Lipedema Reframed: AFS Framework for Surgical and Transdisciplinary Management

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 .