Interstitial Fluid in Lipedema and Control Skin

Abstract

Background: Fluid in lymphedema tissue appears histologically as spaces around vessels and between dermal skin fibers. Lipedema is a painful disease of excess loose connective tissue (fat) in limbs, almost exclusively of women, that worsens by stage, increasing lymphedema risk. Many women with lipedema have hypermobile joints suggesting a connective tissue disorder that may affect vessel structure and compliance of tissue resulting in excess fluid entering the interstitial space. It is unclear if excess fluid is present in lipedema tissue. The purpose of this study is to determine if fluid accumulates around vessels and between skin fibers in the thigh tissue of women with lipedema. Methods: Skin biopsies from the thigh and abdomen from 30 controls and 80 women with lipedema were evaluated for dermal spaces and abnormal vessel phenotype (AVP): (1) rounded endothelial cells; (2) perivascular spaces; and (3) perivascular immune cell infiltrate. Women matched for body mass index (BMI) and age were considered controls if they did not have lipedema on clinical examination. Data were analyzed by analysis of variance (ANOVA) or unpaired t-tests using GraphPad Prism Software 7. p < 0.05 was considered significant. Results: Lipedema tissue mass increases beginning with Stage 1 up to Stage 3, with lipedema fat accumulating more on the limbs than the abdomen. AVP was higher in lipedema thigh (p = 0.003) but not abdomen skin compared with controls. AVP was higher in thigh skin of women with Stage 1 (p = 0.001) and Stage 2 (p = 0.03) but not Stage 3 lipedema versus controls. AVP also was greater in the thigh skin of women with lipedema without obesity versus lipedema with obesity (p < 0.0001). Dermal space was increased in lipedema thigh (p = 0.0003) but not abdomen versus controls. Dermal spaces were also increased in women with lipedema Stage 3 (p < 0.0001) and Stage 2 (p = 0.0007) compared with controls. Conclusion: Excess interstitial fluid in lipedema tissue may originate from dysfunctional blood vessels (microangiopathy). Increased compliance of connective tissue in higher stages of lipedema may allow fluid to disperse into the interstitial space, including between skin dermal fibers. Lipedema may be an early form of lymphedema. ClinicalTrials.gov: NCT02838277.

Letter: Could endothelial dysfunction and vascular damage contribute to pain, inflammation and post-exertional malaise in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)?

“…As researchers study this phenomenon, I would encourage consideration of the additional possibility that the leaking fluid causes independent damage. Lipedema researchers have found that leakages from microangiopathic blood vessels cause an excess of interstitial fluid that stimulates the formation of subcutaneous adipose tissue [ 3 ], which generates hypoxic conditions and becomes fibrotic, contributing to pain and inflammation [ 4 ].…”

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

“…Specifically, elevated macrophages surround adipocytes in lipedema SAT forming adipose crown-like structures were noted [ 87 ]. CD45+ lymphocytes and CD68+ macrophages were also observed in lipedema adipose tissue [ 88 , 89 ] and skin [ 91 ]. However, this infiltrate does not appear to contain the same T cell involvement identified as a key feature seen in lymphedema [ 88 , 89 , 91 ].…”

“…CD45+ lymphocytes and CD68+ macrophages were also observed in lipedema adipose tissue [ 88 , 89 ] and skin [ 91 ]. However, this infiltrate does not appear to contain the same T cell involvement identified as a key feature seen in lymphedema [ 88 , 89 , 91 ].…”

“…Another potential inflammatory route in lipedema is via interstitial fluid accumulation resulting from microvascular dysfunction. Interstitial fluid and tissue volume homeostasis are disrupted in lipedema, with evidence of interstitial fluid accumulation [ 91 ] and tissue sodium and adipose deposition [ 95 , 96 ]. Indeed, lymphatic bulk transport is compromised in lipedema [ 100 , 101 , 102 , 103 , 104 ], lending clinically significant evidence of lymphatic disease.…”

Multi-level analysis of adipose tissue reveals the relevance of perivascular subpopulations and an increased endothelial permeability in early-stage lipedema

“…Microangiopathy associated with the fat growth very early in the disease might lead to a disruption of the endothelial barrier function and to an increase in the permeability of the capillaries [14, 20]. As a result, protein-rich fluid from the vascular system could enter the tissue [21]. In addition, also macroangiopathy develops, which mainly affects the venous vasculature.…”