Cell injury Flashcards
What are the 2 types of cell injury?
reversible and irreversible
Definition of reversible cell injury
cell adapts to changes in environment in order to survive
How is reversible injury resolved?
once the stimulus is removed, the cell returns to its normal shape and function
Irreversible injury definition
a permanent change that results from an environmental change
What is the consequence of irreversible cell injury?
cell death (apoptosis / necrosis)
What leads to a cell injury progressing from reversible to irreversible?
the cell can no longer survive in the environment in its current state - passes the ‘point of no return’
What factors determine whether an injury is reversible or irreversible?
Dose intensity (type, duration, severity of injury) and cell susceptibility/adaptability (nutritional status, metabolic needs)
Example of cell type affecting injury extent (cardiac vs skeletal muscle)
cardiac myocytes are more sensitive than skeletal myocytes and will be injured more when exposed to same low oxygen environment
Aetiologies (causes) of cell injury
hypoxia, ischaemia, physical agents, chemicals/drugs, infections, immunological reactions, nutritional imbalance, genetic defects
Hypoxia definition
oxygen deficiency
Causes of hypoxia
anaemia, respiratory failure
How does hypoxia affect cells?
disrupts oxidative respiratory process which greatly decreases ATP / cell energy supply
How do cells adapt to hypoxia?
release energy via anaerobic mechanisms (limited)
Ischaemia definition
reduction in blood supply to tissue (depletion of oxygen and nutrients)
Cause of ischaemia
blockage of arterial supply or venous drainage e.g. atherosclerosis
Which imposes more severe/rapid damage: hypoxia or ischaemia?
Ischaemia
Why does ischaemia cause more severe/rapid damage than hypoxia?
Ischaemia causes oxygen AND nutrient depletion so anaerobic respiration also stops (no glucose supply)
What physical agents can cause cell injury?
mechanical trauma, extreme temperatures, ionising radiation, electric shock
How can mechanical trauma lead to cell injury?
by affecting cell membranes and cell structure
How can extreme temperatures (hot/cold) cause cell injury?
affects proteins and chemical reactions
How can ionising radiation cause cell injury?
can lead to DNA damage that is irreparable by the cell. Can lead to cancer
How can electric shock cause cell injury?
causes burns
Which physical agent can cause cell injury that is not immediately apparent?
ionising radiation (DNA damage can appear as cancer years down the line)
What are the infectious agents that can cause cell injury?
bacteria, viruses, fungi, parasites, prions
What chemicals/drugs can cause cell injury?
simple chemicals, poisons, occupational hazards, alcohol, smoking, recreational drugs
How can simple chemicals (e.g. glucose) cause cell injury?
an excess of the chemical (e.g. glucose) can cause an osmotic disturbance
How can poisons (e.g. cyanide) cause cell injury?
cyanide blocks oxidative phosphorylation leading to ATP deprivation
Example of an occupational hazard that can cause inflammation
asbestos
Examples of immunological reactions that can cause cell injury
anaphylaxis (severe type I hypersensitivity), autoimmune reactions (e.g. type II - haemolytic anaemia, type III - antigen-antibody immune complexes embedded in endothelium)
How do immunological reactions cause cell injury?
due to inflammation (complement - membrane attack complexes, clotting, neutrophil products e.g. enzymes, …)
Example of cellular injury that occurs due to inadequate intake of a specific nutrient (cause cell injury)
scurvy, rickets
Which nutrient is deficient in scurvy?
vitamin C
Which nutrient is deficient in rickets?
vitamin D
Example of a disease that occurs due to a generalised inadequate nutrient intake (cause cell injury)
anorexia
Examples of diseases that occur due to excess intake of a specific nutrient (leads to cell injury)
hypervitaminosis A/D
Example of a disease that occurs due to a generalised excessive nutrient intake (cause cell injury)
obesity
What genetic defects can cause cell injury?
sickle cell anaemia, inborn error of metabolism, cancer
What are inborn errors of metabolism?
genetic disorders that cause failure of a metabolic pathway due to a lack of enzyme causing accumulation of the substrate
Why must individuals of an Afro-Caribbean background be screened for sickle cell anaemia before undergoing general anaesthetic?
low oxygen tension during GA can cause individuals to undergo sickling
What cellular processes can be disrupted due to reversible cell injury?
aerobic respiration/ATP synthesis, plasma membrane integrity, enzyme and structural protein synthesis, DNA maintenance
What 2 morphological changes can occur during reversible cell injury?
cloudy swelling or fatty change
What happens during cloudy swellings?
Lack of energy leads to pumps in the plasma membrane failing. Cells are incapable of maintaining ionic and fluid homeostasis. Leads to influx of Na+ and water, and accumulation of intracellular metabolites. Cells swell
What happens during fatty change?
There is a disruption of fatty acid metabolism so triglycerides cannot be released from the cell. Causes accumulation of lipid vacuoles in cytoplasm.
Causes of fatty change
toxic and hypoxic injury (alcohol abuse, diabetes, obesity)
Which organ is particularly affected by fatty change?
liver (can also occur in heart)
What is the macroscopic appearance of a liver that has undergone fatty change?
enlarged and pale liver
What happens at the ‘point of no return’ following reversible fatty change?
cells cannot accumulate any more triglycerides which leads to cirrhosis/fibrosis
What reversible changes can occur during cell injury?
swelling of cell and organelles, blebbing
What is blebbing?
A process where part of the cell breaks off
What changes occur inside the cell at the ‘point of no return’?
extreme organelle swelling, violent blebbing (cell damage becomes permanent)
What cellular changes occur in irreversible injury?
membrane rupture, dispersal of organelles (prompts inflammation), lysosome breakdown
Does necrosis require energy?
no
What is necrosis?
cell death
Cause of necrosis
irreversible cell injury usually due to pathology
How is the cell broken down during necrosis?
lysosomes digest cell and dispersed organelles (due to cell membrane rupture) are removed via phagocytosis by macrophages
What type of response occurs in tissue surrounding necrosis?
inflammatory response
What are the nuclear changes that occur during necrosis?
pyknosis, karyorrhexis, karyolysis
What is a useful microscopic sign that a cell is necrotic?
there is a loss of the blue staining nucleus
What happens during pyknosis (stage of necrosis)?
nucleus shrinks and becomes darker staining
What is the term used to describe the fragmentation of the nucleus during necrosis?
karyorrhexis
What happens during karyolysis?
the blue staining DNA in nucleus is digested by endonucleases and the blue staining fades away
What are the cytoplasmic changes that occur during necrosis?
cytoplasm either appears paler due to swelling or more eosinophilic (pink) due to denaturation of cytoplasmic structural and enzyme proteins
What are the 3 main types of necrosis?
- coagulative necrosis
- liquefactive necrosis (colliquative)
- caseous necrosis
What is the most common type of necrosis?
coagulative necrosis
Example of coagulative necrosis
myocardial infarction
Infarct definition
localised area of coagulative necrosis
What is the microscopical appearance of coagulative necrosis?
eosinophilic cells with no nucleus and a preserved structure (for a few days)
Why is the architecture of tissue that has undergone coagulative necrosis preserved for a few days?
enzymes have denatured therefore there is no proteolysis of the dead cells
How are the cells broken down in coagulative necrosis?
by lysosomes of leukocytes
What is the cause of coagulative necrosis?
ischaemia - (thrombus can cause) blocked blood supply to tissue leading to cell death due to lack of oxygen / nutrients
What are the dark spots that appear on a slide of tissue that has undergone coagulative necrosis?
inflammatory cells (leukocytes)
What is the gross texture of tissue that has undergone coagulative necrosis?
grossly firm in texture
What is the more common term used to describe liquefactive necrosis?
pus
Definition of colliquative necrosis
digestion of dead tissues into a liquid viscous state
Causes of liquefactive necrosis
focal bacterial or fungal infections (abscess)
What is an abscess?
collection of pus
What is the gross appearance of liquefactive necrotic tissue?
thick, pale yellow coloured liquid
What type of necrosis does CNS necrosis due to hypoxia often manifest as?
liquefactive necrosis (colliquative)
What is the gross appearance of caseous necrosis?
friable white appearance (like cheese)
Example of infection in which caseous necrosis occurs
tuberculous infection
What is the microscopic appearance of caseous necrosis?
granular debris (mass apoptosis) and granuloma-fragmented cells surrounded by inflammatory cells
What cells exist in a caseous necrosis granuloma?
chronic inflammatory cells, multinucleated giant cells, fibroblasts
What is the name of a form of necrosis that involves both coagulative and liquefactive necrosis?
gangrenous necrosis
What is gangrenous necrosis?
coagulative necrosis with superimposed anaerobic bacterial infection - liquefactive necrosis
What is the sequalae for gangrenous necrosis?
amputation
What is fat necrosis?
focal areas of fat destruction
What is the cause of fat necrosis?
acute pancreatitis or trauma may lead to the release of activated pancreatic enzymes which liquefy fat cells
What special type of necrosis can be seen in immune reactions in blood vessels?
fibrinoid necrosis
What happens during fibrinoid necrosis?
antigen-antibody immune complexes are deposited in artery walls together with fibrin that leaks out of the vessels
What is the appearance of fibrinoid necrosis in H&E stain?
bright pink (eosinophilic) and amorphous substance
What are the effects of necrosis?
function loss (depends on organ/tissues) and inflammation
Why does necrosis cause inflammation?
release of cell contents activates inflammation so that cell remains are then phagocytosed
What happens to the necrotic area?
replaced by a scar (undergoes organisation or repair)
What happens if the necrotic remains are not removed?
calcium salts may be deposited in necrotic tissue (esp fat necrosis)
What part of the cell reveals whether the cell is vital or non vital?
nucleus
How may the nuclei of non-vital cells appear?
pyknosis (small and darkly staining), karyorrhexis (nuclei fragmented), karyolysis (nuclear fading)
What part of the cell explains how cells have died?
cytoplasm
What cell injuries can cause coagulation necrosis (except in CNS where liquefactive necrosis occurs)?
hypoxia or free radicals
What type of necrosis occurs due to denatured cytoplasm?
coagulative necrosis (except in CNS)
What cell injuries can cause liquefactive necrosis?
strogn acids/alkalis, clostridia, snake venom, neutrophils
What happens to cells when they undergo liquefaction necrosis?
hydrolysed
What cell injuries cause caseous necrosis?
tuberculosis or some fungi
What happens to cells that undergo caseous necrosis?
mass apoptosis (forms granuloma)
What happens to cells that undergo fat necrosis?
saponified and Ca deposited
What is apoptosis?
genetically programmed cell death
Function of apoptosis
has an important physiological role by eliminating unwanted cells
When can apoptosis occur?
pathological situations or as part of normal physiology
Does apoptosis require energy?
yes
Which type of cell death requires energy?
apoptosis (not necrosis)
Which type of cell death causes inflammation?
Necrosis (apoptosis does not cause inflammation)
What is the appearance of apoptotic cells with H&E?
cells are smaller and more darkly stained
What are potential pathological triggers of apoptosis?
hypoxia/ischaemia, viral infection, DNA damage
How can a viral infection trigger apoptosis?
cytotoxic T-lymphocytes contain enzymes that can induce apoptosis
How can DNA damage trigger apoptosis?
if DNA damage is irreparable, Tp53 gene synthesises the protein p53 which triggers apoptosis
Which gene is known as the ‘guardian of the genome’?
Tp53 (tumour suppressor gene)
What enzymes trigger apoptosis?
caspases
What is the physiological role of apoptosis during embryo/fetal development?
deletion of cell populations during embryogenesis
What is the physiological role of apoptosis in females during ageing?
hormone change dependent involution of uterus, breasts, ovaries
What is the physiological role of apoptosis in proliferating cell populations?
to maintain constant cell numbers (e.g. in epithelium)
What are the physiological roles of apoptosis within the immune system?
deletion of inflammatory cells following immune response, deletion of self reactive B and T lymphocytes
What diseases can result from excess apoptosis?
degenerative diseases
What diseases can result from too little apoptosis?
cancer
What are the cellular morphological changes that occur during apoptosis?
cell shrinkage, chromatin condenses and nucleus fragments (becomes darker staining), cytoplasmic blebs form which break off into apoptotic bodies, phagocytosed
Why does apoptosis not trigger inflammation (unlike necrosis)?
during apoptosis, the cell contents are still contained within the plasma membrane whereas in necrosis the membrane ruptures
What is the difference that occurs in cell size during necrosis compared to apoptosis?
the cell is enlarged in necrosis and reduced in apoptosis
What 2 groups of substances can accumulate in cells?
excessive normal cellular constituent or abnormal endogenous/exogenous material
Examples of normal cellular constituent that can undergo intracellular accumulation
water, lipid (fatty change), glycogen
Examples of abnormal endogenous/exogenous materials that can accumulate intracellularly
carbon, silica, metabolites, cholesterol
Where can intracellular accumulation occur?
nucleus or cytoplasm
Atherosclerosis definition
accumulation of cholesterol in macrophages and smooth muscle cells in blood vessel walls
Where can cholesterol accumulation occur?
in blood vessel walls (atherosclerosis), sites of haemorrhage and necrosis
What type of cells are found in areas of cholesterol accumulation?
foam cells
What are foam cells?
macrophages that have ingested lipids (large, pale cells)
What is amyloid?
a fibrillar protein material deposited due to pathologic processes that lead to increased production of amyloid
Where is amyloid deposited?
extracellular location (mostly on basement membrane) in various tissues and organs
Examples of tissues and organs where amyloid deposition can occur
kidney and tongue
What are the different types of amyloid?
AL (amyloid light chain)
AA (amyloid associated)
AB (beta)
Where is AL (amyloid light chain) derived from?
light chain immunoglobulins from plasma cells
Where is AA (amyloid associated) derived from?
proteins synthesised in the liver
Which disease has AB (beta) deposition?
Alzheimer’s disease (deposition in brain)
What are the possible stimuli for amyloid deposition?
chronic inflammation, multiple myeloma, ageing, drug abuse
What is multiple myeloma?
type of bone marrow cancer caused by malignant plasma cells (produce lots of light chain Ig leading to AL deposition)
What stain should be used to identify amyloid?
special stains e.g. congo red has an affinity for amyloid
Why is H&E staining not suitable for identifying amyloid?
amyloid has a microscopically pink hyaline appearance so is difficult to identify with H&E
What is pathological pigmentation?
Build up of pigmented substances in cytoplasm
What are the 2 types of pathological pigmentation?
endogenous and exogenous pigmentation
What colour do all endogenous pigmentations appear?
brown
What are the different types of endogenous pigmentation?
lipofuscin, melanin, haemosiderin, bilirubin
What is lipofuscin?
a type of pigment consisting of cellular lipid breakdown products formed by wear and tear of cells
What is localised bruising termed?
haemosiderin
Example of a stimulus that increases melanin pigmentation
sun - increases melanocytes’ activity resulting in increased melanin production (tan)
What are the potential exogenous pathological pigments?
carbon deposition, tattoos, heavy metal salts (e.g. lead), pigmentation associated with IV drug use
What is the most common exogenous pathological pigmentation?
carbon deposition
Where does carbon deposition occur?
in macrophages in alveoli of lungs
Causes of carbon deposition
inhaled soot/smoke (e.g. coal workers can have severe C deposition)
What is the name of the black pigment that results due to a large volume of C deposition?
anthracosis
What is the name of a group of lung conditions where fibrosis occurs due to severe deposition?
pneumoconiosis
What are the 2 types of pathologic calcification?
dystrophic and metastatic calcifications
What are dystrophic calcifications?
deposits of calcium phosphate in necrotic tissue. serum calcium is normal
What are the serum calcium levels in dystrophic calcification?
normal serum calcium levels
Example of disease where dystrophic calcification can occur
valvular heart disease
What are metastatic calcifications?
deposits of calcium salts in normal, vital tissue with raised serum calcium levels (excess Ca causes deposition)
What is the serum calcium level like in metastatic calcification?
raised serum calcium levels
Where does metastatic calcification often occur?
in connective tissue of blood vessels
How may metastatic calcification lead to compromised tissue function?
calcium salts in blood vessel walls can affect elasticity
What is the term used to describe raised serum calcium?
hypercalcaemia
Causes of raised serum calcium
- increased levels of PTH
- destruction of bone tissue
- excess vitamin D
- renal failure
What is the term used to describe increased levels of parathyroid hormone?
hyperparathyroidism
What is a potential cause of hyperparathyroidism?
parathyroid gland tumour (benign tumours)
How does PTH increase serum calcium?
PTH activates osteoclasts leading to bone resorption (osteoclastogenesis) which releases Ca
What are possible causes of bone tissue destruction that can lead to hypercalcaemia?
hyperparathyroidism, leukaemia, malignant metastasis to bone, immobilisation (disuse)
How can renal failure result in hypercalcaemia?
renal failure may cause secondary hyperparathyroidism
