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Pathology 1st LE > Cellular respones to stress and toxic insults: adaptation, injury and death (Kumar Ch. 2, trans 1-2) > Flashcards

Cellular respones to stress and toxic insults: adaptation, injury and death (Kumar Ch. 2, trans 1-2) Flashcards

1
Q

What are the four aspects of a disease process that form the core of pathology?

A
  1. Cause (etiology)
  2. Biochemical and molecular mechanims of its development (pathogenesis)
  3. The structural alterations induced in the cells and organs of the body (morphologic changes)
  4. Functional consequences of these changes (clinical manifestations)
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2
Q

True or False

Virtually, all forms of disease start with molecular or structural alterations in cells

A

True

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3
Q

This refers to reversible functional and structural responses to changes in physiologic states and some pathologic stimuli

A

Adaptation
**Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment

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4
Q

2 pathways of cell death

A

Necrosis and apoptosis

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5
Q

REMEMBER
Stresses of different types may induce changes in cells and tissues other than typical adaptations, cell injury, and death

A

Other processes that affect cells and tissues: intracellular accumulations, pathologic calcification, and cell aging

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6
Q

Refers to an increase in the size of cells, that results in an increase in the size of the affected organ

A

Hypertrophy

**The hypertrophied organ has no new cells, just larger cells

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7
Q

Increased functional demand or by stimulation by hormones and growth factors will lead to _____

A

physiologic hypertrophy
**The striated muscle cells in the heart and skeletal muscles have only a limited capacity for division, and respond to increased metabolic demands mainly by undergoing hypertrophy

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8
Q

REMEMBER
In molecular pathogenesis of cardiac hypertrophy:
There is an integrateed actions among

  1. mechanical sensors (triggered by increasing workload)
  2. growth factors (TGF-B, insulin-like growth factor 1, fibroblast growth factor)
  3. vasoactive agents (a-adrenergic agonists, endothelin-1 and angiotensin)
A

These signals originating in the cell membrane activate a complex web of signal transduction pathways

  1. Phosphoinositide 3-kinase (PI3K)/AKT pathway (postulated to be most important in physiologic, e.g., exercise-induced, hypertrophy)
  2. G-protein coupled receptors (induced by many growth factors and vasoactive agents, and thought to be more important in pathologic hypertrophy)
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9
Q

REMEMBER

Hypertrophy is also associated with a switch of contractile proteins from adult to fetal or neonatal forms

A

α isoform of myosin heavy chain is replaced by the β isoform, which has a slower, more energetically economical contraction.

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10
Q

REMEMBER

Cardiac hypertrophy is associated with increased atrial natriuretic factor gene expression.

A

Atrial natriuretic factor is a peptide hormone that causes salt secretion by the
kidney, decreases blood volume and pressure, and therefore serves to reduce hemodynamic load

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11
Q

Defined as an increase in the number of cells in an organ or tissue in response to a stimulus

A

Hyperplasia

**may occur together with hypertrophy in organs with cells capable of DIVIDING

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12
Q

REMEMBER
Examples of physiologic hyperplasia
1. proliferation of the glandular epithelium of the female breast at puberty and during pregnancy, usually accompanied by enlargement of glandular epithelial cells.
2. liver regeneration after partial hepatectomy
3. marrow hyperplasia in response to a deficiency of terminally differentiated blood cells

A

Physiologic hyperplasia due to the action of hormones or growth factors occurs in several circumstances: when there is a need to increase functional capacity of hormone sensitive organs; when there is need for compensatory increase after damage or resection

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13
Q

REMEMBER
Examples of pathologic hyperplasia
1. Endometrial hyperplasia
2. benign prostatic hyperplasia

A

Most forms of pathologic hyperplasia are caused by excessive or inappropriate actions of hormones or growth factors acting on target cells

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14
Q

REMEMBER
Although pathologic hyperplasias are abnormal, the process remains controlled and the hyperplasia regresses if the hormonal stimulation is eliminated

A

Pathologic hyperplasia is different from cancer, in that the growth control mechanisms in cancer become deregulated or ineffective because of genetic aberrations
**Thus, while hyperplasia is distinct from cancer, pathologic hyperplasia constitutes a fertile soil in which cancerous proliferations may eventually arise

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15
Q

Defined as a reduction in the size of an organ or tissue due to a decrease in cell size and number

A

Atrophy

**The degradation of cellular proteins occurs mainly by the ubiquitin proteasome pathway

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16
Q

It is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type

A

Metaplasia
**It often represents an adaptive response in which one cell type that is sensitive to a particular stress is replaced by another cell type that is better able to withstand the adverse environment

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17
Q

REMEMBER

The most common epithelial metaplasia is columnar to squamous….

A

…as occurs in the respiratory tract in response to chronic irritation, stones in the excretory ducts of the salivary glands, pancreas, or bile ducts, which are normally lined by secretory columnar epithelium, may also lead to squamous metaplasia by stratified squamous epithelium

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18
Q

Barrett esophagus displays what type of metaplasia?

A

Metaplasia from squamous to columnar type
**the esophageal squamous epithelium is replaced by intestinal-like columnar cells under the influence of refluxed gastric acid

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19
Q

Type of metaplasia characterized by the formation of cartilage, bone or adipose tissue in tissues that normally do not contain these elements.

A

Connective tissue metaplasia

**myositis ossifcans - bone formation in muscle that occasionally occurs after intramuscular hemorrhage.

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20
Q

REMEMBER

Metaplasia does not result from a change in the phenotype of an already differentiated cell type…

A

…it is the result of a reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue

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21
Q

What are the hallmarks of reversible injury?

A
  1. reduced oxidative phosphorylation with resultant depletion of energy stores in the form of adenosine triphosphate
  2. cellular swelling caused by changes in ion concentrations and water influx.
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22
Q

It is considered an “accidental” and unregulated form of cell death resulting from damage to cell membranes and loss of ion homeostasis

A

Necrosis

  • *When damage to membranes is severe, lysosomal enzymes enter the cytoplasm and digest the cell
  • *Cellular contents also leak through the damaged plasma membrane into the extracellular space, where they elicit a host reaction (inflammation)
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23
Q

REMEMBER

Necrosis = pathway of cell death resulting from ischemia, toxins, various infections and trauma

A

Apoptosis = pathway of cell death resulting from damaged DNA or proteins

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24
Q

Form of cell death that is characterized by NUCLEAR DISSOLUTION, FRAGMENTATION of the cell without complete loss of membrane integrity, and rapid removal of the cellular debris

A

Apoptosis

**Because cellular contents do not leak out, unlike in necrosis, there is no inflammatory reaction

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25
Q

REMEMBER

Necrosis is always PATHOLOGIC

A

Apoptosis serves many normal functions and is not necessarily associated with cell injury

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26
Q

Two features of reversible cell injury can be recognized under the light microscope:

A

Cellular swelling - appears whenever cells are incapable of maintaining ionic and fluid homeostasis and is the result of failure of energy-dependent ion pumps in the plasma membrane

Fatty change - occurs in hypoxic injury and various forms of toxic or metabolic injury

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27
Q

It is the first manifestation of almost all forms of injury to cells

A

Cellular swelling

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28
Q

True or False

Cellular swelling is easy to appreciate with the light microscope

A

False
**It is a difficult morphologic change to appreciate with the light microscope; it may be more apparent at the level of the whole organ. When it affects many cells, it causes some pallor, increased turgor, and increase in weight of the organ

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29
Q

This pattern of nonlethal injury can be seen on microscopic examination as small clear vacuoles within the cytoplasm

A

Hydrophobic change or vacuolar degeneration

**these represent distended and pinched-off segments of the ER

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30
Q

Ultrastrucutral changes of reversible cell injury

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 the 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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31
Q

REMEMBER

Necrotic cells show increased eosinophilia in hematoxylin and eosin (H & E) stains

A

This is attributable in part to the loss of cytoplasmic RNA (which binds the blue dye, hematoxylin) and in part to denatured cytoplasmic proteins (which bind the red dye, eosin)

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32
Q

REMEMBER

The necrotic cell may have a more glassy homogeneous appearance than do normal cells…

A

…mainly as a result of the loss of glycogen particles

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33
Q

Nuclear changes appear in one of three patterns, all due to nonspecific breakdown of DNA

A
  1. Karyolysis
  2. Pyknosis
  3. Karyorrhexis
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34
Q

In this type of nuclear change, the basophilia of the chromatin may fade, a change that presumably reflects loss of DNA because of enzymatic degradation by endonucleases

A

Karyolysis

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35
Q

Characterized by nuclear shrinkage and increased basophilia. Here the chromatin condenses into a solid, shrunken basophilic mass

A

Pyknosis

**also seen in apoptotic cell death

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36
Q

In this patter of nuclear change the pyknotic nucleus undergoes fragmentation. With the passage of time (a day or two), the nucleus in the necrotic cell totally disappears

A

Karyorrhexis

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37
Q

A form of necrosis in which the architecture of dead tissues is preserved for a span of at least some days. The affected tissues exhibit a firm texture.

A

Coagulative necrosis
**the injury denatures not only structural proteins but also enzymes and so blocks the proteolysis of the dead cells; as a result, eosinophilic, anucleate cells may persist for days or weeks

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38
Q

Characterized by digestion of the dead cells, resulting in transformation of the tissue into a liquid viscous mass

A

Liquefactive necrosis

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39
Q

This term is usually applied to a limb, generally the lower leg, that has lost its blood supply and has undergone necrosis (typically coagulative necrosis) involving multiple tissue planes

A

Gangrenous necrosis
**When bacterial infection is superimposed there is more liquefactive necrosis because of the actions of degradative enzymes in the bacteria and the attracted leukocytes (giving rise to so-called wet gangrene)

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40
Q

This type of necrosis is encountered most often in foci of tuberculous infection.

A

Caseous necrosis

  • *The term “caseous” (cheeselike) is derived from the friable white appearance of the area of necrosis
  • *On microscopic examination, the necrotic area appears as a structureless collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border; this appearance is characteristic of a focus of inflammation known as a granuloma
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41
Q

It refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity

A

Fat necrosis

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42
Q

A special form of necrosis usually seen in immune reactions involving blood vessels. This pattern of necrosis typically occurs when complexes of antigens and antibodies are deposited in the walls of arteries

A

Fibrinoid necrosis

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43
Q

REMEMBER
Mitochondrial damage can be caused by:
1. Decrease ATP
2 Increase ROS

A

Decrease ATP = multiple downstream effects

Increase ROS = damage to lipids, proteins, DNA

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44
Q

In the biochemical mechanism of cell injury, ENTRY of calcium leads to? (2)

A

Increase mitochondrial permeability and activation of multiple cellular enzymes

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45
Q

REMEMBER

ATP depletion and decreased ATP synthesis are frequently associated with both hypoxic and chemical (toxic) injury

A

The major causes of ATP depletion are reduced supply of oxygen and nutrients, mitochondrial damage, and the actions of some toxins (e.g., cyanide)

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46
Q

What are the functional and morphologic consequences of decreased intracellular adenosine triphosphate (ATP) during cell injury?

A
  1. Decreased Na pump -> increase influx of calcium, H2O and Na -> efflux of K - > ER swelling, loss of microvilli and surface blebs
  2. Increased Anaerobic glycolysis -> decreased glycogen and increased lactic acid -> decreased pH -> clumping of nuclear chromatin
  3. Detachment of ribosomes -> decreased protein synthesis
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47
Q

REMEMBER
The mitochondria sequester between their outer and inner membranes several proteins that are capable of activating apoptotic pathways; these include cytochrome c and proteins that indirectly activate apoptosis inducing enzymes called caspases

A

Increased permeability of the outer mitochondrial membrane may result in leakage of these proteins into the cytosol and death by apoptosis

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48
Q

Increased intracellular Ca2+ causes cell injury by several mechanisms

A
  1. accumulation of Ca2+ in mitochondria results in opening of the mitochondrial permeability transition pore -> failure of ATP generation
  2. Activates a number of enzymes with potentially deleterious effects on cells (phospholipases, proteases, endonucleases and ATPases)
  3. Activation of caspases by increasing mitochondrial permeability
49
Q

REMEMBER
Cell injury induced by free radicals, particularly reactive oxygen species, is an important mechanism of cell damage in many pathologic conditions…

A

….such as chemical and radiation injury, ischemia-reperfusion injury (induced by restoration of blood flow in ischemic tissue), cellular aging, and microbial killing by phagocytes

50
Q

REMEMBER

Free radicals may be generated within cells in several ways

A
  1. REDOX reaction
  2. Absorption of radiant energy
  3. Produced by activated leukocytes during inflammation
  4. Enzymatic metabolism of exogenous chemicals or drugs
  5. From transition metals during intracellular reactions
  6. From Nitric Oxide
51
Q 
SUPEROXIDE ANION (O2-)
Mechanisms of production:
Mechanisms of inactivation:
Pathologic effects:
A 
SUPEROXIDE ANION (O2-)
Mechanisms of production: Incomplete reduction of O2 during oxidative phosphorylation; by phagocyte oxidase in leukocytes
Mechanisms of inactivation: Conversion to H2O2 and O2 by superoxide dismutase
Pathologic effects: Stimulates production of degradative enzymes in leukocytes and other cells; may directly damage lipids, proteins, DNA; acts close to site of production
52
Q 
HYDROGEN PEROXIDE (H2O2)
Mechanisms of production:
Mechanisms of inactivation:
Pathologic effects:
A 
HYDROGEN PEROXIDE (H2O2)
Mechanisms of production: Generated by superoxide dismutase from superoxide anion by oxidses in the peroxisomes
Mechanisms of inactivation: Conversion to H2O and O2 by catalase (peroxisomes), glutathione peroxidase (cytosol, mitochondria)
Pathologic effects: Can be converted to OH and OCl−, which destroy microbes and cells; can act distant from site of production
53
Q

HYDROXYL (OH)
Mechanisms of production:
Mechanisms of inactivation:
Pathologic effects:

A

HYDROXYL (OH)
Mechanisms of production: Generated from H2O by hydrolysis, H2O2 by Fenton reaction
Mechanisms of inactivation: Conversion to H2O by glutathione peroxidase
Pathologic effects: Most reactive oxygen-derived free radical; principal ROS responsible for damaging lipids, proteins, and DNA

54
Q

PEROXYNITRITE (ONOO-)
Mechanisms of production:
Mechanisms of inactivation:
Pathologic effects:

A

PEROXYNITRITE (ONOO-)
Mechanisms of production: Produced by the interaction of superoxide anion and nitric oxide
Mechanisms of inactivation: Conversion to HNO2 by peroxiredoxins (cytosol, mitochondria)
Pathologic effects: Damages lipids, proteins, DNA

55
Q

What are the most important

sites of membrane damage during cell injury

A
  1. Mitochondrial membrane
  2. Plasma membrane
  3. Membranes of lysosomes
56
Q

True or False

Ischemia tends to cause more rapid and severe cell and tissue injury than does hypoxia in the absence of ischemia

A

True
**In contrast to hypoxia, during which energy production by anaerobic glycolysis can continue, ischemia compromises the delivery of substrates for glycolysis. Thus, in ischemic tissues, not only is aerobic metabolism compromised but anaerobic energy generation also stops after glycolytic substrates are exhausted

57
Q

REMEMBER
Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured, but can also paradoxically exacerbate the injury and cause cell death

A

This process, called ischemia-reperfusion injury, is clinically important because it contributes to tissue damage during myocardial and cerebral infarction and following therapies to restore blood flow

58
Q

Physiologic or pathologic apoptosis

The destruction of cells during embryogenesis

A

Physiologic

59
Q

Physiologic or pathologic apoptosis

Involution of hormone-dependent tissues upon hormone withdrawal

A

Physiologic

60
Q

Physiologic or pathologic apoptosis

Cell loss in proliferating cell populations

A

Physiologic

61
Q

Physiologic or pathologic apoptosis

Elimination of potentially harmful self-reactive lymphocytes

A

Physiologic

62
Q

Physiologic or pathologic apoptosis

Death of host cells that have served their useful purpose

A

Physiologic

63
Q

Physiologic or pathologic apoptosis

DNA damage

A

Pathologic

64
Q

Physiologic or pathologic apoptosis

Accumulation of misfolded proteins

A

Pathologic

65
Q

Physiologic or pathologic apoptosis

Cell death in certain infections

A

Pathologic

66
Q

Physiologic or pathologic apoptosis

Atrophy in parenchymal organs after duct obstruction

A

Pathologic

67
Q

What morphologic features characterize cells undergoing apoptosis

A
  1. Cell shrinkage
  2. Chromatin condensation
  3. Formation of cytoplasmic blebs and apoptotic bodies
  4. Phagocytosis of apoptotic cells by macrophages
68
Q

What are the two pathways of apoptosis upon caspase activation?

A

Mitochondrial (intrinsic) pathway and the death receptor (extrinsic) pathway

69
Q

It is the major mechanism of apoptosis in all mammalian cells

A

Mitochondrial pathway
**It results from increased permeability of the mitochondrial outer membrane with consequent release of death inducing molecules from the mitochondrial intermembrane space into the cytoplasm

70
Q

REMEMBER

The two pathways of apoptosis differ in their induction and regulation, but both culminate in the activation of caspases

A
  1. In the mitochondrial pathway, proteins of the BCL2 family, which regulate mitochondrial permeability, become imbalanced and leakage of various substances from mitochondria leads to caspase activation
  2. In death receptor pathway, signals from plasma membrane receptors lead to the assembly of adaptor proteins into a “death-including signaling complex,” which activates caspases, and the end result is the same
71
Q

In the intrinsic (mitochondrial) pathway of apoptosis, cell viability is maintained by the induction of anti-apoptotic proteins such as

A

BCL2 or BCL-XL

72
Q

Loss of survival signals, DNA damage, and other insults activate sensors that antagonize the anti-apoptotic proteins and activate these pro-apoptotic proteins

A

BAX and BAK

73
Q

REMEMBER
The release of mitochondrial pro-apoptotic proteins is tightly controlled by the BCL2 family of proteins. There are more than 20 members of the BCL family, which can be divided into three groups based on their pro-apoptotic or antiapoptotic function and the BCL2 homology (BH) domain they possess

A 
Anti-apoptotic:
- BCL2, BCL-XL, and MCL1
- possess four BH domains (called BH1-4)
- reside in the outer mitochondrial membranes as well as the cytosol and ER membranes
Pro-apoptotic
- BAX and BAK
- possess four BH domains
Sensors
- BAD, BIM, BID, Puma, and Noxa
- One BH domain (BH3-only proteins)
74
Q

Once released into the cytosol, cytochrome c binds to a protein called

A

APAF-1 (apoptosis-activating factor-1)

  • *which forms a wheel-like hexamer that has been called the apoptosome
  • *This complex is able to bind caspase-9
75
Q

What is the critical initiator caspase of the mitochondrial pathway

A

caspase-9

76
Q

Death receptors are members of what receptor family?

A

TNF receptor family
**contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain because it is essential for delivering apoptotic signals

77
Q

The mechanism of apoptosis induced by these death receptors is well illustrated by Fas. The ligand for Fas is called Fas ligand (FasL). FasL is expressed on T cells that recognize self antigens (and functions to eliminate self-reactive lymphocytes), and on some cytotoxic T lymphocytes (which kill virus-infected and tumor cells)

A

When FasL binds to Fas, three or more molecules of Fas are brought together, and their cytoplasmic death domains form a binding site for an adaptor protein that also contains a death domain and is called FADD (Fas-associated death domain). FADD that is attached to the death receptors in turn binds an inactive form of caspase-8 (and, in humans, caspase-10). Multiple pro-caspase-8 molecules are thus brought into proximity, and they cleave one another to generate active caspase-8. The subsequent events are the same as mitochondrial pathway and culminate in the activation of executioner caspases

78
Q

The extrinsic pathway of apoptosis can be inhibited by a protein called

A

FLIP

**which binds to pro-caspase-8 but cannot cleave and activate the caspase because it lacks a protease domain

79
Q

REMEMBER
The two initiating pathways converge to a cascade of caspase activation. The mitochondrial pathway leads to activation of the initiator caspase-9

A

the death receptor pathway to the initiator caspases-8 and -10

80
Q

In healthy cells, phosphatidylserine is present on the inner leaflet of the plasma membrane…

A

…but in apoptotic cells this phospholipid “flips” out and is expressed on the outer layer of the membrane, where it is recognized by several macrophage receptors

81
Q

Exposure of cells to radiation or chemotherapeutic agents induces apoptosis by a mechanism that is initiated by DNA damage (genotoxic stress) and that involves the tumor-suppressor gene TP53

A

p53 protein accumulates in cells when DNA is damaged, and it arrests the cell cycle (at the G1 phase) to allow time for repair

82
Q

Morphologically, and to some extent biochemically, necroptosis resembles necrosis, both characterized by loss of ATP, swelling of the cell and organelles, generation of ROS, release of lysosomal enzymes and ultimately rupture of the plasma membrane

A

The DIFFERENCE of necroptosis to necrosis is that necrosis is driven passively by toxic or anoxic iinjury to the cell, while necroptosis is triggered by genetically programmed signal transduction events that culminate in cell death

83
Q

REMEMBER

Necroptosis and apoptosis are both genetically programmed

A

However, the genetic program that drives necroptosis does not result in caspase activation and hence it is also sometimes referred to as “caspase-independent” programmed cell death

84
Q

3 types of autophagy

A
  1. Chaperone-mediated autophagy (direct translocation across the lysosomal membrane by chaperone proteins)
  2. Microautophagy (inward invagination of lysosomal membrane for delivery)
  3. Macroautophagy (major form of autophagy involving the sequestration and transportation of portions of cytosol in a double membrane bound autophagic vacuole)
85
Q

TYPES OF NECROSIS - Coagulation Necrosis

A

 Most common type; caused by protein denaturation
 Cell and tissue network is preserved
 Result of sudden, severe ischemia
 Affects the heart, kidneys, adrenal, and liver
 Cell outline is maintained, but all other details are lost (i.e. nucleus) resulting in “opaque tombstone” appearance
 A localized area of coagulative necrosis is called an INFARCT

86
Q

TYPES OF NECROSIS - Liquefaction Necrosis

A

 Caused by hydrolytic enzymes
 Brain infarcts
 Autolysis and heterolysis predominate over CHON denaturation
 Necrotic areas are soft and filled with fluid
 Frequently seen in localized bacterial infections and abscesses in the brain
 Tissue is transformed into liquid viscous mass
- Presence of pus (dead leukocytes) appearing creamy yellow
 Also seen in bacterial infection , suppuration, and amoebic abscesses

87
Q

TYPES OF NECROSIS - Fat Necrosis

A

 Due to action of LIPASES on adipose tissue
o Lipase activation, from injured pancreatic cells or macrophages, releases fatty acids from TAGs
 Characteristic of pancreatitis/acute pancreatic necrosis
 Grossly seen as chalky white deposits
 Histologically seen as vague cell outlines and calcium deposition
 TAGs from damaged fat cells are released as FFAs which complex to form calcium soaps. (Fat Saponification)
 Also seen in breast tissue after trauma

88
Q

TYPES OF NECROSIS - Caseous (Cheesy) Necrosis
 Combination of coagulative and liquefactive necrosis
 Characteristic of tuberculosis lesions (Center of a TB granuloma)
 Granuloma scattered or involved most of the lung (tuberculous pneumonia if consolidated)
 Diminished oxygen in the area of necrosis => no live tubercle bacilli (facultative aerobe)

A
  • *Lung with TB. May manifest with soft, friable, whitish (cheesy) gray appearance; bacteria found in periphery lesion are obligate anaerobes; there may be multiple granulomas, if they coalesce, condition is known as tuberculous pneumonia
  • *Liquefaction manifests as amorphous, granular, pinkish debris
89
Q

TYPES OF NECROSIS - Gangrenous Necrosis

A

 A combination of coagulation and liquefaction necrosis in addition to the action of bacteria and leukocytes
 Coagulative – if due to decreased blood flow
 Liquefactive – if due to bacterial infection (due to increase digestive enzymes of bacteria and WBCs)
 Characteristic of limbs (usually lower) that has lost its blood
 Dry Gangrene: Coagulation predominates; tissue looks dry and black (usually lower ext.)
 Wet Gangrene: Liquefaction predominates; tissue is swollen, red, and odorous (usually found in the intestines)

90
Q

TYPES OF NECROSIS - Fibrinoid Necrosis

A

 Seen in immune reactions involving blood vessels
 Antigen-antibody complexes are deposited in walls of arteries together with fibrin resulting in bright pinkish amorphous appearance (fibrinoid) in the arterial-walls
**Fibrinoid necrosis in an artery. CT and arterial walls are infiltrated by eosinophilic hyaline material, which shows some fibrin characteristics

91
Q

SUBCELLULAR ALTERATIONS IN NECROSIS

A
  1. Lysosymes
  2. Hypertrophy of smooth endoplasmic reticulum
  3. Mitochondrial alterations in size, shape, and number
  4. Abnormalities of cytoskeleton, contractile proteins, and membrane skeleton
  5. Membrane skeleton
92
Q

SUBCELLULAR ALTERATIONS IN NECROSIS - Lysosymes

A

Heterophagy
o Lysosomal digestion of ingested extracellular material; examples are endocytosis, phagocytosis, and pinocytosis
Autophagy
o Lysosomal digestion of cell’s own components
o Depending on how material is delivered, can be categorized into 3 types: chaperone mediated autophagy, microautophagy, and macroautophagy1
o Dysregulation occurs in many disease states including cancer, inflammatory bowel disease, and neurodegenerative disorders

93
Q

SUBCELLULAR ALTERATIONS IN NECROSIS - Abnormalities of cytoskeleton, contractile proteins, and membrane skeleton
 Chediak-Higashi syndrome- defect in microtubule polymerization
 Cytochalasin B- inhibits microfilament action and phagocytosis
 Colchicine- disrupts microtubules; inhibits mitosis in metaphase
 Immotile cilia syndrome- microtubule defect in respiratory cilia leads to increased risk for respiratory infection
 Intermediate filaments accumulation- presence of Mallory body

A

 Mallory-Denk bodies are usually present as clumped, amorphous, eosinophilic material in ballooned hepatocytes. They are made up of tangled skeins of intermediate filaments such as keratins 8 and 18 in complex with other proteins such as ubiquitin

94
Q

Apoptosis
In Physiologic conditions:
 Programmed cell death during embryogenesis
 Hormone-dependent involution
 Cell deletion in proliferating cell populations
 Elimination of potentially harmful self-reactive lymphocytes
 Cell death in cells that served their purpose

A

In Pathologic conditions:
 DNA damage
 Accumulation of misfolded proteins (ER stress)
 Cell Death in Tumor and Immune Cells (by cytotoxic T cells) or cell death in certain viral diseases by cytotoxic T cells
 Pathologic Atrophy in parenchymal organs after ductobstruction (pancreas, parotid, kidney)

95
Q

Apoptosis - Morphologic features of Apoptosis

A

 Cell shrinkage
 Chromatin condensation (main characteristic feature)
 Formation of cytoplasmic blebs and apoptotic bodies
 Phagocytosis of apoptotic bodies and cells

96
Q

INTRACELLULAR ACCUMULATION
 Pathologic (abnormal) accumulation of substances within cells and tissues
 May be associated with varying degrees of injury

A

Four Major Mechanisms of Intracellular Accumulations

  1. Abnormal Metabolism
  2. Defect in Protein Production/Folding/Transport
  3. Enzyme Deficiency
  4. Inability to Degrade/Transport Abnormal Exogenous Substances
97
Q

INTRACELLULAR ACCUMULATION - Four Major Mechanisms of Intracellular Accumulations

A
  1. Abnormal Metabolism
    o Inadequate rate of metabolism to eliminate normal endogenous substances
    o Excessive amounts of a substance normally found in the cell/tissue/organ
  2. Defect in Protein Production/Folding/Transport
    o Formation of defective proteins due to mutation, or buildup of proteins that cannot be transported out
    o Presence a substance not normally found in the cell/tissue/organ
  3. Enzyme Deficiency
    o Intracellular buildup of metabolite/s due to the lack of necessary enzyme/s; resulting disorders are called storage diseases
    o Excessive amounts of a substance normally found in the cell/tissue/organ
  4. Inability to Degrade/Transport Abnormal Exogenous Substances
    o Presence a substance not normally found in the cell/tissue/organ that cannot be metabolized or transported out
98
Q

INTRACELLULAR ACCUMULATION - Substances Involved in Intracellular Accumulation

A 
A. Lipids
B. Proteins
C. Glycogen accumulation
D. Complex Lipids and Carbohydrates
E. Pigments
99
Q

INTRACELLULAR ACCUMULATION:
Substances Involved in Intracellular Accumulation - Lipids
- Accumulation occurs in parenchymal and stromal cells

A

Fatty Change (Steatosis)
 Abnormal accumulation of triacylglycerols (TAGs) within parenchymal cells
 Primarily within the liver; may also occur in other organs such as the heart, kidneys and muscles
Causes:
1. Alcohol
- most common cause of adult fatty liver
2. Protein Malnutrition
- most common cause of pediatric fatty liver
3. Diabetes Mellitus
- associated with non-alcoholic fatty liver disease (affects CHO and lipid metabolism)
4. Pregnancy
- may cause acute fatty change
5. Obesity
6. Hepatotoxins

100
Q

INTRACELLULAR ACCUMULATION:

Substances Involved in Intracellular Accumulation - Lipids

A

Pathogenesis of Fatty Liver

  1. Excessive entry of FFA’s into the liver
    - Mobilization of adipose tissue into the liver due to starvation or corticosteroid use
  2. Increased esterification of FA’s into TAG’s
    - Increased α-glycerophosphate (alcohol poisoning)
    - Enhanced FA synthesis
    - Decreased FA oxidation (hypoxia)
  3. Decrease in apoprotein synthesis (CCl4 or phosphorus poisoning, CHON malnutrition)
  4. Impaired lipoprotein secretion from the liver
    - ↓ lipoproteins → ↓ TAG transport from the liver → ↑ TAG accumulation → fatty liver
101
Q

INTRACELLULAR ACCUMULATION:

Substances Involved in Intracellular Accumulation - Proteins

A

Accumulations appear rounded, eosinophilic droplets vacuoles, or aggregates in the cytoplasm
o Pink hyaline droplets in epithelial cells of the renal PCT
- Excessive proteinuria results in increased pinocytotic reabsorption of albumin in the renal PCT → intravesicular accumulation of albumin
o Russel Bodies – pink eosinophilic inclusions
- Accumulation of newly synthesized immunoglobulins in the RER of plasma cells
o Defective intracellular transport and secretion of critical proteins
o Accumulations of cytoskeletal proteins (microtubules, actin filaments, etc)
o Aggregation of abnormal/misfolded proteins may alter normal functions

102
Q

INTRACELLULAR ACCUMULATION:
Substances Involved in Intracellular Accumulation - Glycogen accumulation
- Associated with defects in glucose or glycogen metabolism
o Diabetes Mellitus
 Abnormal levels of glucose in the blood due to lack of insulin, or insufficient activity of insulin
 Glucose accumulates in epithelial cells of the renal PCT, liver cells, pancreatic β-cells, and cardiac muscle

A

o Glycogen Storage Diseases (Glycogenoses)
 Von Gierke’s disease
- Glucose-6-phosphatase deficiency (inability to convert glucose 6-PO4 into glucose → accumulation of glucose 6-PO4 )
 McArdle’s syndrome
- Myophosphorylase deficiency (muscles unable to convert glycogen into glucose → accumulation of glycogen )
 Pompe’s disease
- Lysosomal glucosidase deficiency (inability to break the glycosidic linkages in glycogen → accumulation of glycogen )

103
Q

INTRACELLULAR ACCUMULATION:
Substances Involved in Intracellular Accumulation - Complex Lipids and Carbohydrates
 Primary site of accumulation in reticuloendothelial (RES) cells

A

Results from inborn errors of metabolism:
o Mucopolysaccharidoses
 Mucopolysaccharidase deficiencies
o Gaucher’s Disease
 Glucocerebrosidase deficiency
 Intracellular accumulation of glucosylceramide
o Tay-sach’s Disease
 Hexosaminidase A deficiency
 Intracellular accumulation of gangliosides
o Nieman-Pick’s Disease
 Sphingomyelinase deficiency
 Lysosomal accumulation of sphingomyelin

104
Q

INTRACELLULAR ACCUMULATION:

Substances Involved in Intracellular Accumulation - Pigments

A

 Colored substances; may be either endogenous or exogenous

105
Q

INTRACELLULAR ACCUMULATION:

Substances Involved in Intracellular Accumulation - Exogenous Pigment Accumulation

A

 Carbon Accumulation (Anthracosis)
- Black discoloration of pulmonary parenchyma
 Tattoo
- Pigment inoculation of dermal macrophages
 Coal Workers’ Pneumoconiosis
- Coal dust accumulation in the lungs

106
Q

INTRACELLULAR ACCUMULATION:
Substances Involved in Intracellular Accumulation - Endogenous Pigment Accumulation
**Lipofuscin

A
  • “wear and tear pigment”, marks past injury
  • Brownish-yellow granular intracellular pigment
  • Composed of complexes of protein and lipids
  • Derived through lipid peroxidation of membrane lipids (polyunsaturated)
  • Excessive accumulation results in a “brown atrophy” appearance; prominent in the liver and heart of aging patients or those with severe malnutrition
107
Q

INTRACELLULAR ACCUMULATION:
Substances Involved in Intracellular Accumulation - Endogenous Pigment Accumulation
**Melanin

A
  • Brown-black pigment synthesized by melanocytes
  • Acts as a screen versus harmful UV light
  • Tyrosinase activity oxidizes tyrosine into dihydroxyphenylalanine (melanin precursor)
  • Ochronosis
     Accumulation of homogentisic acid
     Associated with alkaptonuria
108
Q

INTRACELLULAR ACCUMULATION:
Substances Involved in Intracellular Accumulation - Endogenous Pigment Accumulation
**Hemosiderin

A
  • Hemoglobin-derived pigment containing iron
  • Golden yellow to brown in color
  • (+) for Prussian Blue
  • Accumulation in tissues represents large quantities of ferritin micelles (iron)
  • Hemosiderosis
     Iron overload disorder associated without organ damage
     Caused by: increased absorption of dietary iron, impaired iron use, hemolytic anemia, repeated blood transfusions
  • Hemochromatosis
     Iron overload disorder associated with organ damage
     Associated with liver fibrosis, cardiomegaly, and pancreatic fibrosis
109
Q

INTRACELLULAR ACCUMULATION:
Substances Involved in Intracellular Accumulation - Endogenous Pigment Accumulation
**Bilirubin

A
  • Brownish-green pigment
  • Major component of bile
  • Hemoglobin-derived pigment with no iron
  • Accumulation leads to jaundice, and then to kernicterus
  • Jaundice
     Yellow pigmentation of the skin, conjunctiva of the eyes, and mucus membranes due to hyperbilirubinemia
     Indicative of hepatic disease or blockage of the biliary tract
  • Kernicterus
     Caused by deposition of the unconjugated form of bilirubin in the brain through prolonged hyperbilirubinemia
110
Q

INTRACELLULAR ACCUMULATION:
Substances Involved in Intracellular Accumulation - Endogenous Pigment Accumulation
**Hematin (hemozoin)

A
  • Malarial pigment
  • Mainly deposited in the liver and spleen
  • (-) for Prussian Blue
  • Can cause cerebral malaria
111
Q

INTRACELLULAR ACCUMULATION:
Substances Involved in Intracellular Accumulation - Endogenous Pigment Accumulation
**Copper

A
  • found in Wilson’s Disease/Hepatolenticular Degeneration
112
Q

DYSPLASIA

Epithelial or mesenchymal cells undergo proliferation and atypical cytologic changes such as:

A

o Loss of polarity
o Increased mitosis
o Increased nuclear/cytoplasmic ratio (N/C ratio)
o Irregular or thickening of the nuclear membrane
o Hyperchromasia (increase in color)
o Chromatin clumps

113
Q

CALCIFICATION

A

 Cells can have a deposition of certain substances, one of them is calcium
 Calcium deposition can be dystrophic or metastatic

114
Q

CALCIFICATION - Dystrophic Calcification
GROSS APPEARANCE: Fine, white granules, felt as gritty deposits
HISTOLOGIC APPEARANCE: Intracellular and/or Extracellular basophilic deposits

A

o Occurs in non-viable tissues (REMEMBER: Dystrophic = Dead), within sites of necrosis of any type2
o Occurs without calcium derangement (normal serum calcium levels)
EXAMPLES
a. Psammoma bodies or asbestos bodies (in psammomatous menangioma; can be indicative of papillary carcinoma in the thyroid)
b. Atheromas associated with injury to the intima
c. Calcification of the aortic valve -> aortic stenosis -> aortic regurgitation detected as murmurs on auscultation

115
Q

CALCIFICATION - Metastatic Calcification
GROSS APPEARANCE: Non-crystalline amorphous crystals or as hydroxyapatite crystals
HISTOLOGIC APPEARANCE: Intracellular and/or Extracellular basophilic deposits

A

o May occur in normal tissues, almost always secondary to hypercalcemia
o Does not produce clinical dysfunctions, except if deposits have occurred extensively, as in the lungs and kidneys.
o Major causes of hypercalcemia:
 Hyperparathyroidism
 Bone destruction, which can be caused by..
a. Multiple myeloma – malignant tumor involving plasma cells
b. Paget disease – accelerated calcium turnover
c. Immobilization
 Vitamin D-related disorders – sarcoidosis, Vit. D intoxication
 Renal failure leading to secondary hyperparathyroidism

116
Q

CELLULAR AGING
Individuals age because their cells age
o one of the strongest independent risk factors for many chronic diseases, such as cancer, Alzheimer disease, and ischemic heart disease
o regulated by a limited number of genes and signaling pathways that are evolutionarily conserved from yeast to mammals

A

 Progressive decline in cellular function and viability
 Effects of continuous exposure to exogenous influences that result in the progressive accumulation of cellular and molecular damage

117
Q

CELLULAR AGING
Combination of:
o Accumulation of cell damage (e.g. free radicals):
 defective DNA repair mechanisms
 DNA repair may be activated by calorie restriction
o Decrease capacity to divide
 Replicative senescence
 All normal cells have a limited capacity for replication, and after a fixed number of divisions cells become arrested in a terminally nondividing state
 decreasing amounts of telomerase
o Defective protein homeotasis
 due to increased turnover and decreased synthesis caused by reduced translation of proteins and defective activity of chaperones (which promote normal protein folding), proteasomes (which destroy misfolded proteins) and repair enzymes

A

Telomerase – maintains the telomere length
 specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes
 activity is expressed in germ cells and is present at low levels in stem cells, but it is absent in most somatic tissues
**Mechanism: When somatic cells replicate, a small section of the telomere is not duplicated and telomeres become progressively shortened. As telomeres become shorter, the ends of chromosomes cannot be protected and are seen as broken DNA, which signals cell cycle arrest

118
Q

CELLULAR AGING - Defining signaling pathways that counteract the aging process

A

 reduced signaling by insulin-like growth factor receptors, reduced activation of kinases (notably the “target of rapamycin,” [TOR], and the AKT kinase, and altered transcriptional activity => lead to improved DNA repair and protein homeostasis and enhanced immunity
 may also activate proteins of the Sirtuin family, such as Sir2, which function as protein deacetylases and thereby activate DNA repair enzymes, thus stabilizing the DNA; in the absence of these proteins, DNA is more prone to damage

Pathology 1st LE (12 decks)

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