Mechanisms Of Disease

Question 0

What is hypoxaemic hypoxia?

Answer 0

Arterial content of oxygen is low (high altitude, secondary to lung disease)

Question 1

What are the 7 main causes of cell injury?

Answer 1

Hypoxia- oxygen deprivation
Toxins- glucose and salt in hypertonic solutions, high [CO2], poisons, asbestos, asbestos, alcohol, narcotic drugs, medicine, pollutants, insecticides, herbicides
Physical agents- direct trauma, extreme of temp, change in pressure, electrical currents
Immune mechanisms- immune system can damage cells: hypersensitivity reactions (host tissue damaged secondary to overlying vigorous immune reaction HIVES) and autoimmune reactions (immune system fails to distinguish self from no self GRAVES)
Microorganisms
Radiation
Dietary insufficiencies, deficiencies and excess

Question 2

What is anaemic hypoxia?

Answer 2

Decreased ability of Hb to carry oxygen (anaemia, CO poisoning)

Question 3

What is ischaemic hypoxia?

Answer 3

Interruption to blood supply (blockage of vessels, heart failure)

Question 4

What is histiocytic hypoxia?

Answer 4

Inability to utilise oxygen, in cells dues to disabled ox phos enzymes (cyanide poisoning)

Question 5

What reversible metabolic cell injury occurs as a result of hypoxia?

Answer 5

In mitochondria, there is less ox phos, less ATP=

• less sodium-potassium pump (dependent on ATP), influx of sodium followed by water influx of calcium, ONCOSIS
• increased anaerobic glycolysis, decreased pH (lactate build up), less glycogen, clumping of nuclear chromatin
• detachment of ribosomes from ER, less protein synthesis, increased lipid deposition

Question 6

What reversible structural cell injury occurs as a result of hypoxia?

Answer 6

Swelling
Chromatin clumping
Autophagy with lysosomes (normal functioning)
Ribosomes dispersal
Bless (little bumps on the membrane surface where cytoskeleton has detached)

Question 7

What irreversible metabolic cell injury occurs as a result of hypoxia?

Answer 7

Massive accumulation of cytosolic calcium (biologically very active)
Activates enzymes in the cytoplasm
- endonucleases (breakdown DNA)
- ATPase (breakdown ATP)
- Phospholipases (breakdown membrane)
- Proteases (breakdown membrane and cytoskeleton of proteins)

Question 8

What irreversible structural cell injury occurs as a result of hypoxia?

Answer 8

Nuclear changes - pyknosis (shrinkage), karyorrhexis (fragmentation), karyolysis (dissolution)
Lysosomal rupturing (out flux of harmful enzymes)
Membrane defects (appearance of myelin figures- damaged membrane)
ER lysis due to phospholipases and professes
Amorphous densities in swollen mitochondria

Question 9

What are the two main types of cell death?

Answer 9

Oncosis/ Necrosis

Apoptosis

Question 10

What is Oncosis?

Answer 10

Spectrum of changes that occur in injured cells prior to death
Swelling of the cell
Contiguous groups of cells

Question 11

What is necrosis?

Answer 11

(What we see)
Morphological changes that occur after a cell has been dead some time in a living organism, largely due to the progressive degradation of enzymes on a lethally injured cell
With oncosis

Question 12

What are the two main types of necrosis and the two not so common types of necrosis?

Answer 12

Coagulative and liquefactive necrosis

Fat and caseous necrosis

Question 13

What is coagulative necrosis?

Answer 13

More protein denaturation than release of protease enzymes
Cellular architecture is preserved - ghost outline
Solid consistency of dead tissue
Followed by acute inflammatory reaction
Tends to be due to ischaemia (=infarcts) and hypoxia
Heart, spleen and liver

Question 14

What is liquefactive necrosis?

Answer 14

More protease enzyme release than protein denaturation
Tissue is lysed and disappears
Tends to be due to infection
Brain (even with no infection- in this case due to ischaemia = infarcts)

Question 15

What is gangrene?

Answer 15

Necrosis visible to the naked eye

Question 16

What type of gangrene forms as a result of coagulative necrosis?

Answer 16

Dry gangrene (umbilical cord)

Question 17

What type of gangrene forms as a result of liquefactive necrosis?

Answer 17

Wet gangrene - usually due to infection

Question 18

Where is gangrene most like to appear the body?

Answer 18

In ischaemic limbs - legs

It is dead and so cannot be salvaged

Question 19

What is an infarct?

Answer 19

Area of necrosis due to ischaemia
(coagulative- heart, liver and spleen/ liquefactive- brain)
Can be white and red

Question 20

What is white infarct and its causes?

Answer 20

Area of no blood

Obstruction of end artery (heart, kidney, spleen)

Question 21

What is a red infarct and its causes?

Answer 21

Area full of blood
In organs with dual blood supplies, blockage of vein (exceeding arterial pressure), loose tissue ( haemorrhage from surrounding tissue), reperfusion (white–>red), collateral circulation (lots of anastomising blood vessels)
Bowel

Question 22

What is an infarction?

Answer 22

Process of ischaemic necrosis

Question 23

What is infarction caused by?

Answer 23

Thrombosis
Embolism
External compression of vein
Twisting of vessels

Question 24

What is apoptosis?

Answer 24

Cell death with shrinkage Induced by a regulated intracellular program where a cell activates enzymes that degrade its own DNA and proteins Membrane integrity is maintained Cells activate enzymes that deactivate its own DNA and proteins Active process - requires energy Single cells

Question 25

When does apoptosis occur?

Answer 25

When cells which are no longer needed are removed to remain in a steady state During hormone controlled involution Cytotoxic T cell killing of virus infected or neoplastic cells Embryogenesis When cells are damages and there is DNA damage

Question 26

What is caseous necrosis?

Answer 26

``` Amorphous (structureless) debris (no ghost outline) Particularly associated with TB Granulomatous inflammation (chronic) ```

Question 27

What is fat necrosis?

Answer 27

Destruction of adipose tissue Seen as a consequence of acute pancreatitis - release of lipase from acinar cells- acts on fatty tissue of pancreas and on fat elsewhere in abdominal cavity - fat necrosis causes release of free fatty acids which react with calcium to form chalky deposits (calcium soaps)- can be seen on X rays or with the naked eye at surgery/ autopsy

Question 28

What are the two initiation and execution processes of apoptosis?

Answer 28

Intrinsic | Extrinsic

Question 29

Describe intrinsic initiation and execution of apoptosis

Answer 29

Mitochondrial (apoptotic machinery within cell) Various triggers- DNA damage, withdrawal of hormones or growth factors (p53 important) Increased permeability of membrane Release of cytochrome c from mitochondria Cytochrome c interacts with APAF1 and caspase 9 to for, an apoptosome Activates downstream caspases

Question 30

Describe the extrinsic initiation and execution process of apoptosis

Answer 30

Rector mediated Caused by external ligands (TRAIL and Fas) Bind to death receptors (TRAIL R) Activates caspases (independently of mitochondria)

Question 31

Describe the degradation/ phagocytosis stage of apoptosis

Answer 31

Cell membrane breaks into membrane bound fragments by caspase action - APOPTOTIC BODIES Apoptotic bodies express proteins on their surface that induces phagocytosis by neighbouring cell or phagocytes

Question 32

Review free radicals and how they can cause cell damage

Answer 32

Free radicals are reactive oxygen species. They have a single unpaired electron in an outer orbit. This is an unstable configuration and because of this free radicals react with other molecules, often producing further free radicals. Free radicals are particularly produced in chemical and radiation injury, ischaemia-reperfusion injury, cellular aging, and at high oxygen concentrations. Free radicals attack lipids in cell membranes and cause lipid peroxidation. They can also damage proteins and nucleic acids. They are also known to be mutagenic. However they also have important roles in the body as they are produced by leucocytes and used for bacteria killing. They are also used in cell signalling. Three free radicals are of particular biological significance in cells: OH• (hydroxyl) (the most dangerous), 02- (superoxide) and H202 (hydrogen peroxide). OH• can be formed in a number of ways:  Radiation can directly lyse water → OH•  The Fenton and Haber-Weiss reactions produce OH• (see below). Note that H202 and 02- are substrates for these reactions. This is one reason why it is important to rapidly remove 02- and H202 so that the more dangerous OH• cannot be generated. The body has defence systems to prevent injury caused by free radicals. These are known as the anti-oxidant system. If there is an imbalance between free radical production and free radical scavenging and free radicals build up the cell or tissue is said to be in oxidative stress. This causes cell injury. The anti-oxidant system consists of:  Enzymes: o Superoxide dismutase (SOD) catalyses the reaction O2- →H202. H2O2 is significantly less toxic to cells. o Catalases and peroxidases complete the process of free radical removal: H202 → 02 + H20  Free radical scavengers that neutralise free radicals. Vitamins A, C and E and glutathione are free radical scavengers  In the extracellular matrix, storage proteins (e.g., transferrin and ceruloplasmin) sequester transition metals, e.g., iron and copper, which catalyse the formation of free radicals.

Question 33

Review alcohol metabolism and how it can cause cell damage

Answer 33

Chronic excessive alcohol intake can result in psychological and physical dependence on alcohol. Ethanol (the type of alcohol that we drink) is metabolised by alcohol dehydrogenase, the cytochrome p450 enzyme CYP2E1 and catalase to acetaldehyde. This in turn is metabolised by aldehyde dehydrogenase to acetic acid. There are lower concentrations of alcohol dehydrogenase in women and this means that they can have a higher blood alcohol concentration then men who have drunk the same amount of alcohol. Approximately 50% of oriental people have reduced activity of aldehyde dehydrogenase resulting in a build-up of acetaldehyde when they drink alcohol. This results in symptoms such as facial flushing. Metabolic tolerance to alcohol can occur due to induction of CYP2E1. This increases the rate of metabolism of ethanol and will also increase the rate of metabolism of other drugs that are metabolised by this enzyme. Excessive alcohol intake can affect many organs. Here we will consider its three major effects on the liver:  Fatty change – the toxicity of alcohol to the liver results in steatosis which can be so marked as to cause hepatomegaly. This happens acutely, is reversible and generally asymptomatic.  Acute alcoholic hepatitis – as alcohol and its metabolites are directly toxic, a binge of alcohol can result in acute hepatitis with focal hepatocyte necrosis, the formation of Mallory bodies and a neutrophilic infiltrate. It can give symptoms of fever, liver tenderness and jaundice. It is usually reversible.  Cirrhosis – this occurs in 10-15% of alcoholics. It results in a hard, shrunken liver and histologically appears as micronodules of regenerating hepatocytes surrounded by bands of collagen. It is irreversible and serious, sometimes fatal.

Question 34

Review paracetamol metabolism and overdose and how it can cause cell damage

Answer 34

Paracetamol is detoxified in the liver by sulphonation and glucuronidation, Small amounts are metabolised by cytochrome p450 oxidation (CYP 2E1) to a highly toxic metabolite (N-acetyl-p-benzoquinone imine (NAPQI)). NAPQI is detoxified by interaction with glutathione. If a large dose of paracetamol is ingested, glutathione is depleted and NAPQI accumulates. It binds with sulphydryl groups on liver cell membranes, eventually causing hepatocyte necrosis and liver failure. With a large paracetamol overdose massive liver necrosis occurs 3-5 days after the overdose. This can be fatal. Some people have lower reserves of glutathione and in them paracetamol overdose is more dangerous. Such people include:  Those who took alcohol with the paracetamol overdose.  Those who are alcohol dependent.  Malnourished people.  People on enzyme-inducing drugs, e.g., carbamazepine.  People who are HIV positive or who have AIDS. People who have taken an overdose of paracetamol can be given an antidote called N-acetylcysteine (NAC). This increases availability of hepatic glutathione. To decide whether NAC is required, from 4 hours after the overdose the serum concentration of paracetamol is measured. The prothrombin time (or the INR) measured 24 hours after the overdose is a guide to the severity of the liver damage in these patients.

Question 35

Review aspirin overdose and how it can cause cell damage

Answer 35

Aspirin (acetylsalicylic acid) is a drug which acetylates platelet cyclooxygenase and blocks platelets’ ability to make thromboxane A2, a substance which activates platelet aggregation. The major consequences of aspirin overdose are metabolic. Aspirin stimulates the respiratory centre which results in a respiratory alkalosis. Compensatory mechanisms result in a metabolic acidosis. A fall in serum pH indicates serious poisoning. Aspirin in overdose also interferes with carbohydrate, fat and protein metabolism and oxidative phosphorylation. This results in an increase in lactate, pyruvate and ketone bodies all of which contribute to acidosis. As platelet cyclooxygenase is inhibited there is decreased platelet aggregation and petechaie may be present. Aspirin in overdose can also cause acute erosive gastritis producing GI bleeding.

Question 36

What is acute inflammation?

Answer 36

Acute inflammation is the response of living tissue to injury, initiated to limit the tissue damage.

Question 37

What are the main causes of acute inflammation?

Answer 37

``` Causes of Acute Inflammation: - Microbial infections o E.g. Pyogenic Organisms - Hypersensitivity reactions (acute phase) - Physical agents - Chemicals - Tissue necrosis ```

Question 38

What are the macroscopic features of acute inflammation?

Answer 38

Calor – Heat Rubor – Erytherma (Redness) Tumor – Oedema (Swelling) Dolor – Pain and loss of function

Question 39

What are the main microscopic features of acute inflammation?

Answer 39

1. Vasodilation Small adjacent blood vessels dilate with increased blood flow. 2. Gaps form in endothelium Endothelial cells swell and retract; there is no longer a completed intact internal lining. 3. Exudation Vessels become leaky. Water, salts and small plasma proteins leak through. (Exudate) 4. Margination and Emigration Circulating neutrophils adhere to swollen endothelial cells. (Margination.) Neutrophils then migrate through the vessel basement membrane. (Emigration). 5. Macrophages and Lymphocytes Migrate in a similar way to Neutrophils.

Question 40

What are some of the chemical mediators of acute inflammation?

Answer 40

Vasodilation- histamine, prostaglandins, C3a and C5- Increase vascular permeability- histamine, prostaglandins, kinins Emigration of leukocytes- leukotrienes, IL 8, C5a

Question 41

Describe the initiation and the action of neutrophils

Answer 41

Stasis causes neutrophils to line up at the edge of the blood vessels along the endothelium = MARGINATION Neutrophils then roll along the endothelium sticking to it intermittently = ROLLING They can stick more avidly = ADHESION Followed by EMIGRATION (diapedesis) of neutrophils through the blood vessel wall (due to relaxation of inter endothelial cell junctions, digestion of vascular basement membrane and movements by chemo taxis) Chemo taxis- movement of neutrophils along concentration gradients of chemo attractants Neutrophils phagocytose microorganisms, by making contact, recognising and internalising them. Phagosomes are then fused with lysosomes to destroy the contents. An activated neutrophil may also release toxic metabolites and enzymes, causing damage to the host tissue.

Question 42

What are some local complications of acute inflammation?

Answer 42

``` Swelling - Blockage of tubes, e.g. bile duct, intestine Exudate - Compression, e.g. cardiac tamponade (fluid builds up in pericardial sac exerting pressure on the heart) - Serositis Loss of fluid - E.g. burns Pain and loss of function - Especially if prolonged ```

Question 43

What are some systemic complications of acute inflammation?

Answer 43

Acute Phase Response Decreased appetite, raised heart rate, altered sleep patterns and changes in plasma concentration of Acute Phase Proteins, such as C-Reactive Protein (CRP), Fibrinogen and a1-antitrypsin. The spread of micro-organisms and toxins can lead to Shock, a clinical syndrome of circulatory failure (See CVS Session 12) ``` Fever Endogenous pyrogens (substances that produce fever) IL-1, TNFa and prostaglandin are produced. ``` Leukocytosis IL-1 and TNFa produce an accelerated release from marrow. Macrophages, T-Lymphocytes produce colony-stimulating factors.

Question 44

What may happen after the development of acute inflammation? (Sequelae)

Answer 44

1. Complete resolution 2. Suppurations- pus and abscess formation 3. Organisation- formation of granulation tissue- a bit of chronic inflammation and fibrous repair 4. Progression of acute inflammation onto chronic inflammation 5. Death

Question 45

What is resolution?

Answer 45

Complete restoration of tissues to normal after an episode of acute inflammation All mediators of acute inflammation have short half-lives and may be inactivated by degradation, dilution in exudate or inhibition. Gradually all of the changes of acute inflammation reverse, and the vascular changes stop. Neutrophils no longer marginate, and the vessel permeability and calibre returns tot normal. Therefore, the exudate drains via the lymphatics, fibrin is degraded by plasmin/other proteases and the neutrophils die. Damaged tissue may then be able to regenerate, but if tissue architecture has been destroyed, complete resolution is not possible.

Question 46

What are skin blisters? (As an example of acute inflammation)

Answer 46

Skin Blister - Caused by heat, sunlight, chemicals - Pain and profuse exudate - Collection of fluid strips off overlying epithelium - Inflammatory cells relatively few, therefore exudate is clear - Resolution or scarring

Question 47

What is an abscess? (As an example of acute inflammation)

Answer 47

Abscess - Forms as a result of suppuration (pus formation) in acute inflammation - Solid Tissues - Inflammatory exudate forces tissue apart - Liquefactive necrosis in centre - May cause high pressure, therefore pain - May cause tissue damage and squash adjacent structures

Question 48

What is pericarditis? (As an example of acute inflammation)

Answer 48

Pericarditis - Inflammation of serous cavity - Pericardium becomes inflamed and increases pressure on the heart

Question 49

Lobar pneumoniae ? (As an example of acute inflammation)

Answer 49

Lobar Pneumonia · Causative microorganism: Streptococcus Pneumoniae (Pneumococcus) · Clinical course: worsening fever, prostration, hypoxaemia, over a few days, dry cough, breathlessness, can resolve completely if treated

Question 50

Bacterial meningitis? (As an example of acute inflammation)

Answer 50

· Bacterial Meningitis · Fluid accumulates in space between pia and arachnoid mater · Acute inflammation in meninges can cause vascular thrombosis and reduced cerebral perfusion

Question 51

What is chronic inflammation?

Answer 51

Chronic response to injury with associated FIBROSIS

Question 52

What are the main causes of chronic inflammation?

Answer 52

1. May ‘take over’ from acute inflammation o If damage is too severe to be resolved within a few days, take over from suppurative inflammation (pus forms abscess)- abscess has thick pyogenic membrane (granulation and fibrous tissue; rigid abscess cavity walls fail to come together after drainage- fibrous scar formation) 2. May arise de novo o Some autoimmune conditions (organ specific (hashimotos), non organ specific (RA) or contact hypersensitivity) o Some Chronic Infections (E.g. viral hepatitis) o Endogenous materials (necrotic adipose tissue and bone) o Exogenous materials ( silica, asbestos fibres) o Resistance of infective agent to phagocytosis and intracellular killing ( TB, leprosy) o Diseases with unknown causes (chronic IBS - ulcerative colitis) o Primary granulomatous disease (Crohns disease and sarcoidosis) 3. May develop alongside acute inflammation o In severe, persistent or repeated irritation o Chronic low-level irritation

Question 53

What are the main effects of chronic inflammation and what are some examples of diseases/conditions where these effects are apparent?

Answer 53

o Fibrosis- Gall bladder (chronic cholecystitis), chronic peptic ulcers, cirrhosis o Impaired function- Chronic Inflammatory Bowel Disease • Rarely, increased function, e.g. mucus secretion, thyrotoxicosis o Atrophy- Gastric mucosa, adrenal glands o Stimulation of immune response- Macrophage-Lymphocyte interactions o Granulomatous inflammation/ GRANULOMA- tuberculosis

Question 54

What is chronic cholecystitis? (As an example of chronic inflammation)

Answer 54

``` FIBROSIS caused by chronic inflammation Chronic inflammation of the gall bladder - damaged mucosa - blocked neck of gall duct - blocked cystic duct Gall stones cause repeated obstructions Thick fibrotic wall of gal, bladder Repeated attacks of acute inflammation leads to chronic inflammation ```

Question 55

What is gastric ulceration? (As an example of chronic inflammation)

Answer 55

FIBROSIS caused by chronic inflammation - acute gastritis (due to alcohol and drugs) = abdominal pain and reflux - chronic gastritis (due to helicobacter pyolori) Ulceration occurs because of the imbalance of acid production and mucosal defence

Question 56

What is Inflammatory bowel disease? (As an example of chronic inflammation)

Answer 56

IMPAIRED FUNCTION caused by chronic inflammation Idiopathic inflammatory disease affecting the large and small bowel Patients present with diarrhoea, rectal bleeding and other symptoms - Ulcerative colitis (superficial) --- colon, causes ulcers, diarrhoea, bleeding - Crohn's disease (transmural/ heterogenous/ not stereotyped) --- Small and large bowel, strictures = narrowing, fistulae = abnormal connection between two epithelium lined organs

Question 57

What is cirrhosis? (As an example of chronic inflammation)

Answer 57

IMPAIRED FUNCTION AND FIBROSIS caused by chronic inflammation Common causes: alcohol, infection with HPV/HCD, immunological, fatty liver disease (obesity and DM2), drugs and toxins Normal liver cells are replaced with nodules of hepatocytes Chronic information with fibrosis – formation of lots of bands of fibrous tissue Disorganisation of architecture, and attempted regeneration

Question 58

What is thyrotoxicosis? (As an example of chronic inflammation)

Answer 58

INCREASED FUNCTION caused by chronic inflammation | Graves' disease – autoimmune, stimulates TSH receptors, causes hyperthyroidism

Question 59

What is atrophic gastritis? (As an example of chronic inflammation)

Answer 59

ATROPHY caused by chronic inflammation Tightly packed cells in gastric mucosa normally produce enzymes, acid and mucus Auto antibodies destroy the parietal cells so that acid production stops Causing atrophy

Question 60

What is rheumatoid arthritis? (As an example of chronic inflammation)

Answer 60

STIMULATION OF IMMUNE RESPONSE caused by chronic inflammation Autoimmune disease Localised and systemic immune response Localised chronic information needs to joint destruction (synovial inflammation) Systemic immune response- can affect other organs (skin, subcutaneous tissue and lungs) and cause amyloidoses

Question 61

What are the 7 main types of cells involved in chronic inflammation?

Answer 61

``` Macrophages Lymphocytes Eosinophils Plasma cells Fibroblasts Myofibroblasts Giant cells ```

Question 62

How are macrophages involved in chronic inflammation?

Answer 62

- recruited due to adhesion molecules present on endothelial cells - Important in acute and chronic inflammation - derived from blood monocytes - Various levels of activation - Structure: lots of granular cytoplasm, large central nucleus - Functions o Phagocytosis and destruction of debris and bacteria; opsonisation o Processing and presentation of antigen to the immune system o Synthesis of cytokines, complement components, clotting factors and proteases o Control of other cells via cytokine release o Important in granuloma formation o Important in angiogenesis

Question 63

How are lymphocytes involved in chronic inflammation?

Answer 63

Lymphocytes - Sometimes called ‘chronic inflammatory cells’ - normal component of many tissues - Structure: large nuclei: little or no cytoplasm - Functions o Complex, mainly immunological o B Lymphocytes (Plasma Cells) differentiate to produce antibodies o T Lymphocytes involved in control (CD4+) and some cytotoxic (CD8+) functions

Question 64

How are eosinophils involved in chronic inflammation?

Answer 64

- Structure: bilobed nucleus (Mickey Mouse head) - Function: o Allergic reactions o Parasite infections o Some tumours

Question 65

How are fibroblasts/ myofibroblasts involved in chronic inflammation?

Answer 65

- Recruited my macrophages - Structure: spindle shaped - Function- make collagen-FIBROSIS; contract in repair/healing

Question 66

How are giant cells involved in chronic inflammation?

Answer 66

Giant cells are multinucleate cells made by the fusion of macrophages, through the process of frustrated phagocytosis (where organisms cannot be dealt with by macrophages) There are several types recognised: - Langhans - Tuberculosis (horseshoe arrangement of nuclei around periphery) - Foreign Body Type (distorted mish mash) - Touton - Fat Necrosis (smaller Langhans)

Question 67

What do macrophages look like?

Answer 67

Lots of granular cytoplasm | Large central nucleus

Question 68

What do you lymphocytes look like?

Answer 68

Large nucleus | Little/no cytoplasm

Question 69

What do Plasma cells look like?

Answer 69

Clockface nucleus/lumpy bumpy chromatin Abundant pink/blue cytoplasm filled with ER Pale halo around nucleus= Golgi apparatus

Question 70

What do Eosinophils look like?

Answer 70

Bilobed nucleus | Mickeys mouse head

Question 71

What do fibroblasts/Myofibroblasts look like?

Answer 71

Spindle-shaped

Question 72

What do Langhans giant cells look like?

Answer 72

Horseshoe arrangement of nuclei around periphery

Question 73

What do Touton giant cells look like?

Answer 73

Like Langhans but smaller

Question 74

What do foreign body giant cells look like?

Answer 74

Distorted mishmash

Question 75

Give examples of how proportions of each cell type may vary in different conditions

Answer 75

Morphology of most chronic inflammatory reactions is non-specific but proportions of each cell type may vary in different conditions Rheumatoid arthritis – mostly plasma cells Chronic gastritis – mostly lymphocytes Leishmaniasis (protozoan infection) - mostly macrophages Giant cell type may be a help to diagnosis

Question 76

What is granulomatous inflammation?

Answer 76

Chronic inflammation with granulomas

Question 77

What is a granuloma?

Answer 77

Mass of macrophages (epitheloid histiocytes- modified and immobile) and lymphocytes

Question 78

When do granulomas form?

Answer 78

Granulomas form when the immune system walls off something that it is unable to eliminate, for example bacteria, fungi and other foreign material. Granulomas arise with persistent, low-grade antigenic stimulation and hypersensitivity.

Question 79

What are the main causes of granulomatous inflammation?

Answer 79

- Mildly irritant foreign material - Infections o Mycobacteria: Tuberculosis, leprosy o Syphilis o Some fungi - Unknown causes o Sarcoid o Wegener’s Granulomatosis o Crohn’s disease

Question 80

What is Tuberculosis? (an example of chronic inflammation)

Answer 80

GRANULOMA/ granulomatous chronic inflammation Caused by mycobacteria, especially Mycobacterium tuberculosis which is difficult and slow to culture Contains wall lipid mycosides Produces no toxins or lytic enzymes Causes disease by persistent and induction of cell mediated immunity Lymphocytes, Macrophages, giant cells (Langhans), caseous necrosis Miliary TB equals many bugs Single organ TB equals few bugs

Question 81

What are some outcomes of tuberculosis?

Answer 81

1. Arrest, fibrosis, scarring 2. Erosion into bronchus (bronchopneumonia- severe acute inflammation process in living, TB in GIT- coughed up and swallowed from lungs) 3. Tuberculous empyema (collection of pus) 4. Erosion into blood stream

Question 82

What are some other examples of granulomatous infections?

Answer 82

Leprosy, syphilis,chronic fungal infections, cat scratch disease, xanthogranulomatous, pyelonephritis and Malakoplakia

Question 83

What are some examples of granulomatous diseases of unknown cause?

Answer 83

Sarcoidosis Crohn's disease Wegener's granulomatosis

Question 84

What is sarcoidosis? (an example of chronic inflammation of unknown cause)

Answer 84

Variable clinical manifestations/unknown cause Young adult women Non caseating granulomas, giant cells Involves lymph nodes, lungs

Question 85

What is Crohn's disease?

Answer 85

Regional enteritis: patchy full thickness inflammation thoughout the bowel

Question 86

What is regeneration?

Answer 86

The replacement of dead or damage cells by functional, differentiated cells

Question 87

Where do differentiated cells needed in regeneration derive from?

Answer 87

Stem cells

Question 88

What are stem cells?

Answer 88

Cells that have potentially limitless proliferation Daughter cells can either remain as a stem cell to maintain the stem cell pool or differentiate into a specialised cell type

Question 89

What are 3 examples of where stem cells are used?

Answer 89

Early life Internal repair system to repair lost or damage cells and tissues Therapeutic utility in degenerative disease

Question 90

What does Unipotent mean?

Answer 90

Cell can only produce one type of differentiated cell | For example, epithelia

Question 91

What does multipotent mean?

Answer 91

Cell can produce several different types of differentiated cell For example, haematopoetic cells

Question 92

What does totipotent mean?

Answer 92

Cell can produce any type of cell | For example, embryonic stem cells

Question 93

How does the propensity to regenerate vary between cell types?

Answer 93

Labile cells- e.g. Epithelia or haematopoeitic cells Normal state is active in cell division G1 to M to G1 Usually rapid proliferation (hallmark= mitotic figures) Stable cells- e.g. Hepatocytes, osteoblasts, fibroblasts, Resting state- G0 Speed of regeneration is variable Permanent cells- e.g. Neurones, cardiac myocytes Unable to divide- G0 Unable to regenerate

Question 94

What factors are thought to control regeneration?

Answer 94

-Growth factors- Promote proliferation in stem cell population Extracellular signals transduced into the cell Promote expression of genes controlling the cell cycle Proteins EGF, PDGF, FGF Hormones e.g. Oestrogen, testosterone, growth hormone Autocrine, paracrine, and endocrine signals from many cell types: inflammatory, mesenchymal cells -Contact between basement membranes and adjacent cells- Signalling through adhesion molecules Inhibits proliferation in intact tissue Contact inhibition Loss of contact promotes proliferation leading to a tumour These mechanisms are deranged in cancer

Question 95

What is fibrous repair?

Answer 95

The replacement of functional tissue by scar tissue

Question 96

What are three key components of fibrous repair?

Answer 96

Cell migration Angiogenesis Extracellular matrix

Question 97

How is cell migration involved in fibrous repair?

Answer 97

Migration of: - Inflammatory cells: Phagocytosis of debris – neutrophils and macrophages; mediators – lymphocytes and macrophages - Endothelial cells: Angiogenesis - Fibroblast/Myofibroblasts: Extracellular matrix proteins E.g. collagen; Wound contraction

Question 98

How is angiogenesis involved in fibrous repair?

Answer 98

Development of the blood supply is vital to wound healing – provides access to the wound for inflammatory cells and fibroblast; delivery of oxygen and other nutrients Endothelial proliferation induced by pro angiogenic growth factors such as VEGF Pre-existing blood vessels sprout new vessels Mechanisms are exploited by malignant cells CANCER

Question 99

What is the process of angiogenesis?

Answer 99

Endothelial proteolysis of basement membrane Migration of endothelial cells by chemotaxis Endothelial proliferation Endothelial maturation and tubular remodelling Recruitment of periendothelial cells

Question 100

How is the extracellular matrix involved in cellular repair?

Answer 100

It facilitates cell migration and contains collagen important in fibrous repair

Question 101

What are the functions of the extracellular matrix?

Answer 101

``` Supports and anchors cell Separates tissue compartments (e.g. Basement membrane) Sequesters growth factors Allows communication between cells Facilitates cell migration ```

Question 102

What does the extracellular matrix in fibrous repair contain?

Answer 102

Collagen Matrix glycoproteins Proteoglycans Elastin

Question 103

What is collagen?

Answer 103

The most abundant protein in animals Provide extracellular framework Composed of triple helices of various polypeptide alpha chains The fibrillar collagen for type IV to type VI e.g. BM Remodelled by specific collagenases

Question 104

What are matrix glycoproteins important for in fibrous repair and give some examples?

Answer 104

Organise and orientate cells, support cell migration | Fibronectin, laminin, and tenascin

Question 105

What are proteoglycans important for in fibrous repair and give some examples?

Answer 105

Matrix organisation, cell support, regulate availability of growth factors Heparan sulphate proteoglycan

Question 106

What is elastin important for in fibrous repair?

Answer 106

Provides tissue elasticity

Question 107

Describe collagen synthesis

Answer 107

Polypeptide Alpha chain synthesised in endoplasmic reticulum Enzymatic modification steps including vitamin C dependent hydroxylation Alpha chains align and cross-link to form procollagen triple helix Soluble procollagen is secreted After secretion procollagen is cleaved to give tropocollagen Tropocollagen polymerises to form fibrils Bundles of fibrils form fibres Slow remodelling by specific collagenases

Question 108

What are some defects of the synthesis of collagen?

Answer 108

-Vitamin C deficiency, scurvy Inadequate hydroxylation of the chains implies defective helix formation Lack strength, vulnerable to enzymatic degradation Particularly affects collagen supporting blood vessels Haemorrhage and skeletal changes in infants -Ehlers Danlos syndrome Defective conversion of procollagen to troprocollagen -Osteogenesis imperfecta Defective type 1 collagen - Alport syndrome Defective type 4 collagen

Question 109

What is the mechanism of fibrous repair?

Answer 109

-Inflammatory cells infiltrate Blood clot forms Acute information around the edges- neutrophils infiltrate and digest the clot Chronic inflammation: macrophages and lymphocytes migrate into the clot -Clot replaced by granulation tissue Angiogenesis – capillaries and lymphatics then sprout and infiltrate Myo/fibroblasts migrate and differentiate ECmatrix is produced by myo/fibroblasts, collagen is synthesised by fibroblasts, glycoproteins synthesised by Myofibroblasts - Maturation Comparatively long lasting Cell population falls, collagen increases, matures and remodels Myofibroblast contracts – reduces volume of defect Vessels differentiate and are reduced Left with a fibrous scar

Question 110

How was the mechanism of fibrous repair discovered?

Answer 110

Discovered using rabbit ear chamber model Plastic chambers surgically inserted into the ear of lop rabbit Thin tissue bed develops between layers of chamber Enables in-vivo microscopic visualisation of healing and repair

Question 111

How is fibrous repair controlled?

Answer 111

Inflammatory cells are recruited by chemotaxis Angiogenesis – platelets, extracellular matrix and others produce angiogenic cytokines in response to hypoxia (VEGF, bFGF) Fibrosis- macrophages produce various profibrotic cytokines: e.g. IL1, TNF alpha, TGF beta; Fibroblast proliferation and ECM production

Question 112

Describe the regeneration and repair of skin

Answer 112

Primary intention- Incised wound Apposed edges Minimal clot and granulation tissue Epidermis regenerates Dermis undergoes fibrous repair Sutures out at about 10 days: approx 10 % normal strength Transition from granulation tissue to scar tissue Maturation of scar continues up to 2 years Minimal contraction and scaring, good strength Risk of trapping infection – abscess Secondary intention- In part, ulcer, abscess, any LARGE wound Quantitative differences -Unopposed wound edges -Large clot dries to form a scab/ ESCHAR -Epidermis regenerates from the base up -Repair process produces much more granulation tissue

Question 113

Compare secondary with primary intention healing of skin

Answer 113

Produces more contraction to reduce volume of defect Produces more a larger scar, not necessarily weaker Takes longer

Question 114

Describe the regeneration and repair of bone

Answer 114

Haematoma forms from ruptured vessels within the marrow cavity and periosteum Organising haematoma provides a framework for ingress of macrophages, endothelial cells, fibroblasts and osteoblasts Necrotic tissue is removed Capillaries develop Specialised mixture of cells is called a callus Bone is laid down in an irregular woven pattern sometimes with islands of cartilage (soft callus to hard callus) External callus provides splint like support Woven bone gradually replaced by more organised lamellar bone Lamellar bone is gradually remodelled to the direction of mechanical stress

Question 115

Describe the regeneration and repair of the liver

Answer 115

Can regenerate to repair damage by proliferating hepatocytes (uni potent) – both acute and chronic liver damage Resection of the liver can induce proliferation of remaining hepatocytes until lost mass is restored

Question 116

Describe the regeneration and repair of the kidney

Answer 116

Regenerative capacity of mammalian kidney is limited compared to that of lower vertebrates Proximal tubule and glomerulus is believed to regenerate after acute injury Bone marrow stem cells are involved

Question 117

Describe the regeneration repair of the heart

Answer 117

Cannot regenerate Causes scarring and fibrosis Cardiomyocytes are terminally differentiated and cannot divide

Question 118

Describe the regeneration and repair of cartilage

Answer 118

Cannot regenerate

Question 119

Describe the regeneration and repair of peripheral nerves

Answer 119

Wallerian degeneration Neurofilaments break up, axons break up into short lengths Myelin sheaths break down into lipid droplets around the axon Myelin gets denatured chemically Macro phages from endoneurium invade the degenerating myelin sheath and axis cylinder and phagocytose debris Pre axon sprouts and innervates the post axon

Question 120

Describe the regeneration and repair of the central nervous system

Answer 120

``` In demyelination, axon retraction, sprouting, cell death Neurotrophic factor delivery Cellular replacement Modulation of immune response Manipulation of intracellular signalling Axon guidance Removal of growth inhibition ```

Question 121

What are some local factors which influence wound healing?

Answer 121

Type, size, location of wound Apposition, lack of movement – skin wounds, bone fractures, severed nerves Blood supply: arterial, venous Infection – suppuration, gangrene, systemic Foreign material: dirt, glass, sutures, necrotic tissue Radiation damage

Question 122

What are some systemic factors which influence wound healing?

Answer 122

Age Drugs (steroids) and hormones General dietary deficiencies (protein) Specific dietary deficiencies (vitamin C, essential amino acids) General state of health/chronic diseases (diabetes, rheumatoid arthritis) General cardiovascular status

Question 123

What are some complications of repair?

Answer 123

Insufficient fibrosis- - wound dehiscence, hernia, ulceration - obesity, elderly, malnutrition, steroids etc. Excessive fibrosis- -cosmetic scarring, keloid, cirrhosis, lung fibrosis Excessive contraction- - obstruction of tubes and channels = strictures - limitation of joint movement = contractures Infection- -resistance of wounds to infection is proportional to their blood supply- leukocytes become deprived of oxygen so there is no oxygen burst

Question 124

What is a stricture?

Answer 124

Obstruction of a tube and channel

Question 125

What is a contracture?

Answer 125

Iimitation of the joint movement

Question 126

What is chronic granulomatous disease?

Answer 126

Group of disorders – XLR or AR Failure to produce high concentrations of toxic oxygen radicals during a respiratory burst that accompanies activation of phagocytes Failure to produce functional NADPH oxidase enzyme Typically presents in first three months of life as severe skin sepsis caused by Staphylococcus aureus or fungal infection Results in regional lymphogenopathy , hepatosplenomegaly, hepatic abscesses and osteomyelitis Affected organs show multiple abscesses and noncaseating giant cell granulomas

Question 127

What is angio-oedema?

Answer 127

Inherited Deficiency of inhibitor of first component of complement (C1 inhibitor) which also regulates bradykinin metabolism Patients are non susceptible to infections but do experience recurrent attacks of cutaneous, intestinal or laryngeal oedema which can be fatal airway is occluded Loss of regulation complement pathway

Question 128

What is haemostasis?

Answer 128

Process of stopping a haemorrhage/excessive bleeding

Question 129

How fast does haemostasis have to occur and why?

Answer 129

Has to occur within seconds to prevent blood loss

Question 130

What are the three steps of haemostasis?

Answer 130

1. Severed artery contracts not enough to stop the bleeding but enough to decrease the pressure downstream (contraction doesn't occur in the veins but the pressure in them is much lower) 2. Primary haemostatic plug of activated platelets forms at the mouth of the vessel sticking to the injured artery and connective tissue outside it. This is fragile but may control the bleeding. It forms in seconds to minutes. 3. Secondary haemostatic plug forms as fibrin filaments stabilise to the platelet plug. This forms in approximately 30 minutes. It eventually becomes organised and is replaced by granulation tissue and a tiny scar.

Question 131

What are two conditions where there is defective haemostasis?

Answer 131

Patients with low platelet count or non functional platelets- lack step 2 Haemophiliacs (have normal platelets but impaired clotting so they can't produce fibrin- lack step 3

Question 132

What four things does successful haemostasis depend on?

Answer 132

Blood vessel walls Platelets Coagulation Fibrinolysis

Question 133

What are some activators of platelets?

Answer 133

Collagen surfaces (within extravascular areas) Thrombin (tells platelets that the clotting sequence is activated) ADP (released by activated platelets and injured red blood cells and amplifies the platelet response) Some prostaglandins Adrenaline

Question 134

How are platelets involved in haemostasis?

Answer 134

STEP 2 -Platelets adhere to the subendothelium specifically to von Willebrand factor which is concentrated on the subendothelial basement membrane. (vWF glues platelets to subendothelium) -Platelets adhere with other platelets (aggregation). This is how the primary haemostatic (platelet) plug grows. (fibrinogen glues platelets to other platelets) - Swelling -The secretion of factors that help clotting for example fibrinogen, ADP (which activates more platelets), thromboxane A2 (a powerful platelet aggregator). This helps platelet plug to grow. (Platelet release reaction: ATP --> ADP; ADP, thromboxane A2 cause platelet aggregation; 5HT, Platelet factor 3 is also released- important in coagulation)

Question 135

Describe some features of the platelets release reaction

Answer 135

ATP is converted to ADP (energy is required) ADP, thromboxane A2 causes platelet aggregation 5 HT, platelet factor 3 also released Platelet factor 3 also important in coagulation Platelets coalesce after aggregation

Question 136

How is coagulation involved in haemostasis?

Answer 136

STEP 3 Basic purpose is to produce fibrin clot Thrombin cleaves fibrinogen to fibrin (series of inactive components converted to active components) Thrombin can't circulate in an active state or blood would be a solid, therefore thrombin is activated by an array of circulating molecules numbered I to XIII (in order of discovery) At several steps there are feedback loops that inhibit or accelerate the reactions Blood can clot in the absence of platelets but not as well 1ml of blood contains enough fibrin to convert all the fibrinogen in the body into fibrin- so tight regulation is required (by thrombin inhibitors- antithrombin III, alpha 1 antitrypsin, alpha 2 macro globulin, protein C and S (inherited deficiencies in these May cause thrombosis)

Question 137

What are the two pathways of coagulation and what are there differences?

Answer 137

Intrinsic pathway- involves factors contained in the blood; triggered by a negatively charged surface (e.g. Glass, subendothelium); no vessels need to be broken open. Extrinsic pathway- needs a 'tissue factor' (thromboplastin) from outside the blood. Triggered by thromboplastin released from damaged cells when blood is spilled out of vessels.

Question 138

What is retraction/contraction of a clot?

Answer 138

As platelets die they cling to the filaments of fibrin and pull by the actin- myosin system. Therefore the mechanism is basically the same as muscle contraction

Question 139

What is the purpose of clot retraction?

Answer 139

Possibly to toughen the clot by squeezing out fluid. It also helps in pulling together the sides of small wounds.

Question 140

What factors oppose clotting?

Answer 140

``` Dilution of clotting factors by blood flow Natural anticoagulants (oppose the formation of fibrin, don't destroy it after it has been formed – that is fibrinolysis) – antithrombin III, protein C and S. If you lack these in inherited deficiencies, you get repeated episodes of thrombosis. Alpha-1-anti trypsin, alpha-2-macroglobulin ```

Question 141

How is fibrinolysis involved in haemostasis?

Answer 141

Breakdown of fibrin clot after bleeding has stopped Fibrin has a built in short term absolescence Macrophages recognise it and break it down and it is destroyed by free floating enzymes (plasmin). Also the split products of fibrin inhibit blood clotting.

Question 142

How does plasmin breakdown a fibrin clot?

Answer 142

Plasmin is the enzyme responsible for fibrinolysis It circulates as an inactive precursor (plasminogen produced by the liver) with its activator tissue plasminogen activator (tPA) tPA, streptokinase (plasminogen activator obtained from streptococci) and urokinase (plasminogen activator found in urine) Plasminogen --(tPA, sk, uk)--> Plasmin Fibrin clot--(plasmin)--> fibrin fragments

Question 143

How are plasminogen factors used therapeutically?

Answer 143

They dissolve fibrin and therefore thrombi and thromboemboli Streptokinase and urokinase also attack fibrinogen and cause a general depletion of fibrinogen (preventing formation of fibrin clots) Streptokinase is antigenic tPA has a higher affinity for fibrin and is not antigenic Recombinant tPA was obtained from a human melanoma- therapeutic use of a malignant tumour! As tPA breaks down fibrin in thrombi and in a haemostatic clot it can cause bleeding

Question 144

How is the blood vessel (vascular) wall involved in haemostasis?

Answer 144

It is not passive - the arterial media contracts and the subendothelium traps platelets Only endothelium, WBCs, platelets and RBCs can be in contact with blood and not clot it- artificial blood vessels are hard to make

Question 145

How does the endothelium perform a balancing act between opposing and favouring clotting?

Answer 145

Opposing (stops haemostasis) - the endothelium: - opposes platelet aggregation- it secretes prostacyclin that inhibits platelet aggregation - opposes thrombin - favours fibrinolysis - it secretes tPA and urokinase Favouring (promotes haemostasis) - favours platelet aggregation- it produces von Willebrands factor (glue that sticks platelets to subendothelium) - favours coagulation cascade - opposes fibrinolysis

Question 146

What are some antithrombotic substances that the endothelium secretes?

Answer 146

Plasminogen activators Prostacyclin Nitric oxide Thrombomodulin

Question 147

Define thrombosis

Answer 147

Formation of a solid mass of blood within the circulatory system Inappropriate haemostasis

Question 148

When does a thrombus form?

Answer 148

When normal haemostatic mechanisms are turned on inappropriately, thrombi form in the blood vessels or heart Thrombus forms within heart or vessels, from constituents of the loos, during life

Question 149

Why do thrombi form?

Answer 149

Virchow's triad Changes in the vascular wall (endothelial damage, atheroma, direct injury, inflammation) Changes in blood flow (stagnation, turbulence) Changes in blood components (hypercoagulabilty, smokers, post partum, post op) Just two are needed for a thrombus to form

Question 150

How does a change in vessel wall (in particular endothelial damage) affect the formation of a thrombus?

Answer 150

Endothelial damage Occurs after trauma or surgery, in inflammation, on the surface of atherosclerotic plaques when they break open Platelets adhere to exposed von Willebrand factor/factor VIII complex In arteries the platelet thrombi generally don't grow because swift currents wash away the platelets and the chemical mediators

Question 151

How does a change in blood flow (in particular sluggish flow) affect the formation of a thrombus?

Answer 151

Sluggish flow Gives platelets better chance to stick and clotting factors a chance to accumulate Thrombosis is more frequent in veins as they have slower flow and valves produce eddies and pockets of stagnant blood In pregnancy (and after surgery) two of Virchow's triad are present and thrombi in the lower limbs are more common – stasis due to pressure on large veins of the pelvis and the blood is hypercoagulable

Question 152

How do changes in blood components (in particular hypercoaguability) affect formation of a thrombus?

Answer 152

Smoking activates Hageman factor (factor VII) Pregnancy and recent surgery result in increased levels of fibrinogen and factor VIII These all cause hypercoaguability which increases the likelihood of formation of a thrombus

Question 153

How is a thrombus formed in a post surgical patient?

Answer 153

Platelets in a vein are more concentrated along the endothelium because they are the smallest formed elements in the blood (rocks flow in the centre of a stream, sand is deposited along the banks) Platelets post surgery aggregate more easily Platelets catch in an eddy behind a valve, form an aggregate, settle on the wall, and other platelets stick to the collection Fibrin grows out of the platelet layer (it is not clear how) and traps red blood cells. So a white layer of platelets is covered by a red layer of fibrin and red blood cells. The surface of the red layer is thrombogenic as platelets stick to the fibrin. A second white layer of platelets then forms and the process continues. Laminations are visible to the naked eye as lines of zahn

Question 154

What is a parietal thrombus?

Answer 154

Thrombus which restricts the lumen of the vessel

Question 155

What is an occlusive thrombus?

Answer 155

Thrombus which fills and obstructs a lumen

Question 156

What is the most important mechanism for limiting the spread of thrombus?

Answer 156

Blood flow

Question 157

What does an arterial thrombi look like?

Answer 157

Pale, granular, lines of zahn (white- platelets/ red- red blood cells), lower cell content

Question 158

What does a venous thrombi look like?

Answer 158

Soft Gelatinous Dee red Higher cell content

Question 159

What are the outcomes of thrombosis?

Answer 159

Resolution and lysis- complete dissolution of thrombus, fibrinolytic system active, blood flow reestablished, most likely when thrombi are small Propagation- progressive spread of thrombus, distally in arteries and proximally in veins Organisation- reparative process, in growth of fibroblasts, macrophages and capillaries (similar to granulation tissue), lumen remains obstructed, fibrous scar forms on wall of vessel Recanalisation- blood flow reestablished but usually incompletely, one or more channels formed through organising thrombus Embolism- parts of thrombus break off and travel through look stream, lodging at a distant site Partial calcification Occlusion of the vessel

Question 160

What is the difference between a thrombus and post mortem clot?

Answer 160

Thrombi are typically laminated with lines of zahn and are opposed to the intimal surface; can cause death Post mortem clots are rubbery and shiny and are never laminated (as this requires blood flow). They are also not attached to the intima; cannot cause death as person is already dead!

Question 161

What is a thrombus on a cardiac valve called and what are some key features?

Answer 161

Vegetation They can be 2-3 cm long and easily embolism Usually occur on valves of the elf heart as they are exposed to a greater pressure and therefore micro trauma Subendothelial tissue that is exposed is thrombogenic- they can become infected

Question 162

What are the most dangerous sources of emboli?

Answer 162

Thrombi in the large veins of the lower limbs – femoral/iliac/popliteal veins

Question 163

Is pain always present when a thrombus forms?

Answer 163

Pain is not always present when a thrombus forms (although it often is in thrombi in superficial veins (thrombophlebitis – even though there are aseptic))

Question 164

How does aspirin prevent thrombus formation?

Answer 164

Aspirin is antithrombogenic It irreversibly acetylates in platelets an enzyme of prostaglandin metabolism so that platelets can't produce thromboxane A2 – a platelet activator The formation of a haemostatic plug is inhibited and the bleeding time is prolonged

Question 165

What is disseminated intravascular coagulation?

Answer 165

In this condition blood clots throughout the circulation It never occurs as a disease in itself but is a complication of a primary event that triggers generalised blood clotting for example sepsis (especially gram negative sepsis as such bacteria produce an endotoxin which activates clotting, Severe trauma (especially to the brain as it contains large amounts of thromboplastin), complications of childbirth (amniotic fluid embolism, retained dead foetus), shock, tumour, snakebite It is a combination of clotting and nonclotting resulting in thromboembolism and haemorrhage. It has also been called haemorrhagic micro thrombosis and consumption coagulopathy. Clotting factors and platelets are used up by the widespread clotting resulting in susceptibility to haemorrhage – a therapeutic nightmare There are signs of: Microvascular thrombosis – neurological impairment, gangrene of the skin, renal failure, respiratory distress, Gastro intestinal ulceration Haemorrhage – intracerebral bleeding, petechiae, haematuria, epistaxis, gastrointestinal bleeding An activator of clotting gets into the blood. Microthrombi (but not large thrombi) form. The fibrinolytic system is activated and they fibrin degradation products (FDPs) are released. Red blood cells can be traumatised by fibrin in the microthrombi = microangiopathic haemolytic anaemia

Question 166

Define embolus

Answer 166

An embolus is a solid, liquid or gas that is carried by the blood and is large enough to become impacted in a vascular lumen

Question 167

What is an embolism?

Answer 167

Impaction open embolus

Question 168

Why can't an embolism form in a vein?

Answer 168

It can't occur in veins as bloodflow is from smaller to larger vessels

Question 169

Where do most emboli arise from?

Answer 169

From thrombus in Thromboembolism

Question 170

Besides arising from a thrombus, what else can an emboli arise from?

Answer 170

``` Body fat Bone marrow (usually after trauma) Atheromatous plaque Tumour Parasites Bubbles of air or other gases Debris injected intravenously Bits of brain or liver after trauma ```

Question 171

Where do emboli from peripheral veins or the right heart end up in?

Answer 171

Lungs

Question 172

Where do emboli from the left heart or aorta end up in?

Answer 172

Anywhere in the systemic circulation especially the lower limbs

Question 173

Describe pulmonary saddle emboli

Answer 173

Large emboli become lodged in both pulmonary arteries= saddle emboli. They are usually fatal.

Question 174

Where do majority of pulmonary emboli arise?

Answer 174

Approximately 80% arise in thrombi in the deep veins of the thigh and the popliteal vein

Question 175

What are the three severities of pulmonary emboli?

Answer 175

Massive PE >60% reduction in blood flow Major PE medium sized vessels blocked, patients short of breath, +/- cough, blood stained sputum Minor PE small peripheral pulmonary artery blocked, asymptomatic, shortness of breath, recurrent minor PEs lead to pulmonary hypertension

Question 176

What are some predisposing factors of deep vein thrombosis?

Answer 176

``` Immobility Bed rest Post operative Pregnancy Postpartum Oral contraceptives Severe burns Cardiac failure Disseminated cancer ```

Question 177

How can DVT be prevented?

Answer 177

``` High risk patients must be identified and offered prophylaxis Heparin subcutaneously Leg compression during surgery Mobility after surgery Thrombolytic drugs ```

Question 178

How can DVT be treated?

Answer 178

Surgery – embolectomy Intravenous heparin- anticoagulant, co factor for antithrombin III Oral warfarin- interferes with synthesis of vit K dependent clotting factors; slow effect Thrombolytic drugs – streptokinase, tPA

Question 179

How can pulmonary embolism be prevented?

Answer 179

By putting an umbrella shaped filter in the inferior vena cava

Question 180

Why are thrombi often seen in the left heart?

Answer 180

Infarcts commonly affect the left ventricle causing thrombosis in the ventricular cavity. As heart is beating these often embolise. Vegetations are commoner on valves on the left side of the heart. Atrial fibrillation results in decreased atrial contraction, dilatation of the left atrium, stagnation of blood in the atrium and hence thrombi.

Question 181

What are paradoxial emboli?

Answer 181

Emboli that arise in systemic veins that embolise in the systemic arteries

Question 182

How do paradoxical emboli bypass the lungs?

Answer 182

Small emboli pass through arterio-venous anastomoses in the pulmonary circulation (these are 29-40 times the diameter of a capillary). Fat droplets pass through the lungs this way in fat embolism. Larger emboli pass through defects in the intraventricular septum or foramen ovale during coughing, lifting or straining which increases the pressure in the right side of the heart.

Question 183

What is a TIA?

Answer 183

Transient ischaemic attack Atheromatous emboli Microscopic atheroembolism to the brain Episodes of neurological dysfunction that appear suddenly, last minutes to hours and then disappear Usually arise in carotid arteries or left heart As the emboli are very small they break up before any lasting harm is done

Question 184

What is a gas emboli?

Answer 184

Air embolism- there is a negative pressure in the veins of chest and head during inspiration in the upright position and these veins can draw in air after e.g. Trauma to neck or chest Fatal amount of air = 100mls Bubbles gather in the right heart as a frothy mass that stops the circulation During labour air can enter the uterus and be forced into open veins during uterine contraction

Question 185

What is fat and bone marrow emboli?

Answer 185

- Fractures of long bones - Lacerations of adipose tissue - Rash, shortness of breath, confusion - usually a complication of bone fractures, after liposuction; bone marrow fat cells break up, oil droplets coalesce and are sucked into gaping venules torn by the fracture; emboli lodge in the lungs and some droplets pass through the lungs to the systemic circulation and into organs such as the brain, kidneys and skin

Question 186

What is latrogenic embolism?

Answer 186

Embolism due to medical treatment, e.g. air embolism from an injection or axilla surgery

Question 187

What is nitrogen embolism?

Answer 187

Nitrogen bubbles form in the blood with rapid decompression The bends- underwater, the body tissues and blood become saturated with gas at a high pressure. If a diver resurfaces too quickly, dissolved gases come out of solution and are released into the body as bubbles,p. The bubbles distort the tissues and act as emboli in the blood. Nitrogen is a particular problem as it is a fat soluble and can result in persistent bubbles in lipid rich tissues (CNS)

Question 188

What is cerebral embolism?

Answer 188

- Atrial fibrillation --> Stasis -->Thrombus | - If in left heart, can go to the brain and cause a stoke or transient ischaemic attack

Question 189

Where will a thromboembolism from the systemic veins go?

Answer 189

Pass to the lungs (Pulmonary Emboli), as they will not get stuck in the large veins near the heart. The next time the emboli meets a vessel smaller than itself where it can get stuck is the lung.

Question 190

Where will thromboembolism from the heart go?

Answer 190

Pass via the aorta to renal, mesenteric and other arteries

Question 191

Where will thromboembolisms from the atheromatous carotid arteries go?

Answer 191

To the brain (Stroke)

Question 192

Where will thromboembolisms from the atheromatous abdominal aorta go?

Answer 192

To the arteries of the legs

Question 193

Describe haemophilia

Answer 193

- Type A and Type B - X-linked recessive, so more common in boys - Deficiencies in different clotting factors o A = Factor VIII o B = Factor IX - Can be mild, moderate or severe due to various mutations - Due to a nonsense point mutation - Haemorrhage into major joints, synovial hypertrophy, pain - Muscle bleeding causes pressure and necrosis of nerves (painful) - Can haemorrhage into retroperitoneum / urinary tract - Treat with self-administered factor replacement therapy

Question 194

Describe Thrombocytopenia

Answer 194

- Platelet count is way below the reference range - Due to either: o Failure of platelet production o Increase in platelet destruction o Sequestering of platelets - Usually accompanied by a bone marrow dysfunction, E.g. leukaemia, anaemia - If it is due to sequestering, cause may be DIC

Question 195

What is atheroma?

Answer 195

Atheroma is the accumulation of intracellular and extracellular lipid in the intima and media of large and medium-sized arteries

Question 196

What is atherosclerosis?

Answer 196

The thickening and hardening of arterial walls as a consequence of atheroma

Question 197

What is arteriosclerosis?

Answer 197

The thickening of walls of arteries and arterioles usually as a result of hypertension or diabetes mellitus

Question 198

What are the three broad macroscopic features of atheroma?

Answer 198

A fatty streak A simple plaque The complicated plaque

Question 199

Describe some features of the fatty streak

Answer 199

Lipid deposits in intima Yellow, slightly raised Precursor to atheroma

Question 200

Describe some features of the simple plaque

Answer 200

Raised yellow/white Irregular outline Widely distributed Enlarge and coalesce to form the extensive atheroma

Question 201

Describe some features of the complicated plaque

Answer 201

Thrombosis- due to abnormalities of vessel wall and blood flow Haemorrhaging to the plaque- pressure of blood in the artery an disrupt the plaque forming a haemorrhage Calcification Aneurysm formation – stretching of the wall of the artery, loss of elastic lamina and loss of normal elastic recoil

Question 202

What are some common sites of atheroma?

Answer 202

``` Aorta – especially abdominal (between renal and aortic bifurcation) Coronary arteries Carotid arteries (--> strokes) Cerebral arteries (--> strokes) Leg arteries ```

Question 203

What is the normal basic arterial structure?

Answer 203

``` Endothelia Subendothelial connective-tissue Internal elastic lamina Muscular media External elastic lamina Adventitia ``` Elastic lamina decreases in thickness as arteries get further away from the heart

Question 204

What are the microscopic features of atheroma?

Answer 204

``` Early changes: Proliferation of smooth-muscle cells Accumulation of home cells Extracellular lipid Later changes: Fibrosis (fibrous cap) Necrosis Cholesterol clefts (seen as a clear hole- cholesterol crystallises to form needle shaped tissue) +/- inflammatory cells Disruption of external elastic lamina- aneurysm formation Damage extends to media In growth of blood vessels- increased likelihood of haemorrhaging Plaque fissuring ```

Question 205

What are some clinical effects of atheroma?

Answer 205

``` Ischaemic heart disease Myocardial infarction Cerebral ischaemia Mesenteric ischaemia Peripheral vascular disease Abdominal aortic aneurysm ```

Question 206

What are some possible consequences of ischaemic heart disease?

Answer 206

``` Sudden death Myocardial infarction Angina pectoris Arrhythmias Cardiac failure ```

Question 207

Describe cerebral ischaemia

Answer 207

Transient ischaemic attack (T I A) - infarction of brain, symptoms for 24 hours Due to atheroma in carotid artery increasing the risk of stroke Treatment may include a carotid endarterectomy May result in stroke (cerebral infarction) Multi-infarct dementia

Question 208

Describe mesenteric ischaemia

Answer 208

Ischaemic colitis Malabsorption Intestinal infarction Aneurysm- high-pressure – hardened and weakened wall

Question 209

Describe peripheral vascular disease

Answer 209

Intermittent claudication - calf pain on walking- distance walking without pain becomes shorter and shorter Leriches syndrome (intermittent claudication in iliac artery --> gluteal pain) Ischaemic rest pain Gangrene (may result in forefoot/ below the knee amputation)

Question 210

What are the risk factors of atheroma?

Answer 210

``` Age Gender Hyperlipidaemia Cigarette smoking Hypertension Diabetes mellitus Alcohol consumption Infection Lack of exercise Obesity Softwater Oral contraceptives Stress and personality type Genetic predisposition ```

Question 211

How is age related to atheroma formation?

Answer 211

Slowly progressive throughout life of adults | Risk factors operate over years

Question 212

How is gender associated with atheroma formation?

Answer 212

Women protected relatively before menopause Presumed hormonal basis Men are more likely to develop atheroma that women

Question 213

How is hyperlipidaemia associated with atheroma formation?

Answer 213

High plasma cholesterol is associated with atheroma LDL is most significant HDL is protective Lipid is carried in blood on lipoproteins- carry cholesterol and triglycerides- hydrophobic core and hydrophilic shell (phospho lipoprotein/ apolipoproteins) Genetic conditions- resulting in defects to ApoE and LDL receptors can result in cholesterol deposits in vessel walls and tissues (familial hypercholesterolaemia) Xanthelasma (eyes), xanthoma of tendons, corneal arcus

Question 214

How is cigarette smoking associated with atheroma formation?

Answer 214

Powerful risk factor for IHD Risk falls after giving up- stopping can reverse the coaguability effect of smoking Mode of action is uncertain- coagulation system, reduced Pg12, increased platelet aggregation Most important avoidable risk factor

Question 215

How is hypertension associated with atheroma formation?

Answer 215

Strong liking between IHD and high systolic and diastolic blood pressure Uncertain mechanism Endothelial damage caused by raised pressure Some sites are more prone to high pressure and supposedly atheroma formation - e.g. Arms- atheromas do not form here

Question 216

How is diabetes mellitus associated with atheroma formation?

Answer 216

Diabetes mellitus doubles the IHD risk Protective effect in premenopausal women is lost DM is also associated with a high risk of cerebrovascular disease Related to hyperlipidaemia and hypertension

Question 217

How is alcohol consumption related to atheroma formation?

Answer 217

More than five units per day is associated with an increased risk of IHD Alcohol consumption is often associated with other risk factors – smoking and high blood pressure but still an in independent risk factor Smaller amounts of alcohol may be protective

Question 218

How is infection associated with atheroma formation?

Answer 218

Chlamydia pneumoniae Helicobacter pylori – stomach Cytomegalovirus

Question 219

How is genetic predisposition associated with atheroma formation?

Answer 219

Familial predisposition is well known Possibly due to – variations in apolipoprotein metabolism, variations in apolipoproteins receptors Not a single gene defect – genetic and environmental

Question 220

What is the pathogenesis of atherosclerosis?

Answer 220

Trans-endothelial passage of lipid droplets (which become oxidised) and monocytes (which pick up the lipid and turn into foam cells). NB. The endothelium is intact. Crowded foam cells cause endothelium to bulge. Smooth muscle cells arise from the media. The lesion at this stage is called a fatty streak. Growth of the plaque by an increase in the number foam cells and smooth-muscle cells. Some smooth muscle cells will also take up lipid. Platelets adhere where endothelial cells allow gaps to develop. Some smooth muscle cells lie beneath endothelium forming a roof reinforced by collagen, elastin and other matrix proteins= a fibrous cap. The lesion at this stage is called a fibrofatty plaque. Necrosis occurs in the plaque, followed by the development of cholesterol crystals, calcification and vascularisation from the adventitia- I.e. atheroma forms

Question 221

What are some complications of atheromatous plaques?

Answer 221

Ulceration - fibrous cap is eroded from underneath and the core is exposed- can lead to Thrombosis- may develop on ulcerated plaque or even on a structurally intact endothelium Thrombi can release vasoconstrictors which can cause spasm at the site of the plaque and The exposed atheroma may break up and shed atheromatous emboli Calcification may develop in an around the plaque making the artery even stiffer Vascularisation as the plaque is invaded by vessels from the Adventitia. One of the vessels may break resulting in haemorrhage into the plaque, the pressure form which may break the plaque open Local dilatation (an aneurysm) may be caused by a local weakening of the wall Rupture of the atherosclerotic artery and bleeding secondary to weakening of the media layer. These can be seen in cerebral arteries especially associated with hypertension.

Question 222

What cells are involved in atheroma formation?

Answer 222

``` Endothelial cells Platelets Smooth muscle cells Macrophages Lymphocytes Neutrophils ```

Question 223

How are endothelial cells involved in atheroma formation?

Answer 223

Key role in haemostasis Altered Permeability to lipoproteins Secretion of collagen Stimulation of proliferation and migration of smooth-muscle cells

Question 224

How are platelets involved in atheroma formation?

Answer 224

Key role in haemostasis | Stimulate proliferation and migration of smooth muscle cells (PDGF)

Question 225

How are macrophages involved in atheroma formation?

Answer 225

``` Oxidise LDL Take up lipids to become foam cells Secret proteases which modify the matrix Stimulate proliferation and migration of smooth-muscle cells Cytokine release ```

Question 226

How are lymphocytes involved in atheroma formation?

Answer 226

TNF may affect lipoprotein metabolism | Stimulates proliferation and migration of smooth muscle cells

Question 227

How are neutrophils involved in atheroma formation?

Answer 227

Secrete proteases leading to continued local damage and inflammation

Question 228

How can atheroma be prevented?

Answer 228

``` No smoking Reduced fat intake Treat hypertension Not too much alcohol Regular exercise, weight control But still may develop atheroma ```

Question 229

What interventions can be taken to reduce the likelihood of an atheroma?

Answer 229

``` Stop smoking Modify diet Treat hypertension Treat diabetes mellitus Lipid-lowering drugs like statins ```

Question 230

What does the size of the cell population depend on?

Answer 230

The rate of: Cell proliferation Cell differentiation Cell death by apoptosis

Question 231

In what two ways do the number of cells increase?

Answer 231

Increased cell proliferation | Decreased cell death

Question 232

What is cell proliferation regulated by?

Answer 232

Proto oncogenes

Question 233

What do cells use to communicate with one another?

Answer 233

Chemical signals which can be contact dependent or soluble

Question 234

How do chemical signals affect cell proliferation?

Answer 234

They inhibit or stimulate cell proliferation

Question 235

What are four outcomes that chemical signals can have on cell proliferation?

Answer 235

Divide (enter the cell cycle) Differentiate (take on specialised form or function) Survive (resist apoptosis) Die (ungrounded apoptosis)

Question 236

What three categories can chemical signals fall into?

Answer 236

Autocrine- Intracrine Paracrine Endocrine

Question 237

What does autocrine mean?

Answer 237

Cells respond to signals they produce

Question 238

What does paracrine mean?

Answer 238

Cells produce signals that act on close and different cells (e.g. Local mediators)

Question 239

What does endocrine mean?

Answer 239

Cells produce hormones that go into the bloodstream to target cells to effect physiological activity

Question 240

What does intracrine mean?

Answer 240

Specialised type of autocrine | Signalsacts inside the cell

Question 241

Generally what is the effect of a chemical signal binding to a receptor?

Answer 241

Binding to a receptor (membrane /nucleus) causes a series of events which result in the modulation of gene expressions

Question 242

What are growth factors?

Answer 242

Important for cell proliferation Affect cell locomotion, contractility, differentiation, angiogenesis, Bind to specific receptors, stimulate transcription of genes that regulate the entry of the cell into the cell cycle and the cells passage through it

Question 243

What are three examples of growth factors?

Answer 243

Epidermal growth factor Vascular endothelial growth factor Platelet derived growth factor

Question 244

How does epidermal growth factor work?

Answer 244

Mitogenic for epithelial cells and fibroblasts Produced by keratinocytes, macrophages and inflammatory cells Binds to epidermal growth factor receptor

Question 245

How does vascular endothelial growth factor work?

Answer 245

Potent inducer of blood vessel development (vasculogenesis) | Role in growth of new blood vessels (angiogenesis) – tumours, chronic inflammation, wound healing

Question 246

How does platelet-derived growth factor work?

Answer 246

Stored in platelet alpha granules and released on platelet activation Produced by macrophages, endothelial cells, smooth muscle cells and tumour cells Causes migration and proliferation of fibroblasts, smooth muscle cells and monocytes

Question 247

What are the four main stages of the cell cycle?

Answer 247

G1 S1 G2 M

Question 248

In G1 what is the phase called in which there is a permanent exit from the cycle?

Answer 248

G0

Question 249

What happens in G1 of the cell cycle?

Answer 249

Gap 1 Presynthetic Cell grows (proteins/ organelles)

Question 250

What happens in S1 of the cell cycle?

Answer 250

DNA synthesis / replication of DNA

Question 251

What happens in G2 of the cell cycle?

Answer 251

Gap 2 Premitotic Cell prepares to divide

Question 252

What happens in M of the cell cycle?

Answer 252

Mitosis, cell division

Question 253

What 3 stages make up interphase?

Answer 253

G1, S1, G2

Question 254

What is cell cycle progression controlled by?

Answer 254

Key "checkpoints"found at end of G1 (R) and end of G2

Question 255

What is the importance of the the R/ G1 checkpoint?

Answer 255

Is the cell big enough? Is the environment favourable? Is DNA damaged? Period prior to R/ G1 checkpoint is period in which cells are responsive to mitogenic GFs and to TGF-beta R point is the most commonly altered checkpoint in cancer cells R point is known as the point of no return- majority of cells that pass R will complete the cell cycle Activation of this check point delays cell cycle, and stimulates DNA repair mechanisms or apoptosis to damaged cells

Question 256

What is the importance of the G2 checkpoint?

Answer 256

Is the cell big enough? Is all DNA replicated? Activation of this check point delays cell cycle, and stimulates DNA repair mechanisms or apoptosis to damaged cells

Question 257

In what two ways does increased growth of a tissue occur?

Answer 257

Shortening the cell cycle | Conversion of quiescent cells (in G0) into proliferating cells by making them enter the cell cycle

Question 258

What proteins are involved in controlling the progression of the cell cycle at checkpoints?

Answer 258

Cyclins and associated enzymes called cyclin dependent kinases (CDKs)

Question 259

What happens upon binding of a cyclin to a CDK?

Answer 259

Cycling bind and activate CDK forming a cyclin-CDK complex Activated complex drives the cell cycle by phosphorylation proteins (e.g. Retinoblastoma susceptibility (RB) protein) Phosphorylation is critical for the next stage of the cell cycle

Question 260

What tightly regulates cyclin-CDK complexes?

Answer 260

CDK inhibitors

Question 261

How do growth factors affect the cell cycle?

Answer 261

Stimulate the production of cyclins- promoting cyclin-CDK complex formation, phosphorylation and progression Shutting off production of CDK inhibitors- increasing complex formation, phosphorylation and progression

Question 262

Describe labile cells

Answer 262

Epithelial or haematopoietic cells Normal state is active in cell division Usually rapid proliferation Stem cells divide persistently to replenish losses

Question 263

Describe stable cells

Answer 263

Hepatocytes, osteoblasts and fibroblasts Resting state: G0 Speed of regeneration is variable Stem cells are normally quiescent/ proliferate very slowly– proliferate persistently to replenish losses when required

Question 264

Describe permanent cells

Answer 264

Neurones, cardiac myocytes Unable to divide:G0/ unable to regenerate Stem cells present but can't mount effective proliferative response to significant cell loss

Question 265

In what five ways can the reversible state between a normal unstressed cell and overstressed injured cell be described?

Answer 265

``` Regeneration Hyperplasia Hypertrophy Atrophy Metaplasia ```

Question 266

Define regeneration

Answer 266

Replacement of cell losses by identical cells to maintain tissue or organ size

Question 267

What causes regeneration to occur?

Answer 267

After injury, if harmful agent is removed and there is limited tissue damage

Question 268

Can regeneration occur if tissue damage is bad or if damage occurs to a permanent cell? If not what happens instead?

Answer 268

No | Scar forms

Question 269

What are two examples of regeneration?

Answer 269

Liver after partial hepatectomy | Epidermis replacement by keratinocytes after a skin burn

Question 270

Which of theses types of cells can regeneration occur in? Labile, stable or permanent?

Answer 270

Labile | Stable

Question 271

Define hyperplasia

Answer 271

Increase in tissue or organ size due to increase in cell numbers

Question 272

What causes hyperplasia to occur?

Answer 272

In response to increased functional demand and/or external stimulation

Question 273

Which of theses types of cells can hyperplasia occur in? Labile, stable or permanent?

Answer 273

Labile | Stable

Question 274

Is hyperplasia mostly under physiological or pathological control?

Answer 274

Physiological control | Can be secondary to a pathological cause (excessive hormone stimulation/ growth factor production)

Question 275

What are the two types of physiological hyperplasia?

Answer 275

Hormonal- increase in functional capacity | Compensatory- increase in tissue mass after tissue damage

Question 276

How is hyperplasia related to neoplasia?

Answer 276

Repeated cell divisions that occur in hyperplasia expose the cell to risk of mutations and hence neoplasia is a risk

Question 277

What are two examples of physiological hyperplasia?

Answer 277

Bone marrow production of erythrocytes (low oxygen) | Proliferation of endometrium under oestrogen influence

Question 278

What are two examples of pathological hyperplasia?

Answer 278

Epidermal thickening in chronic eczema or psoriasis | Enlargement of thyroid gland in response to iodine deficiency

Question 279

Define hypertrophy

Answer 279

Increase in tissue or organ size due to increased cell size

Question 280

How does cell size increase in hypertrophy?

Answer 280

Cells contain more structural components – so cellular workload is shared by a greater mass of cellular components

Question 281

Which of theses types of cells can hypertrophy occur in? Labile, stable or permanent?

Answer 281

Mostly seen in permanent cell populations (it's the only well organ size of these populations of cells can increase) In labile/stable cells – hypertrophy may occur alongside hyperplasia – triggered by the same stimulus

Question 282

What causes hypertrophy to occur?

Answer 282

In response to increased functional demand and or external stimulation

Question 283

What are two examples of physiological hypertrophy?

Answer 283

Skeletal muscle hypertrophy of a bodybuilder | Smooth muscle hypertrophy of the pregnant uterus

Question 284

What are two examples of pathological hypertrophy?

Answer 284

Ventricular cardiac muscle hypertrophy in response to systemic hypertension or valvular disease Bladder smooth muscle hyper trophy with bladder obstruction due to an enlarged prostate gland (hypertrophy and hyperplasia)

Question 285

Define atrophy

Answer 285

Shrinkage of the tissue or organ due to an acquired decrease in size and/ or number of cells

Question 286

What causes atrophy to occur?

Answer 286

Caused by reduced supply of growth factors and/or nutrients

Question 287

What's the difference between atrophy at a cellular level and at an organ/tissue level?

Answer 287

At a cellular level – decrease in cell size | At an organ/tissue level – combination of cellular atrophy and apoptosis; when many cells undergo atrophy

Question 288

How does cell size decrease in atrophy?

Answer 288

Involves shrinkage of size of the cell to size which is still survivable Cells contain a reduced number of structural components and reduced function

Question 289

How may atrophy result in cell death?

Answer 289

It is a form of an adaptive response which may result in cell death

Question 290

What are two examples of physiological atrophy?

Answer 290

Ovarian atrophy in postmenopausal women | Decrease in the size of uterus after parturition

Question 291

What are eight examples of pathological atrophy?

Answer 291

``` Disuse atrophy Denervation atrophy Inadequate blood supply Inadequate nutrition Loss of endocrine stimulation Persistent injury Senile atrophy (permanent cells) Pressure atrophy ```

Question 292

Which of theses types of cells can atrophy occur in? Labile, stable or permanent?

Answer 292

Labile Stable Permanent

Question 293

Define metaplasia

Answer 293

Reversible change of one differentiated cell type to another more suited to the altered environment

Question 294

In what tissues is metaplasia most often seen?

Answer 294

Epithelial tissue

Question 295

What causes metaplasia to occur?

Answer 295

Altered stem cell differentiation | Occurs secondary to signals from molecules such as cytokines and growth factors

Question 296

What is the most common epithelial metaplasia seen? And what is the effect of this?

Answer 296

Columnar epithelia (fragile) undergoes metaplasia and becomes squamous epithelia (resilient) May result in loss of function (e.g. In this case loss of mucus secretion)

Question 297

What is the difference between metaplastic, dysplastic and cancerous differentiation?

Answer 297

Metaplastic epithelia are fully differentiated Unlike dysplastic epithelial which has disorganised and abnormal differentiation while cancerous epithelia differentiation is also disorganised and abnormal and irreversible

Question 298

What is metaplasia often a prelude to?

Answer 298

Dysplasia and cancer

Question 299

What are three examples of metaplasia?

Answer 299

Transformation of bronchial pseudo stratified ciliated epithelium to stratified squamous epithelium due to the effect of cigarette smoke Change of oesophageal stratified squamous epithelia to gastric type epithelia with acid reflux (Barrett's oesophagus) Change of columnar epithelia lining ducts such as those of the salivary glands or pancreas or bile ducts to stratified squamous epithelia secondary to chronic inflammation by stones

Question 300

Define aplasia

Answer 300

Complete failure of a specific tissue or organ to develop | Embryonic development disorder

Question 301

Define hypoplasia

Answer 301

Underdevelopment or incomplete development of a tissue or organ There are an inadequate number of cells within the tissue which is present Embryonic development disorder – in spectrum with Aplasia

Question 302

Define dysplasia

Answer 302

The abnormal maturation of cells within a tissue | Potentially reversible but often precancerous

Question 303

Define a benign neoplasm

Answer 303

The abnormal growth of cells which persists after the initiating stimulus has been removed

Question 304

Define a malignant neoplasm

Answer 304

Abnormal growth of cells, which persists after initiating stimulus has been removed AND invades and spreads to distant sites

Question 305

Describe the appearance of a benign neoplasm

Answer 305

Rounded mass due to the pushing growth Remains at site of origin in confined local area Well differentiated (low grade)- retention of tissue specialisation Variation in size and shape (pleomorphism) is minimal Low mitotic count- mitoses have normal form

Question 306

Describe the appearance of a malignant neoplasm

Answer 306

Irregular mass due to infiltrative growth edges May spread to distant site forming secondary growth (metastasis) Well to poorly differentiated (low to high grade)- variable loss of tissue specialisation Variation in size and shape (pleomorphism) minimal to marked Low to high mitotic count- mitosis may have abnormal forms On a surface- necrosis and ulceration

Question 307

What is pleomorphism?

Answer 307

Increasing variation in size and shape of cells and nuclei

Question 308

What is a tumour?

Answer 308

Any clinically detectable lump or swelling | Can be neoplastic or non neoplastic

Question 309

What is another word for malignant neoplasm?

Answer 309

Cancer

Question 310

What is the name given to cells that are so poorly differentiated that they have no resemblance to any tissue?

Answer 310

Anaplastic cells

Question 311

What are some key features of worsening differentiation in a neoplasm?

Answer 311

``` Increasing nuclear size Increasing nuclear: cytoplasmic ratio Nuclear hyperchromasia More mitotic figures Increasing variation in size and shape of cells and nuclei- pleomorphism ```

Question 312

What is neoplasia?

Answer 312

Preneoplastic alteration in which cells show disordered cell organisation

Question 313

What is one similarity and two differences between dysphasia and neoplasia

Answer 313

Sim- both involve altered differentiation | Dif- dysplasia occurs before neoplasia, dysplasia is reversible whereas neoplasia is not

Question 314

Give two examples of non neoplastic tumours

Answer 314

Abscess | Swelling

Question 315

What alterations to DNA cause neoplasia?

Answer 315

For a neoplasm to develop there has to be a change in DNA which must cause an alteration in cell growth and behaviour (change must not be lethal and must be passed on to daughter cells) Neoplasms arise from about 7 genetic alterations - Protooncogenes--> Oncogenes- permanent activation of cell cycle results in neoplasm Tumour suppression gene- permanent inactivation results in neoplasm HER2 gene amplification- self sufficient growth signals CDKN2A gene deletion- resistance to anti growth signals Telomerase gene activation- grow indefinitely Activation of VEGF expression- induce new blood vessels BCL2 gene translocation- resistance to apoptosis Altered E cadherin expression- invade and produce metastases

Question 316

What causes a neoplasm to occur?

Answer 316

Neoplasia is caused by accumulated mutations in somatic cells - external mutagenic agents- chemicals, infections, radiation cause INITIATION, followed by PROMOTION and PROGRESSSION onto a neoplasm - inherited- germline mutation- neoplastic cells get a head start

Question 317

What is the clonality of neoplasms?

Answer 317

Monoclonal- collection of cells in neoplasm are all originated from a single founding cell

Question 318

What is the evidence for monoclonality of neoplasms?

Answer 318

X linked gene for G6PD enzyme in tumour tissue from women Gene has several alleles encoding different isoenzymes Early in female embryogenesis one allele is randomly inactivated in each cell (lyonisation) In a heterozygous woman- heat stable isoenzyme allele & heat labile isoenzyme allele exist as a patchwork in normal tissue BUT In neoplastic tissue only one isoenzyme is present indicating a monoclonal group of cells

Question 319

What is an in situ carcinoma?

Answer 319

All the features of a malignant neoplasm in epithelium but no invasion through the basement membrane

Question 320

What is an invasive carcinoma?

Answer 320

All the features of a malignant neoplasm in epithelium with invasion through the basement membrane

Question 321

What is the name of a benign neoplasm in stratified squamous epithelial cells and where does it occur?

Answer 321

Squamous papilloma (finger like projections) Skin Buccal mucosa

Question 322

What is the name of a benign neoplasm in transitional epithelial cells and where does it occur?

Answer 322

Transitional cell papilloma | Bladder mucosa

Question 323

What is the name of a benign neoplasm in glandular epithelial cells and where does it occur?

Answer 323

Adenoma | Adenamatous polyp of colon

Question 324

What is the name of a malignant neoplasm in stratified squamous epithelial cells and where does it occur?

Answer 324

Squamous cell carcinoma | Skin larynx oesophagus

Question 325

What is the name of a malignant neoplasm in transitional epithelial cells and where does it occur?

Answer 325

Transitional cell carcinoma | Bladder ureter

Question 326

What is the name of a malignant neoplasm in glandular epithelial cells and where does it occur?

Answer 326

Adenocarcinoma | Stomach colon lung prostate breast pancreas oesophagus

Question 327

What are two examples of malignant neoplasm in the skin?

Answer 327

Basal cell carcinoma | Melanoma

Question 328

What is the basic stem of a benign tumour?

Answer 328

-oma

Question 329

What is the basic stem of an epithelial cell malignant neoplasm?

Answer 329

-carcinoma

Question 330

What is the basic stem of a connective tissue/ stromal neoplasm?

Answer 330

-sarcoma

Question 331

What is the name of a benign smooth muscle neoplasm?

Answer 331

Leiomyoma

Question 332

What is the name of a malignant smooth muscle neoplasm?

Answer 332

Leiomyosarcoma

Question 333

What is the name of a benign fibrous tissue neoplasm?

Answer 333

Fibroma

Question 334

What is the name of a malignant fibrous tissue neoplasm?

Answer 334

Fibrosarcoma

Question 335

What is the name of a benign bone neoplasm?

Answer 335

Osteoma

Question 336

What is the name of a malignant bone neoplasm?

Answer 336

Osteosarcoma

Question 337

What is the name of a benign cartilage neoplasm?

Answer 337

Chondroma

Question 338

What is the name of a malignant cartilage neoplasm?

Answer 338

Chondrosarcoma

Question 339

What is the name of a benign fat neoplasm?

Answer 339

Lipoma

Question 340

What is the name of a malignant fat neoplasm?

Answer 340

Liposarcoma

Question 341

What is the name of a benign nerve neoplasm?

Answer 341

Neurofibroma

Question 342

What is the name of a malignant nerve neoplasm?

Answer 342

Neurofibrosarcoma

Question 343

What is the name of a benign nerve sheath neoplasm?

Answer 343

Neurolemmoma

Question 344

What is the name of a malignant nerve sheath neoplasm?

Answer 344

Neurolemmosarcoma

Question 345

What is the name of a benign glial cell neoplasm?

Answer 345

Glioma

Question 346

What is the name of a malignant glial cell neoplasm?

Answer 346

Malignant glioma

Question 347

Are all lymphoid and haematopoeitic neoplasms regarded as benign or malignant?

Answer 347

Malignant

Question 348

What is the name given to a lymphoid neoplasm?

Answer 348

Lymphoma B and T In lymphoid tissue - usually in lymph nodes Hodgkin's disease and non Hodgkin's lymphoma

Question 349

What is the name given to a haematopoietic neoplasm?

Answer 349

Acute and chronic leukaemia occurs in bone marrow | Abnormal cells then enter the blood

Question 350

What is a myeloma?

Answer 350

Sounds like a benign muscle neoplasm BUT IT'S NOT! Malignant plasma cell neoplasm in bone marrow, destroying adjacent bone

Question 351

What is a germ cell neoplasm in the testes?

Answer 351

Malignant teratoma Seminoma BOTH MALIGNANT

Question 352

What is a germ cell neoplasm in the ovaries?

Answer 352

BENIGN Teratoma (dermoid cyst)

Question 353

What are the four main abnormal cellular accumulations?

Answer 353

Fluid Lipids Proteins Pigments

Question 354

How is fluid an abnormal cellular accumulation?

Answer 354

``` Water and electrolyte Vacuoles, hydropic swelling Osmotic disturbance to cell Severe cellular distress Problem to cell, organ, person Swelling in the brain – disrupts bloodflow ```

Question 355

How are lipids an abnormal cellular accumulation?

Answer 355

Steatosis (fatty change) – Accumulation of triglycerides – Often in liver – major organ of fat metabolism – Commonly caused by alcohol abuse, diabetes mellitus, obesity and toxins (carbon tetra chloride) – Mild steatosis – no effect on cell function Cholesterol – Accumulates within smooth-muscle cells and macrophages in atherosclerotic plaques – foam cells (due to foamy cytoplasm microscopically) – Cholesterol seen in macrophages within the skin or tendons of people with acquired or hereditary hyperlipidaemias – Xanthoma, xanthelasma

Question 356

How are proteins an abnormal cellular accumulation?

Answer 356

Seen as eosinophilic droplets or aggregates in cytoplasm – Mallory's hyaline is a damaged protein which is seen in hepatocytes in alcoholic liver disease and is due to accumulation of altered keratin filaments – In alpha-1 antitrypsin deficiency (genetically inherited disorder) the liver produces a version of alpha-1 antitrypsin which is incorrectly folded – can't be packaged by the endoplasmic reticulum and accumulates within this organelle and is not secreted by the liver – – Systemic deficiency of the enzyme means that proteases in the lung can act unchecked and so patients can develop emphysema as lung tissue is broken down

Question 357

How are pigments abnormal cellular accumulations?

Answer 357

Coloured substances – can be normal cellular constituents like Melanin Exogenous # ccarbon/coal/dust – Inhaled and phagocytosed by macrophages within the lung tissue – Seen as black and lung tissue (anthracosis) or blackened peribronchial lymph nodes (contains macrophages which have migrated from lungs) – High exposures (coalminers) lungs become fibrotic or emphysematous – Coal worker pneumoconiosis #Tattooing – Pigments phagocytosed by macrophages within the skin dermis which remain there indefinitely Endogenous # Lipofusin - brown pigment, ageing cells, no injury to cell, sign of previous free radical injury and lipid peroxidation # Haemosiderin - derived from Hb, brown/yellow, contains iron, forms where there is systemic accumulation of iron- e.g. A bruise - Haemosiderosis- excess deposition, can occur in haemolytic anaemias, blood transfusion and hereditary haemochromatosis (genetic increase in uptake of iron in the gut) - liver (cirrhosis), heart (dysfunction) and pancreas damage (bronzed diabetes) - Treatment- bleed people regularly # Bilirubin - bile pigment, jaundice- haemolytic anaemia, abnormal liver function

Question 358

What is pathological calcification and the two main types?

Answer 358

Abnormal deposition of calcium salts in tissues Dystrophic calcification Metastatic calcification

Question 359

What is dystrophic calcification?

Answer 359

Occurs in- are of dying tissue, atherosclerotic plaques, ageing, damaged heart valves(aortic not pulmonary- as it's believed that the acidic blood near pulmonary valves prevent calcification), tuberculus lymph nodes No abnormality in calcium metabolism or serum calcium concentration Can cause organ dysfunction (esp in atherosclerosis or calcified heart valves)

Question 360

What is metastatic calcification?

Answer 360

Calcium deposited in normal tissues where there is hypercalcaemia secondary to disturbances in calcium metabolism Asymptomatic Four main causes: – Increased secretion of parathyroid hormone resulting in bone resorption – due to parathyroid tumours/ectopic secretion of parathyroid hormone related peptide by malignant tumours – Destruction of bones secondary to primary tumours in the bone – for example leukaemia, metastases to bone, Paget's disease or immobilisation – Vitamin D related disorders – Renal failure

Question 361

Describe cellular ageing

Answer 361

All cells age – - they accumulate damage to cellular constituents - they accumulate lipofuscin pigment and abnormally folded proteins - replicative senescence (stop cells replicating when old) – Telomeres (ends on chromosome = aglets on shoelaces) get shorter with application – telomerase – make cells immortal; rebuilds telomeres back to normal length; believed that cancer cells can make telomerase

Question 362

What three substances can leak out of cells during oncosis?

Answer 362

Potassium Enzymes Myoglobin Causes inflammation, general toxic effects on body, substances to appear in high concentrations in the blood- this they can aid in diagnosis of illness

Question 363

What is the effect of high concentrations of K+ as a result of oncosis?

Answer 363

Toxic to heart cells High concentration of potassium causes heart to stop Liquid high in potassium is used in cardiac surgery to hold the heart still Potassium concentration the heart is usually low due to low circulation from affected peripheral parts of the body High potassium concentration in the heart is usually due to heart injury itself, or massive necrosis elsewhere (significant burns, tourniquet shock, tumour lysis)

Question 364

What is the effect of high concentrations of enzymes as a result of oncosis?

Answer 364

Enzymes with the smallest molecular weight and released first from oncotic cells – Heart – creatine kinase, troponins – Liver – AST

Question 365

What is the effect of high concentrations of myoglobin as a result of oncosis?

Answer 365

High concentration in striated muscle and endocardium Large damage to striated muscle – rabdomyolysis – increased by strenuous exercise and hot climate Excess myoglobin produced by striated muscle blocks up renal tubules – renal failure and DARK URINE

Question 366

What are the macroscopic features of necrosis?

Answer 366

Gangrene (Black) – necrosis visible to the naked eye Wet (pus) – infection; liquefactive; can lead to septicaemia Dry (umbilical cord) – ischaemia, hypoxaemia, infarcts; coagulative E.g. Ischaemic limbs

Question 367

What are the microscopic features of necrosis?

Answer 367

Contiguous groups of cells Coagulative – ischaemia, hypoxia, infarction – Protein denaturation > protease enzyme released – Ghost outline- cellular architecture preserved – Solid consistency of dead tissue – Followed by acute inflammatory reaction Liquefactive – infection – Protein denaturation < protease enzyme release – Tissue is lysed and disappears – Liquid/ pus Inflammation, enzymatic degradation, phagocytosis and dystrophic calcification of remaining necrotic tissue

Question 368

What are the electron microscopic features of necrosis?

Answer 368

Reversible – Decrease in oxidative phosphorylation causes a decrease in ATP… – Chromatin clumping – Swellings and blebs (oncosis) – Ribosome dispersal – Autophagy of lysozymes Irreversible – Large increase in cytosolic calcium activate enzymes… – Nuclear changes: pyknosis/karyolysis/ karyohexis – Lysosomal rupture – release of harmful enzymes – Plasma membrane rupture – myelin figures – ER lysis (proteases in Boston lipases) – Amorpheus densities in swollen mitochondrion (ATP breakdown) – Lipid peroxidation due to free radicals

Question 369

What are the microscopic features of apoptosis?

Answer 369

Single cells Cell shrinkage Plasma membrane intact

Question 370

What are the electron microscopic features of apoptosis?

Answer 370

Fragmentation in nucleus (karyohexis) to nucleosome sized fragments Apoptotic bodies – cell membrane breaks down into membrane-bound fragments (with constituents intact) by Caspase action Chromatin condensation Membrane budding

Question 371

What are the 5 main mechanisms of cell injury?

Answer 371

Metabolic derangements- e.g. Cyanide Inadequate production of reactive intermediates- glutathione Production of free radicals Alterations in calcium homeostasis Depletion of mitochondrial nucleotides and ATP

Question 372

What is another way (besides antioxidants) that the body protects itself from cell injury?

Answer 372

Another way in which the cell protects itself against the effects of injury is by utilising heat shock proteins. These proteins are concerned with the upkeep of cellular proteins. They are important when the folding step in protein synthesis goes astray or when proteins become denatured during cell injury. They ensure proteins are re-folded correctly. If this isn’t possible then the mis-folded protein is destroyed. Heat shock proteins are important in cell injury as the heat shock response plays a key role in maintaining protein viability and thus maximising cell survival.

Question 373

Describe how chemical injury to cells can occur?

Answer 373

Some chemicals act by combining with a cellular component, e.g., cyanide binds to mitochondrial cytochrome oxidase and blocks oxidative phosphorylation.

Question 374

What is ischaemic reperfusion injury?

Answer 374

If blood flow is returned to a tissue which has been subject to ischaemia but isn’t yet necrotic, sometimes the tissue injury that is then sustained is worse than if blood flow was not restored. This is called ischaemia-reperfusion injury. It may be due to:  Increased production of oxygen free radicals (see below) 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.

Question 375

What conditions favour resolution?

Answer 375

§ Minimal cell death and tissue damage § Occurrence in an organ or tissue that has regenerative capacity (e.g. liver) rather than one that cannot regenerate (e.g. heart, CNS) § Rapid destruction of causal agent (e.g. phagocytosis of bacteria) § Rapid removal of fluid and debris by good local vascular drainage

Question 376

What are the sequences of events that lead to resolution of acute inflammation?

Answer 376

§ Phagocytosis of bacteria by neutrophils and intracellular killing § Fibrinolysis § Phagocytosis of debris, especially by macrophages and carriage through lymphatics to the hilar lymph nodes § Disappearance of vascular dilatation (due to short half life of chemical mediators which cause vascular dilatation)

Question 377

What is suppuration wrt acute inflammation?

Answer 377

Formation of pus, a mixture of living and dying and dead neutrophils and bacteria, cellular debris and sometimes globules of lipid · Causative stimulus must be fairly persistent and is virtually always an infective agent, usually pyogenic bacteria (Staphylococcus aureus, Streptococcus pyogenes, Neisseria species) · Once pus begins to accumulate in a tissue it becomes surrounded by a pyogenic membrane (with sprouting capillaries, neutrophils and occasional fibroblasts)- manifestation of healing which results in granulation tissue and scarring = ABSCESS

Question 378

Describe an abscess

Answer 378

g = ABSCESS § Abscess: solid tissue, inflammatory exudate forces tissue apart, liquefactive necrosis in centre, may cause high pressure and pain, may cause tissue damage and squash adjacent tissues, difficult to treat as bacteria within cavity are inaccessible to antibodies and antibiotic drugs

Question 379

What is organisation wrt acute inflammation?

Answer 379

Replacement of tissues by granulation tissue as a part of the process of repair

Question 380

What circumstances favour organisation of tissue wrt acute inflammation?

Answer 380

§ Large amounts of fibrin are formed, which cannot be removed completely by fibrinolytic enzymes from the plasma or from neutrophil polymorphs § Substantial volumes of tissue become necrotic or if the dead tissue (fibrous tissue) is not easily digested § Exudate or debris cannot be removed or discharged

Question 381

What happens in organisation of tissue wrt acute inflammation?

Answer 381

During organisation: § New capillaries grow into the inert material § Macrophages migrate into the zone § Fibroblasts proliferate under the influence of TGF beta resulting in fibrosis and scar formation

Question 382

Why may acute inflammation progress onto chronic inflammation?

Answer 382

· Progression onto chronic inflammation · If the agent causing acute inflammation is not removed, the acute inflammation may progress to a chronic stage · In addition to organisation, character of cellular exudate changes, with lymphocytes, plasma cells and macrophages ( and multinucleate giant cells) replace the neutrophil polymorphs · Most of the time, chronic inflammation occurs as a primary event with no preceding acute inflammation

Question 383

What are 3 examples of hereditary conditions in which acute inflammation features?

Answer 383

Hereditary angio-oedema Alpha-1 antitrypsin deficiency Chronic granulomatous disease

Question 384

What is hereditary angio-oedema?

Answer 384

Hereditary acute inflammation o Hereditary Angio-Oedema is caused by a deficiency of C1 inhibitor. o C1 is a complement protein that cleaves C2 and C4 to form C3. o C1 inhibitor does not only inhibit C1, but Bradykinin too. Uninhibited Bradykinin vastly increases the permeability of endothelia, causing Oedema. o Hereditary Angio-Oedema is treated with C1 inhibitor infusion or fresh frozen plasma.

Question 385

What is α1-antitrpysin Deficiency?

Answer 385

Hereditary acute inflammation o α1-antitrpysin inhibits Elastase. o Without this inhibition elastase breaks down lung/liver tissue o Causes emphysema and Liver Sclerosis.

Question 386

What is chronic granulomatous disease?

Answer 386

``` Hereditary acute inflammation o Recessive sex linked o Immune phagocytes can't form ROS o Can't kill some bacteria without ROS o Granulomas formed in an attempt to contain the bacteria ```

Question 387

What are the main cells involved in acute inflammation?

Answer 387

Neutrophils | Macrophages

Question 388

What are some beneficial effects of acute inflammation?

Answer 388

§ Dilution of toxins (produced by bacteria) allows them to be carried away via lymphatics § There is entry of antibodies due to increased permeability of blood vessels into the extravascular space, where they may lead to either lysis of microorganisms (complement) or phagocytosis (opsonins) § Transport of drugs such as antibiotics to site where bacteria are multiplying § Fibrin formation from exuded fibrinogen may impede the movement of microorganisms, facilitating phagocytosis, and may also serve as a matrix for the formation of granulation tissue § Delivery of nutrients and oxygen, essential for neutrophil cells that may have high metabolic activity, aided by increased flow of blood through the region § Stimulation of an immune response by drainage of the fluid exudate to into the lymphatics, allows particulate soluble antigens to reach local lymph nodes, where they may stimulate an immune response § Triggers repair

Question 389

What are some harmful effects of acute inflammation?

Answer 389

§ Digestion of normal tissues- collegenases and proteases may cause vascular damage and digestion § Swelling- e.g. obstruction of airways (haemophilus influenza), cranial cavity (acute meningitis may raise intercranial pressure to the point where blood flow into the brain is impaired resulting in ischaemic damage) § Inappropriate inflammatory response- e.g. in type I hypersensitivity reactions (hay fever)

Question 390

What are the biological purposes of acute inflammation?

Answer 390

· Serves to destroy, dilute or wall off the injurious agent · Induces repair · Protective response

Question 391

What chemical mediators cause vasodilatation of arterioles and capillaries in acute inflammation?

Answer 391

Prostaglandins Histamine C3 C5a

Question 392

What chemical mediators cause increased vascular permeability of arterioles and capillaries in acute inflammation?

Answer 392

histamine, leukotrienes, bradykinin, nitric oxide (histamine, prostaglandins and kinins)

Question 393

What chemical mediators are involved in chemo taxis of neutrophils in acute inflammation?

Answer 393

C5a, LTB4, bacterial peptides

Question 394

In fever (a systemic consequence of acute inflammation) what chemical mediators are released?

Answer 394

IL1, TNF alpha and prostaglandins produced

Question 395

In acute phase response (a systemic consequence of acute inflammation) what acute phase proteins have altered plasma concentrations?

Answer 395

C reactive protein (CRP), alpha 1 antitrypsin, Haptoglobin, Fibrinogen, serum amyloid A protein

Question 396

What are the five main effects of chronic inflammation?

Answer 396

``` o Fibrosis o Impaired function • Rarely, increased function o Atrophy o Stimulation of immune response o Granulomatous inflammation/ GRANULOMA ```

Question 397

How are plasma cells involved in chronic inflammation?

Answer 397

Differentiated B cells Imply considerable chronicity Structure: clock faced nuclei/ lumpy bumpy chromatin; abundant pink blue cytoplasm filled with ER; pale halo around nucleus (Golgi) Function: Produce antibodies

Question 398

How can chronic cholecystitis (an example of chronic inflammation) be treated?

Answer 398

Surgical removal of gall bladder

Question 399

How can ulcerative colitis (an example of chronic inflammation) be treated?

Answer 399

Immunosuppression | Surgical removal of large bowel

Question 400

How can Crohn's disease (an example of chronic inflammation) be treated?

Answer 400

Lifestyle modifications Diet Hydration Immunosuppressants

Question 401

How can RA (an example of chronic inflammation) be treated?

Answer 401

Immunosuppressants

Question 402

When does fibrous repair and scarring occur?

Answer 402

Injury and inflammation- necrosis of permanent cells Injury and inflammation- necrosis of labile and stabile cells whose collagen framework is destroyed (if collagen framework is intact- results in resolution)

Question 403

Why does thrombosis occur?

Answer 403

Abnormalities of vessel walls- atheroma, direct injury, inflammation Abnormalities of blood flow- stagnation, turbulence Abnormalities of blood component- smokers, post partum, post operative; hypercoaguability

Question 404

What do arterial thrombi look like?

Answer 404

Pale Granular Lines of zahn Lower cell content

Question 405

What do venous thrombi look like?

Answer 405

Soft Gelatinous Deep red Higher cell content

Question 406

Where do thrombi most commonly occur?

Answer 406

In veins

Question 407

What are some arterial effects of thrombi?

Answer 407

Ischaemia Infarction Depends on site and collateral circulation

Question 408

What are some venous effects of thrombosis?

Answer 408

Congestion Infarction Oedema Ischaemia

Question 409

Briefly describe disseminated intravascular coagulation

Answer 409

DIC is a pathological activation of coagulation mechanisms that happens in response to a variety of diseases – infection, trauma, liver disease, obstetric complications Small clots form throughout the body, disrupting normal coagulation as they use up all the clotting factors Abnormal bleeding occurs from the skin

Question 410

What is invasion?

Answer 410

Invasion – The ability of cells to break through the basement membrane and spread Direct invasion – Into surrounding tissue Into Lymphatic/vascular channels

Question 411

What is metastasis?

Answer 411

Metastasis – The spread of a malignant tumour to a distant (i.e. non adjacent) site A metastasis is often referred to as a secondary tumour, with the site of origin being the primary tumour.

Question 412

What are the three main mechanisms that facilitate invasion and metastases?

Answer 412

-Altered Cell Adhesion Cell – Cell Interactions Reduced expression of Cadherins, which normally bind cells together, allows cells to move apart. Cell – Stroma Interactions Reduced expression of Integrins in malignant cells allows for movement. -Altered Enzyme Synthesis and Interaction Metastatic cells synthesise and release Matrix Metalloproteinases. These enzymes digest collagen, allowing the metastatic cells to digest the ECM and move to and break through the basement membrane. MMP1 – Type I Collagen MMP2/9 – Type IV Collagen -Angiogenesis Once a tumour has reached 1-2mm3 it’s growth is halted due to lack of nutrients/oxygen. This alters the tumour’s microenvironment, making it hypoxic. This causes the upregulation of pro-angiogenesis factors, e.g. angiopoietin, VEGF. This causes the growth of new, thin wall blood vessels that not only allows for the continued growth of the tumour but provides another opportunity to enter the bloodstream as well.

Question 413

How do tumours metastasise through the lymphatics?

Answer 413

Lymphatics - Spread to local and distant lymph nodes - Frequent route of spread of carcinomas (malignant epithelial tumour) - Can involve lymphatics of the lung

Question 414

How do tumours metastasise through the blood?

Answer 414

Spread through capillaries and veins to various organs. Common sites are lung, liver, bone and brain. - To Lung o Can occur with a wide range of malignant neoplasms o Sarcomas, e.g. osteocarcoma o Carcinomas, e.g. breast, stomach, large intestine o Kidney, e.g. “cannonball” o Testis, e.g. malignant teratoma - To Liver o Common site for carcinomas of the large intestine (portal vein) o Carcinomas, e.g. Bronchial, Breast - To Bone o Can cause destruction of bone, leading to pathological fracture • Carcinomas, e.g. Bronchial, Breast, Thyroid, Renal o Can cause produce of dense bone (Osteosclerosis) • Prostate - To Brain o Cause a wide range of neurological symptoms and act as a space occupying lesion (SOL) o Metastasis commonly from: • Bronchial carcinoma • Breast carcinoma • Testicular carcinoma • Malignant melanoma

Question 415

What are some local effects of a benign neoplasm?

Answer 415

``` Benign - Cause compression o Pressure atrophy o Altered function e.g. pituitary - In a hollow viscus cause partial or complete obstruction - Ulceration of surface mucosa - Space occupying lesion (brain) ```

Question 416

What are some local effects of a malignant neoplasm?

Answer 416

Malignant - Tend to destroy surrounding tissue - In a hollow viscus cause partial or complete obstruction, constriction - Ulceration - Infiltration around and into nerves, blood vessels, lymphatics - Space occupying lesion (brain)

Question 417

What are some systemic effects of benign and malignant neoplasms?

Answer 417

``` Haematological - Anaemia o Due to malignant infiltration of bone marrow (Leukaemia, metastasis) - Low white cell and platelets o Infiltration of bone marrow o Consequence of treatments - Thrombosis o Carcinoma of pancreas Endocrine - Excessive secretion of hormones o Benign and malignant neoplasms of endocrine glands e.g. parathyroid hormone, corticosteroids - Ectopic hormone secretion o ACTH by small cell carcinoma of bronchus Skin - Increased pigmentation o Many carcinomas - Pruritis (Itching) o Jaudice, Hodgkin’s disease - Herpes zoster o Lymphoma - Dermatomyositis o Bronchial carcinoma Neuromuscular - Problems with balance - Sensory/sensorimotor neuropathies - Myopathy and myasthenia - Progressive multifocal leucoencepalopathy - Not due to metastasis to the brain Cachexia Malaise Pyrexia ```

Question 418

What is cachexia?

Answer 418

Cachexia – Loss of weight, muscle atrophy, loss of appetite in someone who is not actively trying to lose weight

Question 419

What is malaise?

Answer 419

A feeling of general discomfort or uneasiness

Question 420

What is pyrexia?

Answer 420

Fever

Question 421

In what local and systemic ways can neoplasms kill people?

Answer 421

Local Effects – Raised ICP, perforation, haemorrhage (Benign or malignant) Systemic Effects – Replacement of essential body organs, bone marrow, lung tissue, liver parenchyma (Malignant neoplasms).

Question 422

What are 3 examples of inherited susceptibility to the formation of tumours?

Answer 422

Retinitis (Xeroderma) Pigmentosum Increased risk of skin cancers when exposed to UV rays in sunlight Ataxia Telangiectasia Defective response to radiation damage, profound susceptibility to lymphoid malignancies, usually die before age 20 Fanconi’s Anaemia Sensitivity to DNA cross-linking agents, marrow hypo function and multiple congenital anomalies, predisposition to cancer

Question 423

What are protooncogenes? And how can changes to these genes result in neoplasia?

Answer 423

Proto-Oncogenes – A normal gene that can become an oncogene due to mutations or increased expression Proto-oncogenes are present in all normal cells, and are involved in normal growth and differentiation. They have a DNA sequence identical to viral oncogenes. Proto-Oncogenes can be modified to become oncogenes (Mutation, amplification, translocation), making their products oncoproteins. This allows the cell to escape normal growth control, becoming self sufficient without external signals required to grow. Only one allele of a proto-oncogene needs to be mutated to cause neoplasia.

Question 424

What is the role of Ras? (an oncogene)

Answer 424

Normally transmits growth-promoting signals to the nucleus - Mutant Ras is permanently activated resulting in continuous stimulation of cells - 15-20% of all Cancers - Colon and lung cancer

Question 425

What is the role of c-myc? (An oncogene)

Answer 425

- Binds to DNA, stimulates synthesis - Amplified (over-expressed) o Neuroblastoma, breast cancer - Translocation 8 à 14 o Burkitt’s lymphoma

Question 426

What is the role of HER-2? (An oncogene)

Answer 426

- Encodes for a growth factor receptor - Amplified (over-expressed) - ~25% of breast cancers - Herceptin is a competitive antagonist at the HER-2 Receptor

Question 427

What are tumour suppressor genes? And how can changes to these genes result in neoplasia?

Answer 427

Tumour Suppressor Genes – A gene that encodes proteins that suppress growth and therefore cancer In normal cells, Tumour Suppressor Genes encode proteins that suppress growth. Loss or alteration of the gene results in the loss of growth suppression. Both alleles of a Tumour Suppressor gene need to be mutated to produce neoplasia (Knudson’s 2-hit hypothesis). Inheritance of the ‘First Hit’ can lead to susceptibility to cancers.

Question 428

What is the role of pRb? (A tumour suppressor gene)

Answer 428

- Passage beyond the R checkpoint at G1àS boundary is governed by the phosphorylation of pRb. - A defect in both alleles of pRb leads to the cell escaping cell cycle control. - Retinoblastoma

Question 429

What is the role of p53? (A tumour suppressor gene)

Answer 429

- ‘Guardian of the genome’ - Approximately 50% of tumour contain p53 mutations - Gene encodes a nuclear protein, which binds to and modulates expression of genes important for cell-cycle arrest, DNA repair and Apoptosis

Question 430

Describe the initiation and promotion stages of neoplasm

Answer 430

Initiator Carcinogenic agent, e.g. polycyclic hydrocarbon, radiation - Exposure of cells to a sufficient dose of initiator - Cell is altered, potentially capable of producing tumour - Permanent DNA damage (mutations) - Irreversible and has ‘memory’ - Effect modified by genetic factors, DNA repair - Initiation alone is not sufficient for tumour formation Promoters: E.g. Hormones, local tissue responses, immune responses - Can induce tumours in initiated cells - Non-tumourigenic on their own - Need exposure after initiation - Cellular changes are reversible o Remove promoter and cell should be okay and return to normal - Enhance proliferations, especially in mutated cells and increase incidence of further mutations – can result in cancer o Think of all the mutations necessary for metastasis… this makes it more likely

Question 431

What are the 3 stages of neoplasm formation?

Answer 431

Initiation Promotion Progression

Question 432

How can radiation cause neoplasm?

Answer 432

Radiation Causes a wide range of different types of damage to DNA, including single/double strand breaks and base damage. The effect depend on the quality of radiation and the dose. If DNA repair mechanisms are overwhelmed, leaving DNA damage unrepaired, mutations in oncogenes/Tumour suppressor genes can lead to cancer. - Ionising radiation o E.g. Hiroshima (Early leukaemia/lymphoma à Late Thyroid/breast) - Ultraviolet radiation o E.g. Squamous cell carcinoma, Basal cell carcinoma, Malignant melanoma

Question 433

How can chemicals cause neoplasm?

Answer 433

Chemicals Carcinogens interact with DNA in one of a number of ways. Some act directly, others require metabolic conversion to an active form. - Polycyclic aromatic hydrocarbons o Produced in combustion of tobacco and fossil fueld o Hydroxylated to active form o Lung Cancer, bladder cancer, skin cancer (scrotal skin in chimney sweeps) - Aromatic Amines o Hydroxylated in liver and conjugated with glucuronic acid (Phase 2 drug metabolism, non toxic) o Deconjugated to active form in urinary tract by urinary glucuronidase o Active form sits in bladder à Bladder cancer o Rubber and dye workers - Alkylating Agents o Bind directly to DNA – Nitrogen mustard

Question 434

How can viruses cause neoplasm?

Answer 434

Viruses - Hepatitis B o Associated with hepatocellular carcinoma o Viral DNA integrated into host cell genome o Virus causes liver cell injury à Regenerative hyperplasia o Increased cell division gives increased risk of genetic changes - Epstein Barr o Implicated in the pathogenesis of Burkitt’s Lymphoma, Some Hodgkin’s lymphoma, Nasopharyneal carcinoma o Infects epithelial cells or oropharynx and B cells o Viral genes dysregulate normal proliferative and survival signals o Sets the stage for acquisition of mutations - Human Papilloma o HPV genes disrupt normal cell cycle o Viral genes incorporated into host cell genome, driving proliferation

Question 435

How do other agents besides radiation, viruses and chemicals cause neoplasms?

Answer 435

``` Other Agents - Asbestos o Malignant mesothelioma, lung cancer - Aflatoxins o Hepatocellular carcinoma (collaborates with HBV) - Schistosoma o Bladder cancer - Helicobacter o Gastric cancer and lymphoma - Hormones o Androgens and hepatocellular carcinoma ```

Question 436

What 3 conditions predispose individuals to the development of neoplasms?

Answer 436

Ulcerative Colitis - Colorectal carcinoma - DNA damage and microsatellite instability - May mask symptom of cancer Cirrhosis - In west present in 85-90% of hepatocellular carcinoma - Some of association due to chronic viral hepatitis Adenoma of colon/rectum - Adenocarcinoma

Question 437

What is staging? And describe the basic staging process?

Answer 437

Staging – The extent of spread of tumour TMN Staging System - T = Primary Tumour - N = Regional Lymph Node involvement - M = Metastasis TMN varies for each specific form of cancer, but the general principles are: - With increasing size in primary lesion, T1 à T4 - N0 = No nodal involvement, N1 à N3 = involvement of an increasing no./range of nodes - M0 = No distant metastases, M1 = Presence of blood borne metastases

Question 438

Describe TNM staging for breast cancer

Answer 438

``` TNM Staging for Breast Cancer TIS – Carcinoma in situ T1 - < 2cm T2 – 2-5cm T3 - > 5 cm T4 – Through the chest wall/skin ``` N0 – No nodal N1 – Axillary N2 – Mammary N3 - Supraclavicular M0 – No metastasis M1 – Presence of metastasis

Question 439

Describe dukes staging for colorectal carcinomas

Answer 439

``` Dukes’ Staging for Colorectal Carcinomas - A o Confined to bowel wall o Not extending through muscularis propria o >90% 5 year survival - B o Through bowel wall (Muscularis propria) o 70% 5 year survival - C1/2 o Lymph nodes involved o 30% 5 year survival o C1 = Regional Lymph nodes involved o C2 = Apical node (furthest away node) involved ```

Question 440

What system is used to classify Hodgkin's disease?

Answer 440

Hodgkin’s Disease – Ann Arbor Classification I – One lymph node involved II – Two lymph nodes on one side of the diaphragm III - > Two lymph nodes on both sides of the diaphragm IV – Multiple foci (Bloody everywhere)

Question 441

What is grading?

Answer 441

Grading – Based on the degree of differentiation of tumour cells. Attempts to judge the extent to which tumour cells resemble or fail to resemble their normal counterparts. Graded 1-3 or 1-4 with increasing anaplasia. Gx = Grade of differentiation cannot be assessed G1 = Well differentiated G2 = Moderately differentiated G3 = Poorly differentiated G4 = Undifferentiated

Question 442

How is breast carcinoma graded?

Answer 442

``` Grading of Breast Carcinoma Scarff-Bloom-Richardson Grading system - Degree of tubule formation - Extent of nuclear variation - Number of mitoses ``` Grade 1 – 85% 10-year survival Grade 2 – 60% 10-year survival Grade 3 – 15% 10-year survival

Question 443

How is prostate carcinoma graded?

Answer 443

Prostate Carcinoma – Gleason Grading System

Question 444

What is radiotherapy and how is it used in treatment of cancer?

Answer 444

Radiotherapy - External radiation to rumour at fractionated doses with shielding of adjacent normal tissues - Causes damage to DNA of rapidly dividing cells - If DNA damage is extensive à Apoptosis ``` Sensitivity: - High o Lymphoma o Leukaemia o Seminoma (Testicular) - Fairly High o Squamous carcinomas - Moderate o GI, Breast - Low o Sarcoma ```

Question 445

What is chemotherapy and how is it used in the treatment of cancer?

Answer 445

``` Chemotherapy Drugs used have effects at particular stages of the cell cycle. Also have effects on rapidly dividing cells, e.g. bone marrow. - Cyclophosphamide o Act on cells in G1/S and mitosis - Vincristine o Block cells entering cell cycle/act on mitosis - Methotrexate o Acts on cells in S phase ```

Question 446

What is hormone therapy and how is it used in the treatment of cancer?

Answer 446

Hormone Therapy - Tamoxifen o Competes for binding to Oestrogen Receptor o 50-80% of Breast Cancers express oestrogen receptors o Surgical (Orchidectomy)/clinical castration - Herceptin o HER-2 Growth factor receptor o Overexpressed in 20-30% of breast carcinomas o Herceptin = Humanised monoclonal antibody o Side effects – Cardiac/pulmonary toxicity, can be fatal - Prostate Cancer o Depends on androgens o To treat, deprive tumour of testosterone

Question 447

What three tumour markers are used the diagnosis and monitoring of cancer?

Answer 447

Carcinoembryonic Antigen Human Chorionic Gonadotrophin Alpha-Fetoprotein (AFP)

Question 448

What is carcinoembryonic antigen?

Answer 448

Tumour marker used in the diagnosis and monitoring of cancer. Normally only in embryonic tissue, but cancer basically does what it wants and expresses it again. It is clinically useful to see if there is any residual disease left after the removal of tumours.

Question 449

What is human chorionic gonadotropin?

Answer 449

Tumour marker used in the diagnosis and monitoring of cancer. Used in: - The evaluation of testicular masses - To indicate residual disease after Orchidectomy - In monitoring response to therapy and prediction of recurrence - Raised in nonseminomatous testicular tumours, especially when choriocarcinomatous elements present (high levels) - Seminomas with syncytiotrophoblastic giant cells

Question 450

What is alpha feto protein (AFP)?

Answer 450

Tumour marker used in the diagnosis and monitoring of cancer. - Normally synthesised early in foetal life by yolk sac, foetal liver and foetal GIT. - Raised plasma levels associated with cancer of liver and yolk sac tumour of testis (nonseminomatous testicular tumours)

Question 451

Why is screening for cancers beneficial?

Answer 451

Screening aims to detect pre-malignant, non invasive and early invasive cancers to improve prognosis

Question 452

Describe cervical screening

Answer 452

Cervix - Cytological smears to detect “early” pre-cancerous changes o Cervical Intraepithelial Neoplasia (CIN) - Treatment can then be given before invasion occurs and is curative ``` Age 25 Years- First invitation 25-49- 3 Yearly 50-64- 5 Yearly 65+ - Those who have no been screened since age 50 or who have had recent abnormalities ```

Question 453

Describe breast screening

Answer 453

Identify invasive cancers before they can be felt o 10-15mm in size - Relies on mammography (x-ray of breast) o Identifies densities and calcifications - Of every 500 women screened, one life will be saved - 50-69 years o Every 3 years