U-shaped or J-shaped association of hsCRP with SUA levels


Experimental and epidemiological studies have demonstrated that hyperuricemia participates in the development of metabolic and cardiovascular diseases by inducing inflammation.1.2 In turn, however, the changing pattern of serum uric acid (SUA) levels in the inflammatory environment reported in the available literature is still inconsistent. Several studies had reported that high-sensitivity C-reactive protein (hsCRP), a general marker of systemic inflammation, was positively associated with elevated levels of SUA.3 On the contrary, a significant decrease in SUA levels has also been observed during acute gout and some other inflammatory arthritis.4 Thus, we propose a hypothesis that there may be a nonlinear relationship between CRP and SUA.

In order to comprehensively assess the association of hsCRP with SUA levels, a combined cross-sectional and longitudinal study design was used. Cross-sectional and longitudinal clinical data were extracted from our routine health examination database (2013-2021). Inclusion criteria were people who had complete anthropometric, biochemical, and hsCRP data. Exclusion criteria included the acute phase of infectious disease, autoimmune disease, and the use of UA-lowering drugs and immunomodulators. The use of these data and the study protocols were approved by the ethics committee of Punan Hospital of Pudong New District.

Height, weight, waist circumference (WC) and hip circumference were measured by well-trained nurses. Venous blood samples were collected in the morning on an empty stomach. Fasting blood glucose (FPG), SUA and lipid parameters were measured by a biochemical autoanalyzer (Hitachi 7100). Plasma hsCRP was measured using particle-assisted immunonephelometry on a biochemical autoanalyzer (Hitachi 7100). Body mass index (BMI) was calculated by dividing weight by the square of height; hyperuricemia was defined as SUA ≥ 420 μmol/L.

Natural logarithmic transformation of hsCRP was performed to normalize its distribution. A smooth curve fit was used to visualize associations of hsCRP with SUA levels. Logistic regression (adjusting for age, sex, smoking, alcohol, BMI, waist circumference, FPG and lipid parameters) and Cox proportional hazards models (adjusting for based on baseline age, sex, smoking, alcohol, BMI, WC, FPG, lipid parameters and tracking time) with cubic spline functions were performed to examine the association of hsCRP with hyperuricemia.

A total of 29,926 adults were enrolled in the cross-sectional analysis, with a mean age of 46.5 years and 37% being female. Their mean SUA and hsCRP concentrations were 348.8 μmol/L and 1.68 mg/L, respectively. Another 7178 adults were included in the longitudinal analyses. Their initial average age was 48.0 years and 33.8% were women. The average observation period was 4.1 (1–7) years. Their mean baseline SUA and hsCRP concentrations were 357.9 μmol/L and 1.95 mg/L, respectively.

As shown in Figure 1, the fully fitted smooth curve fit exhibited a nonlinear association of hsCRP with SUA and hyperuricemia. It can be seen intuitively that when the Ln (hsCRP) was less than 1.5 (hsCRP

Figure 1 Cross section (A and B) and longitudinal (VS and D) association of hsCRP with SUA and hyperuricemia.

Abbreviations: SUA, serum uric acid; hsCRP, high sensitivity C-reactive protein.

DU is not only a pro-inflammatory agent, but also an antioxidant, which accounts for about 50% of the antioxidant capacity present in human biological fluids. Due to the protective effect of UA, theoretically, chronic low-grade subclinical inflammation can lead to an adaptive increase in UAS levels. This may explain the rising part of the fitted curve (hsCRP

When hsCRP continued to increase (>4.5 mg/L), we found that SUA levels or the risk of hyperuricaemia began to decline. This trend of changing SUA levels can also find good examples in clinical practice. For example, serum AU levels typically decrease during gout flares.4 In the situation of acute systemic inflammatory response induced by elective knee or hip surgery, a decrease in SUA concentrations has been observed.5 Conversely, when systemic inflammation was suppressed, an increase in SUA levels in patients with systemic autoimmune rheumatic diseases was also observed.6

There are several possible explanations for the decrease in SUA levels in higher inflammatory states. First, increased UA excretion in high-grade inflammation may explain the decrease in UAS levels. Second, the neutralizing effect of DU on free radicals and other oxidative stressors can consume some of the DU. DU can be non-enzymatically oxidized to allantoin by ROS despite the absence of uricase.seven Higher levels of allantoin seen in people with active rheumatoid arthritis and gout flares are good evidence of the above process.

Briefly, we confirmed the U-shaped or inverted J-shaped association of hsCRP with SUA levels among the “apparently healthy” population, both cross-sectionally and longitudinally. Their nonlinear relationship may not only help us better understand some interesting clinical phenomena, but also the etiology of hyperuricemia.

Data Sharing Statement

Datasets used and/or analyzed in this study are available from the corresponding author upon reasonable request.

Ethical approval and consent to participate

The research protocol was approved by the ethics committee or review committee of Punan Hospital of Pudong New District.

Consent to publication

All authors agree to publish this work.

Thanks

We would like to thank the colleagues at the Center for Health Management, whose long-term work has accumulated a great deal of clinical data for us.

Author’s contributions

All authors made significant contributions to the work reported, whether in conception, study design, execution, data acquisition, analysis and interpretation, or all of these areas; participated in writing, editing or critically reviewing the article; gave final approval to the version to be published; have agreed on the journal to which the article has been submitted; and agree to be responsible for all aspects of the job.

Funding

This study was supported in part by Shanghai Pudong Health Bureau’s Outstanding Leader Training Program (PWRI2018-02), People’s Liberation Army Special Health Care Scientific Research Project (14BJZ31 ) and the general project of Hangzhou Aviation Sanatorium for China Special Service. Air Force (20TLMS004).

Disclosure

The authors report no conflict of interest.

The references

1. Joosten LAB, Crisan TO, Bjornstad P, Johnson RJ. Asymptomatic hyperuricaemia: a silent activator of the innate immune system. Nat Rev Rheumatol. 2020;16(2):75–86. doi:10.1038/s41584-019-0334-3

2. Kocak MZ, Aktas G, Erkus E, Sincer I, Atak B, Duman T. Serum uric acid to HDL cholesterol ratio is a strong predictor of metabolic syndrome in type 2 diabetes mellitus. Rev Assoc Med Bras. 2019;65(1):9–15. doi:10.1590/1806-9282.65.1.9

3. Dai HX, Zhao ZY, Xia Y, Wu QJ, Zhao YH. Higher levels of high-sensitivity C-reactive protein are positively associated with the incidence of hyperuricemia in the Chinese population: a report from the China Health and Retirement Longitudinal Study. Inflamm Mediators. 2020;2020:3854982. doi:10.1155/2020/3854982

4. Urano W, Yamanaka H, ​​Tsutani H, et al. The inflammatory process in the mechanism of decreased serum uric acid concentrations during acute gouty arthritis. J Rheumatol. 2002;29(9):1950–1953.

5. Waldron JL, Ashby HL, Razavi C, et al. The effect of systemic inflammatory response, as elicited by elective orthopedic surgery, on serum uric acid in patients without gout: a prospective study. Rheumatology. 2013;52(4):676–678. doi:10.1093/rheumatology/kes327

6. Pietsch DEW, Kubler P, Robinson PC. The effect of reducing systemic inflammation on serum urate. Rheumatology. 2020;59(10):3108–3109. doi:10.1093/rheumatology/keaa085

7. Kaur H, Halliwell B. Action of biologically relevant oxidant species on uric acid. Identification of uric acid oxidation products. Chem Biol Interact. 1990;73(2–3):235–247. doi:10.1016/0009-2797(90)90006-9

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