Mechanisms Of Disease Flashcards
What is hypoxaemic hypoxia?
Arterial content of oxygen is low (high altitude, secondary to lung disease)
What are the 7 main causes of cell injury?
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
What is anaemic hypoxia?
Decreased ability of Hb to carry oxygen (anaemia, CO poisoning)
What is ischaemic hypoxia?
Interruption to blood supply (blockage of vessels, heart failure)
What is histiocytic hypoxia?
Inability to utilise oxygen, in cells dues to disabled ox phos enzymes (cyanide poisoning)
What reversible metabolic cell injury occurs as a result of hypoxia?
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
What reversible structural cell injury occurs as a result of hypoxia?
Swelling
Chromatin clumping
Autophagy with lysosomes (normal functioning)
Ribosomes dispersal
Bless (little bumps on the membrane surface where cytoskeleton has detached)
What irreversible metabolic cell injury occurs as a result of hypoxia?
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)
What irreversible structural cell injury occurs as a result of hypoxia?
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
What are the two main types of cell death?
Oncosis/ Necrosis
Apoptosis
What is Oncosis?
Spectrum of changes that occur in injured cells prior to death
Swelling of the cell
Contiguous groups of cells
What is necrosis?
(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
What are the two main types of necrosis and the two not so common types of necrosis?
Coagulative and liquefactive necrosis
Fat and caseous necrosis
What is coagulative necrosis?
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
What is liquefactive necrosis?
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)
What is gangrene?
Necrosis visible to the naked eye
What type of gangrene forms as a result of coagulative necrosis?
Dry gangrene (umbilical cord)
What type of gangrene forms as a result of liquefactive necrosis?
Wet gangrene - usually due to infection
Where is gangrene most like to appear the body?
In ischaemic limbs - legs
It is dead and so cannot be salvaged
What is an infarct?
Area of necrosis due to ischaemia
(coagulative- heart, liver and spleen/ liquefactive- brain)
Can be white and red
What is white infarct and its causes?
Area of no blood
Obstruction of end artery (heart, kidney, spleen)
What is a red infarct and its causes?
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
What is an infarction?
Process of ischaemic necrosis
What is infarction caused by?
Thrombosis
Embolism
External compression of vein
Twisting of vessels
What is apoptosis?
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
When does apoptosis occur?
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
What is caseous necrosis?
Amorphous (structureless) debris (no ghost outline) Particularly associated with TB Granulomatous inflammation (chronic)
What is fat necrosis?
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
What are the two initiation and execution processes of apoptosis?
Intrinsic
Extrinsic
Describe intrinsic initiation and execution of apoptosis
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
Describe the extrinsic initiation and execution process of apoptosis
Rector mediated
Caused by external ligands (TRAIL and Fas)
Bind to death receptors (TRAIL R)
Activates caspases (independently of mitochondria)
Describe the degradation/ phagocytosis stage of apoptosis
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
Review free radicals and how they can cause cell damage
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.
Review alcohol metabolism and how it can cause cell damage
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.
Review paracetamol metabolism and overdose and how it can cause cell damage
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.
Review aspirin overdose and how it can cause cell damage
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.
What is acute inflammation?
Acute inflammation is the response of living tissue to injury, initiated to limit the tissue damage.
What are the main causes of acute inflammation?
Causes of Acute Inflammation: - Microbial infections o E.g. Pyogenic Organisms - Hypersensitivity reactions (acute phase) - Physical agents - Chemicals - Tissue necrosis
What are the macroscopic features of acute inflammation?
Calor – Heat
Rubor – Erytherma (Redness)
Tumor – Oedema (Swelling)
Dolor – Pain and loss of function
What are the main microscopic features of acute inflammation?
- Vasodilation
Small adjacent blood vessels dilate with increased blood flow. - Gaps form in endothelium
Endothelial cells swell and retract; there is no longer a completed intact internal lining. - Exudation
Vessels become leaky. Water, salts and small plasma proteins leak through. (Exudate) - Margination and Emigration
Circulating neutrophils adhere to swollen endothelial cells. (Margination.)
Neutrophils then migrate through the vessel basement membrane. (Emigration). - Macrophages and Lymphocytes
Migrate in a similar way to Neutrophils.
What are some of the chemical mediators of acute inflammation?
Vasodilation- histamine, prostaglandins, C3a and C5-
Increase vascular permeability- histamine, prostaglandins, kinins
Emigration of leukocytes- leukotrienes, IL 8, C5a
Describe the initiation and the action of neutrophils
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.
What are some local complications of acute inflammation?
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
What are some systemic complications of acute inflammation?
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.
What may happen after the development of acute inflammation? (Sequelae)
- Complete resolution
- Suppurations- pus and abscess formation
- Organisation- formation of granulation tissue- a bit of chronic inflammation and fibrous repair
- Progression of acute inflammation onto chronic inflammation
- Death
What is resolution?
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.
What are skin blisters? (As an example of acute inflammation)
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
What is an abscess? (As an example of acute inflammation)
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
What is pericarditis? (As an example of acute inflammation)
Pericarditis
- Inflammation of serous cavity
- Pericardium becomes inflamed and increases pressure on the heart
Lobar pneumoniae ? (As an example of acute inflammation)
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
Bacterial meningitis? (As an example of acute inflammation)
· Bacterial Meningitis
· Fluid accumulates in space between pia and arachnoid mater
· Acute inflammation in meninges can cause vascular thrombosis and reduced cerebral perfusion
What is chronic inflammation?
Chronic response to injury with associated FIBROSIS
What are the main causes of chronic inflammation?
- 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) - 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) - May develop alongside acute inflammation
o In severe, persistent or repeated irritation
o Chronic low-level irritation
What are the main effects of chronic inflammation and what are some examples of diseases/conditions where these effects are apparent?
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
What is chronic cholecystitis? (As an example of chronic inflammation)
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
What is gastric ulceration? (As an example of chronic inflammation)
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
What is Inflammatory bowel disease? (As an example of chronic inflammation)
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
What is cirrhosis? (As an example of chronic inflammation)
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
What is thyrotoxicosis? (As an example of chronic inflammation)
INCREASED FUNCTION caused by chronic inflammation
Graves’ disease – autoimmune, stimulates TSH receptors, causes hyperthyroidism
What is atrophic gastritis? (As an example of chronic inflammation)
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
What is rheumatoid arthritis? (As an example of chronic inflammation)
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
What are the 7 main types of cells involved in chronic inflammation?
Macrophages Lymphocytes Eosinophils Plasma cells Fibroblasts Myofibroblasts Giant cells
How are macrophages involved in chronic inflammation?
- 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
How are lymphocytes involved in chronic inflammation?
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
How are eosinophils involved in chronic inflammation?
- Structure: bilobed nucleus (Mickey Mouse head)
- Function:
o Allergic reactions
o Parasite infections
o Some tumours
How are fibroblasts/ myofibroblasts involved in chronic inflammation?
- Recruited my macrophages
- Structure: spindle shaped
- Function- make collagen-FIBROSIS; contract in repair/healing
How are giant cells involved in chronic inflammation?
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)
What do macrophages look like?
Lots of granular cytoplasm
Large central nucleus
What do you lymphocytes look like?
Large nucleus
Little/no cytoplasm
What do Plasma cells look like?
Clockface nucleus/lumpy bumpy chromatin
Abundant pink/blue cytoplasm filled with ER
Pale halo around nucleus= Golgi apparatus
What do Eosinophils look like?
Bilobed nucleus
Mickeys mouse head
What do fibroblasts/Myofibroblasts look like?
Spindle-shaped
What do Langhans giant cells look like?
Horseshoe arrangement of nuclei around periphery
What do Touton giant cells look like?
Like Langhans but smaller
What do foreign body giant cells look like?
Distorted mishmash
Give examples of how proportions of each cell type may vary in different conditions
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
What is granulomatous inflammation?
Chronic inflammation with granulomas
What is a granuloma?
Mass of macrophages (epitheloid histiocytes- modified and immobile) and lymphocytes
When do granulomas form?
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.
What are the main causes of granulomatous inflammation?
- 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
What is Tuberculosis? (an example of chronic inflammation)
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
What are some outcomes of tuberculosis?
- Arrest, fibrosis, scarring
- Erosion into bronchus (bronchopneumonia- severe acute inflammation process in living, TB in GIT- coughed up and swallowed from lungs)
- Tuberculous empyema (collection of pus)
- Erosion into blood stream
What are some other examples of granulomatous infections?
Leprosy, syphilis,chronic fungal infections, cat scratch disease, xanthogranulomatous, pyelonephritis and Malakoplakia
What are some examples of granulomatous diseases of unknown cause?
Sarcoidosis
Crohn’s disease
Wegener’s granulomatosis
What is sarcoidosis? (an example of chronic inflammation of unknown cause)
Variable clinical manifestations/unknown cause
Young adult women
Non caseating granulomas, giant cells
Involves lymph nodes, lungs
What is Crohn’s disease?
Regional enteritis: patchy full thickness inflammation thoughout the bowel
What is regeneration?
The replacement of dead or damage cells by functional, differentiated cells
Where do differentiated cells needed in regeneration derive from?
Stem cells
What are stem cells?
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
What are 3 examples of where stem cells are used?
Early life
Internal repair system to repair lost or damage cells and tissues
Therapeutic utility in degenerative disease
What does Unipotent mean?
Cell can only produce one type of differentiated cell
For example, epithelia
What does multipotent mean?
Cell can produce several different types of differentiated cell
For example, haematopoetic cells
What does totipotent mean?
Cell can produce any type of cell
For example, embryonic stem cells
How does the propensity to regenerate vary between cell types?
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
What factors are thought to control regeneration?
-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
What is fibrous repair?
The replacement of functional tissue by scar tissue
What are three key components of fibrous repair?
Cell migration
Angiogenesis
Extracellular matrix
How is cell migration involved in fibrous repair?
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
How is angiogenesis involved in fibrous repair?
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
What is the process of angiogenesis?
Endothelial proteolysis of basement membrane
Migration of endothelial cells by chemotaxis
Endothelial proliferation
Endothelial maturation and tubular remodelling
Recruitment of periendothelial cells
How is the extracellular matrix involved in cellular repair?
It facilitates cell migration and contains collagen important in fibrous repair
What are the functions of the extracellular matrix?
Supports and anchors cell Separates tissue compartments (e.g. Basement membrane) Sequesters growth factors Allows communication between cells Facilitates cell migration
What does the extracellular matrix in fibrous repair contain?
Collagen
Matrix glycoproteins
Proteoglycans
Elastin
What is collagen?
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
What are matrix glycoproteins important for in fibrous repair and give some examples?
Organise and orientate cells, support cell migration
Fibronectin, laminin, and tenascin
What are proteoglycans important for in fibrous repair and give some examples?
Matrix organisation, cell support, regulate availability of growth factors
Heparan sulphate proteoglycan
What is elastin important for in fibrous repair?
Provides tissue elasticity
Describe collagen synthesis
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
What are some defects of the synthesis of collagen?
-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
What is the mechanism of fibrous repair?
-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
How was the mechanism of fibrous repair discovered?
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
How is fibrous repair controlled?
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
Describe the regeneration and repair of skin
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
Compare secondary with primary intention healing of skin
Produces more contraction to reduce volume of defect
Produces more a larger scar, not necessarily weaker
Takes longer
Describe the regeneration and repair of bone
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
Describe the regeneration and repair of the liver
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
Describe the regeneration and repair of the kidney
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
Describe the regeneration repair of the heart
Cannot regenerate
Causes scarring and fibrosis
Cardiomyocytes are terminally differentiated and cannot divide
Describe the regeneration and repair of cartilage
Cannot regenerate
Describe the regeneration and repair of peripheral nerves
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
Describe the regeneration and repair of the central nervous system
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
What are some local factors which influence wound healing?
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
What are some systemic factors which influence wound healing?
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
What are some complications of repair?
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
What is a stricture?
Obstruction of a tube and channel
What is a contracture?
Iimitation of the joint movement
What is chronic granulomatous disease?
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
What is angio-oedema?
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
What is haemostasis?
Process of stopping a haemorrhage/excessive bleeding
How fast does haemostasis have to occur and why?
Has to occur within seconds to prevent blood loss
What are the three steps of haemostasis?
- 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)
- 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.
- 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.
What are two conditions where there is defective haemostasis?
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
What four things does successful haemostasis depend on?
Blood vessel walls
Platelets
Coagulation
Fibrinolysis
What are some activators of platelets?
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
How are platelets involved in haemostasis?
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)
Describe some features of the platelets release reaction
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
How is coagulation involved in haemostasis?
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)
What are the two pathways of coagulation and what are there differences?
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.
What is retraction/contraction of a clot?
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
What is the purpose of clot retraction?
Possibly to toughen the clot by squeezing out fluid. It also helps in pulling together the sides of small wounds.
What factors oppose clotting?
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
How is fibrinolysis involved in haemostasis?
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.
How does plasmin breakdown a fibrin clot?
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
How are plasminogen factors used therapeutically?
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
How is the blood vessel (vascular) wall involved in haemostasis?
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
How does the endothelium perform a balancing act between opposing and favouring clotting?
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
What are some antithrombotic substances that the endothelium secretes?
Plasminogen activators
Prostacyclin
Nitric oxide
Thrombomodulin
Define thrombosis
Formation of a solid mass of blood within the circulatory system
Inappropriate haemostasis
When does a thrombus form?
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
Why do thrombi form?
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
How does a change in vessel wall (in particular endothelial damage) affect the formation of a thrombus?
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
How does a change in blood flow (in particular sluggish flow) affect the formation of a thrombus?
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
How do changes in blood components (in particular hypercoaguability) affect formation of a thrombus?
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
How is a thrombus formed in a post surgical patient?
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
What is a parietal thrombus?
Thrombus which restricts the lumen of the vessel
What is an occlusive thrombus?
Thrombus which fills and obstructs a lumen
What is the most important mechanism for limiting the spread of thrombus?
Blood flow
What does an arterial thrombi look like?
Pale, granular, lines of zahn (white- platelets/ red- red blood cells), lower cell content
What does a venous thrombi look like?
Soft
Gelatinous
Dee red
Higher cell content
What are the outcomes of thrombosis?
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
What is the difference between a thrombus and post mortem clot?
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!
What is a thrombus on a cardiac valve called and what are some key features?
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
What are the most dangerous sources of emboli?
Thrombi in the large veins of the lower limbs – femoral/iliac/popliteal veins
Is pain always present when a thrombus forms?
Pain is not always present when a thrombus forms (although it often is in thrombi in superficial veins (thrombophlebitis – even though there are aseptic))
How does aspirin prevent thrombus formation?
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
What is disseminated intravascular coagulation?
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
Define embolus
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
What is an embolism?
Impaction open embolus
Why can’t an embolism form in a vein?
It can’t occur in veins as bloodflow is from smaller to larger vessels
Where do most emboli arise from?
From thrombus in Thromboembolism
Besides arising from a thrombus, what else can an emboli arise from?
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
Where do emboli from peripheral veins or the right heart end up in?
Lungs
Where do emboli from the left heart or aorta end up in?
Anywhere in the systemic circulation especially the lower limbs
Describe pulmonary saddle emboli
Large emboli become lodged in both pulmonary arteries= saddle emboli. They are usually fatal.
Where do majority of pulmonary emboli arise?
Approximately 80% arise in thrombi in the deep veins of the thigh and the popliteal vein
What are the three severities of pulmonary emboli?
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
What are some predisposing factors of deep vein thrombosis?
Immobility Bed rest Post operative Pregnancy Postpartum Oral contraceptives Severe burns Cardiac failure Disseminated cancer
How can DVT be prevented?
High risk patients must be identified and offered prophylaxis Heparin subcutaneously Leg compression during surgery Mobility after surgery Thrombolytic drugs
How can DVT be treated?
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
How can pulmonary embolism be prevented?
By putting an umbrella shaped filter in the inferior vena cava
Why are thrombi often seen in the left heart?
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.
What are paradoxial emboli?
Emboli that arise in systemic veins that embolise in the systemic arteries
How do paradoxical emboli bypass the lungs?
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.
What is a TIA?
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
What is a gas emboli?
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
What is fat and bone marrow emboli?
- 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
What is latrogenic embolism?
Embolism due to medical treatment, e.g. air embolism from an injection or axilla surgery
What is nitrogen embolism?
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)
What is cerebral embolism?
- Atrial fibrillation –> Stasis –>Thrombus
- If in left heart, can go to the brain and cause a stoke or transient ischaemic attack
Where will a thromboembolism from the systemic veins go?
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.
Where will thromboembolism from the heart go?
Pass via the aorta to renal, mesenteric and other arteries
Where will thromboembolisms from the atheromatous carotid arteries go?
To the brain (Stroke)
Where will thromboembolisms from the atheromatous abdominal aorta go?
To the arteries of the legs
Describe haemophilia
- 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
Describe Thrombocytopenia
- 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
What is atheroma?
Atheroma is the accumulation of intracellular and extracellular lipid in the intima and media of large and medium-sized arteries
What is atherosclerosis?
The thickening and hardening of arterial walls as a consequence of atheroma
What is arteriosclerosis?
The thickening of walls of arteries and arterioles usually as a result of hypertension or diabetes mellitus
What are the three broad macroscopic features of atheroma?
A fatty streak
A simple plaque
The complicated plaque
Describe some features of the fatty streak
Lipid deposits in intima
Yellow, slightly raised
Precursor to atheroma
Describe some features of the simple plaque
Raised yellow/white
Irregular outline
Widely distributed
Enlarge and coalesce to form the extensive atheroma
Describe some features of the complicated plaque
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
What are some common sites of atheroma?
Aorta – especially abdominal (between renal and aortic bifurcation) Coronary arteries Carotid arteries (--> strokes) Cerebral arteries (--> strokes) Leg arteries
What is the normal basic arterial structure?
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
What are the microscopic features of atheroma?
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
What are some clinical effects of atheroma?
Ischaemic heart disease Myocardial infarction Cerebral ischaemia Mesenteric ischaemia Peripheral vascular disease Abdominal aortic aneurysm
What are some possible consequences of ischaemic heart disease?
Sudden death Myocardial infarction Angina pectoris Arrhythmias Cardiac failure
Describe cerebral ischaemia
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
Describe mesenteric ischaemia
Ischaemic colitis
Malabsorption
Intestinal infarction
Aneurysm- high-pressure – hardened and weakened wall
Describe peripheral vascular disease
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)
What are the risk factors of atheroma?
Age Gender Hyperlipidaemia Cigarette smoking Hypertension Diabetes mellitus Alcohol consumption Infection Lack of exercise Obesity Softwater Oral contraceptives Stress and personality type Genetic predisposition
How is age related to atheroma formation?
Slowly progressive throughout life of adults
Risk factors operate over years
How is gender associated with atheroma formation?
Women protected relatively before menopause
Presumed hormonal basis
Men are more likely to develop atheroma that women
How is hyperlipidaemia associated with atheroma formation?
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
How is cigarette smoking associated with atheroma formation?
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
How is hypertension associated with atheroma formation?
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
How is diabetes mellitus associated with atheroma formation?
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
How is alcohol consumption related to atheroma formation?
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
How is infection associated with atheroma formation?
Chlamydia pneumoniae
Helicobacter pylori – stomach
Cytomegalovirus
How is genetic predisposition associated with atheroma formation?
Familial predisposition is well known
Possibly due to – variations in apolipoprotein metabolism, variations in apolipoproteins receptors
Not a single gene defect – genetic and environmental
What is the pathogenesis of atherosclerosis?
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
What are some complications of atheromatous plaques?
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.
What cells are involved in atheroma formation?
Endothelial cells Platelets Smooth muscle cells Macrophages Lymphocytes Neutrophils
How are endothelial cells involved in atheroma formation?
Key role in haemostasis
Altered Permeability to lipoproteins
Secretion of collagen
Stimulation of proliferation and migration of smooth-muscle cells
How are platelets involved in atheroma formation?
Key role in haemostasis
Stimulate proliferation and migration of smooth muscle cells (PDGF)
How are macrophages involved in atheroma formation?
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
How are lymphocytes involved in atheroma formation?
TNF may affect lipoprotein metabolism
Stimulates proliferation and migration of smooth muscle cells
How are neutrophils involved in atheroma formation?
Secrete proteases leading to continued local damage and inflammation
How can atheroma be prevented?
No smoking Reduced fat intake Treat hypertension Not too much alcohol Regular exercise, weight control But still may develop atheroma
What interventions can be taken to reduce the likelihood of an atheroma?
Stop smoking Modify diet Treat hypertension Treat diabetes mellitus Lipid-lowering drugs like statins
What does the size of the cell population depend on?
The rate of:
Cell proliferation
Cell differentiation
Cell death by apoptosis
In what two ways do the number of cells increase?
Increased cell proliferation
Decreased cell death
What is cell proliferation regulated by?
Proto oncogenes
What do cells use to communicate with one another?
Chemical signals which can be contact dependent or soluble
How do chemical signals affect cell proliferation?
They inhibit or stimulate cell proliferation
What are four outcomes that chemical signals can have on cell proliferation?
Divide (enter the cell cycle)
Differentiate (take on specialised form or function)
Survive (resist apoptosis)
Die (ungrounded apoptosis)
What three categories can chemical signals fall into?
Autocrine- Intracrine
Paracrine
Endocrine
What does autocrine mean?
Cells respond to signals they produce
What does paracrine mean?
Cells produce signals that act on close and different cells (e.g. Local mediators)
What does endocrine mean?
Cells produce hormones that go into the bloodstream to target cells to effect physiological activity
What does intracrine mean?
Specialised type of autocrine
Signalsacts inside the cell
Generally what is the effect of a chemical signal binding to a receptor?
Binding to a receptor (membrane /nucleus) causes a series of events which result in the modulation of gene expressions
What are growth factors?
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
What are three examples of growth factors?
Epidermal growth factor
Vascular endothelial growth factor
Platelet derived growth factor
How does epidermal growth factor work?
Mitogenic for epithelial cells and fibroblasts
Produced by keratinocytes, macrophages and inflammatory cells
Binds to epidermal growth factor receptor
How does vascular endothelial growth factor work?
Potent inducer of blood vessel development (vasculogenesis)
Role in growth of new blood vessels (angiogenesis) – tumours, chronic inflammation, wound healing
How does platelet-derived growth factor work?
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
What are the four main stages of the cell cycle?
G1
S1
G2
M
In G1 what is the phase called in which there is a permanent exit from the cycle?
G0
What happens in G1 of the cell cycle?
Gap 1
Presynthetic
Cell grows (proteins/ organelles)
What happens in S1 of the cell cycle?
DNA synthesis / replication of DNA
What happens in G2 of the cell cycle?
Gap 2
Premitotic
Cell prepares to divide
What happens in M of the cell cycle?
Mitosis, cell division
What 3 stages make up interphase?
G1, S1, G2
What is cell cycle progression controlled by?
Key “checkpoints”found at end of G1 (R) and end of G2
What is the importance of the the R/ G1 checkpoint?
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
What is the importance of the G2 checkpoint?
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
In what two ways does increased growth of a tissue occur?
Shortening the cell cycle
Conversion of quiescent cells (in G0) into proliferating cells by making them enter the cell cycle
What proteins are involved in controlling the progression of the cell cycle at checkpoints?
Cyclins and associated enzymes called cyclin dependent kinases (CDKs)
What happens upon binding of a cyclin to a CDK?
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
What tightly regulates cyclin-CDK complexes?
CDK inhibitors
How do growth factors affect the cell cycle?
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
Describe labile cells
Epithelial or haematopoietic cells
Normal state is active in cell division
Usually rapid proliferation
Stem cells divide persistently to replenish losses
Describe stable cells
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
Describe permanent cells
Neurones, cardiac myocytes
Unable to divide:G0/ unable to regenerate
Stem cells present but can’t mount effective proliferative response to significant cell loss
In what five ways can the reversible state between a normal unstressed cell and overstressed injured cell be described?
Regeneration Hyperplasia Hypertrophy Atrophy Metaplasia
Define regeneration
Replacement of cell losses by identical cells to maintain tissue or organ size
What causes regeneration to occur?
After injury, if harmful agent is removed and there is limited tissue damage
Can regeneration occur if tissue damage is bad or if damage occurs to a permanent cell? If not what happens instead?
No
Scar forms
What are two examples of regeneration?
Liver after partial hepatectomy
Epidermis replacement by keratinocytes after a skin burn
Which of theses types of cells can regeneration occur in? Labile, stable or permanent?
Labile
Stable
Define hyperplasia
Increase in tissue or organ size due to increase in cell numbers
What causes hyperplasia to occur?
In response to increased functional demand and/or external stimulation
Which of theses types of cells can hyperplasia occur in? Labile, stable or permanent?
Labile
Stable
Is hyperplasia mostly under physiological or pathological control?
Physiological control
Can be secondary to a pathological cause (excessive hormone stimulation/ growth factor production)
What are the two types of physiological hyperplasia?
Hormonal- increase in functional capacity
Compensatory- increase in tissue mass after tissue damage
How is hyperplasia related to neoplasia?
Repeated cell divisions that occur in hyperplasia expose the cell to risk of mutations and hence neoplasia is a risk
What are two examples of physiological hyperplasia?
Bone marrow production of erythrocytes (low oxygen)
Proliferation of endometrium under oestrogen influence
What are two examples of pathological hyperplasia?
Epidermal thickening in chronic eczema or psoriasis
Enlargement of thyroid gland in response to iodine deficiency
Define hypertrophy
Increase in tissue or organ size due to increased cell size
How does cell size increase in hypertrophy?
Cells contain more structural components – so cellular workload is shared by a greater mass of cellular components
Which of theses types of cells can hypertrophy occur in? Labile, stable or permanent?
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
What causes hypertrophy to occur?
In response to increased functional demand and or external stimulation
What are two examples of physiological hypertrophy?
Skeletal muscle hypertrophy of a bodybuilder
Smooth muscle hypertrophy of the pregnant uterus
What are two examples of pathological hypertrophy?
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)
Define atrophy
Shrinkage of the tissue or organ due to an acquired decrease in size and/ or number of cells
What causes atrophy to occur?
Caused by reduced supply of growth factors and/or nutrients
What’s the difference between atrophy at a cellular level and at an organ/tissue level?
At a cellular level – decrease in cell size
At an organ/tissue level – combination of cellular atrophy and apoptosis; when many cells undergo atrophy
How does cell size decrease in atrophy?
Involves shrinkage of size of the cell to size which is still survivable
Cells contain a reduced number of structural components and reduced function
How may atrophy result in cell death?
It is a form of an adaptive response which may result in cell death
What are two examples of physiological atrophy?
Ovarian atrophy in postmenopausal women
Decrease in the size of uterus after parturition
What are eight examples of pathological atrophy?
Disuse atrophy Denervation atrophy Inadequate blood supply Inadequate nutrition Loss of endocrine stimulation Persistent injury Senile atrophy (permanent cells) Pressure atrophy
Which of theses types of cells can atrophy occur in? Labile, stable or permanent?
Labile
Stable
Permanent
Define metaplasia
Reversible change of one differentiated cell type to another more suited to the altered environment
In what tissues is metaplasia most often seen?
Epithelial tissue
What causes metaplasia to occur?
Altered stem cell differentiation
Occurs secondary to signals from molecules such as cytokines and growth factors
What is the most common epithelial metaplasia seen? And what is the effect of this?
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)
What is the difference between metaplastic, dysplastic and cancerous differentiation?
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
What is metaplasia often a prelude to?
Dysplasia and cancer
What are three examples of metaplasia?
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
Define aplasia
Complete failure of a specific tissue or organ to develop
Embryonic development disorder
Define hypoplasia
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
Define dysplasia
The abnormal maturation of cells within a tissue
Potentially reversible but often precancerous
Define a benign neoplasm
The abnormal growth of cells which persists after the initiating stimulus has been removed
Define a malignant neoplasm
Abnormal growth of cells, which persists after initiating stimulus has been removed AND invades and spreads to distant sites
Describe the appearance of a benign neoplasm
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
Describe the appearance of a malignant neoplasm
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
What is pleomorphism?
Increasing variation in size and shape of cells and nuclei
What is a tumour?
Any clinically detectable lump or swelling
Can be neoplastic or non neoplastic
What is another word for malignant neoplasm?
Cancer
What is the name given to cells that are so poorly differentiated that they have no resemblance to any tissue?
Anaplastic cells
What are some key features of worsening differentiation in a neoplasm?
Increasing nuclear size Increasing nuclear: cytoplasmic ratio Nuclear hyperchromasia More mitotic figures Increasing variation in size and shape of cells and nuclei- pleomorphism
What is neoplasia?
Preneoplastic alteration in which cells show disordered cell organisation
What is one similarity and two differences between dysphasia and neoplasia
Sim- both involve altered differentiation
Dif- dysplasia occurs before neoplasia, dysplasia is reversible whereas neoplasia is not
Give two examples of non neoplastic tumours
Abscess
Swelling
What alterations to DNA cause neoplasia?
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
What causes a neoplasm to occur?
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
What is the clonality of neoplasms?
Monoclonal- collection of cells in neoplasm are all originated from a single founding cell
What is the evidence for monoclonality of neoplasms?
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
What is an in situ carcinoma?
All the features of a malignant neoplasm in epithelium but no invasion through the basement membrane
What is an invasive carcinoma?
All the features of a malignant neoplasm in epithelium with invasion through the basement membrane
What is the name of a benign neoplasm in stratified squamous epithelial cells and where does it occur?
Squamous papilloma (finger like projections)
Skin
Buccal mucosa
What is the name of a benign neoplasm in transitional epithelial cells and where does it occur?
Transitional cell papilloma
Bladder mucosa
What is the name of a benign neoplasm in glandular epithelial cells and where does it occur?
Adenoma
Adenamatous polyp of colon
What is the name of a malignant neoplasm in stratified squamous epithelial cells and where does it occur?
Squamous cell carcinoma
Skin larynx oesophagus
What is the name of a malignant neoplasm in transitional epithelial cells and where does it occur?
Transitional cell carcinoma
Bladder ureter
What is the name of a malignant neoplasm in glandular epithelial cells and where does it occur?
Adenocarcinoma
Stomach colon lung prostate breast pancreas oesophagus
What are two examples of malignant neoplasm in the skin?
Basal cell carcinoma
Melanoma
What is the basic stem of a benign tumour?
-oma
What is the basic stem of an epithelial cell malignant neoplasm?
-carcinoma
What is the basic stem of a connective tissue/ stromal neoplasm?
-sarcoma
What is the name of a benign smooth muscle neoplasm?
Leiomyoma
What is the name of a malignant smooth muscle neoplasm?
Leiomyosarcoma
What is the name of a benign fibrous tissue neoplasm?
Fibroma
What is the name of a malignant fibrous tissue neoplasm?
Fibrosarcoma
What is the name of a benign bone neoplasm?
Osteoma
What is the name of a malignant bone neoplasm?
Osteosarcoma
What is the name of a benign cartilage neoplasm?
Chondroma
What is the name of a malignant cartilage neoplasm?
Chondrosarcoma
What is the name of a benign fat neoplasm?
Lipoma
What is the name of a malignant fat neoplasm?
Liposarcoma
What is the name of a benign nerve neoplasm?
Neurofibroma
What is the name of a malignant nerve neoplasm?
Neurofibrosarcoma
What is the name of a benign nerve sheath neoplasm?
Neurolemmoma
What is the name of a malignant nerve sheath neoplasm?
Neurolemmosarcoma
What is the name of a benign glial cell neoplasm?
Glioma
What is the name of a malignant glial cell neoplasm?
Malignant glioma
Are all lymphoid and haematopoeitic neoplasms regarded as benign or malignant?
Malignant
What is the name given to a lymphoid neoplasm?
Lymphoma B and T
In lymphoid tissue - usually in lymph nodes
Hodgkin’s disease and non Hodgkin’s lymphoma
What is the name given to a haematopoietic neoplasm?
Acute and chronic leukaemia occurs in bone marrow
Abnormal cells then enter the blood
What is a myeloma?
Sounds like a benign muscle neoplasm
BUT IT’S NOT!
Malignant plasma cell neoplasm in bone marrow, destroying adjacent bone
What is a germ cell neoplasm in the testes?
Malignant teratoma
Seminoma
BOTH MALIGNANT
What is a germ cell neoplasm in the ovaries?
BENIGN Teratoma (dermoid cyst)
What are the four main abnormal cellular accumulations?
Fluid
Lipids
Proteins
Pigments
How is fluid an abnormal cellular accumulation?
Water and electrolyte Vacuoles, hydropic swelling Osmotic disturbance to cell Severe cellular distress Problem to cell, organ, person Swelling in the brain – disrupts bloodflow
How are lipids an abnormal cellular accumulation?
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
How are proteins an abnormal cellular accumulation?
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
How are pigments abnormal cellular accumulations?
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
What is pathological calcification and the two main types?
Abnormal deposition of calcium salts in tissues
Dystrophic calcification
Metastatic calcification
What is dystrophic calcification?
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)
What is metastatic calcification?
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
Describe cellular ageing
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
What three substances can leak out of cells during oncosis?
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
What is the effect of high concentrations of K+ as a result of oncosis?
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)
What is the effect of high concentrations of enzymes as a result of oncosis?
Enzymes with the smallest molecular weight and released first from oncotic cells
– Heart – creatine kinase, troponins
– Liver – AST
What is the effect of high concentrations of myoglobin as a result of oncosis?
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
What are the macroscopic features of necrosis?
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
What are the microscopic features of necrosis?
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
What are the electron microscopic features of necrosis?
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
What are the microscopic features of apoptosis?
Single cells
Cell shrinkage
Plasma membrane intact
What are the electron microscopic features of apoptosis?
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
What are the 5 main mechanisms of cell injury?
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
What is another way (besides antioxidants) that the body protects itself from cell injury?
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.
Describe how chemical injury to cells can occur?
Some chemicals act by combining with a cellular component, e.g., cyanide binds to mitochondrial cytochrome oxidase and blocks oxidative phosphorylation.
What is ischaemic reperfusion injury?
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.
What conditions favour resolution?
§ 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
What are the sequences of events that lead to resolution of acute inflammation?
§ 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)
What is suppuration wrt acute inflammation?
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
Describe an abscess
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
What is organisation wrt acute inflammation?
Replacement of tissues by granulation tissue as a part of the process of repair
What circumstances favour organisation of tissue wrt acute inflammation?
§ 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
What happens in organisation of tissue wrt acute inflammation?
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
Why may acute inflammation progress onto chronic inflammation?
· 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
What are 3 examples of hereditary conditions in which acute inflammation features?
Hereditary angio-oedema
Alpha-1 antitrypsin deficiency
Chronic granulomatous disease
What is hereditary angio-oedema?
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.
What is α1-antitrpysin Deficiency?
Hereditary acute inflammation
o α1-antitrpysin inhibits Elastase.
o Without this inhibition elastase breaks down lung/liver tissue
o Causes emphysema and Liver Sclerosis.
What is chronic granulomatous disease?
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
What are the main cells involved in acute inflammation?
Neutrophils
Macrophages
What are some beneficial effects of acute inflammation?
§ 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
What are some harmful effects of acute inflammation?
§ 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)
What are the biological purposes of acute inflammation?
· Serves to destroy, dilute or wall off the injurious agent
· Induces repair
· Protective response
What chemical mediators cause vasodilatation of arterioles and capillaries in acute inflammation?
Prostaglandins
Histamine
C3
C5a
What chemical mediators cause increased vascular permeability of arterioles and capillaries in acute inflammation?
histamine, leukotrienes, bradykinin, nitric oxide (histamine, prostaglandins and kinins)
What chemical mediators are involved in chemo taxis of neutrophils in acute inflammation?
C5a, LTB4, bacterial peptides
In fever (a systemic consequence of acute inflammation) what chemical mediators are released?
IL1, TNF alpha and prostaglandins produced
In acute phase response (a systemic consequence of acute inflammation) what acute phase proteins have altered plasma concentrations?
C reactive protein (CRP), alpha 1 antitrypsin, Haptoglobin, Fibrinogen, serum amyloid A protein
What are the five main effects of chronic inflammation?
o Fibrosis o Impaired function • Rarely, increased function o Atrophy o Stimulation of immune response o Granulomatous inflammation/ GRANULOMA
How are plasma cells involved in chronic inflammation?
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
How can chronic cholecystitis (an example of chronic inflammation) be treated?
Surgical removal of gall bladder
How can ulcerative colitis (an example of chronic inflammation) be treated?
Immunosuppression
Surgical removal of large bowel
How can Crohn’s disease (an example of chronic inflammation) be treated?
Lifestyle modifications
Diet
Hydration
Immunosuppressants
How can RA (an example of chronic inflammation) be treated?
Immunosuppressants
When does fibrous repair and scarring occur?
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)
Why does thrombosis occur?
Abnormalities of vessel walls- atheroma, direct injury, inflammation
Abnormalities of blood flow- stagnation, turbulence
Abnormalities of blood component- smokers, post partum, post operative; hypercoaguability
What do arterial thrombi look like?
Pale
Granular
Lines of zahn
Lower cell content
What do venous thrombi look like?
Soft
Gelatinous
Deep red
Higher cell content
Where do thrombi most commonly occur?
In veins
What are some arterial effects of thrombi?
Ischaemia
Infarction
Depends on site and collateral circulation
What are some venous effects of thrombosis?
Congestion
Infarction
Oedema
Ischaemia
Briefly describe disseminated intravascular coagulation
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
What is invasion?
Invasion – The ability of cells to break through the basement membrane and spread
Direct invasion – Into surrounding tissue
Into Lymphatic/vascular channels
What is metastasis?
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.
What are the three main mechanisms that facilitate invasion and metastases?
-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.
How do tumours metastasise through the lymphatics?
Lymphatics
- Spread to local and distant lymph nodes
- Frequent route of spread of carcinomas (malignant epithelial tumour)
- Can involve lymphatics of the lung
How do tumours metastasise through the blood?
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
What are some local effects of a benign neoplasm?
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)
What are some local effects of a malignant neoplasm?
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)
What are some systemic effects of benign and malignant neoplasms?
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
What is cachexia?
Cachexia – Loss of weight, muscle atrophy, loss of appetite in someone who is not actively trying to lose weight
What is malaise?
A feeling of general discomfort or uneasiness
What is pyrexia?
Fever
In what local and systemic ways can neoplasms kill people?
Local Effects – Raised ICP, perforation, haemorrhage (Benign or malignant)
Systemic Effects – Replacement of essential body organs, bone marrow, lung tissue, liver parenchyma (Malignant neoplasms).
What are 3 examples of inherited susceptibility to the formation of tumours?
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
What are protooncogenes? And how can changes to these genes result in neoplasia?
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.
What is the role of Ras? (an oncogene)
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
What is the role of c-myc? (An oncogene)
- Binds to DNA, stimulates synthesis
- Amplified (over-expressed)
o Neuroblastoma, breast cancer - Translocation 8 à 14
o Burkitt’s lymphoma
What is the role of HER-2? (An oncogene)
- Encodes for a growth factor receptor
- Amplified (over-expressed)
- ~25% of breast cancers
- Herceptin is a competitive antagonist at the HER-2 Receptor
What are tumour suppressor genes? And how can changes to these genes result in neoplasia?
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.
What is the role of pRb? (A tumour suppressor gene)
- 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
What is the role of p53? (A tumour suppressor gene)
- ‘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
Describe the initiation and promotion stages of neoplasm
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
What are the 3 stages of neoplasm formation?
Initiation
Promotion
Progression
How can radiation cause neoplasm?
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
How can chemicals cause neoplasm?
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
How can viruses cause neoplasm?
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
How do other agents besides radiation, viruses and chemicals cause neoplasms?
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
What 3 conditions predispose individuals to the development of neoplasms?
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
What is staging? And describe the basic staging process?
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
Describe TNM staging for breast cancer
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
Describe dukes staging for colorectal carcinomas
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
What system is used to classify Hodgkin’s disease?
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)
What is grading?
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
How is breast carcinoma graded?
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
How is prostate carcinoma graded?
Prostate Carcinoma – Gleason Grading System
What is radiotherapy and how is it used in treatment of cancer?
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
What is chemotherapy and how is it used in the treatment of cancer?
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
What is hormone therapy and how is it used in the treatment of cancer?
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
What three tumour markers are used the diagnosis and monitoring of cancer?
Carcinoembryonic Antigen
Human Chorionic Gonadotrophin
Alpha-Fetoprotein (AFP)
What is carcinoembryonic antigen?
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.
What is human chorionic gonadotropin?
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
What is alpha feto protein (AFP)?
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)
Why is screening for cancers beneficial?
Screening aims to detect pre-malignant, non invasive and early invasive cancers to improve prognosis
Describe cervical screening
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
Describe breast screening
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
