Continuing Education Activity

American physicians Allen and Hines described an abnormal deposition of adipose tissue affecting females in the 1940s in a Mayo Clinic termed lipedema. Lipedema is the disproportionate and symmetrical distribution of adipose tissue involving the lower extremities to a greater degree than the trunk or upper extremities. History and physical examination provide clues regarding the lipedema, which is evaluated more with nuclear medicine lymphangioscintigraphy, ultrasound, or MRI of the legs. To avoid more complications, it should be diagnosed and intervene early. This activity reviews the evaluation and management of lipedema. Treatment starts with conservative management, like diet and exercise, but then surgical options like bariatric surgery and liposuction should be considered.

Objectives:

• Identify the etiology, pathophysiology, and epidemiology of lipedema.
• Review the evaluation of lipedema.
• Summarize the management for lipedema.
• Outline some strategies that will improve patient care and outcomes for individuals with lipedema.

Introduction

Dr. Allen and Dr. Hines pioneered and first described lipedema in the 1940s, a common subcutaneous adipose tissue disorder characterized by enlargement of both lower extremities. Lipedema is not edema; it is a genetically determined disturbance of adipose tissue mass and distribution. In 1951, a second seminal paper provided more description of lipedema. Fat distribution involves the lower extremities, upper arms, hips, buttocks, thighs, sparing trunks, and feet. Lower extremities are characterized by pain, easy bruising, firm subcutaneous nodules of adipose tissue, and resistance of fat to traditional diet and exercise.[1]

Etiology

Lipedema is considered to have a genetic basis, either X-linked dominant or autosomal dominant. Child et al studied 330 family members of patients with lipedema and described autosomal inheritance as the major mode, with a few cases of X-linked dominant inheritance.[2][3] Few cases have been reported with POU1F1/PIT-1 gene mutation in short mothers, but no phenotypic features have been noted in the sons who carried the gene from short mothers or in normal-height daughters. Lipedema is also found in cases of Williams syndrome, caused by a microdeletion of approximately 1.6 million base pairs on chromosome 7q11.23, which includes the ELN (elastin gene).[4]

Epidemiology

It is proposed that the prevalence of lipedema is approximately 1 in 72,000 of the population. Lipedema is often misdiagnosed or underdiagnosed, so these prevalence estimates are likely underestimated.[2] Lipedema occurs predominantly in women but has been reported rarely in men. Few reports have reported lipedema prevalence of around 11% in adults and 6.5% in the United States, with rates ranging from 15% to 18% in European countries.[5]

Pathophysiology

In 1940, Allen and Hives proposed that edema in lipedema probably results from the poor resistance of the fat against the hydrostatic passage of fluid from the capillaries into the interstitium. Presumably, hormonal influence may contribute to its pubertal onset or post-pregnancy lipedema development in women when estrogen levels are high. Lipedema in men is uncommon, but a few cases have been reported in liver disease or low testosterone, both of which have high estrogen states. Lipedema is also found in cases with polycystic ovarian disease, where testosterone levels are high. The role of estrogen as a causative factor in lipedema is not well established.[6]

Several theories have been postulated to describe lipedema. One theory mentions the loss of elastic tissue and abnormal vasculature. Structures in loose connective tissue include blood vessels, lymph nodes, and connective tissue fascia, which contain elastin that helps maintain their shape. Lymphatic vessels lack elastic fibers, but they support the closure and opening of lymph vessels in response to tissue pressure. Similarly, capillaries lack elastic tissue, but the loose connective tissue surrounding them contains elastic fibers. Therefore, with adipose tissue growth in lipedema, loss of elasticity prevents lymph vessels from opening under increased pressure in the extracellular matrix, leading to capillary leakage in the tissue. Subsequently, hypoxia triggers vascular endothelial growth factor signaling, which promotes stem cell proliferation in adipose tissue.[7]

Eventually, lymph vessels lose their function, resulting in microaneurysm formation in the lymph vessels responsible for lymphedema development. Another theory of abnormal lymphatic vasculature depicts a primary defect in lymphatic vessels that results in increased fluid accumulation in the extracellular matrix, which enhances permeability in surrounding microvessels. Lipedema is associated with altered left ventricular rotational mechanics and increased aortic stiffness.[8][9]

Histopathology

Diagnosis of lipedema is often challenging to differentiate from obesity. According to the WHO guidelines, people with a BMI of more than 25 kg/m² are considered overweight, and those with a BMI of greater than 30 kg/m² are considered obese. In lipedema patients, BMI is elevated, but distinguishing features such as diet and exercise favor obesity, whereas disproportionate fat distribution above and below the trunk, tissue tenderness, and easy bruising favor lipedema. Lipedema can be complicated by obesity or lymphedema later in life.[2] Lymphatic vessels regulate the sodium, chloride, and water in the skin. In the case of lipedema failure of a lymphatic vessel, the function is observed, which is supported by the dilatation of lymphatic vessels in the MRI of the legs. Per Crescenzi et al, increased salt is found in the skin of women with lipedema and loose connective tissues.[5] Despite higher BMI, a lower prevalence of diabetes, normal blood pressure, and normal lipid levels have been observed in cases of lipedema.

Classification

Lipedema is classified into stages and types (see Image. Lipedema Types). Stage 1 represents the normal skin surface over a thick and nodular hypodermis, but pea-sized fat nodules can be palpated. These nodules are fibrosed and enlarged structures in the extracellular matrix and connective tissue surrounding the fat lobule. In this stage, skin appearance is normal and smooth on palpation, but nodules can be palpated and may be associated with pain or easy bruising. Stage 2 represents an uneven skin surface over hypodermal masses.

Dimpling, indentations, and mattress-like patterns on the skin are due to thickening and contraction of connective tissue over increased fat. Stage 3 represents lobular extrusions of skin, fat, and fascia tissue. Inflammation and fibrosis of adipofascia result in loss of elasticity; therefore, blood flow and lymph flow out of lobules are reduced. In this stage, the appearance of both lower extremities can be columnar, with large, visible folds of skin and palpable fat due to fibrosis in the tissues and a loose connection to the underlying hypodermis. This may compromise joint integrity, mobility, and balance. Stage 4 is often classified when lipedema is associated with lymphedema, also called lipo-lymphedema.[5][10][11]

Lipedema is classified by anatomical location. Type I lipedema fat is distributed from the umbilicus to the hips, including the pelvis and buttocks. Type II includes fat distribution from around the pelvis to the knees. Type III includes from around the pelvis to the ankles with a prominent cuff at the ankle, sparing the dorsum of the feet. Type IV includes the area from the shoulders to the wrists. Type V is a rare occurrence that involves fat distribution from or below the knees and extends through the ankles, sparing the dorsum of the feet. Type II & IV, or Type III & IV, are common combinations. Involvement of the arm can be varied in fat distribution from the elbows to the wrists or from the shoulders to the wrists.[5][12]

History and Physical

Child et al (2009) mentioned about the age of onset of lipedema during puberty (55%), reduction of fat above the waist only through diet (96%), no effect on lower extremities making it more disproportionate fat distribution, pain upon pressure (71%), easy bruising (82%), varicose veins (39.5%), vein telangiectasia (53%), fat pads (bulging protuberance of fat above or below the knee; pre-tibial fat pads) (58%). Surprisingly, 4% of lipedema patients recorded to have normal BMI (18.5 to 24.99 kg/m²), 11% were pre-obese or overweight (BMI 25.0 to 29.99 kg/m²), 8% obese class I group (BMI 30 to 34.99kg/m²), 27% obese class II (BMI 35.0 to 39.99%) and 50% obese class III (BMI greater than or equal to 40%).[2]

Table

Characteristic Lipedema

Adapted from a table proposed by Wold et al (1951) & Child et al (2009), Dayan et al (2017).[2][3][13][14]

Evaluation

Laboratory tests, including liver, kidney, and thyroid function tests, lipid profile, and insulin resistance, should be ruled out before proceeding with imaging.[3] With recent advances in imaging, nuclear medicine can help differentiate lipedema from lymphedema. In nuclear medicine lymphangioscintigraphy, NMLAS technetium-99m-sulfur colloid is injected dermally. Remarkable asymmetry of the lymphatic system and slower lymphatic flow have been found.[5][15] Bioimpedance spectroscopy reveals higher impedance (extracellular water content) in the lower extremities than in the upper extremities.[10] 

A dual-energy X-ray absorptiometry (DEXA) scan is used to measure bone mineral density; it is also very useful for assessing fat mass and lean body mass. It differentiates patients without lipedema by a cut-off value of 0.46 for fat mass in the legs (adjusted for BMI). Ultrasound of lipedema tissue demonstrates thinner skin, increased thickness, and increased hypoechogenicity of subcutaneous fat, more prominent towards the medial calf and distal extremities. Based on subcutaneous thickness, Marschall and Schwahn-Schreiber have classified lipedema severity as mild (12 to 15 mm), moderate (15 to 20 mm), distinct (> 20 mm), and severe (> 30 mm). Ironically, similar values have been identified in the case of obesity as well. Therefore, the proposed value can misdiagnose lipedema in the absence of other symptoms.[5][16]

Magnetic resonance imaging (MRI) of the legs shows a widening of lymphatic vessels up to 2 mm, whereas, in the case of lipedema, the widening can be more than 3 mm. In transthoracic 2D echocardiography, enlarged left atrial diameter, increased LV end-diastolic diameter and volume, increased LV end-systolic volume, impaired left ventricular apical rotation, left ventricular twist, and aortic stiffness, along with increased ascending aortic systolic and diastolic diameters, have been reported. Ejection fraction has been preserved in patients with Lipedema. In 3D speckle-tracking echocardiography, dilated end-systolic and end-diastolic mitral annular disjunction has been observed, with increased mitral annular area.[8]

Treatment / Management

The diet helps to manage obesity that often accompanies lipedema. Generally, lipedema fat is resistant to weight loss with diet.[5] However, few reports suggest a ketogenic diet helps in lipolysis.[13] Despite exercise of body parts, those affected with lipedema continue to grow. Still, graded exercise is recommended for women who have unhealthy lifestyles. A carbohydrate-restricted diet may also be more useful in some cases when lipedema is resistant to the ketogenic diet. A few reports suggested that water exercise helps mobilize the fluid and soften the fibrotic tissues, and a few suggested that speed walking or bicycle riding can also be helpful. Exercise activates calf and foot muscles to pump, which increases lymphatic drainage and reduces edema formation and the risk of further weight gain.[16]

Compression garments are recommended for cosmetic reasons. Circular knit garments are seamless and better suited for women with less lymphedema, whereas flat knit garments are suited for women with ankle cuffs or unusual shapes.[5] 25% of women with lipedema have venous insufficiency. Conservative treatment should be tried first, as data are lacking to show that correcting venous insufficiency with surgery improves lipedema. Conservative therapy aims to reduce edema, pain, and the development of associated obesity.[5][11][16] Patient education on understanding the disease is of prime importance in determining the goals of treatment and expectations for the disease.[3]

Bariatric surgery, such as gastric bypass or sleeve gastrectomy, should be suggested for the benefits on overall glucometabolic aspects, especially prediabetes, diabetes, or cardiovascular risk. Women should be counseled before bariatric surgery that the post-surgery lipedema may become more pronounced. Compression garments and decongestive therapy should be offered to prevent the development of lymphedema, and a consultation with a plastic surgeon should also be recommended for excess skin removal post-bariatric surgery.[17]

Liposuction is a very effective treatment for lipedema when conservative therapies fail. In this procedure, lipedema fat is removed, sparing the lymphatic vessels. Several techniques are used as follows.

1. Tumescent technique: Klein solution (normal saline or lactated Ringer's, lidocaine or prilocaine, epinephrine, sodium bicarbonate) is used to saturate the fat. This tumescence provides turgor to the tissue through which the microcannula slides; tiny, rapid vibrations break the fat, which is then suctioned out.
2. Water-jet-assisted liposuction (WAL): Klein solution or saline is used as a jet to release the fat for liposuction. No waiting period is required to tumescent the tissue.
3. Laser-assisted liposuction: This technique is reserved for areas with fibrosis, like the posterior thighs. Liposuction performed without general anesthesia has a rapid recovery; also, it is recommended to undergo liposuction in stages rather than removing all fat in one sitting. 3-5 liposuction sessions, with a good interval between them, are suggested.

The quality of life has significantly improved regarding pain, muscle cramps, tightening, itching, edema, bruising, and cosmetic appearance after liposuction. The aim of surgical treatment is mainly to reduce the volume and alleviate the mechanical impairment of walking. But liposuction is a very costly therapy; insurance coverage and reimbursement are the main issues.[18][19]

A pneumatic compression device is used for both lipedema and lymphedema. In treating lymphedema, manual lymphatic drainage, myofascial therapy, deep tissue therapy (Astym, Graston technique), and compression reduction techniques have been shown to reduce fibrosis in lipedema fat and increase blood flow to the tissues.[5][20] In lipedema, poor quality of life, immobility, and stress related to physical appearance can result in depression. Appropriate education about the disease, motivational interviewing, and counseling focused on healthy eating patterns, activity, and social interaction, including internet groups and national and local groups, significantly improve outcomes. Referring to a psychotherapist, physical therapy, and pain management specialist is very useful when needed.[3][21][22]

No specific medication or supplement is used to treat lipedema, but drugs are used as an adjunctive treatment, especially to prevent lymphedema and venous disease; both are complications of lipedema. Sympathomimetics like amphetamine or phentermine bind to adrenergic receptors that induce lipolysis. Adrenergic receptors are located on lymphatic and blood vessels. Metformin and resveratrol are useful for preventing fibrosis and the development of hypoxia-inducible factor (an inflammatory factor). Diosmin, a bioflavonoid found in citrus fruits, functions as a lymphagogue, reduces swelling, and is helpful in lipedema and associated chronic venous insufficiency. Selenium, a mineral, has been shown to reduce inflammation and reduce leg volume in lipedema and lymphedema.[5][9][23] Several drugs that cause fluid retention should be avoided, like calcium channel blockers, thiazolidinediones, gabapentin, oral corticosteroids, and beta-blockers. Furosemide, a diuretic, should also be avoided, as it increases protein concentration in the interstitial fluid, which halts fluid movement.[5][24]

Differential Diagnosis

Lipohypertrophy in obesity, lymphedema, phlebedema, Dercum disease, panniculitis, Cushing syndrome, hypothyroidism, familial multiple lipomatosis, adipose tissue tumors, neurofibromatosis type I, multiple symmetric lipomatosis (Madelung disease, Lanois-Bensaude syndrome), fibromyalgia or chronic polyarthritis, depression with obesity, angiolipomatosis.[9][25]

Prognosis

With current treatment options, lipedema is not curable, but patients can positively influence its course. Compliance with treatment, such as regular exercise, compression stockings, and participation in sports activities, is associated with a better prognosis and milder course than noncompliance. The course of the disease is not predetermined, as the associated comorbidities, like depression or other psychiatric disorders, obesity, lymphedema, or peripheral artery disease, greatly influence severity.[16]

Complications

Lipedema can be complicated by lymphedema later in life. Lymphedema can be primary or secondary. Intrinsic abnormality (ie, hypoplasia or dysfunction of lymph vessels) is responsible for primary lymphedema, and extrinsic abnormality (ie, surgical lymphadenectomy) causes secondary lymphedema. It is characterized by bilateral, asymmetric swelling of both lower extremities due to inadequate drainage of fluids, cells, and proteins, leading to excessive accumulation of interstitial fluid. The inability to pick up the fold of skin (or pinch the skin) at the base of the second toe called the “Stemmer sign” (Described by the scientist Stemmer in 1976) is pathognomonic for lymphedema. Also, pitting is evident in lymphedema. Lipedema is often complicated by secondary lymphedema and is referred to as lipolymphedema.[2] Lymphedema increases the risk of cellulitis and the development of wounds.[5]

The association between obesity and lipedema is common. The important differentiating point between these 2 conditions is tissue tenderness; easy bruising is not found in obesity. Also, diet and exercise can reduce fat deposition in obesity. In lipedema, fat distribution is disproportionate between the upper and lower body, unlike in obesity.[5] Obesity and or polycystic ovarian disease can worsen the lipedema severity. Contributing factors may be adipokines, leptin, or tumor necrosis factor-alpha (TNFα).[5]

Development of depression, appearance-related distress, self-loathing, poor quality of life, and social isolation are highly prevalent in patients with lipedema. Higher rates of suicide in women with lipedema have also been reported. Several other comorbidities and complications are associated with lipedema, including lordosis, genu valgum, knee arthritis, antalgic gait, ankle pronation, varicose veins, and cellulitis.[5][20]

Cardiovascular risk includes increased aortic stiffness index and increased mean systolic and diastolic aortic diameters, while decreased aortic strain and distensibility have been reported. Connective tissue changes in the aorta, which are considered responsible for higher aortic distensibility, aortic strain, and arterial elasticity, may be risk factors for cardiovascular mortality.[20] The use of compression stockings does not improve mitral annulus enlargement and functional impairment.[8][11]

Consultations

Endocrinologists, rheumatologists, orthopedic surgeons, vascular surgeons, physical therapists, and lymphedema specialists.

Deterrence and Patient Education

Lipedema should be recognized before weight-loss programs, so knowledge of the disease and expectations can be discussed. Manual therapies, medicines, supplements, other conservative treatments, and bariatric surgery can be tried; if they fail, liposuction should be considered. A careful diagnosis should be performed to prevent unnecessary frustration and therapy costs, and only then should therapy goals be formulated.[16] Associated comorbidities, genetic, and environmental factors should be considered; each patient with lipedema should be considered on a different spectrum, and treatment should be personalized.[5]

Enhancing Healthcare Team Outcomes

Lipedema requires an interprofessional healthcare team that includes clinicians (MDs, DOs, PAs, NPs), specialists, surgeons, nursing staff, and pharmacists. The condition requires careful diagnosis and strong collaboration among multiple medical disciplines. Psychological professionals may also be part of the clinical picture to help the patient with self-esteem issues. Interprofessional cooperation can help improve patient outcomes.

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Disclosure: Ankit Vyas declares no relevant financial relationships with ineligible companies.

Disclosure: Ghufran Adnan declares no relevant financial relationships with ineligible companies.