Pathology Study Guide - Weeks 5-8 PDF

PATHOLOGY STUDY GUIDE WEEKS 5-8 By Assoc Prof Roula P Kyriacou (Lecturer and Course Coordinator of MEDS1075 and MEDS2118) Copyright © RMIT UNIVERSITY 2024  PATHOLOGY STUDY GUIDE WEEKS 5-8 This guide...

PATHOLOGY STUDY GUIDE WEEKS 5-8 By Assoc Prof Roula P Kyriacou (Lecturer and Course Coordinator of MEDS1075 and MEDS2118) Copyright © RMIT UNIVERSITY 2024  PATHOLOGY STUDY GUIDE WEEKS 5-8 This guide will provide you with a flexible learning resource that helps you to review your lectures delivered in Weeks 5, 7, 8 in a flexible way and at your own pace. If you have any questions, please let me know. I hope you find it useful. WEEK 5 LEARNING OBJECTIVES ❖ To define and understand the process of carcinogenesis ❖ To outline the aetiological factors leading to cancer and to provide examples of carcinogens ❖ To distinguish between primary and secondary immunodeficiencies ❖ To understand the four types of hypersensitivities, their mechanisms and to provide examples ❖ To distinguish between organ-specific and systemic autoimmune disorders KEY SUMMARY POINTS Carcinogenesis refers to the initiation and promotion of cancer & involves genetic alterations in four classes of genes Gene mutations may be caused by carcinogens (chemicals, radiation, viruses) Aetiology is multifactorial in which carcinogens play only one part, interaction of intrinsic and extrinsic factors is important Primary immunodeficiencies: 1) Agammaglobulinaemia -  B cells 2) Thymic aplasia -  T cells 3) Combined immunodeficiency -  T & B cells Secondary immunodeficiencies: 1) Miscellaneous causes such as ageing, infections, tumours, drugs, radiation exposure 2) Infection with HIV → AIDS Type I Immediate hypersensitivity due to sensitized mast cells,  IgE → acute inflammtion & tissue damage Type II Antibody Mediated hypersensitivity due to IgG or IgM Abs causing cell lysis, or stimulation or inhibition → tissue damage Type III Immune Complex Mediated hypersensitivity due to immune complex deposition→ tissue damage Type IV T Cell Mediated (Delayed) hypersensitivity due to sensitized lymphocytes & activated macrophages → tissue damage Autoimmune disorders involve failure of self recognition and a reaction of the immune system against components of the body Autoantigens and auto-antibodies are involved in tissue damage; cell mediated immune mechanisms are also important Organ specific diseases are confined to a single tissue or a small group of related tissues e.g. Hashimoto’s disease of thyroid; Chronic autoimmune gastritis; RHD Systemic autoimmune diseases affect many tissues of the body e.g. SLE; Rheumatoid arthritis 1  WEEK 5 CARCINOGENESIS Firstly, let’s define some terms: Carcinogenesis is the process of initiation and promotion of cancer while a carcinogen is any agent or substance which initiates cancer e.g. chemicals, radiation, viruses. The process involves: Changes in the genome of cells (i.e. mutations) Over-expression of genes Loss of activity of gene products Mutations may be gross defects (e.g. translocations or breaks in chromosome arms) OR they may be a defect involving a single base-pair of DNA (e.g. point mutations; substitutions, deletions). There are four classes of normal regulatory genes which are the principle targets of genetic damage: 1. Growth promoting proto-oncogenes (normally code for proteins involved in the control of normal cell growth & differentiation i.e. they promote cell growth & mitosis). 2. Growth-inhibiting tumour suppressor genes (normally discourage cell growth, or temporarily halt cell division to carry out DNA repair). 3. Genes that regulate apoptosis (normally allow programmed cell death to occur, preventing further cell growth). 4. Genes involved in DNA repair (normally allow repair of DNA following damage/mutations by stimuli). Genetic alterations in the above genes leads to abnormal uncontrolled proliferation of cells (i.e. normal cells develop abnormalities in key genes that normally regulate growth and are then transformed into neoplastic cells – these cells develop with growth & survival advantages over normal cells). 2 As a tumour develops, cells undergo further somatic mutation causing mutations in other oncogenes (that is, we see additional oncogene expression or loss of tumour suppressor genes). A tumour will consist of many different subclones of cells, some with greater growth potential which will eventually dominate. Furthermore, tumours have a multifactorial aetiology in which carcinogens play only one part. The factors that cause tumours or have been associated with the causation of certain tumours are subdivided into two groups, depending on whether they are acting from within the body of the individual or whether they are originating from the environment: INTRINSIC FACTORS Genetic factors (within the body) Racial and geographic factors Immunological factors Sex and hormonal factors Age Pre-existing benign tumours EXTRINSIC FACTORS Chemical agents (environment) Physical agents Biological agents Note that there is often an overlap between intrinsic and extrinsic agents. A person’s genetic make-up, what race they belong to, the climactic conditions they are exposed to, what environmental agents they encounter, what food they eat, may all contribute to the causation of cancer. This explains why two people who seem to be exposed to the same single carcinogen do not both develop the same cancer. Review carcinogenesis and the different types of intrinsic and extrinsic agents in your lecture, and then attempt the following questions: QUESTION 1: Which of the following genes are targets for genetic damage, leading to the development of cancer? a) Growth promoting proto-oncogenes b) Growth inhibiting tumour suppressor genes c) Genes that regulate apoptosis d) Genes involved in DNA repair e) All of the above. 3 QUESTION 2: Which of the following is an intrinsic factor that is associated with carcinogenesis? a) Radiation exposure b) Increasing age c) Hepatitis B virus d) Helicobacter pylori e) Urethane. QUESTION 3: Match the carcinogen on the left with a tumour that it is often associated with on the right: 1) Ultraviolet radiation a) Cervical carcinoma 2) Cigarette smoking b) Leukaemia 3) Asbestos exposure c) Malignant melanoma 4) -naphthylamine d) Carcinoma of the bronchus 5) Human papilloma virus e) Hepatocarcinoma 6) X-irradiation f) Mesothelioma 7) Aflatoxins g) Urinary bladder carcinoma IMMUNOPATHOLOGY Immunopathology refers to any abnormality in the immune system function which leads to a pathological state. Immunopathology is subdivided into the immunodeficiencies, hypersensitivities & autoimmune disorders. A) Immunodeficiencies: The immune response is inadequate and cannot protect the body against microorganisms. This leads to multiple infections and a higher incidence of some neoplasms. Immunodeficiencies are classified into primary or secondary, depending on their aetiology. NATURE PRIMARY IMMUNODEFICIENCY SECONDARY IMMUNODEFICIENCY B cell functional defect Agammaglobulinaemia Multiple myeloma (Bruton’s disease) Some viral infections T cell functional defect Congenital thymic aplasia HIV infection (AIDS) (Di George syndrome) Immunosuppressive drugs Hodgkin’s disease Ageing Both B & T cell Combined immunodeficiency Radiation functional defect (Swiss syndrome) (bone marrow aplasia) Immunosuppressive agents (nitrogen mustards) Primary immunodeficiency is typically seen in babies and infants as it associated with congenital disease. Secondary immunodeficiency is usually acquired later in life when individuals are exposed to environmental agents. Most primary immunodeficiencies are quite rare but can be debilitating, while some secondary immunodeficiencies have minimal effects (e.g. those associated with ageing). A secondary immunodeficiency is one caused by Human Immunodeficiency Virus (HIV) infection which leads to acquired immunodeficiency syndrome (AIDS). AIDS was first identified in 1981 in the USA in male patients that presented with an unusual pneumonia caused by Pneumocystis jiroveci (previously P. carinii). The mode of spread was via blood, body fluids and sexual contact. HIV arose in Africa by mutation of human and monkey retroviruses and while the disease was confined to Africa until the 1970s, Haitian workers brought the virus back to Haiti and from there it spread to the USA and the rest of the world. 4 Please review your lecture on immunodeficiencies and then attempt the following questions: QUESTION 4: The human immunodeficiency virus infects which cells in the body? (Select all correct responses). a) Epidermal cells of skin b) Helper T cells c) Smooth muscle cells d) Monocytes and macrophages e) CD4+ cells. QUESTION 5: A baby diagnosed with agammaglobulinaemia (Bruton’s disease) will present with what type of infection? a) Predominantly viral infections b) Fungal and protozoal infections c) Pyogenic bacterial infections d) Infection with Candida albicans e) Any of the above. QUESTION 6: A viral infection associated with secondary immunodeficiency is: a) Influenza virus b) Rhinovirus c) Poliovirus d) Herpes simplex virus e) Any of the above. B) Hypersensitivities: The immune response is functioning, but there is an excessive immune response that also causes tissue damage. These reactions are also called allergies and only occur in some genetically predisposed individuals. TYPE I - ANAPHYLACTIC HYPERSENSITIVITY Here we see excessive formation of IgE antibody upon exposure to an allergen (e.g. pollen, house dust). IgE antibody inactivates the allergen but the excess binds by its non-antigen combining part onto the surface of mast cells in connective tissue. The next time the allergen is encountered, it combines with the antibody on the surface of mast cells and this causes degranulation of the mast cell with release of histamine and serotonin from granules in the cell. These mediators then cause inflammation (vasodilatation and increased vascular permeability) while localised or generalised reactions may be seen. Bronchial asthma is an example of a localized reaction in the respiratory system where bronchoconstriction is seen. Anaphylactic shock is the generalized reaction and may be seen after exposure to allergens such as peanuts. TYPE II - CYTOTOXIC HYPERSENSITIVITY Here we see the formation of IgG or IgM antibody which bind to cells causing lysis and destruction. Antibodies may be directed against a cell surface receptor as in the case of red blood cells or platelets which is why clinically this hypersensitivity may present as anaemia or thrombocytopenia. Incompatible blood transfusions and erythroblastosis foetalis (haemolytic disease of the newborn) are caused by this type of reaction. Alternatively, antibodies may be directed against a small molecule that has attached itself to the cell surface (e.g. drugs/antibiotics may attach to cells of genetically predisposed people). Another mechanism involves antibodies stimulating or inhibiting a receptor (as opposed to causing cell lysis) as is seen in thyrotoxicosis and Myasthenia gravis, respectively. 5 TYPE III - COMPLEX MEDIATED HYPERSENSITIVITY Here we see the formation of insoluble immune complexes when excess soluble antigens combine with antibodies in the tissues. These complexes circulate in the blood, localise in the blood vessel walls and in kidney glomeruli causing inflammation and tissue destruction (through activation of complement and formation of platelet microthrombi). Clinical manifestations are vasculitis and glomerulonephritis. Streptococcal infection (which causes a sore throat) may lead to a glomerulonephritis in predisposed individuals if these immune complexes deposit in the kidney. TYPE IV - CELL MEDIATED HYPERSENSITIVITY Here we see sensitized T cells and macrophages causing tissue damage. As the migration of these cells into tissue takes 24-72 hours to occur after the contact with allergen, the symptoms and signs are delayed (also known as “delayed hypersensitivity”. A common manifestation of this type of reaction is contact dermatitis where in predisposed individuals, skin contact with an allergen will bring about the infiltration of lymphocytes and macrophages causing tissue damage to the area. The mechanism by which transplanted organs or grafts are rejected also involves a Type IV reaction. After reviewing your lecture on hypersensitivities, please attempt the following questions: QUESTION 7: Which of the following stimuli are likely to cause a cell mediated hypersensitivity in predisposed individuals? (Select all correct responses). a) Bee stings b) Skin contact with perfume c) Mosquito bites d) Skin contact with nickel e) Inhalation of pollen. QUESTION 8: A cell that is important in type I hypersensitivity reactions is the: a) Mast cell b) B lymphocyte c) Plasma cell d) T lymphocyte e) Neutrophil. QUESTION 9: A patient was given an incompatible blood transfusion. What type of reaction is likely to have occurred? a) Type I anaphylactic reaction b) Type II cytotoxic reaction c) Type III immune complex mediated reaction d) Type IV delayed hypersensitivity reaction e) Type I immediate reaction. QUESTION 10: An example of type III hypersensitivity is “serum sickness”. a) True b) False. 6 C) Autoimmune disorders: The immune response is inappropriate as it cannot distinguish between what is “self” and what is “non-self”. When this self-recognition fails, the immune response attacks cells of the body, causing cell and tissue damage. The components of the cells that generate this autoimmune response are called “autoantigens”. The antibodies that form against these autoantigens are termed “autoantibodies”. A triggering factor for this inappropriate immune response maybe known or unknown, while hypersensitivity mechanisms may also be active. Once again, these disorders occur in genetically predisposed individuals. In the organ specific autoimmune diseases, the autoantigens are confined to an organ. For example, in Hashimoto’s disease the autoantigens are only found in the thyroid gland, so the disease is limited to this gland. In systemic autoimmune diseases, the autoantigens are found in a wide variety of tissues and organs around the body, especially in connective tissues. An example of a systemic disorder is systemic lupus erythematosus (SLE). After reviewing your lecture on autoimmune disorders, please attempt the following questions: QUESTION 11: A systemic autoimmune disease is: a) Grave’s disease b) Chronic atrophic gastritis c) Rheumatoid arthritis d) Rheumatic heart disease e) Hashimoto’s disease. QUESTION 12: Autoantibodies are involved in: a) Contact dermatitis b) Chronic atrophic gastritis c) Mosquito bite lesions d) Anaphylactic reactions e) All of the above. *********************************************************** 7  WEEK 6 LEARNING OBJECTIVES ❖ To provide examples of localised & generalised oedema, and to understand the mechanisms involved ❖ To outline the different types of haemorrhage and to provide examples of haemorrhagic diatheses ❖ To outline the different types of purpura ❖ To distinguish between primary and secondary shock ❖ To outline the types, causes and effects of thrombosis and embolism KEY SUMMARY POINTS Oedema is increased intercellular fluid or increased fluid within body cavities Localized oedema is due to: Acute inflammation, allergic reactions, lymphatic obstruction, or impaired venous drainage Generalized oedema is due to: Right heart failure, kidney disease, liver disease, malnutrition, or other states ( oestrogen levels) Pathogenesis involves kidneys, adrenal gland, pituitary gland and hormonal mechanisms Haemorrhage may be internal or external Haemorrhagic diatheses are inherited or acquired and predispose to bleeding Haemophilia A is a common inherited haemorrhagic diathesis Purpura is a condition of increased likelihood of haemorrhages from small vessels – may be related to reduced platelet number, abnormalities in small vessels or abnormal platelet function Shock is a syndrome indicating a problem in supplying the tissues of the body with adequate amounts of nutrients and O2 Primary shock is a mild neurovascular reaction to pain, emotion or injury Secondary shock is more severe and involves fluid and electrolyte imbalance in the body - due to hypovolaemia, heart failure or septicaemia Thrombosis is clotting of blood within the circulation during life Three types of thrombi: white, red and mixed Virchow’s triad relates to general factors predisposing to thrombosis: 1) Changes in the vessel wall 2) Change in blood flow 3) Changes in blood constituents Fates of thrombosis (x7) Embolism is occlusion of a vessel by a mass of material that is transported in the bloodstream – types of emboli (x6) 8 OEDEMA Oedema is the abnormal accumulation of fluid in intercellular spaces (interstitial space) or in body cavities. It is different to hydropic change in that the fluid is found between cells in oedema, whereas in hydropic change, the fluid is found within cells. It is subdivided into two major types: Localised oedema: Confined to a relatively small area of the body Generalised oedema: Involves all the body Review your lecture to make sure you are familiar with terms that signify special forms of oedema: Ascites, hydrothorax, hydropericardium, hydrocoele, anasarca, hydrops/hydrops foetalis Localized oedema is due to: Acute inflammation (e.g. after a burn to the skin) Allergic hypersensitivity reaction (e.g. after an allergic reaction to a bee sting) Obstruction to lymphatics (e.g. in parasitic infestations) Impaired venous drainage (e.g. in varicose veins) Generalized oedema is due to: Right heart failure (e.g. associated with lung fibrosis) Renal disease (e.g. glomerulonephritis) Cirrhosis of the liver (e.g. as seen in alcoholics or in Hepatitis B virus infection) Malnutrition (e.g. in kwashiorkor) Hyperoestrinism (e.g. in ovarian disease) The pathogenesis of generalised oedema involves disrupted Starling forces as seen in reduced plasma protein (hypoproteinemia) that causes reduced plasma osmotic pressure. It also depends on hormonal mechanisms that involve the kidneys, adrenal gland and pituitary gland. Review your lecture where I outline the pathogenesis of generalised oedema across 2 slides with flow charts Clinically, oedema is very important in two situations as it can be life threatening: Pulmonary oedema (e.g. as seen in heart failure or in pneumonia) Cerebral oedema (e.g. as seen after head trauma causing raised intracranial pressure) QUESTION 13: The accumulation of oedema fluid in the peritoneal cavity is termed: a) Hydrothorax b) Hydropericardium c) Anasarca d) Ascites e) Hydrops. QUESTION 14: Generalized oedema involves increased secretion of: a) Thyroid hormone b) Aldosterone c) Oxytocin d) Erythropoietin e) Adrenal corticosteroids. 9 HAEMORRHAGE Haemorrhage is the escape of blood from the circulation and represents a situation where normal haemostasis (the physiological process preventing blood loss from the circulation) fails. Haemorrhage may be of two types: External: Blood is shed outside the body (e.g. blood leaking into the gastrointestinal tract or respiratory passages) Internal: Blood lost into the interstitial tissues or internal body cavities (e.g. blood loss in muscle or within the peritoneal cavity). Revisit your lecture to review the main effect of haemorrhage and the following terms that relate to types of haemorrhage: Petechiae/petechial haemorrhages, haematoma, ecchymosis, purpura QUESTION 15: Which of the following blood losses is an example of an internal haemorrhage? a) Blood loss into the stomach lumen b) Blood loss into the genital tract c) Blood loss from a surgical cut to the abdominal skin d) Haemoptysis e) Blood loss into the pleura. QUESTION 16: In which part of the body may a small volume of haemorrhage be fatal? a) The lumen of the stomach b) Subcutaneous tissue c) Kidney d) Brain e) Bladder. QUESTION 17: Which of the following terms describes a very small spot of haemorrhage? a) Bruise b) Petechia c) Haematoma d) Ecchymosis e) Coagulum. QUESTION 18: What is the main effect of haemorrhage? a) Increased blood pressure b) Purpura c) Increased cardiac output d) Petechial haemorrhages e) Hypovolaemia. Blood within tissues excites an inflammatory response that will break down red blood cells and catabolise the haemoglobin into various by-products such as biliverdin, bilirubin, haemosiderin. Revisit the lecture to review the colour changes in tissue reflecting the breakdown of haemoglobin. Loss of much blood from the circulation can be fatal because of hypovolaemia and shock that may develop. If a little volume of blood loss occurs over a long period of time, anaemia may result clinically. 10 Haemorrhagic diatheses are disorders that predispose to haemorrhage occurring in the body. These conditions may be congenital or acquired. Congenital: e.g. Haemophilia A (X-linked recessive; factor VIII deficiency) Haemarthrosis, melaena, haematemesis may be seen Acquired: Clotting factor deficiencies due to: Malnutrition; malabsorption syndromes Liver disease (as the liver forms many of the clotting factors) Premature birth (immature liver) Anticoagulant administration Purpura is a form of haemorrhage where blood loss occurs from capillaries throughout the body, leading to small petechial haemorrhages. It is of three types: Thrombocytopenic: Due to decreased circulating platelet numbers (e.g. autoimmunity as seen in SLE or due to cytotoxic drugs) Non-thrombocytopenic: Due to vascular defects (seen with normal platelet numbers) (e.g. infections causing capillary damage; haemorrhagic telangiectasia) Thrombasthenic: Due to platelets abnormal in function (platelet numbers are normal/increased) (e.g. congenital bone marrow disease or due to cytotoxic drugs) SHOCK Shock is not a distinct pathological entity but rather a clinical syndrome (a collection of symptoms and signs - e.g. pallor, nausea, hypotension, confusion). Primary shock is seen after injury (e.g. involved in a car accident), great pain (e.g. advanced malignancy) or strong emotion (e.g. witnessing a murder). Low blood pressure mediated by a transient neurovascular reaction occurs, while fluid balance is not affected. It frequently results in SYNCOPE (fainting) and patients recover soon after. Secondary shock is seen when there is disturbance of fluid balance. Peripheral circulatory deficiency is seen manifested by a decreased blood volume and renal functional deficiency. 1) Hypovolaemic shock is due to haemorrhage, plasma loss (burns), fluid/electrolyte loss (sweating, diarrhoea) 2) Cardiogenic shock is due to cardiac diseases (e.g. MI), respiratory disorders affecting heart (e.g. lung failure) 3) Septic shock is due to septicaemia (e.g. production of endotoxin by Gram-ve bacteria) QUESTION 19: Haemorrhage into a joint is termed: a) Haematoma b) Haemarthrosis c) Haematemesis d) Haemoptysis e) Haemosiderin. QUESTION 20: The condition where multiple small haemorrhages are seen in the skin and mucous membranes due to a very low circulating platelet number is termed: a) Thrombasthenia b) Non-thrombocytopenic purpura c) Thrombocytopenic purpura d) Thrombocytosis e) Thrombosis. QUESTION 21: A characteristic of primary shock is low blood pressure mediated by a transient neurovascular reaction: a) True b) False. 11 THROMBOSIS and EMBOLISM Firstly, let’s define some terms: Thrombosis: The process that results in the formation of a solid or semi-solid mass from the constituents of the blood, within the vascular system during life. The mass formed is called a thrombus (plural = thrombi). Embolism: The transfer of abnormal material by the bloodstream and its subsequent lodgement in the vessels downstream. The mass of abnormal material is called an embolus (plural = emboli). Infarction: An area of anoxic necrosis produced by an acute interference with a tissue’s blood supply. The region of necrotic tissue is termed an infarct. These three processes are related. The usual sequence of events being that a thrombus forms in some part of the circulation, it then dislodges and forms a thromboembolus. When the thromboembolus lodges in a vessel smaller than its own diameter, it blocks blood flow to the tissue and causes an infarct. Capillaries Direction of blood flow Thrombus Thromboembolus Arteriolar end Infarct The three major factors predisposing to thrombosis were first identified by Rudolf Virchow which is why they are termed Virchow’s triad: 1) Changes in the vessel wall (e.g. damage to the intima by atherosclerosis) 2) Changes in the blood flow (e.g. stasis of blood - complete stoppage of flow) 3) Changes in the blood constituents (e.g. increased clotting factors). Many disease states can affect all of these factors relating to thrombosis. One disease that causes an increased predisposition to thrombosis is atherosclerosis. Atherosclerosis is a disease of large arteries where lipid is deposited in the intima of vessels. This narrows the lumen of the vessel, alters blood flow and due to high lipid levels also predisposes to thrombosis. Important clinical risk factors for thrombosis include increased age, heart conditions, health status, immobility and cigarette smoking. Review the various types of thrombi (classified according to composition and clinical behaviour) and then attempt the following questions: QUESTION 22: Which type of thrombus would appear to be layered (i.e. showing the lines of Zahn in its cut surface) and would only partially block the vascular lumen? a) Occlusive, red thrombus b) Mural, red thrombus c) Occlusive, mixed thrombus d) Mural, mixed thrombus e) Mural white thrombus. 12 QUESTION 23: Which type of thrombus would be found on a heart valve? a) Propagating thrombus b) Mural, red thrombus c) Ball thrombus d) Mural, mixed thrombus e) White vegetation. The sequelae of thrombosis are summarised below: 1) Propagation (thrombus enlarges along a vessel, involving more branches) 2) Lysis (which may result in resolution) 3) Calcification (thrombus undergoes necrosis and dystrophic calcification) 4) Infection (leading to abscesses or septic infarcts) 5) Retraction, organization, recanalization (organization of the thrombus into scar) 6) Thromboembolism (detachment and embolism which may lead to infarction) 7) Infarction (thrombus interrupts blood flow, anoxia and necrosis of tissue will result) EMBOLISM An embolus can be: 1) A solid (e.g. a dislodged thrombus) 2) A liquid (e.g. amniotic fluid embolus) 3) A gas (e.g. air injected into the circulation). The most common emboli are dislodged thrombi: 1) Venous thromboemboli are very common (especially after surgery) and usually originate from the deep leg veins or pelvic veins. They lodge in the pulmonary arteries and may cause death or pulmonary infarcts. 2) Arterial thromboemboli are most often associated with atherosclerosis and may cause fatal myocardial infarcts (i.e. “heart attacks”) or cerebral infarcts (i.e. “strokes”). Review the various types of emboli in your lecture and answer the following question: QUESTION 24: Match the appropriate condition on the left with its aetiology on the right: 1. Fat embolism a) A venous thrombus dislodging from a deep leg vein 2. Caisson disease b) Malignant tumour invading a vein 3. Air embolism c) Ruptured atheromatous plaque in an artery 4. Amniotic fluid embolism d) Contaminated needle used by an intravenous drug user 5. Tumour cell embolism e) Deep sea divers coming to the surface too quickly 6. Talc grain embolism f) Incision of large neck veins 7. Pulmonary embolus g) Thrombus dislodging from coronary artery 8. Arterial embolus h) A bone fracture of the tibia 9. Cholesterol embolus i) A prolonged labour and difficult childbirth. 13  WEEK 8 LEARNING OBJECTIVES ❖ To define the terms infarction and hypertension, and to outline the types, causes & effects of each ❖ To distinguish between primary, secondary, benign and malignant hypertension ❖ To provide examples of arteriosclerotic disorders and to outline the causes & effects ❖ To outline the aetiology and pathogenesis of atherosclerosis, outlining the hard and soft risk factors, the characteristic lesions and the clinical effects KEY SUMMARY POINTS Infarction is the process whereby an area of tissue in the body undergoes anoxic necrosis due to an acute interference of its blood supply Infarcts are pale, red or mixed; Arterial & venous infarcts have the same effect (anoxia of tissue) Sequelae of infarction: Minimal clinical effects or death; organization; dystrophic calcification; sepsis Hypertension is a persistent rise in systemic blood pressure to levels >140/90 mmHg Aetiological subtypes are: Primary hypertension (~90% of cases) Secondary hypertension (~10% of cases) Clinical subtypes are: Benign hypertension (~95% of cases) Malignant hypertension (~5% of cases) Primary hypertension is idiopathic, but shows characteristics of a multifactorial disorder where genetic & acquired factors interact Secondary hypertension may have renal, renal artery stenotic, endocrine or iatrogenic causes Benign hypertension has a long course, renal function is preserved, patients more likely to have cardiac disease Malignant hypertension causes rapid deterioration of kidney function - many patients die in renal failure; characteristic lesion is “onion skinning” of vessels Arteriosclerosis describes a group of disorders all involving loss of elasticity and hardening of arteries 1. Atherosclerosis most widespread and most important clinically 2. Mönckeberg’s medial calcification is common but causes few clinical effects 3. Arteriolosclerosis affects small arteries and arterioles and has important ischaemic effects Lesions seen in the development of atherosclerosis: Fatty streaks (?), musculoelastic lesions, typical & complicated atheromatous plaques Pathogenesis involves hard & soft risk factors, reaction to injury theory of Ross Clinical effects: i) Intermittent ischaemic effects ii) Thrombosis, embolism, infarction iii) Aneurysms Thrombosis may arise independent of atherosclerosis OR in late stage atherosclerosis leading to thromboembolism and infarction - possibly fatal 14 INFARCTION Infarction is the process whereby an area of tissue in the body undergoes anoxic necrosis due to an acute interference of its blood supply. The region of necrotic tissue is termed an infarct. Most infarcts are due to an acute interruption of the arterial blood supply to a tissue that does not have a collateral blood supply. Less likely, infarcts may be due to venous occlusion compromising venous drainage of a tissue. Make sure you understand the interrelationship of the processes of thrombosis, embolism and infarction, as outlined in the lecture. Infarcts are classified as pale, red, mixed: Pale infarcts arise when the arterial blood supply is obstructed and there are no collateral arterial vessels to the ischaemic site; veins drain away the blood in the infarct and coagulative necrosis ensues Red infarcts arise when: 1) Venous drainage is obstructed and there are no collateral vessels to drain the site, hence anoxia develops 2) Arterial blood supply is obstructed and there are some but not enough collateral vessels to the ischaemic site, leading to anoxia (e.g. organs with double blood supply) 3) Pale infarcts that have blood readmitted to them after necrosis has occurred, i.e. haemorrhage in necrotic tissue Mixed infarcts begin as pale infarcts, and as a thrombus embolizes, blood supply is partially readmitted to some areas and not others. The sequelae of infarction are summarised in the flow chart below: DEATH e.g. heart Review the lecture on infarction and answer the following question: QUESTION 25: If a patient survives an infarct in the myocardium, the condition is most commonly followed by: a) Fibrosis b) Gliosis c) Abscess formation d) Calcification e) Gangrene. 15 HYPERTENSION Hypertension is a persistent rise in systemic blood pressure. To diagnose hypertension, several readings taken over consecutive days on different occasions must be consistently high, above 140 mmHg systolic and 95 mmHg diastolic. Hypertension is classified aetiologically and clinically: Aetiological classification: ~90% of cases are primary/essential/idiopathic hypertension (cause unknown) ~10% of cases are secondary hypertension (cause known) Clinical classification: ~95% of cases are benign hypertension (long course; compatible with long life) ~5% of cases are malignant hypertension (short course; life threatening) Malignant (or “accelerated”) hypertension has a rapid course and if untreated is rapidly life threatening. Benign hypertension has a slower course and is easier to treat. Important organ and tissue changes, especially in the kidneys, are seen with both types. Hypertension is also a major risk factor in the development of many vascular system disorders such as atherosclerosis. BENIGN HYPERTENSION (HT) MALIGNANT HYPERTENSION (HT) INCIDENCE ~95% of cases ~5% of cases MACROSCOPIC Kidneys small, granular, scarred Kidneys generally normal size with some haemorrhages many cortical petechial haemorrhages FINDINGS MICROSCOPIC fibrinoid necrosis of arterioles & glomeruli Kidney lesions (same as benign HT) elastosis of arterioles develop quickly; characteristic lesion is FINDINGS protein casts of tubules “onion skinning” of arterioles RESULTS Rarely kidney failure Renal failure is common Hypertensive heart disease, MI, CI Review the lecture on the causes of hypertension (HT) and the features that characterise each type of hypertension, and then answer the following questions: QUESTION 26: Match the appropriate term on the left with its definition or association on the right: 1. Phaeochromocytoma a) Glomerular fibrinoid necrosis, associated with HT 2. Renal artery stenosis b) Slowly rising blood pressure over many years 3. Malignant hypertension c) Hardening of arterioles, fibrinoid necrosis of their wall 4. Renal failure d) Secondary hypertension is caused by this condition 5. Heart failure e) Patients with malignant HT most often die of this 6. Glomerulosclerosis f) Patients with benign HT may die of this 7. Benign hypertension g) Hormone-secreting adrenal tumour causing hypertension 8. Arteriolosclerosis h) Characterized by “onion-skinning” in renal arterioles QUESTION 27: Individuals with primary hyperaldosteronism may develop secondary hypertension. a) True b) False. 16 ARTERIOSCLEROSIS Arteriosclerosis is a group of disorders that all have in common a hardening and a loss of elasticity of arteries. The most common and important of these disorders are: ATHEROSCLEROSIS: A disease of the intima of large elastic arteries involving lipid deposition and calcification. The arterial lumen becomes progressively occluded over many years with ischaemic effects. MÖNCKEBERG’S MEDIAL CALCIFICATION: A disease of the media of medium-sized muscular arteries. Focal regions of necrosis and dystrophic calcification develop in the middle region of the artery making it less elastic and hardened, but the lumen is not narrowed. ARTERIOLOSCLEROSIS: A disease of small arteries and arterioles. The wall undergoes fibrinoid necrosis with microthrombus formation. The artery becomes progressively narrowed with ischaemic effects. The development of atheromatous plaques and the risk factors involved in the development of these plaques are what you should understand after reading this part. (A) ATHEROSCLEROSIS The aorta and its major branches are mainly affected and the typical lesion is referred to as an atheroma or an atheromatous plaque. Atheromatous plaques develop in distinct stages: 1) Fatty streaks: These are disputed precursors in the development of atheroma (consist of lipid-laden macrophages) 2) Musculoelastic lesions (= early atheromatous plaques; = intimal cushions): These are definite precursors of the typical atheromatous plaque. (consist of smooth muscle cells, connective tissue fibres and matrix, plasma proteins and few lipids) 3) Typical atheromatous plaques (= atheroma): These lead to thickening of the intima and cause the lumen to narrow, while the media become thinner. (consist of lipids & necrosis in the intima, a fibrous cap, chronic inflammation) 4) Complicated plaques: The atheroma becomes complicated by ulceration, haemorrhage, dystrophic calcification, thrombosis, and aneurysm formation. Atherosclerosis is a multifactorial disease. Hard risk factors and soft risk factors are involved in the aetiology. HARD RISK FACTORS SOFT RISK FACTORS Hyperlipidaemia (genetics important here) Dietary factors Hypertension Obesity Cigarette smoking Lack of exercise Diabetes mellitus Stress, lifestyle factors, personality type Genetics Hormonal factors (influenced by genetics) Hard risk factors are multiplicative e.g. a hypertensive, diabetic who smokes has a higher risk of developing atherosclerosis compared to a normotensive, non-diabetic, non-smoker (all other risks being equal). The major effects of atherosclerosis relate to thrombosis, thromboembolism and infarction which manifest as myocardial and cerebral infarcts. Review the lecture on the aetiology & pathogenesis of atherosclerosis and then answer the following questions: 17 QUESTION 28: Which person is likely to have the most severe and advanced atherosclerosis (all patients being of the same age and sex)? a) A diabetic who does not smoke nor is hypertensive b) A hypertensive cigarette smoker who has low blood lipids c) A hypertensive cigarette smoker with diabetes mellitus d) A normotensive, non-diabetic who has high levels of blood lipids e) A diabetic non-smoker who is normotensive. QUESTION 29: Match the appropriate term with its definition or association: 1. Foam cell a) High levels of such lipoproteins protect against atheroma 2. Aneurysm b) “Ballooning” of a blood vessel due to its weakened wall 3. Atheroma c) A “hard” risk factor in atherosclerosis 4. Intimal cushion d) A macrophage full of lipids 5. HDL e) The fully developed plaque of atherosclerosis 6. LDL f) Outlines the pathogenesis of atherosclerosis 7. Hypertension g) The same as a “musculoelastic lesion” 8. Response to injury theory of Ross h) High levels of such lipoproteins predispose to atheroma (B) MÖNCKEBERG’S MEDIAL CALCIFICATION This disorder involves medium sized muscular arteries predominantly (e.g. femoral, tibial, coronary) and is characterised by degeneration and necrosis of the medial smooth muscle followed by dystrophic calcification. The intima is not affected and the lumen remains patent unless there is coincident atheroma. (C) ARTERIOLOSCLEROSIS This disorder involves arterioles & small arteries of many tissues (e.g. kidneys, pancreas, spleen, retina, extremities). As previously discussed, it is most commonly associated with systemic hypertension, however, it is also seen in normotensive, elderly people and in patients with diabetes mellitus. QUESTION 30: Which person is likely to have the most severe arteriolosclerosis in their renal arterioles? a) A 56 year old normotensive, non-diabetic male with mönckeberg’s medial calcification b) A 32 year old normotensive woman with low blood lipids and mönckeberg’s medial calcification c) A 41 year old normotensive and non-diabetic woman d) A 54 year old male that has suffered from diabetes mellitus since childhood e) A 45 year old male that has just developed benign hypertension. *********************************************************** 18 ANSWERS TO QUESTIONS Make sure to attempt the questions before you look at the answers as this defeats the purpose of testing your understanding, progress and learning needs. Q1. e Q2. b Q3. 1) c 2) d 3) f 4) g 5) a 6) b 7) e Q4. b, d and e Q5. c Q6. a Q7. b, c and d Q8. a Q9. b Q10. a Q11. c Q12. b Q13. d Q14. b Q15. e Q16. d Q17. b Q18. e Q19. b Q20. c Q21. a Q22. d Q23. e Q24. 1) h 2) e 3) f 4) i 5) b 6) d 7) a 8) g 9) c Q25. a Q26. 1) g 2) d 3) h 4) e 5) f 6) a 7) b 8) c Q27. a Q28. c Q29. 1) d 2) b 3) e 4) g 5) a 6) h 7) c 8) f Q30. d 19