1
Q
What does Diagnostic Pathology involve and why is it important?
A
- Studying the structural and functioal alterations in cells and tissues e.g. by microscopy, in order to arrive at a diagnosis
- The MORPHOLOGICAL changes in cell and tissues and their distribution within an organ results in the symptoms and signs of disease
- All disease starts with molecular or structural alterations in cels
2
Q
How can Disease be Considered?
A
- As a conseqence of failed homeostasis with consequent morphological and function disturbances
- Cells are to maintain homeostasis when subjeced to MILD changsin environmental conditions. BUT when changes are more SEVERE cells undergo physiological and miorphological adaptations in an attempt to remain viable.
- When cells reach the limits of their adaptive response, they may show evidence of reversible or irreversible injury and death.
- The degree of injury depends on the type, duration and severity of an injury and the type of tissue involve.
3
Q
List the Various Causes of Cell Injury and Death
A
- Hypoxia
- Physical agents e.g. direct trauma, extremes of temperature (burns and severe cold), sudden changes in atmospheric pressure, electric currents and radiation
- Chemical agents and drugs e.g. glucose or salt in hypertonic solutions, oxygen in high concentrations, poisons, insecticides, herbicides, asbestos, alcohol and illicit drugs, therapeutic drugs
- Micro-organisms e.g. viruses, bacteria, fungi, parasites
- Immune mechanisms: hypersensitivity and autoimmune reactions
- Dietary insufficiencies and deficiencies and dietary excess
- Genetic abormalities e.g. inborn errors of metabolism.
4
Q
Explain about Hypoxia
A
- Oxygen deprivation results in decreased aerobic oxidative respiration which if persistent will cause cell adaptation (e.g. atrophy), cell injury or cell death.
- The length of time a cell can tolerate hypoxia varies: neurones can only tolerate a few minutes while dermal fibroblasts can tolerate a number of hours.
5
Q
What are the causes of hypoxia?
A
- Hypoaxaemic: arterial content of oxygen is low e.g. reduced inspired pO2 at altitude
- Anaemic: decreased ability of haemoglobin to carry oxygen e.g. anaemia, carbon monoxide poisoning
- Ischaemic: interruption to blood supply e.g. blockage of a vessel, heart failure
- Histiocytic: inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzyme (cyanide poisoning)
6
Q
What is Ischaemia?
A
- Loss of blood supply due to reduced arterial supply eg. obstruction of an artery, hypotension, OR reduced venous drainage
- This causes a reduced supply of oxygen and metabolic substrates e.g. glucose for glycolyis and the resultant injury therefore occurs more rapidly and is more severe than that seen with hypoxia.
7
Q
Explain how immune mechnisms can cause injury
A
Principally by two mechanisms:
- Hypersensitivity reactions: the host tissue is injured secondary to an overly vigorous immune reaction e.g. urticaria (hives)
- Autoimmune reactin: immune system fails to distinguish self from non-self e.g. Grave’s
8
Q
What are the principal targets of cell injury?
A
- Cell membrane: the plasma membrane plays a vital role in homeostasis and the organellar membranes whch compartmentalise organelles such as Lysosomes (particularly important as they contain enzymes which cause cell damage)
- Nucleus (contains genetic material of the cell)
- Proteins (structural proteins forming the cytoskeleton and the enzymes involved in the metabolic processes of the cell)
- Mitochondra where oxidative phosphorylation and production of ATP occurs.
9
Q
Describe Reversible Hypoxic Injury
A
- Oxygen deprivation leads to decreased production of ATP in mitochonria. When the levels of ATP drop to less than 5-10% of normal concentrations, vital cellular functions become compromised.
- Loss of activity of the Sodium Pump (ATP-dependent). As the intracellular concentrations of Na+ rises, water enters the cell and the cell and its organelles swell up. Ca2+ also enters causing damage to cell components.
- The cell switches to the glycolytic pathway of ATP prodution leading to accumulation of lactic acid, lowering the pH inside the cell. Low pH affects the activity of many enzymes within the cell. Chromtin clumping occurs.
- Ribosomes detach from the ER and protein synthesis is disrupted. This can result in intracellular accumulations of substances such as fat and denatured proteins.
10
Q
What does Irreversible Hypoxic Injury mean and when does it occur?
A
- Not well understood but at some point, injury becomes irreversile and cell eventually dies
- Usually appers as necrosis
- Develomentof profound disturbances in membrane integrity and the associated massive cytosolc accumulation of Ca2+ is a key even
11
Q
What happens when Ca2+ enters the cell across the damaged plasma membrane and is released from intracellular stores in severely damaged cells?
A
Activate an array of potent enzymes:
- ATPases (decrease [ATP} even further)
- Phospholipases (causes further embrane damage)
- Proteases (break down membranes and cytoskeletal proteins)
- Endonucleases (damage DNA)
When Ca2+ enters cells whose membranes are irreversibly damaged, intracellular substances leak into the circulation. These can be detected in blood samples and particular substances can be indicative of location of cellular damage e.g if liver cells are injured, transminases will be detected in the blood.
12
Q
What happens when lysosomal membranesare damaged?
A
Lysosomal hydrolases leak into the cytoplasm further damaging the cell
13
Q
Describe an Ischaemia-Reperfusion Injury
A
- This is when blood is returned to a tissue which has been subject to ischaemia but isn’t yet necrotic.
- Sometimes the injury that is then sustained is worse than if blood flow was not restored
- This may be due to:
- increased production of oxgen free radicals with reoxygenation
- Increased number of neutrophils following reinstatement of blood suppy resulting in more inflammation and increased tissue injury
- Delivery of complement proteins and activation of the complement pathway
14
Q
What are free radicals and how can they cause cell damage?
A
- Single unpaired electron (unstable configuration) so they react with other molecules, often producing further free radicals (autocatalytc chain reaction)
- Produced particularly in chemical and radiation injury, ischaemia-reperfusion injury, cellular aging and at high oxygen concentrations.
- They attack lipids in membranes and cause lipid peroxidation.
- They aso damage proteins, carbohydrates and nucleic acids - molecules become bent - deformed, broken or cross-linked.
- Known to be mutagenic
15
Q
What important roles do free radicals have in the body?
A
- Leukocytes produce free radials - used for bacteria killing ‘oxidative burst’
- Also used in cell signalling
16
Q
What are three main radicals and how can they be produced?
A
- Three free radicals: OH● (hydroxyl, most dangerous), O2- (superoxide) and H2O2 (hydrogen peroxide).
- Hydroxyl can be formed in a number of ways
- Radiation can directly lyse water → OH●
- The Fenton and Haber-Weiss reactions produce OH●. NB: H2O2 and O2- are substrates for these reactions which is one reason why it is important to rapidly remove hydrogen peroxide and superoxide so that the more dangerous OH● can’t be generated.
- Generation of H2O2 and O2- occurs in normal metabolic reactions in cytoplasm and mitochondria.
17
Q
What is meant by Oxidative Stress
A
When there is an imbalance between free radical production and free radical scavenging so free radicals accumulate in the cell/tissue causing cell injury.
18
Q
What is the Anti-oxidant System?
A
- Defence system to protect against free radicals. Consists of:
Ezymes: Superoxide Dismutase catalyses O2- to H2O2 (which is significantly less toxic)
Catalases amd peroxidises complete the process of free radical remova: H2O2 –> O2 and H2O
Free radical scavengers (Vit A, C, E and glutathione) that neutralise free radicals
In the extracellular matrix, storage proteins e.g. transferrin and ceruloplasmin sequester transition metals e.g. iron and copper, which catalyse the formation of free radicals.
19
Q
What are Heat Shock proteins
A
- When the folding step in protein synthesis goes astray or when proteins become denatured during cell injury, heat shock proteins ensure proteins are re-folded correctly.
- If this isn’t posible, then the mis-folded protein is destroyed.
- Important in cell injury as heat shock response plays a key role in maintaining protein viabiity and thus maximisig cell survival.
- Unfoldases or chaperonins e.g ubiquitin
20
Q
Describe the Reversible Morphological Changes Under Light Microscopy
A
- Reduced pink staining of the cytoplasm due to accumulation of water
- Chromatin is subtly clumped
- Abnormal intracellular accumulations
21
Q
Describe the Irreversible Morphological Changes Under Light Micrsoscopy
A
- Increased pink staining due to detachment and loss of ribosmes from the ER and accumulation of denatured proteins.
- After chromatin clumping, various combinatiions of pyknosis, karryohexis and karryolysis follow
- Pyknosis: shrinkage due to condensation of chromatin
- Karryohexis: fragmentation
- Karryolysis: dissolution of the nucleus
22
Q
Describe the Reversible Morphological Changes under Electron Microscopy
A
- Swelling of the cell and organelles due to Sodium Pump failure
- Autophagy by lysosomes
- Cytoplasmic blebs (symptomatic of cell swelling - little bumps on membrane surface where cytoskeleton has detached)
- Clumped chromatin due to reduced pH
- Ribosome separation and dispersal from the ER due to failure of energy-dependent process of maintaining ribosomes in the correct location.
23
Q
Describe the Irreversible Morphological Changes of Cell Injury Under Electron Microscopy
A
- Further cell swelling
- Nuclear changes: pyknosis, karryolysis or karryohexis
- Swelling and rupture of lysosomes - reflects membrane damage
- Membrane defects
- Appearance of myelin figures (which are damaged membranes)
- Lysis of the ER due to membrane defects
- Amorphous densities in swollen mitochondria
24
Q
Define Oncosis
A
The spectrum of changes that occur in injured cells prior to death - cell death with swelling
25
Define Necrosis
The Morphological changes that follow cell death in living tissue, largely due to the progressive degradative action of enzymes on a lethally injured cell. 'What the tissue looks like'
26
Define Apoptosis
Cell death induced by a regulated intracellular program where cell activates enzymes that degrade it's own nuclear DNA and proteins. Cell death with shrinkage; cell induced suicide
27
When is necrosis seen?
When there is damage to cell membranes (plasma and organelle) and lysosomal enzymes are released into the cytoplasm and digest the cell. As a result cell contents leak out of the cell and inflammation is often seen.
Changes develop over a number of hours.
Eventually necrotic tissue is removed by enzymatic degadation and phagocytosis by white cells.
If some necrotic remains, it may calcify - process is called DYTROPHIC CALCIFICATION
28
What is Coagulative necrosis?
* When protein denaturation is dominant over release of active proteases, the proteins tend to clump together leading to the solidity of dead cell and consequently of the dead tissue
29
What is Liquefactive Necrosis?
When release of active enzymes, especially proteases is dominant over protein denaturation, the dead cells and consequently the dead tissue tends to liquefy.
30
Describe what determines which type of necrosis is seen
balance between protein denaturation and release of active enzymes.
Types of necrosis: Coagulative, Liquefactive (aka colliquitive), Caseous and Fat
***GANGRENE AND INFARCT ARE TERMS NOT TYPES OF NECROSIS***
31
Describe Coagulative Necrosis
* Common when the cause of death is ischaemia in most solid tissue
* Dead tissue has a solid consistency
* Histologically the cellular architecture is somewhat preserved creating a ghost outline of the cells.
* Such changes will only be seen in first few days
* After that the appearances are modified by the fact that the dead tissue incites an acute inflammatory reaction with consequent infiltration by phagocytes.
32
Describe Liquefactive Necrosis
* When cell death is associated with large numbers of neutrophils, their released proteolytic enzymes lead to liquefactive necrosis
* enzymatic digestion of tissues
* Seen in massive neutrophil infiltration (e.g. in abscesses) because neurophils release proteases.
* Seen in bacterial infections
* Seen in the brain because this is a fragile tissue without support from a robust collagenous matrix
* The tissue becomes a viscous mass and if there is acute inflammation pus is present.
33
Describe Caseous Necrosis
* Cheese appearance (macroscopically)
* Characterised by amorphous (i.e. structureless) debris not 'ghost outlines' as in coagulative necrosis.
* Particularly associated with infections especially tuberculosis
* It is often associatedwith a particular form of inflammation known as "granulomatous"
34
Describe Fat Necrosis
* Destruction of adipose tissue
* Typically seen as a consequence of astute pancreatitis as during inflammation of the pancreas, there is a release of lipases from the injured pancreatic acinar cells.
* These lipases act on the fatty tissue of the pancreas and on fat elsewhere in the abdominal cavity causing fat necrosis.
* Fat necrosis causes release of free fatty acis which can react with calcium to form chalky deposits (calcium soaps) in fatty tissue which can be seen on X-rays and with the naked eye at surgery and autopsy
* Fat necrosis can also occur after direct truma to fatty tissue especially breast tissue which contain a lot of adipose tissue. After it heals it leaves an irregular scar that can mimic a nodule of breast cancer.
35
Define Gangrene
* Clinical term to describe necrosis visible to the naked eye (macroscopic)
* Dry, Wet, Gas
* Gangene is mot commonly seen in ischaemic limbs
* Gangrenous tissue is dead and therefore cannot be salvaged.
36
Describe Dry, Wet and Gas Gangrene
* Dry gangrene in which the underlying proess is coagulative ncrosis
* Wet gangrene is see with liquefactive necrosis. Typically due to infection and is very serious as it can result in septicaemia
* Gas is a particular type of wet gangrene; tissue has become infected with anaeobic bacteria which produces bubbles of gas.
37
What doe Infarction mean?
* Refer to a cause of necrosis, namely Ischaemia
* An area of tissue death caused by an obstruction of a tissue's blood supply is an infarct.
* Infarction can result in gangrene.
* Most infarctions are due to thromosis or embolism. Can occasonally be due to extenal compression of a vessel e.g. by a tumour or within a hernia
* Can be coagulative or liquefactive
* Can be described as White or Red
38
Give an example of infarction due to coagulative necrosis
Ischaemic necrosis in the heart (myocardial infarction) shows coagulative necrosis
39
Give an example of Liquefactive Infarction
Ischaemic necrosis in the brain (cerebral infarction)
40
What is a White Infarct and where can it occur?
* Anaemic infarct occurs in solid organs with good stromal support after occlusion of an end artery (sole source of arterial blood).
* The solid nature limits the amount of haemorrhage that can occur into the infarct from adjacent capillaries.
* The tissue supplied by the end artery dies and appears pale/white due to lack of blood in the tissue
* Can occur in heart, spleen and kidneys
* Most are wedge-shaped with the occluded artery at the apex of the wedge
* Histologically, white infarcts appear as coagulative necrosis
41
What is Red Infarct and where does it occur?
* Haemorrhagic infarct occurs when there is extensive haemorrhage into dead tissue:
* In organs with a dual blood supply e.g. lung. Occlusion of the main arterial supply causes an infarct. The second arterial supply is insufficient to rescue the tissue but does allow blood to enter the dead tissue.
* If numerous anatomoses (where the capillary beds of two separate arterial supplies merge) are present within the tissues e.g. intestines
* In loose tissue e.g. lung wher there is poor stromal support for capillaries and therefore there is more than usual haemorrhage into the dead tissue
* When there has been previous congestion e.g. in congestive cardiac failure, tissues can be congested and there is more than the usual amount of blood in the necrotic tissue
* Where there is raised venous pressure
42
How can raised venous pressure cause a red infarct?
Increased pressure is transmitted to the capillary bed. As the tissue pressure increases, eventually there is reduced arterial filling pressure in the tissue which causes ischaemia and subsequent necrosis. Because the tissue was engorged with blood, the resulting infarct is red.
43
What are the consequences of Infarcts
Varies. Ranges from none to death. Depend on:
* if an alternative blood supply is available e.g. the lung and forearm has alternative blood supply
* how quickly the ischaemia occurred. If slowly, then there is time for the development of additional perfusion pathways.
* How vulnerable a tissue is to hypxia
* The oxygen content of the blood; An infarct occurring in an anaemic patient may have more serious consequences.
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