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Pathoma Enhanced > CH1 - Growth Adaptations, Cellular Injury, and Cell Death > Flashcards

CH1 - Growth Adaptations, Cellular Injury, and Cell Death Flashcards

1
Q

What are the basic principles of growth adapdations?

A

An organ is in homeostasis with the physiologic stress placed on it. An increase, decrease, or change in stress on an organ can result in growth adaptations.

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2
Q

What leads to an increase in organ size?

A

An increase in stress

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3
Q

Hypertrophy occurs via what?

A

an increase in the size

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4
Q

Hyperplasia occurs via what?

A

an increase in the number of cells

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5
Q

What does hypertrophy involve?

A

gene activation, protein synthesis, and production of organelles.

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6
Q

What does Hyperplasia involve?

A

the production of new cells from stem cells.

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7
Q

Permanent tissues are… Do they undergo hypertrophy or hyperplasia?

A

cardiac muscle, skeletal muscle, and nerve, cannot make new cells and undergo hypertrophy only.

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8
Q

Pathologic hyperplasia leads to what?

A

(e.g., endometrial hyperplasia) can progress to dysplasia and,eventually cancer.

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9
Q

What is an exception to pathologic hyperplasia leading to cancer?

A

benign prostatic hyperplasia (BPH), which does notincrease the risk for prostate cancer,

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10
Q

What leads to a decrease in organ size?

A

A decrease in stress (e.g., decreased hormonal stimulation, disuse, or decreased nutrients/blood supply) (atrophy).

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11
Q

Atrophy occurs via?

A

a decrease in the size and number of cells

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12
Q

How does a decrease in cell number occur?

A

via apoptosis.

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13
Q

Decrease in cell size occurs via what?

A

ubiquitin-proteosome degradation of the cytoskeleton and autophagy of cellular components.

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14
Q

What happens in ubiquitin-proteosome degradation?

A

intermediate filaments of the cytoskeleton are tagged with ubiquitin and destroyed by proteosomes.

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15
Q

What does autophagy of cellular components involve?

A

generation of autophagic vacuoles that fuse with lysosomes whose hydrolytic enzymes breakdown cellular components.

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16
Q

What happens in METAPLASIA?

A

change in stress on an organ leads to a change in cell type

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17
Q

Metaplasia most commonly involves?

A

change of one type of surface epithelium (squamous, columnar, or urothelial) to another

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18
Q

How do metaplastic cells handle the new stress?

A

they are better able to handle the new stress.

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19
Q

Esophagus is normally lined by what?

A

nonkeratinizing squamous epithelium (suited to handle friction of a food bolus)

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20
Q

Barrett esophagus

A

Acid reflux from the stomach causes metaplasia to nonciliated mucin-producing columnar cells (better able to handle the stress of acid

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21
Q

Metaplasia occurs via what?

A

programming of stem cells, which then produce the new cell type.

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22
Q

Is Metaplasia reversible?

A

with removal of the driving stressor.

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23
Q

Can metaplasia progress to cancer?

A

Under persistent stress, can progress to dysplasia and eventually result in cancer.

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24
Q

What is an exception to metaplasia leading to cancer?

A

apocrine metaplasia of breast with benign epithelial alteration of breast tissue, which means that epithelial cells are undergoing an unexpected change.

(apocrine means related to sweat glands, but this is only a resemblance. It’s not actually sweat gland related), which carries no increased risk for cancer.

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25
Q

Vitamin A deficiency can result in what?

A

metaplasia,

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26
Q

Vitamin A is necessary for what?

A

differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye.

conjunctiva - the mucous membrane that covers the front of the eye and lines the inside of the eyelids, composed of non-keratinized, stratified squamous epithelium with goblet cells, and also stratified columnar epithelium. The conjunctiva is highly vascularised, with many microvessels. Conjunct- latin origin for join together = eye lid and eye ball

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27
Q

Keratomalacia

A

In vitamin A deficiency, the thin squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium.

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28
Q

Myositis Ossificans

A

Mesenchymal (connective) tissues can undergo metaplasia. A classic example is myositis ossificans in which muscle tissue changes to bone during healing after trauma

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29
Q

DYSPLASIA is?

A

Disordered cellular growth

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30
Q

Dysplasia most often refers to?

A

proliferation of precancerous cells

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31
Q

Cervical intraepithelial neoplasia (CIN)

A

represents dysplasia and is a precursor to cervical cancer

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32
Q

Dysplasia often arises from?

A

longstanding pathologic hyperplasia (e.g., endometrial hyperplasia) or metaplasia (e.g., Barrett esophagus)

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33
Q

Is dysplasia is reversible?

A

yes, with alleviation of inciting stress.

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34
Q

In dysplasia what happens if stress persists?

A

dysplasia progresses to carcinoma irreversible)

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35
Q

What is aplasia?

A

it is failure of cell production during embryogenesis (e.g., unilateral renal agenesis)

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36
Q

What is hypoplasia?

A

it is a decrease in cell production during embryogenesis, resulting in a relatively small organ (e.g., streak ovary in Turner syndrome)

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37
Q

When does cellular injury occur?

A

when a stress exceeds the cells ability to adapt

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38
Q

The likelihood of injury depends on what?

A

the type of stress, its severity, and the type of cell affected.

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39
Q

What are highly susceptible to ischemic injury? As opposed to?

A

neurons whereas, skeletal muscle is relatively more resistant.

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40
Q

Slowly developing ischemia

A

eg: renal artery atherosclerosis, results in ATROPHY

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41
Q

acute ischemia

A

eg: renal artery embolus, results in INJURY

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42
Q

What are common causes of cellular injury?

A

inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations.

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43
Q

What is HYPOXIA?

A

Low oxygen delivery to tissue; important cause of cellular injury

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44
Q

What is the final electron acceptor in the electron transport chain of oxidative phosphorylation?

A

Oxygen

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45
Q

Decreased oxygen results in what?

A

impairs oxidative phosphorylation, resulting in decreased ATP production

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46
Q

What does a lack of ATP leads to?

A

cellular injury

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47
Q

What are some causes of hypoxia?

A

include ischemia, hypoxemia, and decreased 02 - carrying capacity of blood = anemia

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48
Q

Ischemia is?

A

decreased blood flow through an organ

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49
Q

Ischemia arises with?

A
  1. Decreased arterial perfusion (eg atherosclerosis) 2. Decreased venous drainage (eg Budd-Chiari syndrome) 3. Shock?generalized hypotension resulting in poor tissue perfusion
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50
Q

Hypoxemia is?

A

a low partial pressure of oxygen in the blood (Pao2< 60 mm Hg, SaO2<90%).

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51
Q

Hypoxemia arises with

A
  1. High altitude 2. Hypoventilation 3. Diffusion defect 4. V/Q mismatch
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52
Q

High altitude to hypoxemia, how?

A

Decreased barometric pressure results in decreased PaO2

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53
Q

Hypoventilation to hypoxemia, how?

A

Increased Paco, results in decreased PaO2

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54
Q

Diffusion defect to hypoxemia, how?

A

PAO2 not able to push as much O2 into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis)

Latin interstitium “interval,” literally “space between,” from inter “between” + stare “to stand,”

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55
Q

V/Q mismatch to hypoxemia, how?

A

Blood bypasses oxygenated lung (circulation problem, eg: right-to-left shunt), or oxygenated air cannot reach blood (ventilation problem, eg: atelectasis)

Atelectasis is the collapse of part or, much less commonly, all of a lung

Greek atelēs ‘imperfect’ + ektasis ‘extension.’

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56
Q

Decreased O2-carrying capacity arises with what?

A

hemoglobin (Hb) loss or dysfunction

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57
Q

What are some examples of Decreased O2-carrying capacity?

A
  1. Anemia 2. Carbon monoxide poisoning 3. Methemoglobinemia

Methemoglobinemia is a condition caused by elevated levels of methemoglobin in the blood. Methemoglobin is a form of hemoglobin that contains the ferric [Fe3+] form of iron. The affinity for oxygen of ferric iron is impaired.

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58
Q

Anemia leading to decreased O2 carrying capacity.

A

(decrease in RBC mass) PaO2 normal; SaO2 normal

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59
Q

Carbon monoxide poisoning

A

CO binds hemoglobin more avidly than oxygen

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60
Q

What is the PaO2 and SaO2 for carbon monoxide poisoning?

A

PaO2 normal; SaO2 decreased

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61
Q

Exposures for Carbon monoxide poisoning

A

include smoke from fires and exhaust from cars or gas heaters.

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62
Q

Classic finding for Carbon monoxide poisoning

A

cherry-red appearance of skin.

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63
Q

Early sign of exposure for Carbon monoxide poisoning

A

headache; significant exposure leads to coma and death.

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64
Q

What is Methemoglobinemia?

A

Iron in heme is oxidized to Fe3+ which cannot bind oxygen

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65
Q

PaO2 and SaO2 for Methemoglobinemia?

A

PaO2 normal; SaO2 decreased

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66
Q

Methemoglobinemia is Seen with?

A

oxidant stress (eg sulfa and nitrate drugs) or in newborns

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67
Q

Classic finding for Methemoglobinemia?

A

cyanosis with chocolate-colored blood.

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68
Q

Treatment for Methemoglobinemia?

A

intravenous methylene blue, which helps reduce Fe3+ back to Fe2+ state.

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69
Q

Hypoxia results in low ATP how?

A

impairs oxidative phosphorylation resulting in decreased ATP.

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70
Q

Low ATP disrupts what?

A

key cellular functions including 1. Na/K pump 2. Ca2+ pump 3. Aerobic glycolysis

71
Q

Disruption of Na/K pump results in what?

A

sodium and water buildup in the cell

72
Q

Disruption of Ca2+ pump results in what?

A

Ca2+ buildup in the cytosol of the cell

73
Q

Disruption of Aerobic glycolysis results in what?

A

switch to anaerobic glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DMA.

74
Q

The hallmark of reversible injury is

A

cellular swelling.

75
Q

Cytosol swelling results in

A

loss or microvilli and membrane blebbing.

76
Q

Swelling of the rough endoplasmic reticulum (RER) results in

A

dissociation of ribosomes and decreased protein synthesis.

77
Q

The hallmark of irreversible injury is

A

membrane damage.

78
Q

Plasma membrane damage results in

A
  1. Cytosolic enzymes leaking into the serum {e.g cardiac troponin) 2. Additional calcium entering into the cell
79
Q

Mitochondrial membrane damage results in

A
  1. Loss of the electron transport chain (inner mitochondrial membrane) 2. Cytochrome c leaking into cytosol (activates apoptosis)
80
Q

Lysosome membrane damage results in

A

hydrolytic enzymes leaking into the cytosol, which in turn, are activated by the high intracellular calcium.

81
Q

The end result of irreversible injury is

A

cell death.

82
Q

The morphologic hallmark of cell death is

A

loss of the nucleus,

83
Q

loss of the nucleus occurs via

A

nuclear condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis = nuclear fragments broken down into building blocks)

greek = puknós, “compact”

karyo- greek kernel

Greek rexis- breaking, bursting

Greek lusis ‘loosening,’

84
Q

The two mechanisms of cell death are

A

necrosis and apoptosis.

85
Q

NECROSIS

A

A. Death of large groups of cells followed by acute inflammation B. Due to some underlying pathologic process; never physiologic C. Divided into several types based on gross features

86
Q

GROSS PATTERNS OF NECROSIS

A
  1. Coagulative necrosis, 2. liquefactive necrosis, 3. Gangrenous necrosis 4. Caseous necrosis 5. Fat necrosis 6. Fibrinoid necrosis
87
Q

What is Coagulative necrosis?

A

Necrotic tissue that remains firm, cell shape and organ structure are preserved by coagulation of proteins, but the nucleus disappears

cell structure remains but nucleus is gone

coagulation - changing into solid or semi-solid state

Usually NOT CAUSED by severe trauma, toxins or an acute or chronic immune response. As a result protein cytoskeleton is not digested by proteolytic enzymes.

Latin coagulat- ‘curdled,

88
Q

Coagulative necrosis is Characteristic of?

A

ischemic infarction of any organ except the brain

89
Q

Area of infarcted tissue for Coagulative necrosis?

A

It is often wedge-shaped (pointing to focus of vascular occlusion) and pale (because won’t enter tissue).

90
Q

What is Red infarction

A

arises if blood re-enters a loosely organized (so it can hold blood) tissue (e.g. pulmonary or testicular infarction)

when testicular torsion occurs, the thick walled artery still allows blood to enter testicle, but thin walled vein collapses. The result is blood enters but can not leave.

Fresh blood can not enter because blood piles up.

91
Q

What is Liquefactive necrosis?

A

Necrotic tissue that becomes liquefied because of hydrolytic enzymes - usually from immune cells;

enzymatic lysis of cells and protein results in liquefaction.

92
Q

Liquefactive necrosis is Characteristic of?

A

Brain infarction, abscess, pancreatitis

93
Q

What type of necrosis for brain infarction?

A

Liquefactive necrosis - Proteolytic enzymes from microglial cells liquefy the brain using hydrolytic enzymes.

94
Q

What type of necrosis for abscess?

A

Liquefactive necrosis - hydrolytic enzymes from neutrophils liquefy tissue

95
Q

What type of necrosis for pancreatitis?

A

Liquefactive necrosis - Proteolytic enzymes from pancreas liquefy parenchyma. auto-digestion

96
Q

What is Gangrenous necrosis?

A

Coagulative necrosis that resembles mummified tissue (dry gangrene) - often lower extremeties of popliteal artery partially obstructed -> ischemia of lower limb.

seen in diabetics

“looks like gangrene”

gran- “to gnaw,” gras- “to devour

97
Q

Gangrenous necrosis is characteristic of?

A

ischemia of lower limb and GI tract

98
Q

What is wet gangrene?

A

superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene).

Infection -> acute inflmmation-> PMN’s -> hydrolytic enzymes -> liquefactive necrosis.

99
Q

What is Caseous necrosis?

A

Soft and friable necrotic tissue with cottage cheese-like appearance. It’s liquefactive necrosis, that is thickened into a “coagulative-like” gel due to thinkening agents (wall of fungus ro TB)

100
Q

What is caseous necrosis characteristic of?

A

granulomatous inflammation due to tuberculous or fungal infection

101
Q

What is fat necrosis?

A

Necrotic adipose tissue with chalky-white appearance due to deposition of calcium on fat released from necrotic acdipocytes

102
Q

What is fat necrosis characteristic of?

A

trauma to fat (eg. breast) and pancreatitis-mediated damage of peripancreatic fat

103
Q

Fat necrosis and saponification

A

Fatty acids released by trauma (eg to breast) or lipase (eg pancreatitis) join with calcium via a process called saponification which is an example of dystrophic calcification in which calcium deposits on dead tissues.

sapon- “soap” (see soap (n.)) + -ficare - to make

dystrophic - dys - bad, trophic- nourishment

104
Q

dystrophic calcification

A

the necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate e.g. saponification = dead fat reacts with Calcium

Dystrophic calcification with saponification seen also in tumors that outgrow their blood supply causing neoplastic cells in tumor core to necrose and be saponified with calcium.

Examples

1) psammoma bodies in papillary carcinoma of the thyroid
2) meningiomas
3) papillary serious carcinoma of the ovary

105
Q

Dystrophic calcification vs metastatic calcification

A

high serum calcium or phosphate levels lead to calcium deposition in normal tissues throughout the body (eg. hyperparathyroidism leading to nephrocalcinosis)

106
Q

Fibrinoid necrosis

A

Necrotic damage to blood vessel wall endothelial cells, Leaking of proteins (including fibrin) into vessel wall results in bright pink staining of the wall microscopically

107
Q

What is fibrinoid necrosis characteristic of?

A

malignant hypertension and vasculitis

malignant hypertension -> can be seen in preeclampsia -> fibrinoid necrosis of placenta

1) headache
2) renal failure
3) papilledema - condition in which increased pressure in or around the brain causes the part of the optic nerve inside the eye to swell.

108
Q

What is apoptosis?

A

Energy (ATP)-dependent, genetically programmed cell death involving single cells or small groups of cells.

109
Q

Examples of apoptosis include

A
  1. Endometrial shedding during menstrual cycle 2. Removal of cells during embryogenesis 3. CD8+ T cell-mediated killing of virally infected cells
110
Q

Morphology of apoptosis

A
  1. Dying cell shrinks, leading cytoplasm to become more eosinophilic (pink -> because cytoplasm becomes concentrated in cell as cell shrinks) 2. Nucleus condenses (pyknosis) and fragments (karyorrhexis).

puknós, “compact”

[karyo- kernel + G. rhexis, rupture]

111
Q

Apoptotic bodies

A

fall from the cell and are removed by macrophages; apoptosis is not followed by inflammation

112
Q

Apoptosis is mediated by

A

caspases

1) activate proteases (trash cytoskeleton)
2) endonucleases (an enzyme that cleaves DNA by separating nucleotides)

due to

1) ) cellular injury
2) DNA damage
3) decreased hormonal activation of bcl2

113
Q

Proteases

A

break down the cytoskeleton.

114
Q

Endonucleases

A

break down DNA,

115
Q

How are caspases activated?

A
  1. Intrinsic mitochondrial pathway 2. Extrinsic receptor-ligand pathway 3. Cytotoxic CD8+ Tcell-mediated pathway
116
Q

What is the main molecule in the intrinsic mitochondrial pathway?

A

Cytochrome C

Bcl2 stabilizes Cyt C in Mitochondria

when Bcl2 get inactivated by (membrane damage, DNA damage, or decreased hormonal stimulation) CytC can leak out of mitochondria ancaspasese caspapses.

117
Q

What happens to Bcl2 in the intrinsic mitochondrial pathway?

A

Cellular injury, DNA damage, or loss of hormonal stimulation leads to inactivation of Bcl2

118
Q

In the intrinsic mitochondrial pathway lack of Bcl 2 results in what?

A

allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases.

119
Q

What is the extrinsic receptor-ligand pathway?

A

FAS ligand binds to (CD95) FAS death receptor and TNF binds TNF receptor (both activate caspases)

Tcells leave BM and go to thymus for education

1) positive selection -> can you bing self-antigen + MHC
2) Negative selection -> do you bind self-antigen too strongly -> if they do, TCell is destroyed because bound cell ex[resses FAS ligand which binds to death receptor on Tcell

120
Q

What is an example of FAS ligand binding to FAS death receptor (CD95) on the target cell activating caspases

A

negative selection of thymocytes in thymus

121
Q

Cytotoxic CD8+ T cell-mediated pathway releases what?

A

perforins and granzyme ex CD8+ T-cell killing of virally infected cells is an example.

Perforin is a pore forming cytolytic protein found in the granules of cytotoxic T lymphocytes

Granzymes are serine proteases that are released by cytoplasmic granules within cytotoxic T cells and natural killer (NK) cells. They induce apoptosis in cancerous or virally infected cells

122
Q

Perforins

A

secreted by CD8+ T cell create pores in membrane of target cell

123
Q

Granzyme

A

secreted from CD8+ T cell enters pores and activates caspases

124
Q

Free radicals are what?

A

chemical species with an unpaired electron in their outer orbit.

125
Q

When does physiologic generation of free radicals occur?

A

it occurs during oxidative phosphorylation

oxygen accepts 4 electrons to make water. If oxygen does not accept all 4 electrons, free radicals are generated “physiologically”

126
Q

How are free radicals generated physiologically?

A

Cytochrome c oxidase (complex IV) transfers electrons to oxygen. Partial reduction of O2 + e’ -> superoxide (O2.-) + e’

  • >hydrogen peroxide (H202)+ e’ ->hydroxyl radicals (OH.-) + e’
  • > H2O (water)
127
Q

Pathologic generation of free radicals arises with?

A

Ionizing radiation, inflammation, metals, drugs and chemicals

128
Q

Ionizing radiation and Pathologic generation of free radicals

A

water hydrolyzed to hydroxyl free radical OH.-

Hydroxyl Free Radical is MOST DAMAGING

129
Q

Inflammation and Pathologic generation of free radicals

A

PMN’s kill microbe via 1) oxygen dependent 2) oxygen INDEPENDENT mechanisms

1) oxygen dependent = Oxidative Burst

NADPH oxidase generates superoxide (O·̄2) ions from O2

during oxygen dependent killing by neutrophils.

Superoxide dismutase will convert SUPEROXIDE -> Hydrogen Peroxide

Myeolperoxidase will convert Hydrogen Peroxide to HOCl (Bleach)

Hypochlorous acid (HClO) is a weak acid that forms when chlorine dissolves in water, and itself partially dissociates, forming ClO-. HClO and ClO- are oxidizers, and the primary disinfection agents of chlorine solutions

130
Q

Metals and Pathologic generation of free radicals

A

(e.g., copper and iron) Fe generates hydroxyl free radicals (Fenton reaction).

hydroxyl free radicals are the most dangerous free radical

IN diseases where Fe builds up, e.g. Hemochromatosis -> cirrhosis in liver and tissue damage throughout the body is mediated through excess Fe generated hydroxyl free radicals (Fenton reaction).

Wilson’s disease- excess of Cu -> Generates free radicals -> tissue damage

131
Q

Drugs and chemicals and Pathologic generation of free radicals

A

P450 system of liver metabolizes drugs (e.g acetaminophen), generating free radicals.

132
Q

Free radicals cause

A

cellular injury via

1) peroxidation of lipids -> damage cells
2) oxidation of DNA and proteins, damage cells -> oncogenesis b/c damage DNA -> mutation, aging

DNA damage is implicated in aging and oncogenesis.

133
Q

Elimination of free radicals occurs via what?

A

1) Antioxidants -
2) Enzymes
3) Metal carrier proteins e.g. transferrin in blood or ferritin in liver and Mphage. They hide away metal so that free radicals not generated

134
Q

Elimination of free radicals via Antioxidants

A

glutathione and vitamins A , C, and E

135
Q

Elimination of free radicals via Enzymes

A

SOD (takes Superoxide radical -> H2O2 )

catalase (H2O2 -> Hydroxyl radical)

glutathione peroxidase (Hydroxyl radical to water) using glutathione antioxidant for part of the reaction

136
Q

Superoxide dismutase

A

(in mitochondria) superoxide (O2.- ->H202)

137
Q

Glutathione peroxidase

A

(in mitochondria) GSH + free radical GSSH and H202

138
Q

Catalase

A

(in peroxisomes) H2O2 ?> O2 and H202

peroxisomes- organelles involved in catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, and polyamines, reduction of reactive oxygen species – specifically hydrogen peroxide

139
Q

Elimination of free radicals via Metal carrier proteins

A

transferrin and ceruloplasmin (keep Fe and Cu sequestered while traveling in blood)

140
Q

Free Radical Injury

A

Carbon tetrachloride (CCl4) and Reperfusion Injury

141
Q

Carbon tetrachloride - What is it used for?

A

Organic solvent used in the dry cleaning industry

142
Q

How is CCl4 metabolized?

A

Converted to CCl3’-(Carbon trichloride) free radicals by P450 system of hepatocytes -> damages membrane of Hepatocytes

Step 1 ) reversible (cell swelling), Rough ER swells, Ribosomes pop off -> Protein synthesis ↓

Protein synthesis ↓ -> Apolipoproteins can not bind up cholesterol and lipids and take it out of liver to other sites via blood -> FATTY CHANGE OF THE LIVER (because fat is accumulating in liver)

143
Q

CCl4 results in what?

A

cell injury with swelling of RER, ribosomes detach, impairing protein synthesis. Decreased apolipoproteins lead to fatty change in the liver

Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fat and cholesterol) to form lipoproteins. They transport the lipids through the lymphatic and circulatory systems. The lipid components of lipoproteins are insoluble in water.

144
Q

Reperfusion injury

A

Return of blood to ischemic tissue results in production of O2-derived free radicals, which further damage tissue. Leads to a continued rise in cardiac enzymes (troponin) after reperfusion of infarcted myocardial tissue

Return of blood brings inflammatory cells to necrotic tissue _ fresh O2 coming in -> Free radical generation -> further damage to an even larger area of surrounding cardiac myocytes -> Increased cardiac enzymes in blood after reperfusion of the blocked artery

145
Q

What is an amyloid?

A

It is a misfolded protein that deposits in the extracellular space (OUTSIDE THE CELL), thereby damaging tissues.

146
Q

What are the shared features of amyloid proteins?

A

1) beta-pleated sheet configuration
2) Congo red staining
3) apple-green birefringence when viewed microscopically under polarized light
4) Deposition can be systemic or localized
5) Deposition often around blood vessels in Extracellular space

systemic amyloidosis can be split into Primary and secondary types

147
Q

What is primary amyloidosis?

A

It is systemic deposition of AL amyloid, which is derived from immunoglobulin light chain

AL amyloid deposit in various tissues around the body = primary amyloidosis

148
Q

What is primary amyloidosis associated with?

A

plasma cell dyscrasias (e.g multiple myeloma) = abnormalities of the plasma cell -> overproduction of light chain relative to heavy chain -> leaks out into blood -> becomes misfolded -> deposits in ECS of tissues

dyscrasia - abnormal or disordered state of the body or of a bodily part

dus- ‘bad’ + krasis ‘mixture.’

149
Q

Secondary amyloidosis is?

A

systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA = acute phase reactant).

Therefore, Secondary amyloidosis is the product of chronic inflammation

150
Q

What is SAA?

A

It is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean Fever (FMF).

inflammatory states e.g.

1) autoimmune disease
2) rheumatoid arthritis
3) chronic osteomyelitis - long progressive infection in bone marrow
4) Cancer can cause a low grade chronic inflammatory state as a reaction to tumros

SAA-> AA-> deposits

151
Q

What is FMF due to?

A

a dysfunction of neutrophils (autosomal recessive) and occurs in persons of Mediterranean origin.

Dysfunctioning neutrophils can create attack of acute inflammation NOT in response to infection -> fever, and causes inflammatsurfacessal surfases -> classic findings

heart serosa affected -> pericardium -> can mimic Myoc Infarc

Abdomen serosa -> mimics acute appendicitis

Acute serosal inflammation, and inflammation in general -> production of acute phase reactants by liver (SAA) -> gets released into blood where misfolds and deposits in tissues Extracellular space as AA

152
Q

What does FMF present with?

A

episodes of fever and acute serosal inflammation

153
Q

FMF can mimic what?

A

appendicitis, arthritis, or myocardial infarction

154
Q

How does FMF result in AA amyloid deposition in tissues?

A

High SAA during attacks deposits as AA amyloid in tissues

155
Q

What is the most common organ involved in systemic amyloidosis?

A

kidney (usually nephrotic syndrome = <3.5 g/day of protein loss in urine)

156
Q

What are the clinical findings of systemic amyloidosis?

A

Nephrotic syndrome

Restrictive cardiomyopathy or arrhythmia - heart can’t fill properly because walls become less compliant

Tongue enlargement

malabsorption due to thickening of the wall of bowel

hepatosplenomegaly

157
Q

Diagnosis of systemic amyloidosis requires what?

A

tissue biopsy, Abdominal fat pad and rectum are easily accessible biopsy targets.

158
Q

Damaged organs of systemic amyloidosis must be…

A

transplanted. Amyloid cannot be removed.

159
Q

What is localized amyloidosis?

A

Amyloid deposition that is usually localized to a single organ

160
Q

What is senile cardiac amyloidosis?

A

Non-mutated serum transthyretin (second to albumin most common protein in blood) deposits in the heart slowly over lifetime.

Usually asymptomatic; present in 25% of individuals > 80 years of age

Transthyretin (TTR) is a transport protein in the serum and cerebrospinal fluid that carries the thyroid hormone thyroxine (T4)

senile - having or showing the weaknesses or diseases of old age

Latin senilis, from senex ‘old man.’

161
Q

Familial amyloid cardiomyopathy

A

Mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy -> can’t pump properly -> eventually cardiac failure, 5% of African Americans carry the mutated gene.

IS NOT asymptomatic like NON-MUtated form

162
Q

Non-insulin-dependent diabetes mellitus (type II -> reistance to insulin at the level of skeletal muscle and adipose tissue)

A

Initially body fights insulin insensitivity by overproducing insulin. Amylin (derived from insulin) deposits in the islets of the pancreas

co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1. Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

163
Q

Alzheimer disease

A

amyloid beta (derived from J-amyloid precursor protein) deposits in the brain forming amyloid plaques

164
Q

Gene for J-APP is present on…

A

chromosome 21.

165
Q

Downs syndrome and Alzheimers?

A

Most individuals with Down syndrome (trisomy 21) develop Alzheimer disease by the age of 40 (early-onset).

166
Q

Dialysis-associated amyloidosis

A

β₂ microglobulin-deposits in joints, because not filtered well via dialysis

β₂ microglobulin also known as B2M is a component of MHC class I molecules, which are present on all nucleated cells. It stabilizes MHC class I

167
Q

Medullary carcinoma of the thyroid

A

Calcitonin (produced by tumor cells) deposits within the tumor (‘tumor cells in an amyloid background’).

Calcitonin - made by parafollicular cells C-cells of the thyroid. Acts to reduce blood calcium (Ca2+), opposing effects of PTH

168
Q

Why can’t permanent tissues make new cells?

A

Because they do not have stem cells.

169
Q

Fibrocystic breast disease

A

noncancerous breast lumps. sometimes cause discomfort periodically related to hormones of menstrual cycle. affects 30-60% of women lifetime prevalence of FBC may be as high as 70% to 90%.

170
Q

Apocrine metaplasia

A

reversible transformation of cells to an apocrine phenotype.

Apocrine - exocrine gland cells that Cells bud their secretions off by producing membrane-bound vesicles in the lumen.

female >50.y.o. Metaplasia happens when there is an irritation to the breast (breast cyst).

apo- away + Greek krinein ‘to separate.’

171
Q

KERATOMALACIA

A

Replacement of the normal NON-KERATINIZED SQUAMOUS EPITHELIUM OF conjunctivae by an inappropriate keratinized stratified squamous epithelium.

172
Q

Is inflammation more likely to cause growth adaptation or injury?

A

adaptation

173
Q

Fat necrosis

A

often seen in breast trauma

as a mass - giant cell immune reaction to the fat - > calcification

NOT ductal carcinoma is situ which also has calcification

Pathoma Enhanced (19 decks)

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