PATHOPHYSIOLOGY
Lipoedema was first described by Allen and Hines in 1940 as a condition characterised by “abnormally poor resistance to the passage of fluid into the tissue from the blood thus permitting oedema to occur". There is not enough research about lipoedema pathophysiology although some studies have suggested that polygenic susceptibility combined with hormonal, microvascular, and lymphatic disorders may be partly responsible for its development. The adipose tissue enlargement might not be the initial step instead lymphangiopathy and/or microvascular dysfunction can initiate a vicious cycle, resulting in alterations in the blood and lymphatic microcirculation.
Genetic Background
There can be involvement of several genes in endothelial dysfunction and lymphangiopathy under the influence of oestrogen that are involved in vasculo or lymphangiogenesis. The imbalanced oestrogen mediated mechanisms of weight control can be involved in lipoedema pathogenesis. In 60% of patients there is genetic background with familial predisposition. There is a possible autosomal dominant inheritance with the range of 16- 64 % positive family history in affected patients .
Hormonal influence
The disease starts predominantly at puberty, mainly in women and it is interesting to speculate that lipoedema's pathophysiology is largely influenced by sex hormones. Estrogen is known to directly modulate lipid metabolism in white adipose tissue, mainly through estrogen receptor alpha and beta (ER-α and -β), and G-protein-coupled estrogen receptors. Some studies suggest that, there is defective ER expression, distribution, and signaling pathway that may be involved in lipoedema development and it has the predilection for the female sex and the peculiar distribution of adiposity.
Microangiopathy
Although there is not enough scientific data, microangiopathy has been considered a typical histological feature of lipoedema by some researchers. Microangiopathy is one of the earliest changes in lipo-edematous tissue that could be related to endothelial barrier function. In some studies it is suggested that angiogenesis and increased capillary permeability may be consequences of imbalanced adipogenesis, leading to abnormal fat expansion and subsequent tissue hypoxia. Due to hypoxia there is adipocyte hyperproliferation and this may lead to adipocyte necrosis, production of inflammatory cytokines, and macrophage infiltration. Despite these interesting researches the features of microangiopathy in lipoedema are still speculative and more research is required for further confirmation.
Lymphangiopathy
The patients of lipoedema display similar features as lymphedema in their advanced stages of the disease. In a study it was reported that abnormal lymphoscintigraphy pattern and slowing of lymphatic flow was observed in lipoedema affected women just similar to patients of lymphedema. The abnormal fat deposition in lipoedema can lead to micro-lymphatic disturbances and further progress to lipolymphedema after prolonged presence of the disease. The exact role of lymphangiopathy in lipoedema has not been yet determined and it may not be entirely due to a primary venous or lymphatic disturbance but rather a form of lipodystrophy or diffuse lipomatosis .
Adipogenesis
According to previous research, patients with lipoedema have enhanced adipose stem cell proliferation which causes massive adipose tissue enlargement. Several hypotheses explain that patients with lipoedema are unable to expand their adipose tissue in a healthy manner. Several researchers have demonstrated a capillary reduction in the subcutaneous adipose tissue of patients. Due to this phenomenon there can be hypoxia and impaired secretion of adipokines, which can contribute to low-grade inflammation of the adipose tissue, which in turn affect the adipogenic program. However, it is still unclear whether these series of events are caused by obesity and lipoedema.
