Necrosis

What are the nuclear changes in necrosis?

1. Karyolysis = fading of staining due to chromatin digestion. 2. Karyorrhexis = nuclear fragmentation of a pyknotic nucleus. 3. Pyknosis = nuclear shrinkage with increased staining. 4. Total loss of nuclei.

What does chronic cell stress due to prolonged injury of low intensity lead to?

Cellular adaptations such as atrophy, hypertrophy, and intracellular accumulations.

Cytoplasmic changes in necrosis?

Coagulation of cytoplasmic proteins is the most common morphologic change associated with necrosis. Protein coagulation is best seen when frying an egg! Note how the clear white of the uncooked egg changes as heating progresses during frying. The end result is a dense, opaque, white coagulation of protein. Proteolytic enzymes released from ruptured lysosomes and by calcium ion activation leads to similar protein denaturation. Necrotic myocardium has a denser pink staining!!! Necrotic is darker!

What is the likeliest morphologic change seen at autopsy 48 hours after an MI?

Coagulative necrosis (cell death is due to ischemic injury from an occluded coronary artery)

Changes in heart myocardium at the margin of ischemic injury?

Demonstrates the progression from normal to necrosis. On the left is normal. The nuclei are in the center of the myocytes and there's no cytoplasmic alteration. To the right is an area of *hydropic change*. The nuclei are still in the middle of the myocytes, but now they're swollen and vacuolated due to intracellular accumulation of water, but they're not dead.

What would you expect to see in the kidney of this patient? (who had recent myocardial infarction)?

Hydropic change (there would be a reduction of blood flow to the kidneys due to heart injury. This would cause hypoxic injury of the renal cells)

What compensatory change would the remaining myocardial cells exhibit if the patient had lived following an MI?

Hypertrophy (This is associated with increased functional demand. The myocytes have to enlarge to maintain normal cardiac function. The next slide demonstrates this)

Identify the following nuclear changes in this image of coagulative necrosis of heart muscle following ischemic injury?

Red = karyolysis Blue = protein coagulation Yellow = karyorexis Black = pyknosis Green = acute inflammation

What is fat necrosis?

*Omentum in pancreatitis* Fat necrosis is often associated with pancreatitis and can also be seen in direct trauma to adipose tissue. The gross appearance is that of chalky white-yellow plaques in adipose tissue. Low mag of pancreatitis inflammation of the pancreas. A = normal pancreas. B = area of inflammation fibrosis and damaged pancreatic parenchyma. C refers to fat necrosis. In fat necrosis the ruptured fat cells (dead adipocytes) release FA that are degraded by lipases from the damaged pancreatic acinar cells. Deposition of Ca2+ yields blue hued *soap bubble* appearance or *saponification*.

What are the morphologic types of necrosis?

- Coagulative necrosis - Liquefactive necrosis - Fat necrosis - Caseous necrosis

What are the etiologies of necrosis?

- Ischemic injury (like a blood clot in an artery supplying the heart or brain) - Cancer - Chemical injury - Unaltered chemicals may directly injure cells (e.g. Hg, CN) - Metabolites of P-450 mixed function oxidases metabolism may result in toxic intermediates or metabolites (e.g. CCl4 or acetaminophen) that damage cells. - Infections such as TB

Sequela (possibilities) of necrosis?

- Scarring and loss of organ function - Inflammation - Formation of ulcers and cavitary lesions - Calcification - Resolution (we'd like this!) - Autoimmune response due to tissue destruction release of self-antigen (we'd NOT like to see this!)

Define necrosis?

A morphologic expression of cell death resulting from different patterns of lysosomal enzyme degradation of cells and ECM, the type of necrotic debris, and by bacterial products when present. It's a morphologic expression of cell death!

What does necrosis result from?

ACUTE, high-intensity cell injury Necrosis is *always pathologic* while apoptosis may be physiologically programmed or pathologic. Think of the changing colors of the leaves in the fall as apoptosis and a forest fire as necrosis!

Caseous necrosis?

Lung TB! Caseating necrosis is a form of coagulative that gets its name from the appearance of the gross specimen as seen in this lung with a large, cream-colored, cottage cheese-like, apical mass. Classically, caseating necrosis is associated with *M. tuberculosis infections*. The microscopic appearance of caseating necrosis is that of destruction of tissue architecture combined with an irregular, round mass, whose center is an eosinophilic, amorphous, acellular debris surrounded by *granulomatous inflammation with its multinucleated giant cell*. The effect is that of an ovoid mass or masses. Think soft center cookie!

Which one of the following inflammatory cells would characterize the inflammatory response in a patient with a MI after 5 weeks?

Macrophages (these cells replace the neutrophils and orchestrate the healing/repair process that leads to scar formation) - you'd see neutrophils 1-3 days after

What is coagulative necrosis?

Most common! Results from ischemic injury of tissue. Black arrow = neutrophils, the acute inflammatory response! Picture the myocardium with the dark brown area that is dead. Compare this to the lighter colored uninvolved myocardium! This is due to *ischemia* secondary to *atherosclerosis*. *Ischemic injury* is a very common cause of coagulative necrosis. *Drugs* are another cause.

What is liquefactive necrosis? Etiology?

Think abscess! Clinical example of an abscess before and during draining of the pus. The etiology of liquefactive necrosis includes *purulent* (pus producing) bacterial and fungal infections, as well as ischemia injury of the brain. Associated with rapid digestion of the stroma (= the supportive tissue of an epithelial organ, tumor, gonad, etc., consisting of connective tissues and blood vessels.) by lysosomal enzymes released from neutrophils. The released lysosomal enzymes digest (*liquefy*) the tissue beyond the ability for repair, often leading to formation of an abscess. In image: cellular debris and acute inflammatory cells that characterize these lesions!

How is coagulative necrosis characterized?

This is an example of coagulative necrosis as seen in an acute MI that is 24-36 hours old. Intact myocardial muscle cells are present in the lower left corner -- note their intact nuclei and light pink staining cytoplasm. Characterized by: 1. Initial retention of the cell outline (think of a tombstone) 2. Karolysis is the prominent nuclear change 3. Hypereosinophilic staining of the cytoplasm is indicative of protein denaturation. At this EARLY stage of MI, there's no inflammatory response. An acute inflammatory response occurs after 24 hours. Coagulative necrosis is characterized by acute inflammatory response to cell death. The presence of *neutrophils* (aka polys, PMNs) -- the little black dots -- define this as *acute inflammation*. Neutrophils are the *first cells to arrive* usually after *18 hours* at the site of the cell injury. Neutrophils begin the destruction of the dead cells! *They live for about 24 hours* and are *replaced by macrophages*. Destruction of the dead cells is accomplished by cellular phagocytosis and intracellular digestion and by their release of proteolytic enzymes, especially when the neutrophils die after 24 hours.

What are the membrane changes in necrosis?

With progressive injury, there is a breakdown of plasma membrane, organelles, and nucleus; leakage of contents. There's amorphous densities in the mitochondria. Myelin figures. Inflammation. The permeability of the plasma membrane is significantly altered during necrosis. The first changes involve cell swelling. With progressive injury comes an influx of Ca2+ ions from the extracellular fluid into the cytoplasm and activation of various enzymes that leads a breakdown of the plasma membrane and cellular organelles and the release of cytoplasmic molecules into the extracellular fluid. We use these cellular proteins as a biomarker of injury to specific cells. The injured cells also release numerous factors that stimulate an inflammatory response. The morphology of this response -- either acute or chronic depending on the etiology -- helps to define the type of necrosis. In the case of ischemic myocardial injury, the inflammatory response is characterized by *neutrophils* which are then replaced by *macrophages*.