L3) Types of Necrosis and Apoptosis PDF

OG THOL Y TEA M PA Types of Necrosis; and Apoptosis Color Index: Main text Important...

OG THOL Y TEA M PA Types of Necrosis; and Apoptosis Color Index: Main text Important Boys slides only Girls slides only Doctor’s Notes Extra info Editing file OBJECTIVES: Understand the concept of cells and tissue adaptation to environmental stress including the meaning of hypertrophy, hyperplasia, aplasia, atrophy, hypoplasia and metaplasia with their clinical manifestations. Is aware of the concept of hypoxic cell injury and its major causes. Understand the definitions and mechanisms of free radical injury. Knows the definition of apoptosis, tissue necrosis and its various types with clinical examples. Able to differentiate between necrosis and apoptosis. Understand the causes of and pathologic changes occurring in fatty change (steatosis), accumulations of exogenous and endogenous pigments (carbon, silica, iron, melanin, bilirubin and lipofuscin). 7 Understand the causes of and differences between dystrophic and metastatic calcifications.  Outline Types of Necrosis: Coagulative, Liquefactive, Caseous, Gangrenous, fibrinogen and fat necrosis Apoptosis: definition, morphological features, regulation of apoptosis Comparison: between necrosis and apoptosis  Necrosis A type of cell death, in which there is enzymatic digestion of the dying cell. In necrosis, enzymes leak out of lysosomes, enter the cytoplasm and digest the cell. It is always a pathologic process, associated with pathological cell injury. It occurs in irreversible cell injury that cannot be corrected, It is usually associated with inflammation in the surrounding tissue. Involves the death of a group of cells in one area. In necrosis: There is a loss of function of the involved tissue/organ. There is an inflammatory response. The necrotic cell releases certain enzymes into the blood and these enzymes can be detected in blood tests. The level of these enzymes can be used as markers to diagnose the injury and also can help determine the time and the extent of injury e.g. Detection of cardiac enzymes in myocardial infarction (Heart Attack). Note: Note: Theenzymes usedused The enzymes in this degradation in this of aof degradation cell come a cell from come either: from either ○ Lysosomes of the ○ Lysosomes ofdying cell cell the dying itself itself Autolysis Autolysis ○ Lysosomes of neighboring ○ Lysosomes leukocytes of neighboring leukocytes Heterolysis Heterolysis Autolysis is the death/disintegration of cells or tissues by their own enzymes Autolysis is seen in cells in necrosis and after death/post mortem Types of Necrosis: you need to know which type of necrosis affect which organ Cougulative Liquefactive Caseous Fat Fibrinogen necrosis Necrosis Necrosis Necrosis Necrosis Cougulative necrosis Definition Coagulative Necrosis is characteristically seen when blood glow to an organ is affected, leading to ischemic hypoxic death of cells in that organ. Location Coagulative Necrosis is seen in all organs except the brain. Heart Myocardial Infarction Kidney Renal Cortical necrosis or Renal infarct Spleen Splenic infarct Liver Hepatic infarct etc. Appearance Grossly: Affected organ looks pale (no blood supply) and is firm/solid. Looks like cooked meat/boiled egg. The tissue is firm and architecture is maintained for days after cell death. Microscopy: At the beginning there is preservation of the general tissue architecture. The basic ghost outline of the affected/coagulated cell remains preserved for a few days but the nucleus is lost. The cell cytoplasm is eosinophilic. Ultimately the necrotic cells are removed by phagocytosis by the macrophages (they act like vacuum cleaners) and the affected area is replaced by fibrosis.  Kidney: coagulative Gross: tissue is firm necrosis Coagulative necrosis Microscopy: Cell outlines are preserved (cells look ghostly),and everything looks red. Liver: coagulative necrosis Liquefactive necrosis Definition It is a type of necrosis which results in transformation of the tissue into a liquid viscous material. Ultimately the necrotic cells are phagocytosed. Location Ischemic (hypoxic) cell death in the brain or in the central nervous system. Infections, especially suppurative bacterial infection. (Suppurative=pus or abscess producing) Notes In infections: 1- The affected tissue is softened/liquefied by the action of hydrolytic (digestive) enzymes released from the lysosomes of neutrophiles. 2- The affected area becomes soft and liquid-fired with a creamy yellow center containing necrotic cells and neutrophils which is called pus/abscess. It is still poorly understood as to why liquefaction necrosis happens after ischemic injury in the brain. Center labeled 1 is necrosis and surrounded by neutrophils  Caseous Necrosis Definition It’s a type of coagulative necrosis classically seen in patients diagnosed with tuberculosis (Mycobacterium Tuberculi). Appearance what comes in my The architecture of the tissue is completely obliterated. mind when i hear caseous Grossly: It’s white soft, cheesy (like blue cheese)-looking Caseous material. Microscopy: The Necrotic area appears as amorphous (without shape) pink granular debris surrounded by a collar of epithelioid cells (modified macrophages), giant cells and lymphocytes. This is known as a Granuloma. A tuberculosis lung with A large area of caseous necrotic tissue. The caseous debris cheesy and yellowish Questions that can be asked: 1. Which kind of Necrosis is caused by Mycobacterium Tuberculi? 2. What kind of lesion can you see in caseous necrosis? 3. Practical: (Epithelioid cells): names of the Epithelioid cells: (modified macrophages, activated macrophages, and epithelioid cells)  Fat Necrosis Definition Necrosis of fat cells (adipocytes), (it’s benign and is usually caused by trauma or injury). Also called enzymatic necrosis. Location Typically seen in acute pancreatitis in which the injured pancreatic cells release lipase (Catalyst for fat breakdown) into the surrounding fat in the abdominal cavity which causes the enzymatic breakdown of fat. Can also be seen in breast fat and other fatty areas due to trauma or injury. Appearance Microscopy: The foci of necrosis contains shadowy outlines of necrotic fat cells surrounded by basophilic calcium deposits and an inflammatory reaction. the outlines of necrotic/dead fat cells can be seen. Inflammation is minimal. Notes The released lipase breaks down the fat cells into glycerol and free fatty acids the produced fatty acids combine with calcium circulating in the blood to produce calcium soaps which looks like chalky white spots in the necrotic fat. This process is called as fat saponification. normal fat Fat necrosis Question that could be asked: A person comes to the ER with abdominal pain, they have been diagnosed with pancreatitis, what type of necrosis does he have? ER is emergency room not endoplasmic reticulum you nerds  Fibrinoid Necrosis Definition The necrosis in the blood vessels (Arteries, Arterioles, Capillaries). Location Autoimmune Diseases (vasculitis) Malignant Hypertension Appearance Deposition of fibrin material in the arterial walls, gives: Smudgy appearance Acidophilic/Eosinophilic Notes Antigen-antibody complex: is a large abdominal molecule set in the blood vessel walls that may cause inflammatory reactions: Fibrinoid Fibrinoid Necrosis in an artery. The wall is necrosis bright pink and the neutrophils are dark Diseases like ulcer Renal Failure Gangrenous Necrosis Definition Non Pathological term/clinical. This term is commonly used by clinical practitioners (surgeons). It can either be dry or wet. The only treatment is amputation. Types: 1. Dry (Mummified) 2. Wet (Infected) Dry Only in Coagulative -It’s typically seen in limbs with inadequate blood supply (Ischemia). -It‘s non-infected ischemic coagulative necrosis. -Seen in complications such as: peripheral artery diseases e.g. atherosclerosis + diabetes mellitus. -The affected part is dry, shrunken and dark reddish black. Wet Coagulative + Liquefactive -Dry gangrene (Coagulative necrosis) with superadded bacterial (putrefactive) infection resulting in a liquefactive necrosis. -Coagulative Necrosis is initial and is followed by a superadded infection associated with liquefactive necrosis. -The bacteria is usually saprogenic (lives in the gut or the soil and can thrive in low oxygen states (anaerobic) e.g. gram-positive Clostridia or Bacillus fusiformis. -It has a poor prognosis compared to dry gangrene due to the infection spreading and causing (septicemia) which leads to death. -This limb or part affected becomes foul smelling and starts to decompose and turns black. Notes It’s not a distinctive pattern of cell death. Usually refers to the condition of a limb (Lower limb) that has lost blood supply and has undergone coagulative necrosis involving multiple tissue layers. Dry Gangrene is always prior to wet. Diabetes mellitus is a risk-factor for dry gangrene and for wet gangrene (as elevated serum glucose creates a favorable environment for bacterial infection).  boy’s Biomarkers for necrosis slides Leakage of intracellular proteins through the damaged cell membrane and ultimately into the circulation provides a means of detecting tissue- specific necrosis using blood or serum samples. Cardiac muscle, for example, contains a unique isoform of the enzyme creatine kinase and of the contractile protein troponin. Irreversible injury and cell death in these tissues elevate the serum levels of these proteins, which makes them clinically useful markers of tissue damage.  APOPTOSIS Definition Apoptosis is programmed cell death. Apoptosis means “falling off”. It is a type of cell suicide. Is results from activation of ‘death pathway genes’. It is a pathway of cell death in which cells destined to die activate their own enzymes to degrade their own nuclear DNA and proteins. When a cell is deprived of growth factors or the cell's DNA or proteins are damaged beyond repair, the cell kills itself by apoptosis. Apoptosis is characterized by nuclear dissolution without complete loss of membrane integrity. It is an active, energy- dependent, tightly regulated type of cell death. Apoptosis serves many normal functions and is not necessarily associated with pathologic cell injury. It could be : NOTE: Apoptosis and necrosis can sometimes coexist. Physiological Pathological  apotosis in Physiological Pathological The programmed Cell death produced by injury destruction of cells during e.g. radiation. embryogenesis. (Such as the apoptosis of cells between the fingers of a fetus) Hormone-dependent: e.g. In certain diseases e.g. in viral endometrial cell breakdown hepatitis the infected during the menstrual cycle, hepatocytes undergo apoptosis the regression of the (acidophilic bodies) or injury of lactating breast after skin epidermal cells weaning, and prostatic (keratinocytes) leads to atrophy after castration apoptosis of keratinocytes (adaptive atrophy). (Civatte bodies). Apoptosis in proliferating cells e.g. intestinal epithelial Pathologic atrophy in organs lining is always being e.g. pancreas, parotid gland, and replaced. kidney. Corticosteroid induced atrophy of the neonatal thymus. Cells that after performing their function undergo apoptosis e.g. neutrophils Cell death in tumors (usually and lymphocytes in accompanied by necrosis). inflammation. Sometimes body produces harmful lymphocytes and they are also destroyed by apoptosis.  boy`s slides Mechanism of Apoptosis Apoptosis is regulated by biochemical pathways that control the balance of death- and survival-inducing signals and ultimately the activation of enzymes called caspases. Mitochondrial (Intrinsic) Death Receptor (Extrinsic) Pathway Pathway Cell Injury: Growth factor withdrawal Receptor Ligand Interactions: DNA damage (by radiation, Fas toxins, free radicals) TNF receptor Protein misfolding (ER stress) Mechanism of Apoptosis The death pathway genes are activated which trigger apoptosis. Cell shrinkage Chromatin condensation in the nucleus: This is the most characteristic feature of apoptosis. The nucleus may break up into fragments. Formation of cytoplasmic blebs and apoptotic bodies: The apoptotic cell first shows surface blebbing, then fragments into membrane-bound apoptotic bodies. The apoptotic bodies contain cytoplasmic content with or without nuclear material. The cell's plasma membrane remains intact. The plasma membrane of the apoptotic cell sends signal to macrophages, inviting the macrophages to phagocytose it. phagocytosis of apoptotic bodies by the macrophages: Because, during the entire process, the apoptotic body is bound by plasma membrane, there is no release of the cytoplasmic content into the surrounding tissue and therefore there is no inflammation.  Morphology of Apoptosis On histology apoptosis involves single cells or small clusters of cells. The apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with dense nucleus. There is no inflammation. Cysteine proteases named caspases Important enzymes for Ca2+ dependent endonucleases apoptosis Mg2+ dependent endonucleases bcl-2 gene inhibits apoptosis Regulation of apoptosis It is mediated by a number of genes bax genes facilitates apoptosis and their products p53 facilitates apoptosis by inhibiting bcl2 and promoting bax genes.  Apoptosis is different from necrosis. In necrosis there is loss of membrane integrity, enzymatic digestion of cells, and frequently an inflammatory reaction. Apoptosis and necrosis sometimes coexist. The changes seen in: necrosis (left) apoptosis (right)  feature Necrosis Aptosis cell size Enlarged (swelling) Reduced (shrinkage) Pyknosis Nucleus Fragmentation into Karyorrhexis nucleosome size fragments karyolysis Intact; altered structure, Plasma membrane Disrupted especially orientation of lipids Enzymatic digestion; may Intact; may be released in Cellular contents leak out of cell apoptotic bodies Adjacent Frequent No inflammation Often physiologic, means of Invariably pathologic eliminating unwanted cells; Physiologic or (culmination of may be pathologic after some pathologic role irreversible cell injury) forms of cell injury, especially DNA damage  OG THOL Y TEA M PA MCQs 1 Fibrinoid necrosis is most commonly associated with: Autoimmune Infectious Malignant Trauma diseases diseases tumors 2 Fat necrosis is characterized by: Transformation of Formation of a Coagulative Enzymatic tissue into pus granuloma necrosis in the breakdown of fat brain cells 3 What is necrosis primarily associated with? Programmed Inflammation and Normal physiological irreversible cell injury Cell division cell death processes 4 Which type of necrosis is typically seen in myocardial infarction? Liquefactive Coagulative Caseous Fat necrosis necrosis necrosis necrosis Answers Key: 1.A 2.D 3.B 4.B  OG THOL Y TEA M PA MCQs 5 In liquefactive necrosis, the affected tissue transforms into: Firm, pale Cheesy Liquid viscous Shadowy tissue material material outlines of cells 6 Caseous necrosis is most commonly associated with which infection? Bacterial Fungal Tuberculosis Viral hepatitis pneumonia infections 7 What is the primary mechanism behind apoptosis? Enzymatic digestion Activation of death Accumulation of Inflammation of surrounding tissue pathway genes necrotic debris 8 Which of the following statements is true regarding apoptosis? It results in It involves the It always leads to It is always inflammation activation of caspases pathological tissue necrosis Answers Key: 5.C 6.B 7.C 8.B  OG THOL Y TEA M PA Pathology Team 445 TEAM LEADERS : Fahad Alruwaily Mohammed Ruba aldibas Deemah alotaibi Alnoshan TEAM MEMBERS : Faisal Yara Alsowailem Abdulrahim