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

Disclosures

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

In This Article

Diagnosis

Diagnosis

The differential diagnosis of edema is presented in Table 1 , Table 2 , and Table 3 . Figures 1 through 5 provide an algorithm for diagnostic evaluation.

Figure 2.

Common causes.

Figure 3.

Systemic evaluation.

Figure 4.

Unilateral edema.

Figure 5.

Chronic unilateral edema.

History

Key elements of the history include

  • What is the duration of the edema (acute [<72 hours] vs. chronic)? If the onset is acute, deep vein thrombosis should be strongly considered.[6,9,10,11] The 72-hour cutoff is commonly cited[9,11] but arbitrary and not well supported with evidence. Deep vein thrombosis should be considered in patients presenting after 72 hours with otherwise consistent findings.

  • Is the edema painful? Deep vein thrombosis and reflex sympathetic dystrophy are usually painful.[10,12] Chronic venous insufficiency can cause low-grade aching. Lymphedema is usually painless.[9,10,12,13,14,15]

  • What drugs are being taken? Calcium channel blockers, prednisone, and anti-inflammatory drugs are common causes of leg edema.[9,14,16,17] Other drugs that may cause edema are listed in Table 4 .

  • Is there a history of systemic disease (heart, liver, or kidney disease)?

  • Is there a history of pelvic/abdominal neoplasm or radiation?

  • Does the edema improve overnight? Venous edema is more likely than lymphedema to improve overnight.[13]

  • Is there a history consistent with sleep apnea? Sleep apnea can cause pulmonary hypertension, which is a common cause of leg edema.[4] Findings that may increase suspicion of sleep apnea include loud snoring or apnea noted by the sleep partner, daytime somnolence, or a neck circumference >17 inches.

Physical Examination

Key elements of the physical examination include

  • Body mass index. Obesity is associated with sleep apnea and venous insufficiency.[18,19,20]

  • Distribution of edema: unilateral leg edema is generally due to a local cause such as deep vein thrombosis, venous insufficiency, or lymphedema. Bilateral edema can be due to a local cause or systemic disease, such as heart failure or kidney disease. Generalized edema is due to systemic disease. The dorsum of the foot is spared in lipidema but prominently involved in lymphedema.[8]

  • Tenderness: deep vein thrombosis and lipidema are often tender. Lymphedema is usually nontender.

  • Pitting: deep vein thrombosis, venous insufficiency, and early lymphedema usually pit. Myxedema and the advanced fibrotic form of lymphedema typically do not pit.[9,12,14,21]

  • Varicose veins: leg varicosities are often present in patients with chronic venous insufficiency, but venous insufficiency can occur without varicose veins.[10]

  • Kaposi-Stemmer sign: inability to pinch a fold of skin on the dorsum of the foot at the base of the second toe is a sign of lymphedema.[15,22]

  • Skin changes: a warty texture (hyperkeratosis) with papillomatosis and brawny induration are characteristic of chronic lymphedema.[9,14] Brown hemosiderin deposits on the lower legs and ankles are consistent with venous insufficiency. Reflex sympathetic dystrophy initially leads to warm tender skin with increased sweating. Later the skin is thin, shiny, and cool. In the chronic stage, the skin becomes atrophic and dry with flexion contractures.

  • Signs of systemic disease: findings of heart failure (especially jugular venous distension and lung crackles) and liver disease (ascites, spider hemangiomas, and jaundice) may be helpful in detecting a systemic cause.

Diagnostic Studies

Laboratory Tests. Most patients over age 50 with leg edema have venous insufficiency, but if the etiology is unclear, a short list of laboratory tests will help rule out systemic disease: complete blood count, urinalysis, electrolytes, creatinine, blood sugar, thyroid-stimulating hormone, and albumin. A serum albumin below 2 g/dL often leads to edema and can be caused by liver disease, nephrotic syndrome, or protein-losing enteropathy.[14] Additional tests are indicated depending on the clinical presentation:

  • Patients who may have a cardiac etiology should have an electrocardiogram, echocardiogram, and chest radiograph. Dyspneic patients should have a brain natriuretic peptide (BNP) determination to help detect heart failure. The BNP is most helpful for ruling out (rather than ruling in) heart failure because the sensitivity is high (90%).[23]

  • Idiopathic edema can be diagnosed in young women without further testing if there is no reason to suspect another etiology based on history and physical examination.[5] However, tests to confirm idiopathic edema have been described and may be helpful in difficult cases ( Table 5 ).[12,24]

  • In patients with acute edema (<72 hours), a normal D-dimer will essentially rule out deep vein thrombosis if the clinical suspicion is low because false negative D-dimers are rare.[25,26,27] However, an elevated D-dimer should be followed up with a Doppler examination because false positive D-dimers are common.[28] The variability among laboratory assays has been problematic, but a recent systematic review recommended the rapid quantitative ELISA as the most useful test.[25]

  • Patients with possible nephrotic syndrome should have serum lipids in addition to the basic laboratory studies listed above.

Imaging Studies. Patients over age 45 with edema of unclear etiology should have an echocardiogram to rule out pulmonary hypertension.[4] Lymphoscintigraphy can be helpful to distinguish lymphedema from venous edema and to determine the cause of lymphedema. Lymphoscintigraphy is performed by injecting a radioactive tracer into the first web space and monitoring lymphatic flow with a gamma camera.[13]

Common Causes of Leg Edema

Venous Insufficiency. Venous insufficiency is characterized by chronic pitting edema, often associated with brown hemosiderin skin deposits on the lower legs. The skin changes can progress to dermatitis and ulceration, which usually occur over the medial maleoli. Other common findings include varicose veins and obesity. Most patients are asymptomatic but a sensation of aching or heaviness can occur.[2] The diagnosis is usually made clinically but can be confirmed with a Doppler study.[2,29] Although chronic venous insufficiency is thought to result from previous deep vein thrombosis, only one third of patients will give that history.[2] "Dependent edema" is a variant of venous insufficiency and often occurs in patients following stroke who sit in wheelchairs for long periods.

Heart Failure. Patients with congestive heart failure complain of dyspnea, dependent edema, and fatigue. On physical examination they may have elevated jugular venous pressure, basilar crackles on chest auscultation, gallop rhythm, and pitting edema. In one study, BNP was found to be helpful in diagnosing heart failure among dyspneic patients.[23] Using a cutoff value of 100 pg/mL, this test had a sensitivity of 90% and specificity of 76% when compared with a clinical diagnosis by 2 independent cardiologists.[23]

Pulmonary Hypertension. Pulmonary hypertension commonly results from sleep apnea, is under-recognized as a cause of edema,[4] and can be diagnosed by echocardiography. Other causes of pulmonary hypertension include left heart failure and chronic lung disease. In a study of primary care patients, Blankfield and colleagues[4] obtained echocardiograms on 45 patients with edema. The initial clinical impression was venous insufficiency in 71% of these patients. However, the final impression was pulmonary hypertension (>40 mm Hg) in 20% and "borderline pulmonary hypertension" (31 to 40 mm Hg) in 22%. Only 22% of the patients were found to have venous insufficiency. This study was not designed to determine whether borderline pulmonary hypertension was the primary cause of edema or simply an incidental finding. Treating sleep apnea might improve the leg edema that results from pulmonary hypertension, but this also is unknown. Given these uncertainties, we recommend an echocardiogram in patients who are at risk for pulmonary hypertension and in patients over age 45 with leg edema of unclear etiology.

Drugs. Drugs that can cause edema are listed in Table 4 . Calcium channel blockers and nonsteroidal anti-inflammatory drugs (NSAIDS) are most commonly implicated.[14] The incidence of edema in patients taking NSAIDS is approximately 5%.[17] Up to 50% of patients on calcium-channel blockers develop edema.[13] Dihydropyridines (amlodipine, nifedipine) may be more likely to induce edema than phenylalkylamines (verapamil) or benzothiazepines (diltiazem).[14]

Idiopathic Edema. Idiopathic edema occurs only in menstruating women and is most common in the 20s and 30s. Synonyms include fluid-retention edema, orthostatic edema, cyclical edema, and periodic edema. However, the symptoms persist throughout the menstrual cycle, and idiopathic edema should be distinguished from premenstrual edema. Idiopathic edema leads to pathologic fluid retention in the upright position, and women typically notice a weight gain of >1.4 kg as the day progresses.[30] However, the weight gain may be as little as 0.7 kg.[31] Patients often complain of face and hand edema in addition to leg swelling.[31] Several confirmatory tests are available ( Table 5 ), but the diagnosis is usually made clinically after ruling out systemic disease by history and physical examination.[31] The confirmatory tests in Table 5 are indicated only when there is significant doubt about the diagnosis. Obesity and depression can be associated with this syndrome, and diuretic abuse is common.[14]

Lymphedema.Primary lymphedema is a rare disorder that is divided into 3 types according to age of presentation.[21]

Congenital lymphedema may be present at birth or becomes manifest by age 2 years. The familial form of congenital lymphedema is an autosomal dominant disorder known as Milroy disease.

Lymphedema praecox, the most common form of primary lymphedema, has its onset between age 2 and 35 and has a female to male ratio of 10:1. Lymphedema praecox is usually unilateral and is limited to the foot and calf in most patients.[32] The familial form of lymphedema praecox is an autosomal dominant disorder known as Meige disease.

Lymphedema tarda presents after age 35.

Secondary lymphedema is much more common than primary, and the cause is generally apparent from the history. The most common causes of leg lymphedema are tumor (eg, lymphoma, prostate cancer, ovarian cancer), surgery involving lymphatics, radiation therapy, and infection (bacterial infection or filariasis).[21] Chronic lymphedema is usually distinguished from venous edema based on characteristic skin changes, absence of pitting, and history of an inciting cause. The skin becomes thickened and darkened and may develop multiple projections called lymphostatic verrucosis.[9] The dorsum of the foot is prominently involved and may have a squared-off appearance. The examiner is unable to pinch a fold of skin on the dorsal aspect of the base of the second toe (Kaposi-Stemmer sign).[12,14,22] However, early lymphedema may be difficult to distinguish from venous edema because pitting is present in both, and the skin changes are absent early in the course. If the distinction between early lymphedema and venous edema cannot be made clinically, lymphoscintigraphy may be indicated.[33] However, the distinction cannot always be made because chronic venous insufficiency can lead to secondary lymphedema with abnormally delayed lymph drainage on lymphoscintigram.[15,34]

Deep Vein Thrombosis. Deep vein thrombosis classically results in an acutely swollen, painful leg that may be discolored. However, the presentation can be more subtle with mild, painless, asymmetric edema. The physical examination is often unreliable and patients with acute edema usually require further evaluation, which may include a D-dimer determination and a Doppler study (Figures 1-5). Risk factors for deep vein thrombosis include cancer, immobilization (especially following surgery or an injury), and a hypercoagulable state.

Obesity. Obesity itself does not cause leg edema but obesity can lead to many other causes such as chronic venous insufficiency, lymphedema, idiopathic edema, and obstructive sleep apnea.

Premenstrual Edema. Most women experience some premenstrual edema and weight gain. The edema tends to be generalized, occurs a few days before the beginning of menses, and resolves during a diuresis that occurs with the onset of menses. The etiology is poorly understood.[35]

Pregnancy. Increased venous pressure resulting from an enlarging uterus near term commonly leads to lower extremity edema and varicosities. Edema is commonly present in patients with preeclampsia but is no longer considered a factor in making the diagnosis.[36]

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