Current Mechanistic Understandings of Lymphedema and Lipedema: Tales of Fluid, Fat, and Fibrosis

Abstract

Lymphedema and lipedema are complex diseases. While the external presentation of swollen legs in lower-extremity lymphedema and lipedema appear similar, current mechanistic understandings of these diseases indicate unique aspects of their underlying pathophysiology. They share certain clinical features, such as fluid (edema), fat (adipose expansion), and fibrosis (extracellular matrix remodeling). Yet, these diverge on their time course and known molecular regulators of pathophysiology and genetics. This divergence likely indicates a unique route leading to interstitial fluid accumulation and subsequent inflammation in lymphedema versus lipedema. Identifying disease mechanisms that are causal and which are merely indicative of the condition is far more explored in lymphedema than in lipedema. In primary lymphedema, discoveries of genetic mutations link molecular markers to mechanisms of lymphatic disease. Much work remains in this area towards better risk assessment of secondary lymphedema and the hopeful discovery of validated genetic diagnostics for lipedema. The purpose of this review is to expose the distinct and shared (i) clinical criteria and symptomatology, (ii) molecular regulators and pathophysiology, and (iii) genetic markers of lymphedema and lipedema to help inform future research in this field.

Keywords: adipogenesis; extracellular matrix; fibrosis; inflammation; lipedema; lymphedema; obesity; pain; vascular disease.

Figure 1

Pathophysiological features of lymphedema and lipedema are represented graphically to emphasize (i) the overlapping pathologies involved in each disease, and yet (ii) their different prominence in disease progression. Pathologies which are most prominent are graphed in the widest section, with fluid being most prominent in lymphedema and adiposity most prominent in lipedema. The time course of these pathologies is potentially reversed, represented by a solid arrow for the well-established disease progression of lymphedema, and a dashed arrow in reverse order for lipedema where adipose tissue or extracellular matrix dysfunction could give way to inflammation and an increased immune response.