Lipedema: A Call to Action!

Giacomo Buso, Michele Depairon, Didier Tomson, Wassim Raffoul, Roberto Vettor, Lucia Mazzolai, Giacomo Buso, Michele Depairon, Didier Tomson, Wassim Raffoul, Roberto Vettor, Lucia Mazzolai

Abstract

Lipedema is a chronic progressive disease characterized by abnormal fat distribution resulting in disproportionate, painful limbs. It almost exclusively affects women, leading to considerable disability, daily functioning impairment, and psychosocial distress. Literature shows both scarce and conflicting data regarding its prevalence. Lipedema has been considered a rare entity by several authors, though it may be a far more frequent condition than thought. Despite the clinical impact on women's health, lipedema is in fact mostly unknown, underdiagnosed, and too often misdiagnosed with other similarly presenting diseases. Polygenic susceptibility combined with hormonal, microvascular, and lymphatic disorders may be partly responsible for its development. Furthermore, consistent information on lipedema pathophysiology is still lacking, and an etiological treatment is not yet available. Weight loss measures exhibit minimal effect on the abnormal body fat distribution, resulting in eating disorders, increased obesity risk, depression, and other psychological complaints. Surgical techniques, such as liposuction and excisional lipectomy, represent therapeutic options in selected cases. This review aims to outline current evidence regarding lipedema epidemiology, pathophysiology, clinical presentation, differential diagnosis, and management. Increased awareness and a better understanding of its clinical presentation and pathophysiology are warranted to enable clinicians to diagnose and treat affected patients at an earlier stage.

© 2019 The Authors. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).

Figures

Figure 1
Figure 1
(A) Types and (B) stages of lipedema.
Figure 2
Figure 2
Algorithm for work‐up in patients presenting with suspected lipedema. DLT, decongestive lymphatic therapy; CDP, complex decongestive physiotherapy; WHR, waist‐hip ratio; WHtR: waist‐height ratio; DXA, dual‐energy x‐ray absorptiometry; CT, computed tomography; MRI, magnetic resonance imaging.

References

    1. Forner‐Cordero I, Szolnoky G, Forner‐Cordero A, Kemény L. Lipedema an overview of its clinical manifestations, diagnosis and treatment of the disproportional fatty deposition syndrome ‐ systematic review. Clin Obes 2012;2:86‐95.
    1. Okhovat JP, Alavi A. Lipedema: a review of the literature. Int J Low Extrem Wounds 2015;14: 262‐267.
    1. Fife CE, Maus EA, Carter MJ. Lipedema: a frequently misdiagnosed and misunderstood fatty deposition syndrome. Adv Skin Wound Care 2010;23:81‐92; quiz 93‐94.
    1. Szel E, Kemeny L, Groma G, Szolnoky G. Pathophysiological dilemmas of lipedema. Med Hypotheses 2014;83:599‐606.
    1. Child AH1, Gordon KD, Sharpe P, et al. Lipedema: an inherited condition. Am J Med Genet A 2010;152A:970‐976.
    1. Tiwari A1, Myint F, Hamilton G. Management of lower limb lymphoedema in the United Kingdom. Eur J Vasc Endovasc Surg 2006;31:311‐315.
    1. Földi M, Földi E, Kubik S. Textbook of Lymphology. New York: Elsevier; 2005.
    1. Meier‐Vollrath I, Schneider W, Schmeller W. Lipödem: Verbesserte Lebensqualität durch Therapiekombination. Dtsch Arztebl 2005;102:A‐1061/B‐892/C‐840.
    1. Vignes S, Vidal F, Arrault M. Specialized consultations in a hospital‐based referral center for patients suspected of having limb lymphedema: impact on diagnosis. Vasc Med 2017;22:331‐336.
    1. Marshall MS‐SC. Prevalence of lipoedema in professional women in Germany. Phlebologie 2011;40:127‐134.
    1. Bano G1, Mansour S, Brice G, et al. Pit‐1 mutation and lipoedema in a family. Exp Clin Endocrinol Diabetes 2010;118:377‐380.
    1. Chen SG, Hsu SD, Chen TM, Wang HJ. Painful fat syndrome in a male patient. Br J Plast Surg 2004;57:282‐286.
    1. Schook CC, Mulliken JB, Fishman SJ, Alomari AI, Grant FD, Greene AK. Differential diagnosis of lower extremity enlargement in pediatric patients referred with a diagnosis of lymphedema. Plast Reconstr Surg 2011;127:1571‐1581.
    1. Xu Y, Lopez M. Central regulation of energy metabolism by estrogens. Mol Metab 2018;15:104‐115.
    1. Schmeller W, Hueppe M, Meier‐Vollrath I. Tumescent liposuction in lipoedema yields good long‐term results. Br J Dermatol 2012;166:161‐168.
    1. Langendoen SI, Habbema L, Nijsten TE, Neumann HA. Lipoedema: from clinical presentation to therapy. A review of the literature. Br J Dermatol 2009;161:980‐986.
    1. Wold LE, Hines EA Jr, Allen EV. Lipedema of the legs; a syndrome characterized by fat legs and edema. Ann Intern Med 1951;34:1243‐1250.
    1. Torre YS, Wadeea R, Rosas V2, Herbst KL. Lipedema: friend and foe. Horm Mol Biol Clin Investig 2018;33. doi:10.1515/hmbci-2017-0076
    1. Waxler JL, Guardino C, Feinn RS, Lee H, Pober BR, Stanley TL. Altered body composition, lipedema, and decreased bone density in individuals with Williams syndrome: a preliminary report. Eur J Med Genet 2017;60:250‐256.
    1. Szolnoky G, Nemes A, Gavaller H, Forster T, Kemeny L. Lipedema is associated with increased aortic stiffness. Lymphology 2012;45:71‐79.
    1. Kozel BA, Danback JR, Waxler JL, et al. Williams syndrome predisposes to vascular stiffness modified by antihypertensive use and copy number changes in NCF1. Hypertension 2014;63:74‐79.
    1. Harvey NL, Srinivasan RS, Dillard ME, et al. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult‐onset obesity. Nat Genet 2005;37:1072‐1081.
    1. Karkkainen MJ, Saaristo A, Jussila L, et al. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A 2001;98:12677‐12682.
    1. Makinen T, Jussila L, Veikkola T, et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor‐3. Nat Med 2001;7:199‐205.
    1. Gonzalez‐Parra S, Chowen JA, Garcia‐Segura LM, Argente J. In vivo and in vitro regulation of pituitary transcription factor‐1 (Pit‐1) by changes in the hormone environment. Neuroendocrinology 1996;63:3‐15.
    1. Zechner U, Kohlschmidt N, Kempf O, et al. Familial Sotos syndrome caused by a novel missense mutation, C2175S, in NSD1 and associated with normal intelligence, insulin dependent diabetes, bronchial asthma, and lipedema. Eur J Med Genet 2009;52:306‐310.
    1. Okazaki R, Inoue D, Shibata M, et al. Estrogen promotes early osteoblast differentiation and inhibits adipocyte differentiation in mouse bone marrow stromal cell lines that express estrogen receptor (ER) alpha or beta. Endocrinology 2002;143:2349‐2356.
    1. Benglis D, Wang MY, Levi AD. A comprehensive review of the safety profile of bone morphogenetic protein in spine surgery. Neurosurgery 2008;62 (5 suppl 2):ONS423–ONS431.
    1. Kang Q, Song WX, Luo Q, et al. A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells. Stem Cells Dev 2009;18:545‐559.
    1. Merrick MT, Hamilton KD, Russo SS. Acute epidural lipedema: a novel entity and potential complication of bone morphogenetic protein use in lumbar spine fusion. Spine J 2013;13:e15‐e19.
    1. Mayes JS, Watson GH. Direct effects of sex steroid hormones on adipose tissues and obesity. Obes Rev 2004;5:197‐216.
    1. Van Pelt RE, Gozansky WS, Hickner RC, Schwartz RS, Kohrt WM. Acute modulation of adipose tissue lipolysis by intravenous estrogens. Obesity (Silver Spring) 2006;14:2163‐2172.
    1. Gavin KM, Cooper EE, Hickner RC. Estrogen receptor protein content is different in abdominal than gluteal subcutaneous adipose tissue of overweight‐to‐obese premenopausal women. Metabolism 2013;62:1180‐1188.
    1. Herbst KL. Rare adipose disorders (RADs) masquerading as obesity. Acta Pharmacol Sin 2012;33:155‐172.
    1. Xu Y, Nedungadi TP, Zhu L, et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab 2011;14:453‐465.
    1. Elias CF, Aschkenasi C, Lee C, et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 1999;23:775‐786.
    1. Elmquist JK, Elias CF, Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 1999;22:221‐232.
    1. Musatov S, Chen W, Pfaff DW, et al. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci U S A 2007;104:2501‐2506.
    1. Wenczl E, Daroczy J. Lipedema, a barely known disease: diagnosis, associated diseases and therapy [in Hungarian]. Orv Hetil 2008;149:2121‐2127.
    1. Siems W, Grune T, Voss P, Brenke R. Anti‐fibrosclerotic effects of shock wave therapy in lipedema and cellulite. BioFactors 2005;24:275‐282.
    1. Suga H, Araki J, Aoi N, Kato H, Higashino T, Yoshimura K. Adipose tissue remodeling in lipedema: adipocyte death and concurrent regeneration. J Cutan Pathol 2009;36:1293‐1298.
    1. Al‐Ghadban S, Cromer W, Allen M, et al. Dilated blood and lymphatic microvessels, angiogenesis, increased macrophages, and adipocyte hypertrophy in lipedema thigh skin and fat tissue. J Obes 2019;2019:8747461. doi:10.1155/2019/8747461
    1. de Kreutzenberg SV, Crepaldi C, Marchetto S, et al. Plasma free fatty acids and endothelium‐dependent vasodilation: effect of chain‐length and cyclooxygenase inhibition. J Clin Endocrinol Metab 2000;85:793‐798.
    1. Kim F, Tysseling KA, Rice J, et al. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol 2005;25:989‐994.
    1. Birmingham JM, Busik JV, Hansen‐Smith FM, Fenton JI. Novel mechanism for obesity‐induced colon cancer progression. Carcinogenesis 2009;30:690‐697.
    1. Cao Y. Angiogenesis modulates adipogenesis and obesity. J Clin Invest 2007;117:2362‐2368.
    1. Rathbun S, Heath PJ, Whitsett T. Images in vascular medicine. The venoarterial reflex. Vasc Med 2008;13:315‐316.
    1. Gollasch M, Dubrovska G. Paracrine role for periadventitial adipose tissue in the regulation of arterial tone. Trends Pharmacol Sci 2004;25:647‐653.
    1. Bilancini S, Lucchi M, Tucci S, Eleuteri P. Functional lymphatic alterations in patients suffering from lipedema. Angiology 1995;46:333‐339.
    1. Amann‐Vesti BR, Franzeck UK, Bollinger A. Microlymphatic aneurysms in patients with lipedema. Lymphology 2001;34:170‐175.
    1. Lohrmann C, Foeldi E, Langer M. MR imaging of the lymphatic system in patients with lipedema and lipo‐lymphedema. Microvasc Res 2009;77:335‐339.
    1. Wollina U, Heinig B, Schonlebe J, Nowak A. Debulking surgery for elephantiasis nostras with large ectatic podoplanin‐negative lymphatic vessels in patients with lipo‐lymphedema. Eplasty 2014;14:e11‐20
    1. Partsch H, Stoberl C, Urbanek A, Wenzel‐Hora BI. Clinical use of indirect lymphography in different forms of leg edema. Lymphology 1988;21:152‐160.
    1. Schneider M, Conway EM, Carmeliet P. Lymph makes you fat. Nat Genet 2005;37:1023‐1024.
    1. Nougues J, Reyne Y, Dulor JP. Differentiation of rabbit adipocyte precursors in primary culture. Int J Obes 1988;12:321‐333.
    1. Blum KS, Karaman S, Proulx ST, et al. Chronic high‐fat diet impairs collecting lymphatic vessel function in mice. PLoS One 2014;9:e94713. doi:10.1371/journal.pone.0094713
    1. Silha JV, Krsek M, Sucharda P, Murphy LJ. Angiogenic factors are elevated in overweight and obese individuals. Int J Obes (Lond) 2005;29:1308‐1314.
    1. Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF‐C transgenic mice. Science 1997;276:1423‐1425.
    1. Halberg N, Khan T, Trujillo ME, et al. Hypoxia‐inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 2009;29:4467‐4483.
    1. Priglinger E, Wurzer C, Steffenhagen C, et al. The adipose tissue‐derived stromal vascular fraction cells from lipedema patients: are they different? Cytotherapy 2017;19:849‐860.
    1. Li H, Zimmerlin L, Marra KG, Donnenberg VS, Donnenberg AD, Rubin JP. Adipogenic potential of adipose stem cell subpopulations. Plast Reconstr Surg 2011;128:663‐672.
    1. Hu L, Yang G, Hagg D, et al. IGF1 promotes adipogenesis by a lineage bias of endogenous adipose stem/progenitor cells. Stem Cells 2015;33:2483‐2495.
    1. Isakson P, Hammarstedt A, Gustafson B, Smith U. Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor‐alpha, and inflammation. Diabetes 2009;58:1550‐1557.
    1. Corvera S, Gealekman O. Adipose tissue angiogenesis: impact on obesity and type‐2 diabetes. Biochim Biophys Acta 2014;1842:463‐472.
    1. Cao Y. Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity. Cell Metab 2013;18:478‐489.
    1. Rapprich S, Dingler A, Podda M. Liposuction is an effective treatment for lipedema‐results of a study with 25 patients. J Dtsch Dermatol Ges 2011;9:33‐40.
    1. Shin BW, Sim YJ, Jeong HJ, Kim GC. Lipedema, a rare disease. Ann Rehabil Med 2011;35:922‐927.
    1. Cucchi F, Rossmeislova L, Simonsen L, Jensen MR, Bulow J. A vicious circle in chronic lymphoedema pathophysiology? An adipocentric view. Obes Rev 2017;18:1159‐1269.
    1. Stutz J. Liposuction in lipedema to prevent later joint complications. Vasomed 2011;23.
    1. Beltran K, Herbst KL. Differentiating lipedema and Dercum's disease. Int J Obes (Lond) 2017;41:240‐245.
    1. Reich‐Schupke S, Schmeller W, Brauer WJ, et al. S1 guidelines: lipedema. J Dtsch Dermatol Ges 2017;15:758‐767.
    1. Pinnick KE, Nicholson G, Manolopoulos KN, et al. Distinct developmental profile of lower‐body adipose tissue defines resistance against obesity‐associated metabolic complications. Diabetes 2014;63:3785‐3797.
    1. Mekki N, Christofilis MA, Charbonnier M, et al. Influence of obesity and body fat distribution on postprandial lipemia and triglyceride‐rich lipoproteins in adult women. J Clin Endocrinol Metab 1999;84:184‐191.
    1. Halk AB, Damstra RJ. First Dutch guidelines on lipedema using the international classification of functioning, disability and health. Phlebology 2017;32:152‐159.
    1. Dietzel R, Reisshauer A, Jahr S, Calafiore D, Armbrecht G. Body composition in lipoedema of the legs using dual‐energy X‐ray absorptiometry: a case‐control study. Br J Dermatol 2015;173:594‐596.
    1. Ibarra M, Eekema A, Ussery C, Neuhardt D, Garby K, Herbst KL. Subcutaneous adipose tissue therapy reduces fat by dual X‐ray absorptiometry scan and improves tissue structure by ultrasound in women with lipoedema and Dercum disease. Clin Obes 2018;8:398‐406.
    1. Harwood CA, Bull RH, Evans J, Mortimer PS. Lymphatic and venous function in lipoedema. Br J Dermatol 1996;134:1‐6.
    1. Boursier V, Pecking A, Vignes S. Comparative analysis of lymphoscintigraphy between lipedema and lower limb lymphedema [in French]. J Mal Vasc 2004;29:257‐261.
    1. Naouri M, Samimi M, Atlan M, et al. High‐resolution cutaneous ultrasonography to differentiate lipoedema from lymphoedema. Br J Dermatol 2010;163:296‐301.
    1. Iker E, Mayfield CK, Gould DJ, Patel KM. Characterizing lower extremity lymphedema and lipedema with cutaneous ultrasonography and an objective computer‐assisted measurement of dermal echogenicity [published online January 7, 2019]. Lymphat Res Biol. doi:10.1089/lrb.2017.0090
    1. Bast JH, Ahmed L, Engdahl R. Lipedema in patients after bariatric surgery. Surg Obes Relat Dis 2016;12:1131‐1132.
    1. Brodovsky S, Westreich M, Leibowitz A, Schwartz Y. Adiposis dolorosa (Dercum's disease): 10‐year follow‐up. Ann Plast Surg 1994;33:664‐668.
    1. Warren Peled A, Kappos EA. Lipedema: diagnostic and management challenges. Int J Womens Health 2016;8:389‐395.
    1. Goodliffe JM, Ormerod JO, Beale A, Ramcharitar S. An under‐diagnosed cause of leg swelling. BMJ Case Rep 2013;2013. doi:10.1136/bcr-2013-009538
    1. Fetzer A, Wise C. Living with lipoedema: reviewing different self‐management techniques. Br J Community Nurs 2015;20 (suppl 10):S14‐S19.
    1. Dudek JE, Bialaszek W, Ostaszewski P. Quality of life in women with lipoedema: a contextual behavioral approach. Qual Life Res 2016;25:401‐408.
    1. Larsen TM, Dalskov SM, van Baak M, et al. Diets with high or low protein content and glycemic index for weight‐loss maintenance. N Engl J Med 2010;363:2102‐2113.
    1. Ebbeling CB, Swain JF, Feldman HA, et al. Effects of dietary composition on energy expenditure during weight‐loss maintenance. JAMA 2012;307:2627‐2634.
    1. Faerber G. Der übergewichtige Patient mit CVI oder Lymphö‐dem. Risikofaktor oder Ursache? Vasomed 2014;26:19.
    1. Partsch H, Flour M, Smith PC; International Compression Club. Indications for compression therapy in venous and lymphatic disease consensus based on experimental data and scientific evidence. Under the auspices of the IUP. Int Angiol 2008;27:193‐219.
    1. Szolnoky G, Borsos B, Barsony K, Balogh M, Kemeny L. Complete decongestive physiotherapy with and without pneumatic compression for treatment of lipedema: a pilot study. Lymphology 2008;41:40‐44.
    1. Shallwani SM, Hodgson P, Towers A. Comparisons between cancer‐related and noncancer‐related lymphedema: an overview of new patients referred to a specialized hospital‐based center in Canada. Lymphat Res Biol 2017;15:64‐69.
    1. Buck DW 2nd, Herbst KL. Lipedema: a relatively common disease with extremely common misconceptions. Plast Reconstr Surg Glob Open 2016;4:e1043. doi:10.1097/GOX.0000000000001043
    1. Warren AG, Janz BA, Borud LJ, Slavin SA. Evaluation and management of the fat leg syndrome. Plast Reconstr Surg 2007;119:9e‐15e.
    1. Stutz JJ, Krahl D. Water jet‐assisted liposuction for patients with lipoedema: histologic and immunohistologic analysis of the aspirates of 30 lipoedema patients. Aesthetic Plast Surg 2009;33:153‐162.
    1. Stiefelhagen P. No lymphedema, no obesity. How can lipedema be treated? [in German]. MMW Fortschr Med 2001;143:15.
    1. Wollina U, Heinig B. Treatment of lipedema by low‐volume micro‐cannular liposuction in tumescent anesthesia: results in 111 patients. Dermatol Ther 2019;32:e12820. doi:10.1111/dth.12820
    1. Baumgartner A, Hueppe M, Schmeller W. Long‐term benefit of liposuction in patients with lipoedema: a follow‐up study after an average of 4 and 8 years. Br J Dermatol 2016;174:1061‐1067.
    1. Peled AW, Slavin SA, Brorson H. Long‐term outcome after surgical treatment of lipedema. Ann Plast Surg 2012;68:303‐307.
    1. Rudkin GH, Miller TA. Lipedema: a clinical entity distinct from lymphedema. Plast Reconstr Surg 1994;94:841‐847; discussion 48‐49.

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