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PURPOSE: Lipedema is a painful subcutaneous adipose tissue (SAT) disease involving disproportionate SAT accumulation in the lower extremities that is frequently misdiagnosed as obesity. We developed a semiautomatic segmentation pipeline to quantify the unique lower-extremity SAT quantity in lipedema from multislice chemical-shift-encoded (CSE) magnetic resonance imaging (MRI). APPROACH: Patients with lipedema (n=15) and controls (n=13) matched for age and body mass index (BMI) underwent CSE-MRI acquired from the thighs to ankles. Images were segmented to partition SAT and skeletal muscle with a semiautomated algorithm incorporating classical image processing techniques (thresholding, active contours, Boolean operations, and morphological operations). The Dice similarity coefficient (DSC) was computed for SAT and muscle automated versus ground truth segmentations in the calf and thigh. SAT and muscle volumes and the SAT-to-muscle volume ratio were calculated across slices for decades containing 10% of total slices per participant. The effect size was calculated, and Mann-Whitney U test applied to compare metrics in each decade between groups (significance: two-sided P<0.05). RESULTS: Mean DSC for SAT segmentations was 0.96 in the calf and 0.98 in the thigh, and for muscle was 0.97 in the calf and 0.97 in the thigh. In all decades, mean SAT volume was significantly elevated in participants with versus without lipedema (P<0.01), whereas muscle volume did not differ. Mean SAT-to-muscle volume ratio was significantly elevated (P<0.001) in all decades, where the greatest effect size for distinguishing lipedema was in the seventh decade approximately midthigh (r=0.76). CONCLUSIONS: The semiautomated segmentation of lower-extremity SAT and muscle from CSE-MRI could enable fast multislice analysis of SAT deposition throughout the legs relevant to distinguishing patients with lipedema from females with similar BMI but without SAT disease.

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.

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.

Introduction: Lipedema is a bilateral enlargement of the legs due to abnormal depositions of subcutaneous fat. Recent studies using lymphoscintigraphy documented that lipedema associates with lymphatic alterations. It is still not known, whether non-lipedema obesity also leads to similar lymphoscintigraphic changes within lower legs. Clinically, both, lipedema and obesity may progress to secondary lymphedema. The aim of the study was to evaluate lymphoscintigraphy of lower limbs in women with lipedema in comparison to overweight/obese women. Methods: 51 women (in the mean age of 43.3 ± 13.56) with the diagnosis of lipedema and 31 women (in the mean age of 44.7 ± 13.48) with overweight/obesity were enrolled into the study. Women in both study groups had no clinical signs of lymphedema. The groups were matched by mean volume of their legs, calculated using the formula for a truncated cone. Lymphoscintigraphy was evaluated in every women qualitatively. Body composition parameters were assessed using bioelectric impedance analysis (BIA). Results: Lymphoscintigraphic alterations within lower extremities were similar in both, lipedema and overweight/obese groups and were present in majority of women in both study groups. The most common lymphoscintigraphic alteration in both groups were additional lymphatic vessels (in the lipedema group observed in 76.5% of patients and in the overweight/obesity group – in 93.5%). Visualization of popliteal lymph nodes and dermal backflow were observed respectively in 33% and in 5.9% in the group with lipedema and in 45.2% and in 9.7% in the overweight/obesity group. There were significant relationships between severity of lymphoscintigraphic alterations and weight, lean body mass (LBM), total body water (TBW), volume of both legs and thigh circumference in the lipedema group. Such relationships were absent in the overweight/obesity group. Discussion: Our study indicates that lymphatic alterations are present before development to clinically visible secondary lymphedema in both conditions, lipedema and overweight/obesity. In majority of women from both study groups they indicate rather an overload of the lymphatic system than insufficiency. Lymphoscintigraphic alterations are similar in both groups, therefore, lymphoscintigraphy is not a diagnostic tool that might distinguish lipedema from overweight/obesity.

Lipoedema is an adipose tissue disorder almost exclusively affecting women. Evidence shows lipoedema is both poorly recognised and misdiagnosed which results in many women struggling to get a diagnosis and to gain access to specialist NHS services. This article aims to raise awareness of lipoedema and highlight the main role that community and primary care nurses can play in identifying this long-term condition earlier. It provides detail on the condition to help signpost, refer for diagnosis and initiate conservative management for those individuals with this challenging condition.

Background: To define the usefulness of three-dimensional (3D) ultrasound diagnostics for lipedema. Methods and Results: In this study, starting in May 2021, it was decided to apply 3D ultrasound diagnostics in the evaluation of the tissue in 40 patients affected with lipedema (stage I-II-III) who arrived at the Pianeta Linfedema Study Centre. Furthermore, subjects with lipohypertrophy were also included in this study to evaluate the structural features of the adipo-fascia and eventual structural similarity with lipedema. With an adequate instrument (SonoScape 20-3D ultrasound) and probe (17 MHz) on bilateral symmetric marker points, the epidermis-dermis complex and subcutaneous tissue were evaluated. In all patients with lipedema, a normal ultrasound representation of the epidermis-dermis complex, the thickness of subcutaneous tissue, due to hypertrophy of the adipose lobules and of interlobular connective septa, the thickness of the fibers that connect the derma to superficial fascia, and the thickness of the superficial fascia itself as well as of the deep fascia have been highlighted; moreover, fibrotic connective areas in the connective septa that correspond to the palpable nodules has been highlighted. The structural feature, present in all the clinical stages, unexpectedly, was the presence along the superficial fascia of anechogenicity due to the presence of fluid. In lipohypertrophy, structural characteristics similar to those in the initial stage of lipedema have been highlighted. Conclusion: 3D ultrasound diagnostics have led to the discovery of important features of adipo-fascia in lipedema not previously highlighted by two-dimensional ultrasound diagnostic studies.

OBJECTIVE: Symmetrical bilateral lower extremity edema (BLEE) needs to be treated effectively. Finding the cause of this condition increases the success of treatment. Fluid increase in the interstitial space (FIIS) is always present as a cause or a result. Subcutaneously administered nanocolloid is transported by uptake by lymphatic pre-collectors, and this uptake takes place in the interstitium. We aimed to evaluate the interstitium with labeled nanocolloid and contribute to the differential diagnosis in cases with BLEE. METHODS: Our retrospective study included 74 female patients who underwent lymphoscintigraphy for bilateral lower extremity edema. Technetium 99m (Tc-99m) albumin colloid (nanocolloid), a marked colloidal suspension, was applied subcutaneously to two different areas on the dorsum of both feet with a 26 gauge needle The dose volume administered intradermally is approximately 0.2-0.3 ml, and each injector has 22-25MBq of activity. Siemens E-Cam dual-headed SPECT gamma camera was used for imaging. Dynamic and scanning images were taken with a high-resolution parallel hole collimator. Ankle images were re-evaluated by two nuclear medicine specialists, independent of physical examination and scintigraphy findings. RESULTS: 74 female patients with bilateral lower extremity edema were divided into two groups based on physical examination and lymphoscintigraphy findings. There were 40 and 34 patients in Groups I and II, respectively. In the physical examination, patients in Group I were evaluated as lymphedema, and patients in Group II were evaluated as lipedema. The main lymphatic channel (MLC) was not observed in any of the patients in Group I in the early images, and the MLC was observed at a low level in the late imaging in 12 patients. The sensitivity of the presence of distal collateral flows (DCF) in the presence of significant MLC in early imaging in demonstrating increased fluid in the interstitial space (FIIS) was calculated as 80%, specificity as 80%, PPV 80%, and NPV 84%. CONCLUSIONS: While MLC is present in early images, concomitant DCF occurs in cases of lipoedema. The transport of increased lymph fluid production in this group of patients can be covered by the existing MLC. Although MLC is evident, the presence of significant DCF supports the presence of lipedema. It can be used as an important parameter in the diagnosis in early cases where physical examination findings are not evident.

A large and growing body of research suggests that the skin plays an important role in regulating total body sodium, challenging traditional models of sodium homeostasis that focused exclusively on blood pressure and the kidney. In addition, skin sodium may help to prevent water loss and facilitate macrophage-driven antimicrobial host defense, but may also trigger immune dysregulation via upregulation of pro-inflammatory markers and downregulation of anti-inflammatory processes. We performed a systematic search of PubMed for published literature on skin sodium and disease outcomes and found that skin sodium concentration is increased in patients with cardiometabolic conditions including hypertension, diabetes, and end-stage renal disease; autoimmune conditions including multiple sclerosis and systemic sclerosis; and dermatologic conditions including atopic dermatitis, psoriasis, and lipedema. Several patient characteristics are associated with increased skin sodium concentration including older age and male sex. While animal evidence suggests that increased salt intake results in higher skin sodium levels, there are conflicting results from small trials in humans. Additionally, limited data suggest that pharmaceuticals such as diuretics and SGLT-2 inhibitors approved for diabetes, as well as hemodialysis may reduce skin sodium levels. In summary, emerging research supports an important role for skin sodium in physiologic processes related to osmoregulation and immunity. With the advent of new non-invasive MRI measurement techniques and continued research on skin sodium, it may emerge as a marker of immune-mediated disease activity or a potential therapeutic target.

Abstract Background and Aim: Chronic lower extremity edema has been associated with postural impairment, sacroiliac joint dysfunction (SIJD), and abnormal gait. Lymphedema and lipedema are important chronic lower extremity causes. This study aimed to detect the presence of SIJD and postural disorders in patients with lower extremity edema and the relationship between them. Methods: This is a comparative, prospective cohort study. Fifty-three patients with lower extremity edema and 53 healthy subjects were included in the study. Pain provocation tests were used to determine SIJD. Postural analysis was conducted with PostureScreen® Mobile 11.2 (PostureCo, Inc., Trinity, FL) software. The life quality of participants was determined by the Lymphedema Quality of Life (LYMQOL) scale. The functional status of the patients was determined by the Oswestry Disability Index and Lower Extremity Functional Scale. Results: SIJD (18.9%) was more common in the edema group. There was a positive correlation between volume differences, percentages, and the development of SIJD. We found deviations in the head, shoulder, and hip angulations in the edema group. Q angle and lateral shoulder angulation were significantly higher in patients with SIJD in the edema group. In the edema group, LYMQOL-leg total score was higher in patients with SIJD. Conclusion: Chronic lower extremity edema was found to be associated with postural deviations and SIJD. Besides edema control, postural disorders and SIJD should also be considered in these patients.

Lipedema is still a little-known disease, and the internet and social networks have been increasing the identification of many people with the condition, its characteristics, and diagnostic criteria. It is a disease of the adipose tissue that causes changes in body shape in the regions of the body's extremities, hips, and thighs. Classification of lipedema is based on the distribution of adipose tissue and severity of the disease (stages I, II, III, and IV) [ [1] ]. Lymphedema, venous disease, and hypermobile joints are co-morbidities [ [2] ]. Its overlap with overweight and obesity is common. Also, weight fluctuations and metabolic changes stem from body dissatisfaction commonly affecting women.

Background/Aim: YouTube provides information on several health-conditions including lipedema. The aim of this study was to investigate the properties, quality, and quantity of YouTube videos on lipedema. Methods: We explored YouTube using the key word lipedema and the initial top 50 videos were included to review. The properties comprising informers, target, and domains of videos covering number of views, likes, dislikes, duration, viewing rate (VR), and video power index (VPI) were recorded. A modified DISCERN tool and global quality scale (GQS) were used to assess the reliability and quality of videos, respectively. Results: The top 50 videos had a mean of 35,805 views, 282 likes, 12 dislikes, and 30 comments. The mean VPI (96.4) and VR (63.8%) were high. The videos were generally uploaded by health professionals for patient/public and health professional targets with the same ratio (50%). The majority of video contents was related to general information (68%) followed by surgical treatment (62%). Only a small ratio of their content (22%) was about nonsurgical management. The reliability and quality of the videos were intermediate to low. The median DISCERN and GQS scores were higher in the videos uploaded by health professional group compared with nonhealth professionals, but the number of views, VPI, and VR were similar between the groups with regard to the source. Conclusion: YouTube videos on lipedema are mostly provided by health professionals targeting both public/patients and health care providers but the content is limited and the quality and reliability of them were low to intermediate. Therefore, the lipedema specialists are suggested to work together to create up-to-date, high-quality, accessible online educational content to meet the needs of both patients/public and the health professionals. In addition, control mechanisms and careful peer reviewing of the videos informed by nonhealth professionals are warranted to avoid misleading information.

BACKGROUND: Lipedema is a progressive disease, diagnosed most often in women, which is characterized by the unproportionate and symmetrical distribution of adipose tissue primarily in the extremities. Despite numerous results from in vitro and in vivo studies, many questions regarding the pathology and genetic background of lipedema have remained unanswered. METHODS: Adipose tissue-derived stromal/stem cells (ASCs) were isolated from lipoaspirates derived from non-obese and obese lipedema and non-lipedema donors. Growth/morphology, metabolic activity, differentiation potential and gene expression were evaluated using quantification of lipid accumulation, metabolic activity assay, live-cell imaging, RT-PCR, quantitative PCR and immunocytochemical staining. RESULTS: The adipogenic potential of lipedema and non-lipedema ASCs did not rise in parallel with the donors' BMI and did not differ significantly between groups. However, in vitro differentiated adipocytes from non-obese lipedema donors showed significant upregulation of adipogenic gene expression compared to non-obese controls. All other genes tested were equally expressed in lipedema and non-lipedema adipocytes. The ADIPOQ/LEP ratio (ALR) was significantly reduced in adipocytes from obese lipedema donors compared to their non-obese lipedema counterparts. Increased stress fiber-integrated SMA was visible in lipedema adipocytes compared to non-lipedema controls and appeared enhanced in adipocytes from obese lipedema donors. CONCLUSIONS: Not only lipedema per se but also BMI of donors impact adipogenic gene expression substantially in vitro. The significantly reduced ALR and the increased occurrence of myofibroblast-like cells in "obese" lipedema adipocyte cultures underlines the importance of attention towards the co-occurrence of lipedema and obesity. These are important findings towards accurate diagnosis of lipedema.

Expert representatives from 11 professional societies, as part of an autonomous work group, researched and developed appropriate use criteria (AUC) for lymphoscintigraphy in sentinel lymph node mapping and lymphedema. The complete findings and discussions of the work group, including example clinical scenarios, were published on October 8, 2022, and are available at https://www.snmmi.org/ClinicalPractice/ content.aspx?ItemNumber=42021. The complete AUC document includes clinical scenarios for scintigraphy in patients with breast, cutaneous, and other cancers, as well as for mapping lymphatic flow in lymphedema. Pediatric considerations are addressed. These AUC are intended to assist health care practitioners considering lymphoscintigraphy. Presented here is a brief overview of the AUC, including the rationale and methodology behind development of the document. For detailed findings of the work group, the reader should refer to the complete AUC document online.

Dysfunction of collecting lymphatic vessel pumping is associated with an array of pathologies. S-(-)-Bay K8644 (BayK), a small-molecule agonist of L-type calcium channels, improves vessel contractility ex vivo but has been left unexplored in vivo because of poor lymphatic access and risk of deleterious off-target effects. When formulated within lymph-draining nanoparticles (NPs), BayK acutely improved lymphatic vessel function, effects not seen from treatment with BayK in its free form. By preventing rapid drug access to the circulation, NP formulation also reduced BayK's dose-limiting side effects. When applied to a mouse model of lymphedema, treatment with BayK formulated in lymph-draining NPs, but not free BayK, improved pumping pressure generated by intact lymphatic vessels and tissue remodeling associated with the pathology. This work reveals the utility of a lymph-targeting NP platform to pharmacologically enhance lymphatic pumping in vivo and highlights a promising approach to treating lymphatic dysfunction.

Lipoedema is characterized by disproportionate painful fat accumulation mostly in the lower limbs. The presence of lymphoedema in lipoedema remains controversial. This study aimed to assess the presence or absence of lymphoedema in the lower limbs of women with lipoedema using indocyanine green (ICG) lymphography. A cross-sectional retrospective study was undertaken in women with a clinical diagnosis of lipoedema whose lower limbs were examined with ICG lymphography. MD Anderson Cancer Center (MDACC) ICG staging was used to determine lymphoedema presence and severity. Patient characteristics, ICG lymphography findings, Stemmer sign, body mass index, waist-to-hip ratio, limb volume and bioimpedance spectroscopy measures were recorded. Forty women with lipoedema underwent ICG lymphography for the lower limbs from January 2018 to July 2022. Thirty-four women (85.0%) were determined by ICG lymphography as MDACC ICG Stage 0 representing normal lymphatics. Of the six women who demonstrated dermal backflow on ICG lymphography, all were determined as ICG Stage 1, four had localized traumatic dermal backflow area at their ankles, one had previously diagnosed with primary lymphoedema and one was classified as lipoedema stage 4. ICG lymphography findings suggested the absence of lymphoedema in a clear majority of women with lower limb lipoedema.

Lymphangiogenesis is the mechanism by which the lymphatic system develops and expands new vessels facilitating fluid drainage and immune cell trafficking. Models to study lymphangiogenesis are necessary for a better understanding of the underlying mechanisms and to identify or test new therapeutic agents that target lymphangiogenesis. Across the lymphatic literature, multiple models have been developed to study lymphangiogenesis in vitro and in vivo. In vitro, lymphangiogenesis can be modeled with varying complexity, from monolayers to hydrogels to explants, with common metrics for characterizing proliferation, migration, and sprouting of lymphatic endothelial cells (LECs) and vessels. In comparison, in vivo models of lymphangiogenesis often use genetically modified zebrafish and mice, with in situ mouse models in the ear, cornea, hind leg, and tail. In vivo metrics, such as activation of LECs, number of new lymphatic vessels, and sprouting, mirror those most used in vitro, with the addition of lymphatic vessel hyperplasia and drainage. The impacts of lymphangiogenesis vary by context of tissue and pathology. Therapeutic targeting of lymphangiogenesis can have paradoxical effects depending on the pathology including lymphedema, cancer, organ transplant, and inflammation. In this review, we describe and compare lymphangiogenic outcomes and metrics between in vitro and in vivo studies, specifically reviewing only those publications in which both testing formats are used. We find that in vitro studies correlate well with in vivo in wound healing and development, but not in the reproductive tract or the complex tumor microenvironment. Considerations for improving in vitro models are to increase complexity with perfusable microfluidic devices, co-cultures with tissue-specific support cells, the inclusion of fluid flow, and pairing in vitro models of differing complexities. We believe that these changes would strengthen the correlation between in vitro and in vivo outcomes, giving more insight into lymphangiogenesis in healthy and pathological states.

The lymphatic circulation regulates transfer of tissue fluid and immune cells towards the venous circulation. While obesity impairs lymphatic vessel function, the contribution of lymphatic endothelial cells (LEC) to metabolic disease phenotypes is poorly understood. LEC of lymphatic microvessels are in direct contact with the interstitial fluid, whose composition changes during the development of obesity, markedly by increases in saturated fatty acids. Palmitate, the most prevalent saturated fatty acid in lymph and blood, is detrimental to metabolism and function of diverse tissues, but its impact on LEC function is relatively unknown. Here, palmitate (but not its unsaturated counterpart palmitoleate) destabilized adherens junctions in human microvascular LEC in culture, visualized as changes in VE-cadherin, ⍺-catenin, and β-catenin localization. Detachment of these proteins from cortical actin filaments was associated with abundant actomyosin stress fibers. The effects were Rho-associated protein kinase (ROCK)- and myosin-dependent, as inhibition with Y-27632 or blebbistatin, respectively, prevented stress fiber accumulation and preserved junctions. Without functional junctions, palmitate-treated LEC failed to directionally migrate to close wounds in 2-dimensions and failed to form endothelial tubes in 3-dimensions. A reorganization of the lymphatic endothelial actin cytoskeleton may contribute to lymphatic dysfunction in obesity and could be considered as a therapeutic target.

Liposuction plays an important role as a surgical treatment option for lipoedema. This document serves to critically review the evidence in the literature, as well as explain the differences between the lipoedema population compared to the aesthetic surgery population undergoing liposuction. It is not a comprehensive text on lipoedema management but serves to guide surgeons. This guidance was produced on behalf of the British Association of Aesthetic Plastic Surgeons (BAAPS) and British Association of Plastic Reconstructive and Aesthetic Surgeons (BAPRAS) by the expert liposuction group. The guidance is based on evidence available in the literature along with specialist expert opinion on liposuction for lipoedema to provide plastic surgeons with consensus recommendation for surgical treatment. The aim is to identify best practice to maximise the safety of patients. This article summarises current practises and safety considerations and outlines recommendations covering various aspects of patient care.