Journal Logo

Clinical Methods and Pathophysiology

Serum uric acid concentration is associated with hyperhomocysteinemia in hypertensive Chinese adults

Wang, Wen; Wang, Qian; Yang, Nan

Author Information
doi: 10.1097/MBP.0000000000000581
  • Free

Abstract

Introduction

Hypertension is one of the most prevalent chronic diseases in the world and especially in China. Researchers estimate that over a quarter (27.6%) of Chinese adults suffer from hypertension [1]. Homocysteine is a thiol-containing amino acid intermediate to methionine synthesis used in the transmethylation reaction [2], and hyperhomocysteinemia (HCY) is a medical condition characterized by an abnormally high level (above 15 μmol/L) of homocysteine in the blood [3]. Hyperhomocysteinemia is an independent risk factor for a variety of cardiovascular disease and its complications, such as heart attacks, strokes, dementia and Alzheimer, coronary artery diseases, preeclampsia, and diabetes [4]. Researchers believe that hyperhomocysteinemia damages endothelial cells, reduces the flexibility of vessels, and adversely affects the process of hemostasis [5].

In addition, hyperhomocysteinemia can enhance the adverse effects of risk factors such as hypertension, smoking, impaired glucose, and lipid and lipoprotein metabolism as well as promote the development of inflammation [4,6]. Hypertension and hyperhomocysteine often coexist because of the same risk factor, and this type of hypertension is called hyperhomocysteinemia hypertension. Hyperhomocysteine not only causes the occurrence of hypertension but also aggravates the development of hypertension and can even lead to the occurrence of cardiovascular and cerebrovascular diseases such as stroke.

This paper in particular examines the relationship between hyperhomocysteinemia hypertension and uric acid, which is the end product of purine metabolism. Elevated plasma levels of uric acid are usually the final result of almost three different mechanisms under genetic control and involve uric acid production, renal excretion, and gut absorption. Hyperuricemia is characterized by an abnormally elevated concentration of serum uric acid (SUA) as a direct result of endogenous overproduction or insufficient excretion in the body [7]. Numerous studies have shown that there is a complex relationship between SUA and hypertension and that it is an independent risk factor for hypertension. The results of two published meta-analysis studies showed that for every 1 mg/dL increase in SUA level, the overall risk of hypertension increased by 13 and 15% [8,9]. Additionally, some studies have shown that there is a significant correlation between hyperhomocysteinemia and SUA [10]. The study of Kim et al. [11] found that serum SUA was higher in subjects with hyperhomocysteinemia in an elderly population with cognitive impairment. However, little attention has been paid to the correlation between SUA levels and hyperhomocysteinemia in patients with hypertension, and the relationship between SUA level and hyperhomocysteinemia remains unclear. Our study investigates the association between SUA and hyperhomocysteinemia in patients with hypertension in order to provide an augmented theoretical basis for the clinical prevention and treatment of hyperhomocysteinemia hypertension.

Participants and methods

Participants

All 981 patients with essential hypertension in this study came from the Health Management Department of the Second Affiliated Hospital of Xi’an Jiaotong University. The study was conducted from 1 January 2020 to 30 December 2020 and included 649 males and 332 females aged 25 to 90 years old with an average age of 55 ± 9.66. The patients were divided into two groups according to whether their hypertension was complicated with hyperhomocysteine: the hypertension combined with hyperhomocysteine (hyperhomocysteinemia hypertension) group, 453 cases, including 364 males and 89 females with an average age of 55.11 ± 10.23, and the hypertension without hyperhomocysteinemia (ordinary hypertension), 528 cases, including 285 males and 243 females with an average age of 54.9 ± 9.13.

Diagnostic criteria

The 2020 International Society of Hypertension Global Hypertension Practice Guideline [12], defines essential hypertension as, in the absence of antihypertensive drugs, systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg. This definition excludes secondary hypertension caused by drugs, kidney disease, or other means. Hyperhomocysteinemia is defined as fasting plasma levels of homocysteine above 15 μmol/L [13].

Exclusion criteria

We excluded patients who met any of the following criteria had secondary hypertension; had hypertension associated with some stressful situation, such as acute complications, infection, recent surgery, or trauma; had hemodialysis; were pregnant or lactating; had used drugs that affect the metabolism of uric acid 1 month before the physical examination including allopurinol, fibulin, benzbromarone, probenecid, sodium bicarbonate, immunosuppressants, diuretics, and antihypertensive drugs that contain diuretics; had taken supplements that affect HCY levels 1 month before the physical examination, including folic acid, vitamin B12, vitamin B6, and vitamin B2.

Methods

We recorded the gender, age, height, weight, smoking status, history of coronary heart disease (CHD), and history of diabetes for all enrolled patients. We also calculated their BMI as weight (kilograms) divided by height (meters) squared. We defined smoking status as current if a patient had smoked one cigarette per day for at least half a year. We measured patients’ resting blood pressures in the morning after 30 minutes of rest. Patients remained in a sitting position, while this was done, keeping their right arms the same level as their hearts. Using a mercury sphygmomanometer with a suitable cuff for measurement, we measured three times with 1-minute intervals between each time and took the average value of the last two measurements, Finally, we also recorded patients’ fasting SUA, serum total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), serum creatinine (SCr), and homocysteine, which were detected by a Roche Cobas C501 automatic biochemical analyzer.

Statistical analysis

All analysis was performed using SPSS 26.0 software. Data are presented as frequencies (percentages) for enumeration data and means ± SD for measurement data. We analyze the measurement data by t-test and the comparison among groups of enumeration data by χ2 test. Binary logistic regression analysis is used to assess the associations between the risk of hyperhomocysteinemia in patients with hypertension and their SUA concentration. We conduct three models of binary logistic regression analysis under different confounding factors, In the first (model 1), confounding factors are not adjusted. In the second (model 2), we include those variables with statistically significant (defined as P < 0.05) differences in univariate analysis (including gender, age, BMI, SCr, total cholesterol, history of diabetes, and history of smoking). In the third model (model 3), we include variables (including gender, age, BMI, SCr, total cholesterol, SBP, DBP, LDL-C, history of diabetes, and history of smoking) that are not statistically significant in univariate analysis but are considered clinically to be closely related to SUA. Although we find no statistical difference in age, we do find that age as a confounding factor has a great influence on SUA, so we include in the analysis in model 2 and model 3. The Q1 group in each model was used as reference.

Results

We find significant differences in gender distribution, SUA, BMI, SCr, total cholesterol, and DBP in the two study groups, those with hyperhomocysteinemia and those without (P < 0.05), and there were more men in the hyperhomocysteinemia hypertension group. In addition, our statistical analysis shows that there were more diabetic patients in the ordinary hypertension group and more smokers in the hyperhomocysteinemia hypertension group (P < 0.05). However, we find no significant difference in age, triglycerides, LDL-C, SBP, or history of CHD between the two groups (P > 0.05) (Table 1).

Table 1 - Baseline characteristics of the study participants
Total (n = 981) Ordinary hypertension group (n = 528, 53.82%) Hhcy hypertension group (n = 453, 46.18%) P value
Age (years) 55.00 ± 9.66 54.90 ± 9.13 55.11 ± 10.23 0.869
Gender
 Male 649 285 364 < 0.05
 Female 332 243 89
Diabetes 40 28 12 < 0.05
Nondiabetes 941 500 441
Smoking 463 200 263 < 0.05
Nonsmoking 518 328 190
CHD 93 51 42 0.836
Non-CHD 888 477 411
BMI (kg/m2) 26.08 ± 3.15 25.68 ± 3.01 26.39 ± 3.26 < 0.05
SBP (mmHg) 153.19 ± 11.16 152.60 ± 10.49 153.90 ± 11.86 < 0.05
DBP (mmHg) 99.10 ± 6.72 98.46 ± 6.41 99.82 ± 6.99 < 0.05
SUA (μmol/L) 326.1 ± 83.05 306.4 ± 77.88 348.3 ± 83.20 < 0.05
SCr (μmol/L) 72.70 ± 29.38 67.19 ± 13.93 78.93 ± 39.37 < 0.05
TG (mmol/L) 1.92 ± 1.59 1.91 ± 1.75 1.93 ± 1.39 0.493
TC (mmol/L) 4.65 ± 0.89 4.69 ± 0.91 4.60 ± 0.87 < 0.05
LDL-C (mmol/L) 2.81 ± 0.75 2.82 ± 0.76 2.80 ± 0.74 0.108
CHD, coronary heart disease; DBP, diastolic blood pressure; Hhcy, hyperhomocysteinemia; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; SCr, serum creatinine; SUA, serum uric acid; TC, total cholesterol; TG, triglyceride.

From our logistic regression analysis results of SUA levels and hyperhomocysteinemia risk in patients with hypertension we see that SUA levels ranged from 126 to 599 μmol/L among all participants. The percentage of hyperhomocysteinemia prevalence was 26.91% for subjects in the first SUA quartile (≤268 μmol/L), 45.31% in the second SUA quartile (269–322 μmol/L), 47.01% in the third SUA quartile (323–378 μmol/L), and 65.02% in the fourth SUA quartile (≥379 μmol/L). We find significant differences among the four groups (χ2 = 72.3, P < 0.01). In addition, our logistic regression analysis shows that the risk of hyperhomocysteinemia increased with an increase in SUA levels and that the difference is statistically significant (P < 0.05). After adjusting for related confounding factors, our results show that the prevalence of hyperhomocysteinemia in Q4 group was significantly higher than that in group Q1 (odds ratio = 3.00, 95% confidence interval, 1.83–4.93) (Table 2).

Table 2 - Logistic regression analysis of serum uric acid levels and risk of hyperhomocysteinemia in patients with hypertension
Group OR 95% CI P value
Model 1 Q1 1 ND
Q2 2.25 1.54–3.28 < 0.05
Q3 2.50 1.72–3.65 < 0.05
Q4 5.05 3.44–7.42 < 0.05
Model 2 Q1 1 ND
Q2 1.27 0.85–1.89 0.246
Q3 1.57 1.02–2.42 < 0.05
Q4 2.96 1.81–4.84 < 0.05
Model 3 Q1 1 ND
Q2 1.27 0.85–1.89 0.247
Q3 1.61 1.04–2.49 < 0.05
Q4 3.00 1.83–4.93 < 0.05
Taking Q1 group as a reference. Model 1: uncorrected influencing factors; Model 2: adjusted for gender, age, BMI, SCr, TC, history of smoking, and diabetes; and Model 3: adjusted for gender, age, BMI, SCr, SBP, DBP, TC, LDL-C, history of smoking, and diabetes.
CI, confidence interval; DBP, systolic blood pressure; LDL-C, low-density lipoprotein cholesterol; ND, no data; SBP, systolic blood pressure; SCr, serum creatinine; TC, total cholesterol.

Conclusion

Homocysteine is a toxic, nonessential, sulphur-containing, nonproteinogenic amino acids in humans [13]. Usually, the concentration of homocysteine ranges from 5 to 10 μmol/L in human plasma but does not exceed 15 μmol/L. Elevation of the plasma levels of homocysteine above 15 μmol/L is defined as hyperhomocysteinemia [14]. Several studies have shown that homocysteine is a risk factor for hypertension [4,6]. Moreover, homocysteine can mediate the formation of hypertension by several different mechanisms, such as its adverse effects on vascular endothelium and smooth muscle cells with resultant alterations in subclinical arterial structure and function and promotion of inflammation [5]. Strikingly, research has shown that the risk of cardiovascular events in patients with hyperhomocysteine hypertension is 25 to 30 fold higher than those without hypertension [15]. Therefore, we need to pay great attention to the treatment of hypertension combined with hyperhomocysteinemia.

According to recent research SUA is considered to be an independent factor in the development of a wide variety of vascular disorders such as hypertension [16], metabolic syndrome [17,18], coronary artery disease, diabetes [19], cerebrovascular disease [20,21], CKD [22], and other CVDs. Studies have also shown that there is a certain correlation between SUA and hyperhomocysteinemia. Cohen et al. [10] found a significant positive correlation between hyperhomocysteinemia and SUA. The study by Kim et al. [11] also found that the serum SUA was higher in subjects with hyperhomocysteinemia in an elderly population with cognitive impairment[11]. However, for patients with hypertension, there are few studies on the correlation between SUA and homocysteine.

Our study finds that there were more males and smokers in the hyperhomocysteinemia hypertension group and more diabetic patients in the ordinary hypertension group (P < 0.05). This may be due to the fact that there are too few patients with diabetes in our sample, which leads to a certain bias in the statistical results. We think that further analysis will require a larger sample size. Our analysis also shows that the levels of SUA, BMI, DBP, and SCr were significantly higher than those in the group of hypertension without hyperhomocysteinemia. We find no statistically significant differences in age, SBP, triglycerides, LDL-C, and history of CHD between the two groups.

Interestingly, we find that total cholesterol in patients with hyperhomocysteinemia was lower than that in patients without hyperhomocysteinemia. However, this could be because the patients had received treatment to control blood pressure and lipids before being included in the study. In addition, our logistic regression analysis shows that levels of SUA in patients with hypertension with hyperhomocysteinemia were significantly higher than those in patients without hyperhomocysteinemia, and the risk of hyperhomocysteinemia gradually increased with an increase in SUA. After adjusting for related factors, we find that SUA levels are still an independent risk factor for hyperhomocysteinemia in patients with hypertension. This suggests that patients with hypertension complicated with hyperhomocysteinemia may benefit from close monitoring of SUA levels in addition to treatment of hypertension, homocysteine, and lipid regulation.

At the same time, we found stress management can effectively reduce blood uric acid levels.As studies have shown chronic stress is closely linked to the metabolic syndrome, diabetes, and hyperuricemia [23], and other studies have also suggested that the involvement of stress states, such as shift work, may also contribute to the development of hyperuricemia [24,25]. Therefore, for patients with hyperuricemia, we should also pay attention to their life pressure and psychological stress, and conduct psychological interventions for them to more effectively reduce blood uric acid levels and further improve the prognosis of patients with H-type hypertension.

However, our study has some limitations. First, this study was a cross-sectional survey, and a large-sample prospective study may be needed to explore the relationship between SUA and hyperhomocysteinemia further. Second, we did not check the patient’s medication history in detail, which may have a potential impact on the level of SUA and homocysteine. Nevertheless, our study is still novel in that we find a positive correlation between SUA and hyperhomocysteinemia in patients with hypertension.

Acknowledgements

We acknowledge Qian Wang and Nan Yang for providing statistical support. And we thank AiMi Academic Services (www.aimieditor.com) for the English language editing and review services.

Conflicts of interest

There are no conflicts of interest.

References

1. Wei J., Mi Y., Li Y., et al. Factors associated with awareness, treatment and control of hypertension among 3579 hypertensive adults in China: data from the China Health and Nutrition Survey. BMC Public Health. 2021; 21:423.
2. Joshi MB, Baipadithaya G, Balakrishnan A, Hegde M, Vohra M, Ahamed R, et al. Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps. Sci Rep. 2016; 6:36362.
3. Guo H, Chi J, Xing Y, Wang P. Influence of folic acid on plasma homocysteine levels & arterial endothelial function in patients with unstable angina. Indian J Med Res. 2009; 129:279–284.
4. Ganguly P, Alam S. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015; 14:1–10.
5. Zhang S, Bai YY, Luo LM, Xiao WK, Wu HM, Ye P. Association between serum homocysteine and arterial stiffness in elderly: a community-based study. J Geriatr Cardiol. 2014; 11:32–38.
6. Baszczuk A, Kopczyński Z. Hyperhomocysteinemia in patients with cardiovascular disease. Postepy Hig Med Dosw. 2014; 68:579–589.
7. Borghi C, Domienik-Karowicz J, Tykarski A, Widecka K, Filipiak KJ, Jaguszewski MJ, et al. Expert consensus for the diagnosis and treatment of patient with hyperuricemia and high cardiovascular risk: 2021 update. Cardiol J. 2021; 28:1–14.
8. Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2011; 63:102–110.
9. Wang J, Qin T, Chen J, Li Y, Wang L, Huang H, Li J. Hyperuricemia and risk of incident hypertension: a systematic review and meta-analysis of observational studies. PLoS One. 2014; 9:e114259.
10. Cohen E, Levi A, Vecht-Lifshitz S E, et al. Assessment of a possible link between hyperhomocysteinemia and hyperuricemia. J Investig Med. 2015; 63:534.
11. Kim HJ, Sohn IW, Kim YS, Jun JB. The different relationship between homocysteine and uric acid levels with respect to the MTHFR C677T polymorphism according to gender in patients with cognitive impairment. Nutrients. 2020; 12:1147.
12. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, et al. 2020 International Society of Hypertension global hypertension practice guidelines. J Hypertens. 2020; 38:982–1004.
13. Fu Y, Wang X, Kong W. Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets. Br J Pharmacol. 2017; 175:1173–1189.
14. Ji C, Kaplowitz N. Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury. World J Gastroenterol. 2004; 10:1699–1708.
15. Wu W, Guan Y, Xu K, Fu XJ, Lei XF, Lei LJ, et al. Plasma homocysteine levels predict the risk of acute cerebral infarction in patients with carotid artery lesions. Mol Neurobiol. 2016; 53:2510–2517.
16. Cannon PJ, Stason WB, Demartini FE, Sommers SC, Laragh JH. Hyperuricemia in primary and renal hypertension. N Engl J Med. 1966; 275:457–464.
17. Ford ES, Li C, Cook S, Choi HK. Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents. Circulation. 2007; 115:2526–2532.
18. Puig JG, Martínez MA. Hyperuricemia, gout and the metabolic syndrome. Curr Opin Rheumatol. 2008; 20:187–191.
19. Dehghan A, van Hoek M, Sijbrands EJ, Hofman A, Witteman JC. High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care. 2008; 31:361–362.
20. Schretlen DJ, Inscore AB, Vannorsdall TD, Kraut M, Pearlson GD, Gordon B, Jinnah HA. Serum uric acid and brain ischemia in normal elderly adults. Neurology. 2007; 69:1418–1423.
21. Lehto S, Niskanen L, Rönnemaa T, Laakso M. Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke. 1998; 29:635–639.
22. Yu KH, Kuo CF, Luo SF, See LC, Chou IJ, Chang HC, Chiou MJ. Risk of end-stage renal disease associated with gout: a nationwide population study. Arthritis Res Ther. 2012; 14:R83–R83.
23. Yisireyili M, Hayashi M, Wu H, Uchida Y, Yamamoto K, Kikuchi R, et al. Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice. Sci Rep. 2017; 7:1266.
24. Uetani M, Suwazono Y, Kobayashi E, et al. A longitudinal study of the influence of shift work on serum uric acid levels in workers at a telecommunications company. Occup Med (Lond). 2006; 56:83–88.
25. Oh JS, Choi WJ, Lee MK, Han SW, Song SH, Yun JW, Han SH. The association between shift work and hyperuricemia in steelmaking male workers. Ann Occup Environ Med. 2014; 26:42.
Keywords:

hyperhomocysteinemia; hypertension; serum uric acid

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.