Comorbidities in lipedema: toward a systemic perspective – a narrative review

Lipedema has historically been classified within obesity- and lymphedema-related frameworks, despite its distinct clinical features and frequent occurrence in individuals with normal or low body mass index. This narrative review examines whether the distribution of associated conditions reported in clinical cohorts is more consistent with a localized adipose-centered model or may suggest broader systemic involvement. Recent clinical and epidemiological studies have reported a clustering of manifestations affecting multiple biological domains in patients with lipedema, including connective tissue laxity and hypermobility, chronic venous disease, thyroid dysfunction and autoimmunity, endocrine–gynecological alterations, vitamin D deficiency, gastrointestinal disturbances, chronic widespread pain, and neuropsychological burden. Histopathological and microvascular investigations have also described alterations in extracellular matrix organization, stromal components, and endothelial structures within affected tissues. However, much of the available evidence derives from observational, cross-sectional, or survey-based studies, and potential confounding factors such as referral bias, obesity, and healthcare-seeking behavior should be considered when interpreting these associations. Taken together, these observations raise the possibility that lipedema may involve biological processes extending beyond adipose tissue alone. While current evidence does not yet establish a unified mechanism, the recurrent co-occurrence of connective, vascular, endocrine, and systemic features across multiple cohorts may be compatible with a broader vulnerability affecting connective tissue integrity and stromal microenvironment regulation. A multisystem perspective may therefore provide a useful conceptual framework for interpreting the clinical heterogeneity of lipedema and for guiding future mechanistic and longitudinal studies.