Pathology - Cell Injury

Question 1

What is apoptosis and describe the stimuli and features

Answer 1

• programmed cell death, removes unwanted cells and stops excess growth
  –cell dies by internal suicide program
• 2 phases: initiation phase (via intrinsic and extrinsic pathway) and execution phase
  causing protein breakdown by caspases
• plasma membrane remains intact and does not involve inflammation, cell becomes target for phagocytosis

features:
cells shrinkage
no inflammation
chromatin condensation, fragmentation, cell blebbing, phagocytosis
stimuli: embryogenesis, hormone dependent involution, DNA damage, developmental atrophy, post inflammation

Question 2

What happens at the cellular level in apoptosis

Answer 2

cell shrinkage
chromatin condensation
fragmentation
formation of blebs
phagocytosis by macrophages

Question 3

Describe the mechanisms involved in apoptosis

Answer 3

1) Initiation phase
- intrinsic pathway = mitochondrial permeability increased, causes cytochrome c release, activates caspases
- extrinsic pathway = activation of death receptors (TNF family) causing activation of caspases (protease enzymes)

2) Execution phase
- caspases act on cell components causing protein degradation, removal of dead cells by phagocytosis

Question 4

Describe the cellular changes in necrosis

Answer 4

• cellular swelling, eosinophilia, myelin figures, nuclear changes (pyknosis, karyolysis, karyorrhexis)
• organelle disruption, cell rupture, inflammation

Question 5

What are the patterns of tissue necrosis

Answer 5

• coagulative: characterised by protein denaturation, architecture preserved, common after MI
• liquefactive: characterised by enzymatic digestion, common after CNS hypoxia
• caseous: exhibits coagulation and liquefaction, seen in Tb
• fat: characterised by lipase activation
• fibrinoid: due to antigen-antibody complex deposition in blood vessel walls

Question 6

What happens inside cells when they are injured (damage that occurs after severe ischaemia)

Answer 6

• depletion of ATP: causes failure of ion pumps and cell swelling
• mitochondrial damage: causes leaking of cytochrome c leading to apoptosis
• increased intracellular calcium: causes activation of phospholipase which degrades membrane phospholipids
• accumulation of oxygen-derived free radicals: causes damage to DNA and RNA
• defects in membrane permeability: effects intracellular osmolarity and enzyme activity
• damage to DNA and protein: leads to activation of apoptosis

Question 7

What are the morphological and chemical changes associated with early cell injury

Answer 7

morphological: cell swelling, membrane blebbing, chromatin clumping, ribosomes detach from ER
chemical: depletion of ATP, failure of Na+/K+ATPase, increased intracellular Ca+2, generation of free radicals

Question 8

What is a free radical and what are their pathologic effects

Answer 8

unstable, partially reduced molecules with unpaired electrons in the outer orbit
causes necrosis or apoptosis

effects: lipid peroxidation, oxidation of proteins, DNA lesions

Question 9

What are the stages of ischaemic cell injury

Answer 9

• reversible: cell swelling, membrane blebbing, nuclear chromatin clumping, ribosome detachment from ER
• irreversible: nuclear pyknosis/karyorrhexis/karyolysis, lysosome rupture, mitochondrial vacuolisation

Question 10

Describe the sequence of events in reversible ischaemia

Answer 10

• initially reduced oxidative phosphorylation causing reduced ATP production
• failure of Na+/K+ pump, cause increased intracellular Na+ and decreased K+ and cellular swelling
• failure of Ca+2 pump, cause increased intracellular Ca+2 which activates phospholipase (degrades membranes)

features: cellular swelling, membrane blebbing, nuclear chromatin clumping, ribosomes detach from ER

Question 11

What are the phenomena that characterise irreversible cell injury

Answer 11

inability to reverse mitochondrial dysfunction and development of profound disturbances in membrane function

Question 12

What are the morphological features of irreversible ischaemia

Answer 12

nuclear destruction
lysosomal rupture
severe mitochondrial vacuolization
death by necrosis or apoptosis

Question 13

What are some examples of proteins that leak across a degraded cell membrane

Answer 13

cardiac (creatinine kinase and troponin)
bile duct epithelium (alkaline phosphatase)
hepatocytes (transaminases)

Question 14

Describe reperfusion injury

Answer 14

• increased injury to ischaemic cells with restoration of perfusion
• due to generation of reactive oxygen and nitrogen species
• activation of inflammatory/complement cascades

Question 15

What is atrophy and what are the causes and mechanisms

Answer 15

• decrease in cell size and number, may be physiological or pathological
  causes: decreased workload, denervation, reduced blood flow, inadequate nutrition, loss of endocrine stimulation
  mechanisms: decreased protein synthesis or increased protein degradation (mainly by ubiquitin-proteasome path)
  examples: fracture disuse, damage to nerves causing muscle atrophy, reproductive organs from lack of estrogen

Question 16

What is hyperplasia and what are the types

Answer 16

increase in the number of cells

physiologic: hormone (breast size in puberty), compensatory (post partial hepatectomy)
pathologic: excess hormone (BPH), viral infection (papillomavirus)

Question 17

What are the cellular mechanisms of physiological hyperplasia

Answer 17

increased growth factor production
increased growth factor receptors
activation of intracellular signalling

Question 18

What are the clinical features of BPH

Answer 18

increased frequency, nocturia, difficulty starting and stopping stream, dribbling, dysuria, increased infections

Question 19

What are some features of diffuse toxic hyperplasia of the thyroid gland (graves disease)

Answer 19

tachycardia, palpitations, heart failure, eye staring, lid lag, proptosis, malabsorption, diarrhoea, tremor, anxiety

Question 20

What is hypertrophy and what are the types

Answer 20

-increase in the size of a cell due to synthesis of structural components

• physiologic: increase in size of breast during lactation and uterus during pregnancy, skeletal muscle with exercise
• pathologic: heart in chronic hypertension

Question 21

What is metaplasia and describe the mechanism, some examples and what are possible outcomes

Answer 21

• replacement of one normal cell type with another normal cell type, reversible and may be adaptive or pathological
  mechanism: reprogramming of cells involving signals from cytokines, growth factors, genes, ect
  examples: squamous to columnar in barrett esophagus, columnar to squamous in smoking (most common)
  outcomes: reversibility, ongoing, malignant transformation

Question 22

What are the 2 different forms of pathological calcification and give an example of each

Answer 22

1. Dystrophic calcification = arises in non-viable tissue in presence of normal calcium levels
   - example: arteries in atherosclerosis
2. Metastatic calcification = arises in viable tissue in setting of hypercalcaemia
   - example: gastric mucosa, pulmonary calcinosis, nephrocalcinosis

Question 23

What are the causes of hypercalcaemia (what are the causes of metastatic calcification)

Answer 23

• increased PTH secretion: hyperparathyroidism
• destruction of bone tissue: skeletal metastasis
• vitamin D related disorders: sarcoidosis
• renal failure: secondary hyperparathyroidism

Question 24

What is steatosis and what are causes of hepatic steatosis

Answer 24

• the abnormal accumulation of TAG within parenchymal cells due to excessive entry or defective metabolism
• can occur in: heart muscle, kidney, liver, skeletal muscle
• cause of hepatic steatosis: alcohol, toxins, protein malnutrition, diabetes, obesity