Your search

The lymphatic system regulates tissue fluid homeostasis, intestinal fat absorption, and immune cell trafficing. Lymphedema is soft tissue swelling secondary to lymphatic dysfunction, which results in the accumulation of tissue fluid in the interstitial space. This might occur as a primary disorder of the developing lymphatic system, or alternatively lymphedema might be an acquired disorder secondary to lymphatic injury. For example, secondary lymphedema is a common problem following cancer and cancer treatments such as lymph node surgery and radiotherapy, resulting in significant morbidity. Radiotherapy is an established risk factor for lymphedema, and in addition to causing direct injury to the lymphatic vessel, it is possible that alternative mechanisms might also contribute to radiation-induced lymphatic dysfunction, such as localized ischemia of the lymphatic wall. It is also likely that predisposing genetic risk factors are at play, as not all individuals exposed to the same risk factors will develop secondary lymphedema. Lipoedema is a different form of soft tissue swelling due to the abnormal accumulation of adipose tissue. Lipoedema and lymphatic dysfunction appear to be linked, as individuals frequently develop a degree of lymphedema, particularly as the condition progresses in severity, where it may be decribed as lipo-lymphedema. The cause of lipoedema and the genetic basis of the condition are currently unknown. This thesis aims to discover and define alternative mechanisms for lymphtic dysfunction in the context of secondary lymphedema, particularly focussing on the supply of oxygenated blood to the lymphatic vessel wall. We also aim to describe inheritance patterns and the genetic factors involved in lipoedema and lipo-lymphedema. Such knowledge might uncover therapeutic targets and facilitate the development of treatments for lymphedema and lipoedema, including gene therapy.

Das Lipödem ist gekennzeichnet durch eine dispropor tionale Vermehrung des subkutanen Fettgewebes an Hüf ten, Beinen und Armen. Von der asymptomatischen Lipo hypertrophie unterscheidet es sich durch das Vorhandensein der typischen Symptome (Spontan und Berührungsempfindlichkeit, Ödeme). Auch wenn die Pathogenese des Lipödems immer noch weitgehend unbe kannt ist, deutet vieles darauf hin, dass neben hormonel len Faktoren entzündliche Prozesse eine wesentliche Rolle spielen. Dabei ist nicht geklärt, ob und in welcher Weise diese selbst ursächlich für das Auftreten des Lipödems sind oder Folge anderer körperlicher Veränderungen wie Adipositas oder hormoneller Dysbalancen. Der Circulus vitiosus aus Adipositas, die bei über der Hälfte der Patientinnen vorliegt, und der sich hierdurch entwickelnden Hyperinsulinämie bewirkt nicht nur eine weitere Fettgewebszunahme, sondern wirkt über die Zyto kine des viszeralen Fettgewebes auch proinflammatorisch und ödemfördernd,

EXECUTIVE SUMMARY Lipedema is a chronic condition that occurs almost exclusively in women and manifests as symmetrical buildup of painful fat and swelling in the limbs, sparing the hands and feet. A critical issue is the poorly understood disease biology, which for diagnosed patients results in limited treatment options that, at best, ameliorate the symptoms of lipedema. Individuals who suffer from the disease are further impacted by the absence of diagnostic tools, the lack of public and medical awareness of lipedema, and the stigma associated with weight gain. As a result, the true number of women with lipedema, or its epidemiology, is unknown. Braving these challenges is an active, numerous, and engaged patient community eager to participate in lipedema research. Supported by equally devoted caregivers and researchers, the lipedema field presents an immense opportunity for scientific and medical advancements. To capitalize on this potential, the Lipedema Foundation and the Milken Institute’s Center for Strategic Philanthropy convened leading stakeholders to discuss the current state of lipedema science and identify the key philanthropic research opportunities to advance the field. Little is known about how and why lipedema develops in a patient. Although the disease is reported to occur during puberty and other periods of hormonal changes, why this happens is not understood. The painful fat and swelling in some patients can be so debilitating that their mobility is impaired; yet what drives these symptoms is unknown. Psychosocial issues are also prevalent in women with lipedema, contributing to health burden and complexity of disease management. Furthermore, many patients develop the disease alongside obesity; however, diet, exercise, and weight loss surgery have limited effect on lipedema fat. Although the lack of disease biology is staggering, philanthropic investments in research can leverage the desire of patients to participate in studies to improve their and the entire field’s understanding of lipedema. The convergence of multiple scientific topics around lipedema indicates that addressing these gaps in research will also improve the understanding of hormone, pain and edema, mental health, and metabolic biology. There are no diagnostic tools or tests for lipedema. Diagnosis of lipedema involves a clinical assessment and discussion of the individual’s medical history, a process that is difficult to scale within the current healthcare system. The absence of diagnostic tools to streamline or confirm a clinical diagnosis is a key unmet need, which if addressed by philanthropy, has the potential to dramatically change the trajectory of the disease. Investing in research efforts to advance novel imaging technologies to diagnose lipedema is a promising research avenue that would simultaneously benefit individuals who suffer from the disease and healthcare providers unfamiliar with the condition. The public and medical community are not aware of lipedema. Lipedema was initially described in 1940, yet little knowledge about the disease has permeated the general public, with a concomitant lack of mention in the educational curriculum of medical trainees. Addressing this challenge will require philanthropic efforts to define the disease from a basic, clinical, and diagnostic perspective. A key philanthropic opportunity is support for a lipedema patient registry linked to a tissue biorepository. This effort has the potential to generate and support the needed disease research, while engaging patients as partners in understanding the science of lipedema.

The invention provides carbazole derivatives for the treatment of fibrotic diseases (pathological collagen deposition) in tissues and organs, and related symptoms, and conditions thereof.

Lipedema, or adiposis dolorosa, is a common adipose tissue disorder that is believed to affect nearly 11% of adult women worldwide. It is characterized most commonly by disproportionate adipocyte hypertrophy of the lower extremities, significant tenderness to palpation, and a failure to respond to extreme weight loss modalities. Women with lipedema report a rapid growth of the lipedema subcutaneous adipose tissue in the setting of stress, surgery, and/or hormonal changes. Women with later stages of lipedema have a classic "column leg" appearance, with masses of nodular fat, easy bruising, and pain. Despite this relatively common disease, there are few physicians who are aware of it. As a result, patients are often misdiagnosed with lifestyle-induced obesity, and/or lymphedema, and subjected to unnecessary medical interventions and fat-shaming. Diagnosis is largely clinical and based on criteria initially established in 1951. Treatment of lipedema is effective and includes lymphatic support, such as complete decongestive therapy, and specialized suction lipectomy to spare injury to lymphatic channels and remove the diseased lipedema fat. With an incidence that may affect nearly 1 in 9 adult women, it is important to generate appropriate awareness, conduct additional research, and identify better diagnostic and treatment modalities for lipedema so these women can obtain the care that they need and deserve.

Lipoedema is a long-term, progressive condition, usually presenting as symmetrical enlargement of the legs and buttocks, and mainly affecting women. Distinct from obesity or lymphoedema, lipoedema is associated with an unusual distribution and proliferation of diet-resistant inflammatory fat tissue. This article provides background to lipoedema diagnosis and discusses self-care support for women with lipoedema.

Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A “multiple-hit” pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the “imperfect” gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g. , magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention.

Lipedema is an uncommon disorder characterized by localized adiposity of the lower extremities, often occurring in females with a family history of the condition. The adiposity extends from hips to ankles and is typically unresponsive to weight loss. In addition to the aesthetic deformity, women also describe pain in the lower extremities, particularly with pressure, as well as easy bruising. Although the condition is well described, it is relatively rare and often misdiagnosed. The purpose of this review is to describe the initial evaluation and diagnosis of lipedema and discuss treatment options.

Objective: The purpose of this study was to investigate the clinical significance of lymphoscintigraphy imaging in the evaluation of lower extremity lymphedema. Methods: Technetium-99m-labeled nanocolloid was injected subcutaneously in the first web spaces of both feet of 123 patients (M/F: 43/80, mean age 57.5±13.1 years, range 16-78 years) who had clinical evidence of lower extremity swelling with suspicion of lymphedema, and were referred for routine lymphoscintigraphy. Lymphoscintigraphy scan was started as dynamic viewing followed by static whole body imaging at 10 minute, 1 hour and 4 hours after injection. Results: Eighty-seven patients had lymphedema. Patients who had lymphedema were divided into two groups according to their scintigraphy findings: Group I included 58 patients without uptake in the popliteal nodes, and group II included 29 patients with positive popliteal nodes. The rate of popliteal node visualization was higher in patients with dermal backflow as compared to those without dermal backflow (p<0.001). The duration of lymphedema was also longer in patients with dermal backflow and popliteal nodes (p<0.004). Conclusion: Lymphoscintigraphy is a reliable, easily applied and well-tolerated objective method to diagnose lower extremity lymphedema. Uptake by popliteal lymph nodes and the presence of dermal backflow on lymphoscintigraphy, which is performed for evaluation of the lower limb lymphedema, were important signs indicating longer disease duration and higher severity of lymphatic dysfunction.

The increasing prevalence of obesity causes a major interest in white adipose tissue biology. Adipose tissue cells are surrounded by extracellular matrix proteins whose composition and remodeling is of crucial importance for cell function. The expansion ...

Lipedema is a disfiguring disorder with abnormal and progressive deposition of adipose tissue in the hips and lower extremities almost exclusively occurring in women. There is a hereditary tendency and a substantial variability in disease severity. Lipedema is often misdiagnosed as lymphedema or morbid obesity. The etiology and pathogenesis are not understood. Early diagnosis and treatment are critical to minimize physical and psychological morbidity. The diagnosis is usually made by history and clinical examination. Non-invasive imaging techniques such as computed tomography or magnetic resonance can differentiate lipedema from other causes of edematous lower extremities. Lymphoscintigraphy may be helpful in cases which are associated with lymphedema (lipo-lymphedema). Management with manual lymphatic drainage and compression therapy are considered the most appropriate treatment. Use of conventional liposuction is controversial since it may further damage the lymphatic vessels. Newer techniques such as tumescent micro annular laser assisted liposuction and water jet-assisted liposuction have shown some promising results. Variety of other surgical procedures combined with manual lymphatic drainage and tailored post-surgical care are under investigation.

Upper- and lower-body fat depots exhibit opposing associations with obesity-related metabolic disease. We defined the relationship between DEXA-quantified fat depots and diabetes/cardiovascular risk factors in a healthy population-based cohort (n = 3,399). Gynoid fat mass correlated negatively with insulin resistance after total fat mass adjustment, whereas the opposite was seen for abdominal fat. Paired transcriptomic analysis of gluteal subcutaneous adipose tissue (GSAT) and abdominal subcutaneous adipose tissue (ASAT) was performed across the BMI spectrum (n = 49; 21.4-45.5 kg/m(2)). In both depots, energy-generating metabolic genes were negatively associated and inflammatory genes were positively associated with obesity. However, associations were significantly weaker in GSAT. At the systemic level, arteriovenous release of the proinflammatory cytokine interleukin-6 (n = 34) was lower from GSAT than ASAT. Isolated preadipocytes retained a depot-specific transcriptional "memory" of embryonic developmental genes and exhibited differential promoter DNA methylation of selected genes (HOTAIR, TBX5) between GSAT and ASAT. Short hairpin RNA-mediated silencing identified TBX5 as a regulator of preadipocyte proliferation and adipogenic differentiation in ASAT. In conclusion, intrinsic differences in the expression of developmental genes in regional adipocytes provide a mechanistic basis for diversity in adipose tissue (AT) function. The less inflammatory nature of lower-body AT offers insight into the opposing metabolic disease risk associations between upper- and lower-body obesity.

OBJECTIVES: Patient-relevant treatment benefit is traditionally measured with health-related quality of life (HRQoL) instruments. The Patient Benefit Index (PBI) methodology allows for a more direct measurement, with the patients rating both importance and achievement of treatment goals. Here, we developed and validated a PBI version specific for the assessment of benefit in lymphedema and lipedema treatment (PBI-L). METHODS: The development included five steps: (1) open item collection; (2) consensus of items in a multidisciplinary expert panel; (3) application of the German PBI-L in a cross-sectional study (n = 301); (4) translation into English; (5) application of the English PBI-L in a randomized clinical trial (n = 82). Subscales were developed using factor analysis. Construct validity was analyzed by correlating PBI-L and convergent criteria such as HRQoL and quality of care. To test for responsiveness, the association to change in HRQoL measures was computed. RESULTS: Floor and ceiling effects were low. There were few missing values. Two well-interpretable subscales were found with Cronbach's alpha >0.8 each. Global and subscale scores correlated with convergent criteria and with change in disease-specific HRQoL, but not with change in generic HRQoL. CONCLUSIONS: The PBI-L is an internally consistent, valid, and responsive instrument for the assessment of patient-relevant benefit of edema treatment.

Lipedema is a chronic, incurable, often progressive affliction that occasionally causes significant morbidity. Initially, patients develop a disproportionate increase of body fat in the legs, buttocks and/or arms. Dieting and physical exercise have only limited effect on this disproportionate body fat distribution. The legs may be sensitive and are prone to bruising after only mild trauma. This can deteriorate into severe pain and reduced mobility, ultimately leading to a limitation of activity and social participation. As a result, lipedema patients may often be diagnosed with obesity. Dietary measures generally affect the obesity component but have little effect on the disproportionate body fat distribution. Because lipedema contributes to an increased BMI, even in non-­‐obese patients, a connection between lipedema and excessive calorie-­‐intake or obesity is often incorrectly assumed. In addition to physical problems, lipedema can also lead to psychoso-­‐ cial problems. These are often caused by the failure of consulting professionals to recognize or acknowledge the condition, or because (incorrect) recommendations for weight loss and physical exercise do not contribute to improvements in the complaints. Therefore, it is important to recognize lipedema early so that its accompanying symptoms can be acknowl-­‐ edged at an early stage and be incorporated into an integrated treatment. Little consistent information regarding the diagnosis or treatment of lipedema is found in the literature. Therefore, the goal of this directive is to attempt to establish a consensus for the diagnosis of lipedema and to discuss its symptoms and influencing factors, as well as its effects on activity and social limitations, as these negatively influence the life of the patient.

In 2014 250 women with Lipoedema took part in our survey about their experiences with Lipoedema. The results give a clear picture of what living with Lipoedema is like and reveal that along with the pain and discomfort caused by Lipoedema, many simple tasks that other people regard as straightforward become extremely challenging for people with Lipoedema. Lipoedema UK’s Big Survey 2014 led to the development of the Royal College of GPs’ e-learning course, a half hour course, which enables GPs to recognise Lipoedema and diagnose patients Our survey was created by Lipoedema UK, the Lymphoedema Department at St George’s Hospital, London, and the support of the Lymphoedema Support Network.