Tissue edema is characterized by an excess of fluid entering the interstitium due to several principles: increased capillary pressure, decreased capillary oncotic pressure, increased capillary permeability. These fluid volume changes are represented as Starling forces which describe how fluid flows in capillaries. Common causes of transudative edema are congestive heart failure, nephrotic syndromes, and distributive shock. Common causes of exudative edema are lymphatic blockage secondary to malignancy or surgery.
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Focal segmental glomerulosclerosis

Image: “Very high magnification micrograph of focal segmental glomerulosclerosis, hilar variant.” by Nephron – Own work. License: CC BY-SA 3.0


Starling’s Law of the Capillary

Starling’s laws represent the movement of fluid across a capillary membrane. The law is represented by four different forces:

  1. Capillary fluid pressure (CP) forces fluid out of the capillary, can be referred to as capillary hydrostatic pressure.
  2. Interstitial fluid pressure (IP) forces fluid into the capillary.
  3. Plasma colloid osmotic pressure (PCOP) pulls fluid into capillary.
  4. Interstitial fluid colloid osmotic pressure (IFCO) pulls fluid out of capillary.

These forces can be represented as an equation for the net filtration pressure:

Net Filtration Pressure = [(CP – IP0)] – (PCOP – IFCO)]

On top of the Starling forces, the capillaries themselves have a constant for permeability (CAPp) which represents filtration.

From the Net filtration pressure and CAPp you can calculate the net fluid flow:

Net Fluid Flow = (Net Filtration Pressure) (CAPp)

Transudate vs exudate: when fluid leaves the capillaries it can become one of two forms – a transudate or exudate. A transudate is excess fluid that is protein poor due to increased capillary pressure. It will have a low specific gravity <1.012, a fluid protein to serum ratio <0.5, and LDH 1.012, a fluid protein to serum ratio of >0.5, and LDH >0.6.

Edema

Edema is a common topic when it comes to fluid flow within capillaries. It can be thought of as excess fluid that has entered into the interstitium of the surrounding tissue. There are two forms of tissue edema that you will hear about: pitting and non-pitting.

Pitting and non-pitting tissue edema

Pitting edema during and after the application of pressure to the skin.

Image: “Pitting edema during and after the application of pressure to the skin.” by James Heilman, MD. License: CC BY-SA 3.0

Pitting edema is caused by excess fluid without extra colloid. Non-pitting is the inverse where there is an excess of colloid.

The difference can be detected clinically by applying tactile pressure for a sustained period of time to an area over a bone such as the lateral malleolus of the ankle. The force presses the fluid out of the tissue and into the surrounding interstitium leaving behind an divot or pit in the skin.

Non-pitting edema is usually caused by lymphatic problems that have lead to blockage. When you apply pressure to non-pitting edema such as on the lateral malleolus the fluid will not leave the tissue because the protein keeps it in place. An impression that quickly resolves will be seen.

Common Causes of Edema

Edema is caused primarily by the following pathophysical states:

  • Increased capillary fluid pressure as seen in heart failure
  • Decreased plasma oncotic pressure due to loss of proteins as seen in nephrotic syndrome and liver failure
  • Increased capillary permeability as seen in burns, sepsis, and response to toxins
  • Increased interstitial fluid colloid osmotic pressure as seen in cases of lymphatic blockage

Heart failure is a condition in which the heart is unable to pump enough blood to the rest of the body. For the USMLE it is divided into two categories of left and right heart failure.

Left sided heart failure is characterized by a failure of the left ventricle to be able to pump blood to the rest of the body. This failure results in a backup of blood within the pulmonary system. Signs and symptoms include pulmonary edema, orthopnea, and paroxysmal nocturnal dyspnea.

Pulmonary edema in left sided heart failure is due to an increase in capillary pressure and an increase in pulmonary venous pressure. This increase in pressure pushes a transudate into the interstitium and then finally into the alveoli. There are three stages of pulmonary edema.

  1. Left atrial pressure increase results in an opening of pulmonary vessels. It does not result in a deterioration of oxygen saturation.
  2. There is a shift of transudate into the interstitium of the lungs. The lymphatic system picks up the excess fluid and is able to manage it in most cases. In the deep regions of the lung, fluid can accumulate and compress small airways.
  3. Continuation from stage 2 where fluid continues to fill the more interstitial spaces. In most patients there can accumulate up to 0.5L of fluid. Eventually, the fluid can cross into the alveoli. This results in significant problems with gas exchange. The patient will become hypoxemic and can also cough up pink frothy sputum.

In addition to heart failure, other causes include alveolar capillary barrier damage or idiopathic causes. Eventually pulmonary edema can lead to respiratory fatigue and failure.

Diagnosis can be made with chest x-ray which would show hilary prominency and patchy infiltrates throughout the lungs. Treatment will include oxygen support, diuretic (Furosemide), and a low salt diet.

Right sided heart failure is characterized by failure of the right ventricle to pump blood to the pulmonary system. This results in blood building up in the liver and the periphery. Signs and symptoms include increased jugular venous distension, peripheral edema, and hepatomegaly.

Peripheral edema will occur in right sided heart failure. Increased capillary pressure results in a cosmetically undesirable swelling bilaterally in the lower extremities. In bed bound patients, they can have pitting edema on the back. It is pitting due to it having a low colloid content.

Signs and symptoms include swollen lower extremities, difficulty with ambulation, stasis dermatitis, and lasting tense edema. Treatment can include positional changes where the lower limbs are elevated for 30 minutes up to four times a day, compression stockings, and a reduction in dietary salt intake. Medical treatment includes diuretics such as furosemide.

Diseases that result in protein wasting cause a loss of capillary osmotic pressure and result in fluid leaving the capillaries and entering the interstitium.

Nephrotic Syndrome

Nephrotic syndrome is a group of conditions that lead to approximately 3-3.5 grams of protein lost in the urine (proteinuria) in a 24 hour period. The loss of protein leads to a lower albumin level and subsequent edema due to loss of capillary oncotic pressure.

For the USMLE you should know the difference between the primary (disease of the kidney) and secondary causes (from a systemic illness) of nephrotic syndrome. You should review further each of the causes and know their pattern on path imaging and pathophysiology.

Focal segmental glomerulosclerosis

Image: “Intermediate magnification micrograph of focal segmental glomerulosclerosis, hilar variant.” by Nephron – Own work. License: CC BY-SA 3.0

Primary causes

Focal segmental glomerulosclerosis is the most common form of nephrotic syndrome seen in african americans and hispanics. It is characterized by segmental sclerosis and hyalinosis on histology.

Minimal change nephropathy is seen in the pediatric population. Usually occurs after a recent infection or immunization. The children will look puffy in the face, particularly in the periorbital. Path imaging will show minimal change of the glomeruli. Treatment is done with steroids.

Membranous nephropathy is the number one nephrotic syndrome seen in caucasians. It is caused by Phospholipase A2 antibodies, response to NSAIDS, HBV, or HCV. Leads to chronic renal disease.

Secondary causes

Amyloidosis: Amyloid deposits secondary to multiple myeloma, TB, rheumatoid arthritis. Stain apple green with congo red stain.

Diabetic glomerulonephropathy results from glycosylation of the glomerular basement membrane which results in diffuse mesangial expansion in the glomeruli. ACE inhibitors help to reduce kidney injury by preventing hyperfiltration.

Liver cirrhosis leads to a portal hypertension which can result in ascites. The ascites is a transudate due to an increased amount of fluid entering the space of disse. Signs and symptoms include abdominal distension, shifting dullness, and an enlarged flank. Paracentesis to check the protein levels will show protein that is less than 2.5g/dL. Treatment involves low salt diet, diuretic, and in severe cases the fluid must be drained.

Increased capillary permeability is seen in conditions such as distributive shock. It results in a serious condition where there is a physiological state of low systemic vascular resistance and high cardiac output. There are several types of distributive shock you should know for the USMLE.

Septic Shock

For the USMLE, it is important to remember that septic shock originates from SIRS. SIRS has four criteria whereby only two are needed to make a diagnosis of SIRS: temperature greater than 38C or less than 36C, tachycardia, respiratory rate greater than 20, leukocytosis (greater than 12,000/uL) or leukopenia (less than 4000/uL).

It is defined as sepsis if two blood cultures come back positive for bacterial growth. It then becomes septic shock when there is hypotension that results from circulatory compromise with cell and metabolic abnormalities. Patients will present with a high cardiac output, severe hypotension, a widened pulse pressure, normal capillary refill, and warm extremities. The blood pressure also does not correct with the administration of IV fluids. Treatment includes antibiotics, IV fluids, and vasopressors such as norepinephrine.

Anaphylaxis is another form of distributive shock where there is an IgE mediated mast cell and basophil mediator release. Causes of anaphylaxis include food and animal allergies.

These mediators result in smooth muscle spasm, vasodilation, vascular permeability. In the bronchus there is an increase in secretions and smooth muscle tone.

The vascular effects include decreased vascular tone and increased capillary permeability. These result in hypotension and vasodilation. Vascular fluid can rapidly shift to the interstitium within 10 minutes of the onset of anaphylaxis.

Anaphylaxis is a medical emergency that needs to be treated rapidly in severe cases. Proper airway management, fluid resuscitation, and the administration of epinephrine intravenously or intramuscularly.

Toxic shock syndrome is associated with tampon use in females that are kept in for a longer than the recommended period of time. The most common infection is from Staph aureus and Strep pyogenes. These bacteria release a toxin that is absorbed by the patient. The toxin they produce acts as a superantigen that binds to T cells to cause a large cytokine release. Signs and symptoms are fever, rash, hypotension, desquamation, and can lead to multi organ failure.

Burns depending upon their severity will cause different levels of edema. Burns that are greater than ~30% of the total body surface area create a condition where blood plasma can leak out of capillaries due to inflammatory mediators. Within 8 hours of a large burn the patient can have hypovolemia and hypoproteinemia. Prompt fluid resuscitation is needed to treat as well as thermal regulation.

USMLE pearl: You may get a question about estimating total body surface area based upon burn location. The rule of 9’s is a quick and well supported method to determine how much of the body is burned. The head is 9%, Each arm is 9%, the trunk’s front and back are 18% individually, each leg is 18%, and finally the genitals make up 1%. You should review a diagram of this for visual reference.

Lymphedema

Interstitial fluid colloid osmotic pressure increases result in conditions such as lymphedema.

Lymphedema is characterized by an increase in protein content within the interstitium that is due to obstruction of the normal lymphatic drainage. The excess protein pulls water with it generating swollen non-pitting soft tissue. Normally the lymphatic system serves as a way to return excess protein from the interstitium to the venous circulation. Blockage results in large amounts of protein being trapped in the interstitium and can generate a fluid concentration 1-5.5g/mL.

CT of axillary lymphadenopathy

Image: “CT scan of axillary lymphadenopathy in a 57 year old man with multiple myeloma.” by Mikael Häggström – Own work. License: CC0 1.0

Patients can present with skin changes of peau d’orange and elephantiasis. Causes occur from congenital hypoplasia of lymphatics (Milroy disease), malignancy, obesity, or from surgery.

  • Malignancy that metastasizes can lead to blockage and conversely surgery to remove tumor and lymph nodes paired with radiotherapy can lead to lymphadenopathy. This is very commonly seen in breast cancer.

Treatment for lymphadenopathy depends upon its etiology. With infections or malignancy treatment can restore function. In case of congenital or fibrosis lymphatics life long treatment with physical therapy and wrapping of the affecting limb. Often the overlying skin can have trophic changes which make it more vulnerable to infection and proper skin care is needed to avoid them.

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