What Do These Diseases Have in Common? David Zawieja, PhD • Lymphedema • Lymphatic vascular malformations • Visceral lymphatic diseases • Gastrointestinal infections and Clostridium difficile colitis Lymphatic • Peritonitis • Cancer and metastasis dysfunction, • Chronic infections and inflammation inflammation, • Organ transplantation • Autoimmune diseases (inflammatory bowel and altered Lymphedema disease, arthritis) • Neuro-immune disorders immunity • Metabolic syndrome • Burn and hemorrhagic shock • Obesity, lipedema, and fat disorders • Diabetes mellitus • Integumentary impairment 263 Relationship of AVL Systems • Circulatory system: 3 components a=artery – Closed blood circulatory system v= vein • Arteries l=lymph vessel • Veins – Half-open lymphatic system • Veins and lymphatics: Similar embryologic origin and anatomy http://jeltsch.org/static/public • When pathologic changes occur in venous system, ations/jeltsch03/index.html microangiopathic changes of both the vascular and lymphatic networks 265 Anatomy Circulation of interstitial • Connected to every organ and space fluid system of the body except the central nervous system Safety valve Defense for fluid • Lymphatic structures are found Removes and overload - destroys toxic helps control substances everywhere except Lymphatic edema – Cornea System – Striated muscles Functions – Bone marrow Digestive aid – Joint cartilage Transports Homeostasis lipids from of extracellular – Hair, nails, teeth intestine to environment blood steam – Alveoli of lungs Lymphoid Organs • Part of lymphatic system • Called lymphoid organs because home to lymphocytes • Sites where cells of immune system originate and develop • Include: • Spleen • Thymus • Small oval structures that • Tonsils filter lymph, • Peyer’s patches catching debris or • Bone marrow cells • Lymph nodes • Responsible for • MALT-Mucosa Associated purifying and Lymphoid Tissue draining lymph fluid The Lymphatic System: Immune Function of Lymphatic System The Body’s Drainage System • Production, maintenance, and distribution of: Lymphocyte – Macrophages – B- and T-lymphocytes – Plasma cells – Reticular cells Lymphocytes attacking a cancer cell Lymphatic capillaries—> precollectors—> collectors—> lymph nodes 270 Lymphokinetic Motion & Lymphangiomotoricity Pressure Gradient (flow of the lymph) • Lymph collects in angions (between two valves) Single angion • Smooth muscle and respiratory pumps force lymph forward • Aided by function of the Interstitial one-way semilunar valves fluid • Ultimately lymph fluid empties Valve Lymph Blood Interstitial Lymph Lymph Lymph Large cir. into venous system opens flows capillaries fluid capillaries veins ducts veins Highest Pressure Lowest Pressure Lymph Angion Valve collects contracts closes Lymphatic Load • Plasma and plasma proteins escape from small blood vessels • Lymphatic reabsorbs/transports substances not absorbed by venous system (Starling’s Law/Equilibrium) • Lymphatic load includes: Incidence & Prevalence Etiology – Dead cells Stages – Bacteria Assessment – Endotoxins – Enzymes (MMPs: matrix metalloproteinases) WOUND MILIEU/CHRONIC WOUND FLUID COMPONENTS What Is Lymphedema? Lymphedema Definition • Chronic condition; swelling in one or more limbs • Chronic, incurable condition characterized • May include corresponding quadrant of by an abnormal accumulation of interstitial trunk proteins causing edema as a result of an • Swelling may affect other areas anatomic alteration in the lymphatic (eg, head/neck, breast, genitalia) system • Not curable at this time Massive localized lymphedema (MLL) • Ultimately failure of lymphatic drainage • Manageable appropriately Associated with morbid if treated early obesity Attribution: Caroline Fife • Ignored or inappropriately treated (eg, diuretics), progresses; becomes difficult to manage Incidence and Prevalence Incidence and Prevalence (cont) • Worldwide • In the United States (numbers likely – Chronic venous insufficiency (CVI) edema affects 300 million under-reported) – Phlebolymphedema numbers likely underreported in the CVI – Primary lymphedema: 2 million population – Secondary lymphedema: 2.5 to 3 million • Medscape 2015: “2%‐5% of all Americans have some changes associated with CVI: 6‐16 million with 2° • ~1% of the population lymphedema from CVI” • In the world • ESVS 2015: “CVI (C3-C6) affects about 5% of the – Post-filarial (parasitic) lymphedema: population—16 million with 2° lymphedema from CVI” 90-120 million – Post-mastectomy lymphedema affects ~20 million • Leading cause of lymphedema in the – Primary lymphedema and post-traumatic edema cases ~40 world million – Considering all causes, 1 of every 40 people in the world • More than a billion people at risk may be affected by lymphedema Lymphedema is the biggest problem you never knew about! Weiss R. Venous Insufficiency. eMedicine. Updated October 12, 2015. Wittens C, et al. Management of Chronic Venous Disease: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg. 2015 Jun;49(6):678-737. Cancer and Lymphedema Statistics Lymphedema • ~30% of patients who undergo mastectomy with lymph node • Etiology: obstruction of lymphatic channels & resection due to breast cancer impairment in return of lymph to venous channels develop secondary lymphedema of the upper • Lymphatic transport capacity decreases extremity • Result: increased accumulation of high protein fluid • Lower extremity lymphedema (and/or genital lymphedema) after radical lymph node dissections secondary to prostate cancer ~ >70% • Lymphedema may present immediately or years after treatment – Most occur within first 18 months Hayes SC, et al. J Clin Oncol. 2008;26(21):3536-3542. Cormier JN, Askew RL, Mungovan KS, et al. 280 Lymphedema beyond breast cancer. Cancer. 2010;116:5138-5149. Etiology of Lymphedema Etiology of Lymphedema (cont) • Primary lymphedema: Hereditary malfunction of lymph • Secondary lymphedema system resulting in impaired lymph node or lymph vessel development – Most common form • Inherited autosomal-dominant trait – Caused by known insult to lymphatic system • Forms Milroy’s disease – Contributing factors include: • Lymphadenectomy (related to malignancy) – Milroy’s disease: Congenital (present at birth); 2% of primary lymphedemas • Radiation • Venous disease**** – Meige disease/lymphedema praecox (onset early in life, typically late teens or shortly thereafter); 65%- • Post-surgical complications in legs or abdomen 80% primary lymphedemas – Vascular reconstruction – Lymphedema tarda – Joint replacement (usually after age 35 years) – Venous harvesting for CABG • Primary lymphedema accounts for • Trauma (crush injury) 10% of patients with lymphedema Meige disease • Malignant tumors blocking lymphatic pathways • Inflammatory/infection (i.e. tuberculosis, filaria, silica) Fife, CE, Kline RA. Venous Disease and Lymphedema Management in Chapter 14 Wound Care Essentials: Practice Principles, 4th ed. Wolters Kluwer, 2016 Lymphatic Filariasis Stage 0 Lymphedema • Most common cause of lymphedema world • Sub-clinical stage, pre-stage, wide latency stage • Identified by World Health Organization as a leading cause of permanent and long-term • Transport capacity of lymphatic disability in world system reduced but still able to cope • Endemic in more than 80 countries-tropics with normal amount of lymphatic load and subtropics • Often not clinically detectable • Affects 120 million people in 83 countries • Caused by threadlike, parasitic filarial worm • Patient may have subjective that live almost exclusively in humans symptoms • Worms transmitted by mosquitoes • Sensations of heaviness and tightness • Toxic waste produced by worms results in • Patients at risk of lymphedema inflammation and obliteration of lymphatic system progression Available at: http://www.who.int/lymphatic_filariasis/epidemiology/en/. Accessed 1/2/2017 https://www.bestveintreatment.com/vein-disease-symptoms/lymphedema/ Stage 1 Lymphedema Stage 2 Lymphedema • Spontaneously irreversible • Reversible stage • Clinically persistent edema • Edema reduced with elevation not reduced by elevation • Pitting edema that begins distally (at the hand/foot) • « Positive Stemmer’s sign • Negative or borderline Stemmer’s sign • Pronounced fibrosis • No palpable fibrosis or secondary tissue changes • Connective tissue proliferation (fibrosis) due to long-standing accumulation of protein-rich fluid • Frequent infections – cellulitis • Can become life-long stage Photos courtesy of Heather Hettrick, PT, PhD, CWS Photo courtesy of John Macdonald, MD Before After Stage 3 (Lymphatic Elephantiasis) Classifications of Edema • Massive enlargement and distortion of limb caused by • High-protein and low-protein breakdown of skin’s elastic components • Chronic venous insufficiency edema: Low-protein, mostly • Pronounced skin alterations water • Lymphostatic fibrosis • Lymphedema: High-protein edema • Lymphatic system responsible for picking up and • Papillomas transporting proteins (large molecules) back into venous • Cysts system • Fistulas • When proteins not picked up by lymphatic capillaries (due • Deep skin folds to some problem with the lymphatic system), they are left behind in interstitial tissues • Hyperkeratosis • Proteins cause fibrosis of tissues • Infections Photo courtesy of John • Proteins hydrophilic: Attract more water to the interstitial • Cellulitis Macdonald, MD tissues, making the swelling or lymphedema worse • Fungal infections (skin, nails) Photos courtesy of Heather Hettrick, PT, PhD CWS Pathophysiology