Approach to Leg Edema of Unclear Etiology

John W. Ely, MD, MSPH; Jerome A. Osheroff, MD; M. Lee Chambliss, MD, MSPH; Mark H. Ebell, MD, MS

J Am Board Fam Med. 2006;19(2):148-160.

Classification

There are 2 types of leg edema: venous edema and lymphedema. Venous edema consists of excess low-viscosity, protein-poor interstitial fluid resulting from increased capillary filtration that cannot be accommodated by a normal lymphatic system.^[6] Lymphedema consists of excess protein-rich interstitial fluid within the skin and subcutaneous tissue resulting from lymphatic dysfunction.^[7] A third type, lipidema, is more accurately considered a form of fat maldistribution rather than true edema.^[8]

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Common Causes of Leg Edema in the United States
Unilateral		Bilateral
Acute (<72 hours)	Chronic	Acute (<72 hours)	Chronic
Deep vein thrombosis	Venous insufficiency		Venous insufficiency
			Pulmonary hypertension
			Heart failure
			Idiopathic edema
			Lymphedema
			Drugs
			Premenstrual edema
			Pregnancy
			Obesity

Less Common Causes of Leg Edema in the United States
Unilateral		Bilateral
Acute (<72 hours)	Chronic	Acute (<72 hours)	Chronic
Ruptured Baker's cyst	Secondary lymphedema (tumor, radiation, surgery, bacterial infection)	Bilateral deep vein thrombosis	Renal disease (nephrotic syndrome, glomerulonephritis)
Ruptured medial head of gastrocnemius	Pelvic tumor or lymphoma causing external pressure on veins	Acute worsening of systemic cause (heart failure, renal disease)	Liver disease
Compartment syndrome	Reflex sympathetic dystrophy		Secondary lymphedema (secondary to tumor, radiation, bacterial infection, filariasis)
			Pelvic tumor or lymphoma causing external pressure
			Dependent edema
			Diuretic-induced edema
			Dependent edema
			Preeclampsia
			Lipidema^[8]
			Anemia

Table 3. Rare Causes of Leg Edema in the United States
Unilateral		Bilateral
Acute (<72 hours)	Chronic	Acute (<72 hours)	Chronic
	Primary lymphedema (congenital lymphedema, lymphedema praecox, lymphedema tarda)		Primary lymphedema (congenital lymphedema, lymphedema praecox, lymphedema tarda)
	Congenital venous malformations		Protein losing enteropathy, malnutrition, malabsorption
	May-Thurner syndrome (iliac-vein compression syndrome)^[51]		Restrictive pericarditis
			Restrictive cardiomyopathy
			Beri Beri
			Myxedema

Drugs That May Cause Leg Edema ^{[9,12,14,16,17]}
Antihypertensive drugs
Calcium channel blockers
Beta blockers
Clonidine
Hydralazine
Minoxidil
Methyldopa
Hormones
Corticosteroids
Estrogen
Progesterone
Testosterone
Other
Nonsteroidal anti-inflammatory drugs
Pioglitazone, Rosiglitazone
Monoamine oxidase inhibitors

Tests for Idiopathic Edema ^{[12,30,31,52]}
Morning and Evening Weights: Patients should weigh themselves nude and with an empty bladder before food or fluids in the morning and at bedtime. A mean weight gain >0.7 kg is consistent with idiopathic edema.
Water Load Test: After avoiding diuretics for at least 10 days, the patient drinks 20 mL/kg body weight (maximum 1500 mL) uniced water over 20 minutes, sometime between 7:30 AM and 9:00 AM. The patient collects urine every hour, starting 1 hour before the oral fluid load and ending 4 hours after. On the first day, the patient should be walking slowly or standing during this 4-hour period. On the second day, the patient repeats the fluid load and urine collection, but should be recumbent during the 4-hour period. In patients with idiopathic edema, less than 55% of water load is excreted in the upright position and more than 65% in the recumbent position.

Drugs That May Cause Leg Edema ^{[9,12,14,16,17]}
Antihypertensive drugs
Calcium channel blockers
Beta blockers
Clonidine
Hydralazine
Minoxidil
Methyldopa
Hormones
Corticosteroids
Estrogen
Progesterone
Testosterone
Other
Nonsteroidal anti-inflammatory drugs
Pioglitazone, Rosiglitazone
Monoamine oxidase inhibitors

Tests for Idiopathic Edema ^{[12,30,31,52]}
Morning and Evening Weights: Patients should weigh themselves nude and with an empty bladder before food or fluids in the morning and at bedtime. A mean weight gain >0.7 kg is consistent with idiopathic edema.
Water Load Test: After avoiding diuretics for at least 10 days, the patient drinks 20 mL/kg body weight (maximum 1500 mL) uniced water over 20 minutes, sometime between 7:30 AM and 9:00 AM. The patient collects urine every hour, starting 1 hour before the oral fluid load and ending 4 hours after. On the first day, the patient should be walking slowly or standing during this 4-hour period. On the second day, the patient repeats the fluid load and urine collection, but should be recumbent during the 4-hour period. In patients with idiopathic edema, less than 55% of water load is excreted in the upright position and more than 65% in the recumbent position.

Tests for Idiopathic Edema ^{[12,30,31,52]}
Morning and Evening Weights: Patients should weigh themselves nude and with an empty bladder before food or fluids in the morning and at bedtime. A mean weight gain >0.7 kg is consistent with idiopathic edema.
Water Load Test: After avoiding diuretics for at least 10 days, the patient drinks 20 mL/kg body weight (maximum 1500 mL) uniced water over 20 minutes, sometime between 7:30 AM and 9:00 AM. The patient collects urine every hour, starting 1 hour before the oral fluid load and ending 4 hours after. On the first day, the patient should be walking slowly or standing during this 4-hour period. On the second day, the patient repeats the fluid load and urine collection, but should be recumbent during the 4-hour period. In patients with idiopathic edema, less than 55% of water load is excreted in the upright position and more than 65% in the recumbent position.

Strength of Evidence for Major Recommendations
	Strength of Recommendation*
Diagnostic recommendations
Relative frequencies of causes of edema in Tables 1-3^[1,4,53]	C
Clinical findings that help distinguish venous edema, lymphedema, and lipidema^{[8,9,11,12,21,22,24]}	C
Important components of the patient history^{[9,10,11,12,24,54]}	C
Important components of physical exam^{[2,9,10,11,12,22,24]}	C
Echocardiogram recommended in patients over age 45^[4]	C
Medications that cause edema^{[4,13,14,16,17,24,55]}	C
Normal D-dimer rules out deep vein thrombosis^[25,56]	B
Use of Doppler exam to confirm or rule out deep vein thrombosis^[57,58,59]	B
Treatment recommendations
Diuretics to treat venous insufficiency^[2]	C
Horse chestnut seed extract to treat venous insufficiency^{[41,42,43,44]}	B
Compression stockings to treat venous insufficiency^[60]	C
Diuretics to treat idiopathic edema^[5,31,46]	C

* Strength of recommendation classified according to the 3-component SORT system:^[61] A, denotes recommendation based on consistent and good-quality patient-oriented evidence;^[61] B, denotes recommendation based on inconsistent or limited-quality patient-oriented evidence;^[61] C, denotes recommendation based on consensus, usual practice, opinion, disease-oriented evidence, or case series for studies of diagnosis, treatment, prevention, or screening.^[61]