Systemic and Medical Causes of Edema Suman W Rathbun MD, MS Director, Vascular Medicine University of Oklahoma Health Sciences Center

Disclosure Grant support: Diagnostica Stago Inc.

APPROACH TO THE PATIENT WITH LEG PAIN AND SWELLING New or worsening symptoms Yes No Objective testing for DVT Chronic swelling Drug Induced Abnormal: Treat DVT Normal: Withhold DVT Treatment Tumors Vascular Lymphatic Possible Diagnoses Systemic, medical Orthopedic Abscess Muscle strain from Baker’s cyst, unaccustomed exercise cyst rupture muscle tear Cellulitis superficial phlebitis Compartment Swelling in paralyzed leg syndrome, Twisting leg injury revascularization Venous valvular Lymphedema, lymphangitis insufficiency Major orthopedic surgery, leg trama Miscellaneous Dependency Factitial limb swelling Lipedema Obesity Reflex sympathetic dystrophy Retroperitoneal fibrosis IM July 1995;16:50

Systemic causes of edema Cardiac disease Hepatic disease Malabsorption/protein-calorie malnutrition Obstructive sleep apnea Pregnancy and premenstrual edema Renal disease Thyroid disease Allergy, urticaria, angioedema Medications

Cardiac disease Increased capillary permeability from systemic venous hypertension Increased plasma volume Right sided heart failure Pulmonary hypertension Physical exam: bilateral pitting edema, distension of jugular veins, right upper quadrant abdominal tenderness due to liver congestion Diagnostic Testing: echocardiogram, BNP Treatment: diuretics, ACEI, ARB, other chamber specific therapies

Hepatic disease Increased capillary permeability from systemic venous hypertension; portal Decreased plasma oncotic pressure from reduced protein synthesis Cirrhosis Physical exam: ascites, splenomegaly, jaundice, weight loss, nausea, bruising Diagnostic testing: liver function tests, Hepatitis panel, CT, Albumin, PT/INR Treatment: Water restriction, low sodium diet, TIPS procedure

Malabsorption/protein-calorie malnutrition Reduced protein synthesis leading to decreased plasma oncotic pressure Sometimes obstruction of lymphatic system: intestinal lymphangiectasia causing protein loss Reflux of fluid into interstitial space Pancreatic insufficiency, biliary disease, intestinal overgrowth, sprue, celiac, Crohn’s, lactase deficiency, AIDS enteropathy etc. Diarrhea, steatorrhea, weight loss, fatigue, anemia, bleeding, neuro manifestations Physical exam: low BP, muscle wasting, pale, ecchymosis, motor weakness, neuropathy, glossitis, dermatitis Diagnosis: CBC, iron, PT/INR, cholesterol, vitamin concentrations, bowel imaging, fat malabsorption studies Treatment: Nutritional support, MCT or gluten free diet, supplements

Obstructive sleep apnea Pulmonary hypertension resulting in increased capillary hydrostatic pressure Elevated right heart pressure Snoring, abrupt awakenings, morning headache, insomnia, daytime sleepiness Physical exam: obesity, enlarged neck circumference Diagnosis: polysomnography and echocardiography Treatment: CPAP, oral appliance, elevate legs, compression

Pregnancy and premenstrual edema 92% of women in second phase of their menstrual cycle: progesterone driven Progesterone acts as agonist for aldosterone, inducing natiuresis with increased renin-secretion levels. Physical exam: Edema in legs, arms, face, abdomen, mammary areas also Diagnostic testing: None Treatment: Compression stockings Int J Womens Health 2015;7:297

Renal disease Increased plasma volume (salt retention) Decreased oncotic pressure from protein loss (nephrotic syndrome) Acute or chronic renal failure Physical exam: leg swelling and periorbital swelling Diagnostic testing: Creatinine and chemistries, urinalysis, CT, US, renal biopsy Treatment: ACEI, ARB, fluid restriction, salt restriction, diuretics, dialysis

Thyroid disease Hypo or hyperthyroidism Hypothyroidism: deposition of mucopolysacchrides in the dermis resulting in edema. Hypothyroidism: myxedema with dry, thick skin, non pitting periorbital edema, yellow discoloration of skin over knees, elbows, palms and soles Graves: deposition of hyaluronic acid in the skin, localized pretibial myxedema, often non pitting edema, anterior/lateral legs Treatment: topical steroids, compression, correct underlying cause

Graves myxedema

Allergy, urticaria and angioedema Increased capillary permeability Urticaria or hives: pruritic welts or blotches Angioedema: affects deeper layers of the skin, eyes and lips Causes: food, medications, pollen, emotional, heat/cold, exercise Physical exam: swollen pale patches welts on face, lips, tongue, throat, ears with hives. Diagnostic testing: CBC with eosinophils, allergy testing Treatment: antihistamines, corticosteroids, autoimmune

Increased extracellular fluid volume Ca-channel blockers: selective precapillary sphincter dilatation with increased capillary hydrostatic pressure and leakage of fluid into the interstitium Occurs weeks after initiation of medication Resolves within days of discontinuation Soft, pitting edema

Evaluation of Systemic Causes of Edema Acute edema: d-Dimer, follow with Doppler exam if d-Dimer elevated OR clinical suspicion of DVT high Age > 45 years: echocardiogram to rule out pulmonary hypertension, heart failure Suspicion of heart disease: ECG, echocardiogram, chest radiograph Suspicion of liver disease: ALT, AST, total bilirubin, alkaline phosphase, prothrombin time, serum albumin Suspicion of kidney disease: urinalysis with exam of sediment, serum lipids Suspicion of malignancy: abdominal/pelvic CT scan Suspicion of sleep apnea: sleep study, echocardiogram Lymphedema: abdominal/pelvic CT scan Medications known to cause edema Adapted from Ely J et al. JABFM 2206;19:148

Approach to Leg Edema Systemic Evaluation Leg edema without apparent cause History and physical exam Bilateral edema Unilateral Edema Are there any red flags? Acute onset Age > 45 Clinical suspicion of systemic cause Suspicion of pelvic malignancy Symptoms of sleep apnea Medications Systemic Evaluation Consider common causes Adapted from Ely J et al. JABFM 2206;19:148