Interstitial Fluid in Lipedema and Control Skin

Marisol Allen, Michael Schwartz, Karen L Herbst, Marisol Allen, Michael Schwartz, Karen L Herbst

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.

Keywords: extracellular matrix; glycosaminoglycan; interstitium; leaky lymphatics; lipedema; lymphedema; microangiopathy.

Conflict of interest statement

No competing financial interests exist.

© Marisol Allen et al., 2020; Published by Mary Ann Liebert, Inc.

Figures

FIG. 1.
FIG. 1.
Dermal vessels from thigh skin of women with lipedema. (A) Lumens of two dermal vessels (*) from a woman with Stage 1 lipedema. Abnormal vessel phenotype: black arrows denote rounded endothelial cells. Dotted arrow points to perivascular immune cell infiltrate. The white arrow denotes the enlarged perivascular space. Note the close packing of the maroon-colored collagen fibers in the dermis with almost no space between. H&E. 60 × . (B) An elongated vessel with multiple lumens (*) in the dermis of a woman with Stage 3 lipedema; the base of the epidermis can be seen at the top of the picture. Note the lack of AVP and the wide spacing of collagen fibrils in the dermis (black arrows). H&E. 40 × to allow clear visualization of spaces. AVP, abnormal vessel phenotype; H&E, hematoxylin and eosin.
FIG. 2.
FIG. 2.
Leaky vessel phenotype in women with and without lipedema (controls) matched for age and BMI for the thigh (A) and matched separately for age and BMI for the abdomen (B). Capped lines show significant differences between groups. Significance by unpaired t-test. BMI, body mass index.
FIG. 3.
FIG. 3.
Women with Stage 1 lipedema have a greater percentage of AVP in the thigh than women with Stage 3 lipedema or controls. (A) Percent vessels with AVP in controls and all stages of lipedema by ANOVA. Capped lines show significant differences between groups. (B) Simple linear regression of means of percent abnormal vessels from all stages of lipedema. L1, lipedema Stage 1; L2, lipedema Stage 2; L3, lipedema Stage 3. ANOVA, analysis of variance.
FIG. 4.
FIG. 4.
(A) Women with lipedema who are not obese have more vessels with a leaky vessel phenotype in the thigh compared with women with lipedema with obesity, who are obese or controls with and without obesity by ANOVA. Capped lines show significant differences between groups. (B) There was a negative relationship between BMI and leaky vessel phenotype in women with lipedema but not controls by Pearson correlation.
FIG. 5.
FIG. 5.
Space between collagen fibers in the dermis of the thigh in controls and women with lipedema with or without obesity. (A) Collagen space was significantly greater in women with Stage 3 lipedema compared with women with Stage 1 lipedema or controls, and women with Stage 2 lipedema compared with controls by ANOVA. (B) Dermal spaces were significantly larger in thigh skin of women with lipedema whether obese or not obese compared with controls. Capped lines show significant differences between groups. L1, lipedema Stage 1; L2, lipedema Stage 2; L3, lipedema Stage 3.

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