Adipose tissue is a particular type of connective tissue consisting of adipose cells (adipocytes) which, by grouping together, form lobules separated by fibrous septa of connective tissue. Every single adipose cell has its own blood support guaranteed by a capillary system and its own innervation mediated by adrenergic nerve fibers. It is also claimed that the adipose tissue has sensory innervation. Lymphatic capillaries can be detected at levels of the fibrous septa, but not between the adipocytes. The few reticular fibers between the fat cells constitute the initial (or prelymphatic) lymphatic drainage system.

Microangiopathy, which develops in the area of ​​adipose tissue, causing an increase in protein permeability and, likewise, an increase in capillary fragility, is one of the initial mechanisms that characterises lipedema. As a consequence of the increase in permeability, accumulation of liquid with a high protein content occurs in the surrounding cellular area, while as a consequence of the increase in capillary fragility, typical bruising appears.

The soft consistency of adipose tissue can be associated with a neurogenic inflammatory state, which further complicates the condition of microangiopathy. Some scholars are of the opinion that this extremely soft consistency is linked to damage to the autonomic nervous system. According to this theory, this alteration could lead to erroneous interpretation of the protopathic sensory inputs (linked to pressure, temperature, or posture) and this is known, for example, in Sudeck-Leriche syndrome.

The pericellular accumulation of liquid is associated with dilatation of the prelymphatic drainage system, with the result that the liquid flows very slowly through the initial lymphatic vessels. At the level of the skin, typical pathological changes are appreciable in the lymphatic capillaries. In particular, the permeability of the capillary wall is markedly increased and some studies, characterized by the use of fluorescent microlymphangiography, have shown some aneurysmal-like formations in association with numerous capillary segments of extremely reduced caliber.

In this way, it is possible to understand how dilation of the prelymphatic channels, together with morphological and functional alterations of the lymphatic capillaries, gives rise to progressive damage to the lymphatic drainage capacity.

In addition to this, a disturbance of the motor activity of the lymphangion (which represents the anatomical-functional unit of the lymphatic collector, ie the segment interposed between a valvular apparatus and the other segment) has been observed. Early pictures, highlighted by the use of lymphangiographic examination with oil contrast, have shown the presence of suprafascial lymphatic collectors in a corrugated form, so-called “corkscrew”. In cases associated with elephantiasis, the condition of progressive immobility exerts a detrimental effect on the formation of lymph and the motor activity of the lymphangion. Furthermore, isotopic lymphography demonstrated accelerated aging of the lymphatic pump.

In lipedema, skin elasticity is greatly reduced, while skin “compliance” (hardness index, expressed in mmHg, measured by tonometer) is increased. This has serious consequences:

• The skin loses its role as a ‘help’ to the venous pump of the lower limbs. In healthy subjects, in an upright position, the pressure in the veins of the back of the foot is 100 mmHg; during walking this pressure drops to 30 mmHg. This mechanism does not work properly in patients with lipedema and the resulting passive hyperemia leads to a high volume of ultrafiltration. Due to the increased “compliance” of the skin, a larger volume of interstitial fluid is needed to increase the interstitial pressure. In this way the lymph drainage function is further compromised and, consequently, an important passive defense mechanism against the development of edema is lost.
• Another significant aggravating factor is the fact that the venous-arteriolar reflex is absent. Normally, in healthy subjects, this reflex involves vasoconstriction in orthostasis: the resulting reduction in the perfused capillary area in turn reduces the volume of ultrafiltrate in the lower limbs. Therefore this reflex, missing in the lipedema, represents a relevant defense mechanism against the establishment of edema.
• In adipose tissue, macrophages able to eliminate plasma proteins outside the lymphatic vessels are rarely found. For this reason, fibrosis develops rapidly among the adipocytes and collagen fibers appear.

In lipedema, pitting edema (fovea sign) often develops in the second half of the day during the more temperate seasons. The reason for this is related to the fact that heat leads to the development of reactive hyperaemia which, in turn, increases the lymphatic fluid load. If edema associated with water retention occurs with lipedema, the lymphatic vascular insufficiency becomes manifest. This is because a good function of the valvular system of the lymphatic system promotes good lymphatic drainage and prevents gravitational reflux. Therefore, in lipedema, on one hand the lymphatic, water, and protein loads are increased, lymph formation and the motor activity of the lymphangion are altered, and on the other side the valvular apparatus of the lymphatic system is seriously insufficient.