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When studying the current literature, one might get the impression that lipedema is a “modern” disease, with increasing incidence and augmenting prevalence throughout Western countries during the last decade. However, a quick look into older textbooks shows that disproportionate accumulation of fat in female bodies has long been known without being recognized as an independent disease. Nevertheless, it was not until 1940 that Allen and Hines described a “syndrome characterized by fat legs and orthostatic edema” in a seminal publication. The mere awareness that people who have lipedema are not just overweight but suffer from a yet poorly defined pathological condition, may be considered a decisive leap forward in the understanding of lipedema. A number of comprehensive publications have since dealt with the clinical presentation of lipedema and have provided the first clues towards the potential pathological mechanisms underlying its initiation and progression. Nevertheless, despite all effort that has been undertaken to unravel lipedema pathology, many questions have remained unanswered. What can be deduced with certainty from all experimental and medical evidence available so far is that lipedema is neither a cosmetic problem nor is it a problem of lifestyle but should be accepted as a serious disease with yet undetermined genetic background, which makes women’s lives unbearable from both a physical and psychological point of view. To date, results from clinical inspections have led to the categorization of various types and stages of lipedema, describing how the extremities are affected and evaluating its progression, as demonstrated by skin alterations, adipose tissue volume increase and physical and everyday-behavioral impediments. There is accumulating evidence showing that advanced stages of lipedema are usually accompanied by excessive weight or obesity. Thus, it is not unreasonable to assume that the progression of lipedema is largely driven by weight gain and the pathological alterations associated with it. Similarly, secondary lymphedema is frequently found in lipedema patients at advanced stages. Needless to say, both conditions considerably blur the clinical presentation of lipedema, making diagnosis difficult and scientific research challenging. The present literature review will focus on lipedema research, based on evidence fromex vivo and in vitro data, which has accumulated throughout the last few decades. We will also open the discussion as to whether the currently used categorization of lipedema stages is still sufficient and up-to-date for the accurate description of this enigmatic disease, whose name, strangely enough, does not match its pathologic correlate.

Lipoedema is a painful non-pitting diffuse “fatty” swelling, usually confined to the legs, that occurs mainly in women. This scoping review aimed to provide an overview of the available research on the functioning of people with lipoedema, according to the International Classification of Functioning, Disability and Health (ICF) framework. Relevant publications and gray literature were retrieved until October 2022. The results sections of each publication were organized using a thematic framework approach. All included studies reported at least one outcome fitting within the domains of body functions and body structures, with most studies focusing on the categories of “sensation of pain”, “immunological system functions”, and “weight maintenance functions”. The ICF domains of activities and participation and environmental factors were mentioned in a small number of the included studies (17 and 13%, respectively), while the domain of personal factors was studied in half of the included studies. In conclusion, the emphasis of lipoedema research is on its description from a disorder-oriented point of view in the form of body functions and body structures, with a lack of information about the other domains of functioning.

The aim was to analyze the effect of compression tights on skin temperature in women with lipedema and to assess the effect of different knitting on skin temperature. Twenty-four women with lipedema (Grade I = 25%; Grade II = 75%) were divided into three groups according to the compression tights prototype assigned: control (n = 9), Flat (n = 7) and circular (n = 8). The participants performed a gait test two times, separated by 15 days: before wearing the tights of the study and after the treatment (15 days employing compression tights). Skin temperature was measured using infrared thermography before and after the gait test on both days, and six regions of interest were determined in the anterior and posterior leg. The skin temperature decreased in the different regions of interest after exercise in all the groups (e.g., anterior thigh (IC95% (−1.1, −0.7 °C) p < 0.001), but no differences were observed in skin temperature between groups before and after walking (p > 0.05). The use of compressing tights for 15 days does not alter skin temperature in women with lipedema before and after walking. The absence of differences in skin temperature between tights in the different assessments allows for obtaining the benefits of wearing compression tights during exercise without negative thermal effects.

Introduction: The pathologic features of fatty tissue in lipedema are often challenging to diagnose, thus allowing for variable bias and leading to underdiagnosis. Lipedema is a disease that is currently little known worldwide, but it represents a public health problem and demands immediate, well-directed healthcare. Insufficient scientific information limits medical action, which limits making diagnoses and addressing an adequate multidisciplinary treatment. This study aims to evaluate the current state of lipedema in Spain to contextualize the disease’s pathophysiological characteristics and thus achieve a consensus that unifies and defines its diagnostic criteria and medical management. Likewise, this study aims to determine the effectiveness of the various treatments applied to the study patients and to evaluate the consequences of the pandemic related to this disease. Material and methods: The present work is a descriptive, cross-sectional study that analyzed online questionnaires. It was applied to 1069 patients and collected over 9 months between 2021 and 2022. The questionnaires were distributed to the leading national and regional associations of patients affected by lipedema. The study included all patients in a group who had a diagnosis of lipedema and in a group of undiagnosed patients with six or more symptoms. The variables analyzed were age, weight, height, body mass index (BMI), type of lipedema (according to Schingale’s classification), symptoms (according to Wolf’s classification, modified by Herbst), and treatments performed (physiotherapy, compression garments, sports, diet, radiofrequency, mesotherapy, and surgery), associated with the score given by the patients regarding the degree of improvement in their disease with each of these treatments. Results: There were 967 women and 2 men between 18 and 75 years old (mean of 38.5 years); a body weight between 33 and 150 kg (mean 75.8 kg); a height between 144 and 180 cm (mean 164 cm); and an average body mass index (BMI) of 28.1. The most common kind of lipedema in our study population was type III (affecting the hips, thighs, and calves). The treatment that individually improved patients’ quality of life the most was surgery, only surpassed by the multidisciplinary approach to the disease, including conservative measures. Conclusions: With this study, we can conclude that, in Spain, there is a real problem associated with the diagnosis of lipedema, specifying the need to seek this diagnosis actively and propose multidisciplinary management, since it offers the best overall results, of course not without forgetting that surgery is one of the most critical pillars in the approach to this disease. Consistent with the results obtained in this study, criteria were proposed and applied to represent a statistical value at the time of ruling on the clinical diagnosis of lipedema, considering that a patient who presents six or more of these diagnostic criteria, with a very high probability, will have lipedema.

Often regarded as the forgotten second circulatory system, the lymphatic system is critical in working with the venous and arterial system to maintain fluid equilibrium, circulate cells and signaling molecules in the immune system, and transport fat molecules and nutrients. When there is an alteration in the flow of lymphatic fluid, lymphedema is the result, usually manifesting as significant swelling of a particular region of the body with protein-rich fluid accumulation in the interstitial spaces. The result of this disease ranges from psychological disturbance to significant disability and morbidity, even leading to aggressive malignancy. The prevalence of lymphedema is in the hundreds of millions worldwide; however, it is routinely under-diagnosed and under-recognized as a disease, especially in the United States. Treatment rates for lymphedema are variable, ranging from low rates of treatment in non-cancer etiologies, to high treatment rates seen in breast cancer related etiologies. Furthermore, treatment modalities are equally notorious for being unsuccessful, either as a result of non-compliance or lack of efficacious therapeutic techniques, or a combination of both. There is no cure for lymphedema and treatment mainly focuses on minimizing limb swelling, maintaining functionality, and preventative treatments to reduce complications.

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.

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.

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].

In this study an analysis of identified ICG lymphography features of the superficial lymphatics of the lower extremity was undertaken [Table 2.2]. The absence or presence and extent of the superficial lymphatics in the limb with LLLE was assessed to identify if any of these features or combination of features were significantly associated with particular diagnostic groups of primary or secondary cancer related or secondary non-cancer related LLLE. ICG lymphography studies undertaken by the researcher (submitted for publication) had identified two compensatory lymph drainage regions, the contralateral inguinal and axillo-inguinal nodal regions, associated with secondary cancer related LLLE which were not seen or very rarely seen in clinically diagnosed primary LLLE and less so in secondary non-cancer related LLLE. Conversely, retrograde flow in lymph vessels demonstrated during the ICG lymphography procedure was not seen in secondary cancer related LLLE. These observations provided a background rationale to exploring the diagnostic capacity of ICG lymphography in LLLE. One purpose of this study was to explore the feasibility of using ICG lymphography features as a diagnostic tool. It was hoped that identified ICG lymphographic features would allow the individual presenting with persistent leg swelling of unknown causation to be able to be advised that their condition is most likely a secondary non cancer related LLLE rather than an adult onset primary LE and therefore be possibly less likely to progress or deteriorate. This may potentially provide better prognostic information and improve individualised therapeutic plans of management and support compliance (Pigott, 2021). The aim of Part A of this study was to identify the prevalence and characteristics of ICG lymphography features of the lymph vessels, position and extent of DBF and drainage patterns. In addition, Part B of this study was to explore whether using the ALERT standardised ICG lymphography technique and a structured analysis of ICG lymphography features could be translated into a simple score to distinguish the ICG pattern of adult onset primary LLLE from secondary non-cancer related LLLE.

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.

An abstract is unavailable.

Lipedema is a disease with abnormally increased adipose tissue deposition and distribution. Pain sensations have been described in the clinical evaluation of lipedema, but its etiology remains poorly understood. We hypothesized that pain sensitivity measurements and ex vivo quantitation of neuronal cell body distribution in the skin would be lipedema stage-dependent, and could, thus, serve to objectively characterize neuropathic pain in lipedema. The pain was assessed by questionnaire and peripheral cutaneous mechanical sensitization (von-Frey) in lipedema (n = 27) and control (n = 23) consenting female volunteers. Dermal biopsies from (n = 11) Stages 1–3 lipedema and control (n = 10) participants were characterized for neuronal cell body and nociceptive neuropeptide calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) distribution. Stage 2 or 3 lipedema participants responded positively to von Frey sensitization in the calf and thigh, and Stage 3 participants also responded in the arm. Lipedema abdominal skin displayed reduced Tuj-1+ neuronal cell body density, compared to healthy controls, while CGRP and NGF was significantly elevated in Stage 3 lipedema tissues. Together, dermal neuronal cell body loss is consistent with hyper-sensitization in patients with lipedema. Further study of neuropathic pain in lipedema may elucidate underlying disease mechanisms and inform lipedema clinical management and treatment impact.