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BVSc3 General Path

Aetiology is the cause of a disease.

What does aetiology mean?

Pathogenesis is the mechanism of development of a disease.

What does pathogenesis mean?

Aetiological agents act the cellular level, disrupting homeostasis, initiating the pathogenesis, a sequence of events that develop the disease.

How are aetiology and pathogenesis related?

Cellular injury occurs when the stress of an aetiological agent is too severe for the cell to adapt.

When does cellular injury occur?

Potentially reversible - degenerative
Irreversible - necrosis & apoptosis

What forms of cellular injury can occur? Are they reversible or non-reversible?

Non-lethal, potentially reversible cellular damage.

What is cellular degeneration?

It is only reversible if the trauma ceases, membrane damage is repaired and oxygen is supplied BEFORE the point of no return.

Why is cellular degeneration only "potentially reversible"?

Due to membrane changes, water enters cells and dilutes the cytoplasm, resulting in a slight swelling and paleness.

What is cloudy swelling?

No changes are visible.

What can be seen microscopically with cloudy swelling? Why?

Water moves into cells forming large fluid-filled vacuoles. Pale colour.

What is hydropic/vacuolar degeneration?

Swelling of the cell due to loss of ion and fluid homeostasis.

What can be seen microscopically with hydropic/vacuolar degeneration? Why?

Fatty change is a TYPE of vacuolar degeneration.
An abnormal accumulation of triglycerides/cholesterol/phospholipids within vacuoles of parenchymal cells.

What is fatty change?

Usually in parenchymal cells of the liver, although it can also occur in cardiac muscle, skeletal muscle and kidney.

Where does fatty change occur?

Hepatic lipidosis.

What is another term for fatty change occuring in the liver?

Toxins, protein malnutrition, starvation, diabetes mellitus, obesity, anoxia (and alcohol abuse).

What are some possible aetiologies of fatty change?

From adipose tissue, in chylomicrons or via the portal blood from the gut.

How are fatty acids normally delivered to the liver?

Some are used for hepatic mitochondria, but most are converted to triglycerides, which are processed into lipoproteins and secereted as very-low-density-lipoproteins (VLDL). They are transported to muscle/adipose tissue via the blood and hydrolysed.

How are fatty acids processed in the liver?

If there is a defect in one of three steps: fatty acid uptake/catabolism/secretion.

Why will fatty change occur?

If there is a rapid or excessive release of FFA from adipose tissue, there will be an excess delivered to the liver where it cannot be be utilised and is stored instead.

What is a possible defect of fatty acid uptake in the liver that can cause fatty change? Why might this occur?

Decreased utilisation or oxidation of FFA as a result of damaged hepatocytes (anoxia, toxins) or due to a co-factor deficiency that interrupts the catabolic pathway.

What is a possible defect of fatty acid catabolism in the liver that can cause fatty change? Why might this occur?

Lipotrope/troph deficiency - required for apoprotein synthesis.
Protein deficiency - impairs apoprotein synthesis, inhibits lipoprotein synthesis, so fat cannot be excreted.

What is a possible defect of fatty acid secretion in the liver that can cause fatty change? Why might this occur?

By freezing the tissue sample and staining with oil red O; fat will turn red.

How can you distinguish between fluid and fat filled vacuoles post mortem?

Normally, a liver should be dark brown/red.
A fatty liver will be enlarged, yellow and greasy.

Grossly, how would you expect a fatty liver to look?
How should it look normally?

Accidental cell death that is ALWAYS pathological.

What is necrosis?

Hypoxia, toxins, free radicals, trauma.

What are some possible aetiologies of necrosis?

The aetiological agents cause:
-irreversible mitochondrial damage
-severe disruption to membrane function

What is the effect of aetiological agents in necrosis?

Mitochondrial and lysosomal enzymes enter the cytoplasm and begin digesting cellular contents.

How does disruption of membrane function cause necrosis?

Due to a lack of ATP to supply energy to ion pumps, there is a high influx of Ca2+ that activates catabolic enzymes which break down the cell and cause local inflammation.

What is the effect of cellular and mitochondrial membrane damage in necrosis? Why?

Catabolic enzymes, such as:
-phospholipase, causing membrane degradation.
-ATPases, depleting ATP levels further.
-proteases, breaking down membranes and cytoskeleton.
-endonucleases, breaking down DNA.

What enzymes are activated by ceullar Ca2+ influx in necrosis?

Dead cells leak inflammatory mediators.

How does necrosis cause inflammation?

- If necrosis occurs too quickly, no time for mediators.
- Some organs do not become inflammed, e.g., the liver. Unknown why.

When does necrosis not cause inflammation?

The tissue is usually pale, soft and friable (crumbles easily). If a focus of necrotic tissue in an otherwise viable organ, necrotic area is sharply demarcated, often with peripheral red rim due to increased blood flow.

What gross morphologic changes are expected in necrosis?

Cell appearance varies depending on type, cause and duration.
Cytoplasm often swollen, cells eosinophilic (very pink) and detached.

What microscopic morphologic changes are expected in necrosis?

Pyknosis, karyorrhexis and karyolysis.

What nuclear changes may be observed in necrosis?

Condensed chromatin.

What is pyknosis?

Rupture of the nuclear membrane, nucleus begins to fragment.

What is karyorrhexis?

Nucleus lyses completely, only a ghost outline may remain.

What is karyolysis?

Karyolysis. Complete dissolution of nuclear membrane.

What is occurring here?

Karyorrhexis. Nuclear membrane breaks down.

What is occurring here?

Pyknosis. Condensation of nuclear chromatin.

What is occurring here?

Coagulative, liquefactive, caseous, gangrenous and fat necrosis.

What are the different patterns of necrosis?

Depnends on the tissue, aetiology and duration of necrosis.

What determines the type of necrosis?

Usually due to hypoxic injury, due to ischaemia.

Why does coagulative necrosis occur?

Gross - tissue is firm and pale.
Micro - Basic cell outline remains.

What gross and micro morphological changes are present in coagulative necrosis?

No. Proteins become denatured, which includes enzymes, so proteolysis stops.

Do cells rupture in coagulative necrosis?

Nuclear and cytoplasmic debris.

What is caseous necrosis composed of?

Caseous is more chronic, with a loss of cellular architecture, and is often calcified.

How does caseous necrosis compare to coagulative?

In tuberculosis.

When is caseous necrosis common?

Gross - granular, friable (crumbly), white/cream. Supposed to resemble cottage cheese!
Micro - Tissue architecture oblitered, coagulated cells surround by granulomatous reaction.

What gross and micro morphological changes are present in caseous necrosis?

Complete tissue obliteration, no visible architecture left.

Do cells rupture in caseous necrosis?

Occurs in the CNS and also in, e.g., abscesses/bacterial infections.
This is due to the high lipid content and little connective tissue - structure disintegrates easily.

Where does liquefactive necrosis occur? Why?

May occur after coagulative necrosis. Once neutrophils arrive, enzymatic digestion/liquefaction of tissue.

What might liquefactive necrosis follow? Why?

Gross - cavity filled with liquid, viscous mass e.g. pus.
Micro - NO normal architecture as enzyme digestion dominates and all cells are digested. Background of eosinophilic and nuclear debris.

What gross and micro morphological changes are present in liquefactive necrosis?

A TYPE of coagulative necrosis. A clinical term that is often applied to an extremity that has lost blood supply and developed coagulative.

What is gangrenous necrosis?

Dry gangrene - tissues are dry and there is no bacterial growth. Tissues look mummified, black/brown and crispy.
Wet gangrene - progression to liquefactive necrosis.
Gas gangrene - bacterial infection producing gas within tissues.

How many types of gangrenous necrosis are there?

Focal areas of adipose tissue destruction.

What is fat necrosis?

Usually due to the release of pancreatic lipases during pancreatitis or pancreatic necrosis. FFAs combine with Ca2+ to form soaps. Can also be:
-trauma e.g. fat is crushed during first time calving heifers, blood supply is cut off.
-lipomatosis in cattle.

Why does fat necrosis occur?

Gross - white/cream, firm and chalky.
Micro - nuclei are lost, adipocytes maintain eosinophilic outline, calcified basophilic tissue.

What gross and micro morphological changes are present in fat necrosis?

Necrotic cells and debris usually 'disappear' due to enzymatic digestion, followed by phagocytosis by neutrophils and macrophages.

What will happen to necrotic cells following necrosis?

Necrotic tissue may become encapsulated in or fibrous tissue (e.g. abscess), replaced or occasionally regenerated in certain tissues.

What will happen to necrotic tissue following necrosis?

If necrotic tissue sequestrated, an isolated mass of tissue is formed (a sequestrum). Most likely to be bone, which may fragment and pass out via sinus tract if small enough.

What sequestration might occur in necrosis? What tissue is this likely to be?

There may be desquamation or sloughing off.

What will happen to surface necrotic tissue?

Usually deposition of calcium (and other minerals). Causes dystrophic calcification.

What happens if necrotic tissue is not promptly removed?

Autolysis - cell/tissue degeneration occuring post mortem (but no inflammation).

With what might necrosis be confused during a post mortem exam?

Occuring post mortem, autolysis is celluar/tissue degeneration that occurs due to the release of lysosomal enzymes. Occurs faster in warmer conditions.

What is autolysis and when does it occur?

It doesn't; there is no blood flow.

How does autolysis cause inflamamtion?

If PM exam not occuring immediately after death, the tissue should be chilled (not frozen, as ice crystals form).
Fixation of tissue halts autolysis by denaturing proteins (including enzymes).

How is autolysis slowed or stopped?

Putrefaction; invasion of bacterial colonies which produce gas, destroying tissue architecture.

Aside from autolysis, what other process is likely to occur post mortem?

Apoptosis is programmed cell death that may be physiological or pathogical.

What is apoptosis?

In tumours, allowing excessive cell replication and accumulation.

When might you have decreased apoptosis?

-activation of genes prematurely.
-activation of genes that are normally suppressed.
-induced by cytotoxic T-cells, e.g., viral infected cells.

What pathological causes of apoptosis are there?

Inflammatory mediators, DNA damage, mitochondrial damage, T-cells.

What are some possible aetiologies of apoptosis?

Two phases:
i) initiation phase - activation of caspases, proteolytic enzymes.
ii) execution phase - caspases cause cell death by activating proteases and endonucleases.

What is the process of apoptosis?

Apoptosis is an energy dependent process.

What does apoptosis require?

It doesn't; no inflammatory mediators are released.

How does apoptosis cause inflammation?

Phagocytosis of the cell; the cell membrane remains intact until the end stages, but is altered to allow phagocytic recognition.

What is the final stage of apoptosis?

Groups of cells, due to leakage of cellular enzymes.

How many cells are affected by necrosis?

Individual cells only.

How many cells are affected by apoptosis?

Necroptosis is a combination of apoptosis and necrosis.

What is necroptosis?

In the event of apoptosis failing (i.e. elimination of T-cells), necroptosis can be considered a back up, as programmed necrosis.

What is the purpose of necroptosis?

Coagulative necrosis - bovine kidney

What is occurring here?

Liquefactive necrosis - abscess.

What is occurring here?

Fat necrosis.

What is occurring here?

Caseous necrosis.

What is occurring here?

Caseous necrosis - ovine lymph node.

What is occurring here?

Coagulative necrosis - bovine kidney (cut open)

What is occurring here?

Gangrenous necrosis - porcine.

What is occurring here?

Coagulative necrosis - kidney

What is occurring here?

Fat necrosis.

What is occurring here?

Gangrenous necrosis.

What is occurring here?

Liquefactive necrosis.

What is occurring here?

Hepatic lipidosis.

What is occurring here?

Hepatic lipidosis - tissue has been frozen and stained with oil red O. Red is indicative of fat.

What does this tissue sample show?

Hepatocyte degeneration. RHS normal, LHS shows swelling of cells and large vacuoles.

What is occurring here?

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