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Pathology > Irreversible/reversible injury > Flashcards

Irreversible/reversible injury Flashcards

1
Q

Reversible cell injury

A

Morphologic correlates:

  • cellular swelling
  • fatty changes (lipidosis)

Reversible until a certain point

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2
Q

Irreversible cell injury and cell death

A

Morphologic correlates:

  • necrosis
  • apoptosis
  • other types of cell death
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3
Q

Reversible cell injury: acute cell swelling

A

Hydropic degeneration; hydropic change; cytotoxic edema (CNS); ballooning degeneration (epidermis)

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4
Q

Cells highly vulnerable to hypoxia and cell swelling

A 
Cardiomyocytes
Proximal renal tubule epithelium
Hepatocytes
Endothelium
CNS neurons, oligodendrocytes, astrocytes (cytotoxic edema)
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5
Q

Definition of acute swelling

A

Early, sub-lethal manifestation of cell damage, characterized by increase cell size and volume due to H2O overload
Most common and fundamental expression of cell injusry

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6
Q

Etiology of acute swelling

A 
Loss of ionic and fluid homeostasis
 -failure of cell energy production
 -cell membrane damage
 -injury to enzymes regulating ion channels of membranes
Examples: physical mechanical injury
-hypoxia
-toxic agents
-free radicals
-viral organisms
-bacterial organisms
-immune-mediated injury
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7
Q

Gross appearance of acute cell swelling

A

Slightly swollen organ with rounded edges
Pallor when compared to normal
Cut surface: tissue bulges and cannot be easily put in correct apposition
Slightly heavy (wet organ)

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8
Q

Histologic appearance of cell swelling

A

H2O uptake dilutes the cytoplasm
Cells are enlarges with pale cytoplasm
May show increased cytoplasmic eosinophilia
Nucleus in normal position, with no morphological changes
Ballooning degeneration (extreme variant of hydropic degeneration)

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9
Q

Morphological changes of cellular swelling

A
  1. Plasma membrane alterations such as blebbing, blunting, and loss of microvilli
  2. Mitochondrial changes, including swelling and the appearance of small amorphous densities
  3. Dilation of ER, with detachment of polysomes; intracytoplasmic myelin figures may be present
  4. Nuclear alterations, with disaggregation of granular and fibrillar elements
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10
Q

Increase in cell size due to:

A

Hydropic change, fatty change: cell swelling
-Due to increased uptake of H2O and then to diffuse disintegration of organelles and cytoplasmic proteins

Hypertrophy: cell enlargement
-The cell enlargement is caused by increase of normal organelles

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11
Q

Prognosis of cellular swelling

A

Depends on the number of cells affected and importance of cells
Good (if O2 is restored before the “point of no return”)
Poor (progression to irreversible cell injury)

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12
Q

The initial change in hydropic degenerative change in cells is:

A

Malfunctioning of the Na/K ATPase pump

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13
Q

Definition of fatty change

A

Sub-lethal cell damage characterized by intracytoplasmic fatty vacuolation
May be preceded or accompanied by cell swelling
All major classes of lipids can accumulate in cell:
-triglycerides
-cholesterol/cholesterol esters
-phospholipids
-abnormal complexes of lipids and carbohydrates (lysosomal storage diseases)

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14
Q

Lipidosis

A

Accumulation of triglycerides and other lipid metabolites (neutral fats and cholesterol) within parenchymal cells

  • heart muscle
  • skeletal muscle
  • kidney
  • liver (clinical manifestations are most commonly detected as alterations in function (elevated liver enzymes, icterus) because the liver is the organ most central to lipid metabolism
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15
Q

Etiology of Fat change

A

Main causes: hypoxia, toxicity, metabolic disorders

Seen in abnormalities of synthesis, utilization and/or mobilization of fat

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16
Q

Pathogenesis of fatty change

A

Impaired metabolism of fatty acids
Accumulation of triglycerides
Formation of intracytoplasmic fat vacuoles

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17
Q

Pathogenesis of fatty liver

A

Hepatic lipid metabolism and mechanisms resulting in lipid accumulation

  1. Excessive delivery of free fatty acids (FFA) from fat stores diet
  2. Decreased oxidation or use of FFAs
  3. Impaired synthesis of apoprotein
  4. Impaired combination of protein and triglycerides to form lipoproteins
  5. Impaired release of lipoproteins from hepatocytes
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18
Q

Gross appearance: fatty change

A

Fatty liver, hepatic steatosis/lipidosis
Liver: diffuse yellow (if all cells are affected)
-enhanced reticular pattern if specific zones of hepatocytes are affected
-edges are rounded and will bulge on section
-tissue is soft, often friable, cuts easily and has a greasy texture
-if condition is severe, small liver sections may float in fixative or water

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19
Q

Hepatic lipidosis: cause

A

Physiologic: esp in ruminants
-in late pregnancy (pregnancy toxemia)- heavy early lactation (ketosis)
Ketone bodies: are alternative fuel for cells
Produced in liver by mitochondria
Conversion of aceryl CoA from fatty acid oxidation= lipolysis
Nutritional disorders
-obesity
-protein- calorie malnutrition (impaired apolipoprotein synthesis)
-starvation (increase mobilization of triglycerides)
Endocrine diseases
-diabetes mellitus (increased mobilization of triglycerides)
Genetic disorders
-niemann pick disease (phospholipid sphingomyelin)- a lysosomal storage disease

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20
Q

Histological appearance of fatty change

A

Well delineated, lipid filled vacuoles in the cytoplasm
Vacuoles are single to multiple, either small or large
Vacuoles may displace the cell nucleus to the periphery

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21
Q

Prognosis of fatty change

A

Initially reversible- can lead to hepatocyte death (irreversible)
Hepatic lipidosis: is seen in cats, ruminants, camelids, and miniature equines, but is rare in dogs and uncommon in other horses
Identification and treatment of any predisposing diseases and aggressive nutritional support is required for therapy of hepatic lipidosis
e.g seen in obese cats, secondary to anorexia of any cause. Mortality is high without treatment
Oral appetite stimulants can be given but are usually inadequate alone

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22
Q

Irreversible injury

A 
Associated morphologically with: 
 -severe swelling of mitochondira
 -extensive damage to plasma membranes (giving rise to myelin figures)
 -swelling of lysosomes
Myocardium - 30-40 min agter ischemia
Cell death: 
 -mainly by necrosis
 -apoptosis also contributes
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23
Q

Irreversible injury: Necrosis

A

Necrotic change: seen..
Ultrastructurally- less than 6 hours
Histologically- 6-12 hours
Grossly- 24 - 48 hours

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24
Q

Necrosis (oncosis, oncotic nectosis)

A

Cell death after irreversible cell injury by hypoxia, ischemia, and direct cell membrane injury
Morphologic aspect is dur to 2 concurrent processes:
-denaturation of proteins
-enzymatic digestion of cell
by endogenous enzymes derived from the lysosomes of the dying cells=autolysis (self digestion)
by release of lysosome’s content from infiltrating WBCs
Outcome: accompanied by inflammation

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25
Q

Light microscopy nuclear changes

A

pyknotic cell- condensed nucleus
karyorrhectic cell- fragmented nucleus
Karyolytic cell- dissolution of nucleus

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26
Q

Necrosis: Gross appearance

A

Multiple soft, friable, slightly depressed foci sharply demarcated from viable tissue

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27
Q

Light microscopy cytoplasmic changed of necrotic cells

A

Denatured proteins: increase binding of eosin (pink)
Loss of RNA: loosing basophilia
Loss of glycogen particles: Glassy homogeneous
Enzyme digested cytoplasm: Vacuolation and moth eaten appearance
Organelles
Calcification may be seen

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28
Q

The liver is often the site of fatty change or lipidosis because

A

It is the central organ in the metabolism of fat

29
Q

Type of oncotic necrosis

A 
Coagulative necrosis
Caseous necrosis
Liquefactive necrosis
Gangrenous necrosis
Fat necrosis
Fibrinoid necrosis
30
Q

Coagulative necrosis

A

Typical early response to hypoxia, ischaemia, toxic injury
Occurs because of widespread denaturation of cell proteins= both structural proteins (so maintains cell shape) and lysosomal protein enzymes (so cell auto-digested delayed)
Nucleus still shows features of necrosis= pyknosis, karyorrexhis, karyolysis i.e. eosinophillic cell outlines visible, nucleus necrotic, retention of tissue aechitecture
Most commonly seen in some tissues e.g liver, kidney, heart, skeletal muscle
Ultimately the necrotic cells are removed:
-phagocytosis by WBCs
-digestion by the action of lysosomal enzymes of WBCs

31
Q

Liquefactive necrosis

A

Necrotic architecture is liquefied= liquid
Dead cells are digested -> transformation of the tissue into a liquid viscous mass
Occurs in:
-tissue with high lipid content- CNS
-tissue with high neutrophil recruitment and enzymatic release with digestion of tissue- abscess
-focal bacterial and occasionally, fungal infections
microbes stimulate the accumulation of WBCs and liberation of enzymes from these cells

32
Q

Liquefactive necrosis- pathogenesis

A

Overgrowth of intestinal Cl. perfringens bacteria type D
Release and absorption of epsilon toxin- targets endothelial cells in brain (and lung)
Endothelial necrosis
Anoxia and edema of neural parenchyma
Liquefactive necrosis of surrounding area
Necrotic material is frequently creamy yellow beacuase of the presence of dead WBCs= pus

33
Q

Leukoencephalomalacia- pathogenesis

A

Ingestion of moldy corn containing toxin-producing (fumonisin B1) Fusarium verticilioides
Inhibits sphingolipid synthesis
Accumulation of toxic sphingosine and sphingonine
Direct cellular toxicity
Leukoencephalomalacia

Necrosis of white matter of cerebral hemispheres, brain stem and cerebellum

34
Q

Abscess

A

A localized collection of pus (liquefied tissue) in a cavity formed by disintegration of tissues surrounded by fibrous connective tissue (not in CNS)
It is the result of the body’s defensive reaction to foreign material
2 types of abscesses
1. septic
2. sterile

35
Q

Septic abscesses

A

The majority

Infection, release of enzymes from WBCs and infectious agent (pyogenic bacteria, like S aureus)

36
Q

Sterile abscesses

A

Process caused by nonliving irritants such as drugs

Likely to turn into firm solid lumps as they scar, rather than remaining pockets of pus

37
Q

Gangrenous necrosis

A

Not a specific pattern of cell death but begins mostly as coagulative necrosis– likely due to ischemia
Term commonly used in clinical practice
- it is usually applied to distal extremities (also toes, ear, udder, pinna)
-involving multiple planes of tissue

Dry gangrene-no bacterial superinfection; tissue appears dry

38
Q

Wet gangrene

A

Bacterial superinfection has occurred
Tissue looks wet and liquefactive
By actions of degradative enzymes in the bacteria and the attracted WBCs

39
Q

Caseous necrosis

A

Caseous= cheeselike
Friable (crumble) white: area of necrosis
Necrotic debris represents dead WBCs
Possible causes: often with bacterial infections in which bacteria replicate within phagosomes
-mycobacterium
-corynebacterium
-fusobacterium
-fungal infections
Compared with coagulation necrosis- caseous is chronic
Often associated with poorly degradable lipids of bacterial origin

40
Q

Caseous necrosis- histology

A

Necrotic area
eosinophilic granular cell debris with a rim of inflammatory cells, often macrophages
Obliterated tissue architecture
Dystrophic calcification-> commonly to occur in center of lesion

41
Q

Fat necrosis- types

A

Enzymatic necrosis
Traumatic necrosis of fat
Necrosis of abdominal fat

42
Q

Fat necrosis- enzymatic necrosis

A

Pancreatic necrosis of fat
Action of activated pancreatic lipases in escaped pancreatic fluid
Neutral fat (lipase -> triglycerides)
Free fatty acids + Ca -> calcium soaps (saponification)

Exocrine pancreas- breakdown fats in GI tract
Common with pancreatitis

43
Q

Fat necrosis- pancreatitis, dog

A

Enzymatic necrosis of fat (fat necrosis), dog with previous bouts of pancreatitis. Necrotic fat often becomes saponified and so grossly the lesion is chalky to gritty and pale white
Large area of fat necrosis with acute inflammation and saponification (basophilic areas)

44
Q

Fat necrosis- Traumatic necrosis of fat

A

Dystocia (difficult birth)
Subcutaneously in inter muscular fat at sternum- recumbent cattle
Manipulating organs harshly during surgery

45
Q

Fat necrosis- necrosis of abdominal fat (cattle)

A

Unknown cause- mesentery, omentum, retroperitoneum
Extreme cases intestinal stenosis
Channel island breeds

46
Q

Fibrinoid necrosis

A

Special form of necrosis usually seen in immune reactions involving blood vessels
Occurs when Ag-Ab complexes are deposited in the walls of arteries
Deposits of these “immune complexes” together with fibrin that has leaked out of vessels, result in a bright pink and amorphous appearance in H & E stains called fibrinoid (fibrin-like) by pathologists

47
Q

What type of necrosis often occurs within the brain

A

Liquefactive

48
Q

Apoptosis

A

Discovered in the 70s
Induced by a tightly regulated suicide program, it is genetically regulated -> sometimes called programmed cell death
may be physiologic or pathologic
Is not accompanied by inflammation
Cells destined to die activate intrinsic enzymes that degrade the cells own DNA and nuclear and cytoplasmic proteins
-apoptotic cells break up into fragments called apoptotic bodies which contain portions of the cytoplasm and nucleus
-plasma membrane: remains intact; its structure is altered-> becomes tasty target for phagocytes

49
Q

Apoptosis- physiologic processes

A

Most common, occurring all the time
Programmed cell death during embryogenesis
Hormone-dependent involution of organs in the adult (thymus, uterus-post-parturition)
Cell deletion in proliferating cell populations (intestinal epith. elimination of T/B cells that have poor ag receptors)
Deletion of auto-reactive T cells in the thymus (by cytotoxic T cells)
Death of cells after served useful function

50
Q

Apoptosis- pathologic processes

A

Eliminated cells injured beyond repair
DNA damage
accumulation of misfolded proteins
Cell death in certain infections (mainly viral), and some neoplastic cells
Pathologic atrophy in parenchymal organs after duct obstruction

51
Q

Apoptosis- morphology

A

Cell shrinkage with increased cytoplasmic density
Chromatic condensation (pyknosis)
Formation of cytoplasmic blebs and apoptotic bodies (fragmentation)
Phagocytosis of apoptotic cells by adjacent healthy cells

52
Q

Apoptosis mechanisms

A

Specific feature: activation of caspases
Initiator caspases: 9 and 8
Executioner caspases: 3 and 6
1. major inducers of apoptosis
2. regulators of apoptosis
3. executioner caspases
4. end results
Extrinsic: cell surface receptor death domain/FAS
Intrinsic: mitochondrial membrane permeability change
Both to initiator caspases and to effector caspases

53
Q

Protein damage

A

Accumulation of misfolded proteins
-genetic mutations
-free radical damage
Cells have repair mechanism for misfolded proteins
When overwhelmed -> proteins accumulated in the ER -> ER stress -> initiates apoptosis

54
Q

Intrinsic pathway

A

Major mechanism of apoptosis in all mammalian cells
Result of increased mitochondrial permeability and release of proapoptotic molecules (death inducers) into the cytoplasm
Cytochrome-C: essential for life: released into cytoplasm-> initiated suicide program of apoptosis
Controlled release by: pro and anti apoptotic members of the Bcl family of proteins

55
Q

Anti/pro apoptotic proteins

A

Anti=pro basal state
BH3 only proteins: sensors of damage/stress
Pro apoptotic proteins: Bak, Bax: effectors
Anti-apoptotic proteins: Bcl proteins: outer membrane mitochondria, keeps it impermeable

56
Q

Extrinsic pathway

A

Initiated by death receptors: members of TNF receptor family
1. death domain
2. best known type: TNF receptor (TNFR1) and Fas (CD95)
Fas-L expressed on
-T cells that identify self Ag
-cytotoxic T cells (perforin, granzymes)
Forming a binding site for an adapter protein, that also contains a death domain: FADD (Fas associated death domain)
FADD in turn binds an inactive Caspase-8 -> active caspase-8 -> activation of execution phase of apoptosis

57
Q

Removal of apoptotic cells- apoptotic bodies

A

Edible for phagocytes
Expressed phospholipids in outer layer of the membrane (instead inner leaflet) to be identified by macrophage receptors
May become coated with natural Ab and proteins of the complement system (C1q)

58
Q

Removal of apoptotic cells- apoptotic cells

A

Secrete soluble factors that recruit phagocytes
Some express thrombospondin (adhesine glycoprotein that is identified by phagocytes)
Macrophages may produce protiens that bidn to apoptotic cells (not to live cells) for engulfment

59
Q

Disorders associated with dysregulated apoptosis- too little

A

increased cell survival: abnormal cells survive
Cells with mutations in p53 are subjected to DNA damage, not only fail to die but are susceptible to the accumulation of mutations bc of defective DNA repair, these can = neoplasia
Lymphocytes that react against self Ag and failure to eliminate dead cells = autoimmune disorders

60
Q

Disorders associated with dysregulated apoptosis- too much

A

Excessive cell death

  1. neurodegenerative dz: manifested by loss of specific sets of neurons (apoptosis caused by mutations and misfolded proteins)
  2. Ischemic injury, as in myocardial infarction and stroke
  3. Death of virus infected cells
61
Q

Necrosis vs apoptosis: cell size

A

Necrosis: enlarged (swelling)
Apoptosis: Reduced (shrinkage)

62
Q

Necrosis vs apoptosis: Nucleus

A

Necrosis: pyknosis, karyorrhexis, karyolysis
Apoptosis: fragmentation into nucleosome-size fragments

63
Q

Necrosis vs apoptosis: Plasma membrane

A

Necrosis: disrupted
Apoptosis: intact; altered structure, esp orientation of lipids

64
Q

Necrosis vs apoptosis: Cellular contents

A

Necrosis: enzymatic digestion; may leak out of cell
Apoptosis: Intact; may be released in apoptotic bodies

65
Q

Necrosis vs apoptosis: adjacent inflammation

A

Necrosis: frequent
Apoptosis: no

66
Q

Necrosis vs apoptosis: physiologic or pathologic role

A

Necrosis: invariably pathologic (culmination of irreversible cell injury)
Apoptosis: Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, esp DNA damage

67
Q

Necroptosis

A

Programed necrosis
Resembles necrosis morphologically and apoptosis mechanistically as a form of programmed cell death
Necroptosis is triggered by ligation of TNFR1 and viral proteins of RNA and DNA viruses
Necroptosis is caspase-independent but dependent on signaling by the RIP1 and RIP3 complex
Occurs inL mammalian bone growth plate; associated with cell death in steatohepatitis, acute pancreatits, reperfusion injury, and neurodegenerative diseases
Release of cellular contents evokes an inflammatory reaction as in necrosis

68
Q

Pyroptosis

A

So called because it is accompanied by the release of fever inducing cytokine IL-1 and because it bears some biochemical similarities with apoptosis
Occurs in cells infected by microbes

Pathology (13 decks)

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