Cell Injury PDF

Cellular Injury Cellular Response to Stress  i.e. any change in intra- or extra-cellular environment Stress Couldn’t be adapted Mild, Transient  Cellular Responses to Stress Irreversible injury “death” Re...

Cellular Injury Cellular Response to Stress  i.e. any change in intra- or extra-cellular environment Stress Couldn’t be adapted Mild, Transient  Cellular Responses to Stress Irreversible injury “death” Reversible injury “degeneration” Adaptation  Causes of cell injury - Hypoxia/ Ischemia - Autoimmune diseases - Infections - Nutritional deficiency or excess - Physical agents (trauma, radiation) - Chemicals agents (drugs, toxins) - Genetic mutations  Causes of Cell Injury Hypoxia is the most common cause of cell injury Due to low oxygen delivery to tissue, it results in impaired oxidative phosphorylation & decrease ATP level (lower energy  lower functions) Mechanisms of hypoxia: Decreased blood supply Decreased blood Decreased blood (Ischemia) oxygenation (Hypoxemia) capability to carry oxygen Arterial thrombosis Cardiorespiratory failure Anemia  Factors Affecting Cell Injury Stressors Cells Severity Vulnerability to injury Duration Metabolic activity (needs) Onset of irreversible injury induced by hypoxia varies between different cell types: Minutes for neurons. Few hours for myocardial cells and hepatocytes Many hours for skeletal muscle cells  Pathogenesis of Cell Injury ATP depletion [Early “Reversible”] Increased Calcium Membranes damage – Cell membrane – Mitochondria Late “Irreversible” – Lysosomes Nuclear damage  Reversible cell injury (degeneration) Morphological changes due to disturbance of cellular metabolism caused by mild (non lethal) injury Parenchymal cells, e.g. liver cells and cardiac muscle, are metabolically active, thus more vulnerable to degeneration  Examples of degeneration Hydropic degeneration Fatty degeneration  Hydropic degeneration (Cloudy swelling) Intracellular / Cytoplasmic accumulation of water One of the earliest changes to cell injury Reversible when the injurious stimulus is removed Pathogenesis: ATP depletion  Na/K pump failure  Na and water accumulation  Hydropic change (Cloudy swelling) Grossly: Commonly seen in highly specialized organs such as kidney, liver, pancreas, or heart Affected organ is enlarged, swollen & pallor Microscopically: Cells are swollen & pale with cytoplasmic clear vacuoles Normal kidney Hydropic degeneration of renal tubules Normal hepatocytes Hydropic “ballooning” degeneration of hepatocytes  Fatty degeneration Cytoplasmic accumulation of fat (triglycerides) Reversible when the injurious stimulus is removed General Pathogenesis Liver-Specific Pathogenesis Cause: that cause cell injury Cause: that affect hepatocytes Hypoxia Drugs (Alcohol) Diet-related: Drugs Diabetes Mellitus Obesity Toxins Disease (Hepatic) Starvation Protein  Pathogenesis: Pathogenesis: Organelles damage will affect fat metabolism Increased lipid deposition within the liver (as within the cells it’s the main organ for fat metabolism) Mitochondria damage Increased fat entry to liver Smooth endoplasmic reticulum damage Decreased fat removal from liver Rough endoplasmic reticulum damage Alteration of fat metabolism within liver  General pathogenesis Liver-specific pathogenesis Causes: Hypoxia Fat Metabolism Alteration Drugs & Toxins 1 Within The Liver Organelles Damage ↑ Fatty Acid ↓ Fatty Acid Synthesis Oxidation Mitochondria Smooth ER No energy for fat Altered fat metabolism metabolism Rough ER Fat Altered lipo-protein synthesis with Fat Fat trapped fat within cytoplasm Fat Fat 2 ↑ Fat Entry Fat Fat Fat Fat Fat Fat Into Liver Fat Fat 3 ↓ Fat Release Fat From Liver Fat ↑ Fat mobilization (from adipose tissue) P ↓ Lipo-proteins P synthesis ↑ Fat intake P (lipid-binding proteins) (from GIT) Liver-related causes of injury: Drugs (Alcohol): alter fat metabolism ( FA synthesis &  FA oxidation) DM: alter metabolism (as alcohol) plus  mobilization from adipose tissue Diet: (Obesity -  fat intake), (Starvation -  mobilization from adipose tissue), (Protein malnutrition -  Apo-proteins synthesis) Disease (Hepatic):  Apo-proteins synthesis  Fatty degeneration Grossly: commonly affects liver, but can be also seen in heart, kidney or other organs affected organ is enlarged, soft and yellowish Microscopically: Cells are swollen & pale with cytoplasmic clear vacuoles Vacuoles are multiply small (micro-vesicular) or single large (macro-vesicular) Macro-vesicular pattern showed signet ring appearance (nuclei bushed to one side by large vesicle) Fatty Liver “steatosis” Fatty liver “steatosis”  Fatty change Notes: Fat appears as non-staining vacuoles in the cytoplasm because it is dissolved in alcohol during tissue processing. Fat can be demonstrated in fresh unfixed tissue by frozen section followed by fat stains (Sudan III, Sudan black, oil red O and osmic acid).  Cell Death  Pathologic condition Necrosis Vital reaction (in living organism) Associate with inflammation Nucleus Cytoplasm Pyknosis (condensation) Increased eosinophilia Protein denaturation Karyorrhexis (fragmentation) (high affinity to eosin) Loss of basophilia Karyolysis (dissolution) Loss of RNA Cell lysis Lysosomal enzymes from recruited WBCs Lysosomal enzymes from dead tissue itself  Necrosis Definition: – Death of a large group of cells at once – Within the living body – Accompanied by inflammatory reaction. Cause/ Pathogenesis: see before “cell injury” Morphology: The appearance of necrotic cells depends on two factors Hypoxia Anaerobic Injured Cells Glycolysis Cellular Proteins Lactic Lysis Denaturation Acidosis Recruited WBCs Lytic Injured Enzymes Cells  Necrosis When protein denaturation exceeds cellular lysis: – Preserve cell shape and outline – Cytoplasmic & nuclear details are lost – Necrotic cells will appear as “ghost cells” – Examples: Coagulative necrosis When cellular lysis exceeds protein denaturation: – Necrotic cells will be rapidly and completely lysed – No preservation of cellular details or outlines – Structureless necrotic material – When emptied (engulfed by macrophages or evacuated)  cystic space or cavity – Examples: Liquefactive necrosis  Necrosis Microscopic features: Necrotic cells Associated findings Cytoplasm: bright eosinophilic Severe congestion +/- hemorrhage Nucleus: nuclear changes Inflammation Cell lysis & removal by If survive (fate): inflammatory cells Resolution (regeneration) Healing (granulation tissue, fibrosis, gliosis “CNS”) Capsulation (fibrous capsule) Calcification (dystrophic)  Types of Necrosis Coagulative necrosis Liquefactive necrosis Caseous necrosis Fat necrosis Fibrinoid necrosis  Coagulative necrosis Cause: Ischemic injury (infarction) to any organ EXCEPT brain Pathogenesis: Early: Protein denaturation overcomes the enzymatic lysis Later: complete enzymatic lysis and removal by WBCs Morphology: Firm at beginning, then become softer Microscopic Features: Necrotic tissue: as before Early: preserve cell outlines and architecture (ghost cells) Later: complete lysis occurs Associated features: as before Myocardial infarction – Recent  Liquefactive necrosis Cause: Ischemic injury to brain – some infections Brain (due to   lipid and fluid content of CNS “easily liquified by enzymes”) Pyogenic abscess (due to   organism toxins & WBCs lytic enzymes) Pathogenesis: Enzymatic lysis predominates from the start Morphology: Soft with liquefied center (may form cystic spaces or cavities)  Liquefactive necrosis Microscopic features: Necrotic tissue: as before Rapid & early cell lysis with lost cellular & architectural details May form cystic space/ cavity filled with necrotic debris & inflammatory cells Associated features: as before Brain infarction with cyst formation  Caseous necrosis Cause: Occurs as part of granulomatous inflammation (TB) Pathogenesis: Necrosis with slow, partial liquefaction (midway between coagulative and liquefactive) Morphology: granular, tan-yellowish & cheese-like (caseous) material (semi-soft/ semi-firm) Microscopically: Caseous material: structureless, granular eosinophilic appearance Associated features: surrounded by granulomatous reaction Caseous necrosis - lung Caseating granuloma – lung  Fat necrosis Causes & Pathogenesis:  Traumatic: Severe trauma to tissue with high fat content (breast)  Enzymatic: Acute pancreatitis, results in digestion of abdominal fat by lipolytic pancreatic enzymes released from damaged pancreas Morphology: Fatty acids (liberated by trauma or lytic enzymes) will deposit with calcium  calcium soaps “Dull opaque chalky-white patches” Microscopic: Necrotic fat cells surrounded by inflammation (foamy macrophages, multinucleated giant cells) together with calcifications Fat necrosis – omental fat Fat necrosis – female breast  Fibrinoid necrosis Cause & Pathogenesis: it affects muscle fibers and collagen which become fragmented –< finer particles resembling fibrin Examples: Autoimmune vasculitis Microscopically: Blood vessels wall showed homogeneous eosinophilic (fibrin like) deposition Normal blood vessel - kidney Fibrinoid necrosis – autoimmune vasculitis  Apoptosis Definition: – Death of a single or few cells – Programmed = need certain signals to initiate “death code” – Not accompanied by inflammatory reaction. Physiologic Pathologic Embryogenesis (otherwise DNA damage (of malignant tumor cells) anomalies will be developed) Viral hepatitis (Councilman body) Hormone-dependent (menstrual cycle) Thymus (selective death of potentially self-reacting lymphocytes)  Apoptosis Necrosis Programmed, needs certain signals Unprogrammed, initiated by cell injury Affects single or few cells Affects large group of cells at once Either physiologic or pathologic Always pathologic Apoptotic Cells: Necrotic Cells: Cytoplasm: Cytoplasm: Cell shrinkage Cell swelling, blebs (initially) Cytoplasmic membrane blebs Cytoplasmic membrane rupture Apoptotic bodies contain intact Damaged organelles and organelles and lysosomes lysosomes Nucleus: Nucleus: Nuclear condensation & Nuclear lysis fragmentations Inflammatory reaction: Absent Inflammatory reaction: PRESENT (apoptotic bodies keeps the cellular (because of released contents of contents intact till been engulfed my necrotic cells) macrophages)  Abnormal Accumulations  Abnormal Deposits Normal Exogenous Endogenous Abnormal Pigments Substance Endogenous Endogenous Carbon Water Substance Pigments Lead Fat Tattoos Amyloidosis Lipofuscin Proteins α1-antitrypsin Hemosiderin Glycogen disease Bilirubin (jaundice) Mucin Neurodegenerative Melanin diseases  Fats Accumulation Triglycerides: Fatty change (see before) Cholesterol: normally required for cell membrane or lipid-soluble hormone synthesis Atherosclerosis: foamy macrophages within arterial wall Xanthomas: foamy macrophages within skin dermis Cholesterolosis: foamy macrophages within gallbladder wall. Complex lipids: as seen in lipid storage diseases Atheromatous streaks & plaques - Aorta Foamy macrophages - astherosclerosis Eyelid Xanthoma Gallbladder cholesterolosis  Proteins Accumulation (Hyaline Change) Hyaline = homogeneous glassy pink appearance on M/P Intra-cellular hyaline change Lesion Organ Pathogenesis Russell bodies Plasma cells Excess IGs within cytoplasm; in persistent chronic inflammation Hyaline droplets Renal proximal Excess proteins reabsorption; in tubules heavy proteinuria Mallory' s hyaline Hepatocytes Aggregates of intermediate filaments; in alcohol liver disease Russell bodies – plasma cells Mallory’s bodies – liver cells  Proteins Accumulation (Hyaline Change) Extra-cellular hyaline change Lesion Organ Pathogenesis Hyaline Small Hyalinized vessel wall; seen in Arteriolosclerosis arterioles systemic hypertension Hyalinized Renal Hyalinized glomerular vessels; seen Glomeruli Glomeruli in Chronic glomerulonephritis Hyaline Long-standing Hyalinized collagen fibers; seen in degeneration fibrosis or old scars & keloid mesenchymal Tumors e.g. leiomyomas tumors Corpora amylacea Prostate gland Masses of concentric hyaline lamina; seen in prostatic hyperplasia Hyaline arteriolosclerosis – kidney Hyalinized glomeruli – chronic glomerulonephritis Hyalinized collagen fibers – Skin scars Corpora amylacea - prostate  Amyloidosis Extracellular deposition of amyloid substance, mainly in the walls of blood vessels and basement membranes Gross: Affected organs are firm, heavy & enlarged (may be atrophic by prolonged ischemia) Pale waxy cut section Microscopic: deposits in wall of blood vessels, basement membranes & interstitial tissue Pale eosinophilic (H&E stain). Orange-red (with Congo red stain), and apple green birefringence under polarized light  Systemic Amyloidosis Localized Amyloidosis Affects multiple organs Affect single organ (kidney, GIT, liver, spleen, heart) Senile Transthyretin Amyloid Light chain protein (Heart) Primary Immunoglobulin light chain Alzheimer (AL) Seen in Plasma cells disorders (e.g., multiple myeloma) disease Amyloid beta (Brain) Amyloid Associated protein Serum Amyloid A (Acute phase Medullary Secondary Calcitonin reactant, synthesized in liver) carcinoma (AA) Seen in Chronic diseases (e.g., (Thyroid) RA, SLE, TB, FMF, Cancer) Type II diabetes Amylin (Pancreas) Dialysis- Beta-2 associated microglobulin (Joints) Amyloidosis – Liver Amyloidosis – Liver (H&E) Amyloidosis – kidney Amyloidosis – kidney (H&E) Amyloid plaques – Alzheimer disease (H&E) Amyloidosis – Congo red & with polarized light  Amyloidosis Clinical findings varied according to the affected organ: Kidney Proteinuria, renal failure Heart Restrictive cardiomyopathy, arrythmia, heart failure Liver/ Spleen Hepatosplenomegaly, failure GIT Macroglossia, intestinal malabsorption Adrenal gland Addison’s disease  Mucoid/ Myxoid change Mucin = glycosylated protein substance, appears by H&E as pale basophilic material Produced by mucin-secreting epithelial cells (mucous membranes and mucous glands) Mucinous material can be also seen within connective tissue Excess epithelial mucin = mucoid change Excess connective tissue mucin = myxoid change  Mucoid Change Myxoid Change Epithelial mucin Connective tissue mucinous Intra-cellular accumulation material (but can be seen extra-cellular if cells Extra-cellular only ruptured) Examples: Examples: Catarrhal inflammation of Myxoid degeneration in mucous membranes (e.g., mesenchymal tumors (e.g. catarrhal rhinitis) fibroadenoma, neurofibroma and soft tissue sarcomas) Mucin-secreting tumors (e.g. mucoid carcinoma of large intestine) Mucoid adenocarcinoma - Intestine Myxoid change - Fibroadenoma  Lipofuscin Pigments Wear-and-tear pigment; end product of membrane lipid peroxidation Fine yellow-brown intracytoplasmic granules More evident in old age Common in the liver and heart Combination of lipofuscin accumulation and organ atrophy of organs is called brown atrophy Lipofuscin pigments – cardiac msucles  Melanin Pigments Normally found in skin, hair, eyes, meninges & basal ganglia Formed from tyrosine by the action of tyrosinase (melanosomes of melanocytes) In skin, the melanin pigments located at epidermal keratinocytes and dermal macrophages (melanocytes actually have clear cytoplasm)  Melanin Pigments Increased Melanin Decreased Melanin Sun tanning Albinism (generalized Addison’s disease (ACTH hypopigmentation; defect in increase melanin pigments) tyrosinase) Pigmented tumors (nevi, Vitiligo (patchy melanoma) hypopigmentation; associated with skin diseases) Cafe’ au lait patches (neurofibromatosis) Skin melanin & melanocytes  Hemoglobin-derived pigments Hemosiderin Bilirubin Hematin Iron-containing Iron-free pigment Formed by action of pigment Greenish-yellow acids on Brownish Normally seen in hemoglobin Normally seen in the body Brownish the body (iron stores Excessive deposition Not formed e.g. liver & spleen)  jaundice normally in the Also in areas of old Negative Prussian body hemorrhage blue Negative Prussian Excessive deposition blue  hemosiderosis & hemochromatosis Positive Prussian blue reaction  Systemic Hemosiderin Deposition Affects multiple organs Hemochromatosis Hemosiderosis (with tissue damage) (without tissue damage) Pathogenesis: Pathogenesis: 1ry (genetic defect of enzymes Increased iron intake in diet involved in iron absorption) Repeated blood transfusion 2ry (prolonged systemic Hemolytic anemia hemosiderosis) Affected sites: Affected sites: Liver, spleen, Bone marrow, Liver: cirrhosis Lymph nodes Pancreas: fibrosis, diabetes Skin: increase melanin Localized Hemosiderin Deposition deposition (so called bronzed DM) Heart: fibrosis, heart failure Affect single organ/area Site of Site of severe hemorrhage congestion Localized hemosiderin deposition – alveolar macrophages “chronic lung congestion” Hemochromatosis - hepatocytes Hemochromatosis – hepatocytes (positive prussian blue stain)  Abnormal Calcium Deposits Deposition of calcium salts in sites other than bone & teeth Affected areas is thickened, hard, with chalky white appearance Basophilic, granular densities by H&E stain  Dystrophic Calcification Metastatic Calcification Dead or degenerated tissue Normal tissue Normal Calcium level (renal, GIT, lungs, joints) High Calcium level Necrotic tissues Old fibrosis Any type especially Skin scar Excess calcium intake Fat necrosis Fibrosed heart valve Dietary “Milk” Drugs containing calcium Vascular diseases Parasite Hypervitaminosis D Atherosclerosis or its ova Vitamin D intoxication Monckeberg sclerosis Bilharziasis Sarcoidosis Paraneoplastic syndrome Tumors Degenerated mesenchymal tumors (e.g. Excess mobilization from bone leiomyoma) Hyperparathyroidism Psammoma bodies 1ry “parathyroid adenoma” Meningiomas 2ry “renal failure” Papillary carcinoma of thyroid Bone tumors Papillary serous carcinoma of ovary Primary or metastatic Atherosclerosis with calcification Psammoma bodies – meningioma Metastatic calcification - kidney  Exogenous pigments Anthracosis Tattoos Lead poisoning “Plumbism” Route: inhalation Route: skin Route: ingestion inoculation Pigment: carbon Pigment: lead dust Pigment: tattoo ink Sites: oral mucosa Site: lungs & hilar & gums LNs Sites: skin dermis “engulfed by Color: bluish-black Color: black macrophages” Color: variable Anthracosis - Lung Thank You