In 1940 Allen and Hines described a pathology characterized by symmetrical swelling of the lower limbs, caused by enlargement of subcutaneous adipose tissue.
Although less frequently, sometimes the upper limbs develop lipedema and, in rare cases, the abdomen too. This condition was called lipedema or lipoedema. It is frequently confused with a disease with similar physical characteristics called lymphedema.
Lipedema is a chronic progressive disorder whose cause is believed to involve genetics and hormonal, inflammatory and nutritional factors. It affects subcutaneous cell tissue, especially adipocytes (fat cells) in specific parts of the body.
An increase in volume and consistency is observed in the affected area which usually progresses over time.
The condition usually affects the lower limbs. In the early stages it affects the thighs advancing into the area below the knee to the ankle (97%). Around them, the sign of cuff will develop.
However, occasionally, the area below the knee is affected from early stages. The feet will only be involved in very severe stages (lipo-lymphedema).
About 30 % of people with lipedema also have affected arms (especially in their proximal half), sometimes the abdomen is affected too.
Lipedema is bilateral and almost symmetrical. However, a thorough examination will show that one of the limbs is always slightly more affected than the other.
Lipedema is poorly known and frequently misdiagnosed both by the general public and healthcare professionals. This is one of the reasons why the medical literature includes a wide variety of terms to speak about it (lipomatosis dolorosa/ painful fat syndrome, lipo-hypertrophy dolorosa, lipalgia, adiposalgia/adipoalgesia, painful column-like legs)
Lipedema is a condition which affects mainly only women without distinction of race.
According to several studies 10 %-16% of women suffer from lipedema in its different stages (some studies state that 39 % of women worldwide may be affected by lipedema).
About 50 % of women diagnosed with lipedema present overweight or obesity. Almost all patients with advanced cases of lipedema have obesity too.
The onset of the disease is generally related to hormonal changes. In most cases it begins at puberty. In few occasions lipedema may develop after pregnancies, oral contraceptive use, menopause and ovarian surgery.
Lipedema is a hereditary disease. According to some authors 16%-20% of the patients have a family history of lipedema.
Genetic inheritance is not linked to mitochondrial DNA since sometimes, unaffected males transmit the disease to female offspring.
Only 2%-4% of the patients who suffer from lipedema are men, most of whom, are also affected by estrogenic hormonal disorders and/or liver diseases.
Currently, the cause of lipedema is still unknown. Recent research shows there is inflammation of the adipose tissue with an increase in the proportion of inflammatory macrophages (M1), which produce adipocyte hypertrophy (increase in volume) and hyperplasia (increase in number), from stem cells present in these tissues.
Enlargement of adipocytes produces as it progresses, insufficient vascularization, and poor venous return and lymphatic drainage. This produces tissue hypoxia with the subsequent increased inflammation and the establishment of the following vicious circle: inflammation-proliferation-inflammation.
The proliferation of adipocytes will produce macro lobes which will be easily observed and palpable both manually and through ultrasound scanning. The more developed the disease is the easier it will be to palpate the lobes. This is why, the histologic assessment takes into account the number and size of this macro lobes. Theses macro lobes are clearly visible in pieces of dermolipectomy when this surgery is performed in the affected areas.
Finally, in the most advanced stages of the disease, with lymphatic affectation due to compression, there will be a very important disabling affectation of the limbs, including the feet (the hands are less frequently affected). This last stage of lipedema is called lipo-lymphedema.
Regarding the subcutaneous cellular tissue, in the early stages, the fat which lies next to the superficial fascia (fascia superficialis) is the most affected. This fascia divides the fat layer in two compartments, superficial (areoral fat tissue) and deep (deep fat tissue).
As the condition progresses, in the late stages, the areolar fat tissue is affected close to the deep dermis. This is easily observed and palpable on ultrasound scanning and elastography.
The result of these factors combined, involves altered metabolism of adipocytes, which develop resistance to the action of some lipolytic hormones.
NUTRITIONAL - INFLAMMATORY - HORMONAL - GENETIC HYPOTHESIS
- Genetic basis.
In women who suffer from lipedema it is quite likely that, the fat cell membrane receptors in the subcutaneous tissue in some parts of the body, in specific mesodermal cells, are more sensitive to pro-inflammatory cytokines. Besides, their insulin receptors might be different from the ones women who not suffer from lipedema have. This hypothesis is supported by a recent paper.
- Hormonal basis.
Undoubtedly, there is a clear involvement of female hormones because 94%-96% of the patients are women. Furthermore, it is extremely unusual that the condition starts after menopause.
One of the causes may be that women show higher levels of adiponectin and leptin in fat tissue, probably mediated by estrogens.
- Inflammatory basis.
The occurrence of "increased intestinal permeability" will produce increased blood circulation of bacterial lipopolysaccharides (LPS) by translocation through enterocytes’ tight junctions.
These lipopolysaccharides will trigger a generalized inflammatory response. In women who have a genetic susceptibility to lipedema, inflammation will happen especially at the subcutaneous tissue level, in specific mesodermal cells.
The adipocytes in these areas will show a bad response to lipolytic stimuli (thyroid hormones and adrenaline), increasing progressively in size (hypertrophy). If adipocytes grow too much hypoxia occurs, releasing inflammatory substances (Reactive Oxygen Species) (ROS), which will affect the metabolism and circulation in near stroma.
This inflammatory situation will stimulate the development of inflammatory macrophages (M1), which likewise will produce pro-inflammatory proteins that will turn mesenchymal stem cells into adipocytes.
These inflammatory macrophages might also decrease the bioavailability of noradrenaline, which a decrease in lipolysis too.
On the other hand, it seems that the transformation of T4 in T3 is diminished due to pro-inflammatory interleukin (produced by the chronic low-grade inflammation situation)( TNα, IFNα IL6).
This happens due to the fact that inflammatory interleukin block the effect of deiodinase enzymes which enable that T4 turns into T3. (Deiodinases are selenoproteínas, ie they contain selenium, hence the importance of this mineral in lipid metabolism.)
Since T3 is the metabolically active hormone, its decrease might cause a limited triglyceride release, building-up more and more lipids inside the adipocyte.
In this way, it is triggered the inflammatory cascade with fibrosis and pro-inflammatory macrophages which close the vicious circle (inflammation-proliferation-compression-inflammation)
The "increased intestinal permeability" will produce a chronic low-grade inflammation situation steadily but continuously, which might trigger the symptoms described above in women with a genetic susceptibility to lipedema.
- Nutritional basis.
Undoubtedly, weight gain will worsen lipedema. However, there is certain type of food which not only makes you gain weight but it is also inflammatory. Gluten produces zonulin, the same as lactose does to those who are intolerant. Increased zonulin increases the passage of bacterial lipopolysaccharides through the tight junctions producing a further increase in inflammation.
Besides, in a chronic sub-inflammatory situation there is a subclinical alteration of the endocrine system, being affected thyroid hormones, cortisol, estrogens and insulin. That is why peripheral resistance to insulin is generally present too.
Peripheral resistance to insulin will cause hypoglycemic and hyperglycemic episodes during which there will be a strong tendency to intake refined carbohydrates (flours and sugar). This will increase up to an ever higher extent the tendency to obesity. On the other hand, it is well known that inadequate eating habits might produce changes in the microbiota in the medium and long term. These changes in the microbiota (which becomes inflammatory) will worsen the " increased intestinal permeability".
In simple terms, the area affected by lipedema works like a money box in which fat can be introduced but not taken out. Because of this, this area is resistant to weight loss through diets and exercise.
Therefore there are four factors affecting lipedema: Genetics, nutrition, hormones and inflammation. (Yet to be proved)
Clinical signs and diagnosis
The diagnosis of lipedema is made based on the patient’s clinical evaluation, especially of the legs and with supporting tests such as ultrasound scanning and elastography.
It is frequent that the clinical signs worsen becoming easier to identify. Stage I lipedema might not be diagnosed, however Stage III lipedema might definitely be diagnosed.
Generally, the progression of the condition goes alongside with weight gain or is triggered by it.
Clinical signs will be clearer as the conditions progresses.
The most common symptoms are:
- The affected area shows an increase in volume due to the subcutaneous cell tissue. It is mainly observed in the lower limbs (97%) but it might also be observed in the upper limbs and in the rest of the body (37 %). It is always bilateral and almost symmetrical. However, under thorough examination we will realize that one of the limbs is always slightly more affected. The feet and the hands are hardly ever affected and only in advanced stages. The affected skin surface is generally wrongly called cellulite or orange peel skin. However, we believe it should be called “cellulosis”.
- Bloated feeling and swelling which improve after night rest in the early stages (it does not in the advanced ones). It is painful in 85%-50 % of the cases. In Stage I lipedema , nearly 50 % of the patients do not report pain or tired legs.
- Subcutaneous cell tissue is hard to the touch, with lumps (macro lobes) and holes only in the affected area. It is not very obvious in early stages.
- Non-pitting edema and disproportion between the affected area and the rest of the body are observed.
- The symptoms often worsen with heat and menstrual periods. Also, they frequently worsen when practicing sport (except swimming)
- Lipedema has a poor response to diets. However, if the patient gains weight, the area affected by lipedema will gain more weight than the rest of the body.
- When lipedema affects the ankles the sign of cuff is observed as the deposits of fat end abruptly just above the ankles. This sign might disappear in advanced stages (lipo-lymphedema) as the feet are affected too.
- Severe localized pain is reported when the medial below the knee joint area (at the fibula head level) is pinched deeply. (Simarro’s sign) It is a pathognomonic sign of lipedema which is present from the early stages of lipedema. Any other part of the leg must be pinched with the same degree of intensity to check that it is not painful and confirm a positive result.
- The patient refers pain when pressing with the index finger 2 centimetres above the medial ankle. The patient would not refer pain when pressing a different area in a similar way.
- Spider veins appear in the inner lateral side of the thigh caused by pressure of the fat tissue which obstructs the subcutaneous vessels. Easy bruising even due to minor traumatisms. It is common to find it at fat pad level (back medial above the knee joint area)
- Increase in tenderness to touch, pressure and cold. In advanced stages the limbs are cold.
- Decrease in skin elasticity and in knee and ankle flexion.
- Trophic changes in the skin (hyperpigmentation, dermatosclerosis) only happen in advanced stages.
- Numbness, tiredness and joint and muscle pain are common in lipo-lymphedema but not in early stages of lipedema.
- In advanced stages, fibrosis, skin tightening and subcutaneous cell tissue might produce musculoskeletal alterations and difficulty with walking which may lead to disability due to orthophedic complications.
- According to different authors, other symptoms may appear throughout the progress of the disease. Some of them are joint hypermobility (especially of the knee), which ultimately causes joint damage. Loss of skin elasticity and temperature in the affected area. Fatigue.
Types and stages of lipedema
(see patient information)
Ultrasound and Elastography diagnosis.
The reports in which ultrasound scanning is used as a tool for differential diagnosis of lipedema and other conditions that affect the fat tissue, study how lipedema affects the skin (dermis and epidermis). However, they do not mention the ultrasound changes which occur in the lipedematous fat tissue as the condition progresses.
Ultrasound will show a hepatisation pattern in the subcutaneous cell tissue with snowstorm appearance image. The whole steatomeric layer and the deepest part of the areolar fat layer (the closest to fascia superficialis) turn from hypoechoic to hyperechoic. Increased thickness of the areolar fat layer is also observed.
In late stages the most superficial area of the areolar layer is affected too, losing its ultrasound characteristics. We will only see fluid deposits and increased dermis thickness in lipo-lymphedema.
In this image we can see two ultrasound of the same patient. One of them shows a lipedematous area and the other a non-lipedematous one. We can see that the lipedematous area is much more whitish (hypoechoic) due to hyper-proliferation of adipocytes and decrease in interstitial fluids (fat similar to sebum)
Elastography will show further decrease in elasticity as the condition progresses. From Stage II the most affected area will be the fat layer which is close to the superficial fascia, mainly the steatomeric layer. (The image shows decrease in elasticity at steatomeric layer level. Red area) (Medial sub-epicondyle area)
Differential diagnosis. (further examination available at the bottom of this page)
The main differential diagnosis is performed with lymphedema. Only in few occasions we might have to perform differential diagnosis with lipodystrophy, lipohypertrophy, Dercum´s disease and lipomatosis.
Through correct medical assessment and ultrasound scanning we will diagnose lipedema in such early stages that, without this means, it would be easily confused with cellulite and obesity.
- Negative Stemmer’s sign (pathognomonic sign of lymphedema)
- Lymphedema is generally unilateral (only primary lymphedema is bilateral). Lipedema is always bilateral.
- In most cases, lymphedema occurs after surgery, with surgical affectation of lymphatic nodes.
- Lymphedema is generally painless but patients with lipedema refer pain to minimum pressure.
- Pitting edema occurs in lymphedema.
- Simarro’s sign does not occur in lymphedema.
Since genetic and hormonal components cannot be changed, our treatment will be based on decreasing the level of affectation dealing with inflammatory and nutritional components.
Regarding the inflammatory factor, as we have previously mentioned, we believe that its onset is caused by “Leaky Gut”.
Increased intestinal permeability occurs when tight junctions loosen. This is caused mainly by a protein called zonulin. There is evidence that gluten causes a large zonulin release. Furthermore, we suspect that lactose intolerance might produce dysbiosis (pathological change in the composition of microbiota) which might increase hyper-permeability even more.
When tight junctions loosen, protein structures (LPS and others) go into the bloodstream without being digested. the immune system (dendritic cells and macrophages) reacts against them, causing an immune/inflammatory reaction.
Most patients have shown gluten related pathologies, celiac disease (1,5%), non-celiac gluten sensitivity (2-10 %) and other intolerances.
Due to this, we use anti-inflammatory medication, antioxidants, draining medication and vitamins. We never use NSAIDs or corticoids are they are contraindicated.
Following a ketogenic diet in the short and medium term (never in the long term), under medical control and supervision, is anti-inflammatory. It is the type of diet which we prescribe in this treatment.
This diet must not only be ketogenic but also anti-inflammatory, so that increased intestinal permeability is improved. It must be followed my new eating habits and maintenance treatment during six months to avoid suffering from “rebound effect”.
Due to all the aspects mentioned above, our treatment is based on the following points (always after ruling out celiac disease)
- Eliminating gluten and other foods which might produce intolerances (mainly lactose and fructose).
- Specific dietary treatment to ameliorate the increased intestinal permeability.
- Generous intake of specific pre and probiotics (not all of them are suitable)
- Local treatment with lipomesoplasty (non surgical technique)
Both the specific dietary treatment and local treatment with lipomesoplasty will eliminate chronic low-degree inflammation, locally and generally , improving blood circulation and metabolism in the area affected by lipedema.
The area affected by lipedema will be very responsive to treatment so, discomfort, inflammation and pain will improve largely from the first week of treatment.
Metabolic increase in the treated area is observed. Due to this, the response to the specific diet will be more noticeable than in untreated areas. On the other hand, this metabolic increase will produce a more efficient response to the ketogenic diet.
As inflammation decreases, fluid retention decreases too. Clear loss of weight and liquids is observed in the area treated with lipomesoplasty by sequential measure of impedance.
Objectively, after treatment, a clear decrease in volume of the treated limb is observed and also a great improvement of the overall symptomatology of lipedema.
To sum up, this treatment not only treats lipedema but also its origin, avoiding relapse in the medium and the long term. This might happen if undergoing strictly surgical treatments.
|Gender||Almost exclusively female||Male and female||Male and female|
|Onset||Most frequently at puberty||At any age (frequent after surgery)||At any age|
|Response to elevation/compression||Poor||May be effective||None|
|Response to diet||Irresponsive||Irresponsive||Significant|
|Cellulitis||Infrequent, except in advanced stages||Frequent||Rare|
|Affected areas||Hips and legs||Arms and legs||Whole body|
|Sign of Cuff||Present (not always)||Absent||Absent|
|Symmetry||Bilateral, almost symmetrical||Hardly ever bilateral||Bilateral|
|Skin consistency||Soft to hard||Tight and hard||Soft|
|Pain and heaviness||Common||Infrequent||Rare|
|Bruising and redness||Common||No||No|
|Involvement of the feet||Only in lipo-lymphedema||Always||No|
|Stemmer´s sign||Only in lipo-lymphedema||Always||No|
|Metabolic diseases||Only in late stages||No||Frequent|
|Lymphoscintigraphy||Normal, except in late stages||Pathological||Normal|
|CAT scan||Altered only in advanced cases||Pathological||Normal|
|MRI||Altered only in advanced cases||Pathological||Normal|
|Ultrasound scan||Specific pattern. Variable depending on stage||Pathological||Normal|
|Eco-Elastography||Specific pattern. Variable depending on stage||Unknown||Normal|