VIVA: Pathology - Cellular injury and adaptation Flashcards
What is apoptosis?
Programmed cell death*
Induced by tightly regulated intracellular programme (non-inflammatory)
Cell that is destined to die activates enzymes that degrade the cell’s own nuclear DNA and nuclear/cytoplasmic proteins
Cell’s plasma membrane remains intact
Apoptotic cell becomes target for phagocytosis
Dead cell rapidly cleared by phagocytosis before contents leak out*, so this does not elicit an inflammatory reaction in the host
Cell shrinks
*needed to pass + one other
Describe the physiologic situations where apoptosis occurs
3 needed to pass:
- Hormone-dependent involution in adults (e.g. endometrial breakdown)
- Programmed destruction of cells during embryogenesis (developmental atrophy)
- Cell deletion in proliferating cell populations (e.g. intestinal crypt cells)
- Death of host cells that have served their purpose (e.g. neutrophils in acute inflammation)
- Elimination of potentially harmful self-reactive lymphocytes
- Cell death induced by cytotoxic T cells (e.g. in virus-infected cells, cells with excessive DNA damage or unfolded protein build-up)
Describe the pathological situations where apoptosis occurs
1 needed to pass:
- Cell death secondary to low dose noxious stimuli (e.g. radiation, cytotoxins, heat, hypoxia, ageing)
- Viral hepatitis
- Pathologic atrophy after duct obstruction in pancreas, parotid, or kidney
- Cell death in tumours
What happens at a cellular level in apoptosis?
Cell shrinkage
Chromatin condensation (pyknosis)
Formation of cytoplasmic blebs and apoptotic bodies
Phagocytosis of apoptotic cells or cell bodies, usually by macrophages
What is atrophy?
Decrease in the size of an organ or tissue resulting from a decrease in cell size and number*
Can be physiological or pathological
*needed to pass
What are the causes of atrophy?
4/7 needed to pass:
- Decreased workload (e.g. immobilisation in plaster)
- Denervation
- Diminished blood supply (e.g. due to arterial occlusion)
- Inadequate nutrition (e.g. protein-calorie deficit / marasmus -> use of adipose stores and muscle for energy)
- Loss of endocrine stimulation (e.g. endometrial atrophy after menopause)
- Ageing
- Pressure
What are the mechanisms of atrophy?
Decreased protein synthesis*
Increased protein degradation*
May be accompanied by increased autophagy (self-eating), where a starved cell eats its own components in an attempt to find nutrients and survive
*1/2 needed to pass
Give some examples of atrophy
2 needed to pass:
- Fracture disuse
- Damage to nerves causing muscle atrophy
- Breast and reproductive organ atrophy from decreased oestrogen (e.g. postmenopausal)
Describe the two different forms of pathological calcification and give an example of each
- Dystrophic calcification:
- Normal serum calcium, no derangements in calcium metabolism
- Calcification occurs in necrotic or dying tissue
- E.g. atherosclerosis, calcific aortic stenosis, tuberculous node - Metastatic calcification:
- Deposition of calcium in otherwise normal tissues
- Due to hypercalcaemia secondary to disturbance in calcium metabolism
- Typically affects tissues that excrete acid and therefore have an internal alkaline compartment (e.g. gastric mucosa, kidneys, lungs)
- E.g. nephrocalcinosis, pulmonary calcinosis, gastric mucosal calcification
Describe the different principal pathological causes of hypercalcaemia, with some clinical examples
- Hyperparathyroidism:
- Increases bone resorption
- E.g. primary hyperparathyroidism - Destruction of bone tissue:
- E.g. skeletal metastases, multiple myeloma, Paget’s disease - Vitamin D related disorders:
- E.g. sarcoidosis, hypervitaminosis D - Renal failure:
- Causes secondary hyperparathyroidism and phosphate retention
What are the causes of metastatic calcification?
3 needed to pass:
- Primary hyperparathyroidism
- Vitamin D intoxication
- Systemic sarcoidosis
- Milk alkali syndrome
- Hyperthyroidism
- Idiopathic hypercalcaemia
- Renal failure
- Destructive bone disease (e.g. multiple myeloma, osteolytic skeletal metastases)
What tissues are most commonly affected by metastatic calcification:
1 needed to pass:
- Gastric mucosa
- Kidney
- Lungs
- Systemic arteries and pulmonary veins
Describe the biochemical features of cell injury
3/6 needed to pass:
1. ATP depletion:
- Loss of Na+/K+ ATPase pump function results in increased Na+ influx and K+ efflux -> increased osmotic load and swelling
- Anaerobic metabolism -> lactic acid accumulation, initial decrease in pH followed by normalisation or increase in pH
2. Mitochondrial damage:
- Decreased protein synthesis
- Increased lipid breakdown products
- Decreased intracellular glycine
3. Calcium influx
4. Accumulation of free radicals or ROS
5. Defects of membrane permeability:
- Leakage of intracellular substances (e.g. myoglobin, CK, troponin, other enzymes)
6. DNA/protein damage
What is a free radical?
Chemical species with a single unpaired electron* in outer orbit (e.g. reactive oxygen species including superoxide, hydrogen peroxide, hydroxyl, ONOO- peroxynitrite)
*needed to pass + one example
What are the pathologic effects of free radicals?
Overall can cause necrosis* or apoptosis, or can stimulate production of degrading enzymes
Directly can cause:
- Lipid peroxidation (plasma or organelle membrane damage)
- Oxidation of proteins (affects protein structure e.g. enzymes)
- DNA lesions (breaks in DNA or cross-linkages)
*needed to pass + 1/3 direct effects
What is hyperplasia?
Increase in number of cells* in organ/tissue
Usually results in increased mass
*needed to pass
What are the different types of hyperplasia and give examples
Physiologic *:
- Hormonal (reversible with withdrawal of hormonal stimulation; e.g. female breast at puberty and in pregnancy)
- Compensatory (e.g. post partial hepatectomy, skeletal muscle with increased workload)
Pathologic *:
- Excess hormones or growth factors (e.g. BPH, DUB)
- Viral infection (e.g. papillomavirus)
*needed to pass + one example in each category
Apart from urinary retention what are the clinical features of BPH?
2 needed to pass:
- Increased urinary frequency
- Nocturia
- Difficulty in starting and stopping stream
- Dribbling
- Dysuria
- Increased risk of infection
Name some clinical manifestations of diffuse toxic hyperplasia of the thyroid
4 needed to pass:
- Cardiac: tachycardia, palpitations, heart failure
- Ophthalmic: staring, lid lag, proptosis
- GIT: malabsorption, diarrhoea
- Neurological: tremor, anxiety, poor concentration
- Other: heat intolerance, myopathy
What is hypertrophy?
Increased size of a tissue due to increased cell size*
Due to synthesis of structural components
Triggered by increased functional demand or stimulation by hormones or growth factors
Can be selective hypertrophy of specific sub-organelles
*needed to pass
What are the types of hypertrophy?
May be physiological or pathological* depending on increased functional demand or specific hormonal stimulation
Cell hypertrophy can occur in dividing or non-dividing cells
*needed to pass
Describe examples of each type of hypertrophy
Physiological:
- Skeletal muscle with exercise
- Uterus in pregnancy (hormonal)
- Breast in lactation
Pathological:
- Heart in chronic hypertension or valve stenosis
What are the differences between hypertrophy and hyperplasia?
Hyperplasia:
- Increase in number of cells in organ/tissue
- Usually results in increase in volume
- Occurs if cellular population is capable of synthesising DNA thus permitting mitotic division
Hypertrophy:
- Increase in size of cells in organ/tissue
- Causes increase in size of organs
Hyperplasia and hypertrophy often co-exist
Describe the sequence of events that occur in reversible ischaemic cellular injury
- Decreased oxidative phosphorylation and decreased ATP production* -> increased anaerobic metabolism and increased lactate (decreased cellular pH)
- Failure of the Na+/K+ ATPase pump* -> K+ efflux, Na+ and H2O influx, iso-osmotic cell swelling
- Ca2+ influx* (initially released from intracellular stores then influx across plasma membrane) -> further failure of ATP production, enzyme activation, induction of apoptosis -> membrane and nuclear damage
- Decreased glycogen and protein synthesis
- Cytoskeleton changes* (loss of microvilli, “bleb” formation, “myelin figures” from degenerating cell membranes)
- Mitochondrial and ER swelling -> ribosome detachment, clumping of nuclear chromatin, fatty change
*3/4 needed to pass
