For the first time, we found a independently U-shaped association between TBiL and PAD among hypertensive male subjects, and then revealed a turn point (LgTBiL = 1.08, TBiL = 12.02 µmol/L) by threshold effect analysis.
Several previous studies had examined the relationships between TBiL levels and PAD(17–19). Ozeki et al.(17)reported that serum bilirubin concentration was significantly negatively associated with PAD prevalence in 935 cardiology patients. Lan et al.(18)conducted a cross-section study, which included 543 participants with hypertension (mean age: 62.7 ± 12.4 years). The result showed that per 1 unit increment of TBiL was associated with 8.6% (OR, 0.914; 95% CI: 0.845–0.990) lower risk of PAD; besides, an independently negatively relationship between TBiL and PAD (OR,0.884; 95% CI: 0.792–0.985) was merely found in males but not in females. A cross-sectional examination from the National Health and Nutrition Examination Survey (1999 to 2004) analyzed 7075 adults with data available on the ankle brachial index, serum total bilirubin level, and PAD risk factors. The result showed that a 0.1 mg/dL increase in bilirubin level was associated with a 6% reduction in the odds of PAD (OR 0.94 [95% CI 0.90 to 0.98]), and this association is more influential in men compared with women(19). However, these studies did not discuss a nonlinear relationship between TBiL and PAD.
In the current study, some new insights were demonstrated in hypertensive males patients. Our in-depth study showed that the association between TBiL and PAD risk was not a simple linear association but a U-shaped curve, suggesting that low and high TBiL levels were associated with increased PAD risk. The reasons for these contradictory findings might be different total serum bilirubin levels, and the distribution of total serum bilirubin levels may vary depending on the race(26, 27), age(28), health status(29, 30), and sample size of the subjects. We conducted a cross-section study included 5,129 Chinese hypertensive males subjects, the mean age of our study participants was 63.86 ± 9.25 years, the median serum concentrations of TBiL was14.10 µmol/L (interquartile range 11.00 to 18.60 µmol/L); However, Ozeki et al.'s study(17) enrolled 935 Japanese cardiology patients ( median serum bilirubin: about 8.55 µmol/L), and Lan et al.'s study(18) analyzed 543 Chinese participants with hypertension, the mean serum bilirubin was 12.2 ± 5.6 µmol/L, respectively. At the same time, Perlstein et al.(19)conducted a cross-sectional examination that included 7075 various racial groups adults; the median total bilirubin level was 11.97 (interquartile range 8.55 to 13.68) µmol/L. Due to the small sample size of the above study and the relatively lower bilirubin levels. Thence, we speculate that the negative relationship might be part of the U-shaped curve in this study. Secondly, previous studies were carried out in patients with cardiology and hypertension, and the general people, while the current study conducted in participants with hypertension accompanied by hyper-homocysteinemia (HHcy). About 75% of hypertension patients in China have hyper-homocysteinemia simultaneously(31), HHcy was defined as Hcy level ≥ 10 µmol/L(32), TBiL may be heterogeneous for different diseases; the threshold point of injury is different in different diseases.
The current study found that the OR value of Model 1 has changed direction compared with the crude model. The differences in outcomes between the crude model and Model 1 in our study may be explained by the widespread influence of covariates, such as smoking, blood pressure, age, and BMI. Lu et al.(33) conducted a meta-analysis of the association between cigarette smoking and PAD. The result demonstrated that smoking increased risk of PAD. According to the 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery, the major risk factors for PAD are smoking, hypertension, diabetes, abnormal lipid metabolism, obesity, etc.(8). Because the effect of these covariates on PAD is too significant to cover up the effect of serum bilirubin on PAD, the independent effect of serum bilirubin on PAD is only reflected after adjusting it.
To our knowledge, TBiL is a potent endogenous antioxidant protecting cells from a 10 000-fold higher concentration of oxidants(34–36); Enhance, lower bilirubin levels could induce the oxidative stress and inflammation which are related to the pathogenesis and development of arteriosclerosis(37). However, the exact mechanisms of excessive TBiL levels with PAD remain unknown. One possible reason could account for the association between excessive TBiL and increased risk of PAD, which was that excessive TBiL such as dominant jaundice might indicate potential liver cell damage, such as hepatocellular or obstructive jaundice, which in turn causes elevated levels of transaminases and alkaline phosphatase(38), the increased levels of transaminase and alkaline phosphatase are associated with an increased risk of CVD(20, 39).
The potential limitations of our study should also be noted. First, we cannot draw any causal relationship between serum bilirubin and PAD from the data because this is a cross-sectional study. Second, the serum bilirubin was only assessed at the baseline in the present study; multiple tests may make the results more accurate. Lastly, this study was conducted in Chinese hypertension male participants, the generalizability of the findings to other populations remains to be determined.