Association between Serum Bilirubin Concentration and Parkinson’s Disease: A Meta-Analysis
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1% to 2% of individuals over the age of 65. The disease is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies, leading to motor symptoms such as bradykinesia, static tremor, rigidity, and postural imbalance, as well as non-motor symptoms. Oxidative stress has been implicated in the pathogenesis of PD, with heme oxygenase (HO) playing a critical role in the oxidative regulation system. HO catalyzes the breakdown of heme into biliverdin, which is subsequently converted into bilirubin by biliverdin reductase. Bilirubin, traditionally considered a cytotoxic metabolite, has recently been recognized for its potent antioxidant properties. This meta-analysis aims to explore the relationship between serum bilirubin concentration and the risk of PD, providing insights into its potential role as a diagnostic and prognostic marker.
The meta-analysis was conducted following the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. A systematic literature search was performed across five databases—MEDLINE, PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials—to identify case-control studies published up to April 2020. The search strategy included keywords such as “bilirubin,” “Parkinson’s disease,” and “primary parkinsonism.” Studies were included if they met the following criteria: (1) case-control design, (2) PD diagnosis confirmed by a neurologist using the United Kingdom Parkinson’s Disease Society Brain Bank criteria, and (3) sufficient data on serum total bilirubin (TBIL) concentration in PD patients and healthy controls. Studies were excluded if they were not case-control studies, involved overlapping samples, lacked complete data, or included samples taken before PD diagnosis. Data extraction and quality assessment were performed independently by two reviewers, with discrepancies resolved by a third reviewer. The Newcastle-Ottawa Scale (NOS) was used to assess study quality, with a score ≥6 indicating high quality. Statistical analysis was conducted using Stata version 12.0, with the standard mean difference (SMD) and 95% confidence interval (CI) used as effect sizes. Heterogeneity was assessed using the Q test and I² statistics, with a random-effects model applied if significant heterogeneity was detected. Publication bias was evaluated using Egger’s test, and sensitivity analysis was performed to assess the stability of the results.
The initial search yielded 14,977 records, of which eight case-control studies involving 1,463 PD patients and 1,490 healthy controls were included in the meta-analysis. The studies primarily involved Asian and Caucasian populations. The meta-analysis revealed a significant association between serum TBIL concentration and PD, with PD patients exhibiting higher TBIL levels compared to healthy controls (SMD: 0.300, 95% CI: 0.050–0.549, P = 0.018). Similarly, serum direct bilirubin (DBIL) levels were significantly elevated in PD patients (SMD: 0.395, 95% CI: 0.102–0.688, P = 0.008). However, no significant relationship was found between serum indirect bilirubin and PD (SMD: −0.223, 95% CI: −0.952–0.505, P = 0.548). Subgroup analysis based on ethnicity indicated that the association between TBIL and PD was significant in the Caucasian population (SMD: 0.511, 95% CI: 0.324–0.698, P = 0.000) but not in the Asian population (SMD: 0.057, 95% CI: −0.286–0.399, P = 0.746). Subgroup analysis based on gender showed no significant differences in TBIL levels between male and female PD patients. Sensitivity analysis confirmed the stability of the results, and Egger’s test indicated no significant publication bias.
The findings of this meta-analysis suggest that elevated serum bilirubin levels may play a role in the pathogenesis of PD. Bilirubin, as the only endogenous lipid-soluble antioxidant in the human body, has been shown to exert neuroprotective effects by mitigating oxidative stress. The overexpression of heme oxygenase-1 (HO-1) in the central nervous system during the early stages of PD may contribute to increased bilirubin production, potentially serving as a compensatory mechanism to counteract oxidative damage. The significant association between TBIL and PD in the Caucasian population but not in the Asian population may be attributed to genetic and environmental differences, as well as variations in study design and sample selection. The lack of association between indirect bilirubin and PD may be due to the limited number of studies and small sample sizes available for analysis. Future research should focus on large-scale, prospective studies to further elucidate the role of bilirubin in PD and explore its potential as a biomarker for diagnosis and prognosis.
In conclusion, this meta-analysis provides evidence of a significant association between elevated serum bilirubin levels and PD, particularly in the Caucasian population. The findings highlight the potential role of bilirubin as a neuroprotective agent and a biomarker for PD. However, the high heterogeneity among studies and the limited number of studies on indirect bilirubin warrant caution in interpreting the results. Further research is needed to confirm these findings and explore the underlying mechanisms of bilirubin’s role in PD.
doi.org/10.1097/CM9.0000000000001300
Was this helpful?
0 / 0