mechanisms of disease

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mechanisms of disease
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  1. 6 causes of cell injury/death
    • hypoxia: ischaemia, hypoxaemia, cyanide poisoning
    • chemicals: drugs, alcohol
    • infections: bacteria, viruses, worms, fungi
    • physical: trauma, extremes of temp/pressure, electric currents
    • immune: hypersensitivity, autoimmune
    • nutritional: deficiency, excess
  2. what are the structural targets for cell damage?
    • membranes
    • nucleus
    • proteins
    • mitochondria
  3. define necrosis
    a spectrum of morphological changes that occur after cell death in a living tissue
  4. define apoptosis
    an active process of single cell death that can be pathological or physiological
  5. explain the different types of necrosis
    • necrosis is a dynamic process between protein denaturation (coagulation) and enzyme release (liquifactive)
    • coagulative necrosis: protein denaturation dominates, the proteins clump making a solid tissue. Histologically the cell outlines are preserved (ghost cells), there are increased eosinophils in the cytoplasm and karolysis, after a few days an acute inflammation response is induced and phagocytes infiltrate the tissue
    • liquifactive necrosis: enzyme release prodominates, enzymes digest the tissue, seen in abscesses
    • caseous necrosis: characterised by structureless debris, seen in granulomatous inflammation in TB
    • fat necrosis: think pancreas/breast, lipases damage adipocytes, release of free FAs interact with Ca to form chalky deposits which can be seen on an x-ray
    • GANGRENE: is necrosis that is visible to the naked eye - can be liquifactive or coagulative (wet/dry)
    • INFARCTION: is ischaemic necrosis can be red (haemorrhage into dead tissue - venous occulsions, dual blood supply, rich anastomoses) or white (occlusion of end artery).
  6. what are the mechanisms of apoptosis?
    how is apoptosis identified under the microscope?
    • INTRINSIC: trigger (eg. DNA damage) > P53 activation > inc. mitochondrial membrane permeability > mitochondria release cyctochrome C > interacts with APAF1 and capase 9 > formation of apoptosome > apoptosis
    • EXTRINSIC: external ligand (eg.FAS or trail) binds to receptor > capase activation > apoptosis
    • apoptosis is detected by a LADDER PATTERN in gel electrophoresis as capases cut DNA between nucleosomes
  7. what are the cell differences between apoptosis and necrosis?
  8. what structural changes do injured cells undergo?
    • ELECTRON MICROSCOPE
    • reversible changes: swelling (Na pump failure), clumped chromatin (low pH), ribosome dispersion, cytoplasmic blebs
    • irreversible changes: Nuclear changes, lysosome rupture, lysis of ER
    • LIGHT MICROSCOPE
    • reversible changes: pale oink cytoplasm, subtle clumped chromatin
    • irreversible changes: increased pink cytoplasm (protein denaturation), nuclear changes (pyknosis, karyolysis, karyorrhexis), accumulation of fat/protein.
  9. describe the mechanism of cell injury due to ischaemic hypoxia
    • reversible: 1. loss of ATP > failure of Na/K ATPase > swelling off cytoplasm and organelles. 2. anaerobic metabolism > inc. lactate > low pH > chromatin clumps. 3. reduced protein synthesis > altered metabolism > intracellular accumulation of fat/protein
    • irreversible: massive inc in intracellular Ca > activaation of degenerative enzymes > cell death
  10. describe the mechanism of non ischaemic cell injury
    what are the 4 mechanisms
    describe 3 of these mechansims
    • can be due to: 1. reduced ATP or mitochondrial damage 2. loss of Ca homeostasis, 3. disrupted membrane permeability, 4. free radicals
    • - 1. reduced ATP/ mitochondrial damage > failure of biosyntheis and membrane pumps
    • - 2. loss of calcium homeostasis > rises in intracelluar calcium > activation of protein kinases > phosphorylation of proteins > activation of phospholipases > membrane damage and proteases > cytoskeleton disassembly
    • - 4. these are associated with cell injury in many settings (drugs such as CCl4 cause liver damage, reperfusion of ischaemic tissue leads to inc formation, inflammation as released by leucocytes, radiation, neoplasms). they can be generated by lysing of water (H2O > H* + OH*), the fenton reaction ( Fe2+ + H2O > Fe3+ + OH- + OH*), or the harber weiss reaction (O2- + H+ > O2 + H2O + OH*). it is important to quickly remove O2- and H2O2 generated in oxidative phosphorylation, P450 reactions and by chemicals quickly so that OH* is not formed, their removal can be via spontaneous decay or anti-oxidants (enzymes - SOD, catalases, perioxidases OR scavengers - vitE, pre-vitA, vitC). free radicals injure cells by - unsaturated membrane lipid perioxidation, fragmentation and x-linking of proteins, causing breaks in mitochondrial and cell DNA
  11. what happens with chronic excessive alcohol intake?
    • alcohol is a hepatoxin
    • during its breakdown acetaldehyde is formed
    • it causes fatty liver, acute hepatitis (focal necrosis of liver cells, function tests show raised transaminases) and cirrhosis (normal liver tissue replaced by fibrous tissue, function is lost) > jaundice, hyperammonaemia, low albumin, oedema, low clotting factors
  12. what is paracetamol toxicity?
    • causes acute hepatic necrosis
    • characterised by raised alanine, transaminase and asparate transaminase
    • in paracetamol toxicity the sulphate and glucuronide pathways become saturated and the cytochrome P450 pathway system takes over this produces NAPQI a toxic chemical which is detoxified by glutathione but this is quickly saturated leaving NAPQI to interact with membranes resulting in wide spread damage and death > acute hepatic necrosis
  13. what is acute inflammation?
    - causes
    - clinical features
    • innate, immediate short lived stereotyped response to living tissue injury
    • it is a vascular reaction controlled by chemical mediators
    • it is a protective mechanism but can lead to local complications and systemic effects
    • it is caused by microbial infections, hypersensitivity reactions, physical agents, chemicals and tissue necrosis
    • the clinical features : rubor (redness), calor (heat), tumour (swelling), and dolor (pain and loss of function)
  14. what happens in acute inflammation?
    what are the main mediators for each process
    • 1. changes in vascular flow and calibre: vasoconstriction of arterioles, vasodilation of arterioles and capillaries, inc permeability of BVs, stasis of blood
    • vasodilation: HISTAMINE, PROSTAGLANDINS, NITRIC OXIDE
    • permeability: HISTAMINE, BRADYKININ, LEUKOTRIENES C4, D4, E4
    • 2. migration of neutrophils: migration (stasis allows line up along endothelium), rolling (stick intermittently), adhesion (emigrate through endothelium -active process)
    • emigration: C5a, LEUKOTRIENE B4
    • 3. neutrophil chemotaxis and phagocytosis: neutrophils migrate to site of injury down chemotactic gradient, phagocytose organisms etc, may release toxins/enzymes
  15. how do the changes that occur in acute inflammation help to combat injury?
    • exudation of fluid: delivery of plasma proteins (immunoglobulins, antibodies, fibrinogen, inflam mediators) to the injured area, dilutes toxins, increases lymphatic drainage delivering micro-organisms to the immune system
    • infiltrate of cells: removes pathogenic organisms and necrotic tissue by phagocytosis
    • vasodilation: increases delivery and temperature
    • pain: enforces rest, prevents further trauma
  16. what are the chemical mediators involved in acute inflammation?
    • proteases: plasma proteins produced in the liver - kinins (eg. bradykinin, kallikrein), complement system, coagulation and fibrinolytic system
    • prostaglandins (inc.body temp)/leucotrienes: metabolites of arachidonic acid found in cell membranes, their synthesis is blocked by NSAIDs by inhibiting the action of Cox-2
    • cytokines/chemokines: produces by WBCs include interleukins (communicate between WBCs), TNF-a and IL-1 (increase body temp)
    • others: ADP and histamine (from platelets), free radicals, plasminogen and prostacyclin & nitric oxide (from endothelium)
  17. describe in detail the vascular changes in acute inflammation
    • immediate early response: 1/2 hour - histamine released from mast cells, basophils and platelets in response to physical damage, immunological reactions, C5a, C3a, IL-1 factors from neutrophils etc.it causes vasodilation, transient increase in permeability and pain
    • immediated sustained response: not always evident
    • delayed response: peaks at around 3 hours - many important chemical mediators eg. bradykinin, leukotrienes - possibility of therapeutic intervention
  18. describe the mechanism of vascular leakage in acute inflammation
    • endothelial cell contraction in response to histamine and leukotrienes causes gaps
    • they can also be caused by cytoskeleton rearrangement in response to cytokines, TNF-a, IL-1, hypoxia
    • direct injury, leukocyte injury - using enzymes and toxic O2 species, increased transcytosis (channels)
  19. describe the mechanism of neutrophil migration and the roles of neutrophils in acute inflammation
    • selectrins, immunoglobulins and integrins change the cells surface of adhesion molecules making more for the neutrophils to bind to.
    • relaxation of the inter-endothelial cell junctions and digestion of the basement membrane allows neutrophils out of the cell.
    • then they move to the site of injury by diapedesis, emigration and chemotaxis
    • their role is: phagocytosis by contact, recognition, internalisation and microbial killing
    • recognition is facilitated by opsonins eg. Fc and C3b receptors on the neutrophil recognise organisms coated with immunoglobulin or comlement
    • killing mechanims: 02 dependant (very toxic & effective produces O2- and H2O2), O2 independent (lysosomes and hydrolases)
  20. Complications of acute inflammation
    • locally: swelling can block tubes, exudate can cause compression, pain
    • systemic: fever, septic shock, decreased appetite, altered sleep pattern
  21. sequelae - what happens after acute inflammation?
    • 4 options:
    • complete resolution
    • continued acute inflammation with chronic inflammation > abscess
    • chronic inflammation and fibrous repair
    • death
  22. how does resolution occur after acute inflammation?
    • vascular changes stop - neutrophils no longer migrate, vessels permeability and calibre return to normal
    • exudate drains to lymphatics
    • fibrin degenerated by plasmin
    • neutrophils die and break up
    • tissue damage may be able to regenerate
    • this happens because mediators of acute inflammation have short half lives
  23. name a inherited disorder of acute inflammation
    • these are very rare
    • a1-antitrypsin deficiency
  24. what is chronic inflammation?
    • more specific and complex
    • overlaps with the immune system
    • results in healing by fibrosis
  25. how does chronic inflammation arise?
    • may take over from acute inflammation is damage is not resolved in a few days
    • from autoimmune conditions
    • from chronic infections
    • from chronic low level irritation
  26. describe the microscopic appearance of chronic inflammation
    • macrophages
    • lymphocytes
    • plasma cells
    • fibroblasts
    • giant cells - langhans (20-30 nuclei in horse shoe -TB), foriegn body cell (nuclei scattered randomly), touton (fat necrosis)
  27. what are the effects of chronic inflammation?
    • fibrosis
    • impaired function
    • atrophy
    • stimulation of immune response
  28. what is granulomatous inflammation?
    -main causes
    • chronic inflammation with granulomas, occur with persistent low grade antigenic stimulation and hypersensivity
    • :
    • the main causes are: midly irritant foreign materials eg.keratin, urate crystals, altered collagen/elastin
    • - TB causes persistant induction of cell mediated immunity. destruction of the tissues occurs by necrosis from the granulomatous tissue.
    • - sarcoidosis- chronic granulomatous disease
    • - syphilis - primary lesion heals but becomes chronic condition of many organs
  29. what is regeneration?
    what are stem cells?
    • regeneration = the replacement of dead or damaged cells by functional differentiated cells from stem cells
    • stem cells = potentially limitless proliferation daughter cells either remain as stem cells to maintain the pool or differentiate into a specialised cell type
  30. what are the three cell types with different regeneration capacities?
    • labile: normal state is active division, usually rapid proliferation eg. epithelia, haemopoetic cells
    • stable: not normally dividing at significant rate variable regeneration speed eg. hepatocytes, osteoblasts, fibroblasts
    • permanent: unable to divide, cannot regenerate eg. neurones, cardiac myocytes
  31. what is fibrous repair?
    describe the mechanism
    what controls fibrous repair?
    • replacement of functional tissue with scar tissue
    • 1. cell migration (inflammatory cells): blood clot forms, exudate goes into tissues, acute inflammation occurs around edges, neutrophils and macrophages phagocytose debris > chronic inflammation, macrophages and lymphocytes digest the clot
    • 2. formation of granulation tissue: a) angiogenesis- provides blood supply for wound healing - endothelial cells activation, proteolysis of basement membrane, migration of endothelial cells by chemotaxis, endothelial proliferation, maturation and tubular remodelling, recruitment of periendothelial cells. b) myofibroblasts - migrate, infiltrate and differnentiate. c) extracellular matrix produced: its function is to support and anchor cells, separates tissue compartments, sequesters growth compartments, communication, migration. its components are: collagen, elastin, glycoproteins, proteoglycans
    • 3. maturation: cell population falls, collagen increases matures and remodels, blood vessels differentiate and reduce, myofibroblasts contract > fibrous scar
    • CONTROL: 1. chemotaxis, 2. angiogenic cytokines (VEGF, bFGF), 3. pro-fibrotic cytokines from macrophages (TNF-b, PDGF, FGF)
  32. what is the difference between healing by primary intention and healing by secondary intention?
    • primary: eg clean sutured wound. Apposed edges, minimal clot and granulation tissue. epidermis regenerates, dermis undergoes fibrous repair (maturation up to 2 yrs), risk of trapped infection > abscess
    • secondary: open wound, clot dries to form eschar/scab, epidermis regenerates underneath
  33. what factors influence wound healing?
    • local: type, size, location of wound, apposition, infection, blood supply, foreign material, radiation damage
    • general: age, drugs and hormones, general and specific dietary deficiencies, general state of health, cardiovascular state
  34. list some complications of repair
    • insufficient fibrosis - hernia, ulceration
    • excessive fibrosis - keloid
    • excessive contraction - strictures, limitation of joint movement, obstruction of tubes/channels
  35. describe healing in different tissues - heart, brain, bone, liver, PNS, cartilage, kidney, smooth muscle, voluntary muscle.
    • heart - no regeneration just scarring, inflexible collagen affects contraction and can cause arrhythmias or cardiac failure
    • brain - liquifactive necrosis > cystic spac
    • bone - complete repair
    • liver - stable hepatocyte cells allow about 70% of the liver to regenerate
    • PNS - regeneration down channel
    • cartilage - can regenerate is adequate blood supply
    • kidney - epithelium regenerates but not architeture
    • smooth muscle - replaced by scar tissue
    • voluntary muscle - limited regeneration from satellite cells
  36. what is haemostasis?
    • arrest of bleeding
    • involving physiological processes of blood coagulation and the contraction of damaged vessels
  37. what is the mechanism of haemostasis?
    • constriction of blood vessels: limits blood loss
    • platelets: adhere to the damaged vessel wall to form a plug and the platelet release reaction - they release lots of ADP which stimulates platelet aggregating factor and seritonin as well as thromboxane A2, these activate the coagulation cascade and cause vessel constriction
    • coagulation system: formation of fibrin clot
    • fibrinolytic system: breaking down of the clot, plasminogen cuts the fibrin mesh so it can be destroyed by other proteases in the liver or kidney
  38. what is thrombosis?
    why does it occur?
    • pathological formation of a solid mass of blood within the circulation system during life
    • VIRCHOWS TRIAD
    • abnormalities of the vessel wall: atheroma, direct injury, inflammation
    • abnormalities of the blood flow: stagnation, turbulence
    • abnormalities of blood components: smoking, post-partum, post-op
  39. what is the appearance of thrombi?
    • arterial: pale granular, lines of zahn, low cell content
    • venous: soft, gelatinous, deep red, higher cell content
  40. what is the outcomes of thrombi?
    • lysis: if small
    • propagation: progressive spread due to stasis of blood
    • organisation: repairative but lumen remains obstructive
    • recanalisation: endothelial tissue burrows through clot re-establishing some blood flow
    • embolism - part of clot breaks off and lodges at different site
  41. what are the effects of thrombi?
    • arterial - ischaemia, infarct
    • venous - congestion, oedema, ischaemia, infarct
  42. what is an embolism?
    this is the blockage of a blood vessel by a solid, liquid or gas at a distant site from its origin
  43. describe deep vein thrombosis
    • high risk group = immobile, post op, pregnancy, severe burns, cardiac failure, disseminated cancer, smokers
    • prevention = movement, TED stockings
    • likely effects = massive - fatal, major - SOB, blood stained sputum, cough, minor - asymptomatic or mild SOB
  44. describe 4 disorders of the coagulation system
    • DIC - disseminated intravascular coagulation: underlying causes can be pregnancy, severe infection, cancer - lots of small emboli are formed using all the clotting factors and fibrinolytic factors leads to RBC destruction and bleeding. Treated by reversal of underlying disorder - platelet transfusion, anti-thrombin transfusion.
    • thrombocytopenia: loss of platelets quicker than replacement
    • thrombophillia: inherited tendency to develop thrombi
    • haemophillia: x-linked recessive trait - serious bleeding - reduction in blood clotting factors - A=factor VIII, B=IX
  45. what is atheroma?
    the accumulation of intra and extracellular lipids in the intima and media of large and medium arteries
  46. what is atherosclerosis?
    this is hardening of the arterial vessel walls as a result of atheroma
  47. what is arteriosclerosis?
    this is the hardening of the walls of arteries and arterioles as a result of hypertension or diabetes melitus
  48. where are the common sites of atheroma?
    • bends and branches
    • abdominal aorta > mesenteric ischaemia > malabsoption, intestinal infarct, aneurysm
    • coronary arteries > ischaemic heart disease - angina, MI, arrhythmia, cardiac failure
    • cerebral and carotid arteries > TIA, stroke, multi-infarct dementia
    • leg arteries > PVD - intermittent claudication, pain, gangrene
  49. what are the mechanisms of atheroma?
    • 1. monoclonal hypothesis: viral cause, smooth muscle is crucial, each plaque is monoclonal
    • 2. insudation theory: endothelial damage > inflammation > increase permeability to lipid
    • 3. thrombogenic theory: plaque formed by repeated thrombi
    • 4. reaction to in jury hypothesis: endothelial damage > increase permeability to lipid and platelet adhesion, monocytes penetrate, smooth muscle proliferates and migrates
    • UNIFYING HYPOTHESIS
    • a) endothelial injury causes by - raised LDLs, toxins from cigarette smoke, hypertension, haemodynamic stress
    • b) endothelial injury causes: i)platelet adhesion which releases PDGF stimulating smooth muscle proliferation and migration. ii) change in membrane permeability > uptake of lipoproteins > injury so macrophages and neutrophils invade. iii)macrophages oxidise LDLs and take up lipid becoming foam cells
    • c) foam cells then release cytokines causing further smooth muscle proliferation and further inflammatory cell recruitment
  50. what are the macro/microscopic features of atheroma?
    • MACROSCOPIC
    • - fatty streak: accumulation of lipid in intima - yellow streak slightly raised
    • - simple plaque: raised yellow/white with irregular outline, widely distributed enlarged and coalesced
    • - complicated plaque: thrombosis, haemorrhage into plaque, calcification, aneurysm formation
    • MICROSCOPIC
    • early changes: proliferation of smooth muscle, accumulation of foam cells and extracellular lipid
    • later changes: fibrosis, necrosis, cholesterol clefts and +/- inflammatory cells
    • also: disruption of the elastic lamina, damage extends into media, ingrowth of blood vessels, plaque fissuring
  51. list some signs of atheroma
    • corneal arcus
    • xanthalasma
  52. what are the risk factors for atheroma?
    • age
    • gender
    • hyperlipidaemia
    • smoking
    • hypertension
    • diabetes mellitus
    • alcohol consumption
    • infection
    • lack of exercise
    • obesity
    • oral contraceptive
    • stress
    • apoprotein E genotype
    • familial hyperlipidaemia
  53. what are some prevention and interventions for atheroma?
    • prevention: don't smoke, low sat fat intake, restrict alcohol, maintain healthy weight, control other illnesses
    • intervention: stop smoking, modify diet, control hypertension, treat diabetes, statins
  54. what local mediators are important in cell proliferation?
    growth factors: EGF (epidermal growth factor), PDGF (platelet derived growth factor), FGF (fibroblast growth factor), TGF-B and cytokines
  55. what are the normal responses to cellular adaptation stimuli?
    • survive
    • divide (proliferate)
    • differentiate
    • die (apoptosis)
  56. describe the cell cycle
    • labile and stable cells can enter the cell cycle but permanent cells are terminally differentiated
    • the cell cycle lasts 18-24 hrs
    • the system has check points 2 are very important one just before S phase and one on entering mitosis
    • - the G1 check point: up until this point cells are acting in response to outside stimuli at this point the are checked to make sure they are large enough the environment is favourable and there is no DNA damage. RETINOBLASTOMA protein is responsible for passage through this site and it acts as a tumour suppressant
  57. what is cell adaptation?
    this is the reversible state between a normal cell and an overstressed injured cell
  58. what are the different types of adaptation?
    • regeneration: replacement of cell loses by identical cells to maintain tissue or organ size - can only occur in labile and stable populations
    • hyperplasia: increase in tissue/organ size by increase number of cells
    • hypertrophy: inc. organ/tissue size due to inc. cell size
    • atrophy: dec. in organ/tissue size due to dec. size/number of cells
    • metaplasia: change of one differentiated cell type to another
    • aplasia: complete failure of an organ to develop
    • hypoplasia: incomplete development of tissue or organ
    • dysplasia: abnormal maturation of cells within a tissue
  59. what is neoplasia?
    the process of abnormal and uncontrolled growth of cells causing a neoplasm/tumour
  60. difference between benign and malignant?
    • benign: cell growth as compact mass, remains at site of origin, more regular, acts like normal tissue,
    • malignant: growth is uncontrolled, can spread, grows faster, more vascular, central necrosis,
  61. how do tumours/neoplasms develop?
    • change to DNA > alteration in cell growth and behaviour, this must be non lethal and passed onto daughter cells
    • alteration is to more than one gene > oncogenes and tumour suppressor genes are affected, cell goes from normal to benign to malignant
  62. how are neoplastic cells different from normal cells?
    • alterations in growth control - inc. proliferation, inc lifespan, modified metabolism
    • change in growth factor receptors
    • loss of receptors
    • abnormal shape
  63. types of neoplasms?
    • benign epithelial neoplasms: papilloma for squamous and transitional, adenoma for glandular
    • malignant epithelial neoplams: carcinomas
    • benign connective tissue neoplasm: leiomyoma - smooth muscle, fibroma - fibrous tissue, osteoma - bone, chondroma - cartilage, lipoma - fat, neurofibroma - nerve
    • malignant connective tissue neoplasms: leiomyosarcoma - smooth muscle, fibrosarcoma - fibrous tissue, osteosarcoma - bone, chondrosarcoma - cartilage, liposarcoma - fat, neurofibrosarcoma - nerve
    • germ cells: testis - teratoma and seminoma (malignant), ovaries - dermatoid cyst (benign)
    • lymphoid: malignant lymphoma = hodgkins/non-hodgkins - presence of Reed Steinburg cell
    • bone marrow: acute/chronic lymphoma
  64. what is invasion?
    • in malignancy only
    • the ability of cells to break through the basement membrane and then spread through the stroma either into surrounding tissues or vascular/lymphatic channels
    • factors involved:
    • 1. cadherin Ca dependant glycoproteins reduced expression allowing cells to move apart
    • 2. altered synthesis of enzymes that break down the BM
    • 3. factors produced that increase motility
  65. what are metastasis?
    • the ability of cancer cells to invade lymphatics, blood vessels and cavities and spread to different sites
    • common places of metastases:
    • lung from bone, breast, stomach. large intestine, kidney, testis
    • liver from large intestine, bronchi, breast
    • bone from bronchi, breast, thyroid, renal, liver, prostrate
    • brain from bronchi, breast, testis, malignant melanoma
  66. what are the effects of tumours?
    • local effects of benign neoplasms: compression, atrophy, obstruction, ulceration, bleeding
    • local effects of malignant neoplasms: destruction of surrounding tissue, obstruction, ulceration, infiltration into blood, nerves, lymph
    • possible systemic effects: anaemia, thrombosis, low WBC count, excessive/ectopic hormone secretion, increased pigmentation (gastric), herpes zoster (lymphoma), pruritis, cachexia, pyrexia
  67. how and why do tumours occur?
    • there are both intrinsic and extrinsic factors:
    • - inheritance of conditions that predispose to cancer eg. retinitis pigmentosa > skin cancer, ataxis telangiectasia > lymphoid, retinoblastoma
    • - radiation - overwhelming of repair mechanism > mutation
    • - chemicals > DNA damage eg 3,4 benzpyrene from fossil fuels, smoking > lung, bladder and skin cancer, aromatic amines from the dye and rubber industry > bladder cancer, asbestos > mesothelioma, aflatoxins > liver cancer
    • - viruses eg. Hep B>heptocellular carcinoma, EBV > lymphoma, HPV > cervical carcinoma, helicobacter pylori > gastric cancer
    • - parasites eg. schistomsomiasis > bladder cancer, malaria > burkitts lymphoma
    • - hormones
    • - geographical variability - diet, parasites prevalence etc
    • - age - cummulative exposure to mutagens > increased risk
  68. what are oncogenes?
    • pro oncogenes are genes that code for normal growth and differentiation they are present in all cells BUT any alteration > oncogene, only one allele needs to be effected
    • examples:
    • - C-myc - binds to DNA stimulating synthesis > oncogene seen in burkitt's lymphoma, breast cancer and neuroblastoma
    • - ras - involved in intracellular signalling > oncogene seen in lung cancer
    • - C-erb-2 (HER2) - growth factor reecptor > seen in breast adenocarcinoma
    • - Ret - thyroid cancer in children
  69. what are tumour suppressor genes?
    • in normal cells the protein encoded by this gene suppresses growth
    • examples:
    • - p53 - nuclear protein binds to and modulates expression of genes for DNA repair/division/apoptosis - seen in many cancers
    • - retinoblastoma - G1 check - retinoblastoma and osteosarcoma
  70. what are the stages of carcinogenesis?
  71. initiation - exposed to initiator > left susceptible to neoplasm but no genetic change
    • ... much later...
    • promotion - exposed to promoter (hormone, virus, immune response etc.) > enhanced proliferation, increased incidence of mutation
    • Progression and development of neoplastic cell
  72. what are the most common cancers?
    • breast
    • lung
    • large bowel
    • prostrate
  73. what are the most prevalent cancers in different age groups?
    • < 10 = nephroblastoma, retinoblastoma, leukaemia, CNS tumour
    • 10-19 = leukaemia, osteosarcoma
    • 20-29 = leukaemia, teratoma, lymphoma
    • 30-39 = carcinomas, seminomas, lymphoma, sarcoma
    • 40-49 = carcinoma, lymphoma, glioma, sarcoma
    • > 50 = carcinomas, sarcomas, lymphoma, chronic leukaemia
  74. what is the staging for breast and lung cancer?
    • TNM
    • t1=<2cm, t2=2-5cm, t3=>5cm, t4=skin/chest wall involved
    • n0=no lymph nodes involved, n1=mobile node involved
    • m0=no metastases, m1=metastases
  75. how do we stage prostrate cancer?
    • TMN
    • t1=sampling, t2=confined to prostrate, t3=through capsule, t4=other organ
    • n0=no lymph, n1=one lymph<2cm, n1=more than one 2-5cm, n3=any >5cm
    • m0=no spread beyond pelvis, m1= cancer outside pelvis
  76. what is the staging for colo-rectal cancer?
    • dukes staging
    • A = not extending through muscularis propria/externae - 90% 5 year survival
    • B = extending through MP - 70% 5 year survival
    • C = lymph nodes involved - 30% 5 year survival
  77. what is the staging for Hodgkin's lymphoma?
    • Ann Arbor
    • i = one group of nodes involved
    • ii = two groups involved - same side of diaphragm
    • iii = node involved on both sides of the diaphragm/spleen
    • iv = bone marrow, lungs, other site
    • A = no symptoms, B=fever, night sweats, weightloss
  78. how do we grade breast cancer?
    Richardson - 1-3 - degree of tubular formation, extent of nuclear variation, number of mitoses
  79. how do we grade prostrate cancer?
    gleasons grade - 1-5 - degree of gland formation, architectural pattern
  80. how do we grade squamous cell and colon cancer?
    1-4 - well differentiate > anaplastic
  81. what treatment options are there for cancer?
    • surgery
    • radiotherapy
    • chemotherapy
    • hormone therapy
    • new drugs eg.HERCEPTIN
  82. what tumour markers are useful?
    • AFP -alphafetoprotein - hepatocellular carcinoma, germ cell tumours
    • HCG - human chronic gonadotropin - trophoblastic tumours
    • acid phosphatase or PSA - prostrate specific antigen - prostrate carcinoma
    • CEA - carcinoembryonic antigen - GI tract cancer
    • hormone products
  83. what is screening?
    • detect pre-malignant in situ and early
    • improve prognosis
    • cervical - smear test
    • breast - mamogram

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