ABSTRACT
Keywords: Bilirubin; Ischaemic Stroke; Neuroprotection
Abbreviations: IS: Ischemic Stroke; AIS: Acute Ischaemic Stroke; DM: Diabetes Mellitus; BP: Blood Pressure; TBIL: Total Serum Bilirubin
Mini Review
Stroke is a multifactorial disease with high rate of morbidity,
mortality and disability. It is categorized into two types: ischemic
and hemorrhagic stroke (IS), and ischemic stroke (IS) accounts
for about 80% of all strokes (AS). Although some certain factors,
such as atrial thrombosis and hypertension, are closely related
to the occurrence of IS, its mechanism is still unclear [1,2]. Once
ischaemia occurs, excessive oxidative stress ensues and leads
to structural and functional damage to the brain, which is an
important pathophysiological process of ischaemic brain damage
[3-5]. Recently, a number of biomarkers pertaining to vascular
injury, metabolic changes, oxidative injury, and inflammation have
shown encouraging results in occurrence and prognosis of acute
ischaemic stroke (AIS) [6].
Bilirubin, an end-product of heme catabolism, long been
seen as a potentially toxic agent at high levels in the human
body [7], has been shown to harbour anti-inflammatory [8],
antioxidant [7,9], neuroprotective [10], and platelet activation
inhibiting [11] properties. These properties of bilirubin have
recently emerged as a feasible endogenous defense mechanism
against diverse diseases associated with increased oxidative
stress, such as IS [12]. Studies have demonstrated that the level of
bilirubin may serve as a predictor of some vascular events, such as
hypertension [13], coronary artery diseases [14], diabetes mellitus
(DM) [15], diabetic kidney disease [16], metabolic syndrome [17],
peripheral artery disease [18] and carotid atherosclerosis [19],
which are vascular risk factors of IS. Some other studies found
that a low level of total serum bilirubin (TBIL) was associated with
an increased risk of stroke in patients with bilirubin metabolismrelated
diseases, such as type 2 DM [20] and overweight/obese [21].
Multifaceted interventions achieving the blood pressure (BP), lipid
and glycaemia control targets may reduce the risk of developing
stroke associated with low levels of bilirubin. Nowadays, several
studies have shown the neuroprotective effects of bilirubin in the
occurrence and prognosis of IS; however, there is still controversy
on this issue. Here, we will propose our ideas about the relationship
between bilirubin and IS based on previous work.
In 2017, our study group performed a systemic review and
meta-analysis of 11 population-based observational studies
involving 5,060 stroke cases among 131,450 subjects investigating
the relationship between total serum bilirubin and risk for stroke,
supporting an inverse association between serum total bilirubin and
risk for IS and AS in males [12]. A large number of studies showed
that bilirubin is involved in antioxidation defense mechanisms and
a higher level of serum bilirubin in the normal range was associated
with a decreased risk of IS [22]. In order to make this issue more
accurate, we conducted a dose-response meta-analyses to quantify
the relationship between TBIL levels within physiologic range
and risk of stroke in 2020, and it has been accepted by Chinese
Circulation Journal and will soon be published online in April 2021.
Eleven observational studies involving 202,641 participants and
4,904 stroke cases from China, Japan, Korea, Sweden, the United
States, and other countries were included for this analysis. The
results showed that 1 μmol/L increment of serum TBIL level was
associated with a 1.2% decreased risk of IS (OR=0.988, 95%CI:
0.981-0.996, P=0.002) and a 1.5% decreased risk of AS (OR=0.985,
95% CI: 0.979-0.992, P<0.001). These results are consistent with
previous observational studies [23-25] and support the protective
effects of bilirubin on stroke occurrence. Choi et al conducted a
two-sample Mendelian Randomization study to examine whether
elevated serum bilirubin levels were causally associated with
decreased stroke risk and found genetically increased bilirubin
levels are causally associated with decreased total stroke risk
and when limiting the outcome to IS, the magnitude of relevance
became stronger [26]. However, a small number of studies showed
only moderately positive or null relationship [27,28]. In addition,
as described in our previous published review, the relationship
between bilirubin and stroke risk may be influenced by gender and
stroke types [22]. In this article, we also reviewed the relationship
between bilirubin and stroke prognosis. Though the prognostic
value of serum bilirubin in AIS seems controversial, the majority
of them appear to support that an elevated level of serum bilirubin
is an independent predictor of greater stroke severity and poorer
functional outcome after AIS. The level of serum bilirubin might
be a marker of oxidative stress after AIS. Higher bilirubin level is
associated with greater IS severity, and the latter in turn results in
poorer functional outcomes and increased mortality in AIS patients.
In summary, most of these studies show a protective effect of
bilirubin within physiologic range in the occurrence of IS. However,
majority of them only studied the effect of total bilirubin on IS.
Bilirubin levels are reported as total bilirubin (direct and indirect)
and direct bilirubin (conjugated bilirubin) in clinical, and indirect
bilirubin (unconjugated bilirubin) can be calculated separately. In
addition, bilirubin also flows in the plasma in the unbound (free)
form [29]. All types of bilirubin share some of the same antioxidant
properties, yet during an IS, only unbound, bioactive bilirubin is
effective in treatment, as it can cross the blood-brain barrier [9]. To
compare the relationship between different types of bilirubin and
stroke prevalence should be a future endeavor to better understand
bilirubin’s protective effects. Also, majority of published studies
only looked at one type of stroke, IS. It would be beneficial to
expand the current research to HS and traumatic brain injury to see
the potential benefits of bilirubin in these pathological states.
Bilirubin is not only one of the most potent endogenous
antioxidants [30] but also an excellent marker of oxidative stress
[31]. Studies have shown the beneficial effects of bilirubin in
cardiovascular disease; however, the same extent of research has
not yet been replicated in stroke. Can we increase neuroprotection
or reduce neurotoxicity of bilirubin by modulate bilirubin
concentration? Can multifaceted intervention achieving the BP,
lipid and glycaemia control targets attenuate the increased risk of
IS associated with low bilirubin level? Rigorous research is needed
to provide evidence supporting the existing studies, expand on
these studies.
Acknowledgment
This study was supported by the Class A Projects of key Medical Discipline in Yangpu District (YP19ZA08 awarded to Ping Zhong).
References
- Soleimanpour H, Pashapour A, Mohammadi N, Golzari SE, Khodaverdizadeh H (2014) Juvenile ischemic stroke secondary to cardiogenic embolism: A rare case report. Int J Prev Med 5: 117-122.
- Caldwell M, Martinez L, Foster JG, Sherling D, Hennekens CH (2019) Prospects for the Primary Prevention of Myocardial Infarction and Stroke. J Cardiovasc Pharmacol Ther 24(3) :207-214.
- Xia D, Zhang Z, Zhao Y (2018) Acteoside Attenuates Oxidative Stress and Neuronal Apoptosis in Rats with Focal Cerebral Ischemia-Reperfusion Injury. Biol Pharm Bull 41(11): 1645-1651.
- Li P, Stetler RA, Leak RK, Shi Y, Li Y, et al. (2018) Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery. Neuropharmacology 134(Pt B): 208-217.
- Regenhardt RW, Das AS, Lo EH, Caplan LR (2018) Advances in Understanding the Pathophysiology of Lacunar Stroke: A Review. JAMA Neurol 75(10): 1273-1281.
- Miao Y, Liao JK (2014) Potential serum biomarkers in the pathophysiological processes of stroke. Expert Rev Neurother 14(2): 173-185.
- Mancuso C (2017) Bilirubin and brain: A pharmacological approach. Neuropharmacology 118: 113-123.
- Sedlak TW, Saleh M, Higginson DS, Paul BD, Juluri KR, et al. (2009) Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc Natl Acad Sci U S A 106(13): 5171-5176.
- Watchko JF, Tiribelli C (2013) Bilirubin-induced neurologic damage--mechanisms and management approaches. N Engl J Med 369(21): 2021-2030.
- Syapin PJ (2008) Regulation of haeme oxygenase-1 for treatment of neuroinflammation and brain disorders. Br J Pharmacol 155(5): 623-640.
- Kundur AR, Singh I, Bulmer AC (2015) Bilirubin, platelet activation and heart disease: A missing link to cardiovascular protection in Gilbert's syndrome? Atherosclerosis 239(1): 73-84.
- Zhong P, Wu D, Ye X, Wang X, Zhou Y, et al. (2019) Association of circulating total bilirubin level with ischemic stroke: A systemic review and meta-analysis of observational evidence. Ann Transl Med 7(14): 335.
- Wang L, Bautista LE (2015) Serum bilirubin and the risk of hypertension. Int J Epidemiol 44: 142-152.
- Nguyen A, Adams H, Gin J, Yap N, Wilson O'Brien A, et al. (2016) Total serum bilirubin is an independent risk factor for coronary artery disease in men compared to women. Acta Cardiol 71(6): 685-689.
- Zhong P, Sun D, Wu D, Liu X (2019) Total bilirubin is negatively related to diabetes mellitus in Chinese elderly: A community study. Ann Transl Med 7(18): 474.
- Liu M, Li J, Lv X, He Y (2018) Bilirubin and its changes were negatively associated with diabetic kidney disease incidence and progression: A five-year's cohort study based on 5323 Chinese male diabetic patients. J Diabetes Complications 32: 1012-1017.
- Zhong P, Sun DM, Wu DH, Li TM, Liu XY, et al. (2017) Serum total bilirubin levels are negatively correlated with metabolic syndrome in aged Chinese women: A community-based study. Braz J Med Biol Res 50: e5252.
- Perlstein TS, Pande RL, Beckman JA, Creager MA (2008) 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 28(1): 166-172.
- Kawamoto R, Ninomiya D, Hasegawa Y, Kasai Y, Kusunoki T, et al. (2016) Mildly elevated serum total bilirubin levels are negatively associated with carotid atherosclerosis among elderly persons with type 2 diabetes. Clin Exp Hypertens 38(1): 107-112.
- Ren Y, Jin N, Hong T, Mu Y, Guo L, et al. (2016) Interactive effect of serum uric acid and total bilirubin for cardiovascular disease in chinese patients with type 2 diabetes. Sci Rep 6: 36437.
- Jørgensen ME, Torp Pedersen C, Finer N, Caterson I, James WP, et al. (2014) Association between serum bilirubin and cardiovascular disease in an overweight high-risk population from the SCOUT trial. Nutr Metab Cardiovasc Dis 24(6): 656-662.
- Wang X, Wu D, Zhong P (2020) Serum bilirubin and ischaemic stroke: A review of literature. Stroke Vasc Neuro 5(2): 198-204.
- Perlstein TS, Pande RL, Creager MA, Weuve J, Beckman JA (2008) Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999–2004. Am J Med 121(9): 781-788.e1.
- Kunutsor SK, Bakker SJ, Gansevoort RT, Chowdhury R, Dullaart RP (2015) Circulating total bilirubin and risk of incident cardiovascular disease in the general population. Arterioscler Thromb Vasc Biol 35(3): 716-724.
- Kimm H, Yun JE, Jo J, Jee SH (2009) Low serum bilirubin level as an independent predictor of stroke incidence: A prospective study in Korean men and women. Stroke 40(11): 3422-3427.
- Choi Y, Lee SJ, Spiller W, Jung KJ, Lee JY, et al. (2020) Causal Associations Between Serum Bilirubin Levels and Decreased Stroke Risk: A Two-Sample Mendelian Randomization Study. Arterioscler Thromb Vasc Biol 40(2): 437-445.
- Schooling CM, Kelvin EA, Jones HE (2012) Alanine transaminase has opposite associations with death from diabetes and ischemic heart disease in NHANES III. Ann Epidemiol 22(11): 789-798.
- Temme EH, Zhang J, Schouten EG, Kesteloot H (2001) Serum bilirubin and 10-year mortality risk in a Belgian population. Cancer Causes Control 12: 887-894.
- Ahlfors CE, Wennberg RP, Ostrow JD, Tiribelli C (2009) Unbound (free) bilirubin: Improving the paradigm for evaluating neonatal jaundice. Clin Chem 55(7): 1288-1299.
- Ziberna L, Martelanc M, Franko M, Passamonti S (2016) Bilirubin is an endogenous antioxidant in human vascular endothelial cells. Sci Rep 6: 29240.
- Qaisiya M, Coda Zabetta CD, Bellarosa C, Tiribelli C (2014) Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. Cell Signal 26: 512-520.