Mechanisms Of Disease Flashcards
Give four differences between the processes of oncosis+necrosis and apoptosis.
Oncosis - blebbing
Apoptosis - budding
Oncosis - inflammation
Apoptosis - no inflammation
Oncosis - swelling
Apoptosis - no swelling
Oncosis no membranes maintained
Apoptosis - membranes maintained
Name four types of necrosis and give an example of where each might be found.
Coagulative - heart in MI. Caused by protein denaturation
Liquefactive - brain. Caused by enzyme digestion in areas of little stromal support
Caseous - lungs in TB
Fat - pancreas
Which type of necrosis is associated with granulomas?
Caseous
What happens to the nucleus after cell death (necrosis)?
Pyknosis - shrinks
Karyorrhexis - breaks apart
Karyolysis - completely dissipates
Give one example of apoptosis occurring in a useful way and one example of it occurring in a pathological way.
Sculpting during embryogenesis eg the interdigitation of the fingers.
Graft vs host disease or cancer
What is the difference between hypoxia and ischaemia?
Hypoxia is the lack of oxygen to the tissues due to a number of reasons eg anaemia, reduced respiration rate. Another reason for hypoxia might be ischaemia which is the blockage of the blood supply to the tissues. Ischaemic tissue is not only missing oxygen but the other plasma contents.
What is the difference between blood plasma and serum?
Plasma contains platelets
Describe 3 physiological processes which occur during reversible hypoxia injury.
- Na/k ATPase stops working. Gradient no longer upheld and Ca+ and Na+ enter the cell. Water follows and it swells.
- Glycolysis is unregulated to try to produce more ATP. This makes the pH more acidic and chromatin clumps together.
- Without ATP ribosomes detach from the ER and protein production reduces.
When hypoxic injury is irreversible, what happens to the cell?
The membrane becomes leaky and there is a huge influx of calcium. This activates a number of enzymes eg ATPase, phospholipase, protease, endonuclease which digest the cell. ATPase makes it happen even faster.
What pigment builds up in the cell to form a bruise?
Haemosiderin
What five classic symptoms are observable during acute inflammation?
Rubor, tumor, calor, dolor and loss of function.
What is the mechanism of acute inflammation?
- Changes in blood flow
- (constrict) dilation
- increase permeability
- increase viscosity (rbcs) - Exudate
- Infiltration of neutrophils and fibrin
In acute inflammation what four changes occur to the blood flow?
- Transient vasoconstriction
- Vasodilation
- Increased permeability
- Increased viscosity/stasis
What are the two key differences between an exudate and a transudate? When might each of them be found?
Exudate - 1. protein rich fluid loss 2. due to both osmotic pressure and oncotic pressure in the interstitium. Found in acute inflammation.
Transudate - 1. Low in protein 2. due to osmotic pressure only. Found in heart failure.
Name four key chemical mediators of acute inflammation.
Histamine
Cytokines - bradykinin
Leukotrines
Complement - C3a, C5a, IL-1
Give 4 systemic effects of acute inflammation.
Fever
Leukocytosis
Increase in c reactive protein
Possible shock
What is the main white blood cell type involved in acute inflammation?
Neutrophils/polymorphs (same thing)
Describe how neutrophils leave the blood vessel and enter the tissue. Is it an active or passive process?
- Chemotaxis - attracted along chemical gradient
- Rolling along the sides of the vessel.
- Adhesion by integrins
- Aggregation
- Diapedesis - force their way between cell junctions and digest the basement membrane
Passive
When might a chronic inflammation arise in relation to an acute inflammation?
- After an unresolved acute inflammation
- Alongside a severe acute inflammation
- Without an acute inflammation eg TB, autoimmune arthritis
What are the key features of chronic inflammation?
Fibrosis
Macrophages
Lymphocytes
Can have - pus, granuloma, giant cells
What is the major white blood cell involved with chronic inflammation?
Macrophages
Give three functions of a macrophage.
- Phagocytosis
- Present antigens to T lymphocytes to trigger production of antibodies
- Secrete substances such as cytokines to further immune response
What are antigens and antibodies?
Antigens are signal proteins on bacteria cell walls which are recognised by lymphocytes. The T lymphocytes then produce antibodies to specifically attack that bacteria.
How is fibrosis caused? Give an example.
Overstimulation of fibroblasts by cytokines during chronic inflammation leads to excessive scar tissue and shrinkage. Eg cirrhosis of the liver.
What is a granuloma? Give two situations which might cause a granulomatous inflammation.
The body’s response to insoluble particles.
- Foreign body eg a splinter
- Hypersensitivity to a molecule eg. TB, sarcoidosis, crohns
What is a giant cell? Give three specific types of giant cell and describe their nuclei.
When macrophages fuse together.
- Langhans - nuclei in a peripheral ring
- Touton - nuclei in a central ring
- Foreign body - nuclei randomly spaced
In what type of inflammation would you find a giant cell?
Chronic granulomatous inflammation.
Describe the type of inflammatory response you would expect to see with a TB infection.
Caseous necrosis
Granulomatous inflammation with Langhans giant cells
What kind of protein can build up in an alcoholic liver?
Malory’s hyaline from altered keratin
What causes reperfusion injury?
When blood is returned to an area after ischaemia, endothelial cells produce more reactive oxygen species, causing damage to the reperfused tissue.
What are free radicals? Give 4 ways they can be produced in the body.
Highly reactive ions which cause damage to tissue. Eg. OH, 1/2o2, ONOO, H2O2
Can be produced by Fenton reaction, Haber Weiss reaction, radiation, escape from electron transport chain.
What is the difference between a red and white infarct? Where math they occur?
A White infarct is simple occlusion of blood and tissue death.
Red infarct haemorrhages after death.
White occur where there is solid stroma eg heart, kidney, spleen
Red occur where there is loose stroma eg lungs, gonads, colon
What are the body’s natural defences against reactive oxygen species?
SOD enzyme plus catalase
NADPH keeps up stores of glutathione
ACE vitamins
Describe the mechanism of apoptosis.
Intrinsic - activation of p53 increases permeability of mitochondria, cytochrome c is released which creates an apoptosome and interacts with caspases
Extrinsic - ligand such as TRAIL activates caspases
Caspases cleave up the cytoskeleton
What is the function of heat shock proteins? Give an example.
After cell damage, they collect up damaged proteins, unfold them and take them back to the endoplasmic reticulum to be re folded.
Eg chaperonins
What is granulation tissue? Name some of its contents.
Early scar tissue - proud flesh
Fibroblasts
Type 3 collagen (later replaced by type 1)
Macrophages and neutrophils
Lots of new blood vessels
Define haemostasis
The collection of processes which maintain blood volume by preventing excess bleeding.
Requires vessel wall, platelets, coagulation and afterwards fibrinolysis
What is virchow’s triad?
Triad of risk factors for thrombosis:
Blood components
Blood flow
Vessel wall
Define thrombosis
Formation of a solid mass of blood in the circulation
Give three differences between the appearances of venous and arterial thrombosis.
Venous - dark red
- lots of cells
- soft
Arterial - pale
- not many cells - lines of zahn form striped between cells and fibrin
- hard
-What are the 5 possible outcomes of a thrombus?
- Lysis
- Propagation - progressive spread towards the heart because of stagnant blood. (Backwards in arteries and forwards in veins.)
- Organisation - granulation tissue then scar
- Re canalisation - channels form through the scar
- Ischaemia - eg DVT, MI, stroke depending on location
Define an embolus and give 4 substances which can form one.
Obstruction of a blood vessel at a distant site. Can be formed by- 1. Thrombus (thrombo embolus) 2. Air 3. Fat 4. Nitrogen 5. Amniotic fluid
What are the contents of granulomatous inflammation? (Granulomas)
Epithelioid cells and macrophages
Plus sometimes fibroblasts and giant cells
What happens during the vascular phase of the clotting cascade?
Vessels transiently dilate then constrict
Tissue factors from endothelium activate extrinsic pathway
Collagen activates the intrinsic pathway
Von willebrand factor activates platelets
What happens during the platelet phase of the clotting cascade?
Platelets are released from megakaryocytes
Formation of the primary plug
Gla residues attract the clotting factors
What happens during the coagulation phase of the clotting cascade?
Extrinsic pathway and intrinsic pathway meet at factor 10 - prothrombin
Activate thrombin which activates fibrin which attaches to the primary plug and forms a clot
What is measured by 1. Bleeding time 2. Prothrombin time 3. PTTK?
- Platelet activation and formation of primary plug
- Extrinsic pathway of clotting cascade
- Intrinsic pathway of clotting cascade
What tissue factors are absent in Haemophilia? What measure will increase?
8 and 9
Increase in PTTK
What is missing in Von Willebrands disease? What measure will increase?
Von willebrand factor which activates platelets
Bleeding time will increase
What measure will increase in a vitamin k deficiency?
INR (prothrombin time)
Name 4 substances which help fibrinolysis and name the substance they act on.
Anti thrombin c - clotting factors
Plasminogen - fibrin
Protein c and thrombomodulin - thrombin
Prostacyclin - platelets
When would each of the following drugs be used to break down a clot? Aspirin Streptokinase Heparin Warfarin
- Chronic - platelet action
- Emergency - clotting factor action
- Acute - clotting factor action
- Chronic - clotting factor action
What is the difference between atheroma and atherosclerosis?
Atheroma is the accumulation of intra and extra cellular lipid in the intima of arteries.
Atherosclerosis is the hardening of the arterial wall as a consequence.
How does atheroma develop macroscopically?
Fatty streak
Simple plaque - fibrosis/necrosis
Complicated plaque - extends to media
How does atheroma develop microscopically?
Smooth muscle proliferation
Macrophages, Foam cells and extra cellular lipid
Fibrosis/necrosis
Extends to the intima
Describe the pathogenesis of atheroma.
- Endothelial injury - eg high ldl, bp, ox stress
- Platelet adhesion, releases growth factor, smooth muscle proliferates
- Lipid insudation - uptake by smooth muscle and free lipid
- Macrophages and foam cells aggregate in the intima
What is intermittent claudication and what does it indicate?
Aching pain on exercise, classically in the leg that eases with rest.
Indicative of peripheral vascular disease - atheroma in the peripheral arteries
What are the risk factors for atheroma?
Age and gender
Smoking and alcohol
Hyperlipidaemia
Hypertension
Diabetes
What are stem cells?
Undifferentiated cells which can both divide and differentiate. They can divide indefinitely because they express telomerase.
Adult - uni potent except haemopoetic
Embryonic - pluripotent
How do stem cells divide and differentiate?
- Stem cell divides - one for self renewal and one differentiates into a progenitor cell
- Progenitor cell is the one which divides continuously
This protects the original stem cells from too much division which would increase the risk of mutation.
What are the three types of stem cell and where are they found?
Labile - divide constantly eg blood, epithelia
Stable - normally quiescent but can divide eg liver, bone
Permanent - cannot mount an effective proliferation eg neurones, skeletal muscle
What is the difference between hyperplasia and hypertrophy? Give examples of each.
Hyperplasia is an increase in cell number eg psoriasis, thyroid goitre
Hypertrophy is an increase in cell size eg skeletal muscle, pregnant uterus
Define metaplasia. Give two examples.
The process of a cell being replaced by another differentiated cell type.
Eg barratts oesophagus
Or pseudo stratified ciliates respiratory - stratified squamous in a smoker
Define atrophy. Give two examples.
Decrease in cell size and cell number
Eg dementia, post menopause ovary
Define aplasia.
Congenital hypoplasia - a complete failure to develop a body part
What are the 5 parts of the cell cycle? What happens during each one?
M - mitosis
G1 or G0
S - DNA synthesis
G2
What are the options for a cell entering G0?
Quiescence - transient
Replicative senescence - run out of telomere so permanent
Carcinogenic senescence - protective mechanism, permanent
What is the restriction point of the cell cycle and when does it occur?
The point of no return- after which a cell will enter the next stage of the cycle. During G1
Describe the mechanism which encourages a cell to proliferate beyond the restriction point and enter the cell cycle.
- Growth factor binds to receptor which activates tyrosine kinase
- Tyrosine kinase activates RAS
- RAS activates cyclin D and CDKinase
- CDKinase phosphorylates and deactivates pRb so it releases transcription factors
- Cell can progress to DNA synthesis
Describe the mechanism that prevents a cell from proliferating and moving beyond the restriction point of the cell cycle.
- P53 activates CDKinase inhibitor
2. CDKinase does not deactivate pRb so transcription factors are not released
Define a tumor suppressor gene and give two examples.
A normal gene which, when altered by mutation can act against the growth of cancer.
P53
pRb
Define a protooncogene and give an example
A normal gene which, when altered by a mutation, can contribute to cancer. Eg RAS
Define neoplasia.
An abnormal growth of cells that persists after a stimulus is removed.
What is the difference between a benign and a malignant neoplasm?
Potential to spread to distant sites.
Define dysplasia.
Poorly differentiated cells
Describe the features of poorly differentiated cells.
Increase in size of nucleus Increase in ratio nucleus:cytoplasm Hyperchromasia (darker) Mitotic figures Pleomorphism (variation)
What is a telomere? What happens over time? Which type of cell is an exception to this rule?
A region of repetitive nucleotide sequences at the end of each chromatid which protects the DNA.
They slowly degrade over time and when they run out, a cell will enter G0 due to replicative senescence
Stem cells secrete telomerase so this does not happen and they can relplicate indefinitely .
What is a carcinoma in situ?
As dysplasia (cell differentiation) worsens it will become malignant. Carcinoma in situ is a malignant dysplasia in a state prior to invasion of the basement membrane.
What is the name given to a dysplasia which invades the basement membrane?
Invasive carcinoma
Why does ulceration occur around a malignant neoplasm?
Because the neoplasm is growing faster than angiogenesis can occur so the tissue dies.
What is the name given to cancer of epithelia?
Carcinoma
What is the name given to cancer of stroma such as smooth muscle or fibroblasts?
Sarcoma
What is the name given to cancer of haemopoetic cells in the bone marrow?
Leukaemia
What is the name given to cancer of white blood cells?
Lymphoma
What is the name given to cancer of glands?
Adenocarcinoma
Describe 4 local effects of neoplasm.
- Direct invasion
- Ulceration
- Perforation
- Compression/blocking
What are 3 general systemic effects of neoplasm?
- Increased tumour burden
- Hormone and growth factor secretion
- Paraneoplastic syndrome
Define tumour burden. If it is increased, what are the effects?
The total amount of neoplastic material distributed throughout the body, increasing metabolic load.
- Weight loss
- Malaise
- Decreased appetite
- Immunosuppression
- Increased cytokines and and platelet derived growth factor - thrombosis
Define metastasis.
The development and growth of a neoplasm at a secondary site not contiguous with the primary site.
What is the difference between the stage and grade of a tumour?
Stage - extent of metastasis and growth
Grade - extent of dysplasia (how poorly differentiated)
Is stage or grade a better indicator of current morbidity?
Stage
What are the 4 processes which must occur for a neoplasm to grow and invade at its primary site?
- Epithelial to mesenchymal transmission
- Adhesion
- Stromal proteolysis
- Motility
Is stage or grade a better indicator of potential morbidity?
Grade
What is epithelial to mesenchymal transmission?
Cancer cell changes to look like a mesenchymal cell so that is can invade unnoticed.
How does a cancer cell increase adhesion as it grows?
Decreases E cadherin secretion which allows the cancer cells to bind together
Decreases integrin secretion which allows the cancer cells to bind to the stroma
How does a cancer cell activate stromal proteolysis as it grows?
Increases protease secretion from “niche” spy cells
How does a cancer cell increase its motility as it invades the basement membrane?
G protein signalling to weaken the actin cytoskeleton
What are the three modes of transport available to a cancer cell?
- Blood
- Lymph
- Transcoelomic
Where will a cancer cell tend to end up if it travels by blood?
Lung, liver, bone, brain
Where are the most common sites for metastasis?
Lung, liver, bone, brain
Where will a cancer cell tend to end up if it travels by lymph?
Regional lymph nodes, beginning at the sentinel node.
Where will a cancer cell tend to end up if it travels across the coelom?
Within the same coelom eg pouch of Douglas to the rest of the peritoneum
Which types of cancer commonly spread to bone?
Hexagon of bone mets
- thyroid/ bronchus
- breast
- kidney
- prostate
What is DIC?
Disseminated intravascular coagulation
Lots of clotting everywhere, ischaemia in small vessels
Use up all the clotting factors and platelets so there is uncontrolled bleeding.
Give four examples of growth factors.
Epidermal
Vascular endothelial
Platelet derived
Granulocyte colony stimulating
What is meant by regeneration/resolution? What must be in tact for it to occur completely?
The growth of functional, differentiated cells and tissues to replace lost structures.
Complete resolution requires a connective tissue scaffold to remain in tact.
Describe the processes involved in the formation of a fibrous scar.
Blot clot Acute inflammation Chronic inflammation Angiogenesis Myofibroblasts infiltrate Glycoproteins and collagen are produced Collagen matures and contracts
Give four differences between healing by primary and secondary intention.
Primary -
Smaller scar
Quicker to heal, earlier contraction
No granulation tissue
Only occurs with clean incision where there is contact between the layers of epidermis
What happens if there is insufficient fibrosis over a wound?
Hernia, ulceration
What happens if there is excessive fibrosis over a wound?
Excessive scarring eg keloids
What happens if there is excessive contraction of the collagen following fibrous repair?
Limited joint movement - contractures
Obstruction of tubes and channels - strictures
Why can’t cartilage repair easily?
Lack of blood supply.
Why do some cancers consistently spread to apparently odd sites? Give an example.
Seed and soil explanation. Some cancers need a certain type of host cell.
Eg stomach cancer spreads to the ovary
Why do some cancers lie dormant?
They might travel to a secondary site but fail to colonise. They leave dormant micrometastases. When the conditions become favourable the micrometastases can develop properly. This is why cancer can’t be cured.
What is the name given to the process of growth of a neoplasm at a secondary site?
Colonisation
Why is colonisation an inefficient process?
Cancer cells face immune attack, hostile secondary site - lack of niche cells, slow rate of angiogenesis.
Why do some cancers consistently spread to apparently odd sites? Give an example.
Seed and soil explanation. Some cancers need a certain type of host cell.
Eg stomach cancer spreads to the ovary
What is the name given to the process of growth of a neoplasm at a secondary site?
Colonisation
What tissue types have no (very limited) ability to heal?
Cartilage
Cardiac muscle
Which tissue types use outside cells to aid healing? What are the names of these cells?
Central nervous system - glial cells
Skeletal muscle - satellite cells
Describe how bone heals.
- Haematoma
- Granulation tissue - fibrin, blood vessels, macrophages,..
- Cytokines activate osteoblasts
- Soft callus - fibrocartilage
- Hard callus - woven bone
- Remodelling
Describe how a peripheral nerve heals.
- Axons degenerate
- Stumps sprout
- Old Schwann cells guide the path back to the tissue
- Growth is slow - 1-3mm per day
What is the name of adhesion molecules that bind cells to each other?
Cadherins
What is the name of adhesion molecules that bind cells to the extracellular matrix?
Integrins
What is contact inhibition?
When a cell is in contact with other cells by cadherins and integrins, it is inhibited from replicating.
When it becomes isolated from other cells, it enters the cell cycle to aid wound healing.
What causes sputum to be yellow? What does it indicate?
Neutrophils and eosinophils
Allergic reaction or infection
What causes sputum to be green? What does it indicate?
Broken down neutrophils
Chronic infection
What causes sputum to be brown/black? What does it indicate?
Old blood
Chronic coughing or tobacco
Possible lung cancer/pneumonia
What causes sputum to be red? What does it indicate?
New blood
PE, left heart failure, lung cancer, pneumonia
What is sarcoidosis? Which organs are commonly affected?
Diagnosis of exclusion describing chronic granulomatous inflammation.
Commonly affects lung and lymph.
How does thrombosis differ from clotting?
Pathological versus physiological response
Thrombus occurs too fast for fibrinolysis to occur effectively
What is the most common cause of aneurysm?
Atherosclerosis weakens wall
Give three tumour biomarkers and their associated cancer.
Hcg - testicular and Choriocarcinoma
PSA - prostate
CA 125 - ovarian
Which type of cancer secretes ADH and ACTH? What can this cause?
Bronchial small cell carcinoma
ADH - water retention
ACTH - cortisol - cushings
What type of cancer secretes PTH? What is the effect of this?
Bronchial squamous cell carcinoma
PTH - hypercalcaemia
List some functions of the complement system and give some examples of complement.
C3a and c5a
Generally compliments the immune response
- Opsonisation - identifying pathogens for phagocytosis
- Amplification of proteases and cytokines
- Activation of membrane attack complex
Which cells are infected by HPV virus? What can infection lead to?
Keratinocytes in basal layer of stratified epithelium
Can cause cervical, vulval cancer
Also genital warts
How does a pulmonary embolus kill you?
- Mechanical shock due to sudden decreased preload of the left heart
- Right sided heart failure due to severe pulmonary hypertension
