genpath 1-11

Carcinogenesis:

initiation and promotion of cancer, involves genetic alterations in four classes of genes

Carcinogen:

agent or substance that initiates cancer 

Growth promoting proto-oncogenes:

code for proteins involved with control of normal cell growth and differentiation

Damage = uncontrollable growth, lots of differentiation 

Growth-inhibiting tumour suppressor genes:

discourage cell growth or temporarily halt cell division to carry out DNA repair 

• Damage = growth 

Four classes of normal regulatory genes are the principle targets of genetic damages  

• Growth promoting proto-oncogenes

• Growth-inhibiting tumour suppressor genes:

• Genes that regulate apoptosis 

  • Damage = inc proliferation, p53 

• Genes involved in DNA repair 

  • Damage = mutations passed on in generations 

Intrinsic factors to cancer (6)

genetic factors 

2. racial and geographical  

3. immunological factors  

4. sex and hormonal influences 

5. age 

6. pre-existing benign neoplasms 

Leukaemia:

trisomy 21 predisposes to leukaemia 

• Extra chromosome = more genes = more gene products 

Chronic myeloid leukaemia:

philadelphia chromosome is seen in 90% cases 

• Reciprocal translocation between chromosome 9 and 22 

Polyposis coli

benign tumours form on colonic mucosa 

• Sigmoid, rectum; ♂~55yrs; Adenomatous polyps 90%; Villous adenomata

Kaposi's sarcoma:

malignancy of BV 

example of immunological factor to cancer

pre-existing benign neoplasms examples

• Polyposis coli 

• Adenomatous polyp  

extrinsic factors to cancer

chemical agents 

2. physical agents 

3. Biological agents  

chemical agents examples (cancer)

• Soot exposure and carcinoma of scrotum 

• Polycyclic aromatic compounds are carcinogenic  

  • DMBA – cigarettes 

  • Margarine colouring 

  • Dyes 

  • Pesticides  

physical agents examples (cancer)

• Ionizing radiation: UV, x rays, gamma rays, radioactive decay 

• Trauma: chronic injury and tissue damage 

• Inert substances in body: plastic films, glass, fibres, methylcellulose, metal foils and wires, asbestos fibres 

  • Mesothelioma  

Biological agents: parasites examples (cancer)

• Schistosoma spp causes chronic infection of bladder, predisposes to cancer  

Biological agents: fungi and bacteria examples (cancer)

• Aspergillus flavus: produces aflatoxin in starchy foods 

  • Primary hepatocarcinoma 

• Helicobacter pylori: carcinoma of stomach  

  • Ulceration 

Biological agents: viruses examples (cancer)

• directly cause tumours 

  • Hep B > hepatocarcinoma 

  • Human herpes virus 8 > kaposi's sarcoma 

  • Epstein barr virus > burkitt's lymphoma  

  • HPV > cervical cancer  

IMMUNOPATHOLOGY 

• Disorders due to an abnormality in immune system function 

• Immunodeficiencies  

• Hypersensitivities  

• Autoimmune diseases 

Primary immunodeficiency 

• Present at birth due to genetic/congenital disorder 

agammaglobulinemia = bruton's disease  

• primary immunodeficiency example

• X-linked disorder 

• Low to absent B cells 

• Decreased antibody production 

• Normal T cell function 

• Severe bacterial infection 

• Eg. Strep infection  

congenital thymic aplasia = Di George syndrome 

• primary immunodeficiency example

• Developmental disorder 

• Absent thymus/functional tissue 

• No parathyroids > hypocalcaemia 

  • Dec parathyroid horomone = deceased bone absorption  

• Absent T cells, no cellular immunity 

• Near normal B cell function 

• Severe viral, fungal and protozoal infections  

• Eg. Herpes virus  

3. Combined immunodeficiency = swiss-type syndrome 

• primary immunodeficiency example

• Developmental disorder 

• Absent lymphocyte stem cells in bone marrow 

• Absent B and T cells 

• Recurrent infections of various types 

• Bubble boy  

Secondary immunodeficiency 

1. Miscellaneous immunodeficiencies: ageing, infections, tumours, drugs, radiation exposure

2. acquired immune deficiency syndrome (AIDS), hodgkin’s disease

Miscellaneous immunodeficiencies 

• Ageing: dec production of BM stem cells 

• Infection: depress immunity 

• Neoplasm: Depress immunity 

• Immunosuppressive drugs: lower immunity 

• Radiation: lymphocyte depletion due to radiation

ageing miscellaneous immunodeficiency example

erysipelas 

Infection miscellaneous immunodeficiency example

• H.influenzae 

• Influenza virus  

Neoplasm miscellaneous immunodeficiency example

• Thymoma: tumours in thymus glands  

• Hodkins disease 

Immunosuppressive drugs miscellaneous immunodeficiency example

Transplantation rejection 

acquired immune deficiency syndrome (AIDS) 

• Human immunodeficiency virus  

• Targets immune system and CNS 

• Infects CD4 cells 

• Leads to severe impairment of cell-mediated immunity  

• <200 CD4 cells/uL 

• leads to opportunistic infections, secondary neoplasms, neurological disorders

AIDS symptoms

• Debility: physical weakness, frailty, or a significant lack of vigor and strength 

• Emaciation: state of extreme, dangerous thinness and muscle wasting, typically caused by severe malnutrition, starvation, or underlying disease 

• Continual dry cough 

• Sore throat 

• Pale furry tongue 

• Purple skin lesions  

Hypersensitivies

Excessive immune response > tissue damage  

• Type I: immediate, anaphylactic 

• Type II: antibody mediated 

• Type III: immune complex mediated 

• Type IV: T cell mediated (delayed) 

  • Not antibody mediated 

Type I hypersensitivity example

Bronchial asthma, bee stings, hay fever, hives 

Type I hypersensitivity

1. First encounter with allergen (sensitizing agent) 

• Stimulates formation of IgE instead of IgG or IgA 

• No reaction (IgE inactivates Ag but excess attaches onto mast cell surface) 

2. Second and subsequent encounters with allergen causes degranulation of mast cells 

• Mediators of AI released – histamine, serotonin 

• Anaphylaxis 

• Bronchoconstriction, inflammation, oedema, vasodilation and inc vascular permeability  

Type II hypersensitivity

• IgG or IgM 

• Direct cell damage and lysis 

• Cytotoxic hypersensitivity: lysis of cells due to 'foreign' cell surface component  

• Or Abs stimulate or inhibit a receptor 

type II hypersensivity example - cytotoxic hypersensitivity

Erythroblastosis foetalis: haemolytic disease of the newborn 

incompatible blood transfusions

type II hypersensivity example - Abs stimulate or inhibit a receptor 

• Eg. Grave's disease (stimulating) thyrotoxicosis

  • Formation of thyroid stimulating antibodies bind to TSH receptor 

  • Excessive secretion of thyroid hormones  

  • Hyperplasia of thyroid follicular epithelium 

  • Goitre, inc metabolism, dec weight, exophthalmos (bulging eyes) 

• myasthenia gravis (inhibiting) 

  • Abs form against acetylcholine receptors of skeletal muscles, blocking action 

  • Fatigue, weakness of muscles 

  • Ocular, facial muscles involved early, ptosis, difficulty speaking, chewing, swalling 

Type III immune complex mediated hypersensitivity  

Soluble antigen combines with specific antibodies to form immune (ag-ab) complexes 

Type III immune complex mediated hypersensitivity examples

Serum sickness: Horse-driven antitoxin administered to treat advanced toxaemias (tetanus) 

glomerulonephritis: Following strep infection

• Soluble Ag still present 

• Immune complex form 

• Filtered by glomeruli 

Type IV T cell mediated (delayed) 

• No antibodies 

• Sensitized T cells, killer cells, activated macrophages and secretion of cytokines cause tissue damage 

• Granulomata formation 

Type IV T cell mediated (delayed) examples

• Eg. Tuberculin reaction: Mantoux test 

  • Tuberculin (protein extract of M.tuberculosis) is administered intradermally 

• Eg. contact dermatitis 

  • Nickel plated buckle, nickel plated stud, perfume, rubber soles  

• Eg. graft rejection 

• Eg. Mosquito bite  

Autoimmune diseases 

1. Organ specific diseases 

   1. Hashimoto's: autoantibodies against thyroid gland 

   2. Chronic auto-immune atrophic gastritis: Autoab against parietal cells 

   3. Rheumatic heart disease: excess abs cross react

   4. Autoab can form to a cell receptor 

      1. Eg. Grave's disease (stimulating), myasthenia gravis (inhibitory)  

2. systemic disease

   1.  Systemic lupus erythematosus (SLE): Antinuclear abs (ANAs) 

   2. Rheumatoid arthritis; Autoag is an abnormal IgG to which another ab is formed 

hashimotos

• example of organ specific autoimmune disease

• autoantibodies against thyroid gland

• Loss of gland, replacement by lymphocytes, thyroid resembles lymph nodes 

• Goitre = hypothyroidism  

• Dec metabolism, weight gain, oedema, dry skin, puffy face, goitre 

• Treat with thyroxine 

Chronic auto-immune atrophic gastritis 

• example of organ specific autoimmune disease

• Autoab against parietal cells 

• Atrophy and fibrosis of acid-secreting gastric mucosa 

• Autoab also produced against intrinsic factor 

  • Pernicious anaemia 

• Atrophy of mucosa, loss of folds, achlorhydria, dyspepsia  

. Rheumatic heart disease 

• example of organ specific autoimmune disease

• Infection with group A strep – strep pyogenes 

• Excess ab form, react and destroy CTs 

• Aschoff nodule 

• Pancarditis: lesions in all layers   

Systemic lupus erythematosus (SLE)

• example of systemic autoimmunity

• Antinuclear abs (ANAs) 

• Synovial joints, skin, kidneys, brain, connective tissues are major targets 

• Characteristic rash (butterfly) 

• Joint and muscle involvement with arthritis 

rheumatoid arthritis

• example of systemic autoimmunity

• Damage to bone, joints and CT 

• Subcutaneous and visceral lesions  

• Symmetrical  

• Rheumatoid nodules (granulomas) 

• Autoag is an abnormal IgG to which another ab is formed 

  • = rheumatoid factor 

  • IgM and less frequently IgG 

• Immune complexes deposit in tissues, esp joints 

• T cell-mediated immunity also causes tissue damage – type III hypersensitivity  

• Degenerating collagen, CI, polyarthritis  

Oedema 

• Abnormal accumulation of fluid in intercellular spaces or within body cavities  

• In AI due to inc vascular permeability 

• And in other states due to disruption in starling forces 

  • Hydrostatic pressure increase 

  • Or plasma osmotic pressure decreases 

  • Leads to net accumulation of extravascular fluid  

ascites

oedema in peritoneum 

Hydrothorax:

oedema in thoracic cavity 

Hydropericardium:

oedema in pericardium 

Hydrocoele:

oedema in tunica vaginitis 

• Serous membrane covering testes  

causes to localised oedema

1. Acute inflammation (e.g. after a burn to the skin)

2. Type I hypersensitivity (e.g. after an allergic reaction to a bee sting)

3. Lymphatic obstruction (e.g. in parasitic infestations)

4. Impaired venous drainage (e.g. in varicose veins)

acute inflammation oedema

• Increased vascular permeability 

• Protein rich exudate 

• Quickly reabsorbed  

• Eg. Ankle sprain 

3. Lymphatic obstruction oedema

• Prevent of normal drainage of tissue fluid 

• Transudate 

• Eg. Fibrosis of tissue, tumour invasion in tissue, radiotherapy, parasitic infection 

• Severe cases lead to elephantiasis  

  • Due to constant injury and increasing collagen deposition 

4. Impaired venous drainage oedema

• Inc venous hydrostatic pressure 

• Inc pressure within lumen of vein, so fluid moves into tissue space 

• Eg. Tumour invasion, fibrosis, varicose veins, thrombosis, pregnancy, immobility, long periods of standing  

generalised oedema

• Anasarca: liver and renal failure 

• Hydrops or hydrops foetalis: babies, foetal anaemia, less blood flowing through kidney  

• Fluid retention > 5L 

• Lower limbs, gravity 

• Pitting oedema 

• Fluid balance of the body is disrupted and pathogenesis involves hormonal mechanisms  

generalised oedema pathogenesis

1. Malnutrition (decreased protein in diet), renal disease (protein lost to urine) or liver disease (not enough albumin made) 

2. Reduced plasma protein 

3. Oedema and reduced blood volume 

4. Reduced blood flow through kidney 

   1. Could also be directly due to renal disease, right heart faliure 

   2. Pooling blood 

5. Renin-aldosterone mechanism 

   1. Kidney stimulated to increase renin 

   2. Stimulates adrenal gland to release aldosterone 

   3. Aldosterone stimulates kidney  

      1. Stimulates pituitary gland to Increase Na+ retention 

         1. Positive feedback loop, PG releases antidiuretic hormone to stimulate kidney again 

   4. Increased water retention 

   5. Oedema  

causes to generalised oedema

1. Right heart failure (e.g. associated with lung fibrosis)

2. Renal disorders (e.g. glomerulonephritis)

3. cirrhosis of the disease (e.g. as seen in alcoholics or in Hepatitis B virus infection)

4. Malnutrition (e.g. in kwashiorkor)

5. Hyperoestrinism (e.g. in ovarian disease)

1. Right heart failure oedema

• Eg. Obstructive lung disease where scarring is in lungs 

• Right ventricle fails, blood pools in venous system 

• Increased hydrostatic pressure in veins 

• Disruption of starling forces 

• Reduced blood flow through kidney stimulates renin-aldosterone system  

2. Renal disorders oedema

• Eg. Glomerulonephritis, renal failure 

• Kidney fails > loss of plasma protein from glomeruli to urine 

• Hypoproteinaemia: less protein going to blood stream 

• Disruption of starling forces 

• Plasma volume decreases 

• Reduced blood flow through kidney stimulates renin-aldosterone system  

3. Liver disease oedema

• Eg. Cirrhosis, liver failure 

• Liver fails > dec albumin production 

• Hypoalbuminaemia: low albumin in blood 

• Disrupted starling forces 

• Plasma volume decreases 

• Reduced blood flow through kidney stimulates renin-aldosterone system  

• Impaired lymphatic drainage to liver > portal hypertension, ascites 

• Liver catabolizes oestrogens, so inc oestrogen levels > Inc Na+ retention 

4. Malnutrition oedema

• Eg. Kwashiorkor – severe dietary protein deficiency 

• Decreased plasma protein levels 

• Hypoalbuminaemia 

• Disrupted starling forces 

• Plasma volume decreases 

• Reduced blood flow through kidney stimulates renin-aldosterone system  

• Ascities: abnormal buildup of excess fluid in the abdominal cavity (oedema) 

5. Other clinical states oedema

• Eg. Pregnancy, contraceptive pill 

• Increased oestrogen 

• Oestrogen inc angiotensinogen secretion by liver, stimulating sodium and water retention 

Transudate:

non-inflammatory tissue fluid, little protein content 

Exudate:

acute inflammatory fluid, high protein content 

• Serous 

• Fibrinous 

• Haemorrhagic 

• Supprative  

1. Pumonary oedema 

• Eg. LV fail, infections – pneumoniae 

• life threatening oedema

2. Cerebral oedema 

• Eg. Due to head trauma, infections  

• life threatening oedema

haemorrhage Causes 

• Trauma damaging vessels 

• Vascular disease 

• Destruction of vessels in cancer 

• High blood pressure 

• Aneurysm 

Haemostasis 

• Physiological process preventing blood loss from the circulation 

Intrinsic pathway 

• Coagulation initiated by contact with surface antigens such as collagen or proteases, acting through factor XII 

Extrinsic pathway 

• Coagulation initiated by tissue factor (from damaged tissues) and its interaction with factor VII 

Common pathway 

• Series of steps that leads to generation of cross-linked fibrin  

injury of vessel

1. Vasoconstriction 

   1. Spasm > dec volume of blood flowing through injured vessel 

2. Blood coagulation cascade activated 

   1. Fibrinogen (soluble protein) forms fibrin (insoluble protein) via thrombin 

   2. Fibrin and platelets form haemostatic plug sealing defect in vessel wall 

   3. Prevent further blood loss  

3. Fibrinolytic mechanism 

   1. Plugged and vessel wall repaired > haemostatic plug is removed by fibronolysis 

   2. Plasminogen (inactive form) converts to plasmin (active) to dissolve fibrin 

4. Clot retraction, organization, recanilization 

   1. Shrinkage of clotted blood partially unblocks vessel 

   2. Fibrous tissue replaces clot > new channels form 

In vitro anticoagulant

oxalate or citrate ions bind Ca++ 

In vivo anticoagulant

heparin, warfarin, aspirin used therapeutically  

Hypovolaemia =

decreased blood volume 

External haemorrhage

• Blood lost to exterior of body 

• Eg. Bleeding into GI tract 

• Body loses haemoglobin/iron 

internal haemorrhage

• Blood lost to tissue or internal body cavities 

• Eg. Bleeding into pleura 

• Body doesn't lose iron 

Petechiae:

very small spots of haemorrhage – microvasculature 

Haematoma:

large, bruise – larger vessels 

Eccymosis:

very large haematoma – pt on anticoagulants  

Bright red haematoma

oxygenated Hb, arteriole  

Cherry red haematoma

unoxygenated Hb, veins

Greenish haematoma

biliverdin, catabolised  

Orange/yellow haematoma

bilirubin 

Brownish haematoma

haemosiderin, final insoluble product which is digested by macrophages  

Haemorrhagic diathesis 

• inherited or acquired and predispose to bleeding

• Caused by abnormalities in blood coagulation or anticoagulatn administration 

Inherited haemorrhagic diathesis

haemophilia A 

• X linked recessive 

• Deficiency of factor VIII 

• Haemarthroses, melaena, haematemesis can be seen

Acquired haemorrhagic diathesis

clotting factor deficiencies due to:

liver disease

• Liver synthesizes clotting factors, I, II, V, IX, X 

malnutrition or malabsorption 

• Vitamin K deficiency affects factors II, VII, XI 

premature birth (immature liver)

anticoagulant administration

purpura

increased likelihood of haemorrhages from small vessels – form of haemorrhage where blood loss occurs from capillaries throughout the body, leading to small petechial haemorrhages

1. Thrombocytopenia:

• type of purpura

• Eg. Dec platelet production from BM – chemo 

• Eg. Antibodies against platelets as seen in SLE – lupus  

2. Non-thrombocytopenic purpura 

• Vascular defects, normal platelet numbers 

• Congenital vascular defects 

  • Eg. Hereditary haemorrhagic telangiectasia 

• Acquired vascular defects  

  • Eg. infections causing capillary damage  

3. Thrombasthenia 

• type of purpura

• Platelets are abnormal in function 

• Eg. Cytotoxic drugs, rare congenital BM conditions  

Shock 

• Clinical syndrome 

• Collection of symptoms and signs 

• Pallor, nausea, hypotension, confusion 

• "low perfusion circulatory insufficiency leading to an imbalance between the metabolic needs of the tissues and the blood available to perfuse them" 

Primary shock 

• Seen after 

  • Injury: car accident

  • Great pain: advanced malignancy

  • Strong emotion: witnessing murder

• Low BP mediated by a transient neurovascular reaction  

• Fluid balance not affected – just redistributed

• syncope (fainting)

Secondary shock 

• More serious 

• Disturbance of fluid balance  

• Peripheral circulatory deficiency 

• Manifested by decreased volume of blood and renal functional deficiency

• due to hypovolaemia, heart failure or septicaemia

Hypovolaemic shock:

cause to secondary shock

haemorrhage, plasma loss (burns), fluid/electrolyte loss (sweating, diarrhoea) 

Cardiogenic shock:

cause of secondary shock

cardiac disease (heart attack), respiratory disorders affecting heart (lung faliure)

Septic shock:

cause to secondary shock

septicaemia (gram- bacteria) 

1. Production of endotoxin as bacteria are destroyed in body  

Thrombosis  

• Formation of solid or semi-solid mass composed of blood constituents 

• Mass = thrombus 

• During life