Correlation between the Severity of Metabolic Dysfunction-Associated Fatty Liver Disease and Serum Uric Acid to Serum Creatinine Ratio

Purpose As one of the most common chronic liver diseases, metabolic dysfunction-associated fatty liver disease (MAFLD) had different prognoses between mild and moderate-severe levels. Serum uric acid to serum creatinine ratio (sUA/Cr) can reflect the overall metabolic status of the body. To explore a convenient indicator to screen MAFLD and distinguish the severity of the disease, this study analyzed the correlation between sUA/Cr and the severity of MAFLD. Methods 228 participants were enrolled and divided into 2 groups, including mild MAFLD and non-MAFLD group and moderate-severe MAFLD group, based on liver/spleen computed tomography (CT) ratios. The correlations between sUA/Cr and the severity of MAFLD were analyzed by logistic and linear regression. Receiver operating characteristics (ROCs) analyzed the predictive ability of sUA/Cr for the severity of MAFLD expressed by the area under curve (AUC). Results The level of sUA/Cr was higher in themoderate-severe MAFLD group than mild MAFLD and non-MAFLD group (6.14 ± 1.55 vs. 5.51 ± 1.19, P = 0.008). After adjustment for confounders, the correlation analysis showed that patients with elevated sUA/Cr had a higher risk of moderate-severe MAFLD (OR: 1.350, P = 0.036). A higher sUA/Cr level was associated with lower liver CT values (β = −0.133, P = 0.039) and liver/spleen CT ratio (β = −0.154, P = 0.016). sUA/Cr had the ability to discriminate the severity of MAFLD (AUC: 0.623). Conclusion sUA/Cr was positively associated with the risk of moderate-severe MAFLD and had the predictive ability to discriminate the moderate-severe MAFLD from mild MAFLD and non-MAFLD. The sUA/Cr level was suggested to be monitored and controlled in the screening and treatment of MAFLD.


Introduction
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly named nonalcoholic fatty liver disease (NAFLD), has become one of the most common chronic liver diseases in the world [1]. It was reported to afect more than a third of the global population [2]. Mild MAFLD can be reversed through lifestyle intervention. However, moderate-severe MAFLD is predisposed to developing into steatohepatitis, cirrhosis, terminal liver failure, and hepatocellular carcinoma [3], and even associated with a higher risk of cardiovascular disease events [4]. Hence, it is signifcant to discriminate the severity of MAFLD and take measures timely to control the progression. As the diagnostic gold standard, the biopsy is invasive and hard to perform. Commonly, ultrasonography and computed tomography (CT) are used to classify the severity of MAFLD in clinical practice, while ultrasonography is inaccurate and CT has a risk of radiation exposure with a high cost [5]. Transient elastography (FibroScan) is a tool used to evaluate liver fatty infltration and fbrosis by measuring liver stifness but not available in routine physical examinations, especially in primary care [6]. Some anthropometric indexes used to diagnose MAFLD are with complex calculations and controversial diagnostic abilities [7]. Terefore, a noninvasive and convenient serum biomarker is required for the classifcation of the MAFLD severity.
Serum uric acid (sUA), the fnal product of purine metabolism, can refect the metabolic status of human beings. Te level of sUA has been proven to be associated with MAFLD in the US population [8]. In addition, renal function plays a key role in the excretion of UA via the kidney [9]. Serum creatinine (sCr), a chemical waste product of creatine, is afected by the number of muscles, meat intake, and kidney function [10]. sUA to sCr ratio (sUA/Cr) integrally represents the metabolic status excluding the infuence of renal function. A few studies suggested that sUA/Cr may be associated with MAFLD [11]. Te correlation between sUA/Cr and the severity of MAFLD still needs more research.
In clinical practices, since ultrasonography cannot reliably diagnose steatosis at <20%, mild MAFLD patients are frequently missed diagnosis or unreported, which results in mild MAFLD patients being blended with non-MAFLD people. In addition, mild and moderate-severe MAFLD had diferent prognoses. In order to be more in line with the real clinical situation, in this study, all the participants were divided into two groups, including mild MAFLD and non-MAFLD group, and moderate-severe MAFLD group, classifed by the severity of MAFLD based on liver/spleen CT ratios [12]. Te correlation analysis between sUA/Cr and the severity of MAFLD and the predictive ability of sUA/Cr for the severity of MAFLD were performed.

Study Design and Participants.
Tis is a retrospective case-control of Chinese participants recruited at the China-Japan Friendship Hospital from January 2021 to October 2021. All participants were divided into 2 groups, one mild MAFLD and non-MAFLD group and the other moderatesevere MAFLD group.
All study protocols and materials were reviewed and approved by the Clinical Research Ethics Committee of CJFH (2018-110-K79-1). Tis study was conducted in accordance with the Declaration of Helsinki. All participants signed informed consent forms before enrollment. (2) Imaging and laboratory data were completed and anthropometric indicators could be collected as required.

Exclusion
Criteria. Exclusion criteria are as follows: (a) missing important information (such as ultrasonography or CT results, height, and weight); (b) Cushing's syndrome, total parenteral nutrition, drugs (amiodarone, ammonium valproate, glucocorticoids, and methotrexate), etc., which can lead to fatty liver; (c) sufering from serious cardiovascular and cerebrovascular diseases, lung diseases, kidney diseases, and so on; (d) malignant tumors of the liver and other system; (e) pregnancy and lactation; (f ) medication history of antihyperuricemic agents.

Data Collection.
Te researcher administered a structured questionnaire to document specifed data on demographic, health-related behaviors, previous history, and medication history. Anthropometric indices were measured by an eligible physician, including weight, height, waist circumference (WC), and blood pressure (BP). Weight and height were measured in light indoor clothing without shoes and heavy clothes, using a calibrated measuring apparatus. WC was measured using an inelastic measuring tape at midway between the lowest rib and the iliac crest. Te BP was measured using an automatic electronic sphygmomanometer with the arm supported at the level of the heart. Te mean readings of three replicate measurements were recorded. Health examinations were performed in the morning after the examinees fasted overnight. Laboratory evaluation included sUA, sCr, aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), low-density lipoprotein cholesterol (LDL-C), highdensity lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG), total bilirubin (TBil), direct bilirubin (DBil), and fasting plasma glucose (FPG).

CT Scan Method and CT Value Measurement.
Images were obtained using a Philips 256-slice iCT scanner operated by an experienced CT examination technician. All subjects were scanned from the top of the diaphragm to the lower costal margin in the supine position after fasting overnight. Te scan began when the subjects hold their breath at the end of the exhalation. Te scan parameters were as follows: tube voltage, 120 kV; tube current, 250 mA; slice thickness and interval, 5 mm; feld of view (FOV), 40 cm × 40 cm; window level, 40 Hu; window width, 400 Hu.
Te measurement of CT value, which was designed referring to the research of Yu et al. [14], was as follows: three region-of-interest (ROI) in the liver and two ROIs in the spleen were selected at the level of porta hepatis to avoid blood vessels, bile ducts, and calcifcation. Each ROI was a circle of about 300 mm 2 . Te respective means of the 3 CT values of the liver and 2 CT values of the spleen were calculated as the liver and the spleen CT value. Te liver/spleen CT ratio, defned as liver CT value to spleen CT value, was calculated to refect the degree of steatosis, which determined the severity of MAFLD.
Moderate MAFLD was defned as MAFLD patients with the liver/spleen CT ratio ≥0.5 but <0.7.
Severe MAFLD was defned as MAFLD patients with the liver/spleen CT ratio <0.5.
Abdominal obesity was defned as WC ≥ 90 cm for male or ≥80 cm for female [17].

Statistical
Analysis. Data analysis was conducted using SPSS 26.0 and Medcalc 20.022 statistical software. Measurement data were expressed as mean ± standard deviation (x ± s) and analyzed by the Student's t test when approximately normally distributed. Continuous variables were shown as median (25th-75th percentiles) and analyzed by the Mann-Whitney U test as most variables were non-normally distributed. Counting data expressed as number (%) were analyzed by the chi-square test. Logistic regression was used to assess the correlation, expressed by odds ratios (ORs) with their 95% confdence intervals (CI). Linear trends were analyzed with linear regression. Areas under the curves (AUCs) with a 95% CI of receiver operating characteristic (ROC) were calculated to compare the predictive values of sUA/Cr for the level of MAFLD and determine the optimal cutof point and the Youden index with maximum concomitant sensitivity and specifcity. P < 0.05 was considered statistically signifcant.

Comparisons of Baseline and Clinical Characteristics.
A total of 228 subjects were included in this study. Te demographic and clinical data of mild MAFLD and non-MAFLD subjects (n � 175), and moderate-severe MAFLD patients (n � 53) are shown in Table 1. Compared with participants in mild MAFLD and non-MAFLD group, patients in the moderate-severe MAFLD group had higher BMI, ALT, AST, sUA, sUA/Cr, percentages of male and abnormal liver function, and lower liver CT values, liver/ spleen CT ratios (P all <0.05).

Linear Regression Analysis of Assessing the Relationship between sUA/Cr and Liver CT Values.
Te univariate analysis showed that sUA/Cr was negatively correlated with liver CT values (β � −0.194, P < 0.01) ( Table 2). Te multivariate analysis showed that sUA/Cr was negatively correlated with the level of MAFLD (β � −0.133, P < 0.05) after adjusting for sex, BMI, dyslipidemia, and abnormal liver function factors ( Table 2).

Linear Regression Analysis of Assessing the Relationship between sUA/Cr and Liver/Spleen CT Ratios.
Te univariate analysis showed that sUA/Cr was negatively correlated with liver/spleen CT ratios (β � −0.204, P < 0.01) ( Table 3). Te multivariate analysis showed that sUA/Cr was negatively correlated with liver/spleen CT ratios (β � −0.154, P < 0.05) after adjusting for sex, BMI, dyslipidemia, abnormal liver function, and drinking history factors (Table 3).

Discussion
Given the major signifcance of discriminating the severity of MAFLD for prognosis and the disadvantages of commonly recommended examination methods, this study analyzed the correlation between sUA/Cr and the severity of MAFLD.
MAFLD is the liver manifestation of abnormal metabolism. As an end product of purine metabolism, UA is mainly synthesized from adenine-and guanine-based purines by the enzyme xanthine oxidase [18], which plays a vital role in lipid metabolism [19]. Even though the sUA level was within the normal range, its elevated level was signifcantly associated with hyperlipemia and atherosis [20]. Ali et al. demonstrated that sUA was positively correlated with TG, TC, and LDL-C, and negatively with HDL-C [21]. A retrospective cohort study in the Japanese population revealed that in addition to the baseline sUA level, a higher sUA changing trajectory was positively associated with fatty liver disease (FLD) risk independently [22]. A meta-analysis conducted by Zhou and colleagues that included 9 observational studies also showed that the risk of FLD with a high sUA level was 1.92 times higher than that in patients with a low sUA level [23]. Te association between sUA and MAFLD may be due to the fact that sUA could interact with oxidants and induce the production of free radicals and oxidative stress [24], which are key factors in the development of FLD [25]. Terefore, sUA, as a pro-oxidant, may have a direct efect on FLD. Besides, sUA accelerated chronic infammatory processes by stimulating the production of proinfammatory mediators. In addition, insulin resistance (IR) was known as a risk factor for the development and progression of hepatic steatosis and metabolic syndrome (MetS) [26].
Te kidney could regulate hyperuricemia by modulating urinary uric acid excretion. A lower glomerular fltration rate elevates the level of sUA, and Cr is commonly used as an indicator of renal function. Compared with sUA, sUA/Cr is more reasonable to accurately refect the endogenous UA level. Kawamoto et al. indicated that sUA/Cr was the independent predictor of MetS [27]. In this study, both sUA levels and sUA/Cr were signifcantly higher in the moderate-severe MAFLD group than that in the mild MAFLD and non-MAFLD groups. Te severity of MAFLD was positively associated with increased sUA/Cr, even after adjustment for sex, BMI, dyslipidemia, and abnormal liver function. In line with our results, Han and Lee found MAFLD was related to sUA/Cr, and the amount of alcohol consumption and smoking infuenced the association [28]. Similarly, Liu et al. observed that the strength of association between sUA/Cr and MetS showed a linear dose-response relationship [29]. Ma et al. demonstrated that sUA/Cr was an independent risk factor of NAFLD in individuals with normal sUA levels and had a direct efect on NAFLD by mediation analysis [11].
In addition, this study found that sUA/Cr had the predictive ability to discriminate the severity of MAFLD. When sUA/Cr ≥ 6.268, the risk of moderate-severe MAFLD was signifcantly increased. In another Chinese study, sUA/  Figure 1: Te univariate and multivariate analysis. (a) Univariate odds ratios of metabolic dysfunction-associated fatty liver disease. (b) Multivariate odds ratios of metabolic dysfunction-associated fatty liver disease. Logistic regression analysis was used to assess the relationship between serum uric acid to serum creatinine ratio and moderate-severe metabolic dysfunction-associated fatty liver disease. ORs, odds ratios; BMI, body mass index; sUA/Cr, serum uric acid to serum creatinine ratio; MAFLD, metabolic dysfunction-associated fatty liver disease.
International Journal of Endocrinology the causal factor or the consequence. Further exploration of the causal efect of sUA/Cr on MAFLD will be needed. Secondly, MAFLD was diagnosed by CT and blood tests without biopsy, which is considered as the gold standard.
However, CT is still a noninvasive and efcient tool for the diagnosis of steatosis. Finally, the objects in this study were from the Chinese population, and the fndings may not be generalizable to other countries.

Conclusion
Te risk of moderate-severe MAFLD was positively associated with increased sUA/Cr, even after adjustment for sex, BMI, dyslipidemia, and abnormal liver function. Te level of sUA/Cr had the ability to discriminate the moderate-severe MAFLD from mild MAFLD and non-MAFLD. Although the UA is not included in the diagnostic standards of MAFLD, this study suggested that the sUA/Cr level should be monitored and controlled in the screening and treatment of MAFLD, which contributes to preventing the deterioration of the disease.

Data Availability
All data relevant to the study are included in the article. Data can be provided upon request to credible investigators on verifcation for patient confdentiality.

Consent
Informed consent was obtained from all individual participants included in the study.

Disclosure
Jing Liu and Hongye Peng are the authors who share the frst authorship.

Conflicts of Interest
Te authors declare that there are no conficts of interest. International Journal of Endocrinology 7