General Pathology Cellular Injury and Death PDF

# General Pathology ## Cellular Injury and Death - **Normal Cell (Homeostasis)** - **Stress, Increased Demand** - **Adaptation** - Adapted Myocyte (Hypertrophy) - Adaptation: Response to Increased Load - **Injurious Stimulus** - **Inability to Adapt** - Cell...

# General Pathology ## Cellular Injury and Death - **Normal Cell (Homeostasis)** - **Stress, Increased Demand** - **Adaptation** - Adapted Myocyte (Hypertrophy) - Adaptation: Response to Increased Load - **Injurious Stimulus** - **Inability to Adapt** - Cell Injury - Cell Death - **Causes of Cell Injury** 1. **Hypoxia** - **Definition:** Lack of oxygen - Most common cause of cell injury - Leads to inability of the cell to synthesize sufficient ATP by aerobic oxidation - Hypoxia is due to either: - **Ischemia:** Insufficient blood supply to tissues or organs. - Atherosclerosis, thrombosis, embolism and cardiopulmonary failure - **Decreased Oxygen Carrying Capacity of Blood:** As in cases of anemia 2. **Infection:** - Due to bacteria, viruses, parasites and fungi - Mechanism: - Direct effect of organisms on cells - Production of toxins - Host immune response 3. **Chemical Causes:** Such as: - Strong acids and alkalies - Drugs - Poisons - Accumulation of endogenous toxins such as in uremia and jaundice - Occupational disease: Such as asbestosis, silicosis and carbon monoxide poisoning - Social lifestyle: Such as alcohol intake and intravenous (I.V) drug abuse 4. **Physical Causes:** Such as: - Heat - Cold - Radiation - Burns 5. **Mechanical Causes:** Such as: - Trauma - Prolonged Compression 6. **Nutritional Causes:** Such as: - Inadequate calorie intake: Such as in marasmus and kwashiorkor - Excess calorie intake: Such as obesity - Vitamin deficiency: Vit. A, B, D, E, K - Hypervitaminosis 7. **Immunologic Reaction:** Such as in: - Hypersensitivity reaction - Auto-immune diseases 8. **Congenital Disorders:** Inborn errors of metabolism ## Types of Cellular Adaptive Changes - When cells are exposed to one of the above irritants, they will undergo one or more of the following types of adaptive changes: 1. **Accumulation of abnormal substances:** Like - **Water:** Results in cellular swelling - **Lipid:** Results in fatty change - **Glycogen:** Results in glycogen storage diseases - **Calcium:** Results in pathological calcification - **Hyaline material:** Results in intra- or extra-cellular hyalinosis 2. **Change of the cellular size or number:** Results in increase or decrease of size or number of the cells (hyperplasia, hypertrophy, atrophy, metaplasia and dysplasia) 3. **Undergo a lethal change:** This results in apoptosis or necrosis ## Reversible Cell Injury ### A. Cellular Swelling - **Definition:** It is a disturbance in the metabolism of the cell resulting in accumulation of water in the cytoplasm. - Usually affects the cytoplasm and nucleus is free, so it is reversible - It can be reversed when the stimulus or the cause of injury is removed. - **It is either:** 1. **Cloudy Swelling:** Accumulation of water inside the cell in the form of fine droplets. 2. **Hydropic Degeneration:** Accumulation of water inside the cell in the form of large vacuoles - **Mechanism:** - **Decreased ATP production:** By oxidative phosphorylation due to affection of mitochondria - **Failure of sodium pump:** Resulting in: - Influx of sodium (Na) and water - Efflux of potassium (K) - Swelling of endoplasmic reticulum - Swelling of the cell (hydropic swelling) ### B. Fatty Change - **Definition:** It is a form of reversible cell injury characterized by accumulation of fat in non-fatty tissue. - **Sites:** Liver, kidney, heart and muscles - **Causes:** - **Fatty change of the liver** 1. Excess intake of fat and carbohydrates (obesity) 2. Specific liver diseases: Such as viral hepatitis 3. Starvation 4. Diabetes mellitus - **Mechanism:** Under normal conditions, free fatty acids brought to the liver cells are conjugated with proteins to form lipoproteins. Damaged liver cells cannot perform this conjugation and free fatty acids accumulate within the liver cells. - **Pathology:** - **Gross:** - The liver is enlarged, yellow, soft, and greasy - Cut section is yellowish with round border - **Microscopic:** - Hepatocytes with vacuolated cytoplasm and compressed nucleus at one side (signet ring appearance) - The early fatty change is reversible if the cause is removed ## Irreversible Cell Injury - **Usually affects the nucleus, so it is irreversible** - **It is either: necrosis or apoptosis** ## Necrosis - **Definition:** Localized tissue death in living body - In the dead cell, energy production and anabolic activities stop completely; whereas the lytic activities of released lysosomal enzymes continue. As a result of this, the cell undergoes a process of self digestion (autolysis), and within few hours characteristic morphological changes start to appear. - This triggers an acute inflammatory reaction in which white blood cells migrate to the necrotic area and begin to digest the dead cells - **Mechanism of irreversible cell injury:** - Severe membrane damage: This results in massive intracellular influx of calcium - Increased intracellular calcium results in activation of intracellular enzymes (phosphlipases: digests cell membrane; proteases: digests the cytoskeleton; and endonucleases: digests the nucleus) - Efflux of intracellular proteins and enzymes into circulation - Marked mitochondrial dysfunction: - Mitochondrial swelling - Rupture of lysosomes: - Release of lysosomal enzymes into cytoplasm - Activation of acid hydrolases followed by autolysis - The hallmark of irreversible injury is membrane damage - The end result of irreversible injury is cell death ## Cellular Changes in Necrosis 1. **Cytoplasmic:** The cytoplasm becomes homogenous, eosinophilc and structureless 2. **Nuclear:** The nucleus may show: - **Pyknosis:** Small shrunken deeply stained nucleus with condensation of its chromatin - **Karyorrhexis:** Fragmentation of the nucleus - **Karyolysis:** Dissolution and fading of the nucleus ## Types of necrosis 1. **Coagulative Necrosis:** - **Most common type.** - Most often due to ischemia. - **Common Examples:** Infarction of heart, liver, spleen and kidney. - **Gross:** The tissue becomes firm and opaque due to protein denaturation - **Microscopic:** The general outline of cells is preserved with loss of cellular details (City of ghosts) 2. **Liquefactive Necrosis:** - **Common Examples:** Abscess and brain infarction. - **Rapid liquefaction of necrotic tissue due to high lipid content as in nervous tissue or due to the effect of proteolytic enzymes of polymorphs as in abscess** 3. **Caseation Necrosis:** - **Characteristic for tuberculosis.** - It is a variety of coagulative necrosis with slow liquefaction. - **Gross:** The tissue becomes yellowish and cheesy-like. - **Microscopic:** There is complete loss of cellular details. 4. **Fat Necrosis:** - **Traumatic fat necrosis:** Due to trauma to fatty organs like breast and subcutaneous tissue. - **Enzymatic fat necrosis:** Occurs in acute hemorrhagic pancreatitis due to the action of released pancreatic lipase on the fat cells of the omentum. 5. **Fibrinoid Necrosis:** - Swelling and fragmentation of collagen fibers. - **It occurs in collagen diseases, rheumatic myocarditis and malignant hypertension.** 6. **Gangrenous Necrosis:** - **Common sites, lower limbs and GIT.** - Gangrene means necrosis followed by putrefaction. - **Dry Gangrene:** Microscopic pattern is coagulative necrosis. - **Wet Gangrene:** Microscopic pattern is liquefactive necrosis. ## Apoptosis - **Definition:** It is a programmed cell death without inflammatory response. - Only affects single cell or small groups of cells. - **Morphological Changes:** - Cell shrinks in size and has dense eosinophilic cytoplasm. - Nuclear chromatin condensation followed by fragmentation. - Formation of cytoplasmic blebs. - Breakdown of cell into fragments (apoptotic bodies). - Phagocytosis of apoptotic bodies by the adjacent cells or macrophages. - Lack of inflammatory response. - **Regulator Genes of Apoptosis:** - **Bcl-2 (Inhibits Apoptosis) by:** - Prevents release of cytochrome C from mitochondria. - Binding pro-apoptosis protease activating factor. - **P 53 (Stimulates Apoptosis) by:** - Elevated by DNA injury and inhibition of cell cycle. - If DNA repair is impossible, p53 stimulates apoptosis. - **Physiological Examples of Apoptosis:** - Removal of cells during embryogenesis. - Endometrial shedding during menstrual cycle. - Thymus after puberty - Post inflammatory "Clean-up". - **Pathological Examples of Apoptosis:** - Councilman bodies in viral hepatitis. - Atrophy of pancreatic cells due to obstruction of pancreatic duct. - Tumor cells. - Toxic effect on cells: By chemicals and pathogens. ## Intracellular Accumulations - **Lipids:** - **Triglycerides:** Such as fatty change (discussed before). - **Cholesterol and LDL:** Such as atherosclerosis and xanthomas. - **Hyaline Change:** - **Definition:** Non-specific term used to describe any intra- or extracellular alteration that has homogenous pink and structureless appearance on H&E stains - **Examples of intracellular hyaline change:** - Russel bodies in rhinoscleroma. - Mallory bodies in liver in cases of alcoholism. - Renal tubules in cases of proteinuria. - **Examples of extracellular hyaline change:** - Arteriolar wall in cases of hyaline arteriolosclerosis - Amyloidosis - Hyaline membrane disease of newborn - Corpora amylacea in benign prostatic hyperplasia - **Glycogen:** - In cases of glycogen storage disease. ## Exogenous Pigments - **Anthracosis:** Deposition of carbon particles in the interstitial tissue of lung due to inhalation of carbon particles. - **Lead:** Ingestion of lead resulting in gingival lead line. - **Tattooing:** It is the introduction of colored dyes as India ink in the skin by injection. Pigment is taken by dermal macrophages and persists forever. ## Endogenous Pigments - **Lipofuscin:** - Peri-nuclear yellow-brown pigment deposition in cases of brown atrophy of the heart - **Melanin:** - Black-brown pigment deposition in the skin in cases of navi and melanoma. - **Hemosiderin:** - Golden-yellow-brown pigment deposition, as in cases of hemorrhage, heart failure cells in cases of CVC of lung. - **Bilirubin:** - Such as in jaundice and kernicterus (deposition of bilirubin ins basal ganglia) of newborn. ## Pathological Calcification - **Definition:** Abnormal deposition of calcium salts in areas other than bone and teeth. - **Types:** 1. **Dystrophic Calcification:** - **Definition:** It is abnormal deposition of calcium phosphates in necrotic and dead tissue. - **Examples:** - Psammoma bodies: Laminated calcified bodies in cases of meningiomas and papillary carcinoma of thyroid and ovary. - Traumatic fat necrosis of breast. - Enzymatic fat necrosis in cases of acute hemorrhagic pancreatitis. - Atherosclerotic plaques. 2. **Metastatic Calcification:** - **Definition:** Precipitation of calcium salts in normal tissues due to hypercalcemia. - **Causes:** - Hyperparathyroidism - Renal failure - Para-neoplastic syndrome - Vitamin D intoxication - Milk-alkalie syndrome - Sarcoidosis - Paget disease - Multiple myeloma - Location of calcification in interstitial tissue of stomach, kidneys, lungs and blood vessels ## Cellular Adaptation - Cellular adaptation either: Increase in size or number or decrease in size or number, or change from one type to another type, or variation in size, shape and arrangement. ### Hyperplasia - **Definition:** Increase in size of an organ due to increase in the number of its cells. - **Causes:** - **Physiologic Causes:** - Compensatory: Such as in liver after partial hepatectomy. - Hormonal: Such as breast after puberty and genitalia. - Antigenic stimulation: Such as lymphoid tissue in inflammation. - **Pathologic Causes:** - Endometrial hyperplasia. - Prostatic hyperplasia. ### Hypertrophy - **Definition:** Increase in size of an organ due to increase in the size of its cells. - **Causes:** - **Increase Mechanical Demand:** - Physiologic: Striated muscles of athletes and weight lifters. - Pathologic: Left ventricle of the heart in hypertension and aortic stenosis. - **Increased Endocrine Stimulation:** - Gravid uterus. - Lactating breast. - Hypertrophy and hyperplasia often occur together. ### Atrophy - **Definition:** Decrease in the size of an organ after its full development. - **Causes:** - **May be in number** - **Immobilization:** Decrease of workload or disuse of an organ. - **Ischemia:** Such as in atherosclerosis - **Lack of hormonal stimulation:** Such as breast and uterus after menopause. - **Lack of neural stimulation:** Such as in paralysis. - **Malnutrition**. - **Aging:** Loss of muscle bulk with ageing. - **Hypoplasia:** Failure of the organ to reach its full development: Such as hypoplastic kidneys and uterus. - **Agenesis:** Complete absence of the organ. ### Metaplasia - **Definition:** Change of one cell type to another cell type in response to irritation. - **Examples:** - **Epithelial Metaplasia:** - Bronchial epithelium replaced by stratified squamous epithelium due to irritation and smoking. - Urinary bladder epithelium replaced by stratified squamous epithelium due to bilharziasis and urinary stones. - Gall bladder epithelium replaced by stratified squamous epithelium due to gall bladder stones - **Mesenchymal Metaplasia:** As in cases of myositis ossificans (the fibroblasts are replaced by osteoblasts with lying down of osteoid material within the inflamed muscles. ### Dysplasia - **Definition:** Abnormal proliferation of cells characterized by variation of size, shape and arrangement of these cells. - **Epithelial cells are common sites for dysplastic changes.** - **Examples:** - Bronchial epithelium: Due to smoking. - Cervix of the uterus: Due to chronic irritation and infection by human papilloma virus (HPV). - **Cervical Intraepithelial Neoplasia (CIN):** It is graded as: - CIN grade 1: Affects inner 1/3 of epithelial lining. - CIN grade 2: Affects inner 2/3 of epithelial lining - CIN grade 3: Affects thickness of epithelial lining. - Other examples of dysplasia; Actinic keratosis of skin and oral leukoplakia. - Dysplasia is not a cancer but may progress to cancer (pre-neoplastic). - Severe dysplasia (dysplasia grade III) is considered as carcinoma in situ ## Review Questions 1. List the types of cellular adaptive changes? 2. List the differences between necrosis and apoptosis? 3. Describe types of necrosis and give example for each type? 4. Describe fatty change of the liver (causes, gross and microscopic appearance) 5. Dystrophic calcification could be seen in healthy gastric mucosa (true or false) 6. Define the following: - Necrosis - Apoptosis - Hyperplasia - Metaplasia - Hypertrophy - Atrophy 7. Which of the following adaptive change have higher chance of malignant transformation? - Hyperplasia - Hypertrophy - Dysplasia - None of the above 8. Which cellular adaptation describes an increase in the number of cells in response to an increased workload? - Hyperplasia - Hypertrophy - Atrophy - Metaplasia 9. Which of the following is not included among the mechanisms of cell injury? - ATP depletion - Mitochondrial damage - Reduced cytoplasmic calcium - Cell membranes rupture - DNA damage 10. The following statement is TRUE regarding dystrophic calcification: - Associated with high serum calcium. - Calcium deposits occur also in healthy tissue. - It is considered as an adaptive cellular response. - Abnormal deposits of calcium in necrotic tissue. - Affects mainly old age group. ## Answers - 5 = false - 7 = c - 8 = a - 9 = c - 10 = d