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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.

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.

INTRODUCTION: Lipoedema is a chronic disorder of adipose tissue, characterised by disproportionate fat deposits in the lower limbs and pain with preservation of the feet. The condition usually only affects women. Diagnosis is clinical and mainly by exclusion. This disorder is little known and underdiagnosed. The objective of this article was to perform a non-systematic review of the literature on lipoedema, its diagnostic criteria and proposed treatments. METHODOLOGY: A literature search was carried out from January 2012 to January 2018, in the following databases: Pubmed, Scopus, Medline, Web of Science and CINAHL. SELECTION OF STUDIES: A total of 12 articles were included, of which 10 were reviews, one was a cross-sectional study and another was a case series. CONCLUSIONS: Diagnosis of lipoedema is mainly clinical and through exclusion of other disorders. There is no consensus on its treatment, but treatment focuses on attempting to minimise symptoms and prevent disease progression and the disability it may generate.

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

Lipoedema used to be a rather unknown disease. In the past five years, it has gained increasing awareness, especially through media attention. Besides non-surgical treatment by complex conservative decongestion, there are an increasing number of studies pointing out the potential of liposuction for a successful treatment of lipoedema. As a result, an increasing number of affected patients present to plastic surgeons and request correction and pain relief.As the German Federal Joint Committee (Gemeinsamer Bundesausschuss (G-BA)) has not positively acknowledged liposuction as a treatment for lipoedema so far, coverage of the procedure by the statutory health insurance is still a decision on a by-case basis. Therefore, patients seeking liposuction treatment must apply for prior cost approval from the statutory health insurance in cooperation with their plastic surgeon. The review at hand provides a summary of the current prevailing legal norms and gives advice on how to apply for prior cost approval.

In case of an acute leg swelling a deep leg vein thrombosis needs to be excluded. In order to do this, compression sonography and the D-dimer-test are applied in the framework of an established diagnostic algorithm. The ensuing therapy consists in anticoagulation and compression.In case of a chronic leg swelling anamnesis and a clinical check-up often lead to a differential diagnosis. Chronic venous insufficiency is a generic term for a disturbed venous backflow. It is caused by an obstruction or an antegrade or retrograde flow insufficiency. Most common diseases in this context are varicosis or a post-thrombotic syndrome. Sonography and special function tests provide a diagnosis. The basic therapy consists in regular exercise, normalization of weight and compression therapy. In case of a hemodynamically relevant varicose vein surgery or endovascular treatment is advisable. The post-thrombotic syndrome must be treated consistently with the basic therapy.A lymphedema may be hereditary or acquired. In a first step diseases like neoplasia need to be excluded. The initial therapy consists in manual lymph drainage in combination with special compression bandages. Flat knit stockings should be prescribed. Surgical treatment is reserved for special circumstances.A lipedema is clinically diagnosed. It is characterized by lipohypertrophia, pressure sensitivity of the tissue and susceptibility to hematomas. Treatment options include weight reduction, regular exercise, lymph drainage and compression therapy, in some cases liposuction.

Lipedema is a chronic disabilitating disease affecting the subcutaneous adipose tissue of the extremities in females during or after puberty. The disease is characterized by bilateral swelling of legs and/or arms, bruising, and pain. In contrast to lymphedema, the most distal parts remain unaffected. In contrast to obesity, patients with lipedema have a lower risk of diabetes mellitus. The pathogenesis is not well understood. However, hormonal factors seem to play a vital role, as it is an exclusively female disorder. The recent advantages in understanding and treating lipedema are reviewed.

Lipedema is a painful disease of subcutaneous adipose tissue leading to bilateral increase of leg and/or arm volume, but sparing hands and feet. Although conservative treatment with complex decongestive therapy has been considered as the fundamental treatment, micro-cannular liposuction in tumescent anesthesia has become a surgical option. We report on 111 patients mostly with advanced lipedema treated by this technique in our center between 2007 and 2018. The median age of the patients was 44 years. Eighty percent of patients had at least one comorbidity. There was an association of longstanding and advanced disease to obesity and diseases of the metabolic syndrome-spectrum. The median total amount of lipoaspirate was 4,700 ml, with a range of 950-14,250 ml. The median reduction of limb circumference was 6 cm. The median pain level before treatment was 7.8 and 2.2 at the end of the treatment. An improvement of mobility could be achieved in all patients. Bruising was also reduced. Serious adverse events were observed in 1.2% of procedures, the infection rate was 0% and the bleeding rate was 0.3%. Liposuction is an effective treatment for painful lipedema. The procedure should be performed in specialized centers.

<p>Um das Lipödem ranken sich zahlreiche Mythen! In diesem vierten Beitrag unserer Artikelserie setzen wir uns mit dem Stellenwert der Liposuktion beim Lipödem auseinander. Wir diskutieren das von vielen die Liposuktion durchführenden Ärzten verbreitete Statement: „Die Liposuktion führt zu ausgeprägter und dauerhafter Verbesserung des Lipödems“. Wir konnten zeigen, dass zwischen den oft euphorischen Versprechungen der chirurgisch tätigen Kollegen und der aktuellen Studienlage zur Liposuktion eine erhebliche Lücke klafft. Sowohl Studienqualität als auch Studiensetting weisen erhebliche Mängel auf, Mängel, die Zweifel an diesem verbreiteten Statement aufkommen lassen. Eine ähnliche Lücke klafft darüber hinaus zwischen den Empfehlungen der S1-Leitlinie Lipödem und der tatsächlichen „Absaugpraxis“ bei adipösen Lipödempatientinnen. Die in den Leitlinien empfohlene „kritische Indikationsstellung“ bei gleichzeitigem Auftreten von Lipödem und Adipositas findet kaum Gehör. Es kann daher nicht genug betont werden, dass Liposuktion keine Methode ist, um Adipositas zu behandeln. Gleichwohl kann die Liposuktion durchaus zu einer Verbesserung des Lipödems beitragen. Entscheidend für den Therapieerfolg ist die Auswahl der Patientinnen, die aufgrund – medizinischer – Kriterien erfolgen muss. Darüber sollte die Liposuktion in ein Gesamtkonzept eingebunden werden, welches psychosoziale, ernährungs- und sportmedizinische Gesichtspunkte berücksichtigt.</p>

Methemoglobinemia is characterized by an increased level of methemoglobin (MetHb) in the peripheral blood. MetHb levels increase after tumescent anesthesia and need to be monitored. If a patient becomes symptomatic and/or the MetHb levels increase >10%, intravenous injection of an antidote is recommended. Toluidine blue is twice as effective as methylene blue in this respect.A 27-year-old woman with advanced lipedema underwent her third liposuction under tumescent anesthesia. After surgery, her MetHb levels increased and needed injection of toluidine blue. She developed an acute and painful edema after extravasation of some toluidine blue due to a bursting vein. This is the first report in the recent medical literature. Clinical presentation, course, and treatment are described.

Background and Aim: Lipedema is a common painful SAT disorder characterized by enlargement of fat primarily in the legs of women. Case reports of lipedema tissue samples demonstrate fluid and fibrosis in the interstitial matrix, increased macrophages, and adipocyte hypertrophy. The aims of this project are to investigate blood vasculature, immune cells, and structure of lipedema tissue in a cohort of women. Methods: Forty-nine participants, 19 controls and 30 with lipedema, were divided into groups based on body mass index (BMI): Non-Obese (BMI 20 to <30 kg/m2) and Obese (BMI 30 to <40 kg/m2). Histological sections from thigh skin and fat were stained with H&E. Adipocyte area and blood vessel size and number were quantified using ImageJ software. Markers for macrophages (CD68), mast cells (CD117), T cells (CD3), endothelial cells (CD31), blood (SMA), and lymphatic (D2-40 and Lyve-1) vessels were investigated by IHC and IF. Results: Non-Obese Lipedema adipocyte area was larger than Non-Obese Controls (p=0.005) and similar to Obese Lipedema and Obese Controls. Macrophage numbers were significantly increased in Non-Obese (p < 0.005) and Obese (p < 0.05) Lipedema skin and fat compared to Control groups. No differences in T lymphocytes or mast cells were observed when comparing Lipedema to Control in both groups. SMA staining revealed increased dermal vessels in Non-Obese Lipedema patients (p < 0.001) compared to Non-Obese Controls. Lyve-1 and D2-40 staining showed a significant increase in lymphatic vessel area but not in number or perimeter in Obese Lipedema participants (p < 0.05) compared to Controls (Obese and Non-Obese). Areas of angiogenesis were found in the fat in 30% of lipedema participants but not controls. Conclusion: Hypertrophic adipocytes, increased numbers of macrophages and blood vessels, and dilation of capillaries in thigh tissue of non-obese women with lipedema suggest inflammation, and angiogenesis occurs independent of obesity and demonstrates a role of altered vasculature in the manifestation of the disease.

Advanced lymphedema is associated with a number of adverse skin changes including color, thickening of the epidermis, dryness, and hyperkeratosis. These changes are related to prolonged lymph stasis and contribute to an increased risk of infection. Similarly, lipedema is associated with skin thickening and appearance of nodular adipose deposition. Skin care is essential in both conditions. We examined whether inclusion of targeted skin products for 2 weeks to an established pre-surgical conservative treatment program was associated with beneficial effects on the skin condition in 150 patients with lymphedema and lipedema. Patients were randomly assigned to control or one of two treatment groups. All three groups (and for both lymphedema and lipedema) demonstrated a significant reduction in softness. Dimpling/ redness was significantly reduced in the targeted skin product groups for both patients with lymphedema or lipedema. Only patients with lipedema demonstrated a significant reduction in dryness/ hyperkeratosis following targeted skin product treatment. This study demonstrates that short-term use of targeted skin products in both patients with lymphedema and lipedema can be of benefit and further studies are needed to replicate these results and explore possible mechanisms.

Lipedema is a chronic fat disorder with disproportional fat distribution, especially around the legs, hips, and sometimes arms, and it affects women almost exclusively. The major symptoms and complaints include pain in the soft tissue and the feeling of “heavy legs.” The perception of pain depends to a high degree on the psychological condition of the patient. Obesity is the major comorbidity and can worsen lipedema. In combination with impaired levels of physical activity, there is an increase in interstitial filtration, and noninfectious inflammation with capillary leakage can occur. Eventually, chronic edema develops due to the dynamic insufficiency of the lymphatic system. However, edema is not a pathognomonic aspect of lipedema. There are many controversies and myths about the condition lipedema, and no objective diagnostic tool is available to confirm the diagnosis. Therapeutic approaches in lipedema are multimodal and focus on the biomedical, psychological, and functional aspects involved with the disorder. A lifestyle change is often part of the therapeutic program, along with other therapeutic interventions, such as exercise, compression, weight management, and nutritional and psychological support. Clinimetrics with validated techniques in all fields of human functioning of a lipedema patient are mandatory to objectively evaluate the improvements that are due to the treatment program. Liposuction is a technique to remove fat and is therefore introduced to treat lipedema. Some doctors who offer the procedure state that “liposuction leads to comprehensive and long-term improvements in lipedema and cures the disease.” These statements are often too optimistic and lead to high costs for the patient and disappointment in the end. However, liposuction can lead to improvements in lipedema when offered within a therapeutic program that includes other nonoperative modalities for the correct selection of patients according to their medical criteria. It cannot be emphasized enough that liposuction is not a method that should be used to treat obesity.

Subcutaneous adipose tissue diseases involving adipose tissue and its fascia, also known as adipofascial disorders, represent variations in the spectrum of obesity. The adipofascia diseases discussed in this chapter can be localized or generalized and include a common disorder primarily affecting women, lipedema, and four rare diseases, familial multiple lipomatosis, angiolipomatosis, Dercum disease, and multiple symmetric lipomatosis. The fat in adipofascial disorders is difficult to lose by standard weight loss approaches, including lifestyle (diet, exercise), pharmacologic therapy, and even bariatric surgery, due in part to tissue fibrosis. In the management of obesity, healthcare providers should be aware of this difficulty and be able to provide appropriate counseling and care of these conditions. Endocrinologists and primary care providers alike will encounter these conditions and should consider their occurrence during workup for bariatric surgery or hypothyroidism (lipedema) and in those that manifest, or are referred for, dyslipidemia or diabetes (Dercum disease). People with angiolipomas should be worked up for Cowden’s disease where a mutation in the gene PTEN increases their risk for thyroid and breast cancer. This chapter provides details on the pathophysiology, prevalence, genetics and treatments for these adipofascial disorders along with recommendations for the care of people with these diseases. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.