Post on 13-Jan-2016
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RHY/CH0576
Biology of Disease CH0576
Irreversible Cell Injury & Death
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Irreversible Cell Injury
• Cells can adapt to worsening environmental conditions and persistent injuring factors.
• However, there is a limit to the extent of the adaptations which are possible
• If the acute stress is > capacity to adapt then the resulting changes in both structure and function will inevitably lead to cell death
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Irreversible Cell Injury• The theoretical ‘point of no return’ is
passed.• The injury becomes irreversible• The cell will inevitably proceed to cell
death.• Cell death is almost always accompanied
by a series of morphological changes which can be recognised in the light microscope
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Irreversible Injury & Cell Death
• These recognisable changes are usually referred to as Coagulative Necrosis.
• We are unable to recognise when a cell is irreversibly injured until it is dead, and the feature of necrosis are apparent.
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Morphology of Coagulative Necrosis
• Coagulative necrosis involves changes in the cytoplasm, nucleus and membrane.
• When stained with H & E, the cell cytoplasm is much more eosinophilic than normal.
• Initially the nucleus of a necrotic cell shows clumping of the chromatin, followed by a redistribution around the periphery of the nuclear membrane.
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Nuclear Changes in CN.• The nucleus becomes
smaller and stains more basophilic as the chromatin within it continues to clump
• This is referred to as PYKNOSIS.
• Basophilia indicating the end of DNA transcription
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Normal v Pyknotic Cell
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Nuclear changes in CN.• Necrotic process
continues, with the action of nucleases, causing the nucleus to fragment.
• The fragments become scattered throughout the cytoplasm.– KARYORRHEXIS
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Karyorrhexis
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Nuclear Changes in CN.
• The pyknotic or fragmented nucleus may be actively extruded from the cell or it may undergo further and complete dissolution, a process known as:- – KARYOLYSIS
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Normal v Necrotic Cell
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Pathogenesis of Necrosis• The necrotic cell is left as a mass of
partly denatured protein, still having the same rough cellular outline as the surrounding cells.
• The cytoplasm is deeply eosinophilic.• Coagulative necrosis is the same no
matter what the cause of cell death: virus, radiation or ischaemia, for example.
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Pathogenesis of Necrosis• A characteristic of living cells is that
they maintain large differences between their internal and external environments.
• These differences are maintained by the plasma membrane.
• With cell death, these characteristic differences in ionic concentrations are dissipated or lost.
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Pathogenesis of Necrosis
• One of the most significant gradients maintained across a living cell membrane is that of Ca2+.
• The concentration of Ca2+ in the external fluid is in the millimolar range.
• Concentration within the cell is around 10,000 times lower.
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Pathogenesis of Necrosis
• This gradient is actively maintained.• Cell death is accompanied by an
accumulation of Ca2+ within the cell.• Calcium ions have a wide range of
biological functions and their accumulation may account for many of the features of coagulative necrosis.
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Pathogenesis of Necrosis
• The sequence of events leading to CN may be:– Irreversible cell injury and death– loss of membrane’s ability to
maintain the calcium gradients.– Influx and accumulation of Ca2+
– Morphologic appearance of Coagulative Necrosis.
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Morphology of Necrosis
• Several different patterns of necrosis are described.
• These largely reflect various macroscopic appearances of the dead tissues.
• These include:-
• Coagulative• Liquefactive• Fat necrosis• Gummatous• Haemorrhagic• Fibrinoid • Caseous
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Coagulative Necrosis
• This describes dead tissue which appears pale and firm - giving the appearance almost of cooked meat!
• Even though the cells are dead, much of the cellular outline and tissue architecture can still be recognised
• Tissues with relatively low levels of lysosomes exhibit this form.
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Coagulative Necrosis• The most common cause of CN is
ischaemia due to the occlusion of the arterial blood supply to a tissue.
• In some cases of CN, the proteins and enzymes which are released from dead cells can be used as a diagnostic indicator or marker of specific disease.
• Their presence in blood indicating specific cellular damage.
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Coagulative Necrosis• In order for a particular protein or
enzyme assay to be of use as a diagnostic aid, the substance must satisfy two major criteria:– It must have a restricted cellular
distribution– It must be normally present in blood in
only low concentrations, making an elevation in concentration significant.
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Diagnostic Assays
• A number of fairly routine diagnostic clinical chemistry assays for the following, rely on this process:-– Myocardial infarct– Liver damage– Striated muscle– Exocrine pancreas
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Coagulative Necrosis• In coagulative necrosis the dead cells
remain in situ long enough to be recognised and identified.
• In most cases the necrotic debris is eventually removed as a consequence of the inflammatory reaction.
• In cases where the are large areas of coagulative necrosis the necrotic tissue may remain in place for years.
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Coagulative Necrosis
• Examples would include occlusion of a coronary artery and the resultant infarction of a large area of the myocardium.
• The central area of necrosis may be inaccessible to the inflammatory reaction and the necrotic debris remains in situ.
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Coagulative Necrosis• This explains how, on post mortem
studies, previous infarcts are evident as fibrous scars.
• In most cases regeneration and repair mechanisms are responsible for the active removal of necrotic tissue.
• Unfortunately, the heart is composed of a permanent tissue - cardiac muscle.
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Coagulative Necrosis
• Coagulative necrosis in area of the kidney
• Ischaemia has led to an infarction
• Tissue architecture is maintained despite all of the cells in the area being dead
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Normal v Coagulative Necrosis
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Liquefactive Necrosis• This pattern of necrosis describes tissue
which appears semi-liquid.• The appearance is due to the dissolution
of the necrotic tissue under the influence of powerful hydrolytic enzymes.
• Two main instances:– Necrosis in the brain– Necrosis due to bacterial infection.
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Liquefactive Necrosis• Liquefactive necrosis in
a cerebral infarct• No residual tissue
architecture is retained.• The area of the brain is
transformed into a semi-liquid mass of protein with numerous macrophages
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Fat Necrosis
• This affects adipose tissue and is most commonly the result of either:– Physical trauma to adipose tissue e.g.
breast– Pancreatitis.
• Unique feature in this form of necrosis is the presence of triglycerides released from damaged fat cells.
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Fat Necrosis - Pancreas• The process begins with the
inappropriate release of digestive enzymes.
• These are normally restricted to:– pancreatic acinar cells– pancreatic ducts– small intestine.
• They are released inappropriately from damaged pancreatic acinar cells.
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Fat Necrosis• The enzymes gain access to the
extracellular compartment.• They commence to digest the tissue of
the pancreas itself as well as the surrounding tissue, especially adipose cells.
• Phospholipases and proteases released attack the plasma membranes of the fat cells. Stored triglycerides are released.
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Fat Necrosis• The pancreatic enzymes then
digest the triglycerides in to free fatty acids.
• These precipitate in the form of ‘calcium soaps’.
• These accumulate as amorphous, basophilic deposits at the edge of irregular islands of necrotic adipose cells.
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Fat Necrosis
• On macrosciopic examination (left) fat necrosis appears as chalky-white areas, embedded in otherwise normal tissue. Histologically these areas of fat necrosis are composed of large areas of necrotic fat, usually around 5 mm diameter, with surrounding areas of reactive inflammation (right)
Foci of fat necrosis
Necrotic Fat
Inflammation
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Caseous Necrosis
• This form of necrosis is highly characteristic of Tuberculosis.
• The lesions associated with TB are tuberculous granulomas or tubercles.
• In the centre of the granulomas the chronic inflammatory cells (mononuclear cells) which are mediating the response against the infection are killed along with the tissue cells.
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Caseous Necrosis
• In caseous necrosis the necrotic cells don’t retain their cellular outlines nor are they completely lysed as in liquefactive necrosis.
• The dead cells persist as amorphous, coarsely granular eosinophilic debris.
• Macroscopically the debris appears greyish white and crumbly.
• It has an appearance resembling crumbly cheese - hence ‘caseous’ necrosis.
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Caseous Necrosis
• This form of necrosis is not seen at the centre of granulomas caused by other agents.
• This highly characteristic pattern of necrosis is thought to be due to the toxic effects of the unusual cell wall of the mycobacterium, which contains complex waxes, known as peptidoglycolipids.
• Viable mycobacteria are present within the necrotic debris.
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Caseous Necrosis - Tuberculosis
CN
AM
L
GC
A tuberculous granuloma with central caseous necrosis
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Gummatous Necrosis
• This describes dead tissue that is firm and rubbery.
• None of the original tissue architecture can be seen histologically.
• The dead cells form an amorphous mass.
• Seen in syphillis due to spirochaete T.pallidum
N
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Haemorrhagic Necrosis• This describes necrotic tissues which are
engorged or suffused with extravascular red blood cells.
• This pattern of necrosis is seen particularly when cell death is due to a blockage of the venous drainage from the tissue e.g. torsion of the testis.
• Congestion of the tissue by blood with a result of failure in arterial perfusion ischaemia.
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Haemorrhagic Necrosis - Testicular torsion
• Torsion of the testis, due to torsion or twisting of the spermatic cord.
• Venous return is blocked• Blood cannot escape the
tissue which becomes engorged.
• Arterial perfusion fails as tissue is full of venous blood ischaemia.
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Fibrinoid Necrosis - Vasculitis
• Term used to describe the appearance of arteries in cases of vasculitis or in severe hypertension.
• Plasma proteins, and in particular fibrin, become deposited in the damaged necrotic vessel wall producing marked eosionophilia FN