Integrative Summary questions Flashcards
explain how the hypothalamus corrects raised plasma osmolality
osmoreceptors in OVLT and subfornical organ detect raised osmolality
they stimulate posterior pituitary which releases ADH
ADH acts on the collecting duct of the kidney nephron to increase its permeability to H20 via the insertion of AQP-2 channels on the apical membrane, so more H20 is reabsorbed, correcting plasma osmolality and producing concentrated urine.
how are AQP-2 channels inserted into apical membrane during ADH release?
ADH binds to V2 receptors (Gs GPCRs) on BL memebrane on late DCT and CD
activates adenylate cyclase
increases cAMP
activates protein kinase A
increase number of channels and inserts more
how is CD made impermeable to H20 following ADH removal?
AQP-2 channels endocytosed from apical membrane
in addition to osmoreceptor stimulation in the OVLT due to increased plasma osmolality, how else is ADH release stimulated?
Ang II acts on subfornical organ
baroreceptors detect decrease in BP when plasma vol reduced, causing increased osmolality, and stimulate ADH release from post pituitary
which hormone limits ECF volume expansion promoted by ADH?
ANP- released from atrial walls when ECF volume high.
Promotes Na+ excretion (and inhibits Na+ reabsorption along nephron), but main role is promoting excretion: vasodilates afferent arteriole via activation of guanyly cyclase, increase cGMP, stimulate protein kinase G, reduce Ca2+ causing relaxation of vascular smooth muscle, hence dilation, which increases GFR as increased renal b.flow, so more Na+ excreted.
functions of ADH other than increaseing permeability of CD to H20?
increases H20 permeability of late DT
stimulates NaCL reabsorption at thick ascending limb of LOH, DT and cortical part of CD. This may help to maintain hyperosmotic medullary interstitium necessary for H20 reabsorption from medullary part of CD.
increases permeability of medullary CD to urea
K+ secretion in cortical CD
vasoconstriction at the glomerulus to reduce the effective filtering SA
what proportion of H20 filtered by the kidney is reabsorbed in the early part of the DCT?
none!
where does ADH act to regulate urea reabsorption when H20 must be conserved?
medullary CD
urea will concentrate medullat interstitium to allow more H20 reabsorption by thin descending limb of LOH
what 3 factors control renin release?
reduced NaCl delivery to DCT- as reduced GFR will reduce NaCl filtration.
reduced perfusion pressure- detected by baroreceptors in afferent arteriole
SNS stimulation- NA acts on beta 2 adrenoceptors on granular cells.
why do ACEIs have SE of a cough?
stop ACE breaking down bradykinin- a potent vasodilator and can cause coughing
what is the main danger with acidaemia, and how does this come about?
hyperkalaemia- H+ moves out of ECF into ICF, and K+ moves in opposite direction into ECF.
AND kidneys: H+ is secreted by a H+-K+ ATPase in the alpha intercalated cells of the DCT and CD and so if there is more H+ in the ECF, more will be secreted across the apical memebrane, which results in more K+ being reabsorbed.
why is a H+-K+ ATPase used to expel H+ into the urine in the DCT and CD, rather than a transporter coupled to Na+ movement?
most Na+ has been reabsorbed by this point, so insufficient Na+ gradient to provide energy to move H+ against its concentration gradient.
how does aldosterone affect Na+ and K+ concentrations in the body?
increases Na+- increasing BP, by increasing expression of Na+ pump on BL membrane of principal cells in cortical CD (and DCT), and ENaC expression on apical membrane.
reduces K+ as increase Na+ pump expression, and ROMK channel expression on apical membrane, and ENaC. Na+ pump brings K+ into principal cell from ECF, creating a chemical gradient for diffusion into filtrate, and ENaC bring Na+ into cell from filtrate, creating a +ve lumen potential that promotes a favourable electrical gradient for K+ diffusion out into the filtrate via the ROMK channels.
What stimulates increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex in the body?
hyperkalaemia
AngII- RAAS activation if decrease in BP (decrease in mean by about 30mmHg) or low blood volume
contrast the effects of acute and chronic increases in aldosterone secretion
acute: Na+ pump stimulated but secretion of K+ not increased as increased Na+ and H20 reabsorption reduces tubular flow so there is less K+ wash out to maintain gradient for K+ secretion by principal cells of cortical CD. BUT chronic secretion, ECF expands with Na+ reabsorption, so tubular flow returned to normal and K+ secretion enhanced?
why does alkalosis become life-threatening more quickly than acidosis?
alkalosis reduces solubility of Ca2+ in plasma, so it binds to plasma proteins and gets uptaken into bone, causing hypocalcaemia which produces tetany and paraesthesia as low Ca2+ in ECF increases Na+ permeability of neuronal membranes causing a progressive depolarisation that increases the chance of AP firing.
Hypokalaemia also occurs but this change is less dangerous.
2 treatment’s for Conn’s syndrome?
aldosterone antagonist e.g. spironolactone
remove tumour
blood results show low [HCO3-], low pCO2 and a relatively normal pH. What is this acid base state, and what may have caused it?
1 of 2: compensated respiratory alkalosis, or compensated metabolic acidosis. the 1st occurs acutely with hyperventilation following anxiety or panic attacks, or more LT with type 1 respiratory failure. If no resp disease present, unlikely to be alkalosis. To determine if metabolic acidosis, check anion gap. If increased, indicates metabolic acidosis e.g. lactic acidosis.
why does diabetic ketoacidosis occur?
in diabetes, low insulin:anti-insulin ration coupled to high rates of beta oxidation of FA promotes ketone production as an alternative energy source as glucose unable to be uptake by tissues for metabolism ,and ketones are capable of crossing BB barrier to provide energy to the brain.
blood results show high pCO2, high [HCO3-] and relatively normal pH. What is this acid base state, and what may have caused it?
compensated respiratory acidosis e.g. type 2 resp failure e.g. COPD, asthma, myasthenia gravis, kyphosis, respiratory depression caused by opiates e.g. morphine.
although results also suggest compensated metabolic alkalosis, this can’t occur as pH won’t be fully compensated for as would have to reduce breathing rate to increase pCO2 but this wouldn’t provided body with sufficient O2 to function normally.
factors promoting K+ uptake into cells?
insulin aldosterone catecholamines alkalosis increased [K+] in ECF
factors promoting K+ shift out of cells?
exercise cell lysis e.g. rhabdomyolysis- myoglobin appears in urine* acidosis reduced [K+] in ECF increase in ECF osomolarity
why is it difficult for kidneys to correct a metabolic alkalosis caused by vomiting?
patient will be dehydrated, reduced blood volume and BP, stimulating RAAS ( if mean BP decrease by 30mmHg), which results in Na+ and H20 reabsorption by kidney tubules, and HCO3- reabsorbed with Na+, so worsens alkalosis.
ALSO, Cl- lost in vomit, so kidneys want to reabsorb more H+ to correct acidosis but H+ reabsorbed via cotransporter which moves Cl- out and there is insufficient Cl- to move out, so H+ can’t be moved in to ECF.
what is the atrial kick?
the additional blood flow into the ventricles during atrial systole (remember, most filling of ventricles occurs in diastole.)
what might a higher intensity than normal 2nd heart sound indicate?
systemic or pulmonary hypertension causing abnormally high aortic or pulmonary pressure.
how is the first heart sound produced?
at onset of ventricular systole, AV valves forced shut as ventricular pressure becomes > atrial pressure. On closing, impact of valve leaflets induces oscillations in a variety of structures so these vibrate, producing sound. Louder and longer duration than S2.
how is the second heart sound produced?
closure of outflow valves (aortic and pulmonary) at end of ventricular systole when pressure on vessel exceeds pressure in ventricle. Lower intensity, shorter duration and higher pitch than S1.
what is the gap between the 1st and 2nd heart sounds?
280 ms at rest between 1st and 2nd (approx. length of systole). S2 to S1 =700ms.
when might a third heart sound be heard?
early in diastole due to rapid ventricular filling.
when might a fourth heart sound be heard?
in atrial systole, rarely heard unless high EDP
what is the dicrotic notch in the cardiac cycle?
increase in aortic pressure following aortic valve closure as brief backflow of blood into L ventricle allows aortic valve to close so now blood can’t move back into heart from aorta.
why does atrial pressure briefly increase following the onset of ventricular systole?
as ventricle contracts, ventricular pressure increases rapidly, causing AV valves to bulge into the atria, which causes increase in atrial pressure.
define preload and afterload
preload= filling pressure of heart afterload= pressure heart has to pump against
approximate cardiac output at rest?
5L/min
symptoms and signs of left sided HF?
dyspnoea- exertional, orthopnoea, paroxysmal nocturnal dyspnoea
chest pain resulting from dyspnoea
fatigue
ankle swelling- peripheral oedema
heart murmur- mitral regurge- systolic murmur
anorexia
dizziness
basal crackles- fluid overload, pulmonary oedema as fluid backs up from L heart, airways forced shut during expiration as compressed by fluid in pulmonary interstitium, crackles produced as airways forced shut reopen during inspiration- ‘pop’ open.
symptoms and signs of right sided HF?
raised JVP
peripheral oedema- pitting ankle oedema
pleural effusion
ascites
why are ACEIs best avoided in patient with HF who also has known/suspected renovascular disease e.g. severe bilateral renal artery stenosis?
cause significant reduction/abolishment of GFR, causing severe and progressive renal failure as ACEIs stop AngII from preferentially constricting the efferent arteriole to increase GFR when blood flow to kidney limited e.g. renal artery stenosis.
most common cause of HF?
IHD
what SE may you have to warn a patient about when treating HF with an ACEI?
cough- due to bradykinin increase as not broken down by ACE
define systolic heart failure
impaired ventricular contraction resulting in inadequate pumping of heart to meet the metabolic needs of the body.
ejection fraction <45%.
define diastolic heart failure
impaired ventricular filling during diastole, so heart not pumping out adequate blood supply to meet metabolic needs of body as not able to fill with sufficient blood.
why might hypertension be responsible for diastolic heart failure?
hypertension results in increased afterload on heart, so heart must work harder to pump blood out into the systemic circulation, so in an attempt to generate more focre may hypertrophy- cardiac myocytes grow larger and ventricular wall thickness increases, but thicker ventricle less compliant so ability to fill is reduced, contributing to diastolic failure.
what structural heart changes occur in systolic HF?
increased LV capacity as heart dilation occurs. Myocardial wall thins- mycoardial fibres replaced by fibrous tissue, and undergo necrosis, matrix proteinases function in cardiac remodelling, changing the overall structure of collagen so contractility is lost.
mitral valve becomes incompetent as valve leaflets unable to come together fully when valve closes due to ventricle dilation.
neuro-hormonal activation causes failing heart to work harder, causing energy defecit, dysfunction of ATP dependent transporters and subsequent Ca2+ overload, which impairs relaxation and causes AP lengthening- long QT syndrome, and arrhythmia generation- major cause of sudden death- VF.
what ventricular remodelling occurs after an MI?
myocytes= permanent cells, can’t regenerate, so ischameic necrosis occurs and fibrous tissue is laid down with scar formation, so loss of contractile myocardium. Heart remodels around scar to reduce risk of scar rupturing, so heart subsequently dilates.
what features may indicate HF on a chest X-ray?
increased cardiac:thoracic, >50% on a PA view )heart would be enlarged if AP view as situated anteriorly in chest)
bat’s wing shadowing= bilateral perihilar shadowing that may occur with pulmonary oedema, shows as increased lung markings
upper zone blood vessel enlargement- due to pulmonary venous hypertension
septal (Kerley) B lines- horizontal lines reaching lung edge, fluid accumulating between secondary lobules of lung due to pulmonary oedema
pleural effusions= homogeneous white opacification, meniscus sign
why is there a rise in resting heart rate with increasing age?
progressive decrease in vagal tone, so sympathetic influence on heart rate becomes more dominant
example of a +ve inotropic drug?
digoxin
adrenaline
how does the SNS contribute to progressive decline in myocardial function in chronic heart failure?
Ca2+ overload in myocytes, excessive Ca2+ uptake by SR and mitochondria
why can lactic acidosis occur with heart failure and why in this condition is it even more problematic?
poor perfusion so inadequate O2 for aerobic respiration, so proceeds anaerobically producing lactate= acidic.
Acidosis is -vly inotropic as interferes with actions of Ca2+, so cardiac fiunction will be depressed further.
how does the PNS slow HR?
ACh acts on M2 receptors: Gi GPCRs- inhibited cAMP production so depolarisation slowed and increase K+ channel opening, causing hyperpolarisation. This makes pacemaker action potential shallower, so increases the time between beats.
how does ANP act to support CO in HF?
vasodilates afferent arteriole, and constricts efferent arteriole, so increasing GFR and hence increasing Na excretion, so less Na+ and H20 retained by body, so reduce afterload so less pressure that the heart has to pump against so reduce w.load of heart.
acts through guanylyl cyclase stimulation- increase cGMP, PKG stimulation, reduce IC Ca2+ so smooth muscle relaxation in afferent arteriole.
define hypersensitivity
antigen-specific immune responses that are inappropriate or excessive and result in harm to host.
examples of extrinsic antigens triggering hypersensitivity?
non infectious substances e.g. peanuts
infectious microbes
drugs e.g. Penicillin
can control these
examples of intrinsic antigens triggering hypersensitivity?
infectious microbes e.g. Strep. pyogenes
self-antigens- AI diseases- women more susceptible, genetic susceptibility- HLA classes run in families, link to environ factors, cause of most endocrine diseases.
why might a patient suffering from a sore throat later develop rheumatic heart disease following an AI response?
sore throat caused by strep pyogenes and the microbial antigens of this organism are very similar to host antigens in cardiac muscle so when MHC molecules present the microbial antigen to T cells, the immune response may also be targeted against cardiac muscle as the antigens displayed are similar.
what virus is linked to the development of type 1 diabetes due to its antigens being similar to those displayed by beta cells of islets of Langerhans in the pancreas?
coxsackie
describe the common feature of hypersensitivity reactions in terms of how they come about
2 phases: sensitization and effector
sensitization: 1st encounter wiht antigen, host recognises antigen and immune response occurs but no tissue damage results
effector: clinical pathology on re-exposure to the same antigen, so tissue damage occurs.
how do types I, II and III hypersensitivity reactions differ from type IV?
I-III are antibody dependent:
I=IgE
II and III= IgG and IgM
timings of type I hypersensitivity?
immediate response=<30min, to non-infectious environmental antigens.
describe the immune mechanism of type I hypersensitivity
on 1st exposure to the allergen, antigen-specific IgE binds to mast cells but there are no symptoms.
2nd exposure is required, on which the allergen cross-links antigen-specific IgE molecules on mast cells causing mast cell activation and histmaine release.
Histamine causes vasodilation, increased vascular permeability through endothelial cell contraction and bronchial constriction.
effects mediated via histamine release in type I hypersensitivity reactions?
vasodilation
increased vascular permeability
bronchial constriction
how are type I hypersensitivity reactions diagnosed?
clinical history: atopy, allergens, seasonality, route of exposure
measure blood/serum levels of mast cell products e.g. mast cell tryptase, serum allergen specific IgE.
skin prick test- apply liquid allergen extract to determine which type of allergen causing hypersensitivity. Wheal (raised swelling) and flare (red as increased b.flow) reaction, >3mm, patient mustn’t be on antihistamines. BUT risk of anaphylaxis in those highly sensitive and requires trained personnel. Targets mast cells in
epidermis.
food and drug allergy challenge tests
what is urticaria and why might it occur with type I hypersensitivity reactions?
itchy rash that occurs with activation of mast cells in the epidermis.
what happens with mast cell activation in the deep dermis in type I hypersensitivity reactions?
angioedema= non-itchy swelling e.g. of lips, eyes, tongue and upper respiratory airways, may be a medical emergency- airway blockage.
describe the mechanism behind hereditary angioedema
complement component deficiency: lack C1 inhibitor, so complement system remains activated, if airways involvement in attack can be fatal as oedema blocks airways- unable to breathe.
tment of type I hypersensitivity reactions?
AVOID ALLERGEN
Epipen- IM adrenaline 0.5mg- vasoconstriction, IV fluids- increase BP as vasodilation can cause hypotension on systemic activation of mast cells.
Antihistamine (IM or slow IV)
Hydrocortisone (corticosteroid-anti-inflammatory- inhibits gene expression, transrepression and transactivation functions)- IM or slow IV
allergen desensitisation in patients at high risk of systemic attacks
carry medical alert bracelet
result of systemic activation of mast cells in type I hypersensitivity reactions?
hypotension
angioedema
generalised urticaria
wheezing as a result of bronchial constriction
clinical examples of type I hypersensitivity reactions?
asthma hayfever (allergic rhinitis) food allergies e.g. peanuts, fish, milk acute urticaria systemic anaphylaxis
what is lost in vomiting?
H2O, H+ and Cl-
severe vomiting- loss of K+ and Na+
describe the mechanism of type II hypersensitivity reactions
antibody-mediated- IgG or IgM, bind to antigens on cell surface to disrupt function, binding to other cellular components causes tissue damage. Antibody bound to antigen activates complement, and antibody dependent cellular toxicity. Phagocytes may also have a role. May be self-antigen or exogenous chemicals.
Describe hypersensitivity reaction in Grave’s disease
Type 2: antibody-mediated to change function. Anti-thyroid stimulating hormone receptor antibody, bind to TSH receptors on follicular cells of thyroid and chronically stimulate them, most common cause of hyperthyroidism, more common in females, only cause of hyperthyroidism that produces exopthalmos.
Describe hypersensitivity reaction in Myasthenia Gravis
type 2, anti-ACh receptor antibody. Skeletal muscle weakness, ptosis.
Tensilon test= diagnostic test where drug given which inhibits ACh breakdown.
Can treat with neostigmine= ACh esterase inhibitor so more ACh around.
Describe hypersensitivity reaction in pernicious anemia
type 2: anti-intrinsic factor antibody, intrinsic factor necessary for Vit B12 absorption from at the terminal ileum. Deficiency can cause paraesthesia, numbness, cognitive or visual disturbance, angular chelitis, macroglossia. Megaloblastic anaemia.
Schilling test= diagnostic. Radio-labelled Vit B12 given to see if can be absorbed.
how does good pasture’s syndrome occur?
type II hypersensitivity reaction causing tissue damage, mediated by anti-glomerular basement membrane antibody= tye of IgG= against type IV collagen in glomerular BM and also expression on alveolar BM so causes pulmonary haemorrhage, and haemoptysis.
Rapidly progressive glomerulonephritis- all glomeruli can be lost within 48 hrs of onset. Acute onset of nephritic syndrome: high BP, haematuria, feel very unwell.
Tment= immunosuppression and plasmaphoresis
Diagnostic test= IgG deposition on renal biopsy, and ELISA to detect antibodies against alpha 3 chain of type IV collagen
examples of haematological diseases where tissue damage occurs due to type II hypersensitivity reaction?
trasnsfusion reactions (blood grouping)
rhesus haemolytic anaemia
AI haemolytic anaemia
immune thrombocytopenia purpura
How does haemolytic disease of the newborn come about?
rhesus -ve mother gives birth to a rhesus +ve fetus. At birth, fetal rbc with rhesus antigen can enter mother’s circulation due to damaged placenta, and mother produces antibodies against this antigen, which can then cross the placenta in future pregnancies where if fetus is rhesus +ve, a serious anaemia in fetus can occur.
Reduce risk by giving anti-Rh (D) antibodies to mother at time of birth to rapidly remove fetal rbc from mother’s circulation and hence prevent immunisation of mother.
how can AI haemolytic anaemia be tested for?
direct and indirect coombs tests
what happens in type III hypersensitivity reactions?
IgG or IgM mediated, exogenous or endogenous soluble antigen so immunce complexes circulate, so non-organ specific. Tissue damage due to deposition
RA auto-antibody and what systemic manifestations may occur?
anti-rheumatoid factor IgG- can be measured in blood, high titre of rheumatoid factor= poor prognosis extra-articular features and systemic disease as non-organ specific due to soluble immune complexes: rheumatoid nodules scleritis, corneal melt CVD osteoporosis anaemia fatigue
examples of type III hypersensitivity diseases?
RA
glomerulonephritis (infectious)- HepB or bacterial endocarditis
SLE
antibodies in SLE?
anti-nuclear antibody (ANA)
anti-dsDNA antibody
cells involved in tuberculin hypersensitivity?
Thelper 1 cell recognises antigen, releases cytokines which act on vascular endothelium, phagocytes recruited to site of injection.
examples of conditions assoicated with granuloma formation?
TB sarcoidosis extrinsic allergic alveolitis Crohn's disease leprosy schistosomiasis
type IV hypersensitivity diseases?
Insulin-dependent diabetes mellitus (Islet cells)
Hashimoto’s thyroiditis (Thyroid peroxidase)
Coeliac disease (Intrinsic factor)
Rheumatoid arthritis (IgG)
what 3 processes halt bleeding after injury?
vasoconstriction
gap-plugging by platelets
activation of clotting cascade
pattern of bleeding in vascular and platelet disorders e.g. with VW’s disease and following aspirin administration?
prolonged bleeding from cuts
bleeding into skin- easy brusing, purpura
bleeding from mucous membranes- epistaxis, bleeding from gums, menorrhagia
pattern of bleeding with coagulation disorders?
delayed bleeding into joints (haemarthroses), pain, deformity, and muscle
intracerebral haemorrhage
examples of congenital coagulation disorders?
haemophilia A and B
what is haemophilia A and how can it be treated?
factor VIII deficiency- inherited in X-linked recessive pattern
presentation often early in life with bleeding into joints, causing crippling arthropathy, and into muscles causing haematomas- can increase pressure causing nerve palsies and compartment syndrome.
Avoid NSAIDs and IM injections
can give desmopressin- raises factor VIII levels
how is haemophilia A diagnsoed?
raised APTT- measure of intrinsic pathway- factor VIII part of this pathway
decrease factor VIII assay
what is haemophilia B (Christmas disease)?
factor IX deficiency- X-linked recessive disease
acquired coagulation disorders?
liver disease
anticoagulants e.g. warfarin
Vit K deficiecny
DIC
what is prothrombin time (PT), what does it measure?
test of extrinsic system of clotting cascade
PT expressed as a ratio compared to control= INR- normal range= 0.9-1.2
tests for abnormalities in clotting factors I, II (pro-thrombin), V, VII, X.
prolonged by warfarin, Vit K deficiency, liver disease, DIC.
warfarin- inhibits synthesis of II, VII, IX and X.
what is activated partial thromboplastin time (APTT) and what does it measure?
tests intrinsic system of clotting cascade
tests for abnormalities in factors I, II, V, VIII, IX, X, XI and XII.
normal range= 35-45s
prolonged by heparin tment (unfractionated?), haemophilia- factor VIII or IX deficiency, DIC, liver disease.
heparin= cofactor for anti-thrombin III- inactivates factor IIa (thrombin), IXa, Xa, XIa and XIIa= factors of common pathway and intrinsic pathway.
what diagnosis may you be thinking of if both PT and APTT raised (so delayed clotting via both extrinsic and intrinsic pathways), with low platelets, and increase D-dimers= fibrin degradation product?
DIC= disseminated intravascular coagulaton e.g. with sepsis e.g. N.meningitis induced.
what is needed for extrinsic pathway to be activated?
factor NOT normally present in blood= tissue factor= released on exposure of sub-endothelial material on blood vessel wall damage
what is needed for intrinsic pathway to be activated?
collagen*
target INR in warfarin dosing?
between 2 and 3
why is warfarin a pro-coagulant within 36hrs of giving the drug?
as inhibits epoxide reductase enzyme necessary for forming active Vit K, which is needed for Protein C synthesis. So lack protein C which normally forms a complex with its cofactor protein S to degrade some clotting factors so as this not being carried out, these clotting factors will still be around to favour clotting.
AND due to t1/2 of clotting factors, it takes a few days for them to removed from the circulation and so for warfarin to have a anti-thrombotic effect by reducing synthesis of factors II, VII, IX and X.
by which cells is hameoglobin converted to haem?
macrophages
cells which produce and maintain ECM in liver, and are responsible for fibrous tissue laid down in a cirrhotic liver?
stellate cells
features of liver failure, how is it defined?
ascites
hepatic encephalopathy
abnormal bleeding
jaundice
classification of liver failure?
fulminant= failure takes place within 8 weeks of onset of underlying illness
late-onset= gap of 8-26 weeks
chronic decompensated= latent period over 6 mnths
causes of liver failure?
toxins e.g. paracetemol, alcohol, drugs e.g. statins, cyclophosphamide, MTX, ciprofloxacin
infections e.g. viral hepatitis, EBV, cytomegalovirus
wilson’s disease- excess Cu deposition
AI liver disease
what signs related to hepatic encephalopathy may be found on examination of a patient with liver failure?
drowsy, possibly confused on mental state exam.
asterixis- flapping tremor of outstretched hands
papilloedema, hypertension and bradycardia may occur with raised ICP due to cerebral oedema- astrocytes swell due to osmotic imbalance as cells convert glutamate to glutamine to clear NH3 built up in blood, and glutamine causes osmotic imbalance.
major complications of liver failure which cause death?
sepsis, spontaneous bacterial peritonitis
respiratory failure
acute kidney injury
bleeding
cerebral oedema- raised ICP- brain herniation
what is hereditary haemochromatosis?
inherited disorder of Fe metabolism, intestinal iron absorption is increased so deposited in multiple organs e.g. liver, pancreas, skin.
tends to present late in women as menstrual blood loss is protective.
may be tired, arthralgia and impotence, then slate grey skin colour, DM, signs of chronic liver disease, hepatomegaly, cirrhosis.
can use venesection to treat.
what is primary biliary cirrhosis?
AI, more common in females, chronic granulomatous inflammation damages interlobular bile ducts, causing progressive cholestasis, cirrhosis and portal hypertension.
raised ALP on LFTs.
maybe lethargy, pruritis, these can precede jaundice.
may be hepatomegaly and splenomegaly
reduced absorption of fat-soluble Vits can cause coagulopathy and osteomalacia.
PH- can cause variceal haemorrhage
anti-mitochondrial antibody mediated
liver biopsy=granulomas around bile ducts- lypmphocytic infiltration, progressing to cirrhosis.
assoc with RA, systemic sclerosis, thyroid disease, sjrogen’s syndrome.
what is primary sclerosing cholangitis?
disorder of unknown cause, non-malignant non-bacterial inflammation, fibrosis and strictures of intra- and extra-hepatic bile ducts. most commonly in men, especially those with UC**
chronic biliary obstruction and secondary biliary cirrhosis cause liver failure and death.
ALP raised, may be jaundice, pruritis, abdom pain, fatigue.
jaundice, hepatomegaly and portal hypertension on exam.
may be at risk of cholangiocarcinoma
what might you give a patient to combat pruritis in primary sclerosing cholangitis?
bile salt sequestrant e.g. cholestyramine, as bile salts in blood deposited under skin cause itching? (or bilirubin?)
components of bile?
bilirubin bile salts- conjugated bile acids= cholic acid and chenodeoxycholic acid cholesterol phospholipids water electrolytes
what forms bile acid dependent fraction of bile?
bile acids
bilirubin
cholesterol
developmental pathway of rbc?
erythroblast, late erythroblast following ribosome synthesis, Hb accumulates forming a normoblast, nucleus is lost forming a reticulocyte, and then erythrocyte formed with its biconcave disc shape.
what is erythropoiesis regulated by?
erythropoietin= produced by kidneys, production increase d if hypoxia detected, and this increases number of erythroid progenitior cells, stimulates their proliferation and differentiation. Kidney then detects increased oxygenation and erythropoietin production is reduced.
structure of HbA, HbA2 and HbF?
A= 2 alpha and 2 beta globin chains, each with a haem group comprising Fe2+ A2= 2 alpha, 2 zeta F= 2 alpha and 2 gamma
functions of Fe in the body?
essential for Hb formation to carry O2 to the tissues
for myoglobin- facilitates O2 use and storage in muscles
cytochromes- transports e- in cells
integral part of enzyme reactions in various tissues e.g. Fe2+ and vit C necessary for prolyl hydroxylase activity for forming hydrogen bonds necessary for forming strong triple helical structure of collagen.**
problems with making Hb that can therefore cause anaemia?
thalassaemia and sickle cell disease= mutations in genes encoding the globin proteins, abnormal rbc produced with shorter life span resulting in a haemolytic anaemia.
Fe lack e.g. Fe deficiency of in anaemia of chronic disease e.g. in RA- lots of cytokines produced meaning rbc can’t use Fe, Fe is decreased in serum and pushed into stores so giving Fe would be of no help.
deficiency in building blocks for DNA synthesis e.g. folate and vit B12.
why would giving Fe in anaemia of chronic disease where functional lack of Fe not be helpful?
rbc unable to use Fe, as excessive cytokine production reduces Fe in serum, pushes Fe into stores.
examples of anaemias due to problems with the proteins making up membranes of rbc?
hereditary eliptocytosis
hereditary spherocytosis
why do patients with hereditary spherocytosis often need a cholecystectomy (GB removal)?
chronic haemolytic anaemia due to defect in rbc membrane, so excess bilirubin produced, so increased bile production and increased stone formation in GB.
2 main metabolic pathways in rbc?
1) glucose met. to lactate, and ATP generated= Embden Meyerhof Pathway
2) G6P met., producing NADPH- important for protection against free O2 radicals, via cycle with glutathione. =hexose monophosphate pathway.
2 problems with metabolism within rbc producing haemolytic anaemias?
glucose 6-phosphate DD
pyruvate kinase deficiency- catalyses last step in glycolysis pathway for glucose metab.= phosphoenolpyruvate to pyruvate, pyruvate can then be converted to lactate via lactate dehydrogenase*rbc= glucose dependent
most common type of anaemia?
Fe deficiency anaemia
may be due to blood loss e.g. menorrhagia, GI bleeding, poor absorption of Fe e.g. celiac disease, poor intake of Fe e.g. vegetarian, excessive use of Fe e.g. pregnancy.
via what system are rbc removed by the body?
reticulo-endothelial system- predominantly the spleen
damaged rbc, or those coated by Abs are removed.
in what conditions might the spleen be enlarged, causing a haemolytic anaemia?
liver disease (cirrhosis) e.g. causing portal hypertension, venous pressure back up into slenic vein and spleen enlarged.
malaria
malignancy e.g. lymphoma
if spleen enlarged,more blood filtered so more rbc removed!
definition of anaemia in adult men?
reduced Hb concentration in the blood to <130g/L
definition of anaemia in adult women?
reduced Hb conc in blood to <115g/L
physiological adaptations to anaemia?
CVS: increase CO
increase SV =both LT
acutely=tachycardia = e.g. ruptured oesophageal varices= blood loss by haematemesis and malaena,and would also by tachcardia in this case due to amount of blood loss- decrease BP- activate SNS via baroreceptors. increase HR will try and increase oxygenation of the tissues.
shift in O2 dissoc curve- would want to shift to right to increase O2 release to tissues- T state of Hb promoted, e.g. increased 2,3 BPG synthesis.
increased erythropoiesis- hypoxia detected by kidneys, so erythropiesis stimulated.
what does ptnt’s presentation of anemia depend on?
severity
speed of onset
age
anaemia symptoms?
shortness of breath, reduced exercise tolerance
palpitations- awareness of heart beating
faintness
fatigue, lethargy, myalgia
headache, may feel pulsation in temples
exacerbation of angina if underlying IHD, or claudication if PVD.
anaemia signs?
pallor
tachcardia
systolic flow murmur- as CO increased
signs of heart failure
what might cause glossitis (enlarged, smooth and sore tongue)?
Fe deficiency- also cause spooning of the nails= koilonychia, and angular stomatitis- also with vit B12 defic.
vit B12 deficiency
high reticulocyte count, what does this indicate?
BM trying to churn out more rbc, maybe be bleeding
low reticulocyte count, platelets and wbc, what is this and what might it indicate?
pancytopenia
BM failure/infiltration
what would stain in reticulocytes which wouldn’t stain in erythrocytes?
ribosomal RNA
3 causes of reticulocytosis?
haemolysis e.g.
immune HA- AI or Abs from somebody else e.g. blood transfusion reaction, pregnancy- rhesus disease
mechanical e.g. heart valves, microangiopathic haemolytic anemia
Hbopathies e.g. sickle cell, thalassaemia
enzyme defects
met. defects
bleeding
splenic sequestration e.g. in malignancy, malaria, liver cirrhosis
what might cause an immune haemolytic anaemia?
could be AI or from someone else e.g. blood transfusion reaction, Rhesus disease.
AI e.g. in SLE, chronic lymphocytic leukaemia
causes of haemolytic anaemia?
herditary:
defects in rbc membrane e.g. HE, HS
defects in rbc met. e.g. G6PDD, PKD
abnormal Hb e.g. thals, SCD
acquired:
Alloimmune- rhesus disease, incompatible transfusion
Autoimmune- SLE, mycoplasma pneumoniae, EBV, lymphoma
Non-immune- hypersplenism,prosthetic heart valves,
sepsis, malaria
indications of haemolytic anaemia?
blood film- spherocytes, rbc fragments, lots of young rbc- polychromasia
LDH
bilirubin
direct coombs test- look for AI haemolytic anaemia, are Igs bound to rbc?
haptoglobin= acute phase reactant which binds free Hb, complex will then be removed by reticulo-endothelial system.
causes of microcytic anaemia?
TAILS
thalassaemia
anaemia of chronic disease (only if Fe deficiency results?)
iron deficency
how is Fe deficiency confirmed with blood tests?
serum ferritin low
Low serum iron/Low % transferrin saturation
Tment of Fe deficency anaemia?
dietary advice
oral Fe supplements- better absorption with Vit C e.g. take with orange juice, NOT tea- chelating agent.**
IM Fe injection
IV Fe
transfusion- only if severe anemia with immediate cardiac compromise
describe where Fe supplements absorbed?
Duodenum and jejunum Ferrous state Max absorption in 1s few wks tment absorp inhibited by antacids, H2 blockers, PPIs tetracyclines, calcium, phytates Absorption enhanced by ascorbic acid Take between meals
how is response to Fe supplements monitored?
Increase in Hb by 2g/dl in 3 weeks Clinical improvement in symptoms Changes in reticulocyte count Increase in MCV Increase in serum ferritin
what type of anemia is Fe deficiency anaemia?
hypochromic-pale, microcytic
causes of macrocytic anaemias?
B12 deficiency- often if vegan diet, may be malabsoprtion e.g. pernicious anemia- auto-Ab against intrinsic factor. Takes yrs to become deficient.
Folate deficiency-mnths to become deficient, common in alcoholics, or malabsorption, can be caused by drugs e.g. MTX.
Myelodysplasia-other dysplastic features
on film
tests for macrocytic anemia?
Check B12/folate
Check TFT- may be caused by hyperthyroidism/LFT
Check Igs (MGUS, myeloma)
Consider referral for BM exam
causes of normocytic normochromic anaemia
anaemia of chronic disease
Mixed deficiency of iron and Vitb12/folate
BM failure
why is serum Fe reduced in anaemia of chronic disease?
reduced gut absorption due to high cytokines which cause an increase in hepcidin, and recycles iron is pushed into stores so none available to rbc.
blood results in anaemia of chronic disease?
Normocytic Normochromic anaemia (or microcytic anaemia- with Fe deficiency) Ferritin normal or raised Serum iron reduced Normal transferrin saturation (if reduced indicates associated iron deficiency)
most common presentation of patients with primary antibody deficiences e.g. common variable immunodeficiency?
recurrent upper and lower RTIs= bacteria e.g. H influenzae and S.pneumoniae, chronic infection can produce bronchiectasis
may also be GI complications such as infections, arthropathies, increased incidence of AI disease and increased incidence of lymphoma and gastric carcinoma
what is Bruton’s disease?
impaired B cell development, X-linked agammaglobulinaemia, IgG low, IgA undetectable
how is severe combined immunodeficiency treated?
BM transplant
both B and T cells low
what is Ataxia telangiectasia?
recessive primary immunodeficiency, thymic hypoplasia, low B cells, treated with BM transplant
mode of inheritence of chronic granulomatous disease?
X-linked recessive
defect in NADPH oxidase system, so lack resp oxidative burst in neutrophils so bacterial killing defective
susceptible to persistent infections of skin, resp tract and GI tract
how is CGD treated?
BM transplant
examples of acquired immunodeficiencies associated with B cells?
produce hypogammaglobulinaemia:
chronic lymphatic leukaemia
myeloma
nephrotic syndrome
what cells does a myeloma arise from?
plasma cells= antibody producing cells derived from the BM
what causes acquired immunodeficiency of T cells?
HIV, chemotherapy, Hodgkin’s disease,
immunosuppression e.g. transplantation- e.g. giving mycophenolate mofetil- impairs B and T cell proliferation by interfering with guanosine synthesis.
causes of acquired immunodeficiency of both B and T cells?
radiation
chronic lymphocytic leukaemia
malnutrition
Cryptococcus neoformans is a fungus which can infect people with HIV. What infections does it cause and how is it detected under microscopy?
meningo-encephalitis
pneumonia
silver staining used, carbohydrate in cell wall appears black ( silver staining also used to detect P.jirovecii?)
how is P.jirovecii pneumonia diagnosed?
direct microscopy of broncho-alveolar lavage
what is seen clinically with candida albicans infection?
white plaques
how can candida albicans infections be treated?
fluconazole
topical nystatin
diseases produced by cytomegalovirus?
oesophagitis
colitis
hepatitis
pneumonitis
how is CMV treated?
aciclovir- also used in tment of herpes simplex virus (HSV-1 and 2, 1= cold sores, 2= genital herpes)
or gancyclovir
what is post-transplant lymphoproliferative disorder?
B cell proliferation driven by EBV
May progress to lymphoma
Responds to reduced immunosuppression, but this will lead to transplant rejection.
sites of haemopoiesis?
fetus= yolk sac for 0-2mnths, BM between 5 and 9 mnths infants= BM= all bones adults= BM= axial skeleton, can develop haemopoiesis elsewhere if problem
difference between BM at birth and in adults?
birth= all red adults= 1/2 red, 1/2 yellow, can convert back to red in stress
derivatives of common myeloid progenitor cell?
erythrocytes, mast cells, megakaryotes- forms platelets, and myeloblasts= form neutrophils, basophils, eosinophils, and monocytes- form macrophages
what is platelet prod controlled by?
thrombopoietin
differences between red and white pulp of spleen?
red= rbc preferentially travel through, macrophages present to remove old red cells, sinuses lined by endothelial macrophages white= immunological, plasma and leucocytes preferentially pass through
spleen b supply?
splenic artery= from celiac trunk= from abdominal aorta at T12
specialised macrophages in body?
granuloma= epithelioid histiocytes
giant cells e.g. langhans, foreign body and touton
kupffer cells= liver
4 spleen functions?
Sequestration and phagocytosis – old/abnormal red cells removed by macrophages in red pulp
Blood pooling – platelets and red cells can be
rapidly mobilised during bleeding
Extramedullary haemopoiesis – pluripotential
stem cells proliferate during haematological
stress
Immunological function – 25% of T cells
and 15% of B cells are present in the spleen, important for getting rid of encapsulated bacteria
problem with numbers of blood cells if splenomegaly?
may get a pancytopenia= low rbc, wbc and platelets as pooling of blood in enlarged spleen
causes of hyposplenism?
sickle cell disease
splenectomy
celiac disease
what are ptnts at risk of with hyposplenism?
overwhelming sepsis,particularly from encapsulated organisms eg Pneumococcus, Haemophilus influenzae, and Meningococcus.
can give prophylactic penicillin and vaccinate
what is seen on blood film with hyposplenism?
Howell Jolley bodies= DNA remnants
what can cause increased removal of platelets?
non-immune destruction e.g. DIC and HUS
immune destruction
splenic pooling
1st line tment for immune thrombocytopenic purpura?
immunosuppression e.g. corticosteroids or IVIg
disease= auto-Abs to GP IIb/IIIa
what can cause reduced platelet prod?
B12/folate deficiency Infiltration by malignancy Aplastic anaemia Drugs – chemotherapy, antibiotics inc chloramphenicol and septrin Viruses – HIV, infective hepatitis, EBV, CMV
what is neutropenia?
<1.5-1.0 x 10^9/L
what is aplastic anaemia, a cause of pancytopenia?
Pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin (fibrosis)
idiopathic aplastic anaemia thought to be due to T cell mediated destruction of stem cells
3 non-haematological malignancies which can cause pancytopenia?
breast cancer
prostate cancer
lung cancer
haematological malignancies which can cause pancytopenia?
Acute and chronic leukaemias
◦ Lymphoma
◦ Myeloma
◦ Myelofibrosis
◦ Myelodysplastic syndromes – clonal disorder
leading to ineffective and disordered haemopoiesis
symptoms of pancytopenia?
Symptoms of anaemia – fatigue, dizziness,
chest pain, shortness of breath etc..
Symptoms of thrombocytopenia – bleeding,
bruising etc…
Symptoms of neutropenia – infection, ulcers,
fevers etc…
Symptoms of underlying cause
