Generating a differential diagnosis for edema

A patient presents with distal swelling and you identify it as edema. What mechanisms of edema formation can you think of? In this video, our expert gives you the ultimate guide to the underlying pathophysiology.

John K. Roberts, MD MS MEd
John K. Roberts, MD MS MEd
21st Dec 2021 • 6m read

A patient presents with distal swelling and you identify it as edema. What mechanisms of edema formation can you think of? In this video, our expert gives you the ultimate guide to the underlying pathophysiology.

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Video transcript

Pretend you're seeing a patient with edema. This is the abnormal accumulation of fluid in body tissues, the legs tend to be the most common location where edema develops, patients might also notice weight gain or a change in the appearance of the involved tissue. At the tissue level, edema develops from increased movement of fluid out of the capillary. Let's discuss the variety of factors that could be causing this edema. As you may remember from our last lesson, the variables that guide fluid or movement across the capillary are determined by the starling equation. First, let's start with the leakiness factor.

As you can imagine the leakier the capillary, the more fluid that can flow across its membrane. Some tissue beds have different capillary permeabilities that are built into the system. But what determines how capillary permeability can be changed? The most important factor to discuss is the inflammatory response. In response to tissue injury or infection, the immune system will innately release cytokines, specifically, histamine, bradykinin, interleukin six, and tumor necrosis factor alpha or TNF alpha.

These are all potent cytokines that cause vasodilation and increased capillary permeability. The big picture here is that at sites of inflammation or injury, the body needs to mobilize immune cells, plasma proteins and fluid to the surrounding tissues to deal with the problem. It is important to note the role that glycocalyx plays in capillary permeability. The glycocalyx is a thick layer of mucopolysaccharides associated with proteoglycans and glycosaminoglycans. attached to all cell membranes, it serves as a barrier to keep plasma proteins such as albumin in the vascular space. Inflammation in endothelial injuries such as sepsis can compromise the glycocalyx.

When this layer gets damaged, sigma will go down, leading to more protein leaking across the capillary into the interstitium. This will change the osmotic pressure terms which oppose fluid filtration. So in turn, this will favor the movement of more fluid into surrounding tissues. Therefore, the few things that result in increased capillary permeability relate directly to inflammation. Local tissue injury from trauma or an infection leads to local inflammation and soft tissue swelling. Sustained in systemic inflammation, or sepsis can cause this type of reaction throughout the entire body, leading to a significant amount of fluid accumulation in the interstitial space.

Finally, there is a rare idiopathic disorder called capillary leak syndrome, where a dysregulated immune system causes sudden episodes of cytokine release and capillary permeability throughout the entire body. Next, let's talk about the things that can increase the capillary hydrostatic pressure. These include increased capillary inflow, venous thrombosis or compression, and extracellular fluid volume expansion. Let's start with increased capillary inflow. The most common contributors to increase capillary inflow are dihydropyridine calcium channel blockers, for example, amlodipine, nifedipine, and felodipine.

The capillary beds have pre capillaries sphincters made of smooth muscle that can regulate blood flow into the capillary. These bands of smooth muscle will be relaxed by calcium channel blockers. So if we decrease the pre capillary sphincter tone, we will directly increase the capillary hydrostatic pressure and with a higher PC, there will be an increase net fluid movement across the capillary. Next, let's talk about venous thrombosis or compression. Imagine our capillary schematic, there is still an arterial inflow, but if the outflow is obstructed due to thrombosis or compression. This will increase capillary hydrostatic pressure, which in turn increases the net movement of fluid out of the capillary.

There is something called May Thurner Syndrome in which the right common iliac artery overlays and causes compression of the left common iliac vein. This compression can lead to venous obstruction and left lower limb edema or thrombosis. And of course, any intra abdominal or pelvic tumor mass or fluid collection could compress central veins and cause distal swelling. Venous thrombosis can cause significant swelling in the affected area. Deep vein thrombosis, especially in the lower extremities tends to be unilateral and leads to unilateral symptoms such as edema, erythema and pain. While rare, a complete thrombosis of the inferior vena cava would generate bilateral lower extremity swelling because the pressure in the veins of both legs will be significantly elevated.

Finally, increased central venous pressure can increase the hydrostatic pressure of the capillary. Recall that in normal states, the PC decreases as you go from the arterial end of the capillary to the venous end of the capillary. You might be wondering then how does this affect net fluid movement as you move from one end to the other? The answer is that it limits net fluid movement out into the interstitial space. However, with an elevated central venous pressure, the pressure on the venous end remains elevated. Therefore, pressures in the capillary remain higher for longer leading to a net increase in fluid moving out of the capillary.

The next variable to consider that increases fluid movement across a capillary is the oncotic pressure. Oncotic pressure also known as colloid osmotic pressure is the pressure caused by proteins, such as albumin, that pull fluid towards themselves. We will start with the plasma oncotic pressure. It is important to note that the oncotic pressure of the capillary opposes the filtration of fluid out of the capillary. As previously mentioned, albumin contributes the most to oncotic pressure. If the plasma albumin concentration is decreased, then there was a net increase in the filtration of fluid out of a capillary. Sometimes patients present with low albumin levels in their blood, this is called hypoalbuminemia. Why would someone develop hypoalbuminemia?hypoalbuminemia can result from loss of liver synthetic function.

This is often seen in patients with cirrhosis or in stage liver disease. Other high risk groups are patients with severe protein calorie malnutrition, critical illnesses or sustained inflammation. Part of this may be due to the high vascular permeability, loss of the glycocalyx and the inability to effectively keep albumin in the vascular space. Now that we've discussed the plasma oncotic pressure, let's examine the interstitial oncotic pressure. Don't forget oncotic pressure of the capillary opposes the filtration of fluid out of the capillary. There are several rare conditions in which connected tissue molecules accumulate in the interstitial spaces, generating tissue oncotic pressure, which in turn pulls fluid from the capillary.

One of these conditions is called generalized myxedema. General myxedema is seen in patients with hypothyroidism and it is due to the dermal accumulation of mucopolysaccharides and other proteins. Pretibial myxedema is confined to the pretibial area, as seen in patients with Graves disease, and it is caused by this dermal accumulation of mucopolysaccharides. scleromyxedema is a rare condition associated with mucopolysaccharide deposition and increased tissue fibrosis.

Finally, remember that there is net filtration of fluid across normal capillary membranes, and this fluid returns to the vascular space via the lymphatic system. If there is lymphatic obstruction, the patient develops lymphedema. Lymphedema is seen with morbid obesity, surgical removal of lymph nodes or lymphatics, radiation treatment, malignant infiltration of lymphatics and some tropical parasitic infections like filariasis.

So, for our patient with edema, we have to consider a wide differential across all these categories. Inflammation that mediates capillary permeability, things that increase capillary hydrostatic pressure, either through increased inflow or decreased outflow, a decrease in plasma oncotic pressure from hypoalbuminemia, increased tissue oncotic pressure for myxedema or inadequate lymphatic drainage leading to lymphedema. Returning to our original patient, we have now studied all the variables that could cause edema.