Etiology
A variety of disease states or medications can cause peripheral edema by altering the mechanisms that maintain the normal volume of interstitial fluid. In many cases, the edema may be multifactorial, with various contributing factors.
Interstitial fluid and the extracellular matrix (comprised of structural and connective molecules such as collagen fibers and glycosaminoglycans) form the interstitial space. This space exists outside the blood vessels, lymphatic vessels, and parenchymal cells. Interstitial fluid is formed from an ultrafiltrate of blood. It transports nutrients and waste products between cells and capillaries, delivers antigens and cytokines to draining lymph nodes, and transports intercellular signaling molecules.[3]
Interstitial fluid is initially drained through noncontractile terminal lymphatic channels, which are present in nearly all tissues. These terminal lymphatic channels deliver lymph to larger collecting lymphatic channels, which are surrounded by smooth muscle and contain valves to assist unidirectional flow. From there, lymph flows through lymph nodes, then passes through progressively larger lymphatic channels and finally enters the central venous circulation.[3]
Several physiologic mechanisms regulate the volume of interstitial fluid production and lymphatic drainage. When one or more of these mechanisms is overwhelmed, edema develops.
Chronic edema is a common problem in hospitalized patients. One study, enrolling hospitalized patients from Denmark, France, Australia, the United Kingdom and Ireland, reported chronic edema prevalence of 38%.[4] The risk factors associated with presence of chronic edema were age, morbid obesity, heart failure, immobility, and neurologic deficiency.[4]
Increased microvascular filtration
Microvascular filtration occurs in the venules and capillaries. Filtration rate depends on the hydrostatic pressure in the vessel, which drives fluid out of the vessel into the interstitial space, and the colloid osmotic pressure in the vessel, which promotes retention of fluid in the vessel. Microvascular filtration may increase when hydrostatic pressure increases and/or colloid osmotic pressure decreases.
Increased hydrostatic pressure occurs when systemic venous pressure increases: for example, in heart failure, cor pulmonale, venous insufficiency (e.g., due to a failure in calf muscle pump action), venous obstruction (e.g., by pelvic tumor or venous thrombosis). Premenstrual edema occurs when hormonally-mediated renal salt and water retention increases total body fluid.
Following a deep vein thrombosis in the leg, up to 50% of patients develop postthrombotic syndrome with symptoms and signs of chronic venous insufficiency.[5] The pathophysiology is incompletely understood; venous hypertension probably results from several mechanisms including residual venous obstruction and valvular reflux. Ultimately, microvascular permeability increases and interstitial fluid accumulates locally.[5]
Pregnancy is commonly associated with lower-extremity edema starting in the second trimester. This is due to increased total body fluid as a result of neurohormonal changes and to mechanical pressure on the inferior vena cava from the gravid uterus.[6]
Drugs that cause renal fluid and salt retention, such as nonsteroidal anti-inflammatory drugs, may precipitate peripheral edema.[7][8]
Nephrotic syndrome, cirrhosis, kwashiorkor, and protein-losing enteropathies all cause reduced serum colloid osmotic pressure.[6]
When blood vessel walls become more permeable in response to the actions of cytokines, prostaglandins, or nitric oxide, large serum proteins move into the interstitial space. This reduces the colloid osmotic gradient and increases the rate of interstitial fluid production.[6][9] Patients who have sepsis have increased vascular permeability as a result of circulating cytokines and frequently develop extensive peripheral edema.[9] This mechanism also plays a role in the edema seen in hypothyroid myxedema, angioedema, and allergic reactions.[6]
In some disease states, the pathophysiology of increased microvascular filtration is multifactorial. For example, cirrhosis causes fluid retention, and therefore raised venous pressure, by a number of complementary mechanisms: splanchnic vasodilation reduces effective renal perfusion, inducing sodium and water retention; serum colloid osmotic pressure declines as a result of synthetic liver dysfunction; and altered architecture of the hepatic sinusoids results in mechanical congestion with venous hypertension and increased hydrostatic gradient in the abdomen and lower extremities.[6][10][11]
Patients who have a normal lymphatic system that is overwhelmed by excess interstitial fluid production will develop edema. Over time, this can cause permanent structural damage to the lymphatic vessels, so that even if microvascular filtration returns to normal, peripheral edema persists because lymphatic drainage is impaired.
Decreased lymphatic drainage
The lymphatic system drains fluid from the interstitial space and ultimately returns it to the venous circulation. Approximately 80% of lymphatic drainage must be nonfunctional before lymphedema (caused by inadequate lymphatic drainage) becomes clinically evident.[12] Lymphatic stasis leads to fat hypertrophy, with associated thickening of subcutaneous tissue, and immunologic dysfunction. Elevated concentrations of interstitial protein cause inflammation and fibrosis, leading to further damage.[12]
Lymphedema may be primary (caused by hypoplastic lymph vessel development) or secondary.[13] Primary lymphedema accounts for approximately 1% of cases.[12] Secondary causes include:
Surgical removal or irradiation of lymph nodes. Approximately 20% of patients with breast cancer who undergo axillary lymph node dissection and 5% who undergo sentinel lymph node biopsy develop arm lymphedema.[14]
Neoplastic infiltration of lymph nodes
Trauma
Parasitic nematode infections (e.g., filariasis)
Some medications (e.g., calcium-channel blockers)
Reduced mobility.
Movement and exercise generate movement of interstitial fluid into the initial lymphatics, so when a patient has impaired mobility, lymph drainage often decreases.[15][16]
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