Introduction to Pathophysiology PDF

8/19/2024 lecture Physiology: The study of life processes or how living systems work at : - Molecular level - Organ and system level - Whole organism level It involves how living systems respond to: - Physical activity - Environmental conditions Patho - Physical Physi - Functio...

8/19/2024 lecture Physiology: The study of life processes or how living systems work at : - Molecular level - Organ and system level - Whole organism level It involves how living systems respond to: - Physical activity - Environmental conditions Patho - Physical Physi - Functional Ology - Study Disease pathophysiology encompasses understanding in the body molecular, cellular, and systemic responses involved in the development and progression of disease, Why study? - Disease identification - Diagnosis and treatment - Prognosis and prevention Common disease processes - Inflammation - A complex response to tissue injury or infection - Involves the release of various chemical mediators - Chronic inflammation is associated with many diseases - Pathogens - Bacteria, viruses, fungi, and parasites, can cause infectious diseases -The pathophysiology of infectious diseases involve the invasion and proliferation of these microorganisms within the body - They can disrupt normal cellular processes, release toxins, induce an inflammatory response, and damage tissues. - Cancer - Uncontrolled cell growth and the ability to invade surrounding tissues - Pathophysiology of cancer involves genetic mutation that lead to abnormal cell division, reduced apoptosis, and angiogenesis - Cancer can affect any organ or tissue and has various forms - Cardiovascular diseases  - Affects the heart and blood vessels, leading to conditions like coronary artery disease, heart failure, and hypertension - The pathophysiology often involves the accumulation of fatty plaques in the arteries, leading to atherosclerosis and in some cases, myocardial infarction or stroke. - Metabolic disorders - Results from defects in biochemical processes that regulate energy production and utilization - The pathophysiology of metabolic disorders involves imbalances in hormone levels, impaired glucose metabolism, and dysregulation of lipid and protein metabolism - Neurological disorders - Affects the brain, spinal cord, and peripheral nerves. - Conditions like Alzheimers, parkinson, and multiple sclerosis - Neurodegenerative diseases involve the progressive loss of neurons and impaired neuronal communication leading to cognitive decline, motor dysfunction, and sensory deficits. Example: Diabetes - Carbohydrate intake - Insulin secretion decrease - Peripheral glucose uptake decrease - Hepatic glucose production increase - This leads to an increase of blood glucose: type 1 Learning the words Disease = dis-ease(not at ease) = - Any disturbance of structure and function of the body - Can be symptomatic and asymptomatic - Pathology = The study of structural and functional changes in the body caused by disease - Etiology = the cause of the disease - Pathogenesis = a sequence of events that lead to disease Pathology refers to the study of essential nature of diseases - medical discipline (direct observation of the symptoms of the disease are studied) Pathophysiology refers to the study of disordered physiological processes associated with diseases - biological discipline (experimental measurements are studied) Etiology -> Pathogenesis Classification of disease - Congenital and hereditary disease - caused by changes in DNA (down syndrome) - Inflammatory disease - caused by body’s reaction to an injurious agent (autoimmune diseases) - Generative diseases - generation of various parts due to aging (arthritis) - Metabolic diseases - caused by a disturbance in some metabolic processes ( hyper/hypothyroidism, diabetes) - Neoplastic diseases - conditions that cause tumor growth - both benign and malignant (cancer) Cells adapting to stress Goal = maintain homeostasis Cells adapt to changed in the internal environment Organisms adapt to changes in the external environment Cells adapt by changing cell size, number, and type Cellular adaptation may be functional in response to normal physiological changes(physiological adaptation) - Enlargement of the uterus in pregnancy Cellular adaptation may be pathogenic in response to adverse condition(pathologic adaption) - Formation of atherosclerotic plaques due to high cholesterol - Enlargement of the heart and cardiomyopathy(heart failure) due to hypertension Hypertrophic cardiomyopathy - enlarged stiff septum: less blood can be pumped by the left ventricle which can't fully relax between heartbeats. Dilated cardiomyopathy: enlarged and weakened ventricle Atrophy: wasting away due to reduction in size of cells Causes of atrophy - Disuse - Denervation - Loss of endocrine stimulation - Inadequate nutrition - Ischemia or decrease in blood flow Hypertrophy: increased in cell size and tissue mass - Caused by increased workload on the organ or body part - Cells increase in size to meet demand - Common in cardiac and skeletal muscle Physiologic hypertrophy - increased muscle mass associated with exercise Pathologic hypertrophy - result of disease - Adaptive = thickening of bladder after continuous obstruction or urine flow, cardiac hypertrophy after high blood pressure - Compensatory - increase in size of single kidney if second kidney is removed Hyperplasia: increase in cell number and tissue mass Can only occur in tissues where cells divide normally - Yes: epidermis, intestinal epithelium, and glandular tissue - No: nerve, skeletal and cardiac muscle - Involves activating gene controlling cell division Physiologic hyperplasia: results of hormonal stimulation, increased workload, or a compensation mechanism Non-physiologic hyperplasia: - Results of excessive hormonal stimulation - Excess estrogen -> endometrial -> hyperplasia, excess estrogen + androgen -> benign prostate hyperplasia - Results of excessive growth factors - Skin warts caused by growth factors produced by human papillomavirus, HPV Metaplasia: one cell type is replaced by another - Due to chronic irritation or inflammation. Allies for substitution of more robust cells when the environment is too harsh for fragile cells - Stays with the same type of cell: epithelial cell -> another epithelial cell In patients with chronic acid reflux, normal squamous cell epithelium -> goblet cells in the esophagus. Dysplasia: abnormal development of cells  - Results in cells that vary in size, shape, and appearance - Associated with chronic irritation or inflammation - Seen in the squamous epithelium of the respiratory tract and uterine cervix - Can lead to cancer, but also can be reversible if irritation is removed Cell injury Reversible - Membrane blebbing - Mitochondrial swelling - Cellular swelling - Nuclear chromatin clumping - Endoplasmic reticulum swelling - Ribosomal detachment Irreversible - Lysosomal rupture - Phospholipid membrane damage - Mitochondrial permeability - Nuclear changed can result in - Pyknosis (condensation) - Karyorrhexis (fragmentation) - Karyolysis (nuclear pallor) 5 Major ways cells can get injured: - Injury from nutritional imbalances - Hypoxia/Reperfusion - Injury from physical agents - Radiation injury - Chemical injury - Injury from biologic agents Example: - Hypoxia -> sodium and water move into cell, potassium move out of cell -> osmotic pressure increases -> more water moves into cell -> rupture and other damages -> extensive vacuolation -> hydropic degeneration (swelling of cell) Hypoxia - (lack of oxygen) in the most common cause of cellular injury Ischemia - reduced blood supply -> hypoxia Anoxia - total lack of oxygen In myocardial infarction, a blot clot in the coronary artery causes myocardial hypoxia leading to myocardial cells death In ischemia stroke, a blood clot in the brain leads to neuronal cell death Mechanisms of cell injury involves a reduction of ATP, dysfunction of the Na+/K+ ATPase, altered intracellular ion levels, altered enzyme activation, and cell death Anoxia blood vessel -> swollen cell Reperfusion - radicals in necrotic cell O2-, h2o2, oh’ Ischemic and hypoxic injury : Altered membrane permeability -> loss of membrane potential -> can’t produce ATP -> necrosis Proapoptotic proteins -> apoptosis Cellular injury mechanisms Free radicals and reactive oxygen species - Electrically uncharged atom or group of atoms having an unpaired electron that damage: - Lipid peroxidation - Alteration of protein - Alteration of DNA - Mitochondria Free radical - Constraints a single unpaired electron in an outer orbit Reactive oxygen species (ROS) are chemically reactive oxygen molecules ROS form by normal cellular processes and are usually balanced by endogenous antioxidants Oxidative stress occurs when there is an imbalance between the production of ROS and antioxidant defenses Ischemia-Reperfusion injury Mechanisms - During ischemia, degradation of ATP produces hypoxanthine - During reperfusion, oxygen catalyzes xanthine oxidase to degrade hypoxanthine to uric acid and releasing highly reactive superoxide anion  - Superoxide is converted to h2o2 and the hydroxyl radical - Hydroxyl radical causes peroxidation of lipid structures of cell membranes resulting in the release of proinflammatory eicosanoids Free radicals and ROS play a key role in many diseases including heart attacks, stroke, cancer, radiation, , lung diseases Free radicals -> DNA damage, mutations Free radical -> lipid -> loss of membrane integrity Free radical -> nucleotides -> genetic damage Free radical -> proteins -> enzyme inactivation Normal cells respond to physiologic and pathologic stresses by adapting (atrophy, hypertrophy, hyperplasia, metaplasia) Normal cell -> stress -> adapt -> if mild/temporary = reversible, if not -> cell injury -> irreversible injury -> cell death Chemical injury - Xenobiotics - Carbon tetrachloride - Lead - Carbon monoxide - Ethanol - Mercury - Social or street drugs Chemical agents including drugs - Over the counter and prescribed drugs - Leading cause of child poisoning - Direct damage - Chemicals and drugs injure cells by combining directly with critical molecular substances - Chemotherapeutic drugs - Drugs of abuse - Hypersensitivity reactions - Range from mild skin rashes to immune mediated organ failure Direct liver injury, idiosyncratic liver injury, indirect liver injury = DILI Chemical or Toxic injury  - Exposure to chemicals is an important cause of cell injury - Chemicals can be directly or indirectly toxic (indirect means it becomes toxic after interacting with the body - formation of toxic metabolite - The liver is the initial site for contact for most ingested chemicals, so it is the most susceptible to chemically induced injury Xenobiotics -> entrance to body -> inhalation, dermal, ingestion -> absorption into bloodstream and distribution to body tissues and organs -> leads to storage, biotransformation phase 1 and phase 2 reactions, toxicity/action, or excretion Unintentional and intentional injuries Blunt force injuries - Results of application of mechanical force to body - Results in tearing, shearing, or crushing of tissues - Motor vehicle accidents and falls - Contusion, laceration, fractures Sharp force injuries - Incised wound - Stab wound - Puncture wound - Chopping wound Gunshot wounds Asphyxial injuries - Caused by failure of cells to receive or use oxygen - Suffocation: choking asphyxiation - Strangulation - Hanging, ligature, and manual strangulation - Chemical asphyxiants - Cyanide and hydrogen sulfide - Drowning Infectious injury Pathogenicity of a microorganism-viruses, fungi, protozoa, bacteria  - Disease-producing potential - Invasion and destruction - Toxic production - Production of hypersensitivity reactions Viral replication -> attachment -> penetration -> transcription genome replication -> assembly -> release Immunologic and inflammatory injury Phagocytic cells Immune and inflammatory substances - Histamine, antibodies, lymphokines, complement, and proteases Membrane alteration Inducers: infection, tissue damage -> sensors: macrophage, dendritic cells, mast cell, neutrophil, mediators: cytokines, chemokines, autacoids -> targeting tissues Acculations due to injury Cellular injury can result in intracellular accumulation of endogenous or exogenous substances. Mechanisms of abnormal accumulations - Abnormal metabolism leading to insufficient removal of endogenous substances (fatty liver disease) - Accumulation of abnormal substance due to mutation, defect in protein folding, or abnormal degradation (Alzheimer’s disease) - Lack of enzyme leading to ineffective catabolism of substance (Hunter disease) - Harmful exogenous material due such as heavy metals, microorganisms (lead poisoning) Systemic manifestation of cellular injury - Cellular injury can result in several non-specific systemic signs including fever and tachycardia - Fever due to release of endogenous pyrogens from macrophages or bacteria - Tachycardia due to increase in metabolic processes resulting from fever - Pain due to various mechanisms including bradykinin, obstruction, pressure - Presence of cellular enzymes in blood - Creatinine kinase(CK) - skeletal muscle, heart - Aspartate aminotransferase (AST) - liver - Alanine aminotransferase (ALT) - liver  - Amylase - pancreas - Troponins - Heart, skeletal muscle Blood plasma constraints many enzyme which can be functional and non-functional plasma enzyme Functional : present in plasma in higher concentrations in comparison to tissues, have known functions, their substrates are always present in the blood, site of synthesis in the liver, decrease in liver diseases: Example - clotting factors, lipoprotein lipase and pseudo- choline esterase Non-functional plasma enzymes: normally present in plasma in very low concentrations in comparison to tissues, no known functions, their substrates are absent from the blood, site of synthesis is different organs such as liver, heart, brain, and skeletal muscles, different enzyme increase in different organ diseases: example - ALT, AST, CK, LDH, alkaline-phosphatase, and amylase. Sources of non-functional plasma enzymes - Increase in the rate of enzyme synthesis e.g. bilirubin increases the rate of synthesis of alkaline phosphatase in obstructive liver diseases. - Obstruction of normal pathway e.g. obstruction of bile ducts increases alkaline phosphatase - Increased permeability of cell membrane e.g. in tissue hypoxia - Cell damage with the release of its content of enzyme into the blood e.g. Myocardial infarction and viral hepatitis Increase of non-functional plasma enzyme - Tissue damage or necrosis resulting from injury or disease in generally accompanied by increases in the levels of several nonfunctional enzyme Medical importance of non-functional plasma enzyme Measurement of non-functional plasma enzyme is important for: - Diagnosis of diseases - Diseases of different organs causes elevation of different plasma enzymes - Prognosis of the disease - The effect of treatment can be followed up by measuring plasma enzymes before and after treatment Examples of medically important non-functional plasma enzymes  - Amylase and lipase enzymes increase in diseases of the pancreas as acute pancreatitis - CK enzyme increases heart, brain, and skeletal muscle diseases - Acid phosphatase enzyme increases in prostate cancer - Alkaline phosphatase ALP enzyme increases in obstructive liver disease, bone diseases, and hyperparathyroidism - Lactate dehydrogenase LDL enzyme increases in heart, liver, and blood diseases - ALT enzyme, aka serum glutamic pyruvic transaminase SGPT increases in liver and heart diseases - AST aka serum glutamic oxaloacetic transaminase SGOT increases in liver and heart disease Overview of cell death Programmed cell death is regulated processes which occur through apoptosis and autophagy Necrosis is cells earth due to extensive damage and cellular swelling - Historically considered passive/accidental, but recent evidence indicates programmed necrosis or necroptosis can occur Cell death: Stimuli inducing cell death - non self directed or self-directed Regulation of cell death process - Self-directed: caspase activation pathways and autophagy signaling Degradation of cellular structures and cells earth Non Self-directed -> necrosis Self directed -> apoptosis type 1 cell death and autophagy type 2 cell death Lethal cell injury - cell death 3 types of cell deaths: apoptosis, autophagy, and necrosis Apoptosis - programmed and controlled cell death, involved in normal cell deletion and renewal (DNA damage) Autophagy - conserved degradation of the cell that removed unnecessary or dysfunctional components through a lysosome-depending regulated mechanism Necrosis - cell swelling, rupture of the cell membrane, and inflammation due to cell injury Apoptosis: Fallen apart - Involves caspases - Eliminates cells that are - Worn out - Have been produced in excess - Have developed improperly - Have genetic damage - Turned over during normal functioning Autophagy: - Basal autophagy exists in cells to aid in the regular turnover of intracellular material - Autophagy is also critical cellular response to stress, such as nutritional depletion - Delivers cytoplasmic material to membrane-bound organelles called lysosomes, thereby allowing the recycling of intracellular components - - Deregulation of autophagy is linked to several diseases: cancer Necrosis: - Unregulated enzymatic digestion of cell components - Loss of cell membrane integrity -> uncontrolled release of cell content into extracellular space -> inflammatory response - Necrosis interferes with cell replacement and tissue regeneration Key points - cell injury Cell injury if severe and irreversible -> necrosis and apoptosis Mild injury -> reversible injury -> normal cell in homeostasis or steady state Injurious stimulus -> stress -> adaptation: - Hypertrophy - Hyperplasia - Atrophy - Metaplasia Mutagen - Agent known to increase the frequency of mutations - Radiation - Chemicals - Nitrogen mustard, vinyl chloride, alkylating agents, formaldehyde, sodium nitrite  Mutations - Any inherited alteration of genetic material - Chromosome- aberrations - Base pair substitution - One base pair is substituted for another - Frameshift mutation - Insertion or deletion of one or more base pairs - Causes a change in the entire “reading frame” - Spontaneous mutation - Mutation that occurs in absence of exposure of known mutagens - Mutational hot spots - Areas of the chromosomes that have high mutation rates Single- Gene disorders - Autosomal dominant inheritance - Affected offspring usually produced by union of normal parent with affected heterozygous parent - Allele may be disease causing or normal - On average half of offspring will be normal, half will be heterozygous and express disease - Recurrence risk - The probability that an individual will develop a genetic disease - Recurrence risk of an autosomal dominant trait - When one parent is affected by an autosomal dominant disease and the other is normal, the occurrence and recurrence risks from each are one half - Must remember each birth if an independent event- every child born, regardless of siblings outcome, has a recurrence risk of one half - Epigenetics - Same DNA sequence can produce different phenotypes due to chemical modification that alters expression of genes - Genomic imprinting - One parent imprints(inactivates) the gene during transmission to offspring - Autosomal recessive inheritance - In most cases, both parents of affected individuals are heterozygous carriers - Recurrence risk for offspring is 25% - Male and females equally affected - Example - Cystic fibrosis Epigenetrics and human development - Embryonic stem cells - Totipotent - Gives rise to all cell types of an organism - Specific genes are expressed only in the cells and tissues types in which their gene products typically function - Factor VII expression in hepatocytes - Dopamine receptor expression neurons -All cells in an individual contain almost same information - Epigenetic modification enables cells to achieve diverse functions - Housekeeping gene remain transcriptionally active in almost all cells - Encoding histones - DNA and RNA polymerases - Ribosomal RNA genes Epigenetrics and Cancer DNA methylation - Tumor cells typically exhibit genome wide hypomethylation - Tumor-suppressor genes often hypermethylated RB1 gene - retinoblastoma BRCA1 gene - some inherited breast cancers miRNAs - Encode small RNA molecules that bind to ends of mRNA Degrades and prevents translation - When microRNA genes are methylated, their mRNA, targets are overexpressed - Associated with metastasis Epigenetic screening for cancer - Shows promise as a tool for early cancer diagnosis Strategies for treatment for epigenetic diseases - Pharmaceutical agents may reverse changes associated with disease phenotype - DNA demethylating agents 5-azacytidine - - Histone deacetylase inhibitors - miRNA coding Common mechanisms in cell injury - Mitochondrial damage: ATP decrease and ROS increase - Entry of Ca++ : mitochondrial permeability increase and active of cellular enzyme - Membrane damage - loss of cellular components and enzymatic digestion of cellular components - Protein misfolding, DNA damage - activation of proapoptotic proteins