Chemical Pathology Flashcards
3 most important buffering systems in the body
Bicarbonate (ECF, glomerular filtrate) H + HCO3
Haemoglobin (red cells) H + Hb
Phosphate (renal tubular cells / intracellular) H + HPO4
How are bicarbonate ions regenerated?
Reaction of water and carbon dioxide produces carbonic acid which generates a bicarbonate ion. The bicarbonate ion can then be reabsorbed in the proximal tubule.
NB: The hydrogen ion produced is excreted through a hydrogen/sodium pump (exchanged with sodium).
How to calculate bicarbonate?
[H+] = (k x [CO2]) / [HCO3-]
NB: on a blood gas, bicarbonate is calculated not measured
Causes of metabolic acidosis
- Increased H+ production eg. DKA, lactic acidosis (decreased blood supply)
- Decreased H+ excretion eg. renal tubular acidosis
- Bicarbonate loss eg. intestinal fistula
Causes of respiratory acidosis
Decreased ventilation
Poor lung perfusion
Impaired gas exchange eg. PE, emphysema
(primary abnormality is increased CO2 which drives reaction to left, increasing hydrogen ion concentration)
Causes of metabolic alkalosis
Hydrogen ion loss eg. pyloris stenosis or vomiting
Hypokalaemia (Na/K/H+ pump)
Ingestion of bicarbonate
Causes of respiratory alkalosis
Due to hyperventilation which can be caused by:
Voluntary
Artificial ventilation
Stimulation of respiratory centre (rare drugs)
Compensation for chronic respiratory alkalosis
Kidney excretion of hydrogen ions decreases so hydrogen ion increases. On blood gas:
pH starts to normalise
CO2 and HCO3- remain low
What does deficient enzyme activity lead to?
Lack of end product
Build-up of precursors
Abnormal, often toxic metabolites (high concentrations of precursors causes activation of enzymes that may not usually be active for these substrates in their low concentrations)
IMD Screening Criteria
(Wilson & Junger 1968)
- Important health problem
- Accepted treatment
- Facilities for diagnosis and treatment
- Latent or early symptomatic stage
- Suitable test or examination
- Test should be acceptable to population
- Natural history understood
- Agreed policy on whom to treat as patients
- Economically balanced
- Continuing process
Classical Phenylketonuria (PKU)
Low IQ (<50)
Common 1:5000 to 1:50000
Over 400 gene mutations
Treatment only effective if started within first 6 weeks of life
Sensitivity & Specificity
Sensitivity = proportion of people with true presence of disease (out of everyone who has disease, how many tested positive?)
Specificity = proportion of people with true absence of disease
Positive & Negative predictive Value
PPV = out of everyone who tested positive, how many actually have disease?
NPV = out of everyone who tested negative, how many actually don’t have disease?
Depends on disease prevalence/incidence
UK Screening for IMD
Carried out in first 5-8 days of life
Heel-prick capillary from posterior medial third of foot, blood is spotted onto Guthrie card (thick filter paper)
Bloodspot card sent to specialist lab, bloodspots are punched out, blood sample eluted and phenylalanine measured.
PPV for classic PKU = 80%
UK screening for congenital hypothyroidism
incidence 1:4000
inherited only 15%
usually dysgenesis/agenesis of thyroid gland
not always detected clinically but may have puffy face, skin mottling, large tongue, umbilical hernia, hoarse cry
based on high TSH
PPV 60-70%
treatable with thyroxine
Why was CF added to UK screening programme?
Irrefutable evidence that early intervention improves outcome
Cystic Fibrosis pathology
6 classes of defect
failure of chloride ion movement from inside epithelial cell into lumen leading to increased absorption of sodium and water resulting in viscous secretions and doctule blockage
Manifestations of CF
Lungs: recurrent infection
Pancreas: malabsorption, steatorrhoea, diabetes
Liver: cirrhosis
Neonatal test for CF
high blood immune reactive trypsin (IRT)
if level is above 99.5th (70ng/mL) centile in 3 bloodspots, do DNA mutation detection (panel of 4)
2 mutations = diagnosis of CF
1 mutation -> expand panel to 28, and if another mutation is detected -> diagnosis of CF
0 mutations -> another IRT (>99.9th centile) -> 2nd IRT at 21-28 days
Current UK screening for IMDs
PKU from 1969
Congenital hypothyroidism 1970
Sickle cell disease 2006
CF 2007
Medium chain AcylCoA dehydrogenase deficiency (MCADD) 2009 (fatty acid oxidation disorder)
MCADD
cause of cot death;
in between feeding, baby cannot break down fats, dies of hypoglycaemia
MCADD screening
using acylcarnitine levels by tandem mass spec
incidence 1:10,000
treatable: make sure babies never become hypoglycaemic
Homocystinuria
failure of remethylation of homocysteine
causes: lens dislocation, mental retardation, thromboembolism from an early age
currently screened for in Wales and in trial in UK to decide if it should be added
amino acid disorder
Urea cycle defects
7 enzymes so 7 recorded defects
Also includes 3 conditions: Lysinuric protein intolerance, HHH, Citrullinaemia type II
all autosomal recessive except OTC (X-linked)
Urea cycle begins with ammonia and ends with urea so any defect will result in hyperammonaemia (ammonia is very toxic)
ammonia > 300 micromol/L results in hyperammonaemic coma (1 day in this condition results in very low IQ)
Incidence: 1:30,000
Testing after discovering hyperammonaemia
Plasma glutamine will be high as well as other plasma amino acids as your body tries to remove the excessive ammonia by adding an ammonium group to glutamate (to make glutamine) and other amino acids
Urine orotic acid will also be raised
Treating hyperammonaemia
Remove ammonia by giving sodium benzoate or sodium phenylacetate or dialyse
Reduce ammonia production: low protein diet
Symptoms of hyperammonaemia
Nausea & Vomiting without diarrhoea
Protein intolerance/avoidance/changes in diet
long term neurological/psychiatric illness (tactile hallucinations/ADHD) / neurological encephalopathy
dehydration
respiratory alkalosis
Organic acidurias
hyperammonaemia with metabolic acidosis and high anion gap
most important involve complex metabolism of branched chain amino acids (leucine, isoleucine and valine)
Isovaleric acidaemia
Defect in isovaleryl CoA dehydrogenase in cycle of leucine breakdown
build of isovaleryl CoA so exported as isovaleryl carnitine and excreted as isovaleryl glycine and 3OH-isovaleric acid (has a cheesy or sweaty smell)
Organic aciduria presentation
Unusual odour (person or urine)
lethargy
feeding problems
truncal hypotonia / limb hypertonia, myoclonic jerks
hyperammonaemia with metabolic acidosis and high anion gap not caused by lactate
hypocalcaemia
neutropenia, thrombopenia, pancytopenia
Chronic intermittent forms of organic acidurias
recurrent episodes of ketoacidotic coma, cerebral abnormalities
Reye syndrome: vomiting, lethargy, increasing confusion, seizures, decerebration, respiratory arrest. Triggered by: salicylates, antiemetics, valproate
Reye syndrome metabolic screen
plasma ammonia
plasma/urine amino acid
urine organic acids
plasma/blood glucose and lactate
(all of these during acute episode)
blood spot carnitine profile (stays abnormal even in remission)
Mitochondrial fatty acid beta oxidation defects
hypoketotic hypoglycaemia (normally if hypoglycaemic, should have high ketones to compensate)
hepatomegaly and cardiomyopathy
Tests for Mitochondrial fatty acid beta oxidation defects
Blood ketones
urine organic acids
blood spot acylcarnitine profile
Galactosaemia
3 known disorders of galactose metabolism
Most severe and common is galactose-1-phosphate uridyl transferase disorder (Gal-1-PUT)
raised gal-1-phosphate causes liver and kidney disease
not screened for as more likely that patients will present early
treatment: galactose-free diet
Galactosaemia presentation
vomiting
diarrhoea
hepatomegaly
hypoglycaemia
sepsis (E. coli because galactose-1-phosphate inhibits immune responses)
conjugate hyperbilirubinaemia (always pathological in infant)
Untreated galactosaemia
galactitiol is formed by the action of aldolase on gal-1-phospgate leading to bilateral cataracts
Testing for galactosaemia
Urine reducing substances (pick up huge amounts of galactase)
Red cell Gal-1-PUT
Glycogen storage disease type 1
also called von gierke’s
glycogen cannot be broken down as glucose-6-phosphatase is defective so G6P cannot be exported and therefore builds up in tissue making it a storage disease (glycogen is excessively stored in tissue)
most severe of GSDs
Glycogen storage disease type 1 presentation
hepatomegaly
nephromegaly
hypoglycaemia
lactic acidosis
Mitochondrial disorders
heteroplasmy (high turnover) means that clinical manifestations become evident at a certain threshold of mutant DNA
mtDNA is maternally inherited but nuclear genomes play a huge role in mitochondrial function - transporting and assembly
therefore disorders can present in any organ at any age in any form of inheritance
Organs affected by mitochondrial disorders
defective ATP production leads multisystem disease especially affecting organs with a high energy requirement:
brain, muscle, kidney, retina, endocrine organs
Mitochondrial disorders at birth
Barth syndrome (cardiomyopathy, neutropenia, myopathy)
Mitochondrial disorders at age 5-15
MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes)
Mitochondrial disorders at age 12-30
Kearns-Sayre (chronic progressive external ophthalmoplegia, retinopathy, deafness, ataxia)
Investigating mitochondrial disorders
Elevated lactate (alanine) after periods of fasting
CSF lactate/pyruvate (deproteinised at bedside so inconvenient)
CSF protein (raised in Kearns-Sayre syndrome)
CK elevation (unexplained)
Muscle biopsy (looking for ragged red fibres or measuring oxphos compounds)
Mitochondrial DNA analysis (not in children)
Common problems in low-birth weight infants
respiratory distress syndrome (RDS) - can lead to retinopathy of prematurity (ROP) due to low oxygen
intraventricular haemorrhage (IVH)
patent ductus arteriosus (PDA)
necrotising enterocolitis (NEC)
Necrotising enterocolitis
inflammation of the bowel wall progressing to necrosis and perforation
Signs/Symptoms: bloody stools, abdominal distension, intramural air on abdo x-ray
Renal function in gestation
develop from week 6
start producing urine from week 10
full complement from week 36
functional maturity of GFR not reached until 2 years of age
Renal function in newborns
newborns are very susceptible to acidosis as they cannot exchange hydrogen due to low availability of sodium because of slow excretion (small surface area of glomerulus) and short proximal tubule means there is a lower reabsorptive capability of bicarbonate
loops of henle and distal collecting ducts are short so osmalility cannot reach above 700
distal tubule is quite unresponsive to aldosterone leading to a persistent loss of sodium (1.8 mmol/kg/day) therefore reduced potential potassium excretion
Water redistribution in neonates
in first week of life ECF falls due to decreased pulmonary resistance and release of ANP
therefore all babies lose weight in first week of life - upto 10% of birthweight is acceptable and will regain day 7-10
ECF falls by 40ml/Kg in full term and 100ml/Kg in pre-term
Requirements for healthy neonates
require high sodium and potassium (2-3 mmol/kg/day)
only give potassium after urine output of > 1ml/kg/h is established otherwise you risk hypernatraemia
Electrolyte disturbance in neonates
High insensible water loss due to: high surface area, high skin blood flow, high metabolic/respiratory rate, high transepidermal fluid loss
Drugs: bicarbonate for acidosis (give sodium bicarb so high sodium content), antibiotics (have sodium), caffeine/theophylline for apnoea (increases renal sodium losses), indomethacin for PDA (causes oliguria)
Lack of growth means hypernatraemia
Hypernatraemia in neonate
uncommon after 2 weeks of age, usually associated with dehydration
repeated hypernatraemia without obvious cause could indicate salt poisoning or osmoregulatory dysfunction (both rare but should be considered) - can be diagnosed via routine measurement of urea, creatinine and electrolytes on paired urine and plasma
Hyponatraemia in neonates
relatively rare
caused by congenital adrenal hyperplasia: pregnenolone is not converted into aldosterone so there is salt loss (21-hydroxylase deficiency), nb: also decreased cortisol
Increased precursors: pregnenolone and 17-OH progesterone
Congenital Adrenal hyperplasia (CAH) presentation
hyponatraemia with hyperkalaemia and marked volume depletion
elevated precursors lead to high levels of androgens leading to ambiguous genitalia in female neonates (male neonates often die in salt-losing crisis)
growth acceleration
Hyperbilirubinaemia in neonates
High level of synthesis (rbc breakdown)
low rate of transport into liver
enhanced enterohepatic circulation (even if bilirubin gets into liver, gets exported quickly)
hyperbilirubinaemia in first 10 days of life very common but bilirubin is unconjugated
free bilirubin (>340 cannot be bound by albumin) crosses the blood-brain barrier and causes kernicterus (bilirubin encephalopathy) -> long-term neurological defects
Treating neonatal hyperbilirubinaemia
In full-term: phototherapy (>340), exchange transfusion (>450)
In pre-term: phototherapy (>120), exchange transfusion (>230) because albumin is lower and BBB is more leaky so more susceptible
Causes of hyperbilirubinaemia in neonate
haemolytic disease (ABO, rhesus etc)
G-6-PD deficiency
Crigler-Najjar syndrome
Prolonged jaundice in neonates
jaundice that lasts more than 14 days in term babies and more than 21 days in preterm babes
Causes: prenatal infection/sepsis/hepatitis, hypothyroidism (screened day 6-8), breast milk jaundice
Conjugated hyperbilirubinaemia in neonates
> 20 micromol/L
always pathological
most common cause: biliary atresia & choledocal cyst, often associated with cardiac malformations, polysplenia, situs inversus, early surgery (before 6 months of age) is essential
Other most common cause ascending cholangitis in babies who have been on total parenteral nutrition caused by lipid content
Calcium & phosphate levels in neonates
calcium levels fall after birth so reference range for hypocalcaemia is lower than in adult
phosphate reference ranges higher as babies are good at reabsorbing phosphate
Osteopenia of prematurity
Fraying, splaying and cupping of long bones (on x-ray)
if untreated can progress to flail chest
biochemistry: calcium within reference range (last thing to go), low phosphate < 1mmol/L, alk phos > 1200 U/L, vitamin D rarely measured in neonates and osteopenia is due to susbtrate deficiency
Treatment: phosphate / calcium supplements but not at same time (may give 1 alpha calcidol)
Rickets
osteopenia due to deficient activity of vitamin D
frontal bossing, bow legs / knock knees, muscular hypotonia, abdominal laxity
alternative presentation (more common now): tetany/hypocalcaemic seizure, hypocalcaemic cardiomyopathy
Genetic causes of rickets
pseudo vitamin D deficiency I - defective renal hydroxylation
pseudo vitamin D deficiency II - receptor defect
familial hypophosphataemias - low tubular maximum reabsorption of phosphate, raised urine phosphoethanolamine
What are purines?
ubiquitous biomolecules
Adenosine & Guanine (Inosine = intermediate)
genetic code A & G
second messengers for hormone action (eg. cAMP)
Energy transfer eg (ATP)
Purine catabolism
purines are broken down into hypo-xanthine
hypo-xanthine is broken down into xanthine by xanthine oxidase
xanthine is broken down into urate by xanthine oxidase
urate is broken down into allantoin by uricase
allantoin is highly soluble and excreted in urine therefore this process does not cause problems
most humans have an inactive coding gene for uricase meaning we have to excrete urate rather than allantoin which is not very soluble and circulates in the blood at a concentration similar to its solubility limit (means it can easily crystalise and form gout) - urate precipitates at lower temperature hence why extremities are more likely to be affected by gout
Fractional excretion of uric acid (FEUA)
approx 10%
other 90% is reabsorbed in nephrons to prevent oxidative stress (urate is important anti-oxidant)
How to make purines?
De novo synthesis (lots of energy needed, not used unless utterly mandated by high demand)
Salvage pathway - recycling (highly energy efficient so used whereever possible, so predominates in all cells bone marrow [frantically synthesising new cells all the time so salvage pathway alone is inadequate])
Purine de-novo synthesis rate-limiting step
catalysed by PAT
under feedback inhibition control by ANP and GNP
accelerated by build up of PPRP
HPRT/HGPRT
hypo-xanthine guanine phosphoribosyltransferase
scoops up partially catabolised purines and brings them up to beginning of metabolic pathway (transfer hypo-xanthine into inosinic acid and guanine into guanylic acid)
main enzyme of salvage pathway
Lesch Nyhan syndrome
absolute HGPRT deficiency
normal at birth
developmental delay apparent at 6/12
hyperuricaemia (–> gout)
choreiform movements (1 year) - abnormality in basal ganglion function
spasticity, mental retardation
self mutilation (85%) aged 1-6 (esp biting lips and biting digits so hard that seriously injure themselves and bleed)
X-linked disease, almost exclusively affects males
effect of HGPRT deficiency metabolically
no recycling of hypo-xanthine into inosinic acid (INP) and guanine into guanylic acid (GNP) therefore no negative feedback on PAT causing increased production of INP and GNP by de-novo synthetic pathway.
INP and GNP get metabolised and there is a build-up of urate.
(de-novo pathway is in overdrive)
Gout
crystal arthropathy: monosodium urate crystals
crystal are very intense inflammatory stimuli
very painful
can be acute (podagra) or chronic (tophaceous)
chronic: deposition in soft tissue peri-articular (next to joints) and ear lobes
can progress from acute to chronic
males prevalence 0.5-3%
females prevalence 0.1-0.6%
(post-pubertal males and post-menopausal females)
Acute gout clinical features
rapid build of pain
exquisite pain
affected joint is red, hot and swollen
1st MTP joint is first site in 50% (involved in 90% overall)
Acute gout management (reducing inflammation)
NSAIDs
colchicine (inhibits mircotubule assembly by inhibiting polymerisation, cell turnover is suppressed as mitosis is inhibited, works in gout by reducing motility of neutrophils so unable to migrate into joint and cause inflammation)
glucocorticoids (systemic or intra-articular)
(do not attempt to modify plasma urate concentrations)
Chronic gout management (managing hyperuricaemia)
drink lots of water
reverse factors putting up urate (eg stop thiazide diuretics)
reduce synthesis with allopurinol
increase renal excretion with probenecid (uricosuric)
allopurinol
inhibits xanthine oxidase
thereby inhibits production of urate
Uricosuric drugs
increased FEUA
enhance tubular excretion of urate (loop of henle)
Allopurinol side effects
interacts with azathioprine (makes it more toxic on bone marrow) - never give both together
azathioprine is metabolised into mercaptopurine and then into thioinosinate which interferes with purine metabolism
allopurinol makes the mercaptopurine last longer (inhibiting its metabolism)
Diagnosis of gout
tap effusion
view under polarised light
use red filter
looking for birefringence
birefringence = ability of crystal to rotate light
gout: negatively birefringent (appear blue perpendicular to red filter axis and yellow parallel)
pseudogout: positively birefringent, pyrophosphate (blue parallel to red filter axis, yellow perpendicular)
Pseudogout
occurs in patients with osteoarthritis
pyrophosphate crystals
self limiting 1-3 weeks
Roles of calcium
skeleton (99% of body calcium)
metabolic: action potentials and IC signalling
Calcium in serum
3 forms:
1. free (ionised) 50% - biologically active
2. protein-bound 40% - bound to albumin
3. complexed 10% - citrate/phosphate
reported calcium is corrected for albumin
= serum calcium + 0.02*(40-serum albumin in g/L) - if albumin is normal corrected and total will be the same
total serum calcium: 2.2-2.6 mmol/L (can be affected by amount of albumin hence correction)
ionised calcium can also be measured
Circulating calcium
important for normal nerve and muscle function
plasma conc must be maintained despite calcium and vitamin d deficiency
chronic calcium deficiency results in loss of calcium from in bone in order to maintain circulating calcium (–> osteoporosis)
Calcium homeostasis
low Ca detected by parathyroid gland which will release PTH
PTH increases Ca from 3 sources:
bone (resorption)
gut (absorption increased by 1,25 OH vit D - also increases phosphate absorption)
kidney (resorption and renal 1 alpha hydroxylase activation - increased 1,25 OH vit D)
PTH
84 aa protein
only released from parathyroids (unless ectopic production by tumour)
bone and ca resorption
stimulates 1,25 OH vit d synthesis (hydroxylation)
stimulates renal phosphate wasting (phosphate trashing hormone)
Vit D synthesis
7-dehydrocholesterol converted to cholecalciferol (vit D3) by sunlight in skin
(cholecalciferol is inactive and large amounts are not dangerous - bought OTC)
cholecalciferol stored in liver and then converted to 25-hydroxycholecalciferol (25-OH D3) in liver by 25 hydroxylase
converted to 1,25-dihydroxycholecalciferol (1,25-(OH)2 D3 aka calcitriol) in kidney by 1 alpha hydroxylase- rate-limiting step, only carried out in presence of PTH
calcitriol is physiologically active form (drug - given in kidney failure and regularly measured)
Ergocalciferol
plant product
vit d2
can be taken as supplement (same effect as cholecalciferol)
Vitamin d blood test
measures stored vitamin d in form of 25-hydroxy vitamin D
(active form [calcitriol] is made and immediately used up so not measured)
1 alpha hydroxylase
rarely can be expressed in lung cells of sarcoid tissue
usually affects resp but can sometimes activate vitamin D and cause hypercalcaemia
roles of 1,25 (OH)2 vit D (calcitriol)
increases calcium and phosphate absorption in gut
critical for bone formation
Also: vit d receptor controls many genes eg. for cell proliferation and immune system –> deficiency associated with cancer, autoimmune disease, metabolic syndrome (not causative)
Role of skeleton
structural framework - strong, relatively lightweight, mobile, protects vital organs, capable of orderly growth and remodelling (with use)
metabolic role in calcium homeostasis - reservoir for calcium, phosphate, magnesium
metabolic bone diseases
osteoporosis
osteomalacia
paget’s disease
parathyroid bone disease
renal osteodystrophy
vitamin d deficiency
defective bone mineralisation
childhood -> rickets
adulthood -> osteomalacia (not same as osteoporosis)
> 50% of adults in the UK have deficiency but not necessarily osteomalacia - take supplements, 16% have severe deficiency during winter and spring
risk factors: lack of sunlight exposure, dark skin, dietary, malabsorption
clinical features of osteomalacia
bone and muscle pain
increased fracture risk
biochem: low Ca and low phosphate with raised ALP (osteoblasts trying to rebuild bone) (other LFTs normal)
Looser’s zone (pseudofractures - looks like fracture but doesn’t go through bone completely)
osteomalacia in mother increases risk of rickets in child
clinical features of rickets
bowed legs
costochondral swelling
widened epiphyses at wrists
myopathy –> unusual gait
Osteomalacia key facts
bone is demineralised
caused by:
vit d deficiency
renal failure
lack of sunlight
anticonvulsants in children induce breakdown of vit d (anticonvulsant rickets) - can also happen in adults but they have sufficient reserves
phytic acid (in chappatis) chelates vitamin D
uncalficied osteoid cells if biopsy bone
Osteoporosis
causes pathological fracture
occurring more often as people live longer (becoming more common)
loss of bone mass due to reduced use (reduced bone density but normal mineralisation)
bone slowly lost after age 20
residual bone is normal in structure
biochem: normal ca and normal phosphate
asymptomatic until fracture (typically: neck of femur and, vertebral, Colle’s [wrist]) - too late
Causes of osteoporosis
age
cushing’s (causes colles fractures more commonly)
hyperprolactinaemia
thyrotoxicosis
steroids (causes vertebral fractures more commonly)
menopause
childhood illness (peak bone density not reached)
testosterone deficiency
liver cirrhosis
acromegaly
dietary - protein, calcium, vitamin C (scurvy) deficiency
alcohol
smoking
sedentary lifestyle
hyponatraemia
serum sodium < 135 mmol/L
commonest electrolyte abnormality in hospitalised patients
underlying pathogenesis of hyponatraemia
= water problem (not salt problem)
increased extracellular water
water balance controlled by ADH (vasopressin) - released from posterior pituitary and acts on distal nephrons of kidney, inserts aquaporin-2 and increases water retention
therefore underlying pathogenesis is excess ADH
ADH
acts on V2 receptors of collecting duct
insertion of aquaporin-2
V1 receptors: vascular smooth muscle, vasoconstriction (higher concentrations) = vasopressin
stimuli for ADH secretion
increased serum osmolality (mediated by hypothalamic osmoreceptors)
decreased blood volume/pressure (mediated by baroreceptors in carotids, atria, aorta)
Clinical assessment of patient with hyponatraemia
clinical assessment of volume status (urine output, blood pressure (postural), mucus membranes, cap refill, pulse, skin turgor, alertness) to assess volaemic status: urine sodium (low <20 –> hypovolaemic), hypervolaemic: oedema, raised JVP, crackles)
NB: can’t use urine sodium as reliable test in patients taking diuretics
hyponatreamic hypovolaemia causes
diarrhoea
vomiting
diuretics
salt-losing nephropathy
hyponatreamic hypervolaemia causes
cardiac failure (reduced contractility –>reduced cardiac output –> low pressure/volume detected by baroreceptors)
cirrhosis (nitric oxide –> vasodilation)
nephrotic syndrome
hyponatreamic euvolaemia causes
hypothryoidism
adrenal insufficiency
SIADH –> everything else has appropriate ADH secretion as a physiological response
to diagnose SIADH have to exclude hypothyroidism and adrenal insufficiency first through TFTs and short synacthen test, then low plasma osmolality and high urine osmolality (>100) for SIADH
why is SIADH euvolaemic?
excess water gets distributed in extra and intracellular compartments
also detected and leads to natriuresis leading to sodium loss in the urine
Causes of SIADH
CNS pathology
lung pathology
drugs (SSRI, TCA, opiates, PPIs, carbamazepine)
tumours
surgery
Hypovolaemic hyponatraemia management
0.9% saline volume replacement (remove stimulus for excess ADH production - ADH production is being driven by hypovolaemia)
Hypervolaemic/Euvolaemic hyponatraemia management
fluid restriction
treat underlying cause
giving 0.9% sodium chloride is dangerous here because you’re exacerbating the problem
Severe hyponatraemia
reduced GCS
seizures
treat with hypertonic 3% saline (seek expert help)
Correcting hyponatraemia slowly
serum sodium must not be corrected by > 8-10 mmol/L in first 24 hours due to risk of osmotic demyelination
central pontine myelinolysis - quadriplegia, dysarthria, dysphagia, seizures, coma, death
drugs to treat SIADH
if water restriction (500ml/24h) is insufficient:
- demeclocycline: reduces responsiveness of collecting tubule cells to ADH, need to monitor U&Es due to risk of nephrotoxicity (not commonly used now because of this)
- tolvaptan: V2 receptor antagonist
- salt + furosemide?
Hypernatraemia
serum sodium > 145 mmol/L
much less common than hypo
main causes:
unreplaced water loss: GI losses, sweat losses, renal losses: osmotic diuresis, reduced ADH release/action (diabetes insipidus)
patient cannot control water intakes (eg. children, elderly)
Investigations for diabetes insipidus
serum glucose (exclude DM - much more common)
serum potassium (exclude hypokalaemia)
serum calcium (exclude hypercalcaemia)
plasma and urine osmolality (high plasma osmolality, low urine osmolality)
water deprivation test (normal response: increased urine osmolality, DI: urine remains dilute)
NB: hypokalaemia and hypercalcaemia can cause nephrogenic DI
diabetes insipidus new terminology: vasopressin deficiency/resistance
Hypernatraemia treatment
replace fluid
treat underlying cause
eg. for diarrhoea: give 5% dextrose as fluid replacement, then correct extracellular fluid volume depletion using 0.9% saline, serial na measurements every 4-6 hours
effect of diabetes mellitus on serum sodium
variable
hyperglycaemia draws water out of the cells leading to hyponatraemia
osmotic diuresis in uncontrolled diabetes leads to loss of water and hypernatraemia
PCSK9 monoclonal antibody (inhibitor)
PCSK9 = proprotein convertase subtilisin kexin 9
PCSK9 regulates the levels of the LDL receptor
gain of function mutations in PCSK9 reduce LDL receptor levels in the liver resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease
loss of function mutations lead to higher levels of LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease
drops cholesterol significantly and reduces incidence of cardiovasc events but doesn’t decrease death rate compared to placebo
Adrenal histology
from outside inwards: glomerulosa –> fasciculata (cortisol) –> reticularis –> medulla
lots of arteries and one central vein
Schmidt’s syndrome
Addison’s disease and primary hypothyroidism occur together more commonly than by chance alone.
(both autoimmune)
Addison’s disease presentation
Hyponatraemia, hyperkalaemia
–> Deficiency of mineralocorticoid.
Hypoglycaemia
–> Deficiency of glucocorticoid.
Investigating Addison’s
Short synacthen test
measure ACTH and cortisol, give pt an injection of synthetic ACTH (250 mcg IM), then measure ACTH and cortisol after 30 mins and 1 hour
normal: cortisol should rise to > 400
Addison’s: cortisol doesn’t rise because of primary adrenal failure
Adrenal masses
Phaeochromocytoma (Adrenal medullary tumour secreting adrenaline).
Conn’s syndrome (adrenal tumour secreting aldosterone)
Cushing’s syndrome (secretes cortisol)
Phaeochromocytoma
Adrenal medullary tumour that secretes adrenaline, and can cause severe hypertension, arrhythmias and death.
–>THUS A MEDICAL EMERGENCY
Urgent alpha blockade with phenoxybenzamine.
Add beta blockade.
Finally arrange surgery.
Conn’s syndrome
The adrenal gland secretes high levels of aldosterone autonomously. This will cause hypertension and this will in turn suppress the renin at the JGA.
on bloods: high Na, low K, raised aldosterone, suppressed renin
treatment: spironolactone, better to remove tumour if present
Cushing’s syndrome investigations
initial:
9am cortisol (high)
midnight cortisol (normal would be low and cushing’s would still be high, don’t tell pt in advance, allow them to sleep and then wake them up and take sample 5 mins later)
dynamic test if cannot do midnight cortisol: dexamethasone suppression test (normal –> cortisol is suppressed to undetectable, cushing’s –> cortisol remains high, tumour continues producing cortisol/ACTH)
ACTH to determine cause (if suppressed ACTH –> adrenal cause, if high ACTH –> pituitary cause)
Scan (adrenal CT or pituitary MRI to confirm)
Causes of cushing’s
Being on oral steroids for something else
Pituitary dependent Cushings disease (85%)
Ectopic ACTH (5%) - lung cancer
Adrenal adenoma (10%)
Adrenal cushing’s management
due to suppressed ACTH by high cortisol from adrenal tumour, other adrenal gland atrophies due to lack of stimulation
after excision of tumour, have to give steroids and slowly wean off while HPA axis and other adrenal gland starts getting stimulated again (use nihr letter for weaning protocol to avoid pts feeling really unwell)
IPSS (inferior petrosal sinus sampling) with CRH stimulation
taking blood sample from pituitary through catheters from groin, measure ACTH
if pituitary ACTH is high then pituitary cause, if not then ectopic
hard to see on MRI so IPSS better
made high dose dexamethasone suppression test redundant due to high false positive rate and fact that IPSS provides definitive distinction
Osteoporosis diagnosis
usually using DEXA scan
Dual energy X-ray absorptiometry
hip (femoral neck etc) & lumbar spine
T-score – sd from mean of young healthy (20 year-old) population (useful to determine risk)
Z-score – sd from mean of aged-matched control (useful to identify accelerated bone loss in younger patients)
Osteoporosis – T-score <-2.5
Osteopenia – T-score between -1 & -2.5
Osteoporosis treatment
Lifestyle:
Weight-bearing exercise
Stop smoking
Reduce EtOH
Drugs:
Vitamin D/Ca
Bisphosphonates (eg alendronate) –↓ bone resorption (not biodegradable by osteoclasts)
Teriparatide (PTH derivative) – anabolic (stimulates osteoblasts more than clasts, pulses of PTH so not chronically raised)
Strontium – anabolic + anti-resorptive
(Oestrogens – HRT)
SERMs (selective oestrogen receptor modulators) eg raloxifene, tamoxifen is antagonist in breast cancer and agonist in bone
Hypercalcaemia symptoms
Polyuria / polydipsia (calcium is osmotic diuretic)
Constipation & abdo pain
Neuro – confusion / seizures / coma - Unlikely unless Ca2+ > 3.0 mmol/L
Overlap with Sx of hyperPTH (see later)
Primary hyperparathyroidism
Commonest cause of hypercalcaemia
Parathyroid adenoma / hyperplasia / carcinoma
Hyperplasia associated with MEN1
Women > men
↑serum Ca, ↑ or inappropriately N PTH, ↓serum Pi, urine ↑Ca (due to hypercalcaemia)
BONES (PTH bone disease) and STONES (renal calculi)
Hypercalcaemia -> abdominal MOANS (constipation, pancreatitis), psychiatric GROANS (confusion)
Hypercalcaemia in malignancy
3 types:
Humoral hypercalcaemia of malignancy (eg small cell lung Ca)
PTHrP
Bone metastases (eg breast Ca)
Local bone osteolysis
Haematological malignancy (eg myeloma)
cytokines
Other causes of non-PTH-driven hypercalcaemia
Sarcoidosis (non-renal 1α hydroxylation)
Thyrotoxicosis (thyroxine -> bone resorption)
Hypoadrenalism (renal Ca2+ transport)
Thiazide diuretics (renal Ca2+ transport)
Excess vitamin D (eg sunbeds…)
Hypercalcaemia treatment
Acute management
Fluids+++ (IV saline, give 1L in first hour because very dehydrated when they first present)
Bisphosphonates (if cause known to be cancer - prevents cancer cells from invading bone and helps with pain) otherwise avoid.
Treat underlying cause
Hypocalcaemia presentation
Neuro-muscular excitability:
- Chovstek’s sign (tap cheek; twitching)
- Trosseau’s sign (with BP cuff)
- hyperreflexia
- convulsions
- laryngeal spasm (stridor)
- prolonged QT
- choked disk on fundoscopy
Hypocalcaemia causes
non-PTH driven:
vit D deficiency (dietary, malabsorption, lack of sunlight)
chronic kidney disease (1 alpha hydroxylation)
PTH resistance (pseudohypoparathyroidism)
- in these conditions should have secondary hyperPTHism as normal response and can progress to tertiary (after kidney transplant) with hypercalcaemia
PTH-driven:
Surgical (post-thyroidectomy)
auto-immune hypoPTHism
congenital absence of parathyroids (DiGeorge syndrome)
Mg deficiency (PTH regulation)
Paget’s disease
Focal disorder of bone remodeling (bone thickening)
Focal PAIN, warmth, deformity, fracture, SC compression, malignancy, cardiac failure
Pelvis, femur, skull and tibia
Elevated alkaline phosphatase (with normal Ca and Phos)
Nuclear med scan / XR
Treatment = Bisphosphonates for pain
Other metabolic bone disorders
In primary hyperparathyroidism:
Loss of cortical bone -> # risk
Osteitis fibrosa
Renal osteodystrophy
Due to secondary hyperparathyroidism (due to no 1-alpha hydroxylase) + retention of aluminium from dialysis fluid
Both rare due to modern Rx of underlying disorders
Management of hypercalcaemia (primary hyperparathyroidism)
Immediate: IV fluids:
0.9% saline, 1L over first hour and then 1L every 4 hours but be careful of pulmonary oedema in older patients
If worried about pulmonary oedema, can give furosemide then fluids
eventual management: parathyroidectomy
NB: only give bisphosphonates in hypercalcemia of malignancy
Mechanism of hypercalcaemia in sarcoidosis
systemic disease where macrophages express 1 alpha hydroxylase which is released and causes increased hydroxylation of vitamin D and therefore raises calcium
hormones involved in renal regulation of potassium
angiotensin II
aldosterone
(angiotensin II stimulates adrenal gland to produce aldosterone which stimulates potassium excretion from nephrons - principal cells in cortical collecting tubule [sodium in, potassium out])
(potassium also stimulates aldosterone production to induce potassium excretion)
Aldosterone mechanism of action
Aldosterone increases number of open Na+ channels in the luminal membrane
Increased Sodium reabsorption
makes the lumen electronegative & creates an electrical gradient
Potassium is secreted into the lumen
(via electrical gradient)
Causes of hyperkalaemia (anything that decreases aldosterone)
reduced GFR
reduced renin: type 4 renal tubular acidosis, NSAIDs
ACE inhibitors
Angiotensin II receptor blockers (ARBs)
Addison’s disease (adrenal cortex destruction)
Aldosterone antagonists (spironolactone)
Also leakage from cells: rhabdomyolysis, acidosis (maintain electroneutrality while hydrogen ions enter cells)
Management of hyperkalaemia
10 ml (30ml if severe, K>6.5 or ECG changes) 10% calcium gluconate (stabilises myocardium)
50 ml 50% dextrose + 10 units of insulin (drives potassium into cells)
Nebulized salbutamol (drives potassium into cells)
Treat the underlying cause
Causes of hypokalaemia
GI loss (vomiting)
Renal loss
- Hyperaldosteronism, (Excess cortisol - Cushing’s)
- Increased sodium delivery to distal nephron (Loop diuretics/ bartter syndrome or Thiazide diuretics/Gitelman syndrome), increased positive charge in lumen so potassium pushed out
- Osmotic diuresis (uncontrolled diabetes)
redistribution into cells
- insulin
- beta-agonists
- alkalosis
rare causes: renal tubular acidosis type 1&2, hypomagnesaemia
Clinical features of hypokalaemia
muscle weakness
cardiac arrhythmia
polyuria and polydipsia (arginine vasopressin resistance = nephrogenic DI)
Screening test for patient with hypokalaemia and hypertension
aldosterone: renin ratio
Hypokalaemia management
Serum potassium 3.0-3.5 mmol/L
- Oral potassium chloride (two SandoK tablets tds for 48 hrs)
- Recheck serum potassium
Serum potassium < 3.0 mmol/L
- IV potassium chloride
- Maximum rate 10 mmol per hour
- Rates > 20 mmol per hour are highly irritating to peripheral veins
Treat the underlying cause e.g. spironolactone
Best measurement of kidney function
GFR
- not easy to measure
- has limitations (depends on sex, age, ethnicity, muscle mass etc.)
AKI vs CKD
AKI:
abrupt decline in GFR
potentially reversible
Treatment targeted to precise diagnosis and reversal of disease
CKD:
Longstanding decline in GFR
Irreversible
Treatment targeted to prevention of complications of CKD and limitation of progression
AKI
Defined as a rapid reduction in kidney function, leading to an inability to maintain electrolyte, acid-base and fluid homeostasis.
It is a medical emergency necessitating referral to a nephrologist for diagnosis and treatment.
NHS England has standardised the definitions of AKI based on serial measurements of serum Creatinine (sCr) as follows:
- AKI Stage 1: Increase in sCr by ≥26 µmol/L, or by 1.5 to 1.9x the reference sCr
- AKI Stage 2: Increase in sCr by 2.0 to 2.9x the reference sCr
- AKI Stage 3: Increase in sCr by ≥3x the reference sCr, or increase by ≥354 µmol/L
3 types: pre-renal, renal (intrinsic), post-renal
Pre-renal AKI
Hallmark is reduced renal perfusion
as part of generalised reduction in tissue perfusion
or selective renal ischaemia
No structural abnormality
Causes:
True volume depletion
Hypotension
Oedematous states
Selective renal ischaemia
Drugs affecting glomerular blood flow
Pre-renal AKI vs Acute tubular necrosis (ATN)
Pre-Renal AKI is not associated with structural renal damage and responds immediately to restoration of circulating volume
Prolonged insult leads to ischaemic injury
Acute Tubular Necrosis does not respond to restoration of circulating volume
Intrinsic (Renal) AKI
Pathophysiologically more diverse group
May represent abnormality of any part of nephron
Vascular Disease e.g. vasculitis
Glomerular Disease e.g. glomerulonephritis
Tubular Disease e.g. ATN
Interstitial Disease e.g. analgesic nephropathy
Common mechanisms of renal injury
DIRECT TUBULAR INJURY:
Most commonly ischaemic
Endogenous toxins
- Myoglobin (rhabdomyolysis)
- Immunoglobulins
Exogenous toxins - contrast, drugs
- Aminoglycosides (gentamicin)
- Amphotericin
- Acyclovir
IMMUNE DYSFUNCTION CAUSING RENAL INFLAMMATION:
Glomerulonephritis
Vasculitis
INFILTRATION/ABNORMAL PROTEIN DEPOSITION:
Amyloidosis
Lymphoma
Myeloma-related renal disease
Post-renal AKI
Hallmark is physical obstruction to urine flow
(Intra-renal obstruction)
Ureteric obstruction (bilateral)
Prostatic / Urethral obstruction
Blocked urinary catheter
Obstructive uropathy pathophysiology
GFR is dependent on hydraulic pressure gradient
Obstruction results in increased tubular pressure
Immediate decline in GFR
Immediate relief of obstruction restores GFR fully, with no structural damage
But, prolonged obstruction results in structural damage:
Glomerular ischaemia
Tubular damage
Long term interstitial scarring
2 measures used to define AKI severity
Serum creatinine (compared to baseline)
Urine output
Why do some AKIs resolve and some not?
Acute wounds heal via four phases:
- Haemostasis
- Inflammation
- Proliferation
- Remodeling
Pathological responses to renal injury are characterized by imbalance between scarring and remodeling
Replacement of renal tissue by scar tissue results in chronic disease
CKD process
Increased risk ->
Early damage ->
Decreased GFR ->
Renal failure ->
Death
CKD stages
Stage 1-5
increasing stage depending on worsening eGFR
Stage 1: kidney damage with normal eGFR
Stage 5: end-stage renal failure with eGFR<15 or on dialysis
Causes of CKD
Diabetes
Atherosclerotic renal disease
Hypertension
Chronic Glomerulonephritis
Infective or obstructive uropathy
Polycystic kidney disease
Consequences of CKD
1]Progressive failure of homeostatic function
-Acidosis
-Hyperkalaemia
2]Progressive failure of hormonal function
-Anaemia
-Renal Bone Disease
3]Cardiovascular disease
-Vascular calcification
-Uraemic cardiomyopathy
4]Uraemia and Death
Renal Acidosis
Metabolic acidosis
Failure of renal excretion of protons
Results in:
Muscle and protein degradation
Osteopenia due to mobilization of bone calcium
Cardiac dysfunction
Treated with oral sodium bicarbonate
Anaemia of chronic renal disease
Progressive decline in erythropoietin-producing cells with loss of renal parenchyma
Usually noted when GFR<30mL/min
Normochromic, normocytic anaemia
Distinguish from other causes of anaemia, which are common
iron deficiency
B12 and/or folate deficiency
Erythropoiesis- stimulating agents (ESAs)
Erythropoietin alfa (Eprex)
Erythropoietin beta (NeoRecormon)
Darbopoietin (Aranesp)
aim for Hb of 12
Renal bone disease
Complex entity resulting in reduced bone density, bone pain and fractures:
-Osteitis fibrosa (Osteoclastic resorption of calcified bone and replacement by fibrous tissue) - hyperparathyroidism
-Osteomalacia (Insufficient mineralization of bone osteoid)
-Adynamic bone disease (Excessive suppression of PTH results in low turnover and reduced osteoid)
-Mixed osteodystrophy
Renal bone disease treatment
Phosphate control:
- Dietary
- Phosphate binders
Vit D receptor activators:
- 1-alpha calcidol
- Paricalcitol
Direct PTH suppression:
- Cinacalcet (acts on calcium-sensing receptor)
CKD vascular calcification
Renal vascular lesions are frequently characterised by heavily calcified plaques, rather than traditional lipid-rich atheroma
Uraemic cardiomyopathy
Three phases:
Left ventricle (LV) hypertrophy
LV dilatation
LV dysfunction
(not commonly seen in UK)
Hypoglycaemia definition
- Low glucose (different cut-offs at different sites)
- Symptoms:
- Adrenergic: tremors, palpitations, sweating, hunger
- Neuroglycopenic: somnolence, confusion, incoordination, seizures, coma
- no symptoms (impaired awareness of hypoglycaemia) - Relief of symptoms with glucose administration
Hypoglycaemia counter-regulation
Reduce peripheral uptake of glucose
Increase glycogenolysis
Increase gluconeogenesis
Increase lipolysis
- suppression of insulin
- release of glucagon, adrenaline, cortisol
NB: lipolysis leads to free fatty acid production which are oxidised to form ketone bodies
Drugs that cause hypoglycaemia
Glucose lowering therapies
- Sulphonylureas
- Meglitinides
- GLP-1 agents
Insulin
- Rapid acting with meals: inadequate meal
- Long-acting : at night or in between meals
Other drugs
- B-blockers, salicylates, alcohol ( inhibits lipolysis)
C-peptide
a cleavage product of pro-insulin
therefore secreted in equimolar amounts to endogenous insulin
can be used to identify cause of hypoglycaemia
Low glucose, low insulin, low c-peptide
Hypoinsulinaemic hypoglycaemia
Hypoinsulinaemic hypoglycaemia
This pattern is the appropriate response to hypoglycaemia:
Fasting / starvation
Strenuous exercise
Critical illness
Endocrine deficiencies
Hypopituitarism
Adrenal failure
Liver failure
Anorexia Nervosa
Neonatal hypoglycaemia
Explainable
Premature, co-morbidities, IUGR, SGA
Inadequate glycogen and fat stores
Should improve with feeding
Pathological
Inborn metabolic defects
Neonatal hypoglycaemia with low insulin and c-peptide
Inherited metabolic disorders
Fatty acid oxidation defect : no ketones produced
GSD type 1 ( gluconeogentic disorder)
Medium chain acyl coA dehydrogenase def.
Carnitine disorders
Low glucose, high insulin, high c-peptide
hyperinsulinaemic hypoglycaemia
Hyperinsulinaemic hypoglycaemia
Islet cell tumours – insulinoma
Islet cell hyperplasia
Infant of a diabetic mother
Beckwith Weidemann syndrome
Nesidioblastosis
Rare genetic forms of hyperinsulinism
Rare autoimmune
low glucose, high insulin, low c-peptide
Factitious/Exogenous Insulin
(insulin or insulin-containing drugs)
↓ Glucose ↓ Insulin ↓ C-peptide
↓ FFA ↓ Ketones
Non-islet cell tumour hypoglycaemia:
Tumours that cause a paraneoplastic syndrome
Secretion of ‘big IGF-2’
Big IGF2 binds to IGF-1 receptor and insulin receptor, effectively doing the job of insulin without insulin
Mesenchymal tumours ( mesothelioma /fibroblastoma)
Epithelial tumours ( carcinoma)
Hypoglycaemia in diabetes
Commonest cause of hypoglycaemia
Things to consider:
- Medications
- Inadequate CHO intake / missed meal
- Impaired awareness
- Excessive alcohol
- Strenuous exercise
- Co-existing autoimmune conditions
Reactive/Post-prandial hypoglycaemia
Hypoglycaemia following food intake
Can occur post-gastric bypass
Hereditary fructose intolerance
Early diabetes
In insulin sensitive individuals after exercise or large meal
True post-prandial hypoglycaemia
Difficult to define
What is an enzyme?
Definition: a substance (usually a protein) that increases the rate of a chemical reaction without itself being changed in the overall process.
Km (Michaelis-Menten constant)
= [substrate] at which the reaction velocity is 50% of the maximum.
high Km indicates weak affinity
low Km indicates strong affinity
Raised ALP (alkaline phosphatase)
Intrahepatic/extrahepatic bile ducts: cholestatic liver disease
Bone: fracture, paget’s, osteomalacia, rickets, cancer, primary hyperPTH with bone involvement, renal osteodystrophy, childhood (physiological)
Placenta: pregnancy (last trimester), germ-cell tumours
Raised ALT
Hepatic: toxins (alcohol, paracetamol OD), hepatitis (viral, alcoholic, autoimmune), non-alcoholic fatty liver disease, cancer, ischaemia
Raised GGT
Hepatobiliary disease: hepatitis, alcoholic liver disease, cholestatic liver disease
Enzyme induction: alcoholics (with or without liver disease), rifampicin, phenytoin, phenobarbitone
Pancreas: pancreatitis (serum amylase is better)
Raised LDH
WBC: lymphoma
RBC: haemolysis
Placenta: germ-cell testicular cancer (seminoma)
Skeletal muscle: myositis
Liver injury: hepatic disease (better biomarkers available)
Raised serum amylase
pancreas: acute pancreatitis, perforated duodenal ulcer, bowel obstruction (with secondary injury to pancreas)
salivary gland: stones, infection (eg. mumps)
macro-amylase: benign (amylase bound to Ig)
Raised creatine kinase
skeletal muscle: rhabdomyolysis, myositis, polymyositis, dermatomyositis, severe exercise, myopathy (duchenne, statins)
NB: slightly higher levels in individual of Afro-Caribbean descent
Cardiac muscle: no longer used for MI (troponin used now)
Troponin I
Located within cardiac and skeletal myocytes where it participates in muscle contraction
Causes of elevated troponin I (Hs cTnI)
- acute coronary syndrome
- myocarditis
- cardiomyopathy
- aortic dissection
- PE
- systemic infection
- anaemia (upper GI bleed
History + exam + ECG + Troponin = diagnosis
Factors affecting troponin result: Age, gender, acute or chronic kidney disease, number of myocytes injured, time of test
BNP
released in response to ventricular wall stretch
now NT-proBNP is used more commonly due to being more stable
supports diagnosis of HF (usually clinical diagnosis)
if patient is using angiotensin receptor/neprilysin inhibitor (ARNI), cannot measure BNP as they increase it so have to use NT-proBNP
lower NT-proBNP levels indicate better prognosis
How is a diabetes diagnosis confirmed?
fasting glucose more than 7
2 hour plasma glucose in GGT 11.1 or greater
HbA1c > 48
How to diagnose Pituitary cushing’s vs ectopic ACTH
most of the time: pituitary cushings, cortisol will fall to half on high dose dexamethasone suppression
however, not always so nowadays usually do angiogram
reason: pituitary secretion of ACTH more regulated with some negative feedback as less aggressive compared to lung cancer secreting ACTH in uncontrolled manner however, there is some crossover hence why dex suppression is no longer used
Enzyme most increased post acute MI
troponin
CK
AST
LDH
Enzyme most increased in osteomalacia
ALP
NB: calcium and vit D low
Electrolyte abnormalities in addison’s
low sodium
high potassium
Enzyme most increased in viral hepatitis
widespread inflamed hepatocytes –> raised ALT
(AST too but ALT more)
Enzyme most increased in chronic alcoholic liver cirrhosis
damaged liver architecture due to recurrent regeneration and cell death –> raised AST (ALT too but AST more)
Enzyme raised in prostatic carcinoma
Acid phosphatase = PSA
Acute vs chronic renal failure biomarkers
Acute (dehydration) –> urea markedly raised
Chronic (fall in GFR) –> creatinine markedly raised
Measure of blood glucose control for preceding 2-3 weeks
fructosamine
(= glycated peptide)
Leptospirosis
unwell with jaundice, feeling run down, conjunctival haemorrhage
travel history: canoeing
Hearing loss in paget’s disease
bone overgrowth (foramen): compresses 8th nerve as leaves skull causing neural hearing loss
also can affect ossicles in ears causing conductive hearing loss also
so can have both
Thyroid physiology
TSH controls uptake of iodide to thyroid via Na/K ATPase (blocked by perchlorate)
Iodide converted to iodine by TPO (thyroid peroxidase)
Iodine taken up by thyroglobulin (incolloid)
Tyrosine residues iodinated (blocked by thionamides)
Iodotyrosines join to form thyroxine
Thyroxine re-enters thyroid gland cells and is excreted
after excretion can be transported bound to TBG, TBPA, and albumin or converted to T3
Hypothryoidism aetiology
Hashimoto’s
Atrophic thyroid gland
Post Graves’ disease (after treatment eg. RAI, surgery)
Less common: post thyroiditis, drugs, thyroid agenesis, secondary hypothyroidism
Hypothyroidism symptoms
low metabolic rate
cardiovascular: bradycardic
GI: constipation
Resp: bradypnoea
reproductive issues (amenorrhoea)
weight gain and poor appetite
cold and dry hand and feet
hyponatraemia
normocytic anaemia
myxoedema
goitre
(can be subtle in elderly)
Hypothyroidism management
- make diagnosis
- diagnose cause (TPO autoantibodies = hashimoto’s)
- think of other autoimmune conditions (pernicious anaemia, coeliac, addison’s)
- ECG before starting thyroxine replacement (hypervascular disease can lead to contractility issues)
- T4 (levothyroxine); titrated to normal TSH
too much thyroxine: osteopenia, AF
Subclinical hypothyroidism
T4 levels normal
Pituitary detects T4 as low so produces more TSH so TSH is elevated
unlikely to cause symptoms as T4 is normal
TPO autoantibodies may predict later thyroid disease
‘compensated hypothyroidism’
only treated if cholesterol levels high
Thyroid function in pregnancy
elevated hCG
hCG has similar structure to TSH so can bind and slightly increase T4
(normal ranges are different in pregnancy)
TBG increases with increased oestrogen
Later in pregnancy; hCG levels normalise and so do TSH and T4
Neonatal hypothyroidism
tested for on heel-prick test (Guthrie’s) within 48-72 hours of life
if tested too early, TSH will be high as it will be from mother
if tested after 5 days, window is missed and may have long-term problems
Sick euthyroid
alteration in pituitary thyroid axis in non-thyroidal illness (any severe illness)
low T4 when severe
High/normal TSH (later falls)
low T3 and reduced action
normal physiological reaction to illness (will not have hypothyroid symptoms)
Causes of hyperthyroidism
Graves’ disease (autoimmune, TSH receptor antibodies stimulated excessively)
Toxic multinodular goitre
Single toxic adenoma
(above 3 will have high uptake on technetium scan)
Subacute thyroiditis
Postpartum thyroiditis
(above 2 will have low uptake on technetium scan)
Other causes: silent (immune and amiodarone), factitious thyroiditis, TSH-induced, thyroid cancer, trophoblastic tumour (excessive hCG production) and struma ovarii
Hyperthyroidism symptoms
high metabolic rate
tachycardia
diarrhoea
tachypnoea
osteopenia/osteoporosis
reproductive issues (amenorrhoea/infertility)
Hyperthyroidism management
- make diagnosis
- diagnose cause (technetium scan, thyroid microsomal autoantibodies)
- beta blocker (if pulse>100)
- think of other autoimmune diseases
- ECG and assess bone mineral density
- Radioactive iodine/Surgery
Radioactive iodine
slowly releases radioactive waves which eventually destroy thyroid gland
may precipitate a thyroid storm
Graves’ diseases signs
diffuse goitre
thyroid associated ophthalmopathy (iodine can make this worse so usually avoided)
thyroid associated dermopathy
thyroid acropachy
other autoimmune disease
Thionamides
used to treat hyperthyroidism if unresponsive to RAI
eg. carbimazole, propylthiouracil (works at TPO level to prevent conversion of iodide into iodine)
rarely cause agranulocytosis (if have sore throat or fever, stop meds and check FBC)
can either titrate dose or can block and replace (levothyroxine)
Potassium perchlorate
can also be used for hyperthyroidism
inhibits uptake of iodide into thyroid gland by TSH
Post-viral & post-partum thyroiditis
will be initially hyperthyroid and then will become hypothyroid (thyroid gland completely stops working)
treatment is with levothyroxine (no need to block)
Thyroid cancers
common causes (differentiated): papillary thyroid carcinoma, follicular thyroid carcinoma
good prognosis compared to other cancers
treatment: total thyroidectomy (surgery) +/- RAI and then levothyroxine (lower TSH to prevent recurrence)
can measure thyroglobulin to detect functioning thyroid tissue post treatment to see if tumour cells are still present
can also be causes by medullary carcinoma
Medullary carcinoma of thyroid
MTC sporadic / familiar / part of MEN2
C cells of thyroid
measure: calcitonin / carcinoembryonic antigen (CEA) as tumour marker (produced by C cells)
Fat soluble vitamins
A: retinol
Deficiency: colour blindness
Excess: exfoliation, hepatitis
Test: serum
D: cholecalciferol
Deficiency: osteomalacia/rickets
Excess: hypercalcaemia
Test: serum (25-vitamin D)
E: tocopherol
Deficiency (very rare): anaemia / neuropathy / ? malignancy / IHD
Test: serum
K: phytomenadione
Deficiency: defective clotting
Test: PTT
Water soluble vitamins
(excess is very rare)
B1: thiamin
Deficiency: Beri-Beri, neuropathy, Wernicke syndrome
Test: RBC transketolase
B2: riboflavin
Deficiency: Glossitis
Test: RBC glutathione reductase
B6: pyridoxine
Deficiency: dermatitis/anaemia
Excess: neuropathy
Test: RBC AST activation
(all of above tests, rarely done)
B12: cobalamin
Deficiency: pernicious anaemia
Test: serum B12
C: ascorbate
Deficiency: scurvy
Excess: renal stones
Test: plasma
Folate
Deficiency: megaloblastic anaemia, neural tube defects
Test: RBC folate
Niacin
Deficiency: pellagra (4 Ds: diarrhoea, dermatitis, dementia, ultimately death if untreated)
Trace elements
Iron
Deficiency: hypochromic anaemia
Excess: haemochromatosis
Test: FBC, Fe, ferritin
Iodine
Deficiency: goitre hypothyroid
Test: TFT
Zinc
Deficiency: dermatitis
Copper
Deficiency: anaemia
Excess: Wilson’s
Test: Cu, caeroplasmin (low in Wilson’s)
Fluoride
Deficiency: dental caries
Excess: fluorosis
Energy expenditure
Majority = resting (metabolism)
Exercise
Thermogenesis
Facultative T
Energy/fat homeostasis
Hypothalamus: induces satiety and increases energy expenditure (thermogenesis) via Insulin
White adipose tissue also releases adiponectin which if deficient in people causes insulin resistance
Adipose tissue also produces leptin which is anti-hunger hormone (acts on hypothalamus)
Hunger hormone = ghrelin (acts on hypothalamus)
PYY produced by gut and acts on hypothalamus to induce satiety
Body composition
Normal weight individual
- 98% O2, C, H, Na, Ca
- 60-70% H2O, 10-35% fat, 10-15% protein, 3-5% minerals
Variation body composition considerable, variation in LBM less
Definition of obesity
Weight
Body mass index
- weight/height2
- 25-30 kg/m2 overweight
- >30 kg/m2 obese
- >40 kg/m2 morbidly obese
waist hip ratio
NB: BMI unreliable in muscular people, also varies with ethnicity (lower threshold in south asians –> higher risk of diabetes and cardiovascular disease)
Obesity-associated comorbidities
psychological
sleep apnoea
chest disease
malignancy
diabetes and metabolic syndrome
cardiovascular disease
gynaecological disease (PCOS)
rheumatological disease
pregnancy: risks to fetus, mother and outcomes of pregnancy, future risk of obesity to fetus
Waist circumference and CHD risk
Men:
Increased >94
Major >102
Women:
Increased >80
Major >88
Protein
INTAKE 84g men, 64g women
Utility:
- Indispensable (e.g. leucine)
- “conditionally” indispensable (e.g. Cysteine)
- Dispensable (e.g. alanine) - only 5 of them, body can synthesise them on day-to-day basis
Protein synthesis/breakdown/oxidation
Assessment:
- N excretion and balance
- Tracer techniques
Lipid
Polyunsaturated fatty acid (PUFA) include essential fatty acids (EFA) - good lipids
Dietary fat determines LDL-C
- saturated fat high [chol]
- PUFA low [chol]
Increased [HDL] associated reduced IHD risk
(women, alcohol, obesity)
non HDL level >4 increased IHD risk
trans fatty acids are the worst
Carbohydrate
40-80% total energy intake
Polymerisation into sugars, oligosaccharides and polysaccharides
80 % complex (starch products, wholemeal) 20 % simple (fruit)
NSP - non-starch polysaccharides (fibre)
Metabolic syndrome
At risk of obesity-associated illnesses
Parameters:
Fasting glucose > 6mmol/L
Waist circumference >102 M, >88 F
HDL <1 M, <1.3 F
Hypertension BP>135/80
Microalbumin
Insulin resistance
Treatment of obesity
Exclude endocrine cause (hypothyroid, Cushing’s, acromegaly/GH deficiency)
Exclude complications of obesity
Educate
Diet and exercise
Medical therapy (Orlistat, GLP-1 agonist)
Surgical therapy
Bariatric surgery procedures
Adjustable band (silicone ring above top of stomach, attached to port where fluid can be used to make band tighter or looser; band can erode into gastric adipose)
Sleeve gastrectomy
(in the middle of band and bypass)
Gastric bypass
(better metabolic procedure; first part of duodenum and majority of stomach are bypassed, very good for diabetes; induces remission)
Marasmus
(protein energy malnutrition)
Low intake of carb, protein and lipid
Shrivelled
Growth retarded
Severe muscle wasting
No s/c fat
Kwashiorkor
(protein energy malnutrition)
Lack of protein only, carbohydrate and lipid content intact
(more common in times of famine)
Oedematous
Scaling/ulcerated
Lethargic
Large liver, s/c fat
Autoimmune disease types
Organ specific with organ specific Ag
eg. Pernicious anaemia (antibodies to parietal cells)
Organ specific without organ specific Ag
eg. primary biliary cirrhosis
Multisystem diseases
eg. rheumatoid arthritis, Sjogren’s syndrome, SLE
SLE organs involved
skins (malar rash, photosensitivity, discoid lesions)
oral ulcers
joints
neurological (psychosis, depression)
serositis (recurrent, pleuritic chest pain, or abdominal pain)
renal (glomerulonephritis)
haematological (pancytopenia)
immunological (autoantibodies)
ANA (for SLE)
anti-nuclear antibodies
immunofluorescence
screening test
if still positive at high dilution (eg. 1in 1000) then more significant levels
Autoantibodies in SLE
anti-dsDNA (using crithidia luciliae or ELISA)
anti-smith (against ribonucleoproteins) - most specific but not very sensitive
anti-histone (drug related eg. hydralazine)
SLE histopathology
Skin: lymphocytic infiltration of upper dermis, extravasation of red blood cells (causing rash), damage to basal epidermis
immune complex deposition at dermis-epidermis junction (immunofluorescence using IgG)
Renal: thickening (thick pink walls) of glomerular capillaries (wire loop) due to immune complex deposition in BM, immunofluorescence for immune deposition (also seen on electron microscopy)
Heart: Libman-sacks (non-infective endocarditis) - vegetations caused by deposition of lymphocytes/neutrophils/eosinophils etc.
Scleroderma (systemic sclerosis)
Fibrosis and excess collagen (localised form is called morphoea in skin)
diffuse form: antibodies to DNA topoisomerase (Scl70)
Limited form (no skin involvement above trunk): anticentromere antibody
CREST features:
- calcinosis
- raynauds
- esophageal dysmotility
- sclerodactyly
- telangiectasia
nuclear pattern immunofluorescence
nail fold capillary dilatation
microstomia (difficulty opening mouth)
Scleroderma histopathology
skin: excess collagen deposition (sclerodactyly)
stomach: excess collagen (staining) –> oesophageal dysmotility
small arteries: intimal proliferation (onion skin), obliteration of the lumen, may have microangiopathic thrombi
Mixed connective tissue disease
SLE
Scleroderma
Polymyositis
Dermatomyositis (Gottron’s papules, muscle inflammation and pain etc.)
(features of diseases above overlapping)
ANA test: speckled pattern
anti-rnp
Organs involved in sarcoidosis
joints (arthralgia)
skin (nodules and papules, lupus pernio, erythema nodosum)
lungs (fibrosis, hilar lymphadenopathy)
lymphadenopathy
heart (pericarditis, heart failure, endocarditis)
eyes (uveitis, conjunctivitis)
neuro (meningitis, cranial nerves)
liver (hepatitis, cholestasis, cirrhosis)
parotids (bilateral enlargement)
non-caseating granulomas (activated macrophages = histiocytes)
Sarcoidosis tests
hypergammaglobulinaemia
Raised ACE
hypercalcaemia: activated macrophages hydroxylate vitamin D
Vasculitis classification
Large vessel:
Takayasu arteritis
Giant cell arteritis
Medium vessel:
Polyarteritis nodosa
Kawasaki disease
ANCA-associated small vessel:
microscopic polyangitis
granulomatosis with polyangitis (wegner’s)
Eosinophilic granulomatosis with polyangitis (Churg-Strauss)
Immune complex small vessel:
Cryoglobulinemic
IgA (henoch-schonlein)
hypocomplementenmic urticarial
Kawasaki’s disease
Fever
erythema of palms and soles, desquamation
conjunctivitis
lymphadenopathy
coronary arteries may be affected (MI)
otherwise disease is self-limiting
Temporal arteritis histology
granulomas with giant cell formation
narrowing of lumen
lymphocytic infiltration of tunica intima
Polyarteritis nodosa
necrotising arteritis
polymorphs, lymphocytes, eosinophils
arteritis is focal and sharply demarcated
heals by fibrosis
more often renal and mesenteric arteries
nodular appearance on angiography (small aneurysm)
Granulomatosis with polyangiitis
ENT, lung, kidneys
C-ANCA (cytoplasmic ANCA) directed against proteinase 3
Eosinophilic granulomatosis with polyangiitis
Asthma, eosinophilia, vasculitis
P-ANCA (perinuclear ANCA) directed against myeloperoxidase
