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Purpose To quantify chemical exchange saturation transfer contrast in upper extremities of participants with lymphedema before and after standardized lymphatic mobilization therapy using correction procedures for B0 and B1 heterogeneity, and T1 relaxation. Methods Females with (n = 12) and without (n = 17) breast cancer treatment-related lymphedema (BCRL) matched for age and body mass index were scanned at 3.0T MRI. B1 efficiency and T1 were calculated in series with chemical exchange saturation transfer in bilateral axilla (B1 amplitude = 2µT, Δω = ±5.5 ppm, slices = 9, spatial resolution = 1.8 × 1.47 × 5.5 mm3). B1 dispersion measurements (B1 = 1-3 µT; increment = 0.5 µT) were performed in controls (n = 6 arms in 3 subjects). BCRL participants were scanned pre- and post-manual lymphatic drainage (MLD) therapy. Chemical exchange saturation transfer amide proton transfer (APT) and nuclear Overhauser effect (NOE) metrics corrected for B1 efficiency were calculated, including proton transfer ratio (PTR'), magnetization transfer ratio asymmetry , and apparent exchange-dependent relaxation (AREX'). Nonparametric tests were used to evaluate relationships between metrics in BCRL participants pre- versus post-MLD (two-sided P < 0.05 required for significance). Results B1 dispersion experiments showed nonlinear dependence of Z-values on B1 efficiency in the upper extremities; PTR' showed < 1% mean fractional difference between subject-specific and group-level correction procedures. PTR'APT significantly correlated with T1 (Spearman's rho = 0.57, P < 0.001) and body mass index (Spearman's rho = −0.37, P = 0.029) in controls and with lymphedema stage (Spearman's rho = 0.48, P = 0.017) in BCRL participants. Following MLD therapy, PTR'APT significantly increased in the affected arm of BCRL participants (pre- vs. post-MLD: 0.41 ± 0.05 vs. 0.43 ± 0.03, P = 0.02), consistent with treatment effects from mobilized lymphatic fluid. Conclusion Chemical exchange saturation transfer metrics, following appropriate correction procedures, respond to lymphatic mobilization therapies and may have potential for evaluating treatments in participants with secondary lymphedema.

Lipedema is a chronic and progressive disease of adipose tissue caused by abnormal fat accumulation in subcutaneous tissue. Although there is no known cure for lipedema, possible complications can be prevented with conservative and surgical treatments. One of the conservative treatment options is physiotherapy and rehabilitation (PR). When the literature is examined, few studies focusing on the efficacy of PR were found for this patient group. The purpose of this review is to provide a better understanding of the effectiveness of PR applications by compiling existing studies. A bibliographic PubMed search was performed for published studies regarding PR in lipedema management in June 2019 including the last 58 years (1951-2019). Articles were chosen by reading the abstracts and subsequently data were analyzed by reading the entire text through full-text resources. A total of 15 studies met inclusion criteria. Results document how lipedema patients are benefited by PR and the effectiveness of different types of PR programs. The current review also showed that complex decongestive physiotherapy, gait training, hydrotherapy, aerobic exercise, and resistance exercise training each have value in the management of lipedema. The effects of PR for the treatment of lipedema are variable among studies, although overall PR seems to be effective in lipedema management. Although physiotherapy applications have a potentially important role in the management of lipedema, they should be used in combination with other treatment modalities. More studies with higher quality are needed to fully demonstrate the effect and efficacy of PR in lipedema patients.

Lipedema can cause chronic pain and increases patients’ risk for conditions such as lymphedema and venous disease. This author explores how lipedema affects the body, why its effects are disproportionate in the lower body, and how to diagnose and manage the condition.

Obesity is a leading cause of cardiovascular diseases and cancer. Body mass is regulated by the balance between energy uptake and energy expenditure. The etiology of obesity is determined by multiple factors including genetics, nutrient absorption, and inflammation. Lymphatic vasculature is starting to be appreciated as a critical modulator of metabolism and obesity. The primary function of lymphatic vasculature is to maintain interstitial fluid homeostasis. Lymphatic vessels absorb fluids that extravasate from blood vessels and return them to blood circulation. In addition, lymphatic vessels absorb digested lipids from the intestine and regulate inflammation. Hence, lymphatic vessels could be an exciting target for treating obesity. In this article, we will review our current understanding regarding the relationship between lymphatic vasculature and obesity, and highlight some open questions.

Lipedema is a chronic, progressive, painful, increased deposition subcutaneous fat tissue in women with a clear disproportion between the trunk and extremities. Lipedema offen lead to oedema, which are worsened by orthostasis, and hematoma after minor injury. The pathogenesis is unknown and no curative treatment is available. Conservative therapy consisting of lymphatic drainage and compression stockings is often recommended, but is only effective against the edema component. Some patients show a short-term improvement when treated in this way. Permanent reduction of the pathological subcutaneous fat on the legs and arms has become possible by employing advanced liposuction techniques using microcannula technology in local tumescent anaesthesia.

Genetic or acquired defects of the lymphatic vasculature often result in disfiguring, disabling, and, occasionally, life-threatening clinical consequences. Advanced forms of lymphedema are readily diagnosed clinically, but more subtle presentations often require invasive imaging or other technologies for a conclusive diagnosis. On the other hand, lipedema, a chronic lymphatic microvascular disease with pathological accumulation of subcutaneous adipose tissue, is often misdiagnosed as obesity or lymphedema; currently there are no biomarkers or imaging criteria available for a conclusive diagnosis. Recent evidence suggests that otherwise-asymptomatic defective lymphatic vasculature likely contributes to an array of other pathologies, including obesity, inflammatory bowel disease, and neurological disorders. Accordingly, identification of biomarkers of lymphatic malfunction will provide a valuable resource for the diagnosis and clinical differentiation of lymphedema, lipedema, obesity, and other potential lymphatic pathologies. In this paper, we profiled and compared blood plasma exosomes isolated from mouse models and from human subjects with and without symptomatic lymphatic pathologies. We identified platelet factor 4 (PF4/CXCL4) as a biomarker that could be used to diagnose lymphatic vasculature dysfunction. Furthermore, we determined that PF4 levels in circulating blood plasma exosomes were also elevated in patients with lipedema, supporting current claims arguing that at least some of the underlying attributes of this disease are also the consequence of lymphatic defects., , Characterization of plasma-circulating exosomes from mouse models and patients with lymphatic dysfunction indicate that PF4 is a promising biomarker for the diagnosis of lymphatic disorders.

In recent years stem cell research has become increasingly important for regenerativemedicine and tissue engineering. The isolation of stem cells from adipose tissue evades ethicalconcerns with which embryonic stem cells and induces pluripotent stem cells (iPS) are afflicted,because of its declaration as clinical waste material. Tumescent liposuction is a minimallyinvasive procedure providing high amounts of adipose tissue rich in therapeutically relevantcells within a short time. The isolated stromal vascular fraction (SVF) and the adipose derivedstromal/stem cells (ASC) contained therein show a high regenerative potential and have beensuccessfully used in many clinical studies. Maintaining SVF cells in their natural environmentand therefore providing the maximum possible regenerative potential of adipose tissue-derivedcells is a prerequisite for successful autologous clinical application. With an improved gentleand fast isolation process by minor manipulation it is possible to obtain a therapeuticallyrelevant cell population. A physical stimulus already used in clinics is the extracorporealshockwave therapy (ESWT), shockwaves are characterized by their high rise in pressurewithin a very short time followed by cavitation wave with a negative amplitude. By applyinglow-energy ESWT on freshly obtained human liposuction material and isolated SVF cells (invitro) we aimed to equalize and enhance stem cell properties and their functionality. We wereable to show an increased adenosine tri-phosphate (ATP) concentration after applying ESWTon adipose tissue as well as a significantly increased expression of single mesenchymal andvascular surface markers in comparison with the untreated group. Additionally, the proteinsecretion of insulin-like growth factor 1 (IGF-1) and placental growth factor (PLGF) wassignificantly enhanced. Further it was investigated if there is the same beneficial effect whenapplying ESWT on the adipose tissue harvest site before liposuction to improve cell propertiesin situ. We showed a significantly enhanced viability, ATP concentration and populationdoublings after 3 weeks in culture for cells isolated from ESW treated adipose tissue harvestsite. Further the expression of mesenchymal and endothelial/pericytic markers was elevatedcollaborating with the increased angiogenic differentiation potential as well as the increasedsecretion of certain angiogenic proteins after ESWT in situ. Besides ESWT the effect of anotherphysical stimulus on SVF/ASC cells was tested - Low level laser therapy (LLLT) has alreadyshown beneficial effects. Therefore, we investigated effects of pulsed blue (475nm), green(516nm) and red (635nm) light from light-emitting diodes (LEDs) applied on freshly isolatedSVF cells. Cells had a stronger capacity to vascular tube formation after exposure to greenand red light concomitant with an increased concentration of vascular endothelial growth factor(VEGF) in the secretome. In a side project during the PhD program the hormone-relatedwomens disease lipedema was investigated. The SVF cell properties of healthy and lipedemapatients were investigated and a significant enhancement in cell yield as well as a reduction inadipogenic differentiation capacity of lipedema SVF cells was revealed. Within this workdifferent physical forces applied on adipose tissue and adipose tissue-derived cells werepresented as well as an improved isolation method and characteristics of degenerated adiposetissue. This are promising applications for the clinical use in the field of regenerative medicineand tissue regeneration.

Aim: The aim of the present study was to evaluate the prevalence of subclinical and clinical systemic lymphedema in patients with lipedema and different body mass index (BMI) values., Method: A cross-sectional study was conducted to determine the prevalence of subclinical systemic lymphedema and clinical lymphedema of the lower limbs detected by bioimpedance (InBody S10 device, Seoul, Korea) in 258 women with clinically diagnosed lipedema. The patients were divided into three groups based on BMI: Group I - BMI below 30 kg/m2; Group II - BMI between 30 and 40 kg/m2; and Group III - BMI 40 to 50 kg/m2., Results: Fisher's exact test revealed a statistically significant difference between Group I and both Groups II and III (p = 0.0001) regarding the occurrence of lower limb lymphedema., Conclusion: Patients with lipedema can develop edema even when their weight is within the standards of normality. However, obesity is an aggravating factor, as the prevalence of lipedema increases progressively with the increase in weight.

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.

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.

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.