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Lipedema, lipohypertrophy and secondary lymphedema are three conditions characterized by disproportionate subcutaneous fat accumulation affecting the extremities. Despite the apparent similarities and differences among their phenotypes, a comprehensive histological and molecular comparison does not yet exist, supporting the idea that there is an insufficient understanding of the conditions and particularly of lipohypertrophy. In our study, we performed histological and molecular analysis in anatomically-, BMI- and gender-matched samples of lipedema, lipohypertrophy and secondary lymphedema versus healthy control patients. Hereby, we found a significantly increased epidermal thickness only in patients with lipedema and secondary lymphedema, while significant adipocyte hypertrophy was identified in both lipedema and lipohypertrophy. Interestingly, the assessment of lymphatic vessel morphology showed significantly decreased total area coverage in lipohypertrophy versus the other conditions, while VEGF-D expression was significantly decreased across all conditions. The analysis of junctional genes often associated with permeability indicated a distinct and higher expression only in secondary lymphedema. Finally, the evaluation of the immune cell infiltrate verified the increased CD4+ cell and macrophage infiltration in lymphedema and lipedema respectively, without depicting a distinct immune cell profile in lipohypertrophy. Our study describes the distinct histological and molecular characteristics of lipohypertrophy, clearly distinguishing it from its two most important differential diagnoses.

OBJECTIVE: Upper extremity lymphedema (UEL) is a burdensome disease with significant impact on quality of life underscoring the importance of quality of life measurements in this patient population. Only recently, the LYMPH Q Upper Extremity Module, a new patient-reported outcome measurement (PROM), has been developed. The aim of the study was to translate the LYMPH Q Upper Extremity Module from English to German and perform a comprehensive validation. METHODS: Translation was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) best-practice guidelines. To validate the German LYMPH Q, a multicenter study was conducted. Internal consistency was determined by Cronbach's alpha. Reliability was assessed by the intra-class correlation coefficient (ICC). To analyse construct validity, a Pearson correlation coefficient between the LYMPH Q, quickDASH and SF-36 was calculated. Responsiveness was assessed by comparing the pre- and postoperative LYMPH Q scores in five patients receiving lymphatic reconstructive surgery. RESULTS: Validation was performed in a cohort of 65 patients. Internal consistency of the different domains was good to excellent (α: 0.87-0.97). ICC ranged from 0.74 to 0.92. The domains of the LYMPH Q correlated significantly with the corresponding domains of the SF-36 and quick DASH. Construct validity was good with eight of ten hypotheses confirmed. Significant improvements of function (46.4 ± 13.3 vs. 77.8 ± 11.5; p= 0.03), symptoms (42.0 ± 10.7 vs. 70.6 ± 11.6; p= 0.02) and psychological well-being (40.4 ± 14.6 vs. 78.0 ± 17.3; p= 0.03) were observed after lymphatic reconstructive surgery. CONCLUSION: The German version of The LYMPH Q Upper Extremity Module is conceptually equivalent to the original English version. It is a reliable and valid PROM to assess physical and psychological impairments in patients with UEL.

Lipedema is an adipose tissue disorder characterized by the disproportionate increase of subcutaneous fat tissue in the lower and/or upper extremities. The underlying pathomechanism remains unclear and no molecular biomarkers to distinguish the disease exist, leading to a large number of undiagnosed and misdiagnosed patients. To unravel the distinct molecular characteristic of lipedema we performed lipidomic analysis of the adipose tissue and serum of lipedema versus anatomically- and body mass index (BMI)-matched control patients. Both tissue groups showed no significant changes regarding lipid composition. As hyperplastic adipose tissue represents low-grade inflammation, the potential systemic effects on circulating cytokines were evaluated in lipedema and control patients using the Multiplex immunoassay system. Interestingly, increased systemic levels of interleukin 11 (p = 0.03), interleukin 28A (p = 0.04) and interleukin 29 (p = 0.04) were observed. As cytokines can influence metabolic activity, the metabolic phenotype of the stromal vascular fraction was examined, revealing significantly increased mitochondrial respiration in lipedema. In conclusion, despite sharing a comparable lipid profile with healthy adipose tissue, lipedema is characterized by a distinct systemic cytokine profile and metabolic activity of the stromal vascular fraction.

Lipedema is a chronic adipose tissue disorder characterized by the disproportional subcutaneous deposition of fat and is commonly misdiagnosed as lymphedema or obesity. The molecular determinants of the lipedema remain largely unknown and only speculations exist regarding the lymphatic system involvement. The aim of the present study is to characterize the lymphatic vascular involvement in established lipedema. The histological and molecular characterization was conducted on anatomically-matched skin and fat biopsies as well as serum samples from eleven lipedema and ten BMI-matched healthy patients. Increased systemic levels of vascular endothelial growth factor (VEGF)-C (P = 0.02) were identified in the serum of lipedema patients. Surprisingly, despite the increased VEGF-C levels no morphological changes of the lymphatic vessels were observed. Importantly, expression analysis of lymphatic and blood vessel-related genes revealed a marked downregulation of Tie2 (P < 0.0001) and FLT4 (VEGFR-3) (P = 0.02) consistent with an increased macrophage infiltration (P = 0.009), without changes in the expression of other lymphatic markers. Interestingly, a distinct local cytokine milieu, with decreased VEGF-A (P = 0.04) and VEGF-D (P = 0.02) expression was identified. No apparent lymphatic anomaly underlies lipedema, providing evidence for the different disease nature in comparison to lymphedema. The changes in the lymphatic-related cytokine milieu might be related to a modified vascular permeability developed secondarily to lipedema progression.

Lipedema is a chronic and progressive adipose tissue disorder, characterized by the painful and disproportionate increase of the subcutaneous fat in the lower and/or upper extremities. While distinct immune cell infiltration is a known hallmark of the disease, its role in the onset and development of lipedema remains unclear. To analyze the macrophage composition and involved signaling pathways, anatomically matched lipedema and control tissue samples were collected intra-operatively from gender- and BMI-matched patients, and the Stromal Vascular Fraction (SVF) was used for Cytometry by Time-of-Flight (CyTOF) and RNA sequencing. The phenotypic characterization of the immune component of lipedema versus control SVF using CyTOF revealed significantly increased numbers of CD163 macrophages. To gain further insight into this macrophage composition and molecular pathways, RNA sequencing of isolated CD11b+ cells was performed. The analysis suggested a significant modification of distinct gene ontology clusters in lipedema, including cytokine-mediated signaling activity, interleukin-1 receptor activity, extracellular matrix organization, and regulation of androgen receptor signaling. As distinct macrophage populations are known to affect adipose tissue differentiation and metabolism, we evaluated the effect of M2 to M1 macrophage polarization in lipedema using the selective PI3Kγ inhibitor IPI-549. Surprisingly, the differentiation of adipose tissue-derived stem cells with conditioned medium from IPI-549 treated SVF resulted in a significant decreased accumulation of lipids in lipedema versus control SVF. In conclusion, our results indicate that CD163+ macrophages are a critical component in lipedema and re-polarization of lipedema macrophages can normalize the differentiation of adipose-derived stem cells in vitro evaluated by the cellular lipid accumulation. These data open a new chapter in understanding lipedema pathophysiology and may indicate potential treatment options.