Introduction

The definition of edema is a swelling due to the expansion of interstitial fluid volume in tissues or an organ. Several clinical conditions present with edema, making it a critical clinical feature for diagnostic medicine. Edema can present in numerous forms including unilateral, bilateral, localized, or generalized edema. Therefore, it is vital to assess the unique presentation and mechanism of edema to understand how it relates to disease pathophysiology, clinical presentation, and treatment. This review will present an overview of the general and cellular characteristics of edema, the mechanism, and pathophysiology of edema, and how edema relates to a specific disease presentation and development.

Issues of Concern

The average human is made up of between 50 to 60 percent water. Total body water divides into two main compartments: intracellular and extracellular comprising two-thirds and one-third total body water, respectively. Of these compartments, the extracellular space is subdivided into two additional categories: interstitial and intravascular, making up sixty and forty percent of extracellular space, respectively. Fluid maintenance in the human body is a delicate balance of fluid intake and output. The interstitial fluid, the fluid between cells, is derived from capillaries with a similar solute content to plasma except for protein content.[1][2]

Several factors control the direction of flow of interstitial fluid including hydrostatic pressure, oncotic pressure, endothelial integrity, and lymphatic systems. These factors are thought to be driven by Starling’s law, which describes fluid movement across capillaries being proportional to capillary permeability, trans-capillary hydrostatic pressure differences, and trans-capillary oncotic pressure differences. The equation for Starling’s law is as follows: Filtration= Kf x (Pc – Pif – Oc + Oif). Where Pc is the hydrostatic capillary pressure, Pif is the interstitial fluid hydrostatic pressure, Oc is the capillary plasma colloid osmotic pressure, Oif is the interstitial fluid colloid osmotic pressure, and Kf is the capillary filtration coefficient (permeability x surface area).[3]

Capillary pressure forces fluid from the capillaries into the interstitium where the arterial end pressure is higher than the venous end. The interstitial fluid pressure varies partly based on the density of tissues, with higher values in dense connective tissue. The value of interstitial fluid pressure can be a positive or negative value, with positive values being due to fluid forced into the capillary and negative values being fluid forced into the interstitium. Plasma oncotic pressure is due to proteins, which do not pass freely between the interstitium and plasma, and therefore the proteins exert an osmotic effect across capillary walls. Albumin is the most abundant plasma protein. A small amount of protein exists in the interstitium and forces some fluid out of capillary walls. This force is the interstitial oncotic pressure. Together, these factors contribute independently or cooperatively to form edema.

Cellular Level

Edema is believed to be the outward filtration predominating the arterial end of the capillary, and as hydrostatic pressures fall, fluid reverts to the capillary from the interstitium driven by the oncotic pressure gradient. However, further investigation shows that in most capillary beds, there is a net filtration that continues throughout the capillary length, and many Starling relationships are invalid.[4] Traditionally, the reflection coefficient of proteins across the capillary wall is assumed to be approximately one. Albumin diffusion through capillary pores, however, leads to half of the body’s albumin content as extravascular, and interstitial oncotic pressure is 30 to 60 percent of plasma oncotic pressure when measured.[3] The structure of the interstitial space leads to a hemodynamic difference compared to the Starling equation because these structures are far more complicated than previously believed. Interstitial space cannot be protein-free ultrafiltrates of plasma, and as a result, they become a triphasic system with free-flowing fluids, a gel phase with large polyanionic glycosaminoglycans (GAG) molecules, and a collagen matrix. GAG, with sodium ions bound to it, exerts an osmotic pressure via capillary filtration, while the collagen matrix hydrostatic pressure opposes this force.[3].

The capillary is lined with glycocalyx with a complex network of GAG molecules and other glycoproteins, creating a filtration barrier that contains clefs where capillary filtration occurs.[4][5][6] Albumin gets excluded from the luminal surface, and therefore, intravascular albumin exerts more oncotic pressure than initially predicted from direct measurements of interstitial albumin concentration. Therefore, the actual net filtration depends more on colloid oncotic pressure of fluid below the endothelial glycocalyx than on the capillary membrane. There is emerging data suggesting that lymphangiogenesis regulation is by interstitial sodium bound to GAG molecules.[7] This begs the question of the precise etiology and pathophysiology of edema, and if multiple factors are more often contributing to the onset of edema. 

Development

Despite current research developments on the cellular mechanisms of edema, edema development requires alteration in one or more Starling forces in the direction favoring increased net filtration and/or inadequate removal of filtered fluid by lymphatic drainage. Possible alterations include elevated capillary hydrostatic pressure, increased capillary permeability, higher interstitial oncotic pressure, lower plasma oncotic pressure, lymphatic obstruction, or a combination of these factors.[3]

Several factors protect against edema including increased lymphatic flow and contractility in the presence of tissue edema and/or removal of excessive fluid. Fluid entry in the interstitium ultimately raises the interstitial hydraulic pressure and thus reduces the pressure gradient to favor filtration. Fluid entry into the interstitium also lowers interstitial oncotic pressure by dilution and lymphatic removal of interstitial proteins.

Organ Systems Involved

Several organs play a role in edema. The lymphatic system drives fluid and protein away from the interstitium, and a system of fine lymphatics provide a network of channels throughout the body via lymph nodes to the thoracic duct. Valves function in the lymphatic system to provide a one-way outflow. As fluid moves through the body, it undergoes excretion through the kidneys, lungs, feces, sweat, and skin. Therefore, a variety of organs may be involved in situations of fluid overload.

Capillary dynamics is critically different in the vasculature of various organs.[8] For example, hepatic sinusoids are permeable to proteins, and consequently, the capillary and interstitial oncotic pressure is approximately equal with a minimal transcapillary oncotic pressure gradient.[9] As a result, the hydraulic pressure gradient, which favors filtration, is essentially unopposed.

Alveolar capillaries also have a lower capillary hydraulic pressure, which is due to perfusion from the low pressures in the right ventricle. Alveolar capillaries are also more permeable than skeletal muscle to protein, resulting in smaller transcapillary hydraulic and oncotic pressure gradients.[10]

Kidneys also play a critical role in edema. The renal sodium and water retention seen in heart failure and cirrhosis result from a hypovolemic-induced fall in glomerular filtration rate (GFR) and increased tubular reabsorption.[11] The hypovolemia induced state leads to excess demand on the kidneys to retain sodium and water to maintain perceived volume loss, which is partly mediated by increased activity of the renin-angiotensin-aldosterone and sympathetic nervous systems. The goal of this response is to, at least initially, increase venous return to the heart, thereby allowing hemodynamic stability.[11][12]

Function

It is important to consider that often sodium and water retention in edematous states can be an appropriate compensation to restore tissue perfusion. Consequentially diuretics may improve symptoms due to edema but may reduce tissue perfusion. The hemodynamic effects are drastically affected by inappropriate renal fluid retention. In this case, interstitial volumes expand, and it is critical to remove the excess fluids.

Edema rarely occurs with minor changes in hemodynamic forces. In fact, studies have identified that a 15 mmHg increase in the gradient favoring filtration is needed to identify edema clinically.[9] This protective response is due to lymphatic flow and contractility increasing in the setting of edema and fluid entering the interstitium, eventually leading to increased interstitial hydraulic pressure. Thus, there is a reduced pressure gradient that favors filtration.[9] Edema, therefore, occurs when there is excessive interstitial fluid volume, leading to the clinical presentation edema.

Mechanism

Edema formation occurs into two fundamental steps. Firstly, an alteration in capillary hemodynamics favoring the movement of fluids from the vascular space into the interstitium. Additionally, retention of dietary or intravenously administered sodium and water via the kidneys can cause edema. Initially, fluid moves from the vascular space into the interstitium, and consequently reduces plasma volume and reduces tissue perfusion. To respond to these changes the kidney retains sodium and water. There is some fluid that stays in the vascular space, and plasma volume returns towards normal. However, this change in capillary hemodynamic leads to retained fluid entering the interstitium and results in edema.[3]

Edema can also form as a response to elevated capillary hydraulic pressures or increased capillary permeability, disruption of the endothelial glycocalyx, decreased interstitial compliance, lower plasma oncotic pressure, or a combination of these factors. Lymphatic obstruction can also lead to fluid buildup because, under normal conditions, filtered fluids do not return to the systemic circulation.[5] Edema can be generalized or localized, and gravity plays a critical role in fluid accumulation; thus the lower extremities are particularly prone to fluid collection.

Related Testing

Proteinuria is an effective way to distinguish between different causes of edema. If there is severe proteinuria (>0.5 g/dL), this may suggest renal disease, preeclampsia, or renal vein thrombosis. On the other hand, minimal proteinuria (<0.5 g/dL) suggests etiologies such as congestive heart failure, chronic liver disease, malnutrition/malabsorption, hypothyroidism, varicose veins, and inferior vena cava thrombosis below the renal vein. In patients with generalized edema, it is beneficial to obtain urine tests for red blood cells, casts, and albuminuria. Blood chemistries can also be helpful including urea, creatinine, albumin, brain natriuretic peptide (BNP)/proBNP, bilirubin, alkaline phosphatase, transaminases, and INR to rule in or rule out renal disease, cardiac failure, chronic liver disease, etc. A complete blood count to evaluate for anemia, leukocytosis, or leukopenia can also help to identify the etiology of edema. D-dimer has a high sensitivity and therefore has a role in ruling out conditions such as deep vein thrombosis or a pulmonary embolism. Additional testing such as chest x-ray, ultrasound of the abdomen, and echocardiography have their basis in the clinical presentation and core laboratory investigations. Rarely, renal biopsy hepatic biopsy is needed to make a precise diagnosis that will dictate therapy.  

Pathophysiology

Anything that raises capillary pressures, reduces oncotic pressure, increases endothelial permeability, or impairs lymphatic drainage will result in edema. Raised capillary pressure is a common cause of edema including cardiac failure such as right ventricular failure, left ventricular failure leading from pulmonary edema, or congestive cardiac failure. Capillary hydraulic pressure has autoregulatory capacity allowing changes in resistance at the precapillary sphincter and thus determines the arterial pressure forced onto the capillary. In contrast, the venous end of the capillary has poor regulation, and, as a result, venous pressure changes lead to parallel changes in capillary hydraulic pressure. Venous pressure can increase in two settings. First, when blood volume is expanded, and second, when there obstruction at the venous end. Heart failure and renal disease lead to volume expansion, while cirrhosis or right heart failure leads to venous obstruction, both instances ultimately resulting in edema.[4][5][6][7] Local venous obstruction can also cause increased capillary pressure such as deep vein thrombosis, external compression, and superior vena cava obstruction.

Reduced oncotic pressure, typically due to hypoalbuminemia, occurs in several diseases such as renal disease where the loss of albumin occurs across the glomerulus (nephrotic syndrome), and common causes may include diabetic nephropathy, lupus nephropathy, amyloidosis, minimal change disease, membranous glomerulonephritis, HIV-associated nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, light chain associated renal disorders, chronic glomerulonephritis, and radiation nephropathy. Hepatic disease, such as cirrhosis and chronic liver disease, from inadequate albumin synthesis, as well as malabsorption/malnutrition, such as kwashiorkor, from inadequate albumin intake and synthesis, can also lead to reduced oncotic pressure and ultimately edema.

Increased capillary permeability, typically due to vascular injury, results in edema for several reasons. When vessels become injured, the porosity of the capillary walls increases, and, consequently, net filtration increases. Furthermore, the coefficient of proteins across the capillary wall decreases, thus narrowing the difference between the oncotic pressure of the capillary and the oncotic pressure below the endothelial glycocalyx. The oncotic pressure gradient reduces and edema results. Typically, capillary permeability increases in the setting of burn patients where both histamine and oxygen free radicals induce microvascular and direct physical injury.[13] Treatment with recombinant human interleukin 2 or vascular endothelial growth factor also promotes capillary permeability (PMID:3495213, PMID:10836914). Any instance where the release of cytokines such as interleukin 1 or tumor necrosis factor occurs, as in respiratory distress syndrome, increases pulmonary capillary permeability resulting in edema, especially pulmonary edema.[14][15]  Some even suggest that kwashiorkor or diabetes mellitus may also lead to edema in part due to increased capillary permeability.[16][17]

Eating after three or more days of fasting leads to edema, which is speculated to be due to increased insulin levels after re-feeding with carbohydrates and thus resulting in enhanced reabsorption of sodium.[18]

Additionally, lymphatic obstruction is a well-known cause of edema, and common causes include lymphedema, tumors, fibrosis, inflammation, infection such as Filariasis due to Wuchereria bancrofti, surgery, and congenital abnormalities. Myxedema, typically due to thyroid abnormalities, leads to accumulation of interstitial albumin and other proteins, thus leading to excessive interstitial protein and fluid without increased lymphatic flow. Some suggest that this is due to filtered proteins binding to interstitial mucopolysaccharides and preventing removal by the lymphatics.[19] There are many reasons edema exists, but the specific physiology depends on the underlying cause of the edema.

Clinical Significance

There are many causes of edema and presentation will differ according to the etiology. Generally, edema presents as ankle swelling and may extend higher. Common causes include congestive cardiac failure, constrictive pericarditis, nephrotic syndromes, liver disease (cirrhosis), allergic reactions (urticaria or angioedema), malabsorption, protein calorie malnutrition, obstructive sleep apnea, pregnancy, or medication side effects. When there is unilateral or asymmetric edema, venous thrombosis is suspected. In the case of heart failure, the specific etiology is important when distinguishing the exact location of edema[20]. For example, coronary heart disease, hypertension, or left-sided valvular disease, typically have pulmonary but not peripheral edema. In contrast, cor pulmonale, is initially pure right ventricular failure, and thus there is edema in the extremities. Cardiomyopathies produce equivalent involvement of right and left ventricles and often lead to simultaneous pulmonary and peripheral edema[21].  An S3 heart sound, especially in the presence of pulmonary or generalized edema, is also highly suggestive of heart failure. Classic signs of congestive heart failure include a chest x-ray showing increased pulmonary vasculature, cardiomegaly, haziness of vascular margins, which suggest fluid overload. Patients may also present with shortness of breath and pitting edema.

Localized edema is generally due to cellulitis, chronic venous insufficiency, deep vein thrombosis, lymphedema, or May-Thurner syndrome. When the edematous area is warm and patient’s vitals are unstable (febrile, tachycardic, or tachypneic), then infectious and/or thrombotic causes should be suspected.

Medications causing edema are generally anti-hypertensives (calcium channel blockers, minoxidil, or hydralazine), antidepressants (trazodone and MAO inhibitors), antivirals (acyclovir), chemotherapeutics (docetaxel, cyclophosphamide, and cyclosporine), fludrocortisone, pramipexole, hormones (estrogens, progesterones, and anabolic steroids), thiazolidinediones, and non-steroidal anti-inflammatory drugs (celecoxib and ibuprofen)[22][23][24][25][26]

Edema can also occur in the brain leading to increased intracranial pressure. This is often fatal if left untreated. Intracranial edema can occur due to several causes including generalized hypoxia, injury, abscesses, or tumors.

Fluid in the body cavities is another clinical cause of edema. Etiologies include pleural effusion (such as heart failure, inflammation, or tumors), pericardial effusion (such as in inflammation or tumors), or ascites (due to cirrhosis, heart failure, or tumors). Ascites will typically present with abdominal distention, shifting dullness, and a fluid wave on percussion of the abdomen.

The treatment for generalized edema largely depends on the etiology. The first step in treatment is to treat the underlying cause. Certain instances, such as pulmonary edema, can be a life-threatening condition requiring immediate therapy.[10]. In other cases, the reduction of interstitial fluids can be accomplished more slowly. If retention occurs because of compensatory causes, such as in cirrhosis or heart failure, then fluid removal with diuretics needs to be well-balanced since arterial blood volume, and thus tissue perfusion, can be compromised during treatment[27]. When edema is caused by heart failure, nephrotic syndrome, or sodium retention, mobilization of edema fluid can occur rapidly[28]. Specifically, when a patient has anasarca, removal of two to three liters of fluid in 24 hours is acceptable without clinically significant changes in plasma volume[29]

Dietary modifications can also help reduce fluid overload and consider decreasing dietary sodium intake to 2 g/dL and increase protein intake to 1g/kg/dL if hypoalbuminemia exists. Diuretics, specifically loop diuretics such as furosemide, bumetanide, and torsemide, can reduce edema fluid. Caution needs to be taken when using diuretics in patients with cirrhosis and ascites of the liver with no peripheral edema or with localized edema due to venous of lymphatic obstruction, or malignancy[30]. These cases may lead to hypovolemia after the decrease of fluid[27] The clinical profile for edema depends on the etiology, and management is maintained by careful analysis of the patient’s underlying disease.