Week 2 - General pathological mechanisms Flashcards
What site are antibacterial factors commonly found at?
Mucosal surfaces i.e. nose, back of throat
Lysozyme is an antibacterial factor. How does it fight infection?
Breaks down the gram positive cell wall of bacterial cells.
Lactoferrin is an antibacterial factor. How does it fight infection?
Inhibits bacterial growth through iron chelation.
What are the three potential outcomes of the complement pathway?
Recruitment of inflammatory cells, opsonization of pathogens, killing of pathogens.
List 3 functions of macrophages.
Phagocytosis
Cytokine production
Antigen presentation
List 3 function of neutrophils.
Phagocytosis
Chemotaxis
Degranulation (release factors which kill microbes.)
Which WBC characteristically produces pus?
Neutrophils
Which WBC targets parasites and has a role in allergy?
Eosinophils
The degranulation of which WBC causes the histamine mediated weal and flare reaction?
Basophils
Which immune cell can initiate an an adaptive immune response by presenting antigens to CD4 T cells in the lymph node?
Dendritic cells
Which type of adaptive immune cells predominantly targets extracellular pathogens such as bacteria?
B cells
Which type of adaptive immune cells predominantly targets intracellular pathogens i.e. viruses?
Cytotoxic T cells
What is the role of CD4 helper T cells?
Activates B cells and Killer T cells in response to antigen presentation.
What are the three roles of antibodies?
Opsonize pathogens for phagocytosis, activate complement for lysis and neutralise toxins and pathogen binding sites
Which antibody looks like a star, is present in the primary immune response and has a low affinity?
IgM
Which antibody is the main antibody of the secondary immune response and has a high affinity?
IgG
Which antibody is present in secretions and lines epithelial surface and looks like two antibodies standing end to end?
IgA
Which antibody has a high affinity and binds to mast cells, having a role in allergy?
IgE
Describe the process by which autoimmunity is prevented as B cells and T cells are produced.
B cells undergo screening in the bone marrow and T cells in the thymus. If they strongly bind to self antigens they are destroyed by apoptosis.
What cells are MHC class 1 found on? To what cells do they present antigens to?
All nucleated cells
CD8 killer T cells
What cells are MHC class 2 found on? To what cells do they present antigens to?
Antigen presenting cells
CD4 helper T cells
Type I (allergic/atopic) hypersensitivity is mediated by…
IgE bound to mast cells
Type II hypersensitivity is mediated by…
IgM or IgG bound to cell/matrix antigen
Type III hypersensitivity is mediated by…
IgM or IgG bound to soluble antigen
Type IV hypersensitivity is mediated by…
CD4 or CD8 T cells
Type V (which is sometimes considered a subgroup of Type II) is mediated by…
IgM or IgG bound to receptors
What are the six stages of allergic response?
- Sensitisation
- Mast cells primed with IgE
- Re-exposure to antigens
- IgE binds to antigens
- Mast cells degranulate
- Pro-inflammatory response stimulates and amplifies future responses
Name 3 things that are released when mast cells degranulate as part of the allergy process.
Histamine pro-inflammatory cytokines chemokines prostaglandins leukotrienes
The early phase response in type I hypersensitivity occurs minutes after exposure to allergen. What changes occur in body tissues this phase? What mediates this phase?
Increased vascular permeability and smooth muscle contraction. Prostaglandins and histamine.
The late phase response in type I hypersensitivity occurs over hours/days after exposure to allergen. What changes occur in body tissues this phase? What mediates this phase?
Sustained smooth muscle contraction and tissue remodelling. Mediated through recruitment of T cells and other immune cells to site.
Why is anaphylaxis an immediate danger to life?
Increased vascular permeability causes:
Soft tissue swelling, threatening the airway
Loss of circulatory volume, causing shock
What are the three stages of type II hypersensitivity?
- Sensitisation
- Opsonisation of cells
- Cytotoxicity (through complement activation)
Type III hypersensitivity is mediated by immune complexes bound to soluble antigens. Where do these immune complexes accumulate? What is the effect of this?
They accumulate in small blood vessels.
Occlusion of blood vessels, complement activation and perivascular inflammation.
In type 4 hypersensitivity, how long does it take for the reaction to occur?
Several days after exposure to the antigen.
Type 1 diabetes is an autoimmune disease. What types of hypersensitivity is it caused by?
Type II and type IV
In myasthenia gravis, what causes the fatigueable muscle weakness? What type of hypersensitivity is this?
IgG binds to ACh receptor, preventing signal transduction required for muscle contraction. Type 5.
Name two systemic autoimmune diseases.
Rheumatoid arthritis and inflammatory bowel disease.
What protein is a good indicator for rheumatoid arthritis?
Anti-citrullinated protein
Inflammation is the universal response to tissue damage. 1. Name three causes of tissue damage that result in inflammation.
2. What is the purpose of inflammation?
- Infection, trauma, necrosis
2. Destroy or control the harmful stimulus, initiate repair and restore function.
What are the 5 clinical signs of inflammation and what causes them?
Redness - caused by hyperaemia (increased blood flow)
Swelling - fluid exudate and hyperaemia
Heat - hyperaemia
Pain - release of bradykinin and PGE2 (prostaglandin E2)
Loss of function - all of the above
Vascular dilatation occurs during inflammation. What 3 factors cause blood vessels to dilate? How does vascular dilatation cause swelling?
Histamine (from mast cells), prostaglandins, NO.
As the blood flow is increased, you get more fluid passing into tissues causing swelling.
During inflammation neutrophils are activated. What three factors cause neutrophils to be actiavted?
C5a, bacterial products, leukotriene B4
Vascular endothelial activation occurs during inflammation. Name 3 factors that causes this.
5HT, Histamine, C5a
Endothelial activation allows plasma proteins to leak out into the endothelium. Name three of these proteins.
Complement, immunoglobulin, fibrinogen.
An exudate is a fluid that has leaked out of a blood vessel into the extracellular space. Name 3 exudates.
Neutrophilic (purulent)
Fibrinous
Serous
What are some of the main ways that infection can spread?
Through natural barriers, in the air, in the blood, through weakened immune system (i.e. HIV, steroid use)
What are the 4 potential sequelae following acute inflammation?
Abscess, resolution, healing by repair or chronic inflammation.
Define chronic inflammation.
Prolonged and persistent inflammation resulting from ongoing tissue damage.
What inflammatory cells are associated with chronic inflammation? What does chronic inflammation often lead to in tissues?
Lymphocytes, macrophages and plasma cells.
Fibrosis and scarring.
Granulomatous inflammation is a subtype of chronic inflammation. What is granulomatous inflammation defined by? Name 3 of its subtypes.
Defined by the presence of granulomas, collections of epithelioid macrophages and multinucleate giant cells.
Necrotising, non-necrotising, foreign body granulomas.
Describe how a superficial, clean, simple incised wound would heal.
By primary intention - edges would approximate together, epithelium would form cover and granulation tissue would form underneath.
Describe how a large gaping dirty wound would heal.
Heals by secondary intention, loss of granulation tissue, scab will form and the end will be a fibrous irregular scar.
How does bone heal?
Through regeneration rather than repair via callus formation.
Define pathology and disease.
Pathology is the study of disease. Disease is an abnormality of cell/tissue structure and/or function.
What are the 4 main levels of magnification in pathology? At which level do changes occur first?
Gross (what can be seen with naked eye)
Light microscopy
Electron microscopy
Molecular cell biology
Changes first occur at molecular level then electron microscopy etc…
Disease can be described in terms of: - epidemiology -aetiology - pathogenesis - sequelae Explain these terms and give an example of each.
- epidemiology = broad patterns of disease, how often diseases occur in different groups of people and why.
- aetiology = cause
- Pathogenesis = mechanism of disease
- Sequelae = complications
What are the 6 main levels of organisation in the body? Describe each of these briefly.
Body
System - different organs working together for an organised funtion.
Organ - a group of tissues working together for an organised function.
Tissue - a group of similar cells together that carry out a specific function
Cell - basic unit of life
Molecule - regulate cell processes
What are the main broad tissue types?
Epithelial
Connective
Haemato-lymphoid
Neuro-glial
What are the three types of epithelial tissue?
squamous, glandular, solid organs i.e. liver, kidney
Name some different types of connective tissue.
Fibrous, blood vessel, fat, muscle, bone, cartilage
If a change in a cell's environment (stress) is more than can be dealt with by homeostasis the cell may undergo further adaptation. Define the following words: Atrophy Hyperplasia Hypertrophy Metaplasia Dysplasia
Atrophy - cell shrinking or decreasing in number
Hyperplasia - cells inceasing in number
Hypetrophy - cells getting bigger
Metaplasia - cells changes from one mature cell type to another.
Dysplasia - cells undergoing genetic changes.
If a cell experiences intense, long lasting stress or if a cell is particularly sensitive, the cell may undergo injury. What 3 things could this lead to?
Cell death
Acute or chronic inflammation
Years later, possible neoplasia
VITAMIN CDEF is a mnemonic to remember categories of disease. What do the letters in the mnemonic stand for?
V - vascular I - infective/inflammatory T - traumatic A - autoimmune M - metabolic I - iatriogenic/idiopathic N - neoplastic
C - congential
D - degenerative, developmental
E - endocrine, environmental
F - functional
List some of the possible causes of disease to consider.
- congenital/acquired
- Physical agents
- Chemicals/drugs
- Infections
- Hypoxia/ischaemia
- Immunological reactions
- Nutritional
- Endocrine/metabolic
- Genetic
‘Political Correctness Is Highly Important Not Gonna-lie’ is a mnemonic for remembering the causes of cell injury, what does each letter stand for?
P - Physical agents C - chemicals/drugs I - infections H - Hypoxia/ischaemia I - Immunological reactions N - nutritional G - Genetic disease
Describe what is meant by reversible and
non-reversible cell injury.
Reversible cell injury is due to changes in the cells environment (stresses) and cells will return to normal when the stimulus is removed. Irreversible cell injury is permanent and cell death (usually necrosis follows).
There is a continuum between reversible and irreversible cell injury. What factors determine where the point of no return is?
Type, duration and severity of cell injury.
Describe the mechanism of cell injury when there is damage to:
a) mitochondria
b) cell membrane
c) cytoplasm + ribosomes
d) Nucleus
a) mitochondria - disrupted ATP synthesis
b) cell membrane - disrupted ion concentrations
c) cytoplasm + ribosomes - disrupted protein synthesis and architecture
d) Nucleus - DNA damage
Cell injury can be caused by oxidative stress due to reactive oxygen species. How are ROS formed normally and pathologically?
Normally in small amounts as a by product of respiration.
Pathologically by absorption of radiation, toxic chemicals, hypoxia.
What histological changes can be seen in reversible cell injury? What changes can be seen with irreversible damage?
Reversible: Cloudy swelling, damaged microvilli, swollen mitochondria, cytoplasmic blebs, fatty change (accumulation of fatty vacuoles in the cytoplasm).
Irreversible: disrupted membranes, pyknotic (shrunken) nucleus.
What is the difference between necrosis and apoptosis?
Necrosis - uncontrolled, due to external stimuli, always pathological, cell contents leak out.
Apoptosis - programmed therefore controlled, usually physiological but can also be pathological, cell contacts do not leak.
What do you call necrosis caused by loss of blood supply?
Infarction
What histological changes can be seen in necrosis?
- cell swelling, vacuolation, disruption of membranes and organelles
- Release of cell contents (lysis) causing adjacent damage and acute inflammation
- DNA disruption and hydrolysis
What are the 4 different types of necrosis in tissue based on morphology? Describe them briefly and provide an example for each.
- Coagulative - firm, tissue outline remains e.g. Haemorrhagic due to blockage of venous drainage.
- Colliquitive - tissue becomes liquid and loses structure e.g. cerebral infarct, abscess
- Caseous - mixture of coagulative and colliquitive appearing cheese like. e.g. granulomatous inflammation, especially TB
- Fat - due to the action of lipases on fatty tissue.
Give two physiological causes of apoptosis.
Deletion of cell populations during embryogenesis.
Deletion of self - reactive lymphocytes in the thymus.
Give two pathological causes of apoptosis.
Cytotoxic T lymphocytes in viral infection.
DNA damage.
Describe the morphology of apoptosis.
Cell shrinkage, chromatin condensation, cell membranes remain in tact, cytoplasmic blebs form and break off to form apoptotic bodies which macrophages phagocytose.
What are depositions?
Depositions are abnormal accumulations of substances.
What is the nature of amyloid? Is amyloid produced by just one type of protein or multiple? What stain can be used to show amyloid?
It is an abnormal aggregation of proteins that accumulates outside cells in fibrils.
Multiple
Congo red
How does amyloid occur? Give three mechanisms.
- excessive accumulation of a normal protein
- accumulation of an abnormal protein
- tendency of a protein to misfold
Give two examples of amyloids caused by excessive accumulation of normal proteins.
AL amyloid in multiple myeloma.
AA amyloid in rheumatoid arthritis
Give an example of a condition due to amyloid as a result of accumulation of an abnormal protein.
Alzheimer’s disease
What would be the clinical effect of amyloid deposition on the:
- heart
- kidney
- brain
- heart failure
- renal impairment/failure
- dementia
What is calcification?
Deposition of calcium salts.
What is the difference between dystrophic and metastatic calcification?
Dystrophic - deposition in abnormal tissue with normal serum calcium
Metastatic - deposition in normal, living tissue with raised serum calcium
During a post mortem examination, what will the general pathologist look at prior to performing the autopsy?
Look at patient’s medical notes for past medical history and summary of clinical events and treatment.
What are the two stages of the autopsy and what do they involved?
External examination - look at general appearance, external disease and evidence of medical treatment.
Internal examination - Evisceration and organ dissection completed. Samples may be taken for microscopic assessment.
Why might a hospital consented PM examination be performed?
- to confirm or reveal a diagnosis
- to investigate possible failings in medical care
Why might a medico-legal PM be requested?
- to investigate an unexplained or suspicious death.
Does a post-mortem require consent from family members?
If it is a hospital PM i.e. requested by clinicians you do need consent from the family.
If its a medico-legal PM requested by the procurator fiscal you do not need consent from the family.
What steps are taken after the post mortem?
Organs returned to body cavity.
Pathologist will write a death certificate if this is not already been issued.
PM report sent to PF or if hospital PM to patient’s GP and clinician in charge of care.
Patient’s body reconstructed to allow viewing by family members.
Patient’s body released for burial or cremation.
Name 5 of the most common principal causes of death in Scotland.
Cancer in lung or bronchus. Acute Myocardial Infarction Ischaemic heart disease COPD Dementia
What is the difference between lobar pneumonia and bronchopneumonia?
Lobar pneumonia - spreads through blood, usually localised to one lobe.
Bronchopneumonia - spreads through airways, tends to be more generalised, often develops on top of chronic lung disease.
Describe some differences between meningococcus and pneumococcus.
Meningococcus - spreads by inhaling droplets from carrier. Often previously healthy individual, often rapid illness.
Pneumococcus - usually from infection in the lungs, more common in debilitated people e.g. alcoholics, less rapid illness.
What are some of the reasons you would get an emergency chest x-ray?
Acute respiratory symptoms Chest pain Septic Screen Acute abdomen Post central line / chest drain insertion
What are some of the reasons you would get an elective chest x-ray?
Persistent/chronic respiratory symptoms
Pre-operative work up
Metastatic screen
TB contacts
What is thrombosis?
Haemostasis inside a blood vessel forming an obstruction to blood flow.
Virchow’s triad describes the three broad categories of factors which contribute to the development of thrombosis. What are these three categories?
Hypercoagulable state
Vascular wall injury
Circulatory stasis
Give three reasons why someone might be in a hypercoagulable state?
Malignancy
Pregnancy
Oestrogen therapy
Give three causes of vascular wall injury that could contribute towards thrombosis.
Trauma or surgery
Venepuncture
Atherosclerosis
Give three causes of circulatory stasis that could contribute towards thrombosis.
Atrial fibrillation
Immobility or paralysis
Varicose veins
What are some risk factors for DVT?
Vessel wall - surgery, increasing age, varicose veins.
Blood flow - obesity, immobilisation, pregnancy, IV catheters, external vein compression.
Composition of blood - thrombophilias, oestrogen hormones, inflammatory conditions.
How do we confirm or exclude the diagnosis of DVT?
Clinical decision - determine likelihood of DVT with Well’s clinical score.
Blood tests - fibrin D-dimer (a measure of dissolved thrombus)
Imaging - compression ultrasound, venography (x-ray with dye injection)
What are some of the potential outcomes of DVT?
- Pulmonary embolism
- Recurrent VTE
- Venous insufficiency
- Post thrombotic syndrome
What are some of the potential outcomes of PE?
- Dyspnoea, chest pain, haemoptysis
- Collapse
- Death
- Recurrent VTE
- Chronic Thromboembolic pulmonary hypertension
How is DVT treated?
Anti-coagulation for 3-6 months - heparin, warfarin, direct oral anti-coagulant.
Removal of risk factors.
Pain relief.
Compression stockings.
How is VTE prevented?
- avoidance of risk factors
- risk assess at hospital admission or surgery
- provide thrombo-prophylaxis when appropriate - anti-embolism stockings, Heparin
- Educating patients on risk and avoidance i.e. early mobilisation
What are the different stages of the pathophysiology of Coronary Artery Disease?
- Foam cells
- Fatty Streak
- Intermediate lesion
- Atheroma
- Fibrous plaque
- Rupture of lesion leading to thrombosis
This leads to downstream ischaemia and infarction.
What are the risk factors for atherosclerotic cardiovascular disease?
Smoking Hypertension Hyperlipdiaemia Diabetes Obesity Family history
How is a myocardial infarction or acute coronary syndrome diagnosed?
- suggestive history
- clinical evidence of cardiac dysfunction
- ECG findings
- Troponin levels
- Visualisation of coronary arteries (cardiac catheterisation.)
What two changes may be present on an ECG with an NSTEMI?
ST depression
T wave inversion
How is acute coronary syndrome (ACS) treated?
Prevent thrombus extension - anti-platelet agent i.e. aspirin + anticoagulant i.e. heparin
Remove the thrombus - thrombolysis i.e. alteplase / remove the clot via catheter - PCI
Widen the stenotic plague - balloon angioplasty, insert coronary artery stent.
Prevent further thrombus - anti-platelet agent, statin
What are some of the possible complications following an MI?
Death Arrythmia Pericarditis Myocardial rupture Mitral valve prolapse Left ventricular aneurysm +/- thrombus Heart Failure
How would you investigate a suspected stroke?
CT scan of the brain
How is stroke and AF treated?
(rarely) removal of thrombus - thrombolysis, carotid end arterectomy
Remove source of thromus - anticoagulation (warfarin), revert to sinus rhythm (cardioversion), replace defective heart valve
Address other CVD risk factors - HBP, hyperlipidaemia
