Association between the uric acid to high density lipoprotein cholesterol ratio and alanine transaminase in Chinese short stature children and adolescents: a cross-sectional study

Abstract

Objective

This research aimed to investigate the relationship between the uric acid to high-density lipoprotein cholesterol ratio (UHR) and alanine aminotransferase (ALT) in children and adolescents with short stature.

Methods

In this cross-sectional analysis, the clinical data of 1510 children with height below − 2 SD who were evaluated at the Department of Endocrinology, Affiliated Hospital of Jining Medical University from March 1, 2013, to December 31, 2021, were selected. Anthropometric and biochemical indicators were measured.The relationship between UHR and ALT was analysed.

Results

The univariate analysis results showed that UHR was positively associated with ALT (β 0.43, P < 0.0001). Furthermore, after adjusting for possible confounding factors,a nonlinear relationship was detected between UHR and ALT through smooth curve fitting, and the inflection point of UHR was 10.93% after multivariate piecewise linear regression analysis. ALT increased with UHR elevation when the UHR was greater than 10.93% (β 0.69, 95% CI 0.39, 0.98; P < 0.0001). However, we did not observe a significant relationship when the UHR was less than 10.93% (P = 0.9229).

Conclusion

Our study demonstrated that in Chinese children and adolescents with short stature, UHR may be associated with the regulation of ALT levels, and this relationship merits further investigation.

Introduction

Short stature is defined as a height of less than − 2 standard deviations (SDs) compared to the mean height for the corresponding age and sex[1]. The most common reasons for short stature are growth hormone deficiency (GHD) and idiopathic short stature (ISS)[2]. Growth hormone (GH) is an anterior pituitary hormone, a key regulator of adipolysis that acts on the liver through the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis [3]. Animal experiments have shown that the loss of GH signalling in hepatocytes leads to steatosis and liver damage, promoting the development of metabolic-associated fatty liver disease (MAFLD)[4]. MAFLD is a new concept proposed by the International Expert Consensus Group in 2020, and similar to the previous term nonalcoholic fatty liver disease (NAFLD), MAFLD represents the liver manifestations of a multisystem disease. The change from the NAFLD to the MAFLD nomenclature calls on us to pay more attention to metabolic comorbidities such as obesity, overweight, and diabetes while also focusing on steatosis[5]. With the effective extension of the new definition of MAFLD in adults, it was introduced to children and adolescents in 2021[6]. The increasing global obesity in children and adolescents has prompted an increase in childhood MAFLD. MAFLD is now considered the most common cause of chronic liver disease in adults and children worldwide[7]. A large number of clinical studies suggest that childhood and adolescent GH deficiency are associated with an increased risk of MAFLD[8, 9]. By definition, ISS is defined as short stature in childhood with no known aetiology, and although there is no clear cause, some researchers have attempted to explain the underlying mechanism of impaired linear growth in children with ISS[10, 11]. The GH/IGF-1 axis plays an important role during the critical period of childhood growth and development. Some studies have found low IGF-1 levels in ISS children despite normal endogenous GH levels[12, 13]. A cross-sectional study in the US showed that reduced serum IGF-1 levels were associated with increased histological severity of MAFLD[14]. Recombinant human growth hormone (rhGH) therapy reduces the histological severity of MAFLD[15].

MAFLD is assessed in children and adults with serum alanine aminotransferase (ALT) and ultrasound screening, with liver biopsy for diagnosis. In clinical studies, the most commonly used predictor of childhood MAFLD is elevated ALT levels. The MAFLD Expert Committee has advocated the use of ALT as a screening test for children with MAFLD[16]. In the absence of any other liver injury, high ALT levels often reflect the presence of MAFLD[17]. Therefore, it is necessary to investigate ALT levels and their related factors in short stature children and adolescents.

Children and adolescents with short stature not only have height problems but also, more importantly, have abnormal metabolic function[18]. Existing studies have shown that children with short stature have higher odds of developing metabolic syndrome compared to the normal height group, which leads to a greatly increased chance of cardiovascular events in the future[19]. Recently, it has been reported that the uric acid to high density lipoprotein cholesterol ratio (UHR) is a new inflammatory and metabolic indicator. It has high sensitivity and specificity as compared to other diagnostic criteria for metabolic syndrome[20]. ALT, uric acid levels were reported to be higher in MAFLD patients[21]. Previous studies have also found that uric acid levels can lead to increased ALT levels[22, 23]. As a novel marker, UHR has been shown to be higher in the MAFLD population[24]. In other words, UHR may be related to ALT, but there are few studies in this area, especially in short children and adolescents. Therefore, we conducted this study to explore the relationship between UHR and ALT levels in children and adolescents with short stature.

Subjects And Methods

Study subjects.

According to the inclusion and exclusion criteria, The subjects included a total of 1510 children and adolescents with short stature who visited at the Department of Endocrinology, Affiliated Hospital of Jining Medical University from March 1, 2013, and December 31, 2021. Among them, 1029 were male and 481 were female. Collect and organize clinical data that meet the diagnostic criteria of short stature, and conduct cross-sectional analysis. Data of this study are part of the cohort GDDSD study (Growth and Development Diseases in Shandong Province: a cohort follow-up study, http://www.chictr.org.cn, ChiCTR1900026510). Subjects were included and excluded according to the following criteria: Inclusion criteria: The height of each subject is less than − 2 standard deviations compared with the same age, same sex, same ethnic group. Exclusion criteria: patients with abnormal thyroid function, small for gestational age, intracranial tumor, Turner syndrome, Noonan syndrome, Kallman syndrome, congenital heart disease, skeletal dysplasia, received growth hormone therapy, abnormal liver function, and subjects with incomplete data on ALT, UA and HDL. (Table 1).

Anthropomorphic Measurements.

Height and weight of all subjects were measured by trained professionals. When measuring the height, all participants used the same height measuring instrument (Jiangsu Nantong Best Industrial Co., Ltd., China) to measure with an accuracy of 0.1 cm after taking off their hats and shoes. Height SDS was calculated based on normal values for Chinese children[25]. When measuring the body weight, all participants were on an empty stomach and wearing light clothes, using the same electronic scale (Guangdong Xiangshan Weighing Apparatus Co., Ltd., China), accurate to 0.1 kg. BMI is equal to weight (kg)/height (meter squared). The division of puberty stages is assessed by a specialist physician through a physical examination, which is based on the Turner stage[26]. Boys with testicular volume less than 4 mL and no pubic hair and girls with no breast development and no pubic hair were classified as prepubertal[27, 28]. Measurement of systolic blood pressure (SBP) and diastolic blood pressure (DBP) requires the patient to sit and rest for at least 5 minutes, skilled nurses use Omron HBP-1300 electronic sphygmomanometer to measure the blood pressure of the right arm three times, and the interval between each measurement is not less than 2 minutes. Then, the average of the SBP and DBP measurements was calculated and recorded.

Laboratory Measurements

Morning fasting blood samples were collected from all patients to determine laboratory parameters. Two types of GH stimulation tests are required to determine GH peak. The first trial was the levodopa excitation test. The specific methods are as follows: Participants weighing < 30 kg received oral levodopa 0.25 g, participants weighing ≥ 30 kg received oral levodopa 0.5 g, blood samples were collected at 0, 30, 60, 90 and 120 minutes and GH concentrations were determined. The second trial was the insulin hypoglycaemia test. The specific method is as follows: 0.1 U/kg insulin was injected subcutaneously, and GH levels were measured at time points of 0, 15, 30, 60, 90, and 120 min, respectively. The GH concentration was determined by a chemiluminescence method (ACCESS2, Beckman Coulter; USA) with a sensitivity of 0.010 µg/l. Serum IGF-1 concentration was determined by the chemiluminescence immunometric method (DPC IMMULITE 1000 analyser, SIEMENS, Germany), and the intra-assay and inter-assay coefficients were 3.0% and 6.2%, respectively. Renal function-related indicators including creatinine (Cr) and uric acid (UA) ,blood lipid-related indicators including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein C (LDL-c), and triglycerides (TG), with fasting blood glucose (FBG), alanine aminotransferase (ALT)were measured by an automatic biochemical analyzer (Cobas c702, Roche; Shanghai, China). The UHR was obtained as UA (mg/dl)/HDL (mg/dl).

Results

Factors associated with ALT

As shown in Table 2, univariate linear regression analysis was performed to determine the relationships between the clinical parameters and ALT. For the unadjusted model, UHR and ALT showed a significant positive correlation (p < 0.001). Other variables significantly associated with ALT were sex, age, height SDS, weight, BMI, SBP, DBP, UA, TG, GH peak, and puberty stage (P < 0.05). There was no significant correlation between serum ALT and IGF-1, FBG, Cr, HDL, LDL, or TC (p > 0.05).

Independent correlation between UHR and ALT by multivariate piecewise linear regression

As shown in Fig. 1, smooth curve fitting revealed a nonlinear relationship between UHR and ALT. After adjusting for sex, age, BMI, SBP, DBP, GH peak, and Tanner staging, smooth curve fitting showed a nonlinear relationship between UHR and ALT. This curve has two phase changes and a breakpoint. When the UHR levels were less than the critical point, UHR was inversely associated with ALT. When the UHR levels were greater than the critical point, the UHR was positively associated with ALT. As shown in Table 3, the threshold effects were further analysed by curve fitting, and the data indicated that the inflection point of UHR was 10.93%. When UHR was > 10.93%, ALT levels significantly increased with increasing UHR (0.69, 95% CI 0.39, 0.98; P < 0.0001). When UHR was < 10.93%, the ALT levels decreased with increasing UHR (-0.01, 95% CI -0.24, 0.21; P = 0.9229). However, it was not statistically significant.

Discussion

In this cross-sectional study, we observed a nonlinear relationship between UHR and ALT in short stature children and adolescents, with a turning point of ALT of 10.93%. When UHR levels were greater than 10.93%, UHR was positively associated with ALT.

We observed a positive correlation between UHR and ALT. Previous studies that have directly explored UHR and ALT are limited, but UHR is a new metabolic predictor with high sensitivity and specificity compared to other metabolic syndrome diagnostic criteria[19]. Regarding the association between UHR and ALT, Mehmet Ali Kosekli et al. observed that UHR was positively associated with ALT through a controlled study[24]. Moreover, a positive association between UHR and ALT was also reported in Chinese lean individuals by Ya-Nan Zhang et al. [29]. These results are consistent with the findings of our study.

Uric acid is a product of purine metabolism, and elevated serum uric acid levels are associated with the deterioration of metabolic status[30]. Low HDL-C is also associated with a poor metabolic status and is even a marker of metabolic syndrome[31]. The combination of these two metabolic parameters is UHR, a more useful predictor of metabolic deterioration[32]. Since hepatic steatosis is associated with metabolic syndrome[33, 34], and ALT reflects an excessive deposition of hepatic fat[35], this could explain the increase in ALT with increased UHR.

Uric acid is synthesized by xanthine oxidase during purine metabolism and is excreted through the kidney. Thus, elevated uric acid levels are a result of increased synthesis and decreased excretion[20, 36]. In addition, eating habits greatly affect the production and metabolism of uric acid[37]. Among the participants in our study, there were many unbalanced eating habits, such as picky eating, partial eating, and excessive intake of high-sugar drinks, which may lead to elevated uric acid levels. Elevated uric acid levels contribute to the development of adverse conditions. Previous results suggest a strong association between uric acid levels and metabolic syndrome in children and adolescents, and various mechanisms have been proposed to explain this correlation[38]. HDL-C has the effects of reverse transport of cholesterol to reduce atherosclerosis, anti-inflammation, anti-thrombosis, antiapoptosis and vasodilation[39]. An analysis of a large health and nutrition survey from the United States indicated that low levels of serum HDL are important in the development of metabolic syndrome and identified it as the most powerful predictor[40]. Thus, low serum HDL-C levels with high UA levels reflect a worse metabolic status.

The liver is an important organ of human metabolism. Ageing of the liver and abnormal accumulation of fat can rupture hepatocytes, releasing ALT into the blood. Measurement of ALT levels is a basic test for screening for liver disease and assessing disease progression. However, serum ALT is not only a sensitive indicator for assessing liver function but is also closely related to metabolic factors. In China, through a 7-year follow-up cohort study, even if ALT remained within the range of normal reference values, it was an independent predictor of metabolic syndrome[41]. In other words, both UHR and ALT are associated with metabolic syndrome, and interestingly, our study found a nonlinear relationship between UHR and ALT, with ALT levels increasing with UHR when UHR was above 10.92%, while at lower values, no relationship was observed. Simple linear evaluation may underestimate this correlation. It is well known that obesity is a major risk factor for metabolic deterioration. BMI is a useful indicator to assess obesity and nutritional status[42]. We found a close relationship between ALT and BMI. However, after adjustment for BMI, the UHR remained independently associated with ALT.

Furthermore, UHR, as a novel marker of metabolic syndrome[43], has been used to assess type 2 diabetes mellitus[20, 32], hepatic steatosis[44], Hashimoto's thyroiditis[45], and the control of MAFLD[24]. UHR was also reported to be associated with poor collateral circulation in chronic total occlusion (CTO) patients and to have important predictive value for cardiovascular mortality in patients living on peritoneal dialysis[46, 47].Evidence has shown that short stature children and adolescents also have metabolic abnormalities, so it is necessary to evaluate UHR levels in the diagnosis and treatment of short stature[18].

Study strengths and limitations

The present study has several advantages. First, UHR is a newly proposed novel predictor of metabolism, with previous studies on UHR being few and all in adults; this is the first study of the relationship between UHR and ALT levels in short children and adolescents.Second, in this study, we used smooth curve fitting to find a nonlinear relationship between UHR and ALT levels rather than assuming a simple positive correlation.

However, this study has some limitations. First, we were unable to determine the causal relationships due to the cross-sectional study design. Second, this study was conducted in a homogeneous population of short-stature children and adolescents in China, so our results cannot be extrapolated to other groups. Third, there are many factors affecting uric acid and cholesterol, such as dietary status. In the future, we intend to use questionnaires on dietary habits for a more thorough assessment.

Conclusion

This study describes a nonlinear relationship between UHR and ALT levels in Chinese short stature children and adolescents. When the UHR values reached the inflection point, the ALT levels were positively correlated with elevated UHR.This finding suggests that UHR in short stature children and adolescents affects ALT concentrations, so we should focus on the level of uric acid and HDL clinically.

Abbreviations

Height SDS: height standard deviation scores; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; IGF-1: insulin-like growth factor-1; GH peak: growth hormone peak; HDL-C: high density lipoprotein cholesterol; LDL-C: low density lipoprotein cholesterol; TC: total cholesterol; TG: triglyceride; ALT: alanine aminotransferase; FPG: fasting plasma glucose; UA: uric acid; Cr: creatinine; UHR: uric acid to high density lipoprotein cholesterol ratio.

Declarations

Acknowledgements

Not applicable.

Authors’ contributions

GL carried out the studies and drafted the manuscript. QZ and XZ helped with the statistical analysis. MZ and BB participated in the conceptualization and design of the study, revised the manuscrip critically for important intellectual content and final provided approval of the version to be published. All authors read and approved the final manuscript.

Funding

This study was supported by Jining Science and Technology Bureau (No.2017SMN007). The funding body had no roles in the design of the study and collection, analysis, interpretation of data and in writing the manuscript.

Availability of data and materials

The datasets used and/or analysed in the current study are available from the corresponding authors upon reasonable request.

Ethics approval and consent to participate

The Human Ethics Committee of the Affiliated Hospital of Jining Medical University approved the study. All procedures were performed in accordance with ethical standards of the Declaration of Helsinki. All of the families of the patients were informed of the aims of the study, and written informed consent was obtained from the parents of the patients.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflicts of interest.

References

1. Al SA, Daftardar H, Alghamdi AA, Jamjoom M, Awidah S, Ahmed ME, et al. Effect of growth hormone treatment on children with idiopathic short stature (ISS), idiopathic growth hormone deficiency (IGHD), small for gestational age (SGA) and Turner syndrome (TS) in a tertiary care center. Acta Biomed. 2020; 91(1): 29–40.
2. Yue D, Miller MR, Clarson CL. Evaluation of referrals for short stature: A retrospective chart review. Paediatr Child Health. 2019; 24(2): e74-e77.
3. Takahashi Y. The Role of Growth Hormone and Insulin-Like Growth Factor-I in the Liver. Int J Mol Sci. 2017; 18(7).
4. Sarmento-Cabral A, Del Rio-Moreno M, Vazquez-Borrego MC, Mahmood M, Gutierrez-Casado E, Pelke N, et al. GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner. J Endocrinol. 2021; 248(1): 31–44.
5. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020; 73(1): 202–209.
6. Eslam M, Alkhouri N, Vajro P, Baumann U, Weiss R, Socha P, et al. Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement. Lancet Gastroenterol Hepatol. 2021; 6(10): 864–873.
7. McNeice K, Sandberg K. Updates in non-alcoholic fatty liver disease (NAFLD). Curr Probl Pediatr Adolesc Health Care. 2020; 50(8): 100844.
8. Liang S, Yu Z, Song X, Wang Y, Li M, Xue J. Reduced Growth Hormone Secretion is Associated with Nonalcoholic Fatty Liver Disease in Obese Children. Horm Metab Res. 2018; 50(3): 250–256.
9. Henry RK. Growth Hormone Deficiency and Nonalcoholic Fatty Liver Disease with Insights from Humans and Animals: Pediatric Implications. Metab Syndr Relat Disord. 2018.
10. Savage MO, Storr HL. GH Resistance Is a Component of Idiopathic Short Stature: Implications for rhGH Therapy. Front Endocrinol (Lausanne). 2021; 12:781044.
11. Savage MO, Storr HL, Backeljauw PF. The continuum between GH deficiency and GH insensitivity in children. Rev Endocr Metab Disord. 2021; 22(1): 91–99.
12. Wang DD, Sun M, Wang X, Cheng YY. Changes in serum levels of IGF-1, ghrelin and nesfatin-1 and clinical significance after treatment with recombinant human growth hormone in children with idiopathic short stature. J Biol Regul Homeost Agents. 2019; 33(6): 1759–1763.
13. Soliman A, Rogol AD, Elsiddig S, Khalil A, Alaaraj N, Alyafie F, et al. Growth response to growth hormone (GH) treatment in children with GH deficiency (GHD) and those with idiopathic short stature (ISS) based on their pretreatment insulin-like growth factor 1 (IGFI) levels and at diagnosis and IGFI increment on treatment. J Pediatr Endocrinol Metab. 2021; 34(10): 1263–1271.
14. Dichtel LE, Corey KE, Misdraji J, Bredella MA, Schorr M, Osganian SA, et al. The Association Between IGF-1 Levels and the Histologic Severity of Nonalcoholic Fatty Liver Disease. Clin Transl Gastroenterol. 2017; 8(1): e217.
15. Pan CS, Weiss JJ, Fourman LT, Buckless C, Branch KL,Lee H, et al. Effect of recombinant human growth hormone on liver fat content in young adults with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf). 2021; 94(2): 183–192.
16. Vos MB, Abrams SH, Barlow SE, Caprio S, Daniels SR, Kohli R, et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017; 64(2): 319–334.
17. Nobili V, Alisi A, Valenti L, Miele L, Feldstein AE, Alkhouri N. NAFLD in children: new genes, new diagnostic modalities and new drugs. Nat Rev Gastroenterol Hepatol. 2019; 16(9): 517–530.
18. Xu R, Zhu H, Zhang C, Shen G, Feng J. Metabolomic analysis reveals metabolic characteristics of children with short stature caused by growth hormone deficiency. Clin Sci (Lond). 2019; 133(6): 777–788.
19. Safari O, Ejtahed HS, Namazi N, Heshmat R, Arjmand R, Karbalahi SS, et al. Association of short stature and obesity with cardio-metabolic risk factors in Iranian children and adolescents: the CASPIAN-V study. J Diabetes Metab Disord. 2021; 20(2): 1137–1144.
20. 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 (1992). 2019; 65(1): 9–15.
21. Yang H, Li D, Song X, Liu F, Wang X, Ma Q, et al. Joint associations of serum uric acid and ALT with NAFLD in elderly men and women: a Chinese cross-sectional study. J Transl Med. 2018; 16(1): 285.
22. Chen S, Guo X, Yu S, Sun G, Yang H, Li Z, et al. Association between Serum Uric Acid and Elevated Alanine Aminotransferase in the General Population. Int J Environ Res Public Health. 2016; 13(9).
23. Zelber-Sagi S, Ben-Assuli O, Rabinowich L, Goldstein A, Magid A, Shalev V, et al. The association between the serum levels of uric acid and alanine aminotransferase in a population-based cohort. Liver Int. 2015; 35(11): 2408–15.
24. Kosekli MA, Kurtkulagii O, Kahveci G, Duman TT, Tel BMA, Bilgin S, et al. The association between serum uric acid to high density lipoprotein-cholesterol ratio and non-alcoholic fatty liver disease: the abund study. Rev Assoc Med Bras (1992). 2021; 67(4): 549–554.
25. Li H, Ji CY, Zong XN, Zhang YQ. [Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years]. Zhonghua Er Ke Za Zhi. 2009; 47(7): 487–92.
26. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child. 1976; 51(3): 170–9.
27. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 1970; 45(239): 13–23.
28. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969; 44(235): 291–303.
29. Yang S, Zhong J, Ye M, Miao L, Lu G, Xu C, et al. Association between the non-HDL-cholesterol to HDL-cholesterol ratio and non-alcoholic fatty liver disease in Chinese children and adolescents: a large single-center cross-sectional study. Lipids Health Dis. 2020; 19(1): 242.
30. Chen S, Wu N, Yu C, Xu Y, Xu C, Huang Y, et al. Association between baseline and changes in serum uric acid and incident metabolic syndrome: a nation-wide cohort study and updated meta-analysis. Nutr Metab (Lond). 2021; 18(1): 59.
31. Hoffman EL, VonWald T, Hansen K. The metabolic syndrome. S D Med. 2015; Spec No: 24 – 8.
32. Aktas G, Kocak MZ, Bilgin S, Atak BM, Duman TT, Kurtkulagi O. Uric acid to HDL cholesterol ratio is a strong predictor of diabetic control in men with type 2 diabetes mellitus. Aging Male. 2020; 23(5): 1098–1102.
33. Ting YW, Wong SW, Anuar ZA, Mohamed R, Jalaludin MY. Metabolic Syndrome Is Associated With Advanced Liver Fibrosis Among Pediatric Patients With Non-alcoholic Fatty Liver Disease. Front Pediatr. 2019; 7: 491.
34. Paudel MS, Tiwari A, Mandal A, Shrestha B, Kafle P, Chaulagai B, et al. Metabolic Syndrome in Patients with Non-alcoholic Fatty Liver Disease: A Community Based Cross-sectional study. Cureus. 2019; 11(2): e4099.
35. Kang Y, Park S, Kim S, Koh H. Normal serum alanine aminotransferase and non-alcoholic fatty liver disease among Korean adolescents: a cross-sectional study using data from KNHANES 2010–2015. BMC Pediatr. 2018; 18(1): 215.
36. Fathallah-Shaykh SA, Cramer MT. Uric acid and the kidney. Pediatr Nephrol. 2014; 29(6): 999–1008.
37. Cui N, Dong X, Liao W, Xue Y, Liu X, Li X, et al. Association of eating out frequency and other factors with serum uric acid levels and hyperuricemia in Chinese population. Eur J Nutr. 2022; 61(1): 243–254.
38. Cho MH, Kim YM, Yoon JH, Kim DH, Lim JS. Serum uric acid in Korean children and adolescents: reference percentiles and association with metabolic syndrome. Ann Pediatr Endocrinol Metab. 2020; 25(2): 104–111.
39. Nagao M, Nakajima H, Toh R, Hirata KI, Ishida T. Cardioprotective Effects of High-Density Lipoprotein Beyond its Anti-Atherogenic Action. J Atheroscler Thromb. 2018; 25(10): 985–993.
40. Castaneda G, Bhuket T, Liu B, Wong RJ. Low serum high density lipoprotein is associated with the greatest risk of metabolic syndrome among U.S. adults. Diabetes Metab Syndr. 2018; 12(1): 5–8.
41. Sun H, Liu Q, Wang X, Li M, Fan Y, Song G, et al. The longitudinal increments of serum alanine aminotransferase increased the incidence risk of metabolic syndrome: A large cohort population in China. Clin Chim Acta. 2019; 488: 242–247.
42. Gierach M, Junik R. Metabolic syndrome in women - correlation between BMI and waist circumference. Endokrynol Pol. 2022.
43. Yazdi F, Baghaei MH, Baniasad A, Naghibzadeh-Tahami A, Najafipour H, Gozashti MH. Investigating the relationship between serum uric acid to high-density lipoprotein ratio and metabolic syndrome. Endocrinol Diabetes Metab. 2022; 5(1): e00311.
44. Zhang YN, Wang QQ, Chen YS, Shen C, Xu CF. Association between Serum Uric Acid to HDL-Cholesterol Ratio and Nonalcoholic Fatty Liver Disease in Lean Chinese Adults. Int J Endocrinol. 2020; 2020: 5953461.
45. Kurtkulagi O, Tel BMA, Kahveci G, Bilgin S, Duman TT, Erturk A, et al. Hashimoto's thyroiditis is associated with elevated serum uric acid to high density lipoprotein-cholesterol ratio. Rom J Intern Med. 2021; 59(4): 403–408.
46. Aydin C, Emlek N. The relationship between uric acid to high-density lipoprotein cholesterol ratio and collateral index in patients with chronic total occlusion. Kardiologiia. 2021; 61(9): 61–65.
47. Liu R, Peng Y, Wu H, Diao X, Ye H, Huang X, et al. Uric acid to high-density lipoprotein cholesterol ratio predicts cardiovascular mortality in patients on peritoneal dialysis. Nutr Metab Cardiovasc Dis. 2021; 31(2): 561–569.