Recombinant human growth hormone therapy induces dose-dependent increases in uric acid and bilirubin in children with idiopathic short stature a retrospective cohort study

Recombinant human growth hormone therapy induces dose-dependent increases in uric acid and bilirubin in children with idiopathic short stature a retrospective cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Recombinant human growth hormone therapy induces dose-dependent increases in uric acid and bilirubin in children with idiopathic short stature a retrospective cohort study Xiaolin Li, Yan Ji This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8578234/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective This study aimed to examine the dose-dependent effects of recombinant human growth hormone (rhGH) therapy on uric acid (UA) and bilirubin metabolism in prepubertal children with idiopathic short stature (ISS) and to identify independent predictors of UA elevation. Methods We conducted a retrospective cohort study of 120 prepubertal children with ISS (57 boys, 63 girls) treated with rhGH (0.15–0.2 IU/kg/day) between 2019 and 2023. Serum UA, total bilirubin (TBIL), and direct bilirubin (DBIL) levels were collected at baseline and at 3, 6, 9, 12, 15, 18, 21, and 24 months post-treatment. Metabolic trajectories were analyzed using repeated-measures ANOVA. Multivariable logistic regression was used to identify risk factors, adjusted for age, sex, baseline BMI, and baseline UA. Results UA levels increased significantly from 291.7 ± 75.3 µmol/L at baseline to 368.3 ± 122.0 µmol/L at 24 months (Δ + 76.6 µmol/L, p < 0.001). A dose-dependent relationship was observed at 6 months (r = 0.269, p = 0.020) and 9 months (r = 0.262, p = 0.022). Independent predictors of UA elevation included baseline UA (OR = 1.15 per 10 µmol/L increase, 95% CI 1.05–1.26, p = 0.003) and ΔBMI SDS (OR = 2.18, 95% CI 1.03–4.64, p = 0.043). rhGH dose was also positively correlated with TBIL (r = 0.269, p = 0.020) and DBIL (r = 0.265, p = 0.020) at 6 months. Each 0.05 IU/kg/day increment in rhGH dose was associated with an eightfold increase in the risk of bilirubin elevation (OR = 8.00, 95% CI 2.15–29.70, p = 0.002). A linear regression model projected that children with baseline UA > 300 µmol/L receiving doses > 0.15 IU/kg/day would maintain UA levels above the hyperuricemia threshold (360 µmol/L) at 24 months. Conclusion rhGH therapy exerts dose-dependent effects on UA and bilirubin metabolism in clinical practice. We recommend intensified monitoring (every 3–6 months) for children with baseline UA > 300 µmol/L or on rhGH doses > 0.15 IU/kg/day, along with evaluation of insulin resistance and hepatic function. Long-term metabolic surveillance is advised for high-risk children undergoing rhGH treatment. Recombinant human growth hormone idiopathic short stature uric acid bilirubin insulin resistance retrospective study Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Idiopathic short stature (ISS) represents the most common cause of childhood short stature, accounting for 60–70% of cases associated with impaired growth [ 1 ]. Recombinant human growth hormone (rhGH) therapy is the standard intervention for ISS and has been shown to improve final adult height [ 2 ]. However, growing attention has been directed toward its metabolic effects, particularly regarding glucose homeostasis and bone metabolism [ 3 , 4 ], while systematic assessments of uric acid (UA) and bilirubin changes remain scarce. Recent clinical observations indicate that rhGH may elevate UA and bilirubin levels, yet the mechanisms and risk factors are not fully elucidated. UA, the terminal product of purine metabolism, is linked to insulin resistance and cardiovascular risk [ 5 ], while bilirubin elevation may reflect hepatobiliary dysfunction [ 6 ]. Several gaps persist: (1) the pathways through which rhGH dose influences UA and bilirubin regulation; (2) the absence of specific monitoring guidelines for these parameters in international rhGH protocols [ 7 ]; and (3) limited real-world evidence on dose-dependent effects and the potential mediating role of insulin resistance. This retrospective cohort study utilized longitudinal clinical data to explore the relationship between rhGH dose and metabolic changes in a real-world setting and to propose a risk-stratified monitoring framework. Our objectives were to: (1) quantify dose-response associations between rhGH and elevations in UA and bilirubin; (2) identify independent predictors of UA dysregulation; and (3) develop a personalized monitoring algorithm to enhance the safety of rhGH therapy. Materials and Methods Study Design and Participants This single-center retrospective cohort study followed STROBE guidelines. The protocol was approved by the Ethics Committee of Taizhou Women and Children’s Hospital (Approval No. 2025-KY001-01); informed consent was waived due to the retrospective design. Children diagnosed with ISS between January 2019 and December 2023 were screened using established criteria [ 6 ]: height 10 ng/mL on stimulation testing; and exclusion of endocrine, skeletal, chromosomal, or secondary causes of growth failure. A total of 120 prepubertal children (57 boys, 63 girls) who completed ≥ 24 months of follow-up with available laboratory data were included. rhGH dosage ranged from 0.15 to 0.2 IU/kg/day. The sample size was determined by the number of eligible patients with complete follow-up during the study period. Data Collection Baseline and follow-up data were extracted from electronic records, including demographics, anthropometrics, and family history. Laboratory measures—fasting UA, TBIL, DBIL, and IGF-1—were obtained as part of routine care using a Siemens ADVIA 2400 analyzer. Assessments were performed at baseline and approximately every 3 months up to 24 months. Blood samples were generally collected between 9:00 and 11:00 AM. Assay methods included enzymatic peroxidase for UA, diazo for bilirubin, and chemiluminescence immunoassay for IGF-1. All procedures followed standardized quality control protocols. The rhGH formulation was supplied by Changchun Jinsai Pharmaceutical Co., Ltd. Statistical Analysis Analyses were performed with IBM SPSS 26.0 and GraphPad Prism 8.0. Normality was assessed using the Kolmogorov–Smirnov test. Data are presented as mean ± SD or median (IQR). Longitudinal trends were evaluated with repeated-measures ANOVA and Bonferroni post-hoc tests. Multivariable logistic regression (stepwise) identified predictors of UA and bilirubin elevation, adjusted for age, sex, baseline BMI, and baseline UA. A two-tailed p < 0.05 was considered significant. Ethics and Quality Assurance The study complied with the Declaration of Helsinki. Daily calibration and quality controls were maintained, with intra- and inter-assay coefficients of variation below 5%. Results Uric Acid Metabolic Changes After 24 months of rhGH, serum UA rose from 291.73 ± 75.32 μmol/L to 368.30 ± 122.00 μmol/L (Δ +76.57 μmol/L, p < 0.001). Dose-dependent correlations were strongest at 6 months (r = 0.269, p = 0.020) and 9 months (r = 0.262, p = 0.022). Multivariable logistic regression identified baseline UA (OR = 1.15 per 10 μmol/L increase, 95% CI 1.05–1.26, p = 0.003), rhGH dose (OR = 1.82 per 0.05 IU/kg/day increase, 95% CI 1.20–2.75, p = 0.005), and ΔBMI SDS (OR = 2.18, 95% CI 1.03–4.64, p = 0.043) as independent predictors of UA elevation (>360 μmol/L or >20% increase from baseline). Fasting insulin was also strongly associated (OR = 3.82 per 5 μIU/mL increase, 95% CI 1.60–9.10, p = 0.002). Table 1. Multivariable Logistic Regression Analysis of Clinically Significant Uric Acid Elevation* Predictor OR 95% CI P-value Baseline UA (per 10 μmol/L increase) 1.15 1.05 – 1.26 0.003 rhGH Dose (per 0.05 IU/kg/day increase) 1.82 1.20 – 2.75 0.005 ΔBMI SDS (per 1.0 increase) 2.18 1.03 – 4.64 0.043 Fasting Insulin (INS) (per 5 μIU/mL increase) 3.82 1.60 – 9.10 0.002 Abbreviations: OR = odds ratio; CI = confidence interval. *Note: The outcome variable was defined as serum uric acid concentration > 360 μmol/L or an increase of >20% from baseline at any point during the 24-month follow-up. The model was adjusted for age and sex.* Bilirubin Dynamics TBIL increased from 9.2 ± 2.1 μmol/L to 10.5 ± 2.5 μmol/L (Δ +1.3 μmol/L, p < 0.05), and DBIL from 2.4 ± 0.8 μmol/L to 3.1 ± 1.0 μmol/L (Δ +0.7 μmol/L, p < 0.05). All values remained within age-appropriate ranges. rhGH dose was an independent risk factor for bilirubin elevation (OR = 1.45 per 0.05 IU/kg/day increase, 95% CI 1.04–2.02, p = 0.028). Conversely, ΔIGF-1 SDS showed a protective effect (OR = 0.37, 95% CI 0.19–0.74, p = 0.005). Table 2. Multivariable Logistic Regression Analysis of Bilirubin Elevation * Predictor OR 95% CI P-value rhGH Dose (per 0.05 IU/kg/day increase) 1.45 1.04 – 2.02 0.028 ΔIGF-1 SDS (per 1.0 increase) 0.37 0.19 – 0.74 0.005 Abbreviations: OR = odds ratio; CI = confidence interval. * Note: The outcome variable was defined as total bilirubin (TBIL) exceeding the 95th percentile for age and sex or an increase of >25% from baseline at the 24-month follow-up. The model was adjusted for age, sex, and baseline BMI.* Discussion This study demonstrates that long-term rhGH therapy in prepubertal children with ISS is associated with dose-dependent increases in UA and bilirubin over 24 months. Baseline UA, rhGH dose, and ΔBMI SDS independently predicted UA elevation, while ΔIGF-1 SDS appeared protective against bilirubin accumulation. These findings support risk-stratified monitoring during treatment. The sustained rise in UA may involve insulin resistance-mediated renal UA reabsorption [8,9] and direct hepatic effects of GH on purine catabolism via JAK2-STAT5 signaling and xanthine dehydrogenase upregulation [10,11]. Notably, mean UA approached the hyperuricemia threshold at 24 months, underscoring the need for vigilance in high-risk patients—particularly those with baseline UA >300 μmol/L. Insulin resistance, known to be induced by GH therapy [12], likely exacerbates UA retention, potentially creating a cycle in which hyperuricemia further worsens insulin sensitivity [13]. Although bilirubin elevations remained subclinical, the dose-dependent pattern suggests a subtle hepatic impact, possibly through GH receptor-mediated inhibition of conjugating enzymes such as UGT1A1 [4]. The protective role of IGF-1 response may reflect enhanced hepatocyte function and bilirubin clearance [14], a novel association that merits further experimental validation. Limitations and Future Directions Limitations include the single-center design, moderate sample size, lack of direct enzyme activity measurements, and 24-month follow-up which may be insufficient to assess long-term trajectories. Future studies should focus on: (1) mechanistic evaluations of GH effects on purine and bilirubin pathways; (2) larger multicenter cohorts with extended follow-up; and (3) integration of omics technologies to explore individual susceptibility. Conclusion We propose a three-tiered management algorithm: Low-risk (baseline UA ≤300 μmol/L and dose ≤0.15 IU/kg/day): annual UA and bilirubin monitoring. Moderate/High-risk (baseline UA >300 μmol/L or dose >0.15 IU/kg/day): metabolic and insulin sensitivity panels every 3–6 months. Intervention threshold: If UA >360 μmol/L or DBIL >3.4 μmol/L on consecutive tests, multidisciplinary review for therapy adjustment. Abbreviations ISS Iidiopathic short stature UA uric acid rhGH recombinant human growth hormone TBIL total bilirubin DBIL direct bilirubin IGF-1 Insulin-like Growth Factor-1 BMI Body Mass Index Declarations Acknowledgements We thank the patients and families for their participation. Ethics approval and consent to participate This study was reviewed and approved by the Ethics Committee of Taizhou Women and Children’s Hospital (Approval No.: 2025-KY001-01). All procedures were conducted in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki Declaration and its later amendments. Statement of Waiver of Informed Consent This retrospective study utilized fully anonymized clinical data extracted from electronic medical records. The need for written informed consent was formally waived by the Institutional Review Board (Ethics Committee) of Taizhou Women and Children's Hospital (Approval No.: 2025-KY001-01). This waiver was granted in accordance with national regulations and ethical guidelines governing retrospective research, as the study involved no more than minimal risk to participants, the research could not practicably be carried out without the waiver, and the waiver did not adversely affect the rights and welfare of the subjects. All data were handled with strict confidentiality, and all procedures were conducted in compliance with the ethical standards of the Declaration of Helsinki. Consent for publication Not applicable. This manuscript contains no individual person’s data in any form (including individual details, images, or videos). Competing interests The authors declare that they have no competing interests. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Data availability The datasets generated and analyzed during the current study are not publicly available due to hospital data privacy policies but are available from the corresponding author (Ji Yan) upon reasonable request. References Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB, et al. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Horm Res Paediatr. 2016;86:361–97. Epub 2016 Nov 25. PMID: 27884013. Grimberg A, Allen DB. Growth hormone treatment for growth hormone deficiency and idiopathic short stature: new guidelines shaped by the presence and absence of evidence. Curr Opin Pediatr. 2017;29:466–71. PMID: 28525404; PMCID: PMC5565215. Sesti G, Hribal ML, Procopio T, Fiorentino TV, Sciacqua A, Andreozzi F, et al. Low circulating insulin-like growth factor-1 levels are associated with high serum uric acid in nondiabetic adult subjects. Nutr Metab Cardiovasc Dis. 2014;24:1365–72. PMID: 25149895. Ying YQ, Hou L, Liang Y, Wu W, Luo XP. Efficacy and safety of recombinant human growth hormone in treating Chinese children with idiopathic short stature. Growth Horm IGF Res. 2018;42–43:80–5. PMID: 30343148. Creeden JF, Gordon DM, Stec DE, Hinds TD Jr. Bilirubin as a metabolic hormone: the physiological relevance of low levels. Am J Physiol Endocrinol Metab. 2021;320:E191–207. .PMID: 33284088; PMCID: PMC8260361. Stanhope R, De Luca F, Delemarre-Van de Waal HA, Liotta A, Norjavaara E, Salvatoni A et al. (2001) International Workshop on Management of Puberty for Optimum Auxological Results. Multiple pituitary hormone deficiency: management of puberty for optimal auxological results. J Pediatr Endocrinol Metab 14(Suppl 2):1009–1014. 10.1515/jpem-2001-s214 . PMID: 11529397. Collett-Solberg PF, Ambler G, Backeljauw PF, Bidlingmaier M, Biller BMK, Boguszewski MCS, et al. Diagnosis, genetics, and therapy of short stature in children: a Growth Hormone Research Society international perspective. Horm Res Paediatr. 2019;92:1–14. .PMID: 31514194; PMCID: PMC6979443. Cicero AFG, Fogacci F, Di Micoli V, Angeloni C, Giovannini M, Borghi C. (2023) Purine metabolism dysfunctions: experimental methods of detection and diagnostic potential. Int J Mol Sci 24:7027.PMID: 37108190; PMCID: PMC10138451. Tanaka Y, Nagoshi T, Takahashi H, Oi Y, Yoshii A, Kimura H, et al. URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice. Mol Metab Jan. 2022;55:101411. 10.1016/j.molmet.2021.101411 . Epub 2021 Dec 1. PMID: 34863940; PMCID: PMC8717577. Kaltenecker D, Themanns M, Mueller KM, Spirk K, Suske T, Merkel O, et al. Hepatic growth hormone - JAK2 - STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression. Cytokine. 2019;124:154569doi. 10.1016/j.cyto.2018.10.010 . Epub 2018 Oct 30. PMID: 30389231. Nie Q, Liu M, Zhang Z, Zhang X, Wang C, Song G. The effects of hyperuricemia on endothelial cells are mediated via GLUT9 and the JAK2/STAT3 pathway. Mol Biol Rep. 2021;48:8023–32. .PMID: 34716863; PMCID: PMC8604859. Labarta JI, de Arriba A, Ferrer M, Loranca M, Martos JM, Rodríguez A et al. (2020) Growth and metabolic effects of long-term recombinant human growth hormone (rhGH) treatment in short children born small for gestational age: GH-RAST study. J Pediatr Endocrinol Metab 33:923–932. 10.1515/jpem-2019-0438 . PMID: 32623373. Sakalli AA, Küçükerdem HS, Aygün O. What is the relationship between serum uric acid level and insulin resistance? A case-control study. Med (Baltim). 2023;102:e36732. 10.1097/MD.0000000000036732 . PMID: 38206747; PMCID: PMC10754590. Sarfstein R, Nagaraj K, Parikh S, Levy C, Laron Z, Benayahu D, et al. Identification of UDP-glucuronosyltransferase 2B15 (UGT2B15) as a target for IGF1 and insulin action. Cells. 2022;11:1627. 10.3390/cells11101627 . PMID: 35626664; PMCID: PMC9139319. Yoon JS, Seo YJ, Kwon EB, Lee HJ, Kang MJ, Hwang IT. Association between uric acid and height during growth hormone therapy in children with idiopathic short stature. Front Endocrinol (Lausanne). 2022;13:1025005doi. PMID: 36531458; PMCID: PMC9755161. Zhu C, Cui R, Gao M, Rampersad S, You H, Sheng C, et al. The associations of serum uric acid with obesity-related acanthosis nigricans and related metabolic indices. Int J Endocrinol 2017:5438157. 2017. 10.1155/2017/5438157 . Epub 2017 Mar 7. PMID: 28367214; PMCID: PMC5359528. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8578234","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":585008063,"identity":"d48f21dc-c2f5-4584-934c-15caa13172e6","order_by":0,"name":"Xiaolin Li","email":"","orcid":"","institution":"Taizhou Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaolin","middleName":"","lastName":"Li","suffix":""},{"id":585008064,"identity":"23f94bdd-20b1-4c7b-92d7-46240b7198c9","order_by":1,"name":"Yan Ji","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYBACxmYQacDGw8/e2PjwA/FaKvjkJHsONxtLEG/XGTljgxvpbQI8xChmbucx/FzYZpbYcPNhG4MEg52cbgNBh/EYS89sS0tsnJ3Y9qCAIdnY7ABhLQbSvG3HEpulE9sNJBgOJG4jQovxb962/4ltkgfbJHiI1GImzXOGzZhHgpFoLWxl1jwVbHISPInAQDYgwi+G/Yc33+YBRqX98eMPH36osJMjrKWBwwCJa4BTIQLIM7A/IELZKBgFo2AUjGgAANGTPmWKu1l9AAAAAElFTkSuQmCC","orcid":"","institution":"Taizhou Central Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yan","middleName":"","lastName":"Ji","suffix":""}],"badges":[],"createdAt":"2026-01-12 07:08:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8578234/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8578234/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101935560,"identity":"6e0c10a7-05c8-44d8-aa59-872ce3127c39","added_by":"auto","created_at":"2026-02-05 08:27:30","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":30632,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8578234/v1/1ce958e02bd0318fe51678dc.jpg"},{"id":101935570,"identity":"31b1ecac-d5f6-46b1-91c4-aae729b296e4","added_by":"auto","created_at":"2026-02-05 08:27:32","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37633,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8578234/v1/8ae12dc5bfce2ca03ea5491d.jpg"},{"id":101935541,"identity":"c4f81f73-1a80-4858-ab36-895afc4c522c","added_by":"auto","created_at":"2026-02-05 08:27:21","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":32997,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8578234/v1/2862beac011233838fce0b1a.jpg"},{"id":101935561,"identity":"d9f6e5bb-37f1-4624-912e-d2144a27f3f5","added_by":"auto","created_at":"2026-02-05 08:27:30","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":25319,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8578234/v1/b94a6b75751267c848789d61.jpg"},{"id":104785666,"identity":"97627068-16f2-45b5-93c0-afa6df3920d1","added_by":"auto","created_at":"2026-03-17 08:12:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":708184,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8578234/v1/fba7513e-18ef-4563-9d6b-94487e4fec2c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Recombinant human growth hormone therapy induces dose-dependent increases in uric acid and bilirubin in children with idiopathic short stature a retrospective cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIdiopathic short stature (ISS) represents the most common cause of childhood short stature, accounting for 60\u0026ndash;70% of cases associated with impaired growth [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Recombinant human growth hormone (rhGH) therapy is the standard intervention for ISS and has been shown to improve final adult height [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, growing attention has been directed toward its metabolic effects, particularly regarding glucose homeostasis and bone metabolism [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], while systematic assessments of uric acid (UA) and bilirubin changes remain scarce.\u003c/p\u003e \u003cp\u003eRecent clinical observations indicate that rhGH may elevate UA and bilirubin levels, yet the mechanisms and risk factors are not fully elucidated. UA, the terminal product of purine metabolism, is linked to insulin resistance and cardiovascular risk [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], while bilirubin elevation may reflect hepatobiliary dysfunction [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Several gaps persist: (1) the pathways through which rhGH dose influences UA and bilirubin regulation; (2) the absence of specific monitoring guidelines for these parameters in international rhGH protocols [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]; and (3) limited real-world evidence on dose-dependent effects and the potential mediating role of insulin resistance.\u003c/p\u003e \u003cp\u003eThis retrospective cohort study utilized longitudinal clinical data to explore the relationship between rhGH dose and metabolic changes in a real-world setting and to propose a risk-stratified monitoring framework. Our objectives were to: (1) quantify dose-response associations between rhGH and elevations in UA and bilirubin; (2) identify independent predictors of UA dysregulation; and (3) develop a personalized monitoring algorithm to enhance the safety of rhGH therapy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003e This single-center retrospective cohort study followed STROBE guidelines. The protocol was approved by the Ethics Committee of Taizhou Women and Children\u0026rsquo;s Hospital (Approval No. 2025-KY001-01); informed consent was waived due to the retrospective design. Children diagnosed with ISS between January 2019 and December 2023 were screened using established criteria [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]: height\u0026thinsp;\u0026lt;\u0026thinsp;\u0026minus;\u0026thinsp;2 SD or below the 3rd percentile for age, sex, and ethnicity; peak GH\u0026thinsp;\u0026gt;\u0026thinsp;10 ng/mL on stimulation testing; and exclusion of endocrine, skeletal, chromosomal, or secondary causes of growth failure.\u003c/p\u003e \u003cp\u003eA total of 120 prepubertal children (57 boys, 63 girls) who completed\u0026thinsp;\u0026ge;\u0026thinsp;24 months of follow-up with available laboratory data were included. rhGH dosage ranged from 0.15 to 0.2 IU/kg/day. The sample size was determined by the number of eligible patients with complete follow-up during the study period.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eBaseline and follow-up data were extracted from electronic records, including demographics, anthropometrics, and family history. Laboratory measures\u0026mdash;fasting UA, TBIL, DBIL, and IGF-1\u0026mdash;were obtained as part of routine care using a Siemens ADVIA 2400 analyzer. Assessments were performed at baseline and approximately every 3 months up to 24 months. Blood samples were generally collected between 9:00 and 11:00 AM.\u003c/p\u003e \u003cp\u003eAssay methods included enzymatic peroxidase for UA, diazo for bilirubin, and chemiluminescence immunoassay for IGF-1. All procedures followed standardized quality control protocols. The rhGH formulation was supplied by Changchun Jinsai Pharmaceutical Co., Ltd.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAnalyses were performed with IBM SPSS 26.0 and GraphPad Prism 8.0. Normality was assessed using the Kolmogorov\u0026ndash;Smirnov test. Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (IQR). Longitudinal trends were evaluated with repeated-measures ANOVA and Bonferroni post-hoc tests. Multivariable logistic regression (stepwise) identified predictors of UA and bilirubin elevation, adjusted for age, sex, baseline BMI, and baseline UA. A two-tailed p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics and Quality Assurance\u003c/h3\u003e\n\u003cp\u003e The study complied with the Declaration of Helsinki. Daily calibration and quality controls were maintained, with intra- and inter-assay coefficients of variation below 5%.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eUric Acid Metabolic Changes\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;After 24 months of rhGH, serum UA rose from 291.73 \u0026plusmn; 75.32 \u0026mu;mol/L to 368.30 \u0026plusmn; 122.00 \u0026mu;mol/L (\u0026Delta; +76.57 \u0026mu;mol/L, p \u0026lt; 0.001). Dose-dependent correlations were strongest at 6 months (r = 0.269, p = 0.020) and 9 months (r = 0.262, p = 0.022).\u003c/p\u003e\n\u003cp\u003eMultivariable logistic regression identified baseline UA (OR = 1.15 per 10 \u0026mu;mol/L increase, 95% CI 1.05\u0026ndash;1.26, p = 0.003), rhGH dose (OR = 1.82 per 0.05 IU/kg/day increase, 95% CI 1.20\u0026ndash;2.75, p = 0.005), and \u0026Delta;BMI SDS (OR = 2.18, 95% CI 1.03\u0026ndash;4.64, p = 0.043) as independent predictors of UA elevation (\u0026gt;360 \u0026mu;mol/L or \u0026gt;20% increase from baseline). Fasting insulin was also strongly associated (OR = 3.82 per 5 \u0026mu;IU/mL increase, 95% CI 1.60\u0026ndash;9.10, p = 0.002).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Multivariable Logistic Regression Analysis of Clinically Significant Uric Acid Elevation*\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePredictor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBaseline UA\u0026nbsp;(per 10 \u0026mu;mol/L increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.05 \u0026ndash; 1.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003erhGH Dose\u0026nbsp;(per 0.05 IU/kg/day increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.20 \u0026ndash; 2.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026Delta;BMI SDS\u0026nbsp;(per 1.0 increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.03 \u0026ndash; 4.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFasting Insulin (INS)\u0026nbsp;(per 5 \u0026mu;IU/mL increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.60 \u0026ndash; 9.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations:\u0026nbsp;OR = odds ratio; CI = confidence interval.\u003cbr\u003e\u0026nbsp;*Note: The outcome variable was defined as serum uric acid concentration \u0026gt; 360 \u0026mu;mol/L or an increase of \u0026gt;20% from baseline at any point during the 24-month follow-up. The model was adjusted for age and sex.*\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBilirubin Dynamics\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;TBIL increased from 9.2 \u0026plusmn; 2.1 \u0026mu;mol/L to 10.5 \u0026plusmn; 2.5 \u0026mu;mol/L (\u0026Delta; +1.3 \u0026mu;mol/L, p \u0026lt; 0.05), and DBIL from 2.4 \u0026plusmn; 0.8 \u0026mu;mol/L to 3.1 \u0026plusmn; 1.0 \u0026mu;mol/L (\u0026Delta; +0.7 \u0026mu;mol/L, p \u0026lt; 0.05). All values remained within age-appropriate ranges.\u003c/p\u003e\n\u003cp\u003erhGH dose was an independent risk factor for bilirubin elevation (OR = 1.45 per 0.05 IU/kg/day increase, 95% CI 1.04\u0026ndash;2.02, p = 0.028). Conversely, \u0026Delta;IGF-1 SDS showed a protective effect (OR = 0.37, 95% CI 0.19\u0026ndash;0.74, p = 0.005).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Multivariable Logistic Regression Analysis of Bilirubin Elevation\u003c/strong\u003e*\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePredictor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003erhGH Dose\u003c/strong\u003e (per 0.05 IU/kg/day increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.04 \u0026ndash; 2.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta;IGF-1 SDS\u003c/strong\u003e (per 1.0 increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.19 \u0026ndash; 0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e\u003cem\u003e\u0026nbsp;OR = odds ratio; CI = confidence interval.\u003c/em\u003e\u003cbr\u003e*\u003cstrong\u003eNote:\u003c/strong\u003e The outcome variable was defined as total bilirubin (TBIL) exceeding the 95th percentile for age and sex or an increase of \u0026gt;25% from baseline at the 24-month follow-up. The model was adjusted for age, sex, and baseline BMI.*\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrates that long-term rhGH therapy in prepubertal children with ISS is associated with dose-dependent increases in UA and bilirubin over 24 months. Baseline UA, rhGH dose, and ΔBMI SDS independently predicted UA elevation, while ΔIGF-1 SDS appeared protective against bilirubin accumulation. These findings support risk-stratified monitoring during treatment.\u003c/p\u003e\n\u003cp\u003eThe sustained rise in UA may involve insulin resistance-mediated renal UA reabsorption [8,9] and direct hepatic effects of GH on purine catabolism via JAK2-STAT5 signaling and xanthine dehydrogenase upregulation [10,11]. Notably, mean UA approached the hyperuricemia threshold at 24 months, underscoring the need for vigilance in high-risk patients—particularly those with baseline UA \u0026gt;300 μmol/L. Insulin resistance, known to be induced by GH therapy [12], likely exacerbates UA retention, potentially creating a cycle in which hyperuricemia further worsens insulin sensitivity [13].\u003c/p\u003e\n\u003cp\u003eAlthough bilirubin elevations remained subclinical, the dose-dependent pattern suggests a subtle hepatic impact, possibly through GH receptor-mediated inhibition of conjugating enzymes such as UGT1A1 [4]. The protective role of IGF-1 response may reflect enhanced hepatocyte function and bilirubin clearance [14], a novel association that merits further experimental validation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations and Future Directions\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Limitations include the single-center design, moderate sample size, lack of direct enzyme activity measurements, and 24-month follow-up which may be insufficient to assess long-term trajectories. Future studies should focus on: (1) mechanistic evaluations of GH effects on purine and bilirubin pathways; (2) larger multicenter cohorts with extended follow-up; and (3) integration of omics technologies to explore individual susceptibility.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe propose a three-tiered management algorithm:\u003c/p\u003e\n\u003cp\u003eLow-risk\u0026nbsp;(baseline UA ≤300 μmol/L and dose ≤0.15 IU/kg/day): annual UA and bilirubin monitoring.\u003c/p\u003e\n\u003cp\u003eModerate/High-risk\u0026nbsp;(baseline UA \u0026gt;300 μmol/L or dose \u0026gt;0.15 IU/kg/day): metabolic and insulin sensitivity panels every 3–6 months.\u003c/p\u003e\n\u003cp\u003eIntervention threshold: If UA \u0026gt;360 μmol/L or DBIL \u0026gt;3.4 μmol/L on consecutive tests, multidisciplinary review for therapy adjustment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eISS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIidiopathic short stature\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003euric acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003erhGH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erecombinant human growth hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTBIL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etotal bilirubin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDBIL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edirect bilirubin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIGF-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInsulin-like Growth Factor-1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBody Mass Index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;We thank the patients and families for their participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was reviewed and approved by the\u0026nbsp;Ethics Committee of Taizhou Women and Children’s Hospital\u0026nbsp;(Approval No.: 2025-KY001-01). All procedures were conducted in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki Declaration and its later amendments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of Waiver of Informed Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study utilized fully anonymized clinical data extracted from electronic medical records. The need for written informed consent was formally waived by the Institutional Review Board (Ethics Committee) of Taizhou Women and Children's Hospital (Approval No.: 2025-KY001-01). This waiver was granted in accordance with national regulations and ethical guidelines governing retrospective research, as the study involved no more than minimal risk to participants, the research could not practicably be carried out without the waiver, and the waiver did not adversely affect the rights and welfare of the subjects. All data were handled with strict confidentiality, and all procedures were conducted in compliance with the ethical standards of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This manuscript contains no individual person’s data in any form (including individual details, images, or videos).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are not publicly available due to hospital data privacy policies but are available from the corresponding author (Ji Yan) upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGrimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB, et al. 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PMID: 28367214; PMCID: PMC5359528.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Recombinant human growth hormone, idiopathic short stature, uric acid, bilirubin, insulin resistance, retrospective study","lastPublishedDoi":"10.21203/rs.3.rs-8578234/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8578234/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aimed to examine the dose-dependent effects of recombinant human growth hormone (rhGH) therapy on uric acid (UA) and bilirubin metabolism in prepubertal children with idiopathic short stature (ISS) and to identify independent predictors of UA elevation.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective cohort study of 120 prepubertal children with ISS (57 boys, 63 girls) treated with rhGH (0.15\u0026ndash;0.2 IU/kg/day) between 2019 and 2023. Serum UA, total bilirubin (TBIL), and direct bilirubin (DBIL) levels were collected at baseline and at 3, 6, 9, 12, 15, 18, 21, and 24 months post-treatment. Metabolic trajectories were analyzed using repeated-measures ANOVA. Multivariable logistic regression was used to identify risk factors, adjusted for age, sex, baseline BMI, and baseline UA.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eUA levels increased significantly from 291.7\u0026thinsp;\u0026plusmn;\u0026thinsp;75.3 \u0026micro;mol/L at baseline to 368.3\u0026thinsp;\u0026plusmn;\u0026thinsp;122.0 \u0026micro;mol/L at 24 months (Δ\u0026thinsp;+\u0026thinsp;76.6 \u0026micro;mol/L, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A dose-dependent relationship was observed at 6 months (r\u0026thinsp;=\u0026thinsp;0.269, p\u0026thinsp;=\u0026thinsp;0.020) and 9 months (r\u0026thinsp;=\u0026thinsp;0.262, p\u0026thinsp;=\u0026thinsp;0.022). Independent predictors of UA elevation included baseline UA (OR\u0026thinsp;=\u0026thinsp;1.15 per 10 \u0026micro;mol/L increase, 95% CI 1.05\u0026ndash;1.26, p\u0026thinsp;=\u0026thinsp;0.003) and ΔBMI SDS (OR\u0026thinsp;=\u0026thinsp;2.18, 95% CI 1.03\u0026ndash;4.64, p\u0026thinsp;=\u0026thinsp;0.043). rhGH dose was also positively correlated with TBIL (r\u0026thinsp;=\u0026thinsp;0.269, p\u0026thinsp;=\u0026thinsp;0.020) and DBIL (r\u0026thinsp;=\u0026thinsp;0.265, p\u0026thinsp;=\u0026thinsp;0.020) at 6 months. Each 0.05 IU/kg/day increment in rhGH dose was associated with an eightfold increase in the risk of bilirubin elevation (OR\u0026thinsp;=\u0026thinsp;8.00, 95% CI 2.15\u0026ndash;29.70, p\u0026thinsp;=\u0026thinsp;0.002). A linear regression model projected that children with baseline UA\u0026thinsp;\u0026gt;\u0026thinsp;300 \u0026micro;mol/L receiving doses\u0026thinsp;\u0026gt;\u0026thinsp;0.15 IU/kg/day would maintain UA levels above the hyperuricemia threshold (360 \u0026micro;mol/L) at 24 months.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003erhGH therapy exerts dose-dependent effects on UA and bilirubin metabolism in clinical practice. We recommend intensified monitoring (every 3\u0026ndash;6 months) for children with baseline UA\u0026thinsp;\u0026gt;\u0026thinsp;300 \u0026micro;mol/L or on rhGH doses\u0026thinsp;\u0026gt;\u0026thinsp;0.15 IU/kg/day, along with evaluation of insulin resistance and hepatic function. Long-term metabolic surveillance is advised for high-risk children undergoing rhGH treatment.\u003c/p\u003e","manuscriptTitle":"Recombinant human growth hormone therapy induces dose-dependent increases in uric acid and bilirubin in children with idiopathic short stature a retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-05 08:24:44","doi":"10.21203/rs.3.rs-8578234/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6437551e-e046-4c1d-8735-c1d365d7fba7","owner":[],"postedDate":"February 5th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-11T13:57:52+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-05 08:24:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8578234","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8578234","identity":"rs-8578234","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}