Lipedema Reframed: AFS Framework for Surgical and Transdisciplinary Management

Abstract Background Lipedema has long been misclassified as a cosmetic concern or a subtype of obesity, leading to delayed diagnosis and suboptimal surgical outcomes. Growing molecular, histopathologic, and imaging evidence supports lipedema as a systemic disorder involving adipose tissue, connective matrix, vascular–lymphatic integrity, and neuroimmune regulation. To integrate these findings into a clinically actionable model, we introduce the concept of Adipoconnective Fragility Syndrome (AFS), framing lipedema as a multisystem condition with direct implications for surgical planning and perioperative management. Methods A narrative review of the literature was conducted, integrating evidence from adipose biology, connective tissue pathology, endocrine signaling, vascular–lymphatic dysfunction, and pain neurobiology relevant to lipedema. Emphasis was placed on mechanisms with established clinical correlations, including disease progression, symptom severity, and surgical outcomes. Results Lipedema tissue demonstrates early adipocyte hyperplasia, immune dysregulation, hypoxia-driven fibrosis, and abnormal sodium handling, resulting in a fragile adipoconnective microenvironment. Alterations in caveolar biology particularly involving CAVEOLIN-1 and its interaction with matrix remodeling pathways emerge as a key molecular mechanism contributing to hormonal hypersensitivity, vascular permeability, lymphatic overload, and pain. Within the AFS framework, these processes explain the resistance to weight-loss strategies, the propensity for recurrence, and the heterogeneity of surgical outcomes observed in clinical practice. Conclusions Reframing lipedema as an Adipoconnective Fragility Syndrome provides a clinically relevant framework that enhances surgical decision-making rather than diminishing the role of surgery. This model supports earlier diagnosis, improved patient selection, individualized perioperative optimization, and structured long-term follow-up, aimed at reducing complications and recurrence. By linking molecular vulnerability to clinical behavior, AFS facilitates a more precise, multidisciplinary, and mechanism-based approach to the surgical management of lipedema. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .