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Rare adipose disorders (RADs) including multiple symmetric lipomatosis (MSL), lipedema and Dercum's disease (DD) may be misdiagnosed as obesity. Lifestyle changes, such as reduced caloric intake and increased physical activity are standard care for obesity. Although lifestyle changes and bariatric surgery work effectively for the obesity component of RADs, these treatments do not routinely reduce the abnormal subcutaneous adipose tissue (SAT) of RADs. RAD SAT likely results from the growth of a brown stem cell population with secondary lymphatic dysfunction in MSL, or by primary vascular and lymphatic dysfunction in lipedema and DD. People with RADs do not lose SAT from caloric limitation and increased energy expenditure alone. In order to improve recognition of RADs apart from obesity, the diagnostic criteria, histology and pathophysiology of RADs are presented and contrasted to familial partial lipodystrophies, acquired partial lipodystrophies and obesity with which they may be confused. Treatment recommendations focus on evidence-based data and include lymphatic decongestive therapy, medications and supplements that support loss of RAD SAT. Associated RAD conditions including depression, anxiety and pain will improve as healthcare providers learn to identify and adopt alternative treatment regimens for the abnormal SAT component of RADs. Effective dietary and exercise regimens are needed in RAD populations to improve quality of life and construct advanced treatment regimens for future generations.

Adiposis dolorosa (AD) is a rare disorder of painful nodular subcutaneous fat accompanied by fatigue, difficulty with weight loss, inflammation, increased fluid in adipose tissue (lipedema and lymphedema), and hyperalgesia. Sequential compression relieves lymphedema pain; we therefore hypothesized that whole body cyclic pneumatic hypobaric compression may relieve pain in AD. To avoid exacerbating hyperalgesia, we utilized a touch-free method, which is delivered via a high-performance altitude simulator, the Cyclic Variations in Altitude Conditioning™ (CVAC™) process. As a pilot study, 10 participants with AD completed pain and quality of life questionnaires before and after 20-40 minutes of CVAC process daily for 5 days. Participants lost weight (195.5 ± 17.6-193.8 ± 17.3 lb; P = 0.03), and bioimpedance significantly decreased (510 ± 36-490 ± 38 ohm; P = 0.01). There was a significant decrease in scores on the Pain Catastrophizing Scale (P = 0.039), in average (P = 0.002), highest (P = 0.029), lowest (P = 0.04), and current pain severity (P = 0.02) on the Visual Analogue Scale, but there was no change in pain quality by the McGill Pain Questionnaire. There were no significant changes in total and physical SF-36 scores, but the mental score improved significantly (P = 0.049). There were no changes in the Pain Disability Index or Pittsburgh Sleep Quality Index. These data present a potential, new, noninvasive means of treating pain in AD by whole body pneumatic compression as part of the CVAC process. Although randomized, controlled trials are needed to confirm these data, the CVAC process could potentially help in treating AD pain and other chronic pain disorders.

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,

Patient: Female, 31-year-old, Final Diagnosis: Lipedema, Symptoms: Bruising • leg edema • leg pain, Medication: —, Clinical Procedure: —, Specialty: Endocrinology and Metabolic • Family Medicine • Medicine, General and Internal • Metabolic Disorders and Diabetics • Plastic Surgery • Psychiatry

Patient: Female, 41-year-old, Final Diagnosis: Malnutrition, Symptoms: Leg edema • weakness, Medication: —, Clinical Procedure: Lymphatic mapping, Specialty: Dermatology • Endocrinology and Metabolic • Surgery

A Case Series of Lymphatic Injuries After Suction Lipectomy in Women with Lipedema - Article abstract #935016

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.

Background Lipedema is a common painful subcutaneous adipose tissue (SAT) disorder in women affecting the limbs. SAT therapy is a manual therapy to improve soft tissue quality. Objective Determine if SAT therapy improves pain and structure of lipedema SAT. Design Single arm prospective pilot study. Setting Academic medical center. Patients Seven women, 46 ± 5 years, weight 90 ± 19 kg, with lipedema. Intervention Twelve 90-min SAT therapy sessions over 4 weeks. Outcomes Dual X-ray absorptiometry (DXA) scans, SAT ultrasound (Vevo 2100), leg volumetrics, skin caliper assessment, tissue exam, weight, resting metabolic rate, pain assessment, lower extremity functional scale (LEFS) and body shape questionnaire (BSQ) at baseline and end of study. Results Weight, resting metabolic rate and BSQ did not change significantly. Limb fat over total body fat mass (p = 0.08) and trunk fat over total body mass trended down from baseline (p = 0.08) by DXA. Leg volume and caliper assessments in eight of nine areas (p < 0.007), LEFS (p = 0.002) and average pain (p = 0.007) significantly decreased from baseline. Fibrosis significantly decreased in the nodules, hips and groin. Ultrasound showed improved SAT structure in some subjects. Side effects included pain, bruising, itching, swelling and gastroesophageal reflux disease. All women said they would recommend SAT therapy to other women with lipedema. Limitations Small number of subjects. Conclusion SAT therapy in 4 weeks improved tissue structure, perceived leg function, and volume although shape was not affected. While side effects of SAT therapy were common, all women felt the therapy was beneficial.

Background: Fluid in lymphedema tissue appears histologically as spaces around vessels and between dermal skin fibers. Lipedema is a painful disease of excess loose connective tissue (fat) in limbs, almost exclusively of women, that worsens by stage, increasing lymphedema risk. Many women with lipedema have hypermobile joints suggesting a connective tissue disorder that may affect vessel structure and compliance of tissue resulting in excess fluid entering the interstitial space. It is unclear if excess fluid is present in lipedema tissue. The purpose of this study is to determine if fluid accumulates around vessels and between skin fibers in the thigh tissue of women with lipedema. Methods: Skin biopsies from the thigh and abdomen from 30 controls and 80 women with lipedema were evaluated for dermal spaces and abnormal vessel phenotype (AVP): (1) rounded endothelial cells; (2) perivascular spaces; and (3) perivascular immune cell infiltrate. Women matched for body mass index (BMI) and age were considered controls if they did not have lipedema on clinical examination. Data were analyzed by analysis of variance (ANOVA) or unpaired t-tests using GraphPad Prism Software 7. p < 0.05 was considered significant. Results: Lipedema tissue mass increases beginning with Stage 1 up to Stage 3, with lipedema fat accumulating more on the limbs than the abdomen. AVP was higher in lipedema thigh (p = 0.003) but not abdomen skin compared with controls. AVP was higher in thigh skin of women with Stage 1 (p = 0.001) and Stage 2 (p = 0.03) but not Stage 3 lipedema versus controls. AVP also was greater in the thigh skin of women with lipedema without obesity versus lipedema with obesity (p < 0.0001). Dermal space was increased in lipedema thigh (p = 0.0003) but not abdomen versus controls. Dermal spaces were also increased in women with lipedema Stage 3 (p < 0.0001) and Stage 2 (p = 0.0007) compared with controls. Conclusion: Excess interstitial fluid in lipedema tissue may originate from dysfunctional blood vessels (microangiopathy). Increased compliance of connective tissue in higher stages of lipedema may allow fluid to disperse into the interstitial space, including between skin dermal fibers. Lipedema may be an early form of lymphedema. ClinicalTrials.gov: NCT02838277.

Background: Elevated stearoyl-CoA desaturase activity has been described in obese states, with an increased desaturation index (DI) suggesting enhanced lipogenesis. Differences in the DI among various phenotypes of abnormal adiposity have not been studied. Abnormal accumulation of subcutaneous adipose tissue occurs in rare adipose disorders (RADs) including Dercum’s disease (DD), multiple symmetric lipomatosis (MSL), and familial multiple lipomatosis (FML). Examining the DI in subcutaneous fat of people with DD, MSL and FML may provide information on adipose tissue fatty acid metabolism in these disorders. The aims of this pilot study were: 1) to determine if differences in adipose tissue DIs are present among RADs, and 2) to determine if the DIs correlate to clinical or biochemical parameters. Methods: Subcutaneous adipose tissue was obtained from human participants with DD (n = 6), MSL (n = 5), FML (n = 8) and obese Controls (n = 6). Fatty acid composition was determined by gas chromatography/mass spectrometry. The DIs (palmitoleic/palmitic, oleic/stearic, vaccenic/stearic ratios) were calculated from the gas chromatogram peak intensities. SCD1 gene expression was determined. Spearman’s correlations between the DIs and available clinical or biochemical data were performed. Results: In DD subjects, the vaccenic/stearic index was lower (p < 0.05) in comparison to Controls. Percent of total of the saturated fatty acid myristic acid was higher in DD compared with Controls and FML. Percent of monounsaturated vaccenic acid in DD trended lower when compared with Controls, and was decreased in comparison to FML. In MSL, total percent of the polyunsaturated fatty acids was significantly lower than in the Control group (p < 0.05). In the total cohort of subjects, the palmitoleic/palmitic and oleic/stearic DIs positively correlated with age, BMI, and percent body fat. Conclusions: The positive associations between the DIs and measures of adiposity (BMI and percent body fat) support increased desaturase activity in obesity. The lower vaccenic/stearic DI in DD SAT compared with Controls suggests presence of other factors involved in fat accumulation in addition to lifestyle. Other mechanisms driving fat accumulation in DD such as inflammation or lymphatic dysfunction should be investigated.

Background: In the USA, the Orphan Drug Act of 1983 defines a rare disease as affecting under 200,000 individuals. Dercum’s disease (DD) is a loose connective (adipose) tissue disease characterized by painful lipomas. While considered a rare disease, the prevalence of DD has not been systematically assessed previously. The objective of this paper is to estimate the prevalence of DD to determine if it is rare or not. Results: Estimates of prevalence of DD using PubMed, the UK Biobank, the US Agency for Health Research and Quality Healthcare Cost and Utilization, physician practices, social media forums and internet searches found the prevalence of DD to be less than 200,000 individuals in the US. These prevalence likely overestimate the disease; however, underestimation may also occur because DD is not well known and may be misdiagnosed. Conclusion: DD meets requirements of the Orphan Drug Act to be classified as a rare disease. Further research should focus on representative population samples in the USA to better estimate the prevalence of DD. Estimating the prevalence is an important first step to increase recognition, research efforts and patient care for people living with DD.

Background Lipedema is a chronic disorder presenting in women during puberty or other times of hormonal change such as childbirth or menopause, characterized by symmetric enlargement of nodular, painful subcutaneous adipose tissue (fat) in the limbs, sparing the hands, feet and trunk. Healthcare providers underdiagnose or misdiagnose lipedema as obesity or lymphedema. Materials and methods The benefits (friend) and negative aspects (foe) of lipedema were collected from published literature, discussions with women with lipedema, and institutional review board approved evaluation of medical charts of 46 women with lipedema. Results Lipedema is a foe because lifestyle change does not reduce lipedema fat, the fat is painful, can become obese, causes gait and joint abnormalities, fatigue, lymphedema and psychosocial distress. Hypermobility associated with lipedema can exacerbate joint disease and aortic disease. In contrast, lipedema fat can be a friend as it is associated with relative reductions in obesity-related metabolic dysfunction. In new data collected, lipedema was associated with a low risk of diabetes (2%), dyslipidemia (11.7%) and hypertension (13%) despite an obese average body mass index (BMI) of 35.3 ± 1.7 kg/m2. Conclusion Lipedema is a painful psychologically distressing fat disorder, more foe than friend especially due to associated obesity and lymphedema. More controlled studies are needed to study the mechanisms and treatments for lipedema.

Background Lipedema is a chronic disorder presenting in women during puberty or other times of hormonal change such as childbirth or menopause, characterized by symmetric enlargement of nodular, painful subcutaneous adipose tissue (fat) in the limbs, sparing the hands, feet and trunk. Healthcare providers underdiagnose or misdiagnose lipedema as obesity or lymphedema. Materials and methods The benefits (friend) and negative aspects (foe) of lipedema were collected from published literature, discussions with women with lipedema, and institutional review board approved evaluation of medical charts of 46 women with lipedema. Results Lipedema is a foe because lifestyle change does not reduce lipedema fat, the fat is painful, can become obese, causes gait and joint abnormalities, fatigue, lymphedema and psychosocial distress. Hypermobility associated with lipedema can exacerbate joint disease and aortic disease. In contrast, lipedema fat can be a friend as it is associated with relative reductions in obesity-related metabolic dysfunction. In new data collected, lipedema was associated with a low risk of diabetes (2%), dyslipidemia (11.7%) and hypertension (13%) despite an obese average body mass index (BMI) of 35.3 ± 1.7 kg/m2. Conclusion Lipedema is a painful psychologically distressing fat disorder, more foe than friend especially due to associated obesity and lymphedema. More controlled studies are needed to study the mechanisms and treatments for lipedema.

Lipedema is a chronic, idiopathic, and painful disease characterized by an excess of adipose tissue in the extremities. The goal of this study is to characterize the gene expression of estrogen receptors (ERα and ERβ), G protein-coupled estrogen receptor (GPER), and ER-metabolizing enzymes: hydroxysteroid 17-beta dehydrogenase (HSD17B1, 7, B12), cytochrome P450 (CYP19A1), hormone-sensitive lipase (LIPE), enzyme steroid sulfatase (STS), and estrogen sulfotransferase (SULT1E1), which are markers in Body Mass Index (BMI) and age-matched non-lipedema (healthy) and lipedema ASCs and spheroids. Flow cytometry and cellular proliferation assays, RT-PCR, and Western Blot techniques were used to determine the expression of ERs and estrogen-metabolizing enzymes. In 2D monolayer culture, estrogen increased the proliferation and the expression of the mesenchymal marker, CD73, in hormone-depleted (HD) healthy ASCs compared to lipedema ASCs. The expression of ERβ was significantly increased in HD lipedema ASCs and spheroids compared to corresponding healthy cells. In contrast, ERα and GPER gene expression was significantly decreased in estrogen-treated lipedema spheroids. CYP19A1 and LIPE gene expressions were significantly increased in estrogen-treated healthy ASCs and spheroids, respectively, while estrogen upregulated the expression of PPAR-ϒ2 and ERα in estrogen-treated lipedema-differentiated adipocytes and spheroids. These results indicate that estrogen may play a role in adipose tissue dysregulation in lipedema.

Background: Lipedema is a poorly known disorder of painful subcutaneous adipose tissue (SAT) likely affecting millions of women worldwide. Stage 1 lipedema has smooth skin with increased underlying fat, Stage 2 has indentations and nodules, and Stage 3 has large extrusions of skin and SAT. Women with lipedema have more SAT below the waist. As this gynoid fat is known to be cardioprotective, we aimed to determine if health declined with increasing stage and extent of lipedema SAT. Methods and Findings: Chart review from June 2012 to February 2013 at a tertiary academic center. Fifty women and one man were included in consecutive order. Fat was assessed in 29 areas for lipomas, size of the depot, and presence of lipedema fat. Pain was assessed by a numerical pain scale. Average age of patients was 50 ± 13 y; average body mass index was 38 ± 12 kg/m2. Median age of development of lipedema was 20 y. Pain occurred daily in 89.7%. None of the patients with Stage 1 lipedema had diabetes, hypertension or dyslipidemia. The amount of lipedema fat differed significantly between Stages of lipedema (p=0.003), with Stage 3 having significantly more. There was no difference in fat depot size or number of lipomas amongst Stages. Only one of 51 patients had type 2 diabetes. There was an increase in shortness of breath, palpitations, urination, and numbness in Stage 3. Conclusions: Lipedema fat can develop in any SAT location and increases in association with increasing signs and symptoms of systemic illness.

The growth and differentiation of adipose tissue-derived stem cells (ASCs) is stimulated and regulated by the adipose tissue (AT) microenvironment. In lipedema, both inflammation and hypoxia influence the expansion and differentiation of ASCs, resulting in hypertrophic adipocytes and deposition of collagen, a primary component of the extracellular matrix (ECM). The goal of this study was to characterize the adipogenic differentiation potential and assess the levels of expression of ECM-remodeling markers in 3D spheroids derived from ASCs isolated from both lipedema and healthy individuals. The data showed an increase in the expression of the adipogenic genes (ADIPOQ, LPL, PPAR-&gamma; and Glut4), a decrease in matrix metalloproteinases (MMP2, 9 and 11), with no significant changes in the expression of ECM markers (collagen and fibronectin), or integrin A5 in 3D differentiated lipedema spheroids as compared to healthy spheroids. In addition, no statistically significant changes in the levels of expression of inflammatory genes were detected in any of the samples. However, immunofluorescence staining showed a decrease in fibronectin and increase in laminin and Collagen VI expression in the 3D differentiated spheroids in both groups. The use of 3D ASC spheroids provide a functional model to study the cellular and molecular characteristics of lipedema AT.

Objective Lipedema is an inflammatory subcutaneous adipose tissue disease that develops in women and may progress to lipolymphedema, a condition similar to lymphedema, in which lymphatic dysfunction results in irresolvable edema. Because it has been shown that dilated lymphatic vessels, impaired pumping, and dermal backflow are associated with presymptomatic, cancer-acquired lymphedema, this study sought to understand whether these abnormal lymphatic characteristics also characterize early stages of lipedema prior to lipolymphedema development. Methods In a pilot study of 20 individuals with Stage I or II lipedema who had not progressed to lipolymphedema, lymphatic vessel anatomy and function in upper and lower extremities were assessed by near-infrared fluorescence lymphatic imaging and compared with that of a control population of similar age and BMI. Results These studies showed that, although lower extremity lymphatic vessels were dilated and showed intravascular pooling, the propulsion rates significantly exceeded those of control individuals. Upper extremity lymphatics of individuals with lipedema were unremarkable. In contrast to individuals with lymphedema, individuals with Stage I and II lipedema did not exhibit dermal backflow. Conclusions These results suggest that, despite the confusion in the diagnoses between lymphedema and lipedema, their etiologies differ, with lipedema associated with lymphatic vessel dilation but not lymphatic dysfunction.

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.

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.