Cellular Injury PDF

General Pathology Department Chapter Two CELLULAR INJURY Professor Name: Amira Nabil Professor title at MSA: Lecturer LECTURE OUTLINE Causes of cellular stress as an underlying cause for different diseases. Outcomes of exposure to cellular stress.  ILOS: ▪ Cause...

General Pathology Department Chapter Two CELLULAR INJURY Professor Name: Amira Nabil Professor title at MSA: Lecturer LECTURE OUTLINE Causes of cellular stress as an underlying cause for different diseases. Outcomes of exposure to cellular stress.  ILOS: ▪ Causes of cellular stress ▪ Outcomes of cellular stress I. Cellular adaptation II. Degeneration III. Intracellular accumulation (Pigmentation) IV. Extracellular Depositions ▪ Amyloidosis ▪ Pathological calcifications V. Irreversible injury  Cell injury underlies all diseases. So, to understand diseases, one must start knowing what cell injury is ?? Define Cell injury = Stress that a cell suffers due to external or internal environmental changes. Causes of cellular stress: 1. Reduced oxygen supply (Hypoxia: hypo→ less, oxia→ oxygen). 2. Decreased blood supply (Ischemia). 3. Physical agents: mechanical trauma, excessive heat or cold, and radiations (ionizing and ultraviolet). 4. Chemical agents: acids, alkalis, and chemical toxins. 5. Infectious agents: viruses, bacteria, and fungi.  Causes of cellular stress: 6. Abnormal immunological reactions: as in autoimmune diseases and hypersensitivity states. 7. Aging: progressive accumulations of cellular and molecular damage results in cell injury. 8. Genetic susceptibility: is one of the major contributors to any disease. 9. Nutritional imbalance: ▪ Nutritional deficiencies: Starvation and vitamin deficiencies. ▪ Nutritional excesses: Obesity.  Outcomes of cellular stress: 1.The cell can adapt to the situation (ADAPTATION). 2. The cell acquires reversible injury (DEGENERATION). 3. Intracellular accumulations (PIGMENTATION). 4.Extracellular depositions (DEPOSITION): as calcium and amyloid. 5. The cell suffers from irreversible injury and may die (NECROSIS or APOPTOSIS), when the severity of the injury exceeds the cell's ability to repair itself.  ILOS: ▪ Causes of cellular stress ▪ Outcomes of cellular stress I. Cellular adaptation II. Degeneration III. Intracellular accumulation (Pigmentation) IV. Extracellular Depositions ▪ Amyloidosis ▪ Pathological calcifications V. Irreversible injury  I) Cellular adaptation How the cell adapt in response to environmental changes ?? Cell adjusts its structure and function in response to physiological stress and pathological stimuli to achieve new steady state that would be compatible with their viability in the new environment.. Reversible when stimulus is eliminated.  They are classified according to: 1- Atrophy Size 2- Hypertrophy Number 3- Hyperplasia Type 4- Metaplasia  1- ATROPHY Definition: Shrinkage in the size of the cell, with the involvement of a sufficient number of cells, an entire organ can become atrophic. Results from decreased protein synthesis or increased protein degradation in cells. 2- HYPERTROPHY Definition: Increase in the size of the cell. Cell hypertrophy results from increased protein synthesis due to hormonal stimulation (anabolic hormones e.g., growth hormone, testosterone) or due to increased functional demand.  3- HYPERPLASIA Definition: Increase in the number of cells. Hyperplasia can occur only in cells capable of division i.e. all body cells except nerve cells, skeletal and cardiac muscle cells. 4- METAPLASIA Definition: One adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.  ILOs: ▪ Causes of cellular stress ▪ Outcomes of cellular stress I. Cellular adaptation II. Degeneration III. Intracellular accumulation (Pigmentation) IV. Extracellular Depositions ▪ Amyloidosis ▪ Pathological calcifications V. Irreversible injury  II) DEGENERATION Definition: Degeneration is a form of deterioration. Metabolic and morphological changes in a tissue due to exposure to mild injury. The process of degeneration is reversible if the cause is eliminated or treated, otherwise death and necrosis of the cells will occur. Types of Degenerations: 1. Cloudy swelling. 2. Fatty degeneration. 3. Mucous degeneration. 4. Hyaline degeneration. 1- Cellular swelling (cloudy swelling) Pathogenesis: Hypoxia mitochondrial damage with decrease in ATP formation and damage in the sodium-potassium membrane pump, this allow excess sodium to enter the cell with shifting of water with it and eventually increase in cellular water. Severe form of cellular swelling = Hydropic degeneration. Macroscopic picture: Enlarged pale soft organ with cloudy appearance. Microscopic picture: Swollen cells with water vacuoles within cytoplasm.  2- Fatty degeneration (Steatosis) Definition: Abnormal accumulation of triglycerides within parenchymal cells due to the inability of the non–fatty tissues to metabolize the amount of fat presented to them. Etiology: Imbalance between the uptake, utilization, & secretion of fat. A) Liver fatty degeneration: Most common location for fatty degeneration is the LIVER (being the major organ involved in fat metabolism). Fatty liver (steatosis) may be caused by: ▪ Alcoholic fatty liver disease (AFLD): alcohol decreases fatty acid oxidation. ▪ Non-alcoholic fatty liver disease (NAFLD): a. Diabetes mellitus: at least half of people living with type 2 diabetes have nonalcoholic fatty liver disease. Diminished suppression of adipose tissue lipolysis by insulin resistance results in increased delivery of free fatty acids to the liver and thus the synthesis of excess triglyceride. b. Obesity: associated with high triglyceride levels. Fate of fatty liver: Steatohepatitis, Cirrhosis, Liver cancer. ▪ Macroscopic picture: liver is enlarged, yellowish, with rounded borders, and soft consistency. ▪ Microscopic picture: lipid vacuoles in the cytoplasm of hepatocytes will displace the nuclei under the cell membranes giving the cells signet-ring appearance. b) Heart: ▪ Macroscopic picture: The heart is soft showing tabby cat appearance (Yellow streaks altering with brown streaks). ▪ Microscopic picture: Fat globules form within the muscle fibers and interfere with muscle contraction and may cause cardiac arrhythmias.  3- Mucous degeneration Definition: Abnormal accumulation of excess mucin. Microscopic picture: ▪ Mucoid degeneration: accumulation of intracellular structureless glycoprotein material inside the cell leading to swelling and ballooning of the cytoplasm, the nucleus is flattened and pushed against cell membrane giving signet-ring appearance. Rupture of the cells loaded with mucin leads to pouring of mucin extracellular as a homogenous matrix giving the cells star-shaped appearance. ▪ Myxomatous degeneration: it is the accumulation of mucin between connective tissue fibers. Signet ring cells with intracytoplasmic mucin  4- HYALINE DEGENERATION (HYALINOSIS) Definition: Homogenous, structureless, translucent, proteinous, eosinophilic (hyaline= glassy) material either intra or extra cellular.  Ilos: ▪ Causes of cellular stress ▪ Outcomes of cellular stress I. Cellular adaptation II. Degeneration III. Intracellular accumulation (Pigmentation) IV. Extracellular Depositions ▪ Amyloidosis ▪ Pathological calcifications V. Irreversible injury Accumulation of pigments  Accumulation of pigments Accumulation of pigments What is a pigment? A pigment is a colored substance that can be both exogenous and endogenous. Endogenous pigments are synthetized within the body and can be melanin, bilirubin, and derivatives of hemoglobin. a) Melanin: ▪ Melanin is a brownish-black pigment produced by the melanocytes. ▪ Decreased melanin pigmentation is seen in albinism & vitiligo. ▪ Increased melanin pigmentation is caused by: i. Sun tanning. ii. Nevus, malignant melanoma. iii. Addison's disease is due to hypofunction of adrenal cortex. The pituitary gland responds by increasing production of ACTH (adrenocorticotropic hormone) which derived from a bigger precursor molecule that it is also a precursor for melanocyte stimulating hormone (MSH)…so in order to make more ACTH, you’ll make more MSH.  Hemosiderosis Hemochromatosis ▪ Focal deposition of iron ▪ Systemic deposition of iron b) Iron Containing Pigment: Definition ▪ Iron It doesn’t cause tissue damage released from hemoglobin is ▪ ▪ It can cause tissue damage Hereditary: HFE gene derived from red blood cell breakdown mutation causing Types: (in the spleen, liver, and bone marrow). uncontrolled iron absorption When the amount of iron becomes from the intestine Pathogenesis excessive and overloads the ferritin ▪ Secondary: Repeated blood 1.Hemosiderosis system storage capacity, iron is transfusion deposited in a brown granular form 2. Hemochromatosis called Hemosiderin as in: ▪ Hemolytic anemia. ▪ Repeated blood transfusion. Presentation Hemosiderin is stored within tissue Bronzed diabetes = atrophy of macrophages beneath the skin as a islet tissue of pancreas causing brown stain. Granules of hemosiderin diabetes mellitus, brownish are stained blue by the Prussian blue coloration of skin, arthritis, and reaction, which is specific for iron. liver cirrhosis. Hemosiderin appears as golden-brown granules in macrophages (H&E stain). Granules of hemosiderin by the Prussian blue reaction.  c) Bilirubin (Iron-Free Pigment) Bilirubin is a yellowish pigment, produced during the degradation of hemoglobin. Jaundice: excess accumulation of bilirubin causes yellowish discoloration of the sclera, mucosa, & internal organs. Jaundice is caused by: i. Hemolytic anemia Increased destruction of red blood cells. ii. Hepatocellular disease Failure of conjugation of bilirubin due to hepatitis, liver cancer or liver cirrhosis. iii. Biliary obstruction Obstruction of intrahepatic or extrahepatic bile ducts by gallstones or bile duct cancer.  d) Lipochrome Pigment (Lipofuscin Pigment): ▪ Brown atrophy of the heart: atrophy of the heart muscle found in the elderly is commonly associated with lipofuscin pigment accumulation (ageing pigment). ▪ The autophagic vacuoles are vacuoles within atrophied cells, containing cellular debris from degraded organelles that resist digestion by lysosomes and persist as residual bodies, example: lipofuscin granules. Microscopically: Cardiac muscle fibers become pigmented by intracellular deposits of lipofuscin around the nucleus. Grossly: The heart appears small, brown, the sub-pericardial fat disappears, and the coronary vessels appear thick and tortuous due to shrinking of the heart.  Ilos: ▪ Causes of cellular stress ▪ Outcomes of cellular stress I. Cellular adaptation II. Degeneration III. Intracellular accumulation (Pigmentation) IV. Extracellular Depositions ▪ Amyloidosis ▪ Pathological calcifications V. Irreversible injury There are four stages of protein folding, primary, secondary, tertiary and quaternary  1- Amyloidosis Pathogenesis: when normally soluble protein become misfolded and adopt a fibril structure, extracellular deposition of an abnormal protein Amyloid is amorphous, homogenous, filamentous called amyloid starts to appear in the connective proteinous material tissues (usually blood vessels wall) in the form of insoluble protein-carbohydrate complex. Grossly: Organ is enlarged, waxy, brownish, firm in consistency. Microscopically: Amyloid is amorphous, homogenous, eosinophilic Congo-red with light microscopy filamentous proteinous material. Stains purplish pink or pink with H&E stain (Haematoxylin & Eosin). Specific stain: Congo stain Pink or red with ordinary light microscopy. Green birefringence with polarized microscopy. “Birefringence= double refraction of light” “ Amorphous =shapeless, Homogenous=similar” CLASSIFICATION OF AMYLOIDOSIS AL amyloidosis (Amyloid light chain protein) (Primary) Associated with multiple myeloma abnormal Ig taken by macrophage and degraded to insoluble fibril. Abnormal plasma cell AA (Amyloid Associated) (Secondary): following chronic disease: TB, Osteomyelitis & rheumatoid arthritis. Site: 1. Renal: the commonest and the most serious type of amyloidosis. 2. Hepatic amyloidosis: between hepatocytes and sinusoids. No serious dysfunction. 3. Alzheimer’s disease: amyloid tissue deposit outside neurons in brain tissue.  Purplish pink or pink with H&E. Specific stain: Congo-red Pink or red with ordinary light microscopy. Green birefringence with polarized microscopy.  2- PATHOLOGIC CALCIFICATION Definition: Abnormal deposition of calcium salts in the tissue other than osteoid or enamel. Types: Dystrophic calcification Metastatic calcification Dystrophic calcification ▪ Calcification occurs in dead and degenerated tissues (enzymes released from the dead cells cause breakdown of organic phosphates and alteration of pH which favors deposition of calcium). ▪ Plasma calcium level is normal. ▪ Examples: 1) Calcifications in coagulative, caseous or fat necrosis. 2) Calcifications in degenerated atheromatous plaques. 3) Calcifications in damaged heart valves. Metastatic calcification This type of calcification occurs in conditions where there is hypercalcemia (increase serum calcium level). It is named as metastatic calcification as calcium from bone is moved out and deposited in the distant tissues. Examples: 1. Milk alkali syndrome: excessive oral intake of calcium in the form of milk and administration of calcium carbonate in treatment of peptic ulcer. 2. Causes of bone resorption: a. Tumors of bone marrow (e.g., Multiple myeloma, leukemia). b. Hyperparathyroidism: ▪ Primary hyperparathyroidism: autonomous increase in parathyroid hormone secretion. ▪ Secondary hyperparathyroidism: due to renal failure. c. Vitamin D intoxication (hypervitaminosis).