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Pathophysiology and etiology of edema in children

Pathophysiology and etiology of edema in children
Author:
Rudolph P Valentini, MD
Section Editor:
Tej K Mattoo, MD, DCH, FRCP
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Jun 2022. | This topic last updated: Feb 05, 2020.

INTRODUCTION — Edema is a clinical condition characterized by an increase in interstitial fluid volume and tissue swelling that can either be localized or generalized. Severe generalized edema is known as anasarca. More localized interstitial fluid collections include ascites and pleural effusions.

The diagnostic approach to edema is based upon a thoughtful approach to the pathogenesis of its formation. Once a diagnosis is established, specific treatment of the underlying disorder can be given. If specific therapy is not available, general treatment, such as optimization of fluid management, can be provided.

The pediatric disease processes associated with edema and the pathogenesis of edema will be described in this topic review. More detailed discussions of evaluation and management of edema in children as well as the pathophysiology of edema are presented separately. (See "Evaluation and management of edema in children".)

OVERVIEW OF PATHOPHYSIOLOGY

Normal physiology — Edema does not occur in normal subjects because of the tight balance of hemodynamic forces along the capillary wall and the intact function of the lymphatic system. While capillary hydrostatic pressure favors transcapillary fluid movement into the interstitium, the colloid oncotic pressure across the capillary favors the retention of fluid within the vessel (figure 1). Under normal circumstances, these competing forces result in a small net movement of fluid into the interstitium. The lymphatic vessels return this interstitial fluid to the venous system thereby preventing edema formation.

Pathophysiology of edema — The following physiologic processes result in edema formation:

An alteration in capillary hemodynamics that favors increased movement of fluid from the vascular space into the interstitium

Failure of interstitial fluid to be returned to the central venous system through the lymphatic vessels

The retention of dietary or intravenously administered sodium and water by the kidneys, resulting in hypervolemia and increased vascular hydrostatic pressure

Altered capillary hemodynamics — Movement of fluid from the vascular space into the interstitium requires a change in one or more components of the balance of capillary hemodynamics:

Increased capillary hydrostatic pressure

Increased capillary permeability

Decreased capillary oncotic pressure

Impaired lymphatic transport — Failure of the return of interstitial fluid into the central vascular system through the lymphatic system is due to abnormal development, dysfunction, or obstruction of the lymphatic system.

Renal salt and water retention — The renal retention of sodium and water can either be a primary event (as in renal failure or acute glomerulonephritis) or a secondary event resulting from a primary reduction in cardiac output (as in heart failure), or systemic vascular resistance (SVR; as in cirrhosis with hepatorenal syndrome). In the latter setting, fluid retention is an appropriate response to return the effective circulating volume toward normal. In these patients, diuretic therapy may have a deleterious effect on systemic hemodynamics even though it reduces the edema.

The increased salt and water retention leads to hypervolemia and increased capillary hydrostatic pressure (as in acute glomerulonephritis).

The pathophysiology and etiology of edema and regulation of effective circulatory volume are discussed in detail separately. (See "Pathophysiology and etiology of edema in adults" and "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Regulation of effective arterial blood volume' and "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Edema'.)

ETIOLOGY — Causes of edema in children produce either localized or generalized edema. As examples, a common cause of localized edema is venous obstruction from venous compression (as can occur with deep venous thrombosis), and for generalized edema, nephrosis. The etiology of edema can also be classified by its pathogenesis. The following section is a review of the most common causes of edema in children based on pathogenesis (table 1).

Increased hydrostatic pressure from sodium and water retention

Heart failure — Heart failure can present with edema due to an increase in venous pressure from sodium and water retention. This produces a parallel rise in capillary hydraulic pressure with increased transcapillary movement of fluid into the interstitial space. The site of edema accumulation is variable and is dependent upon the nature of the cardiac disease:

Patients with impaired left ventricular (LV) function may present with pulmonary, but not peripheral, edema.

Pure right ventricular (RV) failure may result in prominent edema in the lower extremities.

Cardiomyopathies, which are associated with impaired function of both the RV and LV, may often lead to the simultaneous onset of pulmonary and peripheral edema.

Clinical signs of heart failure in the older child include tachycardia, tachypnea, rales or wheezes, gallop rhythm, hepatomegaly, and edema. Infants with heart failure most often present with tachypnea and diaphoresis during feeding, poor feeding, reduced weight gain, lethargy, and irritability. Although facial edema can be seen with RV failure [1], peripheral edema is generally less commonly observed in children with heart failure than in adults. Peripheral edema is unusual in young infants with heart failure [2]. (See "Heart failure in children: Etiology, clinical manifestations, and diagnosis".)

Acute glomerulonephritis — Edema resulting from acute glomerulonephritis (AGN) can be either generalized or localized. The edema is primarily due to renal sodium and water retention.

In addition to edema, clinical findings include hypertension, hematuria and proteinuria, cola-colored urine, and/or azotemia. Not all of these features are present in each patient. As an example, cola-colored urine, which is considered a classic feature of AGN, is present in only 30 to 50 percent of children [3]. The finding of red cell casts, even if only one is seen, is virtually diagnostic of glomerulonephritis. (See "Glomerular disease: Evaluation in children".)

AGN can arise from a number of causes (table 2) (see "Overview of the pathogenesis and causes of glomerulonephritis in children", section on 'Acute nephritic syndrome'):

The most common cause of AGN is postinfectious glomerulonephritis, usually caused by a recent streptococcal infection [4]. (See "Poststreptococcal glomerulonephritis".)

Other causes of primary AGN include immunoglobulin A (IgA) nephropathy, hereditary nephritis (also known as Alport syndrome), and membranoproliferative glomerulonephritis. (See "IgA nephropathy: Clinical features and diagnosis" and "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)" and "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

Systemic diseases associated with glomerulonephritis include systemic lupus erythematosus (SLE), immunoglobulin A vasculitis (IgA vasculitis; Henoch-Schönlein purpura [HSP]), antineutrophil cytoplasmic autoantibody (ANCA)-associated diseases such as granulomatosis with polyangiitis and microscopic polyangiitis, and anti-glomerular basement membrane (anti-GBM) disease. (See "Lupus nephritis: Diagnosis and classification" and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis".)

The serum complement component 3 (C3) level is a useful diagnostic test in determining the etiology of AGN, as the causes of AGN can be classified as either hypocomplementemic or normocomplementemic (table 2).

Renal failure — Children with either acute or chronic renal failure can present with edema due to renal retention of sodium and water. The evaluation and diagnosis of the many different causes of acute or chronic renal failure is discussed in detail separately. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis" and "Chronic kidney disease in children: Clinical manifestations and evaluation".)

Drugs — Antihypertensive agents that are potent vasodilators cause renal sodium and water retention leading to increased hydrostatic pressure. These medications include minoxidil and the dihydropyridine calcium channel blockers (CCBs; eg, nifedipine, amlodipine, felodipine, or nicardipine). (See "Major side effects and safety of calcium channel blockers".)

Increased capillary hydrostatic pressure from obstruction

Venous obstruction — Localized edema from venous obstruction arises from extrinsic venous compression, thrombosis, or congestion. Regardless of the cause of venous obstruction, the edema that develops occurs distal to the site of obstruction. As an example, symptomatic thrombosis in the inferior vena cava (IVC) typically presents as swelling of the lower limbs and lower body. By comparison, superior vena cava (SVC) thrombosis typically presents as swelling of the arm, neck, and head [5]. The severity of the swelling depends upon the size of the thrombus and the degree of alternative collateral venous pathways. Often, thrombophlebitis presents with tenderness, swelling, and, occasionally, a palpable cord.

There are a large number of causes and/or risk factors for venous thrombosis in children (see "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Risk factors'). They include:

Venous catheters – Used short term in critical care settings and more chronically in children with chronic diseases such as short gut syndrome (who are parenteral nutritionally dependent) and some hemodialysis patients (temporary vascular access)

Congenital heart disease (CHD)

Vasculitis

Antiphospholipid syndrome (see "Clinical manifestations of antiphospholipid syndrome", section on 'Thrombotic events')

Hyperviscosity states (eg, polycythemia)

Medications (eg, oral contraceptives)

Immobilization

Malignancies

Systemic diseases (eg, nephrotic syndrome) (see "Complications of nephrotic syndrome in children", section on 'Thromboembolism')

Genetic predisposing factors including disorders of protein C, protein S, antithrombin III, factor V Leiden, and homocystinuria [6] (see "Protein C deficiency" and "Protein S deficiency" and "Antithrombin deficiency" and "Overview of homocysteine")

The pathogenesis and clinical manifestations of venous thromboembolism in children, infants, and neonates are discussed in detail separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis" and "Neonatal thrombosis: Clinical features and diagnosis".)

Cirrhosis — Cirrhosis is defined as irreversible hepatic parenchymal injury with fibrosis of the liver. Children with cirrhosis can develop portal hypertension with an increase in venous pressure below the diseased liver, resulting in ascites and lower extremity edema.

Although cirrhosis is relatively uncommon in children, the disorder can be caused by genetic disorders (alpha-1 antitrypsin deficiency, cystic fibrosis, Wilson disease), infectious etiologies (viral hepatitis), and structural problems of the biliary tree (biliary atresia, Alagille syndrome). (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency" and "Cystic fibrosis: Clinical manifestations and diagnosis" and "Wilson disease: Epidemiology and pathogenesis" and "Approach to evaluation of cholestasis in neonates and young infants".)

Decreased capillary oncotic pressure — Hypoalbuminemia results in a decrease in capillary oncotic pressure that favors the movement of fluid from the vascular to interstitial compartment. Hypoalbuminemia is seen in nephrotic syndrome, liver failure, protein malnutrition and protein losing enteropathy, and it contributes to edema formation in all of these diseases.

Protein malnutrition — Severe protein malnutrition or kwashiorkor can cause insufficient albumin synthesis resulting in hypoalbuminemia. This rarely occurs in developed countries. It should be considered in a child with generalized edema, skin rash over the scalp and extremities, and hypopigmentation of the hair (eg, red hair in a child who should have dark hair) [7]. (See "Malnutrition in children in resource-limited countries: Clinical assessment".)

Protein losing enteropathy — Children with protein-losing enteropathy have severe protein loss through the gut, resulting in low plasma protein levels (hypoalbuminemia) [8]. Causes include hypertrophic gastritis (Ménétrier disease), milk protein allergy, celiac disease, inflammatory bowel disease, giardiasis, intestinal lymphangiectasia, and right-sided heart dysfunction (post-Fontan procedure) [9,10].

Stool level of alpha-1 antitrypsin is an excellent screening test for protein-losing enteropathy, as alpha-1 antitrypsin is a non-dietary, serum protein synthesized in the liver. Its molecular weight of approximately 50 kDa is similar in size to albumin (67 kDa), and it is resistant to intestinal and proteolytic digestion distal to the stomach.

The clinical manifestation and diagnosis of this disorder is discussed in detail separately. (See "Protein-losing gastroenteropathy".)

Increased capillary permeability — Changes in capillary wall permeability are mediated by intrinsic factors, including cytokines (such as tumor necrosis factor and interleukins) and other vasodilators including histamine, bradykinin, prostaglandins, and complement factors (eg, C2a); and extrinsic factors (eg, pit viper venom).

Generalized edema from increased capillary permeability most often occurs in patients with burns or sepsis. A rare cause is idiopathic systemic capillary leak syndrome. (See "Idiopathic systemic capillary leak syndrome".)

In addition to generalized edema, a variety of clinical settings (eg, allergic reactions and infections) result in the local release of these inflammatory factors leading to localized increased capillary permeability and movement of fluid from the vascular space into the interstitium. This condition is referred to as angioedema.

Angioedema — Angioedema is associated with swelling of the deep layers of the cutaneous or submucosal tissues due to increased capillary permeability. Affected regions are usually the face, lips, tongue, or larynx.

Angioedema can be distinguished clinically from generalized edema by the following characteristics:

More rapid onset of presentation (minutes to hours)

Asymmetric distribution

Distribution not in dependent areas

Involvement of lips, larynx, and bowel

Association of some forms of angioedema with anaphylaxis

Angioedema may be due to allergic reactions (including drug reactions [eg, angiotensin converting enzyme (ACE) inhibitors], insect bites, or food) and inherited or acquired deficiency of the C1 esterase inhibitor [11-13]. (See "An overview of angioedema: Pathogenesis and causes".)

Angioedema, when it involves the airway, is a medical emergency and requires emergent intervention. (See "Basic airway management in children".)

Hereditary angioedema (HAE) due to deficiency in C1 inhibitor is quite rare. Affected patients with C1 inhibitor deficiency (HAE) commonly report a familial history of recurrent episodes of nonpainful, nonpruritic, and nonerythematous angioedema (without urticaria). An acquired form of this disorder also exists in which there is an autoantibody to the C1 inhibitor. This disorder is discussed in detail separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

Nephrotic syndrome — The nephrotic syndrome is one of the most common causes of generalized edema in childhood. The classic findings of this disorder include marked proteinuria, hypoalbuminemia, and hyperlipidemia, along with generalized edema.

Edema formation in nephrotic syndrome is a combination of the increased hydrostatic pressure due to primary renal sodium retention and decreased oncotic pressure due to hypoalbuminemia. The relative role for either process varies amongst individual patients. There also appears to be a role for increased capillary permeability mediated by a still unidentified factor or process. One proposed mechanism of sodium retention in nephrotic syndrome is marked proteinuria causing conversion of plasminogen into plasmin (a serine protease) within the tubular lumen, which leads to activation of epithelial sodium channel (ENaC) in the cortical collecting duct [14-16]. Further support of the role of serine proteases on ENaC activation comes from evidence that plasmin cleaves the y-subunit of ENaC, and in an experimental model of nephrotic syndrome volume retention can be inhibited by treatment with the serine protease inhibitor aprotinin [17]. (See "Pathophysiology and treatment of edema in adults with the nephrotic syndrome".)

Nephrotic syndrome with an onset prior to three months of age is known as congenital nephrotic syndrome, which is characterized by profound proteinuria and hypoalbuminemia. (See "Congenital and infantile nephrotic syndrome".)

The childhood nephrotic syndrome is associated with a number of glomerular lesions based on renal histology [18]. They include:

Minimal change disease (MCD) is the most common cause of the nephrotic syndrome in children, accounting for 90 percent of cases in children younger than 10 years of age and more than 50 percent of cases in older children. (See "Treatment of idiopathic nephrotic syndrome in children".)

Other primary glomerular lesions include focal segmental glomerulosclerosis (FSGS), mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, and membranous nephropathy [19,20]. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Minimal change variants' and "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis" and "Membranous nephropathy: Pathogenesis and etiology".)

Secondary causes include systemic diseases, such as SLE, IgA vasculitis (HSP), and diabetes and infections, such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus [21]. (See "Lupus nephritis: Diagnosis and classification" and "Overview of kidney disease in patients with HIV" and "Kidney disease associated with hepatitis B virus infection" and "Overview of kidney disease associated with hepatitis C virus infection".)

The evaluation, diagnosis, and management of the child with nephrotic syndrome are discussed separately. (See "Evaluation of proteinuria in children" and "Treatment of idiopathic nephrotic syndrome in children" and "Etiology, clinical manifestations, and diagnosis of nephrotic syndrome in children".)

Lymphatic dysfunction/obstruction — Dysfunction and obstruction of the lymphatic vessels result in localized edema as the lymphatic load exceeds the transport capacity of the lymphatic system, resulting in accumulation of protein-rich interstitial fluid [22,23]. A child with lymphedema may have either a primary defect of the lymphatics or a secondary (acquired) defect.

Primary lymphedema — Primary lymphedema can be divided into the following three different types based on the age of presentation [24]:

Lymphedema precox (77 to 94 percent) – Typically presents at onset of puberty

Congenital lymphedema (6 to 12 percent) – Presents before two years of age

Lymphedema tarda (11 percent) – Typically presents after 35 years of age

Lymphedema precox — Lymphedema precox is the most common form of primary lymphedema, accounting for 77 to 94 percent of all cases of primary lymphedema [24]. Although it can occur between 2 and 36 years of age, it typically presents at the onset of puberty with unilateral edema, which in the majority of patients is limited to the foot and calf. Females are predominantly affected, with a reported 10-fold increase in prevalence in female versus male patients. The pathogenesis is unknown in the majority of cases, but it is speculated that estrogen may play a contributory role because the presentation of this condition most commonly occurs in girls at the onset of puberty.

Although most cases are sporadic, 10 percent of cases of lymphedema precox are familial (referred to as Meige disease) with an autosomal dominant inheritance pattern [25-28]. Familial lymphedema precox has been associated with a double row of eyelashes (distichiasis) and is referred to as the lymphedema-distichiasis syndrome. A mutation in the FOXC2 gene (located at 16q24.3) has been described in families with lymphedema-distichiasis syndrome [28-30]. Mutation of FOXC2 results in agenesis of the lymphatic valves and enhanced recruitment of vascular mural cells to lymphatic capillaries [31]. In addition, FOXC2 is highly expressed in venous valves, which could explain why approximately one-half of patients with lymphedema-distichiasis have venous insufficiency [32].

Congenital lymphedema — Congenital lymphedema (presentation before two years of age) is due to a congenital and/or inherited condition associated with pathologic development of the lymphatic vessels, which may include the following abnormalities [23]:

Reduced numbers of lymphatic collectors

Lymphatic hypoplasia (decreased diameter of the lymphatic vessels)

Lymphatic hyperplasia (increased diameter of lymphatic collectors)

Lymphatic aplasia (absence of lymphatic system components)

Lymph node fibrosis

The following congenital conditions are associated with primary lymphedema in children:

Hereditary congenital lymphedema – Hereditary congenital lymphedema (primary congenital lymphedema, hereditary lymphedema type I, or Milroy disease) is transmitted as an autosomal dominant trait [33]. Affected individuals usually develop lymphedema in both lower extremities soon after birth, but it typically does not worsen over time. Most affected families carry a missense mutation in the gene encoding VEGFR-3 (expressed in the lymphatic endothelium), resulting in impaired lymphatic development [34-37].

Cholestasis-lymphedema syndrome – Cholestasis-lymphedema syndrome (Aagenaes syndrome) is an autosomal recessive disorder characterized by congenital lymphatic hypoplasia and recurrent cholestasis [38]. The lymphedema characteristically involves the legs of infants. Although the specific gene associated with this syndrome has yet to be identified, it is localized to chromosome 15q [38].

Other conditions – Other conditions associated with congenital lymphedema include Noonan syndrome, Turner syndrome, and trisomy 13, 18, and 21. These conditions are discussed separately. (See "Causes of short stature", section on 'Noonan syndrome' and "Clinical manifestations and diagnosis of Turner syndrome" and "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome'.)

Lymphedema tarda — Lymphedema tarda presents after 35 years of age. It also occurs more commonly in women and affects the lower extremities.

Secondary lymphedema — Lymphedema attributable to an acquired dysfunction of the lymphatic system may be caused by a wide range of conditions, including :

Cancer and its treatment.

Infection – Globally, lymphatic filariasis caused by the nematode Wuscheria bancrofti is the most common cause of acquired pediatric lymphedema [39]. (See "Lymphatic filariasis: Treatment and prevention".)

Autoimmune diseases – Lymphatic involvement can also occur in a variety of autoimmune diseases such as sarcoidosis, juvenile idiopathic arthritis, and Crohn disease [40,41]. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis" and "Polyarticular juvenile idiopathic arthritis: Clinical manifestations, diagnosis, and complications".)

SUMMARY

Edema formation in children is a result of one or a combination of the following processes (see 'Pathophysiology of edema' above):

An alteration in capillary hemodynamics that favors the movement of fluid from the vascular space into the interstitium. These alterations include increased capillary hydrostatic pressure, decreased capillary oncotic pressure, and increased capillary permeability.

A defective lymphatic system that fails to return interstitial fluid to the central venous system. Impaired lymphatic transport can be due to maldevelopment, injury, or obstruction of the lymphatic system. (See 'Lymphatic dysfunction/obstruction' above.)

The retention of dietary or intravenously administered sodium and water by the kidneys.

The etiology of edema in children can be classified by pathogenesis (table 1). Understanding and identifying the underlying pathogenesis and cause of the edema can be helpful in the management of these patients. (See 'Etiology' above and "Evaluation and management of edema in children".)

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