1.03 Ischaemia

Question 1

Define: Hypoxia

Answer 1

Decreased availability of oxygen to tissues

Question 2

Define: Ischaemia

Answer 2

Loss of blood supply from major acute arterial cause or significant decrease in venous drainage

Question 3

What is the difference between hypoxia and ischaemia?

Answer 3

Hypoxia compromises aerobic oxidative metabolism, while ischaemia reduces other substrates (e.g. glucose) as well

Question 4

What are some causes of cellular injury?

Answer 4

Oxygen deprivation
Physical agents (mechanical trauma, temperature, radiation, electric shock)
Chemical agents
Infections agents
Immunologic reactions
Genetic metabolic abnormalities (accumulation of toxic metabolite)
Nutritional imbalances

Question 5

What factors cause some insults to be worse than others?

Answer 5

Site
Environment at time of insult
Magnitude
Rapidity/duration of application
Mechanism of action of the potential injurious agent

Question 6

Describe how the site of the insult affects the severity of the insult

Answer 6

Organ characteristics
- Liver has huge redundancy (designed to cope with huge influx post-prandially. Can loose 90% of the liver before knowing you have liver disease), CNS very little (Some quiet areas of the brain but largely no redundancy)

Question 7

Describe how the environment at the time of the insult affects the severity of the insult

Answer 7

Existing hypoxia (subclinical), add large cardiac arrhythmia (abnormal beat) such that perfusion of the liver is altered –> liver ischaemic damage

Question 8

What are the two possible consequences of cellular injury?

Answer 8

Reversible Cell Injury
- Removal of agent may result in full cell recovery - structure and function OR
- Cell remains viable but appearance and/or function altered
Irreversible Cell Injury (i.e. concept of point of no return)
- Necrosis OR
- Apoptosis

Question 9

What are the common elements in cellular injury?

Answer 9

These happen to different degrees depending upon insult:

• Depletion of ATP in affected cells
• Production of activated oxygen species and free radicals (will attack membrane)
• Increased intracellular calcium and loss of homeostasis
• Increased membrane permeability (as a consequence of all these events)
• Mitochondrial damage

Question 10

Describe Hypoxia

Answer 10

Decreased oxygen to cell (tissue or organ)
Possible causes include:
- Low pO2 of blood (anaemia, high altitude)
- Constriction of artery developing slowly (plaques)
- Pulmonary disease with poor gas transfer
- Environmental pO2 (high altitude)
Depending on severity, cells may adapt, be injured or die

Question 11

What are the cellular changes in reversible cell injury?

Answer 11

Decreased mitochondrial function –> decreased ATP production
ATP dependent enzymes immediately affected (Na+/K+- ATPase) –> intracellular increase in tonicity, water moves in –> cell swells –> ATP deficit become worse
Increased intracellular Ca2+ –> activates cellular phospholipases
Anaerobic metabolism –> decreases intracellular pH

Question 12

What are the consequences of the cellular changes in reversible cell injury

Answer 12

Ribosomes detach from endoplasmic reticule –> decreased protein synthesis
Cytoskeleton affected including loss of microvilli
Early mitochondrial swelling
Lipid deposition
In cardiac cells, if anoxic for 60 sec, contraction stops

Question 13

What happens if circulation is restored early enough to prevent irreversible cell injury?

Answer 13

Ischaemia-reperfusion injury
Reintroduction of oxygen may result in more cell death
Mechanisms:
- Free radical production (from infiltrating leukocytes, damaged endothelium, mitochondria)
- Made worse by released transition metals (iron, copper)
- Loss of anti-oxidant protection
- Cytokine production

Question 14

What are the cellular changes in irreversible cell injury?

Answer 14

Calcium influx++
pH changes
lysosomal membrane allow enzyme leak (proteolysis)
cell membrane integrity altered
Detection of cytoplasmic contents in plasma usefully diagnostically

Question 15

Describe Necrosis

Answer 15

Necrotic cells stain differently as well as losing morphological appearance
Nucleus changes - Becomes shrunken and then very shrunken and basophilic
“Coagulative” necrosis implies outline of cell is maintained for some time (days)
Ultimately necrotic cells and debris are phagocytksed by leucocytes

Question 16

What are the five types of necrosis?

Answer 16

Coagulative
Liquefactive
Caseous
Fat
Fibrinoid

Question 17

Describe Coagulative Necrosis

Answer 17

Coagulative necrosis is characterized by the formation of a gelatinous (gel-like) substance in dead tissues in which the architecture of the tissue is maintained, and can be observed by light microscopy.
Coagulation occurs as a result of protein denaturation, causing the albumin in protein to form a firm and opaque state.
This pattern of necrosis is typically seen in hypoxic (low-oxygen) environments, such as infarction.

Question 18

Describe Liquefactive Necrosis

Answer 18

Liquefactive necrosis (or colliquative necrosis), in contrast to coagulative necrosis, is characterized by the digestion of dead cells to form a viscous liquid mass.
This is typical of bacterial, or sometimes fungal, infections because of their ability to stimulate an inflammatory response.
The necrotic liquid mass is frequently creamy yellow due to the presence of dead leukocytes and is commonly known as pus.

Question 19

Describe Caseous Necrosis

Answer 19

Caseous necrosis can be considered a combination of coagulative and liquefactive necroses, typically caused by mycobacteria (e.g. tuberculosis), fungi and some foreign substances.
The necrotic tissue appears as white and friable, like clumped cheese. Dead cells disintegrate but are not completely digested, leaving granular particles.

Question 20

Describe Apoptosis

Answer 20

Programmed Cell Death
Important in development, tissue remodelling, immune response and in response to injurious agents (hypoxia, repercussion injury, cytotoxic drugs)
Some of the early steps are similar to those in necrosis
Apoptotic bodies are engulfed by macrophages

Question 21

Describe the relationship between pregnancy and apoptosis

Answer 21

After pregnancy, smooth muscle cells undergo apoptosis to return uterus back to original state. The same also happens with breast tissue.

Question 22

Q. BP falls fast, patient successfully resuscitated. The next day, plasma ALT (liver cytosolic enzyme) found to be significantly increased. Explain why.

Answer 22

Very low BP associated with decreased liver perfusion (via both hepatic artery and portal vein). Successful resuscitation restores blood flow and oxygenation improves. This re-perfusion injury seen as damage and death of hepatocytes, ALT released into circulation and measured next day as still circulating in peripheral blood (plasma).