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It has now been *20 years since the original Lymphatic Continuum conference was convened, and this continuum has transitioned from a compelling concept to a reality. The explosive growth in our comprehension of lymphatic genetics, development, and function has expanded and modified our traditional views regarding what is, and is not, lymphatic disease. Groundbreaking investigations over the past decade have now defined a large and growing list of pathological conditions in which morphological or function lymphatic alterations can be identified. This list includes atherosclerosis and dyslipidemia, hypertension and other cardiovascular diseases, inflammation and inflammatory bowel disease, obesity, narrow angle glaucoma, and, most recently and compellingly, neurodegenerative disease. The sometimes overlapping but largely disparate nature of these various aforementioned disease categories suggests that the presence, or absence, of structural or functional lymphatic derangements may represent a previously unrecognized unifying influence in the maintenance of health and the promotion of disease. Future investigation of lymphatic mechanisms in disease will likely continue to elucidate the influences of lymphatic dysfunction, perhaps subtle, that can invest other, seemingly unrelated, diseases. In future, such discoveries will provide mechanistic insights and may potentiate the development of a new lymphatic-based approach to human disease diagnosis and therapeutics.

Lymphatic disease is quite prevalent, and often not well clinically characterized. Beyond lymphedema, there is a broad array of human disease that directly or indirectly alters lymphatic structure and function. The symptomatic and objective presentation of these patients can be quite diverse. In this review, we have attempted to provide a systematic overview of the subjective and objective spectrum of lymphatic disease, with consideration of all of the categories of disease that primarily or secondarily impair the functional integrity of the lymphatic system. Lymphedema is discussed, along with chromosomal disorders, lymphangioma, infectious diseases, lymphangioleiomyomatosis, lipedema, heritable genetic disorders, complex vascular malformations, protein-losing enteropathy, and intestinal lymphangiectasia.

Lipedema is an infrequently recognized and often neglected clinical entity that nearly always affects women. It poses a diagnostic challenge as one of the common disorders that is easily confused with lymphedema.

Genetic or acquired defects of the lymphatic vasculature often result in disfiguring, disabling, and, occasionally, life-threatening clinical consequences. Advanced forms of lymphedema are readily diagnosed clinically, but more subtle presentations often require invasive imaging or other technologies for a conclusive diagnosis. On the other hand, lipedema, a chronic lymphatic microvascular disease with pathological accumulation of subcutaneous adipose tissue, is often misdiagnosed as obesity or lymphedema; currently there are no biomarkers or imaging criteria available for a conclusive diagnosis. Recent evidence suggests that otherwise-asymptomatic defective lymphatic vasculature likely contributes to an array of other pathologies, including obesity, inflammatory bowel disease, and neurological disorders. Accordingly, identification of biomarkers of lymphatic malfunction will provide a valuable resource for the diagnosis and clinical differentiation of lymphedema, lipedema, obesity, and other potential lymphatic pathologies. In this paper, we profiled and compared blood plasma exosomes isolated from mouse models and from human subjects with and without symptomatic lymphatic pathologies. We identified platelet factor 4 (PF4/CXCL4) as a biomarker that could be used to diagnose lymphatic vasculature dysfunction. Furthermore, we determined that PF4 levels in circulating blood plasma exosomes were also elevated in patients with lipedema, supporting current claims arguing that at least some of the underlying attributes of this disease are also the consequence of lymphatic defects., , Characterization of plasma-circulating exosomes from mouse models and patients with lymphatic dysfunction indicate that PF4 is a promising biomarker for the diagnosis of lymphatic disorders.

Background: Our aim is to propose a framework for the development of a research case definition of lipedema, based on current available literature and those observations that can be applied to future lipedema research with the intent to standardize and strengthen the scientific evidence base. Methods and Results: We conducted a narrative review of the literature, and identified consensus characteristics and disputed characteristics that could be included in a research case definition of lipedema. After considering the strength of the evidence and how each characteristic might be measured in a research study, we recommended an approach for the development of a research case definition of lipedema that would be based on consideration of five agreed-upon characteristics, and five disputed, or less substantiated, characteristics as additional evidence to enhance specificity. Conclusions: We present a case definition framework for lipedema drawn from the scientific literature that can be applied to future studies on lipedema. Utilizing this framework should help to increase the sensitivity and specificity of case definition and provide an opportunity for meta-analysis of clinical studies and facilitate future research intercomparisons.

Background: The lymphatic contribution to the circulation is of paramount importance in regulating fluid homeostasis, immune cell trafficking/activation and lipid metabolism. In comparison to the blood vasculature, the impact of the lymphatics has been underappreciated, both in health and disease, likely due to a less well-delineated anatomy and function. Emerging data suggest that lymphatic dysfunction can be pivotal in the initiation and development of a variety of diseases across broad organ systems. Understanding the clinical associations between lymphatic dysfunction and non-lymphatic morbidity provides valuable evidence for future investigations and may foster the discovery of novel biomarkers and therapies. Methods: We retrospectively analysed the electronic medical records of 724 patients referred to the Stanford Center for Lymphatic and Venous Disorders. Patients with an established lymphatic diagnosis were assigned to groups of secondary lymphoedema, lipoedema or primary lymphovascular disease. Individuals found to have no lymphatic disorder were served as the non-lymphatic controls. The prevalence of comorbid conditions was enumerated. Pairwise cooccurrence pattern analyses, validated by Jaccard similarity tests, was utilised to investigate disease–disease interrelationships. Results: Comorbidity analyses underscored the expected relationship between the presence of secondary lymphoedema and those diseases that damage the lymphatics. Cardiovascular conditions were common in all lymphatic subgroups. Additionally, statistically significant alteration of disease–disease interrelationships was noted in all three lymphatic categories when compared to the control population.