Workup for Unexplained Edema:

August 1, 2004

ABSTRACT: The cause of edema can usually be determined by judicious use of clues from the history, physical examination, and laboratory results. Localized edema can be the result of deep venous thrombosis, venous stasis, cellulitis, vascular insufficiency, or diuretic abuse; it can also be idiopathic. Clues that are helpful in distinguishing among these conditions include tenderness, positive Homans sign, hair loss on the legs, nonpalpable pulses, and a history of lower extremity injury. Edema of the lower extremities that is accompanied by massive ascites is typical of cirrhosis. Edema of the lower extremities unaccompanied by ascites can be associated with inferior vena cava or iliac venous thrombosis or with vasodilator therapy. Generalized edema can result from congestive heart failure (strong clues are dyspnea on exertion and paroxysmal nocturnal dyspnea), renal disease (a common clue is edema of the face and eyes), or preeclampsia. The basic studies to order in patients with generalized edema are a urinalysis, complete blood cell count, serum chemistry panel with total protein and albumin levels, and a 24-hour urine collection, which is especially helpful in distinguishing among the various types of renal disease.

Edema is encountered frequently in primary care. Most often, patients present with edema in the lower part of the legs, although generalized edema and facial puffiness are also common.

The causes of edema are numerous. In this article, I describe how to use the clues from the history, physical examination, and laboratory results to determine the origin of edema, which is essential in formulating an appropriate management plan. In a second article, on page 1245, I discuss in detail the various treatment options for patients with edema.

PATHOPHYSIOLOGY OF EDEMA

Water accounts for 60% of total body weight. Fluid in the body accumulates mainly in the extracellular fluid compartment (ECFC), which comprises the intravascular fluid space and the interstitial fluid space. (Fluid can also accumulate in the intracellular fluid compartment.) Of the total amount of fluid in the ECFC, 40% is in the intravascular space (as blood or plasma) and 60% is in the interstitial space.

Fluid is filtered from the intravascular space into the interstitial space at the arteriolar end of a capillary, and then returns into the intravascular space at the venous end of the capillary. This continuous process is effected chiefly by the difference in gradient between the hydrostatic pressure at the venous end of the capillary and the oncotic pressure exerted by plasma albumin. Under normal conditions, fluid does not accumulate in the interstitial space because the interstitial fluid pressure remains negative.

Excessive amounts of fluid can accumulate in the interstitial space in 2 ways:

•Abnormal leakage of fluid from the capillaries (seen in congestive heart failure [CHF], acute glomerulonephritis, angioedema, and venous obstructions-eg, inferior vena cava obstruction caused by thrombosis or the extrinsic pressure produced by a tumor).

•Reduced plasma oncotic pressure that results from low plasma albumin levels (seen in cirrhosis and nephrosis).

Once fluid begins to accumulate in the interstitial space, further accumulation of fluid occurs mainly through renal retention of sodium and water. When the effective circulating blood volume is decreased-which can occur through a change in the absolute volume of the intravascular space, a change in cardiac output, or a change in systemic vascular resistance-aldosterone and vasopressin are activated. These hormones cause the kidneys to retain sodium and water, which results in sustained edema. In chronic edematous conditions, the kidneys' ability to excrete free water is impaired.

The role of the kidneys in sustained edema is demonstrated in the Algorithm. Experimental and clinical studies point toward the distal nephron as the site of avid salt retention in an edematous state.1 However, the proximal tubule may play an active role in excessive salt reabsorption as well; a reduced glomerular filtration rate promotes salt retention through the proximal nephrons.

CAUSES OF EDEMA: CLUES FROM THE HISTORY AND PHYSICAL

A thorough history taking and physical examination can do much to help identify the cause of edema in a particular patient. Together with appropriate laboratory tests, they can point to the correct diagnosis in most cases.

Localized lower extremity edema. Edema that is localized to one or both legs is a common presentation. Leg edema has a number of possible causes. In one study, the most common causes of leg edema in older patients were venous stasis (62.3%), drugs (13.8%), and CHF(15%).2

Deep venous thrombosis. Patients with this condition usually have one leg with an increased circumference, calf tenderness, and a positive Homans sign.

Venous stasis. Clues to this condition include prominent veins over one or both legs but no calf tenderness on palpation.

Cellulitis. Localized leg edema that is accompanied by localized redness and tenderness, and that was preceded by a recent injury to the leg or foot, suggests cellulitis.

Vascular insufficiency. In affected patients, localized leg edema is usually bilateral. Hair loss on the legs is often apparent, especially in men, and pulses may not be palpable (Figure 1). Common causes of vascular insufficiency include diabetes and peripheral vascular disease.

Inferior vena cava or iliac vein thrombosis. This condition can result from a hypercoagulable state, such as nephrotic syndrome or malignancy. Patients may present with proteinuria that has resulted from renal vein thrombosis.

Vasodilator therapy. Inquire about the use of the following agents and drug classes, which have been associated with edema: minoxidil, nifedipine, second-generation dihydropyridine, calcium channel blockers, nitrate drugs, and nitrite drugs.

Idiopathic edema in women of childbearing age. In women in whom localized edema develops during the premenstrual period, estrogen may play a causative role.1 In other women, prolonged upright posture may be the cause.

Diuretic abuse. Long-term diuretic use leads to secondary hyperaldosteronism, sustained sodium retention, and ankle swelling. These symptoms can last for up to 2 weeks after the diuretic is discontinued. Edema associated with diuretic abuse is most often seen in women, who sometimes overuse these agents to lose weight.

Edema of the lower extremities with massive ascites. This presentation is typically associated with cirrhosis of the liver. Other clues to this diagnosis can include an emaciated appearance (sunken face, thin upper extremities); massive ascites (indicated by a fluid thrill and shifting dullness on the abdominal examination) that is out of proportion to the degree of pedal edema; and a history of alcoholism, hematemesis, and melena.

Lower extremity edema with massive ascites is also seen in pelvic malignancy with metastasis.

Generalized edema. Generalized pitting edema is often accompanied by ascites and hydrothorax. This constellation of signs is also known as anasarca. The causes of generalized edema include both cardiac and noncardiac conditions.

CHF. Typical clues from the history that point to this diagnosis include dyspnea on mild to moderate exertion; paroxysmal nocturnal dyspnea (inability to lie flat in bed; sitting up on the bed or propped up on pillows to catch one's breath); and a history of coronary artery disease, hypertension, or diabetes.

You may find pitting edema around the ankle unilaterally or bilaterally; you may also find pitting edema on both lower extremities, the abdominal wall, and the sacrum. In addition, the physical examination is likely to reveal distended and pulsatile neck veins, a gallop heart rhythm, diminished air entry with rales at the lung bases, and hepatomegaly. Dullness on chest percussion and diminished breath sounds on auscultation suggest pleural effusion or hydrothorax (unilaterally or bilaterally).

Renal disease. Generalized edema is most likely of noncardiac origin in a patient who denies shortness of breath; who has no history of coronary artery disease, hypertension, or smoking; and in whom neck veins are flat. Nephrotic syndrome is a common cause of generalized edema of noncardiac origin. Edema accompanied by hypertension suggests renal disease. Edema of the face and eyes-especially in the morning-is a characteristic feature of both nephritic and nephrotic syndromes.

Preeclampsia. Edema and hypertension in a pregnant woman who is less than 20 weeks pregnant suggests preexistent renal disease. However, the same findings in a woman who is more than 20 weeks pregnant suggest preeclampsia.3

WHICH LABORATORY AND IMAGING STUDIES TO ORDER

Localized edema. Deep venous thrombosis can be ruled out by intermittent plethysmography (IPG), Doppler venogram, or contrast venography. IPG is a fast and readily available study; however, the results are dependent on the skill of the operator. A Doppler venogram is usually easily available but is associated with a high rate of false-negative results. Thus, contrast venography is the study of choice; however, this typically must be scheduled at the local radiology department and can only be performed in patients who have a normal serum creatinine level.

When cellulitis is the suspected cause of edema, obtain a complete blood cell count, a blood culture, and a culture of a specimen from the infected area.

When you suspect vascular insufficiency, a contrast arteriogram is the study of choice. A Doppler arterial blood flow study may help to define blood flow.

Generalized edema. The basic studies to order in any patient with generalized edema are:

•Urinalysis.

•Complete blood cell count.

•Serum chemistry panel along with total protein and albumin levels.

•24-hour urine collection (to measure protein and creatinine clearance).

If the urinalysis shows protein and casts, if the hemoglobin level and hematocrit are both low, and if the blood urea nitrogen (BUN) and creatinine level are both elevated, the patient likely has acute or chronic renal disease. However, normal BUN and serum creatinine levels do not rule out renal disease; nephrotic syndrome caused by minimal lesion disease, for example, is likely to result in findings of 4+ protein on dipstick, a protein level on urinalysis of more than 300 mg/dL, and normal BUN and serum creatinine levels.

Urinalysis shows proteinuria but does not provide any information on the severity of the proteinuria. A 24-hour urine collection can help identify the cause of generalized edema by showing the degree of proteinuria. Percutaneous renal biopsy study is the most certain way to establish a diagnosis of renal disease. However, renal function testing-together with the history and physical findings-can help identify specific types of renal disease.

Edema associated with slight or no proteinuria (less than 0.5 g/24 hours). These findings are typical of CHF, cirrhosis, hypertension, malnutrition, inferior vena cava thrombosis below the renal veins, hypothyroidism, and varicose veins.

Edema associated with significant proteinuria (greater than 0.5 g/24 hours, generally 2 g/24 hours or more). Proteinuria in this range is seen in glomerular diseases, preeclampsia, tubulointerstitial disease, hypertension, and vascular diseases. Proteinuria of less than 1 g/24 hours is common in acute and chronic tubulointerstitial renal disease and in hypertensive renal disease (essential hypertension, renovascular hypertension).

Edema associated with heavy proteinuria (3 g/24 hours or more). Nephrotic syndrome is defined by proteinuria of 3 g/24 hours or more, hypoalbuminemia, and hyperlipidemia. Proteinuria of this degree is consistent with both primary and secondary glomerular diseases. Common primary glomerular diseases that cause nephrotic syndrome include:

•Minimal lesion disease (proteinuria usually associated with normal or near-normal renal function [creatinine clearance greater than 50 mL/min], no or mild hypertension, and no retinopathy).

•Membranous glomerulonephritis (proteinuria usually associated with moderate to severe hypertension and mild to moderate impairment of renal function [creatinine clearance less than 50 mL/min]).

•Membranoproliferative glomerulonephritis (proteinuria associated with the same findings seen in membranous glomerulonephritis).

•Focal glomerular sclerosis (proteinuria associated with the same find- ings that are seen in membranous glomerulonephritis).

Common secondary glomerular diseases that cause nephrotic syndrome include:

•Diabetic nephropathy (proteinuria that is often accompanied by exudative retinopathy).

•Amyloidosis (proteinuria often accompanied by cardiomegaly and/or glossomegaly).

Other secondary glomerular diseases that can cause nephrotic syndrome include lupus nephritis, vasculitis (eg, Wegener granulomatosis, polyarteritis nodosa), scleroderma, malignant hypertension, and preeclampsia. Note that the degree of proteinuria cannot be used to distinguish between preeclampsia and primary glomerular diseases.

Additional studies for CHF. When you strongly suspect that CHF is the cause of edema, consider ordering the following studies:

•Chest radiograph.

•Echocardiogram.

•Multigated acquisition (MUGA) scan (or equilibrium radionuclide angiocardiography, which is an equivalent study).

The chest film reveals the extent of cardiomegaly, the severity of pulmonary congestion, and whether pleural effusions (which are usually bilateral) are present (Figure 2). If pleural effusion is present, the radiograph can determine its size and whether thoracentesis is needed.

The echocardiogram and MUGA scan provide estimates of ventricular function and left ventricular ejection fraction. However, an MUGA scan is more accurate in its assessment of left ventricular ejection fraction than an echocardiogram.

The lower the ejection fraction, the more severely impaired renal function tends to be, and the more marked the patient's sodium retention. In the presence of severely impaired renal function, peripheral edema and pulmonary congestion are likely to become worse and progressively resistant to any form of medical management. n

References:

REFERENCES:

1. Bichet DG, Anderson RJ, Schrier RW. Renal sodium excretion, edematous disorders, and diuretic use. In: Schrier RW, ed. Renal and Electrolyte Disorders. Boston: Little, Brown & Co; 1992:89-159.

2. Ciocon JO, Galindo-Ciocon D, Galindo DJ. Raised leg exercises for leg edema in the elderly. Angiology. 1995;46:19-25.

3. Davey DA, MacGillivray I. The classification and definition of hypertensive disorders of pregnancy. Am J Obstet Gynecol. 1988;158:892-898.

FOR MORE INFORMATION:

m de Jonge JW, Knottnerus JA, VanZutphen WM, et al. Short-term effect of withdrawal of diuretic drugs prescribed for ankle edema. BMJ. 1994;308:511-513.

m Karnad DR. Temtulkar P, Abraham P, et al. Head-down as a physiologic diuretic in normal controls and in patients with fluid-retaining states. Lancet. 1987;2:525-528.

m Pockros PJ, Reynolds, TB. Rapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema. Gastroenterology. 1986;90:1827-1833.

m Ritz E, Fliser D, Wiecek A, et al. Pathophysiology and treatment of hypertension and edema due to renal failure. Cardiology. 1994;84(suppl 2):143-154.

m The body fluid compartments: extracellular and intracellular fluids; interstitial fluid and edema. In: Guyton AC, ed. Textbook of Medical Physiology. Philadelphia: WB Saunders Company; 1991:274-285.

m Warner LC, Campbell JC, Morali GA, et al. The response of atrial natriuretic factor and sodium excretion to dietary sodium challenges in patients with chronic liver disease. Hepatology. 1990;12:460-466.