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.

Indications of Peripheral Pain, Dermal Hypersensitivity, and Neurogenic Inflammation in Patients with Lipedema

“…Participants with lipedema met all primary criteria (bilateral swelling leg swelling, a negative Stemmer’s sign, and positive for lipedema by stage and type) and at least two secondary criteria (lower extremity pain, family history of lipedema, joint hypermobility, or easy leg bruising) as previously described [ 31 ]. Lipedema staging followed the criteria recently described in a lipedema “standard of care” manuscript [ 1 , 32 ]. During the physical exam, height and weight were measured and converted to metric units and BMI calculated (kg/m 2 ).…”

MRI of Lymphedema

“…These features seen on imaging exams allow for differentiation from other conditions like phlebedema or lipidema, which can be clinically challenging. [90][91][92] Grading systems that take into account the degree of fat and fluid contributions to extremity swelling in chronic lymphedema would assist in determining whether a patient could undergo debulking vs. direct lymphatic repair. 86 Microreconstruction planning can require a detailed assessment of regional lymph node characteristics and precise depiction of the lymphatic system including number, diameter, and location.…”

“…8). These features seen on imaging exams allow for differentiation from other conditions like phlebedema or lipidema, which can be clinically challenging 90–92 . Grading systems that take into account the degree of fat and fluid contributions to extremity swelling in chronic lymphedema would assist in determining whether a patient could undergo debulking vs. direct lymphatic repair 86 …”

Optimizing Lymphedema Outcomes through Lifestyle

“…Damage to lymphatic structures from traumatic injury such as surgery, radiation treatments, or infection can also result in lymphedema [5]. In addition, since prolonged fluid overload results in further insults to the lymphatic system, lymphedema etiology is often multicausal [6].…”