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Lymphedema and lipedema are chronic debilitating disorders that most commonly affect the upper and lower extremities. Although they can appear similar, they differ in important ways, which the authors of this article review and contrast.

BACKGROUND: Lipedema is the progressive symmetrical deposition of subcutaneous fat and fluid in the lower body, ordinarily sparing the trunk, upper limbs, face, and neck. It may follow an autosomal dominant inheritance pattern. The gold standard treatment for lipedema is complete decongestive therapy, consisting of manual lymphatic drainage and compression garments. This scoping review assessed the existing literature on the effectiveness of liposuction as an alternative treatment for lipedema. METHODS: A scoping review of electronically available literature within PubMed, Scopus, and Cochrane focused on liposuction as a treatment for lipedema considering the following inclusion criteria: human studies, case series of 10 or more, controlled trials, randomized controlled trials, patient-reported outcome measurement studies, survey analyses, descriptive studies, retrospective analyses, recurrence included, follow-up of 6 months or more, age 18 years or older, and treatment modality being liposuction. RESULTS: Thirteen studies were selected. Nine studies reported decreased compression therapy use among patients following liposuction. No studies reported a long-term increase in compression therapy following liposuction. Studies found self-reported improvements in pain, mobility, bruising, and overall quality of life for patients following liposuction, many of whom had previously been on compressive therapy. Studies reported low rates of serious adverse events following liposuction, including deep vein thrombosis, pulmonary embolism, and infection. CONCLUSIONS: These results suggest that liposuction can be a viable treatment alternative to compression therapy for lipedema in patients whose compression therapy has not been helpful. However, there is not enough evidence to say whether liposuction is as effective as compression for patients first presenting with lipedema.

Background: Despite its increasing incidence and prevalence throughout Western countries, lipedema continues to be a very enigmatic disease, often misunderstood or misdiagnosed by the medical community and with an intrinsic pathology that is difficult to trace. The nature of lipedemic tissue is one of hypertrophic adipocytes and poor tissue turnover. So far, there are no identified pathways responsible, and little is known about the cell populations of lipedemic fat. Methods: Adipose tissue samples were collected from affected areas of both lipedema and healthy participants. For single-cell RNA sequencing analysis, the samples were dissociated into single-cell suspensions using enzymatic digestion and then encapsulated into nanoliter-sized droplets containing barcoded beads. Within each droplet, cellular mRNA was converted into complementary DNA. Complementary DNA molecules were then amplified for downstream analysis. Results: The single-cell RNA-sequencing analysis revealed three distinct adipocyte populations at play in lipedema. These populations have unique gene signatures which can be characterized as a lipid generating adipocyte, a disease catalyst adipocyte, and a lipedemic adipocyte. Conclusions: The single-cell RNA sequencing of lipedemic tissue samples highlights a triad of distinct adipocyte subpopulations, each characterized by unique gene signatures and functional roles. The interplay between these adipocyte subtypes offers promising insights into the complex pathophysiology of lipedema.

<p id="p1">Despite extensive research during the last couple of years, lipedema still appears enigmatic in respect to its pathogenesis. In our in vitro study, we have set out to further characterize lipedema adipocytes, concentrating on gene and protein expression, which might help to develop ideas explaining the excessive accumulation of adipose tissue in women with lipedema. Using 2D cultures we show that gene expression in lipedema and non-lipedema adipocytes differs significantly in terms of genes related to lipid droplet size determination, insulin signaling and glucose uptake. A pronounced hypertrophy, recognizable by a significantly increased average lipid droplet size, was visible in differentiated lipedema adipocytes grown in 3D cultures. In addition, gene and protein expression related to inflammation and fibrosis were upregulated in lipedema adipocytes compared to controls, supporting earlier reports. Taken together, results from our in vitro studies suggest that lipedema adipose cells are capable of retaining their hypertrophic nature under culture conditions and open new aspects focusing on insulin signaling and PDGFRA-mediated balancing of adipogenic versus fibrogenic differentiation of lipedema adipose tissue.</p>

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.

The role of artificial intelligence (AI) in healthcare is evolving, offering promising avenues for enhancing clinical decision making and patient management. Limited knowledge about lipedema often leads to patients being frequently misdiagnosed with conditions like lymphedema or obesity rather than correctly identifying lipedema. Furthermore, patients with lipedema often present with intricate and extensive medical histories, resulting in significant time consumption during consultations. AI could, therefore, improve the management of these patients. This research investigates the utilization of OpenAI's Generative Pre-Trained Transformer 4 (GPT-4), a sophisticated large language model (LLM), as an assistant in consultations for lipedema patients. Six simulated scenarios were designed to mirror typical patient consultations commonly encountered in a lipedema clinic. GPT-4 was tasked with conducting patient interviews to gather medical histories, presenting its findings, making preliminary diagnoses, and recommending further diagnostic and therapeutic actions. Advanced prompt engineering techniques were employed to refine the efficacy, relevance, and accuracy of GPT-4's responses. A panel of experts in lipedema treatment, using a Likert Scale, evaluated GPT-4's responses across six key criteria. Scoring ranged from 1 (lowest) to 5 (highest), with GPT-4 achieving an average score of 4.24, indicating good reliability and applicability in a clinical setting. This study is one of the initial forays into applying large language models like GPT-4 in specific clinical scenarios, such as lipedema consultations. It demonstrates the potential of AI in supporting clinical practices and emphasizes the continuing importance of human expertise in the medical field, despite ongoing technological advancements.

Background: Lipedema is a subcutaneous adipose tissue disorder characterized by increased pathological adipocytes mainly in the extremities. Vitamin D is stored in adipocytes, and serum levels inversely correlate with BMI. As adipocytes are removed during liposuction, lipedema patients might be prone to further substantial vitamin D loss while their levels are already decreased. Therefore, we examined the effect of liposuction on perioperative serum 25-hydroxyvitamin D levels. Methods: In patients undergoing lipedema liposuction, blood samples were obtained pre- and postoperatively. Statistical analyses were performed to correlate the volume of lipoaspirate, patients' BMI and number of sessions to vitamin D levels. Results: Overall, 213 patients were analyzed. Mean liposuction volume was 6615.33 ± 3884.25 mL, mean BMI was 32.18 ± 7.26 kg/m2. mean preoperative vitamin D levels were 30.1 ± 14.45 ng/mL (borderline deficient according to the endocrine society) and mean postoperative vitamin D levels were 21.91 ± 9.18 ng/mL (deficient). A significant decrease in serum vitamin D was seen in our patients (p < 0.001) of mean 7.83 ng/mL. The amount of vitamin D loss was not associated with BMI or aspiration volume in our patients (p > 0.05). Interestingly, vitamin D dynamics showed a steady drop regardless of volume aspirated or preoperative levels. Conclusions: Many lipedema patients have low vitamin D levels preoperatively. Liposuction significantly reduced these levels additionally, regardless of aspirated volume or BMI. However, vitamin D loss was constant and predictable; thus, patients at risk are easily identified. Overall, lipedema patients undergoing liposuction are prone to vitamin D deficiency, and the long-term effects in this population are currently unknown.

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.

This study aimed to develop a novel predictive equation for calculating resting metabolic rate (RMR) in women with lipedema. We recruited 119 women diagnosed with lipedema from the Angiology Outpatient Clinic at Wroclaw Medical University, Poland. RMR was assessed using indirect calorimetry, while body composition and anthropometric measurements were conducted using standardized protocols. Due to multicollinearity among predictors, classical multiple regression was deemed inadequate for developing the new equation. Therefore, we employed machine learning techniques, utilizing principal component analysis (PCA) for dimensionality reduction and predictor selection. Regression models, including support vector regression (SVR), random forest regression (RFR), and k-nearest neighbor (kNN) were evaluated in Python's scikit-learn framework, with hyperparameter tuning via GridSearchCV. Model performance was assessed through mean absolute percentage error (MAPE) and cross-validation, complemented by Bland-Altman plots for method comparison. A novel equation incorporating body composition parameters was developed, addressing a gap in accurate RMR prediction methods. By incorporating measurements of body circumference and body composition parameters alongside traditional predictors, the model's accuracy was improved. The segmented regression model outperformed others, achieving an MAPE of 10.78%. The proposed predictive equation for RMR offers a practical tool for personalized treatment planning in patients with lipedema.

OBJECTIVE: The primary objective of this study was to evaluate the effect of a low-carbohydrate diet (LCD) compared with a control diet on pain in female patients with lipedema. The secondary objectives were to compare the impact of the two diets on quality of life (QoL) and investigate potential associations of changes in pain with changes in body weight, body composition, and ketosis. METHODS: Adult female patients with lipedema and obesity were randomized to either the LCD or control diet (energy prescription: 1200 kcal/day) for 8 weeks. Body weight and body composition, pain (Brief Pain Inventory measured pain), and QoL (RAND 36-Item Health Survey [RAND-36], Impact of Weight on Quality of Life [IWQOL]-Lite, and Lymphoedema Quality of Life [LYMQOL]) were measured at baseline and at postintervention. RESULTS: A total of 70 female patients (age, mean [SD], 47 [11] years; BMI 37 [5] kg/m2) were included. The LCD group had greater weight loss (-2.8 kg; 95% CI: -4.1 to -1.0; p < 0.001) and larger reduction in pain now (-1.1; 95% CI: -1.9 to -0.3; p = 0.009) compared with the control group. No association was found between changes in pain now and weight loss. Both groups experienced improvements in several QoL dimensions. CONCLUSIONS: Diet-induced weight loss in women with lipedema can improve QoL. An energy-restricted LCD seems to be superior to a standard control diet in reducing pain.

Lipohyperplasia dolorosa (LiDo), also known as lipedema, is a painful subcutaneous adipose tissue disorder. While the characteristic bilateral accumulation of adipocytes in extremities sparing hands and feet is investigated, an objective characterization of pain and the sensory system of LiDo patients is missing. Accordingly, progress to overcome the unsatisfying response to pain-therapeutics of patients of this widespread, lifelong, and severe disease is missing. We characterized the sensory detection profile of painful and non-painful stimuli in 20 non-obese LiDo patients and 20 waist-to-height-ratio matched controls using the clinically approved QST-protocol of the German Research Association on Neuropathic Pain (DFNS e.V.). Further, pain-reports and participants’-psychometry was assessed using the German Pain Questionnaire. LiDo patients showed no overt psychometric abnormalities. LiDo pain appeared as somatic rather than neuropathic or psychosomatic aversive. All QST measurements were normal with the selective exception of two: The pressure pain threshold (PPT) was strongly reduced and the vibration detection threshold (VDT) was strongly increased selectively at the affected thigh. In contrast, sensory profiles at the dorsum of the hand were normal. ROC-analysis of the combination of PPT and VDT of thigh versus hand shows high sensitivity and specificity, categorizing correctly 96.5% of the measured participants as LiDo patients or healthy controls, respectively. Thus, we propose to assess both, PPT and VDT, at the painful thigh and the pain-free hand as basis to develop a combined PVTH-score for differential diagnosis as a fast and convenient bedside test for the identification of non-obese LiDo patients.

Background: Our aim is to propose a framework for the development of a research case definition of lipedema, based on current available literature and those observations that can be applied to future lipedema research with the intent to standardize and strengthen the scientific evidence base. Methods and Results: We conducted a narrative review of the literature, and identified consensus characteristics and disputed characteristics that could be included in a research case definition of lipedema. After considering the strength of the evidence and how each characteristic might be measured in a research study, we recommended an approach for the development of a research case definition of lipedema that would be based on consideration of five agreed-upon characteristics, and five disputed, or less substantiated, characteristics as additional evidence to enhance specificity. Conclusions: We present a case definition framework for lipedema drawn from the scientific literature that can be applied to future studies on lipedema. Utilizing this framework should help to increase the sensitivity and specificity of case definition and provide an opportunity for meta-analysis of clinical studies and facilitate future research intercomparisons.

Lipoedema is the disproportionate accumulation of adipose tissue in the lower body, often associated with hormonal changes in women. Lipoedema is commonly misdiagnosed as lymphoedema or obesity due to similarities in appearance. The aim of this study is to compare body composition and fluid measures of women with lipoedema, lymphoedema, and matched control participants, to determine differences that may help distinguish between each condition. One hundred and eleven participants aged over 18, who presented with the complaint of leg swelling and underwent indocyanine green lymphography were included in this study. Our analysis showed that the individuals with lymphoedema had a significantly higher overall total body water (lymphoedema: 9.6 ± 4.2 L, lipoedema: 7.4 ± 2.3 L, control: 7.5 ± 1.8 L; p < .001) and extracellular fluid (lymphoedema: 4.6 ± 1.6, lipoedema: 3.4 ± 1.0 L, control: 3.5 ± 0.7 L; p < .001) in the legs when compared to individuals with lipoedema and matched control participants. Individuals with lipoedema had a significantly higher overall fat mass as a percentage of body weight when compared to individuals with lymphoedema (lymphoedema: 33.1% ± 9.5%, lipoedema: 39.4% ± 6.5%; p = .003). We are unable to distinguish between individuals with lipoedema and control participants, therefore further research needs to be conducted to help reduce misdiagnosis.

Lower extremity swelling may be broadly characterized as due to edema, lymphedema, or lipedema. Differentiation between these three conditions is important for providing appropriate treatment. This review analyzes and compares different clinical diagnostic modalities for these conditions, with the aim of assisting in the process of choosing the most appropriate diagnostic modality by highlighting the advantages and limitations of each. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for a systematic search of peer-reviewed literature, the following diagnostic methods for lower extremity swelling were investigated: (1) ultrasound (US), (2) lymphoscintigraphy (LSG), (3) computed tomography (CT), (4) bioimpedance spectroscopy (BIS), (5) tissue dielectric constant (TDC), and (6) magnetic resonance imaging (MRI), including magnetic resonance lymphangiography (MRL). The databases used in the search were PubMed, ProQuest, CINAHL Complete, Web of Science, Embase, and Biomedical Reference Collection. After retrieving 115 studies based on predetermined inclusion criteria, a total of 31 studies were critically evaluated. The main results indicate the following: duplex US is the modality of choice to initially identify lower extremity edema such as deep venous thrombosis (DVT) and venous reflux due to its high sensitivity and specificity. CT venography of the lower extremity appears to be the preferred option for gynecologic cancer patients with lower extremity swelling post-treatment, as it measures subcutaneous tissue volumes to look for DVTs, lymphoceles, and cancer recurrence. TDC is a recommended modality for a variety of conditions, including edema and lymphedema, in part, due to its noninvasive localized assessment capabilities and ease of use. LSG emerges as an effective imaging modality for lymphedema characterization with minimal invasiveness and high sensitivity and specificity. BIS is widely used to identify and monitor lower extremity lymphedema but has been reported to have low sensitivity and lacks the ability to account for changes in tissue composition such as fibrosis. US and MRL are favored for lipedema diagnosis, with MRL providing comprehensive anatomical and functional insights, albeit with cost and accessibility limitations compared to US. While CT, MRI, US, and TDC are all useful for differentiating lymphedema from lipedema, MRI is the preferred modality due to its anatomical and functional diagnostic capabilities. However, US is a pragmatic alternative for use with obese patients or when MRI is not an option.

Body mass index (BMI) is seen as a predictor of cardiovascular disease (CVD) in lipedema patients. A valid predictor of CVD is increased aortic stiffness (IAS), and previous research described IAS in lipedema. However, it is not known if this applies to all patients. In this cross-sectional single-center cohort study, peripheral pulse wave velocity (PWV) as a non-invasive indicator of aortic stiffness was measured in 41 patients with lipedema, irrespective of stage and without pre-existing cardiovascular conditions or a history of smoking and a maximum body mass index (BMI) of 35 kg/m2. Automatically electrocardiogram-triggered oscillometric sensor technology by the Gesenius-Keller method was used. Regardless of the stage of lipedema disease, there was no significant difference in PWV compared to published standard values adjusted to age and blood pressure. BMI alone is not a predictor of cardiovascular risk in lipedema patients. Measuring other anthropometric factors, such as the waist-hip ratio or waist-height ratio, should be included, and the existing cardiovascular risk factors, comorbidities, and adipose tissue distribution for accurate risk stratification should be taken into account. Automated sensor technology recording the PWV represents a valid and reliable method for health monitoring and early detection of cardiovascular risks.

Correction to: Eur Rev Med Pharmacol Sci 2023; 27 (6 Suppl): 127-136-DOI: 10.26355/eurrev_202312_34697 After publication and following some post-publication concerns, the authors have applied the following corrections to the galley proof. -       The conflict of interest section has been amended as follows: J. Kaftalli and G. Marceddu are employees at MAGI EUREGIO. K. Donato is employee at MAGI EUREGIO and MAGISNAT. M. Bertelli is president of MAGI EUREGIO, MAGISNAT, and MAGI's LAB. G. Bonetti, K. Dhuli, A. Macchia, and P.E. Maltese are employees at MAGI's LAB. M. Bertelli, P.E. Maltese, K. Louise Herbst, Sa. Michelini, Se. Michelini, and P. Chiurazzi are patent inventors (US20220362260A1). M. Bertelli, P.E. Maltese, G. Marceddu are patent inventors (US20230173003A1). M. Bertelli, K. Dhuli and P.E. Maltese are patent inventors (WO2022079498A1). M. Bertelli, P.E. Maltese, Sa. Michelini, Se. Michelini, P. Chiurazzi, K. Louise Herbst, J. Kaftalli, K. Donato, and A. Bernini are patent applicants (Application Number 18/516,241). M. Bertelli, K. Donato, P. Chiurazzi, G. Marceddu, K. Dhuli, G. Bonetti and J. Kaftalli are patent applicants (Application Number: 18/466.879). M. Bertelli, G. Bonetti, G. Marceddu, K. Donato, K. Dhuli, J. Kaftalli, Sa. Michelini, and K. Louise Herbst are patent applicants (Application Number 63/495,155). The remaining authors have no conflict of interest to disclose. -       Figure 5 has been modified as follows to better distinguish outliers: -       The legend of Figure 5 has to be modified as follows: Relative expression of AKR1C1 and AKR1C3 in different groups (CTR = non affected controls, L = lipedema patients without overexpression of AKR1C2, L-over = Lipedema patients with overexpression of AKR1C2), showing that lipedema patients expressed AKR1C1 and AKR1C3 levels similar to the control group. Outliers are reported as black triangles. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34697.