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Lipedema and lymphedema are physically similar yet distinct diseases that are commonly misdiagnosed. We previously reported that lipedema and lymphedema are associated with increased risk for venous thromboembolism (VTE). The underlying etiology of the prothrombotic profile observed in lipedema and lymphedema is unclear, but may be related to alterations in platelets. Our objective was to analyze the platelet transcriptome to identify biological pathways that may provide insight into platelet activation and thrombosis. The platelet transcriptome was evaluated in patients with lymphedema and lipedema, then compared to control subjects with obesity. Patients with lipedema were found to have a divergent transcriptome from patients with lymphedema. The platelet transcriptome and impacted biological pathways in lipedema were surprisingly similar to weight-matched comparators, yet different when compared to overweight individuals with a lower body mass index (BMI). Differences in the platelet transcriptome for patients with lipedema and lymphedema were found in biological pathways required for protein synthesis and degradation, as well as metabolism. Key differences in the platelet transcriptome for patients with lipedema compared to BMI-matched subjects involved metabolism and glycosaminoglycan processing. These inherent differences in the platelet transcriptome warrant further investigation, and may contribute to the increased risk of thrombosis in patients with lipedema and lymphedema.

Abstract Background Lipedema is a chronic, incurable disorder characterized by painful fat accumulation in the extremities. While the application of liposuction in lipedema management has become increasingly popular, the safety and effectiveness of this approach remain contentious. Our systematic review and meta-analysis aimed to assess various liposuction modalities in lipedema management to verify their safety and efficacy. Methods In-line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we performed a comprehensive literature review from inception until March 2023 using the following electronic databases: CENTRAL, MEDLINE, Google Scholar, and EMBASE. Results From the 562 initially identified articles, 20 met our inclusion/exclusion criteria for evaluation. Our review encompassed 14 prospective cohort studies, 3 retrospective studies, 2 case series, and 1 cross-sectional study. A meta-analysis of nine articles revealed a notable improvement in the quality of life, pain, pressure sensitivity, bruising, cosmetic impairment, heaviness, walking difficulty, and itching among lipedema patients who underwent liposuction. Although complications such as inflammation, thrombosis, seroma, hematoma, and lymphedema-related skin changes were reported, severe complications were rare. Crucially, no instances of shock, recurrence, or mortality were reported. Conclusion Liposuction is a safe and beneficial therapeutic intervention for managing lipedema symptoms and enhancing quality of life. However, the impact of liposuction on secondary lymphedema remains unreported in the literature. Further high-quality, large-scale trials are necessary to assess the safety and effectiveness of different liposuction modalities. These studies will contribute valuable insights to optimize liposuction as a therapeutic option for individuals with lipedema. Level of Evidence I, risk/prognostic study.

Lipedema is a chronic, idiopathic, and painful disease characterized by an excess of adipose tissue in the extremities. The goal of this study is to characterize the gene expression of estrogen receptors (ERα and ERβ), G protein-coupled estrogen receptor (GPER), and ER-metabolizing enzymes: hydroxysteroid 17-beta dehydrogenase (HSD17B1, 7, B12), cytochrome P450 (CYP19A1), hormone-sensitive lipase (LIPE), enzyme steroid sulfatase (STS), and estrogen sulfotransferase (SULT1E1), which are markers in Body Mass Index (BMI) and age-matched non-lipedema (healthy) and lipedema ASCs and spheroids. Flow cytometry and cellular proliferation assays, RT-PCR, and Western Blot techniques were used to determine the expression of ERs and estrogen-metabolizing enzymes. In 2D monolayer culture, estrogen increased the proliferation and the expression of the mesenchymal marker, CD73, in hormone-depleted (HD) healthy ASCs compared to lipedema ASCs. The expression of ERβ was significantly increased in HD lipedema ASCs and spheroids compared to corresponding healthy cells. In contrast, ERα and GPER gene expression was significantly decreased in estrogen-treated lipedema spheroids. CYP19A1 and LIPE gene expressions were significantly increased in estrogen-treated healthy ASCs and spheroids, respectively, while estrogen upregulated the expression of PPAR-ϒ2 and ERα in estrogen-treated lipedema-differentiated adipocytes and spheroids. These results indicate that estrogen may play a role in adipose tissue dysregulation in lipedema.

Lipedema is a poorly understood disorder of adipose tissue characterized by abnormal but symmetrical deposition of subcutaneous white adipose tissue (WAT) in proximal extremities. Here, we propose that the underlying cause for lipedema could be triggered by a selective accumulation of bacterial lipopolysaccharides (LPS; also known as endotoxin) in gluteofemoral WAT. Together with a malfunctioning complement system, this induces low-grade inflammation in the depot and raises its uncontrollable expansion. Correspondingly, more attention should be paid in future research to the endotoxemia prevalent in patients with lipedema. We would like to propose that proper management of endotoxemia can reduce the progression and even improve the state of disease in patients with lipedema.

Lipedema, a chronic and painful disorder primarily affecting women without a definitive cure, has traditionally been managed with conservative therapy, notably complete decongestive therapy, across many countries. Recently, liposuction has been explored as a potential surgical treatment, prompting this study to evaluate its effectiveness as possibly the first-line therapy for lipedema. Through extensive literature searches in databases such as CrossRef, Web of Science, PubMed, and Google Scholar up to December 2023, and using the Newcastle-Ottawa Scale for quality assessment, the study selected seven studies for inclusion. Results showed significant post-operative improvements in spontaneous pain, edema, bruising, mobility, and quality of life among lipedema patients undergoing liposuction. However, over half of the patients still required conservative therapy after surgery. Despite these promising results, the study suggests caution due to lipedema's complexity, significant reliance on self-reported data, and limitations of the studies reviewed. Thus, while liposuction may offer symptomatic relief, it should be considered an adjunct, experimental therapy rather than a definitive cure, emphasizing the need for a comprehensive approach to care.

We analyzed the medical condition of 360 women affected by lipedema of the lower limbs in stages 1, 2, and 3. The data were assessed for the whole population and compared between different clinical stages, distinguishing between obese and non-obese patients. The most frequent clinical signs were pain when pinching the skin, subcutaneous nodules, and patellar fat pads. The most frequently painful site of the lower limbs was the medial lower third of the thigh. The pain score obtained on lower limb points increased progressively with the clinical stage. In all points evaluated, the thickness of the subcutaneous tissue increased with the clinical stage. Analyzing the data on the lower medial third of the leg and considering only patients with type 3 lipedema, the difference between stages was statistically significant after correction for age and BMI. We found higher levels of C-reactive protein at more severe clinical stages, and the difference was significant after correction for age and BMI between the stages. Overall, the prevalence of alterations of glucose metabolism was 34%, with a progressive increase in prevalence with the clinical stage. The most frequent comorbidities were vitamin D insufficiency, chronic venous disease, allergies, dyslipidemia, headache, and depression of mood. Interestingly, in comparison with the general population, we found higher prevalence of chronic autoimmune thyroiditis and polycystic ovary syndrome. Finally, the clinical stage and the involvement of the upper limbs or obesity suggest a worse clinical, anthropometric, and endocrine–metabolic profile.

Dr. Allen and Dr. Hines pioneered and first described lipedema in the 1940s, a common subcutaneous adipose tissue disorder characterized by enlargement of both lower extremities. Lipedema is not edema; it is a genetically determined disturbance in adipose tissue mass and adipose tissue distribution. In 1951 a second seminal paper provided more description of lipedema. Fat distribution involves the lower extremities, upper arms, hips, buttocks, thighs, sparing trunks, and feet. Lower extremities are characterized by pain, easy bruisability, firm subcutaneous nodules of adipose tissue, and resistance of fat to traditional diet and exercise.

Introdução: O lipedema, recentemente introduzido na 11ª revisão da Classificação Internacional de Doenças. Estima-se que metade das pessoas acometidas pelo lipedema, estejam em sobrepeso ou com obesidade, sendo uma associação de comorbidades que dificulta o diagnóstico. O diagnóstico errôneo é preocupante, pois atrasa o tratamento da doença permitindo a sua progressão. Objetivo: Trata-se de uma revisão integrativa da literatura (RIL) com objetivo de analisar o que se tem construído em pesquisas anteriores relacionadas ao lipedema. Metodologia: A busca dos artigos científicos foram os disponibilizados nos Periódicos da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Os artigos constassem os Descritores em Ciências da Saúde (DeCS) com as palavras: lipedema and procedimento and cirurgia and mulher, e que fossem revisados por pares, nas línguas inglesa e portuguesa. a partir da aplicação dos critérios previamente definidos O período de busca foi realizado nos meses de maio a agosto de 2023. Resultados e Discussão: Foram elegíveis 12 artigos. A análise dos artigos encontrados possibilitou a evidente necessidade de conhecimento e clareza no diagnóstico do lipedema. As mulheres são as mais afetadas pela doença. A área afetada pode incluir os quadris, as pernas bilateral e simetricamente. E uma das principais características distintivas do lipedema é a preservação dos pés, o que pode criar um degrau distinto no tornozelo. Assim, a importância do diagnóstico diferencial. O procedimento cirúrgico como tratamento apresentou melhores resultados. Entretanto, a associação de todos os tratamentos sobressaiu na qualidade de melhora dos aspectos do lipedema. Conclusão: Essa revisão apontou para o complexo  diagnóstico do lipedema.  Esse assunto persiste como um desafio e deve instigar mais pesquisadores na busca para um diagnóstico preciso, opções de tratamento e até mesmo no sentido de prevenção para satisfazer a população assistida, no caso a maioria são as mulheres.  A melhor opção indicada pelos estudos analisados foi o tratamento cirúrgico realizado pela lipoaspiração.

BACKGROUND: Lipedema, a complex and enigmatic adipose tissue disorder, remains poorly understood despite its significant impact on the patients' quality of life. Genetic investigations have uncovered potential contributors to its pathogenesis, including somatic mutations, which are nonheritable genetic alterations that can play a pivotal role in the development of this disease. AIM: This review aims to elucidate the role of somatic mutations in the etiology of lipedema by examining their implications in adipose tissue biology, inflammation, and metabolic dysfunction. RESULTS: Studies focusing on leukocyte clones, genetic alterations like TET2 and DNMT3A, and the intricate interplay between adipose tissue and other organs have shed light on the underlying mechanisms driving lipedema. From the study of the scientific literature, mutations to genes correlated to three main pathways could be involved in the somatic development of lipedema: genes related to mitochondrial activity, genes related to localized disorders of subcutaneous adipose tissue, and genes of leukocyte clones. CONCLUSIONS: The insights gained from these diverse studies converge to highlight the complex genetic underpinnings of lipedema and offer potential avenues for therapeutic interventions targeting somatic mutations to alleviate the burden of this condition on affected individuals.

BACKGROUND: Mast cells are immune cells that mediate hypersensi-tivity and allergic reactions in the body, secreting histamine and other inflammatory molecules. They have been associated with different inflammatory conditions such as obesity and other adipose tissue di-sorders. Lipedema is a chronic disease characterized by an abnormal accumulation of adipose tissue on the legs and arms, pain, and other symptoms. Mast cells may play a role in the pathology of lipedema. OBJECTIVE: Pilot study to determine levels of histamine and its metabolites in lipedema subcutaneous adipose tissue (SAT) biopsy samples, and to test sodium cromoglycate for the treatment of mast cells in women with lipedema. METHODS: Biopsies from lipedema and control SAT were collected and analyzed histologically for the presence of mast cells. Mass spec-trometry was used to measure the levels of histamine, a key marker of mast cells, and its metabolites in SAT in women with lipedema and controls, and after a group of women with lipedema were administered oral and topical doses of sodium cromoglycate for two weeks. RESULTS: Histological examination of biopsies from lipedema patients confirmed the presence of mast cells. Metabolomic analysis revealed high levels of histamine and its metabolites in samples from women with lipedema compared to controls. Following a two-week treatment period, lipedema tissue samples exhibited reduced levels of histamine, suggesting a reduction of mast cell activity. CONCLUSION: Sodium cromoglycate has the ability to stabilize mast cells and reduce histamine levels in lipedema patients, which could be useful in lowering the symptoms of lipedema.

This study aimed to assess the potential benefits of a low-carbohydrate, high-fat (LCHF) diet on body composition, leg volume, and pain reduction in women with lipedema compared to overweight or women with obesity. The study included 113 female participants, 56 with lipedema and 57 with overweight/obesity (BMI >25 kg/m2) without lipedema. All subjects were prescribed a low-carbohydrate, high-fat (LCHF) diet with anti-inflammatory properties to adhere to for a duration of 7 months. Measurements of anthropometry, body weight, composition, and pain (VAS) were conducted at the study’s commencement and conclusion. 52 participants completed the study. Both groups experienced a similar weight reduction, amounting to 12.9% compared to the baseline (−10.8 kg vs. −11.9 kg; p = 0.14, for lipedema and women with overweight/obesity, respectively). The most reduction was in body fat mass. Improvements in various parameters were observed, except for ankle circumferences, which decreased more in the lipedema group. Lipedema participants showed significantly reduced pain levels following the LCHF diet (4.6 ± 2.6 vs 3.0 ± 2.3; ). The LCHF diet holds promise for weight loss, body fat reduction, leg volume management, and pain alleviation in women with lipedema. These findings provide valuable insights into potential therapeutic strategies for lipedema management.

Lipedema is a chronic medical condition characterized by a symmetric buildup of adipose tissue (fat) in the legs and arms. A common but under-recognized disorder, Lipedema may cause pain, swelling, easy bruising, and impaired mobility. During the past decade, Lipedema, which occurs almost exclusively in women, has been demonstrated to be a disease that is distinct from obesity, lymphedema, cellulite, and other adipose conditions. The Lipedema Research Roadmap identifies recommendations to strengthen and grow Lipedema research. It presents a forward-looking summary of gaps in knowledge and opportunities for research and development, sourced from “Lipedema: A Current Understanding of Its Pathology and Natural History” (Lipedema Foundation; preprint, forthcoming), as well as input from authors and advisors. Recommendations are organized into six chapters covering key objectives: fostering the research environment, developing reporting standards and best practices, improving diagnosis, broadening understanding of the biology of the disease, identifying potential treatments, and enhancing epidemiology. The Research Roadmap development process incorporated input from more than 60 stakeholders, including researchers, clinicians, and patients. 24 external reviewers provided more than 1,300 comments and recommended edits.

BACKGROUND: National survey data exploring the patient experience with lipedema are lacking. METHODS: We conducted national surveys from 2016 to 2022 of women with lipedema as well as female controls. Surveys collected information on symptomatology, pain, and therapies. We performed logistic regression comparing symptoms among those with lipedema versus controls adjusting for age and BMI. RESULTS: A total of 707 women with lipedema and 216 controls completed the surveys. Those with lipedema had a mean age of 48.6 years and mean BMI of 40.9 kg/m2. Lipedema symptom onset occurred frequently at puberty (48.0%) or pregnancy (41.2%). Compared to controls, women with lipedema were more likely to report leg swelling in heat (odds ratio [OR], 66.82; 95% CI, 33.04-135.12; p < 0.0001), easy bruising (OR, 26.23; 95% CI, 15.58-44.17; p < 0.0001), altered gait (OR, 15.54; 95% CI, 7.58-31.96; p < 0.0001), flu-like symptoms (OR, 12.99; 95% CI, 4.27-39.49; p < 0.0001), joint hypermobility (OR, 12.88; 95% CI, 6.68-24.81; p < 0.0001), cool skin (OR, 12.21; 95% CI, 5.20-28.69; p < 0.0001), varicose veins (OR, 11.29; 95% CI, 6.71-18.99; p < 0.0001), and fatigue (OR, 9.59; 95% CI, 6.10-15.09; p < 0.0001). Additionally, 70.3% had upper arm involvement, 21.2% reported foot swelling, and 16.6% reported foot pain. Most (52.2%) reported no symptom improvement with diet or exercise. Common therapies used included compression therapy (45.0%), gastric bypass (15.7%), and lower-extremity liposuction (14.0%). CONCLUSION: In a large, national, symptom survey, women with lipedema reported excess pain, swelling, and fat in the legs along with numerous symptoms beyond those classically described. Symptom responses to common therapies remain understudied.

Lipedema is a chronic disorder that mainly affects women. It is often misdiagnosed, and its etiology remains unknown. Recent research indicates an accumulation of macrophages and a shift in macrophage polarization in lipedema. One known protein superfamily that contributes to macrophage accumulation and polarization is the macrophage migration inhibitory factor (MIF) family. MIF-1 and MIF-2 are ubiquitously expressed and also regulate inflammatory processes in adipose tissue. In this study, the expression of MIF-1, MIF-2 and CD74—a common receptor for both cytokines—was analyzed in tissue samples of 11 lipedema and 11 BMI-matched, age-matched and anatomically matched control patients using qPCR and immunohistochemistry (IHC). The mRNA expression of MIF-1 (mean 1.256; SD 0.303; p = 0.0485) and CD74 (mean 1.514; SD 0.397; p = 0.0097) were significantly elevated in lipedema patients, while MIF-2 expression was unaffected (mean 1.004; SD 0.358; p = 0.9718). The IHC analysis corroborated the results for CD74 expression on a cellular level. In conclusion, our results provide first evidence for a potential involvement of the MIF family, presumably via the MIF-1-CD74 axis, in lipedema.

BACKGROUND: Lipedema, also known as lipohyperplasia dolorosa (LiDo), is a painful condition affecting women, causing a disproportionate accumulation of subcutaneous adipose tissue in the extremities. It carries a lower risk of diabetes and cardio-metabolic dysfunctions compared to obesity, but coincident obesity can complicate diagnosis and treatment. PATIENTS AND METHODS: This retrospective study included 607 female LiDo patients, ≥ 18 years, stage 1-3, from Germany, the UK, and Spain. Data were collected as part of the standard initial assessment for LiDo patients. RESULTS: Based on waist-to-height-ratio (WHtR), 15.2% of patients were underweight, 45.5% normal weight, 22.1% overweight and 17.3% obese. There was a significant association between WHtR category and age group. Body mass index (BMI) is often overestimated, leading to misdiagnosis of obesity. CONCLUSIONS: The use of BMI also affects the recent decision of the German Federal Joint Committee on the reimbursement of liposuction costs by health insurance funds. Patients with BMI of more than 40 kg/m2 are excluded from cost coverage, and those with BMI between 35 kg/m2 and 40 kg/m2 must first receive conservative obesity therapy. In conclusion, the sole use of BMI in lipedema is unreliable and, in contrast to WHtR, leads to inaccurate diagnoses overestimating overweight and obesity.

Lipoedema is an adipose tissue disorder that is still not fully understood. The primary purpose of this study is to explore the state of knowledge and understanding of lipoedema among Polish women. The secondary aim is to investigate the possible association between knowledge and factors such as BMI, self-reported symptoms, and age.

In recent years, the use of the ketogenic diet as a proper nutritional treatment for lipedema has been hypothesized in the literature. This is the first clinical study evaluating the ketogenic diet and carboxytherapy in lipedema patients. In the present study, it was decided to use a modified Mediterranean ketogenic diet (MMKD) in combination with carboxytherapy. Since lipedema is characterized by microangiopathy, local hypoxia, and increased subcutaneous adipose tissue (SAT) deposition, carboxytherapy could improve painful symptoms and skin tone. A total of 22 subjects were included in the data analysis, divided into three groups; 8 patients underwent MMKD combined with carboxytherapy sessions (KDCB group), 8 underwent MMKD nutritional treatment alone (KD group), and 6 patients underwent only carboxytherapy sessions (CB group), for a total of 10 weeks of treatment for all three groups. It was observed that the ketogenic diet effectively induced weight and fat mass loss, including in the limbs, areas considered unresponsive to diet therapy in lipedema patients. However, the best results were obtained from the combination of the ketogenic diet and carboxytherapy, which showed improvements in both body composition and skin texture and a reduction in pain, along with an improvement in sleep quality. It would be helpful to conduct a clinical trial on a larger scale and over a more extended period to observe the results in the long term as well.

Background: The presence of edema in patients with lipedema has been investigated in many studies. However, no study has been found that examines the amount of intracellular (ICF) and extracellular fluid (ECF) in these patients together. The aim of this study is to examine the amount of ICF and ECF in patients with stage 2 lipedema. Methods and Results: Twenty-four patients diagnosed with stage 2 lipedema were included in the study. Bioimpedance spectroscopy was applied to measure extracellular and intracellular water levels. The mean age of the participants was 44.58 ± 2.95 years. The mean body mass index (BMI) of the participants was 33.9 ± 1.84 kg/m2. It was observed that the amount of ECF in the patients was above the normal values (p < 0.001), whereas the amount of ICF was within the normal range (p = 0.801). In addition, it was observed that there was a moderate relationship between BMI and the amount of ECF. Conclusion: Although the amount of ICF is within the normal range in patients with lipedema, an increase in ECF is observed. The reason why edema is not observed in these patients despite the increase in ECF may be the increase in glycosaminoglycan and proteoglycan synthesis. In addition, the attention of these patients to weight control may contribute to slowing the course of the disease by preventing the increase in the amount of ECF. For a better diagnosis of lipedema, it is considered important to evaluate the amount of ECF in addition to routine evaluations.

IntroductionLipedema is a painful subcutaneous adipose tissue (SAT) disease characterized by adipocyte hypertrophy, immune cell recruitment, and fibrosis in the affected areas. These features are thought to contribute to the development and progression of the condition. However, the relationship between lipedema disease stage and the associated adipose tissue changes has not been determined so far.MethodsSAT biopsies of 32 lipedema patients, ranging across the pathological stages I to III, and 14 BMI- and age-matched controls were harvested from lipedema-affected thighs and non-symptomatic lower abdominal regions. Histological and immunohistochemical (IHC) staining and expression analysis of markers for adipogenesis, immunomodulation, and fibrosis were performed on the tissue biopsies.ResultsLipedema patients showed increased adipocyte areas and a stage-dependent shift towards larger cell sizes in the thighs. Lipedema SAT was linked with increased interstitial collagen accumulation in the thighs, but not the lower abdominal region when compared to controls. There was a trend toward progressive SAT fibrosis of the affected thighs with increasing lipedema stage. Elevated gene expression levels of macrophage markers were found for thigh SAT biopsies, but not in the abdominal region. IHC staining of lipedema thigh biopsies confirmed a transiently elevated macrophage polarization towards an M2-like (anti-inflammatory) phenotype.ConclusionsIn summary, lipedema SAT is associated with stage-dependent adipocyte hypertrophy, stage-progressive interstitial fibrosis and elevated proportion of M2-like macrophages. The character of the inflammatory response differs from primary obesity and may possess an essential role in the development of lipedema.

Objective The aim of this study is to assess the prevalence of HLA-DQ2 and HLA-DQ8 in women diagnosed with lipedema. Methods Leukocyte histocompatibility antigen (HLA) tests of 95 women diagnosed with lipedema were analyzed using non-probabilistic sampling for convenience. The prevalence of HLA-DQ2 and HLA-DQ8 was compared to the general population. Results The prevalence of HLA-DQ2+ was 47.4%, that of HLA-DQ8+ was 22.2%, the presence of any celiac disease associated HLA (HLA-DQ2+ or HLA-DQ8+) was 61.1%, both HLA (HLA-DQ2+ and HLA-DQ8+) was 7.4%, and the absence of celiac disease associated HLA was 39%. Compared to the general population, there was a significantly higher prevalence of HLA-DQ2, HLA-DQ8, any HLA, and both HLAs in lipedema patients. The mean weight of patients with HLA-DQ2+ was significantly lower than the overall study population, and their mean BMI significantly differed from the overall mean BMI. Conclusion Lipedema patients seeking medical assistance have a higher prevalence of HLA-DQ2 and HLA-DQ8. Considering the role of gluten in inflammation, further research is needed to establish if this association supports the benefit of gluten withdrawal from the diet in managing lipedema symptoms.