Cell Injury Flashcards Preview

ESA 2- Mechanisms of Disease > Cell Injury > Flashcards

Flashcards in Cell Injury Deck (446):
1

What is pathology?

The study of suffering

2

What does pathology investigate?

The structural and functional changes in cells, tissues, and organs that are seen in disease. 
It is the study of disease and cellular malfunction

3

What are diseases the result of?

Intrinsic abnormalities or external factors, or both

4

What is an intrinsic abnormality?

Genetic

5

Give an example of an external factor?

Infections

6

What does diagnostic pathology involve?

Studying the structural and functional alterations in cells and tissues in order to arrive at a diagnosis

7

What results in the symptoms and signs of a disease?

The morphological changes in cells and tissues and their distribution within an organ

8

What does all disease start with?

Molecular or structural alterations in cells

9

When are cells able to maintain homeostasis?

When subjected to mild changes in environmental conditions

10

What happens when environmental changes are more severe?

Cells undergo physiological and morphological adaptations in an attempt to remain viable

11

How may cells react to injury?

They may increase or decrease their level of activity

12

What does wether cells increase or decrease their activity with injury depend on?

The nature and intensity of the injury

13

How may a cell increase its level of injury?

Hyperplasia

14

How may a cell decrease its level of activity?

Atrophy

15

What happens when cells reach their limits of adapative response?

They may show evidence of reversible injury, or become irreversibly injured and due

16

What does the degree of cell damage depend on?

Type, duration and severity of an injury, and the type of tissue thats involved

17

How was it discovered that cells are the basic unit of the body?

Through the microscope

18

Where does the ultimate abnormality lie in disease?

The cell

19

What can damage cells?

Hypoxia 
Physical agents 
Chemical agents and drugs 
Micro-organisms
Immune mechanisms 
Dietary insufficiency and deficiencies, and dietary excess 
Genetic abnormalities

20

What is hypoxia?

Oxygen deprivation

21

What does hypoxia result in?

Decreased aerobic oxidative respiration

22

How can energy production continue in hypoxia?

Through glycolytic energy production

23

What happens if hypoxia is persistent?

Cell adaptation, cell injury and cell death

24

What cell adaptation may be used in hypoxia?

Atrophy

25

How long can a cell tolerate hypoxia?

It varies 
Some neurones can only tolerate a few minutes
Dermal fibroblasts can tolerate a number of hours

26

What is ischaemia?

A loss of blood supply due to reduced arterial supply or reduced venous drainage

27

What can cause a reduced arterial supply of blood?

Obstruction of an artery
Hypotension

28

What does ischaemia cause?

A reduced supply of oxygen and metabolic structure

29

What is the result of ischaemia also causing a decreased supply of metabolic substrates?

It occurs more rapidly and is more severe than seen with hypoxia

30

What can the causes of hypoxia be classified as?

Hypoxaemic 
Anaemic
Histiocytic 
Ischaemic

31

What is meant by hypoxaemic?

The arterial content of oxygen is low

32

Why may hypoxamia occur?

Reduced inspired pO2 at altitude

33

What happens in anaemic hypoxia?

There is a decreased ability of haemoglobin to carry oxygen

34

What can cause anaemic hypoxia?

Anaemia
Carbon monoxide poisioning

35

What causes ischaemic hypoxia?

Interruption to blood supply

36

What causes histiocytic hypoxia?

Inability to utilise oxygen in cells due to disable oxidative phosphorylation enzymes

37

What can cause histiocytic hypoxia?

Cyanide poisioning

38

What physical agents could cause cell injury?

Direct trauma 
Extremes of temperature (burns and severe cold)
Sudden changes in atmospheric pressure 
Electric currents 
Radiation

39

What chemical agents and drugs can cause hypoxia?

Glucose and salt in hypertonic solutions 
Oxygen in high concentrations 
Poisons 
Insecticides 
Herbicides 
Asbestos 
Alcohol
Illicit drugs 
Therapeutic drugs

40

What microorganisms can cause hypoxia?

Viruses
Bacteria 
Fungi 
Other parasites

41

How do immune mechanisms cause cell injury?

Hypersensitivity reactions 
Autoimmune reactions

42

What happens in hypersensitivity reactions?

The host tissue is injured secondary to an overly vigorous immune reaction

43

Give an example of a hypersensitivity reaction

Urticaria (hives)

44

What happens in autoimmune reactions?

The immune system fails to distinguish self from non-self

45

Give an example of an autoimmune reaction

Grave’s disease of the thyroid

46

Give an example of a genetic abnormality that can cause cell injury

Inborn errors of metabolism

47

What are the principal targets of cell injury?

Cell membranes 
Nucleus 
Proteins 
Mitochondria

48

What is the cell membrane important for?

The plasma membrane plays an essential role in homeostasis 
The organellar membrane compartmentalise organelles

49

Why is the compartmentalisation of organelles by membranes important?

Because they contain potent enzymes that can themselves cause damage

50

What does the nucleus contain?

The genetic material of the cell

51

Why are proteins important in the cell?

Structural proteins form the cytoskeleton 
Enzymes involved in the metabolic processes of the cell

52

What happens in the mitochondria?

Oxidative phosphorylation and production of ATP

53

What is the most common cause of cell injury?

Hypoxia and ischaemia

54

How is hypoxia similar to other types of other cell injury?

Many of the changes seen in hypoxia also occur in other causes (although the sequence of events may be different)

55

What happens as the cell becomes deprived of oxygen?

There is decreased production of ATP by oxidative phosphorylation in the mitochondria, and so the levels of ATP in the cell

56

At what level of ATP depletion do vital cellular functions become compromised?

When levels drop to less than 5-10% of normal concentrations

57

Why does a drop in cellular ATP levels cause vital cellular functions to become compromised?

There is a loss of activity of the Na/K plasma membrane pump. 
With the lack of oxygen, the cell switches to the glycolitic pathway of energy production
Ribosomes detach from the endoplasmic reticulum (as energy is required to keep them attached)

58

What is the result of the loss of activity of the Na/K plasma membrane pump?

Intracellular concentration of Na rises, and so water enters the cell. This means the cell and its organelles swell up. 
Ca also enters the cell, and this results in damage to cell components

59

What is the process of cell swelling called?

Oncosis

60

What is the problem with the cell switching to the glycolytic pathway of ATP production?

It results in an accumulation of lactic acid, which reduces the pH of the cell

61

What does the lowering of pH in the cell result in?

Affects the activity of many enzymes within the cell 
Chromatin clumping is seen

62

What happens when ribosomes detach form the endoplasmic reticulum?

Protein synthesis is disrupted

63

What is the result of the disruption of protein synthesis due to detachment of ribosomes?

Can be intracellular accumulations of substances such as fat and denatured proteins

64

What happens at some point when a cell is injured?

The injury becomes irreversible and the cell will eventually die

65

How do most cells die in hypoxia?

Oncosis

66

What will happen when a cell has been irreversibly injured?

The tissue will eventually appear necrotic

67

What actually kills the cell in hypoxia?

It is not clear exactly what kills the cell, but a key event is the development of profound disturbances in membranes integrity and therefore an increase in membrane permeability followed by a massive influx of Ca into the cytoplasm

68

What level is cytosolic free Ca usually?

Usually at a very low level, as its kept within mitochondria and the endoplasmic reticulum

69

What happens to Ca when cells are severely damaged?

It enters the cell from outside, across the damaged plasma membrane, and it released from stores in the endoplasmic reticulum and mitochondria

70

Why is the influx of cytosolic Ca damaging?

Because calcium ions are biologically very active and high concentrations within the cytoplasm results in the activation of an array of potent enzymes such as ATPases, phospholipases, proteases and endonucleases

71

What is the problem with increased action of ATPases?

Decreases the concentrations of ATP further

72

What is the problem with increased action of phospholipases?

Causes further membrane damage

73

What is the problem with increased action of proteases?

Breaks down membrane and cytoskeletal proteins

74

What is the problem with increased action of endonucleases?

Damages DNA, causing nuclear chromatin to clump

75

What happens when lysosomal membranes are damaged?

Their enzymes leak into the cytoplasm further damaging the cell

76

What happens whilst Ca enters cells whose membranes are irreversibly damaged?

Intracellular substances leak out into the circulation

77

How can intracellular substances that have leaked into the circulation be detected?

In blood samples

78

What does the type of substance detected in blood samples indicate?

Where the cellular damage is occurring

79

Give a summary of hypoxic cell injury

- Cell is deprived of oxygen 
- Mitochondrial ATP production stops 
- ATP-driven membrane ionic pump runs down 
- Sodium and water seep into the cell 
- The cell swells, and the plasma membrane is stretched
- Glycolysis enables the cell to limp on for a while 
- The cell initiates a heat-shock (stress) response
- The pH drops as the cells produce energy by glycolysis and lactic acid accumulates 
- Calcium enters the cell
- Calcium activates phosholipases, proteases, ATPase and endonucleases 
- The ER and other organelles swell 
- Enzymes leak out of lysosomes and these enzymes attack cytoplasmic components 
- All cell membranes are damaged and start to show blebbing 
- At some point the cell dies, possibly killed by the burst of a bleb

80

What happens if blood flow is returned to a tissue that has been subject to ischaemia, but isn’t yet necrotic?

Sometimes the tissue injury sustained is worse than if blood flow was not restored

81

What is it called when a cell is injured because blood flow is returned after ischaemia?

Ischaemia-reperfusion injury

82

What may ischaemia reperfusion injury be due to?

Increased production of oxygen free radicals with reoxygenation 
Increased number of neutrophils following reinstatement of blood supply, resulting in more inflammation and increased tissue injury 
Delivery of complement proteins and activation of the complement pathway

83

How do some chemicals act to injure the cell?

By combining with a cellular component

84

How does cyanide act?

It binds to mitochondrial cytochrome oxidase and blocks oxidative phosphorylation

85

What are free radicals?

A reactive oxygen species

86

What do free radicals have?

A single unpaired electron in an outer orbit

87

What is the problem with free radicals having a single unpaired electron?

It is an unstable configuration, and because of this free radicals react with other molecules, often producing more free radicals

88

When are free radicals particularly produced?

In chemical and radiation injury, ischaemia-reperfusion injury, cellular ageing, and at high oxygen concentrations

89

What do free radicals do to cells?

They attach lipids in cell membranes and cause lipid peroxidation 
They can damage proteins, carbohydrates, and nucleic acids.

90

How can free radicals damage proteins, carbohydrates and nucleic acids?

They can become bent out of shape, broken or cross linked

91

What are free radicals known to be?

Mutagenic

92

Are free radicals always pathological?

No- they are also involved in many physiological events

93

What produces free radicals for physiological purposes?

Leukocytes

94

What physiological events are free radicals involved in?

Killing bacteria 
Cell signalling

95

Which free radicals are of particular biological importance in cells?

OHº (hydroxyl)
O 2 -  (superoxide)
H 2 O 2 (hydrogen peroxide)

96

What is the most dangerous free radical?

Hydroxyl (OHº)

97

How can hydroxyl be formed?

Radiation can directly lyse water 
The Fenton and Haber-Weiss reactions

98

What is the Fenton reaction?

Fe 2+  + H 2 O 2 →  Fe 3+  + OH -  + OHº

99

What is the Haber-Weiss reaction?

O 2 - + H + + H 2 O 2  →  O 2 + H 2 O + OHº

100

What do the Haber-Weiss and Fenton reactions show to be important?

The removal of superoxide and hydrogen peroxide rapidly, so the more dangerous hydroxyl can’t be formed

101

Where is the Fenton reaction important?

In injury where bleeding occurs

102

Why is the Fenton reaction important in injury where injury occurs?

As when blood is around, iron is available for the production of free radicals

103

What does the body have to prevent injury caused by free radicals?

Defence systems

104

What is the bodys defence system against free radicals known as?

The anti-oxidant system

105

What happens if there is an imbalance between free radical production and free radical scavenging?

Free radicals build up and the cell or tissue is said to be in oxidative stress

106

What does oxidative stress cause?

Cell injury

107

What does the antioxidant system consist of?

Enzymes 
Free radical scavengers 
Storage proteins

108

What enzymes are involved in the antioxidant system?

Superoxide dismutase (SOD) 
Catalases 
Peroxidases

109

What does SOD do?

Catalyses the reaction O 2 - →  H 2 O 2

110

What is the advantage of SOD?

H 2 O 2 is significantly less toxic to cells

111

What do catalases and peroxidases do?

Complete the process of free radical removal? 
H 2 O 2  →  O 2  + H 2 O

112

What do free radical scavengers do?

Neutralise free radicals

113

Give 4 examples of free radical scavengers

Vitamins A, C and E 
Glutathione

114

What do storage proteins do?

Sequester transition metals in the extracellular matrix

115

Give two examples of storage proteins?

Transferrin and ceruloplasmin

116

What do transferrin and cerulopasmin do?

Sequester iron and copper (which catalyse the formation of free radicals)

117

What are heat shock proteins (HSPs)?

Stress proteins, unfoldases, chaperonins

118

What is the heat shock response triggered by?

Any form of injury (not justhead)

119

Are HSPs found in unstressed cells?

Yes, in lower concentrations

120

What cells show the heat shock response?

All cells from any organism, animal or plant

121

What do cells do when submitted to stress?

Turn down their usual protein synthesis and turn up the synthesis of HSPs

122

What is shown by all organisms using HSPs?

They must play a key role in survival

123

Are HSPs secreted?

No, they remain within the cell

124

What are HSPs concerted with?

Protein repair (analogous to DNA repair)

125

When are HSPs important?

When the folding step in protein synthesis does astray, or when proteins become denatured during cell injury

126

What do HSPs recognise?

Proteins that are incorrectly folded

127

How do HSPs repair proteins?

By ensuring that they are refolded correctly

128

What happens if refolding of a damaged protein is not possible?

It is destroyed

129

Why are HSPs important in cellular injury?

As the heat shock response plays a key role in maintaining protein viability and thus maximising cell survival

130

Give an example of a HSP

Ubiquitin

131

What is the problem with determining when a cell died?

It is hard to identify cells that died minutes ago to hours ago, and hard to distinguish reversible injury from cell death. Histologic sections do not give us the time of cell death, and there is also little to be seen by the naked eye around the time of cell death

132

How is the diagnosis of cell death probably best made?

On functional rather than morphological criteria, e.g. increased permeability of the cell membrane

133

How can permeability of the cell membrane be assessed?

By the dye exclusion technique, where dye is put into the cells’ medium

134

What do the results of the dye exclusion technique mean?

It the dye doesn’t enter the cell, it’s alive.
If the cell soaks it up, they are dead

135

What 3 main alternations can be seen in cell death with swelling?

Cytoplasmic changes 
Nuclear changes 
Abnormal intracellular accumulations

136

What cytoplasmic changes are seen in cell death with swelling?

There is reduced pink staining of the cytoplasm.
This may be followed by increased pink staining.

137

Why is there reduced pink staining in cell death?

Accumulation of water

138

Is reduced pink staining a reversible change?

Yes

139

Why may there be a progression to increased pink staining?

Due to detachment and loss of ribosomes from the ER, and accumulation of denatured proteins

140

Is increased pink staining a reversible change?

No

141

What nuclear changes can be seen in cell injury?

Chromatin is subtly clumped 
May be follow be various combinations of pyknosis, karryohexis, and karryolysis of the nucleus

142

Is subtle clumping of chromatin reversible?

Yes

143

What is pyknosis?

Shrinkage

144

What is karryohexis?

Fragmentation

145

What is karryolysis?

Dissolution

146

What reversible changes have been detected in cellular injury by the electron microscope?

Swelling 
Cytoplasmic blebs 
Clumped chromatin 
Ribosome separation from the ER

147

What swells in reversible cell injury?

Both the cells and the organelles

148

Why is there swelling in cell injury?

Due to the Na/K pump failure

149

What are cytoplasmic blebs symptomatic of?

Cell swelling

150

What causes clumped chromatin?

Reduced pH

151

Why is there ribosome separation from the ER?

Due to failure of energy-dependant process maintaining ribosomes in the correct location

152

What irreversible changes have been detected in cellular injury by the electron microscope?

Increased cell swelling
Nuclear changes- pyknosis, karyolysis, karyorrhexis 
Swelling and rupture of lysosomes 
Membrane defects 
Appearance of myelin figures 
Lysis of the endoplasmic reticulum 
Amorphous densities in swollen mitochondria

153

What does the swelling and rupture of lysosomes reflect?

Membrane damage

154

What are myelin figures?

Damaged membranes

155

What is lysis of the endoplasmic reticulum due to?

Membrane defects

156

In summary, what is cell swelling due to?

The failure of ionic pumps in the cell membrane through lack of energy supply

157

What is implied by cell swelling being due to failure of ionic pumps?

As well as occurring with hypoxia, oncosis would also be expected to occur with poisons that interfere with a cell’s energy metabolism or the integrity of the cell membrane

158

What happens as cells undergo oncosis?

They (and the tissue as a whole) increases in weight

159

What is oncosis?

Cell death with swelling
The spectrum of changes that occur prior to death in cells injured by hypoxia and some other agents

160

What is apoptosis?

Cell death with shrinkage

161

What is apoptosis induced by?

A regulated intracellular program where the cell activates enzymes that degrade its own nuclear DNA and proteins

162

What is necrosis?

In a living organism, the morphological changes that occur after a cell has been dead for some time, e.g. 4-24 hours

163

What are the changes in appearance seen in necrosis due to?

Largely the progressive degradative action of enzymes on the lethally injured cell

164

What does necrosis describe?

Morphological changes, it is NOT a type of cell death

165

What happens to the nucleus in oncosis?

It fades away by karyolysis

166

What happens to the nucleus in apoptosis?

It becomes very dense and breaks up (karyorrhexis)

167

When is necrosis seen?

When there is damage to the cell membranes (plasma and organelle), and lysosomal enzymes are released into the cytoplasm and digest the cell.

168

What is the result of lysosomal enzymes digesting the cell?

Cell contents leaks out, and inflammation is often seen

169

How long do necrotic changes take to develop?

Happens over a number of hours, e.g. it takes 4-12 hours until microscopic changes are seen after a myocardial infarction

170

What eventually happens to necrotic tissue?

It is removed by enzymatic degradation and phagocytosis by white cells

171

What may happen if some necrotic tissue remains?

It may calcify

172

What is the calcification of necrotic tissue called?

Dystrophic calcification

173

What are the two main types of necrosis?

Coagulative and liquifactive

174

What is liquifactive necrosis also known as?

Colliquitive

175

What can happen to cells proteins as cells are dying?

They can either undergo denaturation or autolysis

176

What tends to happen to denatured proteins?

They coagulate

177

What happens when proteins undergo autolysis?

They undergo dissolution by the cells own enzymes

178

When do protein lysis and coagulation start to occur?

When the cell is still alive

179

What determines which of the two main patterns of necrosis are seen?

The balance between the two key processes- coagulation and autolysis

180

What happens when protein denaturation is the dominant feature?

The proteins tend to ‘clump’, leading to solidity of the dead cells and consequently of the dead tissue. The net result is coagulative necrosis

181

What happens when release of active enzymes, particularly proteases, is the dominant feature?

The dead cells and consequently the dead tissue tends to liquefy, leading to liquifactive necrosis

182

What is seen in most solid organs when the cause of death is ischaemia?

Coagulative necrosis

183

What happens when cell death is associated with large numbers of neutrophils?

Their released proteolytic enzymes lead to liquifactive necrosis

184

Give an example of when necrotic changes might be harder to classify?

The pancreas typically shows coagulative necrosis, but being rich in proteolytic enzymes such as trypsin, the changes are modified to a certain extend

185

What are the two other types of necrosis that only occur under a limited set of circumstances?

Caseous and fat necrosis

186

Are gangrene and infarcts types of necrosis?

No

187

What dominates in coagulative necrosis?

Denaturation of proteins over release of active proteases

188

What consistency is the dead tissue in coagulative necrosis?

Solid

189

How does coagulative necrotic tissue appear to the naked eye?

White

190

What happens to the cells proteins in coagulative necrosis?

They uncoil and become less soluble

191

What happens histologically in coagulative necrosis?

The cellular architecture is somewhat preserved, creating a ‘ghost outline’ of the cells

192

When will the typical changes of coagulative necrosis be seen?

In the first few days

193

What happens to the appearance of coagulative necrosis after the first few days?

The appearances are modified by the fact that the dead tissues incite an inflammatory reaction with consequent infiltration by phagocytes

194

What happens in liquifactive necrosis?

Active enzymatic degradation is substantially greater than denaturation, and this leads to enzymatic digestion (liquefaction) of tissues

195

When is liquifactive necrosis seen?

In massive neutrophil infiltration

196

Give an example of necrosis where there would be massive neutrophil infiltration?

In abscesses

197

Why is their liquifactive necrosis when there is massive neutrophil infiltration?

Because neutrophils release proteases

198

What kind of infections is liquifactive necrosis seen in?

Bacterial

199

What organ is liquifactive necrosis seen in?

Brain

200

Why is liquifactive necrosis seen in the brain?

Because this is a fragile tissue without support from a robust collagenous matrix

201

What happens to the tissue in liquifactive necrosis?

If becomes a viscous mass, and if there is acute inflammation, pus is present

202

What is caseous necrosis characterised by?

Its amorphous debris

203

What is caseous necrosis particularly associated with?

Infections, especially TB 
Granulomatous inflammation

204

What is fat necrosis seen?

When there is destruction of adipose tissue

205

When is fat necrosis most typically seen?

As a consequence of acute pancreatitis

206

Why is fat necrosis seen in acute pancreatitis?

As during inflammation of the pancreas there is a release of lipases from the injured pancreatic acinar cells. These lipases act on fatty tissues of the pancreas and on fat elsewhere in the abdominal cavity, causing fat necrosis

207

What does fat necrosis cause?

Release of free fatty acids, which can react with calcium to form chalky deposits (calcium soaps) in fatty tissue

208

How can calcium soaps be detected?

They can be seen on x-rays and with the naked eye at surgery and autopsy

209

What can fat necrosis occur after?

Direct trauma to a fatty tissue, especially breast tissue

210

Why is fat necrosis in the breast significant?

After it heals it leave an irregular scar that can mimic a nodule of breast cancer

211

What is gangrene?

A clinical term used to describe necrosis that is visible to the naked eye 
NOT a type of necrosis

212

How can gangrene be further classified?

Into dry and wet gangrene

213

What does classification of gangrene depend on?

Wether the necrosis is modified by exposure to air resulting in drying (dry gangrene), or by an infection with a mixed bacterial culture (wet gangrene)

214

Can bacteria grow in dry tissue?

No

215

What is dry gangrene responsible for?

The dry, crisp appearance of the gangrenous umbilical cord stump after birth and gangrenous toes

216

What is the underlying process in dry gangrene?

Coagulative necrosis

217

What is the underlying process in wet gangrene?

Liquifactive necrosis

218

Why is wet gangrene, or infected necrosis, very serious?

As bacteria can easily get into the blood stream and it can result in septicaemia

219

What is gas gangrene?

Wet gangrene where the tissue has become infected with anaerobic bacteria that produce visible and palpable bubbles of gas within tissues

220

What is a typical scenario for gas gangrene?

The crushing of a limb in a motorcycle accident

221

How does gas gangrene arise with the crushing of a limb in a motorcycle accident?

The injured tissue loses it blood supply and becomes necrotic resulting in the appearance of gangrene.  The tissue is colonised by anaerobic bacteria picked up from the soil and gas gangrene develops.

222

Where is gangrene most commonly seen in clinical practice?

Ischaemic limbs

223

Can gangrenous tissue be salvaged?

No, it is dead

224

What does infarction refer to?

A cause of necrosis, namely ischaemia

225

What is an infarct?

An area of tissue death caused by obstruction of a tissues blood supply

226

What can infarction result in?

Gangrene

227

What are most infarctions due to?

Thrombosis or embolism

228

What can infarctions occasionally be due to?

External compression of a vessel or by twisting of vessels

229

What may externally compress a vessel?

A tumour, or within a hernia

230

Give two examples of where vessels may be twisted?

Testicular torsion 
Volvulus of the bowel

231

What type of necrosis is found in infarcted tissue?

Can be either

232

How can infarcts be described?

By their colour- white or red

233

What does the colour of an infarct indicate?

How much haemorrhage there is into the infarct

234

Where does a white (anaemic) infarct occur?

In ‘solid’ organs- those with good stromal support- after occlusion of an ‘end’ artery

235

What is an end artery?

Any artery that is the sole source of arterial blood to a segment of an organ

236

What is the result of the solid nature of the tissue in a white infarct?

It limits the amount of haemorrhage that can occur ito the infarct from adjacent capillaries

237

What happens to the tissue supplied by the end artery in a white infarct?

It dies, and appears pale/white because of the lack of blood in the tissue

238

Where do white infarcts occur?

In the heart, spleen and kidneys

239

What shape are most white infarcts?

Wedge-shaped, with the occluded artery at the apex of the wedge

240

How do white infarcts appear histologically?

As coagulative necrosis

241

When does a red (heamorrhagic) infact occur?

When there is extensive haemorrhage into dead tissue

242

When may there be extensive haemorrhage into dead tissue?

In organs with a dual blood supply 
If numerous anastomoses are present within a tissue 
In loose tissue
Where there has been previous congestion 
Where there is raised venous pressure

243

Give an example of an organ with dual blood supply?

The lung

244

What happens when there is an occlusion of an artery in an organ with a dual blood supply?

Occlusion of the main arterial supply causes an infarct. The secondary arterial supply is insufficient to rescue the tissue, but does allow blood to enter the tissue, causing a red infarct

245

Where will there be numerous anastomoses?

Where the capillary beds of two separate arterial supplies merge

246

Give an example of an organ that has numerous anastomoses?

Intestines

247

Why does a red infarct occur when there are numerous anastomoses?

For the same reason as in organs with a dual blood supply

248

Give an example of an organ with loose tissue

The lung

249

Why do red infarcts occur in loose tissue?

There is poor stromal support for capillaries, and therefore there is more than usualy haemorrhage into the dead tissue

250

Give an example of where there may have been previous congestion?

In congestive cardiac failure

251

Why do you get red infarcts where there has been previous congestion?

There is more than the usual amount of blood in the necrotic tissue

252

Why does raised venous pressure cause red infarcts?

Increased pressure is transmitted to the capillary bed. As the tissue pressure increases, eventually there is reduced arterial filling pressure in the tissue, which causes ischaemia and subsequent necrosis. Because the tissue was engorged with blood, the resulting infarct is red

253

What are the consequences of an infarct?

Varying, ranging from none to death

254

What do the consequences of infarcts depend on?

Wether the tissue affected has an alternative blood supply 
How quickly the ischaemia occurred 
How vulnerable a tissue is to hypoxia 
The oxygen content of the blood

255

Give 2 examples of places with alternate blood supplies

Lung
Forearm

256

What may happen if the ischaemia occurred slowly?

There is more time for the development of additional perfusion pathways

257

What may happen if an infarct occurs in an anaemic patient?

It may have more serious consequences

258

What happens as membranes lose their integrity?

Many molecules leak out of the injured cells

259

What are the consequences of molecules leaking out of injured cells?

They can cause local irritation and local inflammation 
They may have general toxic effects on the body 
They may appear in high concentrations in the blood

260

Why is the appearance of molecules in high concentrations in the blood important?

Because they can be measured and thus aid in diagnosis

261

What are the principal molecules released from injured cells?

Potassium 
Enzymes 
Myoglobin

262

What concentrations is potassium normally found in?

High concentrations in cells compared to extracellular fluid

263

In terms of potassium, how can a dying cell be considered?

As a ‘potassium bomb’

264

What happens to the heart with high potassium concentrations?

It stops beating

265

How can high potassium concentrations reach the heart?

From a myocardial infarction, or massive necrosis elsewhere in the body, e.g. severe burns, tourniquet shock or tumour lysis syndrome

266

When does tourniquet shock occur?

After a tourniquet is removed having been in place for several hours

267

What is tumour lysis syndrome?

The paradoxical result of successful chemotherapy, when a large mass of tumour cells becomes acutely necrotic

268

What can enzymes indicate?

The organ involved, and the extent, timing and evolution of tissue damage

269

What enzymes are released from injured tissue first?

Those with the smallest molecular weight

270

What is myoglobin released from?

Dead myocardium and striated muscle

271

What happens if large amount of myoglobin are released by damaged striated muscle?

A condition called rhabdomyolosis occurs

272

When is rhabdomyolysis seen?

In severe burns or trauma, strenuous exercise, with potassium depletion and with alcohol and drug abuse

273

What can happen to myoglobin released from striated muscle?

It can plug the renal tubules, resulting in renal failure

274

What is apoptosis?

The death of a single cell (or small cluster of cells) due to activation of an internally controlled suicide program

275

What can apoptosis be regarded a?

An equal and opposite force to mitosis

276

What is apoptosis characterised by?

It’s morphology, and by the type of DNA breakdown that occurs

277

What type of DNA breakdown occurs with apoptosis?

Characteristic, non-random, internucelosomal cleavage of DNA

278

How does the DNA breakdown in apoptosis differ from that in oncosis?

In oncosis, DNA is chopped into pieces of random length

279

When can apoptosis be a normal physiological process?

When cells are no longer needed, to maintain a steady state, during hormone-controlled involution and cytotoxic T cell killing of virus infected or neoplastic cells. 
It is also seem in embryogenesis

280

What can cell death by apoptosis impart?

Shape

281

What particular type of cell damage would result in apoptosis?

When damage affects the cells DNA

282

When may damage to a cells DNA be seen?

With some forms of toxic injury and in tumours

283

What does a cell due during apoptosis?

Activates enzymes that degrade its own nuclear DNA and proteins

284

What happens to the membrane during apoptosis?

Membrane integrity is maintained

285

Is apoptosis an active or passive process?

Active- requires energy

286

Are lysosomal enzymes involved in apoptosis?

No

287

How long does apoptosis take?

It is quick- cells are gone within a few hours

288

How do apoptotic cells appear under the light microscope?

Shrunken
Intensely eosinophilic
Chromatin condensation, pyknosis and karyorrhexis are seen

289

How many cells does apoptosis affect?

Single cells, or small clusters

290

What do apoptotic cells show under the electron microscope?

Budding (not blebbing), which progresses to fragmentation of membrane bound apoptotic bodies

291

What do the fragmented membrane bound apoptotic bodies contain?

Cytoplasm, organelles and often nuclear fragments

292

What happens to apoptotic bodies?

They are eventually removed by macrophage phagocytosis

293

Does apoptosis induce inflammation?

No, because no leakage of cell contents occurs

294

What are the key phases of apoptosis?

Initiation 
Execution 
Degradation/phagocytosis

295

What is apoptosis triggered by?

Two key mechanisms, intrinsic and extrinsic

296

What do both triggering mechanisms of apoptosis culminate in?

The activation of caspases

297

What are caspases?

Proteases that mediate the cellular effects of apoptosis

298

How do caspases act?

By cleaving proteins, breaking up the cytoskeleton and initiating degradation of DNA

299

What does intrinsic apoptosis have as a central player?

Mitochondria

300

Why is intrinsic apoptosis so named?

Because all the apoptotic machinery is within the cell

301

What triggers intrinsic apoptosis?

Various triggers, for example DNA damage or withdrawal of growth factors or hormones

302

What protein is important in intrinsic apoptosis?

p53

303

What do the triggers for intrinsic apoptosis lead to?

Increased mitochondrial permeability, resulting in the released of cytochrome c from the mitochondria

304

What happens once cytochrome c has been released from the mitochondria?

It interacts with APAF1 and caspase 9 to form an apoptosome that activates downstream caspases

305

What is extrinsic apoptosis cause by?

External ligands, such as TRIAL and Fas, that bind to ‘death receptors’

306

What does binding to death receptors lead to?

Casase activation, independently of mitochondria

307

What happens in the degradation phase of apoptosis?

The cell breaks down into membrane bound fragments called apoptotic bodies

308

What do apoptotic bodies do?

Express molecules on their surface that induce phagocytosis of the apoptotic bodies by either neighbouring cells or phagocytes

309

What are the important apoptotic molecules?

p53
Cytochrome c, APAF1, caspase 9 
Bcl-2
Death ligands
Death receptors 
Caspases

310

What does p53 do?

Mediates apoptosis in response to DNA damage

311

What do cytochrome c, APAF1 and caspase 9 collectively form?

The apoptosome

312

What does Bcl-2 do?

Prevents cytochrome c release from the mitochondria, and therefore inhibits apoptosis

313

Give an example of a death ligand

TRAIL

314

Give an example of a death receptor

TRAIL-R

315

What happens if a cell can’t metabolise something?

It will remain within the cell

316

When are abnormal cellular accumulations seen?

As metabolic processes become deranged

317

What do abnormal cellular accumulations often seen with?

Sublethal or chronic injury

318

What is the outcome of abnormal cellular accumulations?

They may be reversible, and they can be harmless or toxic

319

What can abnormal cellular accumulations be derived from?

The cells own metabolism 
The extracellular space
The outer environment

320

What are the main groups of intracellular accumulations?

Water and electrolytes 
Lipids
Proteins
Pigments 
Carbohydrates

321

How can fluid appear when accumulated in cells?

As discrete droplets, or diffuse waterlogging of the entire cell

322

What are discrete droplets of fluid in the cell called?

Vacuoles

323

What is the result of diffuse waterlogging of the entire cell?

Cell swelling

324

What is swelling due to diffuse waterlogging called?

Hydropic swelling

325

What is hydropic swelling due to?

Osmotic disturbance

326

What happens to cells in hydropic swelling?

They are enlarged, but not hypertrophic

327

When does hydropic swelling occur?

When energy supplies are cut off, e.g. with reduced blood supply, metabolic poisons, and sodium ions and water flood into cell

328

What does hydropic swelling indicate?

Severe cellular distress

329

What may hydropic swelling cause?

Further problems, e.g. in the brain where there is no room for expansion due to the skull

330

What happens as brain swelling occurs?

Blood vessels are squeezed and blood flow to the brain is reduced

331

What is steatosis?

The accumulation of triglycerides

332

Where is steatosis often seen?

In the liver

333

Why is steatosis often seen in the liver?

As this is the major organ of fat metabolism

334

What are common causes of liver steatosis?

Alcohol abuse
Diabetes mellitus 
Obesity 
Toxins, e.g. carbon tetrachloride

335

Does mild steatosis have an affect on cell function?

It doesn’t seem to 
It is clinically asymptomatic

336

Is milk steatosis reversible?

Yes, in about 10 days if the person stops drinking alcohol

337

How can steatosis be diagnosed in the liver?

With the naked eye, as the liver is golden yellow rather than the usual red.

338

What does advanced steatosis do?

Increases the size of the organ

339

What is advanced steatosis the first stage of?

Alcoholic liver disease

340

What is the problem with cholesterol?

It cannot be broken down in the body and is insoluble

341

How is cholesterol eliminated?

Only though the liver

342

How is excess cholesterol in the cells stored?

In membrane-bound droplets

343

Where does cholesterol accumulate?

Within smooth muscle cells and macrophages within atherosclerotic plaques

344

Why does cholesterol accumulate in atherosclerotic plaques?

Perhaps because the adjacent plasma contains mcuh cholesterol

345

How do macrophages containing cholesterol appear microscopically?

Have a foamy cytoplasm- therefore are called foam cells

346

Other than atherosclerotic plaques, where is cholesterol seen?

In macrophages within the skin and tendons of people with acquired and hereditary hyperlipidaemias

347

What do macrophages form in people with acquired and hereditary hyperlipidaemias?

Small masses called xanthomas

348

How are proteins seen in cytoplasm?

As eosinophilic droplets or aggregates in the cytoplasm

349

What is Mallory’s hyaline?

A damaged protein which is seen in hepatocytes in alcoholic liver disease

350

What is Mallory’s hyaline due to?

Accumulation of altered keratin filaments

351

What kind of disorder is α1-antitrypsin deficiency?

Genetics

352

What happens in α1-antitrypsin deficiency?

The liver produces a version of the protein α1-antitrypsin that is incorrectly folded, and so it cannot be packaged by the endoplasmic reticulum and accumulates within this organelle and is not secreted by the liver

353

What does the systemic deficiency of α1-antitrypsin mean?

Proteases within the lung can act unchecked

354

What do patients with α1-antitrypsin deficiency develop?

Emphysema as lung tissue is broken down

355

What are pigments?

Coloured substances

356

Give an example of a pigment that is a normal cellular constituent?

Melanin

357

Give an example of an exogenous pigment?

Soot (carbon)

358

What is soot?

An urban air pollutant

359

What happens once soot is inhaled?

It is phagocytosed by macrophages within lung tissue (alveolar macrophages)

360

How is soot seen in the body?

As blackened lung tissue or as blackened peribronchial lymph nodes

361

What is blackened lung tissue called?

Anthracosis

362

Why are the peribronchial lymph nodes blackened with soot inhalation?

Because they contain macrophages which have migrated from the lungs

363

How long are the tissues discoloured for in soot inhalation?

For life

364

What is the result of soot inhalation?

It is usually harmless, however if particularly high exposure occurs, e.g. in coal miners, the lungs can become fibrotic or emphysematous- this is called coal-works pneumoconiosis

365

Where is the accumulation of exogenous pigments intentional?

Tattooing

366

What happens in tattooing?

The pigments are pricked into the skin and phagocytosed by macrophages in the dermis, which remain their indefinitely

367

What happens to some of the pigments from tattooing?

They will reach the draining lymph nodes and remain their (as the lymph nodes act as a filter)

368

Give 3 examples of endogenous pigments

Lipofuscin 
Haemosiderin 
Bilirubin

369

What is lipofuscin known as?

Age pigment, or wear and tear pigment

370

What colour is lipofuscin?

Brown

371

Where is lipofuscin found?

In ageing cells

372

Does lipofuscin cause injury to the cells?

No

373

What is lipofuscin a sign of?

Previous free radical injury and lipid peroxidation

374

What does lipofuscin consist of?

A polymer of oxidised, indigestible, brownish, intracellular lipids

375

How does lipofuscin appear under the microscope?

As yellow-brown grains within the cytoplasm

376

What cells is lipofuscin found it?

Long lived cells, e.g. neurones, myocardium, hepatocytes

377

What is haemosiderin?

An iron storage molecule

378

What is haemosiderin derived from?

Haemoglobin

379

What colour is haemosiderin?

Yellow/brown

380

When does haemosiderin form?

When there is a systemic or local excess of iron

381

What is a common example of iron overload?

Haemorrhage into tissues including the skin subcutaneous tissues, i.e. a bruise

382

What happens if there is a systemic overload of iron?

Haemosiderin is deposited in many organs

383

What is the deposition of haemosiderin into many organs called?

Haemosiderosis

384

Where is haemosiderosis seen?

In conditions such haemolytic anaemias, blood transfusions and hereditary haemochromatosis

385

What is hereditary haemochromatosis?

A genetically inherited disorder which results in increased intestinal absorption of dietary ion

386

Where is iron deposited in haemochromatosis?

Skin, liver, pancreas, heart and endocrine organs

387

What is haemochromatosis associated with?

Scarring in the liver (cirrhosis) and pancreas

388

What are the symptoms of haemochromatosis?

Liver damage, heart dysfunction and multiple endocrine failures, especially of the pancreas

389

What is the treatment for haemochromatosis?

Repeated bleeding

390

What is bilirubin?

A bile pigment which is bright yellow

391

How is bilirubin produced?

Heme is broken down in biliverdin, which is broken down to bilirubin

392

What does bilirubin consist of?

A stock of porphyrin rings that have broken open and lost their iron

393

What happens once the porphyrin has been broken?

It can never be mended, and must be eliminated in the bile

394

What happens when bile flow is obstructed or overwhelmed?

Bilirubin levels in the blood rise, and jaundice results

395

Why might bile flow be obstructed or overwhelmed?

For example with impacted gallstones, in liver disease, or haemolytic anaemias

396

Where can bilirubin be formed?

Anywhere in the body, not just in the liver

397

Why can bilirubin be formed anywhere in the body?

Because all cells contain heme as cytochromes

398

Where is bilirubin deposited in tissues?

Either extracellularly or intracellularly (in macrophages)

399

What is the problem with bilirubin deposition?

It is very toxic

400

Where is bilirubin taken from the tissues?

To the liver

401

How is bilirubin taken to the liver?

By albumin

402

What happens to bilirubin in the liver?

It is conjugated with glucaronic acid and excreted into the bile

403

What is pathological calcification?

The abnormal deposition of calcium salts within tissues

404

What are the two roads to pathological calcification?

One local, dystrophic calcification 
One general, metastatic calcification

405

Which type of pathological calcification is more common?

Dystrophic

406

Where does dystrophic calcification occur?

In an area of dying tissue, in atherosclerotic plaques, in ageing or damaged heart valves, and in tuberculous lymph nodes

407

Is there any abnormality in calcium metabolism or serum calcium or potassium levels in dystrophic calcification?

No

408

What does a local change or disturbance in the tissue favour?

The nucleation of hydroxyapatite crystals

409

What can dystrophic calcification cause?

Organ dysfunction e.g. in atherosclerosis or calcified heart valves

410

Which valve never calcifies?

The pulmonary valve of the heart

411

Why does the pulmonary valve never calcify?

No one is sure. One theory is that the blood around the pulmonary valves is more acidic that that around the aortic valves, and the acidity prevents calcification

412

Where is the disturbance in metastatic calcification?

Body-wide

413

What happens in metastatic calcification?

Hydroxyapatite crystals are deposited in normal tissues throughout the body

414

When does metastatic calcification occur?

When there is hypercalcaemia secondary to disturbances in calcium metabolism

415

What is the effect of metastatic calcification?

It is usually asymptomatic, however it can be lethal

416

Can metastatic calcification regress?

Potentially, if the cause of the hypercalcaemia is corrected

417

What are the principal causes of hypercalcaemia?

Increased secretion of parathyroid hormone (PTH) resulting in bone resorption 
Destruction bone tissue

418

What is a primary cause of increased secretion of PTH?

Due to parathyroid hyperplasia or tumour

419

What is a secondary cause of increased secretion of PTH?

Due to renal failure and the retention of phosphate

420

What is an ectopic cause of increased secretion of PTH?

Secretion of PTH-related protein by malignant tumours, e.g. carcinoma of the lung

421

What can cause destruction of bone tissue?

Primary tumours of bone marrow 
Diffuse skeletal metastases 
Paget’s disease of bone 
Immobilisation

422

Give two examples of primary tumours of bone marrow

Leukaemia 
Multiple myeloma

423

What happens in Paget’s disease of bone?

Accelerated bone turnover occurs

424

Why does immobilisation of bone cause destruction of bone tissue?

It removes the stimulation to bone formation whilst resorption continues

425

What happens as cells age?

They accumulate damage to cellular constituents and DNA. 
They may also accumulate lipofuscin pigment and abnormally folded proteins. 
There is a decline in their ability to replicate

426

What is the decline in the ability of ageing cells to replicate called?

Replicative senescence

427

Can cells replicate indefinitely?

No- after a certain number of divisions they reach replicative senescene

428

What is replicative senescence related to?

The length of chromosomes

429

What are the end of chromosomes?

Telomeres

430

What happens with every replications?

The telomere is shortened

431

What happens when the telomeres reach a critical length?

The cell can no longer divide

432

Why can germ cells and stem cells continue to divide?

They contain an enzyme called telomerase, which maintains the original length of the telomeres

433

Pathologically, what cells contain telomerase?

Cancer cells, so they have the ability to replicate many times

434

What are the major effects of excessive alcohol intake on the liver?

Fatty change 
Acute alcoholic hepatitis 
Cirrhosis

435

How does excessive alcohol intake cause fatty change?

It affects fat metabolism within the liver, resulting in steatosis

436

What can fatty change in the liver cause?

Hepatomegaly

437

Is fatty change in the liver to due alcohol consumption reversible?

Yes

438

What are the symptoms of fatty change in the liver?

It is generally asymptomatic

439

Why does acute alcoholic hepatitis occur?

As alcohol and its metabolites are directly toxic, so a binge of alcohol can result in acute hepatitis

440

What is seen in acute alcoholic hepatitis?

Focal hepatocyte necrosis 
Formation of Mallory bodies 
A neutrophilic infiltrate

441

What are the symptoms of acute alcoholic hepatitis?

Fever
Liver tenderness
Jaundice

442

Is acute alcoholic hepatitis reversible?

Usually

443

How many alcoholics develop cirrhosis?

10-15%

444

What does cirrhosis result in?

Hard, shrunken liver

445

How does cirrhosis appear histologically?

As micro-nodules of regenerating hepatocytes, surrounded by bands of collagen

446

What is the long-term outcome of cirrhosis?

It is irreversible, serious and sometimes fatal