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OBJECTIVE: This study examines the role of MTHFR gene polymorphism (rs1801133) in women with lipedema (LIPPY) body composition parameters compared to a control group (CTRL). SUBJECTS AND METHODS: We carried out a study on a sample of 45 LIPPY and 50 women as a CTRL. Body composition parameters were examined by Dual-energy X-ray Absorptiometry (DXA). A genetic test was performed for the MTHFR polymorphism (rs1801133, 677C>T) using a saliva sample for LIPPY and CTRL groups. Mann-Whitney tests evaluated statistically significant differences between four groups (carriers and non-carriers of the MTHFR polymorphism for LIPPY and CTRL groups) on anthropometric/body composition parameters to identify patterns. RESULTS: LIPPY showed significantly higher (p<0.05) anthropometric parameters (weight, BMI, waist, abdominal, hip circumferences) and lower waist/hip ratio (p<0.05) compared to the CTRL group. The association between the polymorphism alleles related to the rs1801133 MTHFR gene and the body composition values LIPPY carriers (+) showed an increase in fat tissue of legs and fat region of legs percentage, arm’s fat mass (g), leg’s fat mass (g), and leg’s lean mass (g) (p<0.05) compared to CTRL (+). Lean/fat arms and lean/fat legs were lower (p<0.05) in LIPPY (+) than in CTRL (+). In the LIPPY (+), the risk of developing the lipedema disease was 2.85 times higher (OR=2.85; p<0.05; 95% confidence interval = 0.842-8.625) with respect to LIPPY (-) and CTRL. CONCLUSIONS: The presence or absence of MTHFR polymorphism offers predictive parameters that could better characterize women with lipedema based on the association between body composition and MTHFR presence.

The disease "Lipedema", which has been known since 1940, is increasingly better understood. Dimpled edema in particular is not significant in women with fat distribution disorders on the arms and legs. These and other scientific findings are "work in progress" with the aim of renaming the disease. A "proper name" is "Lipohyperplasia dolorosa" (LiDo). With LiDo, the increase in volume is genetically fixed, but the pain is dynamically progressive. A LiDo must be distinguished from other symmetrical, painless fat distribution disorders on the arms and legs at first sight and after palpatory examination, especially from the occasionally coincident obesity. Obesity is never comorbid, but often coincident with LiDo. Although physical activity and a change in diet can reduce obesity, they cannot eliminate the disproportionate increase in fat tissue on the extremities that is exclusively caused by LiDo. In LiDo patients coincident with obesity, gastric surgery has no effect on the obligatory pain. There are both conservative and surgical treatment options for LiDo. A procedure that has been established since 1997 is surgical treatment using lymphological liposculpture. As part of this operation, large wounds are created under the skin, which, according to the "Rules of Nine" when treating both arms in one session and the suction of the legs in 2 sessions per operation, correspond to an area of ​​18% of the body surface. However, with adequate postoperative management and the administration of antibiotics and antithrombotics, local complications associated with the operation are rare. The most important result of consistent surgical treatment of lipohyperplasia dolorosa is the impact on quality of life: "It ruined her life" becomes "It improves her life".

(1) Background: Although lipedema has gained more interest among researchers, specific treatment methods are still unknown. This study aims to identify the effects of compression therapy combined with exercises compared to exercising only. Moreover, the aim is to assess the methodology and outcome measurements before conducting a larger study. (2) Methods: Six women with lipedema were enrolled in the study; three were undergoing exercise program and compression therapy using compression leggings, and the remaining three were undergoing exercises only. During the first 4 weeks, intervention was under the supervision of a physiotherapist, and in the remaining weeks, participants were exercising independently. Measurements of circumference, weight, thickness of the skin and adipose tissue, symptom severity, and quality of life were taken at baseline, after 4 weeks and after 6 weeks; (3) Results: There was a significant decrease in the subjectively reported tendency for bruising and pain at palpation among patients that received compression therapy. Additionally, there was a tendency to reduce or maintain the circumference of the legs in patients using compression, while it tended to increase in patients without compression. (4) Conclusions: Preliminary results indicate that compression therapy, combined with exercises, could improve the quality of life and decrease the severity of lipedema symptoms. Further studies on a large clinical group are advisable.

Lipedema is a chronic adipose tissue disorder affecting approximately 11% of women worldwide. The illness is often misdiagnosed as obesity, and because of this, women often struggle in meetings with healthcare providers. Few studies have assessed these encounters of younger women with lipedema. The aims of this qualitative study were to explore women’s experiences in meetings with healthcare providers and the importance of social support and belonging, with a focus on younger women. Fifteen women with lipedema between the ages of 21 and 47 years (mean age 36.2 years) were interviewed. The results indicated that women felt stigmatized by healthcare providers and that younger women in their 20s and early 30s struggled more often than women of higher age when receiving their diagnosis. The feeling of shame and stigma were also dependent on the woman’s resources in handling the illness. The younger women reported that their self-confidence and romantic relationships were challenging. Social support and the feeling of belonging through romantic relationships or support groups were important resources for managing the illness. Highlighting the experiences of women may aid in increasing recognition and knowledge of lipedema. This in turn may reduce the stigma and lead to equitable healthcare services.

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.

Lipedema is a pathologic accumulation of adipose tissue in the subcutaneous layer of the extremities. This connective tissue disorder, which predominately affects females, is often misdiagnosed despite an incidence of ∼11%. Misdiagnosis often leads to delays in appropriate treatment, further increasing the morbidity of the condition. The authors report their facilities' experience in treating a patient with lipedema, requiring multiple surgical interventions involving liposuction and skin debulking to achieve desired aesthetic outcomes. The patient presented to the plastic surgery clinic with severe lipedema of the bilateral lower extremities. She previously underwent a panniculectomy and bilateral lower extremity liposuction without achieving the desired aesthetic results. Prior conservative management and liposuction alone were both unsuccessful treatment options and she required debulking procedures, along with further liposuction, as definitive management. The patient underwent 2 procedures at the clinic, both consisting of liposuction and panniculectomy of the lower extremities and buttocks. The procedures were conducted 1 year apart but were able to achieve the patient's desired aesthetics goals. Management of lipedema can be challenging, but not impossible. This case report shows that local excision is a viable option for treatment if minimally invasive options yield limited results.

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.

Enhancing our understanding of lymphatic anatomy from the microscopic to the anatomical scale is essential to discern how the structure and function of the lymphatic system interacts with different tissues and organs within the body and contributes to health and disease. The knowledge of molecular aspects of the lymphatic network is fundamental to understand the mechanisms of disease progression and prevention. Recent advances in mapping components of the lymphatic system using state of the art single cell technologies, the identification of novel biomarkers, new clinical imaging efforts, and computational tools which attempt to identify connections between these diverse technologies hold the potential to catalyze new strategies to address lymphatic diseases such as lymphedema and lipedema. This manuscript summarizes current knowledge of the lymphatic system and identifies prevailing challenges and opportunities to advance the field of lymphatic research as discussed by the experts in the workshop.

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 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).