Pathological Processes Flashcards
1
Q
What are the common causes of cell injury?
A
Hypoxia
Physical agents
Chemical agents
Micro-organisms
Immune mechanisms
Dietary insufficiency and deficiencies and dietary excess
Genetic abnormalities (inborn errors of metabolism)
2
Q
What is the mechanism of hypoxic cell injury?
A
Cell is deprived of oxygen, mitochondrial
ATP production stops. ATP-driven membrane ionic pump runs down. Sodium and water seep into the cell. Cell swells, and membrane is stretched.
Glycolysis allows cell to survive for a little longer. Cell initiates a heat-shock response, won’t be able to cope if hypoxia persists.
pH drops due to glycolysis and lactic acid accumulation. Calcium enters cell - activates phospholipases (membrane lose phospholipid), proteases (cytoskeleton is damaged and membrane proteins attacked), ATPase (causing further loss of ATP), endonucleases (nuclear chromatin clump)
ER and other organelles swell.
Enzymes leak out of lysosomes - these attack cytoplasmic components
All cell membranes are damaged and show blebbing.
Cell dies - possibly killed by bleb bursting.
3
Q
How do the different mechanisms of cell injury target different components of the cell?
A
Cell membranes
Nucleus
Proteins - structural proteins and enzymes
Mitochondria
4
Q
Define hypoxia
A
Oxygen deprivation
5
Q
Define hypoxaemic hypoxia
A
Low level of oxygen in the blood
6
Q
Define anaemic hypoxia
A
The oxygen carrying ability of the blood decreased
Cyanide poisoning, CO poisoning
7
Q
Define ischaemic hypoxia
A
Insufficient blood flow to provide adequate oxygenation
8
Q
Define histiocytic hypoxia
A
Cells can’t utilise the oxygen
9
Q
Name some examples of physical agents that cause cell injury
A
Direct trauma Extreme temperatures (burns and severe cold) Sudden changes in atmospheric pressure Electric currents Radiation
10
Q
Name some examples of chemical agents that cause cell injury
A
Glucose or salt in hypertonic solutions Oxygen in high concentrations Poisons Insecticides Herbicides Asbestos Alcohol Illicit drugs Therapeutic drugs
11
Q
What is the mechanism of ischaemia-reperfusion cell injury?
A
Blood flow returned to a tissue subject to ischaemia but not yet necrotic. The damage to the tissue can be worse than if blood flow was not restored.
May be due to increased production of oxygen free radicals with reoxygenation - due to burst of mitochondrial activity; may be due to increased number of neutrophils following blood supply (more inflammation and increased tissue injury); may be due to delivery of complement proteins and activation of the complement pathway
12
Q
How do free radicals cause cellular damage?
A
Attack lipids in cell membranes and cause lipid peroxidation
Damage proteins, carbohydrates and nucleic acids
Cause mutations (mutagenic)
13
Q
What does the anti-oxidant system consist of?
A
Enzymes (superoxide dismutase), catalases, peroxidases)
Free radical scavengers
Storage proteins
14
Q
How do free radical scavengers form part of the anti-oxidant system?
A
They neutralise free radicals
15
Q
Name examples of free radical scavengers
A
Vitamins A, C, and E
Glutathione
16
Q
How do storage proteins form part of the anti-oxidant system?
A
Sequester “hide away/isolate” transition metals in the extracellular matrix.
Transferrin and ceruloplasmin sequester iron and copper, which catalyse the formation of free radicals.
17
Q
Name some heat shock proteins
A
Stress proteins
Unfoldases
Chaperonins
Ubiquitin
18
Q
What is the heat shock response?
A
All cells from any organism turn down their usual protein synthesis and turn up synthesis of HSPs in response to stress
19
Q
Why are HSPs important in cell injury?
A
Heat shock response plays a key role in maintaining protein viability and thus maximising cell survival
20
Q
Describe the appearance of injured cells in a light microscope
A
Cytoplasmic
Nuclear changes
Abnormal intracellular accumulations
21
Q
What are the reversible changes observed in injured cells in an electron microscope?
A
Swelling - cell and organelles due to Na+/K+ pump failure
Cytoplasmic blebs - symptomatic of cell swelling
Clumped chromatin due to reduced pH
Ribosome separation from ER due to failure of energy-dependant process of maintaining ribosomes in the correct location
22
Q
What are the irreversible changes observed in injured cells in an electron microscope?
A
Increased cell swelling
Nuclear changes - pyknosis, karyolysis, or karyorrhexis
Swelling and rupture of lysosomes - reflects membrane damage
Membrane defects
Appearance of myelin figures (damaged membranes)
Lysis of the endoplasmic reticulum due to membrane defects
Amorphous densities in swollen mitochondria
23
Q
Define oncosis
A
Cell death with swelling; the spectrum of changes that occur prior in cells injured by hypoxia and some other agents
24
Q
Define apotosis
A
Cell death with shrinkage; cell death induced by a regulated intracellular program where a cell activates enzymes that degrade its own nuclear DNA and proteins
25
Define necrosis
In a living organism the morphological changes that occur after a cell has been dead for some time (between 4 and 24 hours).
Necrosis describes morphological changes, not a type of cell death.
It is an appearance and not a process
26
What are the different types of necrosis?
Coagulative
Liquifactive (colliquitive)
Caseous
Fat
27
What happens in coagulative necrosis?
Proteins undergo denaturation, and then coagulate
28
What happens in liquifactive necrosis?
Proteins undergo dissolution by the cells own enzymes
29
What is gangrene?
Clinical term to describe necrosis that is visible to the naked eye
30
What are the different types of gangrene?
Wet and dry gangrene
31
How does dry gangrene come about?
Necrosis is modified by exposure to are resulting in drying
32
How does wet gangrene come about?
Necrosis is modified by by infection with a mixed bacterial culture.
33
What is the underlying process in dry gangrene?
Coagulative necrosis
34
What is the underlying process in wet gangrene?
Liquifactive necrosis
35
What is gas gangrene?
Wet gangrene where the tissue has become infected with anaerobic bacteria that produce visible and palpable bubbles of gas within the tissues
36
What is infarction in relation to necrosis?
Infarction is a cause of necrosis - ischaemia (reduced blood supply)
37
What are the classifications of infarcts?
Red or white
| - indicates how much haemorrhage there is into the infarct
38
What is a white infacrt?
Anaemic
Occurs in 'solid' organs (those with good stromal support) after occlusion of an "end" artery - any artery that is the sole support of arterial blood to a segment of an organ
39
What is a red infarct?
Haemorrhagic
| Occurs where there is extensive haemorrhage into dead tissue
40
What molecules are released by injured, dying and dead cells?
Potassium
Enzymes (can indicate the organ involved and the extent, timing and evolution of the tissue damage)
Myoglobin (this is released from dead myocardium and striated muscle)
41
What are the consequences of dead/dying cells leaking molecules?
Can cause local irritation and local inflammation
May have general toxic effects on the body
May appear in high concentrations in the blood and can be measured and thus aid in diagnosis
42
What is apoptosis?
The death of a single cell (or small cluster of cells) due to activation of an internally controlled suicide programme
43
What is the appearance of apoptotic cells under a light microscope?
They are shrunken, intensely eosinophilic
| Chromatin condensation, pyknosis and karyorrhexis
44
What is the appearance of apoptotic cells under an electron microscope?
Cytoplasmic budding
Fragmentation
Membrane-bound apoptotic bodies which contain cytoplasm, organelles and often nuclear fragments
45
What is the fate of apoptotic cells?
Eventually removed by macrophage phagocytosis
46
Why does apoptosis not induce inflammation?
There is no leakage of cell contents so does not induce inflammation
47
What are the three phases of apoptosis?
Initiation
Execution
Degradation/phagocytosis
48
What are abnormal cellular accumulations?
If the cell is unable to metabolise something it will remain in the cell as one of these
49
When are abnormal cellular accumulations seen?
When metabolic processes become deranged
| Often occur with sublethal or chronic injury
50
Are all abnormal cellular accumulations dangerous?
No, they can be reversible, harmless or toxic
51
What can abnormal cellular accumulations derive from?
Cell's own metabolism
Extracellular space, e.g. spilled blood
Outer environment, e.g. dust
52
What are the five main groups of intracellular accumulations?
```
Water and electrolytes
Lipids - triglycerides and cholesterol
Proteins - e.g. Mallory's hyaline, alpha-1 antitrypsin
'Pigments' - exogenous and endogenous
Carbohydrates
```
53
What are the different types of calcification?
Dystrophic and metastatic
54
What is pathological calcification?
Abnormal deposition of calcium salts within tissues
55
Where does dystrophic calcification occur?
```
Areas of dying tissue
Atherosclerotic plaques
Some neoplastic growths
Aging or damaged heart valves
Tuberculous lymph nodews
```
56
Describe dystrophic calcification
No abnormality in calcium metabolism or serum calcium or phosphate concentrations
A local change of disturbance in the tissue favours the nucleation of hydroxyapatite crystals
57
Describe metastatic calcification
Disturbance is body-wide
Hydroxyapatite crystals are deposited in normal tissues throughout the body when there is hypercalcaemia secondary to disturbances in calcium metabolism.
Usually asymptomatic but it can be lethal
58
What happens when a cell ages?
It accumulates damage to cellular constituents and DNA.
| Decline in the ability to replicate.
59
Why are older cells unable to replicate?
Replicative senescence
The ends of chromosomes are called telomeres and with every replication the telomere is shortened.
When the telomeres reach a critical length, the cell can no longer divide
60
What are the common causes of acute inflammation?
Microbial infections (bacterial, viral, parasitic and microbial toxins)
Hypersensitivity reactions
Physical and chemical agents (thermal injury - burns or frostbite; irradiation, environmental chemicals)
Tissue necrosis (any cause)
Foreign bodies (splinters, dirt, sutures)
61
What is acute inflammation?
Short term process occurring in response to tissue injury, usually appearing within minutes or hours
62
What are the clinical signs of inflammation?
```
Rubor
Calor
Tumor
Dolor
Loss of function
```
63
What is rubor?
Redness
64
What is calor?
Heat
65
What is tumor?
Swelling
66
What is dolor?
Pain
67
What causes rubor?
Caused by increased blood circulation
68
What causes calor?
Increased blood circulation leads to a rise of body temperature at the site of inflammation
69
What causes tumor?
Fluid leaks into the tissues
70
What causes dolor?
Some of the released mediators such as bradykinin increase the sensitivity to pain
71
What tissue changes occur in acute inflammation?
Vascular phase
| Cellular phase
72
What occurs during the vascular phase?
Changes in blood flow
| Accumulation of exudate
73
What occurs during the cellular phase?
Delivery of neutrophils
74
Describe the changes in blood flow in the vascular phase of acute inflammation
Vasoconstriction in seconds
Vasodilatation in minutes (causing heat and redness)
Increased permeability - fluids and cells can escape
75
Describe the movement of fluid in the vascular phase of acute inflammation
Vasodilatation - increased capillary hydrostatic pressure
Increased vessel permeability - plasma proteins move into interstitium, increased interstitial oncotic pressure
Fluid movement - out of vessel into interstitium, causing oedema (tumor)
76
What changes to blood are there in acute inflammation?
Movement of fluid out of vessel - increased viscosity of blood
Reduced flow through the vessel - stasis
77
What is a fluid exudate?
Fluid that filters from the circulatory system into areas of inflammation
78
What is in a fluid exudate?
High protein content
| Many contain some white and red cells
79
What is a neutrophil?
Primary type of leucocyte involved in acute inflammation
80
Why are neutrophils important in mediating acute inflammation?
Each neutrophil contains about 2,000 granules containing bactericidal substances
Must:
1- chemotaxis (summoned to place of injury)
2- activation (switch to higher metabolic level)
3- margination (stick to the endothelial surface)
4- diapedesis (crawl through the endothelium)
5- recognition-attachment (recognise the bacterium and attach to it)
6- phagocytosis (engulf the bacterium)
81
What are some of the key chemical mediators involved in acute inflammation?
```
Vasoactive amines
Vasoactive peptides
Complement components
Clotting and fibrinolytic cascades
Mediators derived from phospholipids
Cytokines and chemokines
Exogenous mediators of inflammation
```
82
Describe vasoactive amines
Histamine and serotonin
| cause vasodilatation, increased vascular permeability
83
Describe vasoactive peptides
Bradykinin
circulates in blood as part of kininogen
effects are: increased vascular permeability, vasodilatation and burning pain
84
Describe mediators derived from phospholipids
Prostaglandins, thromboxanes and leukotrienes
leukotriene B4 - powerful chemotaxis agent
cause vasodilatation and prostaglandins cause pain
85
Describe complement components
C3a, C5a
function is to form a tube which punches holes in bacteria - causing them to die
circulates in the blood as a number of disassembled proteins
86
Describe cytokines and chemokines
Interleukins, tumour necrosis factor (TNF), interferons
polypeptides that act as messengers between cells
Chemokines - cytokines involved in chemotaxis
Cytokines are produced by macrophages, appear in hours following injury
Local and systemic effects - TNF causes cachexia
87
Describe exogenous mediators
Endotoxin produced by gram negative bacteria
when released, causes inflammation - but if released into blood activates numerous inflammatory mechanisms at once - results in septic shock
88
What are the local and systemic short and long term consequences of acute inflammation
Local - damage to normal tissue, obstruction of tubes (i.e. intestine or Fallopian tubes), loss of fluid (due to oedema), pain and loss of function
Systemic - fever, leucocytosis, acute phase response, shock
89
What are the effects of acute inflammation on organs?
Can lose function
90
What are some features of acute inflammation seen in lobar pneumonia?
jk
91
What are some features of acute inflammation seen in acute appendicitis?
ki
92
What are some features of acute inflammation seen in bacterial meningitis?
jk
93
What are some features of acute inflammation seen in ascending cholangitis?
k
94
What are some features of acute inflammation seen in liver abscesses?
jk
95
Name a few inherited disorders of the acute inflammatory process
Hereditary angio-oedema
Alpha-1 antitrypsin deficiency
Chronic granulomatous disease
96
Describe hereditary angio-oedema
Extremely rare, autosomal dominant
Deficiency of C1-esterase inhibitor
Patients have attacks of non-itchy cutaneous angio-oedema (rapid oedema of the dermis, subcutaneous tissue, mucosa and submucosal tissues)
Can also experience recurrent abdominal pain due to intestinal oedema.
Family history of sudden death due to laryngeal involvement
97
Describe alpha-1 antitrypsin deficiency
Autosomal recessive disorder - varying levels of severity
alpha-1 antitrypsin deactivates enzymes released from neutrophils
Patients with this disorder develop emphysema because enzymes destroy normal parenchymal tissue
Liver disease can occur as the hepatocytes produce an abnormal version of the protein - polymerises and can't be exported from the ER. Causes hepatocyte damage and eventually cirrhosis
98
Describe chronic granulomatous disease
Phagocytes are unable to generate superoxide - bacteria are phagocytised by cannot be killed because phagocytes can't generate an oxygen burst
Results in many chronic infections in the first year of life
Numerous granulomas and abscesses affecting skin, lymph nodes, sometimes the lung, liver and bones occur
99
What is the aetiology of chronic inflammation?
Exposure - sometimes, long-term, low-level exposure to an irritant can result in chronic inflammation
Autoimmune disorders - immune system mistakenly attacks normal healthy tissue, as in psoriasis
Hypersensitivity
Autoinflammatory diseases
Persistent acute inflammation
100
Define chronic inflammation
Inflammation of prolonged duration in which active inflammation, tissue injury, and the healing proceed simultaneously
101
What are the actions of macrophages in chronic inflammation?
"big eater"
They phagocytose, secrete numerous substances that summon and activate other cells, present antigens to the immune system and initiate an immune response, stimulate angiogenesis (formation of new blood vessels), induce fibrosis, fever, acute phase reaction and cachexia
102
What are the actions of giant cells in chronic inflammation?
Multiple macrophages fused together
| Can clear up larger molecules via phagocytosis
103
What are the actions of lymphocytes in chronic inflammation?
Process antigens
Secrete antibodies
Secrete cytokines that influence other inflammatory cells
Kill cells (done by natural killer cells which attack virus-infected cells and sometimes cancer cells)
104
What are the actions of eosinophils in chronic inflammation?
They attack large parasites such as worms and they are present in high numbers in some immune responses (i.e. in the bronchi in asthma, and in some tumours)
105
What are the actions of fibroblasts in chronic inflammation?
Can respond to chemotactic stimuli and move to sites where they are needed
Produce connective tissue substances such as collagen, elastin and glycosaminoglycans
106
What are the actions of myofibroblasts in chronic inflammation?
Specialised fibroblasts with contractile activity
107
What are the complications of chronic inflammation?
Fibrosis
Impaired function
Involvement inappropriate immune response
108
How will tissue destruction after chronic inflammation affect organs?
If the tissue is worn away, then organs won't be able to function properly
109
How will excessive fibrosis after chronic inflammation affect organs?
Can impair the function
| If there are enough myofibroblasts - can slowly contract and cause more problems
110
How will atrophy after chronic inflammation affect organs?
If enough of the tissue is atrophied, then the organ will not be able to function and will fail
111
What features of chronic inflammation are seen in rheumatoid arthritis?
The immune system attacks the body's normal tissues - the resulting chronic inflammation becomes a disease process
112
What features of chronic inflammation are seen in ulcerative colitis?
kj
113
What features of chronic inflammation are seen in Crohn's disease?
jk
114
What features of chronic inflammation are seen in chronic cholecystitis?
jk
115
What features of chronic inflammation are seen in chronic gastritis?
jk
116
What features of chronic inflammation are seen in liver cirrhosis?
jkbgfv
117
What are the different types of giant cell?
gdgd
118
What are the actions of Langhan giant cells?
Found in granulomatous conditions
119
What are the actions of foreign body giant cells?
Involved in the foreign body reaction, phagocytosis, and degradation
Often seen when a hard to digest foreign body is present
If the foreign body is small - phagocytised by the giant cell and can be seen within it
If the foreign body is large - giant cell sticks to its surface
120
What are the actions of Touton giant cells?
Form in lesions where there is a high lipid content - fat necrosis and xanthomas
121
What do Langhan giant cells look like?
Nuclei are arranged around the periphery of the giant cell
122
What do foreign body giant cells look like?
Nuclei are arranged randomly in the cell
123
What do Touton giant cells look like?
Nuclei are arranged in a ring towards the centre of the cell
124
Describe a granuloma
Aggregation of macrophages that forms in response to chronic inflammation
Occurs when the immune system attempts to isolate foreign substances which it is unable to eliminate
125
Describe granulomatous inflammation
A type of chronic inflammation in which granulomas are seen
126
What is the aetiology of granulomatous inflammation?
Body's way of dealing with particles that are poorly soluble or difficult to eliminate
This includes foreign bodies such as thorns, splinters, 'tough' bacteria (Mycobacterium tuberculosis) and (Mycobacterium leprae)
127
What is labile tissue?
Continuously dividing tissues
128
What is stable tissue?
```
Quiescent tissues
(quiescent = in a state or period of inactivity or dormancy)
```
129
What is permanent tissue?
Non-dividing tissues
130
What are the differences between labile, stable and permanent tissues?
They all have different proliferative activity
131
Give examples of labile tissue
Surface epithelia
Lining mucosa of secretory ducts of the glands of the body
Columnar epithelia of GI tract and uterus
Transitional epithelium of urinary tract
Cells of bone marrow and haematopoietic tissues
132
Give examples of stable tissue
Parenchymal cells of the liver, kidneys and pancreas
Mesenchymal cells such as fibroblasts, bone osteoclasts and smooth muscle cells
Vascular endothelial cells
Resting lymphocytes
Other white blood cells
133
Give examples of permanent tissue
Neurones
| Skeletal and cardiac muscle cells
134
What is the role of stem cells in regeneration and repair?
In order for tissues to regenerate, cells must be replaced.
| In tissues where regeneration is possible differentiated cells are very often replaced by cells derived from stem cells
135
What does the term 'unipotent' mean?
Stem cells that can usually only give rise to one type of adult - they are lioneage specific
136
What does the term 'multipotent' mean?
Stem cells that can produce several types of differentiated cell
e.g. haematopoietic stem cells
137
What does the term 'totipotent' mean?
Cells that have the ability to self-renew by dividing and the ability to develop into the three primary germ cell layers of the embryo and into extra-embryonic tissues such as placenta
138
What are the different types of communication between cells?
```
Autocrine
Paracrine
Endocrine
Epidermal growth factor
Vascular endothelial growth factor
Platelet-derived growth factor
Tumour necrosis factor
```
139
How does autocrine signalling work?
Cells respond to the signalling molecules that they themselves produce
140
How does paracrine signalling work?
A cell produces the signalling molecules, this acts on adjacent cells
Responding cells are close to the secreting cell and are often a different type
141
How does endocrine signalling work?
Hormones are synthesised by cells in an endocrine organ, they are then conveyed in the blood stream to target cells to effect physiological activity
142
How do growth factors help cells to communicate?
TNF - induces fibroblast migration, fibroblast proliferation and collagenase secretion
143
How do adhesion molecules help cells to communicate?
Bind cells to each other - cadherins
| Bind cells to the extracellular matrix - integrins
144
How does the concept of contact inhibition help cells to communicate?
After becoming isolated, normal cells will replicate until they have cells touching them and then stop - form a monolayer sheet of cells with no overlap
145
What processes are involved in regeneration?
The capacity to regrow parts of an organ or tissue after damage
146
What processes are involved in resolution?
Pathogens and damaged tissue are removed by macrophages
147
What processes are involved in fibrous repair/organisation?
1- phagocytosis of necrotic tissue debris
2- proliferation of endothelial cells which results in small capillaries that grow into the area (angiogenesis)
3- proliferation of fibroblasts and myofibroblasts that synthesise collagen and cause wound contraction
4- granulation tissue becomes less vascular and matures into a fibrous scar
5- scar matures and shrinks due to contractions of fibrils within myofibroblasts
148
How does regeneration, resolution, fibrous repair/organisation affect different tissues?
Some tissues are capable of regenerating, some aren't capable of any at all
149
What are the histological components of granulation tissue?
Presence and proliferation of fibroblasts, keratinocytes, endothelial cells, new thin-walled capillaries, and inflammatory cell infiltration of the extracellular matric
150
Describe the synthesis of collagen
Collagen consists of a triple helix of three polypeptide alpha chains with gly-x-y repeating sequence
Synthesised by fibroblasts and myofibroblasts:
1- preprocollagen is produced
2- modified to procollagen, takes on the triple helix form and secreted
3- procollagen is cleaved to make fibrillar collagen
151
What are the different types of collagen?
Type I (fibrillar) - most common type, present in hard and soft tissues
Type II - part of cartilage, bone and vitreous humour
Type III - found in loose connective tissues and in the muscle
152
What are some defects of collagen synthesis?
Scurvy
Ehlers-Danlos syndrome
Osteogenesis imperfecta
Alport syndrome
153
Describe how scurvy affects collagen synthesis
Vitamin C is required for hydroxylation of procollagen
| Patients with scurvy cannot heal wounds adequately, and have a tendency to bleed as capillaries are fragile
154
Describe how Ehlers-Danlos syndrome affects collagen synthesis
Heterogenous group of 6 inherited disorders where collagen fibres lack adequate tensile strength
Skin is hyperextensible, fragile and susceptible to injury. Joints are hypermobile
155
Describe how osteogenesis affects collagen synthesis
Patients have too little bone tissue and hence extreme skeletal fragility
Too little collagen in the sclera of the eye - making it look blue
156
Describe how Alport syndrome affects collagen synthesis
X-linked disease
Type IV collagen is abnormal, results in dysfunction of the glomerular basement membrane, the cochlea of the ear and the lens of the eye
157
What is primary intention?
Would healing occurring in incisional, closed, non-infected and sutured wounds
There is disruption of epithelial basement membrane continuity but death of only a limited number of epithelial and connective tissue cells
158
What is secondary intention?
Seen in excisional wounds or wounds with tissue loss and separated edges. Seen in infected wounds
The wound is filled with granulation tissues, which grows in from the wound margins
159
How can you distinguish between primary and secondary intention?
Can be primary or secondary intention depending on the size of the wound and the amount of tissue that has been lost
160
What is the healing process of bone fractures?
1- haematoma fills the gap and surrounds the bone injury; provides a foundation for the subsequent cell growth
2- fibrin mesh and granulation tissue is formed; platelets and inflammatory cells release cytokines - these activate osteoprogenitor cells to osteoclastic and osteoblastic activity
3- soft callus forms
4- hard callus forms, is laid down by osteoblasts - initially is woven bone (is weaker and less organised but can be formed quickly)
5- lamellar bone is more organised
6- remodelling of the bone occurs
161
How does size, location and type of wound influence the efficacy of healing and repair?
Foreign bodies - produces persistent inflammation and favours infection
Haematoma - if large, can slow healing
Necrotic tissue - needs clearing, if there's a lot will take longer
Mechanical stress - can pull delicate tissue apart
Protection - keeps wound clean and free from infection
Surgical techniques - good techniques promote rapid healing and minimise scarring
162
What are the systemic factors influencing the efficacy of healing and repair?
Malignancy - due to cachexia seen with malignant tumours
Genetic disorders - affect collagen synthesis
Drugs - steroids (immunosuppressive, inhibit collagen synthesis), cytotoxics (anti-mitogenic, impair cells proliferation and healing), antibiotics (treat bacterial infections, reduce inflammation)
Vitamin deficiency - vit C deficiency inhibits collagen synthesis
Malnutrition or protein loss - can't synthesise protein
163
What are the complications of fibrous repair?
Can form fibrous adhesions compromising organ function or blocking tubes
Can lose function due to replacement of specialised functional cells by non-functioning collagenous scar tissue
Can disrupt complex tissue relationships within an organ
Can overproduce fibrous scar tissue
Can have excessive scar contraction causing obstruction of tubes, disfiguring scars following burns or joint contractures
164
Describe insufficient fibrosis
Insufficient fibrosis would mean the wound would remain open - leaving it susceptible to infection etc
165
Describe excessive fibrosis
Keloid scars can form
A keloid scar is an overgrowth of fibrous tissue, due to an overproduction of collagen, that exceeds the borders of the scar
They don't regress - excision just creates another one
166
Describe excessive contraction
This can lead to deformity characterised by skin constriction and functional limitations
The skin is "contracted" - pulled too tight
167
What are some of the special aspects of regeneration and repair in cardiac muscle?
Has very limited/no regenerative capacity
Myocardial infarction is followed by scar formation
This can compromised cardiac function
168
What are some of the special aspects of regeneration and repair in the liver?
Has remarkable capacity to regenerate
If part is removed, compensatory growth of liver tissue occurs and there is liver restoration of liver mass by enlargement of the lobes that remain
Hepatocytes regenerate first
169
What are some of the special aspects of regeneration and repair in peripheral nerves?
When a nerve is severed, the axons degenerate
Proximal stumps of degenerated axons sprout and elongate
Use Schwann cells vacated by distal degenerated axons to guide them back to tissue that the nerve innervates
170
What are some of the special aspects of regeneration and repair in cartilage?
Doesn't heal well due to lack of blood supply, lymphatic drainage and innervation
171
What are some of the special aspects of regeneration and repair in central nervous system?
Neural tissue is a permanent tissue
| When damage occurs, the neural tissue is replaced by proliferation of CNS supportive elements (glial cells) = gliosis
172
What is haemostasis?
Stopping of haemorrhage
| "halting the blood" - literal definition
173
Describe the principles of haemostasis
1- severed artery contracts to decrease pressure downstream
2- primary haemostatic plug of activated platelets forms - forms in seconds to minutes
3- secondary haemostatic plug forms as fibrin filaments stabilise the platelet plug into a blood clot - forms in 30 minutes
174
Describe the role of the vessel wall in haemostasis
Arterial media contracts when artery is damaged
Subendothelium traps platelets
Endothelium performs a balancing act between opposing and favouring clotting
175
Describe the role of platelets and the platelet plug in haemostasis
Platelets are activated by collagen surfaces, ADP, thromboxane, thrombin
They stick to exposed subendothelium (specifically to von Willebrand factor), then aggregate with other platelets. They then swell and change shape into sticky, spiny spheres. They secrete factors from platelet granules that help platelet plug to grow and aid clotting
176
Describe the role of the coagulation system in haemostasis
This is the whole system of cells, proteins and processes that mediate blood clotting
It is vital
177
Describe the role of the fibrinolytic system and plasmin in haemostasis
Side effect of tPA - bleeding, commonly from the gums or nose, but can occur in the brain
The clotting cascade sets fibrinolysis in motion
After surgery fibrinolytic activity drops and remains low for 7-10 days, the time period that is associated with the increased risk of postoperative thrombosis
178
Describe the role of the production of thrombin and fibrin in haemostasis
In order for blood to clot fibrin has to be produced - thrombin cleaves fibrinogen into fibrin
Can't have fibrin without thrombin
Thrombin can't circulate in the blood otherwise blood would be solid - it is activated by a number of clotting factors
Clotting factors need vitamin K for their synthesis
179
Describe the role of thrombin inhibitors in haemostasis
Natural anticoagulants
They oppose the formation of fibrin - the main natural anticoagulants are antithrombin III, protein C and protein S.
Fibrin degradation products inhibit clotting
180
What are the common tests in a coagulation screen?
Platelet count
Bleeding time
PT (Prothrombin time) - measure of the time taken for blood to clot via the extrinsic pathway
APTT (Activated partial thromboplastin time) - measure of the time taken for blood to clot via the intrinsic pathway
Play Tennis OUTSIDE (PT - extrinsic)
Play Table Tennis INSIDE (APTT - intrinsic)
181
Interpret the common tests in a coagulation screen
PT = 12-13 seconds
APTT = 35-45 seconds
Bleeding time = 1 to 6 minutes
Thrombin time = 10-15 seconds
182
What are some common inherited bleeding disorders?
Haemophilia A and B
| Von Willebrand Disease
183
What is haemophilia A?
```
Factor VIII (8) deficiency (either decreased amounts of decreased activity)
X-linked recessive disease, affects males
```
184
What is haemophilia B?
Factor IX (9) deficiency
Clinically indistinguishable from haemophilia A
X-linked recessive disease with variable clinical severity
Normal platelet count, bleeding time and PT, but prolonged APTT
Treated with recombinant factor IX
185
What is thrombophilia?
Inherited or acquired defects of haemostasis resulting in a predisposition to thrombosis
More likely to get a deep vein thrombosis, for example
186
What is von-Willebrand disease?
Most common inherited bleeding disorder
Due to a deficiency or abnormality in von Willebrand factor
Bleeding time and APTT can be raised in the condition
Common presentation of mucosal bleeding reflects the inadequate platelet function and adhesion
187
What is the pathophysiology of disseminated intravascular coagulation?
Secondary complication in a variety of conditions
An activator of clotting gets into the blood and microthrombi are formed throughout the circulation
Uses platelets, fibrin and coagulation factors and activates fibrinolysis - patient may then experience haemorrhage
188
What is the treatment of disseminated intravascular coagulation?
Treat the underlying cause of DIC
Transfusions of platelets, fresh frozen plasma (FFP), cryoprecipitates (contains factor VIII, fibrinogen, von Willebrand factor and factor XIII), red blood cells
Occasionally may require an anticoagulant such as heparin
189
What are some of the complications associated with disseminated intravascular coagulation?
Conditions such as neurological impairment, gangrene of the skin, renal failure, respiratory distress and gastrointestinal ulceration
Haemorrhagic component results in conditions such as intracerebral bleeding, petechiae, haematuria, epistaxis and GI bleeding
190
What is the mode of action of commonly used anticoagulants?
Suppress the synthesis or function of various clotting factors that are normally present in the blood
191
How are commonly used anticoagulants monitored?
APTT test
192
What are the complications of anticoagulants?
```
Blood in urine
Blood in stool
Severe bruising
Prolonged nosebleeds
Bleeding gums
Vomiting/coughing up blood
Heavy periods in women
```
193
What are the principles of thrombosis?
Changes in the vascular wall (endothelial damage) - platelets will adhere to von Willebrand factor, if there is also stasis then a thrombus will form
Changes in the blood flow (slow or turbulent flow) - thrombosis is more frequent in veins due to slower blood flow. Turbulent flow can itself produce endothelial damage. Abnormal flow allows thrombi to grow more easily
Changes in the blood (hypercoagulability) - increased circulating levels of fibrinogen and factor VIII so blood is hypercoagulable
(appears that only two out of the three are required for a thrombus to form)
194
What are the principles of embolism?
Sudden blocking of an artery by a thrombus or foreign material which has been brought to its site of lodgement by the blood current
Can't have embolization in veins because the blood flow is from smaller to larger vessels
195
What are the different types of embolism?
Thromboemboli - emboli arisen from thrombi
Pulmonary emboli
Paradoxical emboli - thromboemboli from systemic veins embolising in systemic arteries - have to bypass the lungs
Emboli from Atheroma
Fat and Bone Marrow emboli - complication of bone fractures, can occur after liposuction
Gas emboli
Amniotic fluid emboli - complication of labour and C-section
Talcum emboli - microscopic foreign bodies with which drugs have been 'cut', found in lungs of intravenous drug abusers
196
What are the outcomes of thrombosis?
Resolution - dissolved
Propagation - grows
Organisation - undergoes fibrous repair and forms a fibrous scar on the wall of the vessel
Recanalisation - of an occluding thrombus, new channels lined with endothelium run through the occlusion and restore blood flow
Embolisation - part of the thrombus breaks off and embolises
197
What are the outcomes of embolism?
Can die
Chronic damage to lungs (pulmonary hypertension
Can recur
198
What are the complications of thrombosis?
Occlusion of an artery at the site, resulting in ischaemia and infarction
Embolisation of part of the thrombus resulting in occlusion of an artery distant to the site of the thrombus
Congestion and oedema in the venous bed resulting in pain and sometimes skin ulceration
Repeated miscarriages due to thrombosis of the uteroplacental vasculature which often seen in inherited thrombophilias
199
What are the complications of embolism?
gh
200
What are the preventative methods available for thromboembolic disease?
General prophylaxis - preventing venous stasis (mobilise early after operation or illness; during + after surgery, legs can be elevated; compression stockings, calf muscle stimulation and passive calf muscle exercises) or preventing hypercoagulability (anticoagulants)
Aspirin - platelets can't produce thromboxane A2 (a powerful platelet aggregator)
Heparin - activates antithrombin III
Warfarin - interferes with vitamin K metabolism
Filters - pulmonary emboli prevented by putting umbrella-shaped filter in the inferior vena cava
201
What are the treatments for thromboembolic disease?
Aspirin - platelets can't produce thromboxane A2 (a powerful platelet aggregator)
Heparin - activates antithrombin III
Warfarin - interferes with vitamin K metabolism
202
What is meant by the term 'ateriosclerosis'?
Hardening of the arteries
| The walls of arteries are thickened and lose their elasticity
203
What is meant by the term 'atherosclerosis'?
A disease of large and medium sized arteries that begins in the intima
Plaques are formed in the arterial wall and these are filled with atheroma - plaques often calcify
204
What us meant by the term 'atheroma'?
The necrotic core of the atherosclerotic plaque
| Consists of dead cells, debris and cholesterol crystals
205
What are the cellular events that lead to the formation of atherosclerotic lesions?
1- chronic endothelial damage
2- lipid droplets cross the endothelium and accumulate in the intima. Lipids oxidise and macrophages ingest - they are then called foam cells
3- foam cells cause the endothelium to bulge, smooth muscle moves to the lesion and starts to proliferate - then called a fatty streak
4- plaque grows as number of foam cells and smooth muscle cells increases. Some smooth muscle cells will lie over the plaque but underneath the endothelium, forming a roof - this is reinforced by collagen, elastin and other matrix proteins and results in a fibrous cap
5- cells in the centre die and necrosis develops, dead cells release cholesterol and crystals appear in the plaque. Plaque may undergo calcification
206
What cells are involved in the formation of an atherosclerotic plaque?
Macrophages - become foam cells
| Smooth muscle cells
207
What is the role of endothelial cells in the formation of an atherosclerotic plaque?
hj
208
What is the role of platelets in the formation of an atherosclerotic plaque?
As the endothelium stretches over the plaque, gaps appear between the endothelial cells - platelets adhere to these gaps
209
What is the role of smooth muscle cells in the formation of an atherosclerotic plaque?
Some smooth muscle cells take up lipid and appear foamy
| Some smooth muscle cells will lie over the plaque but beneath the endothelium forming a "roof"
210
What is the role of macrophages in the formation of an atherosclerotic plaque?
They ingest the oxidised lipids to become foam cells
211
What are the variable macroscopic appearances of athersclerosis?
White to yellow in colour
| Impinge on the lumen of the artery
212
What are the various microscopic appearances of atherosclerosis?
Intimal foam cells
Smooth muscle cells
Some extracellular lipid
Fibrosis, necrosis, cholesterol clefts, disruption of the internal elastic lamina, extension into the media and ingrowth of small vessels from the adventitia
213
Where are the common sites of atherosclerosis?
```
Heart
Brain
Kidneys
Legs
Bowel
```
214
What are the complications of atheroma in the heart?
Myocardial infarction, chronic ischaemic heart disease, arrhythmias, cardiac failure and sudden cardiac death
215
What are the complications of atheroma in the brain?
Transient ischaemic attacks (TIAs), cerebral infarction, multi-infarct dementia
216
What are the possible complications of atherosclerotic plaques in general?
```
Ulceration
Thrombosis on the plaque
Spasm at the site of the plaque
Embolisation
Calcification
Haemorrhage
Aneurysm formation
Rupture of the atherosclerotic artery
```
217
What are the complications of atheroma in the legs?
Peripheral vascular disease, gangrene
218
What are the complications of atheroma in the bowel?
Ischaemic colitis, malabsorption, bowel infarction
219
What are the modifiable risk factors for the development of atherosclerosis?
```
Hyperlipidaemia
Hypertension
Cigarette smoking
Geography
Obesity - hypertension, diabetes mellitus, hypertriglyceridemia, reduced HDL
Infection - Chlamydia pneumoniae or CMV
```
220
What are the non-modifiable risk factors for the development of atherosclerosis?
Increasing age
Male gender
Genetic predisposition
221
What are some of the interventions involved in preventing atherosclerotic disease?
```
Decreasing total and LDL cholesterol and increasing HDL
Stop smoking
Controlling hypertension
Controlling weight and regular exercise
Sensible alcohol intake
Treating diabetes mellitus
Anti-oxidants
```
222
What are some of the interventions involved in managing atherosclerotic disease?
Lipid-lowering drugs
| Thrombolysis, angioplasty, stents, and coronary artery bypass grafts (CABG)
223
What are the principles of the cell cycle?
G1 -> S -> G2 -> M
| After completion, either re-starts from G1 or exits (G0) until further growth signals occur
224
Define 'hyperplasia'
Increase in tissue or organ size due to increased cell numbers
225
Define 'hypertrophy'
Increase in tissue or organ size due to an increase in cell size without an increase in cell numbers
226
Define 'atrophy'
Shrinkage of a tissue or organ due to an acquired decrease in size and/or number of cells
227
Define 'metaplasia'
Reversible replacement of one adult differentiation cell type by another or a different type
228
Define 'aplasia'
A complete failure of a specific tissue or organ to develop
229
Define 'hypoplasia'
The congenital underdevelopment or incomplete development of a tissue or organ
230
Define 'involution'
Overlaps with atrophy
| Normal programmed shrinkage of an organ
231
Define 'atresia'
'No orifice' - the congenital imperforation of an opening
232
Define 'reconstitution'
Replacement of a lost part of the body rather than a small group of cells
233
Define 'dysplasia'
Abnormal maturation of cells within a tissue
234
Explain hyperplasia
A response to increased functional demand and/or external stimulation
Can only occur in labile or stable cell populations - remains under physiological control, is reversible.
Either hormonal (result is an increase in functional capacity) or compensatory (increase after tissue damage) or pathological (secondary to excessive hormonal stimulation or growth factor production)
A risk of neoplasia in hyperplastic tissue
235
Explain hypertrophy
Can occur in many tissues but seen especially in permanent cell populations - they have little to no replicative potential
It is a response to increased functional demand and/or hormonal stimulation
They synthesise more cytoplasm
236
Explain atrophy
A reduced supply of growth factors and/or nutrients will result in atrophy
Cellular atrophy - decrease in cell size to a size at which survival is still possible
Organ/tissue atrophy - due to combination of cellular atrophy and apoptosis
Atrophy is associated with disease, and senescence
Is reversible up to a point
Best treated by removal of the cause
237
Explain metaplasia
The change from one type of cell to another - may be part of a normal maturation process, or caused by some sort of abnormal stimulus
238
Explain aplasia
Embryonic developmental disorder
| Also is used to describe an organ whose cells have ceased to proliferate
239
Explain hypoplasia
An adequate number of cells within the tissue which is present
It is an embryonic developmental disorder and is in a spectrum with aplasia
240
Explain involution
Programmed shrinkage of an organ
241
Explain atresia
An orifice or passage in the body is closed or absent
242
Explain reconstitution
Requires the coordinated regeneration of several types of cells
Very minimal in a mammal - most mammals can't even reconstitute a lose nail bed or the root of a hair
243
Explain dysplasia
Abnormal maturation of cells within a tissue - potentially reversible but is often a pre-cancerous condition
244
Give examples of hyperplasia
Physiological - increased bone marrow production of erythrocytes in response to hypoxia and the resulting erythropoietin, and the proliferation of the endometrium under the influence of oestrogen
Pathological - epidermal thickening in chronic eczema or psoriasis and enlargement of the thyroid gland in response to iodine deficiency
245
Give examples of hypertrophy
Physiological - skeletal muscle hypertrophy of a bodybuilder and the smooth muscle hypertrophy of a pregnant uterus
Pathological - ventricular cardiac muscle hypertrophy in response to hypertension or valvular disease, smooth muscle hypertrophy above an intestinal stenosis due to extra work and demand required, bladder smooth muscle hypertrophy with bladder obstruction due to enlarged prostate gland
246
Give examples of atrophy
Physiological - ovarian atrophy in post-menopausal woman, and the decrease in the size of the uterus after parturition
Pathological - muscle atrophy after disuse due to immobilisation, tissues around an enlarging brain tumour atrophy, wasting of muscles with malnutrition
247
Give examples of metaplasia
Bone marrow is destroyed by disease, splenic tissue undergoes metaplasia to bone marrow
Bronchial pseudostratified ciliated columnar epithelium to stratified squamous epithelium due to the effect of cigarette smoke
248
Give examples of aplasia
Thymic aplasia which results in infections and auto-immune problems
Aplasia of a kidney
Aplasia of the bone marrow in aplastic anaemia
249
Give examples of hypoplasia
Renal hypoplasia
Breast hypoplasia
Testicular hypoplasia in Klinefelter's syndrome
Hypoplasia of the chambers of the heart
250
Give examples of involution
Uterus after childbirth shrinks
Thymus in early life
Temporary foetal organs such as the pro- and mesonephros
251
Give examples of atresia
Atresia of the anus or vagina
| Aural atresia is a congenital deformity where the ear canal is underdeveloped
252
Give examples of reconstitution
Lizards can regrow their tails
Deer can regrow their antlers
Most mammals cannot regrow a nail bed or the root of the hair
253
Give examples of dysplasia
Epithelial dysplasia
| Hip dysplasia
254
Define 'neoplasm'
An abnormal growth of cells that persists after the initial stimulus is removed
255
Define 'dysplasia'
A pre-neoplastic alteration in which cells show disordered tissue organisation
256
Define 'tumour'
Any clinically detectable lump or swelling
257
Define 'cancer'
Any malignant neoplasm
258
Define 'metastasis'
A malignant neoplasm that has spread from its original site to a new non-contiguous site
259
Define 'anaplasia'
The loss of the mature or specialised features of a cell or tissue
Cells with no resemblance to any tissue are called anaplastic
260
Define 'pleomorphism'
Cells in a tumour have more than one distinct form - increasing variation in size and shape of cells and nuclei
261
Define 'progression'
A neoplasm emerges from the monoclonal population through a process called progression - the accumulation of yet more mutations
262
Define 'in situ'
No invasion through epithelial basement membrane
263
What is the difference between benign and malignant tumours?
Benign - confined to their site or origin and do not produce metastases
Malignant - neoplasm with the potential to metastasise
264
What are the macro- and microscopic features of benign tumours?
Macro - they are in confined local area and so have a pushing outer margin
Micro - cells closely resemble the parent tissue, they are well differentiated
265
What are the macro- and microscopic features of malignant tumours?
Macro - Irregular outer margin and shape and may show areas of necrosis and ulceration
Micro - range from well to poorly differentiated cells
- increasing nuclear size
- increasing nuclear to cytoplasmic ratio
- more mitotic figures
266
What is the biological behaviour of benign tumours?
They remain confined to their site or origin and do not produce metastases
267
What is the biological behaviour of malignant tumours?
They have the potential to metastasise
268
What is the difference between in-situ and invasive malignancy?
```
In-situ = no invasion through epithelial basement membrane
Invasive = penetrated through basement membrane
```
269
How are proto-oncogenes involved in the development of neoplasms?
They become abnormally activated (then called oncogenes), and favour neoplasm formation
270
How are tumour suppressor genes involved in the development of neoplasms?
They can become inactive and stop suppressing neoplasm formation
271
What is the concept of clonality?
c
272
What is the reasoning behind the nomenclature given to benign and malignant neoplasms?
Organised system - takes site into account, benign or malignant, tissue the tumour forms and sometimes gross morphology
Benign neoplasms end in -oma
Malignant ones end in -carcinoma if it is an epithelial malignant neoplasm
Malignant ones end in -sarcoma if it is a stromal malignant neoplasm
273
What are the histological characteristics of a squamous cell carcinoma?
Nests of squamous epithelial cells arising from the epidermis and extending into the dermis
Malignant cells are often large with abundant eosinophilic cytoplasm and a large, often vesicular, nucleus.
Variable keratinisation is present
274
What are the histological characteristics of an adenocarcinoma?
Dark staining, eosinophilic cytoplasm
In lungs:
Lepidic - lacks architectural complexity; no lymphovascular or perineural invasion
Acinar - gland forming, round/oval glands invading the stroma
Papillary - malignant cuboidal/columnar cells replace alveolar lining
Micropapillary - ill defined projection that lacks fibrovascular cores
Solid - sheets of neoplastic cells
275
What the histological characteristics of a malignant melanoma?
Pleomorphic and have hyperchromatic nuclei with prominent nucleoli
Melanin pigment is present as fine granules
Frequent mitosis
276
What is the most common cancer of the bladder?
Transitional cell carcinoma
277
What is the most common cancer of the oesophagus?
Squamous cell carcinoma
| Adenocarcinoma
278
What is the most common cancer of the stomach/bowel?
Adenocarcinoma
279
What are the most common cancers of the skin?
Squamous cell carcinoma
Malignant melanoma
Basal cell carcinoma
280
What are the most common cancers of the lungs?
Adenocarcinoma
Squamous cell carcinoma
Small cell carcinoma
281
What is the most common cancer of the breast/prostate?
Adenocarcinoma
282
What is the most common cancer of the brain?
Astrocytoma
283
What is the most common cancer of the thyroid/pancreas/uterus?
Adenocarcinoma
284
What is the most common cancer of the cervix?
Squamous cell carcinoma
285
What is the process of invasion and metastasis?
1- grow and invade at the primary site
2- enter a transport system and lodge at a secondary site
3- grow at the secondary site to form a new tumour (colonisation)
286
What are the cellular alterations that are required for invasion to occur?
Altered adhesion
Stromal proteolysis
Motility
These three allow a carcinoma cell to appear like a mesenchymal cell rather than an epithelial cell - it is called epithelial-to-mesenchymal transition (EMT)
287
What processes determine the site of a metastasis?
Depends on
1- regional drainage of blood, lymph or coelomic fluid
- lymphatic metastasis is to lymph nodes
- transcoelomic spread is to other areas in the space or to adjacent organs
- blood-borne metastasis is sometimes to the next capillary bed that the cells encounter
2- the "seed and soil" phenomenon is due to interactions between malignant cells and the local tumour environment at the secondary site
288
What processes determine the transportation routes for malignant cells?
Blood vessels via capillaries and venules
Lymphatic vessels
Fluid in body cavities (pleura, peritoneal, pericardial and brain ventricles) - this is known as transcoelomic spread
Carcinomas typically spread via lymphatics first
Sarcomas tend to spread via blood stream
289
Which neoplasms most frequently spread to the bones?
Breast, bronchus, kidney, thyroid and prostate
290
What are lytic lesions?
AKA bone lesions or osteolytic lesions - areas where bone has been destroyed, leaving a hole in the bone as a result of cancerous plasma cells building up in your bone marrow
291
What are sclerotic lesions?
An unusual hardening or thickening of the bone
| Can be benign or malignant
292
What are the differences between lytic and sclerotic lesions?
Lytic - holes
| Sclerotic - excess build up/thickening
293
What are the local effects of neoplasms?
- destroys normal tissue
- ulceration at a surface, leading to bleeding
- compression of adjacent structures
- blocking tubes and orifices
294
What are the systemic effects of neoplasms?
Increasing tumour burden leads to a parasitic effect on the host, paired with secreted factors such as cytokines:
- reduced appetite
- weight loss (cachexia)
- malaise
- immunosuppression
- thrombosis
- can secrete hormones
- can have neuropathic effects
- skin problems
- fever
- finger clubbing
- myositis (inflammation in the muscles)
- hypercalcaemia
- anaemia
- DIC
295
What is the multifactorial nature of neoplasia pathogenesis?
A combination of intrinsic host factors and extrinsic factors related to the environment and behaviour account for cancer risk
296
What are the intrinsic factors of neoplasia pathogenesis?
Hereditary
Age
Gender (especially hormonal)
297
What are the extrinsic factors of neoplasia pathogenesis?
```
High body mass index
Low fruit and vegetable intake
Lack of physical activity
Tobacco use
Alcohol use
Three main categories: (1) chemicals, (2) radiation, and (3) infections
```
298
List extrinsic carcinogenic agents
(1) chemicals
- asbestos
- polycyclic hydrocarbons
- aromatic amines (e.g 2-napthylamine)
- nitrosamines
(2) radiation
- ultraviolet radiation
- ionising radiation
(3) infections
- human papilloma virus
- Epstein Barr virus
- hepatitis B and C viruses
- human immunodeficiency virus
- Helicobacter pylori
- parasites
299
What is the mechanism of action for carcinogenic chemicals?
Some are initiators, some are promoters - have to have I followed by P
Some chemicals are pro-carcinogens, are activated by enzymes in the liver
Some chemicals are both initiators and promoters - these are called complete carcinogens
300
What is the mechanism of action for carcinogenic radiation?
UV doesn't penetrate deeper than the skin - but we come across it everyday from sunlight, so it is very dangerous
Radiation can damage DNA directly and indirectly by producing free radicals
301
What is the mechanism of action for carcinogenic infections?
Some infections directly affect genes that control cell growth
Others cause chronic tissue injury where regeneration acts as a promoter for pre-existing mutations or can cause new mutations
HPV is a direct carcinogen because it expresses E6 and 7 protein which inhibit proteins important in cell proliferation
Hepatitis B and C cause chronic liver cell injury and regeneration - indirect carcinogen
302
What are functions of proto-oncogenes in neoplasia?
The genes that enhance neoplastic growth are known as oncogenes - they are abnormally activated versions of proto-oncogenes
Only one allele of each proto-oncogene needs to be activated to favour neoplastic growth
303
What are the functions of tumour suppressor genes in neoplasia?
Genes that inhibit neoplastic growth are known as tumour suppressor genes
Both alleles must be inactivated because they act like brakes on tumour growth
304
What are the functions of caretaker genes in neoplasia?
Genes that maintain genetic stability - a class of tumour suppressor genes
305
What are the stages of carcinogenesis?
Initiation - a mutagen that causes mutations to DNA that increase cancer risk
Promotion - this is prolonged proliferation in target tissues
Progression - steady accumulation of multiple mutations
306
What alterations in growth control are required to achieve carcinogenesis?
1- self sufficiency in growth signals
2- resistance to growth stops signals
3- no limit on the number of times a cell can divide (cell immortalisation)
4- sustained ability to induce new blood vessels (angiogenesis)
5- resistance to apoptosis
6- the ability to invade and produce metastases
307
Which medical conditions are associated with an increased risk of malignancy?
Ulcerative colitis
| Cirrhosis
308
What tumours can be inherited?
BRCA1 and BRCA2 genes are inherited and carry an increased lifetime risk of ovarian and breast cancers in women
Germline mutations as well as somatic mutations
Familial adenomatous polyposis and colorectal cancer
Hereditary non-polyposis colon cancer syndrome
Familial breast cancer
Retinoblastoma
309
What are the most common types of cancer in adults?
Breast, lung, prostate and bowel carcinomas - accounted for over half of all new cancers in the UK
310
What are the most common types of cancer in children?
Younger than 14 - leukaemias, central nervous system tumours and lymphomas are most common
311
What is the leading causes of cancer-related death?
Lung cancer is the biggest cause of cancer-related deaths in the UK
312
What is meant by tumour stage?
A measure of the malignant neoplasm's overall burden
T refers to the size of the primary tumour (T1 to T4)
N describes the extent of regional node metastasis (N0 to N3)
M describes the distant metastatic spread (M0 or M1)
Stage I - early local disease (M0)
Stage II - advanced local disease (any T, N1 or more, M0)
Stage III - regional metastasis
Stage IV - advanced disease with distant metastasis (any T, any N, M1
313
What is meant by tumour grade?
```
Describes the degree of differentiation of a neoplasm
G1 - well-differentiated
G2 - moderately differentiated
G3 - poorly differentiated
G4 - undifferentiated or anaplastic
```
314
What is the significance of the stage and grade of a tumour?
Staging is a powerful predictor of survival
Grade is important for planning treatment and estimating prognosis in certain types of malignancy (soft tissue sarcoma, primary brain tumours, lymphomas, breast + prostate cancer)
315
What are the principles behind surgery to treat cancer?
The mainstay of treatment for most cancers
316
What are the principles behind radiotherapy to treat cancer?
Kills proliferating cells by triggering apoptosis or interfering with mitosis
Focused on the tumour with shielding of surrounding healthy tissue
Given in fractionated doses to minimise damage
Kills rapidly dividing cells - especially in G2 of the cell cycle - causes either direct or indirect DNA damage, triggering apoptosis
317
What are the principles behind chemotherapy to treat cancer?
Affects proliferating cells
Antimetabolites mimic normal substrates involved in DNA replication
Cisplatin cross-links the two strands of DNA helix
Antibiotics act in different ways - could inhibit enzymes needed for DNA synthesis, or could cause double-stranded DNA breaks
318
What are the principles behind hormone therapy to treat cancer?
Selective oestrogen receptor modulators bind to oestrogen receptors, preventing oestrogen from binding. They are used to treat hormone receptor-positive breast cancer
Androgen blockade is used for prostate cancer
319
What are the principles behind targeted molecular therapies to treat cancer?
Can identify specific mutations in the cancer cells to help target and attack only those cells
New therapies are always emerging
320
What is meant by the term 'adjuvant treatment'?
Treatment that is given in addition to the primary treatment
| Usually refers to surgery followed by chemo- or radiotherapy
321
What is meant by the term 'neoadjuvant treatment'?
The administration of therapeutic agents before a main treatment
Neoadjuvant hormone therapy prior to radical radiotherapy for adenocarcinoma of the prostate
322
Why is adjuvant treatment used?
Additional cancer treatment given after the primary treatment will lower the risk that the cancer will come back
To destroy the remaining cancer cells
323
Why is neoadjuvant treatment used?
To help reduce the size of a tumour or kill cancer cells that have spread
324
How are tumour markers used in diagnosis of disease?
Some tumour markers are released only by certain tumours - could help to identify what tumour is present
325
How are tumour markers used in the monitoring of disease?
Most useful for monitoring tumour burden during treatment and follow up
326
What are the principles behind the UK cervical cancer screening program?
Attempts to detect cancers as early as possible when the chance of cure is highest
327
What are the principles behind the UK breast cancer screening program?
Attempts to detect cancers as early as possible when the chance of cure is highest
328
What are the principles behind the UK colorectal cancer screening program?
Attempts to detect cancers as early as possible when the chance of cure is highest
