Uric Acid in Pediatric MASLD Definition: is It Time to Implement Diagnostic Criteria?

A multisociety Delphi consensus statement on new fatty liver disease nomenclatureJournal of HepatologyVol. 79Issue 6PreviewThe principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Full-Text PDF Open Access We read with great interest the article of He et al.1He L. Qiu K. Zheng W. et al.Uric acid may serve as the sixth cardiometabolic criterion for defining MASLD.J Hepatol. 2023 Dec 16; (S0168-8278(23)05363-1. 29)Abstract Full Text Full Text PDF Scopus (0) Google Scholar suggesting uric acid (UA) as the sixth cardiometabolic criterion for metabolic dysfunction-associated steatotic liver disease (MASLD).2Rinella M.E. Lazarus J.V. Ratziu V. et al.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; 79: 1542-1556Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar Over recent years, UA has garnered remarkable scientific interest owing to its close pathogenic link with fatty liver disease3Russo E. Leoncini G. Esposito P. et al.Fructose and uric acid: major mediators of cardiovascular disease risk starting at pediatric age.Int J Mol Sci. 2020; 21Crossref Scopus (34) Google Scholar and cardiometabolic markers in children with obesity.4Di Bonito P. Valerio G. Licenziati M.R. et al.High uric acid, reduced glomerular filtration rate and non-alcoholic fatty liver in young people with obesity.J Endocrinol Invest. 2020 Apr; 43: 461-468Crossref PubMed Scopus (29) Google Scholar,5Luciano R. Shashaj B. Spreghini M. et al.Percentiles of serum uric acid and cardiometabolic abnormalities in obese Italian children and adolescents.Ital J Pediatr. 2017; 43: 3Crossref PubMed Scopus (26) Google Scholar Given also the strong association of MASLD with cardiometabolic risk,6Platek A.E. Szymanska A. Metabolic dysfunction-associated steatotic liver disease as a cardiovascular risk factor.Clin Exp Hepatol. 2023; 9: 187-192Crossref PubMed Scopus (5) Google Scholar as emphasized in the new definition,2Rinella M.E. Lazarus J.V. Ratziu V. et al.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; 79: 1542-1556Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar the proposed inclusion of UA among MASLD diagnostic criteria also deserves attention in children. Hypothesizing that the inclusion of hyperuricemia (HUA) within the MASLD definition could improve identification of patients with a worse cardiometabolic profile, we aimed to evaluate its feasibility as a further MASLD criterion in a cohort of 4,023 children with obesity (BMI >95th percentile according to reference values). Exclusion criteria were considered secondary forms of obesity and/or non-alcoholic fatty liver disease, both type 1 and 2 diabetes mellitus, consumption of any medication, missing data, or denying consent to undergo diagnostic procedures. To detect hepatic steatosis, all participants underwent an abdominal ultrasound. Ultrasonic steatosis was defined as bright liver sign compared to the right kidney. Having examined a population of children with obesity, we did not consider obesity as a criterion for defining metabolic dysfunction (MD).7Di Sessa A. Guarino S. Umano G.R. et al.MAFLD in obese children: a challenging definition.Children (Basel). 2021; 8 (23) (2021): 247PubMed Google Scholar Therefore, according to diagnostic criteria,2Rinella M.E. Lazarus J.V. Ratziu V. et al.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; 79: 1542-1556Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar patients with at least one of the following five metabolic abnormalities among prediabetes, high blood pressure (BP) (<13 years BP ≥95° percentile; ≥13 years BP ≥130/85 mmHg), high plasma triglycerides (TG) (<10 years ≥100 mg/dl; ≥10 years ≥150 mg/dl) or low high-density lipoprotein-cholesterol (HDL-c) (≤40 mg/dl) levels were categorized as having MD.2Rinella M.E. Lazarus J.V. Ratziu V. et al.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; 79: 1542-1556Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar We categorized patients with obesity, hepatic steatosis, and at least one of the remaining metabolic features as being affected by MASLD. HUA was defined as a UA value ≥75th percentile adjusted for age and sex.5Luciano R. Shashaj B. Spreghini M. et al.Percentiles of serum uric acid and cardiometabolic abnormalities in obese Italian children and adolescents.Ital J Pediatr. 2017; 43: 3Crossref PubMed Scopus (26) Google Scholar On the basis of the presence of MD and HUA, the population was divided into patients with MD and HUA (n = 1,539), patients with only MD (n = 1,076), patients with only HUA (n = 985), and patients without MD or HUA (n = 423). The study population presented with a mean age of 10.73±2.89 years and a mean BMI-SDS of 2.69±0.89. The overall prevalence of HUA was 46.8%. Moreover, 33.9% of children with MD had HUA, while it was detected in 22.4% of those without MD (p = 0.03). Separately considering patients with MD, those with HUA had a higher prevalence of fatty liver (65.4% vs. 34.6%, p = 0.01), systolic BP-SDS, TGs, TG/HDL-c ratio, and homeostasis model assessment of insulin resistance (HOMA-IR) levels than peers without HUA (all p < 0.05). Similarly, among patients without MD, increased BP-SDS and TG levels were found in those with HUA compared to counterparts without HUA (all p < 0.05). Fatty liver was reported in 56.5% of patients with HUA/MD, 19.4% without HUA/MD, 28.7% with HUA, and 34.2% with MD (p = 0.01). As expected, children with HUA/MD had higher BMI-SDS, BP-SDS, TG/HDL-c ratio, triglycerides, and HOMA-IR levels than those without HUA/MD (all p < 0.0001). The odds ratio (OR) of having fatty liver is shown in Table 1. The highest OR was for patients with HUA/MD followed by patients with HUA. Patients without HUA/MD did not have a significant OR for fatty liver (Table 1). According to current diagnostic criteria, the prevalence of MASLD in our population was 32.3%, which increases to 45.9% when adding UA >75th percentile as a further diagnostic criterion (p= 0.01).Table 1Odds ratio for fatty liver according to HUA/MD presence adjusted for age, sex, BMI-SDS, HOMA-IR, and transaminase levels.ORaAdjusted for age, sex, alanine aminotransferase, aspartate aminotransferase, BMI-SDS, and HOMA-IR. (95% CI)p valueHUA1.77 (1.06-2.94)0.02MD1.11 (1.01-1.52)0.04HUA/MD5.13 (2.38-11.06)<0.0001Without HUA/MD0.99 (0.98-1.01)0.62The results were obtained by logistic regression.Values in bold denote statistical significance.HOMA-IR, homeostasis model assessment of insulin resistance; HUA, hyperuricemia; MASLD, metabolic dysfunction-associated steatotic liver disease; MD, metabolic dysfunction with at least one of the cardiometabolic criteria for MASLD except for BMI.a Adjusted for age, sex, alanine aminotransferase, aspartate aminotransferase, BMI-SDS, and HOMA-IR. Open table in a new tab The results were obtained by logistic regression. Values in bold denote statistical significance. HOMA-IR, homeostasis model assessment of insulin resistance; HUA, hyperuricemia; MASLD, metabolic dysfunction-associated steatotic liver disease; MD, metabolic dysfunction with at least one of the cardiometabolic criteria for MASLD except for BMI. As previously demonstrated in adults,1He L. Qiu K. Zheng W. et al.Uric acid may serve as the sixth cardiometabolic criterion for defining MASLD.J Hepatol. 2023 Dec 16; (S0168-8278(23)05363-1. 29)Abstract Full Text Full Text PDF Scopus (0) Google Scholar our results support and strengthen the potential inclusion of UA as a sixth cardiometabolic criterion for the diagnosis of MASLD. Notably, the coexistence of HUA in patients with MD demonstrated a better diagnostic performance in terms of cardiometabolic risk stratification. Indeed, an overall worse cardiometabolic risk profile has been demonstrated in children with HUA, in the presence or absence of MD. Taken together, these findings corroborate the intimate link of UA with metabolic health, as highlighted by its role as an independent risk factor for cardiometabolic morbidity and mortality.8Kanbay M. Segal M. Afsar B. et al.The role of uric acid in the pathogenesis of human cardiovascular disease.Heart. 2013; 99: 759-766Crossref PubMed Scopus (328) Google Scholar,9Vareldzis R. Perez A. Reisin E. Hyperuricemia: an intriguing connection to metabolic syndrome, diabetes, kidney disease, and hypertension.Curr Hypertens Rep. 2024 Jan 25; (Epub ahead of print)https://doi.org/10.1007/s11906-024-01295-3Crossref PubMed Scopus (2) Google Scholar From a pathophysiological point of view, a close relationship between UA and IR has been found through several molecular pathways.3Russo E. Leoncini G. Esposito P. et al.Fructose and uric acid: major mediators of cardiovascular disease risk starting at pediatric age.Int J Mol Sci. 2020; 21Crossref Scopus (34) Google Scholar,9Vareldzis R. Perez A. Reisin E. Hyperuricemia: an intriguing connection to metabolic syndrome, diabetes, kidney disease, and hypertension.Curr Hypertens Rep. 2024 Jan 25; (Epub ahead of print)https://doi.org/10.1007/s11906-024-01295-3Crossref PubMed Scopus (2) Google Scholar To complicate matters, UA has recently been demonstrated to act as an independent risk factor for cardiovascular disease,5Luciano R. Shashaj B. Spreghini M. et al.Percentiles of serum uric acid and cardiometabolic abnormalities in obese Italian children and adolescents.Ital J Pediatr. 2017; 43: 3Crossref PubMed Scopus (26) Google Scholar,9Vareldzis R. Perez A. Reisin E. Hyperuricemia: an intriguing connection to metabolic syndrome, diabetes, kidney disease, and hypertension.Curr Hypertens Rep. 2024 Jan 25; (Epub ahead of print)https://doi.org/10.1007/s11906-024-01295-3Crossref PubMed Scopus (2) Google Scholar further enhancing its role as a robust cardiometabolic risk marker.8Kanbay M. Segal M. Afsar B. et al.The role of uric acid in the pathogenesis of human cardiovascular disease.Heart. 2013; 99: 759-766Crossref PubMed Scopus (328) Google Scholar,9Vareldzis R. Perez A. Reisin E. Hyperuricemia: an intriguing connection to metabolic syndrome, diabetes, kidney disease, and hypertension.Curr Hypertens Rep. 2024 Jan 25; (Epub ahead of print)https://doi.org/10.1007/s11906-024-01295-3Crossref PubMed Scopus (2) Google Scholar Considering the ease of measuring UA levels, unlike the cardiometabolic factors (e.g. HOMA-IR and high-sensitivity C-reactive protein) required for the diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD),10Eslam M. Alkhouri N. Vajro P. et al.Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement.Lancet Gastroenterol Hepatol. 2021; 6: 864-873Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar its inclusion among MASLD criteria might further enhance risk stratification for young patients with obesity and substantially improve their overall management. Although promising, the role of this criterion in clinical practice needs to be confirmed in larger studies. The authors did not receive any financial support to produce this manuscript. The authors of this study declare that they do not have any conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. ADS drafted the paper. ADS, PM, SG, and GRU participated in the conception and the design of the study. ADS, EMDG, and PM supervised the design and execution of the study. All authors read and approved the final manuscript. The following are the supplementary data to this article: Download .pdf (.34 MB) Help with pdf files Multimedia component 1