Fundamentals: Pathology - Cellular adaptations, injury and death

Question 1

Define reversible cell injury

Answer 1

Functional and morphologic changes to a cell secondary to a damaging stimulus, which may be reversible if in early stages or mild forms of injury

Question 2

Define irreversible cell injury

Answer 2

Injury from which the cell cannot recover and will die (either via necrosis or apoptosis, or occasionally autophagy)

Question 3

What are the two hallmarks of irreversible cell injury vs reversible cell injury (the “point of no return”)?

Answer 3

1. Inability to reverse mitochondrial dysfunction even after insult resolution
2. Profound disturbance in membrane function

Question 4

Define necrosis

Answer 4

Cell death occurring after abnormal stresses; always pathologic

Question 5

Define apoptosis

Answer 5

Programmed cell death due to activation of internal “suicide program”; may be pathologic or physiologic, and is not always associated with cell injury

Question 6

Define residual bodies

Answer 6

Vesicles containing cell debris, produced as a result of lysosomal digestion of redundant cellular components (e.g. lipofuscin granules in ageing tissues)

Question 7

Define ischaemia

Answer 7

Reduced blood flow causing decreased supply of oxygen and other metabolic substrates; may be the result of obstructed arterial flow or decreased venous drainage

Question 8

Define hypoxia

Answer 8

Deficiency of oxygen

Question 9

What is reperfusion injury?

Answer 9

When blood flow is restored to previously ischaemic cells, injury can be paradoxically exacerbated

Question 10

Outline three proposed mechanisms underlying reperfusion injury

Answer 10

1. Increased production of reactive oxygen and nitrogen species
2. Inflammation due to chemotaxis
3. Activation of the complement system

Question 11

Define hypertrophy and give an example

Answer 11

Increase in cell size leading to increase in organ size (e.g. uterus during pregnancy, skeletal muscle in exercise, heart with chronic haemodynamic overload)

Question 12

Define hyperplasia and given an example

Answer 12

Increase in cell number usually resulting in an increase in organ or tissue size (e.g. glandular breast tissue during puberty/pregnancy, BPH)

Question 13

Define atrophy and give an example

Answer 13

Decrease in cell size and number, resulting in reduced size of organ or tissue (e.g. atrophy of thyroglossal duct during foetal development)

Question 14

Name 6 mechanisms of atrophy

Answer 14

1. Disuse
2. Denervation
3. Decreased blood supply
4. Inadequate nutrition
5. Loss of endocrine stimulation (e.g. post-menopausal vaginal atrophy)
6. Pressure (e.g. tumour on surrounding tissues)

Question 15

Define metaplasia and give an example

Answer 15

Reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another, often in response to stress (e.g. stratified squamous replaced by columnar in Barrett’s oesophagus)

Question 16

What is the most common metaplastic cell change? Give an example

Answer 16

Columnar to squamous epithelium (e.g. chronic irritation of respiratory tract secondary to smoking)

Question 17

Outline 7 causes of cell injury, giving examples

Answer 17

1. Oxygen deprivation (e.g. ischaemia, anaemia)
2. Physical agents (e.g. mechanical trauma, temperature extremes)
3. Chemical agents and drugs (e.g. toxins, poisons, pollutants, recreational and therapeutic drugs)
4. Infectious agents (e.g. viruses, fungi)
5. Immunologic agents (e.g. autoimmune conditions or in response to infection)
6. Genetic derangements (e.g. sickle cell anaemia, in-born errors of metabolism)
7. Nutritional imbalances (e.g. protein-calorie deficiency, hyperlipidaemia)

Question 18

Draw a flow diagram demonstrating the functional and morphologic changes in reversible cell injury

Answer 18

Question 19

Outline the 6 principle mechanisms of cell injury

Answer 19

1. Decreased ATP: multiple downstream effects (cellular swelling, membrane instability, lipid deposition)
2. Mitochondrial damage: further reduction in ATP, leakage of pro-apoptotic proteins
3. Calcium influx: increased mitochondrial permeability, activation of cellular enzyme (e.g. proteases, phospholipases, caspases)
4. Increased ROS: membrane lipid peroxidation, DNA fragmentation, protein cross-linking and fragmentation
5. Membrane damage: to plasma membrane causing loss of cellular components, and lysosomal membranes causing enzymatic digestion of cellular components
6. Protein misfolding and DNA damage: activation of pro-apoptotic proteins, nuclear condensation/fading/fragmentation

Question 20

List the 6 patterns of tissue necrosis

Answer 20

1. Coagulative
2. Liquefactive
3. Gangrenous
4. Caseous
5. Fat
6. Fibrinoid

Question 21

What is liquefactive necrosis? Give an example

Answer 21

Digestion of dead cells results in transformation of tissue into liquid viscous mass (e.g. pus in bacterial infection, hypoxic death in CNS)

Question 22

What is coagulative necrosis? Give an example

Answer 22

Necrosis in which the tissue architecture is preserved (e.g. hypoxic death in all tissues except CNS, including MI)

Question 23

What is gangrenous necrosis?

Answer 23

Not a specific pattern of cell death; used clinically to describe an area (usually a limb) that has lost blood supply and undergone (typically coagulative “dry” +/- liquefactive “wet”) necrosis

Question 24

What is caseous necrosis?

Answer 24

White granulomatous foci of inflammation, typical of TB

Question 25

What is fat necrosis and how does it occur?

Answer 25

Not a specific pattern of cell death, refers to focal areas of fat destruction
Typically due to the release of pancreatic lipases into the substance of the pancreas and the peritoneal cavity during acute pancreatitis

Question 26

What is fibrinoid necrosis?

Answer 26

Immune complex (Ag-Ab) mediated necrosis (e.g. in autoimmune vasculitis)

Question 27

Compare and contrast the morphological patterns of cell death

Answer 27

Question 28

How do free radicals cause cell injury?

Answer 28

By reacting with:
1. Fatty acids: oxidation -> lipid peroxidases -> plasma and organelle membrane disruption
2. Proteins: oxidation -> abnormal folding, loss of enzymatic activity
3. DNA: oxidation -> mutations, breaks

Question 29

What mechanisms exist to prevent injury from free radical species?

Answer 29

1. Inherent instability: free radicals often decay spontaneously
2. Antioxidants: scavenge ROS (e.g. vitamin A/E, glutathione)
3. Binding of iron and copper to transport/storage proteins: prevents ROS formation
4. Enzyme systems: scavenge and break down ROS (e.g. catalase, superoxide dismutases, glutathione peroxidase)

Question 30

Draw a diagram summarising possible responses to cell injury

Answer 30

Question 31

By what processes do intracellular accumulations occur? Give examples

Answer 31

1. Abnormal metabolism: normal endogenous substance produced at a normal or increased rate, but rate of metabolism is inadequate to remove it (e.g. fatty liver)
2. Defect in protein folding/transport: abnormal endogenous substance is produced (usually the product of a mutated gene) and is unable to be folded/transported/degraded (e.g. abnormal alpha-1 antitrypsin accumulation in the liver)
3. Lack of enzyme: normal endogenous substance accumulates due to defects in enzyme required for its metabolism (e.g. lysosomal storage diseases)
4. Ingestion of indigestible materials: abnormal exogenous substance accumulates because the cell lacks the enzymatic machinery to metabolise or transport it (e.g. silicosis)

Question 32

Define dystrophic calcification

Answer 32

Abnormal accumulation of calcium locally in dying tissues, in the presence of a normal serum calcium and in the absence of derangements in calcium metabolism (e.g. atheroma in advanced atherosclerosis)

Question 33

Define metastatic calcification

Answer 33

Abnormal accumulation of calcium in otherwise normal tissues due to hypercalcaemia secondary to disturbance in calcium metabolism

Question 34

What kind of tissues more commonly undergo metastatic calcification?

Answer 34

Tissues that excrete acid and therefore have an internal alkaline compartment are more susceptible to metastatic calcification (e.g. gastric mucosa, lungs, kidneys where it can cause nephrocalcinosis)

Question 35

Outline the mechanisms of cellular aging