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Lipedema is a relatively common, unrecognized connective tissue disorder. It affects about 11% of women across the globe. In lipedema, there is symmetrical abnormal deposition of fat especially in the lower extremities. Lipedema can be accompanied with pain, spider veins and easy bruising. Lipedema is rare in men. The disease is progressive in nature. Trigger points for lipedema appear to be puberty, pregnancy and menopause. The disease affects various aspects of the connective tissues like lymphatics, veins, skin, ligaments and even joints as it progresses. Oestrogen and progesterone abnormalities seem to have a role in the progression of the condition. Lipedema also appears to have a genetic predisposition. Lipedema is classified into 4 stages depending on the degree and type of abnormal fat deposition. The severe form can be confused with Dercum’s disease. Depending on the site of deposition of abnormal fat, lipedema is also classified into 5 different types. Lipedema is often confused to be obesity or lymphedema and treated accordingly. Treatments are based on the stages and types of lipedema. Lipedema is extremely difficult to manage with diet, exercises and bariatric surgery alone. All treatments are focused around improving the quality of life, improving physical abilities and appearances.

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.

Lipoedema is an overlooked and often misdiagnosed condition, which mainly affects women. This review summarises the present knowledge of the condition. It is characterised by bilateral and symmetrical accumulation of subcutaneous adipose tissue mainly in the legs. Patients with lipoedema often display tenderness to palpation or spontaneous pain in the adipose tissue. Lipoedema is diagnosed based on the medical history and clinical findings. Treatment includes conservative and surgical options with the aim of relieving symptoms and increasing mobility, but there is a paucity of randomised controlled trials.

OBJECTIVE: Does short-term use of pneumatic compression devices (PCD) and off-the-shelf compression alleviate symptoms and improve quality of life in women with lipedema and secondary lipolymphedema? METHODS: Prospective, randomized controlled, industry-sponsored, proof-in-principle study comparing PCD plus conservative care (PCD+CC) to CC alone (control). Adult females with bilateral lipedema and secondary lymphedema were randomized to PCD+CC or CC. Outcome measures were lower limb and truncal circumferential measurements, bioimpedance, and quality-of-life, symptom, and pain intensity questionnaires. RESULTS: Both groups experienced improvements in leg circumference and bioimpedance with more improvement in the PCD+CC group than the CC group. Pain scores of the SF-36 survey and numerical rating scales were improved in the PCD+CC group. Wong-Baker Faces scores showed trends toward improvement in both groups. CONCLUSIONS: This proof-in-principle study supports conservative management with graduated compression and with or without PCD for improvement in leg circumference, bioimpedance measurements, and pain in patients with lipedema.

Edema of the lower extremities is always associated with a pathological condition that should be treated, especially in patients with chronic wounds. Because the underlying causes of edema can vary greatly and sometimes be complex, clinical and, if necessary, various diagnostic tests should also be performed. Often, a suspected clinical diagnosis can already be made after clinical inspection with testing of Stemmer's and Godet's signs. Sonographic examination should then be performed as the next diagnostic test. Although measurement techniques such as water plethysmography are currently considered gold standard for volume measurements, they are very complex and prone to error, so that they are rarely used in clinical routine today. In summary, it is recommended to perform a clinical examination, if possible in combination with sonography, for edema diagnosis. Especially at the beginning of the decongestion phase, regular circumferential measurements should be performed and documented. This documentation is of high relevance for evaluation of therapeutic success.

EXECUTIVE SUMMARY Nuclear medicine is an essential tool in the delivery of high-quality medical care, going beyond simple anatomical imaging to the use of physiological processes for both imaging and therapy. Nuclear medicine techniques were applied to the lymphatic system as early as the 1950s by Sherman et al. (1), using 198Au colloid (a beta emitter) as a therapeutic agent for lymph node metastasis. In the late 1960s and early 1970s, the ready availability of technetium-99m (99mTc) allowed more widespread lymphatic imaging (lymphoscintigraphy) with 99mTc colloid. In 1976, Ege (2) studied lymphatic flow in 848 patients, suggesting lymphoscintigraphy could demonstrate variable lymphatic drainage patterns, therefore allowing more accurate radiation therapy fields. In recent years, advances in radiopharmaceuticals and imaging technology have allowed more accurate localization of lymph nodes during lymphoscintigraphy and the development of the sentinel lymph node (SLN) concept. One of the first mentions of SLN was made in 1960 by Gould and Philben (3). They described a specific location of a node that drained the parotid gland. This node, located at the junction of the anterior and posterior facial veins, was described as the node most likely to contain metastasis. It was recommended that this node be investigated first before carrying out complete node dissection (3). The SLN concept was further explored by Cabanas (4) in 1977 when lymphangiography with contrast was used to identify a specific location for lymphatic drainage from the penis. Similar to what was described by Gould and Philben, Cabanas (4) felt that this 1 specific lymph node (located at the superficial epigastric vein by Cabanas for penile carcinoma) could be defined as the SLN for all patients. Individual variations demonstrated in the lymphatic channels and the location of the sentinel node since the initial investigations have confirmed that mapping of lymphatic drainage needs to be carried out for each patient undergoing SLN sampling. SLN identification can be done with optical agents, such as isosulfan or methylene blue, as well as with radiotracers and fluorescent tracers. Localization of the SLN(s) with these techniques in individual patients has allowed a more focused investigation of nodal drainage from a primary tumor site, preventing the morbidity and mortality of complete node bed dissection in patients with no clinical evidence of tumor in the regional nodal basin (5). One difficulty with reviewing the literature describing lymphoscintigraphy is the variety of tracers in use around the world and throughout the history of lymphoscintigraphy. Smaller particles tend to move through the lymphatics more quickly. Some tracers are more likely to stop at the first node they encounter, while others are more likely to move through the lymphatic system more readily, demonstrating channels, node beds, and central lymphatic structures. The tracer used depends on the clinical indication (e.g., sentinel node scintigraphy, lymphedema, or lymphatic vessel integrity), as well as availability and local regulations. In the United States, there are only 2 tracers generally available for clinical use: 99mTc sulfur colloid and 99mTc tilmanocept. In addition, injection techniques, imaging protocols, and camera technology can vary substantially, making comparisons between studies challenging. A discussion of these technical differences is beyond the scope of this document. These appropriate use criteria (AUC) have been developed to describe the appropriate use of radiopharmaceuticals for lymphoscintigraphy in SLN mapping and lymphedema. It is hoped that through these recommendations, nuclear medicine lymphatic imaging techniques will be used to benefit patients in the most cost-effective manner. Representatives from the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the Society for Vascular Medicine (SVM), the Australia and New Zealand Society of Nuclear Medicine (ANZSNM), the American College of Radiology (ACR), the Society of Surgical Oncology (SSO), the European Association of Nuclear Medicine (EANM), the American Head and Neck Society (AHNS), the American Society of Clinical Oncology (ASCO), the American Society of Breast Surgeons (ASBrS), the American College of Nuclear Medicine (ACNM), and the American College of Surgeons (ACS) assembled as an autonomous workgroup to develop these AUC. This process was performed in accordance with the Protecting Access to Medicare Act of 2014 (6). This legislation requires that all referring physicians consult AUC by using a clinical decision support mechanism before ordering any advanced diagnostic imaging services. Such services are defined as diagnostic magnetic resonance imaging (MRI), computed tomography (CT), and nuclear medicine procedures, including positron emission tomography (PET) and others, as specified by the Secretary of Health and Human Services in consultation with physician specialty organizations and other stakeholders (3). Lymphoscintigraphy usually causes trivial radiation exposures for the patient, the surgeon, and the staff handling any specimens that may contain radioactivity. Local regulations that address the handling of radiopharmaceuticals and exposure of the public should always be followed. Radiation exposures are also trivial for pregnant patients and infants exposed to someone who has been injected with lymphoscintigraphic agents labeled with 99mTc. The amount of radiopharmaceutical transferred from the interstitium into the blood and from the blood to the milk is very low. However, when performing an SLN procedure for breast cancer, it seems prudent to recommend the interruption of direct breastfeeding for 24 hours after administration of the radiopharmaceutical. There is a potential for more fetal or infant exposure if the radioisotope dissociates from the radiopharmaceutical; however, exposures will remain very small and likely of no consequence. The rapid decay of 99mTc (6-hour half-life) also allows for rapid return of radiation exposures to background levels within a short time. More detailed information can be found in the document “Advisory Committee on Medical Uses of Isotopes (ACMUI) Sub-Committee on Nursing Mother Guidelines for the Medical Administration of Radioactive Materials” (https://www.nrc.gov/docs/ML1803/ML18033B034.pdf).

Socio-economic position is a well-established driver of health status in the United Kingdom. However, less is known about the reverse relationship — the effect health conditions have on socio-economic position and social mobility. The purpose of this qualitative study was to explore individual experiences and perceptions of the relationship between ill-health and social mobility amongst people with long-term physical health conditions. Structured, in-depth interviews or focus group discussions were conducted with 37 people with long-term physical health conditions (including asthma, cancer, diabetes, heart disease, back pain, arthritis and lipoedema) between November 2019 and January 2020. Participants were asked about the impact of physical health on their career, education, and social life. Factors affecting their ability to cope with their condition were also explored. Participants reported their conditions had been a barrier to upward, and a facilitator of downward social mobility. Physical health conditions were commonly reported to have affected the participants’ educational attainment, choice of occupation, financial stability, and retirement age. Participants also described a lack of understanding from employers about their conditions, with some experiencing instances of discrimination. Factors that reduced the extent to which their condition affects social mobility included, a feeling of control over their condition, support from their employers and knowledge of the available support systems. Individual experience, psychological make-up, and early-life experience also mediated the impact. Participants described clear regional differences in terms of access to services. Advice and support services were often filled by charitable organisations. In conclusion, physical ill-health was reported to have a substantial downward impact on social mobility; by negatively impacting a person's education, choice of occupation and earning ability. Key changes that may enable people to better manage their condition and its impact on social mobility include, improved training of and support from employers and better and consistent access to multi-disciplinary support services from the health and social care system.

Lipedema is a pathology of the adipose tissue, in evident female prevalence, diagnosed clinically and still of not well-defined etiopathogenesis. Indeed, an estrogen-related component is present, and an inflammatory state and a condition of edema are present in most cases; even pain seems to be a recurring feature, and insulin resistance is also often associated with lipedema. The therapeutic approach is finally becoming holistic. Therefore, with surgery, physiotherapy, and elastic compression therapy, the nutritional aspect of food supplementation is gaining much value. The objective of the present work is to consider the nutritional supplements that could be useful to manage this condition, underlining that, at the moment, the specific literature is practically non-existent. The most promising supplements seem to be omega 3 fish oil, polyphenols, and vitamin C, but the need for studies in this sector is urgent.

Lipedema is an adipofascial disorder that almost exclusively affects women. Lipedema leads to chronic pain, swelling, and other discomforts due to the bilateral and asymmetrical expansion of subcutaneous adipose tissue. Although various distinctive morphological characteristics, such as the hyperproliferation of fat cells, fibrosis, and inflammation, have been characterized in the progression of lipedema, the mechanisms underlying these changes have not yet been fully investigated. In addition, it is challenging to reduce the excessive fat in lipedema patients using conventional weight-loss techniques, such as lifestyle (diet and exercise) changes, bariatric surgery, and pharmacological interventions. Therefore, lipedema patients also go through additional psychosocial distress in the absence of permanent treatment. Research to understand the pathology of lipedema is still in its infancy, but promising markers derived from exosome, cytokine, lipidomic, and metabolomic profiling studies suggest a condition distinct from obesity and lymphedema. Although genetics seems to be a substantial cause of lipedema, due to the small number of patients involved in such studies, the extrapolation of data at a broader scale is challenging. With the current lack of etiology-guided treatments for lipedema, the discovery of new promising biomarkers could provide potential solutions to combat this complex disease. This review aims to address the morphological phenotype of lipedema fat, as well as its unclear pathophysiology, with a primary emphasis on excessive interstitial fluid, extracellular matrix remodeling, and lymphatic and vasculature dysfunction. The potential mechanisms, genetic implications, and proposed biomarkers for lipedema are further discussed in detail. Finally, we mention the challenges related to lipedema and emphasize the prospects of technological interventions to benefit the lipedema community in the future.

Lipoedema is a chronic disease in adipose tissue that almost exclusively affects women during periods of hormonal alterations. Its main symptoms include an abnormal accumulation of subcutaneous fat in the buttock, hips, and legs, which is associated with pain, swelling, and easy bruising. Herein, a grading in three stages is used to determine disease progression. Problematically, lipoedema manifestations are often confused with lifestyle-induced obesity, which is why the various health problems among affected women often remain unrecognized. Overall, research on lipoedema is scarce. As such, this study examined the health, health-related quality of life (HRQOL), and sense of coherence (SOC) among women with lipoedema.

Lipedema is a common disorder characterized by excessive deposition of subcutaneous adipose tissue (SAT) in the legs, hips, and buttocks, mainly occurring in adult women. Although it appears to be heritable, no specific genes have yet been identified. To identify potential genetic risk factors for lipedema, we used bioelectrical impedance analysis and anthropometric data from the UK Biobank to identify women with and without a lipedema phenotype. Specifically, we identified women with both a high percentage of fat in the lower limbs and a relatively small waist, adjusting for hip circumference. We performed a genome-wide association study (GWAS) for this phenotype, and performed multiple sensitivity GWAS. In an independent case/control study of lipedema based on strict clinical criteria, we attempted to replicate our top hits. We identified 18 significant loci (p < 5 × 10−9), several of which have previously been identified in GWAS of waist-to-hip ratio with larger effects in women. Two loci (VEGFA and GRB14-COBLL1) were significantly associated with lipedema in the independent replication study. Follow-up analyses suggest an enrichment of genes expressed in blood vessels and adipose tissue, among other tissues. Our findings provide a starting point towards better understanding the genetic and physiological basis of lipedema.

BackgroundThere are both conservative and surgical treatment options for Lipohyperplasia dolorosa (LiDo). A procedure that has been established since 1997 is the surgical treatment through Lymphological Liposculpture according to Cornely™.AimAfter extensive suctioning of the extremities, an extensive subcutaneous wound cavity with a trabecular connective tissue scaffold remains. Nevertheless, surgery-related complications are rare. Postoperative management and administration of antibiotics and antithrombotics are reviewed. The therapies for complications are presented in detail.Materials and methodsRetrospectively, the frequencies of adverse events in 1400 LiDo surgeries in 2020 were evaluated. The mean age of the patients was 47.81 years (range 16–78 years). Symmetrically, 504 outer legs (outer half of the limb [BO]), 504 inner legs (inner half of the limb [BI]), and 392 arms [A] were surgically treated.ResultsRelevant adverse events rarely occurred: infections (1.79%), seromas (0.79%), erysipelas (0.28%), necrosis (0.14%) and deep vein thrombosis (0.07).DiscussionWe were able to reduce the rate of postoperative complications to 3.07% in the Lymphological Liposculpture™ regime for the surgical treatment of LiDo. In their meta-analysis on liposuction, Kanapathy et al. reported an overall incidence of major surgical complications of 3.35%. The overall incidence of minor surgical complications was 11.62%, with seroma (5.51%) being the most common minor complication [26]. Kruppa et al. report that the liposuction procedure including fat removal for esthetic reasons has a complication rate of 9.5%. Wound infections with 4.5% and the formation of erysipelas with 4% are clearly in the foreground [20].

INTRODUCTION: Lipedema is a poorly known condition. Diagnosis is based almost exclusively on clinical criteria, which may be subjective and not always reliable. This study aimed to investigate regional body composition (BC) by dual-energy X-ray absorptiometry (DXA) in patients with lipedema and healthy controls and to determine cut-off values of fat mass (FM) indices to provide an additional tool for the diagnosis and staging of this condition. METHODS: This study is a single-center case-control study performed at Lausanne University Hospital, Switzerland. Women with clinically diagnosed lipedema underwent regional BC assessment by DXA. The control group without clinical lipedema was matched for age and body mass index (BMI) at a ratio of 1:2 and underwent similar examination. Regional FM (legs, arms, legs and arms, trunk, android and gynoid FM) was measured in (kg) and divided by FM index (FMI) (kg/m2) and total FM (kg). The trunk/legs and android/gynoid ratios were calculated. For all indices of FM distribution showing a significant difference between cases and controls, we defined the receiver operating characteristic (ROC) curves, calculating the area under the curve (AUC), sensitivity, specificity, and Youden's index. Types and stages of lipedema were compared in terms of FM indices. Correlation analyses between all FM distribution indices and lipedema stages were performed. RESULTS: We included 222 women (74 with lipedema and 148 controls). Overall, the mean age was 41 years (standard deviation [SD] 11), and mean BMI was 30.9 kg/m2 (SD 7.6). A statistically significant difference was observed for all DXA-derived indices of FM distribution between groups, except for arm FM indices. The ROC curve analysis of leg FM/total FM, as a potential indicator of lipedema, resulted in an AUC of 0.90 (95% confidence interval 0.86-0.94). According to Youden's index, optimal cut-off value identifying lipedema was 0.384. Sensitivity and specificity were 0.95 and 0.73, respectively. We found no significant differences between lipedema types and stages in terms of FM indices, nor significant correlations between the latter and lipedema stages. DISCUSSION/CONCLUSION: BC assessment by DXA, and particularly calculation of the leg FM/total FM index, is a simple tool that may help clinicians rule out lipedema in doubtful cases.

The most relevant hallmarks of cellulite include a massive protrusion of superficial adipose tissue into the dermis, reduced expression of the extracellular glycoprotein fibulin-3, and an unusually high presence of MUSE cells in gluteofemoral white adipose tissue (gfWAT) that displays cellulite. Also typical for this condition is the hypertrophic nature of the underlying adipose tissue, the interaction of adipocytes with sweat glands, and dysfunctional lymph and blood circulation as well as a low-grade inflammation in the areas of gfWAT affected by cellulite. Here, we propose a new pathophysiology of cellulite, which connects this skin condition with selective accumulation of endogenous lipopolysaccharides (LPS) in gfWAT. The accumulation of LPS within a specific WAT depot has so far not been considered as a possible pathophysiological mechanism triggering localized WAT modifications, but may very well be involved in conditions such as cellulite and, secondary to that, lipedema.

Lipoedema is a chronic adipose tissue disorder mainly affecting women, causing excess subcutaneous fat deposition on the lower limbs with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is currently unclear. A tightly phenotyped cohort of 200 lipoedema patients was recruited from two UK specialist clinics. Objective clinical characteristics and measures of quality of life data were obtained. In an attempt to understand the genetic architecture of the disease better, genome-wide single nucleotide polymorphism (SNP) genotype data were obtained, and a genome wide association study (GWAS) was performed on 130 of the recruits. The analysis revealed genetic loci suggestively associated with the lipoedema phenotype, with further support provided by an independent cohort taken from the 100,000 Genomes Project. The top SNP rs1409440 (ORmeta ≈ 2.01, Pmeta ≈ 4 x 10–6) is located upstream of LHFPL6, which is thought to be involved with lipoma formation. Exactly how this relates to lipoedema is not yet understood. This first GWAS of a UK lipoedema cohort has identified genetic regions of suggestive association with the disease. Further replication of these findings in different populations is warranted.

Lipedema may be considered a model for healthy expandability of subcutaneous adipose tissue (SAT). This condition is characterized by the disproportional and symmetrical SAT accumulation in the lower-body parts and extremities, avoiding the abdominal area. There are no circulating biomarkers facilitating the diagnosis of lipedema. We tested the hypothesis that women living with lipedema present a distinct pattern of circulating parameters compared to age- and BMI-matched women. In 26 women (Age 48.3 ± 13.9 years, BMI 32.6 ± 5.8 kg/m2; lipedema group: n=13; control group: n=13), we assessed circulating parameters of glucose and lipid metabolism, inflammation, oxidative stress, sex hormones and a proteomics panel. We find that women with lipedema have better glucose metabolism regulation represented by lower HbA1c (5.55 ± 0.62%) compared to controls (6.73 ± 0.85%; p<0.001); and higher adiponectin levels (lipedema: 4.69 ± 1.99 mmol/l; control: 3.28 ± 1.00 mmol/l; p=0.038). Despite normal glycemic parameters, women with lipedema have significantly higher levels of total cholesterol (5.84 ± 0.70 mmol/L vs 4.55 ± 0.77 mmol/L in control; p<0.001), LDL-C (3.38 ± 0.68 mmol/L vs 2.38 ± 0.66 mmol/L in control; p=0.002), as well as higher circulating inflammation (top 6 based on p-values: TNFSF14, CASP8, EN-RAGE, EIF4EBP1, ADA, MCP-1) and oxidative stress markers (malondialdehyde, superoxide dismutase and catalase). Our findings suggest that the expected association between activation of inflammatory and oxidative stress pathways and impaired glucose metabolism are counterbalanced by protective factors in lipedema.

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BACKGROUND: The aim of this study was to define outcomes after total knee arthroplasty (TKA) in lymphoedema and lipoedema patients managed by a multidisciplinary team and daily compression bandaging. METHODS: A retrospective study was performed in a single centre. Between 2007 and 2018, 36 TKA procedures were performed on 28 consecutive patients with a diagnosis of lymphoedema and lipoedema. Oxford Knee Scores (OKS), EuroQol-5D (EQ-5D) scores, satisfaction scores, radiographs, and complications were obtained at the final follow-up. Patients were admitted to the hospital up to two weeks prior to surgery and remained on the ward for daily compression bandaging by the specialist lymphoedema team. RESULTS: Over the study period, 36 TKAs were performed on 28 patients (5 males, 23 females) with a mean age of 71 years (range 54-90). Of these, 30 TKAs were in patients with lymphoedema, five with lipoedema, and one with a dual diagnosis. Overall, 28 TKAs (21 patients) were available at the final follow-up with a mean follow-up time of 61 months (range 9-138). The mean BMI was 38.5 kg/m2. The mean pre-operative and post-operative Oxford Knee Score increased from 18 (range 2-38) to 29 (range 10-54); p < 0.001. EQ-5D score increased from 0.48 (range 0.15-0.80) to 0.74 (0.34-1.00) (p < 0.001). Mean post-operative satisfaction was 7.6/10 (range 2-10), with 89.3% TKAs satisfied. Complications were one (4%, 1/28) deep vein thrombosis, one superficial wound infection, one prosthetic joint infection, one stiff knee requiring manipulation, and one intra-operative femoral fracture. CONCLUSIONS: Lymphoedema and lipoedema should not be seen as barriers to TKA if adopting a multidisciplinary approach.