MECHANISMS OF DISEASE Flashcards
What are the three factors of development of thrombosis?
Endothelial injury
Abnormal blood flow
Hypercoagulability
Following injury to a vessel platelets undergo three important reactions, what are they?
- Adhesion
- Secretion (release reaction)
- Aggregation
What is the effect of alterations in normal blood flow? (4)
- Disrupt laminar flow
- Prevent the dilution of coagulation factors
- Retard the inflow of inhibitors of clotting factors
- Promote endothelial cell activation
What does “lines of Zahn” refer to?
Laminations present in a histological sample of a thombus
Pale bands= fibrin + platelets Red bands = RBC
Symptoms of thrombi? (5 P’s)
Perishingly cold, pallor, pain, paraesthesia, pulseless
Classifications of embolisms? (5) SAFAP
- Pulmonary embolism
- Systemic embolism
- Amniotic fluid embolism
- Air embolism
- Fat embolism
Tests for PE (pulmonary embolism)
- Chest x-ray: pulmonary infarct shows as wedge shaped infiltrate
- Scanning using radionuclides
- ECG: shows strain on the heart due to occlusion
Name 4 factors that alter the effect of an infarct on the tissue?
- The nature of the vascular supply
- Rate of development of occlusion
- vulnerability of tissue to hypoxia (neurons vs myocardial cells)
- Oxygen content of blood
What are the 3 types of infarct?
Septic/bland
White (anaemic) - Arterial occlusions
Red (haemorrhagic) - Venous occlusions
Name 4 of the mains stages of the pathogenesis of atherosclerosis?
- Chronic endothelial injury/dysfunction- increases endothelial permeability
- Role of lipids- the LDL’s releases cytokines, impairs endothelial function and accumulates in the intima
- Role of macrophages- produces fatty streak, foam cells engulf oxidised LDL
- Smooth muscle proliferation- the foam cells die and lipids within them crystallise to form the lipid core, smooth muscle cells move to surface and form fibroblasts
How are oxygen free radicals produced, where, and cause?
Oxidative phosphorylation produces oxygen free radicals which are reactive. These lead to cell injury
Describe how an ischemic cell leads to necrosis?
When the blood supply is blocked the cell undergoes anaerobic respiration.
Hence ATP is not generated so Na ions cannot be extruded from the cell leading to necrosis
Define necrosis
The loss of cells ability to maintain homeostasis and hence underdoes catastrophic cell death
Name 5 features of necrosis
- Death of tissues following bioenergetics failure and loss of plasma membrane integrity
- Induces inflammation and repair
- Caused by ischaemia, metabolic trauma
- Pathological process
- Often affects solid mass of tissue not single cells
What are the 6 different forms of necrosis, name one thing about each
Colliquative: in brain when dead area is liquefied
Coagulative: in most tissues, ghost lines are seen
Caseous: TB, yellow semi-solid material
Fibrinoid: in arterioles in malignant hypertension
Fat: appears as multiple white spots
Gangrene: death with putrefaction, is black, follows vascular occlusion/infection
Name two features of apoptosis?
Physiological process
Affects single cells
Stages of apoptosis?
- Cell shrinkage
- Nucleus condensation
- Cell fragmentation. The cell fragments are membrane-bound initially which limits inflammation
- Phagocytosis: to avoid inflammation
What is the function of caspases?
Family of molecules that cleave DNA into nucleosome sized fragments around a histone protein
What is the function of PARP molecules?
Signal for cell to resist death by apoptosis and live
What signals p53?
DNA damage
Why is p53 the main tumour suppressor gene?
It is an inducible transcription factor that decides if the cells should:
- stop growing
- repair (by increasing levels of PARP)
- undergo apoptosis
If it losses its function then the cell will failure to engage in apoptosis following DNA damange
How are apoptotic cell reconised by macrophages?
Clearance of apoptotic cells required reorganization of PHOSPHATIDYLSERINE.
The membrane phospholipids are flipped to expose lipids internal lipids to the external environment to be recognized.
This process is called externalization of phosphatidylserine.
What are the two different forms of extrinsic apoptotic signals?
Receptor mediated and T cells
What do all signals for apoptosis have in common?
They all signal a caspase cascade
What are two examples of receptors that signal for apoptosis?
TNF and Fas CD95
Describe how intracellular stress results in apoptosis?
Mitochondria damage leaks proteins (cytochrome C) into cytosol. The release of cytochrome C triggers caspase cascade and the forming of an apoptosome.
Name 2 mechanisms of controls of apoptosis?
Dimerisation and IAP
How does dimerisaiton control apoptosis?
Apoptosis regulator Bcl-2 are a family of proteins that prevent apoptosis from occurring when two join to form a dimer.
i.e. dimer = no apoptosis
How do IAPs control apoptosis?
Prevent “stressful” signals from the mitochondria reaching the cytosol and activating the caspase cascade. This regulates which signals are sufficient to result in cell death.
IAP=
Inhibitor apoptosis protein
How can IAPs be used to treat cancer?
Anti-IAPs drugs induce apoptosis of cancerous cells (tumours)
How are inactive procaspases activated?
By cleavage via another active caspase
What is unique about pyroptosis?
It has features similar to both apoptosis and necrosis i.e.
- caspase 1 activation, not caspase 3
- nuclear fragmentation but not cytoplasmic blebbing
- proinflammatory
What is anoikis?
Cell death after losing contact with basement membrane/extracellular matrix.
Cancer cells have the ability to overcome anoikis and translocate the body
What is osteomyelitis?
Inflammation of bone/bone marrow, usually due to infection
What organism is mainly responsible for causing osteomyelitis?
S. aureus
What is ESR?
Erythrocyte sedimentation rate: A test to help detect inflammation associated with conditions such as infections, cancers and autoimmune diseases
What is CRP?
C-reactive protein: A marker of inflammation in the body. Therefore it’s level in the body increases if there is any inflammation in the body
What are the standard empirical therapeutic regimens for treating osteomyelitis and septic arthritis ?
Flucloxacillin/fucidin
What are three predisposing conditions of septic arthritis?
Rheumatoid arthritis, infection of joint and a prosthetic joint
What are the 4 stages of chemical carcinogenesis?
- Initiation: Mutations in tumour suppressor genes and oncogenes
- Promotion (reversible):Stimulates proliferation of mutagenic and normal cells
- Progression (irreversible): Repression of gene expression and selection of neoplastic cells for optimal growth
- Malignancy
A carcinogen can act as both an initiator and a promotor. True/false?
True
What two factors are needed for a tumour to develop?
An initiator (e.g. the carcinogen) and a promotor (can be the carcinogen or the promotor)
What is the mechanism of carcinogenesis of 2-naphthylamine (2NTA)?
- Aromatic amines such as 2NTA are pre-carcinogens requiring activation.
- In the liver 2NTA is converted to carcinogenic metabolite 2-amino-naphthol
- 2-amino-naphthol is detoxified to glucuronide (not carcinogenic) which is excreted by kidneys
- Bladder urothelial cells express beta-glucuronide which converts glucuronide to a carcinogen.
What is asbestosis?
Formation of scar tissue in the lung as a result of exposure
What tumours are caused by asbestos?
Bronchogenic carcinomas
Blue asbestos: mesothelioma
What is mesothelium?
The mesothelium is a membrane composed of simple squamous cells that forms the lining of several body cavities: the pleura (thoracic cavity), peritoneum (abdominal cavity including the mesentery), mediastinum and pericardium (heart sac).
What genes are mutated by Benzopyrene?
K-Ras and p53 are mutated (transversion mutation)
What is transversion?
The original G-C base pair is replaced by a T-A base pair
What are the two genes most frequently mutated in smoking-related lung cancers?
p53 and K-Ras
How does tobacco smoke act as a carcinogen?
The active carcinogen in tobacco smoke is the polycyclic aromatic hydrocarbon 3,4-benzopyrene (benzo[a]pyrene). This is converted by Aryl Hydrocarbon hydroxylase (AHH) into benzo[a]pyrene diol epoxide that binds to DNA, forming damaging adducts.
What is the function of glutathione S transferase (GSTM1)?
Detoxifies carcinogens
What is secondary carcinogenesis?
Development of secondary tumours following use of alkylating agents in chemotherapy.
Cause:DNA damage inflicted on surviving normal somatic cells during treatment. DNA strand breakage and base damage induced
Name an example of carcinogens in the diet?
Source: food additive, fertilisers that enter drinking water
When gut bacteria convert nitrates and nitrites to nitroamines, this can lead to cancers of gastro-intestinal tract and liver
What is aflatoxicosis?
Poisoning, especially of the liver, that results from ingestion of aflatoxins (e.g. Aflatoxin B1) from contaminated food
A combination of a………. and h……… predisposes to liver cancer?
A combination of aflatoxins and hepatitis B infection predisposes to liver cancer
Why is there a difference in the incidence of GI tumours in the LI and SI?
Blc-2 is not expressed in the crypts of the small intestine.
It is a growth promoting gene that suppresses apoptosis and increases cell survival. Mutation of blc-2 can lead to abnormal proliferation of damaged cells
How does UV radiation stimulate carcinogenesis?
Form pyrimidine dimers but can also break DNA by indirect mechanisms
What is Xeroderma pigmentosum?
Rare autosomal recessive disease. Inherited deficiency of endonuclease, an enzyme in pathway of thymine dimer removal. Hence repair of UV-induced damaged cells is defective.
Why are children more vulnerable to leukaemia?
More of their blood stem cells are more affected
What are the 6 Hallmarks of Cancer?
Evading apoptosis Self-sufficiency in growth signals Intensive to anti-growth signals Angiogenesis Metastasis Limitless replicative potential
What are the differences in the features of benign and malignant tumours?
Benign: - Well circumscribed - Slow growth - No necrosis - Non-invasive - No metastasis Malignant - Poorly circumscribed - Rapid growth - Often necrotic - Invasive - Metastasis
How do malignant tumours spread?
via lymphatics
via the blood stream
by direct invasion
through body cavities
What are the 6 macroscopic features of tumours?
- Sessile
- Predunculated
- Papillary
- Fungating
- Ulcerated
- Annular
Describe a sessile tumour
Tumour feature meaning it grows on the surface. Not invading but is proliferating
Describe a predunculated polyp
Tumour feature meaning external to the main bulk of the tissue. Common in epithelial tissue
Describe a papillary tumour
Tumour feature meaning on the tissue surface
Describe a fungating tumour
Growth partially on exterior but starting to invade tissue
Describe an ulcerated tumour
Tissue damage with partial necrosis. The cancer cell is merging with tissue structure and growing through it.
Describe an annular tumour
Found in duct/wall with a circular pattern, the cells grow from outside inwards potentially blocking the well
What is the term used for histogenetic classification?
Grade
What is the term use for classification of spread?
Stage
What are the different “grades” and what do they represent in terms of tumour classification?
Grade I: Well differentiation
Grade II: Moderately differentiated
Grade III: Poorly differentiated
Grade IV: Nearly anaplastic
What does TNM mean in the classification of tumour spread?
T: Tumour size
N: Degree of lymph node involvement
M: Extent of distant metastases
The higher the level, the worse the tumour spread
What is the nomenclature for:
a) Benign, epithelial tissue tumours
b) Benign, connective tissue tumours
c) Malignant, epithelial tissue tumours
d) Malignany, connective tissue tumours
a) “papilloma”/ “adenoma”
b) -oma
c) “carcinoma”
d) “sarcoma”
What are the two most common mesenchymal tumours?
Lipoma/liposarcoma
and
Haemangioma/ haemangiosarcoma
What is the function of osteoprogenitor cells?
Stem cell population, gives rise to osteoblasts
What is the function of osteoblasts?
Responsible for bone formation, cover the surface of bone
What is the function of osteocytes?
Mature bone cells which are embedded in the lacunae.
Maintain bone matrix through cell-to-cell communication and influence bone remodelling
What is the function of osteoclasts?
Multinucleated cells derived from haematopoietic cells
Resorb bone matrix by demineralization in response to mechanical stress and physiological demands.
Name 5 features of osteoporotic bone
- Decreased size of osteons
- Thinning of trabeculae
- Enlargement of Haversian and marrow spaces
- Affects both cortical and trabecular bone
- There is an overall loss of bone mass
What are the three types of osteoporosis?
Type 1: post menopausal
Type 2: age related
Disease
Type 1 osteoporosis:
Part of bone mainly affected?
Cause?
Common factures?
Cancellous bone
Loss of oestrogen
Vertebral and distal radius fracture
Type 2 osteoporosis?
Cause?
Common factures?
Cause: ability to generate osteoblast decreases whilst osteoclast remains the same. Related to poor calcium absorption
Hip and pelvic fractures are common
What is DEXA?
Dual-energy x-ray reabsorptiometry scan used to diagnose osteoporosis by showing the patients BMD (bone mineral density)
Name 5 treatment options for osteoporosis?
Bisphosphoinates Anabolic agents Ca++ supplements Hormone replacement therapy Increase exercise
How do bisphosphonates act in preventing osteoporosis?
Name 2 examples
Disrupts activity of osteoclasts hence prevents bone breakdown
e.g. Alendronate, risedronate
How do anabolic agents act in preventing osteoporosis?
Name 2 examples
Promote generation of new bones
e.g. intermittent PTH, strontium ranelate
