The Association between Uric Acid Level and Ischemic Stroke
Taylor’s University, School of Medicine, Faculty of Health and Medical Sciences, 1, Jalan Taylor's, 47500 Subang Jaya, Selangor, Malaysia
Taylor’s University, Medical Advancement for Better Quality of Life Impact Lab, 47500 Subang Jaya, Malaysia
MAHSA University, Faculty of Medicine, Level 7, Main Building, Bandar Saujana Putra, 42610 Jenjarom, Selangor, Malaysia
Academic Editor: Giuseppe Lanza
Collection: New Developments in Brain Injury
Received: July 11, 2023 | Accepted: January 10, 2024 | Published: January 16, 2024
OBM Neurobiology 2024, Volume 8, Issue 1, doi:10.21926/obm.neurobiol.2401209
Recommended citation: Xu Y, Wong EH, Nordin RB, Mohaideen AKM, Earnest BSP, Wong YH. The Association between Uric Acid Level and Ischemic Stroke. OBM Neurobiology 2024; 8(1): 209; doi:10.21926/obm.neurobiol.2401209.
© 2024 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Stroke is the second and third leading cause of death and disability, respectively, all over the world . It poses a substantial economic burden on patients and their families. Globally, the new incidence of stroke reached 13.7 million in 2016, with approximately 87% of cases being ischemic stroke . The highest risk of the incidence of ischemic stroke is mainly found in former Soviet Union countries and developing countries, where it is on the rise year by year compared to developed countries where it has been kept stable. Since currently, there exists no very effective treatment for ischemic stroke, prevention measures through controlling the associated risk factors to reduce morbidity and mortality is a priority. Often reported as an essential risk factor for ischemic stroke, uric acid may be good for the prevention of ischemic stroke in high-risk populations and clinical treatment in stroke patients. However, researchers hold inconsistent views on the effect of uric acid levels on ischemic stroke, the specific association between them being controversial. By summarizing the association between uric acid levels and ischemic stroke according to previous reports, this article can guide researchers to quickly and comprehensively understand the relationship between uric acid and ischemic stroke and develop further studies for its exploration.
2. The Association between Uric Acid Level and Ischemic Stroke
Uric acid is the final product of purine metabolism; it is an essential natural antioxidant in the body's tissues and fluids. It is a very useful oxygen-free radical scavenger of hydroxyl extreme and peroxynitrite, which could sweep away oxygen radicals in the pathological process of ischemic stroke. Studies on the association between uric acid levels and ischemic stroke yielded consistent results in animal experiments with rats and found that uric acid is a protective factor in ischemic stroke; they also showed that uric acid could reduce cerebral infarction size and was beneficial for better prognosis of ischemic stroke. While the results for human clinical experiments were inconsistent, interventional and observational studies showed contrary results. The interventional study was mostly consistent in showing that uric acid provided a protective effect in ischemic stroke, and high uric acid levels contributed to improving patients’ disease conditions and the recovery of neurological function. However, observational studies in clinical human experiments showed two opposite views: some researchers considered uric acid a protective factor. In contrast, for others, it was a risk factor for ischemic stroke (Table 1). Nonetheless, most observation studies reported uric acid as a risk rather than a protective factor.
In an earlier research, Bansal et al.  reported that ischemic cerebrovascular disease patients with thrombus showed noticeable elevated uric acid levels among those under 40 or with abnormal angiograms. On the contrary, a study by Sridharan et al. in 1992 found lower levels of uric acid in stroke patients . This research indicated that the uric acid level was obviously decreased in stroke patients, and a low level of uric acid increased the risk of ischemic stroke. A study of the association between the uric acid level and the prognosis for ischemic stroke in 2002 pointed out that for every 12-milligram increase in uric acid, the probability of a good outcome for ischemic stroke patients would increase 12%. The higher uric acid level of ischemic stroke patients at admission was dependently associated with good prognosis and functional outcome of patients at discharge, while lower level with bad clinical outcomes. This study pointed out that the role of uric acid in ischemic stroke was consistent with animal experiments .
Subsequent studies have reported that high levels of uric acid could increase the risk of ischemic stroke. Weir et al. demonstrated that a high level of uric acid predicted bad prognosis and clinical outcomes of stroke patients and a higher incidence of vascular events . A study in 2006 indicated that a high level of uric acid could increase the risk of ischemic stroke, even among patients with diabetes . However, this result contradicted almost all interventional studies, which showed that uric acid has a beneficial role in ischemic stroke. For instance, Amaro et al. used recombinant tissue plasminogen activator (rt-PA) to treat ischemic stroke and found that simultaneously adding uric acid for stroke treatment achieved good results; uric acid could reduce the peroxidation of lipids, and it prevented the level of uric acid from declining in the early acute period. The uric acid level in stroke patients treated only by rt-PA experienced the most significant decline in the 6 or 7 hours after stroke onset; uric acid was consumed quickly and had more lipid peroxidation. Conversely, the uric acid level in stroke patients treated by rt-PA and 500 mg uric acid did not show an obvious decline in uric acid level, while stroke patients treated by rt-PA 1 g uric acid showed an increase in uric acid level and maintained this high level within 24 hours. Stroke patients who were given a larger dose of uric acid had lower lipid peroxidation. This proved uric acid's protective role and antioxidation in ischemic stroke . Despite having anti-oxidation solid function, the uric acid would be consumed quickly, and its antioxidative capacity would be less if ischemic stroke is severe. Uric acid's level and antioxidation capacity were negatively associated with the degree of damage to neurological function and cerebral infarction size. Supplementing uric acid may enhance its antioxidation capacity to confer better neuroprotective effects in ischemic stroke . The study by Zhang et al. also proved the protective effect of high uric acid levels on ischemic stroke and pointed out that an elevated uric acid on admission is positively associated with a better prognosis after discharge .
Previous clinical studies reported that the association between uric acid level and the risk of ischemic stroke was either a positive or negative relationship. That is because those studies tested uric acid levels mainly at the time of admission, with the uric acid levels of stroke patients tested only one or two times. The researchers were unaware of the changes in uric acid levels in the intermediate stage after stroke onset and the dynamic changes of uric acid level throughout the acute phase of stroke. Hong et al. researched the active detection of uric acid levels in the beginning, in 24 hours, in 48 hours, on the seventh day, and the fourteenth day in ischemic stroke patients (five times test) and found that uric acid levels declined in 48 hours and then gradually rose within 14 days after stroke onset, finally returning to the baseline level or above. The uric acid level was reflected in a U-shape change in ischemic stroke patients, and it fluctuated after acute ischemic stroke. There was a difference in the change of uric acid levels among ischemic stroke patients with or without vessel recanalisation. The correlation between the change of uric acid levels and the volume of cerebral infarction became more robust and the levels were higher in ischemic stroke patients who had vessel recanalisation . Brouns et al. studied uric acid levels at 24 h, 72 h, 7th day, after 1 month and 3 months, and found that uric acid levels significantly decreased within the first seven days and then rose up to return to the baseline level or above, and remained at this level to 3 months after ischemic stroke . Contrary to previous studies, the study by Seet et al. categorized uric acid levels in quartiles: less than 280 μmol/L, 280 to 340 μmol/L, 340 to 410 μmol/L and above 410 μmol/L. They found that ischemic stroke patients with uric acid levels in the fourth quartile (>410 μmol/L) or the first quartile (<280 μmol/L) had worse outcomes and prognosis and higher risk of ischemic stroke while those in the third quarter (340 to 410 μmol/L) had the lowest risk of ischemic stroke. A U-shaped relationship was observed between poor functional outcomes and uric acid levels in stroke patients. There were more patients with poor functional outcomes at both higher and lower uric acid levels, and the lowest incidence of poor outcomes for ischemic stroke was in the intermediate uric acid levels .
Subsequent studies paid more focus on the clinical outcome of ischemic stroke. The study by Chiquete et al. related to the association between uric acid levels and the result of ischemic stroke mainly focused on the prognosis and outcome of ischemic stroke with modified Rankin Scale (mRS) neurological function scores; it tested uric acid levels at admission and assessed neurological function with modified Rankin Scale scores in thirtieth day, third month, sixth month and twelfth month. Results indicated that low uric acid levels had a correlation with good short outcomes. Lower uric acid levels at admission were associated with better clinical outcomes on the thirtieth day after stroke onset compared with higher levels .
Besides studying the outcome of ischemic stroke, more researchers have paid attention to the gender difference in the uric acid levels and ischemic stroke. The study by Storhaug et al. pointed out that uric acid levels were associated with all-cause mortality in both women and men. An increase in serum uric acid levels per 87 μmol/L were associated with a 31% increased risk of ischemic stroke in men and an increased risk of all-cause mortality in both women and men, with a 16% and 11% risk of death in women and men respectively . The study by Zhang et al. focused on the role of gender factors in the clinical prognosis and outcomes of ischemic stroke. Uric acid levels were measured on the day after admission to the hospital, and patients' prognosis was assessed using the mRS score in the third month after the onset of ischemic stroke. Patients were divided into four groups with uric acid levels >380 μmol/L, 316-380 μmol/L, 251-315 μmol/L, and ≤250 μmol/L. Patients with high uric acid levels >380 μmol/L or low uric acid levels ≤250 μmol/L on admission had a worse prognosis at 3 months after stroke, while those with moderate uric acid levels of 316-380 μmol/L had the lowest incidence of adverse functional outcome. This also differed significantly between men and women, with male patients having the worst prognosis for ischemic stroke at high levels of uric acid on admission and the best prognosis at intermediate levels. However, opposite results were obtained for female patients who had the best prognosis for ischemic stroke at high levels of uric acid on admission and the worst prognosis at intermediate levels. Therefore, uric acid may play a dual role after the onset of ischemic stroke, and the relationship between uric acid levels and stroke prognosis was not linear but rather an inverted U-shaped curve. Patients with low uric acid levels on admission tended to have a poor prognosis after stroke. However, high uric acid levels were also associated with a poor prognosis: either too high or too low uric acid levels on admission may be detrimental . Another study on gender differences showed that men had significantly higher uric acid levels than women. In male patients, higher uric acid levels were associated with a lower risk of adverse stroke outcomes, and good clinical prognosis was associated with higher uric acid levels. Higher uric acid levels as predictors of good prognosis had a protective effect on male ischemic stroke patients, but this association was not found in women. Taken together, a good prognosis in female stroke patients tends to be associated with higher uric acid levels, while an excellent clinical prognosis in male patients is at least not significantly associated with very high uric acid levels and may not even be associated with deficient uric acid levels. Male ischemic stroke patients tend to have relatively high uric acid levels, and they are usually in the middle range, which is more conducive to good functional outcomes .
In addition to the study for the clinical outcome and gender difference, some researchers have investigated the association between uric acid levels and its subtypes of ischemic stroke. High uric acid levels in ischemic stroke patients were positively associated with the risk of cardioembolic stroke, which is the subtype of ischemic stroke. Nonetheless, the correlation was more evident in women than men .
Researchers also observed the association between uric acid and ischemic stroke among patients with other medical conditions, such as hypertension or diabetes. A study with patients having hypertension showed that a significant increase in their uric acid was associated with a considerable increase in the risk of ischemic stroke, while a substantial decrease in uric acid levels was also associated with an increased risk of ischemic stroke, though the risk of stroke was not significant .
Although uric acid had been reported to have neuroprotective effects in previous studies, some studies during that period also showed that the uric acid levels of patients with poor prognosis were significantly lower than those with good prognosis. The study by Liu et al. indicated that lower uric acid is associated with poor short-term outcomes of ischemic stroke . Another multicentre study further explored their relationship and confirmed that uric acid levels were significantly lower in patients with poor prognoses than in their counterparts with good prognoses. However, their study indicated that a U-shaped relationship exists between uric acid levels and poor functional outcomes of ischemic stroke. Poor functional outcomes were distributed between 50.6% (first quartile) and 12.4% (third quartile) in quartiles of uric acid levels, and patients at intermediate uric acid levels had the lowest risk of poor functional outcomes .
Although findings for uric acid and ischemic stroke abound, the effect of uric acid levels on ischemic stroke remains disputable and inconsistent. Overall, reports of uric acid as a risk factor for ischemic stroke outweigh those reporting it as a protective factor. A study by Lai et al. showed a higher incidence of ischemic stroke in male patients as the uric acid level is increased. Indeed, the incidence of ischemic stroke in male patients with higher uric acid levels and older age between 45 and 65 years increased significantly, suggesting that high uric acid level was a risk factor for ischemic stroke . In terms of the pattern of the association between uric acid levels and ischemic stroke, some studies showed that their relationship was linear, while in others, it was either U-shaped or J-shaped. The study by Hu et al. indicated that uric acid levels in ischemic stroke patients were higher than those in the control group consisting of non-ischemic stroke patients. Both low and high levels of uric acid were independently associated with an increased risk of ischemic stroke. The risk of ischemic stroke was lowest in patients with intermediate uric acid levels compared with those higher in the bottom and upper quartiles. The results suggested a J-shaped relationship between uric acid levels and the risk of ischemic stroke . The study by Khalil et al. showed that elevated uric acid levels were significantly associated with the risk of ischemic stroke. In a further sex-specific analysis, elevated uric acid levels were significantly associated with an increased risk of ischemic stroke only in women but lost significance and association in men . The uric acid levels also affected the recurrence of ischemic stroke. Recurrent ischemic stroke was associated with higher uric acid levels, older age, and male gender. A nonlinear relationship was observed between uric acid level and the risk of stroke recurrence .
Uric acid is a standard indicator of renal function in clinical tests. As an important influencing factor for ischemic stroke, uric acid has great significance in the prevention and clinical treatment of ischemic stroke. Despite an increasing number of studies on the association between uric acid levels and ischemic stroke in recent years, the specific mechanism of the dual effect of uric acid on the pathogenesis of ischemic stroke remains unclear, such that the influence of uric acid levels on ischemic stroke is still inconsistent among researchers. Given the fluctuations in uric acid levels Therefore, more prospective experiments for testing uric acid levels repeatedly at other times in acute ischemic stroke patients are needed to observe the change of levels by simultaneously combining neurological function scores such as the National Institute of Health Stroke Scale (NIHSS) score and modified Rankin Scale (mRS) score. Additionally, cerebral imaging examinations at admission and discharge can be used to compare cerebral infarct size and neurological function under different uric acid levels. There is also a need for more focused studies on gender differences and the association in subtypes, not to mention stratification studies on their levels in ischemic stroke, together with appropriate animal experiments. Only then can we know the association between uric acid and ischemic stroke profoundly and comprehensively.
Each author contributed equally to the research and the article.
The authors have declared that no competing interests exist.
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