by Guy S Eakin, PhD
In spite of a global pandemic, Lipedema research amassed a record number of publications in 2020. Unfortunately, we have other research challenges - notably the lack of clear laboratory or imaging diagnostic strategies. Lipedema patients rely on experienced physicians to make clinical diagnoses based on their knowledge and observations. For each study, we often question how Lipedema was diagnosed, at what stage, and by whom, meaning that every study in our field must be taken with a grain of salt.
This year, five papers challenged this issue and hinted at potential diagnostic “biomarkers” - measurable signals that indicate an underlying biological issue (think of the way your cholesterol level predicts your cardiac risk). For Lipedema, discovery and confirmation of biomarkers would pave the way for standardized tests and could become a cornerstone for testing future therapeutics.
Full disclosure: we try not to be biased, but the first three of the five biomarker papers were supported by the Lipedema Foundation. This is our focus and passion, so hold tight while we boast about our colleagues a little.
Dr. Rachelle Crescenzi led a team of Vanderbilt University Medical Center researchers exploring new ways of distinguishing Lipedema from other conditions like obesity and lymphedema. These conditions often exist alongside Lipedema, but we don’t fully understand the degree to which they may be independent or related to one another.
For several years, Dr. Crescenzi and other colleagues have been using MRI and other imaging tools to explore what makes Lipedema unique. In 2018, this team used existing MRI techniques to visualize an accumulation of sodium in the skin of Lipedematous legs [1]. In that work, they focused only on the legs of patients with and without Lipedema.
This year, they returned to compare sodium levels between individual study participants’ legs and arms using 15 of the best characterized Lipedema patients we’ve seen [2]. They then compared those findings to women who did not have Lipedema. The team reproduced their earlier findings in the legs, and showed that differences with controls were much greater in the legs than arms. The study went on to support the idea that fat accumulates disproportionately in the legs. Finally, the study correlated tissue sodium levels with both the stage of Lipedema and with the patients’ pain intensity!
We still don’t know whether sodium is a cause or an effect, or if changing sodium levels would help patients. But what does it mean when a patient comments that she gained several pounds after eating a salty pickle? Maybe that the Vanderbilt team is on the right track.
Additionally, hints of a biopsy or even a blood draw based diagnosis came last year, when Dr. Sara Al-Ghadban and colleagues reported inflated capillaries and increased presence of immune cells in Lipedema biposies relative to obese and non-obese women without Lipedema [3]. These “it’s more than fat” type observations expand our notion of what is affected by Lipedema and offer hope that a pathologist might one day be able to diagnose this condition.
That idea was further supported by work from Dr. Epameinondas Gousopoulos and colleagues who, in two papers [4,5] reported specific immune cell (macrophage) infiltration of Lipedematous tissue. This immune invasion could be inferred both by observation of biopsies and by detection of molecular signals secreted by immune cells to the blood. Albeit in small numbers, by carefully controlling Lipedema patients to sex- and BMI- matched controls, they were also able to reveal differences in standard lipid panels that had previously been unreported.
Dr. Eleni Priglinger took us one step closer to a “Lipedema panel” by looking at extracellular vesicles that are deployed by Lipedema tissue into surrounding tissues [6]. These vesicles act like tiny “messages in a bottle” cast by Lipedema tissue into the surrounding tissues. Their cargo, in fact, tend to carry different molecular messages that represent a snap-shot of what may be occurring inside affected cells. In this case, the vesicles focused primarily on communicating with non-fat cells, such as the blood and immune cells collected as part of therapeutic liposuction. While it is not a simple blood draw, it is a powerful way to see if Lipedematous cells are emitting signals that can be recovered from the fluids that surround them.
Although Dr. Priglinger’s team doesn’t report their specific diagnostic criteria, their results in early stage patients suggest that focusing on their non-fat cells pays off. Unlike in healthy controls, these cells are producing many signals that have previously been implicated in issues related to fat production, fibrosis, and the immune system -- all consistent with how we think of Lipedema.
The fifth paper we’re highlighting details the tantalizing observation made by Dr. Guillermo Oliver and his multi-national team of investigators [7]. Similar to Dr. Priglinger, they looked for the molecular messengers “messages-in-bottle”, but this time turned to extracellular vesicles, but this time, they worked with a simple blood draw. When these messengers were recovered and analyzed, the Platelet Factor 4 protein, which is associated with wound repair and inflammation, stood out in both humans and mice with compromised lymphatics. The authors report that the molecule may be good at distinguishing people with traditional lymphatic conditions or Lipedema from obese and non-obese controls. But PF4 would not differentiate Lipedema from patients with conditions we think of as traditional lymphatic disorders.
Dr. Oliver’s paper is not without limitations, the most significant being that the interpretation of these results is complicated by the use of predominantly male control groups (only 5% female) against lymphedema and Lipedema study groups that were 95% and 100% female, respectively. While the paper opens our eyes to possibilities of a future blood test, it also highlights some of the difficulties that will have to be faced in order to run confirmatory studies in larger populations.
Taken together, we leave 2020 believing that these five papers support the vision that Lipedema may be detectable through imaging, and that a blood or biopsy test for molecular signals may be feasible. Unfortunately, we also leave 2020 recognizing that these studies reveal a battle fought on two fronts. On one side, we face the challenge of diagnosing patients consistently. On the other, finding and recruiting not only patients, but also controls, remains an enormous barrier to research progress.
So where do these incredibly precious study volunteers come from? How do we best listen and learn from what they tell us? Join us next week when we honor 2020’s advancements in building a research ecosystem -- one that brings patients and researchers together to solve Lipedema.
In the meantime, consider making yourself a part of the solution to these challenges. We invite you to join the research ecosystem by contributing your story to the Lipedema Foundation Patient Registry, either as a cherished Lipedema patient, or as one of the wonderful allies who enrolls as a control in research studies.
For space, this article refers only to the corresponding author on each paper. For a full list of the teams that contributed to each study, we invite you to look at linked articles in the following cited references.