The Correlation between Traditional Chinese Medicine Constitution and Hyperuricemia and Gout: A Systematic Review and Meta-Analysis

Objective To investigate the correlation between the constitution of traditional Chinese medicine (TCM) and hyperuricemia (HUA) and gout. Method Databases including China National Knowledge Infrastructure (CNKI), WanFang Data, China Science and Technology Journal Database (VIP), China Biology Medicine Disc (CBMdisc), PubMed, The Cochrane Library, Web of Science, and Excerpta Medical Database (Embase) were searched to collect observational studies about TCM constitution in HUA and gout from inception to November 21, 2021. The distribution of TCM constitution types in HUA and gout patients was presented by proportion, while the correlation was presented by odds ratio (OR) and 95% CI. Meta-analysis was performed using StataCorp Stata (STATA) version 16.0 software. Results Twenty-one cross-sectional studies and 10 case-control studies involving 38028 samples were included, among which 27526 patients were diagnosed with HUA and 2048 patients with gout. Phlegm-dampness constitution (PDC), damp-heat constitution (DHC), and qi-deficiency constitution (QDC) are the most common types, accounting for 24% (20%–27%), 22% (16%–27%), and 15% (12%–18%), respectively, in HUA patients, while DHC, PDC, and blood stasis constitution (BSC) accounted for 28% (18%–39%), 23% (17%–29%), and 11% (8%–15%), respectively, in gout patients. PDC and DHC were the main constitution types in patients with HUA or gout in south China, east China, north China, southwest China, northwest China, and northeast China. There was no difference in the distribution of PDC and QDC in male or female patients with HUA, while males with DHC in HUA were more common than females. The proportion of PDC or DHC among HUA patients was 1.93 times and 2.14 times higher than that in the general population (OR and 95% CI: 1.93 (1.27, 2.93), 2.14 (1.47, 3.13)), while the proportions of PDC, DHC, and BSC were 3.59 times, 4.85 times, and 4.35 times higher than that of the general groups (OR and 95% CI: 3.59 (1.65, 7.80), 4.85 (1.62, 14.57), and 4.35(2.33, 8.11)). Conclusion PDC, DHC, and QDC are the main constitution types of patients with HUA, while PDC and QDC may be the risk factors for HUA. DHC, PDC, and BSC are the main constitution types of patients with gout, and they may be the risk factors for gout. In clinical and scientific research, more attention should be paid to the relationship between the above-mentioned TCM constitution in HUA or gout. Nevertheless, because the quality of the included observational studies is low, more prospective cohort studies related to TCM constitution and HUA or gout can be carried out to verify the causality between TCM constitution and HUA or gout.


Introduction
Hyperuricemia (HUA) refers to an abnormally high concentration of serum uric acid (SUA), typically defned as >420 μmol/L twice on a diferent day [1]. When the level of SUA is too high, uric acid crystals are deposited in the joints, causing infammation and tissue destruction, which is called gout. Te prevalence of HUA continues to increase and shows a trend in the world. As of 2019, the prevalence of HUA was up to 17.4% and 16.6% of the population in China [2] and Australia [3], respectively. Men are more likely to get HUA than women [3]. HUA is the main reason for gout, and elevated uric acid in the serum is associated with serious metabolic diseases and cardiovascular diseases such as chronic kidney disease, hyperlipidemia, type 2 diabetes, hypertension, heart diseases, and many other diseases [4,5]. HUA has become another common chronic metabolic disease after diabetes. Te prevention and cure of HUA and gout have also become major problems that remain to be solved at present.
Traditional Chinese medicine emphasizes preventative treatment, that is, identifying the disease before its onset or preventing it from developing into a pathological state. Te TCM constitution is an important entry point for preventative treatment in TCM [6]. Te TCM constitution is a stable and integrated intrinsic characteristic of our body in physiological functions, morphological structure, and psychological state, which is the outcome of both genetic and environmental factors. According to modular theory, the TCM constitution can be divided into 9 basic types: yangdefciency constitution (YADC), qi-defciency constitution (QDC), qi-stagnation constitution (QSC), phlegm-dampness constitution (PDC), yin-defciency constitution (YIDC), damp-heat constitution (DHC), blood stasis constitution (BSC), balance constitution (BC), and inherited special constitution (ISC). Among them, BC has a normal constitution, while the others have diferent characteristics in disease tendency, physiological and pathological states, and other aspects. Based on the TCM constitution, the systems of three-level prevention, the system of Screening-Warningintervention For Chronic Disease, and the system of Early Prediction-Early prevention-Early intervention have gradually become a precision medicine model with TCM theory.
With the recognition of the TCM constitution identifcation into the national public health service system and the China Mid-and Long-term Plan for Prevention and Treatment of Chronic Diseases (2017)(2018)(2019)(2020)(2021)(2022)(2023)(2024)(2025), studies on the correlation of the TCM constitution with HUA or gout have been carried out nationwide, but there has been no systematic review yet. Tus, a systematic review is needed to integrate the enormous clinical research, summarize the distribution of TCM constitution for HUA or gout treatments, and fnd out the exact correlation between TCM constitution and HUA or gout. Te results will come up with a perspective for risk population identifcation, classifed treatment, and prognosis prediction of HUA and gout in the clinical and scientifc felds.

Searching Strategy.
We searched CNKI, WanFang Data, VIP, and CBMdisc 4 Chinese databases with "hyperuricemia," "gout," and "constitution" as the subject terms and "Chinese medicine" as the full text or unlimited felds. We searched Pubmed, Web of Science, Cochrane Library, and Embase 4 databases with "hyperuricemia," "gout," "gouts," "constitution," and "Chinese medicine" as all felds. We reviewed literature published from the day the database was founded to November 21, 2021, and did not set language restrictions on literature. Te search strategies used in the above English databases are presented in Supplementary  Table S1

Outcomes.
Studies that recorded the distribution of basic types of TCM constitution in patients with HUA or gout or studies that recorded the comparative data between the proportions of TCM constitution in HUA or gout patients and the proportions of TCM constitution in the general population were included for further analysis.

Exclusion.
Te exclusion criteria were as follows: (1) studies that did not report the basic information of participants, such as age and gender. (2) Patients included in the studies had serious diseases that may afect the TCM constitution, such as diseases in the cardiovascular, cerebrovascular, liver, kidney, endocrine, or hematopoietic systems.
(3) Reports that used duplicate samples from the same population or reports that had defcient data were excluded.

Data Extraction and Quality Assessment.
Two researchers independently screened the literature and extracted the following information: (1) Te basic information of the studies, including the research topic, the author's name, the presentation time, etc. (2) Baseline information about the objects, including gender and average age. (3) Areas where studies were carried out. (4) Te time that studies started and ended. (5) Number of cases and types of the reported TCM constitution. (6) Key elements of the quality assessment. Te quality of the included crosssectional studies was assessed under 11 items, with the highest mark of 11 published by Te Agency For Health Care Research and Quality (AHRQ) [8]. As for the results of the AHRQ, 0-3 is considered low quality, 4-7 is considered medium quality, and 8-11 is considered high quality. Case-control studies were assessed by the Newcastle-Ottawa Scale (NOS), including 8 items with the highest mark of 9 [8]. Any mark in NOS over 6 is considered high quality.
An individual may be reported with 2 or more than 2 types of TCM constitution at the same time, so if an individual were reported to be with 2 or more than 2 types of TCM constitution at the same time, the individual would be counted in the number of every single type of TCM constitution. For example, if 15 individuals were reported DHC, and 10 individuals were reported QDC, and there were 10 individuals who reported both DHC and QDC, then 25 numbers of DHC and 20 numbers of QDC were included.

Statistical Analysis.
Statistical analysis was performed with the software STATA version 16.0. Te meta-analysis was conducted in two parts. Te frst part was to conduct a metaanalysis based on cross-sectional studies or case-control studies that reported numbers or events on proportions of diferent types of TCM constitution in patients with HUA or gout patients. Te efect values were calculated with a single rate and 95% confdence. Te results of the three TCM constitutions with the highest proportion among the nine types of TCM constitutions were presented in forest maps, and the results of the rest of the TCM constitutions were listed in a table.
Te second part was to conduct a meta-analysis based on case-control studies that reported comparative data between the distribution of TCM constitutions in HUA or gout patients and the distribution of TCM constitutions in the general population. Te efect values were calculated as odds ratio (OR) and 95% confdence interval (95% CI). Comparative results of the distribution of TCM constitutions between HUA or gout patients and general groups were all listed in another table.
Heterogeneity was assessed by I 2 statistics. If I 2 < 50% and P > 0.10, indicating relatively low heterogeneity, then a fxed efects model was chosen. If I 2 > 50% and P < 0.10, indicating relatively high heterogeneity, then a randomefects model was applied and subgroup analysis was applied according to regions and genders. Sensitivity analysis was used to assess the stability and reliability of the results of the meta-analysis. For the results of more than 10 studies included, funnel plots and Egger's test were applied to evaluate the potential publication bias. Te level of the metaanalysis was set to α � 0.05.

Literature Search.
Following the search strategy, the initial search yielded 623 studies, including 612 in Chinese and 11 in English. After duplicates were removed, 392 articles were retrieved for further assessment. And by title and abstract screening, followed by the above selection criteria, 39 studies were fnally included   (Figure 1), with 19 cross-sectional studies [10-17, 19-21, 23, 24, 26,27,29,30,32,33] on HUA, 9 cross-sectional studies about gout [18, 34-37, 39, 41, 43, 44], 6 case-control studies about HUA [9,22,25,28,31,45], and 4 case-control studies about gout [38,40,42,46], and 1 cross-control study [18] on both HUA and gout. Te fundamental information of the studies is shown in Table 1. Te number of people and comparative data of each type of TCM constitution can be found in Supplementary Tables S2 and S3. 3.2. Quality Assessment. All 29 cross-sectional studies had clear data sources and criteria for inclusion or exclusion, and the subjects were from the population. Tere was no missing data in these studies, and the response rates of the subjects were complete. Two studies [23,24] explained the reasons for excluding any patient. Tree studies [23,24] reported measures taken to control confounding factors. One study [37] had follow-up but did not report the results. But 3 [16,27,30] studies did not report the time that studies started and ended. Neither did these studies report whether the evaluators' subjective factors had any efect on the results, nor did they report measures taken to ensure the quality of the main outcome indicators. Te overall quality of the above 29 cross-sectional studies is low, and potential bias may exist. Te details of the quality assessment of 8 casecontrol studies are shown in Table 2.

Meta-Analysis of the Distribution of TCM Constitution in
Patients with HUA or Gout Twenty-six studies 45] containing 27526 patients with HUA reported the distribution of PDC. Because I 2 � 97.6% and P � 0.000, the random-efects model was used for analysis and the result showed that the proportion of PDC in patients with HUA was 24% (95% CI � (0.20, 0.27), Test of ES � 1: z � 13.97, P � 0.000).

QDC.
Twenty-six studies 45] containing 27526 patients with HUA reported the distribution of QDC. Because I 2 � 97.9% and P � 0.000, the random-efects model Evidence-Based Complementary and Alternative Medicine was used for analysis and the result showed that the proportion of DHC in patients with HUA was 15% (95% CI � (0.12, 0.18), Test of ES � 1: z � 11.34, P � 0.000).

Other Types of TCM Constitution.
Te proportions of other types of patients with HUA included in this review were BC, YADC, BSC, YIDC, QSC, and ISC, in descending order. And the proportions of other types of patients with gout included in this review were BSC, YADC, BC, BC, YIDC, QSC, and ISC, in descending order. Details are shown in Table 3.     Evidence-Based Complementary and Alternative Medicine
Tree studies [38,40,42] reported the distribution of TCM constitution in gout patients with gender specifed. Meta-analysis showed that the main types of TCM constitution in both male and female patients with gout were DHC, PDC, and BSC and showed no diference. [9, 20-22, 24, 25, 28, 33, 45] reported the distribution of types of TCM constitution in HUA and healthy groups. Meta-analysis showed that PDC and DHC might be risk factors for HUA, while BC and YADC might be protective factors. Four studies [38,40,42,46] reported the distribution of types of TCM constitution in gout and healthy groups. Meta-analysis showed that PDC, DHC, and BSC might be risk factors for gout, while QDC and BC might be protective factors for gout. Details are shown in Table 4.

Assessment of the Stability and Reliability of Meta-Analysis
Results. Sensitivity analysis was applied by evaluating the efect value of other studies after eliminating the results of every single study one by one. Sensitivity analysis showed 5 studies [10,11,17,20,26] had an impact on the stability of the proportion of PDC in patients with HUA and 6 studies [10,11,17,20,24,27] had an impact on the stability of the proportion of DHC in patients with HUA. One study [11] infuenced the stability of the proportion of QDC in HUA groups. One study [10,11] had an infuence on the proportion of DHC in patients with gout; 1 study [34] had an impact on the proportion of PDC in gout groups; and 1 study [18] infuenced the proportion of BSC in gout groups. Details are shown in Supplementary Figure S1.
Sensitivity analysis showed that the main types of TCM constitution in patients with HUA or gout did not change, and the results of the comparison between HUA or gout groups and healthy groups did not change either.

Analysis of Types of the TCM Constitution in HUA or Gout
Population. Te proportions of PDC and DHC in HUA or gout populations in this review were signifcantly higher than that of the Chinese healthy population, compared to a study in 2009 [47], in which the proportions of PDC and DHC were 7.32% and 9.08%, respectively. Te proportion of BSC in the gout population was 8.10%, which was higher than that of the healthy population, while there was no diference in the QDC of the HUA groups compared with the 13.42% of the healthy population. Te respective proportions of PDC and DHC in the HUA population were 1.93 times and 2.14 times higher than that of the healthy population, while the proportions of BC and YADC were 0.58 and 0.49 in the healthy population. Te proportions of PDC, DHC, and BSC in the gout population were 3.59 times, 4.85 times, and 4.35 times that of the healthy population, while the proportions of BC and QDC were 0.13 and 0.45 of the healthy groups. All the above results were statistically signifcant, which suggests that PDC, DHC, and QDC are the main types of TCM constitution in the HUA population, and DHC, PDC, and BSC are the main types of TCM constitution in the gout population. Among these, PDC and DHC may be the risk factors for HUA, and PDC, DHC, and BSC may be the risk factors for gout.
Te distributions of TCM constitution types are diferent in diferent regions [47]. Compared with a large sample cross-sectional study of 108015 samples, YDC (19.3%), QDC (14.1%), and DHC (9.4%) are the three TCM constitutions with the highest proportions in South China, while YDC (23.2%), QDC (12.9%), and DHC (9.2%) are the most three TCM constitutions in East China [48]. In our study, according to the results of subgroup analysis in diferent  Evidence-Based Complementary and Alternative Medicine regions, both PDC and DHC were the main TCM constitution types in HUA or gout populations in diferent regions, which confrms that PDC and DHC are closely related to HUA or gout. In terms of the distribution by gender, there was no signifcant diference in the distribution of DHC, PDC, and BSC in male or female populations with gout. Tis may be because the pathophysiological mechanism of gout is not associated with gender. As for HUA, PDC, and QDC, there was no diference in the distribution of male and female populations, while men with DHC were much more numerous than women with DHC. Tis may be because men have an overall higher basal metabolism than women, and drinking alcohol is more common in men than in women [49], while alcohol use is positively correlated with PDC and DHC [50].

Te Relationship between PDC, DHC, and HUA.
Increased production of uric acid and decreased excretion of uric acid are the main reasons underlying the pathology of HUA. Glutamine is one of the most important precursor substances in the pathway of purine production and determines the rate of uric acid production. A study [51] on the metabolomics of the population with DHC found that the levels of glutamine increased signifcantly in these people. DHC may promote the synthesis of uric acid through the pathway of purine production. About 2/3 of uric acid is excreted through the kidneys, and the remaining 1/3 is excreted through extrarenal pathways such as the intestine and biliary tract. In recent years, the excretion of uric acid through the intestine has attracted much attention. DHC is related to intestinal microbes and blood or saliva metabolites. A study [52] found that the abundance of probiotics was decreased in the intestinal fora of the population with DHC, while the abundance of conditional pathogenic bacteria was increased. Besides, the basal metabolic rate and daily intake of people with DHC were signifcantly reduced. Te imbalance of intestinal microecology is one of the metabolic characteristics of DHC [53]. PDC has the overall characteristics of metabolic disorders, with pathological characteristics such as abnormal distribution of body fat, lipid metabolism disorders, high levels of insulin, and insulin resistance [54], and is related to a variety of metabolic-related diseases. Patients with HUA have abnormal metabolic pathways such as the metabolism of glucose, lipids, energy, and chronic low-grade infammation induced by changes in the structure of intestinal fora may cause metabolic disorders [55]. Besides, in the view of gut microbial, patients with PDC showed an increased abundance of Bacteroidetes and the prevotella (a conditioned pathogen) and decreased levels of Firmicutes/Bacteroidetes ratio, as well as the Faecalibacterium (a kind of probiotic) [56]. Furthermore, the changed gut microbes in patients with PDC were mainly associated with carbohydrate and amino acid metabolism, mineral absorption, lipopolysaccharide biosynthesis, primary bile acid biosynthesis, and so on. Te altered gut microbial composition and function correspond to the clinical fndings of HUA [57]. Terefore, the metabolic characteristics of people with PDC or DHC may be the reasons underlying the pathology of HUA.
More importantly, early intervention based on the TCM constitution shows an efect on HUA and gout. For example, compared with potassium sodium hydrogen citrate (Uralyt-U), a Traditional Chinese Medicine prescription that aimed at regulating phlegm-damp displayed a better curative efect on patients with PDC in urinary acid calculus [58]. After diet guidance, lifestyle adjustment, and other interventions according to the TCM constitution, patients with HUA developed a decreased number of gout attacks compared with those without TCM constitution intervention [59]. Tese studies confrmed the efciency of intervention based on the TCM constitution in HUA and gout.

Limitations of the Review.
Te proportions of the distribution of diferent TCM constitution types in HUA or gout populations were of high heterogeneity, which was related to regions, research objects, diagnostic criteria, and other confounding factors. Te TCM constitution is different depending on the region, gender, and other factors, which is the same as reported in the study by Wang et al. [48]. Sensitivity analysis showed that the results were consistent, while a few studies were not in the overall confdence interval. We carefully analysed these studies but could not fnd out the reason that might infuence the reliability of the data. Studies on HUA or gout were mainly reported in South China, and there was only one study reported in each of North China, Northeast China, and Northwest China. Te fndings in these 3 regions needed to be verifed by more samples. Only a small number of cross-sectional studies or case-control studies met the cross-sectional study evaluation criteria of the AHRQ or the standards of the NOS scale. Te overall quality of the included observational studies is low.

Conclusion
Te meta-analysis of 38028 subjects fnds that PDC, DHC, and QDC are the main TCM constitution types in patients with HUA, among which PDC and DHC are the risk factors for HUA, and DHC, PDC, and BSC are the main types of TCM constitution for patients with gout and are the risk factors for gout. While BC and YADC are the protective factors for HUA, BC, and QDC are the protective factors for gout. In the clinical feld, early intervention and treatment can be applied to HUA or gout according to the TCM constitution. For scientifc research, it is recommended that relevant scientifc research be carried out in multiple centers to obtain reliable results. Besides, multicrossed techniques can be used to explore the specifc correlation between TCM constitution and HUA or gout. Due to the lack of conclusive evidence on TCM constitution and disease occurrence, more prospective cohort studies related to TCM constitution and HUA or gout can be carried out to verify the causality between TCM constitution and HUA or gout.

Data Availability
Te datasets generated during and/or analysed during the current study are available from the corresponding author upon reasonable request.