Peripheral Edema

Etiology

The causes of peripheral edema can be categorized based on the underlying mechanism.[2]

Increased Capillary Hydrostatic Pressure

• Regional venous hypertension (often unilateral)
  • Deep vein thrombosis
  • Compartment syndrome
  • Chronic venous insufficiency

• Systemic venous hypertension (often bilateral)
  • Heart failure
  • Pericarditis
  • Pulmonary hypertension
  • Liver failure or cirrhosis 

• Increased plasma volume
  • Pregnancy
  • Premenstrual edema
  • Renal failure
  • Heart failure
  • Drugs

Decrease Plasma Oncotic Pressure

• Protein loss
  • Nephrotic syndrome
  • Preeclampsia or eclampsia

• Reduced protein synthesis
  • Malnutrition or malabsorption
  • Liver failure or cirrhosis
  • Vitamin deficiencies

• Increased capillary permeability
  • Burns
  • Insect bites
  • Cellulitis
  • Allergic reactions

• Lymphatic obstruction
  • Filariasis
  • Malignancy involving lymph nodes leading to obstruction
  • Postsurgical after lymphadenectomy radiation

Other Causes

• Myxedema (in hypothyroidism)
• Lipedema
• Idiopathic

Medications Associated with Edema

• More common medications
  • Endocrine medications  
    • Thiazolidinediones (rosiglitazone and pioglitazone)
    • Glucocorticoids
    • Aromatase inhibitors
    • Testosterone
    • Androgens
    • Fludrocortisone
    • Estrogen
    • Progesterone
    • Tamoxifen
  • Calcium channel blockers and other vasodilators
    • Amlodipine
    • Felodipine
    • Nicardipine
    • Nifedipine
    • Nimodipine
    • Alpha-blockers
    • Hydralazine
    • Minoxidil

• Less common medications
  • Antidepressants
    • Trazodone
    • Monoamine oxidase inhibitors
  • Non-dihydropyridine calcium channel blockers
    • Verapamil
    • Diltiazem
  • Antiparkinson medications
    • Ropinirole
    • Pramipexole
  • Anticancer medications [3]
    • Gemcitabine, cyclophosphamide, and clofarabine
    • Taxanes (docetaxel and paclitaxel)
    • Protein kinase inhibitors
      • Anaplastic lymphoma kinase (ceritinib and crizotinib)
      • Bruton tyrosine kinase (ibrutinib)
      • BCR-Abl (dasatanib, imatinib, and ponatinib)
      • Vascular endothelial growth factor (sunitinib)
      • PI3K/AKT (alpelisib and idelalisib)
  • Other medications
    • Proton pump inhibitors
    • Diazoxide
    • Nonsteroidal anti-inflammatory drugs

Epidemiology

The most common cause of peripheral edema in patients aged 50 or older is venous insufficiency, typically associated with aging. However, conditions such as heart, renal, and liver failures, as well as trauma, can cause peripheral edema at any age. This condition is also frequently observed during pregnancy.

Data from the Health and Retirement Study, a survey of US adults, estimated that the prevalence of chronic peripheral edema in older adults ranged from 19% to 20% between 2000 and 2016. Factors associated with an increased risk of developing peripheral edema include female sex, low socioeconomic status, and advanced age. Other contributing factors include non-White race, pain, diabetes mellitus, obesity, hypertension, and limited physical activity.[4]

Pathophysiology

Edema formation involves the following 2 key steps:

• Alterations in the capillary hemodynamics that promote fluid leakage from the vascular compartment into the interstitium.
• Renal retention of sodium and water via the renin-angiotensin-aldosterone system as a compensatory mechanism.

Venous obstruction or plasma volume expansion increases hydrostatic pressure, which predisposes to edema. Since the body's plasma volume is only about 3 liters, large amounts of water and electrolytes diffuse into the interstitial space, prompting the kidneys to retain sodium and water to maintain intravascular volume and hemodynamic stability (see Image. Peripheral Edema—Differential Diagnosis Algorithm).

In conditions such as congestive heart failure (CHF) and liver cirrhosis, effective intravascular volume depletion triggers a neurohumoral cascade to maintain circulating volume. This cascade involves renal vasoconstriction, reduced glomerular filtration, and increased sodium reabsorption, which is proximally mediated by angiotensin II and norepinephrine. Additionally, aldosterone and antidiuretic hormone enhance sodium and water reabsorption in the collecting tubules. Endothelium-derived factors such as nitric oxide and prostaglandins further reduce sodium and water excretion, promoting edema.[2]

The primary contributor to maintaining intravascular oncotic pressure is impermeant proteins, particularly albumin. Albumin is crucial for preserving plasma oncotic pressure, and levels below 2 g/dL often result in edema. Hypoproteinemia can occur due to various conditions, including nephrotic syndrome, severe nutritional deficiencies, and advanced liver disease with impaired hepatic synthetic function. Certain medications, such as calcium channel blockers (especially dihydropyridines), can cause peripheral edema due to their selective arteriolar vasodilation. Other less common causes include myxedema, lymphedema, and idiopathic edema.

Myxedema, associated with hypothyroidism, typically causes edema in the eyelids, face, and hands. This condition results from the accumulation of mucopolysaccharides and proteins in the interstitium due to increased capillary permeability, followed by sodium and water retention. The exact pathophysiology of myxedema remains not fully understood. In contrast, lymphedema is caused by impaired lymphatic transport, leading to the accumulation of lymphatic fluid in the interstitium, primarily in the extremities.[5] 

Inflammatory states, such as sepsis, often lead to the well-known triad of hypovolemia, peripheral edema, and hypoalbuminemia, caused by a combination of factors. A key mechanism in this process is the inhibition of intrinsic lymphatic pumping by nitric oxide and inflammatory mediators such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. These mediators contribute to an acute reduction in interstitial pressure, making it more difficult for the body to maintain normal fluid balance, ultimately resulting in the accumulation of excess fluid in the tissues.[6] This cascade of events exacerbates both fluid retention and the overall inflammatory response.

Idiopathic edema is a poorly understood condition primarily affecting premenopausal women. This condition is characterized by periodic episodes of edema in the hands, legs, and abdominal bloating, which are not clearly related to the menstrual cycle. As a diagnosis of exclusion, idiopathic edema is most commonly observed in women in their third and fourth decades of life. Psychological and emotional disturbances can exacerbate this condition.

Drug-induced peripheral edema can occur through 4 primary mechanisms, as mentioned below.

• Renal edema occurs when medications lead to sodium or water retention by the kidneys, resulting in fluid accumulation in the tissues.
• Vasodilatory edema happens when drugs cause precapillary arteriolar vasodilation, increasing blood flow to the capillaries and leading to fluid leakage into surrounding tissues.
• Permeability edema occurs when drugs increase capillary permeability, allowing more fluid to escape from blood vessels and accumulate in the interstitial space.
• Lymphedema develops when drugs impair lymphatic drainage, reducing the body's ability to remove excess fluid, leading to its accumulation.[3]

History and Physical

A thorough history and physical examination are essential due to the wide range of potential causes of peripheral edema. Key factors to assess include the onset and timing of the edema, any positional changes affecting swelling, whether the edema is unilateral or bilateral, and a detailed medication history. Additionally, evaluating for underlying systemic diseases is crucial in determining the cause and guiding appropriate management. 

Acute swelling of the limb within 72 hours is more commonly associated with conditions such as deep vein thrombosis (DVT), cellulitis, or acute trauma, or the recent initiation of medications such as calcium channel blockers. In contrast, the chronic accumulation of more generalized edema over days, weeks, or months is typically indicative of underlying systemic conditions, including CHF and liver and renal diseases.

Dependent edema is commonly associated with venous insufficiency, often improving with elevation and worsening with prolonged standing or sitting. In contrast, edema due to decreased plasma oncotic pressure—seen in conditions such as malabsorption, liver failure, and nephrotic syndrome—tends to persist regardless of positional changes. Unilateral edema usually suggests a localized cause, such as DVT, cellulitis, venous obstruction, or lymphatic obstruction from malignancy or prior radiation therapy. In contrast, bilateral edema, on the other hand, is more indicative of systemic conditions, including CHF, liver failure, kidney disease, or severe malabsorption syndromes.[7]

A detailed physical examination is essential for differentiating systemic causes of edema, such as CHF and liver, renal, and thyroid diseases. In CHF, typical findings include jugular venous distention, dyspnea, bilateral crackles, and a history of heart disease. Liver disease may present with jaundice, ascites, and a history of hepatitis, intravenous (IV) drug use, or alcohol use disorder. Renal disease can be indicated by proteinuria, oliguria, and a history of uncontrolled diabetes or hypertension, while thyroid disease may cause fatigue, anemia, and weight gain.

Edema should be evaluated for pitting, tenderness, and associated skin changes. In early-stage lymphedema, pitting may occur due to the accumulation of protein-rich fluid in the interstitium before the development of subcutaneous fibrosis; therefore, lymphedema should be included in the differential diagnosis of pitting edema. Tenderness is commonly observed in conditions such as cellulitis and DVT, whereas edema related to systemic diseases such as CHF and renal and liver diseases is usually nontender. Acute DVT and cellulitis can increase the skin temperature over the affected area due to the activation of cellular and humoral factors. Chronic venous insufficiency often presents with a brawny, reddish texture caused by hemosiderin deposition. In advanced stages, venous ulcers may develop and progress to deep, weeping erosions.[8]

Myxedema, resulting from hypothyroidism, presents with generalized thickened skin that often exhibits a yellow to orange discoloration and is commonly associated with nonpitting periorbital edema.[9] In contrast, lipedema—a pathological accumulation of adipose tissue in the extremities—typically spares the feet, helping to distinguish it from other forms of fluid retention or swelling.

Evaluation

The initial workup should focus on ruling out major systemic causes, such as heart, liver, and kidney failure. A thorough history and physical examination are essential to guide the diagnostic process, identify potential underlying conditions, and minimize unnecessary testing, ensuring a more targeted evaluation. 

If systemic causes, such as CHF, are suspected, chest radiography, electrocardiogram (ECG), and serum brain natriuretic peptide (BNP) levels should be checked. Depending on these findings, echocardiography may be warranted for further assessment.[10] A basic metabolic profile (BMP), including serum creatinine and urinalysis to check for proteinuria, is essential in the evaluation of suspected renal disease. If renal disease is strongly suspected, a renal ultrasound may be performed to rule out intrinsic renal pathology.[11]

In cases of suspected liver disease, the evaluation should begin with liver function tests (LFTs) and albumin levels, followed by a liver ultrasound if suspicion remains or laboratory results are abnormal.[12] If hypothyroidism is suspected, thyroid function tests (TFTs) should be performed first, followed by an ultrasound if further assessment is needed. Doppler ultrasonography is the preferred imaging modality for suspected DVT and can also be used to confirm the diagnosis of chronic venous insufficiency. 

Patients with suspected cellulitis should undergo a complete blood count (CBC) to check for leukocytosis, which may suggest an active infection. Blood cultures should be obtained to identify potential bloodstream infections and guide appropriate antibiotic therapy. Additional diagnostic tests, such as imaging, may be considered for severe or atypical cases to evaluate for deeper infections or abscess formation.

Treatment / Management

Treatment should be guided by the underlying condition causing the edema.[13] Pulmonary edema is the only life-threatening form of generalized edema and requires immediate intervention. In contrast, other types of edema are less urgent, allowing for a more gradual approach to fluid removal. This distinction is vital in determining the urgency and intensity of management.

Diuretics are the treatment of choice for edema associated with CHF and liver and renal diseases. Loop diuretics are typically the most effective but require multiple daily doses due to their short half-life. For patients with cirrhosis and secondary hyperaldosteronism, spironolactone is the preferred diuretic, often used in combination with furosemide.[14]

Most patients with isolated ascites can safely mobilize a maximum of 300 to 500 mL of fluid per day.[15] However, rapid diuresis should be avoided in patients with cirrhosis, particularly those without significant peripheral edema, to prevent complications such as hepatorenal syndrome, azotemia, and hemodynamic collapse due to already low intravascular fluid volume. Paracentesis may be performed to reduce the need for diuretics and minimize electrolyte imbalances.

For individuals with idiopathic edema, many may already be on a diuretic. In these cases, treatment generally involves a low-sodium diet and discontinuation of diuretics for at least 2 to 3 weeks.[16] If edema persists in patients not on diuretics or those unresponsive to diuretic withdrawal, a diet restricted in sodium and carbohydrates (approximately 90 g/d) may help alleviate symptoms.[17](B3)

Mechanical therapies, such as leg elevation and compression stockings, are effective for chronic venous insufficiency but are contraindicated in peripheral arterial disease due to the risk of further compromising blood flow. Before initiating compression therapy, it is essential to assess arterial circulation, including measuring the ankle-brachial index, to ensure it is safe and appropriate for the patient.

Lymphedema is managed with conservative measures, including complete decongestive therapy (CDT), which combines manual lymphatic drainage, skin hygiene, compression garments, limb compression, and exercise. CDT requires ongoing treatment and patient compliance to maintain results. Surgical options, including lymphovenous anastomosis, ablative procedures (to remove excess subcutaneous tissues and skin), or vascularized lymph node transfer, may be considered for patients who do not respond to conservative treatment.[18]

DVT anticoagulation therapy typically involves low molecular weight heparin or newer direct oral anticoagulants such as rivaroxaban or apixaban.[19] Warfarin is now used less frequently due to the lower bleeding risk and fewer monitoring requirements associated with newer agents.[20] In addition to anticoagulation, compression stockings are recommended to help reduce the risk of postthrombotic syndrome.[21](A1)

Differential Diagnosis

The differential diagnoses of peripheral edema include:

• Congestive heart failure: Decreased cardiac output or ejection fraction leads to pulmonary and peripheral venous congestion, causing both pulmonary and peripheral edema. In diastolic CHF, ejection fraction may be preserved. Edema is typically bilateral and symmetric.

• Hepatic disease: Bilateral edema arises from portal vein congestion, increased capillary permeability, and decreased plasma oncotic pressure due to reduced hepatic albumin synthesis.

• Renal disease: Bilateral edema results from protein loss (eg, nephrotic syndrome) and increased plasma volume due to renal retention and activation of neurohumoral factors.

• Venous insufficiency: This condition is usually bilateral and is caused by impaired venous return due to chronic damage or incompetence of the deep venous system.

• Deep vein thrombosis: This is acute and usually unilateral and results from DVT obstruction.

• Superficial vein thrombosis: This is mostly unilateral and acute and is caused by thrombosis in the superficial veins.

• Lymphedema: This is a chronic condition that often results from lymphatic obstruction due to trauma, surgery, or filariasis (common in developing countries). This condition can affect the upper or lower extremities, depending on the underlying cause.

• Myxedema: This soft tissue edema is associated with severe and advanced hypothyroidism, often accompanied by bradycardia, constipation, and weight gain.

• Angioedema and urticaria: These conditions are secondary to allergic reactions from insect bites, medications, and other allergens.

• Cellulitis: Edema accompanied by signs of infection, such as fever and elevated white blood cell (WBC) count, commonly occurs in patients with obesity and chronic conditions such as diabetes mellitus.

• Lipedema: This is a chronic condition that begins around or after puberty and primarily affects the thighs, legs, and buttocks while sparing the feet, ankles, and torso.

• Medication-induced: This develops weeks after starting a medication and presents as soft, pitting edema. Symptoms usually resolve within days of discontinuing the offending drug.[22]

• Obstructive sleep apnea: Chronic edema secondary to pulmonary hypertension, commonly observed in obese patients who experience daytime fatigue, snoring, and obesity.[23]

Prognosis

Peripheral edema is a common symptom with diverse causes, ranging from advanced heart failure and liver disease to localized swelling due to allergic reactions. The prognosis depends largely on the underlying cause, with some conditions requiring long-term management, whereas others resolve with appropriate treatment. Identifying and addressing the root cause is crucial for improving outcomes and preventing complications.

Complications

Peripheral edema can be an early warning sign of severe systemic diseases and, if left untreated, may lead to significant morbidity and mortality. Critical conditions to rule out include heart failure and liver and kidney diseases, as these can result in severe complications such as pulmonary edema, organ failure, and chronic disability. Prompt and accurate diagnosis is essential to guide effective treatment and prevent long-term complications associated with the underlying condition.