Lymphedema and Obesity, Part I

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A NEW LOOK AT LYMPHEDEMA AND OBESITY:
BREAKING THE CYCLE

Part I: Statement of the Problem

by Leslyn Keith, OTD, OTR/L, CLT-LANA

The Obesity Epidemic

The incidence of obesity has been on a stunning and rapid rise in the United States, as well as globally, for the last thirty to forty years.⁷ The public health impact is significant. Links between obesity and many indicators of poor health, most notably cardiovascular disease, Type 2 diabetes, and some types of cancer, are well established.^{9, 24} Because of the unique interrelationship between the lymphatic system and adipose tissue, the implications for individuals with, or at risk for, lymphedema are profound. As the obesity epidemic continues to rapidly spiral out of control, lymphedema therapists can take heart. Research about these two body systems can both provide insight into questions about the causes and complications of obesity, and also guide healthcare professionals in the care of people with lymphedema and obesity.

In a six month retrospective chart review of patients from 2013 in my clinic, weight status and other demographic data of 55 patients was studied. It was found that only 27% of the patients during this time period were of normal BMI (n = 15). The remaining 73% were divided as follows: twelve, or 22%, were classified as overweight, sixteen, or 29%, were obese, and twelve patients, or fully 22%, had a BMI of over 40 and were morbidly obese. I have found through informal focus groups that these figures are common in lymphedema clinics around the US.  While moderating networking sessions at conferences for lymphedema therapists, I have asked participants to estimate the percentage of their patients who are overweight or obese. Estimated incidence has ranged from 50% to 80%.  Fife et al.⁶ reported an astonishing gradual increase in weight of their patients after reviewing 1463 patient charts between the years 1999 to 2005. They were unable to calculate BMI due to lack of height data, but noted an astounding trend with almost 15% of patients reviewed weighing at least 300 lbs. Because of the increased prevalence of obesity in their lymphedema patients, Fife et al.⁶ had to establish some ground rules for treatment, one being the requirement of patients to actively engage in weight management.

The prevalence of obesity-related swelling was exemplified on a recent visit to the Duke Lifestyle Medicine Clinic in Durham, North Carolina. I had the opportunity to observe Dr. Eric Westman conducting initial and follow-up visits for patients in his weight management program. Of the patients seen, all exhibited various degrees of lower leg edema, one was additionally at risk for breast cancer-related lymphedema, and another demonstrated a strong indication of primary bilateral lower extremity lymphedema.  In a study performed by Vasileiou et al.,²² lymphangioscintigraphy studies of 49 obese women were reviewed to determine if edema associated with obesity was due to lymphatic system structural defect or to functional overload. They found that 35% of the sample had evidence of structural abnormality of the lymphatics, whereas all sixteen of the subjects with lipedema or lipo-lymphedema examined with MR imaging by Lohrmann et al.¹³ were found to hSchnuave lymphatic abnormalities. Harvey¹⁰ notes that alterations in lymph and blood capillaries are evident in lipedema, a condition in which there is abnormal adipose tissue accumulation in a fairly consistent distribution in the lower body from hips to ankles.  It is currently unclear which occurs first, the fat accumulation or the alteration and dysfunction of vasculature.

The Lymph/Fat Connection

Fascinating research into the intimate relationship between the lymphatic system and adipose tissue has occurred over the last decade.  The role of the lymphatic system with lipid metabolism is far more complex and much more integral to human health than we previously thought. Recent research shows that adipose tissue function is an active, rather than the previously characterized passive, process and dysfunction may have an important role in inflammation, diabetes and obesity.⁵ Lymphedema therapists have long been aware of the propensity of the lymphedematous limb to accumulate fat as well as a seemingly common association between bilateral lower extremity primary lymphedema and obesity. New research illuminates the mechanism for these phenomenons.

Adipose tissue functions as an organ of the endocrine system by the release of hormones and proinflammatory agents. Most notably, C-reactive protein (CRP), a known inflammatory agent, is released from adipose tissue in individuals who are obese, especially those with abdominal obesity. This is a recognized risk factor for heart disease. In addition, the excessive secretion of adipose cytokines and/or the increased presence of CRP seem to trigger a cascade of events, starting with chronic inflammation, followed by insulin resistance, and finally resulting in diabetes and heart disease.⁴ This may give rise to the positive correlation between insulin resistance and lymphatic load.⁸ Aschen et al.³ surmise that because proinflammatory macromolecules can only be evacuated by the larger lymph capillaries, the prolonged presence of these molecules in the adipose tissue can give further rise to local inflammatory effects.

Several studies noted that chronic inflammation results in increased permeability and decreased function of lymphatic vessels.^4,23 Edema occurs in inflammatory conditions when the rate of capillary filtration, and subsequent lymphatic load, exceeds transport capacity of the lymphatic system, but structural defects and reduced drainage capacity is also a factor.¹⁷ Therefore, not only does the obese person develop lower leg edema, but their immune system is depressed and they are at high risk for metabolic syndrome and heart disease.

By far the most interesting relationship between the lymphatic system and adipose tissue is their cooperation for immunological function. Several studies noted the close proximity of fatty deposits and lymph nodes and vasculature.^{4, 23} The lymphatic system is able to deploy agents that can break down adipose tissue to release fatty acids as fuel and other agents that can promote adipogenesis for the maintenance of a readily available energy source. A study by Miura et al.¹⁴ in 1987showed a correlation between lipid ingestion and increased movement of lymphocytes by the lymphatic system. Over ten times the amount of lymphocyte transport was seen after absorption of dietary fat in rats. The authors suggested that there may be an immune system mechanism that prepares and maintains the immune system by movement of lymphocytes in response to the metabolism of lipids.

It is dysfunction in this otherwise fruitful cooperation between lymphatics and adipose tissue that can lead to an unhealthy accumulation of adipose tissue in lymphedema and possibly even trigger obesity.¹⁰ Chakraborty et al.⁴ surmised that adipogenic properties of lymph had a tendency to trigger obesity due to communication between the lymphatics and adipose tissue. An otherwise healthy ability to cultivate a ready fuel source to facilitate quick immune responses instead becomes pathological with the chronic lymph stasis that occurs in lymphedema.

The abdomen, as the depot of the largest concentration of lymph nodes in the body, is particularly vulnerable to the proliferation of adipose tissue in response to a chronic inflammatory state.  The expansion of adipose tissue negatively impacts its own microcirculation due to hypoxia and fibrosis.^{2, 17} This cyclical demise of adipose tissue also leads to further degradation of the lymphatic vasculature. Malformed lymph vessels lack proper drainage ability and lead to edema, which in turn leads to further adipose expansion. The resulting chronic inflammation provokes the continual recruitment of adipose tissue to fuel a compromised immune system, resulting in further obesity. ^{2, 17}

Shimizu et al.²⁰demonstrated in their study the unique relationship between an adipose tissue-derived hormone, adiponectin, lymphatic vessels and lymphedema. It was established that levels of this adipokine are diminished in the presence of obesity. The presence of adiponectin promotes lymphatic vessel formation and healing, while its absence will increase the risk of, or exacerbate, lymphedema. Aschen et al.³ found a temporary increase in adiponectin in initial stages of  fat accumulation with lymphedema, followed by a pattern of decreased expression as adipose tissue alteration occurs with fibrosis, hypoxia and inflammation. By losing weight, adiponectin levels are re-established and significant improvement in lymphatic function is restored, suggesting that weight management is the best option for risk reduction and treatment for obesity-related lymphedema.^{3, 19}

Obesity and Risk of Cancer-related Lymphedema

Although studies predominantly focus on breast cancer-related lymphedema, all seem to indicate that obesity represents a significant increased risk for the development and severity of lymphedema, recurrence of cancer and poorer treatment outcomes. In a review of sixty studies related to cancer-related lymphedema, the majority found obesity to be a significant risk factor for the development of lymphedema.¹⁵ The participants in a study by Ridner et al.¹⁶ were more than three times more likely to develop lymphedema if they had a BMI of thirty or greater at the time of breast cancer surgery, while another study found the risk doubled.¹¹ In a study of 455 women who were breast cancer survivors, 92% of the those with lymphedema were also obese.²¹

Huang et al.¹² found that breast cancer-related lymphedema risk was related to age, radiation treatment and obesity. Obesity may have been a factor because of surgical complications due to obesity, including poorer and slower healing, increased inflammation, and more extensive stress on the lymphatic system with excessive adipose tissue.¹ Additionally, Schmitz et al.¹⁸ found that obesity posed a poor prognosis for cancer survival, diminished cancer treatment efficacy, and increased incidence of adverse cancer treatment effects such as fatigue, peripheral neuropathy, and lymphedema.

Fortunately, addressing a patient’s obesity with an effective weight management program can not only reduce their risk of cancer-related lymphedema, but also facilitate its treatment when lymphedema does occur. A significant correlation between weight loss and reduction in volume in the lymphedematous limb was established in a study by Shaw et al.¹⁹ Because a reduction in volume of both arms occurred with weight loss in this study, albeit a greater reduction in the affected limb, they believe that fluid as well as subcutaneous fat reduction occurred. This study also established that a relatively small amount of weight loss (as little as seven pounds) had significant impact on arm volume. Their findings suggest that a weight reduction plan needs to be part of the treatment for lymphedema.

Conclusion

Morbidly obese patients may have the expectation that healthcare providers will provide accommodations, such as bariatric furniture and fixtures that can support a very large girth or very high weight limit, while simultaneously they may focus on the edema as their greatest problem.⁶ It is incumbent upon us as lymphedema therapists to help our obese patients understand not only the urgency of addressing their weight, but also guide them in a successful weight management program.  Research establishing the intimate link between lymphatic and adipose systems not only highlights the imperative need for these bodily systems for health: many studies also demonstrate that pathology in either system can lead to a cascade of detrimental events with far reaching and profound consequences.

References

1. Ahmed, R. L., Schmitz, K. H., Prizment, A. E., & Folsom, A. R. (2011). Risk factors for lymphedema in breast cancer survivors, the Iowa Women’s Health Study. Breast Cancer Research and Treatment. 130, 981-991.
2. Arngrim, N., Simonsen, L., Holst, J. J., & Bulow, J. (2013). Reduced adipose tissue lymphatic drainage of macromolecules in obese subjects: A possible link between obesity and local tissue inflammation? International Journal of Obesity, 37, 748-750. doi: 10.1038/ijo.2012.98
3. Aschen, S., Zampell, J. C., Elhadad, S., Weitman, E., De Brot Andrade, M., & Mehrara, B. J. (2012). Regulation of adipogenesis by lymphatic fluid stasis Part II: Expression of adipose differentiation genes. Plastic and Reconstructive Surgery, 129(4), 838-847.
4. Chakraborty, S., Zawieja, S., Wang, W., Zawieja, D. C., & Muthuchamy (2010). Lymphatic system acts as a vital link between metabolic syndrome and inflammation. Annals of the New York Academy of Sciences, 1207(Suppl 1), E94-102. doi: 10.1111/j.1749-6632. 2010.05752.x.
5. Dixon, J. B. (2010) Lymphatic lipid transport: Sewer or subway? Trends in Endocrinology and Metabolism, 21(8), 480-487.
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8. Foeldi, E. (personal communication, June 19, 2013).
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12. Huang, H-P., Zeng, Q., & Zhou, J-R (2013). Risk factors associated with lymphoedema among Chinese women after breast cancer surgery. Contemporary Nurse, 44(1), 5-10.
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14. Miura, S., Sekizuka, E. Nagata, H., Oshio, C., Minamitani, H., Suematsu, M., Tsuchiya, M. (1987). Increased lymphocyte transport by lipid absorption in rat mesenteric lymphatics. American Journal of Physiology, 253, G596-G600.
15. Paskett, E. D., Dean, J. A., Oliveri, J. M., & Harrop, J. P. (2012). Cancer-related lymphedema risk factors, diagnosis, treatment, and impact: A review. Journal of Clinical Oncology, 30(30), 3726-3733.
16. Ridner, S. H., Dietrich, M. S., Stewart, B. R., & Armer, J. M. (2011). Body mass index and breast cancer treatment-related lymphedema. Supportive Care in Cancer, 19, 853-857.
17. Rutkowski, J. M., Davis, K. E., & Scherer, P. E. (2009). Mechanisms of obesity and related pathologies: The macro- and microcirculation of adipose tissue. FEBS Journal, 276, 5738-5746.
18. Schmitz, K. H., Neuhouser, M. L., Agurs-Collins, T., Zanetti, K. A., Cadmus-Bertram, L., Dean, L. T., & Drake, B. F. (2013). Impact of obesity on cancer survivorship and the potential relevance of race and ethnicity. Journal of the National Cancer Institute, 105(18), 1344-1354. doi: 10.1093/jnci/djt223
19. Shaw, C., Mortimer, P., & Judd, P. A. (2007). A randomized controlled trial of weight reduction as a treatment for breast cancer-related lymphedema. Cancer, 110(8), 1868-1874.
20. Shimizu, Y., Shibata, R., Ishii, M., Ohashi, K., Kambara, T., Uemura, Y., Ouchi, N. (2013). Adiponectin-mediated modulation of lymphatic vessel formation and lymphedema. Journal of the American Heart Association. doi: 10.1161/JAHA.113.000438
21. Ugar, S., Arici, C., Yaprak, M., Mesci, A., Arici, G. A., Dolay, K., & Ozmen, V. (2013). Risk factors of breast cancer-related lymphedema. Lymphatic Research and Biology, 11(2), 72-75. doi: 10.1089/lrb.2013.0004
22. Vasileiou, A-M., Bull, R. Kitou, D., Alexiadou, K., Garvie, N. J., & Copack, S. W. (2011). Oedema in obesity; role of structural lymphatic abnormalities. International Journal of Obesity, 35, 1247-1250.
23. Wang, Y. & Oliver, G. (2010). Current views on the function of the lymphatic vasculature in health and disease. Genes & Development, 24, 2115-2126. doi: 10.1101/gad.1955910
24. Westman, E. C. & Steelman, G. M. (Eds.). (2010). Obesity: Evaluation and treatment essentials. New York, New York: Informa Healthcare.