Flashcards in MoD Session 1 Deck (154):
What can disease be considered as?
Consequence of failed homeostasis w/consequent morphological and functional disturbance
What does all disease start with?
What are the increasing levels of response mounted by a cell as a stimulus moves from being physiological to harmful?
At what point does cell injury become cell death?
When the injury becomes irreversible
What can cause cell injury?
What is hypoxaemic hypoxia?
Decrease in arterial oxygen content due to altitude or lung disease
What is anaemic hypoxia?
Decreased oxygen carriage by haemoglobin caused by anaemia or carbon monoxide poisoning
What is ischaemic hypoxia?
Interrupted blood supply caused by BV blockage or heart failure
What is histiocytic hypoxia?
Inability of a cell to use oxygen due to disabled oxidative phosphorylation enzymes caused by cyanide poisoning
How does the tolerance of hypoxia vary between neurones and fibroblasts before irreversible injury is caused?
Neurones can tolerate a few minutes
Fibroblasts can tolerate a few hours
Give examples of toxins that could cause cellular injury.
Glucose/salt in hypertonic solutions
Oxygen at high concentration
Give examples of physical agents that may cause cellular injury.
Changes in pressure
How is urticaria (hives) caused?
Hypersensitivity reaction causes host tissue to be injured secondary to an overly vigorous immune response
How does Grave's disease cause cellular injury?
Autoimmune reaction which fails to distinguish b/w self and non-self
What shows cellular injury when caused by immune mechanisms?
Give an example of a genetic abnormality which can cause cellular injury.
Inborn errors of metabolism
By what mechanisms can cellular injury be caused?
Cell membranes, especially lysosomes
Proteins (structural cytoskeleton and enzymes)
How can hypoxia cause reversible cell injury?
Ischaemia decreases oxidative phosphorylation --> decreases ATP to 5-10% of normal concentration --> cell reacts
Why does lipid deposition occur in reversible cell injury caused by hypoxia?
Ribosomes detach from the ER --> protein synthesis is decreased --> lipid is deposited
Why does chromatin clump during reversible cell injury caused by hypoxia?
Increased glycolysis lowers pH which in turn causes chromatin to clump
How are blebs formed in reversible cell injury caused by hypoxia?
The sodium/potassium pump is disrupted so cell swells as osmotic ions move in w/water allowing blebs to form
Why does cytosolic calcium levels increase in irreversible cell injury caused by hypoxia?
Leaky CSM allows calcium entry
ER and mitochondria also increase calcium levels
Which enzymes are affected by the increase in cytosolic calcium in irreversible cell injury caused by hypoxia?
What effects does the high cytosolic calcium levels acting on enzymes within the cell have in irreversible cell injury caused by hypoxia?
Decreases ATP levels
Decreases phospholipid levels
Disrupts membrane and cytoskeleton proteins
Causes nuclear chromatin damage
Is the pathogenesis of cell injury due to all insults the same?
No, it may vary and attack different key structures
Which three free radicals are of biological significance?
How does the Fenton reaction form free hydroxyl radicals?
Iron(II) is oxidised to iron(III) whilst hydrogen peroxide becomes an hydroxide ion and hydroxyl free radical
How does the Haber-Weiss reaction form hydroxyl free radicals?
An oxide ion, hydrogen ion and hydrogen peroxide react to form oxygen, water and a hydroxyl free radical
Which free radical is the most dangerous biologically?
Why must hydrogen peroxide and oxide ions be rapidly removed by the body?
To prevent formation of more dangerous hydroxyl free radicals
Why is the Fenton reaction important in bleeding?
Iron is available so there is an increased risk of hydroxyl free radical formation
What insults particularly cause free radical production?
High oxygen concentration
What damage do free radicals cause to cellular structures?
Bent/broken/cross-linked proteins, carbohydrates and nucleic acids
Why are free radicals required by leucocytes?
How are free radicals removed?
Which enzymes are involved in the antioxidant system?
What are free radical scavengers?
Vitamins A, C, E which can sequester metal ions and prevent Fenton reaction
What type of proteins are used in the antioxidant system?
What is ischaemia reperfusion injury?
When bloodflow is returned to damaged but not yet necrotic tissue causing damage worse than if the bloodflow was not restored
What mechanisms can cause reperfusion injury?
Increased ROS w/reoxygenation
Increased neutrophils causing more inflammation and tissue injury
Delivery of complement proteins activating the complement pathway
What cells are heat shock proteins present in?
All at low concentrations
What is the function of heat shock proteins?
Mend mis-folded proteins
Maintain cell vitality
What type of proteins are heat shock proteins?
Unfoldases/chaperonins e.g. Ubiquitin
How does the cell use heat-shock proteins to maintain cell vitality?
Turns off production of other proteins and increases heat-shock protein synthesis
What happens to a mis-folded protein if it cannot be re-folded?
It is destroyed
What are the stages of cell injury as seen by light microscopy?
Alive --> injured --> dead-pyknosis --> karyorrhexis --> karyolysis
What is pyknosis?
Irreversible cell shrinkage
Why does an injured cell become more darker staining as its injury becomes less reversible?
Denatured proteins accumulate
When does chromatin clumping remain reversible until?
In reversible cell injury, what cellular changes are seen by electron microscopy?
Cell swelling and blebs
Autophagy by lysosomes
Mitochondrial and ER swelling
Dispersion of ribosomes
Aggregation of intramembranous particles
In irreversible cell injury, what cellular changes are seen by electron microscopy?
Rupture of lysosomes and autolysis
Pyknosis of nucleus
Mitochondrial swelling w/large densities formed inside
Lysis of ER
Defects in CSM
What is oncosis?
Cell death w/swelling
Spectrum of changes that occur in injured cells prior to death
What is the relationship between ATP and oncosis?
There is none - it is an ATP independent process
What cellular changes are seen in oncosis?
Cell and mitochondrial swelling
Plasma membrane rupture
What is necrosis?
Morphological changes that occur in a living organism after a cell has been dead for some time
Typically what period of time after cell death is necrosis seen?
What is apoptosis?
Cell death w/shrinkage induced by a regulated intracellular programme where the cell activates enzymes that degrade its own nuclear DNA and proteins
Is apoptosis and active process?
Yes, it's ATP dependent
What cellular changes are seen in apoptosis?
Membrane integrity preserved
What does this describe?
Seen w/damage to cell membranes --> cell contents leak out --> inflammation
What is fat necrosis?
Destruction of adipose
How are chalky deposits formed in fat necrosis?
Lipases free fatty acids which combine with calcium
What can cause fat necrosis?
Trauma to adipose
What can fat necrosis mimic?
Breast cancer nodule
What is caseous necrosis?
Amorphous structureless debris associated with TB
What is liquefactive necrosis?
Enzymatic digestion of tissues seen in tissues lacking stroma
How is pus formed in colliquitive necrosis?
Increased inflammation and neutrophils
What is coagulative necrosis?
Denaturation of proteins causing them to coagulate seen in solid organs
Why is a 'ghost outline' seen in coagulative necrosis?
Cellular architecture is somewhat preserved
How does coagulative necrosis appear histiologically?
Intense pink staining
How can liquefactive and coagulative processes be rescued when occurring in cells which are still alive?
Rescued by heat shock proteins
What is gangrene?
Necrosis that is visible to the naked eye
What is the difference between dry and wet gangrene?
Dry: tissue dries before infection can take hold
Wet: bacteria or fungi invade before drying completes
How can wet gangrene cause septicaemia?
Microorganisms can easily leak into surrounding capillaries
How does gas gangrene lead to the development of palpable pockets of gas in a tissue?
Wet gangrene w/anaerobic bacteria
Which type of necrosis is associated with ischaemia?
What is an infarct?
Area of ischaemic necrosis
What two types of infarct are possible?
Which two types of necrosis can cause an infarct to form?
Coagulative e.g. MI
Liquefactive e.g. Cerebral infarct
What can cause an infarction?
Thrombosis and embolism
Compression/twisting of BV - twisted spermatic cord, hernia, twisted bowel
How is a wedge shaped white infarct formed?
Arteral insufficiency so not reperfused due to single blood supply --> occluded artery at apex of wedge of infarct
How are red infarcts formed?
Venous insufficiency/reperfused/dual blood supply sufficient to cause haemorrhage but not rescue tissue
What features are present in tissue which can form a red infarct?
Loose tissue w/poor stromal support
What reduces arterial filling hence causing ischaemia in red infarction?
Capillaries leak causing venous pressure to increase
What do the consequences of infarction depend on?
Alternative blood supply
Speed of ischaemia
Oxygen content of blood
What causes release of molecules by injured and dying cells?
Calcium entering damaged membranes
What molecules are leaked by injured and dying cells?
What are the affects of molecules released by injured and dying cells?
General toxic effects on body
Why can molecules released by injured and dying cells be used for diagnosis?
They may appear in blood
What can cause potassium to explode out of dead cells?
Tumour necrosis syndrome
What is tumour necrosis syndrome?
Where cancer cells are effectively killed so release lots of potassium
Why is potassium used in cardiac surgery?
High levels stop the heart
In what order are enzymes released by injured and dying cells?
Smallest molecular weight first w/increasing weight w/increasing pore size
Give three examples of enzymes released by injured or dying cells.
How does myoglobin released by injured or dying cells cause brown coloured urine?
Dead myocardium or striated muscle releases myoglobin which plugs renal tubes --> greatly increases myoglobin levels in the urine
What is apoptosis characterised by?
Consistent cleavage of DNA breakdown
Use of ATP
Maintained membrane integrity
Lack of lysosomal emzyme involvement
Rapid completion time
What is apoptosis used physiologically for?
Sculpting during embryogenesis
Involution of hormones and cytotoxic killer T cells
How can apoptosis be identified pathologically?
Individual cell destruction w/shrunken, intensely pink appearance
What is the process seen by a cell undergoing apoptosis?
Normal cell --> condensation --> cell buds --> apoptotic bodies
Why is there no inflammation in apoptosis?
Apoptotic bodies are removed by phagocytes therefore there is no release of cellular contents
How does extrinsic intimation cause apoptosis?
Stressed cell expresses death receptors --> death ligand TRAIL binds --> activates caspase-8
How does intrinsic initiation cause apoptosis?
Stimulated by DNA damage or hormone withdrawal --> p53 stimulates mitochondria which stimulates apoptosome --> activated caspase-9
What is the process of degradation and phagocytosis seen in apoptosis?
Loss of microvilli and junctions +/- nuclear changes --> fragmentation creating apoptotic bodies --> apoptotic body expresses surface proteins for recognition by phagocytosis
Name 7 important apoptotic molecules.
What are caspases?
Effector molecules of apoptosis
What is p53?
'Guardian of the genome' which mediates apoptosis in response to DNA damage
What does Bcl-2 do?
Prevents cytochrome C release from mitochondria therefore inhibiting apoptosis
What causes abnormal accumulations in a cell?
If the cell cannot metabolise something
What can abnormal accumulations in a cell derive from?
Cell's own metabolism
Extracellular space - iron in bleeding
Outer environment - dust
Can abnormal accumulations in a cell be reversed?
Yes, if cell metabolism recovers
What four mechanisms can cause abnormal accumulations in a cell?
Alterations in protein folding and transport
Inability to degrade phagocytosed particles
How does abnormal accumulation of water and electrolytes cause tissues to become heavy?
Vacuoles/hydropic swelling increase water content
What very difficult to treat condition caused by water and electrolyte retention stops breathing?
What causes steatosis?
How are xanthomas formed?
Cholesterol vesicle filled cells form foam cells as cholesterol is not broken down by the body so is stored in membrane bound droplets
What forms myelin figures?
What is the first stage of liver disease?
How does mild steatosis compare to advanced steatosis?
Mild = asymptomatic
Advanced = increased weight and size of liver
What causes abnormal accumulations of carbohydrates?
Secondary to inborn errors of metabolism
How are abnormal accumulations of protein seen in cells?
Eosinophilia droplets in cytoplasm
What is Mallory's hyaline?
Damaged hepatocyte protein due to accumulation of keratin in alcoholic liver disease
How does incorrectly folded alpha 1-antitrypsin lead to emphysema and hepatitis?
Causes alpha 1-antitrypsin deficiency --> accumulates in ER
How do exogenous pigments remain in the skin?
Macrophages pick up pigment and stay indefinitely, replaced when they die and remain stained
Why is some exogenous pigment found in lymph nodes?
Some is taken up by lymph fluid and taken to nodes
Give three examples of endogenous pigments found in the body.
How is heam converted to a toxic endogenous pigment?
Haem --> biliverdin (non-toxic) --> bilirubin (toxic)
What is the irreversible step in bilirubin production from biliverdin?
Breaking of porphyrin ring
Why is bilirubin associated with liver disease when it can be formed by all tissues of the body?
It is transported w/albumin to the liver
What is heamosiderin?
Iron storage molecule seen in systemic/local excess of iron
What causes haemosiderin deposition in tissues?
What is hereditary haemochromatosis?
Absorption of too much iron which affects the liver and pancreas
What is another name for hereditary haemochromatosis?
When is lipofuscin seen?
In age/wear and tear in tissues which have been damaged by free radicals
What type of cells is lipofuscin not seen in?
Rapid turnover cells
What are the three stages of excessive alcohol intake?
Steatosis - reversible
Acute alcohol hepatitis - reversible
Cirrhosis - irreversible
What are the S/S of acute alcoholic hepatitis?
How does the liver appear in cirrhosis?
Hard and nodular w/scar tissue and macrophages
What is dystrophic calcification?
Pathological local deposition of calcium seen in tuberculous lymph nodes and atheroma
Is there abnormal serum calcium or calcium metabolism in dystrophic calcification?
What is favoured in dystrophic calcification?
Hydroxyapatite crystal formation
Which is the commonest type of pathological calcification?
What is metastatic calcification?
Hypercalcaemia leading to deposition of hydroxyapatite crystals in all tissues
What can cause metastatic calcification?
Destruction of bone due to tumour
Immobilisation causing lack of bone formation stimulus
What causes cellular aging?
Shortening of telomeres
What occurs at a critical telomere length?
Why can germ cells and stem cells replicate indefinitely?
They contain telomerase which replicates their telomeres
How does the pattern of oncosis/necrosis compare to apoptosis?
Oncosis/necrosis: contiguous group of cells
Apoptosis: single cells
How does the cell size in oncosis/necrosis compare to that in apoptosis?
Oncosis/necrosis: enlarged (swelling)
Apoptosis: reduced (shrinkage)
How does the nucleus of a cell undergoing oncosis/necrosis compare to that of one undergoing apoptosis?
Apoptosis: fragmentation into nucleosome size fragments
How does the plasma membrane compare in oncosis/necrosis to apoptosis?
Oncosis/necrosis: disrupted, early lysis
Apoptosis: intact but w/altered structure, especially orientation of lipids
How do the cellular contents compare in oncosis/necrosis and apoptosis?
Oncosis/necrosis: enzymatic digestion which may leak out of cell
Apoptosis: remain intact but may be released by apoptotic bodies
Compare adjacent inflammation in oncosis/necrosis to apoptosis.
Apoptosis: does not take place
Does oncosis/necrosis have a physiological or pathological role?