Flashcards in MOD Deck (186):
What are the types of cellular hypoxia?
What are possible causes of each?
Hypoxaemic - low arterial oxygen due to lung disease or reduced atmospheric concentration.
Anaemic - decreased ability of the blood to carry oxygen due to the anaemia or co poisoning
Ischaemic - interruption of blood supply to a region due to thrombus or shock
Histiocytic - inability of the cell to utilise oxygen due to poisoning such as cyanide, carbon dioxide or dinitrophenol
What are causes of cellular injury?
Dietary insufficiency or excess
Physical agent (heat, electricity, trauma etc.)
What reversible changes happen to a cell as it becomes hypoxic?Why?
Lack of oxidative phosphorylation
Fall in ATP
Loss of Na/K ATPase activity
Increased intracellular sodium and calcium and extra cellular potassium
Water follows osmotic gradient into cell causing blebbing of cytoplasm and swelling
Glycolysis increases to raise ATP resulting in lactic acid production lowering pH
This causes clumping of chromatin
Ribosomes detach decreasing protein synthesis
What are the irreversible changes of hypoxic cell injury including the DNA changes?
Cell death by swelling - oncosis
High calcium levels causing inappropriate activation of proteins (e.g. Proteases)
Pyknosis (chromatin shrinking)
Karyohexis (nucleus fragmentation)
Karyolysis (nucleus dissolution)
How can free radicles be created?
Haber Weiss reaction
What are common mechanisms for cell damage other than hypoxia?
Membrane (including organelle) disruption
Proteins (enzymes and structural)
What are the main mechanisms of free radical injury?
Lipid peroxidation - hydroxyl radical reacts with unsaturated hydrocarbon removing one hydrogen to create water. This radical lipid is then react with O2 creating an O2* side group. It can then react with a neighbouring chain creating a OOH side group and making the new chain a radical - this propagates on creating more radical chains.
DNA strand breaking and base alteration
Protein disulphide bridge formation by cysteine oxidation altering structure.
What is the mechanism of reperfusion injury?
Increase O2 for free radical production
Influx of inflammatory components such as neutrophils and complement
How do cells protect themselves from injury?
Heat shock proteins - mend or mark for degradation misfolded proteins e.g. Ubiquitin
ROS protection - SOD, catalase, glutathione, iron sequestration, antioxidants
The morphological changes that occur after a cells has been dead for some time in a living organism.
What are the four main types of necrosis?
Coagulative - cell architecture preserved, proteins denatured
Liquifactive - cell degraded by own active enzymes
Caseous - tb - structureless debris form surrounded by granuloma
Fat - lipids released
What is gangrene? How can it be classified?
The clinical description of a mass of necrotic tissue
Dry - coagulative necrosis following arterial occlusion
Wet - liquifactive necrosis typically following infection
Gas - infection usually with Clostridium perfringens
What is infarction?
Necrosis resulting from ischaemia (thrombus, emboli, vessel twisting or external compression of vessel).
What are white and red infarcts?
White - occurs in solid organs on occlusion of an end artery - no haemorrhage can occur due to solid stroma.
Red - occurs in loose organs, on venous occlusion or where anastamoses or dual supply is present but insufficient to sustain the tissue. There can be haemorrhage into surrounding tissues.
How does potassium release cause damage to the heart?
danger around heart as it causes depolarisation towards threshold of myocytes raising the number of inactive vgNa channels slowing upstroke (and has the paradoxical effect of slowing conduction through HCN channels slowing heart rate)
What cell injury mechanisms can lead to hyperkalaemia around the heart?
Local - MI
Systemic - crush syndrome burns, tumour lysis sydrome
What toxins can be released from cells that die by oncosis?
Enzymes (e.g CKMB, ALT)
What is the main cause and effect of myoglobin release in cell injury?
Rhabdomyolysis - damage renal glomeruli causing acute kidney injury.
How does the process of apoptosis differ from oncosis?
Membrane integrity maintained
Give some examples of physiological apoptosis
Remodelling of an embryo
Distraction of a virus infected cell
Decreasing breast tissue after lactation
Give an example of pathological apoptosis
Amylotrophic lateral sclerosis
How is apoptosis initiated?
Intrinsic - DNA degradation or withdrawal of growth factors, increased mitochondrial permeability, release of cytochrome C, activation of capases
Extrinsic - binding of TRAIL to receptor, activates capases
How do cells degenerate in apoptosis?
Break into small membrane bound fragments called apoptotic bodies.
How are apoptotic bodies removed?
Phagocytosis by neighbouring cells or phagocytotic cells like macrophages.
What is the effector molecule of apoptosis?
What molecules accumulate in cells abnormally?
Lipids - fatty liver, xantholasma, athrosclerosis
Proteins - mallory hyaline in liver disease, misfolded proteins
Pigments - coal dust, tattooing ink, bilirubin, haemosiderin lipofusin
What are the two forms of calcification?
Malignant - raised serum calcium
Dystrophic - normal serum calcium
Why do cells age?
Telomeres shorten with every replication.
What is it termed when telomeres 'run out' for a cell?
What cells telomeres are immortal? Why?
Germ cells, some cancer cells
What enzymes are involved in the metabolism of alcohol?
What is the intermediate and product in alcohol metabolism? What is created?
Why are women more sensitive to alcohol?
Lower levels of alcohol dehydroginase
What are the effects of chronic alcohol intake?
Fatty liver from increased acetyl coA and NAPDH
What could occur in acute very excessive alcohol intake?
Acute alcoholic hepatitis
What is produced when normal paracetamol metabolism is saturated?
What effect does this have?
NAPQI which is conjugated to glutathione
NAPQI is directly toxic binding to sulphydryl groups
Glutathione depletion leaves cells vulnerable to ROS
What patients are high risk in paracetamol overdoses?
Taken with alcohol
Enzyme inducing drug patients
How does n-acetyl cystine work?
Prodrug precursor to l-cysteine which is precursor to glutathione
What occurs in an aspirin OD?
Stimulation of resp centre causing a resp alkalosis
Body compensates with a metabolic acidosis
Decreased platelet aggregation causes bleeding
What are the four signs of inflammation?
What are the two phases of acute inflammation?
What occurs in the vascular phase of acute inflammation?
Vasodilation increasing blood flow and capillary hydrostatic pressure
Increased permeability of blood vessels
Leakage of exudate
Raised cellular concentration of blood slowing it down
What triggers the vascular phase of acute inflammation?
Histamine released from mast cells, basophils and platelets due to:
C3a C5a and IL-1 from neutrophils and platelets
What causes pain in vascular phase of acute inflammation?
What chemical mediators cause increased vascular permeability in acute inflammation?
Differentiate transudate from exudate
Exudate contains proteins and is only formed when vessel permeability increases as well as hydrostatic and osmotic pressure
What proteins leave the vascular compartment during the vascular phase of acute inflammation? What effect does this have?
Fibrin - formation of fibropurilent exudate to contain inflammation
General proteins - increase oncotic pressure increasing exudate formation
What occurs in the cellular phase of acute inflammation?
Extravasation of neutrophils
Phagocytosis of debris and pathogens
How do neutrophils enter the tissue fluid?
Margination - slow blood leads to cells moving to vessel walls
Rolling - adhere to selectins and roll along wall
Adhesion - adhere tightly to adherins
Emigration - squeeze through gaps between cells digesting basement membrane as they do.
How are neutrophils attracted to areas of acute inflammation?
Chemotaxis along concentration gradients of C5a and bacterial peptides
How does acute inflammation aid us?
Swelling and pain - enforces rest
Exudation of fibrin - contains damage
Fluid exudation - dilutes toxins
Increased lymph drainage - removes pathogens
Exudation of immune cells - destroy pathogens and debris
Vasodilation - faster delivery of fluid and cells
What are local complications of acute inflammation?
Loss of function
What are systemic complications of acute inflammation?
Altered plasma proteins
What are outcomes of acute inflammation?
Progression to chronic inflammation
Repeated acute inflammation
What aids acute inflammation resolution?
Short half life of mediators
Binding of inhibitors
How does inflammation cause fever?
ILs, prostaglandins and TNF alpha are pyrogens that effect the hypothalamus
Why does chronic inflammation occur?
Take over from acute inflammation if damage is too severe to be repaired within a few days
Alongside acute inflammation in repeat irritation
Without acute inflammation in some conditions eg. RA, TB, small foreign body
Hw does chronic inflammation differ from acute?
More variable course
Macrophages, lyphocytes, plasma cells and eosinophils
What is the function of macrophages in chronic inflammation?
Release of cytokines, complement and clotting factors
Hw are lymphocytes identified histologically, what is their role in chronic inflammation?
Near invisible plasma membrane and cytoplasm
Specific response to a particular antigen
How do plasma cells appear histologically?
Clock face nuclei (clumped peripheral chromatin)
White halo of golgi
How do eosinophils appear histologically?
Bilobed nuclei in red staining cytoplasm (sunburnt face with sunglasses)
What are the types of giant cells?
Langerhans - TB - ordered crescent of nuclei peripherally
Foreign body type - FB! - disordered nuclei, evidence of debris
Toutons - fat - ordered crescent of nuclei with foamy appearance outside of cell
What causes giant cell formation?
Frustrated macrophages unable to phagocytose pathogen / debris joins with others.
How does chronic inflammation cause fibrosis? In what conditions does this occur?
Mediator production by macrophages cause fibroblast recruitment resulting in collagen production. This causes fibrosis.
This impairs function.
Found in cirrhosis, repeated choleocystitis, fibrotic lung disease
When does chronic inflammation result in up-regulation of function?
What is a granuloma?
A focal discrete collection of immobile macrophages (epitheloid macrophages) surrounded by lymphocytes.
What causes granuloma formation?
Persistent low grade irritation that cant be removed - e.g TB or idiopathic like wegners granulomatoisis and chrones disease
What are the different classifications of stem cells
How can cell division be classified?
Labile - actively dividing, no entry to g0
Stable - divides when signalled but usually at rest
Permanent - unable to divide fixed in g0
What factors upregulate cell division? Give examples
What factors downregulate cell division?
Adhesion molecules in neighbouring cells and basement membrane (contact inhibition)
When would a tissue repair by fibrous repair not regeneration?
Necrosis of permanent cells
Loss of collagen framework of necrosed labile or stable cells
What are the three stages of fibrous repair?
Extracellular matrix production
What are the cells involved in fibrous repair? What do they do?
Inflammatory cells - phagocytosis and mediator release
Endothelial cells for angiogenesis
Fibroblasts and myofibroblasts for matrix production and wound closure.
What occurs in the angiogenesis phase of fibrous repair?
Growth factors (eg VEGF) trigger preexisting vessels to sprout new vessels
- endothelial proteolysis of basement membrane
- migration of endothelial cells by chemotaxis
- endothelial proliferation
- maturation and remodelling with recruitment of pericytes
Explain the rabbit ear chamber model of fibrous repair
- blood clot forms with acute inflammation progressing to chronic inflammation
- clot replaced with granulation tissue with anginogenesis, (myo)fibroblast infiltration, ECM production and decline in immune cell levels
- granulation tissue matures - cell populations decline, collagen increases, myofibroblasts reduce volume.
Differentiate healing by primary and secondary intention
Primary - edges in apposition, little granulation tissue formation, epidermis regenerates over injury, minimal scarring, there is risk of abcess formation if infection trapped under regenerating epidermis
Secondary - edges not in apposition, clot forms creating an eschar, granulation tissue forms from bottom up forming large scar and wound contraction
What local factors could influence wound healing?
Size of wound
What systemic factors could influence wound healing?
Comorbidities - diabetes, CHF, PVD, connective tissue disease, immunosuppressive disease
Medications - steroids, hormones
Dietary deficiency - proteins, vitamins, essential amino acids
What are the complications of insufficient wound healing?
What are the complications of excessive wound healing
What is the initial response to blood vessel damage?
Vasoconstriction and venoconstriction
How does a platelet plug form?
- Platelets adhere to connective tissue vessel walls activating them
- Release of calcium from ER
- Activation of GPIIb/IIIa receptors which bind to fibrinogen creating cross links to other active platelets
- Release of vesicles containing ADP and TXA2
- ADP inhibits adenyl cyclase reducing cAMP reducing inhibition of calcium release
-TXA increases IP3 increasing calcium release
How is inappropriate platelet activation inhibited?
Release of prostacyclin by endothelium which activates adenyl cyclase increasing cAMP reducing calcium release
How can coagulation be activated?
Intrinsic pathway - damaged endothelial cells activating factor XII-XIIa
Extrinsic pathway - release of tissue factor causes factor VII-VIIa - very fast activation.
What is the common pathway of coagulation
Prothrombin - thrombin
Fibrinogen - fibrin and XIII-XIIIa
What are some controls of the coagulation cascade?
Antithrombin III - binds thrombin inactivating it
Protein C - binds thrombin becoming APC
APC - deactivates factors Va and VIIIa
Fibrinolysis - plasmin converted to plasminogen breaking down fibrin
Thrombomodulin - increases activation of PC to APC
What is a thrombosis?
A solid mass of blood in the circulatory system
What raises risk of thrombosis?
Abnormal vessel wall (athroma, injury, inflammation)
Abnormal coagulability (stagnation, turbulence)
Abnormal blood flow (smoker, post partum, post op, disease)
What is the difference between arterial and venous thrombi?
Arterial more platelet based - pale, granular, striated with lines of Zahn
Venous more thrombin based - red and gelatinous
What are the outcomes of thrombosis?
Propagation (proximally in veins, distally in arteries - direction of flow)
Reorganisation (ingrowth of fibroblasts and capillaries - granulation like tissue)
What is an embolism?
What is the commonest cause?
A blockage of a blood vessel by a solid, liquid or gas distant from its site of origin.
90% are thromboembolisms
What are common origins and sites of embolisms?
Systemic veins - lungs
Carotid arteries - cerebral arteries
Abdominal aorta - arteries of the leg
Heart - cerebral arteries
What are risk factors for DVTs?
Post op hypercoagubility
What are mitigations for DVT risk?
Heparin / anticoagulation
Filters in IVC
Intermittent leg compression during surgery
Differentiate athroma, athroscleosis and arteriosclerosis
Athroma - accumulation of extra and intra cellular lipids in the intima and media of medium and large arteries
Athrosclerosis - hardening of arteries as a consequence of athroma
Arteriosclerosis - thickening hardening of arteries, e.g. Hypertension, DM
What are the stages of atroma formation?
What is the macroscopic appearance of each?
Fatty streak - slightly raised white or yellow streak
Simple plaque - raised yellow or white plaque
Complex plaque - raised plaque with haemorrhage, infarction, aneurysm and calcification
How does a complicated athroma appear histologically?
Fibrosis, necrosis, cholesterol clefts, disruption of internal elastic lamina, ingrowth of blood vessels, fissues.
What is the histological appearance of simple athroma?
Proliferated smooth muscle cells and foam cells
What are common locations of athromas with related consequences
Coronary arteries - angina / mi
Cerebral arteries - cva / cve
Superior mesenteric artery - ischemic colitis
Legs - pvd
What are risk factors for athroma formation?
What is the process of athroma formation?
Adhesion of platelets and release of PDGF
Proliferation of smooth muscle, macrophage arrival
Phagocytosis of lipids and ldl by smc and macrophage (foam cells)
Macrophages move into intima
Lipoproteins undergo glycosylation
Smc produce unstable matrix weakening plaque
Cytokines from macrophages recruit more inflammatory cells
Neutraphils secrete proteases causing local damage weakening plaque
Lymphocytes stimulate smooth muscle cells
What cells are involved in athroma formation?
Smooth muscle cells
What are possible outcomes of a cell to growth signals?
What are the categories of cell growth signals?
What are growth factors?
What are the odd things they effect?
Local mediators that bind to receptors to stimulate transcription of genes causing increased return from, G0 and shortening interphase.
Locomotion, contractility, differentiation, viability, angiogenesis.
Give some examples of growth factors
Epidermal growth factor
Vascular endothelial growth factor
Platelet derived growth factor
Granulocyte colony stimulating factor
What are the checkpoints in the cell cycle?
G1 end checkpoint - restriction point
G2 end checkpoint
What does the restriction point do in the cell cycle?
Checks cell size, environment and for dna damage
What does the g2 checkpoint do in the cell cycle?
Ensures all dna has replicated and the cell is of sufficient size.
Which cell checkpoint is the most important in the cell cycle?
How is cell movement through the cell cycle controlled?
What cyclins move the cell through the different stages?
S to G2 is A
G2 to M is B
M to G1 is D (low)
G1 to S is E
How do cyclins work to control cell cycle?
Bind to a cyclin dependant kinase which phosphorylates a regulatory protein.
How do growth factors effect cyclins?
Increase cyclin dependent kinase
Decreased cyclin dependent kinase inhibitors
How are cell losses in tissues replaced?
Division of a stem cell - one daughter cell remaining undiferentiated, one daughter cell replacing the lost cell.
In what ways can cells adapt to stress?
What feature of regeneration aids immunity?
Replacement cells aren't immediately mature / fully functional and therefor infection may not be able to colonise or replicate within them.
What body parts can reconstitute?
End of a finger tip below a certain age
How does the cns 'regenerate'
Origional tissue not restored but plasticity allows for new pathways to form.
Why might the cns not regenerate?
It may disrupt memory formation
Give examples of physiological and pathological hyperplasia
Physiological - endometrial proliferation,
Pathological - goitre, eczema
Give some physiological and pathological examples of hypertrophy
Phys - muscle bulk
Pth - cardiac hypertrophy, prostatic hypertrophy
At what point does atrophy become irreversable?
When a large number of functional cells are lost
Give some examples of atrophy
Thin skin in pvd
How does metaplasia occur.
One differentiated cell type replaced from stem cells by another of the same germ layer
What is a neoplasm?
An abnormal growth of cells that persists after the initial stimulus is removed
What is a malignant neoplasm?
A neoplasm that invades surrounding tissues and has the potential to spread to distant sites
What is a tumour?
A clinically detectable lump or swelling
What is cancer?
A malignant neoplasm
What is dysplasia?
Disordered but reversible cell organisation. Pre neoplastic
How do benign neoplasms appear macroscopically?
A growing mass with a smooth capsule of compressed tissues
What are macroscopic features of malignant neoplasm?
Infiltration of surrounding tissues, irregular outer margin, ulceration, necrosis
What are microscopic features of benign and malignant neoplasms?
Progression from highly differentiated cells to poorly differentiated. More likely to be malignant if poorly differentiated.
What cellular cells can be seen in malignant neoplasms?
Increased nucleus size
Pleomorphism (variation in cell size and shape)
When are cellular changes very important in malignacy diagnosis?
On a needle biopsy.
What makes the majority of ca. Risk? Interinsic or extrinsic factors?
What is the initiator promotor model of cancer?
Initiators are mutagens that result in a primary mutation. Promotors then cause replication of the cell creating many monoclonal copies.
What is the evidence that neoplasms are monoclonal?
In a female (xx) look at 2 isoenzymes for g6p dehydroginase (x linked) some cells produce one, some the other. Stain. All neoplasms create just one isoenzyme.
What are malignant epilthilial neoplasms called?
What are malignant mesenchymal neoplasms called?
What is a leukemia?
A malignacy of blood forming bone marrow
What is a malignancy of lymph nodes?
What is a germ cell neoplasm?
A malignancy of pluripotent cells
What is a blastoma?
A neoplasm of imature precusor cells
What is a tumour of smooth muscle?
What is a glioma?
A benign tumour of glial cells
What is a malignant neoplasm of glial cells?
What are the three steps to metastasis?
Grow at primary site
Enter transport systems and lodge at secondary site
Grow at secondary site
In order to invade at a primary site what changes must tumour cells undergo and how?
Alter adhesion - e-cadherin and integrin must change
Lyse basement membrane - alter niche cells to cause proteolysis
Change cell mobility - alter cytoskeleton such as. Changes to rho family proteins
What are the changes in a primary epithelial malignant tumour preparing for metastasis called?
Epithelial to mesenchymal transition
What is the difference between e-cadherin and integrin?
E-cadherin is cell to cell anchoring
Integrin is cell to basement membrane anchoring
What routes can tumours spread?
What is the easiest route for metastasis? Why?
Lymphatics - thin membranes
What are the common sites of secondaries (very generally!) in each of the three routes of metastasis?
Lymph - regional lymph nodes
Blood - first capillary bed reached
Transcoelomic - gravity assisted (eg. Pouch of Douglass)
What explains variation in then common rules of tumour metastasis distribution?
Seed and soil theory - metastases can only settle where the niche is correct (e.g. Why bronchial tumours metastasis are found in the adrenals but not the kidneys)
What is the main route of carcinoma spread
What is the main route of sarcoma spread?
What common cancers cause bone mets?
What is growth at secondary site of cancer also known as?
What is the theory behind cancer relapse?
Formation of micrometastases at secondary sites that dont develop can reactivate
What are causes of micrometastases dormancy?
Failure of angiogenesis
What are local clinical effects of neoplasms?
Direct invasion and tissue destruction
Blockage of tubes and ducts
Compression of adjacent structures
What are the systemic effects of neoplasm?
Increased tumour burden - weight loss, malaise, immunosuppression, thrombosis
Hormone production (especially well differentiated tumours, therefore more common in benign tumours)
Poorly understood issues such as clubbing, fever, myositis
What are extrinsic causes of cancer?
Environmental factors (e.g. UV exposure)
Lifestyle factors (e.g. Smoking, overweight, alcohol, low exercise, low fruit and veg)
What are examples of intrinisic risk factors for cancer?
What are the three categories of extrinsic carcinogens?
What are the typical characteristics of chemical carcinogens?
Long delay between exposure and cancer
Increased risk with increased dose
Can be organ specific
Give some examples of chemical carcinogens
Asbestos - mesothelioma
Tobacco - bronchial carcinoma
What is the term for a chemical which is a initiator and a promotor of cancer?
What are the types of nuclear radiation?
What are the electromagnetic carcinogenes?
Which radiationn carcinogens cause ionisation?
Alpha, beta and gamma as well as xrays.
Which electormagentic carcinogen has the shortest wavelenght?
How does ionising radiation work?
Strips electrons off atoms
What are examples of direct and indirect damage from radiation?
Direct - alteration of bases etc
Indirect - production of ROS
What are direct and indirect carcinogenic mechanisms of infection?
Direct - influencing protooncogene and tsg
Indirect - cause chronic injury necessitating regeneration (acting as a promotor)
How does HPV cause cancer?
Expresses proteins E6 (inhibits p53) and E7 (inhibits RB)
What infections cause cancer by the indirect route?
How does hiv raise cancer risk?
Lower immune system therefore increased risk of carcinogenic infection such as karposi's sarcoma
What is knudsons two hit hypothesis?
Both copies of a gene must be defective for a tumour suppressor gene to be deactivated. If one is defective due inherited mutation then you are much much more likely to experience the deactivation as only one further mutation is required.
How many copies of a gene need to be mutated to turn a protoncogene into an oncogene
One, it is upregulation.
What do protoncogenes commonly code for?
Growth factors (e.g. Pdgf)
Growth factor receptors (e.g. HER2)
Signal transducers (e.g. RAS activating cyclin D)
Other than oncogenes and protooncogenes what other mutations can increase cancer risk?
Dna repair genes
Xeroderma pigmentosum - mutation in nucleotide excision repair gene responsible for repairing UV damage
HNPCC - mutation in mismatch repair gene
Familial Ca breast - BRCA1/2 repair double stranded DNA breaks therefore mutation increases risk of translocation or gene loss.