Lipedema Is Not Just Fat

Karen L. Herbst, PhD, MD 2020-07-09

Lipedema is not just about abnormal or painful fat. Lipedema fat cells are part of a larger system of loose connective tissue. Understanding the unique features of lipedema fat cells within this environment helps explain lipedema symptoms and holds promise for more effective lipedema treatments.

Lipedema is a disease with symmetrical enlargement of subcutaneous fat tissue of the limbs almost exclusively in women.  The fat in lipedema can be painful[2] and is difficult to lose by diet, exercise or bariatric surgery.[3-5]   The legs are affected initially in lipedema, causing a pathognomonic disproportion of the body with a larger bottom and smaller top.  The enlarged fat on the thighs, inner knees and calves can limit mobility. 

 Lipedema is described by stages:

• Stage 1 lipedema tissue has smooth skin but small nodules within the fat. 

• Stage 2 has irregular skin -  like a mattress pattern -  and larger masses within the fat. 

• Stage 3 has larger extrusions of fat forming lobules and even larger masses. 

People with lipedema can go on to develop lymphedema, especially in later stages.[1] 

There are different types of lipedema meaning the location of the fat can be different.  These types were originally described in women; it is unclear if all the types pertain to men: 

• Type I affects the lower abdomen down over the hips and buttocks.

• Type II affects lower abdomen down to the knees.

• Type III affects the lower abdomen to the ankles. 

• Type IV is when the arms are affected

• Type V affects primarily the lower leg. 

Most women have Types II and IV or Types III and IV.[6]

Lipedema has been labeled a disease of fat or a fat disorder.  By definition, fat is loose connective tissue (LCT).  Loose connective tissue consists of areolar, reticular and adipose tissue.  In this paper, our use of LCT refers specifically to the form and contents of adipose tissue.  Lipedema is therefore a disease of loose connective tissue, or a loose connective tissue disease.

Our body is made of different kinds of connective tissue such as dense and loose connective tissue.  Loose connective tissue is 1) fibers, such as collagen and elastin, 2) cells, including fat cells (adipocytes), immune cells such as macrophages, mast cells and lymphocytes, and fibroblasts that help create more fibers, and 3) a gel consisting of glycosaminoglycans  (GAGs).  Glycosaminoglycans are repeating disaccharide (double sugar) units that can hold large amounts of water and sodium and form a gel. Loose connective tissue is very well hydrated with 1) free-flowing fluid (water) containing proteins such as albumin, electrolytes, nutrients, cell waste material, and 2) water bound to GAGs that can be in liquid (sol or hydrosol) or gel form.   The area outside of cells containing the fibers and free and bound fluid is called the extracellular matrix (ECM). 

Loose Connective Tissue Structure

The structure of LCT (fat) is a web of fibers/fibrils or a fibrillar network described as “transparent veils”[7] that fill the area between anatomical structures such as skin, tendons, bone and muscle.  On a microscopic level, this woven network of fibers has repeating polyhedral structural units called microvacuoles, defined as the volume created by the space between the intersection of fibrils.[7]  Some of the fibrils in the loose connective tissue are continuous with fibrils in the skin (dermis).  The fibrils help determine the shape of fatty lobules (groups of adipocytes) and ensure they move easily under the skin.  The fibrils in LCT also extend into the superficial fascia, a sheet of connective tissue between two layers of fat on the outside of the body helping to give us shape and form. 

Superficial fascia abnormalities, visible as breaks in the fascia lines on ultrasound, appear to be common in lipedema and may be improved following therapy. See for example Figure 2 in [56]. Abnormalities of the superficial fascia can contribute to chronic fatigue, fibromyalgia, pain, and inflammation.[8]

Long-distance Interstitial fluid flows through fibrous matrices within LCT and superficial fascia which are relatively independent of the vascular circulation have been identified and mapped. These long-distance pathways appear to connect to acupuncture points and may be analogous to the Meridians that carry the life-energy known as "qi" and other fundamental substances in Traditional Chinese Medicine, however pathways varied significantly in all subjects.[59]   

Glycosaminoglycans and Proteoglycans

GAGs are repeating disaccharide (double sugar) units that are sulfated and therefore carry a negative charge.   This negative charge allows GAGs to bind sodium and water.  GAGs can bind to a core protein forming a proteoglycan, also known as a glycoprotein (see Figure 1).

The most prevalent GAG is hyaluronan which is not sulfated but can bind to proteoglycans forming a proteoglycan complex (see Figure 1).  GAGs can bind to many different classes of proteins and are therefore integral to the structure of the ECM; they also interact with growth factors and cytokines. Cytokines are signaling molecules produced by cells that have biological activities.[9] 

Lipedema fluid is bound to GAGs

The name lipedema means “fluid in fat”.   Lipedema LCT generally affects the limbs sparing the trunk, hands and feet (see Box 1).  Free fluid flows down with gravity as in lymphedema where the feet or hands are one of the first places for fluid to appear on physical exam, although symptoms (such as aching) can happen earlier.  If the hands and feet of women with lipedema are not affected, then where is the fluid?  We think the fluid in lipedema is bound to GAGs in the ECM.  Fluid that is bound into a GAG gel does not flow as freely as lymph fluid that moves outside of the fibril matrix.  That women with lipedema develop heavy fat tissue[1, 10] suggests there is fluid in the tissue as fluid is denser and heavier than fat (see Box 2). 

Fluid bound to GAGs is not seen easily on ultrasound because it is in the GAG gel surrounded by fibrils, whereas in lymphedema, the fluid is free-flowing outside of the fibril matrix and visible on an ultrasound[11, 12] as shown in Figure 2.

Lipedema is therefore different from lymphedema in that there is minimal free-flowing fluid and more GAG-bound fluid in the ECM; people with lymphedema have both free-flowing fluid and GAG-bound fluid (see Table 1).[13]  Excess fluid and stagnation of fluid causes an inflammation when fat cells cannot get enough oxygen; the end result of inflammation is that body tissue (i.e., the ECM in skin, fat, muscle) becomes fibrotic, and scar-like connective tissue replaces normal tissue.[14] The excess fluid also makes fat grow.[15, 16]  This constellation of findings in lymphedema has been called lympho-fibro-adipo-edema.[17]

Evidence that lipedema has fluid bound to GAG

There are publications that state that lipedema is not a disease with edema because it does not have free-flowing fluid as in lymphedema (see Table 1).[18, 19]  Fluid in the body exists in multiple compartments (see Table 2).

Fluid in lipedema and lymphedema is located in the interstitial fluid (ISF) compartment (see Table 2).  The definition of edema is “an excess of interstitial fluid”.[21]  Interstitial fluid is the fluid between cells in the ECM.  Interstitial fluid is present either as free flowing fluid within which albumin, electrolytes, nutrients, cell waste material and cells are found, or as a gel phase with GAGs bound to water and sodium; the GAGs can be alone or bound to a protein core forming a proteoglycan or glycoprotein.  The GAG gel serves to cushion our LCT and protects our body against edema.  Although there are not a lot of studies on GAG in lipedema, we can learn about how GAGs function in other edemas.  To understand the role of GAG in any edema, we need to understand fluid flux through the ECM.

Fluid flux through the ECM

Glycoproteins in Lipedema Loose Connective Tissue Disease

There is good data to suggest that there is an increased amount of GAG in the LCT ECM of women with lipedema.  Therefore, the edema in lipedema is bound to GAG and/or glycoproteins.  In other words, lipedema edema is a glycoprotein edema.  An older name for glycoproteins disease was mucinosis, and therefore lipedema could be classified as a disease of mucin.

In a study of women with lipedema and women without lipedema (Controls), extracellular fluid (ECF) was higher in women with lipedema by bioimpedance spectroscopy.[27]  This method is not adversely affected by excess lipid (fat).[28]  Extracellular fluid includes interstitial fluid (ISF) and fluid within vessels (intravascular).  These data assume that pressure within the vessels (blood pressure) and oncotic pressure (protein in blood) within vessels is normal in women with lipedema.  ECF was found to be higher than Controls, even in women with Stage 1 lipedema who have normal blood pressure and other indices of metabolism.[29] These data suggest that the excess ECF in women with lipedema was within the interstitial space.   If ECF in lipedema tissue is not free as in lymphedema, then it is bound.

Why would lipedema LCT accumulate excess fluid bound to GAG?  Lipedema LCT is highly compliant.[30]  In compliant tissue, when interstitial volume increases, pressure in the interstitial space/ECM does not increase proportionally as the tissue expands,[25] and fluid accumulation and stasis occur. 

Fluid injected into lipedema LCT will spread out into the ECM (high compliance) before it enters lymphatic vessels.  Whereas in normal LCT, higher interstitial pressure (low compliance) will drive fluid rapidly into the lymphatic vessels before it can spread into the ECM.[31] 

In support of increased compliance in lipedema LCT, many women with lipedema also have hypermobile joints by the Beighton score.[1, 32]   A higher Beighton score is suggestive of a connective tissue disorder such as Ehlers Danlos hypermobile spectrum disorder, Classic Ehlers Danlos Syndrome (EDS) or Classic-like EDS[33] (see Box 1).  When a tissue becomes compliant, there is a reversible unravelling of hyaluronan[34, 35] and fibroblasts, which have attached to ECM fibrils, relax in response to inflammatory mediators allowing the GAG complex to increase in amount or charge.[36]

GAGs are negatively charged and bind sodium and water.  Hyaluronan binds sodium 1:1 and sulfated GAGs can bind even more sodium, up to 1:3.  Sodium content was found to be higher in the skin and tissue of women with lipedema compared to Controls.[37]  Sodium is therefore a marker for altered GAGs, either the amount or charge. 

If we assume the mechanics of edema in congestive heart failure[26] replicate in part the mechanics of fluid flux in lipedema, there is likely an increase in both charge capacity and number of GAG in the ECM of lipedema tissue.  In support, when inflammation occurs in soft tissues, increased sodium and concurrent GAG accumulation is reported.[38] Inflammation in lipedema tissue is demonstrated by increased macrophages in lipedema skin and fat[39-41] and by the structure of blood vessels in the skin suggestive of an inflammatory condition.

Lipedema is also considered to be a form of cellulite pathology.[42]  GAGs are elevated in the skin of women with cellulite.[43]

The interstitial space is enlarged in lipedema fat.[39, 41] Specific for lipedema, fat cells (adipocytes) are spaced further apart from one another than normal (see Figure 3), which moves adipocytes away from the blood microvessels and therefore their oxygen source.  Low oxygen or hypoxia has been proposed to occur in lipedema LCT.[44]  Hypoxia in tissue can lead to necrosis or death of cells in the tissue.  When this happens to adipocytes, macrophages (the “pac man” immune cell that can eat up cell debris) enter the LCT and surround the fat cells to remove the dead tissue and the triglycerides released by the fat cell.  Necrotic adipocytes surrounded by macrophages are called crown like structures and have been found in lipedema LCT.[39, 45]  A main component of the interstitial space is the GAG hyaluronan.  When there is excess fat tissue as in obesity or lipedema, the amount of hyaluronan in the tissue increases in the ECM,[14] which would widen the spaces between cells. 

There is an overgrowth of blood vessels in lipedema skin and LCT.[39]   The increase in blood vessels is not matched by increased numbers of lymphatic vessels, a physiology that would promote the stagnation of fluid in the interstitial space[39] especially when capillaries are leaky in lipedema.[13, 46]

Hands and feet are spared in lipedema. The fluid in the interstitium is bound and does not flow down to the hands and feet.

Other edemas known for non-pitting edema (like lipedema) have increased GAGs in the interstitial space including localized myxedema,[47] lymphedema,[13] and venous disease, the latter due to the presence of edema, increased hyaluronan in the vein wall,[48] and an increase in GAGs in the skin when chronic venous insufficiency occurs.[49]

Why does lipedema tissue occur primarily on the limbs?

In all people, fluid shifts from the trunk to the lower body on standing.  This increases pressure in the blood vessels of the lower abdomen down the leg.[50]   About ½ to 1 liter of fluid shifts from the thorax to the lower body on standing.  About 80% of the fluid shifts into the buttocks and thighs, common places for lipedema tissue to occur in Type II lipedema. 

If a woman with lipedema has compliant LCT because of a connective tissue disorder, blood vessels may also be affected because they are also made of connective tissue.  These weaker more compliant vessels could release their contents into the ECM at a higher level than in a person who had stronger connective tissue.  Capillaries have been shown to be leaky in lipedema.[13, 46] Interestingly, when the fluid shifts during standing, the pooling happens less in the calf and the foot.  Could this be why the foot is less effected in lipedema.  If compliant lipedema tissue is combined with standing but also venous disease, could this then cause additional fluid to pool in the calves resulting in Type III lipedema?

The Importance of Glycoproteins and GAGs in the Treatment of Lipedema

Better understanding of the pathophysiology of lipedema can help us improve treatment protocols for this disease.  The following therapies are recommended for people with lipedema:

Manual therapy: The limbs of a person with lipedema, in the absence of lymphedema, may benefit from deep treatment to access the entire LCT structure.  Fibrosis in the LCT inhibits flow and fluid binds to GAGs.  Since flow through the tissue is stagnant at least in parts of the LCT in people with lipedema, the adipocytes are not in a normal environment and are likely to have a lower rate of lipolysis under a variety of conditions.  As part of MLD for lipedema, therapists use deeper techniques to improve the structure of lipedema LCT.  Manual lymphatic drainage (MLD) remains important for lipedema as it is known to normalize the lower lipolytic responsiveness of femoral (around the groin and thigh) fat tissue and improve microcirculation, important for good oxygenation of the tissues.[51]  MLD also improves capillary fragility[52] and reduces lipedema pain.[53, 54]  Deeper manipulation of lipedema tissue reduces volume of the legs, fibrosis of the tissue by palpation, caliper measurements (that measure thickness of tissue), and fat tissue, measured by the gold standard dual X-ray absorptiometry exam (DEXA), a study requiring only seven women to show significance.[55, 56]  Breakdown of fatty fibrotic tissue by deeper tissue manipulation is also described for lipedema by Casley-Smith.[53]  Deeper manipulation of lipedema LCT improves fluid flow out of the tissue, reduces inflammation, and similar to localized myxedema, can move GAG out of the ECM.[57]

Other Soft Tissue Therapy: The use of instrument assisted soft tissue therapy such as gua sha tools, Astym Therapy, Graston technique can improve microcirculation [59] liquefy the GAG gel allowing the fluid and GAGs, including hyaluronan, to be moved through the ECM and out long-distance channels (the interstitial organ [79]) and lymphatic vessels.[60]

Compression Garments: External forces on pre-adipocyte (precursor) cells in vitro reduces differentiation of the cells into adipocyte/fat cells.[61] Under external forces, cells spend their energy more on ECM remodeling/healing, than on triglyceride storage.[62]  External forces include compression garments, pumps, manual therapies, swimming, stretching and other exercises.

Sequential Pneumatic Compression Pumps: Sequential pneumatic compression pumps (pumps) are devices that when placed external to the body, place pressure on the tissue.  When the external pressure starts at the foot and moves up the body, the pumps can help remove fluid from the tissue.  Pumps have been shown to improve the flow of lymphatic fluid.[63]  Pumps also improve lymphatic flow when applied to the abdomen,[64] a place where women can also develop lipedema tissue.[1]  Increasing fluid flux also increases the movement of hyaluronan out of the ECM into lymphatic vessels.[65]  Hyaluronan is the most abundant GAG in LCT and skin.  We think using pumps can improve the basic etiology of lipedema which is the accumulation of water bound to GAG in the ECM.

Control inflammation: Chemicals that are integral to inflammation include histamine and serotonin, both which cause arteriolar vasodilation (enlargement of the vessels just before the capillary) and venous vasoconstriction (reduced size), which promotes the movement of fluid from the capillaries and post-capillary venules into the interstitial space.  Reducing causes of inflammation in lipedema is important including allergies, infections, processed foods, excess food and inactivity.

Corticosteroids: While corticosteroids or glucocorticoids like Solumedrol and prednisone can decrease GAGs[67] resulting in skin atrophy (thinning), other studies for example in the eye have shown an increase in GAG after corticosteroids.[68] Corticosteroids also increase sodium in the body and extracellular fluid volume.[69]   Excess sodium can damage the lining of blood vessels called the glycocalyx,[70] resulting in increased movement of fluid from blood vessels into the ECM.  Single corticosteroid injections into joints seem to be well tolerated.

Food: Eat anti-inflammatory foods to protect the microvessels.[71, 72]  Avoid processed foods that contain a lot of salt.

Anti-inflammatory supplements: Supplements usually derived from food or plants can help reduce inflammation.  Some people respond to them and some do not; some people absorb supplements well and others do not.  Examples of anti-inflammatory supplements include diosmin[73, 74] and vitamin C[75], where high dose vitamin C has been shown to reduce edema.[76] Vitamin C (lipophilic; subcutaneous injection or intravenous) reverses abnormal lowering of interstitial pressure.[77]

Avoid obesity: Weight gain increases inflammation which can worsen lipedema.  If a person gains weight, they can develop a fatty liver.  A fatty liver increases insulin resistance and inflammation in the body but it also increases the amount of lymph fluid produced by the liver[78] which can increase the risk of edema.

Concluding Remarks

Lipedema has long been thought of as just a fat disorder.  We now believe that lipedema is a disease of LCT and that fluid bound to GAG in lipedema LCT plays a major role, making lipedema a glycoprotein disease as well.  We hope that this new understanding of lipedema opens research in the area of glycoproteins and glycosaminoglycans which can lead to improved care for people with lipedema and progress towards a cure. 

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