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INTRODUCTION: Lipedema is a chronic and progressive disease that predominantly affects women, characterized by a disproportionate increase in subcutaneous adipose tissue (AT), particularly in the lower limbs. It is associated with significant physical disability, chronic pain, thromboembolism, and psychosocial distress. Despite its profound impact on women's health and quality of life, lipedema remains underrecognized and insufficiently studied, with an estimated prevalence of approximately 10% among women worldwide. Although the exact etiology of lipedema remains unclear, emerging evidence suggests a multifactorial origin involving genetic predisposition, hormonal influences, and vascular dysfunction-all contributing to its development and progression. Current therapeutic options provide only partial symptom relief and remain noncurative, highlighting the urgent need for expanded research and improved management strategies. METHODS: A systematic review was conducted to assess the current understanding of lipedema pathophysiology and current treatment options. Research articles were sourced from PubMed, Web of Science, ScienceDirect, and Scopus databases. Over 100 studies were incorporated. RESULTS: This review provides a comprehensive overview of lipedema, encompassing its clinical features, pathophysiological mechanisms, diagnostic challenges, and current treatment modalities. Additionally, the review discusses whether the molecular and metabolic differences between abdominal and femoral AT depots mirror those observed in classical obesity. CONCLUSIONS: Multidisciplinary, research-informed care is essential for managing lipedema, combining conservative therapies, tailored exercise, and liposuction for advanced cases. More research to better understand the underlying pathophysiology is critical to developing targeted treatments, improving diagnostic accuracy, and informing standardized, evidence-based care.

Aims Lipedema is a condition often mistaken for other causes of limb swelling including lymphedema and obesity. Lipedema may have a unique metabolic profile. Interrogation of the metabolome is a strategy that could reveal unique biomarkers to distinguish lipedema from lymphedema and obesity. Methods Unbiased metabolomics was utilized to examine 38 BMI-matched overweight patients compared with patients with lipedema, lymphedema, and lipolymphedema. Machine learning identified biomarkers to distinguish diseases, and further examined in a validation cohort of 198 patients with each disorders. Adjustments were made for baseline clinical and demographic variables. Results Plasma metabolomics firstly revealed uric acid as a biomarker that performs well to distinguish between phenotypically similar diseases in patients with elevated BMI. In a validation cohort of 64 patients with lipedema, uric acid (5.05 mg/dL) was compared with 64 patients with lymphedema (5.4 mg/dl), and 70 overweight patients without these conditions (4.6 mg/dL, p<0.05). Uric acid-to-cystatin c ratio distinguished between all three groups (Lipedema: 5.2; Lymphedema: 6.3; overweight: 4.0, p<0.01); however, significance was lost after adjustment for renal function. Conclusion Metabolomic analysis revealed uric acid may differentiate between lipedema, lymphedema, lipolymphedema and obese individuals without those conditions. In a validation cohort, while uric acid was higher in lipedema and lymphedema, uric acid adjusted by cystatin c clearance revealed uric acid to be a less useful marker to distinguish lipedema from lymphedema in the context of renal insufficiency.

Background: Bioimpedance spectroscopy (BIS) is commonly used for the detection and monitoring of lymphedema and potentially lipedema. BIS measures limb electrical resistance, which decreases with fluid accumulation in these conditions. R0, the index of extracellular fluid and lymph accumulation, is typically estimated using Cole modeling, but technical and biological factors can affect accuracy.Methods: Participants with clinically affirmed bilateral leg lymphedema, lipedema, self-ascribed swelling, and healthy controls were included in this study. Impedance measurements were taken using a stand-on BIS device, and R0 was estimated using both the Cole modeling method and a regression approach. Quality of data fitting was assessed visually and statistically.Results: Control participants were younger and lighter compared with the clinical groups. The regression method was able to analyze 100% of participant data, whereas the Cole method was successful in only 80%–88% of cases in the lymphedema and lipedema groups. Additionally, the regression approach provided better curve fitting accuracy for all participants.Conclusion: The regression method offers a robust alternative for estimating R0 values in BIS data, especially in lower limb assessments where data analysis is challenging. The small difference between methods in absolute R0 values (2.5%) has minimal practical implications, suggesting interchangeability in data analysis. The Cole method showed poorer performance, particularly in participants with lymphedema, possibly due to differences in water proportions and limb size. Overall, the regression method can be effectively used in clinical practice for estimating R0 values in BIS data, offering a more accurate and reliable approach than traditional Cole plotting methods.

Lipedema is a chronic disease in females characterized by pathologic subcutaneous adipose tissue expansion and hitherto remains without druggable targets. In this observational study, we investigated the molecular hallmarks of lipedema using an unbiased multi-omics approach. We found adipokine dysregulation in lipedema patients participating in a cross-sectional clinical study (ClinicalTrial.gov, NCT02838277), pointing towards the adipocyte as a key player. Analyses of newly generated transcriptomic (SRA, PRJNA940039) and proteomic (ProteomeXchange, PXD058489) datasets of early- and late-stage lipedema samples revealed a local downregulation of factors involved in inflammation. Concomitantly, factors involved in cellular respiration, oxidative phosphorylation, as well as in mitochondrial organization were upregulated. Measuring a cytokine and chemokine panel in the serum of non-menopausal women, we observed little systemic changes in inflammatory markers, but a trend towards increased VEGF. Metabolomic and lipidomic analyses highlighted altered circulating glutamic acid, glutathione, and sphingolipid levels, suggesting a broader dysregulation of metabolic and inflammatory processes. We subsequently benchmarked a set of models to accurately predict lipedema using serum factor measurements (sLPM). Our study of the molecular signature of lipedema thus provides not only potential targets for therapeutic intervention, but also candidate markers of disease development and progression.

This longitudinal study indicates liposuction is an effective treatment for improving HRQoL and symptoms in lipedema patients, although it may not completely restore HRQoL to normative levels. Limitations include potential selection bias, sampling bias, and the need for longer follow-up. The finding …