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Background Lipedema is a chronic adipose tissue disorder affecting primarily women and is increasingly associated with immune dysregulation and intestinal permeability. Food-specific IgG testing has been explored in various inflammatory conditions, but its relevance to lipedema remains unknown. Objective The objective of this study is to characterize IgG food sensitivity profiles in women with lipedema and investigate the paradoxical relationship between increased food reactivity and reduced total IgG antibody levels. Methods We conducted a retrospective cross-sectional study involving 234 participants: women with lipedema (n=80), women without lipedema (n=74), and men (n=80). All had undergone IgG testing against 222 food antigens via ELISA. We analyzed qualitative (positive/negative) and quantitative IgG reactivity, applied dimensionality reduction (PCA, t-SNE) and clustering, and developed a multivariable logistic regression model to assess diagnostic performance. Results Women with lipedema exhibited a non-significantly higher number of positive IgG food reactions (14.8 vs 12.6; p=0.186), despite significantly lower total IgG levels (1747.1 vs 2974.8 AU; p<0.001). This paradox was consistent across 79.7% of tested antigens. The most discriminative foods included wild game meats and certain vegetables. A combined IgG-based model achieved an area under the curve of 0.804, outperforming individual IgG metrics. Dimensionality reduction revealed no clear clustering based on reactivity patterns alone. Conclusion Lipedema displays a paradoxical IgG signature, more frequent positives despite lower total IgG, consistent with mucosal immune dysregulation (e.g., increased intestinal permeability, immune exhaustion, or dietary monotony). Single IgG metrics had limited discrimination, but a combined score improved classification, supporting IgG profiling as a complementary, not standalone, biomarker for patient stratification and personalized dietary guidance. Collectively, these findings suggest that the adipose phenotype may be downstream of broader systemic processes; prospective studies should assess IgG subclasses, barrier markers (e.g., zonulin), and gluten-modulated interventions.