At the 2022 American Venous and Lymphatic Society, Dr. José Luis Simarro shared his new comprehensive theory on the cause of lipedema, incorporating new understandings of anatomy, physiology, and immune system biology to explain Lipedema as a subchronic sub-compartmental syndrome of saphenous and peri-saphenous tissue.
New Insights & Current Understandings
To explain this comprehensive theory, we need first to review new insights and current understanding of adipose anatomy, venous and lymphatic physiology, and the interaction between adipose tissue and the immune system.
Adipose Tissue Layers and Deposit Areas
To explain and understand the theory of the cause of lipedema, we first need to review where adipose tissue deposits occur, how the adipose tissue is structured and how it functions.
The global obesity epidemic enhanced contemporary interest in adipose tissue biology. Two structurally and functionally distinct depots, Subcutaneous Adipose Tissue (SAT) and Visceral Adipose Tissue (VAT), are spread throughout the body. The largest amount of fat, about 80% in normal-weight persons, is under the skin (SAT), mainly in the gluteal, femoral, and abdominal regions.
Visceral Adipose Tissue VAT involves deposits surrounding internal organs. Abdominal VAT locations are the omental depot, the mesenteric depot around the intestines, and retroperitoneal fat around the kidney. Smaller deposits of visceral adipose tissue VAT also occur in many places outside of the abdomen: Epicardial fat is in the mediastinum, and perivascular fat lies along blood vessels. Some of this VAT outside the abdomen can become brown or beige fat. VAT also infiltrates some organs like the liver, skeletal muscles, heart, and pancreas.
Adipose Tissue Biology is Different By Body Area and Sex
There are major differences between adipose tissue biology based on where the fat tissue is located.
In mammals, VAT depots at different anatomical locations (subcutaneous, preperitoneal, and visceral) are highly heterogeneous in their morpho-phenotypic profiles and contribute differently to homeostasis and obesity development, depending on their ability to trigger and modulate inflammation. This heterogeneity is likely due to the differential behavior of cells from each depot. The metabolism, fat accumulation, and propensity towards inflammation of VAT and SAT is different, and various studies have shown a different embryonic origin of each of them. Later studies demonstrated that in vivo hyperplasia in VAT varies according to the specific depot and the sex, being influenced by sex hormones.
While males have a higher potential for expansion by hyperplasia in the abdominal VAT only, females exhibit adipose hyperplasia in both visceral and subcutaneous depots after a high-fat diet.
Different Fat Deposits Have Different Inflammation Profiles
Superficial Adipose Tissue SAT, and Visceral Adipose Tissue VAT depots have different secretions of inflammation-related adipokines or adipocytokines. In paired samples studies of adipose tissue gene expression, a higher quantity of pro-inflammatory adipocytokines like interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFa), or monocyte chemoattractant protein-1 was typical for VAT. Adiponectin, with anti-inflammatory and insulin-sensitizing properties, is released predominantly from SAT. The involvement of developmental genes might also reflect the origin of adipose tissue depots from different mesodermal regions.
Superficial Adipose Tissue (SAT) Can Be Divided Into SSAT & DSAT
Superficial Adipose Tissue (SAT) can be further divided into superficial (SSAT) and deep (DSAT), with a layer of connective tissue called the superficial fascia (SF) that marks this division.
A deep fascia (DF) layer separates DSAT from the underlying muscle. Superficial fat compartments from top to bottom would be outer skin, SSAT, SF, then DSAT, which sits on the muscle.
This structure (SSAT and DSAT) is repeated over most of the body’s surface. In the abdomen, we find the so-called superficial (or “Camper’s”) fascia and the so-called deep membranous fascia (or “Scarpa’s”) fascia, which is the superficial fascia (SF). The metabolism of SSAT and DSAT are also different, with different expressions of pro-inflammatory and anti-inflammatory genes. DSAT is more pro-inflammatory .
The Saphenous Compartments: The Third Layer in Subcutaneous Space
There is a third layer in the Subcutaneous space in the legs. In the lower limbs, there are two Saphenous Compartments (SphCs): one covers the Great Saphenous Vein (GSV), and the other covers the Small Saphenous Vein (SSV). These compartments are the Greater Saphenous Compartment (GSphC) and the Small Saphenous Compartment (SSphC).
In the figure below, we see that the GSphC runs from the groin to the dorsum of the foot covering the GSV, while the SSphC starts at the lateral malleolus. It runs up the calf and back of the leg to the popliteal fossa covering the SSV. But in these areas, both Saphenous Fascias are different, i.e., they are thick and tough, more like aponeurosis.
In the legs, there is a third layer of fatty tissue, the fat of the saphenous compartment (SphSAT), which is also separated by a second fascia, the saphenous fascia (SphF). The Saphaneous Compartment has been described by numerous authors, and with ultrasounds, it is easy to observe (below). Furthermore, these authors and anatomical studies show that a nerve runs inside the saphenous compartment. Just as the origin and development of SSAT and DSAT are distinct, we hypothesize that the origin and development of this third fat layer (SphSAT) are distinct from that of SSAT and DSAT.
Therefore its response to different stimuli, lipolytic, lipogenic, hormonal, and inflammatory, will be different, as it occurs in SSAT and DSAT.
Lymphatic Vessels Run In and Around The Saphenous Vein Compartments
Akira Shinaoka Recently published a series of studies  on the lymph vessel and flowed in the leg. According to these studies, many of the lymphatic ducts of the superficial lymphatic system of the leg run through and close to the saphenous compartment.
Role of Saphenous Compartment
Many authors, in relation to the saphenous compartment, have wondered what its function is. Some have concluded that one of its functions is to help with venous drainage during muscular systole, especially at the calf level.
The contraction of the calf muscles during walking will cause stretching of the saphenous fascia, narrowing the saphenous compartment and compressing the saphenous vein. Since the saphenous vein has a one-way valve, this contraction with aid in the upward drainage of the vein. Simarro’s Theory submits that thigh compression will also aid the upward flow of the lymphatics.
The Theory of Subchronic Sub-Compartmental Syndrome (SCS) As The Cause of Lipedema
We know that in Lipedema, there is hypertrophy and hyperplasia of the adipocytes. Dr. Simarro submits the theory that the lipedema changes of the adipocytes inside the saphenous compartment cause the disease. These changes (hypertrophy and hyperplasia of the adipocyte in the saphenous compartments) only occur in women with lipedema. The increase in volume within a space limited by fasciae corresponds to the definition of compartment syndrome. In this case, and given its very slow but progressive, we call it a “Subchronic Compartment Syndrome (SCS) of the saphenous compartment.” Also, because of the increase in fat and inflammation in the DSAT, there will be progressive sub-chronic compartment-like syndrome in the tissue just next to the saphenous sheath.
The progressive loss of the draining function of the saphenous compartment will produce a slow and progressive decrease in lymphatic flow and venous flow in Lipedema.
In addition, due to gravity and orthostasis, the most affected areas will be the most distal areas of the lower limbs, especially in the distal half of the calf. It will be there where we will find an increase in venous pressure, with a retrograde increase in pressure in venules and capillaries, causing the appearance of varicose veins and telangiectasias in advanced lipedema.
The lymphatic system will be affected and will also suffer a retrograde increase in pressure, which is the cause of the lymphatic dilations found in lipedema. However, the pressure will not increase as much as in venous.
Insufficiency Due to Saphenous Vein Reflux
We have to take into account that the drainage system is not obstructed. Therefore, a very important increase in pressure cannot exist, and ulcers will not appear as in venous insufficiency.
On the other hand, the compression exerted by the lipedematous adipocytes will prevent dilation of the saphenous vein; thus, incompetence will not appear. For this reason, in lipedema, it is unusual to find saphenous.
Meet Dr. Thomas Wright, medical director of Laser Lipo and Vein Center. Dr. Wright’s research and interests focus on vein treatments, venous health, and minimally invasive body sculpting. If you have lipedema or know somebody battling this progressive fat disorder, make sure to contact us and schedule an appointment.
- Cancello, R, et al. Molecular and morphologic characterization of superficial and deep subcutaneous adipose tissue subdivisions in human obesity Obesity (Silver Spring), Cancello R, Zulian A, Gentilini D, Maestrini S, Della Barba A, Invitti C, Corà D, Caselle M, Liuzzi A, Di Blasio AM. Molecular and morphologic characterization of superficial- and deep-subcutaneous adipose tissue subdivisions in human obesity. Obesity (Silver Spring). 2013 Dec;21(12):2562-70. doi: 10.1002/oby.20417. Epub 2013 Jun 11. PMID: 23512827. https://pubmed.ncbi.nlm.nih.gov/23512827/