Cardiovascular and Respiratory Flashcards
Describe the basic anatomy of the heart
Deoxygenated blood comes into heart through Superior Vena Cava goes to the Right Atrium then through the Tricuspid Valve into Right Ventricle, it’s then pumped through Left and Right Pulmonary Artery to the lungs.
After being oxygenated the blood returns via the Left and Right pulmonary veins through the mitral valve into the left ventricle and into aorta
Describe the four congenital heart diseases and what happens to the heart
1) Ventricular Septum Defect: hole in the septum between the ventricles so blood mixes, the left side of the heart has higher pressure so oxygenated blood pushed into the right ventricle more which overwhelms it and caused right sided failure.
2) Atrial Septal Defect: like ventricular, blood pushed from higher pressure left side into right mixing blood
3) Tetralogy of Fallot: ventricular septum defect so ventricles connected, aorta is above this defect so is getting blood from both sides, causes ventricular septum hypertrophy and the pulmonary veins become constricted as it’s hard for blood to get through pulmonary valve, just goes straight to aorta which it shouldn’t, this means less blood getting to the lungs and less blood coming back through pulmonary veins
4) Coarctation of the Aorta: wall of aorta is constricted at a point so when left ventricle is in systole not much blood can get through. Causes less cardiac output, less SV, breathlessness because not getting enough oxygenated blood
What are the structural defects of the heart that do not have a congenital cause.
Aortic Stenosis
Aortic Regurgitation
Mitral Stenosis
Mitral Regurgitation
What is the most common valvular disease and its cause
Aortic Stenosis
Describe Aortic Stenosis’ pathophysiology, risk factor, causes, what usually occurs before hand and how suspected
Aortic Stenosis
Risk factors : hypertension, LDL levels, smoking, hugh C reactive protein, congesnital bicuspid valves, CKD, radiotherapy, older age.
Causes: rheumatic heart disease, congenital heart disease, calcium build up
Pathophysiology:
Affects older people, the risk factors cause damage to the valvular endothelium which causes inflammation and leads to leaflet fibrosis and deposition of calcium on the aortic valve. Eventually progressive fibrosis and deposition causes aortic sclerosis where the aortic valve thickens without flow limitation. Suspected by presence of early peaking systolic ejection murmur ( hear a murmur as blood hits against a calcified aortic wall).
Result:
Stenosed valve means blood cannot fully be pushed out causing long standing pressure overload in the left ventricle and leading to left ventricular hypertrophy to combat this stress (gets bigger to reduce the afterload). As stenosis worsens, the left ventricular wall stress then increases because the ventricle dilates due to the continuing filling of blood which makes the afterload too high and the ventricles cannot contract - systolic function therefore declines resulting in systolic heart failure
How is aortic stenosis diagnosed and managed
History: exertional dyspnoea and fatigue, chest pain, ejection systolic murmur (crecendo-decrescendo, peaks mid-systole and radiates to carotid), history of rhematic fever, high LDL or lipoprotein, CKD, over 65
Investigations: Transthoracic echocardiography, ECG Chest X-ray, Cardiac catheterisation, cardiac MRI
Management:
Aortic Valve Replacement - can be mechanical or bioprosthetic
Antihypertensive- to reduce pressure overload like amlodipine
ACE inhibitors - blocks angiotensin converting enzyme to stop reabsorption of fluid and thus lower blood pressure
Statins-
Describe Aortic Regurgitations pathophysiology, risk factor, causes, what usually occurs before hand and how suspected
Causes:
Rheumatic heart disease, Infective endocarditis, Aortic valve stenosis, Congenital heart defects, congenital bicuspid valves
Or aortic root dilation caused by : marfans syndrome, connective tissue diseases, idiopathic, ankylosing spondylitis, trauma
Pathophysiology:
Diastolic leakage of blood from the aorta into the left ventricle. Incompetence of valve leaflets due to valve diseases or aortic root dilation.
ACUTE AR is a medical emergency where presentation would be sudden pulmonary oedema and hypotension or cardiogeneic shock. Acute aortic regurgitation can be due to infective endocarditis which ruptures leaflets, vegetations on valvular cusps or chest trauma. Happens as there is an increased blood volume in the left ventricle dueing systole, so LV end diastolic pressure increases (backpressure on atria and lungs which are trying to put more blood in increases) , this increases pulmonary venous pressure, causes dyspneoa and pulmonary oedema which leads to heart failure and cardiogenic shock
CHRONIC AR leads to cardiac failure, this can be due to a bicuspid aortic valve or rheumatic fever (fever causes fibrotic changes causing thickening and retraction of leaflets) . Happens due to a gradual increase in LV volume, LV enlarges and due to this and eccentric hypertrophy occurs, In early stages the EF normal or slightly raised, in later stages the EF falls and LV end systolic volume rises. Eventually LV dyspnoea, to lower coronary perfusion, ischaemia, necrosis and apoptosis
How is aortic regurgitation diagnosed and managed
History:
ACUTE: tachycardia, cyanosis, pulmonary oedema, cardiogenic shock
CHRONIC: wide pulse pressure(systolic - diastolic blood pressure), corrigan (wate hammer pulse), pistol shot pulse)
Investigations:
Transthoracid echocardigraphy
Chest X ray
cardiac catheterisation
Cardiac MRI/CT
Management:
Acute AR: ionotropes/vasodialtors, valve replacement and repair
Chronic asymtomatic: if LV function normal then drugs or reassurance
Chronic symtpomatic: Valve replacement and vasodilator therapy
Prevent before this by treating rheumatic fever and infective endocarditis
Describe Mitral Stenosis pathophysiology, risk factor, causes, what usually occurs before hand and how suspected
Causes:
Rheumatic fever, Carcinoid syndrome, lupus, mitral calcification due to age, amyloidosis, rheumatoid arthritis, congenital deformity
Pathophysiology:
Obstruction to left ventricular INFLOW due to structural abnormality. Stenosis usually happens decades after rheumatic fever. Rheumatic fever leads to formation of foci and infiltrates in the endocardium and myocardium and along the walls of the valves. After a while it gets thickened, calcified and results in stenosis. Severe mitral stenoss leads to increased left atrial pressure and fluid moving into lung interstitium causing dyspnoea at rest and exertion. Backpressure to the lungs can also cause hypertension and less filling of left ventricle limits cardiac output. Will cough up blood if a bronchial vein ruptures from pressure.
How is mitral stenosis diagnosed and managed
History and Presentation:
history of rheumatic fever, dyspnoea, orthopnoea (breathlessness relieved by sitting or standing), diastolic murmur (when blood goes from atria to ventricle), loud p2, neck vein distention, coughing up blood, 40-50yrs old.
Investigation:
ECG, transthoracic echocardiography, Chest X ray, cardiac catheterisation, cardiac MRI/CT
Management:
if progressive asymptomatic- nothing
if severe asymptomatic- no therapy just baloon valvotomy
severe symptomatic- diuretic, balloon valvotomy, valve replacement,b-blockers
Describe Mitral Regurgitation pathophysiology, risk factor, causes, what usually occurs before hand and how suspected
Causes:
Acute- mitral valve prolapse, Rheumatic heart disease, infective endocarditis, valvular surgery, prostethic mitral valve dysfunction
Chronic- rheumatic heart disease, lupus, scleroderma, hypertropic cardiomyopathy, drugs
Pathophysiology
Infectious endocarditis can cause abscess formation, vegetations, rupture of chordae tendinae and leaflet perforation
Chronic- progression leads to eccentric hypertrophy which elongates myocardial fibres and increases left end diastolic volume. Increase in preload and decrease in afterload as blood is moving back into atria, increase in end diastolic volume as not pushing the blood out so stays in ventricle, decrease in end systolic volume because ventricles not filling much and less wall stress/afterload. Pressure put on LA all the time so leads to left ventricular dysfunction and an increased lv end-systolic diameter
Is the abnormal reversal of blood flow from LV to LA
How is mitral regurgitation diagnosed and managed
History and Presentation:
Dyspnea, diminished S1, fatigue, orthopnea, chest pain, atrial fibrillation
Investigations:
ECG, Transthoracic echocardigraphy, Chest X ray, cardiac catheterisation, cardiac MRI/CT
Management
Acute: emergency surgery with diuretics before and intra-aortic balloon counterpulsation to reduce afterload pressure
Chronic asymptomatic: ACE inhibitors or Beta blockers if ventricular EF is less than 60%, 1st line is surgery
Chronic symptomatic: surgery with medical treatment, if LV EF is less than 30% then intra aortic balloon counterpulsation
What is the name of diseases of the heart muscle that make it harder to pump blood to rest of body
Cardiomyopathies
a problem with the heart tissue
What are the three types of cardiomyopathy
1) Dilated
2) Hypertrophic
3) Restrictive
Describe causes and pathophysiology of dilated cardiomyopathy
usually older people, will see a large ventricle/ ventricular dilation more than 4cm and systolic dysfunction with normal left ventricular wall thickness. get low EF, higher ventricular wall stress and high end systolic volumes. To combat this heart will increase heart rate to inc cardiac output. Will find renin-angiotensin system being activated and higher levels of catecholamines and natriuretic proteins
Causes can be familial or due to myocarditis, alcoholism, after child birth, autoimmune disorders, drugs.
Describe the history and presentation of dilated cardiomyopathy
History and Presentation: displaced apex beat, S3/systolic murmur
Investigation: genetic testing, viral serology, ecg, chest x ray
Management: modify diet, treat underlying cause, ACE, B blockers, add a diuretic and if thats ineffective then Left Ventricle assisted device to help contract
Describe causes and pathophysiology of hypertrophic cardiomyopathy
Genetic cardiovascular disease, autosomal dominant
Increase in left ventricular thickness. (the muscle mass) not the cavity. Often happens to left ventricular wall and the interventricular septum which obstructs outflow to aorta. usually have abnormal diastolic function which decrease ventricular filling and increases filling pressure despite a normal cavity. Abnormal calcium kinetic and subendocardial ischaemia
Describe the history and presentation of hypertrophic cardiomyopathy
normally asymptomatic and sudden cardiac death is first presentation. will have double carotid artery impulse, S3 gallop
Investigate:
Haemoglobin level as anaemia makes chest pain and dyspnea worse
Brain natriuretic preptide and troponin levels, associated with CVD risk
Management: B blocker then Verepamil, add dispyramide then mehcanical therapy
Describe the causes and pathophysiology of restrictive cardiomyopathy
Increased stiffness of myocardium so ventricular pressures rise. Diastolic dysfunction with restrictive ventricular physiology, this may cause atrial enlargement.
Happens when abnormal substances such as amyloid proteins, iron etc are deposited onto the heart which makes the myocardium stiffen which means in diastole they cannot fill, causes a reduced cardiac output.
Describe the history and presentation of restrictive cardiomyopathy
Comfortable when sitting, usually have ascites and pitting oedema of lower limb, liver enlarged and full of fluid. weight loss.
if have easy bruising, raccoon eyes, macroglossia, carpal tunnel syndrome then may be amyloidosis
increased JVP
pulse volume is decreased as stroke volume and cardiac output is decreased
Investigate:
FBC, serology, amyloidosis check, chest x ry, ECG, echocardiography, catheterisation, MRI biopsy
Management
ACEi, B blockers, angiotensin receptor II blockers, diuretics, aldosterone inhibitors.
Antiarrhythmic therapy
immunosuppression
pacemaker
cardiac transplantation
How is Stroke Vol, Cardiac Output, Ejection Fraction and Mean Arterial Pressure calculated
SV= EDV - ESV
CO= HR x SV
EF = SV/EDV x100 (how much ejected stroke volume compared to entire diastolic filling)
MAP= ((2XDBP) +SBP)/3
What is infective endocarditis?
Infective endocarditis is infection of the endocardium or vascular endothelium of the heart, usually occurs at heart valves.
How does infective endocarditis occur and where does it affect?
Bacteria enters the blood stream, binds to damaged endothelium which causes bacterial proliferation and macrophage infiltration resulting in a vegetation. (Streptococci are the most common infection) The vegetations it forms results in changes to thickness or failure to open and close. This happens at the endocardium, especially if already damaged and this occurs at areas of turbulent blood flow such as the valves of the heart. Aortic most common then mitral then right sided ones, because left side is higher pressure system.
What is a vegetation?
Bacterial infection surrounded by a layer of platelets and fibrin
How is infective endocarditis diagnosed?
Fever, malaise, sweat, weight loss, anaemia, raised white cell, microorganism in blood culture, new heart murmur, echocardiogram may show abscess, vegetation, valve perforation, prosthetic valve unstuck.
Transoesoohageal is more sensitive than transthoracic.
Features of heart decomposition in infective endocarditis?
Shortness of breath, coughing, oedema in legs and abdomen.
Raised JVP, crackles and lung oedema
Vascular and embolic phenomena : stroke, janeway lesions (painless on palm), splinter/conjunctival haemorrage
Immunological phenomena: osler nodes (painful on finger), roth spots
How does being an I.V drug user change the risk for infective endocarditis ?
Increases risk due to repeated injection which puts them at risk for bacteria in their bloodstream (either from needle or bacteria on skin). Dental surgeries also increase risk of infective endocarditis.
What groups of people is infective endocarditis most common?
Immunosuppressed, have congenital heart issues, I.V drug users, dental surgeries
Common causes of dilated cardiomyopathy?
Idiopathic, genetic, toxins, after pregnancy, viral infection, tachycardia related, thyroid disease, muscular dystrophy
How is dilated cardiomyopathy managed ?
ACEi, B blockers, mineralcortiocoid receptor agonists, diuretics, anticoagulation for atrial fibrillation, cardiac devices, transplant
Whats risks does having dilated cardiomyopathy put an individual at?
Heart failure hospitalisation
Cardiac arrhythmia
Sudden cardiac death due ti ventricular arryhtmia
Reduced survival
What are the main symptoms of asthma
Wheeze (expiration), dry cough, dyspnoea, persistent symptoms with attacks
Atopy/allergen sensitisation, reversible airway obstruction (on a flow loop graph only the top the expiration will be affected, will have a lower peak expiratory flow rate- y value, and total forced capacity-x value) airway inflammation with eosinophilia and T2 lymphocytes.
what test investigates the effect of allergens on the airways
local allergen challenge
What is the pathogenesis of allergic asthma
If the bronchial epithelium is exposed to allergens such as pollen, dustmites and mold there is parallel development of inflammation and remodelling, eosinophilia also gather in the airway epithelium, the epithelium, muscle and matrix increase even at baseline.
What is the pathogenesis of allergic asthma
If the bronchial epithelium is exposed to allergens such as pollen, dustmites and mold there is parallel development of inflammation and remodelling, eosinophilia also gather in the airway epithelium, the epithelium, muscle and matrix increase even at baseline.
Why do only some who are exposed to allergens develop asthma
Development of asthma is multifactoral- no single gene or cause, the exposure along with genetic susceptibility can cause asthma, but just the allergy alone may not lead to.
What type of immunity is seen in asthma and how does it happen
Type 2 immunity
The allergen is recognised by an antigen presenting cell, this cell takes to mediastinal lymph node to meet naive T cells to become Th2 cells which secrete IL4 (which tells B cells to make plasma cells secrete IgE) , IL5 (Recruits eosinophils which attracts histamine, cytokines, chemokines etc) and IL13 ( increases mucus)
What interleukin is central to allergic asthma
IL-5 which recruits eosinophils
What tests are used to investigate allergic sensitisation
Blood Tests- for aeroallergens, and specific IgE antibiodies
Skin Prick test
What are the tests for eosinophilia
Blood eosinophil count when patient stable: more than 300 cells/mcl is abnormal
Induced sputum eosinophil count : should not be 3% or over
Exhaled nitric oxide: marks airway inflammation and T2 high eosinophilic airway inflammation. Elevated helps to diagnose asthma and also indicates that the patient will respond to corticosteroids.
How is asthma diagnosed
History and Examination
Confirm wheeze
Tests :
- confirm airway obstruction on spirometry FEV1/FVC ratio
- confirm it is a reversible airway obstruction with bronchodilator, improvement of 12% or more
- exhaled nitric oxide of 35 ppb or more
if have symptoms and either FeNO with a positive peak flow OR obstructive spirometry and bronchodilator reversibility
How is asthma managed
1) to reduce airway eosinophilic inflammation with inhaled corticosteroids and leukotriene recptor antagonists
2) Acute symptomatic relief with beta-2 agonists and anticholinergic therapies to relax the smooth muscle
3) Severe asthma- biologics targeted to IgE (anti-IgE antibody) and biologics targeted to airway eosinophils (anti IL-5 antibody and anti IL-5 receptor antibody)
How do corticosteroids work
Inhale so directly gets to tissue and doesn’t cause side effects.
Steroids reduce airway eosinophilia by causing apoptosis, by reducing their recruitment since it decreases numbers of dendritic cells which decreases the cytokines which recruit macrophages, so less macrophages so less mast cells.
It also works on epithelial cells to reduce cytokines and mediators, endothelial cells to reduce leak, airway smooth muscle to increase B2 receptors and decrease cytokines, and the mucus gland to decrease mucus secretion
what is important to discuss with asthma patients
How to use inhalers and the correct technique
Asthma management plan that is simplified
About the importance of inhaled corticosteroids
How is the correct dosage and therapy decided
Start from a low dose and increase until the asthma is controlled
Low dose ICS -> LABA added -> increase ICS dose and add LTRA then specialist care
Describe an acute lung attack in an asthmatic
Acute lung attack is when exposed to smoke, allergen, cold etc.
Asthmatics have a reduce peak expiratory flow and increase airway obstruction, have more eosinophilic inflammation and reduced IFN-alpha, beta and delta. This means a reduced anti-viral response as cant produce antiviral inteferons which are needed.
The patient has underlying inflammation but also exposed to allergens, pathogens such as virus and bacteria, pollution and tobacco smoke so airways close even further
How is anti-IgE therapy used and what is an example of one
Binds and captures circulating IgE so prevents the IgE activating mast cells and basophils which prevents getting worse.
With time using anti-IgE, IgE production can decrease which means it may not be needed to use indefinitely
Example: Omalizumab, which is used for severe persistent allergc asthma in ppl 6 or over who need frequent oral coertiocosterodi treatment- 4 or more attacks in last year, only if have documented compliance.
Given if serum IgE between 30-1500 IU/ml
What is the name of the Anti-IL5 antibody treatment, who is it given to and how does it work
Mepolizumab, binds to IL-5 receptor on eosinophils to stop growth, recruitment and activation of eosinophils.
given to people 6 and over who have severe eosinophilic asthma, have 300 or over cells/mcl and 4 exacerbations needing oral steroids in one year. Having these two characteristics as well as taking inhaled steroids means they are more likely to respond
What is a restrictive lung disease and the two main causes
Lung volumes are small
Intrinsic lung disease- where lung parenchyma is changes such as ILD
Extrinsic disorders- lung is compressed and expansion is limited either pleural, chest wall or neuromuscular such as motor neurone or COPD
What are the cellular components of the lung parenchyma (alveolar regions)
Alveolar type 1 epithelial cells - where gas exchange occurs
Alveolar type 2 epithelial cells- produce surfactant to reduce surface tension, are stem cells which can become type 1
Fibroblasts- produce ECM like collagen type 1 to give lung structural integrity
Alveolar macrophages- phagocytose foreign material and produce surfactant
What is the interstitial space of the lung, what is its function and what is in it
the space between alveolar epithelium and capillary endothelium, gives structural support tot he lung and is very thing so gas exchange can occur.
contains:
lymphatic vessels, fibroblasts, ECM
What cell type is associated with lung epithelium
Alveolar macrophages
What is interstitial lung disease
An intrinsic lung disease, due to inflammation or fibrosis in the interstitial space which causes scarring and damage to the lung parenchyma
What are the five main things that can cause interstitial lung disease
Idiopathic
Autoimmune related: due to rheumatoid arthritis or lupus
Exposure related: Drug or exposed to an antigen
With cysts or airspace filling
Sarcoidosis
What is the clinical presentation of Interstitial lung disease
Progressive breathlessness, especially on exertion
Dry, non productive cough
Limitation in exercise tolerance
Symptoms of connective tissue diseases such as joint problems, rashes, dry eyes
Exposure history including job
Medication history
Familial history
Low oxygen saturations
Fine bilateral inspiratory crackles
Digital clubbing
How is interstitial lung disease is investigated
Blood Test- anti-nuclear antibody, rheumatoid factor, anti-citrullinated peptide
Pulmonary function tests
6 min walk test
High res CT scan
Bronchoalveolar lavage : flood lung with saline, suck out and count cells
Surgical lung biopsy
How would Interstitial Lung Disease affect lung volumes, FEV1/FVC ratio, arterial PO2, FVC, lung compliance,
Scarring makes the lung stiff so
reduced lung compliance
reduced lung volume, lungs get smaller as more scarring so dont expand in those areas
reduced full volume capacity as the lungs are smaller
reduced diffusing capacity of carbon monoxide- this indicated that O2 is not being transferred into bloodstream effectively
reduced arterial PO2- especially with exercise as O2 is not getting into the bloodstream as well
Normal or increased FE1/FVC ratio: as the full volume ratio decreases the ratio will increase
How would the FEV1 and FVC readings and the FEV1/FVC ratio differ in obstructive and restrictive diseases
In obstructive diseases: FEV1 is majorly decreased along with FVC, the ratio is around 40%, much lower than normal lungs. This is because if there is an obstruction it is difficult to get air past that obstruction whether it is in or out
In restrictive diseases: FVC is majorly decreased but FEV1 isnt as there is a problem with filling the lungs not getting the air out, the ratio will be higher than normal lungs
On a HRCT scan what appears white and what appear dark, and why is it needed for ILD diagnosis
The high frequency and high resolution means the pulmonary lobule can be seen
White= high density like bone
Black=low density like air
Describe HRCT patterns
Usual interstitial pneumonia- See honeycomb cysts scattered all over both lungs
Non-specific interstitial pneumonia- not really a honeycomb pattern but small areas of grey/gradient opacity (normally from the edge in)
Organising pneumonia- linear opacities that are closer to the middle ish, large areas of consolidation clumped together in some areas
How is ILD managed in early stages and in later stages
Early stages: pharmacological therapy, patient education, vaccination, stop smoking, treat comorbidities
Late stages: supplemental oxygen, lung transplant, palliative care
What is the name of the condition that causes progressive scarring lung disease of an unknown cause, and what groups are more affected
Idiopathic pulmonary fibrosis
older people, men
In idiopathic pulmonary fibrosis, after how long since onset are they more likely to die
can die at any time, has a poor prognosis
How does idiopathic pulmonary fibrosis occur
Happens when the endothelium is damaged, this means type II cells die and release profibrotic factors and the profibrotic macrophages that are associated with the epithelium start to lay down scar tissue causing the accumulation of ECM which prevents gas exchange. This also means that re-epithelialization is disturbed since Type II cells are the cells that act as stem cells for epithelium cells when damage occurs.
what are the predisposing factors of idiopathic pulmonary fibrosis
Genetic susceptibility: MUSC5B and DSP genes
Environmental trigger: smoke, viruses, pollutants, dust
Cellular ageing: telomere attrition/weakening, ageing in general
All things that can damage the epithelium
Describe how a histological slide of someone with idiopathic pulmonary fibrosis
Most of the air spaces replaced with scar tissue, thick walled and less airspace, looks honeycomb like, see proliferating fibroblasts too
How does idiopathic pulmonary fibrosis look on a HRCT scan
subpleural honeycombing (more central on axial/horizontal plane, starts at base in coronal plane)
traction bronchiestasis : see larger black circles within the honeycomb
What should not be given to a patient with idiopathic pulmonary fibrosis
Immunosuppressants (end in prine)
Name two antifibrotics and describe the effect on IPF
Nintedanib and Pifrenidone
slows progression but doesnt cure
Drugs that target fibrotic pathways, target what layer of the lung
Mesenchyme
The layers from inside to out - alveolar space -> epithelium -> mesencyme -> endothelium -> vascular space
What ILD is caused by an immune-mediated response in sensitised and susceptible individuals who inhale environmental allergens
Hypersensitivity pneumonitis
Where in the lung is affected in hypersensitivity pneumonitis
small airways and parenchyma
What are the types of hypersensitivity pneumonitis
Acute: abrupt symptom onset due to intermittent high level exposure, flu like 4-12 hours after exposure, will resolve by itself
Chronic: long term low level exposure
chronic can be nonfibrotic (just inflammatory) or fibrotic
What groups are most affected in hypersensitivity pneumonitis
50-60 years old
less frequent in smokers
difference in antigen exposure- industrial places or agricultural
male and females equal
What causes hypersensitivity pneumonitis
immunological dysregulation- innate immune system processes antigen exposed to.
when antigen inhaled it interacts with APC’s which present to T cell and stimulate Th1 response, neutrophils are present in early stage. B cells are stimulated and produce IgG antibodies, when IgG meets antigen stimulates macrophages which can bundle to make granulomas.
Reg T cell inhibiton and loss of FoxP3 leads to switch to Th2 response which creates a profribrotic environment
How is hypersensitivity pneumonitis diagnosed
Exposure history, circulating IgG antibodies, broncheoalveolar lavage with high lymphocyte count over 30%.
HRCT- will see patches of black where air has been trapped with white surrounding them, the inflammation and the granuloma formation stops air moving out.
Compare and contrast IPF, HP and SSc
IPF- lots are smokers, more men, over 60, see honeycombing in subpleural space (more central in axial CT) and begins at the base of the lung, traction bronchiectasis- the holes in honeycomb large, antifibrotics can slow progression, immunosuppression worsens
HP- will have high lymphocyte count in bronchoalveolar lavage, less frequent in smokers, 50-60 years old, inspiratory sqeaks, IgG antibodies, on HRCT see air trapping and one black circle surrounded by white as granulomas form and trap air, remove antigen, corticosteroids, antifibrotic, immunosuppresants can be used,
How is hypersensitivity pneumonitis treated
Remove and avoid the antigen
corticosterods
immunosuppresants
for fibrotic HP- nintedanib an antifibrotic
What is systemic sclerosis associated ILD , and who does it affect
autoimmune connective tissue disease characterised by immune dysregulation and progressive fibrosis that affects skin and some organs
affects young middle aged women
leads to ILD
In what group of people does SSc ass ILD have the worst prognosis
if an old male who smokes, more than 20% on CT affected and a FVC of less than 70 then have the worst prognosis
What are the clinical features of SSc ass ILD
Sclerodactyly- thickened and tightened skin
Raynauds - finger changes colour
Telengectasias- see capillaries on face
Digital ulcers
Abnormal capillary in nailbed
What are the two types of systemic sclerosis associated ILD
classified based on skin involvement
- limited cutaneous SSc- usually pulmonary hypertension, skin involvement up to elbow or up to knees
- diffuse cutaneous SSC- ILD more common if face and other parts of the body are impacted
What is the pathogenesis of systemic sclerosis associated
tissue injury and vasular injury, b cells instruct plasma cells to make autoantibodies and IL-6, IL-6 recruits fribrocytes
Describe the pattern seen on a HRCT if a patient has systemic sclerosis associated ILD
Non specific interstitial pneumonia pattern
see haziness and scarring, starts from bottom of lung. patterns of gray/opacity from the edge in
how is systemic sclerosis associated ILD managed
depends how bad, monitor every 3-6 months
immunosuppressives used, corticosteroid is controversial as can risk renal crisis
nitendanib and antifibrotic if immunosuppressants dont work bcs they have genetic predisposition or inflammation isnt checked
What groups of people are most likely to get lung cancer, what are some causes
75-90 yrs
males more common
lower socioeconomic status
smoking history or passive smoking
asbestos exposure- plumbers and carpenters etc
radon/radiation e.g. miners
indoor cooking fumes
chronic lung diseases- COPD and fibrosis
Immunodeficiency
familial/genetic
Describe the pathogenesis of lung cancer
can be from differentiated (ciliated, mucus cells) or undifferentiated (basal) cells. Inhaled carcinogens interact with upper and lower airway epithelium to form DNA adducts (DNA bound to carcinogen- cancer causing chemical). When DNA adducts are not repaired or persist then genomic alterations can occur. If this occur in oncogenes or tumour suppressor genes then get uncontrolled cell differentiation
Describe the four types of lung cancer, where in the lung it affects and what history the cancer is associated with
1) Squamous cell carcinoma- bronchial epithelium- central part of airway, smoking related
2) Adenocarcinoma- from mucus producing glandular tissue, more peripherally/outer sides of the lung, low tar cigarettes that have been retained for longer.
3) Large cell cancer- heterogenous group, undifferentiated
These are all grouped as non small lung cancer
4) Small cell lung cancer - from pulmonary neuroendocrine cells, highly malignant
What are the oncogenes that are related to the different lung cancers
Adenocarcinoma:
epidermal growth factor receptor (EGFR) tyrosine kinase - found in non smoking asian women. (intracellular side of receptor)
Non-small cell lung cancers:
ALK tyrosine kinase - in younger non smokers
ROS1 receptor tyrosine kinase- younger non smokers
BRAF- especially smokers
What are the symptoms/clinical features of lung cancer
cough, weight loss (cachexia- look bony), breathlessness, fatigue, chest pain, haemoptysis, repeated respiratory infections
if metastatic disease then get other issues from where it metastasises to:
brain- focal weakness, seizures and spinal cord compression
bone pain
paraneoplastic syndromes: clubbing, hypercalaemia, hyponatraemia, cushings
Pembertons sign- when raise arms then face gets red, happens if superior vena cava is obstructed then get breathless
horners syndrome- atosis (drooping) and anhydrosis (oss of sweating) of one eye
How is lung cancer diagnosed
establish whats most likely, see if fit to investigate and treat, get tissue biopsy and confirm diagnosis for specific type, then confirm staging by using CT of chest and abdomen but deffo do PET-CT as the glucose given will be used up quickly in areas that have higher cell turnover and energy requirements.
Describe the different types of biopsy when it comes to lung tumours
bronchoscopy for central airway tumours
endobronchial ultrasound and transbronchial needle aspiration of mediatinal lymph nodes
ct guided if accessing peripheral lung tumours
Describe the staging of lung cancer
Tx,0,is- tumour in bronchial wash only, no evidence
T1- less than 3 cm categorised by each cm by 1a,1b,1c
T2- 3-5cm or involves main bronchus but not carina, again between 3-4 c is 2a, 4-5 is 2b
T3- 5-7cm
T4- greater than 7cm or invades diaphragm, mediastinum , carina
N: 1- nodes up to the karina on same side , 2- nodes up the trachea on same side, 3-up to supraclavicular can be contralateral
M1- distant met, 1a in contralat lung, 1b- single extrathoracic, 1c- multiple extrathoracic
What determines treatment in lung cancer
Patient Fitness
Cancer histology
Cancer stage
Patient preference
Health service factors
How is patient fitness assessed, and at what score is radical treatment allowed
WHO performance rated on 0-5
0 is asymptomatic
1 is symptomatic but ambulatory
2 is symptomatic and in bed for less than 50% of day
3 is symptomatic but spend more than 50% in bed
4 is bedbound
5 is dead
radical treatment from 0-2
What are the different treatment options for lung cancer and at what stages would each be offered
1) Surgery: lobectomy and lymphadenectomy usually but if stage 1 then sublobar. wedge is a small section, segmental is a large portion, lobectomy is a lobe, pneumonectomy is an entire lung
2) Radical radiotherapy : for early stage, esp if comorbid and cant handle surgery
3) Systemic treatment
surgery and radiotherapy if early stage
surgery with chemo / radio and chemo with immuno if locally advanced so involves thoracic lymph nodes
tyrosine kinase inhibitor if metastatic with mutation can target
immunotherapy if PDL-1 positive with no mutation
chemo and immunotherapy if PDL-1 neg with no mutation
palliative care
What are the types of systemic treatment of lung cancer, and examples of the medications given
Immunotherapy:
Inhibiting PD-1 or PD-L1 proteins, if a tumour cell has these protein then the cell cant be killed and they can inactivate the T cell. This is because they are proteins which are used in the body as a brake for the immune system. Therefore blocking PD-1 or PD-l1 receptors on tumour cells means that the T cell can recognise the tumour cell antigen and apoptise the cell.
Given if a non small cell lung cancer with no mutation and PDL1 over 50% as improves progression free survival and overall is better than chemo.
pembrolizumab, atezolizumab, nivolumab
Side effects: may have immune side effects
Cytotoxic chemotherapy:
Given if non small cell lung cancer with no mutation and PDL1 of less than 50%, give immunotherapy too.
targets rapidly dividing cells, are platinum based. e.g. carboplatin, cisplatin, paclitaxel.
Side effect: fatigue, nausea, bone marrow suppression, nephrotoxicity
Describe palliative and supportive care
all patients with advanced disease
help to control symptoms, support psychological, education, financial and practical , plan for end of life
lung cancer specialist nurses
Describe the prognosis trend in lung cancer
As present later, less likely to survive
Describe deflections in an ECG
steepness denotes the velocity, downward is towards the negative electrode, upwards to the positive and the width denotes how long it takes
Describe the events in an ECG and what they are related to
P wave - atrial depolarisation, is the sinoatrial node sending signals via autorhythmic myocytes
P-R interval - AP moves through the AV node which is slower
QRS- contraction of the ventricles
Just before Q is conduction through the bundle of His
Q itself - is the bundle branches depolarising the septum, depolarisation happens from left to right so away from lead II making neg deflection.
R- Depolarisation of the purkinje fibres depolarising the muscle of the heart, represents ventrical depolarisation, thick muscle so large deflection
S-late ventricular depolarisation
ST segment- isoelectric as ventricles are fully depolarised
T- relaxation/repolarisation of the ventricles
Describe the electrode placement for ECG
Bipolar Leads
Lead 1- Right Arm (-) to Left Arm (+)
Lead II- Right Arm (-) to Left Leg (+)
Lead III- Left Arm (-) to Left Leg (+)
Augmented Unipolar
aVR- looking from right up
aVL- looking from left up
aVF- looking to foot
Chest Leads- Unipolar
V1-V6
Limb leads give a coronal plane
chest leads give a horizontal plane
What areas on the ECG are looking at which areas of the heart and what structures are being looked at
Inferior - Lead II, Lead III, aVF, looks at right coronary artery
Lateral- Lead I, aVL, V5, V6, looks at left circumflex artery
Anteroseptal- V1-4, V1-2 is septal and V3-4 is anterior, looks at left anterior descending artery
How do you work out cardiac axis
Pick two adjacent leads such as LII and aVL, work out the amount of boxes it deflects upwards in the QRS, minus the amount of downward deflection in both leads
Lead I,II or III will be the Opposite side and the aV the adjacent. Use TOA : tan(degrees)= O/A so degree= tan-1 x(O/A)
If a patient reaches asystole/flatline what do you do
Not shockable as no electrical activity
CPR to try to convert into a shockable rhythm
Describe sinus bradycardia and causes
Regular rate, but slow, can be healthy for example if an athlete, caused by medication or vagal stim
Describe sinus tachycardia and causes
Regular rate but fast, often a physiological response
What is sinus arrhythmia
Irregular rate R-R interval changes but still sinus as each p wave results in a QRS so no problem with atrial to ventricle depolarisation
Describe the findings with atrial fibrillation
Have an oscillating baseline where the atria contract randomly, rhythm may be irregular and slower as problem with the SA node so the slower AV node takes over.
Increased risk of clotting
Describe the findings for atrial flutter
regular sawtooth pattern of the p waves in inferior leads especially.
Describe the findings for first degree heart block
Prolonged PR due to slower AV conduction
See with ageing
Describe the findings for second degree heart block
Mobitz I : gradual prolongation of PR until a beat is skipped, regularly irregular, problem with AVnode
Mobitz II: p waves are regular but only some followed by QRS, no PR prolongation. regularly irregular
Describe the findings for third degree heart block
p waves and QRS are regular but no relationship between the two. ventricles pumping themselves
Describe the findings for ventricular tachycardia
p waves hidden, fast and regular rhythm 100-200 bpm
Really big ice peak looking thing- p wave can be hidden as a small bump when going up.
is a shockable rhythm
Describe the findings for ventricular fibrillation
Heart rate irregular and fast over 250bpm
random shapes going up and down
is a shockable rhythm
What would ST elevation suggest
Infarction - tissue death from hypoperfusion
What would ST depression suggest
Myocardial ischaemia
What can affect a persons exercise capacity
Neurological- motor control or coordination
Respiratory- lung ventilation, pulmonary perfusion
Cardiovascular- heart to get blood from lungs
Muscular- local perfusio, muscle cell enzymes
How is exercise capacity evaluated and the advantages and disadvantages of each method
Cardiopulmonary exercise test: treadmill, inc intensity in increments under clinical supervision. Measure ECG, ventilation, O2 and Co2. Can assess peak VO2 which is peak oxygen uptake. ADV: quantifies performance, precise and reproducible, safe. DISADV: skilled technical support, expensive, space
Six minute walk test: 20-30m flat course and have to cover as much distance as possible. Find total distance and can observe perceived exertion and measure HR and pulse oximetry. ADV: patient sets pace, cheap. DISADV: need unobstructed course.
Incremental shuttle walk test: 10m circuit, paced by audio, each minute has one extra length added. Find total distance walked before cant, observe perceived exertion and measure HR and pulse oximetry. ADV: cheap, external pacing helps to achieve max levels. DISADV: unobstructed course needed, incremental nature might be difficult, patient may manage their pace wrongly and reduce how much they could do
What are the signs of a upper resp infection vs lower resp infection vs pneumonia
Upper- cough, sneeze, runny or stuffy nose, sore throat, headache
Lower- productive cough, muscle aches, wheezing, breathlessness, fever, fatigue
Pneumonia- cyanosis, severe fatigue, fever, chest pain
Why do acute lung infections rank first in global DALYs despite not being deadly
disability-adjusted life years: impairs daily life
What are the general risk factors for pneumonia
Age- under 2 or over 65
cigarrettes
excess alcohol
contact with children under 15
poverty and overcrowding
inhaled corticosteroids, immunosuppressants or proton pump inhibitors
COPD, asthma, heart or liver disease, Diabetes,
in specific locations: Geographical variation, animal contact and healthcare contact
Compare the main causes of community acquired vs hospital acquired pneumonia
CAP; streptococcus pneumoniae, all the other pneumoniaes, haemophilus influenzae, moraxella catarrhalis
HAP: Staph aureus
Describe what happens during acute bacterial pneumonia
Bacteria reach the lower airway and cause bronchitis (inflam and swelling of the bronchi), bronchiolitis (inflam and swelling of the bronchioles) and eventually pneumonia (inflam and swelling of the alveoli)
The pneumonia can then leads to
1) lung injury, since less oxygen then arterial hypoxemia which can lead to organ injury and ARDS
2) Bacteremia, can lead to organ infection which can injur the organ or cause dysfunction which can result in sepsis
3) Systemic Inflammation and Treatment which can both lead to organ injury and deterioration
How is bacterial pneumonia graded
CRB/CURB-65 scoring, max score is 4
confusion, respiratory rate, blood pressure and whether over 65yrs - given 1 point each
if already in hospital then add urea
if 1-2 consider hospital referral
3-4 then urgent hospital admission
What are the treatments for bacterial pneumonia
Supportive Therapy- oxygen, fluids, analgesia
Antibiotics-
- penicillins: amoxicillin- beta lactams, bind to wall to prevent transpeptidation
-macrolides: clarithromycin, bind to bacterial ribosome to stop protein synthesis
combine antibiotics means more successful
How is pneumonia spread
Oropharynx route or through the nose both staph aureus and strep pneumoniae can be spread.
What are the three terms used to describe colonies of microbes in different places
human microbiome- barrier surface
microbiota- found inside multi cellular organisms
Commensal- microbes that like in symbiotic relationship such as gut bacteria
What are the two types of pathogens
1) Opportunistic Pathogen- microbe that takes advantage of a change in condition, e.g. if someone becomes immunosuppressed then bacteria that normally live can cause problems
2) Pathobiont- microbe that is normally commensal but is in the wrong environment so can cause pathology
Why do viral infections result in disease
Can cause cellular inflammation with mediator release which leads to epithelium damage which damages the cilia, reduces the barrier to the antigen and bacterial growth can occur. Also loose chemoreceptors so loose smell and taste
What factors contribute to how severe a viral infection can get
the RNA sequence- the type of infection is important
Viral load- how much it can replicate
Whether have prior immunity or immunodeficiency
whether have predisposing conditions like being elderly, having respiratory problems or diabetes, pregnancy or obesity .
Therefore need to study pathogen, co pathogen and host
What is viral tropism
the ability of a given virus to productively infect a particular cell (cellular tropism), tissue (tissue tropism) or host species (host tropism).
What is virus binding
Most resp viruses can bind throughout the respiratory tract but if existed for a while tend to adapt to bind to upper respiratory and specific receptors there. This means that if something e.g. smoking causes more of the receptor then more likely to get, or if binds to receptors in upper airway then infects there
Describe how the respiratory epithelium defends against infection
Has tight junctions to prevent infection
Also has a mucous lining and cilial clearance to prevent attachment and move the pathogen/particle away
Contains antimicrobials which will recognise, neutralise or degrade microbes and microbial products
Contains pathogen recognition receptors, this means that when a virus binds interferon pathways can be activated which promotes upregulation of anti-viral proteins and apoptosis
What are serotypes
pathogens which cannot be recognised by serum and that recognise other pathogens
aka antibodies
What do serotypes explain about viral immunity
Antibody mediated immunity - humoral/ adaptive so depends on prior exposure b cells activated to differentiate into plasma cells which make antibodies.
Which antibodies dominate the nasal cavity and which dominate the bronchi area
In nasal cavity/ upper resp area, many Ig A plasma cells exist, epithelial cells also express poly IgA receptor which allows export of IgA to mucosal surface, IgA is also a homodimer so suited to the protease rich environment
The lower respiratory tract/ bronchi area are enriched with IgGs, as the thin walled alveolar spaces allow the transfer of IgG
Compare Influenza and RSV (Respiratory Syncytial Virus)
Influenza- cant be infected by same strain, vaccines arent perfect as immunity changes, the immunity is only homotypic and annual vaccination is required
RSV- recurrent re-infection with similar strains, no vaccine available due to poor immunogenecity, vaccine-enhanced disease
How does viral load impact symptoms seen
Correlates with
Infant presents to hospital with nasal flaring, chest wall retractions, hypoxemia, cyanosis, cough, expiratory wheezing, tachypnea, what is the most likely diagnosis
RSV bronchiolitis
most children infected before aged 1
What are the risk factors for RSV bronchiolitis in infants
Premature birth
congenital heart and lung disease
What are the treatment options for viral infections
Supportive Therapy- oxygen, fluids and analgesia
Vaccines (prevention)
Anti inflammatory- steroids, or target IL receptor or cytokine itself
Anti-virals-
Describe the interplay between bacterial infections, viral infections and chronic lung disease
Increase in viral and bacterial infections if there is a spike on one kind. e.g. bacteria pneumonia likely if have a viral infection
Viral bronchiolitis is associated with asthma development
rhinoviruses cause asthma and COPD exacerbations
Describe the structures of blood vessels
Composed of three layers unless its a capillary or venule
Tunica adventitia: outer layer of vasa vasorum and has nerves
Tunica media: has an external elastic membrane and the smooth muscle cells underneath
Tunica intima: has an internal elastic membrane, a lamina propria (which is smooth muscle and connective tissue), a basement membrane and endothelium
Capillaries and venules on the other hand just have a basement membrane and endothelial cells underneath which are supported by pericytes - pericytes aid in vasoconstriction and vasodilation. This is because nutrients and oxygen are exchanged in these areas
What properties do endothelial cells and pericytes have
Organotypic properties and unique gene/protein expression profiles so are all heterogenic
Endothelial cells have a large SA, are very flat and form a monolayer (one cell deep), they form cell-cell junctions and contact inhibition stops it from proliferating. low proliferation rate unless angiogenesis is needed
How do endothelial cells regulate essential functions of blood vessels
Controls :
vascular tone
permeability
angiogenesis
tissue homeostasis and regeneration
inflammation
haemostasis and thrombosis
How do endothelial cells control tissue cell functions
angiocrine factors from endothelial cells needed for tissue homeostasis and regeneration.
The angiocrine profile of each tissue specific microvascular endothelium is different
the tissue specific microenvironment influences endothelial cell phenotype e.g. whether the vessel is continuous (non-fenestrated like in muscles, lungs or fenestrated like in the GI tract and kidney glomerulus) or discontinuous like in the liver
What method examines sequencing information from individual cells
Single-cell RNA sequencing
How do blood gases change around the circulation
blood goes through the systemic circulation and is rich in O2, then drops the oxygen to tissues and back to the heart through the pulmonary artery which carries the mixed venous blood.
Low amounts of O2 circulate so haemoglobin can load on.
Describe pulmonary transit time
is the opportunity for gas exchange to occur, happens in 0.75 second windo. oxygen is slower than Co2. If heart is beating faster and cardiac output increases then pulmonary transit window time is stretched/ decreased/not as fast
How can pH be worked out from proton concentration
-log10[H+]= pH
How can proton concentration be calculated from pH
[H+]= 10 to the power of -pH
Why must pH be tightly regulated and how does blood do this
changes will alter the 3D structure of proteins such as enzymes, hormones and protein channels
blood has enormous buffering capacity so reacts immediately to imbalances
What are acids
Molecule that has a loosely bound H+ which it can donate
What are bases
Anionic, that bind to protons
Why is the volume of respiratory acid so much more than metabolic acid
because Co2 counts as the respiratory acid and we are constantly releasing Co2
How does pH change throughout the circulation
After unloading oxygen at tissues and loading Co2 on the blood becomes more acidic.
CO2 is loaded onto red blood cells and Co2 reacts with H2O inside the cell to make H2Co3 which can dissociate into H+ and HCO3-
How does the body compensate for pH imbalances
Changes in ventilation happen first and are rapid, an increase in ventilation causes a decrease in CO2 which will help to make the blood more alkaline. Decrease in ventialtion will increase Co2 and make the blood more acidic .
Secondary to this, metabolic compensation can help to adjust HCO3 and H+ retention in the kidneys. Its a slower process
Describe the pattern that would be seen in uncompensated mixed acidosis
Acidosis - low pH
Co2- High
Base excess - low
low base = low ph , high Co2 = low pH
Describe the pattern that would be seen in fully compensated respiratory alkalosis
pH would be normal as fully compensated
CO2 would be low as low CO2 is what caused the increase in PH
and base excess low as this is the compensatory mechanism to try to reduce the alkalosis
In partially compensated and fully compensated what patterns do you see
Co2 and Base excess will either be both high or both low
but in partially the pH still wont be in range but in fully it will be
How would you work out the volume of CO2 produced in a 24 hour period
Work out the Co2 flux e.g. 4ml per dL of blood per min
then look at the cardiac output and convert to dL, so 5L/min will become 50dL/min.
this means for every dL of blood 4ml of CO2 is produced, so 50x4 = how much Co2 in ml produced per min e.g. 200
then times this by 60x24
What are the risk factors for coronary heart disease
smoking
lipid intake
blood pressure
diabetes ( esp type 2 since due to obesity) Hyperglycaemia causes glycation (modification) of LDL
obesity
sedentary lifestyle
non mod: age, sex, genetic background, anatomical factors : the branches and bends in vessels
Where do plaques usually form and why
Form plaques at branches and bends, on the inside of bends (side which it bends towards) as it has lower turbulence/pressure and vortex formation
What are the main cell types involved in coronary heart disease/atherosclerosis
Vascular endothelial cells: barrier between blood and fat, damaging causes recruitment of leukocytes
Platelets: generating thrombi which block arteries, also release cytokines and growth factors
Monocyte-macrophages: accumulate lots of fat from the blood and form foam cells, these cells will release cytokine and growth factors. Cytokines are also a major source of free radicals so if it meets fat from the blood it converts the fat to a dangerous form which aggravates inflammation.
Monocyte-macrophages also secrete metalloproteinases which degrade collagen, weaken the plaque and promote plaque rupture
Vascular smooth muscle cells: stabilises the plaque and prevents rupture through collagen synthesis, migrates and proliferates to remodel and form a fibrous cap which shields the lesion from the lumen
T lymphocytes: CD4 Th1 activates macrophages, CD4 Treg cells de activate macrophages, CD8 CTL kills vascular smooth muscle cells to reduce collagen synthesis, CD4 Th2 mediates activation of B cells to make antibodies
atherosclerosis is a __________ process
Inflammatory
How do cholesterol crystals form and what is secreted from macrophages in response
Cholesterol from LDL builds up in plaque, macrophages within the plaque move out leaving non soluble crystals which irritates the macrophage and leads to IL-1 being screted
What is the main inflammatory cell that causes atherosclerosis
Macrophages
What are the two type of macrophages
Inflammatory macrophages- kill microorganisms
Non Inflam/Resident macrophages- homeostatic function e.g alveolar resident macrophages for surfactant lipid homeostasis, or in the spleen for iron homeostasis
What is the role of LDL and HDL
LDL- synthesised in the liver, carries cholesterol from liver to rest of body
HDL- carries cholesterol from tissues back to liver
What are oxidised/modified LDL’s
LDL which has been chemically/physically modified by free radicals, enzymes or aggregation, this happens when it leaks into arterial walls and is met by vortices, turbulence ect
Describe the structure of LDL
Has a lipid monolayer which has cholesterol within it.
Has apoproteins on the outside for docking
Carries tryglycerides and phospholipids on the inside
Describe the pathway from LDL in vessel walls to chronic inflammtion
Endothelial cells are damaged and dysfunctional due to things like chemical irritants, disturbed blood flow and hypertension. This causes LDL’s to leak into the vessel wall and bind to proteoglycan they accumulate here, wall is also sticky for monocytes. LDLs become oxidised by endothelial cells, smooth muscle cells or macrophages and bind to macrophages scavenger receptor and become foam cells. These foam cells are activated, damage artery walls and stimulate chronic inflammation.
Macrophage activation is also due to NFKB
If a patient presents with multiple xanthomas on the skin what condition is most likely, explain this condition
Familial Hyperlipidemia
Autosomal dominant, related to elevated to cholesterol and due to inability to clear LDL from blood. Xanthomas are clusters of foam cells that form: have an outer subendothelial zone and a lipid necrotic core. It also causes atheroslerosis which can lead to MI
Describe how LDL is taken up into cells and how intracellular concentrations affect other mechanisms
LDL Receptors take LDL into cells
higher intracellular LDL decreases the amount of LDL receptors expressed, it also lowers cholesterol synthesis.
(Body detects high levels of LDL so stops taking more up and stops synthesising cholesterol)
LDL can also be taken up on scavenger receptors on WBC’s which bind to abnormal LDL forms (oxidated forms)
What medication is used to lower cholesterol in the blood
Statins aka HMG-CoA reductase inhibitors.
How does intracellular cholesterol stop more cholesterol being made
Cholesterol enters cells, specifically liver cells which then act on transcription factors to switch the gene that makes HMG-CoA off, less of this enzyme means less cholesterol is made
What medication can be used for statin-resistant hyperlipidemia
PCSK9 kill LDL receptors, less receptors means that less cholesterol can be taken up into cells, this means cholesterol synthesis is not inhibited. If PCSK9 is inhibited then there are more LDL receptors and thus more LDL taken up into cells. When there is high LDL intracellularly then cholesterol synthesis reduces.
PCSK9 can be made into an antibody, into antisense or si-RNA
Describe the two types of macrophage scavenger receptors and what they bind to
Macrophage Receptor A/CD204:
binds to oxidised LDL, gram positive bacteria (staphylococci and streptococci) and dead cells
Macrophage Receptor B/CD36:
binds to oxidised LDL, malaria parasites and dead cells
Once macrophages are inside plaques, explain the 5 things they do
1- Release oxidative enzymes/free radicals that further oxidise LDL
2- Phagocytoses oxidised LDL and become foam cells (will see fat globules on histology)
3- Express cytokine and chemokine mediators to recruit monocytes
4- express growth factors for vascular smooth muscle cells
5- express proteinases that degrade tissue
What are the three oxidative enzymes that macrophages make
- NADPH Oxidase : enzyme that adds ad electron onto oxygen
- Myeloperoxidase: e.g. HOCl (bleach)
-Generates H2O2
What cytokine and chemokine do macrophages release that increase risk of atherosclerosis
Cytokines (activates endothelial cell adhesion molecules): IL1, IL1 triggers intracellular cholesterol crystals and NFkB, they elevate CRP and coordinate cell death and proliferation. Atherosclerosis is more common in people with IL-1
Chemokines: chemoattractant. MCP-1 binds to g protein receptor CCR2. MCP-1 and CCR2 cause more atherosclerosis
How do macrophages affect vascular smooth muscle cells
Express growth factors which stimulate them to migrate, survive, proliferate and deposit extracellular matrix/strong collagen.
1) Platelet derived growth factor: for VSMC chemotaxis, survival and division
2) Transforming growth factor beta: increases collagen synthesis and matrix deposition
A normal contractile VSMC has lots of contractile filament and few matrix deposition genes. Due to the platelet derived growth factor and transforming growth factor beta the vascular muscle cells become atherosclerotic/synthetis with fewer contractile filaments and more matrix deposition genes
What do macrophages release to degrade tissue
Metalloproteinases: activate each other by proteolysis, degrade collagen. Degradation of collagen means that arteries become weak and can rupture, when the rupture occurs, the dead macrophages which have lots of fat and activated tissue factors meet the blood and can make an occlusive thrombus
When viewing a ruptured plaque how can you differentiate between the thrombus and the inflammatory macrophage infiltrate
Thrombus more of a solid colour and wont have as many macrophages
What are the characteristics of vulnerable and stable plaques
Large lipid rich necrotic cores
vascular smooth muscle cell apoptosis
loss of VSMC and collagen
thin fibrous cap
infiltrate of activated macrophages expressing MMPs
After myocardial infarction why do tissues become pale
Tissue dies and loses myoglobin, myoglobin is what allows myocardium to bind to O2
Antibodies to what interleukin decreases inflammation
IL-1
Once macrophages undergo apoptosis, where do the contents go
Apoptosis occurs because overwhelmed by oxLDL metabolites.
The contents : macrophage tissue factors, toxic lipids etc are released into the lipid necrotic core., this will accumulate and eventually rupture.
What are the signs and symptoms of atherosclerosis/ plaque rupture
Death of downstream tissues
major ischaemic stroke
coronary occlusion- leads to central crushing pain and nausea eventually MI
angina- central crushing pain made worse with stress and exercise, rest and nitrates make better
What transcription factor coordinates most mechanisms in atherosclerosis
Nuclear Factor Kappa B (NFkB)
regulates inflammation by switching on inflammation genes for metalloproteinases, IL-1 and NO synthase etc.
Becomes activated by inflammatory stimuli such as scavenger, toll-like and cytokine receptors
Compare conjugated and unconjugated bilirubin and what disorders these are associated with
Unconjugated billirubin: insoluble in blood, attached to albumin, pre-hepatic jaundice, is toxic to tissues, not excreted in urine.
Haemolysis, ineffective erythropoeisis
Conjugated billirubin: water soluble, small amounts loosely bound to albumin, in post-hepatic jaundice, non toxic, excreted in urine makes dark colour
liver conjugates bilirubin, so prehepatic will be unconjugated and post hepatic issues will be conjugated
Patient found with jaundice, abnormal liver function tests showed lots of unconjugated bilirubin and blood film showed, increased numbers of reticulocytes, round red blood cells without the central pallor as well as blue tinged cells. what is going on ?
Spherocytosis (disruption of vertical linkages in membrane)
Polychromatic macrocytes.- blue tinged
Haemolytic anaemia- unconjugated so a problem before the liver, likely that lots of RBC’s have been broken down causing the increase in bilirubin. Lots of reticulocytes as lots of young RBCs formed
What is haemolysis and what is haemolytic anaemia
Hameolysis - destruction of RBC’s
Hamolytic anaemia- anemia that decreases RBC’s lifespan
How would a patient with haemolytic anaemia be treated
Folic acid (for erythropoeisis)
splenomectomy to stop killing RBC’s if severe
If haemolytic anaemia occurs, what is often a consequence ?
Likely to be gallstones due to large amounts of breakdown from Hb to bilirubin. This causes obstructive jaundice.
Will get pigment gallstones
What are the classifications of haemolytic anaemia
Inherited- abnormal cell membranes, abnormal Hb or enzymes in the red cells
Acquired- extrinsic factors cause: drugs, chemicals or infections
Intravascular- acute damage
Extravascular- defective RBC’s removed by the spleen
What is a direct antiglobulin test?
Antibodies will bind to antigen on erythrocyte membrane if patient develops an autoimmune condition. A DAT test then introduces an antibody to human immunoglobulin/antibody. If this antibody reacts it means there is human antibody bound to red blood cells, meaning a problem
What are the lab findings in haemolytic anaemia
higher amounts of unconjugated bilirubin
high lactate dehydrogenase
low Hb
low haptoglobins
reticulocytosis
What environmental factors can damage RBC’s
Non-immune- malaria, snake venom, drugs,
Immune mediated- auto immune or allo immune (allo is after blood transfusion)
What is auto immune haemolytic anaemia and what test is used to diagnose it
DAT - if positive then confirms it is an immune mechanism whether Lupus, lymphoma or idiopathic.
also confirms that its acquired
In inherited hameolytic anaemia what parts of the red blood cell can be affected and what condition does it lead to
Red cell membrane- hereditary spherocytosis
Hb is abnormal- sickle cell anaemia
problem in glycotic pathway- pyruvate kinase deficiency
Defect in enzymes - G6PD deficiency
What does G6PD deficiency cause
G6PD is a key enzyme in the HMP shunt which creates glutathione which prevents RBC’s from oxidant damage, so lack of it results in more RBC’s being damaged and haemolysed
How would G6PD show on a blood film
Unconjugated bilirubin
high mean cell volume
high reticulocytes
irregularly contracted cells- ghost cells and heinz bodies - this means there is oxidant damage to the red cell. ghost cells= intravascular hameolysis, heinz bodies (oxidised hameoglobin)
How should a patient with GP6D deficiency be advised
Avoid oxidant drugs
no broad beans
infection may cause hemolysis as infection causes oxidants to be generated
avoid naphthalene
this will precipitate an episodic haemolysis in those with enzyme deficiency
What clinical signs and signs on a blood film would be suggestive of haemolytic anaemia
Spherocytosis or elliptocytosis
High count of reticulocytes
polychromatic macrocytes
pigment stones
yellowing of the sclera
In acquired haemolytic anaemia what parts of the RBC can be damaged and what issues does this lead to
RBC membrane- immune attack from Autoimmune haemolytic anaemia
Whole red cell- mechanical - microangiopathic haemolytic anaemia
Whole red cell- oxidant - drugs and chemicals
WHole red cell- microbiological- malaria
Describe the clinical and blood film findings in iron deficiency anaemia
low ferritin
low serum iron
high transferrin
low transferrin saturation
small cells- low MCV
pale cells/hypochromia: low MCHC
target cells
elliptocytes
Koilonychia
Glossitis/ Angular stomatitis
If a patient has anaemia what questions must be asked?
About their diet
GI symptoms- whether dysphagia (trouble swallowing), dyspepsia or any pain, rectal bleeding, melaena
menstrual history
weight loss
medication
What tests are important to arrange in anaemia which has caused weight loss and abdominal pain
FIT test- blood in stool
Gi investigtion : Upper GI endoscopy, Duodenal biopsy, colonoscopy
coeliac antibody testing
What are the causes of iron deficiency
Increased blood loss- hookworm, menstrual, GI
Insufficient iron intake- diet or malabsorption due to coeliac or H.pylori
Increased iron requirements- pregnancy or infancy
Describe the mechanisms of iron deficiency anaemia
When iron stores are used up, ferritin which stores the iron is also decreased. Decreased ferritin reduces hepcidin production. Reduced hepcidin increases absorption of iron from the gut and release of any stored iron, this increased tranferrin which acts to move iron from gut to inside cells.
What is anaemia of chronic disease, and common causes
If you have high iron stores or the body is in an inflammtory state, hepcidin is produced which reduces iron supply by blocking more iron being taken up, it also binds the iron exporter ferroportin (Fpn), causing internalization and degradation of both proteins and decreasing delivery of iron from macrophages to developing erythrocytes. This impairs erythroid development and leads to anaemia.Inc ferritin to keep it stored in and low tranferrin to also keep it stored
Causes: TB and HIV infections, autoimmune conditions e.g rheumatoid, malignancy
What is megaloblastic anaemia due to and what would be found
B12 deficiency- Needed for DNA synthesis
folate deficiency- need for DNA synthesis
Can also get due to drugs (chemotherapy or azathioprine), folate antagonists like methotrexate or bone marrow cancer
large cells with large nucleocytoplasmic dissociation, impaired DNA synthesis, maturation and cell division
High MCV, mecrocytic RBCs
What are the most common caused of B12 deficiency and how would they be treated
Inadequate diet- oral supplements
loss of intrinsic factor due to gastrectomy or autoimmune condition- Hydroxocobalamic injections
Crohns disease or ileal resection, reduced terminal ileums capability to absorb Vit B12- Hydroxocobalmic injections
What type of anaemia results in Vitamin B12 deficiency and is due to an autoimmune attack
Pernicious anaemia
What causes a reduction in folic acid and how would you treat this
Dietary due to poverty or alcoholism
malabsorption due to coeliac disease or jejunal resection
prenancy or lactation increasing demand
increased cell turn over- haemolysis
All treated with oral suplementation
Microcytic anaemia can be due to what
Not synthesising Haem : iron deficiency anaemia, anaemia of chronic disease
Defect in globin synthesis: alpha thalassaemia or beta thalassaemia
Compare and contrast findings in:
Anaemia of Chronic Disease
Iron Deficiency Anaemia
Anaemia of Chronic Disease: high ferritin, low transferrin
Iron Deficiency Anaemia : low ferritin, high transferrin
What could be the cause of normocytic anaemia
Recent blood loss- GI
Failure to produce RBC- bone marrow failure
Pooling of RBC in spleen- splenic sequestration in sickle cell , hypersplenism from liver cirrhosis
What would be the cause of macrocytic anaemia
Lack of B12 or folic acid - megaloblastic anaemia
drugs interfering with DNA synthesis
liver disease and ethanol toxicity
Hameolytic anaemia
Immune response to a common resp infection in asthmatic vs not asthmatic
infection of nasal and bronchial epithelium.
Infected epithelial cells produce IFN-1 and cytokines TNF, IL-6 and IL_8
resident immune cells like alveolar macrophages sense infection so produce IFN-I/III, pro-inflam and chemotactic cells.
Neighbouring endothelial cells upregulate antiviral interferon stimulate genes.
Recruti more neutrophils and monocytes, activate resident lymphocyte populations. Uptake antigen, DCs migrate to secondary lymphoid tissue, goblet cells secrete mucus.
Makes antiviral T cells expand, recruit virus specific CD8 and CD4 T cellscausing cytotoxic killing of the EC that are infected.
B cells activated, mature immunoglobulins, produce high affinity antibody, neutralise virus
In an asthmatic theres increased inflammation esp of alarmins like IL-33 and TSLP.
decreased IFNI/III release
increased mast cell degrnulation, eosinophil recruitment, and mucus secretion
decreased CD8 and ThI response
Increased Th2 response
increased viral replication due to delayed clearance
get more upper and lower resp symtpoms , decreased lungfunction adn increased airway hyperresponsiveness
What are the risk factors for pneumonia
PMx of asthma, COPD, heart or liver disease, diabetes, HIV, malignancy
Risk factors- geogrpahical location, animal contact, healthcare contacts
Meds- corticosteroids, immunosuppressants, PPI
social factors: contact with children less than 15, poverty, overcrowding
less than 2yrs or over 65, smokes, lots of alcohol
Risk factors for Sars CoV2 mortality
over 65
COPD
diabetes
heart or liver disease
malignancy
