Lipedema


Lipedema is a classically thought of as a congenital fatty enlargement of the legs almost exclusively seen in women by the third decade; very few cases have been reported in men.1-3  According to an epidemiologic study by Földi E and Földi M, lipedema affects 11% of the female population.4 Of women with lymphedema, estimates are that 15%5 or 8% to 17% have lipedema as well6.  German guidelines suggest the prevalence of lipedema is 6-8%7 and this agrees with a prevalence estimate for children in the United States.8

Lipedema was initially described by Allen and Hines9 in 1940; its etiology remains unknown and it remains under-diagnosed. In 1951 Wold et al.1 analyzed 119 cases and provided the diagnostic criteria for lipedema: 

(1)  Almost exclusive occurrence in women
(2)  Bilateral and symmetrical manifestation with minimal involvement of the feet
(3)  Minimal pitting edema; the Kaposi–Stemmer sign is negative
(4)  Pain, tenderness on pressure
(5)  Increased vascular fragility; easy bruising
(6)  Persistent enlargement after elevation of the extremities or weight loss

I have added:
(7)  Arms are affected 30% of the time10
(8)  Hypothermia of the skin
(9)  Swelling worsens with orthostasis in summer
(10)Poorly responsive to caloric restriction11
(11)Telangiectasias

In my practice, I see many people with lipedema, familial multiple lipomatosis (FML), Madelung’s disease and Dercum’s disease (adiposis dolorosa) which can include angiolipomas.12  One description of multiple symmetric lipomatosis (MSL; Madelung’s disease) and representative pictures of MSL13,14 look very similar to a woman with lipedema. A number of women have both lipedema and Dercum’s disease,15 so differentiating these diseases from one another can be difficult.  Synonyms for lipedema also include adiposis dolorosa (Table 1) which is why I do not use the term adiposis dolorosa for either condition as it just confuses things.

Table 1. Synonyms of Lipedema
Lipalgia
Adiposalgia/Adipoalgesia
Adiposis dolorosa
Lipomatosis dolorosa of the legs
Lipohypertrophy dolorosa
Painful column leg
Painful lipedema syndrome



What is going on in lipedema at the level of the tissue?
Since lymphedema is minimal in early lipedema (meaning the ankles and feet do not swell with fluid until later in the disease when the lymphatics begin to fail), the limb swelling is due, in part, to hypertrophy and hyperplasia of fat cells.16  The gross description of the fat in lipedema is similar to that of MSL with copious amounts of watery fluid upon incision of lesions and of ‘free fluid fat’ in biopsy specimens.17 The increased fluid suggests a basic abnormality in the interstitial transport and exchange of fluid, with resulting disruption of fat and accumulation of fluid due to increased hydrostatic pressure from abnormal small blood vessels and likely also lymphatic dysfunction.18,19 So this means that fluid is either entering fat at a faster rate and leaving fat at a slower rate.

I think lipedema has problems in both lymphatics and blood vessels:
 
Here’s why:  
First: Visualization of lymphatic vessels on a gross level by lymphoscintigraphy was normal in women with lipedema.16 Ok, so the big lymphatics seem to be functioning ok in early lipedema. In another report, they compared lymphatics in lymphedema to those in lipedema and found that the spread of dye in the microlymphatic network is enhanced in lymphedema but unremarkable in lipedema.20 Indeed, microlymphatic occlusions are absent in lipedema – Nothing is blocking the flow of lymph in the lymphatics – So early in lipedema, your lymphatics have normal flow; this is a problem because you have edema in your fat that you need to get rid of – the lymphatic system needs to function more or faster but it does not. In fact, lipedema is always accompanied by a dynamic insufficiency of the lymphatic system.10

Second: Here is the kicker, smaller lymphatic vessels in the subcutaneous fat were abnormal by lymphangiography and leaked.21 I am not clear that this problem is confined to fat.  Dr. Al-Ghadban and colleagues showed that there was angiogenesis (growth of new vessels) in lipedema fat that likely contributes to more leak into the fat tissue as these small vessels were dilated and tortuous.22  Lymphatic fluid if it leaks out of vessels can make fat grow,23,24 so pre-lymph fluid between cells also likely contributes to fat growth as lymph fluid is directly derived from interstitial fluid which bathes cellular layers.25 When the fat grows and a woman with lipedema develops secondary obesity, the lymphatic vessels dilate but there are no new lymphatic vessels being formed which contributes to fluid getting stuck in the tissue.22  We do not know why the lymphatic vessel growth (lymphangiogenesis) does not keep up with small blood vessel growth (angiogenesis). 

Third: As lipedema progresses or is simply present for a longer period of time, microaneurysms appear in the lymphatics in the in the skin of lipedema patients by microlymphangiography20 – this means that your lymphatics are stretched out and at risk for leaking

Fourth: But wait. Another report found increased lymphatic transport by functional scintigraphy in lipedema compared to controls and lymphedema.26 By the fifth decade (so after 20 years of having lipedema), values (of lymphatic flow) slightly decrease under the lower limit of normal. This situation may result in lymphedema21,27,28 – The aneurysms in the lymphatics ultimately leak so now there is lipedema (fluid in fat from damaged blood vessels) and lymphedema (leakage from lymphatics) causing lipolymphedema. Also, when did the increased flow start 

Fifth: It could be that increased fat in lipedema recruits macrophages that inflame blood vessels leading to leakage, edema and taxation of the lymphatic system.  Inflammation inhibits lymphatic vessel function and contributes to lymphedema.29  We and others have found increased macrophages in lipedema that surround blood vessels and form oil cysts.22,30 So in this case, we need to find out what makes the fat grow to such an extent.   
 
Sixth: In lipedema, on examination of tissue samples, they found dilation of subdermal blood capillaries, fibrosis of arterioles, fibrosis and dilation of venules, hypertrophy and hyperplasia of adipocytes31,32 – this means that the capillaries just under the surface of your skin are wide and can be seen as little red marks on your skin if you look closely enough, that the walls of small vessels have increased connective tissue (fibrosis). According to German, Italian and Swedish literature, lipedema starts as a microangiopathy.  This means that there is damage to small blood vessels and they leak their contents into fat. This is why you bruise easily – your blood vessels, at least in your fat and skin are not normal.  Something is wrong we just don’t know what!
 
Lipedema as a Connective Tissue Disorder
We know that many women with lipedema have hypermobile joints.33  Many of my patients with lipedema have been diagnosed with Classic Ehlers Danlos or Ehlers Danlos Hypermobile Spectrum Disorder.34,35  This means that lipedema is a connective tissue disorder at least for these patients.  In fact, the definition of fat is that it is loose connective tissue.  The body is essentially different connective tissue types that work together as fascia to make the body work and maintain shape. 
Some findings that suggest that lipedema tissue is a connective tissue disorder are as follows:
  1. Soft velvety skin
  2. Unusual scars
  3. Hypermobile joints by the Beighton Criteria
  4. Antimongoloid slant to the eyes
Connective tissue is important to blood and lymphatic vessels. So, if there is a connective tissue issue, then this could weaken both vessel types leading to increased fluid in the interstitium (area between cells). 
We know that there is increased extracellular water (in the interstitium) in the legs of women with lipedema compared to the arms, increased extracellular water in the legs of women with lipedema compared to controls and increased leg versus arm fluid in women with lipedema compared to women with Dercum’s disease.36
This extracellular fluid is not free flowing through the tissue like in lymphedema, but it stays within the interstitium.  How does that happen? In the interstitial space, there are glycosaminoglycans that bind water and salt.  Glycosaminoglycans (GAGs)are complex linear arrays of sugars that are highly sulfated and live in the interstitium, in cerebrospinal fluid and form part of the glycocalyx that protects our vessels from leakage.  The binding of salt and water to GAGs forms a gel and this is what makes the lipedema tissue heavy.  Women with lipedema have higher salt levels in the tissue than women without lipedema in support of this hypothesis.37


Additional Information
Leaky lymphatics are seen in the homeobox gene Prox1 heterozygote mice.38
Lymph stimulates adipogenesis in culture.23,24 
Abnormally clumped elastic fibers have been seen in lipedematous tissue.39
Free fatty acids may be altered in both blood and the lipedema tissue.17

My Standard of Care for Lipedema

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1)      Complete Decongestive therapy – This includes decongestive massage, wrapping and garments. A trained therapist in your area can be found here: 
      a) http://www.vodderschool.com/
      b) http://www.lymphnet.org/resourceGuide/manualDrainage.htm#CA 
      c) https://klosetraining.com/therapist-directory/
      d) http://www.casleysmithinternational.org/
       e) https://clttraining.wixsite.com/courses/andrea-brennan

This therapy works best for women with heavy limb tissue or lymphedema.  Your therapist will also help you with compression garments and getting a pneumatic compression pump.

2) Deep tissue techniques for lipedema. We have shown that deep tissue treatment that works slowly down from skin down to bone reduces pain, reduces fibrosis, improves quality of life and reduces fat by the gold standard DEXA scan.40,41  Deep tissue techniques include:
  1. Quadrivas Therapy (available in the Netherlands and wherever a trained therapist can be found: https://www.quadrivas.nl/quadrivastherapy/)
  2. Astym therapy (https://astym.com/)
  3. Graston Technique (https://grastontechnique.com/)
  4. Thai massage
  5. Meridian massage
Please be aware that deep tissue therapy techniques can be painful and cause bruising.  Everyone is different so your treatment plan should be one designed by you, your therapist and your healthcare provider.

3)     One of the first things I like to suggest for lipedema is to help the immune system function properly. It is well known that lymphedema reduces local immune function, increasing the risk of cellulitis. The immune system is also overwhelmed by the amount of inflammation in lipo-lymphedema, therefore, I usually suggest you start some sort of immune modulator. 
        a) Mushrooms: To improve immune function, try  Fungi Perfecti Host Defense Cordyceps Energy Support -120          vegetarian Capsules.  Take one capsule daily initially. Can increase up to two daily. Monitor for flu, colds.                         Cordyceps mushrooms are well known to positively modulate immune function.42  Other mushroom preparations           by this same and other companies may work as well.
        b) Epicor: Epicor is a fermented yeast product that has beta-glucan as a main ingredient and which also has data          supporting it’s prevention or improvement of colds/flu.44  Epicor even helps reduce symptoms in the gut by                      improving the gut microbiome.43  I have chosen Drs. Best Epicor as I know their pharmacist and they have an              FDA approved lab for making their products.  They are very careful about quality control and they are priced well.
        c) Beta glucan 1,3/1,6 from the yeast cell wall (yeast Beta 1,3-D glucan) to boost your immune system. There are          thousands of papers in the literature (pub med) demonstrating effects of Beta 1,3-D glucan on the immune system          including increasing IgA in saliva and reduced post-operative infections; Beta 1,3-D glucan may enhance                        hematopoiesis, amplify killing of opsonized tumor cells and increase neutrophil chemotaxis and adhesion. The                dose is 500 mg per day or more (or 2-6 mg/kg).  The problem with beta glucan is its absorption. It tends to clump            when added to water, which prevents a bulk of it from being absorbed. NOW brand's version tend to be less                    expensive which is why I have recommended it here. To help with absorption you can dissolve a few capsules into          a small amount of warm/hot water. Use a spoon to de-clump. Drink with lypophilic vitamin C to help with                       absorption.
4) Selenium: Selenium has been shown to decrease edema in tissue. Selenium decreased edema in two placebo controlled trials for post-mastectomy and head and neck radiation(28, 29), it increases the efficacy of physical therapy for lymphedema, it reduces the incidence of erysipelas infections in patients with chronic lymphedema at various sites(28) (and others); it lowers oxygen radical production in part by increasing glutathione peroxidase and thioredoxin reductase; it dcreases glycoprotein adhesion molecules (eg, P-selectin, ICAM-1, VCAM-1, ELAM-1) in a dose-dependent manner45 which may unclog lymphatic capillaries; it significantly enhanced cellular immunologic reactions improving efficacy of cytotoxic T-lymphocytes and stimulating macrophages degradation of excess tissue proteins.46 The US National Research Council has defined the individual maximum safe dietary intake for selenium as 600 μg daily and the no adverse effect level as 800 μg daily. Anticipate a possible increase in pain or decreased well-being as the toxins come out of the tissue. However, if you don’t feel good taking the selenium, then stop it. Life Extension has a nice inexpensive selenium product you can find here.  Start with just 200 mcg a day.  Have your healthcare provider make sure your blood levels are not too high.  Continue the selenium even if your levels are in the normal range; just be sure to stop if levels get too high.

5. Bioflavonoids: An older effective treatment for lymphedema, 4 benzo-pyrone, coumarin47, is no longer available because of liver toxicity in some people; other 4-benzo-pyrones such as Daflon may or may not be effective.48 Daflon is as flavonoid, that has been used to treat lymphedema; it may be expensive and unlikely available by prescription. I treat lipedema with large doses of bioflavonoids. These can be purchased in powder bulk and mixed into smoothies, soup, spaghetti sauce, etc. These include:
     a)  Horse chestnut seed extract (HCSE): a very well-studied nutraceutical for varicose veins) such as from Nature's Way found here.  HCSE gel has been shown to reduce lower leg edema and the subjective alleviation of leg pain, heaviness, and itching.(49)  You can buy HCSE gel called Venaforce where 1g contains 54-177mg dry extract standardized to 2% aescin.  Apply to affected areas 2 x per day.  This gel works similar to the oral form!
     b) Citrus bioflavonoids
     c) Quercetin: Quercetin is known to inhibit fat growth and may help with allergies (it has antihistaminergic activity) making this bioflavonoid a good choice. 
     d) Pycnogenol: Take smaller doses of pine bark extract (pycnogenol) such as 200 mg daily. 

If you use powders, divide the bioflavonoid powders so you take up to 3 grams a day. Mix up the bioflavonoids so you are not taking the same ones every day. You can buy 1000mg tablets of quercetin and 1000mg citrus bioflavonoids (but be careful – this one might be very tough on your gut so best to work up to anything that contains 1000mg of bioflavonoids). Then you can take 300mg of horse chestnut seed extract or grape seed extract three times a day to equal 3 grams a day. 

CONCLUDING REMARKS
1. Lipedema is a loose connective tissue disorder
2. Women with lipedema should be assessed for hypermobile joints and Ehlers Danlos syndrome
3. Lipedema need not be progressive with good care
4. Maintaining weight is actually good!  Much better than weight gain.

UNDER CONSTRUCTION: COME BACK TOMORROW FOR MORE!

​References
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