Diagnosis and management of lipedema

INTRODUCTION — Lipedema is a subcutaneous lipodystrophy causing lower extremity overgrowth. The condition is associated with many myths and is commonly confused with other conditions.

The clinical features of lymphedema, which can coexist in patients with obesity who may also have underlying lipedema, are reviewed separately. (See "Lower extremity lymphedema".)

INCIDENCE AND PATHOGENESIS — Lipedema is a rare condition, and the incidence is unknown. Patients historically have been erroneously diagnosed with lymphedema and were referred to lymphedema programs. Two studies reported that 4 percent of individuals referred with primary "lymphedema" actually had lipedema [1,2]. Consequently, the incidence of lipedema can be estimated based on the incidence of primary lymphedema, which is about 1/100,000 [3]. The derived estimate for "classic" lipedema could be <1/1,000,000.

Lipedema was described by Allen and Hines in 1940 [4]. They subsequently reported their series of 119 patients in 1951 [5]. Although individuals were referred with a diagnosis of "lymphedema," they noted a unique phenotype. Unlike patients with lymphedema, subjects were always female, both lower extremities were affected, the feet were spared, and the patients did not have infections [5]. They termed the condition "lipedema" because some patients also exhibited minor swelling [5]. However, because "edema" was included in the name of the disease, a misconception has existed that swelling is a primary component of the disorder, causing confusion and mislabeling as lymphedema [6].

The condition is fundamentally a lipodystrophy with abnormal deposition of subcutaneous adipose tissue in the lower extremities. On magnetic resonance imaging (MRI), the subcutaneous fat appears normal but is circumferentially increased. Histology of the adipose does not show an abnormality. Unlike lymphedema, fibrosis and dermal thickening are not present in patients without obesity [1]. One hypothesis to explain reported pain is inflammation and hypoxia from elevated macrophages and fat necrosis [6]. European Consensus Guidelines recommend renaming the disorder "lipalgia syndrome" [6].

The etiology of lipedema is not well understood. The disease appears to be caused by a germline mutation because it follows an autosomal dominant mode of inheritance with incomplete penetrance (16 to 44 percent of patients report their mothers also had the condition) [1,5]. Potential candidate genes responsible for lipedema include VEGFA, GRB14-COBLL1, and LHFPL6 [7,8].

Although edema is not a classic clinical feature of lipedema, it can occur secondarily from obesity and inflammation. Lipedema predisposes patients to obesity because their enlarged lower extremities increase the weight of the patient and interfere with exercise. Based on modern understanding, obesity impairs lymphatic function, and when body mass index (BMI) exceeds 30, lower extremity swelling develops [9-11]. Patients with swelling in the original reports by Allen and Hines likely had a higher BMI. Individuals with a BMI >30 and leg swelling with normal lymphatic function by lymphoscintigraphy have what is termed "obesity without lymphedema" (OWL) [12]. Subjects with a BMI >40 and abnormal lymphatic function have "obesity-induced lymphedema" (OIL) [12]. Consequently, patients can be primarily afflicted with lipedema, gain weight, and then secondarily develop swelling (OWL or OIL) [12].

CLINICAL FEATURES — The onset of lipedema is usually during adolescence [1]. Individuals commonly state that during puberty they had normal or slightly increased weight and their legs became enlarged and out of proportion with the rest of their body. They often report their mothers exhibited a similar phenotype.

Classic features — Classic clinical features of lipedema include the following [1,5]:

●Only females are affected

●Symmetric bilateral overgrowth of the lower extremities

●Prominent malleolar fat pads

●Normal feet

●No infections

●Aching discomfort at rest

●Pain on palpation

●Easy bruising of the lower extremities

●Positive family history (females with same phenotype)

European Consensus Guidelines do not include edema in the diagnostic criteria for lipedema [6]. If swelling is present, it is secondary to localized inflammation caused by the diseased fat or related to increased body mass index (BMI). In the originally reported series, only 25 percent exhibited edema that was "minor" [5]. Many subjects were obese, and it is likely these were the individuals with reported swelling. In a later review, 8 of 9 patients were not obese and only had minor focal edema of the pretibial area [1].

Lipedema does not exhibit significant progression in patients who maintain a normal BMI. However, if patients gain weight their lymphatic function becomes compromised, resulting in edema. As many as 80 percent of patients with lipedema have a BMI >30 [6]. The higher the BMI, the more likely it is that irreversible lymphedema will develop [12]. As BMI increases, patients enter an unfavorable cycle of increased subcutaneous adipose deposition that occurs with both obesity and lymphedema, causing progressive leg enlargement.

Physical examination — The physical examination shows fatty tissue overgrowth variably extending from the hips to the ankles with sparing of the feet (picture 1). Classically, there is a cutoff at the ankle with prominent extra malleolar adipose tissue. Patients may exhibit bruising of their legs and palpation is painful.

The skin proximal to the second toe is able to be pinched (ie, negative Stemmer sign), indicating normal lymphatic function [13].

If the individual with lipedema has a BMI >30, and especially for BMI>40, the classic physical examination signs of lipedema (ie, lower extremities out of proportion with the rest of the body, no involvement of the feet, minimal swelling, negative Stemmer sign) may not be present because of the confounding clinical features of obesity, with or without lymphedema.

Stages and types — While some authors categorize lipedema into stages and types [14], we and others prefer not to do so because they are confounded by obesity [1,5,6,15].

●Stages – A confounding variable to the stages defined below is the weight of the patient because those with a higher BMI will have worse lipedema, lymphatic injury, and fibrosis [14].

•Stage 1 (subcutaneous adipose nodules)

•Stage 2 (skin indentations)

•Stage 3 (excess skin and fibrosis)

●Types – Types based on location include [14]:

•Type 1 (pelvis, hips, buttocks)

•Type 2 (buttocks to knees)

•Type 3 (buttocks to ankles)

•Type 4 (arms)

•Type 5 (below knee [not feet])

It is unclear whether the types represent classic lipedema or if they include obesity or other lipodystrophies.

DIAGNOSIS OF LIPEDEMA — The diagnosis of lipedema is based primarily on history and physical examination. Whether additional diagnostic evaluation is performed depends on the age of the patient, patient and family history, history and presence of obesity, and its severity based on body mass index (BMI) (algorithm 1).

Adolescent females or young adult females are more likely to present with the classical clinical features (ie, lower extremities out of proportion with the rest of the body, no involvement of the feet, minimal swelling, negative Stemmer sign) described above (see 'Classic features' above). The patient typically notes that by age 18 the size of their lower extremities became out of proportion with the rest of their body and that they were either a normal weight or mildly overweight. They complain that their lower extremities ache and bruise easily.

In adults with obesity, historical information may suggest a diagnosis of lipedema. However, the classic physical examination signs of lipedema may not be present if the individual has a BMI >30, and especially for BMI >40.

Lymphoscintigraphy is obtained for patients with a BMI >30 to help differentiate lipedema from obesity without lymphedema (OWL) and obesity-induced lymphedema (OIL).

Lower extremity imaging — If the diagnosis of lipedema is clear based on clinical features (ie, lower extremities out of proportion with the rest of the body, no involvement of the feet, minimal swelling, negative Stemmer sign (see 'Classic features' above)), imaging is not mandatory. However, imaging may be obtained if the diagnosis is not clear, for counseling, or for operative planning.

MRI — MRI may be useful to support a clinical diagnosis or for preoperative planning. In individuals with lipedema, MRI exhibits increased circumferential subcutaneous adipose tissue without evidence of muscle or bone overgrowth.

Lymphoscintigraphy — Lymphoscintigraphy is used to differentiate lipedema from lymphedema (with or without obesity).

Lymphoscintigraphy is 96 percent sensitive and 100 percent specific for lymphedema [16]. In patients with lipedema, lymphoscintigraphy will demonstrate normal lymphatic function provided the patient's BMI is less than 40 [12].

Using lymphoscintigraphy and maximum BMI history will help differentiate lipedema from OWL and from OIL (algorithm 1). (See 'Differential diagnosis' below.)

●A normal lymphoscintigram is consistent with either lipedema or OWL. A patient who presents with classic clinical features (see 'Classic features' above) likely has lipedema, whereas if those features are absent, the diagnosis is likely OWL. (See 'Obesity' below.)

●An abnormal lymphoscintigram in a patient with a normal BMI history means the individual has lymphedema and not lipedema. Lymphatic dysfunction in a patient with a BMI history >40 indicates the patient has OIL. If suggestive clinical features are also present, they could have initially had lipedema. (See 'Incidence and pathogenesis' above and 'Lymphedema' below.)

DIFFERENTIAL DIAGNOSIS — "Lipedema" is often used as a general term to describe any patient with overgrowth of their legs.

Obesity — The most common condition that is confused with lipedema is obesity (table 1). Both conditions have a similar appearance and lipedema predisposes patients to becoming overweight. Unlike obesity, lipedema is a primary lipodystrophy of adipose tissue that affects the bilateral lower extremities; classically, the remainder of the body is not affected. By contrast, lower extremity overgrowth from obesity is secondary to weight gain. Patients with obesity have enlargement of their feet, abdomen, and other areas of their body.

As body mass index (BMI) increases, lymphatics become damaged and swelling worsens. When lymphatic dysfunction occurs, patients will develop additional subcutaneous adipose overgrowth and enter a worsening cycle of weight gain and lymphatic injury. Patients who develop obesity-induced lymphedema (OIL) can further develop localized areas of soft tissue overgrowth of their thighs and genitalia (massive localized lymphedema) [17]. The fundamental treatment for lower extremity overgrowth from obesity is weight loss.

Lymphedema — The second most common condition mistaken for lipedema is lymphedema (table 1) [18]. Lymphedema results from malformed lymphatics (primary lymphedema) or from injury to a normally developed lymphatic system (secondary lymphedema (see 'Obesity' above)).

Primary lymphedema affects the lower extremities (90 percent) or upper extremities (10 percent). There are 31 known mutations can cause primary lymphedema [19]. Primary lymphedema often is an autosomal dominant condition and patients may exhibit a family history, but either sex can be affected. Males most commonly present with bilateral leg edema in infancy, while females typically develop unilateral disease during adolescence [19].

Secondary lymphedema causes 99 percent of cases of lymphedema and usually results from cancer treatment that includes lymphadenectomy or radiation to axillary or inguinal lymph nodes. In resource-abundant countries, the upper extremity is the most common site because of breast cancer management. Other causes of secondary lymphedema include trauma, infection, and OIL.

Lymphedema initially increases extremity volume by high-protein fluid accumulation in the subcutaneous tissue. Over time, the inflammatory fluid stimulates subcutaneous adipose deposition further increasing the size of the leg [19]. In contrast to lipedema and obesity, adipose tissue in lymphedema is much more inflamed and fibrotic. The feet are always involved and typically are the most severely affected part of the extremity. On lymphoscintigraphy, patients exhibit delayed transit of radiolabeled tracer to their inguinal nodes and/or dermal backflow.

Because of the impaired lymphatic system, patients with lymphedema have an elevated risk of developing cellulitis in the affected extremity [19]. Lymphedema is managed with compression strategies, exercise, weight reduction for those with obesity, and maintenance of a normal BMI. Patients with symptoms who are no longer responsive to conservative management can be managed operatively. Similar to lipedema, liposuction effectively removes the excess subcutaneous adipose tissue and also can improve the patient's lymphatic function [20]. (See 'Liposuction' below.)

MANAGEMENT — The goals of management for patients with lipedema are to prevent superimposed lymphedema and thereby complications related to it, and to improve physical and psychological function. These are generally accomplished with weight control and liposuction.

Individuals with a body mass index (BMI) >30 and edema may benefit from compression therapy. Those with a BMI <30 and minimal edema are less likely to find compression therapy helpful, and it can worsen pain [1,5]. Compression therapy might improve symptoms through its anti-inflammatory effects or effects in managing concurrent lymphedema [6]. (See "Clinical staging and conservative management of peripheral lymphedema".)

Weight control — Exercise will benefit lipedema by helping to reduce weight and may also decrease adipose inflammation and enhance psychosocial wellbeing. [6].

Weight loss can reduce the amount of diseased adipose tissue in patients with lipedema [6]. Although the legs will remain disproportionately larger than the rest of the body, symptoms can be improved [6].

For those with a BMI>40, weight loss reduces ongoing injury to their lymphatic system. If the patient already has developed obesity-induced lymphedema (OIL), then reducing BMI <40 is necessary to decrease the progression of lymphedema. Although weight loss in patients with OIL does not cure the disease, it improves lymphatic function [21]. Weight loss also is helpful for patients with a BMI between 30 to 40.

Liposuction — Liposuction removes pathologic subcutaneous adipose, and based on primarily observational studies, it effectively reduces pain and other symptoms and improves appearance and quality of life [6,22-27]. Patients may elect to proceed with liposuction for symptomatic relief, or to improve appearance, or both. (See "Surgical treatment of primary and secondary lymphedema", section on 'Reductive techniques'.)

Liposuction is more effective in early-stage lipedema. Performing liposuction on patients with a BMI >40 is associated with increased complications, unfavorable outcomes, and recurrence [28]. Thus, patients with a BMI >40 are referred to a bariatric surgical weight loss program to help them reduce their BMI prior to liposuction. By contrast, the risks and outcome are favorable in patients who have a BMI <35. Liposuction can also be considered for very symptomatic individuals with a BMI between 36 and 39 if they have achieved their lowest possible BMI. (See "Bariatric surgery for management of obesity: Indications and preoperative preparation".)

Liposuction generally improves quality-of-life measures. In a prospective study, 511 patients with lipedema were provided quality-of-life surveys (World Health Organization Quality of Life BREF [WHOQOL-BREF] and the Patient Health Questionnaire 9 [PHQ-9]) [25]. Among those who proceeded with liposuction and completed both surveys before and after liposuction, there were significant improvements for physical functioning, including limitation in walking and occupational disability, quality of life, and satisfaction with appearance.

Prior to surgery, candidates undergo lymphoscintigraphy (if not already done) and MRI to determine their lymphatic function and ensure there is extra subcutaneous adipose that would benefit from the procedure (picture 2). The author prefers to operate on one extremity at a time with a minimum of six weeks in between procedures. Staging the legs allows immediate ambulation and reduces the risk of deep venous thrombosis.

Following liposuction, patients are discharged to home the day after the procedure. Postoperatively, they are encouraged to ambulate immediately to reduce the risk of venous thromboembolism. The surgical dressing, which consists of gauze and elastic bandages, is changed in the office one week postoperatively. Thereafter, the patients maintain compression (eg, elastic bandages, compression garment) for six weeks postoperatively to maximize skin contraction.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphedema".)

SUMMARY AND RECOMMENDATIONS

●Lipedema – Lipedema is a rare lipodystrophy occurring in females that can follow an autosomal dominant mode of inheritance with incomplete penetrance. Lipedema is commonly confused with obesity and lymphedema. Making the distinction between lipedema and obesity or lymphedema can be difficult because patients with lipedema may develop obesity and then lymphedema. (See 'Incidence and pathogenesis' above.)

●Clinical features – Classic clinical features of lipedema include the following (see 'Clinical features' above):

•Only females are affected

•Bilateral symmetric overgrowth of the lower extremities

•Prominent malleolar fat pads

•Normal feet (ie, negative Stemmer sign)

•No lower extremity infections

•Lower extremity aching discomfort at rest

•Lower extremity pain on palpation

•Easy bruising of the lower extremities

•Positive family history (ie, females with same phenotype)

●Diagnosis and differential diagnosis – The diagnosis of lipedema is based on clinical features including history and physical examination (algorithm 1). Differentiating lipedema from obesity or lymphedema may require additional evaluation predominantly using body mass index (BMI) and lymphoscintigraphy (table 1). (See 'Diagnosis of lipedema' above and 'Differential diagnosis' above.)

•Lipedema – Adolescent females or young adult females are more likely to present with the classical clinical features. These clinical features may not be present if an individual with lipedema has a BMI >30, and especially if BMI >40, because of the confounding clinical features of obesity. Additional evaluation is needed to differentiate lipedema from obesity without lymphedema (OWL) and obesity-induced lymphedema (OIL).

•Obesity – Patients with obesity have enlargement of their feet, abdomen, and other areas of their body and not just the lower extremities. A patient who presents without classical clinical features of lipedema and no evidence of lymphatic dysfunction on lymphoscintigraphy likely has OWL. (See 'Obesity' above.)

•Lymphedema – Lymphedema can be primary or secondary. Primary lymphedema can present as limb swelling in an adolescent but is often unilateral, whereas lipedema is bilateral. Other etiologies may lead to secondary lymphedema, but these are apparent on clinical history (eg, radiation therapy, lymphadenectomy). Severe obesity (BMI >40) can also cause bilateral lower extremity lymphedema (ie, OIL).

-Abnormal lymphoscintigram in a patient with a normal BMI history indicates the individual has lymphedema and not lipedema.

-Abnormal lymphoscintigram in a patient with a history of BMI >40 indicates the patient has OIL, but if suggestive clinical features are also present, the patient could initially have had lipedema. (See 'Lymphedema' above.)

●Management – Management of lipedema includes a combination of weight control and possibly liposuction.

•Weight control – Individuals with a BMI >40 should reduce their BMI below this threshold to alleviate lymphatic injury. Individuals with a BMI between 30 and 40 also benefit from weight loss. (See 'Management' above.)

•Liposuction – Liposuction effectively removes the pathologic subcutaneous adipose tissue and improves symptoms, physical functioning, and overall quality of life. We offer liposuction to patients who are most likely to benefit. This includes younger patients with elastic skin able to maximally contract who have a BMI <35. Symptomatic patients with a BMI between 35 to 40 can be treated with liposuction after achieving their lowest possible weight. (See 'Liposuction' above.)