The Etiology of Pain in Lipedema Is Not Yet Fully Understood. An Integrative Synthesis of Inflammatory, Hypoxic-Hemorrhagic, Adipomyofascial, and Neuromolecular Mechanisms Based on Histopathological Evidences

Lipedema is a chronic disease characterized by the accumulation of subcutaneous adipose tissue in the lower and upper limbs, sparing the trunk, hands and feet. Diagnosis is clinical, with the most frequent symptoms being pain, sensation of heaviness in legs, and spontaneous bruising. The understanding of the etiology of pain in this condition still lacks robust scientific evidence. Based on the integration of histopathological, biomechanical, and neurobiological findings, the authors propose a model that considers the convergence of four main mechanisms: inflammatory, hypoxic-hemorrhagic, adipomyofascial, and neuromolecular. Histopathological studies suggest a state of chronic inflammation in addition to ischemia, leading to the release of pro-nociceptive mediators capable of sensitizing peripheral nerve endings. Hypertrophy and hyperplasia of adipose tissue promote progressive compression of the microcirculation, resulting in sustained hypoxia, venous congestion, and vascular remodeling. This environment may favor erythrocyte extravasation and the accumulation of hemoglobin degradation products, which are highly irritating to hypodermis. Pain may also arise from structural remodeling of the fascia, including thickening, increased disorganized collagen deposition, interstitial fibrosis, and reduced myofascial gliding. This mechanical dysfunction may lead to a chronic fasciitis-like condition. In addition, a synergistic interaction among these factors may result in structural and functional injury to nerve fibers, characterizing a state of painful peripheral neuropathy. Hypotheses inferred from the biology of pain (neuromolecular axis) related to adipose/fascial tissue are also presented, since direct measurements of specific tissue for lipedema are still limited. Adipose tissue, microcirculation, and the fascia act as an integrated system that may contribute to the generation and perpetuation of pain, establishing a pathophysiological vicious cycle. This model provides a basis for therapeutic development aimed at inflammatory modulation, restoration of perfusion, control of vascular leakage, optimization of fascial function, and neuroprotection.