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Basic Pathology > Cell Injury > Flashcards

Cell Injury Flashcards

1
Q

How Hypoxia causes Cell Injury

A
  1. No or reduced oxygen.
  2. Reduced ATP production by oxidative phosphorylation (1) and initiation of anaerobic glycolysis (2).
  3. Cell changes-
    3.1 Reduced organelle function:
    a) Failure of ATP-dependent Na-K pump -> Na into cell -> water into cell.
    b) Ineffective Ca pump –> Ca into cell.
    3.2 Increased lactic acid –> increased acidic environment –> enzymes and proteins denatured including lysosome membranes which releases hydrolytic enzymes.
  4. Cell Injury +/- death^
    a) Cellular swelling ->
    i) swollen surface microvilli –> reduced surface area –> reduced molecule absorption.
    ii) cell blebs (failing cytoskeleton).
    iii) Swollen rough ER –> detachment of ribosomes –> reduced protein synthesis.b1) Activation of enzymes->
    i) Proteases –> breakdown of proteins including cytoskeleton.
    ii) Endonucleases –> breakdown of DNA.
    iii) Hydrolytic enzymes –> digestion of cell contents.
    iv) Phospholipase –> breakdown of cell membrane (NB. most important sign of irreversible cell damage).
    b2) Increased mitochondrial membrane permeability –> leaking of cytochrome C –> activation of cell death.

^ Changes potentially reversible if oxygen returned.

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2
Q

What is
Reversible cell injury and what are the general causes

A
  • Correctable injury (once damaging stimulus removed).
  • Cause: Functional and structural alterations in early stages or mild forms of injury.
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3
Q

Two features consistently seen in Reversible Cell Injury

A
  1. Cellular swelling (including organelle swelling, cell blebbing, detachment of ribosomes from rough ER and clumping of nuclear chromatin).
  2. Fatty change in lipid metabolising organs (accumulation of triglyceride-filled lipid vacuoles).
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4
Q

Earliest manifestation of Cell Injury

A

Cellular swelling.

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5
Q

Microscopic findings of Cellular Swelling / Reversible cell injury

A

Cell membrane:

  • Blebbing / blunting.
  • Loss of microvilli.

Mitochondria:

  • Swelling.
  • +/- small irregular densities.

Cytoplasm:

  • Small clear vacuoles within cytoplasm from small, pinched-off segments of ER (Called Hydropic change / vacuolar degeneration).
  • Eosinophilic cytoplasm from loss of RNA which usually bind haematoxylin in H&E stain.
  • “Myelin figures” (phospholipids from damaged cell membranes).

ER:

  • Swelling with detachment of ribosomes.

Nucleus:

  • Breakdown of granular and fibrillar elements.
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6
Q

Necrosis:
Definition

A

Unplanned cell death due to a pathological process.

Involves:

  • Inflammation.
  • Macrophage digestion.
  • Destruction of cell membrane.
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7
Q

Necrosis:
Causes

A
  • Ischaemia.
  • Microbes.
  • Chemical and physical injury.
  • Pancreatitis.
  • Immune-mediated vasculitis.
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8
Q

Necrosis:
Morphology

A
  • Enlarged cell (swelling).
  • Eosinophilia (due to loss of cytoplasmic RNA + accumulation of denatured proteins).
  • Nuclear shrinkage (pyknosis) –> nuclear fragmentation (karyorrhexis) –> nuclear fading (karyolysis) –> eventually nucleus disappears.
  • Disrupted plasma and organelle membranes.
  • Vacuolated and moth-eaten cytoplasm (digestion of organelles).
  • Myelin figures (precipitated plasma membrane phospholipids).
  • Calcium-rich deposits.
  • Inflammatory cells ++.
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8
Q

Patterns of Tissue Necrosis

A
  • Coagulative Necrosis.
  • Liquefactive Necrosis.
  • Caseous Necrosis.
  • Fat Necrosis.
  • Gangrenous Necrosis.
  • Fibrinoid Necrosis.
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9
Q

Patterns of Tissue Necrosis:
Coagulative Necrosis

A
  • Firm affected tissue.
  • Histology: eosinophilic cells with indistinct / reddish nuclei and inflammatory infiltrate.
  • Cause: Ischaemia (EXCEPT in brain).
  • Localised area of coagulative necrosis = infarct.

“Ghost cells”

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10
Q

Patterns of Tissue Necrosis:
Liquefactive Necrosis:
-Macroscopic, microscopic, and causes

A
  • Creamy yellow necrotic material (pus).
  • Histology: leukocyte infiltrates and debris.
  • Cause: focal bacterial (e.g. abscess from pyogenic bacteria - STAU or GAS) or fungal infections, hypoxic death in brain.

“Liquid”-factive.

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11
Q

Patterns of Tissue Necrosis:
Gangrenous Necrosis

A
  • Not a specific pattern but commonly used in clinical practice.
  • Usually applied to a limb that has lost blood supply (i.e. coagulative necrosis).
  • Wet gangrene = superimposed bacterial infection –> coagulative + liquefactive necrosis.
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12
Q

Patterns of Tissue Necrosis:
Caseous Necrosis

A
  • Caseous = Cheese-like.
  • Tissue = friable white / yellow-white “cheesy” appearing debris.
  • Histology: Granuloma (structureless collection of fragmented / lysed cells and granular debris enclosed within a distinctive inflammatory border (lymphocytes and macrophages)).
  • Cause: TB, fungal infections.
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13
Q

Patterns of Tissue Necrosis:
Fat Necrosis

A
  • Focal areas of fat destruction.
  • Tissue = Fat saponification (chalky-white areas of fatty acids combined with calcium).
  • Histology: shadowy outlines of necrotic fat cells, basophilic calcium deposits, inflammatory reaction.
  • Cause: Acute pancreatitis - leaked pancreatic enzymes liquefy fat cell membranes –> release of TG esters -> split by pancreatic lipases -> free fatty acid.
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14
Q

Patterns of Tissue Necrosis:
Fibrinoid Necrosis:
-Histology and cause

A
  • Histology: fibrinoid (fibrin-like) = confluent bright pink area of deposited immune complexes and plasma proteins within an artery wall.
  • Cause: Immune-mediated vasculitis.
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15
Q

Apoptosis:
Definition

A

Programmed cell death due to normal physiologic processes.
NB. Can sometimes be pathological.

Key features:

  • Non-inflammatory.
  • Involves mitochondrial factor release.
  • Cell membrane remains intact - cell breaks up into plasma membrane-bound fragments (apoptotic bodies).
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16
Q

Apoptosis:
Normal Physiologic Situations

A
  • Elimination of cells no longer needed.
  • Maintainance of constant cell population numbers.

E.g.:

  • Removal of supernumerary cells during development (e.g. formation of fingers and toes, cells in webs between fingers eliminated).
  • Involution of hormone-dependent tissues (menstrual endometrial cell shedding, menopause ovarian follicular atresia).
  • Cell turnover in proliferating cell populations (immature lymphocytes, epithelial cells).
  • Elimination of self-reactive lymphocytes.
  • Removal of cells that have served their purpose (neutrophils after an acute inflammatory response).
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17
Q

Apoptosis:
Pathologic Situations

A

Elimination of injured cells beyond repair WITHOUT eliciting host reaction.

E.g.:
* DNA damage by radiation or cytotoxic chemotherapy.
* Accumulation of misfolded proteins.
* Some infections trigger response (adenovirus, HIV).
* Cytotoxic T lymphocyte host response to viral proteins, tumour cells, transplanted cells.
* Contributes to pathologic atrophy following duct obstruction (pancreas, parotid, kidney).

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18
Q

Apoptosis:
Morphology

A
  • Cell shrinkage.
  • Dense, eosinophilic cytoplasm.
  • Chromatin condensation^ - aggregates peripherally. Nucleus may also break into fragments.
  • Cytoplasmic blebs.
  • Apoptotic bodies (membrane bound dead cell fragments).
  • Macrophages (phagocytose apoptotic cell / cell bodies).

^ Most characteristic feature.

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19
Q

How Apoptosis Occurs

A
  • Requires activation of Caspase enzyme.
  • Regulated by pro-apoptotic and anti-apoptotic proteins.
  • Two phases:
    • Initiation phase (activation of caspase).
    • Execution phase^ (cellular fragmentation triggered through endonuclease activation and breakdown of cytoskeleton).
  • Two pathways for caspase activation:
    • Mitochondrial (Intrinsic) Pathway.
    • Death Receptor (Extrinsic) Pathway.

^ Execution caspases = caspase-3 and caspase-6.

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20
Q

Apoptosis
Caspase Activation:
Mitochondrial (Intrinsic) Pathway - Proteins Involved.

A
  • Anti-apoptotic - BCL2, BCL-XL, MCL1 (maintain cell survival.^)
  • Pro-apoptotic - BAX, BAK.
  • Apoptosis initiators / sensors - BH3 only proteins (BAD, BIM, BID, Puma, Noxa).

^ Mutations of BCL2 –> overactivation –> innappropriate cell survival –> Follicular lymphoma (t14:18)

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21
Q

Apoptosis
Caspase Activation:
Mitochondrial (Intrinsic) Pathway

A
  1. Activation of sensors via lack of survival signals (e.g. growth factor), DNA damage (radiation, toxins, free radicals), or protein misfolding (ER stress).
  2. Blockage of Anti-apoptotic regulators.
  3. Activation of Pro-apoptotic effectors (BAX, BAK).
  4. Release of Cytochrome C from Mitochondria.
  5. Activates Initiator caspase (Caspase-9).
  6. Caspase activation cascade.
  7. Apoptosis execution phase.
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22
Q

Apoptosis
Caspase Activation:
- What are the Receptors and Ligands involved in the Death Receptor (Extrinsic) Pathway

A

Receptors:

  • Fas
  • TNF receptor 1 (TNFR1)

Ligands:

  • Fas-L
  • TNF-a
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23
Q

Apoptosis
Caspase Activation:
Death Receptor (Extrinsic) Pathway

A
  1. Death-receptor ligands binds to death-receptors OR cytotoxic T cell binding to cell.^
  2. Activates initiator caspases (Caspase-8 and Caspase-10).
  3. Caspase activation cascade.
  4. Apoptosis execution phase.

^ Cytotoxic T cell releases Granzyme B –> release of perforin –> caspase activation.

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24
Q

Mechanisms of cell injury:
-Mitochondria Pathways

A

Injury:

  • Hypoxia / ischaemia.
  • Radiation.

2 pathways both leading to necrosis:

  1. Decreased ATP production –> Decreased energy-dependent functions.
  2. Increased ROS –> damage to lipids, proteins, nucleic acids.
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25
Q

Acute sub-lethal radiation exposure of tissue MOST commonly leads to which condition?

A

Endothelial swelling.

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26
Q

Pathological effects of accumulated ROS

A
  • Lipid peroxidation –> membrane damage
  • Protein modifications –> protein breakdowns, protein misfolding.
  • DNA damage –> mutations.

i.e. can lead to necrosis OR apoptosis.

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27
Q

What is ischaemia-reperfusion Injury

A

Paradoxical exacerbation of cell injury and potential cell death on restoration of blood flow to ischaemic tissue.

E.g. tissue damage after therapies (t-PA) to restore blood flow in myocardial and cerebral infarction.

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28
Q

Ischaemia-reperfusion injury is associated with a greatly increased intracellular concentration of which ion?

A

Calcium.

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29
Q

Hyperplasia
-Definition

A

Increase in cell number.

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30
Q

Hyperplasia:
-Occurs in which cells

A

Cells which proliferate.

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31
Q

Hypertrophy:
-Definition

A

Increase in cell size.

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32
Q

Hypertrophy:
-Physiological examples

A
  • Uterine smooth muscle cell hypertrophy during pregnancy.
  • Bodybuilders muslces.
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33
Q

Cause of left ventricular hypertrophy

A

Pressure overload from:
* Uncontrolled hypertension.
* Aortic stenosis.

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34
Q

Metaplasia:
-Definition

A

Reversible replacement of one mature cell type by another.

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35
Q

Metaplasia example:
-Smoking

A

Pseudostratified columnar ciliated epithelium changes to squamous epithelium (Squamous metaplasia).

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36
Q

Metaplasia example:
-Barret’s oesophagus

A

Oesophageal squamous epithelium changes to intestinal-type columnar epithelium with goblet cells (Columnar metaplasia).

Can lead to oesophageal adenocarcinoma

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37
Q

What is telomerase?

A

Reverse transcriptase enzyme which maintains telomere length.

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38
Q

77-year old woman has chronic renal failure. Her serum urea nitrogen is 40 mg / dL. She is given diuretics and loses 2 kg. She reduces her protein in her diet and her serum urea nitrogen decreases to 30 mg / dL.
Which term best describes cellular responses to disease and treatment in this woman?

A

Adaptation.

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39
Q

A well 53-year-old woman is found to have a BP 150/95 mmHg. If her HTN remains untreated for years, which cellular alterations would most likely be seen in her myocardium?

A

Hypertrophy.

HTN –> increased ventricular pressure –> increased SIZE of myofibres = hypertrophy.

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40
Q

22-year-old pregnant woman.
13 / 40 USS: uterus = 7 x 4 x 3 cm.
Delivery: uterus = 34 x 18 x 12 cm.
Which cellular process has contributed most to the increased uterus size?

A

Myometrial smooth muscle hypertrophy.

Hypertrophy = increase cell SIZE.

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41
Q

20-year-old breastfeeding woman has slightly increased in size breasts. Milk is expressed from both nipples. Which process has occured in her breasts to enable breastfeeding?

A

Lobular hyperplasia.

Hyperplasia = increase in cell NUMBERS.
Breast lobule cell numbers increase due to progesterone.

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42
Q

What does intracellular lipid deposition indicate?

A

Sublethal cell injury
OR
Inborn errors in fat metabolism (rare).

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43
Q

16-year-old boy sustained forceful blunt trauma to his abdomen. Peritoneal lavage shows a haemoperitoneum. A small portion of the left lobe of the injured liver is removed. 2 month’s post op, a CT scan shows liver regeneration. Which process best explains this?

A

Hyperplasia.

Hyperplasia = increased cell NUMBERS.
Liver regeneration = compensatory hyperplasia.

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44
Q

What is Hydropic Change

A

Cell swelling.

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45
Q

71-year-old male with difficulty urinating, including hesitancy and increased frequency. Digital rectal exam reveals prostate doubled in size. Transurethral resection performed and microscopy shows nodules of glands with intervening stroma. Which pathologic process has most likely occured?

A

Hyperplasia

Hyperplasia = increased cell NUMBER.

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46
Q

What are the cell changes in Benign Prostatic Hyperplasia

AKA Nodular Prostatic Hyperplasia.
AKA Benign Prostatic Hypertrophy (technically incorrect).

A
  • Proliferation of both prostatic glands and stroma.
  • Example of pathologic hyperplasia.
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47
Q

29-year-old male with femoral fracture. Leg immobilised in a cast for 6 weeks. Following this, it is noted his calf has decreased in size. This change in size is due to which cellular alteration?

A

Atrophy

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48
Q

What is Atrophy?

A
  • Decreaed cell SIZE due to loss of cell substance.
  • Usually from decreased use.
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49
Q

What is Aplasia?

A

Lack of embryonic development i.e. NO cell numbers.

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50
Q

What is Hypoplasia?

A

Poor or subnormal devlopment of tissues i.e. Decreased cell NUMBERS.

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51
Q

What is Dystrophy of muscles?

A

Inherited disorders of skeletal muscles that lead to muscle fibre destruction, weakness and wasting.

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52
Q

What are Hyaline changes (hyalinosis)?

A

Non-specific, pink, glassy, eosinophilic appearance of cells.

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53
Q

34-year-old woman with heartburn from reflux for the past 5 years. Distal oesophageal biopsy from upper GI endoscopy shows change from normal oesophageal squamous epithelium to intestinal-type columnar epithelium with goblet cells.
What has occurred?

A

Columnar metaplasia.

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54
Q

Which intracellular elements are found in intracellular globules of hepatocytes from a chronic alcoholic and stain red with immunohistochemical staining indicating cytokeratin.

A

Intermediate filaments.

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55
Q

What substance is released by endothelial cells to promote vasodilation in areas of ischaemic injury?

A

Nitric oxide.

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56
Q

What effect does bradykinin have on vasculature?

A
  • Increases vascular permeability.
  • Produces pain.^

^Stimulates primary sensory neurons and provokes release of substance P, neurokinin and calcitonin gene-related peptide.

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57
Q

What effect does Leukotrine E4, Platelet-activating factor, and thromboxane A2 have on vasculature?

A

Vasoconstriction.

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58
Q

Mechanisms of cell injury:
-Cellular membrane pathways

A

Injury:

  • ROS.
  • Other.

2 pathways both leading to necrosis:

  1. Damage to lysosomal membranes –> leakage of enzymes.
  2. Damage to plasma membrane –> impaired transport functions (Na+ K+ ATPase) and leakage of cellular contents.
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59
Q

Mechanisms of cell injury:
-Nucleus Pathways

A

Injury:

  • Radiation.
  • Mutations.

2 pathways both starting with DNA damage:

  1. Cell cycle arrest.
  2. Activation of caspases –> apoptosis.
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60
Q

Metabolically active cells are subjected to radiant energy in the form of x-rays. This results in cell injury caused by hydrolysis of water.
Which intracelluar enzyme helps to protect the cells from this type of injury?

A

Glutathione peroxidase.

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61
Q

What are the 4 possible mechanisms for ischaemia-reperfusion injury?

A
  • Production of ROS from reoxygenation.
  • Intracellular calcium overload.
  • Inflammatory response to tissue injury following ‘revascularisation’.
  • Antibody-mediated tissue injury after complement components become available following reperfusion.
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61
Q

Hyperplasia:
-Physiological examples

A
  • Proliferation of female breast tissue during puberty.
  • Liver regeneration following lobe resection.
  • Lobular hyperplasia of breast tissue during pregnancy to allow for breastfeeding.
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61
Q

What is hyperplasia driven by?

A
  • Hormones.
  • Growth Factors.
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62
Q

Hyperplasia:
-Pathological examples

A
  • Endometrial hyperplasia –> irregular PV bleeding.
  • Benign prostatic hyperplasia.
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63
Q

A breastfeeding womans breasts usually increase in size.
Which process occurs in her breasts during pregnancy to allow for breastfeeding?

A

Lobular hyperplasia.

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64
Q

Hypertrophy:
Pathological examples

A
  • Myocyte response to increased cardiac pressure load.
65
Q

Which pathological change is seen in the left ventricular myocardium as a result of the pressure overload of chronic hypertension?

A

Hypertrophy of cardiac myocytes.

66
Q

11-year-old infected with Hepatitis A has mild nausea for 1 week. Examination reveals RUQ tenderness and jaundice. Lab findings show high serum AST, ALT and total bili.
What is the most likely change in her hepatocytes to account for these lab results?

A

Cell membrane breakdown.

AST / ALT / bili should be in hepatocytes. If released, this indicates problem with hepatocyte cell membrane.

67
Q

33-year-old woman has increasing lethargy and decreased urine output for the past week. Lab results show increased serum urea and creatinine.
What is the most likely morphologic change on biopsy to suggest acute tubular necrosis?

A

Nuclear fragmentation.

68
Q

68-year-old woman suddenly loses consciousness and on awakening, she could not speak or move her right arm. Two months later, a head CT shows a large cystic area in the left parietal lobe of the brain.
Which pathological process has most likely occurred?

A

Liquefactive necrosis.

Brain ischaemia = EXCEPTION to coagulative necrosis.
Brain ischaemia = liquefactive necrosis.

69
Q

47-year-old male with lung carcinoma receives chemotherapy. Histology a month later shows many foci where tumour cells appear shrunken and deeply eosinophilic. The cell nuclei also have condensed aggregates of chromatin under the nuclear membrane.
What is the the most likely substance released into the cytoplasm which has triggered this pathological process?

A

Cytochrome C

70
Q

72-year-old man dies suddenly from congestive heart failure. At autopsy, his heart weighs 580g (normal 330g) and shows LVH. His aortic valve leaflets have multiple masses on their surface.
Which pathological process best accounts for the appearance of his aortic valve?

A

Dystrophic calcification.

71
Q

An experiment analyses cells for enzyme activity associated with sustained cellular proliferation.
Which cell is most likely to have the highest telomerase activity?

A

Germ cells.

72
Q

Where is telomerase most active?

A

Germ cells.

73
Q

Where is telomerase less active / inactive?

A
  • Less active in stem cells.
  • Inactive in most somatic cells.
74
Q

How do cancer cells achieve immortality?

A

Through mutations (p53) which reactivate the telomerase enzyme.

75
Q

Cellular aging:
-Normal process

A
  • Each cell division –> incomplete replication of telomeres.
  • Progressive telomere shortening –> cell cycle arrests –> cell reaches ‘replicative senescence’.
76
Q

What is a Kimmelstiel-Wilson nodule and what disease does it represent?

A

Nodules of pink hyaline material within glomerular capillary loops in the glomerulus.

Disease:
Diabetic glomerulosclerosis

77
Q

What are features of diabetic glomerulosclerosis

i.e. Diabetic Nephropathy

A
  • Diffuse increase in mesangium.
  • Thickening of glomerular capillary basement membrane.
  • Kimmelstiel-Wilson nodules.
78
Q

What are some physical agents causing cell injury?

A
  • Mechanical trauma.
  • Extremes of temperature.
  • Sudden atmospheric pressure changes.
  • Radiation.
  • Electric shock.
79
Q

What are some chemical agents / drugs which cause cell injury?

A
  • Hypertonic concentrations of glucose or salt.
  • High concentrations of oxygen.
  • Poisons (e.g. arsenic, cyanide, mercury).
  • Therapeutic drugs.
  • Environmental pollutants.
  • Insecticides / herbicides.
  • Carbon monoxide.
  • Asbestos.
  • EtOH and recreational drugs.
80
Q

What are some genetic defects which cause cell injury?

A
  • Genetic aberrations (loss or gain of chromosomes, loss / gain of nucleotides).
  • Genetic defects causing defect in protein function (e.g. inborn errors of metabolism).
  • Accumulation of damaged DNA or misfolded proteins.
  • DNA sequence variants (polymorphisms) can influence susceptibility of cells to injury by other factors.
81
Q

What are some nutritional imbalances which cause cell injury?

A
  • Obesity.
  • Anorexia nervosa.
  • Nutrient deficiencies from poor diet or food shortages.
82
Q

What is autophagy?

A

Process in which a cell “eats itself”.

Auto: self.
Phagy: eating.

83
Q

What is the main organelle responsible for degradation?

A

Lysosome.

83
Q

What are the steps of autophagy?

A
  1. Cellular stress or aging cell.
  2. Initiation phase: formation of nucleation complex and isolation membrane (known as a phagophore).
  3. Elongation of isolation membrane.
  4. Isolation membrane forms autophagosome (vesicle containing intracellular organelles and cytosolic structures).
  5. Maturation of autophagosome.
  6. Fusion with lysosome.
  7. Degradation of autophagosome contents by lysosomal digestive enzymes (hydrolases).
  8. Recycling of metabolites.

NB. Autophagy can trigger cell death if it is inadequate to cope with the initiating stressor.

83
Q

Which genes are responsible for autophagy?

A

Autophagy-related genes (Atgs).

84
Q

What is a useful marker for identifying cells undergoing autophagy and why?

A

Marker:
PE-lipidated LC3.

Why:
Formation of autophagosome from initiation membrane requires coordination of two ubiquitin-like conjugation systems that result in the linkage of PE to LC3.

PE = Phosphatidylethanolamine.
LC3 = microtubule-associated protein light chain 3.

85
Q

In which disease states does dysregulation of autophagy occur?

A
  • Cancer.
  • Inflammatory bowel diseases.
  • Neurodegenerative disorders.
86
Q

How does autophagy act in cancer?

A
  • Can promote cancer growth.
  • Can acts as a defense against cancer.
87
Q

What are two neurodegenerative disorders associated with dysregulation of autophagy?

A
  • Alzheimer disease.
  • Huntington disease.
88
Q

Which parts of autophagy is impaired in Alzheimer disease?

A
  • Autophagosome maturation.
  • In mouse models: autophagy gene defects accelerate neruodegeneration.
89
Q

What causes impaired autophagy in Huntington disease?

A

Mutant huntingtin

90
Q

What is the link between dysregulated autophagy and Crohn disease / ulcerative colitis?

A

Both Crohns and ulcerative colitis have a SNP in the autophagy-related gene ATG16L1.

91
Q

What are some pathogens degraded by autophagy?

A
  • Mycobacteria.
  • Shigella spp.
  • HSV-1.
92
Q

The macrophage-specific deletion of autophagy-related gene 5 (Atg5) causes increased susceptibility to which infectious disease?

A

TB.

93
Q

What are free radicals?

A

Chemical species that have a single unpaired electron in an outrer orbit.

94
Q

How do free radicals cause injury?

A
  • Unpaired electrons are highly reactive.
  • Unpaired electrons “attack” / modify adjacent molecules e.g. proteins, lipids, carbohdrates, nucleic acids.
  • Reactions can be autocatalytic OR can convert molecule to free radical (propogating chain of damage).
95
Q

What is ROS and how is it produced in a cell?

A

What:

  • Reactive Oxygen Species.
  • Type of oxygen-derived free radical.

How produced:

  • Normal by-product of mitochondrial respiration and energy generation.
96
Q

What is Oxidative stress?

A

Condition caused by excess ROS from either:
1. Increased production.
2. Decreased removal.

97
Q

In what situations are large amounts of ROS produced?

A

From activated leukocytes (neutrophils, macrophages) during:

  • Inflammatory reactions aimed at destroying microbes.
  • Cleaning up of dead cells / other unwanted substances.
98
Q

What are common ROS?

A
  • Superoxide anion (O2 with one electron).
  • Hydrogen peroxide (H2O2).
  • Hydroxyl radical (OH).
  • Peroxynitrite (ONOO-).
99
Q

How are ROS removed?

A
  • Antioxidants.
  • Binding of iron and copper to prevent catalysation of ROS formation.
  • Intracellular ROS scavengers (enzymes):
    - Catalase.
    - Superoxidase dismutases.
    - Glutathione peroxidase.
100
Q

Where is most intracellular calcium stored?

A
  • Mitochondria.
  • Endoplasmic reticulum.
101
Q

What is the misfolded protein in Cystic Fibrosis and what does this protein defect cause?

A

Protein:
Cystic fibrosis transmembrane conductance regulator (CFTR).

Causes:
Loss of CFTR –> defects in chloride transport.

102
Q

What is the misfolded protein in Familial hypercholesterolaemia and what does this protein defect cause?

A

Protein:
LDL receptor.

Causes:
Loss of LDL receptor –> hypercholesterolaemia.

103
Q

What is the misfolded protein in Tay-Sachs disease and what does this protein defect cause?

A

Protein:
Hexosaminidase beta subunit.

Causes:
Lack of lysosomal enzyme –> storage of GM2 gangliosides in neurons.

104
Q

What is the misfolded protein in alpha1-antitrypsin deficiency and what does this protein defect cause?

A

Protein:
alpha1-antitrypsin.

Causes:

  • Liver- Storage of nonfunctional protein in hepatocytes –> apoptosis.
  • Lung- absence of enzymatic activity –> destruction of elastic tissue –> emphysema.
105
Q

What is the misfolded protein in Creutzfeldt-Jacob disease and what does this protein defect cause?

A

Protein:
Prion protein.

Causes:
Neuronal cell death.

106
Q

What is the misfolded protein in Alzheimer disease and what does this protein defect cause?

A

Protein:
A beta peptide.

Causes:
Aggregation of misfolded protein within neurons –> apoptosis.

107
Q

What is ischaemia?

A
  • Cell injury caused by hypoxia induced by reduced blood flow (from mechanical arterial obstruction OR reduced venous drainage).
  • Compromises delivery of substrates for glycolysis.
  • More rapid and severe cell injury compared to hypoxia.
108
Q

What is hypoxia?

A
  • Reduced oxygen levels.
  • Blood flow maintained.
  • Energy production by anaerobic glycolysis can continue.
109
Q

What is induced as a protective response to deal with hypoxic stress and what are its actions?

A

Induction of hypoxia-inducible factor-1 (HIF-1) transcription factor.

Actions:

  • Promotes new blood vessel formation.
  • Stimulates cell survival pathways.
  • Enhances glycolysis.
110
Q

What stategy can be utilised in ischaemic / traumatic brain and spinal cord injury and how does this work?

A

Strategy:
Transient induction of hypothermia (lower to ~33deg).

How works:

  • Reduces metabolic demands of stressed cells.
  • Decreases cell swelling.
  • Suppresses formation of free radicals.
  • Inhibits host inflammatory response.
111
Q

Which molecule causes conversion of chemicals to toxic metabolites and where is this molecule located?

A

Molecule:
Cytochrome P-450.

Location:
Smooth ER of liver and other organs.

112
Q

What causes cell hypertrophy?

A

Increased cell workload –> increased cellular protein production.

113
Q

Which signalling pathway is involved in physiologic hypertrophy?

A

PI3K / AKT pathway.

PI3K = phosphoinositide 3-kinase.

114
Q

Which signalling pathway is involved in pathological hypertrophy?

A

G-protein-coupled receptor pathways.

115
Q

What is the mechanism of hyperplasia?

A

Growth factor-driven proliferation of mature cells,
OR,
Increased output of new cells from tissue stem cells.

116
Q

What are the pathological causes of atrophy?

A
  • Decreased workload (disuse atrophy).
  • Loss of innervation (denervation atrophy).
  • Gradual decreased blood supply (chronic ischaemia).
  • Inadequate nutrition (cachexia).
  • Loss of endocrine stimulation.
  • Pressure.
117
Q

What is the mechanism of atrophy?

A
  • Decreased protein synthesis.
  • Increased protein degradation in cells through ubiquitin-proteosome pathway.
118
Q

What often accompanies atrophy and how is this seen?

A

Autophagy.

Seen by:
increased numbers of autophagic vacuoles.

119
Q

In atrophic cells which are also undergoing autophagy, what happens if some of the autophagosome contents are undigested and what is an example of this?

A

Persistance of membrane bound residual bodies.

Example:
Lipofuscin granules (in high numbers, gives brown appearance to tissue, AKA brown atrophy).

120
Q

What is the mechanism of metaplasia?

A

Stimulation from:

  • Cytokines.
  • Growth factors.
  • Extracellular matrix components

Which lead to:

  • Reprogramming of local tissue stem cells.

OR

  • Colonisation by differentiated cell populations from adjacent sites.
121
Q

What are the four mechanisms leading to abnormal intracellular accumulations and what is an example of each?

A
  1. Abnormal metabolism –> inadequate removal of normal substance e.g. fatty liver.
  2. Defect in protein folding / transport –> accumulation of abnormal protein e.g. alpha1-antitrypsin.
  3. Lack of enzyme –> failure to degrade a metabolite –> accumulation of endogenous material e.g. lysosomal storage disease.
  4. Ingestion of indigestible materials –> accumulation of abnormal exogenous material e.g. Carbon, silica particles.
122
Q

What is steatosis (AKA fatty change) and where is it usually seen?

A

What:
Abnormal accumulations of Tg within parenchymal cells.

Where:

  • Liver (major organ involved in fat metabolism).
  • Heart.
  • Muscles.
  • Kidney.
123
Q

What causes steatosis?

A
  • Toxins.
  • Protein malnutrition.
  • Diabetes.
  • Obesity.
  • Anoxia.
124
Q

What causes steatosis in the liver?

i.e Fatty liver

A
  • EtOH abuse.
  • Non-alcoholic fatty liver from diabetes and obesity.
125
Q

What diseases are associated with accumulation of cholesterol or cholesterol esters?

A
  • Atherosclerosis.
  • Xanthomas.
  • Cholesterolosis.
  • Niemann-Pick disease, type C.
126
Q

What is the characteristic morphology of cells with accumulated cholesterol or cholesterol esters?

A

Foam cells (cells filled with lipid vacuoles giving them a “foamy” appearance).

127
Q

Where are lipid vacuoles seen in atherosclerosis and what happens if these cells rupture?

A

Where:
Within smooth muscle cells and macrophages in the intima of the aorta and large arteries.

Ruptured cells:
Release cholesterol / cholesterol ester into extracellular space –> formation of crystals.

128
Q

Where are lipid vacuoles seen in Xanthomas?

A

Within macrophages in the subepithelial connective tissue of skin and tendons.

129
Q

Where are lipid vacuoles seen in Cholesterolosis?

A

Within macrophages in the lamina propria of the gallbladder.

130
Q

What is Niemann-Pick disease, type C?

A
  • Lysosomal storage disease.
  • Cause: Mutation affecting enzyme involved in cholesterol transport –> cholesterol accumulation in multiple organs.
131
Q

What is the morphology of intracellular accumulations of proteins?

A
  • Rounded, eosinophilic droplets, vacuoles or aggregates within the cytoplasm.
  • EM: amorphous, fibrillar or crystalline structures.
132
Q

What are reabsorption drops, what do they look like and what diseases are they found in?

A

What they are:
Excesses reabsorption of proteins into vesicles from heavy protein leakage across the glomerulus.

Appearance:
Pink, hyaline droplets within the cytoplasm of the tubular cell.

Diseases:
Renal diseases associated with proteinuria.

133
Q

Define hyaline

A
  • Alterations within a cell, or extracellular space, which causes the cell or space to have a homogenous, glassy pink appearance in routine H&E stains.
  • Descriptive term.
134
Q

How do intracellular deposits of glycogen appear on routine H&E and why?

A

Clear vacuoles within the cytoplasm.

Why:
Glycogen dissolves in aqueous fixatives.

135
Q

What special requirements / stains are needed to see accumulated glycogen?

A

Special requirements:
Fix in absolute alcohol.

Special stains:

  • Best carmine
  • PAS^ (glycogen stains rose-to-violet colour)

^Periodic Acid-Schiff

136
Q

What molecules can be stained with PAS, and what can be done to prove it is glycogen?

A

Stains:
* Accumulation of glycogen.
* Protein-bound CHOs.

Prove it’s glycogen:
Diastase digestion of a parallel section which demonstrates loss of staining due to glycohen hydrolysis.

137
Q

Where can accumulated glycogen be found in diabetes?

A
  • Renal tubular epithelial cells.
  • Liver cells.
  • Beta cells of the islets of Langerhans within the pancreas.
  • Heart muscle cells.
138
Q

What is the most common exogenous pigment?

A

Carbon (coal dust).

139
Q

What happens when carbon is inhaled?

A
  1. Ingested by macrophages in the alveoli.
  2. Transported through lymphatics to lymph nodes in the tracheobronchial region.
  3. Accumulation of carbon in lung and LNs.
  4. Blackening of lung tissue (anthracosis) and involved LNs.

NB. In coal miners, the aggregated coal dust –> fibroblast reaction / emphysema –> coal worker’s pneumoconiosis.

140
Q

What is Lipofuscin, what is its appearance in staining and what does it indicate?

AKA lipochrome or wear-and-tear pigment.

A

What it is:

  • Endogenous, insoluble brown pigment.
  • Composed of polymers of lipids and phospholipids in complex with proteins.

Appearance:

  • Yellow-brown colour.
  • Finely granular cytoplasmic pigment.
  • Can be perinuclear.

Indicates:

  • Free radical injury.
  • Lipid peroxidation.
141
Q

What is melanin?

A
  • Endogenous, brown-black pigment.
  • Formed when tyrosinase catalyses the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes.
142
Q

What is haemosiderin?

A
  • Haemoglobin-derived endogenous pigment.
  • Golden yellow-to-brown colour.
  • Granular or crystalline.
  • Represents aggregates of ferritin (storage form of iron) micelles.
143
Q

What is an example of local haemosiderin accumulation?

A

Bruising.

144
Q

What are examples of systemic iron overload and therefore haemosiderosis^?

^Accumulation of haemosiderin in multiple organs and tissues.

A
  • Haemochromatosis.
  • Haemolytic anemia.
  • Repeated RBC transfusions.
145
Q

What is Dystrophic Calcification?

A
  • Abnormal tissue deposits of calcium salts, iron, magnesium, and other mineral salts.
  • Occuring locally in dying tissues.
  • Normal serum calcium.
  • No calcium metabolism disturbance.
146
Q

What is Metastatic Calcification?

A
  • Abnormal tissue deposits of calcium salts, iron, magnesium, and other mineral salts.
  • Due to hypercalcaemia secondary to calcium metabolism disturbance.
147
Q

Where can Dystrophic calcification be found?

A

In areas of necrosis.

E.g.
* Atheromas of advanced atherosclerosis.
* Aging or damaged heart valves.
* TB

148
Q

What is the appearance of calcium salts in dystrophic calcification?

A

Macroscopic:
* Fine, white granules or clumps (“gritty deposits”).

Microscopic (H&E):
* Basophilic.
* Amorphous.
* Granular.
* Sometimes clumped.
* Intracellular or extracellular.

149
Q

What does amorphous mean?

A

No definitive form / characteristic.

150
Q

What can happen to calcium salts in dystrophic calcification over time?

A
  • Heterotopic bone can form in the centre of calcification.
  • Can have outer layers formed from single necrotic cells which become encrusted by the mineral deposits –> lamellated configurations (known as psammoma bodies^).

^“Grains of sand”

151
Q

What diseases can psammoma bodies be seen in?

A

Papillary cancers e.g. thyroid.

152
Q

What are Asbestos bodies and what disease are they seen in?

A

What they are:
Calcium and iron salts which have deposited around long, slender spicules of asbestos –> exotic, beaded, dumbbell forms in the lung.

Disease:
Asbestosis.

153
Q

What are the four principle causes of hypercalcaemia?

A
  1. Increased secretion of PTH –> bone resorption.
  2. Resorption of bone tissue.
  3. Vitamin D-related disorders.
  4. Renal failure.
154
Q

Hypercalcaemia:
-What diseases occur from increased secretion of PTH?

A
  • Hyperparathyroidism secondary to parathyroid tumours.
  • Extopic secretion of PTH-related protein secondary to malignant tumours.
155
Q

Hypercalcaemia:
-What causes resorption of bone tissue?

A
  • Primary tumours of bone marrow (e.g. MM, leukaemia).
  • Diffuse skeletal metastasis (e.g. from breast cancer).
  • Accelerated bone turnover (e.g. Paget disease).
  • Immobilisation.
156
Q

Hypercalcaemia:
-What areVitamin D-related disorders?

A
  • Vitamin D intoxication.
  • Sarcoidosis.
  • Idiopathic hypercalcaemia of infancy (Williams syndrome).
157
Q

How does Sarcoidosis cause hypercalcaemia?

A

Macrophages activate a vitamin D precursor –> increased vitamin D –> increased absorption of Ca from GIT.

158
Q

How does Williams syndrome cause hypercalcaemia?

A

Abnormal sensitivity to vitamin D –> increased Ca absorption from GIT.

159
Q

How does renal failure cause hypercalcaemia?

A

Retention of phosphate –> secondary hyperparathyroidism.

160
Q

What are the common sites to find metastatic calcification and why?

A

Sites:
Interstitial tissues of:

  • Gastric mucosa.
  • Kidneys.
  • Lungs.
  • Systemic arteries.
  • Pulmonary veins.

Why:
Excretion of acid and internal alkaline compartment predisposis to calcification.

161
Q

A 35-year-old woman burns her hand on a hot stove. Over the next 2 weeks, the injury heals without the need for a skin graft. Why?

A
  • Persistance of skin appendages.
  • Skin appendages contain labile (continuously dividing) cells which allow skin to regenerate.
  • Labile tissues can regenerate after injury as long as the pool of stem cells is preserved.
162
Q

A 50-year-old man had surgery 2 months ago. Now he has a small lump beneath the sutured incision site.
Which cell type is most likely to be most characteristic of the inflammatory response in this situation and why?

A

Multinucleated Giant cell.

Why:
The patient has developed a foreign body type granulomatous inflammation in response to the presence of suture material that was left behind, in which epithelioid histiocytes combine together to form large multinucleated giant cells.

Basic Pathology (14 decks)

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