MoD Session 1 Flashcards
0
Q
What does all disease start with?
A
Cell injury
1
Q
What can disease be considered as?
A
Consequence of failed homeostasis w/consequent morphological and functional disturbance
2
Q
What are the increasing levels of response mounted by a cell as a stimulus moves from being physiological to harmful?
A
Homeostasis
Cellular adaptation
Cellular injury
Cell death
3
Q
At what point does cell injury become cell death?
A
When the injury becomes irreversible
4
Q
What can cause cell injury?
A
Hypoxia Toxins Physical agents Radiation Micro-organisms Immune mechanisms Dietary insufficiency Genetic abnormalities
5
Q
What is hypoxaemic hypoxia?
A
Decrease in arterial oxygen content due to altitude or lung disease
6
Q
What is anaemic hypoxia?
A
Decreased oxygen carriage by haemoglobin caused by anaemia or carbon monoxide poisoning
7
Q
What is ischaemic hypoxia?
A
Interrupted blood supply caused by BV blockage or heart failure
8
Q
What is histiocytic hypoxia?
A
Inability of a cell to use oxygen due to disabled oxidative phosphorylation enzymes caused by cyanide poisoning
9
Q
How does the tolerance of hypoxia vary between neurones and fibroblasts before irreversible injury is caused?
A
Neurones can tolerate a few minutes
Fibroblasts can tolerate a few hours
10
Q
Give examples of toxins that could cause cellular injury.
A
Glucose/salt in hypertonic solutions
Oxygen at high concentration
Therapeutic drugs
11
Q
Give examples of physical agents that may cause cellular injury.
A
Direct trauma
Extreme temperature
Changes in pressure
Electric currents
12
Q
How is urticaria (hives) caused?
A
Hypersensitivity reaction causes host tissue to be injured secondary to an overly vigorous immune response
13
Q
How does Grave’s disease cause cellular injury?
A
Autoimmune reaction which fails to distinguish b/w self and non-self
14
Q
What shows cellular injury when caused by immune mechanisms?
A
Redness
15
Q
Give an example of a genetic abnormality which can cause cellular injury.
A
Inborn errors of metabolism
16
Q
By what mechanisms can cellular injury be caused?
A
Target: Cell membranes, especially lysosomes Nucleus Proteins (structural cytoskeleton and enzymes) Mitachondria
17
Q
How can hypoxia cause reversible cell injury?
A
Ischaemia decreases oxidative phosphorylation –> decreases ATP to 5-10% of normal concentration –> cell reacts
18
Q
Why does lipid deposition occur in reversible cell injury caused by hypoxia?
A
Ribosomes detach from the ER –> protein synthesis is decreased –> lipid is deposited
19
Q
Why does chromatin clump during reversible cell injury caused by hypoxia?
A
Increased glycolysis lowers pH which in turn causes chromatin to clump
20
Q
How are blebs formed in reversible cell injury caused by hypoxia?
A
The sodium/potassium pump is disrupted so cell swells as osmotic ions move in w/water allowing blebs to form
21
Q
Why does cytosolic calcium levels increase in irreversible cell injury caused by hypoxia?
A
Leaky CSM allows calcium entry
ER and mitochondria also increase calcium levels
22
Q
Which enzymes are affected by the increase in cytosolic calcium in irreversible cell injury caused by hypoxia?
A
ATPase
Phospholipase
Protease
Endonuclease
23
Q
What effects does the high cytosolic calcium levels acting on enzymes within the cell have in irreversible cell injury caused by hypoxia?
A
Decreases ATP levels
Decreases phospholipid levels
Disrupts membrane and cytoskeleton proteins
Causes nuclear chromatin damage
24
Is the pathogenesis of cell injury due to all insults the same?
No, it may vary and attack different key structures
25
Which three free radicals are of biological significance?
Hydroxyl
Superoxide
Hydrogen peroxide
26
How does the Fenton reaction form free hydroxyl radicals?
Iron(II) is oxidised to iron(III) whilst hydrogen peroxide becomes an hydroxide ion and hydroxyl free radical
27
How does the Haber-Weiss reaction form hydroxyl free radicals?
An oxide ion, hydrogen ion and hydrogen peroxide react to form oxygen, water and a hydroxyl free radical
28
Which free radical is the most dangerous biologically?
Hydroxyl
29
Why must hydrogen peroxide and oxide ions be rapidly removed by the body?
To prevent formation of more dangerous hydroxyl free radicals
30
Why is the Fenton reaction important in bleeding?
Iron is available so there is an increased risk of hydroxyl free radical formation
31
What insults particularly cause free radical production?
```
Chemical (paracetamol)
Radiation
Ischaemia-reperfusion
Cellular aging
High oxygen concentration
```
32
What damage do free radicals cause to cellular structures?
Lipid peroxidation
| Bent/broken/cross-linked proteins, carbohydrates and nucleic acids
33
Why are free radicals required by leucocytes?
Killing bacteria
| Cellular signalling
34
How are free radicals removed?
Antioxidant system
35
Which enzymes are involved in the antioxidant system?
Superoxide dismutase
Catalases
Peroxidases
36
What are free radical scavengers?
Vitamins A, C, E which can sequester metal ions and prevent Fenton reaction
37
What type of proteins are used in the antioxidant system?
Storage
38
What is ischaemia reperfusion injury?
When bloodflow is returned to damaged but not yet necrotic tissue causing damage worse than if the bloodflow was not restored
39
What mechanisms can cause reperfusion injury?
Increased ROS w/reoxygenation
Increased neutrophils causing more inflammation and tissue injury
Delivery of complement proteins activating the complement pathway
40
What cells are heat shock proteins present in?
All at low concentrations
41
What is the function of heat shock proteins?
Mend mis-folded proteins
| Maintain cell vitality
42
What type of proteins are heat shock proteins?
Unfoldases/chaperonins e.g. Ubiquitin
43
How does the cell use heat-shock proteins to maintain cell vitality?
Turns off production of other proteins and increases heat-shock protein synthesis
44
What happens to a mis-folded protein if it cannot be re-folded?
It is destroyed
45
What are the stages of cell injury as seen by light microscopy?
Alive --> injured --> dead-pyknosis --> karyorrhexis --> karyolysis
46
What is pyknosis?
Irreversible cell shrinkage
47
Why does an injured cell become more darker staining as its injury becomes less reversible?
Denatured proteins accumulate
48
When does chromatin clumping remain reversible until?
Pyknosis
49
In reversible cell injury, what cellular changes are seen by electron microscopy?
```
Cell swelling and blebs
Autophagy by lysosomes
Chromatin clumping
Mitochondrial and ER swelling
Dispersion of ribosomes
Aggregation of intramembranous particles
```
50
In irreversible cell injury, what cellular changes are seen by electron microscopy?
```
Rupture of lysosomes and autolysis
Pyknosis of nucleus
Mitochondrial swelling w/large densities formed inside
Lysis of ER
Myelin figures
Defects in CSM
```
51
What is oncosis?
Cell death w/swelling
| Spectrum of changes that occur in injured cells prior to death
52
What is the relationship between ATP and oncosis?
There is none - it is an ATP independent process
53
What cellular changes are seen in oncosis?
Cell and mitochondrial swelling
| Plasma membrane rupture
54
What is necrosis?
Morphological changes that occur in a living organism after a cell has been dead for some time
55
Typically what period of time after cell death is necrosis seen?
4-24 hours
56
What is apoptosis?
Cell death w/shrinkage induced by a regulated intracellular programme where the cell activates enzymes that degrade its own nuclear DNA and proteins
57
Is apoptosis and active process?
Yes, it's ATP dependent
58
What cellular changes are seen in apoptosis?
```
Cell shrinkage
Chromatin condenses
Nuclear fragments
Membrane integrity preserved
Apoptotic bodies
```
59
What does this describe?
Seen w/damage to cell membranes --> cell contents leak out --> inflammation
Necrosis
60
What is fat necrosis?
Destruction of adipose
61
How are chalky deposits formed in fat necrosis?
Lipases free fatty acids which combine with calcium
62
What can cause fat necrosis?
Pancreatitis
| Trauma to adipose
63
What can fat necrosis mimic?
Breast cancer nodule
64
What is caseous necrosis?
Amorphous structureless debris associated with TB
65
What is liquefactive necrosis?
Enzymatic digestion of tissues seen in tissues lacking stroma
66
How is pus formed in colliquitive necrosis?
Increased inflammation and neutrophils
67
What is coagulative necrosis?
Denaturation of proteins causing them to coagulate seen in solid organs
68
Why is a 'ghost outline' seen in coagulative necrosis?
Cellular architecture is somewhat preserved
69
How does coagulative necrosis appear histiologically?
Intense pink staining
| Small nuclei
70
How can liquefactive and coagulative processes be rescued when occurring in cells which are still alive?
Rescued by heat shock proteins
71
What is gangrene?
Necrosis that is visible to the naked eye
72
What is the difference between dry and wet gangrene?
Dry: tissue dries before infection can take hold
Wet: bacteria or fungi invade before drying completes
73
How can wet gangrene cause septicaemia?
Microorganisms can easily leak into surrounding capillaries
74
How does gas gangrene lead to the development of palpable pockets of gas in a tissue?
Wet gangrene w/anaerobic bacteria
75
Which type of necrosis is associated with ischaemia?
Coagulative
76
What is an infarct?
Area of ischaemic necrosis
77
What two types of infarct are possible?
White
| Red
78
Which two types of necrosis can cause an infarct to form?
Coagulative e.g. MI
| Liquefactive e.g. Cerebral infarct
79
What can cause an infarction?
Thrombosis and embolism
| Compression/twisting of BV - twisted spermatic cord, hernia, twisted bowel
80
How is a wedge shaped white infarct formed?
Arteral insufficiency so not reperfused due to single blood supply --> occluded artery at apex of wedge of infarct
81
How are red infarcts formed?
Venous insufficiency/reperfused/dual blood supply sufficient to cause haemorrhage but not rescue tissue
82
What features are present in tissue which can form a red infarct?
Numerous anastomoses
| Loose tissue w/poor stromal support
83
What reduces arterial filling hence causing ischaemia in red infarction?
Capillaries leak causing venous pressure to increase
84
What do the consequences of infarction depend on?
Alternative blood supply
Speed of ischaemia
Tissue involved
Oxygen content of blood
85
What causes release of molecules by injured and dying cells?
Calcium entering damaged membranes
86
What molecules are leaked by injured and dying cells?
Potassium
Enzymes
Myoglobin
87
What are the affects of molecules released by injured and dying cells?
Local inflammation
| General toxic effects on body
88
Why can molecules released by injured and dying cells be used for diagnosis?
They may appear in blood
89
What can cause potassium to explode out of dead cells?
Large MI
Severe burns
Tourniquet removal
Tumour necrosis syndrome
90
What is tumour necrosis syndrome?
Where cancer cells are effectively killed so release lots of potassium
91
Why is potassium used in cardiac surgery?
High levels stop the heart
92
In what order are enzymes released by injured and dying cells?
Smallest molecular weight first w/increasing weight w/increasing pore size
93
Give three examples of enzymes released by injured or dying cells.
Creatine kinase
AST
Troponin
94
How does myoglobin released by injured or dying cells cause brown coloured urine?
Dead myocardium or striated muscle releases myoglobin which plugs renal tubes --> greatly increases myoglobin levels in the urine
95
What is apoptosis characterised by?
```
Shrinkage
Consistent cleavage of DNA breakdown
Use of ATP
Maintained membrane integrity
Lack of lysosomal emzyme involvement
Rapid completion time
```
96
What is apoptosis used physiologically for?
Sculpting during embryogenesis
| Involution of hormones and cytotoxic killer T cells
97
How can apoptosis be identified pathologically?
Individual cell destruction w/shrunken, intensely pink appearance
98
What is the process seen by a cell undergoing apoptosis?
Normal cell --> condensation --> cell buds --> apoptotic bodies
99
Why is there no inflammation in apoptosis?
Apoptotic bodies are removed by phagocytes therefore there is no release of cellular contents
100
How does extrinsic intimation cause apoptosis?
Stressed cell expresses death receptors --> death ligand TRAIL binds --> activates caspase-8
101
How does intrinsic initiation cause apoptosis?
Stimulated by DNA damage or hormone withdrawal --> p53 stimulates mitochondria which stimulates apoptosome --> activated caspase-9
102
What is the process of degradation and phagocytosis seen in apoptosis?
Loss of microvilli and junctions +/- nuclear changes --> fragmentation creating apoptotic bodies --> apoptotic body expresses surface proteins for recognition by phagocytosis
103
Name 7 important apoptotic molecules.
```
Death receptors
Death ligands
Caspases
p53
Cytochrome C
APAFI
Bcl-2
```
104
What are caspases?
Effector molecules of apoptosis
105
What is p53?
'Guardian of the genome' which mediates apoptosis in response to DNA damage
106
What does Bcl-2 do?
Prevents cytochrome C release from mitochondria therefore inhibiting apoptosis
107
What causes abnormal accumulations in a cell?
If the cell cannot metabolise something
108
What can abnormal accumulations in a cell derive from?
Cell's own metabolism
Extracellular space - iron in bleeding
Outer environment - dust
109
Can abnormal accumulations in a cell be reversed?
Yes, if cell metabolism recovers
110
What four mechanisms can cause abnormal accumulations in a cell?
Abnormal metabolism
Alterations in protein folding and transport
Enzyme deficiency
Inability to degrade phagocytosed particles
111
How does abnormal accumulation of water and electrolytes cause tissues to become heavy?
Vacuoles/hydropic swelling increase water content
112
What very difficult to treat condition caused by water and electrolyte retention stops breathing?
Cerebral oedema
113
What causes steatosis?
Alcohol
Diabetes mellitus
Obesity
Toxins
114
How are xanthomas formed?
Cholesterol vesicle filled cells form foam cells as cholesterol is not broken down by the body so is stored in membrane bound droplets
115
What forms myelin figures?
Phospholipids
116
What is the first stage of liver disease?
Steatosis
117
How does mild steatosis compare to advanced steatosis?
```
Mild = asymptomatic
Advanced = increased weight and size of liver
```
118
What causes abnormal accumulations of carbohydrates?
Secondary to inborn errors of metabolism
119
How are abnormal accumulations of protein seen in cells?
Eosinophilia droplets in cytoplasm
120
What is Mallory's hyaline?
Damaged hepatocyte protein due to accumulation of keratin in alcoholic liver disease
121
How does incorrectly folded alpha 1-antitrypsin lead to emphysema and hepatitis?
Causes alpha 1-antitrypsin deficiency --> accumulates in ER
122
How do exogenous pigments remain in the skin?
Macrophages pick up pigment and stay indefinitely, replaced when they die and remain stained
123
Why is some exogenous pigment found in lymph nodes?
Some is taken up by lymph fluid and taken to nodes
124
Give three examples of endogenous pigments found in the body.
Bilirubin
Heamosiderin
Lipfuscin
125
How is heam converted to a toxic endogenous pigment?
Haem --> biliverdin (non-toxic) --> bilirubin (toxic)
126
What is the irreversible step in bilirubin production from biliverdin?
Breaking of porphyrin ring
127
Why is bilirubin associated with liver disease when it can be formed by all tissues of the body?
It is transported w/albumin to the liver
128
What is heamosiderin?
Iron storage molecule seen in systemic/local excess of iron
129
What causes haemosiderin deposition in tissues?
Bruising
130
What is hereditary haemochromatosis?
Absorption of too much iron which affects the liver and pancreas
131
What is another name for hereditary haemochromatosis?
Bronze diabetes
132
When is lipofuscin seen?
In age/wear and tear in tissues which have been damaged by free radicals
133
What type of cells is lipofuscin not seen in?
Rapid turnover cells
134
What are the three stages of excessive alcohol intake?
Steatosis - reversible
Acute alcohol hepatitis - reversible
Cirrhosis - irreversible
135
What are the S/S of acute alcoholic hepatitis?
Fever
| Liver tenderness
136
How does the liver appear in cirrhosis?
Hard and nodular w/scar tissue and macrophages
137
What is dystrophic calcification?
Pathological local deposition of calcium seen in tuberculous lymph nodes and atheroma
138
Is there abnormal serum calcium or calcium metabolism in dystrophic calcification?
Nope
139
What is favoured in dystrophic calcification?
Hydroxyapatite crystal formation
140
Which is the commonest type of pathological calcification?
Dystrophic
141
What is metastatic calcification?
Hypercalcaemia leading to deposition of hydroxyapatite crystals in all tissues
142
What can cause metastatic calcification?
High PTH
Destruction of bone due to tumour
Paget's disease
Immobilisation causing lack of bone formation stimulus
143
What causes cellular aging?
Shortening of telomeres
144
What occurs at a critical telomere length?
Replicating senescence
145
Why can germ cells and stem cells replicate indefinitely?
They contain telomerase which replicates their telomeres
146
How does the pattern of oncosis/necrosis compare to apoptosis?
Oncosis/necrosis: contiguous group of cells
| Apoptosis: single cells
147
How does the cell size in oncosis/necrosis compare to that in apoptosis?
Oncosis/necrosis: enlarged (swelling)
| Apoptosis: reduced (shrinkage)
148
How does the nucleus of a cell undergoing oncosis/necrosis compare to that of one undergoing apoptosis?
Oncosis/necrosis: pyknosis-karyorrhexis-karyolysis
| Apoptosis: fragmentation into nucleosome size fragments
149
How does the plasma membrane compare in oncosis/necrosis to apoptosis?
Oncosis/necrosis: disrupted, early lysis
| Apoptosis: intact but w/altered structure, especially orientation of lipids
150
How do the cellular contents compare in oncosis/necrosis and apoptosis?
Oncosis/necrosis: enzymatic digestion which may leak out of cell
Apoptosis: remain intact but may be released by apoptotic bodies
151
Compare adjacent inflammation in oncosis/necrosis to apoptosis.
Oncosis/necrosis: frequent
| Apoptosis: does not take place
152
Does oncosis/necrosis have a physiological or pathological role?
Invariably pathological
153
When is apoptosis physiological and when is it pathological?
Physiological to eliminate unwanted cells
| Pathological after some forms of cell damage, especially DNA damage
