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Pathophysiology and General Considerations

Definition

Edema is a pathological accumulation of fluid in the interstitial space.

Pathophysiology

Normally there is a balance between the amount of fluid, salts, and proteins that leave the capillary lumen, and the amount of substances that are reabsorbed and transported back. Small molecules are primarily reabsorbed on the venular branch of the capillaries in order to reach the bloodstream again, whereas large protein molecules return preferentially via the lymphatic vessels.

The most significant pathophysiological mechanisms that lead to the formation of edema are:

• increased venous and capillary pressure
• increased permeability of the capillary wall
• diminished drainage efficiency of the lymphatic system

In certain cases several pathogenetic factors add to edema formation. The interstitium is able to absorb several liters of fluid before clinically apparent edema occurs. Therefore a precondition for the development of edema is renal sodium and water retention.

Localization

When considering the differential diagnosis of edema, localization gives the first indication.

Generalized edema leads one to suspect a disorder that affects the whole body. Classic examples are heart failure and hypoproteinemia. In these cases it is important to incorporate the findings in certain organs such as the heart or the kidneys, as they are decisive elements when considering the differential diagnosis.

If edema develops locally, which means it only affects a particular part of the body, then one searches primarily for local causes. Phlebedema, lymphedema, and Quincke edema would be prototypes for edema with a local origin.

When assessing edema of the lower limbs, it must be taken into account that minor swelling can be a physiological phenomenon. After standing or sitting quietly for long periods (for example in a car or airplane), many people experience discreet to moderately pronounced symmetrical edema of the lower limbs. The tendency to premenstrual swelling is also well known.

Generalized Edema

Edema Related to Heart Failure

Pathophysiology

Heart failure leads to an increase of the left ventricular end-diastolic pressure and ultimately to pulmonary edema. If there is a disturbance of the right ventricular function, central venous pressure increases,which may be clinically recognizable by distention of the jugular vein.

The increase in venous pressure may be transferred as far as the venular side of the capillary vessels, so that less insterstitial fluid is reabsorbed. In addition, decreased cardiac output activates humoral and neurohumoral proccesses, which lead to increased water and salt retention by the kidneys and consequently to an increase in the amount of extracellular.

Clinical Features

Due to fluid retention, edema develops and usually presents as pitting edema (image below). It mainly affects dependent parts of the body. Thus mobile patients may develop edema that presents as symmetrical leg swelling. Bedridden patients, on the other hand, may develop edema of the back and buttocks.

Serious biventricular heart failure can cause the edema to affect the genital region and occasionally the upper extremities. In many cases pleural or pericardial effusion is present.

Chronic liver congestion may additionally lead to hypoproteinemia due to diminished liver function (see below). Additional symptoms that suggest valvular, myocardial, or coronary heart disease support the diagnosis.

READ ALSO: Heart Failure: Approach, Evaluation and Management

Hypoproteinemic Edema

Clinical Features and Diagnosis

In contrast to cardiac edema, hypoproteinemic edema is less dependent on the position of the body. The face, and in particular the eyelids, may be affected. The edema is decidedly soft and pitting. The diagnosis is confirmed by determining total protein plasma level and the protein electrophoresis.

Hypoproteinemic edema regularly occurs if the total plasma protein level is less than 5 g/dL (50 g/L) and the plasma albumin content is below 1.5−2.5 g/dL (15−25 g/ L). If the albumin level is below 2.0 g/dL (20 g/L) there is a pronounced tendency to thrombosis, as the plasma level of antithrombin III also decreases.

Etiology

Hypoproteinemic edema may be caused by a number of diseases:

• The Nephrotic Syndrome. The main disease that causes hypoproteinemic edema is nephrotic syndrome. The determining factors for the diagnosis are pronounced proteinuria (3.5 g/day) and hypoproteinemia (2.0 g/dL). The serum albumin is distinctly reduced while high molecular weight proteins (mainly α2- globulin and -globulin) decrease moderately. The serum cholesterol level is increased. Apart fromhypoproteinemia other factors, such as sodium retention and the disturbance of the capillary permeability, are also involved in the pathogenesis of edema.

• Serious liver diseases are usually associated with moderate to pronounced edema formation. Edema due to hypoproteinemia is based on impaired liver protein synthesis (in particular the albumins). Pressure on the intrahepatic part of the inferior vena cava or disturbance of the venous return due to ascites may lead to an increase in venous pressure in the inferior vena cava and thus augments edema formation in the lower limbs.

• Exudative Gastroenteropathy. Hypoproteinemic edema is a main clinical symptom of exudative gastroenteropathy. This disease is characterized by a loss of plasma proteins into the intestinal lumen. Hypoproteinemia results if enteral protein loss is higher than the maximal protein synthesis capacity of the liver. In contrast to nephritis, intestinal protein loss affects all protein fractions. The determination of α1- antitrypsin in serum and stool (physiological loss 2.6 mg/g stool weight) or the more complex quantitative determination of the fecal excretion of radioactively marked macromolecules (e. g., 51Cralbumin) are important when making the diagnosis. Diseases such as ulcerative colitis, polyposis, hypertrophic gastropathy (Ménétrier syndrome), or idiopathic sprue come into question as causes of exudative gastroenteropathy. These diseases can be easily detected endoscopically or radiologically. If intestinal lymph drainage is impaired, the diagnosis of enteral protein loss may be difficult and may require a 51Cr-albumin test and/or a lymphography. Inherited intestinal lymphangiectasia primarily affects children and young adults and is characterized by an ectasia of enteric lymphatics. Valvular insufficiency of draining lymphatic vessels may lead to reflux of the lymph fluid and to chylointestinal fistulas. Chylous reflux due to acquired drainage disorders can develop secondarily, for example, due to abdominal tumors.

• Hunger Edema. Hunger edema as well as edema in cachetic conditions would also normally be considered as hypoproteinemic edema. The underlying cause of this type of edema is an unbalanced diet, especially in times of nutritional insufficiency. A typical example is the chronic alcoholic, who satisfies his/her caloric requirement mainly with carbohydrates. Specific queries as to the patient’s diet will clarify the diagnosis.

• Kwashiorkor. In developing countries there is often a particular form of undernourishment that is called kwashiorkor. After infants have been weaned, they receive cereals as their main source of nourishment. This ultimately leads to underdevelopment and the formation of edema.

Edema Related to Glomerulonephritis

Clinical Symptoms

In cases of acute glomerulonephritis and of acute renal failure due to other causes, edema may occur without nephrotic syndrome. This edema has similar properties to those found in the edema of hypoproteinemic patients. The edema is pale, pits easily, and is found mainly on the face.

In glomerulonephritis, there is evidence of a general increase in capillary permeability. However, in most cases of renal failure the tendency towards edema is primarily due to retention of sodium and water.

Diagnosis

A urinalysis showing hematuria, erythrocyte casts, and dysmorphia, usually accompanied by only moderate proteinuria, leads to the correct diagnosis. Newly developed hypertension and reduced renal function are frequently observed.

READ ALSO: Approach to Hematuria and Proteinuria

Edema Related to the Endocrine System

Myxedema is an important form of endocrine-related edema. Edema may occasionally develop in hyperaldosteronism. An overdose of mineralocorticoids, e. g., in the treatment of Addison disease, or the use of drugs with mineralocorticoid effect (Carbenoxolone, licorice) may lead to edema.

In myxedema, the edema is most commonly found in the pretibial area (image below). It does not pit on pressure. In severe cases, particularly those preceded by thyroidectomy or radioactive iodine treatment, its diagnosis is sometimes overlooked. False diagnoses are also frequent in oligosymptomatic cases.

Inexplicable general fatigue, weight gain, increased sensitivity to cold, dry skin, deepening voice, and a low voltage electrocardiogram (ECG) will raise suspicion for the diagnosis.

Appropriate laboratory evaluation of thyroid gland metabolism can confirm the diagnosis. Interstitial deposits of hydrophilic mucopolysaccharides and the resulting deterioration of lymphatic drainage are pathophysiologically significant.

Pretibial myxedema, often accompanied by reddening of the skin, may occur in hyperthyroidism, albeit rarely. In this case, the clinical and hormonal findings are typical of hyperthyroidism.

READ ALSO: Thyroid Troubles: Hyperthyroidism and Thyrotoxicosis

Edema Related to Electrolyte Imbalance

Hypokalemic edema arises mainly as a result of chronic laxative abuse. Diagnosis can be established on the basis of medical history, general adynamia, and ECG changes.

The abuse of diuretics, often practiced in order to lose weight, may also cause edema. In this case, edema does not occur until the medication has been discontinued, thus forcing the patient into a vicious circle whereby he/she starts taking the medication again if the doctor does not recognize the situation. Once the medication has been discontinued, the edema persists for a few weeks or months until it finally disappears completely. At the same time the hypokalemia and plasma renin return to normal levels.

READ ALSO: Diuretics – An Overview

Edema occurring as a result of hypertonic and hypotonic hyperhydration is iatrogenic edema. The administration of excessive amounts of intravenous fluids leads to an increase in the extravasal fluid volume.

Edema Related to Scleroderma

In individual cases, edema may precede the other symptoms of scleroderma. Although it may initially be relatively soft, the edema becomes harder as the disease progresses. It then feels extremely dense and is difficult to press in. The normal skin creases disappear, e. g., of the face. Deposits of hydrophylic mucopolysaccharides, local inflammation, and increased microvascular permeability all play pathogenetic roles.

The most recent findings suggest that there is also lymphatic microangiopathy. Other symptoms of the disease, such as secondary Raynaud syndrome, pulmonary fibrosis, renal involvement, and dysphagia, clarify the diagnosis.

Edema Related to Diabetes Mellitus

People with diabetes are prone to edema, particularly in the lower extremities, even in the absence of hypoproteinemia (glomerulosclerosis with nephrotic syndrome). This finding is based on the increased permeability of the capillaries, as demonstrated by clearance tests using radioactive substances and by flourescence videomicroscopy.

Drug-Related Edema

There are many drugs that can promote or cause edema. In particular, the adrenocortical hormones, certain antihypertensive drugs (hydralazine, α-methyldopa, minoxidil), and nonsteroidal antirheumatic drugs should be noted in this context. Treatment with calcium antagonists also relatively frequently leads to edema.

Localized Edema

Fig. 1 below demonstrates six different forms of localized, chronic edema and the differential diagnosis of the swollen leg.

Venous Edema

In cases of acute deep vein thrombosis a subfascial, or frequently epifascial painful edema, appears in the affected limb. The livid color is particularly striking when the patient is standing. Superficial veins, functioning as collaterals, appear congested and firm to the touch, when compared to the other limb. Once the acute phase is over, often following a relatively oligosymptomatic period, chronic venous insufficiency (Fig. 1 a) may develop over a period of months or years. Edema which worsens upon standing or sitting is one of the clinical characteristics in chronic venous insufficiency.

Lymphedema

While painful venous edema can be described as a “swollen blue leg,” painless lymphedema could be referred to as a “swollen white leg” (Fig. 1 b). Lymphedema is relatively firm, especially when the disease has reached a chronic stage. Typically lymphedema initially presents as a cushionlike swelling at the dorsum of the foot. The shape of the leg then becomes pillarlike (i. e., the ankle region loses its typical shape). The dorsal skin on the toes cannot easily be lifted with the finger and thumb (positive Stemmer sign). In severe cases verrucas may occasionally develop on the toes.

Primary Lymphedema

Pathogenesis

Primary lymphedema is a congenital disorder. It most commonly occurs in isolation, but may more rarely develop as part of a more complex congenital angiodysplasia. If a baby is born with an edematous leg (rare), this is referred to as hereditary congenital Nonne−Milroy disease, with autosomal dominant inheritance. A familial form, which develops later in life, is more common (hereditary lymphedema praecox; Meige disease).

The most common form of primary lymphedema is sporadic lymphedema. In these cases, family history does not usually give any clues to the diagnosis. The edema generally begins in one leg after puberty. In 50% of cases, the contralateral leg is also affected as the disease progresses.

Primary lymphedema begins in more than 80% of patients before they have reached the age of 40. If it develops during adulthood, it is referred to as lymphedema tarda. Females are affected more often than males, making up 80% of all cases. The severity of the disease is defined according to three stages:

• I: reversible lymphedema (edema subsides overnight)
• II: irreversible lymphedema (edema does not subside overnight)
• III: elephantiasis

Diagnosis

The presence of primary lymphedema can be confirmed by lymphography. If less than four to six lymph vessels are visualised in the lower leg, or less than eight to 12 in the upper leg, this is referred to as hypoplasia. Usually the lymph nodes are also hypoplastic. Total aplasia (absence of puncturable lymph vessels), and dilation of the lymph vessels with valve insufficiency (“varicose” lymph vessels), are less common.

Since lymphography using contrast medium is a relatively invasive procedure, diagnosis is usually established only on the basis of the typical clinical signs. To some extent lymphography has been replaced by lymphscintigraphy. The diagnosis can also be supported by a pathological dye test, indirect lymphography using a subcutaneously administered contrast medium, or flourescence microlymphography.

As a result of lymphatic congestion, flourescence microlymphography, which is a virtually noninvasive procedure, demonstrates a more extensive lymphatic capillary network in lymphedema as compared to a healthy subject. In Nonne−Milroy syndrome microlymphatics are aplastic or hyperplastic.

Chylous Lymphedema

Chylous lymphedema is a special form of lymphedema. Lymphatic valve insufficiency extends as far as the cisterna chyli and there may be a reflux of lymph containing chyle from the bowel. Lymphedema of the genitalia and legs may ensue. Inguinal swellings may be mistaken for a hernia. Milky lymphatic fluid may occasionally be discharged from lymphatic fistulas (superficial blisters). In rare cases, chylous ascites may develop. In cases of so-called “yellow nail syndrome” there are pleural effusions in addition to lymphedema of the extremities.

Secondary Lymphedema

Etiology

Secondary lymphedema must always be ruled out, if swelling of the leg first appears when a patient is over the age of 40 (Fig. 1 b). The most common causes of secondary lymphedema are:

• tumors of the lower pelvis (ovarian, bladder, rectal, and prostate gland carcinoma)
• malignant disease of the lymph nodes
• recurring bacterial lymphangitis (erysipelas)
• direct trauma to the anteromedial lymph vessel bundles (bottlenecks: medial knee area, groin)
• radiotherapy of the groin and pelvis
• tropical filarial infection

Lymphedema of the arm is most commonly seen following mastectomy. Chronically recurring nonspecific infections, e. g., originating from tinea pedis, can lead to occlusive lymphangiopathy.

Clinical Symptoms

Whereas secondary lymphedema usually commences proximally and extends distally (the upper leg is affected first and most seriously), it is typical for the primary form to take the opposite direction. In rare cases, with aplasia or hypoplasia of the pelvic and para-aortal lymph vessels, primary lymphedema may develop in the cranio-caudal direction.

Diagnosis

In addition to taking a thorough medical history, imaging techniques including ultrasound examination or, if necessary, CT or MRT scans are used to rule out pelvic or retroperitoneal tumors.

Complications

The most common complication of both primary and secondary lymphedema is erysipelas, which can be easily distinguished from superficial thrombophlebitis through local examination (a large hot and red area of skin) and through observation of the general symptoms (fever and chills). The protein-rich edema is evidently an ideal medium for pathogenic organisms (particularly Streptococcus and Staphylococcus). Less common complications include lymphatic fistulas and angioplastic sarcoma (Stewart−Treves syndrome), which is almost always fatal.

Lipedema

This condition is peculiar to women. Both legs become symetrically swollen with pads of fat. In contrast to lymphedema, the dorsum of the foot is not affected (Fig. 1 c). The edema pits only slightly, or not at all, and is painful on pressure. It is often, but not always, accompanied by general obesity. The skin shows signs of peau d’orange (“cellulite”).

Inflammatory Edema

Edema as a result of bacterial infection is characterized by the three classic symptoms: rubor, calor, and dolor. It must be kept in mind that, occasionally, the cause may be a tropical parasitic disease. The filarial worm Loa loa causes brief, sporadic recurrences of swelling of various parts of the body. The outlines of filariae can sometimes be seen directly beneath the skin. Eosinophilia, elevated levels of antibodies, the presence of filariae in the blood, and skin biopsy all contribute to the diagnosis.

During its edematous, preatropic phase, acrodermatitis chronica atrophicans may often be mistaken for other diseases, such as venous thrombosis, lymphedema, arthritis, or multiple arteriovenous fistulas (Fig. 1 d). The illness is more easily diagnosed in the advanced stage, in which the skin characteristically becomes atropic and parchment like. The cause of the disease is an infection with Borrelia burgdorferi.

Congenital Angiodysplasia

The causes of edema in angiodysplasia include atypical varicose veins or angiomas, arteriovenous fistulas, and aplasia or hypoplasia of the lymph vessels. These are to be distinguished from soft tissue hypertrophy (Fig. 1 e).

Urticaria and Angioedema

Clinical Symptoms

The characteristics of this distinctive form of edema are that it is transient (episodes lasting minutes or hours), starts suddenly in any part of the body (Fig. 2) and causes itching. If the cutis alone is affected, it is referred to as urticaria. If the subcutaneous layer and the mucuous membranes are affected, it is referred to as angioedema.

The lips and eyelids are most commonly affected and it is, therefore, important not to confuse the diagnosis with Melkersson−Rosenthal syndrome (recurrent facial swelling, facial paresis, lingua plicata), the etiology of which is unknown.

Angioedema of the upper respiratory tract may lead to lifethreatening compression of the glottis. When the intestine is involved, colic and vomiting may be present.

• In allergic edema (Quincke edema), blood tests may show eosinophilia and raised IgE antibody levels immediately and/or at a subsequent time. Usually the cause can be identified. Nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, ACE inhibitors, contrast dyes, blood products, and penicillin may trigger the development of allergic edema.

• Drug-induced angioedema may also be the result of a process induced by IgE, by circulating immune complexes or a direct activation of the complement pathway. Urticaria and angioedema may also be accompanied by cutaneous or systemic angiitis and paraproteinemia.

• Hereditary angioedema (“angioneurotic” edema) is a disturbance of the capillary permeability due to a congenital, autosomal dominantly inherited enzyme deficiency (C1-esterase inhibitor). The disease manifests itself in distinctive attacks of edema occurring mainly in the extremities, the face, the laryngeal area (causing death by asphyxia in approximately one quarter of cases), and in the gastrointestinal tract. In addition to family history, it is essential to determine the C1-esterase inhibitor level in order to obtain a definitive diagnosis. Acquired forms of C1- esterase inhibitor deficiency occur in lymphoproliferative diseases and in systemic lupus erythematosus. In these cases, of course, there is no positive family history of the disease. In both the inherited and the acquired forms there are low levels of complement components.

Ischemic and Postischemic Edema

Both of these forms of edema may be attributable to an ischemic damage of the capillarywalls. After revascularization of an obstructed artery, arterial pressure distal to the obstruction sharply increases, which affects the ischemically damaged peripheral microvascular network, resulting in transient postischemic edema due to increased microvascular permeability.

Local Edema Occurring at High Altitudes

Edema of the legs, backs of hands, and face can be a symptom of acute mountain sickness, which may occur at altitudes of more than 2500 meters above sea level. Edema appears after a latency of six to 12 hours (other symptoms include headache, nausea, vertigo, and insomnia). The symptoms usually disappear spontaneously if the patient remains at the same altitude. Climbing further, despite persistent symptoms, may result in serious cerebral or pulmonary edema.

Factitious Edema

The possibility of factitious edema must be considered in cases of unaccountable edema. Self compression with bandages can give rise to a pronounced swelling. Compression lines on the upper arm or thigh are signs that will aid diagnosis (Fig. 1 f). Edema of the hand is sometimes artificially induced by repeatedly slapping the back of the hand. It sometimes may be necessary to apply a plaster cast in order to protect the hand from further manipulation, to allow the edema to subside and thus confirm the suspected diagnosis.

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