Anasarca

Etiology

Anasarca is a condition characterized by severe generalized edema of the body. Due to various underlying pathologies, the etiology can be varied. It usually occurs due to the shift in the Starling forces that regulate fluid movement between blood vessels and the interstitium. A multitude of conditions can potentially lead to anasarca, including the following:

• Heart failure: One of the most common causes of anasarca is congestive heart failure. Due to impaired ejection fraction, increased afterload, and decreased preload, this causes vascular fluid leakage into the interstitium.[5]

• Kidney failure: Renal diseases (eg, glomerulonephritis) may lead to essential protein loss, resulting in decreased capillary oncotic pressure.[6] Consequent fluid leakage can cause widespread edema. In some cases of kidney diseases, edema is attributable to salt and water retention in the body.

• Liver diseases: Albumin helps maintain the oncotic pressure of the capillaries; therefore, hypoalbuminemia resulting from liver diseases (eg, cirrhosis) can cause fluid movement from blood vessels to the interstitial tissues.

• Malnutrition: Severe protein or caloric deficiency can cause hypoalbuminemia and fluid retention, potentially leading to anasarca.

• Protein-losing enteropathy: Some gastrointestinal diseases (eg, celiac disease) cause intestinal protein loss, resulting in vascular fluid leakage.[7]

• Endocrinopathies: Fluid retention from some endocrinological conditions (eg, hypothyroidism) can cause generalized nonpitting edema.[8]

• Collagenopathies: Certain inflammatory conditions, including systemic lupus erythematosus, dermatomyositis, or rheumatoid arthritis, can cause anasarca due to increased vascular wall permeability.[9]

• Medications: Severe fluid retention may be caused by some medications (eg, corticosteroids, nonsteroidal anti-inflammatory drugs, or calcium channel blockers).[4]

Epidemiology

Research on the precise occurrence of anasarca is quite scarce. Peripheral edema, a more commonly observed clinical condition, is estimated to affect roughly 20% of adults aged >50 years.[4] In contrast, one study reported that the incidence of anasarca in postoperative patients undergoing abdominal surgery was approximately 29.87%.[10]

Pathophysiology

The primary pathophysiological mechanisms underlying anasarca involve several factors: an elevation in capillary hydrostatic pressure, increased capillary permeability, a lower plasma oncotic pressure, lymphatic obstruction, or a combination of these. These mechanisms collectively lead to severe fluid retention in the interstitial space. Conditions that can cause increased capillary hydrostatic pressure include heart failure, kidney disease, early cirrhosis, pregnancy, medications (eg, amlodipine), or conditions characterized by venous obstruction or insufficiencies, such as deep venous thrombosis or hepatic venous congestion. Increased capillary permeability may result from burns, trauma, sepsis, allergic reactions, or malignant ascites. Hypoalbuminemia, which causes decreased plasma oncotic pressure, is associated with conditions like nephrotic syndrome, liver disease, and malnutrition, while malignancy and lymphatic dissection can lead to lymphatic obstruction.[11][12]

The physiologic abnormalities underlying anasarca stem from an imbalance in the forces that regulate fluid movement between vasculature and surrounding tissues, resulting in widespread fluid accumulation in the interstitial spaces throughout the body. Plasma oncotic pressure is primarily determined by the osmotic pressure exerted by blood proteins, especially albumin, in the blood vessels.[13] These proteins help retain fluid within the vessels, preventing excessive leakage into the tissues. Conditions that lead to low levels of plasma proteins can lead to decreased oncotic pressure and fluid retention in tissues. Another mechanism contributing to severe edema is an increase in vascular hydrostatic pressure. Reduced capillary hydrostatic or interstitial oncotic pressure favors fluid movement into the capillaries, known as absorption. However, when capillary hydrostatic or interstitial oncotic pressure rises, fluid shifts out of capillaries, a process called filtration. Additionally, an increase in the permeability of capillary walls can also lead to an increased outflow of fluid and proteins.[14]

As a result of these pathophysiological mechanisms, fluid moves from the vascular space to the interstitium, reducing plasma volume. This decrease in tissue perfusion triggers renal retention of sodium and water, setting off a cascade of effects that worsen interstitial fluid retention. Some excess fluid gained will be retained in the intravascular compartment, but the alteration in capillary hemodynamics causes most of the retained fluid to enter the interstitium, eventually becoming apparent as edema or anasarca.

History and Physical

Clinical Presentation

Anasarca is extensive and generalized fluid accumulation in various body tissues, which may affect multiple areas, including subcutaneous tissues, lungs, abdomen, and extremities. The clinical presentation of anasarca can include the following:

• Significant swelling throughout the body, involving the face, limbs, abdomen, dependent areas, and the genital area [15]
• Restricted movement in swollen extremities
• Increased body weight due to fluid retention
• Pulmonary edema, resulting in shortness of breath that is worse when lying down, cough, and chest pain [4]
• Ascites and abdominal distension [16]
• Oliguria or anuria 
• Fatigue
• Dermatological changes over swollen areas (eg, erythema, stretching, shiny, weeping, and taut) [17]
• Hemosiderin deposits and venous ulcers [8]
• Hypothyroid-associated myxedema [18] 

The patient's history should be comprehensive, including medical, surgical, and medication history. Some medications (eg, amlodipine), postsurgical complications, and comorbidities can result in edema.[19] Clinicians should also inquire about the history of anasarca, including symptom onset and duration, affected areas, associated pain, and positional effects (eg, improvement of edema with elevation). Other symptoms (eg, dyspnea, chest pain) should be included in a detailed history, along with the onset or exacerbation of systemic conditions (eg, congestive heart failure, renal disease, or hepatic disease) that can cause chronic fluid accumulation. An accurate symptom history can help guide clinicians to the correct underlying etiology. For example, venous insufficiency causing dependent edema is often observed to improve with elevation. Conversely, edema caused by decreased plasma oncotic pressure associated with malabsorption or nephrotic syndrome does not improve with positional changes. Therefore, obtaining a careful history can help exclude differential diagnoses.[4]

Physical Examination

Anasarca is primarily diagnosed through characteristic findings on physical examination. Vital signs may reflect conditions secondary to fluid overload (eg, tachycardia, tachypnea, decreased oxygen saturation).[20] Physical examination should focus on identifying the edema pattern, such as peripheral versus generalized and pitting versus nonpitting edema. Clinical findings can also aid in establishing the underlying etiology, which will help guide management. For instance, pitting reflects the movement of excess interstitial water in response to pressure, usually seen in dependent areas, typically the lower extremities in ambulatory patients, and over the sacrum in bed-bound patients. Nonpitting edema more commonly suggests lymphatic obstruction or myxedema associated with hypothyroidism. Ascites suggest a primary hepatic disease, while signs of volume overload or heart failure may indicate cardiovascular-associated anasarca.[4] The following are common exam findings with anasarca:

• Face: nonpitting periorbital edema [8]
• Pulmonary: inspiratory crackles, rhonchi [8]
• Cardiovascular: S3 gallop, jugular venous distension [8]
• Extremities: pitting or nonpitting edema, erythema, venous ulceration, myxedema over the tibia or dorsum of the foot [18]
• Abdominal: ascites, distended abdominal wall veins, and splenomegaly [8]
• Skin: verrucous and hyperkeratotic changes, hyperpigmented, cold or warm to touch over edematous areas [8]
• Genital: scrotal or vulvar edema [21]

Evaluation

The primary focus of anasarca evaluation is identifying the underlying cause and excluding differential diagnoses. Clinicians from various specialties (eg, cardiology, nephrology, gastroenterology, and oncology) frequently must collaborate to determine the primary etiology because multiple organ systems (eg, urinary, cardiovascular, and respiratory) are affected simultaneously.[22] Assessment may include the following studies to diagnose potential etiologies leading to anasarca.

Laboratory Studies

• CBC: Abnormalities may indicate systemic conditions that need evaluation. Also, the necessity for further hematology studies (eg, peripheral blood smear) is guided by initial abnormal findings (eg, thrombocytopenia, leukocytosis).[10][20]
• Comprehensive metabolic panel: Depending on the results, these findings can help assess renal function, albumin level, and liver function. For instance, decreased glomerular filtration rate in combination with hypoalbuminemia could indicate an underlying renal pathology as opposed to raised liver enzymes indicative of liver disease as the cause of anasarca.[4]
• Urinanalysis: Dipstick testing principally detects albumin. A urine protein-to-creatinine ratio or 24-hour urine markedly positive for protein in combination with hypoalbuminemia and clinical edema is virtually diagnostic of nephrotic syndrome.[23]
• Brain natriuretic peptide: An elevated level may indicate a diagnosis of CHF.[24]
• Thyroid studies: Depending on the thyroid impairment, results will help diagnose hyperthyroid or hypothyroid conditions.[4]

Imaging Studies

• Chest X-ray: May help assess patients with findings of cardiac enlargement, pulmonary edema, and pleural effusions.[25]
• CT: Anasarca appears as fluid within affected interstitial tissues, including the axilla, chest wall, pelvis, and pleural and cardiac effusions (see Image. Submucosal Edema in the Abdomen on CT).[22]
• Echocardiogram: If clinically indicated, an echocardiogram can evaluate ventricular function, assess for pericardial effusion, and diagnose cardiac disease. Echocardiography is also recommended to evaluate pulmonary hypertension in patients known or suspected to have obstructive sleep apnea.[8]
• Venous ultrasound: The preferred imaging method in evaluating suspected deep vein thrombosis. A duplex ultrasound may be used for diagnostic confirmation of chronic venous insufficiency.[8]
• Renal ultrasound: The most frequently used imaging modality in patients with renal dysfunction or proteinuria. Ultrasonography clinicians use this to characterize kidney size and assess for cystic renal disease and hydronephrosis.[26]
• Lymphoscintigraphy: The preferred modality to assess lymphedema if clinical evaluation is insufficient.[8] 
• MRI: This may be used to evaluate underlying musculoskeletal causes of anasarca. T1-weighted magnetic resonance lymphangiography may also be used to assess lymphedema.[8]

Treatment / Management

Anasarca is a symptomatic manifestation of an underlying condition; therefore, managing the cause is the primary treatment. Additionally, a majority of patients with anasarca also require the administration of diuretics to help resolve systemic fluid overload. Particularly in volume-overloaded patients with pulmonary edema, recognition of a fluid imbalance by clinicians prompting urgent treatment is critical, as pulmonary edema not treated immediately may lead to poor outcomes, including increased mortality.[4][27]

Anasarca involves various body tissues and may involve the lungs. For anasarca without respiratory distress, secondary to pulmonary edema, is not acutely life-threatening, and removal of the excess fluid can proceed more slowly. However, pulmonary edema can develop quickly, becoming life-threatening, and requires immediate therapy. In patients with generalized edema due to heart failure, nephrotic syndrome, or primary sodium retention, the excess fluid can be mobilized rapidly with the help of loop or thiazide diuretics. According to American Heart Association (AHA) guidelines, fluid-overloaded patients with heart failure presenting with shortness of breath should receive immediate treatment with diuretics, as earlier and more aggressive intervention is associated with improved outcomes.[27][28](A1)

Diuretic therapy can lead to volume depletion in patients with localized edema due to venous or lymphatic obstruction or malignant ascites and, therefore, may not be helpful. However, in severely generalized edematous states, such as congestive heart failure, initial therapy is recommended to begin with a loop diuretic, such as furosemide or bumetanide.[29] Treatment for anasarca due to cirrhosis can begin with spironolactone alone or a combination of spironolactone and a loop diuretic like furosemide. The recommended initial dosage of spironolactone is 100 mg/day, titrating up to 400 mg/day according to patient response; furosemide can be initiated at a dosage between 20 and 40 mg/day. The European Association for the Study of the Liver (EASL) recommends an aldosterone antagonist alone as first-line therapy for the first episode of grade 2 cirrhotic ascites. In patients with a poor response (ie, a body weight reduction of <2 kg/wk) or those who develop hyperkalemia, furosemide should be started at a dosage of 40 mg/day and increased by 40 mg/day as needed, up to a maximum daily dose of 160 mg. Patients with recurrent or long-standing ascites should be started on an antimineralocorticoid and furosemide combination.[30](A1)

However, the American Association for the Study of Liver Diseases (AASLD) recommends combination therapy initially with a starting dosage of spironolactone 100 mg/day and furosemide 40 mg/day. Starting both drugs together is preferred as it achieves rapid natriuresis while maintaining normokalemia. When excess fluid is adequately reduced, the dosage should be tapered to maintain minimal or no ascites. The percentage of patients with cirrhotic ascites that experience adverse effects from diuretics is 20% to 40%. Angeli et al concluded that combined diuretic treatment is the better management approach for moderate ascites without renal failure.[31] The AASLD and EASL management recommendations have minimal differences; both approaches have merits in different situations.(A1)

Furthermore, in patients with conditions causing a significant accumulation of fluid (eg, cirrhosis or heart failure), 2 nonpharmacologic mainstays of treatment include sodium and fluid restriction. The AHA recommends a fluid restriction of 2 L/day in most patients with fluid overload; increased restrictions may be required for patients with hyponatremia or diuretic resistance.[27][28] The International Ascites Club has recommended a sodium intake of 2000 mg daily, while AHA guidelines state that some level of sodium restriction should be considered dependent on the patient's stage of heart failure. In some cases, addressing nutritional deficiencies and achieving a balanced diet helps the management of anasarca. In some patients, intravenous albumin infusions may help draw excess fluid back into the bloodstream and reduce edema. If anasarca is due to an underlying infection, appropriate antimicrobial therapy may be necessary. In patients where kidney failure is the underlying cause of anasarca, hemodialysis may be required to remove excess fluid.[14][27] Nevertheless, these additions to diuretic therapy are critical to preventing the recurrence of anasarca.[32][33][28](A1)

Following initial management, clinicians must adequately monitor patients. Diuretic dosages can be monitored and titrated using a random "spot" urine sodium concentration, increasing dosages until the urine sodium concentration exceeds that of potassium.[34] Higher dosages of <1 mg/kg/day of furosemide and 2 mg/kg/day of spironolactone may be required to treat nephrotic syndrome.[35][36] Some cases of idiopathic edema are medication-induced; in these individuals, initial management consists of medication cessation and nonpharmacologic therapies.[8](A1)

Some ancillary therapies for anasarca are targeted to areas affected by edema. Mechanical therapies (eg, leg elevation and compression stockings) are useful treatments for lower-extremity edema. Leg elevation reduces swelling by assisting fluid return to the heart. A supportive pressure between 30 to 40 mm Hg is often recommended for patients using compression stockings, though not for individuals with peripheral arterial disease.[8] Treatment of areas with lymphedema typically involves lymphatic massage combined with compressive bandages to increase lymphatic drainage. Compression stockings or pneumatic compression devices can then be used for therapeutic maintenance. However, diuretics are not effective in the treatment of lymphedema.[8][37]

Differential Diagnosis

The differential diagnoses of anasarca include any condition that can lead to widespread severe edema, including the following:[38][39][4]

• Heart failure
• Kidney diseases, including glomerular pathologies (eg, IgA nephropathy, glomerulonephritis, and nephrotic syndrome)
• Autoimmune disease (eg, juvenile dermatomyositis)
• Hematological disorders (eg, acute myeloid leukemia) 
• Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome [40]
• Cirrhosis 
• Hypoproteinemia (eg, malnutrition or protein-losing enteropathies)
• Hypothyroidism
• Cellulitis or sepsis
• Deep vein thrombosis
• Medications (eg, calcium channel blockers or nonsteroidal anti-inflammatory drugs) [19]
• Severe allergic reactions
• Lymphedema 
• Pregnancy
• Some malignancies, particularly advanced stages
• Amyloidosis [41]

Prognosis

The prognosis for anasarca depends on the underlying cause and how promptly it can be managed. Anasarca can be a reversible symptom if the etiologic factors can be treated effectively. For instance, anasarca caused by medications or infection has a good prognosis as treatment such as drug cessation or antibiotic therapy will reverse resulting pathophysiological changes.[19][22] However, anasarca due to chronic conditions (eg, advanced heart failure, severe kidney disease, or liver failure) may have a grave prognosis because the underlying disease's severity and advanced progression guide prognostic assessment.[42]

Complications

Anasarca may result in complications involving various organ systems, including the following:[43][22][14][22]

• Organ dysfunction
• Skin ulcers
• Skin infections
• Reduced mobility
• Nutritional deficiencies
• Weight gain
• Impaired wound healing
• Deep vein thrombosis
• Respiratory distress
• Pericardial effusion
• Pericardial tamponade 
• Complications associated with underlying etiologies or diuretic treatment