Higher baseline serum bilirubin levels are associated with increased risk of early neurological deterioration in women with acute ischemic stroke

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Higher baseline serum bilirubin levels are associated with increased risk of early neurological deterioration in women with acute ischemic stroke

Meng Sun^†Yingfeng Weng^†Jiwei ChengGuoyi Li^*Qian Xiao^*

• Department of Neurology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Background and objectives: Early neurological deterioration (END) occurs in up to one-third of patients with acute ischemic stroke (AIS) and associated with poor outcome. The role of serum bilirubin in END remains controversial. This study aims to investigate the association of total bilirubin (TBIL), direct bilirubin (DBIL) and indirect bilirubin (IBIL) with END.

Methods: This study was a cross-sectional retrospective study with 344 AIS patients enrolled. We retrospectively reviewed consecutive AIS patients with END through a medical record retrieval system and enrolled patients as control randomly from the AIS patients without END at the same period. The bilirubin levels were compared between the END group and No END group. The correlations of bilirubin with END were assessed according to the bilirubin tertiles on the cohort of different genders.

Results: In women, as the bilirubin level increased, the occurrence of END showed an increasing trend. The linear association was significant based on the tertiles of all bilirubin types (TBIL p = 0.003; DBIL p = 0.025; IBIL p = 0.025), while in men no similar trend was observed. After adjustment for confounders, higher TBIL (p for trend 0.009) and DBIL (p for trend 0.033) levels were associated with increased risk of END in women. The adjusted OR for T3 relative to T1 was 5.240 (95% CI 1.496–18.347) in TBIL and 3.549 (95% CI 1.089–11.566) in DBIL. Multivariate logistic regression showed that DBIL was independently associated with END in women (OR 1.717, 95% CI 1.106–2.666). The study also found that DBIL was superior to TBIL and IBIL in prediction of END occurrence in women, with greater predictive value.

Discussion: There were gender differences in the relationship between bilirubin and END, and DBIL level was positively associated with END occurrence in women, not in men. DBIL had greater incremental predictive value for END than TBIL and IBIL.

1 Introduction

Ischemic stroke is a severe cerebrovascular disease with high morbidity, disability and mortality, which places a great burden on the patients and the society. Early neurological deterioration (END) occurs in up to one-third of patients with acute ischemic stroke (AIS) and associated with poor stroke outcome (1). Compared with patients without END, patients with END suffered from higher National Institute of Health Stroke Scale (NIHSS) score at discharge, prolonged hospitalization, and poorer functional outcome. Even a 2-point increase in the NIHSS score was associated with a 3-fold risk of death and was an indicator of poor outcome and in-hospital mortality (2). The treatment of END is still not very satisfactory. Therefore, identifying risk factors associated with END is important for clinically predicting the occurrence of END.

Excessive oxidative stress plays a major role in the pathophysiology of ischemic brain damage in the acute phase of stroke. Human brain is more susceptible to oxidative stress than other organs because of its high consumption of oxygen, abundant unsaturated lipids and relative weak endogenous antioxidant capacity (catalase or glutathione peroxidase) (3). Reactive oxygen (ROS) could damage deoxyribonucleic acid (DNA), cause peroxidation of unsaturated fatty acids in cell membranes, which not only alters cellular integrity, but also leads to reaction with other lipids, proteins and nucleic acids, augmenting damage to the brain (3). Therefore the antioxidant defense system is very important to prevent the brain tissue from ischemia-triggered oxidative stress and cell damage.

Serum bilirubin, the end product of heme metabolism, has been known as the endogenous antioxidant. However, when accumulated highly in tissues, it could also be toxic and cause brain damage especially in newborns. It includes two forms: direct bilirubin (DBIL) and indirect bilirubin (IBIL). IBIL is converted to DBIL by the hepatic enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). A number of epidemiological studies showed that moderately high bilirubin was associated with lower risk of cardiovascular disease and mortality (4–6). However, the studies of serum bilirubin in stroke prognosis still remain controversial, without reaching a consensus. Some supported a positive or null relationship between bilirubin and the prognosis of stroke, while others argued that high levels of bilirubin were associated with poor stroke outcomes and mortality. Soleimanpour et al. proposed that bilirubin could be used as a disease predictor and a potential treatment target in stroke, but further researches are required to provide more evidence (7, 8). In addition, there have been a lot of controversies over the gender differences in the relationship of bilirubin with diseases. As far as we know, few studies focused on the relationship of different bilirubin subtypes and END occurrence in different genders.

The objective of our study is to investigate the risk factors of END in AIS, and the association of serum bilirubin subtypes with END occurrence in different genders through a retrospective study.

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