By Guy Eakin, PhD
For many years, an end-of-the-year review of Lipedema literature was a relatively simple exercise. Between 1950 and 2014, there was only one year when the field produced more than 10 papers in a single year. Fast forward to today where we celebrate 50 new publications since January 1, 2021. Remarkably, another metric is shifting as well. There was an almost 10% growth in the ratio of papers presenting new data to articles that summarize prior work (often for medical education, or to present new hypotheses).
Taken together, these numbers mean that half of the studies ever published in Lipedema research have emerged in only the last 3.5 years!
The focus of the Lipedema Foundation is, of course, on that data. We have funded about 20% of the work published in recent years and remain the world’s largest funder of Lipedema research. Our own scientific strategy is to create an environment conducive to effective clinical research. To do that, our attention is on three things – people, ideas to test, and measurements to make – each of which showed advancement this year as described below.
So, to round out 2021, let’s walk through a few of the research publications that are truly advancing a new era of thinking in Lipedema research.
We Need People
Historically, it has been challenging to recruit Lipedema patients for research. That’s one reason why we’re so excited to cross the 2,000-registrant milestone in the Lipedema Foundation Registry. But research requires more than eager volunteers. Bringing Lipedema into a new era will require connecting an expanding ecosystem of people with Lipedema to a professional community of researchers, clinicians, and other professionals.
We toasted some good news this year as the American College of Cardiology and other institutions made Lipedema knowledge a primary goal of advanced practice training [1]. We had important publications of the US Standard of Care [2] and updates on Lipedema management published in Spain [3]. We also take joy in the continued contribution to Lipedema works from outside of the traditional laboratories of Europe, Australia, and the US. Chile [4], Brazil [5,6], Morocco [7], Jordan [8], Russia [9], Turkey [10,11], and China [12] all contributed scholarly works to Lipedema research this year.
We Need New Ideas for New Therapies
What does the future hold? What is science telling us are the levers that future therapies might pull to change the course of Lipedema? Many of these come from early-stage discovery research, where scientists are asking how healthy bodies stay healthy, and what changes begin the chain of falling dominos that we describe as Lipedema. One of the most vexing and hard to pinpoint dominos is the linkage between Lipedema and hormonal change. Countless reviews of Lipedema explain that the symptoms are believed to begin at times of hormonal change, particularly puberty, pregnancy, and menopause. But very little scientific research, beyond astute observations of patients and physicians, definitively supports this belief.
Two peer-reviewed thought pieces were published this year that begin to explore possible hypotheses that connect the role of estrogens and other sex hormones to Lipedema [13,14]. The production of estrogens in the body leads to a myriad of events that can each be associated with adipose (fat) tissue production. In this view of Lipedema, early hormonal changes may directly stimulate adipose proliferation and inflammation through several mechanisms, each of which could, potentially, be targeted by a new therapy. Notably, recent genetics work has begun to highlight specific genes known to be involved in sex hormone regulation as potentially associated with the development of Lipedema-like symptoms [15]. (Disclosure, the three works discussed in this paragraph were supported by the Lipedema Foundation).
What happens after that hypothetical hormonal trigger is largely unknown, but very exciting work published this month supports the idea that Lipedema fat is biologically different from otherwise healthy fat in terms of its ability to proliferate [16]. In this study, materials obtained from liposuction were compared to similar materials from women without Lipedema. Upon analysis, several molecules appeared to be present in a way that differed from Lipedema to controls. One of these molecules, Bub1, is known to be involved in the replication of cells, suggesting that it might be a targetable regulator of fat proliferation, or that it might affect the behavior of other cells, like stem cells, in a way that eventually leads to the symptoms we know as Lipedema.
We Need to Know How Today’s Treatments Work
The goal of research is preventing and treating Lipedema. But how do we do that and what can be tested? Let’s start with the obvious – modifying diets. You can find plenty of websites and social media posts devoted to sharing personal testimonials about which diets work and which do not. What has been missing so far is any published data to document these claims within the structure of a clinical study of Lipedema. On the research side, there have been some well-reasoned surveys and hypotheses for specific approaches to managing Lipedema with diet [17,18]. Unfortunately, these websites and books exist in the absence of published data asking the simple question of “Which diets work, under what conditions, and for whom?”
That began to change in 2021, with work from Italian investigators. In a small but controlled study of 29 women with Lipedema, they documented success in using a low-calorie Mediterranean diet [19] to reduce overall weight and manage pain and fatigue in women with Lipedema. Additionally, two publications on the popular ketogenic diet provided the first structured clinical data (randomized controlled trial and a repeated measures study) suggesting that overall weight loss and reduction in pain symptoms might be accomplished while on modified ketogenic, or other anti-inflammatory diets [9,20].
Collectively, these studies also continued to support the observation Lipedema is not necessarily associated with poor metabolic health, in that patients tended to enter the studies with normal range values for standard metabolic lab measures. Similarly, all studies supported the idea that Lipedema-affected tissues are more resistant to dietary intervention than other areas of the body. Given that different diets and modifications were tested with similar results, it also, to our mind, supports the idea that no one diet will be a “silver bullet”. The best research to guide individual decisions will be personal experimentation, guided by medical advice from a qualified health care professional such as a licensed dietician.
In addition to long-awaited dietary research, new data on other common therapies was published this year and is discussed in the following sections.
We Need Ways to Measure Lipedema
Even as new therapeutic ideas emerged, new studies presented evidence for the effectiveness of other therapies that are commonly used in Lipedema. While it may seem simple to ask “Does it work?”, the answer to that question can be complex. One has to ask, “What symptom is addressed?”, “How much did that symptom change?”, and “Did it change enough to matter to the patient?”. The field of Lipedema is beginning to take inventory, not just of its treatments, but also in ways that address these questions.
As an example, non-surgical, conservative treatment of Lipedema often includes Complete Decongestive Therapy (CDT) and its component parts, including exercise, Manual Lymphatic Drainage (MLD), compression, skin, and self-care. The value of these treatments has been questioned in the absence of strong data. Notable data on both MLD and CDT came this year, first in publications from Turkey that reported that a combination of CDT, including MLD and Intermittent Pneumatic Compression (IPC), resulted in a statistically significant reduction of limb volume after daily treatments for 5-6 weeks [10,11]. Limb volume reduction is a common measurement of Lipedema treatments, but what it means isn’t necessarily clear. With this in mind, one study [10] delved much further, to compare patients receiving exercise with CDT or IPC, or exercise alone in women with Stage 3 and 4 Lipedema. Although a small study (~10 patients per group), a blinded analysis indicated statistically significant improvements in volume, but also alleviation of important symptoms like pain, limb function, and other measures of quality of life.
One exciting result came just last month, when researchers at Vanderbilt University Medical Center asked similar questions about CDT and MLD in a proof of principle study [21] (Disclosure: This study received support from the Lipedema Foundation). But unlike the earlier studies, these researchers examined whether physical therapy benefited earlier stage Lipedema patients at stages 1 and 2. As in the other studies, patient quality of life and pain improved following 6 weeks of MLD, though the investigators are quick to caution that the small sample size makes this difficult to interpret.
What is exciting, however, is that the study also used MRI imaging to measure sodium concentrations in the skin and nearby fat. The same group has previously shown sodium levels to be correlated to pain intensity and stage [22]. They have now demonstrated the remarkable finding of a measurable biomarker, tied to a symptom, that appears to change in response to a therapy! This will have to be replicated in larger studies but may well be a milestone in the field.
Conservative therapies were not the only current Lipedema therapies to be explored with new measurements this year. Liposuction kept up a continual parade of literature that supports improved quality of life measurements in women with Lipedema following tumescent and water-assisted liposuction surgeries. In reviews of medical records [23] and survey techniques [24], two papers added to the body of liposuction literature promoting generally positive outcomes. But the story of liposuction research is the story of so much in Lipedema – a decades-old field – still in its infancy. Despite tremendous growth in the field, the field remains small, and it remains difficult to evaluate the strength of the evidence in small numbers of studies engaging small numbers of participants, lack of comparisons to other treatments, and uncertainty of the measurements.
But for now, we are thankful for the growing field of research. We want to celebrate the people who joined the journey, bringing new interests and new data to the field. And certainly, no one can express enough thanks to the hundreds of courageous women with Lipedema who participated in the studies published this year. We are excited and impatient. And we look to our own scientific strategy to help guide research in the direction of better diagnostics that elevate Lipedema research and build the tools we use to understand and treat this condition.
As we exit this year, the Lipedema Foundation is announcing 16 new awards, focused on measurements, and developing new therapies, two of the three elements needed if a new era of Lipedema clinical research is to occur. The last element is you: Whether you are a medical professional, patient, or healthy friend of a woman with Lipedema, there is certainly a role for you in moving this field forward. Watch our newsletters and blogs in the coming weeks to find ways to get connected to research. From all of us at the Lipedema Foundation, we wish you health and happiness in 2022 and each year after.
CITED REFERENCES and LINKS
(12) Long, L. W. X. [Research Progress of Lipoedema] Mandarin. Basic & Clinical Medicine 2021, 41 (3), 438.
(14) Al-Ghadban, S.; Teeler, M. L.; Bunnell, B. A. Estrogen as a Contributing Factor to the Development of Lipedema. In Physiology and Disorders of Adipose Tissue; IntechOpen, 2021.
(17) Ehrlich, C.; Iker, E.; Herbst, K. L. Lymphedema and Lipedema Nutrition Guide: Foods, Vitamins, Minerals, and Supplements; Lymph Notes: San Francisco, CA, 2017.
(18) Faerber, G. Ernährungstherapie bei Lipödem und Adipositas – Ergebnisse eines leitliniengerechten Therapiekonzepts. Vasomed Journal 2019, 2.