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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.

The objective of the present study was to report that aggravating factors of lymphatic or venous edema contribute to aggravate the evolution of lymphedema. A 54-year-old women with a six-year history of venous thrombosis of the left leg reported that her family had thicker arms and legs and that she had inherited this genetic trait. Electrical bioimpedance analysis was performed with the In Body S10 device. The exam revealed total intracellular and extracellular water beyond the parameters of normality as well as water in the thorax and limbs. In the lower limbs, the total extracellular water/total body water ratio also surpassed the limits of normality. The findings demonstrated bilateral lower limb lymphedema with clinical signs in the left leg. Obesity can trigger a new concept of lymphedema that we denominate subclinical systemic lymphedema, which is characterized by an increase in body water. Moreover, aggravating processes of the venous system, such as deep vein thrombosis, can aggravate the edema.

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.

Summary Lipedema is a painful, chronically progressive disease that is characterized by a symmetrical increase in subcutaneous fat with fluid accumulation on the legs and / or arms. Due to ignorance of the clinical picture, the disease is often not recognized or misinterpreted. Correct diagnosis and treatment are important, however, as the prognosis of the disease can be influenced. A causal therapy for lipedema is not known because the exact etiology is not yet fully understood. A hereditary component is suspected on the basis of a family history of the disease. Since lipedema occurs almost exclusively in women and the onset of the disease is often associated with the onset of hormonal changes (puberty, pregnancy, menopause), In addition, the estrogen is assigned a decisive role in the development. In the present work we present an overview of the symptoms and clinical features of lipedema, its differential diagnoses, treatment options and, lastly, the current hypotheses on the pathogenesis of lipedema.

IN JUNE 2020, the Lipedema ICD-10-CM Committee, with support from the American Vein & Lymphatic Society (AVLS), submitted an application to the US Centers for Disease Control and Prevention to establish new ICD-10-CM codes for lipedema and lipolymphedema, two related adipose tissue disorders. Currently,

Patients with obesity-associated lipoedema minimize by diet only the regular fat especially in the lower leg area. The pathological lipoedema with a possible secondary lymphodynamic oedema remains and causes skin irritation, discomfort and pain wearing the compression elements. The dorsal lower leg lift with previous liposuction is a useful therapeutic strategy to overcome these difficulties. A 37-year-old female patient after post-bariatric surgery and massive weight loss (MWL) presented with a lower leg lipoedema and lymphodynamic oedema. She underwent a liposuction removing lipoedema of the lower leg followed by a calf lift procedure on both sides. With sufficient surgical experience in skin tightening surgery after MWL, a significant improvement in day-to-day problems in patients with lipoedema can be achieved by dorsal lift of the lower leg after liposuction.

Einleitung: Die Diagnostik des Lipödems basiert bislang auf rein klinischen Befunden, objektive Parameter fehlen bislang. Ziel dieser Studie ist es, einen möglichen Zusammen-hang zwischen einer standardisierten, sonographisch gemessenen Kompressibilität der subkutanen Fettschicht sowie dem Vergleich der Hautfettfalten an Abdomen und Oberschenkel und der klinischen Diagnose Lipödem aufzuzeigen. Material und Methode: Das Grundkollektiv zur Probandinnen-Auswahl bestand aus 1100 Patientinnen und Patienten. Davon wurden 1016 Patientinnen und Patienten wegen zutreffender Ausschlusskriterien ausgeschlossen. Die verbliebenen 84 Patientinnen wurden auf die klinische Diagnose „Lipödem der Beine“ untersucht. Die klinische Diagnose „Lipödem“ war bei 71 Patientinnen positiv und bei 13 Patientinnen negativ. Insgesamt haben drei Patientinnen die Teilnahme verweigert (eine mit negativer Diagnose, zwei mit positiver Diagnose); damit wurden 69 Patientinnen in der Gruppe der Lipödempatientinnen und zwölf Patientinnen in der Kontrollgruppe untersucht. Zudem wurden als weitere Kontrollgruppe sieben männliche „gesunde“ Probanden mit derselben Technik vermessen und verglichen. An Daten wurden für alle Probandinnen und Probanden das Alter, BMI, Verhältnis von Abdomen- zu Oberschenkelhautfettfalte (nur rechts), Subkutisdicke am Oberschenkel unkomprimiert und komprimiert auf beiden Seiten erhoben. Resultate: Die Annahme, dass die Subkutis bei Lipödempatientinnen deutlich geringer kompressierbar ist, konnte an 69 Lipödempatientinnen, die keinerlei Lymphödemsymptomatik zeigten, verifiziert werden. Die Kontrollgruppen (sieben Männer, zwölf Frauen) verhielten sich diesbezüglich negativ. Der Mittelwert dieser Kompressibilität lag in der Lipödemgruppe bei 7 %, in den Kontrollgruppen bei 22 % (Männer) bzw. 16 % (Frauen ohne Lipödem). Das Verhältnis der Hautfettfalten an Abdomen und Oberschenkel war bei Lipödempatientinnen mit im Mittel 0,43 signifikant unter den anderen Gruppen (Männer: 1,45; Frauen ohne Lipödem: 1,16). Diskussion: Die sonographisch gemessene Kompressibilität der Subkutis stellt einen wichtigen, objektiven Parameter zur Diagnostik des Lipödems dar. Eine zusätzliche positive Aussage liefert zudem der Vergleich der Hautfettfaltendicke an Abdomen und Oberschenkel mit statistisch signifikanten Unterschieden.

BACKGROUND: Although a large number of adult women worldwide are affected by lipedema, the physiologic conditions triggering onset and progression of this chronic disease remain enigmatic. In the present study, a descriptive epidemiologic situation of postoperative lipedema patients is presented. METHODS: The authors developed an online survey questionnaire for lipedema patients in Germany. The survey was conducted on 209 female patients who had been diagnosed with lipedema and had undergone tumescent liposuction. RESULTS: Most of the participants (average age, 38.5 years) had noticed a first manifestation of the disease at the age of 16. It took a mean of 15 years to accomplish diagnosis. Liposuction led to a significant reduction of pain, swelling, tenderness, and easy bruising as confirmed by the majority of patients. Hypothyroidism [n = 75 (35.9 percent) and depression [n = 48 (23.0 percent)] occurred at a frequency far beyond the average prevalence in the German population. The prevalence of diabetes type 1 [n = 3 (1.4 percent)], and diabetes type 2 [n = 2 (1 percent)] was particularly low among the respondents. Forty-seven of the lipedema patients (approximately 22.5 percent) suffered from a diagnosed migraine. Following liposuction, the frequency and/or intensity of migraine attacks became markedly reduced, as stated by 32 patients (68.1 percent). CONCLUSIONS: Quality of life increases significantly after surgery with a reduction of pain and swelling and decreased tendency to easy bruising. The high prevalence of hypothyroidism in lipedema patients could be related to the frequently observed lipedema-associated obesity. The low prevalence of diabetes, dyslipidemia, and hypertension appears to be a specific characteristic distinguishing lipedema from lifestyle-induced obesity.

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: 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.