Principles Of Disease PATH*3610 2025 PDF

PRINCIPLES OF DISEASE PATH*3610 2025 COURSE INSTRUCTOR-IN-CHARGE Dr Robert A. Foster, BVSc. (Qld), PhD. (JCUNQ), MANZCVS, Diplomate ACVP. Professor CALENDER DESCRIPTION...

PRINCIPLES OF DISEASE PATH*3610 2025 COURSE INSTRUCTOR-IN-CHARGE Dr Robert A. Foster, BVSc. (Qld), PhD. (JCUNQ), MANZCVS, Diplomate ACVP. Professor CALENDER DESCRIPTION A course designed for students with particular interests in nutrition and biology. The course presents basic concepts of disease in the cells, tissues, organs and fluids of the body. Emphasis will be on disease processes resulting from physical, toxic and microbiological and other causes. COURSE OBJECTIVES This course will integrate anatomy, physiology and the mechanisms of disease so that, with a basic knowledge of the organ or tissue, the effect of a disease on the host and the rational of therapy can be explained. You will interpret medically related articles in the popular press, and medically related discussions in an objective and scientific manner. The vocabulary of medicine is acquired in the process. The response of the body, tissues and cells is studied and this enables an understanding of the significance of some common pathologic processes and disease entities. To achieve this, examples of common and/or important diseases such as those caused by physical, toxic and biological agents and metabolic and nutritional imbalances are used. The means by which disease is induced and the response of the organism are emphasized. At the end of this course you will be able to i. Define medical terms used in general pathology and in diseases of body systems ii. Outline the general mechanisms of cell and tissue injury and death. iii. Describe the general response and outcome of injury to all cells and tissues. iv. Outline healing and repair of all tissue types on the body. v. Outline the general features of immunity in the body vi. Describe the mechanisms of infectious disease and the general principles of microbial effects on the body. Outline the principles of prevention of infectious disease. vii. List the principles of development, effects of and treatment of neoplasia. viii. Describe the response and outcome of injury in the major organs of the body, particularly the skin, stomach and intestines, bone marrow and blood, lungs, liver, kidneys, heart and vessels, brain and spinal cord, and bones and joints using a knowledge of anatomy and physiology at a basic level. ix. List the clinical signs seen when each organ fails and explain why each clinical sign occurs based on the specific function of the organ. x. Explain the general approach to treatment of a disease, and when given basic information about a disease, provide general, specific and appropriate examples of treatments.  1. GENERAL CONSIDERATIONS This course is about disease. Two components; Asymptomatic infections are the percentage of ‘dis-’ meaning ‘from’, and ‘ease’ form the term those infected that don’t show signs. ‘disease’. This course will allow you to integrate Infection fatality rate (IFR) is the percentage of anatomy, physiology and the mechanisms of disease so the population that will die from the disease that you can understand common diseases and Case fatality rate (CFR) is the percentage of the therapy. You will be able to interpret medically related population who show signs of a disease that die articles in the popular press, and medically related of the disease. discussions in an objective and scientific manner. For every disease there is a risk or chance of This is a course that looks at the failure of the acquiring that disease. There are several kinds of risk. adaptive mechanisms of the body. The body as a whole Actual risk is a statistical measure of the chance of is in homeostasis. An imbalance of homeostasis is developing or dying from a disease. It is quite often recognized as the clinical signs and symptoms of different to our perceived risk. disease. Signs are the observations of disease and Another term that is used widely in scientific symptoms are what you feel. communities is the word 'association'. Association is a term One of the challenges in a study of disease is to describe a link. In medical terminology an association or the large volume of medical terminology. Every term link does not necessarily mean cause. used in this course will become part of our regular The basis for determining the cause of disease is vocabulary. There are a large number of basic traditionally based on fulfilling Koch postulates. The definitions that we need to understand before we can postulates are as follows: start to talk about disease. i. The suspected organism must always be present in the Pathology comes from the word ‘pathos’ lesions, meaning ‘suffering’. ‘-ology’ is 'the study of'. Pathology ii. It must be grown in a pure culture on laboratory brings together the cause (aetiology) of a disease media, process, its mechanisms of development iii. It must cause the same disease when injected into a (pathogenesis), the structural alterations (lesions) and susceptible animal, and the functional consequences (clinical significance). iv. It must be recovered from the experimental animal. When we talk about disease we often use a Many diseases today do not entirely fulfill Koch variety of terms to describe how it affects the postulates. Many of our diseases involve infectious and population. noninfectious causes, and we have developed a wide and Incidence is the number of new cases of a - large number of associations with diseases. The disease each year. appearance of a disease is often a multifactorial process Prevalence is the number of occurrences of - dependent on the interaction of agent and host. the disease in a year and is the total number Understanding all of the mechanisms is often required to affected. completely understand the condition and the population in which it occurs.  PATH*3610 Principles of Disease General Considerations 7 We will concern ourselves mostly with the ‘what’ 7. The body has a built in redundancy. With a few and ‘how’ of disease, and we will not spend much time exceptions, the functional mass of an organ is reduced with the ‘why’ of disease. An interesting way to look at by 70% before failure and clinical signs are seen. the question ‘Why did I get sick?’ is to consider what is 8. Clinical signs are those changes one can see in a clinical called Darwinian medicine – the application of the setting. Laboratory data is not a clinical sign. principles of evolutionary biology to medicine. Four 9. Functional tests are done to determine if there is main categories of evolutionary thinking are disease and failure. i. Host defences - Clinical disease may be either 10. The functions of an organ are apparent when the organ pathogen offence or host defence (ie fever and fails! Want to know what happens in disease – know the acute phase response). the anatomy, physiology and reactions to injury. ii. Virulence – a pathogen will not want to kill its 11. Labile cells respond to injury with hyperplasia, host, unless it aids its transmissibility permanent cells respond with hypertrophy iii. Genetic conflict – selection of a gene is a basic 12. An ounce of prevention is worth a pound of cure. tenet of evolutionary biology, but selection 13. Prevention involves separating individuals from the typically occurs at the individual level. Parents cause (education is important here), providing and their offspring have a form of genetic resistance to the cause of disease, and prophylactic conflict! treatment. iv. Incomplete adaptation – the occurrence of 14. Inflammation is mostly a local tissue phenomenon, but many diseases are attributed to individuals not there are systemic responses to inflammation. being adapted to them 15. The type and effectiveness of healing and repair is dependent on the inherent abilities of the cells BASIC PRINCIPLES OF DISEASE involved (permanent vs stable vs labile types). Cells Our understanding of disease and its treatment regenerate when they can. Granulation and fibrosis is based on several fundamentals. They include (scarring) occurs when organs cannot regenerate. 1. Disease is inevitable 16. Therapy is aimed at removing the cause (specific 2. The body is a bundle of compromises therapy), relieving the workload, treating the signs and 3. There is no one ‘normal’ body or organism, and symptoms, and replacing function if possible. there is no one ‘normal’ or ‘perfect’ genome. 17. Infection is not the same as disease. Systems are designed with a ‘smoke detector’ 18. Neoplasia usually occurs after initiation, promotion facility. Many false alarms are tolerated to prevent and progression – it is a multi step process. a catastrophe. 19. There is rarely a single cause of a disease. 4. Some so-called defective genes may have benefits. 20. Change in body parameters is abnormal when the 5. Individuals vary in their susceptibility to disease parameter is above or below the normal reference because of innate or acquired factors (individual range for the population or individual. variation). There is a range of normal. Normal 21. Abnormal quantities of any parameter is because of reference range is 2 Standard Deviations above and reduced production, destruction or increased usage. below the Mean in a normal population. 6. Disease is usually a prelude to failure. Organ failure occurs only after considerable disease.  PATH*3610 Principles of Disease General Considerations 8 PROBLEM SOLVING AND DIAGNOSIS IN Correct scientific processes and statistical analysis ensures accuracy of data and subsequent rational behaviour. Saying DISEASE something multiple times does not make it so. Pathogenesis of disease involves three Interesting reading steps. Nesse RM and Williams GC. ‘Evolution and the i. Cause: Providing a cause Origins of Disease’ Scientific American November 1998 p ii. Mechanisms: Outlining the mechanisms 86-93 involved Legrand EK and Brown CC (2002) ‘Darwinian iii. Outcome: Clinical signs or lesions. medicine: applications of evolutionary biology for Solving problems and making a diagnosis works veterinarians. Canadian Vet J 43: 556-559 in reverse. You determine the facts (clinical signs or Bernstein WJ. The Delusion of Crowds: why people lesions) and from there identify the mechanisms to lead go mad in groups. Atlantic Monthly Press. 2021 back to the cause. There is a diagnostic process in this problem- solving and making a diagnosis. This includes: i. Signalment (age, species, breed, sex) ii. History of the disease including clinical signs. iii. Determine the organ system or systems involved. iv. Differential diagnosis list based on broad algorithm. v. Perform observations and tests to expand database. vi. Tentative diagnosis. vii. Begin treatment, prevention strategies as necessary. viii. Perform tests to confirm diagnosis or eliminate possibilities. ix. Final diagnosis. x. Appropriate treatment that is evidence-based. xi. Monitor outcome. An algorithm for diagnosis begins at the very highest point in decision-making with the broadest of categories. The majority of mistakes in diagnosis are made when the differential diagnosis list is too limited. This is known as “jumping to conclusions”. Humans are not rational beings, but they engage in rationalization. Confirmational bias is a constant companion and leads to many emotive mistakes.  PATH*3610 Principles of Disease Cellular Injury and Adaptation 9 2. GENERAL PATHOLOGY 3.2 CELLULAR INJURY, DEATH AND ADAPTATION, Homeostasis is a state where cells are able to b) defects in membrane permeability, cope with the physiological demands placed upon c) mitochondrial damage, them. Increased demand results in increased response d) the accumulation of free radicals such as - or adaptation. If the demand (or an insult) exceeds the reactive oxygen species (ROS) and reactive ability of the cell to adapt, injury occurs. We recognize nitrogen species (RNS), that cause defects in 3 responses to demand - adaptation, reversible injury, membranes and alter membrane and irreversible injury and cell death. These form a permeability. continuum, but for ease of understanding, we divide The formation of free radicals is a frequent and them into distinct phases. The worst insult for a cell common pathway of injury to cells. Free radicals are results in death. An ulcer, pus, and a burn are examples molecules that have an unpaired electron, and they release of cell death. considerable energy. The most common free radical is Cells die and shrink (single cell death, apoptotic derived from oxygen and is called oxygen derived free cell death), stay the same (coagulation) or swell radicals (ODFR). These prooxidants (ROS/RNS) induce (hydropic degeneration and oncotic cell death). oxidative stress. Free radicals are continuously being produced and removed. Free radicals are believed to play a CELL INJURY role in aging, interaction of the body with various There is a wide range of potential causes of cell chemicals, inflammation, microbial injury and irradiation. injury. They include Free radical damage occurs particularly to the lipids and the Oxygen deprivation. A reduction in the amount phospholipids of the cell membranes, to proteins, and of oxygen in tissue is called hypoxia. importantly to nucleic acids and nucleotides. Physical agents The body has scavengers that are designed to Chemical agents and drugs remove free radicals before they can produce severe damage. These free radical scavengers are molecules that Infectious agents neutralize free radicals. Antioxidants neutralize reactive Immunological reactions such as anaphylaxis oxygen species. There are many endogenous and natural Genetic derangements scavengers of free radicals including vitamin A, C and E, and Nutritional imbalances glutathione. It is suggested that aging results from a Aging (intrinsic cellular senescence). lifetime of formation of free radicals. Thus extrinsic The general biochemical mechanisms of cell stressors, such as free radicals, are believed to cause aging injury include by producing wear and tear. This is the basis for the anti- a) depletion of intracellular energy systems aging megavitamin supplementation with vitamin E and (ATP depletion), loss of calcium vitamin C especially. homeostasis (required for membrane Aging or cellular senescence is not just the result of transport mechanisms and enzyme a lifetime of wear and tear – it is multifactorial. Intrinsic activation),  PATH*3610 Principles of Disease Cellular Injury and Adaptation 10 cellular aging theories suggest there is a predetermined intact architecture or extracellular matrix (connective genetic program. Adult human fibroblasts in culture tissue scaffold) of the organ. Without a normal matrix, have a finite lifespan of 50 doublings whereas fibrous (scar) tissue forms in the organ. fibroblasts from neonates will go 65 doublings. When The size of an organ or tissue is dependent on the chromosomes replicate, they shorten. Telomeres are balance between proliferation, differentiation and cell loss nontranscribed sequences at the end of chromosomes including apoptosis. Increased proliferation or reduced that provide a buffer by shortening, instead of the apoptosis will result in an overall increase in the number of transcribed parts. With division, they shorten instead. cells. Stem cells, germ cells and cancer cells have an Proliferation and cell division is dependent on the abundance of telomerase that repairs shortened ability of a cell to enter the cell cycle. The 4 stages of the telomeres and renders the cells ‘immortal’. Some cell cycle are: nematodes have clock genes that are genetically set 1. G1 (presynthetic) clocks that control aging. Clock genes have not been 2. S (DNA synthesis) found in mammals (yet!). Potentially injurious 3. G2 (premitotic) situations are common and have several general 4. M (mitotic) components or underlying etiological mechanisms. Resting cells are in the G0 phase. When they enter These include intrinsic (genetic) factors and extrinsic the cell cycle they enter at the G1 stage. factors. The general groupings include hypoxia, physical Terminally differentiated cells are generally not agents and physical trauma, the effects of chemicals capable of division (are nondividing). They are also called and drugs, infectious agents, immunological reactions permanent cells. Permanent cells include neurons, the and nutritional imbalances. muscle cells of the heart (myocardiocytes; myocardium) and skeletal muscle. These cells have either no or ADAPTATION AND HEALING extremely low rates of replacement. They have left the cell Cells attempt to compensate for a change in cycle and do not reenter. demand. The response of a particular cell or tissue Continuously dividing tissues, also called labile cell depends on its inherent ability to cope with and types, have stem cells that proliferate and replace the respond to the demand. mature or terminally differentiated cells. These terminally Cells in a group of a similar type is a tissue. differentiated cells are short lived, and incapable of Organs are groups of different tissue types. Organs can replication. When stem cells divide, one cell replaces the usually regenerate if certain criteria are met – usually original and the other begins to differentiate and perform the primary tissue is capable of regeneration, and the the required function. Tissues with many stem cells include architecture of the organ is maintained after the injury. the epithelial cells of the skin, intestinal tract and Healing of an injury to an organ involves respiratory tract, and the cells of bone marrow and regeneration and fibrous tissue formation in variable lymphoid system. Dividing cells are prone to injury from amounts. radiation or antimitotic chemotherapy. Regeneration occurs when the injured Many organs are composed of cells that are cells are able to be replaced with cells of an identical or quiescent or stable cells that are present in a resting state, similar type. Fibrosis (scarring) is when the cells are and, when injured, have cells that are able to divide. These replaced with fibrous tissue. Regeneration requires an have adult stem cells that enter the cell cycle in sufficient  PATH*3610 Principles of Disease Cellular Injury and Adaptation 11 numbers to replace loss of cells with senescence. The Metaplasia is when, under sufficient demand liver, kidney, pancreas, mesenchymal cells such as usually chronic irritation, one cell type changes to another. fibroblasts and smooth muscle, vascular endothelial cells, and resting lymphocytes are good examples. Most mature tissues have a combination of terminally CELL DEGENERATION differentiated, quiescent and stem cells. Injury at the cellular level alters the function of Growth factors are low molecular weight individual cells. When a cell is injured and the response is proteins that stimulate cell proliferation and regulate negative, it degenerates. Degeneration is the result of an cellular differentiation. The growth factors include injurious process that results in impairment of cell function members of the following families: from which recovery can occur (reversible injury). epidermal growth factor (EGF), The most common manifestation of cell injury is cell transforming growth factor (TGF) β swelling. Most cells swell because they cannot control insulin like growth factor (IGF) entry or loss of water (hence the name hydropic granulin degeneration). This is usually because they lose the ability fibroblast growth factor (FGF) to maintain ions such as Na+ and K+ concentrations because platelet derived growth factors (PDGF), of membrane damage, loss of energy production, or a including PDGF itself and vascular endothelial failure of ion pumps. growth factor (VEGF) Those cells that are capable of processing fat can These various growth factors have major lose their ability to metabolize and transport fat. Fat roles in controlling cell proliferation and the cell cycle, accumulates and causes the cell to swell. Some rupture and and they are responsible for tightly regulating cell die. Fatty degeneration or fatty change is a manifestation proliferation and differentiation. There are both of this type of reversible injury. It occurs in those organs activators and inhibitors of each part of the cell cycle, where fat is metabolized – especially the liver. and these operate to stop the cycle at transition phases, especially between G1 and S phases. These are called CELL DEATH checkpoints. Cell death is the event or process by which cells Almost every cell in the body is capable of become dead. compensating for increased demand by increasing its The terminology of cell death is evolving and the size. Hypertrophy is an increase in cell size or tissue size material provided here may be different to what others because of an enlargement in the size of the cell or cells. have told you. This information is the latest and follows the The opposite to hypertrophy is atrophy. Nomenclature Committee for Cell Death 2018. In atrophy, a tissue or a cell reduces its size. In Cell death occurs when degeneration proceeds to an organ or tissue, this can be by a reduction of the the point where cell recovery cannot occur (irreversible number of cells or the size of cells. It is usually a injury). Cells are dead when they either exhibit irreversible response to decreased demand. plasma membrane permeability or have undergone Hyperplasia is an increase in the number of cells complete fragmentation. and it is a common response to increased demand of Cell Death is divided into 2 groups cells that are continuously dividing (labile).  PATH*3610 Principles of Disease Cellular Injury and Adaptation 12 1. Accidental Cell Death (ACD) is “instantaneous and Gangrenous necrosis is when there is coagulative catastrophic demise of cells exposed to severe necrosis that proceeds to liquid by bacterial action (moist insults of physical, chemical, or mechanical gangrene) or becomes dry and mummified following nature”. infarction, and gas gangrene when contaminating bacteria 2. Regulated Cell Death is when death occurs from cause necrosis and produce gas. activation of molecular machinery (subroutines) be they preprogrammed or not. There is a lethal 2. MICROSCOPIC DESCRIPTORS trigger. There may be intracellular or extracellular The histological appearance of dead cells alteration in microenvironment that are beyond (morphological descriptors) vary from apoptotic what adaptive mechanisms can cope or adjust to. morphology to necrotic morphology thus from when cells Physiological regulated cell death is programmed shrink (apoptosis), stay the same (coagulation), swell Cell Death, which is thus a subset of regulated cell (oncosis, necrosis, necroptosis) or develop cytoplasmic death. It occurs in embryological / post vacuolation (autophagy). embryological, physiological and homeostatic Apoptosis, autophagy and necrosis share situations (metamorphosis, cornification of skin), biochemical pathways, and represent a continuum – which process occurs is dependent on the insult and cell type and The terminology around the death of cells is physiological state, particularly in the level of intracellular quite confusing. The terms used to describe and ATP. communicate cell death are ever changing. Death by apoptosis Death by apoptosis is when cells undergo shrinkage. 1. MACROSCOPIC DESCRIPTORS It is a process where eventually there is activation of Initially, cell death was described according to caspase enzymes internally. the way it looked at a macroscopic or gross level. Cell Apoptotic cells have nuclear fragmentation, cellular death was called necrosis and dead tissue was necrotic shrinkage, fragmentation and engulfment by surrounding The tissue that is observed to be dead is said to be cells. necrotic. These appearances of necrosis include: Biochemically, apoptosis is the result of biochemical 1. coagulative pathways that involve caspase-induced destruction of 2. liquefactive proteins. 3. caseous Death by autophagy 4. gangrenous Autophagy occurs when parts of the cytoplasm and Coagulative necrosis is a morphological damaged organelles are bound by membranes to become descriptor to describe what happens when cells die and autophagosomes. These then fuse with lysosomes that remain the same size and have the characteristics of contain digestive enzymes. This occurs in a specific living cells (meat in the supermarket is dead, but looks sequence prior to the destruction of the nucleus. The the same as live muscle). cytoplasm of affected cells contain large vacuoles. Liquefactive necrosis is when the tissue is Death by swelling (oncotic cell death) rendered liquid by enzymatic dissolution. Prior to the discovery of apoptosis, it was assumed Caseous necrosis is when tissue partially that all cells die from a breakdown of cell functions, liquefies or was liquid and dehydrates. including the ability to maintain water (and ions). Cells that  PATH*3610 Principles of Disease Cellular Injury and Adaptation 13 die from cell swelling do so if the acute cell swelling they cut and lacerate the normal cytological structures. As (previously called hydropic degeneration) proceeds to the cells begin to thaw, the frozen cells with their disrupted the point of no return (becomes irreversible). membranes will break and undergo hydropic degeneration In oncotic cell death, the cells swell so they are because of the breeches in the cell membrane. In addition larger. The cell membranes including plasma or there is freezing of extracellular fluid so there are knives cytoplasmic membrane and that of the organelles break inside and outside the cells. down and become leaky. Enzymes from lysosomes leak The second cause of necrosis in frostbite is in the cell and degrade nuclear and cytoplasmic vasoconstriction and resultant ischemia. Blood vessels components. Cellular enzymes leak from the cytoplasm constrict as a direct response to cold. This results in a lack into the extracellular space and damage surrounding of blood flow (ischemia) and a reduction in oxygen tension tissues. It is this leakage of enzymes that allows the in the tissues (hypoxia). This then causes hypoxic injury to detection of tissue specific injury by using serum – the cells. When the tissues are warmed and there is reflow creatine kinase is released from damaged heart muscle of blood, reperfusion injury can occur. Reoxygenation and is used to detect necrosis of the heart muscle in a provides a substrate for the formation of ODFR. heart attack. Inflammation induced by damaged cells provides leukocytes that, themselves cause injury. 3. BIOCHEMICAL MANIFESTATIONS OF CELL DEATH FOR FURTHER READING Activation of regulated cell death is divided into Stanner SA, Hughes J, Kelly CNM and Buttriss J. initiation and execution phases. Initiation can be (2003). A review of the epidemiological evidence for the extracellular or external (extrinsic) or intracellular or ‘antioxidant hypothesis’. Public Health Nutrition 7 (3): 407- internal (intrinsic) to the cell. Regardless of the initiating 422. event, each process is stereotyped. The processes Galluzzi L, Vitale I, et al. (2012) Molecular definitions involved are many and have names like intrinsic of cell death subroutines: recommendations of the apoptosis, extrinsic apoptosis, mitochondrial Nomenclature Committee on Cell Death 2012. Cell Death permability transition driven necrosis, necroptosis, and Differentiation 2012, 19: 107–120; ferroptosis, pyroptosis, parthanatosis, entotic cell Galluzzia L, Kepp O, Krautwald S, Kroemer G, death, NETotic cell death, lysosomal dependent cell Linkermann A. Molecular mechanisms of regulated death, autophagy dependent cell death, and necrosis. Sem Cell Develop Biol 2014; 35: 24-32. immunogenic cell death! Galluzzi L, Bravo-San Pedro JM, Vitale I, et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. FOCUS ON DISEASE 2015; 22: 58-73. We have all heard of frostbite. Frostbite involves Galluzzi L, Vitale I et al. Molecular mechanisms of several processes. One process is the freezing of tissues. cell death: recommendations of the Nomenclature Tissues can freeze and still remain viable, but in Committee on Cell Death 2018. Cell Death and frostbite, the freezing usually occurs relatively slowly Differentiation 2018; 25: 486-541 and large ice crystals form within the cells. These ice Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della- crystals have the same effect as a series of knives, and Morte D, Gargiulo G, Testa G, Cacciatore F, Bonaduce D,  PATH*3610 Principles of Disease Cellular Injury and Adaptation 14 Abete P. Oxidative stress, aging, and diseases. Clin Interv Aging. 2018; 13: 757-772. Santagostino SF, Assenmacher CA, Tarrant JC, Adedeji AO, Radaelli E. Mechanisms of Regulated Cell Death: Current Perspectives. Vet Pathol. 2021; 58: 596- 623. Shimokawa I. Mechanisms underlying retardation of aging by dietary energy restriction. Pathol Int. 2023; 73) :579-592. Vitale I, Pietrocola F, et al 2023. Apoptotic cell death in disease - Current understanding of the NCCD 2023. Cell Death Differ. 2023 May;30(5):1097-1154. 2.1 CIRCULATORY DISTURBANCES One of the most important differentiating factors extravascular space. For the purposes of this discussion, we between various types of organisms is the ability to will consider endothelium as a passive and semipermeable maintain a vascular system. The vascular system is a membrane. We will learn in further chapters that the transportation system for cells, nutrients, and wastes, endothelium is far from passive. and it is important in maintaining a normal fluid and Starling’s forces determine the movement of fluid in electrolyte balance. the capillary bed. Starling was a scientist who identified a The fluid in the vascular system of mammals is number of counteracting forces responsible for maintaining Capillary Arteriole Venule blood. The main components of blood are normal blood and tissue fluids. Blood is pumped through the 1. Red blood cells arteries and arterioles under high pressure. Blood pressure is 2. White blood cells created by elastic and muscular forces exerted by the vessel 3. Platelets wall (peripheral resistance) and the heart (cardiac output) 4. Plasma such that blood pressure equals peripheral resistance times Plasma is composed of fluid, proteins, cardiac output. Blood pressure is highest in the arteries. electrolytes and many other substances. The plasma Arteries divide into smaller vessels until the capillary bed is proteins are albumin, clotting proteins and the reached. The capillary bed is the transfer site where there is globulins. The globulins include immunoglobulins. usually a single layer of endothelium separating blood from The vascular system is composed of a central tissue. At the entrance to the capillary bed is the arteriole and pump, the heart, and a system of roads and freeways its vascular tone ensures that pressure is regulated within the that include the arteries and arterioles, and the vascular capillary bed. Excessive pressure would damage the capillary bed near each cell. It is this last area, the capillary bed bed and tissues, so the arteriole has a ‘gate keeper’ function. that is the focus of our attention in this chapter. It is so effective that it is virtually impossible for increased Capillaries are composed of endothelial cells that form a blood pressure to damage a capillary bed or to alter barrier between the intravascular space and the haemodynamic forces. Capillary blood pressure is low, but  PATH*3610 Principles of Disease Circulatory Disturbances 17 must be maintained in a narrow range to ensure a net Edema is an excessive amount of fluid in a tissue movement of fluid from the blood vasculature into the (interstitial or extracellular space) or a body cavity or space. tissue. As blood flows through the capillary, the Another name for excess fluid in a body cavity is effusion. movement of fluid into the extracellular compartment Edema forms when more fluid enters the interstitial space around tissue cells will increase the oncotic pressure between the cells than is being removed. within the blood vascular system. Proteins such as albumin and a variety of other substances create this The usual mechanisms and causes of edema are oncotic pressure. As blood moves from arterial to a. Increased venous hydrostatic pressure venous side, the hydrostatic pressure is overcome by the (postural edema and heart failure draw of oncotic pressure. This relative increase in b. Reduced intravascular oncotic pressure oncotic pressure results in a net flow of water back into (hypoproteinaemia) the vascular system. This ensures a continuous c. Increased endothelial permeability movement of fluid through and flushing of the (inflammation) extravascular space. Excessive fluid in the extravascular d. Lymphatic obstruction (lymph node space is removed by a specialized vascular system called removal) the lymphatic system. e. Increased total body water/sodium retention (menses, renal failure) Lymphatic Extravascular space Hydrostatic Pressure Hydrostatic Pressure Intravascular Oncotic r space Pressure Oncotic pressure Endothelium Arteriole Venule For ease of understanding, edema is divided into EDEMA inflammatory edema and noninflammatory edema. Sixty percent of the body is water. Two thirds is Inflammatory edema (edema of inflammation) is the intracellular and one third is extracellular. Seven percent most common cause of edema and it is mostly the result of is blood and the rest of the extracellular fluid is altered permeability of the endothelium. Direct damage to the interstitial fluid (around the cells outside the blood endothelium, as in burns, increases permeability. vessels). Noninflammatory edema occurs when there are alterations to the forces at the venous end of the capillary,  PATH*3610 Principles of Disease Circulatory Disturbances 18 either with a reduction in oncotic pressure or an of the legs. In either of these two cases, the tissues drained by increase in venous hydrostatic pressure. Examples of an obstructed lymphatic vessel develop edema. noninflammatory edema include ascites (excessive fluid in the abdominal cavity), hydropericardium (excessive CHANGES IN BLOOD FLOW fluid within the pericardial sac), hydrothorax (excessive Another major alteration in circulation is an excessive fluid within the thorax) and peripheral edema which are amount of blood within capillaries. Hyperaemia is an active excessive of fluid within the extravascular space of process where the arteriole opens to allow a greater amount peripheral tissues that is the feet, hands, and other of blood into the capillary beds of a tissue. Nerves or chemicals external appendages. (chemokines) cause the sphincter to open, usually in response In people, edema is often caused by increased to an injury or some other stimulus. A good example of hydrostatic pressure on the venous side either by hyperaemia is blushing. Congestion is a passive process where venous obstruction by postural causes or heart failure. blood builds up in capillaries and is usually caused by Failure of flow back to the heart and increased venous obstruction of veins. pressure is the usual cause for postural edema such as Reduced blood in capillaries is ischaemia. Ischaemia one sees in people as they disembark from literally means ‘to keep back blood’ or ‘the stopping of blood’. intercontinental flights. Ischemia is often the result of vasoconstriction. Reduced Another major cause of edema is blood flow in a tissue frequently results in hypoxia. Hypoxia is hypoproteinemia, a reduced amount of protein (usually a reduction of oxygen tension. Hypoxemia is a reduction of albumin) in the blood. With hypoalbuminaemia, oncotic oxygen tension in the blood. Infarction is when tissue dies pressure in the intravascular space is reduced and there because of ischemia. Tissues affected usually have an is less attraction for fluid to re-enter the blood vascular endartery system of blood flow – they have no collateral system. Children that are severely malnourished are circulation. Brain, heart and kidney are the major ones organs hypoproteinaemic and may have a ‘pot belly’ (ascites) with this type of circulation. Infarction can be the result of and peripheral edema. The condition is called obstruction of an artery (arterial infarct) such as occurs in a kwashiorkor. Other causes of hypoproteinemia include heart attack (myocardial infarction). Obstruction of a vein can protein loosing renal and intestinal disease. reduce the flow of blood, and, although there is a large pooling Another common cause for edema is sodium and of blood or congestion, hypoxia, and necrosis of the tissue water retention. This occurs in people with renal occurs. Torsion or twisting of the intestines is a good example disease and frequently with women of child bearing age of a venous infarct. where hormonal changes (aldosterone) associated with menstruation results in the retention of sodium, HAEMORRHAGE increase in total extracellular fluid of the body, and the Haemorrhage is a very dramatic vascular disturbance. so called bloated feeling and appearance. Haemorrhage means release of blood or red blood cells from The final cause of edema seen in people is the vascular system. We recognize several different types lymphatic obstruction. Lymphatic obstruction occurs depending on the size and degree of haemorrhage. when a lymph node is removed in the staging of cancer, A major division is between external and internal and the lymphatic vessel is therefore obstructed. Less haemorrhage. commonly these days is the disease called elephantiasis. It is caused by a parasite that lives within the lymphatics  PATH*3610 Principles of Disease Circulatory Disturbances 19 a. External haemorrhage is visible outside the Platelets are cell membrane bound fragments of the body or within the stomach and intestines. cytoplasm of megakaryocytes of the bone marrow. They b. Internal haemorrhage is into body cavities or circulate in the blood stream in high numbers. There are into tissues. usually more than one hundred and fifty thousand per mL. Internal haemorrhage into tissues will form Platelets recognize breaches in the endothelial layer, adhere a. a haematoma to collagen and extracellular matrix, secrete substances such b. an ecchymosis as thromboxane that further stimulate platelet function, and c. petechia. they aggregate to form a temporary or primary plug. A haematoma is a swelling (-oma) of blood. It is Aggregation is facilitated by the plasma protein fibrinogen. A the largest. The smallest perceivable haemorrhage into deficiency of platelets usually manifests itself by petechial tissue is petechia and these are pinpoint haemorrhages. haemorrhages. Ecchymosis is a variant in between petechia and Coagulation proteins are found in the blood and are haematoma. Ecchymosis is a group of petechia that most are produced in the liver. They form a coagulation appear as though blood was wiped on the tissue with a cascade. These proteins circulate in an inactive form and are paintbrush - they are often also called paintbrush usually activated at a phospholipid surface. Such a surface is haemorrhages. usually the platelet cell membrane, thus platelets and the coagulation proteins interact closely. The inactive proteins of HAEMOSTASIS the coagulation cascade are activated to form an active It is normal for blood to clot and clotting is the enzyme that acts on the next member of the system as result of a variety of interactions involving proteins and outlined in the figure below. Calcium is an essential cellular components within the blood. A blood clot is a component in haemostasis and some anticoagulants bind very general term for the coagulation of blood. A calcium. A deficiency of factors in the coagulation cascade can thrombus is a blood clot that develops within the vessels of a living organism. The clot that forms in vessels after death is called the postmortem clot. Coagulation Cascade Haemostasis or the stopping of haemorrhage is a Intrinsic Extrinsic normal function of the blood. The three major components to haemostasis are XII XIIa Tissue Damage a. endothelial cells XI XIa Tissue Factor b. platelets IX IXa VIIa VII c. coagulation proteins. VIIIa PF3 Endothelial cells are very active in haemostasis. X Xa They are normally anticoagulative. When endothelial PF3 Prothrombin Thrombin cells are damaged, they become procoagulative and this is a responsive mechanism to ensure that any breach of Fibrinogen Fibrin the endothelium is dealt with very quickly so there is a minimal loss of blood. When damaged endothelial cells release tissue factor (thromboplastin or Factor III) which is the major procoagulative factor.  PATH*3610 Principles of Disease Circulatory Disturbances 20 cause prolonged bleeding including nose bleeds and Endothelial injury, such as occur with atherosclerosis hematoma formation. or trauma, induces the endothelium to become procoagulant. Normal haemostasis at a site of vascular Tissue factor and Factor VII combine to initiate coagulation. injury follows a stereotyped pattern. There is usually an Altered blood flow can induce the formation of initial vasoconstriction induced by a local nerve reflex thrombi. Stagnation of blood, especially in the legs of people and augmented by chemical vasoconstrictors such as after surgery, allows anticoagulant substances normally in the endothelin. Platelets adhere to exposed extracellular blood to be exhausted. Without continuous resupply, thrombi matrix, undergo a shape change and recruit other may form. Turbulence, as may occur around defective heart platelets to form a primary plug. Tissue factor released valves, is a common site for thrombi to form. from endothelial cells activates the coagulation cascade Hypercoagulability is where the blood becomes to produce a fibrin mesh that forms a secondary plug. increasingly susceptible to coagulation. They include exposure Platelets and fibrin combine to form a permanent plug. to smoke, obesity, travelling or sitting for long periods, Regulatory factors, including fibrinolytic enzymes, suffering from chronic diseases, having major surgery or injury ensure the plug does not expand to form a large and suffering from some forms of cancer. thrombus. The ultimate expression of thrombogenesis is a condition of hypercoagulability where there are widespread THROMBOGENESIS (disseminated) thrombi (intravascular coagulation) that is Thrombogenesis is the process whereby blood commonly called disseminated intravascular coagulation clots are formed. There are several situations where (DIC). While there are multiple thrombi and infarcts, thrombogenesis commonly occurs: paradoxically, coagulation factors and platelets are consumed a. endothelial injury and this results in haemorrhage. b. altered blood flow EMBOLISM c. hypercoagulable states Embolism is a general term to denote a clustering or aggregation of a substance within the blood stream. Emboli can be thrombi (thrombotic emboli). Other emboli include Circulating platelets bubbles of gas (the bends), air, bone marrow (a complication Collagen Platelet granules of a fracture), or clusters of neoplastic cells. Pulmonary Adhesion Endothelium embolism, a form of venous thromboembolism, is common in Release reaction people. It usually occurs after deep vein thrombosis of the Collagen Release reaction legs. ADP, thromboxane A2 SHOCK Aggregation Shock is a circulatory disturbance that is a widespread PF-3 hypoperfusion of tissues resulting from reduced cardiac Clotting Thrombin output and or reduced effective circulating blood volume. Fibrin Shock can be divided into Platelet/fibrin plug PATH*3610 Principles of Disease Circulatory Disturbances 21 1) Cardiogenic shock. There is failure of the heart to pump blood. This reduces blood pressure and reduces tissue perfusion. 2) Hypovolaemic shock. There is inadequate blood from hemorrhage, or reduced plasma volume from dehydration, 3) Blood maldistribution. There is reduced peripheral vascular resistance and pooling of blood in the peripheral circulation due to neural or cytokine induced vasodilation. Causes include 4) Neurogenic shock, which is from trauma including spinal cord injury, nontraumatic hypotension from acute stress response. 5) Anaphylactic shock, which is from systemic hypersensitivity reaction 6) Septic shock, which is part of the systemic reaction to inflammation and excessive vascular and inflammatory mediators. 2.2 IMMUNOLOGY 2. soluble/chemical – enzymes (lysozyme) peptides INTRODUCTION TO THE IMMUNE SYSTEM (lactoferrin, defensins), cytokines (interferon  or ), To maintain a state of health in the body, a protein cascades (complement [lectin and alternative number of mechanisms have developed to prevent the pathway], coagulation) entry or persistence of foreign material and to ensure 3. biological – commensal flora removal of altered or damaged cells. Together these 4. cellular - phagocytes = 30-50% of circulating white cells constitute the immune system. (Latin immunitas = Neutrophil (aka polymorphonuclear granulocyte, freedom from). The general term for foreign material PMN) short-lived, rapidly mobilized (