mechanisms of disease

• 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

• membranes
• nucleus
• proteins
• mitochondria

a spectrum of morphological changes that occur after cell death in a living tissue

an active process of single cell death that can be pathological or physiological

• 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).

• 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

• 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.

• 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

• 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

• 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

• 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

• 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)

• 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

• 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

• 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)

• 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

• 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)

• 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)

• locally: swelling can block tubes, exudate can cause compression, pain
• systemic: fever, septic shock, decreased appetite, altered sleep pattern

• 4 options:
• complete resolution
• continued acute inflammation with chronic inflammation > abscess
• chronic inflammation and fibrous repair
• death

• 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

• these are very rare
• a1-antitrypsin deficiency

• more specific and complex
• overlaps with the immune system
• results in healing by fibrosis

• 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

• macrophages
• lymphocytes
• plasma cells
• fibroblasts
• giant cells - langhans (20-30 nuclei in horse shoe -TB), foriegn body cell (nuclei scattered randomly), touton (fat necrosis)

• fibrosis
• impaired function
• atrophy
• stimulation of immune response

• 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

• 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

• 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

• 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)

• 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

• 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

• insufficient fibrosis - hernia, ulceration
• excessive fibrosis - keloid
• excessive contraction - strictures, limitation of joint movement, obstruction of tubes/channels

• 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

• arrest of bleeding
• involving physiological processes of blood coagulation and the contraction of damaged vessels

• 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

• 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

• arterial: pale granular, lines of zahn, low cell content
• venous: soft, gelatinous, deep red, higher cell content

• 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

• arterial - ischaemia, infarct
• venous - congestion, oedema, ischaemia, infarct

this is the blockage of a blood vessel by a solid, liquid or gas at a distant site from its origin

• 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

• 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

the accumulation of intra and extracellular lipids in the intima and media of large and medium arteries

this is hardening of the arterial vessel walls as a result of atheroma

this is the hardening of the walls of arteries and arterioles as a result of hypertension or diabetes melitus

• 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

• 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

• 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

• corneal arcus
• xanthalasma

• age
• gender
• hyperlipidaemia
• smoking
• hypertension
• diabetes mellitus
• alcohol consumption
• infection
• lack of exercise
• obesity
• oral contraceptive
• stress
• apoprotein E genotype
• familial hyperlipidaemia

• 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

growth factors: EGF (epidermal growth factor), PDGF (platelet derived growth factor), FGF (fibroblast growth factor), TGF-B and cytokines

• survive
• divide (proliferate)
• differentiate
• die (apoptosis)

• 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

this is the reversible state between a normal cell and an overstressed injured cell

• 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

the process of abnormal and uncontrolled growth of cells causing a neoplasm/tumour

• 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,

• 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

• alterations in growth control - inc. proliferation, inc lifespan, modified metabolism
• change in growth factor receptors
• loss of receptors
• abnormal shape

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• ... much later...
• promotion - exposed to promoter (hormone, virus, immune response etc.) > enhanced proliferation, increased incidence of mutation
• Progression and development of neoplastic cell

• breast
• lung
• large bowel
• prostrate

• < 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

• 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

• 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

• 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

• 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

Richardson - 1-3 - degree of tubular formation, extent of nuclear variation, number of mitoses

gleasons grade - 1-5 - degree of gland formation, architectural pattern

1-4 - well differentiate > anaplastic

• surgery
• radiotherapy
• chemotherapy
• hormone therapy
• new drugs eg.HERCEPTIN

• 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

• detect pre-malignant in situ and early
• improve prognosis
• cervical - smear test
• breast - mamogram