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First Foundations: Essentials of General Human Pathology

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  1. First Foundations: Essentials of General Human Pathology Paul G. Koles, MD Asst. Prof. Pathology and Surgery Director of Pathology Education Boonshoft School of Medicine at Wright State University

  2. General Pathology Outline • 1: Cellular Adaptations: Injury, Death, and Aging • 2: Acute and Chronic Inflammation • 3: Tissue Regeneration and Repair • 4: Hemodynamic Disorders • 5: Neoplasia

  3. Scope of This Review • Restricted to human diseases • Focus on concepts of general pathology • Definitions for accurate description of disease • Mechanismsexplaining development of disease, including known specific etiologies • Gross and microscopic alterations in cells, tissues, and organs which characterize disease (“morbid anatomy”) • Natural history and prognosis of disease • Clinical signs and symptoms which correlate with a particular disease or group of diseases

  4. Methods of Pathology • Morphologic • Gross observation and description • Microscopic examination: light, fluorescence, electron microscopy (scanning & transmission) • Molecular/Biochemical/Cytogenetic • Applied clinical and research methods • Immunologic • Serum, plasma, cell suspensions, tissues • Microbiologic • Cultures, biochemical assays, immunologic

  5. Why Must Physicians Study Pathology? • Rational diagnosis and treatment must be based on clear understanding of disease: Etiology The cause of a disease Pathogenesis The mechanism producing a disease Morbid anatomy Structural changes due to disease Microscopic abnormalities in tissues Pathologic changes visible to naked eye Histopathology Gross Pathology

  6. Virchow’s Hypothesis • Ruldolf Virchow (1821-1902), German pathologist, father of modern pathology • “All diseases are…reducible to disturbances, either active or passive, of large groups of living units whose functional capacity is altered in accordance with the state of their molecular composition and is thus dependent on physical and chemical changes of their contents.” --Virchow, Cellular Pathology, 1855 • Implication: diseases can be defined by observing morphologic changes in cells

  7. Responses to injurious stimuli • Cells alter their structure and/or function:

  8. Cellular Responses

  9. Major Patterns of Cell Death NECROSIS • Cell death after exogenous stimuli cause irreversible cell injury = • Causes: ischemia, infectious agents, chemical and physical agents, inflammation • Programmed cell death via internal mechanism coordinated by dedicated genes = • Elimination unwanted cells in embryogenesis and normal homeostasis • Dead cells removed with minimal disruption and no significant inflammation • May be accompanied by necrosis in disease APOPTOSIS

  10. Morphology of Necrosis Condensation nuclear chromatin into textureless blob = Fragmentation of nucleus = Dissolution of nucleus = PYKNOSIS Karyorrhexis Karyolysis

  11. Necrosis vs. apoptosis

  12. Embryogenesis Hormone-dependent involution Cell deletion during normal proliferation Deletion of immunocompetent T cells in developing thymus to prevent autoimmunity Cell death in neoplasm Cell death induced by cytotoxic T cells (organ rejection) Cell atrophy secondary to chronic ductal obstruction Cell death in viral infections (eg acidophil bodies in viral hepatitis) Physiologic Apoptosis / Pathologic Apoptosis

  13. Morphology of Apoptosis Normal thymic cortical lymphocyte, scanning EM Apoptotic thymic cortical lymphocyte, scanning EM Formation of cytoplasmic blebs Figs. 3.3b, 3.3c, Oxford Textbook of Pathology, Oxford Press, 1992.

  14. Mechanisms in Apoptosis • Four separable but overlapping components 1) Initiation by two distinct pathways • Extrinsic = • Intrinsic = 2) Family of intracellular regulatory molecules which control apoptosis = 3) Execution phase, or “death program” accomplished by family of proteases 4) Removal of dead cells by Death Receptor-Initiated Mitochondrial Bcl-2 proteins Caspase Phagocytosis

  15. Apoptosis: scheme of events Intrinsic pathway initiated by: Extrinsic pathway initiated by: Engagement of death receptor Withdrawal growth factors, hormones

  16. Role of Bcl-2 in apoptosis control • Major regulator of mitochondrial function • Bcl-2 located in outer mitochondrial membrane, endoplasmic reticulum, and nuclear envelope • Bcl-2 normally apoptosis by: • Direct prevention of cytochrome c release • Binding to & sequestration of pro-apoptotic protease activating factor (Apaf-1) INHIBITS

  17. Bcl-2 suppression of apoptosis Fig. 1-30, Pathologic Basis of Disease, 2005.

  18. Application: Bcl-2 overexpression Diagnosis? Follicular lymphoma vs. reactive follicular hyperplasia IHC for Bcl-2, reactive follicle IHC for Bcl-2, neoplastic follicle Hallmark of follicular lymphoma: which translocation juxtaposes IgH locus and Bcl-2 locus, resulting in overexpression of Bcl-2 in B-lymphocytes? t (14, 18)

  19. Intracellular Systems Maintenance of ionic and osmotic homeostasis Aerobic respiration by oxidative phosphorylation Protein synthesis Preservation genetic apparatus Site of vulnerability Intracellular systems vulnerable to injury Plasma membrane Mitochondria Rough endoplasmic reticulum Nucleus

  20. Mechanisms of cell injury • ATP depletion • Normal biochemical pathways producing ATP = • Oxygen and oxygen-derived free radicals • Loss of calcium homeostasis • Defects in membrane permeability • Irreversible mitochondrial damage Oxidative phosphorylation Glycolysis

  21. Irreversible mitochondrial damage Damage from any cause creates a high-conductance channel in the inner mitochrondrial membrane (Mitochondrial permeability transition), preventing maintenance of proton motive force for oxidative phosphorylation and generation of ATP. Leakage of cytochrome c into cytosol, which promotes cell death via APOPTOSIS Fig 1-12, Pathologic Basis of Disease, 2005

  22. Stimuli causing human cell injury HYPOXIA • Oxygen deprivation = • Most common cause of oxygen deprivation is decreased delivery of blood = • Physical and chemical agents • Infectious agents • Immunologic reactions • Genetic derangements • Nutritional imbalances (deficiency/excess) ISCHEMIA

  23. Role of oxygen in cell injury Fig. 1-2, Pathologic Basis of Disease, WB Saunders, 1999. Imbalance between O2 free-radical generation and O2 free-radical scavenging = OXIDATIVE STRESS

  24. Cell Injury by Reactive Oxygen Species

  25. Scavenging mechanisms which remove free radicals • Spontaneous decay free radicals (unstable) • Antioxidants: block formation free radical or inactivate them • Vitamins E / A / C; • Binding of metal ions to storage and transport proteins, minimizing OH* (hydroxyl ion) formation. • Fe storage protein = • Cu transport protein= • Enzymatic scavenging systems: 3 important ones FERRITIN CERULOPLASMIN 1 superoxide dismutase 2 glutathione peroxidase 3 catalase

  26. Altered calcium homeostasis Increased cytosolic Ca++ by influx and release from organelles: enzyme activation with multiple damaging effects Fig. 1-13, Pathologic Basis of Disease, 2005

  27. Defects in membrane permeability (plasma and organelle membranes) Transmembrane channels on plasma membrane initiated by cytolytic products of CD8+ T lymphocytes are called: PERFORINS

  28. Types of Ischemic Injury • Reversible: Cell damage repaired if adequate blood flow restored (e.g, effort-related angina) • Irreversible: ischemia produces cell damage that cannot be repaired, reaching “point of no return”. • Restoration of blood flow to previously ischemic cells may exacerbate cell injury, causing it to proceed at faster pace (while preserving “at risk” tissue) = REPERFUSION INJURY Clinical implications for interventional therapy of ischemic organs: critical factor is . . . . SPEED!

  29. Ischemic cell injury: cardiac myocyte Exit of _______ allows lab dx of cell death Membrane damage Influx of _______ activates cytosolic enzymes anaerobic glycolysis ATP Fig. 1-22, Pathologic Basis of Disease, 2005

  30. Irreversible Injury • What is the point of no return within cell? • 1) dysfunction causing marked depletion of ATP. • 2) Disturbed function of around mitochondria, lysosomes, and entire cytoplasm Mitochondrial Membranes

  31. Morphology of Reversible Injury • Electron Microscopy • Plasma membrane alterations (blebs, distortions) • Mitochondrial swelling with amorphous densities • Dilation of endoplasmic reticulum • Nuclear alterations • Light microscopy: • Increased intracellular H2O, sodium, & chloride with decreased potassium  marked swelling of cell, called: Hydropic degeneration (hydropic change)

  32. Skin: Epidermal Hydropic Change Intracellular hydropic change Intercellular edema (spaces between cells) Inflammation with eosinophils History: 45 year old woman who applied miracle anti-aging skin cream for the second time and developed a pruritic erythematous papular rash 24 hours later. Diagnosis = Hypersensitivity Dermatitis

  33. Chemical Injury • Two mechanisms of injury • DIRECT: chemical combines with specific organelle, e.g. mercuric chloride binds to sulfhydryl groups on cell membrane, causing increased membrane permeability, especially in two organs: • INDIRECT: Chemical is not biologically active, and must be converted to reactive toxic metabolites, usually by in smooth endoplasmic reticulum of hepatocytes Kidney tubular cells, GI tract epithelial cells P-450 mixed function oxidases

  34. Chemical Injury: Acetominophen Overdose Therapeutic dose: 250-500 milligrams Toxic dose: 15-25 grams Hepatocytes produce small amounts of toxic metabolite neutralized by glutathione; no cellular injury observed Hepatocyte glutathione depleted; toxic metabolite destroys proteins and nucleic acids: liver cell necrosis occurs 2-4 days post-overdose Treatment of overdose with antioxidant sulfhydryl compounds to replenish GSH and reduce oxidative damage to hepatocytes by toxic metabolites. Drug therapy is based on plasma acetominophen levels correlated with time after ingestion. N-acetylcysteine (precursor of glutathione) Drug to treat acetominophen overdose?

  35. Acetominophen and hepatotoxicity: Rumack-Matthew nomogram Case: 33 year old depressed unemployed man ingests unknown amount of acetominophen around 3 pm; brought to ER at 8 pm with plasma level of 250 ug/mL. What to do now?

  36. MorphologicPatterns of Necrosis COAGULATIVE • = most common type • Denaturation of structural and enzymic proteins • Gradual nuclear degeneration • Cell outlines may persist for several days • Typically seen in hypoxia-mediated cell death

  37. Coagulation Necrosis Nuclear karyolysis Neutrophils infiltrate between degenerating myocytes Eosinophilic cytoplasm (denaturation proteins) Normal myocardium Myocardium, early infarction

  38. Morphologic Patterns Necrosis (2) LIQUEFACTIVE • = complete enzymatic digestion of cells, transforming tissue into a viscous mass of amorphous material containing dead cells • Seen in infections with severe, marked degree of inflammation and/or toxin elaboration, such as • Seen in hypoxic death of CNS cells Group A Streptococci, Clostridia (Pseudomonas, Staphylococci)

  39. Liquefaction necrosis Completely acellular necrotic debris (enzymatic digestion) Surrounding zone of inflammatory cells (mediators of necrosis) Kidney, focal necrosis, secondary to systemic fungal infection

  40. Morphologic Patterns Necrosis (3) Caseous necrosis • = a distinctive form of coagulation necrosis in granulomatous inflammation • Gross appearance of necrosis is “caseous”, meaning like cheese (yellow-white, friable) • Seen in tuberculosis and certain fungal infections • Distinctive lesion is characterized by central area of caseous necrosis with surrounding histiocytes, multinucleated giant cells, and lymphocytes Caseating granuloma

  41. Pulmonary tuberculosis Lung with demarcated zone of yellow-white necrosis Caseating granuloma = Mulinucleated giant cells (aggregated histiocytes) Central acellular necrosis Peripheral zone of histiocytes and lymphocytes What may be found by acid-fast stain in the necrotic zone? _______________________

  42. Caseating granulomas Non-caseating granulomas Application: inflammatory diseases with granulomatous inflammation Mycobacterium tuberculosis Foreign materials (e.g., pneumoconiosis of lung) Fungi (many) Hypersensitivity reactions Treponema pallidum Sarcoidosis Leprosy (M. leprae)

  43. Adapatations of Growth and Differentiation = physiologic and morphologic changes in cells which preserve viability while responding to various stimuli = genetically programmed development of cell into mature functional state, demonstrated by specific morphologic features ADAPTATION DIFFERENTIATION

  44. Molecular mechanisms of adaptation • Receptor binding (up and down regulation) • Signal transduction • = DNA-directed synthesis of RNA • = messenger RNA-directed synthesis of protein • Regulation of protein synthesis, packaging, and release Transcription Translation

  45. Adaptations: definitions Hyperplasia = increase in the number of cells in an organ or tissue ** = decrease in the number of cells in an organ or tissue Hypoplasia **Note: in order for cells to respond with this adaptation, they must be capable of undergoing mitosis through synthesis of DNA.

  46. Types of Hyperplasia Physiologic hyperplasia • = appropriate cellular proliferation to maintain normal function • = inappropriate cellular proliferation which goes beyond range of normal function, possibly causing signs or symptoms of disease. Pathologic hyperplasia

  47. Hyperplasia: Physiologic Breast lobule, normal 25-year-old female Breast lobule, 25-year-old pregnant female: increase in number of acini within lobule 25-year-old post-partum female: secretory products in apical cytoplasm of epithelial cells; what kind of secretion? Apocrine (lactation) Fig. 25-2, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.

  48. Mechanism of compensatory hyperplasia Signal to remnant hepatocytes that prepares for response to hepatocyte growth factor (HGF), converting inactive matrix-associated HGF to active form, termed ___________ Priming Marked DNA synthesis within hepatocytes, resulting in cellular _________________ Proliferation PROLIFERATION Cessation of hyperplasia after liver mass is restored, termed ___________________ Growth inhibition Fig. 2-2, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.