A Family-Based Study of Inherited Genetic Risk in Lipedema.

Background: Lipedema is a progressive condition involving excessive deposition of subcutaneous adipose tissue, predominantly in the lower limbs, which severely compromises quality of life. Despite the impact of lipedema, its molecular and genetic bases are poorly understood, making diagnosis and treatment difficult. Historical evaluation of individuals with lipedema indicates a positive family history in 60%-80% of cases; however, genetic investigation of larger family cohorts is required. Here, we report the largest family-based sequencing study to date, aimed at identifying genetic changes that contribute to lipedema. Methods and Results: DNA samples from 31 individuals from 9 lipedema families were analyzed to reveal genetic variants predicted to alter protein function, yielding candidate variants in 469 genes. We did not identify any individual genes that contained likely disease-causing variants across all participating families. However, gene ontology analysis highlighted vasopressin receptor activity, microfibril binding, and patched binding as statistically significantly overrepresented categories for the set of candidate variants. Conclusions: Our study suggests that lipedema is not caused by a single exomic genetic factor, providing support for the hypothesis of genetic heterogeneity in the etiology of lipedema. As the largest study of its kind in the lipedema field, the results advance our understanding of the disease and provide a roadmap for future research aimed at improving the lives of those affected by lipedema.

Venous thromboembolic outcomes in patients with lymphedema and lipedema: An analysis from the National Inpatient Sample.

BACKGROUND: Patients with lymphedema and lipedema share physical exam findings that may lead to misdiagnosis. Poor mobility is common in patients with obesity and patients with lymphedema and lipedema. This may constitute a risk factor for venous thromboembolism (VTE). Our objective was to evaluate the association of VTE in obese patients with lymphedema and lipedema. METHODS: The National Inpatient Sample (NIS) was searched from 2016 to 2020 to identify hospital admissions of obese female patients with lymphedema and lipedema. Patients were analyzed in the context of presence or absence of VTE while adjusting for complex cluster sampling techniques. Predictors of VTE were accessed by multivariable regression. RESULTS: Lymphedema was identified in 189,985 patients and lipedema in 50,645 patients. VTE was observed in 3.12% (n = 374,210) of patients with obesity. In patients with obesity, VTE was more common in patients with lymphedema than without (2.6% vs 1.6%; p < 0.01). Similarly, VTE was more common in patients with lipedema than without (0.6% vs 0.4%; p < 0.01). After multivariable logistic regression, VTE events in obese patients with lymphedema were higher versus without (OR 1.6; CI 1.08-2.43; p = 0.02). Similarly, VTE events were more common in obese patients with lipedema versus obese patients without lipedema (OR 1.20; CI 1.03-1.41; p = 0.02). CONCLUSIONS: In this hypothesis-generating study, lymphedema and lipedema show a positive association with VTE after adjusting for baseline patient characteristics such as obesity, which is a known independent risk factor for VTE. Mechanisms whereby lymphedema and lipedema are associated with VTE should be investigated.

National survey of patient symptoms and therapies among 707 women with a lipedema phenotype in the United States.

BACKGROUND: National survey data exploring the patient experience with lipedema are lacking. METHODS: We conducted national surveys from 2016 to 2022 of women with lipedema as well as female controls. Surveys collected information on symptomatology, pain, and therapies. We performed logistic regression comparing symptoms among those with lipedema versus controls adjusting for age and BMI. RESULTS: A total of 707 women with lipedema and 216 controls completed the surveys. Those with lipedema had a mean age of 48.6 years and mean BMI of 40.9 kg/m2. Lipedema symptom onset occurred frequently at puberty (48.0%) or pregnancy (41.2%). Compared to controls, women with lipedema were more likely to report leg swelling in heat (odds ratio [OR], 66.82; 95% CI, 33.04-135.12; p < 0.0001), easy bruising (OR, 26.23; 95% CI, 15.58-44.17; p < 0.0001), altered gait (OR, 15.54; 95% CI, 7.58-31.96; p < 0.0001), flu-like symptoms (OR, 12.99; 95% CI, 4.27-39.49; p < 0.0001), joint hypermobility (OR, 12.88; 95% CI, 6.68-24.81; p < 0.0001), cool skin (OR, 12.21; 95% CI, 5.20-28.69; p < 0.0001), varicose veins (OR, 11.29; 95% CI, 6.71-18.99; p < 0.0001), and fatigue (OR, 9.59; 95% CI, 6.10-15.09; p < 0.0001). Additionally, 70.3% had upper arm involvement, 21.2% reported foot swelling, and 16.6% reported foot pain. Most (52.2%) reported no symptom improvement with diet or exercise. Common therapies used included compression therapy (45.0%), gastric bypass (15.7%), and lower-extremity liposuction (14.0%). CONCLUSION: In a large, national, symptom survey, women with lipedema reported excess pain, swelling, and fat in the legs along with numerous symptoms beyond those classically described. Symptom responses to common therapies remain understudied.

Effect of Physical Therapy on Circumference Measurement and Extremity Volume in Patients Suffering from Lipedema with Secondary Lymphedema.

Background: Lipedema is a chronic and progressive disease. Many complications can occur if the disease is not treated. The most important of these complications is lipedema with secondary lymphedema. There are very few publications about lipedema with secondary lymphedema. The aim of this study is to investigate the effect of physical therapy on lower extremity circumference and volume in patients suffering from lipedema with secondary lymphedema. Methods and Results: All patients received pneumatic compression and complex decongestive therapy (CDT). Perometer measurement was made at five distinct points. Fifteen patients were included in the study. It was seen that significant reduction was found in the circumference of three of the five points of measurements performed in the left leg, whereas significant reduction was found in the circumference of four of the five points of measurements performed in the right leg. Also, there was a decrease in the extremity volume in both legs. Conclusion: Combined application of CDT and pneumatic compression in patients suffering from lipedema with secondary lymphedema is an effective treatment method in reducing lower extremity volume and circumference measurement.

An uncertain uphill battle - experiences and consequences of living with lipedema.

PURPOSE: To describe and analyse experiences of living with lipedema. Methods: Individual, semi-structured interviews with a purposive sample of 12 women diagnosed with lipedema and analysed by qualitative content analysis utilizing an inductive approach. RESULTS: The overarching theme, "An uncertain uphill battle against a divergent body and societal ignorance", covers the experiences of living with lipedema and is based on five categories; "Captivated by a disintegrating body", "Face the impairments of a chronic condition", "Experience social exclusion", "Need emotional support to go on" and "Mull over an insecure future". The women felt entrapped within their bodies and experienced social exclusion due to the chronic symptoms and the progressive body shape alteration caused by their illness. Having experienced deficient information on the illness, varying support from other people, and a deteriorating economic situation, the women face an uncertain future. CONCLUSIONS: Symptoms and restrictions caused by lipedema affect women's livelihood and future, as there are no indications for disease improvement. Preventive work aimed at reducing health deterioration should be a priority. More research is needed to raise healthcare awareness regarding difficulties experienced by patients with lipedema.

AKR1C1 and hormone metabolism in lipedema pathogenesis: a computational biology approach.

OBJECTIVE: Lipedema is an autosomal dominant genetic disease that mainly affects women. It is characterized by excess deposition of subcutaneous adipose tissue, pain, and anxiety. The genetic and environmental etiology of lipedema is still largely unknown. Although considered a rare disease, this pathology has been suggested to be underdiagnosed or misdiagnosed as obesity or lymphedema. Steroid hormones seem to be involved in the pathogenesis of lipedema. Indeed, aldo-keto reductase family 1 member C1 (AKR1C1), a gene coding for a protein involved in steroid hormones metabolism, was the first proposed to be correlated with lipedema. PATIENTS AND METHODS: In this study, we employed a molecular dynamics approach to assess the pathogenicity of AKR1C1 genetic variants found in patients with lipedema. Moreover, we combined information theory and structural bioinformatics to identify AKR1C1 polymorphisms from the gnomAD database that could predispose to the development of lipedema. RESULTS: Three genetic variants in AKR1C1 found in patients with lipedema were disruptive to the protein's function. Furthermore, eight AKR1C1  variants found in the general population could predispose to the development of lipedema. CONCLUSIONS: The results of this study provide evidence that AKR1C1 may be a key gene in lipedema pathogenesis, and that common polymorphisms could predispose to lipedema development.

[Searching for Evidence: A Systematic Review of the Pathology of Lipoedema]. / Auf der Suche nach der Evidenz: Eine systematische Übersichtsarbeit zur Pathologie des Lipödems.

BACKGROUND: Lipoedema is a symmetrically localised, painful hypertrophy of subcutaneous adipose tissue in the extremities with marked disproportion to the trunk, and almost exclusively affects females. Despite being first described over 80 years ago, the aetiology and pathogenesis of the disease are largely unknown and are currently the subject of intensive research efforts. METHODS: To summarise the current evidence-based literature on the cellular pathologies and aetiology of lipoedema, a PRISMA-based systematic review was conducted within the National Library of Medicine and Cochrane databases. RESULTS: A total of 53 studies were identified and included in this review. The results were classified and summarised into categories. CONCLUSION: Although there has been a significant increase in research activity and recent publication of extensive studies with a histological and molecular genetic focus, the fundamental aetiology and pathology of lipoedema remains largely unclear. The current data shows discrepancies across studies, particularly with regard to the "oedematous" component of lipoedema. The frequently present comorbidities "lymphoedema" and "obesity", primarily in advanced stages of lipoedema, complicate the diagnostic differentiation and clear definition of study cohorts in scientific research.

Ketogenic Diet: A Nutritional Therapeutic Tool for Lipedema?

PURPOSE OF REVIEW: This review aims to provide an overview of the current evidence on the efficacy, also considering the anti-inflammatory properties and safety of very low-calorie ketogenic diet (VLCKD) as a potential treatment for lipedema, particularly in the context of obesity. RECENT FINDINGS: Lipedema is a chronic disease characterized by abnormal and painful fat buildup on the legs and/or arms. It is often misdiagnosed as obesity or lymphedema. However, although lipedema and obesity can coexist, unlike obesity, lipedema usually affects the legs and thighs without affecting the feet or hands, and the abnormal deposition of adipose tissue in lipedema is painful. The current lifestyle interventions are often unsuccessful in the management of lipedema. There is no consensus on the most effective nutritional approach for managing lipedema. Recent studies have suggested that VLCKD may be an effective treatment for lipedema, demonstrating that it is also superior to other nutritional approaches such as Mediterranean diet or intermittent fasting. Lipedema is a chronic and debilitating disease characterized by abnormal and painful accumulation of adipose tissue in the legs. VLCKD has been shown to be an effective treatment for lipedema, especially in the context of obesity, due to its anti-inflammatory properties. However, further research is needed to determine the long-term safety and efficacy of VLCKD as a treatment for lipedema.

The Advanced Care Study: Current Status of Lipedema in Spain, A Descriptive Cross-Sectional Study.

INTRODUCTION: The pathologic features of fatty tissue in lipedema are often challenging to diagnose, thus allowing for variable bias and leading to underdiagnosis. Lipedema is a disease that is currently little known worldwide, but it represents a public health problem and demands immediate, well-directed healthcare. Insufficient scientific information limits medical action, which limits making diagnoses and addressing an adequate multidisciplinary treatment. This study aims to evaluate the current state of lipedema in Spain to contextualize the disease's pathophysiological characteristics and thus achieve a consensus that unifies and defines its diagnostic criteria and medical management. Likewise, this study aims to determine the effectiveness of the various treatments applied to the study patients and to evaluate the consequences of the pandemic related to this disease. MATERIAL AND METHODS: The present work is a descriptive, cross-sectional study that analyzed online questionnaires. It was applied to 1069 patients and collected over 9 months between 2021 and 2022. The questionnaires were distributed to the leading national and regional associations of patients affected by lipedema. The study included all patients in a group who had a diagnosis of lipedema and in a group of undiagnosed patients with six or more symptoms. The variables analyzed were age, weight, height, body mass index (BMI), type of lipedema (according to Schingale's classification), symptoms (according to Wolf's classification, modified by Herbst), and treatments performed (physiotherapy, compression garments, sports, diet, radiofrequency, mesotherapy, and surgery), associated with the score given by the patients regarding the degree of improvement in their disease with each of these treatments. RESULTS: There were 967 women and 2 men between 18 and 75 years old (mean of 38.5 years); a body weight between 33 and 150 kg (mean 75.8 kg); a height between 144 and 180 cm (mean 164 cm); and an average body mass index (BMI) of 28.1. The most common kind of lipedema in our study population was type III (affecting the hips, thighs, and calves). The treatment that individually improved patients' quality of life the most was surgery, only surpassed by the multidisciplinary approach to the disease, including conservative measures. CONCLUSIONS: With this study, we can conclude that, in Spain, there is a real problem associated with the diagnosis of lipedema, specifying the need to seek this diagnosis actively and propose multidisciplinary management, since it offers the best overall results, of course not without forgetting that surgery is one of the most critical pillars in the approach to this disease. Consistent with the results obtained in this study, criteria were proposed and applied to represent a statistical value at the time of ruling on the clinical diagnosis of lipedema, considering that a patient who presents six or more of these diagnostic criteria, with a very high probability, will have lipedema.

Assessment of lipoedema awareness among polish women- online survey study.

BACKGROUND: Lipoedema is an adipose tissue disorder that is still not fully understood. The primary purpose of this study is to explore the state of knowledge and understanding of lipoedema among Polish women. The secondary aim is to investigate the possible association between knowledge and factors such as BMI, self-reported symptoms, and age. METHODS: One hundred seventy polish women took part in an online survey study that was posted to social media groups and forums in January 2022. The survey consisted of 12 questions and aimed at assessing the basic knowledge about lipoedema. RESULTS: The least proportion of participants (4%) could correctly indicate the methods of lipoedema treatment. The accurate definition of lipoedema was indicated only by 7% of women, 12% identified characteristic features of lipoedema, and 37% correctly evaluated lipoedema curability. The greatest proportion of respondents knew the differences between obesity and lipoedema (50%). CONCLUSIONS: Awareness of lipoedema among women is deficient. A significant proportion of the respondents report the occurrence of lipoedema symptoms. In order to improve the situation of lipoedema patients, it is crucial to increase the knowledge about this condition both among medical professionals and the general public.

Body mass index vs. waist-to-height-ratio in patients with lipohyperplasia dolorosa (vulgo lipedema).

BACKGROUND: Lipedema, also known as lipohyperplasia dolorosa (LiDo), is a painful condition affecting women, causing a disproportionate accumulation of subcutaneous adipose tissue in the extremities. It carries a lower risk of diabetes and cardio-metabolic dysfunctions compared to obesity, but coincident obesity can complicate diagnosis and treatment. PATIENTS AND METHODS: This retrospective study included 607 female LiDo patients, ≥ 18 years, stage 1-3, from Germany, the UK, and Spain. Data were collected as part of the standard initial assessment for LiDo patients. RESULTS: Based on waist-to-height-ratio (WHtR), 15.2% of patients were underweight, 45.5% normal weight, 22.1% overweight and 17.3% obese. There was a significant association between WHtR category and age group. Body mass index (BMI) is often overestimated, leading to misdiagnosis of obesity. CONCLUSIONS: The use of BMI also affects the recent decision of the German Federal Joint Committee on the reimbursement of liposuction costs by health insurance funds. Patients with BMI of more than 40 kg/m2 are excluded from cost coverage, and those with BMI between 35 kg/m2 and 40 kg/m2 must first receive conservative obesity therapy. In conclusion, the sole use of BMI in lipedema is unreliable and, in contrast to WHtR, leads to inaccurate diagnoses overestimating overweight and obesity.

[Lipohyperplasia dolorosa : About facts and fiction, clinical presentation and examination]. / Lipohyperplasia dolorosa : Über Fake und Fakten, Klinik und Untersuchung.

Lipohyperplasia dolorosa, also known by the misnomer "lipedema", is a clinical picture first described more than 80 years ago, that in the last 25 years has received increasing attention in medical practices, but also lymphological discussion circles which are otherwise rare in the scientific community. Unfortunately, to put it casually, discussions in social media accelerate the amount of supposed knowledge, an unusual occurrence in the otherwise slow and cautious field of science. Media influences and considerable economic interests resharpen and focus the view, but thus also cloud many women's view of the disease. Combining clinical presentation and a simple clinical examination with a few palpatory findings results in a clear diagnosis that excludes differential diagnoses, in particular obesity. Therapy should only be offered once a precise diagnosis is made. Once the diagnosis is confirmed, it is irreversible and means a lifelong change to the patient's quality of life. Care is, therefore, as always, the first duty of the diagnostician.

[Lipedema pain-the neglected symptom]. / Lipödemschmerz ­ das vernachlässigte Symptom.

Pain, which is a central characteristic of lipedema, allows differentiation from other fat tissue diseases. The analysis of the multiple aspects of pain beyond a quantification of pain scale scores could make molecular disease and therapy mechanisms accessible. Lipedema pain is causally linked to lipedema fat. First robust data show peripheral sensory changes. Tissue weight and systemic inflammation are becoming less likely as causes for the experianced pain. Furthermore, genetics and hormonal influences need to be investigated. Lipedema pain cannot currently be treated with drugs. Physical therapy shows transient relief. Liposuction has been shown to have a long-term effect on pain. The potential of modulating the perception of pain with psychotherapeutic approaches is emerging as a potentially effective new therapeutic approach.

Frequency of lipoedema in patients consulting a vein clinic for mild to moderate superficial venous disorder with symptoms: A retrospective analysis.

INTRODUCTION: Lower limb lipoedema is a chronic condition of the adipose connective tissue of the skin that affects women. Its frequency is not well known, hence the main objective of this study. METHOD: Retrospective analysis of the records of phlebology consultations in private practice in a single center from April 2020 to April 2021. Inclusion criteria were: women aged 18 to 80 years, presenting with symptoms attributable to veins and the presence of at least one dilated reticular vein. RESULTS: The files of 464 patients were analyzed. 7.7% had lipoedema, 3.7% lymphedema, 3% stage 3 obesity. The 36 patients with lipoedema were 54.7±16 years old (mean, Standard Deviation), with a Body Mass Index of 31.3±5.5. Leg pain was the major symptom (32/36) and no patient had a positive pitting test. CONCLUSION: Lipoedema is a frequent condition in phlebology consultations.

[Settlement of the surgical treatment of lipoedema]. / Abrechnung der chirurgischen Therapie des Lipödems.

The billing of lipoedema treatment in Germany has come to be heterogeneous. This is due to the decision of the Federal Joint Committee ("Gemeinsamer Bundesausschuss", G-BA) to acknowledge lipoedema stage III as a treatment to be paid by the statutory health insurance funds ("Gesetzliche Krankenversicherung", GKV) until the completion of the trial study "LipLeg" at the end of 2024. Based on this decision, inpatient and outpatient surgical treatment of stage III lipoedema can be billed to the GKV, while the reimbursement of costs for surgical treatment of the other two stages remains a case-by-case decision of the GKV and is currently often rejected. Therefore, treatment costs are often paid by patients themselves. The question of the correct settlement of lipoedema treatment repeatedly arises in the context of legal disputes, which, in turn, repeatedly faces experts and courts with a major challenge. In the following article, the Task Force Lipoedema of the German Society for Plastic, Reconstructive and Aesthetic Surgery presents an overview of the various billing modalities and presents a proposal for the correct billing of lipoedema within the framework of the German medical fee schedule ("Gebührenordnung für Ärzte", GOÄ).

Lipedema: What we don't know.

BACKGROUND: Lipedema is a loose connective tissue disease characterized by a disproportionate accumulation of adipose tissue in the limbs of women. Despite its incidence of 10-20%, lipedema is often underdiagnosed and misdiagnosed. OBJECTIVES: This review aims to outline current, available evidence regarding this enigmatic syndrome and gives a synopsis of the subjects that are still unknown. MATERIALS AND METHODS: PubMed and Embase searches were conducted to identify relevant articles on lipedema pathophysiology, clinical presentation, diagnosis, and treatment. RESULTS: Lipedema can be considered a disease of the adipocytes or a circulatory disorder of the lymphatics. The relationship between lymphatics and adipose tissue remains controversial. The clinical distinction between lipedema, lymphedema, phlebolymphedema, and lipolymphedema can be difficult. Diagnoses often coexist, further complicating the diagnosis of lipedema, which is currently made on clinical grounds alone. The value of diagnostic imaging studies is unclear. Liposuction appears to be an effective treatment and significantly improves symptoms. CONCLUSION: Diagnosing lipedema remains a challenge due to its heterogeneous presentation, co-existing diseases, and lack of objective diagnostic imaging. Further directions for research include the effect of excess skin resection surgery on lymphatic drainage.

Breaking the circle-effectiveness of liposuction in lipedema.

BACKGROUND: Lipedema is a common chronic fat distribution disorder often aligned with pain and reduced quality of life affecting 6-10% of the female population. Although lipedema has acquired more scientific attention in the last decade, validated diagnosis and treatment still remain challenging for specialists. PATIENTS AND METHODS: In this article we evaluate the effect of liposuction on appearance, pain and coexisting diseases of 860 patients with lipedema. Comparison among stages of lipedema pre- and post-liposuction was performed by using t-Tests for independent samples and Kruskal-Wallis-Tests. RESULTS: Our study demonstrates the positive effect on pain reduction in patients with lipedema after liposuction (NRS 2.24) compared with pre-liposuction pain perception (NRS 6.99) and pain perception of patients with conservative treatment (NRS 6.26). Significant differences were shown in the perception between the stages of lipedema and in the reduction of pain perception by liposuction. Furthermore we examined co-diseases in patients with lipedema, primarily menstruation complaints (43%), sleeplessness (36%) and migraine (35%). CONCLUSIONS: A progress of lipedema disease leads not only to a change of appearance and proportion but also to a progressive increase of pain. Liposuction shows a significant effect on pain reduction -independent of the patients' stage of lipedema.