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OBJECTIVE: To test the hypothesis that tissue sodium and adipose content are elevated in patients with lipedema; if confirmed, this could establish precedence for tissue sodium and adipose content representing a discriminatory biomarker for lipedema. METHODS: Participants with lipedema (n = 10) and control (n = 11) volunteers matched for biological sex, age, BMI, and calf circumference were scanned with 3.0-T sodium and conventional proton magnetic resonance imaging (MRI). Standardized tissue sodium content was quantified in the calf skin, subcutaneous adipose tissue (SAT), and muscle. Dixon MRI was employed to quantify tissue fat and water volumes of the calf. Nonparametric statistical tests were applied to compare regional sodium content and fat-to-water volume between groups (significance: two-sided P ≤ 0.05). RESULTS: Skin (P = 0.01) and SAT (P = 0.04) sodium content were elevated in lipedema (skin: 14.9 ± 2.9 mmol/L; SAT: 11.9 ± 3.1 mmol/L) relative to control participants (skin: 11.9 ± 2.0 mmol/L; SAT: 9.4 ± 1.6 mmol/L). Relative fat-to-water volume in the calf was elevated in lipedema (1.2 ± 0.48 ratio) relative to control participants (0.63 ± 0.26 ratio; P < 0.001). Skin sodium content was directly correlated with fat-to-water volume (Spearman's rho = 0.54; P = 0.01). CONCLUSIONS: Internal metrics of tissue sodium and adipose content are elevated in patients with lipedema, potentially providing objective imaging-based biomarkers for differentially diagnosing the under-recognized condition of lipedema from obesity.

Lymphedema often is confused with other causes of extremity edema and enlargement. Understanding the risk factors and physical examination signs of lymphedema can enable the health care practitioner to accurately diagnose patients ∼90% of the time. Confirmatory diagnosis of the disease is made using lymphoscintigraphy. It is important to correctly diagnose patients with lymphedema so that they can be managed appropriately.

Several imaging modalities have been used to assess lymphatic function, including fluorescence microscopy, near-infrared fluorescence (NIRF) imaging, and Doppler optical coherence tomography (DOCT). They vary in how the mouse is positioned, the invasiveness of the experimental setup, and the volume of contrast agent injected. Here, we present how each of these experimental parameters affects functional measurements of collecting lymphatic vessels. First, fluorescence microscopy showed that supine mice have a statistically lower contraction frequency compared with mice sitting upright. To assess the effect of different injection volumes on these endpoints, mice were injected with 4, 10, or 20 μl of dye. The lowest frequencies were observed after 20-μl injections. Interestingly, lymph-flow DOCT revealed that although there was lower contraction frequency in mice injected with 20 μl versus 4 μl, mice showed a higher volumetric flow with a 20-μl injection. This indicates that contraction frequency alone is not sufficient to understand lymphatic transport. Finally, NIRF revealed that removing the skin reduced contraction frequency. Therefore, this study reveals how sensitive these techniques are to mouse position, removal of skin, and dye volume. Care should be taken when comparing results obtained under different experimental conditions.

Whereas the blood microvasculature constitutes a biological barrier to the action of blood-borne insulin on target tissues, the lymphatic microvasculature might act as a barrier to subcutaneously administrated insulin reaching the circulation. Here, we evaluate the interaction of insulin with primary microvascular endothelial cells of lymphatic [human dermal lymphatic endothelial cells (HDLEC)] and blood [human adipose microvascular endothelial cells (HAMEC)] origin, derived from human dermal and adipose tissues, respectively. HDLEC express higher levels of insulin receptor and signal in response to insulin as low as 2.5 nM, while HAMEC only activate signaling at 100 nM (a dose that blood vessels do not normally encounter). Low insulin acts specifically through the insulin receptor, while supraphysiological insulin acts through both the IR and insulin growth factor-1 receptor. At supraphysiological or injection site-compatible doses pertinent to lymphatic microvessels, insulin enters HAMEC and HDLEC via fluid-phase endocytosis. Conversely, at physiologically circulating doses (0.2 nM) pertinent to blood microvessels, insulin enters HAMEC through a receptor-mediated process requiring IR autophosphorylation but not downstream insulin signaling. At physiological doses, internalized insulin is barely degraded and is instead released intact to the extracellular medium. In conclusion, we document for the first time the mechanism of interaction of insulin with lymphatic endothelial cells, which may be relevant to insulin absorption during therapeutic injections. Furthermore, we describe distinct action and uptake routes for insulin at physiological and supraphysiological doses in blood microvascular endothelial cells, providing a potential explanation for previously conflicting studies on endothelial insulin uptake.

Lipedema, the Unknown Abstract. Lipoedema patients suffer from the widespread ignorance of their pathology. Considering its chronic, progressive and invalidating character, the early diagnosis of the disease must constitute the challenge of their caregivers in order to limit medical wanderings and the occurrence of complex clinical pictures. Treatments allow the reduction of lipedema and its long-term control. Management must be individualized according to the stage of the disease. The adherence of the patient, the supervision and the support of the practitioner are essential for obtaining the best results.

Zusammenfassung Die Prävalenz der Adipositas ist in den letzten 15 Jahren weiter stark angestiegen. Dabei fällt besonders die deutliche Zunahme der morbiden Adipositas auf, die wiederum bei den Älteren besonders ausgeprägt ist. Da mit dem Alter auch venöse Thromboembolien, chronisch venöse Insuffizienz und sekundäre Lymphödeme zunehmen, steigt die Zahl der Patienten mit venösen oder lymphatischen Erkrankungen, die gleichzeitig schwer adipös und häufig multimorbide sind, überproportional an. Die Adipositas, vor allem die viszerale, verschlechtert alle Ödemerkrankungen, erhöht das Risiko für thromboembolische Erkrankungen und postthrombotisches Syndrom und kann alleinige Ursache sein für die Adipositas-assoziierte funktionelle Veneninsuffizienz ohne Nachweis von Obstruktion oder Reflux. Das Adipositasassoziierte Lymphödem stellt inzwischen den größten Anteil unter den sekundären Lymphödemen. Mehr als 50 Prozent der Lipödempatientinnen sind adipös, die bei ihnen im Verlauf zu beobachtenden sekundären Lymphödeme in der Regel Folge der Adipositas, nicht des Lipödems. Die Symptomatik wird bei allen Krankheitsbildern durch Gewichtsreduktion gebessert. Neben mechanischen Faktoren wie der Erhöhung des intraabdominalen und intertriginösen Drucks, der wiederum zu einer venösen Drucksteigerung in den Beingefäßen führt, sind es vor allem die durch die Zunahme des viszeralen Fettgewebes verursachten metabolischen, chronisch inflammatorischen und prothrombotischen Prozesse, die für diese Zusammenhänge verantwortlich sind, erkennbar an niedrigen Spiegeln von Adiponektin und hohen von Leptin, Insulin, intaktem Proinsulin, PAI-1 sowie proinflammatorischen Zytokinen (Il-6, Il-8, TNF-α). Therapeutische Maßnahmen müssen also in erster Linie auf die Reduktion der viszeralen Adipositas und damit der Hyperinsulinämie bzw. der Insulinresistenz sowie auf die Bekämpfung der chronischen Entzündung abzielen. , Summary The prevalence of obesity has continued to rise considerably during the last 15 years. There is a striking increase of cases with morbid obesity (BMI over 40 Kg/m2), especially among the elderly. Since venous thromboembolic events, chronic venous insufficiency and secondary lymphoedema also increase with age, the number of patients who suffer from these conditions and, at the same time, are obese and often multimorbid, rises disproportionately. Obesity, especially if it is visceral, causes all sorts of oedema to deteriorate, increases the risk of thromboembolic events and postthrombotic syndrome and can be the sole cause of the so called obesity-associated dependency- syndrome, or rather the obesity-associated functional venous insufficiency without obstruction or reflux, as it ought to be called, with its skin lesions characteristic of CEAP stages C4 to C6. Among the various causes of secondary lymphoedema obesity is by now the most common. Of patients suffering from lipoedema more than 50 percent are obese, with the secondary lymphoedema often to be seen in those cases being the direct consequence of obesity, not the lipoedema itself. In all the conditions mentioned above symptoms can be ameliorated by weight loss. Aside from mechanical factors like intraabdominal and intertriginous pressure which in turn raise the intravenous pressure in the legs, it is foremost the metabolic, proinflammatory and procoagulatory effects of the augmented visceral fat tissue which can explain the correlation between obesity and thrombosis, oedema and, probably, the skin changes, too. These effects can be identified by low levels of adiponectin, which has antiinflammatory and vasoprotective qualities, and high levels of leptin, characteristic of leptin resistance, inflammation and insulin resistance, insulin and intact proinsulin (precursor of insulin, indicating β-cell insufficiency). Plasminogen Activator Inhibitor-1 (PAI-1), preventing fibrinolysis, and proinflammatory cytokines like Interleukin-6 (Il-6), Interleukin-8 (Il-8) and Tumour Necrosis Factor-α (TNF-α) are also found to be raised. In addition to treating the acute or chronic symptoms by anticoagulation, compression, manual lymphdrainage and wound care, therapeutic measures must endeavour to sustainably reduce visceral fat tissue, and thus hyperinsulinaemia, insulin resistance and inflammation. English version available at: www.phlebologieonline.de

Lipedema: Which Etiological Pathways? Abstract. The pathogenesis and epidemiology of lipedema are uncertain, and its diagnosis often delayed. Lipedema almost exclusively affects women, and a link to sex hormones is likely. The metabolic risk of this accumulation of fat in the lower limbs is not known, and weight loss has no impact on the morphology of the lower limbs. Due to the aesthetic discomfort and frequent initial misdiagnosis which results in inappropriate treatment, this condition can lead to significant psychological suffering for the patient. A better understanding of this disease is essential to the proper diagnosis and support for these patients, as well as guiding them in the effective care.

Zusammenfassung Einleitung: Die aktuelle deutsche Leitlinie zur Behandlung des Lipödems empfiehlt neben der Therapie mit flachgestrickten Kompressionsmaterialien und manueller Lymphdrainage auch die Liposuktion. Die Abgrenzung zu Adipositas und asymptomatischer Lipohypertrophie stellt dabei häufig ein differenzialdiagnostisches Problem dar. Eine reproduzierbare und objektivierbare Differenzialdiagnostik ist aber die Grundlage für eine zielführende und wirtschaftliche Behandlung. Material und Methoden: Im Rahmen einer multizentrischen Registerstudie (5 Zentren) wurden im Zeitraum von 01/2016 bis 05/2017 die Beine (n=294) von Patientinnen mit Lipödem (n=136), Lymphödem (n=20), Lipödem mit sekundärem Lymphödem (n=30), Lipohypertrophie (n=42) und Adipositas (n=30) sowie von Gesunden (n=36) sonografisch untersucht. Es wurden Messungen der Dicke von Kutis und Subkutis an den Unter- und Oberschenkeln sowie von deren Komprimierbarkeit durchgeführt. Zusätzlich erfolgte eine Analyse der Sonomorphologie. Ergebnisse: Spezielle sonomorphologische Eigenschaften, die ein Lipödems von den anderen Krankheitsentitäten bzw. vom Gesunden abgrenzen lassen, konnten bislang nicht übereinstimmend und überzeugend herausgearbeitet werden. Die Komprimierbarkeit des Kutis-Subkutis-Komplexes ist vollkommen unspezifisch und lässt keinen Rückschluss auf die Diagnose Lipödem zu. Der Nachweis von Flüssigkeitseinlagerungen bei Patienten mit einer „schmerzhaften Lipohypertrophie” gelingt nicht, sodass die Krankheitsbezeichnung Lipödem irreführend ist und überdacht werden sollte. , Summary Introduction: The current German guidelines on treating lipoedema recommend using flatknitted compression material and manual lymphatic drainage as well as liposuction. Differentiating lipoedema from obesity and asymptomatic lipohypertrophy frequently proves difficult. However, a reproducible and objective differential diagnosis is the foundation of an expedient and cost-effective treatment. Material and Methods: As part of a multi-centre registry study (5 centres) ultrasound scans were performed between 1/2016 and 5/2017 on the legs (n=294) of a total of 147 patients with lipoedema (n=136), lymphoedema (n=20), lipoedema with secondary lymphoedema (n=30), lipohypertrophy (n=42) and obesity (n=30), as well as healthy individuals (n=36). Measurements were performed on the thickness of the cutis and subcutis of the lower and upper leg and on their compressibility. An analysis of the sonomorphology was also conducted. Results: Special sonomorphological properties that allow lipoedema to be differentiated from other disease entities and from healthy individuals have yet to be consistently and conclusively identified. The compressibility of the cutis-subcutis complex is completely unspecific and does not allow for any conclusions to be drawn concerning lipoedema. It has not been possible to detect fluid retention in patients with “painful lipohypertrophy” so that the description of the disease as lipoedema is misleading and should be reconsidered.

Unilateral lower extremity edema below the knee commonly results from deep venous thrombosis, venous insufficiency, or lymphedema. The patient history, a physical examination, and lower extremity venous duplex ultrasound often reveal the underlying etiology, which is frequently of vascular origin. Presently described is the case of a 23-year-old patient who underwent a diagnostic workup for unilateral leg swelling and was found to have a relatively uncommon cause of edema: lipedema. Lipedema is a disease characterized by subcutaneous adipose tissue deposition, and although diagnosed very rarely in general cardiology outpatient clinics, it has been demonstrated to be a cause of lower extremity edema in approximately one-fifth of cases in specialized clinics.

Unilateral lower extremity edema below the knee commonly results from deep venous thrombosis, venous insufficiency, or lymphedema. The patient history, a physical examination, and lower extremity venous duplex ultrasound often reveal the underlying etiology, which is frequently of vascular origin. Presently described is the case of a 23-year-old patient who underwent a diagnostic workup for unilateral leg swelling and was found to have a relatively uncommon cause of edema: lipedema. Lipedema is a disease characterized by subcutaneous adipose tissue deposition, and although diagnosed very rarely in general cardiology outpatient clinics, it has been demonstrated to be a cause of lower extremity edema in approximately one-fifth of cases in specialized clinics.

In this mini-review pathology, diagnosis, signs and symptoms, as well as treatment of lipedema are discussed. As the cause of lipedema is unknown for nearly 80 years, therapy is supportive and aimed at prevention of progression of the disease. Symptoms, signs and phenotypes of these patients are well defined. Guidelines for treatment are clear. When supportive therapy is inadequate surgical tumescent liposuction is the treatment of first choice. Surprisingly, the unproven compression and manual lymphatic drainage therapies of lipedma patients are covered by insurance, while the rational tumescent liposuction is not covered. Quality of life, mobility, lipedema pain, altered gait all improved by tumescent liposuction and disease progression is slowed. Insurance coverage of this procedure will help lipedema patients greatly. Cost-benefit analyses should be made. Research in pharmacotherapy of lipedema that makes sense should be stimulated

The present study aimed to assess LV rotational mechanics by three-dimensional speckle-tracking echocardiography (3DSTE) in lipedema (n=25), lymphedema (n=26) patient groups with age- and gender-matched healthy controls (n=54). 3 lipedema and 4 lymphedema patients were excluded due to insufficient image quality for 3DSTE analysis. LV apical rotation (9.61 ± 4.25 degree vs. 6.40 ± 2.63 degree, p <0.05) and LV twist (13.83 ± 4.89 degree vs. 10.04 ± 3.56 degree, p <0.05) are impaired in lipedema patients as compared to matched controls; similar alterations in lymphedema were not found. Moreover, in some lipedema and lymphedema patients severe LV rotational abnormalities could be detected. Our results suggest that lipedema-associated impaired LV apical rotation and twist assessed by 3DSTE could be a novel differential diagnostic point between lipedema and lymphedema.

Surgical Treatment for Lipedema Abstract. Lipedema is a progressive disease that occurs in adolescence and affects one in nine women. The signs are limited to the lower limbs. Early signs are nonspecific, which is why the diagnosis is often ignored. Later, pain and heaviness of lower limbs become predominant. Finally, at an advanced stage, tissue fibrosis is associated with significant edema. At this stage, patients become severely disabled and bedridden. At the early stage, the treatment is conservative. Liposuction is indicated at the onset of pain. Its effectiveness pain and long-term control has been demonstrated on. Finally, late stages require heavy and complex surgeries combining dermolipectomy and liposuction.

Introduction Lipedema (meaning edema in fat) and Dercum Disease (DD) are fat disorders in which accumulation of painful subcutaneous adipose tissue (SAT) affects more females than males, especially at times of female hormone change. Patients with both fat disorders are often misdiagnosed as obese. The purpose of this study was to determine if estrogen (ER) and progesterone receptors (PR) are different in lipedema versus DD in SAT and skin versus controls. These receptors are on mast cells that produce histamine causing leakage from blood vessels inducing hypoxia and angiogenesis. Progesterone is known to activate histamine release from mast cells. We aim to determine levels of ER and PR in SAT and if blood vessels replicate at a higher rate in lipedema and DD versus controls to help further understand these conditions and work towards finding a cure. Materials and Methods Immunohistochemistry (San Diego Pathology, San Diego, CA) was used to test for the presence of PR, ER, Ki67 (marker of replicating cells), and CD117 (marker of mast cells). Results and Discussion Mast cell numbers were similar in control, DD and lipedema SAT (Figure). ER were not different in control, DD and lipedema SAT. PR were significantly lower in lipedema SAT. There was no difference in Ki67 in lipedema or DD blood vessels compared to controls. Conclusion Lower numbers of PR in our data suggest mast cell secretions (histamine and others) could be higher inducing leakage from vessels and fluid collection in SAT. Fluid in the tissue should induce hypoxia and growth of more blood vessels. Despite higher PR on mast cells, lipedema blood vessels did not appear to be replicating at a higher level. With further research and additional samples, the relevance of elevated PR in lipedema tissue may become apparent. Support or Funding Information Research reported in this poster was supported by the National Institute of General Medical Sciences of the National Institutes of Health under linked Award Numbers RL5GM118969, TL4GM118971, and UL1GM118970. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Special acknowledgement to the Minority Health Disparities summer research program at the University of Arizona, the College of Medicine Tucson Treatment, Research, and Education of Adipose Tissue Program. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Lipedema is a chronic metabolic disorder of the adipose tissue, of unknown aetiology, and is marked by a bilateral and symmetrical swelling of the lower extremities, caused by extensive deposits of subcutaneous fatty tissue (local lipohypertrophy). Proliferative subcutaneous fatty tissue compresses the lymph collectors of the superficial lymphatic system. Lymphedema is characterized swelling of soft tissues by accumulation of lymphatic fluid [1]. If lipolympedema remains untreated, it will progress through the same stages as pure lymphedema [1,2]. A helpful diagnostic tool to distinguish lipedema from lymphedema is Stemmers sign. Limb circumference or volume measurements are commonly used for diagnosis and for following lymphedema progression [3]. Developing technology also brings new approaches for lymphedema diagnosis: bioimpedance, 99mTc lymphoscintigraphy, magnetic resonance lymphangiography etc. Ultrasound is recently developing imaging technique for both lymphedema diagnosis and follow up [4]. In this case report localized lipedema which diagnosed with ultrasonography, in a patient with osteoarthritis in the knee joint was discussed.

Lipedema is a chronic disorder of subcutaneous adipose tissue of unknown etiology not uncommon among post-puberty women. The disease has a negative impact on selfesteem, mobility, and quality of life. Lipedema is characterized by symmetrical, disfiguring hyperplastic adipose tissue combined with bruising and pain. Untreated lipedema fosters osteoarthritis, secondary lymphedema, limitedmobility, and psychosocial stigmatization. Treatment consists of conservative complex decongestive therapy and surgery by microcannular tumescent liposuction. Liposuction is the only available treatment capable to reduce the pathological adipose tissue durable and to prevent complications.

Lipoedema is a condition characterised by symmetrical lower limb enlargement. It was first described by Allen & Hines who coined the term lipoedema. The result of subcutaneous deposition of fat gives rise to fatty swelling in the buttocks, thighs and lower limbs sparing the feet. It is associated with obesity and hence upper limbs and rarely trunks are also affected.  This Clinical condition affects females predominantly 1:4 and hence has a profound effect on the psychology therefore it is not uncommon to see these patients with a low self esteem, socially isolated and depressed. Due to its resemblance to lymphoedema it is not unusual to be misdiagnosed, thus leading to a spiral of inappropriate tests and improper treatment outcome.