Pathophysiology Chapter 1: Introduction to Pathophysiology Framework for Pathophysiology - Etiology: study of causes or reasons for phenomena • Identifying causal factors that provoke a particular disease or injury, usually multifactorial - Idiopathic: cause is unknown - Iatrogenic: unintended cause is a result of a medical treatment • Risk factor: when link between an etiologic factor and development of a disease is less than certain, but the - - - 1 probability is increased when factor is present • Etiological classification of diseases: congenital/birth defects, degenerative, iatrogenic, idiopathic, immunologic, infectious, inherited, metabolic, neoplastic, nutritional deficiency, physical agent-induced, psychogenic. Pathogenesis: development or evolution of a disease from the initial stimulus to the ultimate expression of the manifestations of the disease; understood on the cellular level • Physiologic events that occurs in response to etiologic agent is interplay of changes in cell, tissue, organs, and systemic functions • Pathologic disruptions in cellular behavior lead to changes in organ and system function that may be detected by clinical or laboratory examination. • Pathogenesis is a description of how etiologic factors are thought to alter physiologic function and lead to the development of clinical manifestations that are observed in a particular disorder or disease Clinical Manifestations: signs of disease (objective) • Symptoms are subjective reported by affected individual • Syndrome: when etiology of a particular set of signs and symptoms has not yet been determined • Stages and Clinical Course: - The interval between exposure of a tissue to an injurious agent and the first appearance of signs and symptoms may be called a latent period or, in the case of infectious diseases, an incubation period. - The prodromal period, or prodrome, refers to the appearance of the first signs and symptoms indicating the onset of a disease. • Nonspecific - Manifest illness/acute phase: disease reaches its full intensity, and signs and symptoms attain greatest severity - Subclinical stage: patient functions normally, although disease processes are well established - Exacerbation or remission (more than 5 years—>cured) - Convalescence: stage of recovering after a disease, injury, or surgical operation Treatment Implications: understanding etiology, pathogenesis, and clinical consequences of a particular disorder suggest, or imply, that the certain treatments could be helpful Summary • Pathophysiology includes four interrelated topics: etiology, pathogenesis, clinical manifestations, and treatment implications. • Etiology refers to study of the proposed cause or causes of a particular disease process. Etiology is a complex notion because most diseases are multifactorial, resulting from interplay between genetic constitution and environmental influences. • • • Pathophysiology Pathogenesis refers to the proposed mechanisms whereby an etiologic stimulus leads to typically observed clinical manifestations. Pathogenesis describes the direct effects of the initiating event, as well as the usual physiologic responses and compensatory mechanisms. Clinical manifestations describe the signs and symptoms that typically accompany a particular pathophysiologic process. Manifestations may vary depending on the stage of the disorder, individual variation, and acuity or chronicity. An understanding of the etiology, pathogenesis, and clinical manifestations of a particular disorder leads to a diagnosis, which suggests that certain treatments may be helpful. Concepts of Normality in Health and Disease • Values occur within a range • Validity/accuracy: degree to which a measurement reflects the TRUE value of the object it is intended to • • measure Reliability/precision: ability of a test to give the same result in repeated measurements Sensitivity/specificity: measures of how well a given test can discriminate between persons with and without a given condition - Sensitivity: probability a test will be positive when applied to a person with the condition • False negative - Specificity: probably that a test will be negative when applied to a person who does not have a given condition • False positive Patterns of Disease in Populations - Concepts of Epidemiology • Endemic: a disease that is native to a local region • Epidemic: the disease is disseminated to many individuals at the same time • Pandemics: affects large geographic regions, spreading worldwide and resulting in millions of deaths - Aggregate Factors • Age - Development processes occur during early years of life - Aging processes occur > 60y.o. • Gerontology - Immune, cardiac, respiratory, musculoskeletal, neurologic, special sensory, endocrine, • • 2 gastrointestinal, and integumentary systems Ethnic group - Medical anthropology: studies racial and ethnic group variation in disease states Gender - Women more likely to get: Alzheimers, pyelonephritis, systemic lupus erythematosus, toxic goiter, hypothyroidism, rheumatoid arthritis. - Men: atherosclerosis, thromboangiitis obliterans • Socioeconomic factors and lifestyle considerations - Poverty, malnutrition, overcrowding, exposure to adverse environmental conditions • Geographic location Pathophysiology - Levels of Prevention • WHO defines health as complete physical, mental, and social well-being and not merely the absence of • • • disease or infirmity. Primary Prevention - Altering susceptibility or reducing exposure for susceptible individuals - Education and prevention - Vaccinations Secondary Prevention - Early detection, screening, and management of the disease - Annual physical examinations and routine screening - Like Pap smears - Amniocentesis: removing small amount of fluid from amniotic sac that surrounds fetus and analyzing the cells and chemicals in the fluid • Blood samples can also be obtained Tertiary Prevention - Rehabilitative and supportive care and attempts to alleviate disability and restore effective functioning - Physical therapy, pharmacotherapy, psychotherapy, radiation therapy, chemotherapy, immunotherapy, experimental gene therapy, surgical. Chapter 2: Homeostasis, Allostasis, and Adaptive Responses to Stressors Homeostasis and Allostasis - Homeostasis: Maintaining internal conditions in a stable state by keeping parameters relatively the same - Homeo - similar - Stasis - standing sill • State of being in which all systems are in balance around a fairly narrow ideal set point • Tendency to stabilize an organism’s functional systems, despite changes both internally and externally • Claude Bernard: French physiologist - Milieu intérieur • Walter B. Cannon: process in which each of the boy’s biochemical or physiologic variables was maintained • 3 within a narrow set-point range - Negative feedback loops sense and correct deviations from set-point ranges for variables, supporting survival of the individual despite threats from external or internal environments. Examples of Homeostatic Systems - Baroreceptor response to acute changes in blood pressure - Vasopressin/antidiuretic hormone release from the posterior pituitary in response to changes in serum osmolality - Pathophysiology - Hypothalamic-mediated responses to changes in body core temperature Central chemoreceptor responses to changes in partial pressure of carbon dioxide (PaCO2 ) - Parathyroid gland response to changes in serum calcium level Allostasis: ability to successfully adapt to challenges - Allo - variable or different - Stasis - standing still • To survive, an organism must vary all the parameters of its internal milieu and match them appropriately to environmental demands • Involves intricate regulatory processes orchestrated by the brain • Sterling and Eyer Stress as a Concept • Stress: physical, chemical, or emotional factors that produce tension in the body or the mind - Real or perceived threat to the balance of homeostasis • Seyle’s General Adaptation Syndrome (GAS): alarm reaction, state of resistance, and a stage of exhaustion - When stress is generated by extreme psychological or environmental demands, balance is disrupted, and 4 allostatic reactions are initiated to restore balance The General Adaptation Syndrome and Allostasis (GAS) Pathophysiology • Alarm Stage: Fight or flight response - Surge of energy and physical alterations to either evade or confront danger - Hypothalamus, which monitors internal and external environment, senses a need to activate GAS in response to a stimulus, a stressor placing the balance of homeostasis at risk - Hypothalamus then releases —> corticotropin-releasing hormone (CRH) to activate —> sympathetic - 5 nervous system (SNS) which stimulates —>adrenal medulla to release —>catecholamines norepinephrine and epinephrine (aka adrenaline) • Part of sympathetic adrenal medullary system aka fight or flight response • Paraventricular nucleus (PVN) in hypothalamus secretes CRH to stimulate anterior pituitary gland to release adrenocorticotropic hormone (ACTH) —> causes adrenal cortex to release substantial amounts of glucocorticoids, cortisol specifically, eliciting diverse responses - Hypothalamic pituitary adrenal axis (HPA) - Once pituitary gland is activated, alarm stage processes to the stage of resistance - Allostasis is activation of these stress responses to evoke changes that return organism to homeostasis - *Can’t stay in this state or may become subject to permanent damage and even death • Resistance or Adaptation Stage - This is supportive of the allostatic return to a state of homeostasis - SNS and adrenal medulla and cortex are functioning at full force to mobilize resources to manage the stressor • Resources: glucose, free fatty acids, amino acids—>elevated through glucocorticoids, mainly cortisol, and catecholamines like epinephrine and norepinephrine - Fuel for metabolically active organs like the brain and heart during stress - Also functions as building blocks, especially amino acids, for later growth and repair of the organism after stress abates - If stressor is resolved, organism returns to steady-state—>allostatic balance • *Also possible that organism functions at new baseline steady-state • Exhaustion Stage - When body is no longer able to return to homeostasis after prolonged exposure to noxious agents - Exhaustion and stress-related disease do not necessarily occur because resources are depleted; they can occur because the actual stress response itself can be harmful when repeatedly activated. - Accumulation of various mediators produced by the systems is damaging to tissues over time —> allostatic load (wear and tear on body and brain). - Toxic stress: something bad happens and person lacks sufficient resources and control to manage the situation Stressors, Sex, and Developmental Influences, and Risk Factors • Common general stressors are physical, chemical, biological, social, cultural, or psychological • HPA axis is prominent and dysregulated in cases of depression and PTSD and when a person’s sense of self is negatively evaluated or the person lacks of sense of control • Sympathetic system is particularly active with anxiety and vigilant states • Study between men and women shows that there was an increase in epinephrine release in men compared to women in stressful situations - May be due to effects of sex hormones on stress response • • Pathophysiology Women have estradiol and estrogen which may account for sex differences since onset of affective mood disorders declines and is more similar to men after menopause - Estradiol may heighten stress reactivity, whereas testosterone suppress HPA axis activity. Children exposed to physical and/or psychosocial maltreatment have been shown to have smaller cortices in the prefrontal region of the brain, reduced hippocampal volume, altered cortisol levels, and elevated levels of inflammation in comparison with other children. Neurohormonal Mediators of Stress and Adaptation • In cases of allostatic overload, pathologies of a physiologic, psychological, or behavioral nature may result. - Catecholamines: Norepinephrine and Epinephrine • Body’s response to threats resulted in activation of adrenal medulla and SNS —> release of catecholamine • • • • 6 neurotransmitters —> sympathico-adrenal system aka fight or flight reaction Activation of hypothalamus gland —>cerebral cortex and limbic system (incl. hippocampus and amygdala) receive info regarding stresses and determine whether something is harmful to the organism - Send info to hypothalamus which prompts release of norepinephrine from the sympathetic branch of the autonomic nervous system ANS and locus cerulean (neurons in brainstem pons) and epinephrine, and some norepinephrine from adrenal medulla - Norepinephrine is released by sympathetic neurons directly into synaptic clefts near effector organs and tissues - Preganglionic fibers from SNS neurons synapse at adrenal medulla, stimulating the release of epinephrine and some norepinephrine - Adrenal catecholamines released into bloodstream and travel to effectors organs and tissues • Same effects as sympathetic nerve stimulation and are seen as extension of SNS - Cold temps—>SNS responds with norepinephrine production - Emotional distress or acute hypoglycemia—>adrenal medulla which increases epinephrine production EFFECTS: - Cardiovascular function - Fluid volume by activating renin-angiotensin-aldosterone mechanism - Role in inflammation and immunity - Affect metabolism - Associated with attentiveness, arousal, memory formation in CNS - Exert immune system effects by influencing the production of cytokines by immune and adipose cells Norepinephrine - Constricts smooth muscle in blood vessels and regulates blood flow through tissues and distribution through organs - Maintenance of blood pressure - Reduces gastric secretion - Inhibits insulin secretion - Innervates the iris and ciliary muscles of the eyes—>dilate pupils and increase night and far vision Epinephrine - 7 Pathophysiology - Enhances myocardial contractility and increases heart rate and venous return to the heart—>increasing cardiac output - Relaxes bronchial smooth muscle and dilates airways to enable better oxygenation - Increases glycogenolysis—>release of glucose from the liver, inhibits insulin secretion thereby elevating blood glucose levels • In the brain: the increase blood flow and availability of glucose lead to augmentations in mental attention and alertness • Catecholamines contribute to the development of atherosclerosis and hypertension, and also increase the risk of developing cardiac dysrhythmias and sudden cardiac death, and even stress-induced cardiomyopathy. - They increase platelet activity, resulting in clot formation, and elevate serum lipid levels, significant factors in the pathogenesis of myocardial infarction and stroke. Adrenocortical Steroids: Cortisol and Aldosterone • EFFECTS - Regulatory role in maintaining fluid volume, metabolism, immunity, inflammatory responses, and brain function - Lipid soluble hormones—>able to pass through cell membranes to bind with receptors in cytosol or nucleus and initiate change in cellular activities. - Every body tissue has intracellular glucocorticoid receptors - Onset of effects is slower, but duration of action is longer - GLUCOSE METABOLISM - Primary glucocorticoid, cortisol, is secreted by adrenal cortex in response to ACTH from anterior pituitary - Release of ACTH is affected by another releasing hormone, CRH, from hypothalamus - Negative feedback looks maintain cortisol level WNL • Cortisol binds to receptors on hypothalamus and anterior pituitary gland to suppress CRH and ACTH release in a negative feedback loop - Actions of HPA axis and catecholamines May synergies or antagonize each other • Catecholamines facilitate release of ACTH which help maintain the function of HPA axis and release of cortisol • Glucocorticoids promote adrenal medulla synthesis of epinephrine through control of major enzyme phenylethanolamine N-methyltransferase (PNMT) • Glucocorticoids support actions of the catecholamines in maintenance of normal BP an cardiac output • In skeletal muscle, catecholamines antagonize the catabolic glucocorticoid effects by impeding breakdown of somatic protein. • Catecholamines and glucocorticoids facilitate the brain’s development of memory • METABOLIC EFFECTS - Affects protein metabolism • Anabolic effect leading to increased rates or protein synthesis in the liver • Catabolic effect in muscle, lymphoid, and adipose tissues and on skin and bone - Protein breakdown produced increased levels of circulating aminos acids—> availability for liver - 8 Pathophysiology - Cortisol stimulate gluconeogenesis in the liver and a sixfold to tenfold increase in rate of amino acid conversion to ketoacids and glucose. - Catabolism of adipose tissue releases free fatty acids and glycerol that can be used for gluconeogenesis to create ketoacids for fuel • Gluconeogenesis ensures adequate supply of glucose for body tissues in general, but nerve cells have priority - Cortisol may act to preserve available glucose for grain nerve cells by limiting uptake and oxidation of glucose by other cells in the body - Cortisol promotes appetite and food-seeking behaviors • IMMUNE EFFECTS - Suppress acute-phase response to infection and inflammation, which helps curtail over activity • Inhibits production of select immune cytokines (signaling molecules), by increase in production of other cytokines, and sometimes by directly inhibiting proliferation and activation of specific immune system cells - Acute stress of tissue injury or infection occurs, release of glucocorticoids and catecholamines assist movement of necessary immune cells to affected location - Chronic stress involves chronic elevated levels of glucocorticoids, desensitization and down-regulation of glucocorticoid receptors (glucocorticoid receptor resistance) May occur on some immune cells— >fewer anti-inflammatory effects overtime. • Aldosterone - Primary mineralocorticoid steroid hormone secreted by the adrenal cortex - Stimulation of SNS activates renin-angiotensin system, and release of aldosterone is final chemical outcome - Specific stressor of fluid volume depletion activates release of renin, similarly initiating reninangiotensin system - PRIMARY effect of aldosterone once bound to receptors in kidneys’ distal tubules and collecting ducts —>reabsorption of sodium and increase in excretion of potassium. • Water follows sodium • Increases ECF volume and increases blood pressure • Greatest effect on circulating volume is through aldosterone, although endogenous glucocorticoids have a small amount of mineralocorticoid effect • Angiotensin II, whose formation stimulates aldosterone release, is potent vasoconstrictor • Provides support for catecholamines-induced increase in BP Endorphins, Enkephalins, and Immune Cytokines • Stress naturally activates inhibition of pain through release of small peptides—>endorphins and enkephalins • Endorphins and enkephalins are endogenous opioids produced within the CNS and released in response to stressors, exercise, certain foods (chocolate), laughter, and from massage or acupuncture - *Endogenous: substances and process that originate form within a living organism, tissue, or cell - Endorphins, like drug morphine, raise pain threshold (reduces pain) and produces sedation and euphoria • During acute stress, may activate SNS by CRH - - 9 Pathophysiology - Immune cells (B and T lymphocytes, granulocytes, macrophages, and monocytes) produce types of endorphins that are released in response to stressors, CRH, anti-inflammatory cytokines, and catecholamines - Opioid receptors identified on immune cells, when activated they modulate immune cell proliferation and immune cell activity • Acute or chronic stress, activated immune cells (mast cells, neutrophils, macrophages, and T lymphocytes) can release pro inflammatory cytokines that enhance pain - Pain is a classic manifestation of the inflammatory response • CNS and PNS and immune system maintain complex patterns of interactions with pain pathways as part of allostatic mechanism to return to homeostasis - Interleukin-1 (IL-1) a cytokine secreted by macrophages and other immune cells • Capable of affecting production of CRH by hypothalamus • Leukocytes are capable of producing other hormones like ACTH involved in signaling system. - Disruption of microbiome is associated with disease like multiple sclerosis, diabetes, rheumatoid arthritis, etc Sex Hormones: Estrogen, Testosterone, and Dehydroepiandrosterone • Cortisol inhibits effects on female reproductive system by suppressing release of gonadotropin-releasing hormone, luteinizing hormone, estradiol, and progesterone - Estradiol normally down-regulates glucocorticoid receptor binding in the brain and alters regulatory feedback control • Androgens, like testosterone and dehydroepiandrosterone (DHEA) may inhibit effects of glucocorticoids - Androgens oppose catabolic effects of glucocorticoids on bone and impact of glucocorticoids o lymphoid tissues, inflammatory cytokines, and leukocytes - DHEA interacts with numerous neurotransmitters in the brain, counteracting depressive tendencies often noted with glucocorticoids - Testosterone has antidepressant and anti anxiety effects as it elevates mood • Reduced circulation when stressful stimuli, like illness, surgery, strenuous physical exercise, and stressful academic programs • In combo with vasopressin hormone, testosterone enhances blood pressure and heart rate reactivity and augments fight or flight response - On the other hand, in combo with oxytocin (impact modulated by estrogen) and endogenous opioids are thought to produce calming effect during times of stress—> women have a tend and befriend response rather than fight or flight response Growth Hormone, Prolactin, and Oxytocin • Somatotropin is released from anterior pituitary gland and affects protein, lipid and carbohydrate metabolism. • Effects: - Anabolic effects, increasing protein synthesis, and bone and muscle mass growth. - Increases fat metabolization (lipolysis) while decreasing rate of carbohydrate utilization by peripheral tissues - Usually secreted in a cyclic basal pattern, primarily at night, and changes with developmental stage. • Highest during adolescence and gradually declines during adulthood • • • Pathophysiology • Serum levels of growth hormone increase acutely after a variety of intensely stressful physical or psychological stimuli, like strenuous exercise or extreme fear • …Though continued activation of stress response eventually results in decreased secretion of growth hormone—>stunted growth in children - Enhances immune function Prolactin is similar in structure to growth hormone and is secreted from the anterior pituitary gland in response to stress, inflammation, sexual activity, pregnancy, and suckling (even in men) and breast feeding. It suppresses ovulation and has roles in lactation, metabolism, hair growth, and bone homeostasis. - Lymphocytes have prolactin receptors—>prolactin in immune regulation - May have neuroprotective effects, preventing loss of neurons in the hippocampus due to stress - Significant increase in level of growth hormone or prolactin requires more intense stimuli than stress that increases concentrations of catecholamines and glucocorticoids Oxytocin - Produced during childbirth, lactation, sexual behavior (in both sexes) and has been associated with promoting bonding and social attachment - Moderate stress response and have calming effect, with reductions in HPA and sympathetic activation and reduced perceived anxiety. - Oxytocin may have analgesic effects - Synthesized by the hypothalamus and secreted by the posterior pituitary gland and other brain regions - Stronger effects in females in comparison to males b/c of interaction of estrogen and oxytocin In some cases, these stress-related hormones have similar and synergistic effects and in others they work in opposition. This state of counterbalancing helps to facilitate allostasis, ideally returning the human organism back toward homeostasis. Adaptation, Coping, and Illness • Allostasis may be seen as the beginning to some degree of the alarm stage (fight or flight activation) • Seyle’s “disease of adaptation” are outcomes of allostatic overload - Adaptation, Coping, and Resilience • Adaptation refers to bio psychosocial process of adjusting physiology, morphology, and behavior in • 10 response to new or altered circumstances, Intel and external in origin, in the physical and social environment Resilience: ability to achieve a successful outcome in the face of adversity and stress - Measure of capacity to adapt to challenges - Capacity to adapt to stressful and adverse events, preventing development of disease and mitigating effects of allostatic load - Incorporates ability to resist, recover, or redirect oneself after traumatic events - Can be affected by genetics, epigenetic changes, availability of social support and coping mechanisms, positive outlook and sense of control, grit, prior learning, lifestyle factors like physical activity, diet and nutrition, adequate sleep, religious/spiritual practices - Influenced by chemical allostatic mediators that promote adaptation like cortisol, neural proteins like brain derived neurotrophic factor (BDNF)—>brain plasticity - - - Pathophysiology • Maladaptation—>ineffective, inadequate, or inappropriate change in response to new or altered circumstances • Coping is seen as a behavioral adaptive response to a stressor - Culturally based and vary with individual within parameters of what is acceptable to the given culture - Dictated by specific stressor and fluctuates with circumstances - Coping that is ineffective or dysfunctional if it does not achieve the desired goal - Coping and adapting used interchangeably • Distress is perceiving an inability to cope with a physiological or psychologic stressor - Activates release of catecholamines from adrenal glad medulla and glucocorticoids through the HPA axis, escalating levels of circulating mediators, and may exacerbate existing allostatic load and preexisting pathophysiologic conditions • Habituate: manipulate or train the hypothalamus to react less forcefully to a perceived threat or stressor - Change brain waves from beta to alpha waves, which are slower and indicative of a more relaxed and less aroused state Allostatic Overload and Illness • Allostatic load can accumulate in an individual by - Repeated exposures to multiple stressors - Inability to habituate or adapt to the stressor - Unnecessarily prolonged stress response or stress response that continues after the stressor is removed - Inadequate response to the stressor that causes other stress response mediators to attempt to compensate Allostatic overload result sin altered and impaired cognitive function Cortisol and norepinephrine help promote long term memory consolidation and retention of traumatic and fearful events • Administration of beta-blockers like propranolol that interferes with effects of norepinephrine has shown to reduce incidence of PTSD in many cases Diabetes associated with elevated cortisol levels which decrease effectiveness of glucose transport into cells —> insulin resistance DMII • Elevated insulin levels directly increase insulin resistance Chapter 4: Cell Injury, Aging, and Death • Cells respond to environmental changes or injury in 3 ways - When change is mild or short lived, the cell may withstand the assault and completely return to normal - —> reversible cell injury Cell may adapt to a persistent by sublethal injury by changing its structure or function… Adaptation is reversible Cell death may occur if the injury is too severe or prolonged. • Irreversible and may occur by 2 processes: - Necrosis: cell death caused by external injury • Pathologic process associated with significant tissue damage - Apoptosis: triggered by intracellular signaling cascades that result in regulated cell death. • May be a normal physiologic process in some instances and pathologic in others Reversible Cell injury • Start with cellular swelling and accumulation of excess substances within the cell 11 - Pathophysiology • Changes reflect cell’s inability to perform normal metabolic functions because of insufficient cellular energy in the form of adenosine triphosphate (ATP) or dysfunction of associated metabolic enzymes Hydropic Swelling or Oncosis • First manifestation of most forms of reversible cell injury • Results fro malfunction of sodium-potassium pumps that normally maintain ionic equilibrium of the cell - Results in accumulation of sodium ions within the cell—>osmotic gradient for water entry - Na+-K+ pump function is dependent on presence of cellular ATP—>injury causing insufficient energy production—>hydronic swelling • Characterized by: - Large, pale cytoplasm; - Dilated endoplasmic reticulum—> severe may rupture and form large water filled vacuoles - Swollen mitochondria - Generalized swelling in cells of a particular organ may cause organ to increase in size and weight • -MEGALY Intracellular Accumulations • Categorized as - Excessive amounts of normal intracellular substances such as fat - Accumulation of abnormal substances produced by the cell b/c of faulty metabolism or synthesis - Accumulation of pigments and particles that the cell is unable to degrade • Composed of - Lipids—>liver where fats are stored, metabolized, and synthesized • Fatty liver—>intake of alcohol • Atherosclerotic diseases and accumulate in blood vessels, kidney, heart, and other organs • Tay-Sachs disease and Gaucher disease—>lipids accumulate in neurologic tissue - Carbohydrates • Glycosaminoglycans (mucopolysaccharides) are large carbs normally composed to extracellular matrix of connective tissues - Connective tissue cells secrete most of the glycosaminoglycan into the extracellular space, but a small portion remains inside the cell and is normally degraded by lysosomal enzymes - Mucopolysaccharidoses are a group of genetic diseases where the enzymatic degradation of these molecules is impaired and they collect within the cell - Glycogen • Diabetes Mellitus—>impaired uptake of glucose—>high serum and urine glucose levels - Cells of renal tubules reabsorb the excess filtered glucose and store is intracellularly as glycogen - Renal tubule cells are also common site for abnormal accumulations of proteins—> renal glomerular capillaries become leaky and allow proteins to pass through them—> where renal tubule cells recapture some of the escaped proteins through endocytosis=abnormal accumulation - Proteins • Denatured proteins which are abnormally folded intracellular proteins may cause serious cell dysfunction and death if they persist in the cell • Chaperone or heat shock proteins are responsible for binding and refolding aberrant proteins back to their correct 3-D forms - 12 - Pathophysiology • …If unsuccessful, the abnormal proteins form complexes with another protein called ubiquitin which targets abnormal proteins to enter a proteasome complex where they are digested into fragments less harmful to cells Pigments and Inorganic Particles • Pigments - Produced by body are endogenous • Melanin • Iron containing substances - Hemosiderin & bilirubin • Excessive amounts may indicate abnormal breakdown of RBCs, prolonged administration of iron, or presence of hepatobiliary disorders - Produced from outside source are exogenous • Inorganic Particles - Calcium, tar, mineral dusts like coal, silica, iron, lead, and silver - Calcium deposits • Impaired renal excretion of phosphate may result in formation of calcium phosphate salts that are deposited in the tissues of the eye, heart, and blood vessels - Calcification of the heart valves—>obstruction of blood flow - Dead and dying tissues become calcified and appear as dense areas on x-ray films • Intracellular accumulations are generally reversible if causative factors are removed… But not inorganic particles Cellular Adaptation • Sometimes adaptive change may not be beneficial - Atrophy • Decreased cell size • Caused by disuse, denervation, ischemia, nutrient starvation, interruption of endocrine signals, and • • • • • • 13 persistent cell injury Represents effort by the cell to minimize its energy and nutrient consumption by decreasing the number of intracellular organelles and other structures Reduction in functional demand, sometimes called disuse atrophy - Immobilized in bed and then resuming activity - Denervation of skeletal muscle—>decreased muscle size caused by loss stimulation Chronic sublethal ischemia—>cell atrophy—> common in heart, brains, kidneys, and lower leg Chronic nutrient starvation - Glandular tissues depend on growth stimulating (trophic) signals to maintain size and function - Ex. Adrenal cortex, thyroid, and gonads are maintained by trophic hormones from pituitary gland and will atrophy in their absence Chronic inflammation and infection can cause persistent cell injury 2 pathways of protein degradation - Ubiquitin-proteosome system degrades target protein into small fragments - Lysosomes that may fuse with intracellular structures, leading to hydrolytic degradation of components (autophagy) Pathophysiology • Autophagy is a normal process that occurs in cells with damaged organelles - lipofuscin is an age-related pigment that accumulates in residual vesicles in atrophied cells, giving them a yellow-brown appearance—>stays in lysosomal vesicles of atrophied cells - Hypertrophy • Increased cell size accompanied by augmented functional capacity • In response to increase physiologic or pathophysiologic demands • Results from net increase in cellular protein content • Like growing muscles—>cells are hypertrophic; may also be with a combination of hyperplasia • Physiologic hypertrophy occurs to trophic hormones in sex organs like breast and uterus. • Liver enlargement can be a response to toxins and cardiac muscle enlargement in response to high BP— >hyperplastic and hypertrophic adaptations to pathological conditions - Hyperplasia • Increased cell number • Results from increased physiologic demands or hormonal stimulation - Persistent cell injury • Increased RBC in response to high altitude and liver enlargement in response to drug detox • Trophic hormones induce hyperplasia in their target tissues - Estrogen leads to increase in number of endometrial and uterine stromal cells • Dysregulation of hormones or growth factors can result in pathologic hyperplasia—>thyroid or prostate - enlargement • Chronic irritation of the epithelial cells—>calluses and corns or bladder hyperplasia from chronic inflammation of cystitis Metaplasia • Conversion of one cell type to another • Occurs as adaptation to persistent injury, with the replacement cell type better able to tolerate injurious stimulation—>fully reversible when stimulus is removed • Involves replacement of glandular epithelium with squamous epithelium - Chronic irritation of bronchial mucosa by smoking—>ciliated columnar epithelium conversion to stratified squamous epithelium. • Some cancers of the lung, cervix, stomach, and bladder derive from areas of metaplastic epithelium Dysplasia • Disorderly growth • Disorganized appearance of cells b/c of abnormal variations in size, shape, and arrangement. • Occurs most frequently in hyperplastic squamous epithelium, but may be seen in mucosa of intestine. • Adaptive effort gone astray • Have significant potential to transform into cancerous cells and regarded as preneoplastic lesions • Severe dysplasia involves entire thickness of the epithelium—>carcinoma in situ - Irreversible Cell Injury - Necrosis • Occurs as a consequence of ischemia or toxic injury and is characterized by cell rupture, spilling of contents into extracellular fluid, and inflammation. 14 • • • 15 Pathophysiology Morphologic changes including: shrunken nucleus (pyknotic) that is degraded (karyolysis), swollen cell volume, dispersed ribosomes, and disrupted plasma and organelle membranes - Disruption of permeability barrier of plasma membrane appears to be a critical event in the death of the cell Localized injury or death of tissue is reflected in the ENTIRE system as body attempts to remove dead cells and compensate for loss of tissue function - Inflammatory response including: malaise, fever, increased heart rate, increased WBC, loss of appetite - Intracellular contents released and go into bloodstream • Elevated serum amylase level—>pancreatic damage • Elevated creatine kinase (MB isoenzyme) or cardiac troponin level—>myocardial damage 4 types of Tissue Necrosis - Coagulative (most common) • Ischemic cellular injury • Loss of plasma membrane’s ability to maintain electrochemical gradients • Influx of calcium ions and mitochondrial dysfunction • Degradation of plasma membrane and nuclear structures • Area of coagulative necrosis is composed of denatured proteins and is solid… Slowly dissolved by proteolytic enzymes, and general tissue architecture is preserved for weeks - Liquefactive • Dissolution of dead cells occurs quickly—>area of lysosomal enzymes and dissolved tissue may result in abscess or cyst • Seen in the brain which has a lot of degradative enzyme and little supportive connective tissue • Bacterial infection that triggers localized collection of WBCs - Fat • Death of adipose tissue resulting from trauma or pancreatitis • Enzymes attack the cell membranes of fat cells, causing release of stores of triglycerides - Pancreatic lipase then hydrolyze the triglycerides into free fatty acids and glycerol—> precipitate as calcium soaps (saponification) • Chalky white area of tissue - Caseous • Lung tissue damage by tuberculosis • Areas of dead lung tissue are white, soft, and fragile—>like clumpy cheese • Dead cells walled off from rest of lung tissue by inflammatory WBCs - Gangrene - Cellular death involving a large area of tissue - Results from interruption of major blood supply to a particular body part like toes, leg, or bowel • Dry gangrene - Form of coagulative necrosis characterized by blackened, dry, wrinkled tissue separate from adjacent healthy tissue by line of demarcation. - Generally only on extremities • Wet gangrene - Liquefactive necrosis - Found in internal organs - Appears cold and black and foul smelling b/c of invasive bacteria - Pathophysiology - Rapid stream of tissue damage and release of toxins into the bloodstream—>life threatening • Gas gangrene - Formation of bubbles of gas in damaged tissue - Result of infection of necrotic tissue by anaerobic bacteria of the genus Clostridium Apoptosis • Occurs in response to injury that does not directly kill the cell but triggers intracellular cascades that activate a cellular suicide response • Generally do not rupture and are ingested by neighboring cells with minimal disruption of the tissue and without inflammation • Not always a pathologic process and occurs as a necessity of development and tissue remodeling • Regulated cell death if cell is not needed—>programmed cell death • Tidy and does not elicit inflammation • Area of tissue death after myocardial infarction is 20% necrotic and 80% ap optic. • Rate of apoptosis is greater than rate or cell replacement—>tissue or organ function may be impaired. • Normal cells require a variety of signal from neighboring cells and from extracellular matrix to stay alive… - If removed, the cell death cascade is activated • Extracellular signals triggering apoptosis—> Fas ligand which bind to cells sand trigger death cascade through activation of death receptors • Intracellular signals - Ex. Mitochondrial damage with leakage of cytochrome c into cytoplasms is activator of intrinsic apoptosis pathway—>governed by protein p53 • p53 is usually low, but increases in response to cellular DNA damage • Large number of cancers associated with mutation in p53 gene, which allows cancer cells to escape monitoring system • Caspases enzymes initiate apoptosis - Proteolytic cascade that degrades key intracellular structures leading to cell death - Caspases are proenzymes that are activated in cascade - Some cleave key proteins, like nuclear lamina to destroy nuclear envelope - Others activate more enzymes to chop up DNA Etiology of Cellular Injury - Ischemia and Hypoxic Injury • Hypoxia results in power failure within the cell - Decreased oxygen delivery to mitochondria causes ATP production to stall and ATP-dependent pumps • 16 like Na+-K+ and Ca2+ pumps to fail. - Sodium accumulation in cell creates osmotic gradient favoring water entry—>hydronic swelling - Excess intracellular Ca2+ collects in mitochondria which further interferes with mitochondria function - Anaerobic glycolytic pathways—>cellular acidification caused by lactate—>into blood stream and lactic acidosis - pH falls Tissue hypoxia is caused by ischemia, or interruption of blood flow to the area, but may also result from heart failure, lung disease, and RBC disorders. - Pathophysiology • Ischemia is the most common cause of cell injury in clinical medicine and injures cells faster than hypoxia alone - Disrupts oxygen supply - Metabolic wastes accumulates and deprives cell of nutrients for glycolysis - Ischemic injury is reversible, but when plasma, mitochondrial, and lysosomal membranes are damaged —>death - Takes minutes to hours - Ischemia reperfusion: when blood supplies to tissue is restored • Calcium overload - ATP stores are depleted and unable to control ion flux across the cell membrane - Accumulation of calcium ions in the cytoplasm can trigger apoptosis or activate enzymes that degrade lipids in membrane (lipid peroxidation) • Formation of reactive oxygen molecules (free radicals) which steal hydrogen atoms and form abnormal molecular bonds… Denature proteins, damage cell membranes, and disrupt cell chromosomes • Known to initiate inflammatory cascade - Superoxide O2- Peroxide H2O2 - Hydroxyl radicals OH• Subsequent inflammation - WBCs recruited to area release enzymes and other chemicals that damage the cells in the area Nutritional Injury • Cell injury results from deficiencies as well as excesses of essential nutrients • Iron deficiency—>affects RBCs • Vitamin D deficiency—>affects bones • Causes of malnutrition - Poverty - Chronic alcoholism - Acute and chronic illnesses - Self imposed dietary restrictions - Malabsorption syndromes • Nutritional excess - DM where some cells do not require glucose, but take them in like neurons. - Overweight and obesity syndromes • Heart and blood vessel disease • Musculoskeletal strain • Diabetes • Hypertension • Gallbladder disease Infectious and Immunologic Injury • Internal bacteria - Mycobacterium tuberculosis - Shigella - Legionella - 17 Pathophysiology - Salmonella - Chlamydia - Clostridium perfringens produce collagenase are and lecithinase which digest cellular membranes and - connective tissues - Exotoxins interfere with cellular functions—>Clostridium botulinum and Clostridium tetani • Cholera and diphtheria • Most exotoxins are proteins and are generally susceptible to destruction by heat - Gram negative bacteria contain endotoxin in cell wall - When bacteria is killed, endotoxin is released - Causes: fever, malaise, and circulatory shock • Escherichia coli • Klebsiella pneumoniae • Viruses - Intracellular parasites - Hepatitis B virus—>indirect cytopathic virus that causes immune mediated cell death • Consists of double stranded DNA that becomes incorporated into host cell’s nucleus and is transcribed by normal DNA polymerase Chemical Injury • Carbon tetrachloride CCl4 is converted to highly toxic free radical CCl3-, by liver cells if ingested. - High dose of acetaminophen can cause toxic effects to the liver • Carbon monoxide binds tightly to hemoglobin, preventing RBC from carrying sufficient oxygen • Lead poisoning: effects on nervous tissue, blood cells, kidney Physical and Mechanical Injury • Extreme temperature - Hypothermic injury—>frostbite • Severe vasoconstriction, increased blood viscosity—>ischemic injury • complicated by gangrenous necrosis - Hyperthermic injury—>burns • Microvascular coagulation and accelerate metabolic process in cell • Burns and degree of tissue destruction • Abrupt changes of atmospheric pressure • Interfere with gas exchange in lungs, cause formation of gas emboli in bloodstream, collapse of thorax, and rupture internal organs - High altitude flying - Deep sea diving • “The bends” from surfacing too quickly—>nitrogen bubbles form in blood which may obstruct circulation and cause ischemic injury - Explosions • Mechanical deformation - Mild abrasion to severe lacerating trauma • Electricity - Cells of body act as conductors of electricity - Damages tissue in 2 ways: • Disruption of neural and cardiac impulses - 18 Pathophysiology - Resistance to flow of electrons—>heat production which damages tissue - Current flows through path of least resistance through neurons and body fluids—> muscle contractions, thermal injury, and coagulation in blood vessels. • Hyperthermic destruction of tissues • Ionizing radiation - Radiation injures cells by breaking chemical bonds and indirectly generating free radicals - Cellular DNA susceptible to damage from radiation exposure • X-RAY and gamma rays - Ionization refers to ability of radiant energy to split water molecules by knocking off orbital electrons - - - (radiolysis) • Creates activated free radicals that steal electrons from other molecules and disrupt molecule bonds Cellular level • Genetic damage • Acute cell destruction • More concerning with tissue that has rapid cellular division and less opportunity to repair damaged DNA before passing onto next generation of cells - Hematopoietic, mucosal, gonadal, and fetal cells High levels of radiation 300 rad—>nuclear accidents and bombings • Acute radiation sickness • Hematopoietic failure • Destruction of epithelial layer of GI tract • Neurological dysfunction Irradiated cells are thought to die through a process of apoptosis rather than from direct killing effects of radiation • Cells susceptible to apoptotic dead tend to have high rates of mitosis or meiosis Cellular Aging - Cellular Basis of Aging • Cumulative result of a progressive decline in the proliferative and reparative capacity of cells coupled with - exposure to environmental factors that cause accumulation of cellular and molecular damage - DNA damage • Ultraviolet radiation • Oxidative stress from normal metabolism • Errors in DNA replication - Reduced proliferative capacity of stem cells • Telomeres • Telomerase enzymes rebuild telomeres - Accumulation of metabolic damage • Metabolic rate determines production of activated oxygen free radicals • Aging thought to result from cumulative and progressive damage to cell structures—> cell membrane especially Physiologic Changes of Aging 19 Pathophysiology Somatic Death - No immunologic or inflammatory response occurs in somatic death - Absence of respiration and heartbeat - Within 6 hours, accumulation of calcium and depletion of ATP result in actin-myosin cross-bridge formation in muscle cells • Stiff muscled throughout body—>rigor mortis: limpness or flaccidity as the tissues of body begin to deteriorate • Putrefaction—> release of lyric enzymes in tissue throughout the body—>postmortem autolysis • Brain death: unresponsive, flaccidity, absence of brain stem reflexes (swallowing, gagging, pupil and eye movements), absence of respiratory effort without help, absence of electrical brain waves, lack of cerebral blood flow Chapter 7: Neoplasia • Neoplasia is used interchangeably with the term tumor and usually means abnormal growth • Cancer is applied only to malignant neoplasms - Associated with altered expression for cellular beans that normally regulate cell proliferation and differentiation Benign Versus Malignant Growth - Characteristics of Benign and Malignant Tumors • Benign tumors - Do not invade adjacent tissue or spread to distant sites - Encapsulated by connective tissue which is indicative of strictly local growth - More closely resemble tissue type of origin - Grow more slowly, little vascular it’s, rarely have necrotic areas, and retain functions similar to tissue of origin • Malignant tumors - Penetrated local tissues (invasive nests), lymphatic, or blood vessels suggests potential to spread to distant sites—>metastasize - Anaplasia: lack of differentiated features in cancer cell correlated with more aggressively malignant - tumor • Indicated by variation in cell size and shape within the tumor, enlarged nuclei, abnormal mitoses, and bizarre-looking giant cells - Grow rapidly, may initiate vessel growth in tumor, have necrotic areas, and are dysfunctional Tumor Terminology • Suffix -oma used to indicated benign tumor • Carcinoma and sarcoma indicate malignant tumors 20 Pathophysiology - Carcinoma refers to malignant tumors of epithelial origin • Adenoma—>tumor of glandular tissue • Majority of human cancers are carcinomas from malignant transformation of epithelial cells - Sarcoma to malignant tumors of mesenchymal (nerve, bone, muscle) origin • Adenocarcinoma—>malignant tumor of glandular tissue • Highly malignant: lymphomas, hepatomas, and melanomas - Malignant Phenotype • Normal cells require survival signals from their environment that their existence is desirable and they • • proliferate when space is available and appropriate mitogen-stimulating signals are present Malignant cells develop antisocial properties that allow them to proliferate at the expense of other cells and tissues in the body General Mechanisms of Cancer Cells - Cancer cells proliferate despite lack of growth-initiating signals from the environment. - Cancer cells escape apoptotic signals and achieve a kind of immortality in that they are capable of unlimited replication. - Cancer cells lose their differentiated features and contribute poorly or not at all to the function of their tissue. - Cancer cells are genetically unstable and evolve by accumulating new mutations at a much faster rate than normal cells. - Cancer cells invade their local tissue and overrun their neighbors (invasion) and spread to distant locations (metastasis). - Cancer cells develop proangiogenic signaling abilities, stimulating the growth of their own vascular supply. - Cancer cells develop reprogrammed energy metabolism, preferentially using glucose as fuel via aerobic glycolysis, giving these cells survival advantage over their normal cell neighbors. - Cancer cells often develop the ability to evade immune surveillance and destruction. Epidemiology and Cancer Risk Factors • Most cancer deaths, 80% occur in persons older than 55 years - Tobacco Use • Causes up to nearly 30% of all cancer related deaths • Lung cancer, pancreas, bladder, kidney, mouth, esophagus, cervix and blood/bone marrow • Carcinogens - Initiators that cause genetic damage • Contains compounds that have known genotoxicity and serve as initiators - Promoters that promote growth of tumor • Spur mutant cells to proliferate - Nutrition - Growing evidence that obesity is an independent risk factor for developing or dying from several types of cancer, including endometrial, esophageal, and liver cancer • Those obese an diagnosed with cancer are at increased risk of cancer recurrence after completion of treatment and of dying from cancer as compared to individuals with normal body weight 21 • • Pathophysiology - American Cancer Society encourages limiting intake of red and processed meats and increasing vegetables, fruits, and whole grains Antioxidants - Beta carotene, vitamine E, vitamine C, selenium, retinol, zinc, riboflavin, and molybdenum The Microbiome - Especially the gut microbiome—>inflammation is major contributor to cancer development, and increased intestinal permeability may be a risk factor for many types of cancer Genetic Mechanism of Cancer • Cancer is primarily a disorder of gene expression • Observation that cancer often resulted from agents known to damage DNA • By the time cancer is diagnosed, it contains billions of cells carrying DNA abnormalities - Some have active role in malignant proliferation (driver mutations) - Many mutations are likely random coexisting changes (passenger mutations) which play no part in - tumorigenesis Grouped in 2 Categories • - Gain of function mutations: overactivity of the gene contributes to cancer • Proto-oncogenes code for components of cellular growth-activating pathways • Mutant, overactive/over expressed form is called an oncogene - Loss of function mutations: under activity is the problem • Tumor suppressor genes which inhibit cell proliferation - BOTH, above, enhance cell proliferation and survival • Genes that Monitor and Maintain Genome Contribute INdirectly - DNA-repair genes - Genes that regulate apoptosis Proto-Oncogenes - Viral identification - Code for components of cell-signaling systems that promote cell proliferation • Growth Factors (Mitogens) - Intercellular communication is accomplished through cell to cell transmission of growth factors - Growth factors are small peptides manufactured by cells and secreted into the extracellular space • Diffuse to nearby cells and interact with receptors on the target cell surface • Binding of growth factors to cell surface receptors activates signaling cascades within the cell that enhance proliferation • Proliferation signal must be produced by the cell’s environment, not by the cells itself • Autocrat signaling—>overproduction of stimulatory growth factors by a mutant proto-oncogene can shift balance of signals and produced excessive self stimulated growth - Examples: • Platelet derived growth factor - PDGF - Over secreted in glial cell cancers —> brain tumors - Connective tissue cancers —> sarcoma • Transforming growth factor-alpha - TGF-alpha • Epidermal growth factor - EGF 22 - Pathophysiology - Receptor abnormality of human epidermal growth factor receptor type 2 —> HER2 • Overactive receptors stimulate proliferation of tumor cells even when little or no EGF bound to them - Peptide growth factors (mitogens) present at cell surface as receptors which are transmembrane proteins with mitogen-binding area outside of cell and enzyme activating area on inside of cell • Excessive responsiveness to mitogens normally present in cell’s environment • Cytoplasmic Signaling Pathways - Manufacture of excessive or abnormal components of the intracellular signaling pathways - Pathways involve numerous enzymes and chemicals that function to transmit signals from activated receptors at the cell surface to the cell nucleus - A mutant proto-oncogene that codes for excessive or abnormal cytoplasmic signaling components could cause activation of pathway even tho no signal was received at cell surface - Mutations of ras gene family • Proteins encoded by ras genes are monomeric G proteins that transmit signals from receptors at the cell surface into the interior of the cell • The ras protein is active when it has guanosine triphosphate GTP bound to it, but quickly hydrolyzes GTP which turns itself off after a brief period of activity • Mutation in ras gene can code for a protein that is unable to hydrolyze GTP, so it remains persistently active and stimulates cell proliferation inappropriately • Occurs in leukemias, lung, ovarian, colon, and pancreatic cancer • Transcription Factors - The entire proliferation pathway, including growth factor (mitogen), the receptor, and the intracellular cascade, affects transcription of a set of genes in the nucleus that spur the cell to enter the S phase - A number of proto-oncogenes code for transcription factors in the nucleus • Transcription factors are proteins that must be assembled at the promoter area to begin gene transcription • Transcription factors are sequestered and prevented from indiscriminate activity until appropriate signals cause their release. • MUTATIONS in transcription factor genes may cause overproduction of transcription factors or interfere with normal mechanisms that keep them in check - Proto-oncogenes that code for nuclear transcription factors: Myc (lung, breast, leukemia, and neuroblastoma), jun, and fos • From Proto-Oncogene to Oncogene - Proto-oncogenes become activated oncogenes when mutations alter their activity so that proliferation promoting signals are generated inappropriately - 4 Ways to Activate • Oncogenes may be introduced into host cell by a retrovirus • Proto-oncogene within the cell may suffer a mutagenic event that changes it structure and function • DNA sequence that normally regulates proto-oncogene expression may be damaged or lost and allow the proto-oncogene to become abnormally active • Error in chromosome replication may cause extra copies of proto-oncogene to be included in the genome (amplification) Tumor Suppressor Genes - Tumor suppressor genes contribute to cancer when they are not there 23 Pathophysiology - Cause • Chromosome deletion, point mutations, chromosome loss through nondisjunction may knock out tumors suppressor gene function • Epigenetics where tumor suppressor gene function may be lost and silenced - Does not change the DNA sequence, so no mutation - Changes the packaging of DNA and chemically modifies it by methylation so gene is inactivated - Appear to inhibit proliferation, repair DNA, or induce apoptosis in defective cells • The Rb Gene - Role in retinoblastoma (eye cancer) • Familial form—> where portion of chromosome 13 is missing… which is where Rb gene is normally located • Recessive gene • Rb gene codes for large protein in cell nucleus (pRb) which is labeled as the master brake of the cell • • 24 cycle - Blocks cell division by binding transcription factors E2F, inhibiting them from transcribing the genes that initiate the cell cycle • Rb protein can be induced to release transcription factors when it is sufficiently phosphorylated • Proliferation promoting signals in the cell increase cyclin dependent kinase (Cdk) enzymes and prompt pRb phosphorylation, whereas growth inhibiting signals prevent phosphorylation • Inactivating mutation of Rb genes removes major restraints on cell division • Defective pRb is common to different cancers The P53 Gene - Named for protein’s molecular mass of 53 kilodaltons. - Nicknamed guardian of the genome - Inhibits cell cycling - Little p53 found in cells, and accumulates in response to cellular, particularly DNA, damage - P53 is a transcription factor that binds damaged DNA and regulates hundreds of genes - Stalls cell division to allow time for DNA repair before DNA replication in the S phase - Excessive damage—>p53 may direct cell to initiate apoptosis - Defect in p53 interrupts quality control system—>which allows genetically damaged and unstable cells to survive and continue to replicate - Chemotherapy and radiation induced cell death is mediated a lot by p53 • Cause enough cellular damage in the target cell to trigger p53 mediated apoptosis • Cancer cells that lack functional p53 may be resistant to some radiation BRCA1 and BRCA2 Genes • Both function in the double-strand DNA repair pathway and are important in maintaining genomic stability • Associated with increased risk of ovarian prostate, and pancreatic cancer - BRCA1 • Associated with regulation of p53 function - BRCA2 Pathophysiology Multistep Nature of Carcinogenesis • Anchorage independence is a typical feature of most transformed cells and are capable of proliferating - even if they are not attached to a matrix… • Whereas normal cells will initiate apoptosis if they do not have a space on the matrix to anchor themselves • Ras and myc oncogenes are capable to grow indefinitely in culture independently, but not able to induce tumor formation… - However, when introduced together to normal cells, they become fully malignant. Initiation • Genetic mutations that inappropriately activate proto-oncogenes and inactivate tumor suppressor genes - But genetic mutations are not evident until the mutant cell proliferates - Proliferation is a requirement for cancer development • Unique combination of mutations that lead to malignant behavior • Carcinogen are agents and substances that are capable of inducing cancer - Some are complete carcinogens and are able to initiate genetic damage and promote cellular proliferation - Partial carcinogens are promoters that stimulate growth but are incapable of causing genetic mutations sufficient to initiate cancer • Inflammation as an initiator and promoter of carcinogenesis - Inflammatory cytokines may cause direct DNA damage or epigenetic change - Inflammation may occur after tumorigenesis and play a role in sustained cellular survival, promotion of growth, and direct angiogenesis, and facilitate tumor invasion in adjacent tissues …Transition from initiation to promotion may involve activation of another oncogene or inactivation of a tumor suppressor gene Promotion • Mutant cell proliferates • Innate immune system may be involved in neoplastic promotion • Supply signal molecules to tumor microenvironment, including growth factors, survival factors that limit apoptosis, proangiogenic factors, ECM modifying enzymes, invasion, and metastasis • Growth hormonal factors - Estrogen hormones and breast, ovarian, and uterine cancer - Testosterone and prostate cancer • Testosterone is a growth factor for prostate gland and can act as a promotor for tumor formation in the tissue • *Tumor cells produce more than normal amount of telomerase which allows the cell to repair telomeres of chromosomes. - Telomerase produced by stem and germ cells Progression • Mutant proliferating cells begin to exhibit malignant behavior • Phenotype refers to the cells traits—>morphology, metabolism, and biochemical composition • Each cycle of proliferation—>change variations arise and highly evolved tumors cells generated - Develop characteristics like laminin receptors, lytic enzymes, anchorage independence - - 25 Pathophysiology Invasion and Metastasis • Tumor cells gain access to blood or lymphatic circulation by escaping basement membrane of the tissue of - origin, moving through extracellular space, and penetrate the basement membrane of the vessel - Involve loss of cell to cell adhesion and binding to matrix components like laminin via specific laminin receptors on tumor cell - Release of enzymes like proteases and collagenases that digest basement membrane - Understood in setting of carcinomas were there is a loss of E-cadherin which is key epithelial cell to cell adhesion molecule - Epithelial to mesenchymal transition—>where cancerous epithelial cells acquire ability to invade, resist apoptosis, and disseminate - Most cancers arise from or contain a small population of stem cells present in tissue • Self renewing undifferentiated stem cells thought to continue to continued local tumor growth, seeding for metastasis throughout body, and resistance to cytotoxic therapies Patterns of Spread • Circulatory flow - Metastatic tumors from colon often seed the liver b/c they travel within the portal vein - Hodgkin disease is a lymph that spreads via lymphatics from node to node • Tumor biomarkers: proteins, genetic markers, hormones, hormone receptors, oncofetal antigens, enzymes, or other substances secreted by tumor cells or in response to tumor growth - Identified in tumors, lymph nodes, body fluids, or distant tissues - Also identified in peripheral circulation Angiogenesis • Process of forming new blood vessels - Tumor cells may begin to produce angiogenic factors like vascular endothelial growth factor VEGF in response to hypoxia or other signals • VEGF stimulates proliferation of vascular endothelial cells which migrate to the tumor and start blood vessel development • Blood vessels have excessive branching, enlarged, and are abnormal—>weak and cause hemorrhage Tumors can’t become larger than 2mm in diameter unless they grow blood vessels to provide oxygen/ • nutrients and remove metabolic waste/carbon dioxide • Late stage of cancer development • Some tumors may be proangiogenic at premalignancy Grading and Staging of Tumors • Grading refers to histologic characterization go tumor cells and determination of the degree of anaplasia - 3-4 systems of grading • Higher degree of anaplasia indicates greater malignant potential - Minimally or undifferentiated • Lower grade tumor is well differentiated and closely resembles tissue of origin • Staging describes location and pattern of spread of a tumor within the host - Tumor size, extent of local growth, lymph node, and organ involvement, and presence of distant metastases are considered - TNM (tumor, node, metastasis) used as a general framework for staging tumors - - 26 - Pathophysiology - CT and MRI are not specific for tumors, but can guide selection of sites for exploration and biopsy since they detect difference in tissue density - PET facilitates cancer detection based on molecular and biochemical processes within the tumor tissues • Used where CTs are limited • Differentiate between benign from malignant lymph nodes or other lesions Genetic/Molecular Testing • Liquid biopsy where a patient’s blood can be examined for the presence of circulating tumor cells or tumor DNA Effects of Cancer on the Body - Pain • Caused by invasion of metastatic cells into organs or bone and subsequent activation of pain and pressure - receptors in these tissues • Tissue destruction and inflammation • Cancer treatments may cause pain • Controlled through analgesics Cachexia • Overall weight loss, loss of muscle mass, and generalized weakness • Affects 60-80% of cancer patients • Loss of appetite and increased metabolic rate • Nausea and vomiting Immune suppression - Cancer cells secrete substances that suppress the immune system - Reduced populations of T and B cells and may respond poorly to injected antigens - Cytotoxic T cells and natural killer cells are needed to detect and destroy cancer cells • Bone marrow suppression contributes to anemia, leukopenia, and thrombocytopenia - Invasion and destruction of blood forming cells in bone marrow, poor nutrition, and chemotherapeutic drugs - Anemia—>deficiency in circulating red blood cells • Chronic or acute bleeding • Side effect of cytotoxic chemotherapies • Fatigue, increased heart rate, increased respiratory rate—>decreased oxygen carrying capacity - Leukopenia—>caused by malignant invasion of bone marrow • Malnutrition • Deficiency in white blood cells reduces patient’s ability to fight infection • Offending organism is opportunistic—>virulent only when person is immunocompromised • Host is unable to mount an immune response - Thrombocytopenia—>deficiency in number of circulating platelets • Platelet deficiency—>risk for life threatening hemorrhage • Platelet count less than 20,000/mm3 - Pt may be treated with erythropoietin (Epogen) or granulocyte-stimulating factors (Neupogen) • Hair loss is a complication of radiation therapy and chemotherapy - Normal cells within high growth rates like mucosal epithelia and hair follicle cells are damaged - 27 Pathophysiology • Paraneoplastic syndromes - Hypercalcemia • Associated with abnormal production of parathyroid hormone-related protein by tumor cells • May be consequence of metastatic bone cancer—>expected finding rather than paraneoplastic syndrome - Cushing syndrome secondary to excess adrenocorticotropic hormone ACTH secretion - Hyponatremia and water overload secondary to excess antidiuretic hormone (syndrome of inappropriate - ADH) secretion Infection • Infection, hemorrhage, and organ failure are primary causes of cancer death Cancer Therapy - Surgery • Localized solid tumors are treated surgically • Removes a margin of the normal appearing tissue around detected tumor to ensure complete tumor - removal • Lymph nodes are also subject to biopsy • Risks: effects of anesthesia, infection, and blood loss • Followed by radiation therapy, chemotherapy, immunotherapy, or hormone based therapy Radiation Therapy • Ionizing radiation used to: - Kill tumor cells that are not resectable because of location - Kill tumor cells that may have escaped a surgeon’s scalpel and remain undetected - Improve or relieve symptoms and maintain organ function • Used with small cell lung cancer as a prophylaxis since this cancer has a high risk of brain metastasis • Causes base damage, single strand and double strand breaks, and DNA-DNA and DNA-protein cross links - Cells rapidly cycling are more susceptible to radiation death b/c little time for DNA repair - Radiation doses cause enough cell damage to initiate apoptosis • P53 tumor suppressor gene important in this response, but many tumors have mutant P53 and may be less susceptible to radiation induced cell death • Harder to kill large tumor because cells are heterogeneous and going through different phases of mitosis • Most effective at removing small groups of tumor cells Chemotherapy • Systemic administration of cytotoxic chemicals as treatment for cancers known or suspected to be dispersed in body • Parenterally and orally administered can find their cancer cell targets in areas throughout entire body • Cytotoxic because they interfere with some aspect of cell division - More rapidly dividing cells are more susceptible to killing effects of chemotherapeutic agents • Tumor cells with mutations of P53 may be resistant to chemotherapeutic agent that work by damaging DNA • Chemotherapeutic agents are not selective for tumor cells, and certain amount of normal cell death occurs - More effective with rapidly dividing cells of bone marrow, intestinal epithelia, and hair follicles • Bone marrow predisposes patient to anemia, bleeding, and infection - 28 Pathophysiology - Immunotherapy • Potential for specificity • Monoclonal antibodies - Antibodies having identical structure - Used for breast and gastroesophageal cancers have over expression of HER2 receptor on surface of - malignant cells • Monoclonal antibody trastuzumab binds to HER2 protein and helps immune cells find and kill tumor cells • Checkpoint inhibitors - Cancer cells may express cell-surface ligands, like programmed cell death protein ligand 1 (PD-L1) that prevent the activation of cytotoxic T cells - Serve as immune checkpoints in normal cells to constrain immune response and preventing autoimmunity - In cancer cells, this allows tumor to hide from innate immune system as it expresses antigens as self - Monoclonal antibody drugs blood PD-1 or ligand PD-L1 activates cytotoxic T cells against cancer cells Molecular/Targeted Therapy • Target cell membrane proteins and cytoplasmic signaling pathways • Imatinib, first tyrosine kinase inhibitor TKI, inhibits abnormal fusion and stops abnormal cell proliferation - Works on chronic myelogenous leukemia CML—>chromosome rearranges to abnormal production of BCR-ABL—->ABL is a type of tyrosine kinase enzyme involved with cell proliferation Gene Therapy • Alter malignant behavior of cells has therapeutic potential • Gene therapy used to suppress overactive oncogene or replenish missing tumor suppressor function - Introducing p53 tumor suppressor gene via adenovirus in treatment for head and neck cancers - Genetic alteration of immune cells to make them more efficient killers of tumor cells • Chimeric antigen receptor T (CAR-T) cells are genetically engineered T cells that produce receptors on surface • Receptors allow T cells to recognize and attach to a specific protein on tumor cells • Used in relapsed/refractory lymphoma and leukemia Stem Cell Transplantation • Transplanting hematologic stem cells used for life threatening disorders where pt’s bone marrow is incapable of manufacturing white blood cells, red blood cells, or platelets - Non functional marrow is consequence of high-dose chemotherapy and radiation used to manage hematologic malignancies like leukemia and lymphoma Stem cells harvested from aspirates of bone marrow or from donor’s peripheral blood stream and derived from umbilical cord blood • Stem cells can be harvested from aspirates of bone marrow or donor’s peripheral bloodstream and from umbilical cord blood • Bone marrow most common graft source from donors younger than 20 years of age • Hematopoietic cells collected from donors older than age 20 from peripheral blood • Allogenic (tissue matched individual) • Syngeneic (identical twin) • Autologous (patient in question) • Closer match is between donor and recipient has better outcome - - - 29 - Pathophysiology Before infusion of donor stem cells, patient’s immune cells must be suppressed to prevent transplant rejection Therapeutic goal is to restore immune/hematopoietic function and also to induce a graft versus cancer effect where immunity of donor cells fight off remaining cancer cells 30
