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Page 2 of 10 Wiedner et al. Plast Aesthet Res 2020;7:10 I http://dx.doi.org/10.20517/2347-9264.2019.51

Lipedema is possibly a common but underdiagnosed disorder, which is almost exclusively found in females,
but, as there is no standardized diagnostic test, the exact prevalence is unknown. According to German
[2-4]
studies, 8%-18% of patients referred to a lymphedema clinic suffer from lipedema .
The pathogenesis is not fully understood yet. Lipedema often affects several female members of the same
[5]
family, suggesting a genetic disorder . A positive family history is common and ranges between 16%
[6]
and 64% , but is likely higher due to under-diagnosis. Autosomal dominant inheritance with incomplete
penetrance and sex limitation is the most likely mode of inheritance . Since the disease usually manifests
[5,7]
or is aggravated around hormonal changes (puberty, pregnancy, and menopause), lipedema is assumed
to be an estrogen-regulated polygenetic disease. It is associated with vasculo- and lymphangiopathy .
[8]
There are numerous theories on pathogenesis. On the one hand, an altered estrogen-receptor pattern and
responsiveness is assumed to exist centrally. On the other hand, pathologic estrogen-receptor patterns
(alpha/beta) in the adipose tissue lead to increased lipogenesis and decreased lipolysis in the affected
areas .
[8]

Histologically, the fat deposition is a result of hyperplasia and hypertrophy of fat cells in the subcutaneous
[8]
adipose tissue . Additional mechanisms were demonstrated to play a role in the pathogenesis of lipedema
including increased vascular permeability and damage (microangiopathy), excessive lipid peroxidation, and
disturbances in adipocyte metabolism and cytokine production [9,10] . Inflammation of the peripheral nerves
and sympathetic innervation abnormalities of the subcutaneous adipose tissue may be responsible for
[8]
neuropathy . One recent investigation on differences between adipose stem cells from lipedema and non-
lipedema donors indicated that in vitro adipogenesis of lipedema adipose stem cells is severely hampered
in comparison to non-lipedema adipose stem cells and that lipedema adipose stem cells not only differ in
their lipid storage capacity but also in their adipokine expression pattern . The findings indicate that this
[11]
might serve as a valuable marker for diagnosis of lipedema, probably from an early stage.

Due to lack of knowledge, lipedema used to be a frequently unrecognized and misdiagnosed disorder. For a
long time, the disease was equated with obesity, although lipedema fat is more resistant to reduction by diet
and exercise than non-lipedema fat. The condition should be clearly distinguished from other dysfunctions
of fat distribution, mixed forms of obesity and lymphedema. In addition to the progressive physical
symptoms and consequences (lymphatic, dermatologic, and orthopedic problems), psychosocial distress
with comfort eating and depression frequently arise in lipedema patients.

The diagnosis of lipedema is usually based on medical history and clinical features . One criterion is the
[6]
onset of the disease in parallel with hormonal changes and occurrence mainly in women [1,12] . Lipedema
typically presents with a disproportionate enlargement of the limbs in relation to the upper part of the
body [6,13] [Figure 1]. Increase of adipose tissue of the limbs is symmetrical, without involvement of feet
[6]
or hands. Fat deposits begin abruptly above the malleoli, which creates the “cuff sign” [Figure 2]. Other
clinical criteria of lipedema comprise spontaneous or minimal trauma induced bruising, pain, and
worsening during the day [5,14] .

The severity of lipedema can be classified into four clinical stages according to skin conditions and the sizes
of the palpable and visible fat nodules [15,16] [Figure 3]:
Stage 1: Flat skin with thickened subcutaneous tissue;
Stage 2: Increasing subcutaneous fat and walnut to apple-like indurations in the skin akin to a mattress;
Stage 3: Larger indurations and deforming skin-fat lobes, especially in the thighs and knee areas;
Stage 4: Development of additional lymphedema (lipolymphedema).

The development of lymphedema with lipedema (often known as lipolymphedema) can occur with any
stage . After a mean of about ten years suffering from lipedema, the lymphatics likely become insufficient.
[10]