Mechanisms Of Disease Flashcards
(243 cards)
1
Q
Define disease
A
Consequence of failed homeostasis with consequent morphological and functional disturbances
2
Q
Give 5 reasons for cell injury/death
A
Hypoxia Toxins Physical changes Radiation Micro organisms Immune mechanisms Dietary deficiencies / excess
3
Q
Define hypoxia
A
Oxygen deficiency causing decreased aerobic oxidative respiration
4
Q
What are the 4 main causes of hypoxia?
A
Hypoxaemic hypoxia- arterial O2 content is low
Anaemic hypoxia- decreased ability of haemoglobin to carry O2
Ischaemic hypoxia- interruption to blood supply
Histiocytic hypoxia- inability to utilise O2 in cells due to disabled oxidative phosphorylation enzymes
5
Q
How can the immune system damage cells?
A
Hypersensitivity reaction- secondary result of overly vigorous immune reaction
Autoimmune reaction- failure to recognise self/non-self
6
Q
What are the principle structural targets for cell damage?
A
cell membranes
nucleus
proteins
mitochondria
7
Q
The build up of what inorganic ion is thought to be the cause/indicator of irreversible cell damage?
A
Ca2+
Increases amount of ATPase, Phospholipase, Protease, Endonuclease…
(See lecture 1 slide 17)
8
Q
What is a free radical?
A
A reactive oxygen species.
Single unpaired electron in an outer orbit- unstable
9
Q
What structures do free radicals damage?
A
Lipids, proteins and nucleic acids.
They are mutagenic
10
Q
What beneficial role do free radicals have in the body?
A
produced by leucocytes to kill bacteria and used in cell signalling
11
Q
What is caused in the body if free radicals are in excess?
A
Oxidative stress
12
Q
Why is it important to remove H2O2 and O2 in the Haber-Weiss and Fenton reactions?
A
They can combine to form harmful OH radical
oxidative phosphorylation also produces H2O2 and O2
13
Q
What does acute inflammation do?
A
limit tissue damage
14
Q
What causes acute inflammation?
A
Microbial infection Necrosis Physical agents Chemicals Hypersensitivity reaction
15
Q
What are the macroscopic features of acute inflammation?
A
Calor - heat
Rumor - Colour
Tumor - swelling
Dolor - pain
loss of function
16
Q
How does acute inflammation occur? (microscopically)
A
- Vasodilation
- Gaps form in endothelium
- Exudation
- Margination and Emigration of neutrophils
- Macrophages and Lymphocytes
Migrate in a similar way to Neutrophils.
17
Q
What is the chemical mediator for vasodilation?
A
Histamine
Prostaglandins
C3a
C5a
18
Q
WHat is the chemical mediator for Vascular permeability?
A
Histamine
Prostaglandins
Kinins
19
Q
What is the chemical mediator for emigration of Leukocytes?
A
Leukotrienes
IL-8
C5a
20
Q
What is the action of neutrophils?
A
phagocytose microorganisms, by making contact, recognising and internalising them. Phagosomes are then fused with lysosomes to destroy the contents.
may also release toxic metabolites and enzymes, causing damage to the host tissue.
21
Q
What is Acute Phase Response?
A
Decreased appetite Raised heart rate Altered ssleep patterns Change in plasma concentration of Acute Phase Proteins Can lead to shock
22
Q
What are the systemic consequences of acute inflammation?
A
Acute Phase Response
Fever
Leukocytosis
23
Q
What may happen after the development of acute inflammation?
A
Complete resolution
Continued acute inflamation with chronic inflammation
Chronic inflammation with fibrous repair, probably with tissue regeneration
Death
24
Q
How are mediators inactivated?
A
Inhibition
deactivation
degradation
dilution in exudate
25
How is resolution of acute inflammation achieved?
changes reverse and vascular changes stop
Neutrophils no longer marginate
vessel permeability and calibre returns to normal
exudate drains via lymphatics
fibrin is degraded and neutrophils die
Damaged tissue may be able to regenerate, however if the tissue architecture is damaged, complete resolution is not possible
26
What are the possible complications of acute inflammation?
Swelling - blockage of tubes
Exudate - compression, serositis
Loss of fluid - burns
Pain and loss of function, especially if prolonged
27
What is an abscess and what are the consequences?
Inflammatory exudate forces tissues apart
Liquefactive necrosis in the centre
May cause high pressure causing pain
May cause tissue damage and squash adjacent structures
28
What is pericaritis and what are the consequences?
Inflammation of the serous cavity
| Pericardium becomes inflamed and increases pressure on the heart
29
What is a skin blister and what are teh consequences?
Collection of fluid strips off overlying epithelium
Relatively few inflammatory cells therefore, clear exudate
Resolution or scarring
30
Name 3 disorders of acute inflammation
Hereditary angio-oedema
alpha 1 - antitrypsin deficiency
Chronic Granulomatous Disease
31
How may chronic inflammation arise?
May take over from acute inflammation if damage is too sever to be resolved within a few days
May arise de novo - Chronic inflammation, autoimmune condition, chronic low level irritation
32
What are the effects of chronic inflammation?
Fibrosis
Impaired function (rarely increased)
Atrophy
Stimulation of immune response
33
What cells are involved in chronic inflammation?
```
Macrophages
Lymphocytes
Eosinophils
Fibroblasts/Myofibroblasts
Giant cells
```
34
What is chronic cholecystitis?
Repeated obstruction of the gall bladder with gallstones
Repeated acute inflammation leads to chronic inflammation and fibrosis of the gall bladder wall
Treated with surgical removal of teh gall bladder wall
35
What is gastric ulceration?
Ulceration due to an imbalance of acid production and mucosal defence
36
What causes acute gastric ulceration?
alcohol
| drugs
37
What causes chronic ulceration?
Helicobacter pylori
Triple treatment: PPI inhibitor and 2 antibiotics
38
What is inflammatory bowel disease?
Inflammatory disease affecting the large/small intestine. Patients present with diarrhoea, rectal bleeding and other symptoms
39
What is ulcerative colitis?
Inflammation and ulcers develop on the inside lining of the colon resulting in pain, urgent and bloody diarrhoea, and continual tiredness.
40
What is crohn's disease?
Crohn's is a chronic inflammatory disease, which can affect the whole of the alimentary tract from mouth to anus. The inflammation extends through all layers of the gut wall (transmural) and is characteristically patchy in distribution (skip lesions) with areas of normal tissue between areas of inflammation.
Treated with lifestyle modifications, diet/hydration, immunosupression
41
What is liver cirrhosis?
Chronic inflammation with fibrosis causing disorganisation of architecture and attempted regeneration - cirrhosis
42
What are the causes of liver cirrhosis?
```
alcohol
infection from HBV/HCV
immunological
fatty liver disease
drugs and toxins
```
Irreversible so treatment is prevention and transplant if necessary
43
What is Rheumatoid arthritis?
Autoimmune disease
Localised and systemic immune response causes chronic inflammation which leads to joint destruction
Can effect other organs and cause amyloidosis
44
What is granulomatous inflammation?
Chronic inflammation with granulomas
45
How do granulomas form?
Granulomas form when the immune system walls off something it cannot eliminate. They arise with persistent, low grade pathogenic stimulation and hypersensitivity
46
What are the main causes of granulomatous inflammation?
Mildly irritant foreign material
Infections
Sometimes the cause is unknown eg. in crohn's disease
47
What causes TB?
Mycobacteria. Produce no toxins/lytic enzymes, they cause disease by persistence and induction of cell mediated immunity
48
What are the outcomes of TB?
```
Arrest, fibrosis, scarring
Erosion into bronchus
Tuberculous empyema (collection of pus)
Erosion into blood stream
```
49
WHat is fibrous repair?
The replacement of functional tissue with scar tissue
50
What are the key components of fibrous repair?
Cell migration
Angiogenesis
ECM production/remodelling
Initiate fibrous repair to form granulation tissue
51
What cell types are involved in cell migration for fibrous repair?
inflammatory cells
endothelial cells
fibroblasts/myofibroblasts
52
What are the 5 steps of angiogenesis?
1. Endothelial proteolysis of the basement membrane
2. Migration of endothelial cells by chemotaxis
3. Endothelial proliferation
4. Endothelial maturation and tubular remodelling
5. Recruitment of periendothelial cells
53
What is the role of the Extracellular Matrix?
```
Supports adn anchors cells
Separates tissue compartments
Sequesters growth factors
Allows communication between cells
Facilitates cell migration
```
54
How is collagen synthesised?
```
A
T
E
I
C
E
```
55
What diseases commonly cause a defect of collagen synthesis?
Scurvy
Ehlers Danlos
Osteogenesis imperfecta
Alport syndrome
56
What are the main constituents of ECM?
Glycoproteins and Proteoglycans - Organise and orientate the cell, support the cell (proteoglycans also regulate the availability of growth factor)
Elastin - Provides tissue elasticity
57
What are the stages in fibrous repair?
Inflammatory cells infiltrate the blood clot
Clot replaced by granulation tissue (angiogenesis occurs)
Maturation
58
What happens in the process of maturation in fibrous repair?
```
Cell population falls
Collagen increases, matures and remodels
Myofibroblasts contract - reduces volume of defect
Vessels differentiate and are reduced
Left with fibrous scar
```
59
Describe regeneration
The replacement of dead or damaged cells by functional cells. Differentiated cells arederived from stem cells
60
What are stem cells?
Cells from which all cells are created - they have potentially limitless proliferation. Daughter cells remain as stem cells or differentiate to a specialised cell type
61
What is the difference between unipotent, multipotent and totipotent cells?
Unipotent - can only differentiate into 1 type of cell
Multipotent - can produce several types of differentiated cells
Totipotent - can produce any type of cell
62
Explain what a labile cell is.
A cell whose normal state is active cell division: G1-M-G1
| Usually rapid regeneration
63
Explain what a stable cell is.
A cell usually in resting state
| Rate of regeneration variable
64
What is a permanent cell?
A cell unable to divide and regenerate
65
What factors control regeneration?
Growth factors
| Contact between basement membranes and adjacent cells
66
How does growth factor control cell regeneration?
Promotes proliferation in the stem cell population
| Promotes expression of gene controlling cell cycle
67
How does contact between basement membranes and adjacent cells control cell regeneration?
```
Signalling through adhesion molecules
Inhibits proliferation in intact tissue
Contact inhibition
Loss of contact promotes proliferation
Exploited in cancer
```
68
On what type of wound does healing by primary intention occur?
Incised wound with apposed edges
69
How does healing by primary intention work?
```
Minimal clot/granulation tissue
Epidermis regenerates
Dermis undergoes fibrous repair
Sutures out at 5-10 days
Maturation of scar up to 2 years
Minimal contraction and scarring good
Risk of trapping infection - abscess
```
70
When does healing by secondary intention occur?
Infarct
ulcer
abscess
any large wound
71
Describe healing by secondary intention
```
Unapposed edges
Large clot dries to form scab
Epidermis regenerates from the base up
Repair process produces much more granulation tissue - larger scar
Contraction to reduce volume of defect
```
72
What are the local factors influencing the efficacy of healing and repair?
```
Type/Size/location of the wound
Apposition - lack of movement
Blood supply
Infection
Foreign material
Radiation damage
```
73
What general factors influence the efficacy of healing and repair?
Age
Drugs and hormones
General/specific dietary deficiencies
General state of health - specifically cardiovascular status
74
How does cardiac muscle heal?
Fibrous repair
75
How does bone heal?
Callus formation
76
How does the liver heal following acute damage?
regeneration
77
How does the liver heal following chronic damage?
cirrhosis. Liver hepatocytes have some regenerative capacity, but hepatocyte architecture does not regenerate. The imbalance between hepatocyte regeneration and the ability to regenerate architectureleads to cirrhosis and nodules
78
How are peripheral nerves repaired?
Wallerian degeneration
| Proximal degeneration distal proliferation
79
How is the CNS repaired?
No regenerative capacity
| Glial cells can proliferate - Gliosis
80
How is skeletal muscle repaired?
Has some regenerative capacity due to satellite cells
81
Define homeostasis
The maintenance of steady states within the body
82
What effects blood homeostasis?
Vessel walls
Platelets
Coagulation system
Fibrinolytic system
83
How does thrombin regulate the coagulation system?
positively feeds back on factors V, VIII, XI
84
What inhibits thrombin?
Anti-thrombin III
Alpha 1 anti-trypsin
Alpha 2 macroglobulin
Protein C/S
85
What do deficiencies in Anti-thrombin III or Protein C/S cause?
Thrombophilia/thrombosis
86
What is fibrinolysis?
The break down of fibrin by plasmin
87
What is fibrinolytic therapy?
Known as clot/thrombus busters
Eg. Streptokinase, activates plasminogen
Very drastic treatment, only used in serious situations
88
What is thrombosis?
The formation of a solid mass of blood within the circulatory system
89
What is Virchow's triad?
Changes in blood flow
Changes in vessel wall
Changes in blood components
90
What are the effects of arterial thrombosis?
Ischaemia
Infarction
Depends on site and collateral circulation
91
What are the effects of venous thrombosis?
Congestion
Oedema
Ischaemia
Infarction
92
What are the outcomes of thrombosis?
```
Lysis
Propargation
Organisation
Recanalisation
Embolism
```
93
What is lysis?
Complete dissolution of the thrombus
Fibrinolytic system active, blood flow re-established
Most likely to occur when thrombus is small
94
What is propagation?
he progressive spread of thrombosis - distally in arteries, proximally in veins
95
What is organisation?
A reparative process with ingrowth of firbroblasts and capillaries. Lumen still obstructed
96
What is recanalisation?
Blood flow reestablished but usually incomplete. One or more channels formed by organisation of thrombi.
97
What is Embolism?
The blockage of a blood vessel by a solid, liquid or gas at a site distant from it's origin
98
Where will a thromboembolism from systemic veins lodge?
Lungs
99
Where will a thromboembolism from the heart lodge?
From the aorta to the renal, mesenteric and other arteries
100
Where will a thromboembolism from atheromatous carotid artery lodge?
Brain (stroke)
101
Where will a thromboembolism from atheromatous abdominal artery lodge?
Legs
102
What is a massive pulmonary embolism?
>60% reduction in blood flow
| Rapidly fatal
103
What is a major PE?
medium blockage of blood vessel
| Shortness of breath, coughing, blood in sputum
104
What is a minor PE?
Small peripheral pulmonary artery blocked
| Asymptomatic or minor shortness of breath
105
What causes Deep Vein Thrombosis?
```
Immobilisation/bed rest
Post-operative
Pregnancy/postpartum
oral contraceptives
severe burns
cardiac failure
Disseminated cancer
```
106
What is the treatment for DVT?
IV Heparin - Anti-coagulant, co-factor for anti-thrombin III
Oral Warfarin - interferes with synthesis of vitamin K dependent clotting factors (slow effect so IV heparin needed at the beginning)
107
How is fat embolism caused?
Trauma eg. bone fracture, laceration of adipose tissue, soft tissue trauma, burns
108
What is fat embolism?
It is aggravated by local platelet and erythrocyte aggregation. The release of fatty acids from the fat globules also causes local toxic injury to endothelium. The vascular damage is aggravated by platelet activation and recruitment of granulocytes.
109
What are the symptoms of fat embolism?
Rash
Shortness of breath
Confusion
110
What is cerebral embolism?
Atrial fibrillation → Stasis → Thrombus
| If in the left heart, can go to the brain and cause a stroke or transient ischaemic heart attack
111
What is an iatrogenic embolism?
Embolism due to medical treatment
| Eg. Air embolism from injection
112
What is nitrogenic embolism?
Nitrogen bubbles form in the bloodwith rapid decompression - the bends
113
What is Disseminated Intravascular Coagulation?
Pathological activation of coagulation mechanisms that happens in response to a variety of diseases.
Small clots form throughout the body, disrupting normal coagulation as they use up all the clotting factors
Abnormal bleeding occurs from the skin
114
What triggers DIC?
Infection
Trauma
Liver disease
Obstetric complications
115
What is the pattern of inheritance of Haemophilia?
X linked recessive therefore more common in boys
116
What factor is defiicient in Haemophilia type A?
factor VIII
117
What factor is deficient in Haemophilia type B?
factor IX
118
What complications does haemophilia cause?
Haemorrhage into major joints, synovial hypertrophy, pain
Muscle bleeding causes pressure and necrosis of nerves
Can haemorrhage into retroperitoneum/urinary tract
119
How is haemophilia treated?
Self administered factor replacement therapy
120
What is thrombocytopenia?
Platelet count is way below the reference range
121
What causes thrombocytopenia?
Failure of platelet production
Increase in platelet destruction
Sequestering of platelets - possibly caused by DIC
Usually accompanied by a bone marrow dysfunction
122
What is an Atheroma?
The accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries
(arteries ONLY!)
123
What is Atherosclerosis?
The thickening and hardening of arterial walls as a consequence of atheroma.
124
What is arteriosclerosis?
The thickening of the walls of arteries usually due to hypertension or diabetes mellitus.
125
What are the macroscopic features of atheroma?
Fatty streak
| Simple/complicated plaque
126
What early changes occur with the development of an atheroma?
Proliferation of smooth muscle cells
Accumulation of foam cells
Extracellular lipid
127
What are the later changes that occur when an atheroma develops?
Fibrosis
Necrosis
Cholesterol clefts (cholesterol develops in the tissue, not the plaque)
+/- inflammatory cells
128
How are foam cells made?
Macrophages phagocytose fat and become foam cells
129
What cellular events occur as an atheroma develops?
Endothelial damage → Platelets → PDGF → Smooth muscle proliferation
Proliferation and migration of smooth muscle takes the lipid with it
Macrophages arrive and phagocytose the fat, becoming foam cells
130
What effects does atherosclerosis in the coronary arteries have?
```
Ishaemic heart disease
MI
Sudden death
Angina pectoris
Arrhythmia
Cardiac failure
```
131
What results from cerebral ischaemia?
Transient ischaemic atack - infarction of part of the brain (24hr symptoms)
Cerebral infarction - stroke
Multi-infarct dementia
132
What are teh results of mesenteric ischaemia?
Ischaemic colitis
Malabsorption
Intestinal infarction
Anneurism due to the high pressure, hardening and weakening
133
What would be the results of atherosclerosis in peripheral arteries?
```
Preipheral vascular disease:
Intermittent claudication
Leriche syndrome
Ischaemic rest pain - IC in iliac artery (gluteal pain)
Gangrene
```
134
Name some lifestyle risk factors for atheroma.
```
Diet
Alcohol
Oral contraceptive
Lack of exercise
Stress
Cigarette smoking
```
135
What makes you more susceptible atheroma?
```
Lifestyle
Age
Gender
Obesity
Hypertension
Hyperlipidaemia
Diabetes mellitus
Infection
```
136
What is hyperlipidaemia?
High cholesterol. LDL transport cholesterol from the liver to the rest of the body therefore is the main contributing factor. HDL protective
137
What are the symptoms/signs of hyperlipidaemia?
Familial hyperlipidaemia
Xantalasma
Corneal Arcus
138
How can you try to prevent atheroma?
```
Stop smoking
Modify diet
Treat hypertension
Treat diabetes
Lipid lowering drugs
```
139
What is the "Unifying Hypothesis for Angiogenesis"?
Endothelial cells damaged
SMC stimulates - produce matrix material
Foam cells secrete cyotkines
140
How does endothelial injury occur?
Raised LDL
Toxins
Hypertension
Heamodynaic stress
141
What does endothelial injury cause?
Platelet adhesion, PDGF release, SMC proliferation and migration
Insudation of lipid, LDL oxidation, uptake of lipid by SMC and macrophages
Migration of monocytes into intima
142
What does the secretion of cytosines from foam cells cause?
Further stimulation of SMC
| Recruitment of other inflammatory cells
143
What factors cause a person to be more susceptible to coronary heart disease?
Geography
Ethnicity
Genetics
144
What are the risk factors of CHD?
```
Smoking
Gender
Hypertension
Diabetes
Alcohol
Infection
```
145
How does normal endothelium prevent thrombosis?
Prostacyclin production
Thrombomodulin production
Prothrombin production
146
What are the risk markers of CHD?
Apolipoprotein E genotype
Angiotensin converting enzyme
genetic polymorphism
147
What is the stage of cell growth in the cell cycle referred to as?
G1
148
What occurs in he restriction (R) point of the cell cycle?
Check point. Cell decides whether or not to divide and continue in the cell cycle.
149
What determines whether or not the cell passes beyond the R point?
Phosphorylation of Retinoblastoma Protein (pRP)
150
What is the phase of DNA replication in the cell cycle referred to as?
S phase
151
What is the G2 phase in the cell cycle?
Preparation for cell division
152
What is the period of mitosis referred to as?
M phase
153
What is the normal state of labile cells?
Give cell division - G1 - M - G1
| Usually rapid proliferation
154
What is the normals taste of stable cells?
Resting state G0
| Variable rate of proliferation
155
What are permanent cells?
Cells unable to divide
156
Define regeneration
Replacement of cell losses identical cells to maintain tissueor organ size.
157
Define hyperplasia
Increase in tissue and organ size due to cell number
158
Define hypertrophy
Increase in tissue or organ size due to increase in cell size
159
Define atrophy
Shrinkage of a tissue or organ due to an acquired decrease in size and/or number of cells
160
Define metaplasia
Reversible change of one differentiated cell type to another
161
Define aplasia
Complete failure of a tissue/organ to develop
162
Define hypoplasia
Incomplete development of a tissue or organ
163
Define dysplasia
Abnormal maturation of cells within a tissue
164
What type of cells does hyperplasia occur in?
Stable and labile only
165
Where do the physiological causes of hyperplasia occur?
Proliferative endometrium
| Bone marrow at altitude
166
Where might the pathological effects of hyperplasia be seen?
Thyroid - goitre
167
In what type of cells may hypertrophy and hyperplasia occur together?
Labile and stable (cells still capable of division)
168
Where might physiological hypertrophy occur?
Skeletal muscle
| Pregnant uterus
169
Is the cause of ovarian atrophying post menopausal women pathological or physiological?
Physiological
170
Where can pathologically caused atrophy occur?
```
Muscle (denervation)
Cerebral atrophy (Alzheimer's disease)
```
171
Where is metaplasia most commonly seen and why?
Epithelial cells to become more suited to a new environment eg. Smokers, pseudo stratified ciliated -> stratified squamous.
172
What can metaplasia often lead to?
Dysplasia and cancer
173
Define Neoplasm
An abnormal growth that persists after the initial stimulus is removed - a type of tumour. Can be benign or malignant
174
What is a malignant neoplasm?
A neoplasm that invades surrounding tissue with the potential to spread to distant sites
175
What is a tumour?
A clinically detectable lump or swelling. Neoplastic/non-neoplastic - NOT NECESSARILY CANCER
176
What is a metastasis?
A malignant neoplasm that has spread from its original site to a new, non-contigious site- secondary cancer
177
What is dysplasia?
A pre-neoplastic alteration in which cells show disordered tissue organisation. Not neoplastic as changes are reversible
178
How do benign and malignant neoplasms differ?
Benign tumours grow in a confined local area and so have a pushing outer margin. THis is why they are so rarely dangerous. Malignant tumours have an irregular outer margin and shape and may show areas of necrosis and ulceration (if on surface)
179
What do benign neoplasm cells look like under the microscope?
Closely resemble parent tissue - well differentiated
180
What do malignant neoplasms look like under the microscope?
Range from well to poorly differentiated
181
What are cells that do not resemble any tissue called?
anaplastic
182
How do poorly differentiated neoplasmic cells appear under the microscope?
With worsening differentiation individual cells have an increased nucleus size and nuclear to cytoplasmic ratio, more mitotic figures and increasing variation in size and shape of cells and nuclei - pleomorphism
183
What does grade indicate?
Differentiation - higher grade, more poorly differentiated. Dysplasia also represents altered differentiation
184
What percentage of risk is due to extrinsic factors?
85%
185
What are initiators?
Mutagenic agents
186
What are promoters?
Agents which cause sustained and prolonged cell proliferation
187
How do initiators and promoters cause proliferation
Initiator initially required and then promoters to sustain it. Result in an expanded, monoclonal population of mutant cells. Neoplasm can be inherited rather than from an external mutagenic agent
188
What is progression?
The process through which a neoplasm emerges from a monoclonal population, characterised by the accumulation of yet more mutations
189
What is a monoclonal collection of cells?
A collection of cells originating from a single founding cell
190
What do genetic alterations effect?
proto-oncogenes and tumoursupressor genes
191
What are oncogenes?
Abnormally activated proto-oncogenes favouring neoplasm formation
192
What do tumour supressor genes do?
Normally supress neoplasm formation
193
What are -oma cancers?
benign
194
What are -carcinomas?
epithelial malignant cancers (90%)
195
What are sarcomas?
stromal malignant neoplasm
196
What are carcinomas in situ?
No ivasionofepithelial basement membrane
197
What is an invasive carcinoma?
penetrated through the basement membrane
198
What is leukaemia?
malignant tumour of blood forming cells arising in the bone marrow
199
What is a lymphoma?
A malignant neoplasm of lymphocytes, mainly affecting lymph nodes
200
From what type of cells do germ cell neoplasms arise?
From pluripotent cells
201
Where do neuroendocrine tumours arise from?
From cells distributed throughout the body
202
What are blastomas?
Formed from immature precursors. Mainlyoccur in children
203
What is the morphology of a reversibly damaged cell?
Swelling - Na/k pump doesn't work
Clumped chromatin due to reduced pH
Autophagy due to catabolic response from low available energy
Ribosome dispersion due to failure of energy-dependant process of maintaining ribosomes
Cytoplasmic blebs
204
What in the morphology of irreversibly damaged cells?
Nuclear changes - pyknosis (shrinkage), karyorrhexis (fragmentation), karyolysis (dissolution)
Lysosome rupture - due to membrane damage
Membrane defects
Myelin figures due to membrane defects
Lysis of endoplasmic reticulum due to membrane defects
205
What are the lethal features of a malignant neoplasm?
The ability to invade (infiltrates and destorys) and metastasis - The spread to distant sites leads to a greatly increased tumour burden. This can result in a vast number of parasitic malignant neoplasms
206
How does a malignant cell get from a primary to secondary site?
1. Grow and invade at the primary site
2. Enter a transport system (vessel)
3. Embolise
4. Arrest
5. Exit and grow at the secondary site to form a new tumour
At all points the cells must evade destruction by immune cells. It is an inefficient process (steps 3,4 and 5)
207
What are the 3 important alterations for invasion?
altered adhesion - reduction in E-cadherin and altered integrin expression
Stromal proteolysis - must degrade basement membrane and stroma by altered expression of proteases, notably matrix metalloproteinases (MMPs)
Motility - reorganisation of actin by Rho (G protein)
208
What is EMT?
Epithelial-to-mesenchymal transition.
Change in cell phenotype to create an appearance more like a mesenchymal cell than an epithelial cell
Crucial for invasion
Transient process
209
What is a cancer niche?
Malignant cells take advantage of nearby non-neoplastic cells. These normal cells provide some growth factors and proteases
210
How are neoplasms transported?
1. Blood vessels
2. Lymph
3. Transcoelomic spread - fluid in body cavity
211
What is extravastation?
Malignant cells leaving a vessel to the secondary site.
212
What are micro metastases?
Surviving microscopic deposits that fail to grow - Many malignant cells lodge at secondary sites but these tiny cell clusters either die or fail to grow into clinically detectable tumours
213
What is tumour dormancy?
An apparently disease free person may harbour many metastases.
214
How may tumours be kept dormant?
- Immune system
- Decreased angiogensis
- adapted for primary site and secondary site may be hostile
215
How is a malignant relapse thought to be caused?
By dormant tumours (micrometastases)
216
What determines the site of a secondary tumour?
1. Regional drainage of blood, lymph or coelomic fluid
2. The seed and soil phenomenon may explain the often unpredictable distribution. Due to interactions between malignant cells and the local tumour environment
217
How do carcinomas tend to spread?
Via lymphatics first
218
How do sarcomas tend to spread?
Via blood stream
219
What are the common sites of blood borne metastasis?
Lung
Bone
Liver
Brain
220
What neoplasms most frequently spread to bone?
```
Breast
Bronchus
Kidney
Thyroid
Prostate
```
221
What do we mean by "personalities" of malignant tumours?
Soem are more aggressive and metastasise very early in their course e.g.. Small cell bronchial carcinoma.
Others almost never metastasise eg. basal cell carcinoma of the skin
222
How is the likelihood of metastasis determined?
Size of the primary neoplasm. This is the basis of cancer staging
223
How can the effects of a neoplasm on a host be classified?
The direct local effects which can be of the primary neoplasm and/or the secondary neoplasm(s) and those due to the indirect systemic effects
224
What are paraneoplastic syndromes?
Indirect systemic effects of neoplasm, including effects of increasing tumour burden, secreted hormones and/or miscellaneous effects
225
What factors effect benign neoplasms most?
Local effects from the primary
| Hormonal effects
226
What are the local effects of primary and secondary neoplasms due to?
1. Direct invasion and destruction of normal tissue
2. Ulceration at a surface leading to bleeding
3. Compression of adjacent structures
4. Blocking tubes and orifices
227
What does increasing tumour burden lead to?
Parasitic effect on the host:
- reduced appetite and weight loss
- malaise
- immunosupression
- thrombosis
228
Why do benign neoplasms typically produce hormones?
Well differentiated
229
What are some miscellaneous systemic effefcts?
Neuropathies - affect the brain and peripheral nerves
Skin problems e.g.. pruritis and abnormal pigmentation
fever
myositis
Pathogenesis poorly understood
230
What are the 5 leading behavioural and dietary risks that cause cancer?
```
High BMI
Low fruit and veg intake
Lack of physical exercise
Tobacco use
Alcohol use
```
231
What are the 3 categories of extrinsic factors causing cancer?
Chemicals
Radiation
Infection
232
What is carcinogenesis?
Causes of cancer
233
What has neoplasms caused by 2-mapthylamine shown?
!. THere is a long delay between carcinogen exposure and malignant neoplasm onset
2. The risk of cancer depends on total carcinogendosage
3. There is sometimes organ specificity for particular carcinogens
234
What are complete carcinogens?
Carcinogens that act as both initiators and promoters
235
What are the classifications of carcinogens?
```
Polycyclic aromatic hydrocarbons
Aromatic amines
N-nitroso compounds
Alkylating agents
Diverse natural products
```
236
What are pro-carcinogens?
Chemicals only converted to carcinogens by the cytochrome P450 enzymes in the liver
237
What is radiation?
ANy type of energy travelling through space. Can be mutagenic. Damage DNA directly or indirectly by generating free radicals.
238
How is ionising radiation a carcinogen?
Strips electrons from atoms. Damages DNA bases and causes single and double strand DNA breaks
239
How can infections be carcinogenic?
Directly affect genes controlling cell cycle
Indirectly cause chronic tissue injury - resulting regeneration acts either as a promoter for any pre-existing mutations or else causes new mutations from DNA replication errors
240
What is the 2 hit hypothesis?
Explains the differences between tumours occurring in families and those occurring in the general population
Familial cancers - first hit through germline, affects all cells in the body, second hit, somatic mutation
Sporadic cancers - no germline mutation and so requires both hits to be somatic mutations and to occur in the same cell
241
WHat are tumour suppressor genes?
Genes that inhibit neoplastic growth. Inactivate both alleles
242
WHat are oncogenes?
Activated pro to-oncogenes that favour neoplastic growth (only one allele of each port-oncogene needs to be activated for neoplastic growth)
243
Compare proto-oncogenes and tumour supressor genes
Proto-oncogenes can be activated to oncogenes which push the cell past the cell cycle restriction point
Tumour suppressors encode proteins with anti-growth effects
