Lipedema is a Lymphatic Disease

In his presentation, Dr Stanely Rockson started by explaining Lipedema. It is a lymphatic defect, but it also can be considered a fat disorder, fat is a touchy subject. It is a subject that embraces both normal and abnormal biology, so we certainly understand that fat distribution is age-dependent biology dependent, and somewhat gender dependent or sex-dependent. In lipedema, of course, we have abnormal adipose biology. However, it is interesting to contemplate that this adipose abnormality is shared with the other lymphatic defects and the other problems that create chronic edema, so in the adult human population, constitutional obesity is a significant problem; is a growing problem. We need to distinguish constitutional obesity from the kind of adipose hypertrophy that occurs in chronic lymphedema. Dr Rockson shared an image of a patient with late stage 2 lymphedema of the lower extremities.   

The problem of stage four lipedema, often called lipolymphedema, is that it progresses, which causes the failure of the larger collecting channels for the lymphatics. 

Lipedema is exclusively a problem of women; it is infrequent in men, but when it occurs, it does require a substrate of excess estrogen production or some imbalance between estrogen and testosterone, so clearly, there is a hormonal substrate to the problem. In terms of the presentation, lipedema and lymphedema are typically primarily confined to the extremities, whereas in lifestyle, obesity, the trunk is very heavily involved and as the middle portion of the adipose excess. Lymphedema is the condition among these three that tends to be most asymmetrical in its presentation. Lipedema is remarkably symmetric in its involvement of both lower extremities or even all four extremities when that occurs, and that tends to be the case in constitutional obesity as well; pitting is only an attribute of those presentations that include a chronic hydrostatic edema component which typically would be lymphedema in its earlier stages this quality is lost over time. Finally, the changes or the differences in tissue turgor mean that lymphedema is the entity that will present with the firmest nature of the tissue. Tenderness and pain are primarily attributes of lipedema.   

So, these are some of how we recognize and make the clinical distinctions among these entities and finally say that lymphedema is the most associated with soft tissue infection. 

The genetic component to this entity of lipedema, although this is very poorly characterized at this point, there is such an issue in lymphedema as well the preponderance of lymphedema is secondary and is a consequence of cancer therapeutics or other forms of iatrogenic trauma and other traumas or directly of infection, but we do have this component as well in lymphedema of the primary presentation which has a genetic substrate is rare, and it is considered a rare disorder.   

In the lipedema population, it is estimated that patients will point to familial distribution of similar problems and the genetic underpinning is interesting. It’s like to be complex and it has to be well-defined. So, we do have a genetic component in both of these aspects.   

Four Stages of Lipedema    

1. Even skin surface with an enlarged hypodermis 
2. Uneven skin pattern with development of a nodular or mass-like appearance of subcutaneous fat, lipomas, and/or angiolipomas  
3. Large growths of nodular fat causing severe contour deformity of the thighs and around the knee  
4. Lipolymphedema

He stated that the problem with lymphedema is that we have little insight into the biology of this disease. Partly, this is a problem because we have no relevant animal models and no bench science we can heavily bring to the table. Everything they understand about the patients is based upon clinical observations.   

Diagnosis   

• The diagnosis of lipedema is purely clinical  
• There are no characteristic imaging attributes  
• Histopathology is not helpful  
• There have been no identified biomarkers (That could change in the near future)

  Lymphedema presentation attributes overlap lipedema in its pathogenesis; this is a framework in which the inherent lymphatic dysfunction leads both to interstitial edema and immune dysfunction because of the immune traffic attributes of the lymphatic circulation.   

These attributes, in turn, lead to chronic inflammation and recurrent infection, and all these forces interplay with progressive fibrosis and adipose deposition. Many of the same forces interact in lipoedema but in a different orientation. These interrelationships are entirely hypothetical because we do not have much scientific insight into the actual pathogenesis. 73% increase in the fat volume representing most of the rise in the lymphedema limb compared to its standard contralateral control.  

There are surgical approaches to this kind of fat hypertrophy, and many are aware that the pioneering work of Hokum Brorson in dry liposuction, a very specialized form of dry liposuction, will render the limb normal in size provided that adequate compression is utilized throughout.   

The liposuction approach is also used in many practice approaches to lipedema for lipedema. In this case, we tend to rely upon tumescent liposuction because of its ability to preserve the underlying lymphatic architecture in theory but remove some of the excess inflamed adipose tissue to reduce symptoms and improve mobility for the patient.   

Dr Rockson also shared images for fluorescein micro lymphangiography and indirect lymphography, mentioning that they demonstrate the dermal backflow in lymphedema. He also shared images for lipedema as compared to regular when looking at the microlymphatics by fluorescence imaging.   

However, we cannot rely upon those imaging characteristics to make the diagnosis, so Dr Rockson turned to the question of biomarkers and specifically to looking at lipedema within the universe of lymphatic abnormalities.   

Thankfully, lipedema has been getting increasing attention over the last five years. Dr Rockson also mentioned that they had completed a research project published in JCI insight that has helped us identify platelet factor 4 as a biomarker for lymphatic promoted disorders, including lipedema.  

They decided to study plasma exosomes. Exosomes are packets of biological material that are formed within cells of a variety of origins; a membrane lines these packets, and they contain protein lipids RNA and DNA, and these small packets can be created within the cell, extruded from the cell, and then circulate freely within body fluids to take these biological messages to remote sites. They chose to look at exosomes in mouse models and human materials to identify this biomarker. Once they isolate the exosomes, they perform mass spectrometry on the protein fraction from the exosomes then they validate their findings through ELISA. 

In order to look at the mouse, they decided to use models regarding lipedema and lymphedema. 

There is a one model called Prox1+/- haploinsufficient mouse in which one of the alleles for Prox1+/- is absent and they know that the mouse in youth has defined lymphatic abnormalities. Although its phenotype is normal but as it ages, it becomes obese because of the lymphatic defect and the subtle leakage of lymph/chyle that promotes visceral accumulation of fat, leading to obesity. 

So, they have the ability to look at both the young mice and the old mice, to look at the impact of lymphatic defect as well as the adipose contribution as the mouse ages. Moreover, in order to have a control of the obesity itself, they had the ability to look at the ob/ob mouse which is known to have constitutional obesity based upon a mutation in the leptin receptor. There is no lymphatic defect that is present in the ob/ob mouse so, they can look at the obesity factor alone. 

In humans, they chose to look at normal controls of a subgroup with lymphedema, another with lymphovascular disease including primary lymphedema, and finally, a subgroup with lipoedema. They found that, in aggregate, all this data led to platelet factor four (Pf4) as a unifying biomarker.   

 He then showed data from the Prox1+/- mice, it showed that on the left-hand panel the finding of the young mice and the right-hand panel the older mice. It showed that the older mice are obese and there are 70 up-regulated genes and 36 down-regulated genes in this subgroup. All the proteins listed in red are those that are shared by the ob/ob mouse and platelet factor four (Pf4) came up as a very interesting and significantly up-regulated protein. 

Having identified the proteins of interest in the mice then they turn into human subjects to see where the overlap might be. An overview of the 75 patients enrolled in this study to isolate their exosomes and study them. They looked at both upper and lower involvement in the limbs in the case of both unilateral and bilateral lymphedema, spanning the spectrum of ISL stages for lymphedema. However, as seen clinically, most commonly in stage two, they had a smattering of stage three in stage one. In lipoedema, they purposefully excluded stage four because they did not want to have the hybrid presentation of lymphedema and lipoedema. Also, various lymphatic disease etiologies were included so really across the spectrum of the lymphatic presentation, and about half of these patients had a cancer-related disease.   

An overview of Platelet factor 4 (PF4), also known as CXCL4   

• Is a chemokine released from alpha granules of platelets  
• Promotes blood coagulation and plays a role in wound repair and inflammation  
• Inhibits angiogenesis  
• Is chemotactic for neutrophils, fibroblasts, and monocytes  
• PF4 is bound to surface glycosaminoglycans on platelets, monocytes, and endothelial cells  
• It is also an immunogenic target in prothrombotic disorders.  
• The concentration of PF4 in serum after platelet activation is a thousand-fold higher than in plasma.  

They’ve undertaken a project that’s now more than 10 years old of creating an international registry for lymphatic diseases. From inception, they have had a heavy contribution to the lipedema population. Patients who participate in this registry can enroll form anywhere in the world through a highly secure URL in which they can directly enter their information to become de-identified. They simply utilize all of the information available to them about their own case and it can be aggregated with the information from all the other patients around the world to bring them more insights into these diseases including lipedema.