[Clinical classification of pediatric non-alcoholic fatty liver disease based on pancreatic islet function]

Objective: To establish a clinical classification of pediatric non-alcoholic fatty liver disease (NAFLD) based on the homeostatic model assessment of insulin resistance (HOMA-IR) derived from healthy children, and to evaluate its clinical utility. Methods: This retrospective cohort study included 201 healthy children who underwent physical examination at the Children's Hospital, Zhejiang University School of Medicine between July 2020 and July 2022, and also 1 918 obese children with NAFLD who underwent metabolic evaluation at the same hospital between January 2003 and March 2023. Clinical and laboratory data including height, weight, blood pressure, transaminase serum uric acid, lipid profile, and glycated hemoglobin were collected. The 95th percentile (P₉₅) of HOMA-IR was calculated by Tanner stage among healthy children, and a "relative HOMA-IR multiple" was derived for each child with NAFLD by comparing their values of HOMA-IR with the stage-specific P₉₅. The optimal cut-off point of the relative HOMA-IR multiple for classification was determined using receiver operating characteristic (ROC) analysis. Based on this cut-off point, children with NAFLD were categorized into 3 subtypes: non-insulin-resistant (relative HOMA-IR multiple ≤1), mild insulin-resistant (>1 to ≤cut-off), and severe insulin-resistant (>cut-off). Comparisons between the groups were performed using Mann-Whitney U test, Kruskal-Wallis H test, and Chi-square test, and binary Logistic regression was used to examine associations between NAFLD subtypes and metabolic abnormalities. Results: Among the 201 healthy children, 103 (51.2%) were boys and 98 (48.8%) were girls, with the body mass index (BMI) of 16.4 (14.9, 18.3) kg/m². Among the 1 918 obese children with NAFLD, 1 422 (74.1%) were boys and 496 (25.9%) were girls, with the BMI of 28.8 (26.3, 31.6) kg/m². Non-alcoholic fatty liver and non-alcoholic steatohepatitis were identified in 1 121 (58.4%) and 797 (41.6%) children, respectively. The optimal classification cut-off for the relative HOMA-IR multiple was determined to be 1.78. Based on the new classification criteria, 486 children (25.3%) were categorized as non-insulin-resistant, 631 children (32.9%) as mild insulin-resistant, and 801 children (41.8%) as severe insulin-resistant. Significant differences were observed among the three groups in terms of sex, BMI, systolic blood pressure, glycated hemoglobin and insulin function (all P<0.05). Compared with the non-insulin resistant group, severe insulin resistance was significantly associated with hypertriglyceridemia, hyperuricemia, hypertension, and non-alcoholic steatohepatitis (OR=2.13, 1.69, 1.51, and 1.63, respectively, all P<0.05). Compared with the mild insulin resistance group, severe insulin resistance was significantly associated with low HDL cholesterol (OR=1.43, P<0.05). Conclusions: Based on HOMA-IR derived from healthy children, obese children with NAFLD can be classified into non-insulin-resistant, mild insulin-resistant, and severe insulin-resistant subtypes. This novel classification is significantly associated with multiple metabolic abnormalities and may provide a reference for the clinical assessment and management of obese children with NAFLD.