Abstract
Background:
Serum bilirubin is considered as a natural antioxidant that may affect the prognosis of stroke.Objectives:
This systematic review aimed at determining the predictive value of serum bilirubin levels in stroke.Methods:
We systematically reviewed the literature published in PubMed, Web of Science, Scopus, Embase, ProQuest, and the Cochrane Library with no time limit until October 2018. The search strategy included a combination of Mesh and free keywords, such as Bilirubin, Stroke, Cerebral Ischemia, Brain Ischemia, and Brain Vascular Accident.Results:
OF A total of 2013 studies, 13 studies were included in this systematic review. The results revealed that, based on the majority of studies, increased bilirubin leads to increased severity of ischemic stroke.Conclusions:
This systematic review showed that there was an association between the increased serum level of bilirubin and increased severity of ischemic stroke.Keywords
1. Background
Stroke, as a cardiovascular condition, is a major cause of death and accounts for a large proportion of disability-adjusted life years (DALYs) lost (1-5). The direct and indirect costs of stroke in 2009 have shown to be about $68.9 billion worldwide. Studies have indicated that the global burden of stroke has increased, especially in low and middle-income countries. Ischemic stroke is caused by intracranial thrombosis or extracranial embolism, which respectively arises from atherosclerosis and extracranial arteries or myocardium (6). Although intravenous thrombolysis is the only approved therapeutic method for acute ischemic stroke, there are some barriers, such as prolonged hospital stay for the implementation of this therapy, especially in the developing world (7, 8). The risk of stroke can be identified using some techniques, such as early cardiac evaluation using echocardiography in the emergency rooms (9-12). It has shown that stroke complications can be improved, and also appropriate therapeutic methods can reduce stroke-related mortality or disability (13-16).
Blood biomarkers associated with acute ischemic stroke might improve the prediction of stroke outcomes, which is helpful for early decision-making (17, 18). Bilirubin, as a major intravascular product of heme catabolism, has been found to have biological actions, including anti‐inflammatory, antioxidant, immunomodulatory, cytoprotective, and neuroprotective activities (19, 20). There is a relationship between serum bilirubin levels and the risk of metabolic disorders, such as cardiovascular diseases, type 2 diabetes, metabolic syndrome, hypertension, and obesity (21). Although the high level of serum bilirubin has shown with some positive impacts in the treatment of diseases caused by oxidative stress, these impacts in the acute ischemic stroke are less known (22).
2. Objectives
Considering the numerous studies available, as well as the lack of a relevant systematic review, this study was conducted to evaluate the predictive value of bilirubin levels in ischemic stroke patients.
3. Methods
3.1. Data Sources and Search strategy
We systematically reviewed the literature published in PubMed, Web of Science, Scopus, Embase, ProQuest, and The Cochrane Library with no time limit until October 2018. The search strategy included a combination of Mesh and free keywords, such as Bilirubin, Stroke, Cerebral Ischemia, Brain Ischemia, and Brain Vascular Accident. The used strategies to search databases are provided in the supplementary file, Appendices1 to 6.
3.2. Inclusion and Exclusion Criteria for Patients in the Included Studies
Inclusion criteria for patients were acute ischemic stroke, acute intracerebral hemorrhagic stroke, an acute attack of stroke, ischemic stroke, acute ischemic stroke (AIS) patients admitted to the department of neurology, AIS patients and transient ischemic attack (TIA) patients, and stroke patients.
On the other hand, the exclusion criteria for patients were as follows: liver diseases, congestive heart failure, hematological disease, traumatic hemorrhage, sub-arachnoidal hemorrhage, brain tumor, abnormal platelet count, vascular anomaly, prolonged prothrombin time or prolonged activated partial thromboplastin time, pregnancy, habitual smoking, history of alcohol abuse, intravenous drug abuse, use of antioxidant supplements, hypertension, pulmonary disease and coronary artery disease, diabetes mellitus, hepatic disease, renal disease or renal failure, inflammatory gastrointestinal disease, recurrent stroke, and aspiration pneumonia, severe medical or psychiatric illness, serum creatinine of > 150 µmol/L, gout, use of antioxidant vitamins, previous history of stroke, missing serum total bilirubin level, missing data for a key covariate, established history of renal, hepatic, or cholecystic disease and tumor, pre-stroke impairment, infections, or inflammatory diseases.
3.3. Study Selection
Following the search, all identified citations were collated and uploaded into EndNote, and the duplicates were removed. Then, titles and abstracts were screened by two independent reviewers who assessed the inclusion criteria. Studies meeting the inclusion criteria were retrieved for their full-texts. The full-text of selected studies was assessed in detail based on the inclusion criteria. Full-text studies that did not meet the inclusion criteria were excluded. Included studies were subjected to a critical appraisal. The disagreements between the two reviewers were resolved through discussion or by the assistance of a third reviewer. The results of the search are provided in the final report and presented in a PRISMA flow diagram.
3.4. Assessment of the Methodological Quality
Selected studies were critically appraised for methodological quality by two independent reviewers using the standardized critical appraisal tools. In case of disagreements, discussion, or negotiation with a third reviewer was considered. Following a critical evaluation, studies that did not meet a predetermined threshold for quality were excluded. Studies were excluded based on the degree of bias in the study. If a study was not accompanied by more than two items of the checklists, it was excluded.
3.5. Data Extraction
Data extraction was done using the standardized data extraction tool by two independent reviewers and included surname of the first author, publication year, study design, biomarker, age, sample size, total bilirubin level in cases and control group, stroke severity (NIHSS) neurological outcomes, the correlation between stroke severity and bilirubin, adjusted odds ratio (Tbil-NIHSS), and non-adjusted adds ratio (Tbil-NIHSS). The disagreement between the reviewers in this step was also resolved through discussion or arbitration by a third reviewer. The authors were contacted when any of the data were missing, or additional data were required.
4. Results
4.1. Study Selection
We initially identified 2013 records using the search strategy, of which 576 articles remained after the removal of duplications. Also, 539 articles did not meet the inclusion criteria and were removed after screening for eligibility by reading the titles and abstracts. Thirty-seven full-texts were assessed further by the exclusion of another 24 papers. Finally, a total of 13 studies were included in this systematic review. Figure 1 shows the details of the study selection process. Tables 1 and 2 indicate the risk of bias in the studies.
Search strategy and study selection process of this systematic review
Risk of Bias of the Cross-Sectional Studies
| Author | Cross-Sectional Studies | |||||||
|---|---|---|---|---|---|---|---|---|
| The Inclusion Criteria in the Sample Were Clearly Defined | The Study Subjects and the Setting Were Described in Detail | The Exposure Was Measured in a Valid and Reliable Manner | The Objective and Standard Criteria Were Used for the Measurement of the Condition | The Confounding Factors Were Identified | The Strategies to Deal with Confounding Factors Were Stated | The Outcomes Were Measured in a Valid and Reliable Manner | An Appropriate Statistical Analysis Was Used | |
| Luo et al. (23) | Y | Y | Y | U | U | Y | Y | Y |
| Arsalan et al. (24) | Y | Y | U | Y | Y | Y | Y | U |
| Kurzepa et al. (25) | Y | Y | U | U | U | Y | Y | Y |
| Xu et al. (26) | Y | Y | N | Y | U | Y | Y | N |
| Perlstein et al. (27) | Y | Y | U | U | U | Y | Y | N |
| Sagheb Asl E. et al. (22) | U | Y | U | U | U | U | Y | U |
Risk of Bias of the Case-Control Studies
| Author | Case Control Studies | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| The Groups Were Comparable Other Than the Presence of Disease in Cases or the Absence of Disease in Controls | The Cases and Controls Were Matched Appropriately | The Same Criteria Were Used for the Identification of Cases and Controls | The Exposure Was Measured in a Standard, Valid and Reliable Manner | The Exposure Was Measured in the Same Way for Cases and Controls | The Confounding Factors Were Identified | The Strategies to Deal with Confounding Factors Were Stated | The Outcomes Were Assessed in a Standard, Valid, and Reliable Way for Cases and Controls | The Exposure Period of Interest Was Long Enough to be Meaningful | An Appropriate Statistical Analysis Was Used | |
| Herishannu et al. (28) | Y | N | U | U | Y | Y | U | Y | Y | Y |
| Gonullu et al. (29) | Y | N | U | U | Y | Y | Y | Y | Y | Y |
| Luo et al. (30) | Y | N | U | U | Y | Y | U | Y | Y | Y |
| Cojocaru et al. (31) | Y | U | U | U | Y | Y | U | Y | Y | Y |
| Muscari et al. (32) | Y | U | U | U | Y | Y | U | Y | Y | Y |
| Lagowska-Lenard et al. (33) | Y | U | U | U | Y | Y | Y | Y | Y | Y |
4.2. Description of the Included Studies
Studies that had been published between 1971 and 2018 in countries of Iran, Israel, Turkey, Pakistan, Romania, Poland, China, Italy, India, and the USA. All included studies were conducted on humans. Six studies had a case-control design (23-28), six had a cross-sectional design (22, 29-33) and one was a case series (34). Studies had been conducted between seven days to five years. The total sample size in this systematic review was 17,557 subjects for case groups and 347 for control groups. The participants, on average aged between 15 and 92 years. Bilirubin was the biomarker in all included studies.
4.3. Findings of Bilirubin Level
The results of five included studies showed an increase in the level of serum bilirubin after acute ischemic stroke, which was related to the severity of stroke (22, 25, 29, 31, 33). Three studies had reported that an increase in the level of serum bilirubin led to a reduction in stroke prevalence and improved the outcomes (24, 26, 32). Three other studies showed no significant relationship between serum bilirubin levels and ischemic stroke (28, 30, 34). Studying the influence of vitamin C on the markers of oxidative stress had shown that although vitamin C increased the levels of antioxidants, it did not improve the clinical and the functional aspects of AIS patients after three months (27). The results of the last study suggested a direct influence of the brain lesion on the polarity of the hepatic cell as a possible mechanism for the hyperbilirubinemia in patients with AIS (23). The mean total and direct bilirubin levels in patients within 24 h are indicated in Table 3. The results were significant in all studies, except for one study.
| Author | Country | Study Design | Biomarker | Age, y | Sample Size | Total Bilirubin Level in Cases | Total Bilirubin Level in Controls | Unit | Neurological Outcomes Associated with Stroke Severity (NIHSS) | Correlation Between Stroke Severity and Bilirubin | Adjusted Odds Ratio (Tbill-NIHHS) | Non-Adjusted Odds Ratio (Tbill-NIHHS) | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Case | Control | ||||||||||||||
| Total | M | F | |||||||||||||
| Herishannu et al. (28) | Israel | Case-control | Bilirubin | 46 - 80 | 73 | 55 | 18 | 63 | < 1.1 | mg/dL | + | ||||
| Gonullu et al. (29) | Turkey | Case-control | Bilirubin | 25 | 9 | 16 | 25 | 9.68 ± 5.02 | 22.05 ± 5.80 | µmol/L | + | ||||
| Luo et al. (30) | China | Case-control | Bilirubin | 15 - 92 | 608 | 383 | 225 | 188 | 18.329 | 16.147 | µmol/L | + | 1.051 | 1.084 | |
| Cojocaru et al. (31) | Romania | Case-control | Bilirubin | 73.4 ± 6.5 | 57 | 24 | 33 | 51 | 1.31 ± 0.07 | 1.04 ± 0.06 | mg/dL | + | |||
| Muscari et al. (32) | Italy | Case-control | Bilirubin | 73.2 ± 13.2 | 180 | 85 | 95 | - | mg/dL | < 10 | - | ||||
| Lagowska-Lenard et al. (33) | Poland | Case-control | Bilirubin | 72.8 ± 10.4 | 30 | - | - | 20 | 0.65 | mg/dL | + | ||||
| Luo et al. (23) | China | Cross-sectional | Bilirubin | 67 ± 0.56 | 531 | 337 | 197 | - | 18.54 ± 0.4 | Umol/l | < 10 | + | 1.005 | 3.352 | |
| Arsalan et al. (24) | Pakistan | Cross-sectional | Bilirubin | 63.5 | 44 | 26 | 18 | - | < 1.1 | mg/dL | 16.26 | + | |||
| Kurzepa et al. (25) | Poland | Cross-sectional | Bilirubin | 71.9 ± 12.1 | 43 | 22 | 21 | - | 15.4 | µmol/L | + | ||||
| Xu et al. (26) | China | Cross-sectional | Bilirubin | 65.05 | 2361 | - | - | - | < 10 | + | 1.584 | 1.866 | |||
| Perlstein et al. (27) | USA | Cross-sectional | Bilirubin | 13214 | - | - | - | 12.1 | µmol/L | + | 0.76 | 0.91 | |||
| Sagheb Asl et al. (22) | Iran | Cross-sectional | Bilirubin | 260 | 146 | 114 | 0.89 ± 0.41 | 16.5 | + | ||||||
| Bhatia et al. (34) | India | CASE sires | Bilirubin | 116 | 77 | 39 | - | mg/dL | < 10 | - | |||||
5. Discussion
This systematic review was conducted to assess the predictive value of serum bilirubin in patients with ischemic stroke. The results of the majority of included studies showed an increase in the level of serum bilirubin after acute ischemic stroke, as well as an increase in the severity of stroke. Three studies showed that an increase in the level of serum bilirubin led to a reduction in stroke prevalence and improved the outcomes of stroke. Three other studies showed no significant relationship between serum bilirubin levels and ischemic stroke. One of the studies had assessed the influence of vitamin C on the markers of oxidative stress, in which vitamin C could not improve the clinical and the functional aspects of AIS patients after three months. Finally, another study had suggested a direct influence of the brain lesion on the polarity of the hepatic cell as a possible mechanism for the hyperbilirubinemia in patients with AIS.
The results of this review revealed that, based on the majority of included studies, increased levels of bilirubin leads to increased severity of ischemic stroke. Similarly, based on another study, serum bilirubin had a significant and positive correlation with stroke severity (35).
In contrast with the findings of this review, which showed that serum bilirubin was a poor prognostic factor of ischemic stroke (25), the results of a meta-analysis including 24 case-control studies conducted in China, showed that serum levels of bilirubin might be a useful biomarker for the prediction of acute stroke (36). Similarly, another study found that the risk of all types of stroke was decreased by an increase in bilirubin level, and serum bilirubin level protected against stroke risk among male patients (37). Also, a study had reported that bilirubin concentration in plasma might be an effective marker of oxidative stress in hemorrhagic stroke patients (38). On the other hand, and in line with our results, Wang et al. indicated in their research that hyperbilirubinemia might be a biomarker for poor prognosis in the early identification of large-artery atherosclerotic stroke patients (39). Cojocaru et al. (40), in their research on 168 patients with different subtypes of acute ischemic strokes, illustrated that parameters of oxidative stress could not be used to differentiate stroke subtypes. Mendelian randomization in a study conducted in Korea in 2017 showed that serum bilirubin level was not a risk determinant for stoke (41). Similarly, the results of a research conducted by Kunutsor et al. (42) showed no significant evidence of an association between total bilirubin level and stroke risk.
The results of the three included studies showed that an increased level of serum bilirubin was linked to the reduced prevalence and improved outcomes of stroke. however, Tang et al. (43) showed in their study that high serum bilirubin level was associated with high post-stroke depression as an outcome of stroke. Results of a recent study indicated a close relationship between high levels of serum uric acid level and total bilirubin level on admission with the occurrence of major post-ischemic stroke depression within three months of stroke. However, there was an inverse relationship between 3 and 6 months post-stroke, meaning that low levels of these two biomarkers on admission led to the occurrence of major post-ischemic stroke depression, whereas six months after stroke, there was no relationship between post-ischemic stroke depression and these two biomarkers (44). Also, another research had indicated that high direct bilirubin level was not associated with discharge outcomes in ischemic stroke patients (45). A cross-sectional community-based study conducted on diabetic patients in China in 2014 aimed at assessing the influence of total bilirubin level on major complications, including stable angina, unstable angina, myocardial infarction, ischemic stroke, peripheral vascular disease, and chronic kidney disease, had indicated a significant association between total bilirubin level and lower prevalence of these complications (46). Also, based on the results of a previous study by Jorgensen et al. (47), low levels of serum bilirubin were associated with increased risk of developing non-fatal stroke as a primary cardiovascular adverse event in patients at risk for cardiovascular diseases. Similarly, Oda and Kawai (48), in their study on the Japanese health screening population, revealed that the prevalence of coronary heart disease and stroke in men, and only stroke in women, were increased as the total bilirubin level decreased. Similar results had been reported in another study (49).
5.1. Conclusions
This review showed that there was an association between the increased serum level of bilirubin and increased severity of ischemic stroke in the majority of included studies. More robust reviews and meta-analyses should be conducted to obtain a conclusion answering the controversy about the prognostic effect of the bilirubin level.
Acknowledgements
References
-
1.
WHO. Time to deliver: report of the WHO Independent high-level commission on noncommunicable diseases. Geneva: World Health Organization; 2018.
-
2.
Low WY, Lee YK, Samy AL. Non-communicable diseases in the Asia-Pacific Region: Prevalence, risk factors and community-based prevention. Int J Occup Med Environ Health. 2015;28(1):20-6. [PubMed ID: 26159943]. https://doi.org/10.2478/s13382-014-0326-0.
-
3.
Khorrami Z, Etemad K, Yarahmadi S, Khodakarim S, Kameli M, Hezaveh AM, et al. Urbanization and noncommunicable disease (NCD) risk factors: WHO STEPwise Iranian NCD risk factors surveillance in 2011. East Mediterr Health J. 2017;23(7):469-79. [PubMed ID: 28853130]. https://doi.org/10.26719/2017.23.7.469.
-
4.
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095-128. [PubMed ID: 23245604]. https://doi.org/10.1016/S0140-6736(12)61728-0.
-
5.
Ghaffar A, Reddy KS, Singhi M. Burden of non-communicable diseases in South Asia. BMJ. 2004;328(7443):807-10. [PubMed ID: 15070638]. [PubMed Central ID: PMC383378]. https://doi.org/10.1136/bmj.328.7443.807.
-
6.
Saenger AK, Christenson RH. Stroke biomarkers: Progress and challenges for diagnosis, prognosis, differentiation, and treatment. Clin Chem. 2010;56(1):21-33. [PubMed ID: 19926776]. https://doi.org/10.1373/clinchem.2009.133801.
-
7.
Ayromlou H, Soleimanpour H, Farhoudi M, Sadeghi-Hokmabadi E, Rajaei Ghafouri R, Sharifipour E, et al. What are the most important barriers for thrombolytic therapy in ischemic stroke patients? Int J Stroke. 2013;8(4). E7. [PubMed ID: 23692492]. https://doi.org/10.1111/ijs.12093.
-
8.
Ayromlou H, Soleimanpour H, Farhoudi M, Taheraghdam A, Sadeghi Hokmabadi E, Rajaei Ghafouri R, et al. Eligibility assessment for intravenous thrombolytic therapy in acute ischemic stroke patients; evaluating barriers for implementation. Iran Red Crescent Med J. 2014;16(5). e11284. [PubMed ID: 25031844]. [PubMed Central ID: PMC4082504]. https://doi.org/10.5812/ircmj.11284.
-
9.
Soleimanpour H, Pashapour A, Mohammadi N, Golzari SE, Khodaverdizadeh H. Juvenile ischemic stroke secondary to cardiogenic embolism: A rare case report. Int J Prev Med. 2014;5(1):117-22. [PubMed ID: 24555001]. [PubMed Central ID: PMC3915464].
-
10.
Mukherjee D, Patil CG. Epidemiology and the global burden of stroke. World Neurosurg. 2011;76(6 Suppl):S85-90. [PubMed ID: 22182277]. https://doi.org/10.1016/j.wneu.2011.07.023.
-
11.
Feigin VL, Roth GA, Naghavi M, Parmar P, Krishnamurthi R, Chugh SS, et al. Global burden of stroke and risk factors in 188 countries, during 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet Neurol. 2016;15(9):913-24. https://doi.org/10.1016/s1474-4422(16)30073-4.
-
12.
Krishnamurthi RV, Feigin VL, Forouzanfar MH, Mensah GA, Connor M, Bennett DA, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: Findings from the Global Burden of Disease Study 2010. Lancet Glob Health. 2013;1(5):e259-81. [PubMed ID: 25104492]. [PubMed Central ID: PMC4181351]. https://doi.org/10.1016/S2214-109X(13)70089-5.
-
13.
Bejot Y, Bailly H, Durier J, Giroud M. Epidemiology of stroke in Europe and trends for the 21st century. Presse Med. 2016;45(12 Pt 2):e391-8. [PubMed ID: 27816343]. https://doi.org/10.1016/j.lpm.2016.10.003.
-
14.
Xu XM, Vestesson E, Paley L, Desikan A, Wonderling D, Hoffman A, et al. The economic burden of stroke care in England, Wales and Northern Ireland: Using a national stroke register to estimate and report patient-level health economic outcomes in stroke. Eur Stroke J. 2018;3(1):82-91. [PubMed ID: 29900412]. [PubMed Central ID: PMC5992739]. https://doi.org/10.1177/2396987317746516.
-
15.
Icagasıoglu A, Baklacioglu HS, Mesci E, Yumusakhuylu Y, Murat S, Mesci N. Economic burden of stroke. Turk J Physic Med Rehabil. 2017;63(2):155.
-
16.
Adams HP, Jr, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, et al. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association. Stroke. 2003;34(4):1056-83. [PubMed ID: 12677087]. https://doi.org/10.1161/01.STR.0000064841.47697.22.
-
17.
Dieplinger B, Bocksrucker C, Egger M, Eggers C, Haltmayer M, Mueller T. Prognostic value of inflammatory and cardiovascular biomarkers for prediction of 90-day all-cause mortality after acute ischemic stroke-results from the linz stroke unit study. Clin Chem. 2017;63(6):1101-9. [PubMed ID: 28348074]. https://doi.org/10.1373/clinchem.2016.269969.
-
18.
Whiteley W, Chong WL, Sengupta A, Sandercock P. Blood markers for the prognosis of ischemic stroke: A systematic review. Stroke. 2009;40(5):e380-9. [PubMed ID: 19286602]. https://doi.org/10.1161/STROKEAHA.108.528752.
-
19.
Li WC, Mo LJ, Shi X, Lin ZY, Li YY, Yang Z, et al. Antioxidant status of serum bilirubin, uric acid and albumin in pemphigus vulgaris. Clin Exp Dermatol. 2018;43(2):158-63. [PubMed ID: 29067729]. https://doi.org/10.1111/ced.13289.
-
20.
Novotny L, Vitek L. Inverse relationship between serum bilirubin and atherosclerosis in men: A meta-analysis of published studies. Exp Biol Med (Maywood). 2003;228(5):568-71. [PubMed ID: 12709588]. https://doi.org/10.1177/15353702-0322805-29.
-
21.
Jung CH, Lee MJ, Kang YM, Hwang JY, Jang JE, Leem J, et al. Higher serum bilirubin level as a protective factor for the development of diabetes in healthy Korean men: A 4 year retrospective longitudinal study. Metabolism. 2014;63(1):87-93. [PubMed ID: 24140099]. https://doi.org/10.1016/j.metabol.2013.09.011.
-
22.
Sagheb Asl E, Taheraghdam A, Rahmani F, Javadrashid R, Golzari SEJ, Ghaemian N, et al. Determination of the predictive value of serum bilirubin in patients with ischemic stroke: A prospective descriptive analytical study. Adv Pharm Bull. 2018;8(4):715-9. [PubMed ID: 30607344]. [PubMed Central ID: PMC6311645]. https://doi.org/10.15171/apb.2018.080.
-
23.
Luo Y, Li JW, Lu ZJ, Wang C, Guan DN, Xu Y. Serum bilirubin after acute ischemic stroke is associated with stroke severity. Curr Neurovasc Res. 2012;9(2):128-32. [PubMed ID: 22475397]. https://doi.org/10.2174/156720212800410876.
-
24.
Ismail M, Khattak MB, Khan F, Anwar MJ, Murtaza Z; Arsalan, et al. Prognostic significance of serum bilirubin in stroke. J Ayub Med Coll Abbottabad. 2011;23(2):104-7. [PubMed ID: 24800356].
-
25.
Kurzepa J, Bielewicz J, Stelmasiak Z, Bartosik-Psujek H. Serum bilirubin and uric acid levels as the bad prognostic factors in the ischemic stroke. Int J Neurosci. 2009;119(12):2243-9. [PubMed ID: 19916852]. https://doi.org/10.3109/00207450903223939.
-
26.
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(1):80-4. [PubMed ID: 23250132]. https://doi.org/10.1017/s0317167100012993.
-
27.
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(9):781-8 e1. [PubMed ID: 18724968]. [PubMed Central ID: PMC2596911]. https://doi.org/10.1016/j.amjmed.2008.03.045.
-
28.
Herishanu Y, Abramsky O, Lavy S. Hyperbilirubinaemia in acute ischaemic stroke. J Neurol Sci. 1971;14(4):417-20. https://doi.org/10.1016/0022-510x(71)90176-6.
-
29.
Gonullu H, Aslan M, Karadas S, Kati C, Duran L, Milanlioglu A, et al. Serum prolidase enzyme activity and oxidative stress levels in patients with acute hemorrhagic stroke. Scand J Clin Lab Invest. 2014;74(3):199-205. [PubMed ID: 24456419]. https://doi.org/10.3109/00365513.2013.873949.
-
30.
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(7):634-8. [PubMed ID: 23994036]. https://doi.org/10.1016/j.ijdevneu.2013.08.002.
-
31.
Cojocaru IM, Cojocaru M, Sapira V, Ionescu A. Evaluation of oxidative stress in patients with acute ischemic stroke. Rom J Intern Med. 2013;51(2):97-106. [PubMed ID: 24294813].
-
32.
Muscari A, Collini A, Fabbri E, Giovagnoli M, Napoli C, Rossi V, et al. Changes of liver enzymes and bilirubin during ischemic stroke: Mechanisms and possible significance. BMC Neurol. 2014;14:122. [PubMed ID: 24903748]. [PubMed Central ID: PMC4055910]. https://doi.org/10.1186/1471-2377-14-122.
-
33.
Lagowska-Lenard M, Stelmasiak Z, Bartosik-Psujek H. Influence of vitamin C on markers of oxidative stress in the earliest period of ischemic stroke. Pharmacol Rep. 2010;62(4):751-6. [PubMed ID: 20885017]. https://doi.org/10.1016/s1734-1140(10)70334-0.
-
34.
Bhatia RS, Garg RK, Gaur SP, Kar AM, Shukla R, Agarwal A, et al. Predictive value of routine hematological and biochemical parameters on 30-day fatality in acute stroke. Neurol India. 2004;52(2):220-3. [PubMed ID: 15269476].
-
35.
Ademiluyi B, Sanya E, Wahab K. Relationship between admission serum bilirubin and severity of acute ischemic stroke in a Nigerian Tertiary Hospital (P5. 239). Neurology. 2016;88(16 Supplement):259.
-
36.
Li HY, Dai B, Shen GL, Liu W, Fu R, He M. Serum bilirubin levels in acute stroke in Chinese population: A meta-analysis. Int J Clin Exp Med. 2017;10(1):905-12.
-
37.
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(11):3422-7. [PubMed ID: 19713538]. https://doi.org/10.1161/STROKEAHA.109.560649.
-
38.
Dohi K, Mochizuki Y, Satoh K, Jimbo H, Hayashi M, Toyoda I, et al. Transient elevation of serum bilirubin (a heme oxygenase-1 metabolite) level in hemorrhagic stroke: Bilirubin is a marker of oxidant stress. Acta Neurochir Suppl. 2003;86:247-9. [PubMed ID: 14753445]. https://doi.org/10.1007/978-3-7091-0651-8_53.
-
39.
Wang Y, Xu S, Pan S, Ouyang H, Zang Z, Tan J. Association of serum neuron-specific enolase and bilirubin levels with cerebral dysfunction and prognosis in large-artery atherosclerotic strokes. J Cell Biochem. 2018;119(12):9685-93. [PubMed ID: 30191604]. https://doi.org/10.1002/jcb.27281.
-
40.
Cojocaru IM, Cojocaru M, Sapira V, Ionescu A, Barlan S, Tacu N. Could pro-BNP, uric acid, bilirubin, albumin and transferrin be used in making the distinction between stroke subtypes? Rom J Intern Med. 2013;51(3-4):188-95. [PubMed ID: 24620632].
-
41.
Lee SJ, Jee YH, Jung KJ, Hong S, Shin ES, Jee SH. Bilirubin and stroke risk using a mendelian randomization design. Stroke. 2017;48(5):1154-60. [PubMed ID: 28389615]. https://doi.org/10.1161/STROKEAHA.116.015083.
-
42.
Kunutsor SK, Bakker SJ, Gansevoort RT, Chowdhury R, Dullaart RP. Circulating total bilirubin and risk of incident cardiovascular disease in the general population. Arterioscler Thromb Vasc Biol. 2015;35(3):716-24. [PubMed ID: 25593130]. https://doi.org/10.1161/ATVBAHA.114.304929.
-
43.
Tang WK, Liang H, Chu WC, Mok V, Ungvari GS, Wong KS. Association between high serum total bilirubin and post-stroke depression. Psychiatry Clin Neurosci. 2013;67(4):259-64. [PubMed ID: 23683157]. https://doi.org/10.1111/pcn.12051.
-
44.
Gao J, Xu W, Han K, Zhu L, Gao L, Shang X. Changes of serum uric acid and total bilirubin in elderly patients with major postischemic stroke depression. Neuropsychiatr Dis Treat. 2018;14:83-93. [PubMed ID: 29343960]. [PubMed Central ID: PMC5749573]. https://doi.org/10.2147/NDT.S149712.
-
45.
Pineda S, Bang OY, Saver JL, Starkman S, Yun SW, Liebeskind DS, et al. Association of serum bilirubin with ischemic stroke outcomes. J Stroke Cerebrovasc Dis. 2008;17(3):147-52. [PubMed ID: 18436156]. [PubMed Central ID: PMC2731670]. https://doi.org/10.1016/j.jstrokecerebrovasdis.2008.01.009.
-
46.
Liu M, Li Y, Li J, Lv X, He Y. Elevated serum total bilirubin levels are negatively associated with major diabetic complications among Chinese senile diabetic patients. J Diabetes Complications. 2017;31(1):213-7. [PubMed ID: 27662781]. https://doi.org/10.1016/j.jdiacomp.2016.08.023.
-
47.
Jorgensen ME, Torp-Pedersen C, Finer N, Caterson I, James WP, Legler UF, et al. Association between serum bilirubin and cardiovascular disease in an overweight high risk population from the SCOUT trial. Nutr Metab Cardiovasc Dis. 2014;24(6):656-62. [PubMed ID: 24534073]. https://doi.org/10.1016/j.numecd.2013.12.009.
-
48.
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(1):29-36. [PubMed ID: 21394643]. https://doi.org/10.1007/s00380-011-0123-7.
-
49.
Suh S, Cho YR, Park MK, Kim DK, Cho NH, Lee MK. Relationship between serum bilirubin levels and cardiovascular disease. PLoS One. 2018;13(2). e0193041. [PubMed ID: 29447261]. [PubMed Central ID: PMC5814053]. https://doi.org/10.1371/journal.pone.0193041.