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The last decade has brought a burgeoning of lymphatic system research that is changing the very fundamentals of our understanding of this complex system. Early last year two of the giants in lymphatic research co-authored a review of our newfound knowledge about lymphatic disease, part of a review series in The Journal of Clinical Investigation March 2014; 124(3):915-921. The full text is available at

The authors Prof. Peter S. Mortimer of the University of London’s St. George’s Hospital Medical School and Prof. Stanley G. Rockson, Allan and Tina Neill Professor of Lymphatic Research and Medicine at Stanford University and Director, Center for Lymphatic and Venous Disorders, Stanford University Medical Center present a clear and concise review of how the lymphatic system is or may be involved in a variety of clinical conditions including edema, infection, cardiovascular disease, autoimmunity, Crohn’s disease, obesity, cancer and lymphedema. They also summarize our current knowledge of the genetic aspects of primary lymphedema and how new knowledge of lymphatic genes and molecular mechanisms demonstrate that lymphatic dysfunction plays a dynamic part in many pathological processes, and may present a target for new therapies.

The knowledge brings new questions and the need for further research. It also shatters some traditional views that have been held for decades. One of the basic functions of the lymphatic system, in conjunction with the circulatory system, is maintenance of fluid balance in body tissue. Physiology of the microvascular system is reviewed and the factors involved in the dynamics of tissue fluid balance are discussed. The findings of Levick and Michel[1] that nearly all interstitial fluid is removed by the lymphatic system, and not through re-absorption by venous capillaries, are clarified, modifying the misunderstanding of the Starling equation still taught in many undergraduate classes. All chronic edema therefore indicates an inadequacy or failure of the lymphatic system, and it is vital for the clinician to determine the source of the edema, whether primary impairment of the lymphatics or secondary overload of the lymphatics due to another systemic failure.

The many pathological mechanisms of impaired lymph drainage are mentioned, including failure of initial lymphatic absorption, aberrant smooth muscle function, faulty lymphatic valve operation and faulty electrical control of lymphangion smooth muscle pumping. [Lymphedema is more than "a blockage in your lymphatic system"[2] as commonly defined in authoritative sources today.] The possible relationship of these pathologies to genetic mutations and molecular factors is discussed as a segue to a fuller discussion of the genetic aspects of primary lymphedema. The clinical classification pathway and diagnostic logic for primary lymphatic dysplasia, revised and updated from Connell[3], are presented with known and postulated genetic associations assigned. [This classification pathway diagram is the basis for my proposed ICD-10-CM Expansion of Lymphedema Diagnostic Codes at RW] A brief summary of known genetic associations with lymphatic dysfunction and lymphedema follows, providing a more structured clinical approach than simply relying on the age of onset (i.e. congenital, praecox, tarda).

Another vital role of the lymphatic system, host defense, is elucidated, with our latest knowledge of the role of the lymphatics in infection, immunity and inflammation. The greatly elevated rate of infection associated with lymphedema of all forms, and potential associations of lymphedema with changes in immunity are noted. "The range of diseases associated with lymphatic dysfunction causing disturbed immunity is likely to be extensive." An example is given of the possible involvement of lymphatic dysfunction in inflammatory bowel disease, particularly Crohn’s disease, pointing to immune deficiency rather than autoimmunity as the functional cause.

The discussion on the relationship between fat and lymphatics focuses on the role of the lymphatic system in the generation, absorption and disposition of fat. Much is still not known, but examples are given not only of the role of the lymphatics in absorption and transport of fat by intestinal lacteals and the fat content of persistent lymphatic tissue, but of the other side of the coin-- the influence of obesity on the incidence of lymphedema. The role of the lymphatic function in lipid pathologies such as obesity, diabetes, hypercholesterolemia and atherosclerosis "remain to be elucidated".

Finally, the role of lymphatics in the maintenance and spread of cancer is discussed and the possibility of harnessing the migration of cancer cells toward, into and along initial lymphatics as an element of cancer treatment. Evidence for the systematic nature of breast cancer-related lymphedema (BCRL) is introduced and the possibilities of screening breast cancer patients for risk stratification and detection of early or subclinical lymphedema is a major impetus for development of lymphatic disease biomarkers (Lin[4]) utilizing proteins representing four central pathogenetic modalities of lymphatic disease: lymphangiogenesis, inflammation, fibrosis and lipid metabolism.

The review ends with the hope that focused therapeutics based on newfound knowledge can be developed which can not only stabilize or delay the progression of lymphedema, but reverse its fundamental pathophysiology.

  2. Levick JR & Michel CC. "Microvascular fluid exchange and the revised Starling Principle" Cardiovasc Res. 2010;87(2):198-210.
  3. Mayo Clinic definition of Lymphedema at (Accessed February 24, 2015)
  4. Connell FC, Gordon K, Brice G, Keeley V, Jeffery S, Mortimer PS, Mansour S and Ostergaard P. "The classification and diagnostic algorithm for primary lymphatic dysplasia: and update from 2010 to include molecular findings" Clin Genet. 2013;84:303-314.
  5. Lin S, Kim J, Lee M-J, Roche L, Yang NL, Tsao PS & Rockson SG. "Prospective Transcriptomic Pathway Analysis of Human Lymphatic Vascular Insufficiency: Identification and Validation of a Circulating Biomarker Panel" PLOS One. 2012;7(12):e52021.