Transcript Causes of disease_adaptive responsesx

Cellular Pathology
Prof Orla Sheils
Causes of Disease
Adaptive Responses
2nd year Pathology 2011
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
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Lecture available on line at:
http://www.medicine.tcd.ie/Histopathology/courses/studentare
a.htm
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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.
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Cell injury
 Reversible.
Cell swelling/Hydropic change.
Fatty Change.
 Irreversible.
Cell Death (Myocardial Infarction)
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Types of Cell Injury
1)
Oxygen Deprivation / Re-oxygenation
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(Free radicals).
2)
Physical Agents.
3)
Chemical Agents / Drugs.
4)
Infectious Agents.
5)
Immunologic Reactions.
6)
Genetic Derangements.
7)
Nutritional Imbalances.
8)
Aging (See next lecture)
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Cell injury
 Exogenous:
 Physical (Heat and cold)
 Chemical (toxins and drugs)
 Biological (Viruses and bacteria)
 Endogenous:
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Genetic defects.
Metabolites.
Hormones.
Cytokines
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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.
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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)
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CO poisoning- cherry pink skin
discolouration
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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:
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Anatomic pattern of vascular supply
Rate of vascular occlusion
Vunerablity of tissue affected
Oxygen content of blood
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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.
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2) Physical Agents.
 Mechanical Trauma.
 Extremes of Temperature.
 Barotrauma.
 Electric Shock.
 Radiation.
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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.
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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.
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 Late effects of radiation:
 Atrophy.
 Narrowing of blood vessels.
 Fibrosis.
 Inflammation
 Cataracts
 Carcinoma.
 Teratogenic.
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3) Chemical Agents and Drugs
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Hypertonic Solutions.
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Oxygen.
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Poisons: Arsenic, Cyanide, Mercury.
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Environmental Pollutants.
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Insecticides/ herbicides.
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CO
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Asbestos
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1) Interstitial lung fibrosis.
2) Bronchogenic carcinoma.
3) Pleural Effusions.
4) Pleural plaques.
5) Mesotheliomas.
Recreational Drugs / C2H5OH
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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.
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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
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4) Infectious Agents.
 Bacteria
 Viruses
 Fungi
 Chlamydiae,Rickettsiae,Mycoplasma
 Protozoa
 Helminths
 Ectoparasites
 Bacteriophages, Plasmids
 Prions.
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How microrganisms cause disease
 Entering cells
 Releasing toxins
 Damaging blood vessels
 Inducing host responses with additional damage
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Suppuration
Scarring
Hypersensitivity reactions
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Exotoxin
Endotoxin
Secreted from living
organism
Protein
Part of dead organism
Elicits immune reaction
No immune reaction (weak)
Heat labile
Heat stable
LPS
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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
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5) Immunologic
 Hypersensitivity
 Exaggerated response of immune system to
exogenous antigens.
 Autoimmunity
 Inappropriate response of immune system to
endogenous antigens.
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6) Genetic Derangements
 Chromosomal abnormalities.
 Single gene disorders.
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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
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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.
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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.
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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).
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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
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Pathologic Hyperplasia
 Hyperoestrogenism and atypical endometrial
hyperplasia.
 Squamous hyperplasia induced by viruses.
 HPV (wart) virus.
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Endometrial hyperplasia
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Benign Prostatic Hyperplasia
Macroscopy
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Microscopy
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
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Hypertrophy
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Left Ventricular Hypertrophy
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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.
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Causes of Atrophy
 Disuse Atrophy -
Workload.
 Denervation atrophy.

blood supply.
 Inadequate nutrition.
 Loss of endocrine stimulation.
 Senile atrophy.
 Pressure/Involution.
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Muscle Atrophy
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Cerebral atrophy
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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.
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Metaplasia
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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 mucinproducing 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
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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")
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Metaplasia
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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
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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.
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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
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