Cellular Pathology Prof Orla Sheils

1. Cellular PathologyProf Orla Sheils Causes of Disease Adaptive Responses 2nd year Pathology 2011

2. References, Reading and Websites • Pathologic Basis of Disease - Robbins. • Cell, Tissue and Disease. The Basis of Pathology- Woolf • Pathology Secrets – Damjanov. Chapters 1 and 7 • http://www.pathguy.com • http://medlib.med.utah.edu/WebPath/webpath.html 2nd year Pathology 2011

3. Lecture available on line at: http://www.medicine.tcd.ie/Histopathology/courses/studentarea.htm 2nd year Pathology 2011

4. Causes of Disease • Disease does not exist except as a reaction to injury. • Concept of Homeostasis. “The Steady State” or equilibrium with the environment. • Cellular adaptation. Physiologic. Morphologic. • At the limits of cellular adaptation or in cases where adaptation is not possible then “cell injury” may occur. 2nd year Pathology 2011

5. Cell injury • Reversible. Cell swelling/Hydropic change. Fatty Change. • Irreversible. Cell Death (Myocardial Infarction) 2nd year Pathology 2011

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8. Types of Cell Injury • Oxygen Deprivation / Re-oxygenation • (Free radicals). • Physical Agents. • Chemical Agents / Drugs. • Infectious Agents. • Immunologic Reactions. • Genetic Derangements. • Nutritional Imbalances. • Aging (See next lecture) 2nd year Pathology 2011

9. Cell injury • Exogenous: • Physical (Heat and cold) • Chemical (toxins and drugs) • Biological (Viruses and bacteria) • Endogenous: • Genetic defects. • Metabolites. • Hormones. • Cytokines 2nd year Pathology 2011

10. 1) Oxygen Deprivation • Terms: Hypoxia/Anoxia. Ischaemia. • Hypoxia is a reduction of the amount of oxygen delivered to cells. It is the most common cause of cell injury and death. • Ischaemia is a reduction in the perfusion of a body part or organ in relation to its needs. 2nd year Pathology 2011

11. Hypoxia V Ischaemia. • Hypoxia affects aerobic oxidative respiration. Glycolytic energy production can continue but there is greatly diminished ATP supply. • Causes of hypoxia: • Ischaemic hypoxia (Acute white limb, Heart Failure) • Hypoxic hypoxia (Altitude, respiratory failure) • Anaemic hypoxia (Anaemia) • Histotoxic hypoxia (CO Poisoning, Cyanide) 2nd year Pathology 2011

12. CO poisoning- cherry pink skin discolouration 2nd year Pathology 2011

13. Hypoxia V Ischaemia. • Ischaemia compromises the availability of metabolic substrates. It is a form of hypoxia. • Causes of Ischaemia: Impeded arterial flow, impeded venous drainage. • Development of an infarct depends on: • Anatomic pattern of vascular supply • Rate of vascular occlusion • Vunerablity of tissue affected • Oxygen content of blood 2nd year Pathology 2011

14. Hypoxia • Neurons: Frank necrosis after being deprived of oxygen for 3-5 minutes at normal temperature clinically, brain damage follows much shorter intervals. • Heart muscle cells can last 30-60 minutes. • Liver cells and renal tubular cells can last for 1-2 hours without oxygen before they are irreversibly damaged ( but easy to replace.) • Skin fibroblasts can last for many hours. 2nd year Pathology 2011

15. 2) Physical Agents. • Mechanical Trauma. • Extremes of Temperature. • Barotrauma. • Electric Shock. • Radiation. 2nd year Pathology 2011

16. Radiation • Electromagnetic (Non-ionizing) radiation: • Long wavelengths, low frequency • Radiowaves, microwaves • Vibration and rotation of atoms • Particulate (Ionizing) radiation: • Short wavelengths, high frequency • X-rays, gamma rays, cosmic rays • Ionize biologic molecules and eject electrons • UV injury- UVA/UVB/UVC: skin cancer • Radiation Dose is measured in rads (1 rad produces absorption of 100 ergs energy/gm tissue, 100 rads = 1 Gray). Background Radiation = .00001Gy. 2nd year Pathology 2011

17. Effects of Radiation • Main target molecule = DNA • Early effects of radiation: • Acute Radiation sickness. • 0.5 - 2 Gy: Fatigue, Nausea, vomiting. • 2 – 6 Gy: Haematopoietic radiation syndrome • 3 – 10 Gy: GIT radiation syndrome. Diarrhea and fluid and electrolyte loss. 50-100% Mortality within 2 weeks. • Over 10 Gy: Cerebral radiation syndrome. RIP in 14-36 hrs. • 1000 Gy: RIP Stat. 2nd year Pathology 2011

18. Late effects of radiation: • Atrophy. • Narrowing of blood vessels. • Fibrosis. • Inflammation • Cataracts • Carcinoma. • Teratogenic. 2nd year Pathology 2011

19. 3) Chemical Agents and Drugs • Hypertonic Solutions. • Oxygen. • Poisons: Arsenic, Cyanide, Mercury. • Environmental Pollutants. • Insecticides/ herbicides. • CO • Asbestos • 1) Interstitial lung fibrosis. • 2) Bronchogenic carcinoma. • 3) Pleural Effusions. • 4) Pleural plaques. • 5) Mesotheliomas. • Recreational Drugs / C2H5OH 2nd year Pathology 2011

20. Chemical Injury • Biological molecules react like any other chemicals. • Acids and alkalis hydrolyze membranes • Poisons like mercuric ion tie up sulfhydryl groups and destroy the cell. • Formalin / formaldehyde crosslink amino groups on proteins and nucleic acids. Histopathologists use this chemistry to “fix tissues”. • Current thinking is that most simple poisons that cause actual cell necrosis require activation to form free radicals. For example, carbon tetrachloride (old-fashioned cleaning fluid) is turned into CCl3.- radical in the smooth endoplasmic reticulum of the liver. 2nd year Pathology 2011

21. Chemical Injury • Other classic poisons affect the more vulnerable parts of the cells. • Depending on the poison and dose, there may or may not be necrosis: • Cell membranes: digitalis • Oxidative phosphorylation: cyanide • Ribosomes: toadstools • Genes: chemotherapeutic agents • Synapses: strychnine, ergot 2nd year Pathology 2011

22. 4) Infectious Agents. • Bacteria • Viruses • Fungi • Chlamydiae,Rickettsiae,Mycoplasma • Protozoa • Helminths • Ectoparasites • Bacteriophages, Plasmids • Prions. 2nd year Pathology 2011

23. How microrganisms cause disease • Entering cells • Releasing toxins • Damaging blood vessels • Inducing host responses with additional damage • Suppuration • Scarring • Hypersensitivity reactions 2nd year Pathology 2011

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25. Toxin Producing Organisms • Vibrio cholera. • Activation of cAMP. Massive secretory diarrhoea. • Diphtheria. • Inactivates ribosomes. • Damage to heart, nerves, liver, kidneys. • Clostridia perfringens/botulinum/tetani • Degrade cell membranes: gangrene • Block ACh release: botulism/tetanus • Staph. aureus. • Scalded skin syndrome 2nd year Pathology 2011

26. 5) Immunologic • Hypersensitivity • Exaggerated response of immune system to exogenous antigens. • Autoimmunity • Inappropriate response of immune system to endogenous antigens. 2nd year Pathology 2011

27. 6) Genetic Derangements • Chromosomal abnormalities. • Single gene disorders. 2nd year Pathology 2011

28. 7) Nutritional Imbalances. • Protein energy deficiency (PEM) • Marasmas. Muscle wasting, wrinkled skin, Hair loss. • Kwashiorkor. Excess protein deficiency: Scaly skin, Swollen abdomen (ascites), swollen ankles, Hypoalbuminemia. • Specific vitamin deficiencies • Vit C: (ascorbic acid) • Vit. D: Rickets, Osteomalacia. • Vit A: Xeropthalmia, Bitot’s spots, keratomalacia, night blindness • Niacin: Pellagra- Dermatitis, Diarrhoea, Dementia • Anorexia nervosa. • Dietary indiscretion – Cholesterol. 2nd year Pathology 2011

29. Cellular adaption • Hyperplasia. • Hypertrophy. • Atrophy. • Metaplasia. • If cell cannot adapt to injury/stress, it may undergo apoptosis (programmed cell death). • If this does not occur, the cell will undergo necrosis. 2nd year Pathology 2011

30. Hyperplasia • An increase in the Number of cells in an organ or tissue. • Hyperplasia means cells growing more numerous. • Usually accompanied by hypertrophy. • Can only occur in cells capable of making new DNA (capable of division). 2nd year Pathology 2011

31. Physiologic Hyperplasia A Demand - led physiological event • Hormonal: Endometrial proliferation after oestrogen stimulation. • Compensatory: Hyperplasia of liver after partial hepatectomy. • Breast and Thyroid at times of puberty and pregnancy 2nd year Pathology 2011

32. Pathologic Hyperplasia • Hyperoestrogenism and atypical endometrial hyperplasia. • Squamous hyperplasia induced by viruses. • HPV (wart) virus. 2nd year Pathology 2011

33. Endometrial hyperplasia 2nd year Pathology 2011

34. Benign Prostatic Hyperplasia Macroscopy Microscopy 2nd year Pathology 2011

35. Hypertrophy • HYPERTROPHY: Increase in the sizes of cells, and hence the size of the organ. • Often occurs in cells that have limited abilities to divide e.g. muscle • Physiological: Skeletal muscle hypertrophy due to exercise • Pathological: Hypertrophy of the overworked heart of an aerobic athlete, hypertension victim, or victim of aortic valve stenosis or other cardiac structural defect 2nd year Pathology 2011

36. Hypertrophy 2nd year Pathology 2011

37. Left Ventricular Hypertrophy 2nd year Pathology 2011

38. Atrophy • ATROPHY: "Shrinkage in the size of the cell by loss of cell substance" (Robbins), without the cell actually dying. When many cells each become smaller, the organ itself become smaller. Defined this way, atrophy is very reversible. 2nd year Pathology 2011

39. Causes of Atrophy • Disuse Atrophy - Workload. • Denervation atrophy. • blood supply. • Inadequate nutrition. • Loss of endocrine stimulation. • Senile atrophy. • Pressure/Involution. 2nd year Pathology 2011

40. Muscle Atrophy 2nd year Pathology 2011

41. Cerebral atrophy 2nd year Pathology 2011

42. Metaplasia • METAPLASIA: (Adaptive) substitution of one type of adult or fully differentiated cell for another type of adult (or fully differentiated) cell. -Robbins. • "A reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type." -Robbins. • "Conversion of a differentiated cell type into another" -- R&F. 2nd year Pathology 2011

43. Metaplasia 2nd year Pathology 2011

44. Metaplasia • Transformation of the gallbladder or urinary bladder epithelium to stratified squamous epithelium in the presence of foreign bodies (stones, schistosome eggs) • Replacement of airway pseudostratified mucin-producing ciliated columnar epithelium by an epithelium consisting almost entirely of goblet cells (cigarette smokers and asthmatics) • Replacement of the columnar mucoid epithelium of the endocervix by stratified squamous epithelium in women infected with wart virus 2nd year Pathology 2011

45. Metaplasia • Replacement of most columnar and transitional epithelium by stratified squamous epithelium, and replacement of corneal epithelium by heavily-keratinized epithelium (vitamin A deficiency) • Replacement of fibrous tissue by calcified bone (many scars, which in the real world may be considered "normal") • Replacement of laryngeal, tracheal, and costal cartilages by bone (old age) • Replacement of normal gastric epithelium with intestinal epithelium in stomach disease ("intestinalization") 2nd year Pathology 2011

46. Metaplasia 2nd year Pathology 2011

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48. Adaptation If underlying stimulus is removed, cells can return to normal. • Hyperplasia  cell loss due to apoptosis  normal number of cells • Hypertrophy lysosome ingestion of excess cell organelles  normal cell size • Atrophy  production of additional organelles  normal cell size • Metaplasia differentiation back to original cell type 2nd year Pathology 2011

49. Adaptation If stimulus persists, pathology results • Cell death • Loss of cell function • Malignant change • The latter is most likely to occur in the setting of metaplasia (of any type) which is often a significant risk factor for the development of carcinoma. • Often preceded by development of pre-invasive neoplastic change = dysplasia. 2nd year Pathology 2011

50. Summary • Causes of disease • Types of injurious agents • Hypoxia & Ischaemia • Physical agents including Radiation • Chemical injury • Infectious agents • Immune / Genetic / Nutritional • Mechanisms of cellular adaption • Consequences 2nd year Pathology 2011