What is the link between lymphedema and obesity?

Research Perspective

What is the link between lymphedema and obesity?

The bidirectional interaction between obesity and lymphatic injury

By Babak Mehrara and George Kokosis

L

ymphedema is a major worldwide problem afflicting over 200 million patients1. A common cause of lymphedema in the United States—and most developed countries—is cancer treatment. In these procedures, lymph nodes or lymphatic channels are injured during the course of cancer staging or treatment; in approximately 20-50% of patients, this injury leads to the development of lymphedema. While breast cancer treatment is the most common cause of cancer-related lymphedema in developed countries, this disease also occurs commonly in patients treated for gynecological or urologic cancers, melanoma, head and neck cancer and sarcoma. It is estimated that at least six million patients in the United States have lymphedema, and many are related to obesity itself. To put the scale of this problem in perspective, this number of patients is roughly equivalent to the number of Americans who suffer from Alzheimer’s disease and nearly six times the number of patients with Parkinson’s disease.

Obesity is a major risk factor for development of lymphedema Researchers have identified a number of risk factors for lymphedema development. This research is useful for patient education and early intervention approaches; in some cases, risk factors are modifiable and can be changed to decrease the risk of disease development.

Although there is debate about the degree of risk for some putative risk factors for cancer-related lymphedema—increasing age,

Dr. Babak Mehrara, MD, is the chief of the Division of Plastic and Reconstructive Surgery at Memorial Sloan Kettering Cancer Center in New York.

His clinical interests include microsurgical oncologic reconstruction. He is also the principal investigator in his NIH funded laboratory studying pathophysiology and treatment of lymphedema.

Dr. George Kokosis, MD, is currently a microsurgical reconstructive fellow in the Plastic and Reconstructive Surgery program at Memorial Sloan Kettering Cancer Center. He has completed his surgical training at Johns Hopkins hospital. His clinical and research interests include surgical treatment of lymphedema and associated clinical and patient reported outcomes.

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the use of adjuvant radiation therapy, the type of chemotherapy used for cancer treatment, among others—a large body of evidence supports the idea that obesity is a major risk factor for disease development2.

In breast cancer survivors, studies have shown that obesity—usually defined as patients with a body mass index (BMI)>30— increases the risk of lymphedema by 3-400%3,4,5. Even gaining weight after surgery in otherwise thin patients increases the risk of lymphedema5,6. Along the same vein, a randomized-controlled-trial comparing patients with arm lymphedema who received nutritional consultation and support for 12 weeks versus patients who were simply given a pamphlet on weight loss measures, showed that active intervention resulted in weight loss and also significantly improved arm swelling7. These studies are important because they show that obesity and lymphedema are related and that dietary modifications or behavioral changes are an important adjunct to the treatment of the disease.

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Obesity and lymphedema are related and dietary modifications or behavioral changes are an important adjunct to the treatment of the disease.

The major question that our laboratory and other researchers have sought to answer is: how does obesity increase the risk of lymphedema? This is important because understanding how obesity and lymphedema are related can help us develop novel methods to treat or prevent the disease. It turns out, that the interaction between obesity and lymphatic injury is not only complex but also bidirectional.

Obesity causes lymphatic dysfunction Evidence for the concept that obesity causes lymphatic dysfunction is derived from studies showing that some extremely obese patients— those with a BMI > 50–spontaneously develop lymphedema and limb swelling even without surgery or trauma8. Obese patients who do not have visible swelling in their extremities, have abnormal lymph node uptake and a decreased ability to transport radioactively labeled molecules from their tissues as compared with normal weight patients9,10.

Laboratory studies using mouse models

have also helped shed light on the cellular mechanisms that link obesity and lymphatic function. Similar to the clinical scenario, we have found that weight gain resulting from a high-fat diet is inversely related to the capacity of the lymphatic system to remove fluid and immune cells from tissues and to the pumping of lymphatic channels. This is important because lymphatic vessel pumping is an important regulator of lymph movement and is thought to account for 70-80% of lymphatic fluid transport11. Obese mice also have leaky lymphatic vessels and this leakiness results in accumulation of fluid in the tissues. Fluid accumulation causes chronic inflammation around the lymphatic vessels, which, in turn, injures the lymphatic channels.

The good news is that the defects in lymphatic function in obese mice are reversible (at least partially) with behavioral changes such as weight loss or aerobic exercise. Obese mice that were placed on a more healthy diet not only lost weight but also had better lymphatic vessel pumping and decreased lymphatic leakiness12. In other studies, we showed that obese mice that underwent a six-week period of mild aerobic exercise (walking on a treadmill at a low speed for one hour per day) did not

lose weight but had significantly improved lymphatic function as compared with sedentary obese mice. Whether or not obesity-associated lymphatic dysfunction is reversible clinically is a topic of debate; a recent case report of a morbidly obese patient who underwent weight loss surgery and lost a substantial amount of weight did not show evidence of improved radio-nucleotide transport13. This may reflect the chronicity of clinical obesity or perhaps other, as yet, undetermined effects of chronic weight gain. Larger studies in this area should shed more light on this problem.

Lymphatic dysfunction causes obesity The most direct evidence that we have showing that lymphatic dysfunction causes obesity is the fact that chronic lymphedema causes fat deposition. Thus, while the early stages of the disease are characterized by fluid accumulation (that is why “pitting” in the skin occurs), the later stages of the disease result in fat deposition. This is the reason why bandaging and lymphatic massage are less effective in these late stages since fat is not compressible. In a sense, we can think of lymphedema as a form of “regional” obesity— thus, while some people have a tendency to accumulate fat in their love handles or

FIGURE 1

The relationship between obesity and lymphedema is bidirectional.

Leaky Lymphatics

Image: Dr Mehrara and Dr Kokosis

Inflammation

Lymphatic injury

Obesity

Decreased Pumping

Lymphedema

Impaired Proliferation

Free Fatty Acids Surgery

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noted in diabetes and obesity and can, as a result, modulate how tissues respond to insulin and other growth factors17.

other areas, patients with lymphedema have a tendency to accumulate fat in their lymphedematous limb.

Laboratory studies also support the idea that lymphatic dysfunction favors fat deposition. For example, mice with genetic abnormalities of the lymphatic system become obese as adults even when they are fed a low-fat or healthy diet14. Lymphatic fluid placed on fat cells in a petri-dish causes the fat cells

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to accumulate fatty acids and expand in size.

This effect is related to changes in fatty acids that activate the fat cell to accumulate lipids.

In other words, lymph makes you fat!

Other studies have shown that lymphatic injury results in chronic inflammation and that this inflammatory response causes adipocytes to grow in size and accumulate fat15,16. This chronic inflammation is important since it can cause many of the genetic changes that are

Conclusions It is clear that obesity and lymphedema are critically linked and that this relationship is bidirectional (Figure 1). The take home message of this article is that for most patients with lymphedema, behavior changes—weight loss, aerobic exercise, and resistance exercise— can improve their lymphedema symptoms. It is also possible to lower the risk of developing lymphedema by maintaining a healthy life style, a healthy balanced diet, and avoiding weight gain. Future clinical and laboratory studies will identify how obesity injures the lymphatic system and how lymphatic injury modulates fat cells. This knowledge will help us develop more targeted treatments that can help patients who suffer from lymphedema. LP A full set of references can be found at www.lymphedemapathways.ca

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