IHP 1001 Pathology Unit 1

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1

cellular adaptation

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  1. the intracellular milieu of cells is normally tightly regulated such that it remains fairly constant, a state referred to as homeostasis.
  2. as cells encounter physiologic stresses or injurious conditions, they undergo adaptation,
  3. if the adaptive capability is exceeded or if the external stress is inherently harmful or excessive, cell injury develops
  4. within limits, injury is reversible; if the stress is severe, persistent, or rapid in onset, it results in irreversible injury
  5. with persistent or excessive noxious exposures, injured cells pass a nebulous “point of no return” and undergo cell death.
2

cell death

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  1. when cells are injured they die by different mechanisms, depending on the nature and severity of the insult;
  2. necrosis ("accidental" cell death) is the major pathway of cell death in many commonly encountered injuries, such as those resulting from ischemia, exposure to toxins, various infections, and trauma.
  3. apoptosis ("programmed" cell death) is a pathway of cell death that occurs when the injury is less severe, or cells need to be eliminated during normal processes.
3

necrosis

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  1. a form of "accidental" cell death in which cellular membranes fall apart, and cellular enzymes leak out and ultimately digest the cell; considered the inevitable end result of severe damage and is not thought to be regulated by specific signals or biochemical mechanisms;
  2. elicits inflammation, that is induced by substances released from dead cells and which serves to eliminate debris and start the repair process;
  3. cells show increased eosinophilia (due to loss of basophilic ribonucleic acid), and may take on a glassy, homogeneous appearance, mostly because of the loss of lighter staining glycogen particles;
  4. by electron microscopy, necrotic cells are characterized by discontinuities in plasma and organelle membranes, dilation of mitochondria and RER, disruption of lysosomes, and intracytoplasmic myelin figures;
  5. nuclear changes assume one of three patterns; pyknosis (shrinkage), karyorrhexis (fragmentation), karyolysis (fading); in 1 to 2 days, the nucleus in a dead cell may completely disappear.
4

coagulative necrosis

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  1. underlying tissue architecture is preserved for at least several days after death of cells in the tissue; affected tissues take on a pale, firm texture
  2. the injury denatures not only structural proteins but also enzymes, thereby blocking proteolysis of the dead cells;
  3. characteristic of infarcts (areas of necrosis caused by ischemia) in all solid organs except the brain (e.g. heart, spleen, kidneys).
5

liquefactive necrosis

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  1. seen in focal bacterial and fungal infections; leukocytes enzymatically digest the dead cells, transforming the tissue into a viscous liquid that is removed by phagocytes;
  2. if the process is initiated by acute inflammation, as in a bacterial infection, the material is frequently creamy yellow and is called pus, which may accumulate in to form an abscess;
  3. characteristic pattern following ischemic injury to the brain, but can occur in many tissues throughout the body
6

gangrenous necrosis

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  1. not a distinctive pattern of cell death, the term is still commonly used in clinical practice; usually secondary to ischemia and often accompanied by superimposed infection
  2. wet gangrene occurs in intestines (e.g. in obstruction, volvulus, or strangulation) and culminates in liquifactive necrosis;
  3. dry gangrene occurs in distal limbs (e.g. feet and toes), is associated with frostbite and diabetes, and culminates in autoamputation.
7

fibrinoid necrosis

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  1. occurs in immune reactions in which complexes of antigens and antibodies are deposited in the walls of blood vessels, but it also may occur in severe hypertension
  2. deposited immune complexes and plasma proteins that leak into the wall of damaged vessels produce a bright pink, amorphous appearance on H&E preparations called fibrinoid (fibrinlike);
8

fat necrosis

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  1. focal areas of fat destruction, typically resulting from the release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity
  2. occurs in acute pancreatitis; pancreatic enzymes leak out of acinar cells and ducts, liquefying the membranes of fat cells in the peritoneum, and lipases split the triglyceride esters contained within fat cells
  3. released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification), which enable the surgeon and the pathologist to identify the lesions
9

caseous necrosis

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  1. most often encountered in foci of tuberculous infection; caseous means “cheeselike,” referring to the friable yellow-white appearance of the area of necrosis on gross examination;
  2. unlike coagulative necrosis, the tissue architecture is completely obliterated and cellular outlines cannot be discerned; often surrounded by a collection of macrophages and other inflammatory cells
10

apoptosis

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  1. a pathway of "programmed" cell death in which cells activate enzymes that degrade their own nuclear DNA and nuclear and cytoplasmic proteins, then break up into fragments;
  2. the plasma membrane of the apoptotic cell remains intact, but it is altered in such a way that the fragments, called apoptotic bodies, become highly “edible,” leading to their rapid consumption by phagocytes;
  3. unlike necrosis, it is not inflammatory; the dead cell and its fragments are cleared with little leakage of cellular contents.
  4. can be physiologic (e.g. when cells are unnecessary or must be replaced) or pathologic (e.g. eliminating cells that are damaged beyond repair)
  5. regulated by biochemical pathways that control the balance of survival signals and ultimately the activation of enzymes called caspases (cysteine aspartate specific proteases)
  6. the mitochondrial (intrinsic) pathway seems to be responsible for apoptosis in most physiologic and pathologic situations (Bcl-2,Bcl-xL, Bax, Bak, cytochrome c, caspase-9)
  7. the death receptor (extrinsic) pathway is involved in the elimination of self-reactive lymphocytes and in the killing of target cells by some cytotoxic T lymphocytes (TNF, Fas CD95, FasL)
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morphologic correlates of reversible cell injury

  1. cellular swelling (hydropic change) is commonly seen in cell injury associated with increased permeability of the plasma membrane; when it affects many cells in an organ, it causes pallor (as a result of compression of capillaries), increased turgor, and an increase in organ weight;
  2. fatty change (steatosis) is manifested by the appearance of triglyceride containing lipid vacuoles in the cytoplasm; it is principally encountered in organs that are involved in lipid metabolism, such as the liver;
  3. other intracellular changes associated with cell injury include
    1. plasma membrane alterations such as blebbing, blunting, or distortion of microvilli, and loosening of intercellular attachments;
    2. organelle changes such as mitochondrial swelling, dilation of the endoplasmic reticulum with detachment of ribosomes and dissociation of polysomes;
    3. cytoplasm may contain so-called “myelin figures,” which are collections of phospholipids from damaged cellular membranes.
12

causes of cell injury

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  1. oxygen deficiency (e.g. anemia, CO poisoning)
  2. free radicals (e.g. super oxide, hydrogen peroxide)
  3. physical (e.g. temperature, trauma, pressure, electric shock)
  4. chemical (e.g. pesticides, pollutants, asbestos, smoke)
  5. infectious (e.g. microbes, viruses)
  6. immunologic (e.g. allergens, autoimmune disorders)
  7. genetic (e.g. damaged DNA, misfolded proteins)
  8. nutritional (e.g. calorie insufficiency, vitamin deficiency)
  9. aging (e.g. DNA mutations, telomere shortening)
13

hyperplasia

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  1. a type of cellular adaptation to stress involving an increase in the number of cells;
  2. physiologic hyperplasia occurs in the glandular breast tissue and uterus during pregnancy
  3. compensatory hyperplasia occurs following partial hepatectomy as liver cells regenerate
  4. pathologic hyperplasia occurs in benign prostatic hyperplasia due to hormone stimulation by androgens
  5. is controlled; will cease if the stimulus is removed (this is what differentiates it from cancer)
14

hypertrophy

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  1. a type of cellular adaptation to stress involving an increase in the size of cells;
  2. physiologic hypertrophy occurs in skeletal muscle in response to resistance training as well as in the uterus during pregnancy
  3. pathologic hypertrophy occurs in the heart in hypertension; increased resistance requires stronger contractions
15

metaplasia

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  1. a type of cellular adaptation to stress involving a change in the type of cells; always pathological;
  2. in smokers, the normal ciliated columnar respiratory epithelium changes to respiratory stratified squamous epithelium
  3. in chronic gastric reflux, the normal stratified squamous esophageal epithelium changes to to gastric-type columnar
  4. these changes may increase survivability, but they are associated with loss of important functional mechanisms
16

atrophy

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  1. a type of cellular adaptation to stress involving a decrease in the number of cells;
  2. physiologic atrophy occurs during menopause as a result of decreased hormonal stimulation
  3. pathologic atrophy can occur due to deinnervation, loss of bloodflow, inactivity, or prolonged pressure
  4. atrophic cells diminish to reach a new, lower function equilibrium, but they are not dead.
17

dysplasia

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  1. disorder in in the size, growth, or shape of cells (always pathological);
  2. Sirregular maturation, abnormal arrangement, and variable nuclear shape and size (pleomorphism)
  3. the most important example of dysplasia is in the cervix at the squamocolumnar junction
  4. cells are disordered in shape and size; this is different from metaplasia in which cells make a distinct change of type.
18

intracellular accumulations

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  1. abnormal amounts of substances within the cell, caused by inadequate removal or excessive production.
  2. triglyceride accumulation (called "fatty change" or "steatosis"); occurs most often in the liver, but also occurs in the heart, kidneys; associated with alcohol abuse, diabetes, obesity or malnutrition;
  3. cholesterol accumulation occurs in most often phagocytic cells and vascular smooth muscle walls in athreosclerosis;
  4. protein accumulation is not common, but it can occur in the kidneys in cases of nephrotic syndrome (protein leakage through glomerular filter)
  5. pigments accumulations include carbon (black, causes anthracosis); lipofuscin (brown, "wear-and tear" pigment, marker of free radical injury, causes brown atrophy); melanin ( brown-black, provides UV protection, synthesized by melanocytes), and hemosiderin (yellow-brown, hemoglobin-derived, marker of excessive iron)
19

pathologic calcification

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  1. common process to many disease states that results in abnormal deposition of calcium salts;
  2. dystrophic calcification is when calcium metabolism is normal, but it deposits in injured or dead tissue (e.g. atherosclerosis)
  3. metastatic calcification is associated with hypercalcemia, which is primarily caused by:
    1. hyperparathyroidism
    2. hypervitaminosis D
    3. increased calcium intake
    4. increased bone breakdown
20

cellular aging

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Cellular aging is the result of a progressive decline in the life span and functionality of cells.

  1. DNA mutations occur due to exposure to ROS; although DNA can be repaired, this damage accumulates over time as repair mechanisms gradually become less eficient
  2. Cell replication begins to decline; after a fixed number of divisions, cells enter a terminally non-dividing state (senescence); this occurs due to progressive shortening of telemeres
  3. Protein homeostasis becomes defective as translation slows and chaperones and proteasomes degrade; this may eventually trigger the misfolded protein response resulting in apoptosis
  4. Persistent inflammation resulting from the accumulation of damaged cells, lipids, and other substances can induce chronic disease (e.g. atheroslcerosis, T2D)

Caloric restriction has been found to slow aging by reducing IGF-1 signaling, which reduces rates of cell growth and metabolism, possibly allowing for improved cellular functions and repair.

21

telomeres

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  1. short, repeated sequences of DNA at the ends of chromosomes that protect DNA from degrading;
  2. each replication cycle, a small section of the telomere cannot be duplicated, resulting in progressive shortening over time
  3. an enzyme called telomerase functions in maintaining telomere length, but it is absent in somatic cells
  4. in cancer cells, telomerase is reactivated, allowing uncontrolled proliferation of cells indefinitely