] (Arterioscler Thromb Vasc Biol. 2014;34:702-704.) © 2014 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.303279
Currently, there is sparse and less convincing evidence for an inverse association between TB levels and risk of ischemic stroke. Perlstein et al11 examined the association of TB levels with the prevalence of stroke among 13 214 US adults. After multivariable adjustment, a 0.1 mg/dL increment in TB levels was associated with a 9% reduced odds of stroke among all participants and with a 10% reduced odds of an adverse stroke outcome among participants with a history of stroke. Similar findings were reported by Oda and Kawai12 in a health screening cohort of 5444 Japanese people. Interestingly and most importantly, in the only published prospective study that involved 78 724 Korean healthy individuals (41 054 men, aged 30–89 years), Kimm et al13 reported that, compared with those with lower TB levels, male individuals with mildly higher TB levels showed a ≈30% decreased risk of incident ischemic stroke (as ascertained by hospital admission discharge records), independently of multiple risk factors, during a median follow-up period of 9.4 years. However, these associations were not observed in hemorrhagic stroke or in women.13 Few recent studies that have explored the association of TB levels with the severity and subtypes of stroke among hospitalized patients with a first-ever acute ischemic stroke have shown that patients with mildly higher TB levels had a significantly greater admission severity of stroke (as assessed by the National Institutes of Health Stroke score), but not short-term clinical outcomes (ie, in-hospital death or National Institutes of Health Stroke score ≥10), than those with lower TB levels.14–16 In a retrospective study of 626 patients with acute ischemic stroke, Zhang et al17 reported that mildly higher TB levels at admission were associated with an increased odds for nonlacunar ischemic stroke. It is possible to assume that higher TB levels after acute ischemic stroke reflect the intensity of the initial oxidative stress induced by the neurological damage. In this scenario, the study published by Li et al18 in this issue of the journal adds to the body of evidence showing, for the first time, a graded, inverse relationship between serum levels of TB (conjugated and unconjugated bilirubin) and increased prevalence of silent cerebral infarctions in middle-aged Chinese individuals. Notably, this relationship remained significant after adjusting for established stroke risk factors and potential confounders. No association was observed between TB levels and the dimensions of brain infarcts on MRI. Although the cross-sectional design of the study does not allow to draw causal inferences, these findings are clinically important because they identify lower TB levels as a possible novel marker for silent cerebral infarctions. Despite not causing identifiable symptoms, silent cerebral infarctions are common in healthy elderly people and place
Downloaded from http://atvb.ahajournals.org/702 at Universitaet Duesseldorf on March 26, 2014
Targher Risk of Ischemic Stroke 703
Figure. Schematic representation of the bilirubin metabolism and the putative biological mechanisms by which higher levels of serum bilirubin might exert vasoprotective effects on the development of silent brain infarcts and other cardiovascular complications. HO-1 indicates heme oxygenase-1.
the patient at increased risk for major stroke, dementia, cognitive decline, and depression in the future.19,20 Collectively, the evidence from this18 and other studies11–17 supports the possibility that the early measurement of TB levels might be useful to assess the risk of silent cerebral infarction(s) and major stroke and that mildly elevated TB levels might protect from stroke events and from neurological damage in stroke. In general, from a pathophysiological perspective, there are some key questions that should be addressed. First, is decreased serum TB associated with increased risk of stroke as a consequence of the coexisting cardiovascular risk factors, or does decreased serum TB contribute to the development of stroke, independently of these risk factors? Second, is it biologically plausible that increased serum TB could confer specific vascular protection? Third, could novel therapeutic approaches (eg,
pharmacological, nonpharmacological, or genetic interventions) that increase TB levels provide more direct evidence on the protective role of bilirubin in stroke prevention? To date, it is uncertain whether decreased TB levels pose an independent risk above and beyond known risk factors. There is a suggestion in that direction, but studies are too few and methodologically not rigorous. Additional large-scale prospective studies of a more extensive panel of known risk factors are needed to draw firm conclusions about an independent prognostic role of decreased TB levels for the development of stroke and other CVD complications. Little information is also currently available on the potentially vasoprotective effects of mildly elevated TB levels. It is uncertain whether genetic variation in the UGT1A1 is associated with variable risk of coronary heart disease (CHD). The
Downloaded from http://atvb.ahajournals.org/ at Universitaet Duesseldorf on March 26, 2014
704 Arterioscler Thromb Vasc Biol April 2014 Framingham Heart Study investigators found that UGT1A1 polymorphism, resulting in higher TB levels, was associated with lower risk of CHD.21 However, other smaller studies have failed to show the same association.22–25 Conversely, it has been shown that patients with Gilbert syndrome have a lower risk of CHD than normobilirubinemic control subjects, thus supporting the concept that mildly elevated (unconjugated) bilirubin levels might help protect against CHD.26 The underlying mechanisms by which increased TB may exert vasoprotective effects are still incompletely understood, and further research is required to uncover other specific mechanisms by which bilirubin may protect from stroke and CHD events. The putative mechanisms of benefit that have been experimentally described are bilirubin-mediated inhibition of lipid oxidation, bilirubin-mediated inhibition of immune reactions and inflammatory processes, bilirubin-mediated inhibition of cell migration and proliferation, bilirubin-mediated inhibition of apoptosis, and bilirubin as a marker reflecting enhanced heme oxygenase-1 activity (Figure).1,2 However, it is important to remember that markedly elevated TB levels may exert neurotoxic effects in some circumstances.1,2 Thus, in the absence of definitive evidence, being bilirubin a Janus Bifrons, I think that prudence is still required. Additional large and long-term observational studies in different ethnic groups are warranted to establish the role of serum TB firmly as a causal risk factor for CHD and, especially, for ischemic stroke. This is also important particularly if one considers that novel therapeutic strategies aimed to achieve mild-to-moderate elevations of serum bilirubin (eg, use of heme oxygenase-1 inducers or drugs that reduce hepatic glucuronidation activity or inhibit hepatocyte uptake)27,28 might be used, in the future, as tools for preventing and treating CHD/stroke and other diseases in which oxidants play a prominent pathogenic role.
Disclosures None.
References 1. Vítek L, Schwertner HA. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem. 2007;43:1–57. 2. Franchini M, Targher G, Lippi G. Serum bilirubin levels and cardiovascular disease risk: a Janus Bifrons? Adv Clin Chem. 2010;50:47–63. 3. Borucki K, Weikert C, Fisher E, Jakubiczka S, Luley C, Westphal S, Dierkes J. Haplotypes in the UGT1A1 gene and their role as genetic determinants of bilirubin concentration in healthy German volunteers. Clin Biochem. 2009;42:1635–1641. 4. Breimer LH, Wannamethee G, Ebrahim S, Shaper AG. Serum bilirubin and risk of ischemic heart disease in middle-aged British men. Clin Chem. 1995;41:1504–1508. 5. Djoussé L, Levy D, Cupples LA, Evans JC, D’Agostino RB, Ellison RC. Total serum bilirubin and risk of cardiovascular disease in the Framingham offspring study. Am J Cardiol. 2001;87:1196–1200; A4, 7. 6. Novotný L, Vítek L. Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies. Exp Biol Med (Maywood). 2003;228:568–571. 7. Perlstein TS, Pande RL, Beckman JA, Creager MA. Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. Arterioscler Thromb Vasc Biol. 2008;28:166–172.
8. Fulks M, Stout RL, Dolan VF. Mortality associated with bilirubin levels in insurance applicants. J Insur Med. 2009;41:49–53. 9. Sung KC, Shin J, Lim YH, Wild SH, Byrne CD. Relation of conjugated bilirubin concentrations to the presence of coronary artery calcium. Am J Cardiol. 2013;112:1873–1879. 10. Horsfall LJ, Nazareth I, Petersen I. Cardiovascular events as a function of serum bilirubin levels in a large, statin-treated cohort. Circulation. 2012;126:2556–2564. 11. Perlstein TS, Pande RL, Creager MA, Weuve J, Beckman JA. Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999-2004. Am J Med. 2008;121:781–788.e1. 12. Oda E, Kawai R. A possible cross-sectional association of serum total bilirubin with coronary heart disease and stroke in a Japanese health screening population. Heart Vessels. 2012;27:29–36. 13. Kimm H, Yun JE, Jo J, Jee SH. Low serum bilirubin level as an independent predictor of stroke incidence: a prospective study in Korean men and women. Stroke. 2009;40:3422–3427. 14. Pineda S, Bang OY, Saver JL, Starkman S, Yun SW, Liebeskind DS, Kim D, Ali LK, Shah SH, Ovbiagele B. Association of serum bilirubin with ischemic stroke outcomes. J Stroke Cerebrovasc Dis. 2008;17:147–152. 15. Xu T, Zhang J, Xu T, Liu W, Kong Y, Zhang Y. Association of serum bilirubin with stroke severity and clinical outcomes. Can J Neurol Sci. 2013;40:80–84. 16. Luo Y, Li J, Zhang J, Xu Y. Elevated bilirubin after acute ischemic stroke linked to the stroke severity. Int J Dev Neurosci. 2013;31:634–638. 17. Zhang B, Zhang W, Li X, Pu S, Yin J, Yang N, Yi Y, Gao Q, Gao C. Admission markers predict lacunar and non-lacunar stroke in young patients. Thromb Res. 2011;128:14–17. 18. Li R-Y, Cao Z-G, Zhang J-R, Li Y, Wang R-T. Decreased serum bilirubin is associated with silent cerebral infarction. Arterioscler Thromb Vasc Biol. 2014;34:946–951. 19. Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM; Rotterdam Scan Study. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke. 2003;34:1126–1129. 20. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003;348:1215–1222. 21. Lin JP, O’Donnell CJ, Schwaiger JP, Cupples LA, Lingenhel A, Hunt SC, Yang S, Kronenberg F. Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. Circulation. 2006;114:1476–1481. 22. Bosma PJ, van der Meer IM, Bakker CT, Hofman A, Paul-Abrahamse M, Witteman JC. UGT1A1*28 allele and coronary heart disease: the Rotterdam Study. Clin Chem. 2003;49:1180–1181. 23. Gajdos V, Petit FM, Perret C, Mollet-Boudjemline A, Colin P, Capel L, Nicaud V, Evans A, Arveiler D, Parisot F, Francoual J, Genin E, Cambien F, Labrune P. Further evidence that the UGT1A1*28 allele is not associated with coronary heart disease: The ECTIM Study. Clin Chem. 2006;52:2313–2314. 24. Ekblom K, Marklund SL, Jansson JH, Osterman P, Hallmans G, Weinehall L, Hultdin J. Plasma bilirubin and UGT1A1*28 are not protective factors against first-time myocardial infarction in a prospective, nested case-referent setting. Circ Cardiovasc Genet. 2010;3:340–347. 25. Ekblom K, Marklund SL, Johansson L, Osterman P, Hallmans G, Weinehall L, Wiklund PG, Hultdin J. Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting. Cerebrovasc Dis. 2010;30:590–596. 26. Vítek L, Jirsa M, Brodanová M, Kalab M, Marecek Z, Danzig V, Novotný L, Kotal P. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis. 2002;160:449–456. 27. McCarty MF. “Iatrogenic Gilbert syndrome”–a strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubin. Med Hypotheses. 2007;69:974–994. 28. Peterson SJ, Frishman WH, Abraham NG. Targeting heme oxygenase: therapeutic implications for diseases of the cardiovascular system. Cardiol Rev. 2009;17:99–111.
Key Words: Editorials ◼ bilirubin ◼ risk factors ◼ stroke
Downloaded from http://atvb.ahajournals.org/ at Universitaet Duesseldorf on March 26, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://atvb.ahajournals.org/content/34/4/702
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Arteriosclerosis, Thrombosis, and Vascular Biology can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Arteriosclerosis, Thrombosis, and Vascular Biology is online at: http://atvb.ahajournals.org//subscriptions/
Downloaded from http://atvb.ahajournals.org/ at Universitaet Duesseldorf on March 26, 2014
Editorial Risk of Ischemic Stroke and Decreased Serum Bilirubin Levels Is There a Causal Link? Giovanni Targher
B
ilirubin, often thought to be a toxic end product of heme, is a potent antioxidant compound in vivo.1,2 As shown in the schematic Figure, degraded red blood cells release heme, which is broken down by heme oxygenase to biliverdin, which is reduced by biliverdin reductase into the hydrophobic compound bilirubin. Unconjugated bilirubin is a lipid-soluble molecule that must be made water soluble to be excreted. Unconjugated bilirubin is carried by albumin to the liver, where it is conjugated into a water-soluble form by hepatic glucuronyl transferase. The hepatic enzyme UDPglucuronyl transferase 1A1 (UGT1A1) converts bilirubin to a soluble (conjugated) form suitable for renal and biliary elimination.1,2 Importantly, in healthy European populations, common genetic variation of the UGT1A1 promoter region explains ≈50% of the variability in serum total (TB) and conjugated bilirubin levels.3 UGT1A1 is also responsible for the glucuronidation of many other small lipophilic molecules, such as steroid hormones and drugs that affect the vasculature.1,2
See accompanying article on page 946 Currently, ample evidence suggests that lower levels of TB are associated with increased risk of cardiovascular disease (CVD), independently of traditional risk factors.4–9 In 2012, further evidence for a possible beneficial role of bilirubin protecting against CVD was provided from a large UK primary care database (n=130 052 patients) with the measurement of TB levels recorded 3 months before first statin treatment. After a median of ≈3.5 years of follow-up, an inverse relationship was noted between TB levels and risk of CVD events and death. After traditional risk factors were accounted for, the associations with TB levels were nonlinear (L shaped), and the models predicted that, compared with patients with a TB level of 0.6 mg/dL, those with a similar CVD risk profile but a TB level of 0.3 mg/dL had an 18% higher risk of any CVD event, a 34% higher risk of myocardial infarction, and a 33% higher risk of death resulting from any cause.10
From the Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy. Correspondence to Giovanni Targher, MD, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale A. Stefani 1, 37126 Verona, Italy. E-mail [email protected] (Arterioscler Thromb Vasc Biol. 2014;34:702-704.) © 2014 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.303279
Currently, there is sparse and less convincing evidence for an inverse association between TB levels and risk of ischemic stroke. Perlstein et al11 examined the association of TB levels with the prevalence of stroke among 13 214 US adults. After multivariable adjustment, a 0.1 mg/dL increment in TB levels was associated with a 9% reduced odds of stroke among all participants and with a 10% reduced odds of an adverse stroke outcome among participants with a history of stroke. Similar findings were reported by Oda and Kawai12 in a health screening cohort of 5444 Japanese people. Interestingly and most importantly, in the only published prospective study that involved 78 724 Korean healthy individuals (41 054 men, aged 30–89 years), Kimm et al13 reported that, compared with those with lower TB levels, male individuals with mildly higher TB levels showed a ≈30% decreased risk of incident ischemic stroke (as ascertained by hospital admission discharge records), independently of multiple risk factors, during a median follow-up period of 9.4 years. However, these associations were not observed in hemorrhagic stroke or in women.13 Few recent studies that have explored the association of TB levels with the severity and subtypes of stroke among hospitalized patients with a first-ever acute ischemic stroke have shown that patients with mildly higher TB levels had a significantly greater admission severity of stroke (as assessed by the National Institutes of Health Stroke score), but not short-term clinical outcomes (ie, in-hospital death or National Institutes of Health Stroke score ≥10), than those with lower TB levels.14–16 In a retrospective study of 626 patients with acute ischemic stroke, Zhang et al17 reported that mildly higher TB levels at admission were associated with an increased odds for nonlacunar ischemic stroke. It is possible to assume that higher TB levels after acute ischemic stroke reflect the intensity of the initial oxidative stress induced by the neurological damage. In this scenario, the study published by Li et al18 in this issue of the journal adds to the body of evidence showing, for the first time, a graded, inverse relationship between serum levels of TB (conjugated and unconjugated bilirubin) and increased prevalence of silent cerebral infarctions in middle-aged Chinese individuals. Notably, this relationship remained significant after adjusting for established stroke risk factors and potential confounders. No association was observed between TB levels and the dimensions of brain infarcts on MRI. Although the cross-sectional design of the study does not allow to draw causal inferences, these findings are clinically important because they identify lower TB levels as a possible novel marker for silent cerebral infarctions. Despite not causing identifiable symptoms, silent cerebral infarctions are common in healthy elderly people and place
Downloaded from http://atvb.ahajournals.org/702 at Universitaet Duesseldorf on March 26, 2014
Targher Risk of Ischemic Stroke 703
Figure. Schematic representation of the bilirubin metabolism and the putative biological mechanisms by which higher levels of serum bilirubin might exert vasoprotective effects on the development of silent brain infarcts and other cardiovascular complications. HO-1 indicates heme oxygenase-1.
the patient at increased risk for major stroke, dementia, cognitive decline, and depression in the future.19,20 Collectively, the evidence from this18 and other studies11–17 supports the possibility that the early measurement of TB levels might be useful to assess the risk of silent cerebral infarction(s) and major stroke and that mildly elevated TB levels might protect from stroke events and from neurological damage in stroke. In general, from a pathophysiological perspective, there are some key questions that should be addressed. First, is decreased serum TB associated with increased risk of stroke as a consequence of the coexisting cardiovascular risk factors, or does decreased serum TB contribute to the development of stroke, independently of these risk factors? Second, is it biologically plausible that increased serum TB could confer specific vascular protection? Third, could novel therapeutic approaches (eg,
pharmacological, nonpharmacological, or genetic interventions) that increase TB levels provide more direct evidence on the protective role of bilirubin in stroke prevention? To date, it is uncertain whether decreased TB levels pose an independent risk above and beyond known risk factors. There is a suggestion in that direction, but studies are too few and methodologically not rigorous. Additional large-scale prospective studies of a more extensive panel of known risk factors are needed to draw firm conclusions about an independent prognostic role of decreased TB levels for the development of stroke and other CVD complications. Little information is also currently available on the potentially vasoprotective effects of mildly elevated TB levels. It is uncertain whether genetic variation in the UGT1A1 is associated with variable risk of coronary heart disease (CHD). The
Downloaded from http://atvb.ahajournals.org/ at Universitaet Duesseldorf on March 26, 2014
704 Arterioscler Thromb Vasc Biol April 2014 Framingham Heart Study investigators found that UGT1A1 polymorphism, resulting in higher TB levels, was associated with lower risk of CHD.21 However, other smaller studies have failed to show the same association.22–25 Conversely, it has been shown that patients with Gilbert syndrome have a lower risk of CHD than normobilirubinemic control subjects, thus supporting the concept that mildly elevated (unconjugated) bilirubin levels might help protect against CHD.26 The underlying mechanisms by which increased TB may exert vasoprotective effects are still incompletely understood, and further research is required to uncover other specific mechanisms by which bilirubin may protect from stroke and CHD events. The putative mechanisms of benefit that have been experimentally described are bilirubin-mediated inhibition of lipid oxidation, bilirubin-mediated inhibition of immune reactions and inflammatory processes, bilirubin-mediated inhibition of cell migration and proliferation, bilirubin-mediated inhibition of apoptosis, and bilirubin as a marker reflecting enhanced heme oxygenase-1 activity (Figure).1,2 However, it is important to remember that markedly elevated TB levels may exert neurotoxic effects in some circumstances.1,2 Thus, in the absence of definitive evidence, being bilirubin a Janus Bifrons, I think that prudence is still required. Additional large and long-term observational studies in different ethnic groups are warranted to establish the role of serum TB firmly as a causal risk factor for CHD and, especially, for ischemic stroke. This is also important particularly if one considers that novel therapeutic strategies aimed to achieve mild-to-moderate elevations of serum bilirubin (eg, use of heme oxygenase-1 inducers or drugs that reduce hepatic glucuronidation activity or inhibit hepatocyte uptake)27,28 might be used, in the future, as tools for preventing and treating CHD/stroke and other diseases in which oxidants play a prominent pathogenic role.
Disclosures None.
References 1. Vítek L, Schwertner HA. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem. 2007;43:1–57. 2. Franchini M, Targher G, Lippi G. Serum bilirubin levels and cardiovascular disease risk: a Janus Bifrons? Adv Clin Chem. 2010;50:47–63. 3. Borucki K, Weikert C, Fisher E, Jakubiczka S, Luley C, Westphal S, Dierkes J. Haplotypes in the UGT1A1 gene and their role as genetic determinants of bilirubin concentration in healthy German volunteers. Clin Biochem. 2009;42:1635–1641. 4. Breimer LH, Wannamethee G, Ebrahim S, Shaper AG. Serum bilirubin and risk of ischemic heart disease in middle-aged British men. Clin Chem. 1995;41:1504–1508. 5. Djoussé L, Levy D, Cupples LA, Evans JC, D’Agostino RB, Ellison RC. Total serum bilirubin and risk of cardiovascular disease in the Framingham offspring study. Am J Cardiol. 2001;87:1196–1200; A4, 7. 6. Novotný L, Vítek L. Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies. Exp Biol Med (Maywood). 2003;228:568–571. 7. Perlstein TS, Pande RL, Beckman JA, Creager MA. Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. Arterioscler Thromb Vasc Biol. 2008;28:166–172.
8. Fulks M, Stout RL, Dolan VF. Mortality associated with bilirubin levels in insurance applicants. J Insur Med. 2009;41:49–53. 9. Sung KC, Shin J, Lim YH, Wild SH, Byrne CD. Relation of conjugated bilirubin concentrations to the presence of coronary artery calcium. Am J Cardiol. 2013;112:1873–1879. 10. Horsfall LJ, Nazareth I, Petersen I. Cardiovascular events as a function of serum bilirubin levels in a large, statin-treated cohort. Circulation. 2012;126:2556–2564. 11. Perlstein TS, Pande RL, Creager MA, Weuve J, Beckman JA. Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999-2004. Am J Med. 2008;121:781–788.e1. 12. Oda E, Kawai R. A possible cross-sectional association of serum total bilirubin with coronary heart disease and stroke in a Japanese health screening population. Heart Vessels. 2012;27:29–36. 13. Kimm H, Yun JE, Jo J, Jee SH. Low serum bilirubin level as an independent predictor of stroke incidence: a prospective study in Korean men and women. Stroke. 2009;40:3422–3427. 14. Pineda S, Bang OY, Saver JL, Starkman S, Yun SW, Liebeskind DS, Kim D, Ali LK, Shah SH, Ovbiagele B. Association of serum bilirubin with ischemic stroke outcomes. J Stroke Cerebrovasc Dis. 2008;17:147–152. 15. Xu T, Zhang J, Xu T, Liu W, Kong Y, Zhang Y. Association of serum bilirubin with stroke severity and clinical outcomes. Can J Neurol Sci. 2013;40:80–84. 16. Luo Y, Li J, Zhang J, Xu Y. Elevated bilirubin after acute ischemic stroke linked to the stroke severity. Int J Dev Neurosci. 2013;31:634–638. 17. Zhang B, Zhang W, Li X, Pu S, Yin J, Yang N, Yi Y, Gao Q, Gao C. Admission markers predict lacunar and non-lacunar stroke in young patients. Thromb Res. 2011;128:14–17. 18. Li R-Y, Cao Z-G, Zhang J-R, Li Y, Wang R-T. Decreased serum bilirubin is associated with silent cerebral infarction. Arterioscler Thromb Vasc Biol. 2014;34:946–951. 19. Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM; Rotterdam Scan Study. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke. 2003;34:1126–1129. 20. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003;348:1215–1222. 21. Lin JP, O’Donnell CJ, Schwaiger JP, Cupples LA, Lingenhel A, Hunt SC, Yang S, Kronenberg F. Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. Circulation. 2006;114:1476–1481. 22. Bosma PJ, van der Meer IM, Bakker CT, Hofman A, Paul-Abrahamse M, Witteman JC. UGT1A1*28 allele and coronary heart disease: the Rotterdam Study. Clin Chem. 2003;49:1180–1181. 23. Gajdos V, Petit FM, Perret C, Mollet-Boudjemline A, Colin P, Capel L, Nicaud V, Evans A, Arveiler D, Parisot F, Francoual J, Genin E, Cambien F, Labrune P. Further evidence that the UGT1A1*28 allele is not associated with coronary heart disease: The ECTIM Study. Clin Chem. 2006;52:2313–2314. 24. Ekblom K, Marklund SL, Jansson JH, Osterman P, Hallmans G, Weinehall L, Hultdin J. Plasma bilirubin and UGT1A1*28 are not protective factors against first-time myocardial infarction in a prospective, nested case-referent setting. Circ Cardiovasc Genet. 2010;3:340–347. 25. Ekblom K, Marklund SL, Johansson L, Osterman P, Hallmans G, Weinehall L, Wiklund PG, Hultdin J. Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting. Cerebrovasc Dis. 2010;30:590–596. 26. Vítek L, Jirsa M, Brodanová M, Kalab M, Marecek Z, Danzig V, Novotný L, Kotal P. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis. 2002;160:449–456. 27. McCarty MF. “Iatrogenic Gilbert syndrome”–a strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubin. Med Hypotheses. 2007;69:974–994. 28. Peterson SJ, Frishman WH, Abraham NG. Targeting heme oxygenase: therapeutic implications for diseases of the cardiovascular system. Cardiol Rev. 2009;17:99–111.
Key Words: Editorials ◼ bilirubin ◼ risk factors ◼ stroke
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