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Background: Lipedema and Dercum's disease (DD) are incompletely characterized adipose tissue diseases, and objective measures of disease profiles are needed to aid in differential diagnosis. We hypothesized that fluid properties, quantified as tissue water bioimpedance in the upper and lower extremities, differ regionally between these conditions. Methods and Results: Women (cumulative n = 156) with lipedema (n = 110), DD (n = 25), or without an adipose disease matched for age and body mass index to early stage lipedema patients (i.e., controls n = 21) were enrolled. Bioimpedance spectroscopy (BIS) was applied to measure impedance values in the arms and legs, indicative of extracellular water levels. Impedance values were recorded for each limb, as well as the leg-to-arm impedance ratio. Regression models were applied to evaluate hypothesized relationships between impedance and clinical indicators of disease (significance criteria: two-sided p < 0.05). Higher extracellular water was indicated (i) in the legs of patients with higher compared with lower stages of lipedema (p = 0.03), (ii) in the leg-to-arm impedance ratio in patients with lipedema compared with patients with DD (p ≤ 0.001), and (iii) in the leg-to-arm impedance ratio in patients with stage 1 lipedema compared with controls (p ≤ 0.01). Conclusion: BIS is a noninvasive portable modality to assess tissue water, and this device is available in both specialized and nonspecialized centers. These findings support that regional bioimpedance measures may help to distinguish lipedema from DD, as well as to identify early stages of lipedema.

Background: Lipedema and Dercum's disease (DD) are incompletely characterized adipose tissue diseases, and objective measures of disease profiles are needed to aid in differential diagnosis. We hypothesized that fluid properties, quantified as tissue water bioimpedance in the upper and lower extremities, differ regionally between these conditions. Methods and Results: Women (cumulative n = 156) with lipedema (n = 110), DD (n = 25), or without an adipose disease matched for age and body mass index to early stage lipedema patients (i.e., controls n = 21) were enrolled. Bioimpedance spectroscopy (BIS) was applied to measure impedance values in the arms and legs, indicative of extracellular water levels. Impedance values were recorded for each limb, as well as the leg-to-arm impedance ratio. Regression models were applied to evaluate hypothesized relationships between impedance and clinical indicators of disease (significance criteria: two-sided p < 0.05). Higher extracellular water was indicated (i) in the legs of patients with higher compared with lower stages of lipedema (p = 0.03), (ii) in the leg-to-arm impedance ratio in patients with lipedema compared with patients with DD (p ≤ 0.001), and (iii) in the leg-to-arm impedance ratio in patients with stage 1 lipedema compared with controls (p ≤ 0.01). Conclusion: BIS is a noninvasive portable modality to assess tissue water, and this device is available in both specialized and nonspecialized centers. These findings support that regional bioimpedance measures may help to distinguish lipedema from DD, as well as to identify early stages of lipedema.

Lipedema is a painful fat disease of loose connective tissue usually misdiagnosed as lifestyle-induced obesity that affects ~10% of women of European descent as well as other populations. Lipedema is characterized by symmetric enlargement of the buttocks, hips, and legs due to increased loose connective tissue; arms are also affected in 80% of patients. Lipedema loose connective tissue is characterized by hypertrophic adipocytes, inflammatory cells, and dilated leaky blood and lymphatic vessels. Altered fluid flux through the tissue causes accumulation of fluid, protein, and other constituents in the interstitium resulting in recruitment of inflammatory cells, which in turn stimulates fibrosis and results in difficulty in weight loss. Inflammation and excess interstitial substance may also activate nerve fibers instigating the painful lipedema fat tissue. More research is needed to characterize lipedema loose connective tissue structure in depth, as well as the form and function of blood and lymphatic vessels. Understanding the pathophysiology of the disease will allow healthcare providers to diagnose the disease and develop treatments.

Lipedema is a chronic progressive disease characterized by abnormal fat distribution resulting in disproportionate, painful limbs. It almost exclusively affects women, leading to considerable disability, daily functioning impairment, and psychosocial distress. Literature shows both scarce and conflicting data regarding its prevalence. Lipedema has been considered a rare entity by several authors, though it may be a far more frequent condition than thought. Despite the clinical impact on women's health, lipedema is in fact mostly unknown, underdiagnosed, and too often misdiagnosed with other similarly presenting diseases. Polygenic susceptibility combined with hormonal, microvascular, and lymphatic disorders may be partly responsible for its development. Furthermore, consistent information on lipedema pathophysiology is still lacking, and an etiological treatment is not yet available. Weight loss measures exhibit minimal effect on the abnormal body fat distribution, resulting in eating disorders, increased obesity risk, depression, and other psychological complaints. Surgical techniques, such as liposuction and excisional lipectomy, represent therapeutic options in selected cases. This review aims to outline current evidence regarding lipedema epidemiology, pathophysiology, clinical presentation, differential diagnosis, and management. Increased awareness and a better understanding of its clinical presentation and pathophysiology are warranted to enable clinicians to diagnose and treat affected patients at an earlier stage.

Lipedema is a chronic progressive disease characterized by abnormal fat distribution resulting in disproportionate, painful limbs. It almost exclusively affects women, leading to considerable disability, daily functioning impairment, and psychosocial distress. Literature shows both scarce and conflicting data regarding its prevalence. Lipedema has been considered a rare entity by several authors, though it may be a far more frequent condition than thought. Despite the clinical impact on women's health, lipedema is in fact mostly unknown, underdiagnosed, and too often misdiagnosed with other similarly presenting diseases. Polygenic susceptibility combined with hormonal, microvascular, and lymphatic disorders may be partly responsible for its development. Furthermore, consistent information on lipedema pathophysiology is still lacking, and an etiological treatment is not yet available. Weight loss measures exhibit minimal effect on the abnormal body fat distribution, resulting in eating disorders, increased obesity risk, depression, and other psychological complaints. Surgical techniques, such as liposuction and excisional lipectomy, represent therapeutic options in selected cases. This review aims to outline current evidence regarding lipedema epidemiology, pathophysiology, clinical presentation, differential diagnosis, and management. Increased awareness and a better understanding of its clinical presentation and pathophysiology are warranted to enable clinicians to diagnose and treat affected patients at an earlier stage.

BACKGROUND: Adipose-derived Stem Cells (ASCs) present great potential for reconstructive procedures. Currently, isolation by enzyme digestion and culturing using xenogenic substances remain the gold standard, impairing clinical use. METHODS: Abdominal lipo-aspirate and blood samples were obtained from healthy patients. A novel mechanical isolation method for ASCs was compared to (the standard) collagenase digestion. ASCs are examined by flowcytometry and multilineage differentiation assays. Cell cultures were performed without xenogenic or toxic substances, using autologous plasma extracted from peripheral blood. After eGFP-transfection, an in vivo differentiation assay was performed. RESULTS: Mechanical isolation is more successful in isolating CD34+/CD31-/CD45-/CD13+/CD73+/CD146- ASCs from lipo-aspirate than isolation via collagenase digestion (p <0 .05). ASCs display multilineage differentiation potential in vitro. Autologous plasma is a valid additive for ASCs culturing. eGFP-ASCs, retrieved after 3 months in vivo, differentiated in adipocytes and endothelial cells. CONCLUSION: A practical method for human ASC isolation and culturing from abdominal lipo-aspirate, without the addition of xenogenic substances, is described. The mechanical protocol is more successful than the current gold standard protocol of enzyme digestion. These results are important in the translation of laboratory-based cell cultures to clinical reconstructive and aesthetic applications.

Background: Sonographic findings differ in patients with primary lipedema from those with lymphedema. This project was designed to quantify those differences and objectively characterize findings of lipedema and lymphedema in the lower extremity. Methods and Results: Patients with a clinical diagnosis of ISL stage I-II lipedema or lower extremity lymphedema that received ultrasound evaluation were included in this study. Thickness and echogenicity of the skin and subcutaneous fat layer were measured at the level of the ankle, calf, and thigh in each patient. The cohort analyzed included 12 patients with lipedema (12 lower extremities) and 10 patients with unilateral lymphedema (10 lower extremities with lymphedema and 8 lower extremities used as controls). Mean skin thickness of the ankle and calf was greatest in the lymphedema group compared to those with lipedema or controls (p < 0.01 and p < 0.01, respectively). The mean thickness of the subcutaneous fat layer of the thigh was greatest in those with lipedema (p < 0.01). Mean dermal to subcutaneous fat echogenicity ratio was decreased in those with lymphedema (ankle, 0.91; calf, 1.05; thigh, 1.19) compared to lipedema (ankle, 1.36; calf, 1.58; thigh, 1.54) and control (ankle, 1.26; calf, 1.54; thigh, 1.56) (p < 0.01, p < 0.01, and p = 0.02, respectively). Conclusions: Lymphedema appears to be associated with increased skin thickness and dermal hypoechogenicity, particularly in the distal lower extremity, compared to lipedema or controls. Conversely, lipedema may be associated with increased thickness and hypoechogenicity of the subcutaneous fat. Overall, these findings suggest that ultrasound may be an effective tool to differentiate these diseases and potentially guide treatment.

Syndromes with localized accumulation of subcutaneous fatty tissue belong to a group of genetically and phenotypically heterogeneous disorders. These diseases may show some common signs, such as nodular fat, symmetrical fat masses, obesity, fatigue, lymphedema and symmetrical lipomas (painful or otherwise). Other symptoms may be specific for the different clinical entities, enabling correct differential diagnosis. Disorders belonging to this spectrum are lipedema, generalized diffuse or nodular forms of Dercum disease, localized nodular Dercum disease and multiple symmetric lipomatosis. Here we summarize the genes involved in syndromes with localized accumulation of subcutaneous fat and the test we use for genetic analysis.

Lipoedema is a progressive disorder that is characterized by an abnormal distribution of subcutaneous adipose tissue, which results in a disproportion between the extremities and the trunk. This vascular/dermatological disease might have a detrimental impact on psychosocial wellbeing and quality of life. In this article, we report on a patient with morbid obesity that had a Roux en-Y Gastric bypass with sufficient weight loss. However, due to this weight loss, an abnormal disproportion came to light. A dermatologist diagnosed lipoedema five years after the surgery. Eventually, she had a dermolipectomy of the upper arms, of which reimbursement was initially rejected by her insurance.

640 patients from a specialist clinic for operative lymphology were surveyed with the help by a questionnaire issued by the German Society of Pain Therapy (Deutsche Schmerzgesellschaft e. V.). This survey collected responses to questions about pain and pain characteristics as well as demographic data. It revealed that only a little more than 50 % of respondents were genuine cases of obesity. Lipoedema and obesity must therefore be regarded as clinical pictures unrelated to one another. The pain was mostly described as pressing and tearing in nature. Attributes such as throbbing or pulsing, consistent with acute inflammation, were rated as "not applicable". Symptoms were independent of the BMI, which is only useable to a limited extent in lipohyperplasia dolorosa. On the whole, the main symptom "pain" is multi-faceted. The study initiated by the German Federal Joint Committee (G-BA) must therefore be viewed critically. Congenital (as opposed to acquired) lipoedema fat on the extremities significantly impairs a person's ability to undertake activities in general as well as leisure activities. Since no objectively verifiable findings in lipoedema can be ascertained thus far, the diagnosis should be based on a careful patient survey.

OBJECTIVE: The aim of this qualitative review is to provide an update on the current understanding of the genetic determinants of lipedema and to develop a genetic test to differentiate lipedema from other diagnoses. MATERIALS AND METHODS: An electronic search was conducted in MEDLINE, PubMed, and Scopus for articles published in English up to March 2019. Lipedema and similar disorders included in the differential diagnosis of lipedema were searched in the clinical synopsis section of OMIM, in GeneCards, Orphanet, and MalaCards. RESULTS: The search identified several genetic factors related to the onset of lipedema and highlighted the utility of developing genetic diagnostic testing to help differentiate lipedema from other diagnoses. CONCLUSIONS: No genetic tests or guidelines for molecular diagnosis of lipedema are currently available, despite the fact that genetic testing is fundamental for the differential diagnosis of lipedema against Mendelian genetic obesity, primary lymphedema, and lipodystrophies.

Background: The Stemmer sign is a physical examination finding used to diagnose lymphedema. If the examiner cannot pinch the skin of the dorsum of the foot or hand then this positive finding is associated with lymphedema. The purpose of the study was to determine the accuracy of the Stemmer sign to predict lymphedema. Methods: All patients referred to our Lymphedema Program between 2016 and 2018 were tested for the Stemmer sign and underwent lymphoscintigraphy to define the patient’s lymphatic function. Patient age, lymphedema type (primary and secondary), disease location (arm and leg), lymphoscintigraphy findings, stage, severity, and body mass index were recorded. Comparison of predictive variables and Stemmer sign result was performed using Fisher’s exact test and Student’s t test. Results: One hundred ten patients were studied: patients with a positive Stemmer sign (n = 87) exhibited abnormal (n = 80) or normal (n = 7) lymphatic function by lymphoscintigraphy (sensitivity = 92%). False-positive Stemmer signs included individuals with obesity (n = 6) or spinal muscle atrophy (n = 1). Subjects with a negative Stemmer sign (n = 23) had normal (n = 13) or abnormal (n = 10) lymphatic function by imaging (specificity = 57%). Patients with a false-negative Stemmer sign were more likely to have a normal body mass index (P = 0.02) and Stage 1 disease (P = 0.01). Conclusions: A positive Stemmer sign is a sensitive predictor for primary and secondary lymphedema of the arms or legs and, thus, is a useful part of the physical examination. Because the test exhibits moderate specificity, lymphoscintigraphy should be considered for patients with a high suspicion of lymphedema that have a negative Stemmer sign.

Lipedema is a disorder characterized by large amount of subcutaneous fat in the upper and lower legs due to both hyperplasia and hypertrophy. It occurs almost exclusively in females, although a few cases in men have been reported.(,) The condition is relatively rare and often seen in patients with a family history of the disease.(,) Lipedema does not yet have a registered diagnosis in the International Classification of Diseases (ICD-10) of the World Health Organization (WHO), making it difficult to establish its prevalence. However, lipedema is believed to affect nearly 11% of adult women, with noted significant differences in prevalence worldwide.(,)(,) The literature search for this report did not find epidemiological data for lipedema in Canada. The cause of lipedema is unknown, and it is likely that the condition is frequently misdiagnosed or wrongly diagnosed as lifestyle-induced obesity or lymphedema (i.e., localized fluid retention and tissue swelling).(,) However, although lipedema and obesity can co-occur, unlike obesity, lipedema usually targets the legs and thighs, without affecting the feet or hands, and the adipose tissue in lipedema is painful.(,)(,)(–) The lymphatic system remains unimpaired in the initial stages and can keep up with the increased amount of interstitial fluid.(,) However, patients with lipedema may develop secondary lymphedema (lipolymphoedema) if the fatty deposits compromise the lymphatic system. Lipedema targets both legs (and sometimes, also both hands) to the same extent and has a bilateral, nearly symmetrical presentation.(–) The excessive fat deposits are typically unresponsive to traditional weight loss interventions such as physical activity or dietary measures.(,)(,) Symptoms of the condition include pain in the lower extremities, particularly with pressure, loss of strength, easy bruising, and deterioration in daily activity levels that can greatly impact the health and quality of life of the individual with lipedema.(,)(,) Untreated lipedema may result in secondary problems including osteoarthritis, reduced mobility, psychological impairment, and lowered self-esteem. Over time, the weight of the excessive fat build-up can cause the knees to knock inward or droop to the side of the leg, and impair the inability to walk. As mentioned, in the later stages, secondary lymphedema can occur due to imbalance in the amount of fluid produced and drained by the lymphatic system.(–)(,)(,)(,) Lipedema poses a significant psychosocial burden for most patients, and associated effects often limit capacity for exercise. In severe cases, lipedema may lead to absence from work or occupational disability. There is no known curative therapy for lipedema. The primarily focus of treatment is to reduce its related lower extremity symptoms, disability, and functional limitations to improve patients’ quality of life, as well as preventing disease progression.(–)(,)(,) Treatment is divided into conservative therapy and surgical interventions. The conservative therapy includes promotion of individually adjusted healthy lifestyle, combined decongestive therapy (CDT), and other supportive measures, such as psychosocial therapy and orthopedic counseling. Conservative therapy can alleviate some lipedema symptoms such as heaviness, pain, and secondary swelling. However, these benefits are short-lived, usually requiring repeat treatment within days. Liposuction is the main surgical interventions for lipedema. Commonly used liposuction methods for lipedema are tumescent anesthesia (TA) liposuction, and water assisted liposuction (WAL). In TA liposuction, tumescent is infused in the subcutaneous tissues to cause the fat cells to swell and vessels to constrict; then blunt micro-cannulas are used to suction the fat.(,)(,) Water assisted liposuction uses a pressure spray of tumescent fluid to dislodge the fat from the connective tissue, rather than utilizing a cannula. Unlike traditional liposuction, both TA and WAL rely on the local anesthetics in the tumescent fluid and do not require general anesthesia. The objective of this report is to summarize the evidence regarding the clinical effectiveness of liposuction for the treatment of lipedema and the recommendations of evidence-based clinical guidelines regarding its use for this condition.

Background: Metastatic tumor cells spread through lymphatic vessels and colonize draining lymph nodes (LNs). It is known that tumors induce lymphangiogenesis to enhance lymphatic metastasis and that metastatic cancer cells are carried by lymph flow to LNs. Methods and Results: Here, we investigated the molecular and cellular regulation of collecting lymphatic vessel contraction in vessels draining a metastatic tumor using intravital microscopy. In tumor-draining collecting lymphatic vessels, we found vessel contraction was suppressed. The infiltration of peritumor tissue by inducible nitric oxide synthase positive and CD11b+Gr1+ myeloid cells played a critical role in the suppression of lymphatic contraction. Depletion of Gr1+ cells with an anti-Gr1 antibody improved contraction of tumor-draining lymphatic vessels. In addition, inducing tumor cell death restored lymphatic contraction in nude mice. Conclusions: These findings indicate that tumors contribute to regulation of lymphatic transport in a reversible manner, warranting further investigation into the role of impaired lymphatic transport in cancer progression.

Background: Lymphedema and chronic edema is a major health care problem in both developed and nondeveloped countries The Lymphoedema Impact and Prevelance - International (LIMPRINT) study is an international health service-based study to determine the prevalence and functional impact in adult populations of member countries of the International Lymphoedema Framework (ILF). Methods and Results: A total of 1051 patients from eight centers in Turkey were recruited using the LIMPRINT study protocol. Data were collected using the core and module tools that assess the demographic and clinical properties as well as disability and quality of life (QoL). Most of the Turkish patients were recruited from specialist lymphedema services and were found to be women, housewives, and having secondary lymphedema because of cancer treatment. The duration of lymphedema was commonly <5 years and most of them had International Society of Lymphology (ISL) grade 2 lymphedema. Cellulitis, infection, and wounds were uncommon. The majority of patients did not get any treatment or advice before. Most of the patients had impaired QoL and decreased functionality, but psychological support was neglected. Although most had social health security access to lymphedema centers, nevertheless access seemed difficult because of distance and cost. Conclusion: The study has shown the current status and characteristics of lymphedema patients, treatment conditions, the unmet need for the diagnosis and treatment, as well as burden of the disease in both patients and families in Turkey. National health policies are needed for the prevention, diagnosis, and treatment in Turkey that utilize this informative data.

Obese adipose tissue expansion is an inflammatory process that results in dysregulated lipolysis, increased circulating lipids, ectopic lipid deposition, and systemic insulin resistance. Lymphatic vessels provide a route of fluid, macromolecule, and immune cell clearance, and lymphangiogenesis increases this capability. Indeed, inflammation-associated lymphangiogenesis is critical in resolving acute and chronic inflammation, but it is largely absent in obese adipose tissue. Enhancing adipose tissue lymphangiogenesis could, therefore, improve metabolism in obesity. To test this hypothesis, transgenic mice with doxycycline-inducible expression of murine vascular endothelial growth factor (VEGF)-D under a tightly controlled Tet-On promoter were crossed with adipocyte-specific adiponectin-reverse tetracycline-dependent transactivator mice (Adipo-VD) to stimulate adipose tissue-specific lymphangiogenesis during 16-week high-fat diet-induced obesity. Adipose VEGF-D overexpression induced de novo lymphangiogenesis in murine adipose tissue, and obese Adipo-VD mice exhibited enhanced glucose clearance, lower insulin levels, and reduced liver triglycerides. On β-3 adrenergic stimulation, Adipo-VD mice exhibited more rapid and increased glycerol flux from adipose tissue, suggesting that the lymphatics are a potential route of glycerol clearance. Resident macrophage crown-like structures were scarce and total F4/80+ macrophages were reduced in obese Adipo-VD s.c. adipose tissue with evidence of increased immune trafficking from the tissue. Augmenting VEGF-D signaling and lymphangiogenesis specifically in adipose tissue, therefore, reduces obesity-associated immune accumulation and improves metabolic responsiveness.