Lipoedema: Paradoxes and possibilities

“It confounds me that a disease that is so biologically complex, has been so profoundly ignored”, Dr Stanley Rockson, cardiologist at Stanford University School of Medicine, summarised the driving paradox of lipoedema in his talk at the 8th online event of the global MOH series, which was co-moderated by Drs Christine Moffatt, clinical professor of skin integrity and emeritus at Nottingham University Hospital in the UK, and Sylvain Gaillard, corporate medical affairs manager at Sigvaris Group in Switzerland.

Lipoedema, a chronic lymphatic microvascular disease with pathological accumulation of subcutaneous adipose tissue, is often misdiagnosed as obesity or lymphedema. Diagnosis and treatment of lipoedema cannot rely upon a strong evidence-based approach and is largely inferential. A tremendous overlap in phenotype among a variety of systemic disorders constitutes a major part of the diagnostic problem. Furthermore, the diagnosis of lipoedema is purely clinical, with histopathology not being supportive. There are neither characteristic imaging attributes, nor any identified diagnostic biomarkers. A familial pattern of lipoedema prevalence is often reported, yet genetic confirmation has been difficult.

Obesity and lymphatic dysfunction are not primarily sex-determined, yet lipoedema is seen almost exclusively in women, mostly occurring in times of hormonal change. There are a number of potential explanations for the role that oestrogens may play in this context. Central effects of oestrogens will lead to the uncoupling of appetite to control body weight, whereas peripheral effects will determine the distribution of gained body weight.

Lipoedema appears to involve an interplay between adipose biology and deranged microcirculatory biology, but the relationship among these manifestations is not well understood.

Dr Rockson’s research group identified platelet factor 4 (PF4/CXCL4) as a biomarker that could be used to diagnose lymphatic vasculature dysfunction. PF4 is an inflammatory chemokine that is expressed in the setting of lymphatic dysfunction. Furthermore, they determined that PF4 levels in circulating blood plasma exosomes were also elevated in patients with lipoedema, supporting current claims arguing that at least some of the underlying attributes of this disease are also the consequence of lymphatic defects. He postulates that an impaired clearance of fluid from the tissue environment might

condition genetically predisposed adipocytes, finally leading to the specific pattern of adipocyte abnormality seen in lipoedema.

What are the possibilities? Dr Rockson’s approach of lipoedema patients in a real-world environment focusses on the intersection of what matters and what can be controlled. Treatment is directed toward relief of symptoms, especially mobility, pain and avoiding sequelae of the disease. Efficacy of treatment interventions has not been fully evaluated and is therefore not evidence-based. In the setting of unsuccessful conservative management, lymph-sparing liposuction can be considered. This intervention is intended for symptom palliation and addresses body dysmorphia as well. Evidence-based assessment of long-term efficacy is required.

The subsequent discussion, which was joined by panellist Dr Ramin Shayan (Australia), stressed the need for biomarkers for the distinction of lipoedema from obesity.

Take Home Messages:

• Lipoedema diagnosis is currently based on clinical grounds, although diagnostic evaluation may be necessary to distinguish from other systemic disorders with overlapping phenotypes.
• Treatment is directed towards symptom relief. Efficacy of treatment interventions has not been fully evaluated and is therefore not evidence-based.
• In the setting of unsuccessful conservative management lymph-sparing liposuction for symptom palliation can be considered. Evidence-based assessment of long-term efficacy is needed.
• Platelet factor 4 could be used as a biomarker to diagnose lymphatic vasculature dysfunction.