Pathologic Cell Injury and Cell Death II – Necrosis

Cell Death:Necrosis


Cell Death

As cellular damage continues, the damage eventually becomes irreversible, after which there is no escape from death for the poor cell. When this occurs, the cell will eventually die, by one of two mechanisms:

  • Necrosis – Pathologic Cell Death
  • Apoptosis – Physiological (usually) Cell Death
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Note that some people also consider autophagy as a method of cell death, but recent studies in fact link this to cell survival.

Necrosis

Necrosis is considered an unregulated and “accidental” form of cell death, caused from exogenous causes associated with damage to cell membranes and loss of ion homeostasis.

Basically, when this damage to membranes is severe, lysosomal enzymes (which we discussed under “Waste Disposal In Cells”), manage to escape the lysosomal membranes and destroy the cell from the inside, causing morphological changes known as necrosis. Furthermore, cell organelles are able to escape via the damaged membrane and into the extracellular space, where they illicit a host reaction, the inflammation associated with necrosis. The lysosomes of leukocytes called in as a result of the inflammatory reaction then also aid in the breakdown of organelles within the cell that have been exuded from it.

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Speaking a little more in depth now:

Cell necrosis is heralded by the loss of the function of the cell permeability barrier, or cell membrane in the case of the cell, meaning that the cell cannot control substances leaving or entering the cell. This holds especially true for ions, most important of which are Na+ and Ca2+, for which the concentration gradients are very steep.

Usually, there are 4 factors required for maintaining the selective ion permeability of the cell:

  1. Considerable amounts of ATP
  2. Structural Integrity of the Phospholipid Bilayer/Cell Membrane
  3. Intact Ion Channel Proteins
  4. Normal association of the Membrane with cytoskeletal elements.

If any of these factors are damaged or interrupted, then the cell isn’t able to maintain normal ionic concentrations within and outside the cell. This is the point of no return for the cell – when it is no longer able to regulate internal ionic concentration.

Special mention must be given to the role of Calcium in cell death. Usually, Ca2+ concentrations inside the cell are 10,000 times lower than Ca2+ concentrations outside the cell (10^-7 M inside vs 10^-3 M outside). Furthermore, several processes within the cell are regulated by very minute changes in Ca2+ concentrations. Thus, once a large influx of Ca2+ occurs, all cell viability is lost and the cell is far beyond the point of no return.

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Let us now talk about some important morphological characteristics of necrotic cells:

1) Increased eosinophilia when a hematoxylin and eosin stain is used, associated with the loss of cytoplasmic RNA (which binds the blue dye, hematoxylin), and increase in denatured protein (which bind the red/pink dye, eosin). Because the blue dye is bound less, it means that necrotic cells under a microscope no longer appear dark purple (blue + red = purple #Colours), but more pale and lighter pink, sometimes called “ghost cells.” Look below and see for yourself: The cells towards the right that are dark purple have not undergone necrosis, but look at the pale, “ghost-like” ones on the left.

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2) Notice from the diagram above that necrotic cells also have a more glossy, homogenous appearance due to loss of glycogen granules.

3) “Moth-eaten” appearance due to digestion of cytoplasmic organelles and increase in vacuolation within the cell.

4) Presence of whorled, phospholipid masses called myelin figures, produced from damaged cell membranes. These myelin figures are then either phagocytosed by other cells, or more importantly, degraded into fatty acids. These fatty acids are significant because they may be calcified to produce “calcium soaps.” We will see the importance of this soon.

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5) Nuclear Changes, which occur in one of 3 patterns:

  1. Karyolysis – which reflects loss of DNA by the action of endonucleases, in which case the basophilia (very dark purple appearance) of chromatin fades.
  2. Pyknosis – which reflects nuclear shrinkage and increased basophilia. In this scenario, the chromatin condenses into a solid, shrunken chromatin mass.
  3. Karyorrhexis – which reflects a scenario where a pyknotic cell undergoes fragmentation into several clumped chromatin strands, after which it disappears.

Usually, the very first nuclear change is pyknosis. Following this, most cells undergoing necrosis proceed directly to karyolysis. Alternatively, some necrotic cells, along with apoptotic cells carry out karyorrhexis after in order to remove the nuclear matter.

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Types of Necrosis:

Now that we know what typical necrosis involves, we can begin to understand that different types of necrosis appear differently in tissues. This is due primarily due to the cause of the necrosis, or the stress that induced the necrosis. There are 6 morphological types of necrosis, along with a clinical 7th type:

Coagulative Necrosis:

This is a type of necrosis in which the external architecture of the cell is preserved for a span of at least a couple days. It is most commonly seen in necrosis associated with conditions of ischemia. Because the external architecture persists, it is highly unlikely this type of necrosis is associated with extremely damaging traumas, destructive acute or chronic immune responses or toxins.

This is because the mechanism that would cause coagulative necrosis would have to be one that damages all parts of the cell, including both structural proteins and enzymes. This means that the external skeleton of the cells are able to persist since the enzymes are also not functioning, for at least a period of time. One of these structural proteins that is able to persist is albumin, which becomes opaque and firm. Eventually, of course, the inflammation that results will cause the skeletons of these cells to be removed by the action of leukocytes, via phagocytosis and the action of leukocytic lysosomal enzymes.

Localized areas of coagulative necrosis manifest as infarcts, in all parts of the body except for the brain and CNS. [This will be explained in the next section].

Under a microscope, it appears as a pale segment of tissue, contrasting against the surrounding well vascularized tissue.

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Liquefactive Necrosis

In contrast to coagulative necrosis, liquefactive necrosis is characterized by literal liquefaction. These cells are completely digested and broken down by the excessive and extreme action of lysosomes and enzymes. Consequently, it is most commonly associated with infection, by focal bacteria and focal fungi. This is because these microbes stimulate the accumulation of a very large number of leukocytes via an immune reaction, and the lysosomal enzymes from these leukocytes destroy a wide range of microbe infected cells.

Even leukocytes begin to die in the vast pool of massive hydrolytic activity that results. (Beware the lysosomes right?) As all these cells are hydrolyzed, finally, a pool of yellow colored pus, results. As the cell debris is drained by other white blood cells, only a fluid filled cyst or space is left, an abscess.

I asked a question earlier: Why doesn’t ischemia in the brain manifest as coagulative necrosis? The reason is because it manifests as liquefactive necrosis, simply because the neurons in the brain simply do not have a very well defined structure. Thus, necrosis simply manifests as liquefactive necrosis as there is no well defined architecture. This literally creates a cavity or a cyst within the brain, and most commonly occurs via occlusion of cerebral arteries.

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Fat Necrosis

Fat necrosis is not specifically a type of necrosis, but rather, specifically refers to focal areas of destruction of lipid deposits in the body by the action of lipases.

It follows then, that this type of necrosis can only occur in cells that contain a very large number of lipid stores or triglycerides, or in tissues that contain a very large amount of lipases.

Basically, it occurs extensively in necrosis of adipose cells, and in the calamity of acute pancreatitis.

When trauma or pancreatitis occurs, lipases are extensively released from the pancreas and small intestine into the extracellular fluid, and these enzymes digest the pancreas itself and surrounding areas of the peritoneal cavity, as well as the triglyceride esters in surrounding adipose tissues. These free fatty acids produced by the action of lipases then bind to Ca2+ ions and become calcium soaps via saponification [Recall the role of myelin figures in this soap formation], which are grossly white, chalky areas, easily identifiable.

Histologically, fat necrosis appears as foci of shadowy outlines of necrotic adipose cells, with basophilic calcium deposits and surrounded by inflammatory reactions.

Caseous Necrosis

This type of necrosis is characteristic of tuberculosis.

It is characterized by an aggregation or accumulation of macrophages or inflammatory cells, known as a granuloma, or tubercles. In the center of such granulomas exist several mononuclear cells such as macrophages and neutroophils that attempt, in vain to kill the tuberculosis causing bacteria, but are killed in the process.

These cells do not retain their outer architecture, as in coagulative necrosis, but are not completely hydrolyzed as well, like in liquefactive necrosis. Thus, they can only be partially broken down, and the remnants become granular. Instead then, they thus persist as structureless collection of amorphous, slightly granular, eosinophilic debris, with fragmented or lysed cells, surrounded by an inflammatory border. Caseous necrosis appears grayish white, soft and friable (easily crumbled), and resembles clumpy cheese, hence the name, “caseous.”

Gangrenous Necrosis

Gangrenous necrosis is not a pathological type of necrosis, but is referred to commonly clinically and thus must be considered. It is typically reserved for use when necrosis, usually coagulative in nature, occurs in a limb, usually the lower limb, in several different planes. Occasionally, there is an infection superimposed onto the necrosis, resulting in liquefaction necrosis occurring on top of coagulation necrosis, and a scenario known as “wet gangrene.”

Because it is very closely related to coagulation necrosis, we can imagine what scenario would produce gangrenous necrosis – severe blood deficiency of ischemia of the limbs, especially lower limbs.

…Yes, we all know how disturbring gangrene can look.

Fibrinoid Necrosis

This is a special type of necrosis seen specifically in immune reactions involving the blood vessels. It occurs when complexes of antigens and antibodies are deposited at the walls of arteries. Deposits of these “immune complexes” coupled with a substance known as fibrin that would have leaked out of arteries forms a bright pink, amorphous (shapeless) appearance in hematoxylin and eosin stains.

It is associated with immune vasculitis, where the immune system attacks blood vessels.

If these immune complexes and fibrin aggregations are not promptly removed from the walls of the arteries, then they attract Calcium ions and induce calcification, which will have serious consequences.

Avascular Necrosis

Avascular necrosis occurs when there is a loss of blood supply to a bone or joint, in which case the cells of the bone or joint die. In the case of the joint, the articular surfaces are damaged.


This diagram wonderfully summaries the causes of each type of necrosis:

Don’t worry guys, all these types will be explained in detail in Mechanisms of Cell Injury, which I will post soon!

That’s all for this one too guys! Next time, I’d be talking about Apoptosis, but for now, enjoy the extra resources!


VIDEOS:

Necrosis vs Apoptosis (Apoptosis is also explained here, even though I did not cover it as yet)

Necrosis by Dr. Rabiul Haque (from. 36:24 onwards)

QUESTIONS:

1. A 63 year old man suddenly experienced substernal pain after a thrombosis of his left anterior descending artery.  Which of the following did he most likely suffer from?

A. Fat Necrosis

B. Coaguative Necrosis

C. Liquefactive Necrosis

D. Gangrenous Necrosis

E. Caseous Necrosis

2. A 68 year old woman suddenly lost consciousness, and when she awoke, she could not speak or move her right arm and leg. There was a large cystic area in her left parietal lobe 2 months later. Which of the following can explain what happened within her brain?

A. Karyolysis

B. Coaguative Necrosis

C. Liquefactive Necrosis

D. Fibrinoid Necrosis

E. Caseous Necrosis

3. This question regards the image below:

A 38 year old woman experienced severe abdominal pain with hypotension and shock that led to her death within 36 hours. Using the image above of an organ within her body, which of the following is the most likely diagnosis?

A. Ischemic Disease

B. Small Intestine Infarction

C. Tuberculosis

D. Gangrenous cholecystitis

E. Acute Pancreatitis

ANSWERS: B, C, E.

[Why E for number 3? – The image demonstrates fat necrosis of the pancreas. A fatal condition that can kill very quickly, acute pancreatitis is the most likely diagnosis as the other options are not associated with an increase in action of lipase enzymes.]

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