Acta Pharmacologica Sinica (2012) 33 195-172 (© 2012 CFS and SIMM All rights reserved $671-4082/22 $3200 ‘wou nature com/ape Review Rare adipose disorders (RADs) masquerading as obesity Karen L HERBST Department of Medicine, University of California, San Diego and Veteran's Affairs San Diego Healthcare System, USA Rare adipose disorders (RADs) including multiple symmetric ipomatosis (MSL, ipedema and Dercum's disease (OD) may be misd- ‘agnosed as obesity. Lifestyle changes, such as reduced caloric intake and increased ptysical activly are standard care for obesity, Athough lifestyle changes and bariatric surgery work effectively fr the obesity component of RADs, these treatments do not routinely reduce the abnormal subcutaneous adipose tissue (SAT) of RADs. RAD SAT likely resuits from the growth ofa brown stem cell popula- tion with secondary lymphatic dysfunction in MSL, orby primary vascular and lymphatic dysfunction in ipedema and DD. People with ADs do not lose SAT trom caloric limitation and increased energy expenditure alone. In order to improve recognition of RADS apart from obesty the diagnostic crteria, histology and pathophysiology of RADS are presented and contrasted to familial partial ipodystro- pies, acquired partial ipodystrophies and obesity with which they may be confused. Treatment recommendations focus on evidence- ‘based data and include lymphatic decongestive therapy, medications and supplements thet 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 forthe abnormal SAT component of RADS. Effective dietary and exercise regimens are needed in RAD populations to improve quality of ife and construct advanced treatment regimens for future generations Keywords: adiposis doloresa; Dercum's dieease tia ipodystrophy; lymph; lymphatics 1ema; multiple symmetric lpomatosis; familial mutipleipomatosi; familial par ‘ota Pharmacologica Sinica (2012) 33: 185-172; dol: 10.1038/aps 2011 153 Introduction Lifestyle-induced obesity in chikdron and adults has reached ‘epidemic proportions worldwide. In the United States (US), a third of adults aged 20 years and over are overweight, third are obese, ancl over five percent are extremely obese" The National Health and Nutrition Examination Survey and, Pediatric Nutrition Surveillance System reported a tripling, of the prevalence of obesity among, US school-age children and adolescents over the past three decades). Numerous published studies validate the weight loss efficacy of lifestyle changes that include decreased amounts and types of food, and improved exercise regimens, Medications used for the treatment of obesity are severoly limited", Bariatric surgery thas beon exceptional in its ability to induce weight loss and. resolve the co-morbidities of obesity, though complications rates can be high", many people are sil cbose by body mass index (BMD after Roux-en-Y gastric bypass (RYGB)", and, woight regain ovcurs”", This review aims to demonstrate lymphatic dysfunction asa component of rare adipose disorders (RADS) that increases the “Ta whom correspondance shouldbe adresses Email keen herbst@va gov Received 2011.08-31 Accepted 2014-042 ‘amount and alters the location of subcutaneous adipose tissue (GAT) while rosisting fat loss ater lifestyle changes of bariatric surgery. Lipodystrophies aro also discussed as they may be confused with rare adipose disorders (RADS). Non-lifestyle causes of obesity Lipodystrophies Lipodystrophies or fat redistribution syndromes involve a primary lack of loss of SAT; however, increased SAT in other ‘areas can be confused with lifestyle-induced obesity. Human immunodeficiency virus (HIV)-associated lipodystrophy, is well-known, but familial partial lipodystrophies are rare and therefore loss well known, and can go undiagnosed for years cr are never recognized. Acquired partial lipodystrophy, also rare, with a progressive and symmetrical lipoatrophy of SAT starting from the face and spreading, to the upper part of the body, sparing the legs, can be confused with the RAD, lipe- cdema, due toa disproportion between upper and lower body SAT (seo below. Acquired lipodystrophies ‘Human immunodeficiency virus (HIVj-sssociated lipodystrophy HIV-and highly active antiretroviral treatment (HAART)- associated lipodystrophy includes loss of SAT from the face,wv. nature com/aps Hert kL 156 buttocks, arms, and legs. In men with lipodysteophy, SAT can be increased on the abdomen and chest (gynecomastia), and a dorsocervical fat pad or “buffalo hump” is common” The SAT in the dorsocervical fat pad is thought to be ident cal to the SAT in multiple symmetric lipomatosis (MSL), one of the RADs (see below). Upper body fat, including, parotid hypertrophy, circumferential enlargement of the neck and a dorsocervical fat pad are associated with insulin resistance in HIV+ men!" as is intermuscular fat and SAT on the legs in HIV+ women!" Large breasts are part of HIV lipodystro- phy in Black women and other non-Caucasian ethnicities”. Women with HIV may also develop increased SAT on the "upper pat of the arm out of context with the usual lipoatro- phy in this area in HIV men suggesting an estrogen and/or [progesterone component to location of the SAT. This upper arm SAT looks visually similar to the SAT in women with the RAD, MSL (soe below and Figure 1), In addition to excision of excoss SAT as treatment for lipodystrophy!, tesamorelin, a synthetic analogue of human geowth hormone-releasing, hormone, is FDA-approved forthe reduction of excess visceral adipose tissue in HIV-infected patients with lipodystrophy. Visceral adipose tissue was reduced up to 18% during active use of tesamorolin! The glucagon-like poptide-1 agonist, exenetide, also improved the HIV- and treatment-induced, obesity through weight less ina single case”. ‘Acquired partial lipodystrophy (APL: BARRAQUER-SIMONS syndrome) ‘Acquired partial lipodystrophy is characterized by a regional loss of SAT primarily in children and adolescents starting at the face and extending to the waist, sparing the legs; in fact SAT may be increased on the logs™! Because ofthe higher amount of SAT inthe legs compared to the upper body, APL ‘eta Pharmacologica Sinica could be confused with the RAD, lipedema (Figute 2). In lipe- clema, thete is increased fat on the legs but the fat of the upper body is normal or increased (See below). APL is thought to be autoimmune occurring after a febrile (viral) illness!” with Figure 2. Aoquied partial ipodyatophy and Iipedeme. A 9 27 year old ‘women wih sequited partial ipodyatophy. C3 leveic16 4 mg/dl (normal ‘ange: 90-280) and Clavel 2321 mg/l nocmal range: 10-40} Note the Joos of SAT from the uppar Sody to tha wast but obeBty of the hip and legs (photo by Dr Alper GURLEK|. 6, 2 woman with ipedera stage Il and 4 previous history of obesity wh 8 400 ke weight los: note redundant skin on arms and abdomen from weightloss of non-RAD fat note also pacers in legs Figure 1. Multiple eymmatic lipamatosis With oF without HIV infection. A ang 2. nan Hiveloted MSL Type nate increased upper farm size and increased fat on back. Not shown is ioreaeed fat in the labia majora (Cand D. increased arm and back fat respestvely in HiVand HAARTinduced MSL Type I tons point to end of MSL ft onthe Upper arm, Nermat abla majera not shown)low levels of complement factor 3 (C3) and the presence of a circulating autoantibody called complement 3-nephritic factor. ‘Treatment with the thiazolidinedione, rosiglitazone, improved levels of C3 and increased SAT in a participant with APL"! Familia partial ipodystrophies (FPLD) FPLD Type 1: FPLDI, also known as Kobberling lipodystro- phy, is a lesser known partial lipodystrophy primarily found, in women causing a lipodystrophy of the arms, legs, and. sometimes breasts, with an increase in fat on the abdomen and remainder of the trunk. The prevalence of FPLDI and any. genetic mutation remains unknown. There are no blood or urine biomarkers for FPLDI. FPLDI may go unrecognized if the practitioner does not recognize the lipodystrophy; finding, a ledge where SAT ends on the buttocks can help in the diag nosis, Diabetes and hypertrighyceridemia are highly prevalent in FPLD1 while acanthosis nigricans is minimal, ‘Treatment is, restricted to usual care of obesity-associated co-morbiditie,, although, RYGBP should be considered as it improved weight, and co-morbidities in acase of FPLDI™ FPLD Type 2 The best studied FPLD is Type 2 (FPLD2), also known as Dunnigan lipodystrophy. In FPLD2, SAT is, Jost around! the time of puberty from the logs, arms, buttocks, abdomen and chest; areas of remaining SAT deposits are on. the back, face and chin, giving a Cushingoid appearance; fat {is increased in the labia majora in women’ this finding also jccurs in women with MSL (Figuee 1). Mutations in the lamin. ‘Aand C gone, LMNA, cause FPLD2°°, Poople with FPLD2 have all the co-morbidites associated with obesity. Leptin levels can be very low in lipodystrophies and leptin treatment has shown benefit but remains investigational”, RYGB has also shown benefit in reducing the co-morbidities associated with FPLD2”. FPLD Type 3: Mutations in the peroxisome proliferator- activated receptor gamma (PPARG) gene can cause partial lipodystrophy with abdominal obesity! known as EPLD3™ people with FPLD3 may look very similar to FPLD2. Treat ‘ment with thiazolicinediones may be useful in people with, PPARG gene mutations” and other cases of FPLD without identified gene mutations" ‘Additional lipodystrophies and single cases of adlitional \ypes of FPLD have been well reviewed, ADs ‘Muttiple Symmetric Lipomatosis (Madelung disease/syndrome; Launois Bensaude syndrome) ‘Multiple symmetric lipomatosis (MSL) is a rare synclrome (Table 1) originally described in 1846, characterized by the painless, symmetrical accumulation of abnormal tumor-lke SAT. The first systematic treatise was by the German surgeon Dr Otto Madelung who collected 30 cases and reported an additional 3 cases in 1888 under the name “Fetthals” or fat neck but the French Physicians Drs Piorro-Emuile LAUNOIS, and Raoul BENSAUDE gave pro ‘pion of MSL by publishing a detailed account of 65 cases in 1898", There are many synonyms for MSL inclacling, nence to and caused ‘ww ohinaphar com Herbst KL 157 Table 1. Identtving codes or numbars for Sa Oiorders ode or number ‘SAT disorder st 0D LUpedeme onan asigoo 303200 «14103, LUstedbyNloRD Yes Yes No NLM MESH ID 008069 DaD02T4 NAY 09/10 2128/6888 NAVESB2 NA ‘Mternatwe CD-9/10 NA 338.4/o0.4 4573/1800 Chronic gain Lymphedema, not syndrome elsewhere classined Orphenetnumber 2388 363077243 IcO-International Clagefication of Diseases, MESH=mecica subject heedings; NLM=national Library of Medicine, NORD=Nationsl Organization of Rare Disease: OMIM=Online Mendelian Inhertance in *Applzation for @ MESH code submited benign symmetric lipomatosis but this disorder is anything, but benign, arguing against its use, Over 300 adult cases are roported in the literature with an age range of 20-71 years. ‘The early literature on MSL was dominated by research on alcoholic men with a reported incidence of 1/2500) in the Italian population, Non-alcoholics and women are also affected *) two cases have been reported in children!) Diagnosis [dentiticaion of MSL is by history and clinical exam. There are no blood or urine biomarkers for MSL andl the gene(s) remains unknown in a majority of eases. Individwals with [MSL have increased SAT, either as diserote non encapsiated lipomas or asa confluent increase in SAT in a symmetrical dis teibution on the neck, the back, the chest, the i conte thighs; MSL usually spares the distal limbs) but notin many women with MSL whore the altro fat may bo glebal!®) (Figure 3), Bocauso the appearance anc! location of SAT in [MSL can vary, MSL has been divided into thee types: tnical types of MSL"! Type I, head and/or neck with extension down the back, co only on the back: In rare cases, MSL SAT can invade the lingual muscles of the tongue) or the vocal cords and compress the recurrent laryngeal nerve causing hoarseness!) or increase periorbital fat Tracheal or esophageal compres sion and the superior vena cava syndrome can be found in 15%-20% of patients!) The presence of a dorsocervical fat ‘pod (buifalo hump) can be found both in MSL!"* and HIV- associated lipodystrophy®! 2"; it has been proposed that {the fat in these two disorders arises from brown adipose tissue Jocated in that area. Type I body: Includes the shoulder girdle, the upper arms, the thorax, the back, the abdomen andl upper buttocks, In one case, fat grew around the testicles in the serotum and was con- tiguous with MSL tissue in the perineum and the root of the penis!) Also rare is growth of the MSL fat on the hands! “Acta Pharmacologica Sinicawv. nature com/aps Hert kL 358 Figure 3. Wrole body MSL and MSLsesceatedlipodytrophy While MSL. |g noted te spare the forearms (s0e tax) the ania body can be clearly affected. A, 60 year old woman with a history of aleahal dependence With globst MSL SAT. note prevalent SAT on the forearms (photo by Ot ‘Andy COREN). This type of MSL may be easily confused with global obesity or lipedema stage Il, 60 year old man with MSL Types | andi With associated mutele and normal fat atopy (also note the increased Deck MBL SAT, errows) this type of MSL may be confused with parti ipoaytropny ‘Many individuals have a combination of Types IU and IIL While the MSL fat grows, normal fat and muscle can undergo, ‘wasting which can be confused with a partial lipodystrophy (Figure 3) ‘Type Ill, thigh (female type): Rarest type. MSL type UL is, clinically similar to and may be instead, the RAD, lipedema {Gee below). Women tend to have Type Hand IIL MSL with widespread altered SAT!" MSL inheritance [MSL is thought to be inherited through mitochondrial muta- tions in a few familial cases including multiple deletions of mitochondrial DNA, and the myoclonus epilepsy and ragged rod fibers (MERRF) (RNA(Lys) A>G(8344) mutation” Klopstock ef al found mitochondrial mutations in only 2 of 12 patients studied", Chalk ef al found no mitochondrial pathology or mutations in four siblings with MSL with a pat tern favoring autosomal recessive. The phenotype of MSL ‘may require a combined effect of alcohol (or other insult) and currently unknown genetic mutation Histology of MSL fot Individual fat cells have been described as smaller than normal" or normal sized"! MSL SAT is thought to be dlerived from brown adipose tissue (BAT) or as white adi- pose tissue (WAT) that transdifferentates into BAT! Ulteastructurally, brown adipocytes have numerous large mitochondria packed with cristae. Under light microscopy, brown adipocytes have cytoplasmic lipids arranged as numer” ‘eta Pharmacologica Sinica ‘ous small droplets (mutileculaity), while white adipocytes have cytoplasmic lipids arranged in a unique vacuole (unt locularty). In BAT, the metabolic reactions of mitochondria are uncoupled from ATP synthesis by uncoupling protein (UCP)-1 so that energy produced is released as heat"! Infants and even adolescents have a substantial amount of BAT, espe- cially betwoen the shoulder blades. BAT persists theowghout adulthood in the peritenal, omental, mesenteric, pericardial, intercostal axillary, cervical, and interscapular fat, embeddext within WATS! with an approximated ratio of 1 brown adi- pocyte for every 200 white adipocytes! By light microscopy, adipocytes in MSL SAT are monovacs- olor or multivacuolae” By electron microscopy of long: term primary cultures from the stromal vascular fraction {GVP), containing stem andl immune cell, cells were polymor- ‘phic with thin microfilaments suggestive of elevated metabolic activity!, were multivacuolar, and had large mitochondria packed with cristae suggesting a more BAT phenotype in NL Physiology of MSL SAT MSL SAT may arise from a stem coll population either dos- tinod to form BAT, or WAT that transdifferentiates to BAT; in either case, UCP-1 levels help track BAT features, SAT calls from subjects with MSL express UCP-1 suggesting its origin as BAT, but this is not substantiated in al cases!” Adconorgic receptors (AR) that respond to sympathetic input, such as the three subtypes of f-AR, Pf anal B-, promote lipolysis and energy expenditure. Colls isolated from the [MSL SVF dic not inerease UCP-1 in response to noradrena- line even though MSL cells expross all throe (AR, Resting tenergy expenditure (REE) may be expected to be higher in [MSL with BAT; indeed REE when normalized to fat free mass ‘was mikilly higher in MSL subjects than normal, suggestive of energy uncoupling and heat generation, however, REE in other subjects with MSL was within normal limits! In [MBL coll culture, catecholamines did not increase lipolysis, expression of inducible nitric oxide synthase (iNOS) o PPARY, coactivator-la (PGC-1a), a coregulator of nuclear receptors, that control metabolic pathways in BAT. Two other {groups found a normally reactive adenylate cyclase system and a normal number of a- and Pradrenergic receptors i MSL SAT" Cytokine and axlipokine levels in MSL are also mixed", While the multilocularity of MSL SAT is sugges- tive of BAT, more dala in a larger number of subjects of well characterized participants are needed to substantiate the col, {ype of origin and functionality of pathways. The increase in MSL fat is extensive and deforming, com- pressing tissue structures and vessels, Early, MSL SAT is, ‘watery but later becomes fibrotic and sears easily, Similarly in obesity, excess fat physically impedes lymph collection and flow, protein-rich lymphatic fluid collects in SAT, result- ing in lymphedema and tissue hypoxia™, SAT also grows in the presence of lymphedema! Further accumulation of fluid in the soting of decreased oxy gen tension leads to fibro sis! Interestingly, ischemia activates the growth of adiposederived progenitor cells!!. Congestion of lymph nodes by other means, such as lymphoma in the neck, induces fat growth similar to MSL", Increased volumes of SAT in MSL, like obesity, may therefore be sufficient to externally compress vasculature ancl lymphatics inducing further growth of SAT a8 seen in other localized fat collections! Impedance of lymph flow into lymph collectors isa local effect and docs not affect flowin larger Iymph trunks, therefore the role of Iymphoscin- tigraphy in MSL is questionable! Conditions associated with MSL Aleohol-induced liver disease is common in MSL. Hyper- lipidemia, hyperuricemia, hypothyroidism, and diabetes mellitus have been reported but are not consistent amongst those affected *!. People with MSL I or II should be tested for sleep apnea! Cancerous transformation of the SAT is uncommon; development of myxoid lipesarcoma was reported in one case!" Slowly progressive axonal sensory and autonomic peripheral neuropathies have been reported to occus after the development of MSL fat and impairment of autonomic function has been suggested asa cause of sudden, dleath?*"! ‘The neuropathology isa distal axonal demyelina- tion diferent from that associated with alcohol intake! *%% this impairment scoms to be provalently parasympathotic* Ina ten year follow-up, ~10% of 31 patients died rom sudden death duc to autonomic neuropathy”, Surgical placement of cardiac pacemaker may be nec. IMSL treatment recommendations Primary cocommendations 1) Alcohol abstinence: Abstinence from alcohol may aerest further progression ofthe MSL SAT but dees nat cause ogres- sion of the SAT doformatios!™ 2) Lymphatic decongestive therapy (LDT): Includes manual lymphatic drainage (MLD), wrapping of the limbs, compros- sion garments, exercise such as pool therapy and other non- impact exercise (s0 as to avoid lactic acid accumulation in tis sue due to poor lymph flow), dietary recommendations, and skin care, Manual lymphatic drainage works well to reduce [MSL SAT before fibrosis! 3) Surgery: Surgical resection and liposuction provide the conly means of dramatically decreasing the MSLSAT®!". In a majority of cases of MSL Type Il and Il, resection oF liposuc= tion of the lspomatosis 4s considered cosmetic and insurance companies are reluctant to cover this procedare™. Unfor- tunately, the fat usually penetrates and surrounds deeper steuctares such as muscle and bone, making total excision of the abnormal tissue difficult the lipomatosis can, therefore, ocur after liposuction or excision!® "in three of eleven patients in one series". Adaltional consilerations for MSL trea 4) Pr-Adrenergic Agonist: After demonstrating an intact lipolytic response of the MSL fat to catecholamines, an oral B= AR specific drug, salbutamol, 15 mg por day in divided doses, roversed the rapid accumulation of the MSL fat and increased ‘ww ohinaphar com Herbst KL 180 [REE in a man with MSL, but was effective only during active el 5) Fibric acid: A man with MSL Type IL with a past history of hypertriglyceridemvia was treated with fenofibrate 200mg, daily. The circumference of his abdomen decreased 119 em (46.9 in) to 108 cm (42.7 in) within a year. Fibric acids are PPAR agonists, Activation of the PPARa receptor may sup: [press expression of proteins involved in the architecture of BAT, thereby maintaining BAT in a quiescent state!” 6) Growth hormone: Growth hormone (GH) treatment has been suggested in the community of individuals with MSL as 2 treatment option (personal communication) but GH levels ‘were normal in one subject with MSL during, a glucose toler ance test! and in three other subjects!™! suggesting a normal GH axis, Testing for GH deficiency should be undertaken and replacement considered only for those deficient in this hor- 7) Lifestyle: Lifestyle improvements provide no resolution ofthe MSL SAT". 8) Local SAT injections: Corticosteroid injections have been suggested as treatment for lipomatosis such as MSL SAT! bt there are @ number of cases demonstrating the develop- ‘ment of lipomatosis after steroid use!" Local injection with thyroxine! enoxaparia!™", dooxycholate™, and phosphatidylcholine™ have also boen proposed for treatment of kpomas but the latter roguiee multiple injections and use of thyroxine injections in the presence of autonomic dystunc- tion would be dangerous. In addition, the extent of the SAT {in MSL doos not allow for single site jection, limiting these teoatments to lipomas Lipedema (ipoedeme:lipalgi: adiposis doleresa; lpomatosis dbolorosa ofthe legs: lioohypertrophy dolorsa: painful column (ea) Lipedema is generally unknown to medical providers, is eas- ‘ly confused as obesity, does not have a MESH term in the [National Library of Medicine, and does not have an Intern tional Classification of Diseases (ICD) code; it does have an Online Mendelian Inheritance in Man code, and is recognized bby Orphanet (a European website providing information about orphan drugs and rare diseases (Table 1). Des. Allen and Hines Jt from the Mayo clini labeled this condition as lipedema in 1940", Outside the US, lipedema is known as “Tipoedema”, meaning edema ofthe fat, Ths disorder is likely very common but underdiagnosed Diagnosis ‘The diagnosis of lipedema is mace clinically by history, visual inspection and physical exam as extensive deposition of SAT between the iliac crest and the malleok and approximately 30% of the time, on the arm!" When the fat is palpated, it will be tenclor and foel like round peas in a plastic bag or a “beanie baby” Larger nodules, lumps, ipomes oF angiokipomas may also be found in the SAT. ‘There are no blood or urine biomarkers for lipedema and the gene(s) is ‘unknown, The skin and SAT i thicker in lipedema compared “Acta Pharmacologica Sinicaww. nature com/aps Heroet KL 160 to healthy controls and muscle mass is not exlematous as it is in lymphedema! The skin is also less clastic and striae are ‘common in lipedeme, In 1951, Wold, Hines and Allen analyzed 119 cases and pro- viel the diagnostic criteria for lipedemal™: 1) Almost exclusive occurrence in women developing by the third decade of life. Prevalence within the population remains grossly under diagnosed". According, to an epide- miologic study by Foldi E and Foldi M°") lipedema affects 111% ofthe female population, At least seven cases have been reported in men with testosterone or GH deficiency, oF liver Gieotnst 2) Bilateral and symmetrical nature with minimal involve- ‘ment of the feet, resulting, in an “inverse shouldering’” oF “pracelet” effect atthe ankle 3) Minimal pitting edema (non-pitting edema is present) 4) Pain, tenderness, and easy bruising, 5) Persistent enlargement despite elevation of the extremi- ties oF weight loss 6) Increased vascular fragility; easy bruising ‘Often women note that the lipedema appears oF is exacer- bated at the time of puberty, pregnancy or menopause sug gesting an estrogen component; that few men have this condi tion except those with hypogonadism or hyporestrogenemia supports this hypothesis, There are five types of lipedema!™”" ‘Type I: Pelvis, buttocks and hips (saddle bag phenomenon) Type I: Buttocks to knees, with formation of folds of fat around the inner side ofthe knee “Type Il: Butocks to ankles Type lV: Arms Type Vi Lower leg “There may be a mixture of lipedema types in one person, for example Type land IV. Only the arms may be affected in 3% of lipedeme cases (Type IV)". The importance of knowing, the different lipedema types is to improve recognition, and ‘dontification of differences, all people with lipeema do not ‘eta Pharmacologica Sinica Took alike; teoatment is similar amongst the types. In addition to types of lipedema, the lipedema progresses through stages; the progression varies greatly amongst those affected and there is no data suggesting everyone need progress through all stages, ‘There are three stages of linedema (Figure 4"! Stage 1: Normal skin surface with enlarged hypodermis, Stage 2 Uneven skin with indentations in the fat"; larger mounds of tissue grow as unencapsulated masses, lipomas and angiolipomas Stage 3 Large extrusions of tissue causing, deformations especially on the thighs and around the knees Stage 4: Lipeciema with lymphedema (ipolymphedema) Progression to lipolymphedema can develop during stage ILIIL, The description and representative pictures of Type LiL (MSL! are that of lipedoma stage II" no study has formerly differentiated those two SAT disorders. Synonyms for lipe- «loma also include adiposis dolorosa, which is another name {or the RAD, Dercum’s disease (see below). However, accord- ing, to Cornely, the trunk, hands and feet are not involved in lipedloma “Thus, lipedema differs clearly from Dercum's, disease” As liposiema progresses to lipolymphedema, the hands, feet, trunk and head develop excess SAT making this statement incorrect. Because lymphatic dysfunction is a part ‘of Dorcum’s disease and many early cases of Dercum’s disease are visually and descriptively lipedema (see below), the two SAT disorders are at a minimum, in the same spectrum. Lipe- «loma may also be confused with APL, however, in APL there isalack of SAT on the face and upper body while in lipedema, SAT is normal or increased in these arvas (Figure 1). Inheritance ofipedema Inheritance has been noted up to 60% of people with lipedoma!”*""" but is likely higher due to under diagno sis, In six families over three generations with lipedema, the inheritance pattern was autosomal dominant with incomplete Figure 4, The thiee steges of lipecema 1 Stage | with lita alteration ofthe skin surface. 8 n stage the surface ofthe skin takes on the appearance of » mattess with lipomas in the fet. 6, In tage I ipedema, ‘here are much arger fat exrusions,penetrance, Histology of ipedema SAT The gross description ofthe fat in Kipecemais simi to that of [MSL with “fre fluid fat” in biopsy specimens. Histologi cal exam is not walike that found for cellulite with dilation of subermal blood capillaries, perivascular cells, fibrosis oF arterioles, fibrosis and dilation of venules, and hypeetrophy and hyperplasia of adipocytes!™* "7, Histochemical studies show adipocytes death and stem cell regeneration'™, There are also increased numbers of blood vessels especially capllar- fos and prominent venules? Large clusters of macrophages are found around multiple fat cells (not isolated crowslike steuctures*), surrounding blood vessels and forming cil cysts in lipedema SAT" macrophages may also he a prominent component of cellulite!" The histology of lipedema SAT can also appear as normal! Physiology of lipedema SAT ‘Tho elasticity of the skin and fascia is decreased in lipedema!™ which in Stage Ill may progress to abnormelly clumped elas- Uic fibers oF pseudoxanthomal™. The skin loses its role as {an abutment for the skeletal muscle venous pump and the increased compliance of the SAT results in an increase in capillary compliance", The permeable capillaries release jexcoss protein-rich fluid into the interstitium along with, blood! "4", The veno-arteriolar rolex in lipedema is also absent so that under orthostatic conditions (standing), there is limited vasoconstriction and inereased net filtration driving, edema! Early on, lymphatic transport increases to accom modate the increased fluid flux from the capillaries!" During this time, visualization of lymphatic vessels on a gross level by Iymphoscintigraphy is normal!" As lipodema progresses, microaneurysms appear in the lymphatics in the skin" which eventually leak" It is during this time that hypertrophy and hyperplasia of fat cols accelerates! further altering the microlymphatic architecture and increas- ing venous congestion, The resultant edema increases hy deo- slatie pressure in the tissue and pain™ ‘As an example of what happens in SAT when Iymph leaks, mutation of prospero homeoboxprotein 1, encoxled by the PROXI gene, causes leakage from lymphatics and resultant cbesity in heterozygote mice". Lymph place on adipocytes in culture also induces robust growth; in essence, “lymph makes you fat"? Although PROX1 mutations are not known tobe associated with lipedema, itis clear that ft grows {in response to lymph? Eventually, the microlymphatics may. become obliterated in lpecomat™Teading to backflow and an overall dynamic insufficiency of the lymphatic system", The increased tissue pressure and lymphatic vessel leakage lead, to the development of lipolymphedemal™""), While lym- pphedema does not usually develop with cellulite in women, the pathophysiology of cellulite development is similar to that in lipedema, and LDT (see treatments below) improves the cosmetic appearance of cellulite”, Lipedloma may there {ore be an extreme form of cellulite. ‘ww ohinaphar com Herbst KL a6 Conditions associated with ipedema ‘Depression and anwioty are very common in people with kipe- cioma for many reasons inclacling the lengthy time to diagno- sis, repeated counseling on diet and exercise by the healtheare community when neither is particularly effective and because ofthe massive and sometimes rapid boxy metamorphosis over a lifetime. In one clinic, women with lipedema weee found to be more depressed than patients with poralysis!™. Painful SAT isa chronic problem in lipedema!" "The excess tis: sue fluid weakens neasby steuctuees leading to the develop: ‘ment of joint pains; with progression of lipedema, arthritis dlevelops, Capillary fragility, occhymosis, hematomas and, ‘venous varicosities are common! The KaposiStemmer sign {is nogative in lipedema (the skin cannot be pinched as a fold by the fingers) until the development of lipolymphedema, Idiopathic edema (IE) is similar to lipedema by description and has been identified in women with kipedemal™®". Other changes in skin include dryness, fangal infections, cellulitis, and slow wound healing. Free fatty acids may be different in bth blood and the lipedoma SA" Lipedema treatments recommendations Primary recommendations 1} Lymphatic Decongestive therapy (LDT) is the standard of care for lipedema. Includes manual lymphatic drainage (MLD), wrapping of the limbs, compression garments, move ‘ment therapy, dietary recommendations, and skin care. LDT has been shown to improve skin elasticity, estore the veno~ arteriolar reflex, increase pre-lymph drainage and lymph transport in lymphatic vessels!" and reduce capillary fragility in lipedemal"™ Intermittent pneumatic compres- sion may not improve limb size over MLD alone!" but may be effective alone when MLD is not available™!, Compres- sion is most effective when tissue edema is present as in its absence, it as little effect", That compression was effective in lipedema was noted by Hines in a woman with lipedema ‘whose fat and edema wore absent uncler the arca covered by hor “high-toppeel shoes" 2) Exercise: Aqua lymphatic therapy (pool hydrotherapy) significantly reduces limb volume in lymphedema". In adidi- tion to improving strength and bone mineral density, whole body vibration (WBY) improves peripheral circulation! and inereases lymph flow, raising the threshold level for ecioma formation inthe legs"! During WBV, the user simply stands (or stretches/ exercises) on a platform for 1013 min _making thisa very accessible exercise modality 3) Pain Control: Must be individually optimized; liposuction improves pain (see below) 4) Psychological support: Many women with lipedema are left on their own to find their diagnosis, convince their healthcare providers about lipedema and then seck treatment, all complicated by depression, anxiety and eating disorders; counseling and support during treatment are necessary when any of these are present", Counseling reduces anxiety by 50% in people with secondary lymphedema" 5) Surgery: Liposuction works effectively for lipedema to “Acta Pharmacologica Sinicaww. nature com/aps Heroet KL 162 reduce SAT and pain!” In patients who have lipolym- pphedema, it may be prudent to undergo Iymphoscintigea- pphy to confirm the absence of large Iymph vessel damage before pursuing liposuction", Bariatric surgery is ineffec- tive in uncomplicated lipedema (without obesity oF lym- phedema)!" "but effective in lipedema and lymphedema associated with obesity as long, as LDT is performed before and after bariatric surgery", 6) Beta-adenergic agonists Modeling, treatment after capil lary leak syndrome, terbutaline sulfate, 5 mg five times daily, and theophyline, 200 mg, twice daily, were given toa woman ‘with lpecema (called lymphedema in the paper) and after 10 ‘months a weight loss of 20 kg was noted. Cessation o lower. {ng the meclcation allowed weight regain 7) Corticosteroids: Corticosteroids produce a fast eduction {n swelling and pain but increase the risk of infection, capil- lary fragihly and SAT growth, A series of corticosteroid joint injections is usually well-tolerated without exacerbation of lipedema '8) Diurotics: Diurotics can quickly deplete lymphedema ‘uid but concentrate protein in edematous tissue promoting fibrosclerosis™™. Uso of diuretics in lipedema before lym- pphedioma may result ia the development of pseudo Baretr's synclromw characterized by hypokalemic-hypochloromic alka- losis, hyperactivity of the renin-angiotensin aldosterone sys- tom and elevation of arial natiurotic peptide!" 9) Flavonoids: Daflon isa flavonoid that has boon used to troat lymphedema!” it may be expensive anc! is unlikely available by prescription. Other flavonoids such as thoso for ‘venous disease!™! have not beon formly tested in lipedema participants. The International Society of Lymphology does ‘not endorse the use of flavonoids as a substitite for LDT. 10) Lifestyle: Obesity can occur along with lipecoma espe- cially in Stage Il when the lipedema linits movement, but can also occur when movement is limited by pain in earkir stages; lifestyle improvements should always be considered but are rot the cause of lipedema!™. Lipedoma SAT is unaffected by caloric restriction alone. 11) Seleniam: Sodium selenite selenium) has proven effec: tive for reduction of secondary Iymphedem!”™"") The US [National Research Council has defined the individual maxi :mum safe dietary intake for selenium as 600 jg daily and the noadverse effect level as 800 pg daily 12) Shock wave therapy: One report suggests that shock ‘wave therapy Functions similarly to LDT in ruc oxidative stress of the tissues and in smoothing the dermis and hypo- lormis™! which may be useful as part of a teatment plan and ‘when lymphatics are still functioning Dercum's disease (adiposis dolorosa; Morbus Dercums) Dercum’s disease (DD) was recognized in 1892 as a clinie cal entity called “adiposis doloresa’, meaning painful fatty, deposits, when Dr Francis X DERCUM from the University, of Pennsylvania published on three cases! This senti- ‘eta Pharmacologica Sinica rel publication was proceded by a report of a single case in 1888 and followed by the published autopsy of that case" [Numerous case studies, case series and descriptions of DD have been published with such a wide variety of locations for the fatty deposits, including misdiagnoses of cbvious cases of lipedema, familial multiple ipomatosis and MSL!" that, tunless one is an expert in SAT disorders it would be dificult to diagnose this often misunderstood syndrome. DD is cur- rently considered tobe a rare disorder (Table 1). Diagnosis Diagnosis of DD is made by history and physical exam. Der- cum’s disease occurs primarily ia women with a ratio of females to males of 5-7:1!""; the average age of develop- _ment in one series was 35 years! but it has been reported to develop in children"! and in adits up to age 80 years (One in a 1,000 are affocted in Sweden!" Many cases of peri- oF post-menopausal women with DD have been reported sug gesting a hormonal component to the development of DD". In adulition to painful SAT, there aro many othor signs and symptoms associated with DD so a lengthy review of systems {is holpial (Table 2) There are three types of DD" Type |, juxta-articular (around the joint): Painful folds oF ‘nodular fat on the inside of the knees and/or on the hips; in rare cases only evident in the upper-arm fat (similar to Type WV lipedoma). Type Il, diffuse, generalized type: Widespread pain from fatty tissue found anywhere from head to the soles ofthe feet. ‘Type Ill, noxtular type: Intense pain in and around multiple “tipomas, sometimes inthe absence of obesity. Interestingly, the painful lumps of fat first noticed around joints in DD Type 1 occur in locations of lymph nodes, for ‘example around the knee (popliteal nodes), the elbow (cubit, nodes), hips and thighs (inguinal nodes), upper arm (axillary ‘nodes) and supraclavicular. As Dr Kling reported in 112 cases of Type I DD, “Juxta-articular adiposis dolorosa is regarded as, the inital and intermediate stage of generalized adiposis dolo~ rosa, Dercum’s disease Type Lis therefore, the first stage of DD, and Type Ila stage with more wicespread dysfunction, ‘Type I DD around the knees is visually consistent with Type 1V and Type Il lipedema Stages 2-3, Type III DD is likely a variant of familial multiple lipoma tosis (FML) in which men present mainly with lipomas and/ or angiolipomas predominating on the lower and upper arms, the lower trunk and thighs andl women present with, lipomas, angiolipomas and obesity". Angiolipomas can be found! in up to 30% of poople with DD", The lipoma ‘are generally not painful in FML except if they are growing, or traumatized frequently, however, they are painful in DD Type 3. Ina DD family, family members may have lipomes without pain! Even if a person with FML has non-paintul lipomas, al some point in time a lipoma can become painful, followed by generalized pain in all lipomas. Pack and Aviel!™ described this as lipoma dolorosa, distinet from DD. It is,‘unclear why the authors make this distinction as others ascribe the same pathological process to both FML and DD Type Ill, with pain in the latter due to “local conditions" The “local congltions” may be increased tissue teasion from fluid accu: ‘mulation, In two cases of DD Type Ill, pain was relieved after local hemorrhage. The underlying pathophysiology of DD anced to be elucidated to further differentiate or group the theee types of DD. DD inheritance: Thought to be autosomal domin-ani 2" In two families, females were more affected than males suggesting a sex-specific influence on the expression of the DD phenotype!" fo 8 ! Histology of DD Some of the tnilocular adipocytes are extremely large in DD SAT compared to weight matched controls!"®". Dr Dercum and others found an infiltration of nerves (newrits)!™* 2" but this has not been substantiated. Increased connective tissue around nerves, blood vessels and as thickened septa has beon noted! #22 Porivascular cell, giant cll and grana- Jomas suggestive ofa foreign body reaction are apparent in some ae The histology of DD SAT can aio appese nor smn Physiology of DD ‘Tho physiology of DD is unknown and many etiologies have boon advanced. These include thyroid dysfunction, pitu- itary dysfunction, polyglandular disease, infection, neuritis, alcohol, trauma, a defect in the synthesis of long chain fatty acids! lower rosting energy expenditure®®, and alterod responses to norepinephrine and insulin. Ballet may have boon closest to the actual etiology when he stated that i isa “chronic intoxication of endogenous origin”®". The eviclence currently points to an underlying vascular and lymphatic «dysfunction in DD Types I/ Il similar to lipedlema (Birgher Fagher, personal communication) forthe following reasons 1) Vascular dysfunction as hematemesis= 2", opis- taxisl® 4) hemaochezial™!, heavy menses, varicose ving, and altered vasoconstrictor responses! in both lipedema and DD. Perivascular infiltration of immune cxlls have boen found in DD tissue!" suggesting damage to cr repair of blood vessels, andl brain vasculitis in DD has been, reported"! 2) LDT has been report to be beneficial in DD as in lipe- oma 3) Multiple lipomas ean develop in lipedema as in DD™ 4) Fibrosis secondary to lymphedema!" is common in lipo ddoma!™! ancl DD" 5) In the presence of lymphatic and vascular dysfunction in lipedema, the fat is paintul”™, similar to DD. '6) In the German literature, lipedema is known as adliposis| dlolorose, another name for DD", 7) Original descriptions of DD match descriptions of lipe- ddema, For example, Spiller deseribed a woman with pain- ful fal as follows: “The obesity was marked! over the thighs, calves, abdomen, nates (buttocks), and back. I was also very ‘ww ohinaphar com Herbst KL 168 _reat in the arms, less marked in the forearms, and absent in the feet and hands", Dr Collins noted that “The fatty accu- ‘mulations have not been noticed in the hands, face or feet, and frequently the contrast between the feet which preserve their normal outline and contour and the legs, when the later are involved, is most striking”, These cases are similar to lipedema in terms ofthe pattern of painful ft (less likely early ‘on in the hands, feet, face, and forearms) and the latter case lescribes well the distint “bracelet of fat seen at the base of the leg above the foot that is classic in lipedema!*, The pub- lished photographs of the columnar legs with the cuff of fat, above the foot, or the mass of tender fat inferomedial to the knee, and the enlarged upper arms in DD are consistent with Tipedema #642 8) The nodular “beans in a bag” feel ofthe fat in lipedema is the same as in DD Types 1 and 2° 9) Dr Dercum described DD as a disorder of the “haemo- lymph system” though the importance of these structures, in humans is unclear. Hemolymph nodes are structures resembling a lymph node, but which can have blood in the sinuses; erythrocytes enter the hemolymph nodes through afferent lymphatics", There are few reports on the function ‘of hemolymph glands in humans. 10) Dr Mills reported “In one case stuclied carefully with Dr Dercum, there was a general disease of the lymphatic sys- tom’, The data suggest that the vascular and lymph system are dysfunctional in both lipedema and DD, that pre-lymph, remains in the tissue longer, inducing fat growth and the characteristic beans in a bag, fet to the fat, In both lipedema and DD there is a hereditary component!" Also in both cases, estrogen and/or progesterone likely play a role rosult- {ng in the predominance of women with lipedema and/or DD; lipeddema is known to occur with the onset puberty and pregnancy, andl DD with menopause, both times of chang ing hormone levels, In DD, a more widespread insult to the vascular and lymphatic system may occur compared to lipedema, Many of the early reported cases of DD hacl syphi- is? 2524, well known to affect the Iymph nodes, consumed alcohol"! which acutely increases mesenteric lymphatic pumping but decreases lymphatic myogenic tone, or had antecedent trauma which may have affected lymphatic fune- tion?” Many patients with DD Type Lor IL noticed their first painful area offal after a vial flu, severe preumonia or trauma" "4, Data are needed on lymphatic function in DD toconfirm these hypotheses, Conditions associated with 0D In addition to the two cardinal symptoms of fatty deposits and pain proposed by Dercumt™', Vitaut added the third car- dlinal symptom of DD, asthenia (abnormal physical weakness or lack of energy)". Accessory symptoms in DD are found in the psychiatric, motor, sensory and sympathetic nervous, systems! as well as the pulmonary, endocrine, gestrointesti- nal and rheumatological systems! 2" (Table 2), Thyroiel dysfunction has been suggested as one etiology of “Acta Pharmacologica Sinicawv. nature com/aps Hert kL 164 Table 2. Cardinal and sccessory signs and symptoms of Dercum’s dgease with checkbox ‘araialSigna/Symotome Detais Fat depoate Painin fat deposits or a Pain eracerbat by ste dul (ipomas) in fat ranging in size om roe grains to aft or lrger sluenuous ectese trauma, changes in weather, or other. pain can be ‘spontaneous of on palpation: may wax and wane ot move around Fatigue (attnena} 222 aocessory symptoms Cognitive changets) Wein gai Vasoular involvement racorbates ty acvuties of daly ving a exercise Memory ificultes cifficutyferming thoughts “brain fo Dncur to lose fat deposits wth Meee changes iibevasoulaty near somes; telangleetasas, mul a cherry angiomas, multiple techie, easy bruising tushing hematuria of unknown etiology. heavy or prolonged menstrual bleeding epistaxis SAT edema Gostiointestinelcomptaints Joint pain and/or sutiness Muscle pain/siffns Shortness of reath Tachycardas Non-iting ‘Gastioesophogealfeflucdiesse. title bowel syndrome, bloating, abdominal pln, ear satiety Inoreosed in areas of fet depos Espaciallyon awakening or the day after physical activity Inthe prosonce of rormal onygn saturation or as part ofthe ne ‘aries from palpitations to supraventricular tachyearda requtingbeta-blockade for engen supplementation DD. While a few cases of DD benefited from thyroid treat ment! many cases of DD failed to improve” #5 2828-291 and DD generally continues to progress during adequate thyroid replacement! Others have suggested multiple ‘endocrine dysfunction as @ cause for DD" (reviewed!) but ACTH and pituitary extract did not improve signs and symp- toms associated with DD!" and hormone testing was nor- ‘mal in other cases", If hypercholesterolemia is present, severe and generalized vascular disease may be found?" 00 treatment recommendations 1) Exercise: Similar to lipedema, Supporting the use of WBV as exercise in DD, WBY slowed the acquisition of fa in female rats?#l and improved pain and fatigue in women with fibro myalgia? 2) LDT: LOT and “massage are known to be beneficial for DD Types [and IL; recommendations are similar to lipe- dema (see above). 3) Pain control: Must be individually optimized; only pub- lished of important anecdotal reports are included hee: (@) Chemotherapy: A patient with DD had improved pain and growth of DD SAT slowed on methotrexate combined with infliximab!" One case had resolution of her lipomas and pain with paclitaxel and carboplatin (unpublished); once the paclitaxel was discontinued because of neuropathy, the pain and lumps returned. {b) Cyclic Variations in Adaptive Conditioning (CVAC™) A novel therapy that reduces tissue uid by variable pattern- ing of different atmospheric pressures around a person siting inn altitude simulator, Peri-corporl pressure patterns vary from sea level to four sequential altitude levels: 3200 m (105K 0), 4419 m (14.5K ft), 5638 m (18.5K ft), and 6858 m (2.5K ft). This body conditioning’ redced flu and pain in 10 DD par- ticipants" and improved YO,max in healthy men?) ‘eta Pharmacologica Sinica {©) Lidocaine: Intravenous (IV) lidocaine has been used with some success to teat the intractable pain associated with DD""2"25, Many individuals with DD obtain good local ‘pain relief using lidocaine patches, cream, gel or MLA? 2% {(€) Moxilitene: Mexilitene (an antiarrhythmic drug) has been used forthe effective treatment of pain in DDE! (6) Pregabalin: LDT combined with pregabalin (an anti- convulsant drug, used for neuropathic pin) has been sed to treat the pain associated with DD? 4) Psychological support Se lipedema (above). 5) Surgery: Liposuction is one of the accepted methods of treatment for DD" resulting, in decreased pain ™* When asked specifically about liposuction in a series of 110 patients, 83 respondents (73.5%) reported having had lipo- suction; of these, 50.6% reported that the painful fat depots ‘grew back!" Surgical resection and liposuction should be preceded by LDT andl compression to support al vasculature and decrease the risk of seroma and hematoma formation. DD ‘may be one reason why RYGBP without LDT failed to result in weight loss in a published caso Additional recommendations 6) Aminoacotic acid (glycine) and prostigmine: In three women with DD, a diet consisting, of 70 grams protein, 70, ‘grams of fat and 100 grams carbohydrate oF 1500 calories day {specifics unavailable}, 10 grams glycine and 45 mg prostig- ‘mine daily improved weight loss and energy’. If glycine binding in the central nervous system is antagonized, fooding, in rats increased! glycine may therefore be an appetite sup ‘prossant while prostigmine improves asthenia. 7) Corticosteroids (oral): Cortisone treatment has been shown to help with pain but with none of the other features of DD", cortisone treatment can also induce DD™. A series of corticosteroid joint injections is usually well-tolerated without ‘exacerbation of symptoms and signs in DD.8) Hormonal testing: Testing, for thyroid function and assessing a complete panel of pituitary hormones at least once alter diagnosis of DD and when symptoms change is prudent 0.48 not to miss accompanying hormonal dysfunction, which should be treated with usttal methods, Adipose tissue is a very hormonally responsive ssc, so estrogen, progester- cone and testosterone levels should be monitored regularly on any replacement regimen 4 as to regulate high and low levels, and avoid wide uctuations 9) Lifestyle: While obesity is prominent in DD, the DD SAT fs resistant to loss with lifestyle changes 4 while normal SAT as part of obesity canbe ost! 10) Oxygen therapy: Many people with DD feel short of breath!"™!, This can progress on to the need for continuous: ‘oxygen therapy. It is unclear why the shortness of breath ‘occurs but its likely a combination of increased interstitial ‘uid moving cells away from their oxygen source and a weal ened diaphragm. Pulmonary function testing should be per formed en everyone with DD that has shortness of breath even {Fi serves simply as a baseline for future changes oF symp- toms, Similar to MSL, if patient has increased thickened fat around the chest or neuropathy, DD patients with shortness of breath and/or edema should be evaluated for thoracic outlet syndrome, sleep apnea and/or autononvc dysfunction. ‘Co-meorbidities associated with obesity in DD are treated as sal Conclusions (Obesity is very common and in the limited time allotted to ‘Patient care, it may be easy to misdliagnosea patient witha lip- ‘dystrophy or a RAD disorder as having simple obesity, and pproseribe lifestyle changes only. The widesproad increase in abnormal SAT in MSL, DD or lipedema Type IL or Ill can eas- ily masquerade as global obesity (Table 3). The loss of normal Table 3. comparigon of RAD characteris ‘ww ohinaphar com Herbst KL 165 fat andl muscle in MSL or the disproportion of fat in ipedema can also be confused with lipodystrophy; lipedema Type is usually overlooked. Lifestyle changes and bariatric surgery ‘work effectively for the obesity component of FPLD and RADs but not for the abnormal SAT tissue in RADs, The RAD SAT likely rosults from the growth of a brown stem cell population that socondarily compresses lymphatics and vessels (in MSL) ‘of a primarily vascular and lymphatic dysfunction with sec- ondary growth of SAT (in lipedema and DD), neither of which respond well to caloric limitation, Academic testing of various ictary regimens, mechanical treatments, surgery, medica- tions, and supplements is needed for RADs. Understanding the genomics of the RADs is also important to help differenti ate lipedema, MSL and DD especially in women where the three disorders can look so much alike, and to assess for RADs in obesity. Improved recognition of RADs may also prove that lipedema and! DD are not RADs at all but common disorders and that understanding the underlying pathophysiology of RADs may improve our understanding of refractory obesity Lymphatic drainage methods used for RADs should be con. sidered in resistant obesity cases or before bariatric surgery, ow to very low calorie diets or other methods that induce rapid weight loss requiring optimal lymphatic function. ‘Acknowledgements ‘This study recoived research support from the UCSD NIDDK Diabetes and Endocrinology Research Center Grant P30 DK063491 and the UCSD General Clinical Research Center by Public Health Grant 5MO1RR000827, This paper is dedicated to people with RADs and to Birgher Fagher, MD, who died in Apel of 2011 Conflicts of interest ‘This study was approved by the University of California, San Rabe Characters Ms oD Lpedema ‘Abnormal SAT avon Upper® bebo LegstArms Diecresistant SAT Yon ves Yes LUpomes Come in malas Cammnan Large nodular fat masses Time of SAT change Adult Chia to aout Puberty by ti decade Pint Sa Not usually vee ves Sexpredominance Male Female Female Lymphatic defunetion Secondary Primary Primary Lockalike candivons Obesity: HV ipedystophy Obesity. FM best. APL Associated condons — Neuronaty Autoimmune, dabetes lymphedema Population trequeney Rave Ukely common LUkely common Innertance patarn Autosomal dominant or recessive Known gene {RNBLys mutations unesmman Hone Known biomarkers No. No ‘ohalaseociaton Yes No ‘Autosomal dominant: sex spec infuancs ‘Autosomal dominant: inoomplete panetance None No * Can be global especially in women: APL=20qui AT-subeutaneous adipore tissue sd partial lipedystrephy. FML=familal multiple lipomatosis: RAD=rare adipose disorder. “Acta Pharmacologica Sinicawv. nature com/aps Hert kL 166 Diego Human Research Protection Program and the Rescarch and Development Committee at the Veterans Affairs San Diego Healthcare System, All subjects described herein com pleted an informed consent process prior to enrollment. References 4 Ogden CL, Carroll MD. 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