Core biochemistry

Question 1

hyponatraemia

Answer 1

serum [Na] below 133-146mmol/L
always consider primary Na depletion, even though water retention is the more common cause, and a near certainty when no evidence of fluid loss from history or examination
water retention almost always impaired excretion, not drinking too much
many have syndrome of inappropriate diuresis SIAD, seen in: infection, malignancy, chest disease, or trauma, due to inappropriate AVP secretion (from 0-5pmol/L up to 500pmol/L) due to hypovolaemia, hypotension, nausea/vomiting, hypoglycaemia, pain; however eg hypovolaemia induced increase is not SIAD as it is not inappropriate
fluid retention can be oedematous due to inc’d uptake (inappropriate saline iv) or dec’d excretion (CCF, nephrotic syndrome) or non-oedematous due to inc’d uptake (eg compulsive drinking) or dec’d excretion (SIAD, renal failure)

Question 2

more on sodium depletion

Answer 2

usually increased loss from kidney, skin or GIT: vomiting/diarrhoea, may be esp severe in patients with fistulas due to bowel disease; urinary loss typically due to mineralocorticoid insufficiency or drugs that antag aldosterone
water loss initially accompanies so serum conc remains the same, this then stimulates AVP leading to hyponatraemia
Na losing patients may also become hyponatraemic due to replacing fluid with just water and not electrolytes too
can also get dec’d Na intake as a cause of sodium depletion but this is very rare
also note of caution: not all patients with Na depletion become hyponatraemic, if the loss is due to osmotic diuresis they may even become hypernatraemic; history and clinical exam more important for spotting Na depletion than the biochemical test

Question 3

pseudohyponatraemia

Answer 3

hyperproteinaemia or hyperlipidaemia: more plasma volume occupied, so water fraction down; thus Na conc within the fluid is the same but in plasma will seem lower - suspect if no real symptoms indicative of hyponatraemia
serum osmolality is not affected

Question 4

assessment and management of hyponatraemia

Answer 4

120mmol/L good threshold as risk sharply incs below this conc and decs above it - but other factors too eg how fast is it falling
hyponatraemia symptoms result from overhydration due to hypoosmolality and include: nausea, headache, malaise, lethargy, reduced consciousness - and then typically below 115mmol/L seizures, coma, focal neurological signs
ask about dizziness/lightheadedness/weakness, and a history of GI or kidney fluid loss
can look to identify cause of water retention eg rigors indicate infection, weight loss indicates malignancy
Na depletion will give symptom of ecf compartment depletion: soft/sunken eyeballs, dry mucous membranes, raised pulse, decrease urine output/consciousness/skin turgor, and postural hypotension
if these present in recumbent state then life threatening Na depletion is present
postural hypotension typically first sign
probably wont see signs of water overload if water retention as evenly distributed in all body comps, and rise is gradual

Question 5

other bits for hyponatraemia

Answer 5

patients with oedema often become hyponatraemic because the various causes trigger hyperaldosteronism, retaining Na and water but water more so due to AVP due to hypovolaemia; thus despite hyponatraemia also have Na overload
if hypovolaemia (Na depleted) then give Na, if normovolaemic restrict fluids instead
diuretic and fluid restriction for oedematous patient
if seems serious, then hypertonic saline may be indicated
in infective diarrhoea, an oral glucose and salt solution is simple and life saving, esp in developing countries; allowing treatment of Na depletion without advance measurements

Question 6

hypernatraemia

Answer 6

inc in serum Na above 133-146mmol/L
water loss or sodium gain
poor intake of water often in elderly, and in patients who have been eg unconscious or otherwise unable to drink
also water loss due to failed AVP secretion: diabetes insipidus, can be central (release) or nephrogenic
also in some osmotic diuresis if more water lost than sodium, seen in patients with poorly controlled diabetes mellitus, excessive sweating, or diarrhoea (though latter usually hyponatraemia)
sodium gain (aka salt poisoning) much rarer; can arise from sodium bicarb solution given to treat acidosis, where possible use a solution with lower Na conc (1.26%); another cause is near-drowning in salt water; a third is if infants given high Na feed, salt to a newborn can raise plasma conc by 70mmol/L
also Conn’s syndrome/primary hyperaldosteronism; may get similar findings in Cushings patients

Question 7

more bits of hypernatraemia

Answer 7

if mild and patient has signs of dehydration then likely loss of Na and water
if more severe (150mmol/L+) then pure water loss more likely, especially if dehydration symptoms mild (depleted from all comps) relative to the hypernatraemia
suspect salt poisoning if no signs of dehydration, especially if the level is 190mmol/L+
salt gain may be accompanied by pulmonary oedema and raised jugular venous pressure
if due to pure water loss then give water orally or iv as 5% dextrose
if dehydration signs then give water and Na
if salt poisoning then diuretics and water given - iv dextrose in these patients exacerbates ecf expansion leading to inc’d risk of pulmonary oedema

Question 8

hyperkalaemia

Answer 8

normal is 3.5-5.3mmol/L
immediately life threatening if >7mmol/L, may cause cardiac arrest
ECG changes seen inc: tall tented T waves and widening of QRS complex
may also see muscle weakness and paraesthesia
almost all have decreased excretion due to renal failure leading to reduced GFR and exacerbated by concurrent metabolic acidosis; or due to hypoaldosteronism reducing GFR, often seen with ACEis and ARBs, or adrenal insufficiency
can also be due to redistribution out of cells: during rhabdomyolysis, trauma, or tumour lysis syndrome; metabolic acidosis also causes; as does insulin deficiency (insulin stims uptake of K, so you may see it in eg diabetic ketoacidosis)
recurrent attacks of weakness/paralysis, often precipitated by rest after exercise, can be due to rare autosomal condition hyperkalaemic periodic paralysis
increased intake is 3rd major cause: esp a risk in patients with impaired renal function; eg the K included in many drugs; iv K shouldnt be given at more than 20mmol/hr unless extreme circumstances; blood products may also cause as RBCs release K when stored so use blood less than 5 days old or wash prior to transfusion

Question 9

treating hyperkalaemia

Answer 9

calcium (gluconate or chloride) counteracts the effects on Em of cells
insulin and glucose given to promote K uptake by muscle
correct reduction of GFR if possible, if not then give dialysis
cation exchange resins only useful in modest, slow increases in K

Question 10

pseudohyperkalaemia

Answer 10

due to increased wbc/platelet count, in vitro haemolysis, or in centrifugation to separate cells from serum (esp common for samples from primary practice)

Question 11

hypokalaemia

Answer 11

reduced intake is rare cause as renal retention of K when levels fall means intake must drop a lot but consider when patient having hypocaloric diet eg for weight loss
redistribution into cells: metabolic alkalosis, insulin treatment (for eg diabetic ketoacidosis), refedding syndrome (after starvation, fed with lots of carbs, seen in eg POWs; phosphate/Mg/K falls due to insulin release for raised glucose; anorexia patients may get, also at risk those with: cancer, alcoholism, post-op; beta agonism (inc stress through b2r); treatment og anaemia with folic acid/vit B12 due to new cells taking up K
heritable hypokalaemic periodic paralysis resembles refeeding syndrome, can be preciptated by rest after exercise, and may also be acquired by thryotoxicosis (esp in males of chinese descent) poss due to inc’d catacholamine sensitivity

Question 12

increased K losses

Answer 12

GIT: vomiting/diarrhoea, esp see in eg cholera, or chronic laxative abuse (but rule out other causes first for the latter)
urinary: loop and thiazide diuretics, mineralocorticoid excess, hypomagnesaemia (if less than 0.6mmol/L Mg then get impaired renal tubular absorption, at higher levels and generally more likely if also using PPIs); tubopathies, often due to platinum containing drugs, rare mutations too
note alcoholic patients esp prone to hypokal for various reasons

Question 13

investigating and treating hypokalaemia

Answer 13

is cause obvious? vomiting/diarrhoea/diuresis
no - is there evidence of redistribution into cells eg high bicarb, low phosphate/glucose
no - check urine K as could be cushings, Conns, low Mg causing loss in urine
no - rarer gut causes: villous adenoma, laxative abuse
no - drugs that could explain: diuretics, amphotericin, salbutamol, dobutamine, vit B12, folate
no - rarer causes: inherited tubulopathies
can give oral K salts in enteric coating for prophylasis, or iv K up to 20mmol/hr to treat if bad (unless extreme, but in this case must have ecg monitoring)

Question 14

iv fluid therapy

Answer 14

if patient cannot take fluids orally or because disturbance is severe enough to warrant rapid correction
3 basic types: plasma (expanders) or whole blood, aka colloids, given when vascular volume reduced after eg bleeding; 0.9% NaCl, isotonic NaCl, confined to ecf and given if that compartments volume reduced eg Na depletion; 5% dextrose (as pure water would haemolyse cells), with the dextrose rapidly metabolised and water redistributed across all comps so for those with reduced total body water eg hypernatraemia
generally per day: water losses of 2-3L, sodium of 100-200mmol, potassium of 20-200mmol; beware though that insensible losses inc when on artificial ventilation or with excessive sweating
after trauma of surgery: AVP secretion, K redistribution due to tissue damage, physiological stress response; so good iv treatment perioperatively per day may be: 1-1.5L fluid containing 30-50mmol Na and no K
do not raise serum Na by more than 10-12mmol/L per day, as otherwise may get osmotic demyelination, esp in pons, giving disability or death
when adjusting regimens, must assess fluid and electrolyte status: besides biochemistry, consider cae records, exam of patient (JVP, CVP, ABP, pulse, oedema, skin turgor, chest sounds), nursing charts (inc fluid input/output)

Question 15

investigating glomerular function

Answer 15

serum creatinine is convenient but insensitive measure as GFR has to halve before sig rise occurs
130micromol/L is expected for young muscular man
using creatinine clearance VxU/p gives volume of plasma cleared during the time period of collection - but this is imprecise and inconvenient for patients, though more sensitive
nowadays use prediction equations to estimate GFR
these are more inaccurate the closer to normal GFR you get and for patients with abnormal body shape eg muscle wasting, amputees
better than serum creatinine as takes into account confounding variables
GFR fluctuates throughout the day so up to 20% difference between sequential measurements may not be anything to worry about

Question 16

investigating tubular function

Answer 16

urine osmolality of 600mmol/kg or more is proxy for tubular function being intact; when its ratio is approx 1:1 with the plasma’s, renal tubules arent reabsorbing water
if inconclusive, can do formal water deprivation: flat osmolalility response to water deprivation suggests diabetes insipidus, and this is excluded if osmolality rises
unpleasant and risky if patient cant retain water: stop if >3L urine passed or >3% body weight lost
an alternative: fluid deprivation overnight (8pm-10am) then urine osmolality check, then give desmopressin (synthetic AVP analogue) and if osmolality rises after this then central diabetes insipidus, and if it doesnt then nephrogenic
if suspect RTA as a cause for unexplained metabolic acidosis, collect fresh urine sample and if its pH <5.3 then RTA unlikely, if unconvincing can give furosemide which should make urine more acidic if RTA not occurring
proteinuria is marker for leaky glomeruli, the small markers beta2 microgblobulin and alpha1 microglobulin is sensitive indicator of tubular damage

Question 17

urinalysis

Answer 17

read too quickly, leave too long, store improperly, or strips out of date are some common sources of error
glucose usually reflects hyperglycaemia - may be diabetes mellitus but also threshold for glucose clearance might be reduced in eg pregnancy so normal plasma conc still enters the urine (renal glycosuria) and also after meals blood glucose temporarily overcomes the threshold (alimentary glycosuria)
bilirubinuria suggests conjugated bilirubin in urine which is always pathological due to disruption of the enterohepatic circulation
urobilinogen usually found in urine, raised levels if bilirubin turnover increased (haemolysis) or enteroepatic circulation disrupted
ketones suggest diabetic/alcoholic ketoacidosis, or can be associated with prolonged fasting or vomiting
proteinuria only if dipstick test not also positive for blood or leucocytes, and may also suggest UTI
haematuria can be many things from UTI and malignancy through to contamination from menstruation; also test for red cells, if not present suggests haemo/myoglobinuria
nitrite points towards UTI (bacti form it from nitrate)

Question 18

acid-base balance

Answer 18

calculate anion gap from diff between sum of Na and K minus sum of Cl and HCO3 but often exclude K as small and usually constant
usually 6-18mmol/L, value may increase in metabolic acidosis
also note proteins in plasma are negative so there isnt an actual anion gap, just one created by the ions selected
sometimes no raised anion gap due to hyperchloraemic acidosis (Cl subs for HCO3) seen in: chronic diarrhoea/intestinal fistula, and RTA
alkalosis usually leads to alkaline urine, but is acidic in K deficiency as to retain more K it is exchanged for Na instead of H, leading to more H in urine

Question 19

cardiac biomarkers - MI

Answer 19

most useful in patients without the ecg changes or having a ‘silent’ MI
from necotic cells releasing their contents with troponin T and I specific to cardiomyocytes: rise within a few hours of symptom onset and remain elevated for a couple of weeks with diagnostic sensitivity of 100% after 12 hrs from onset of chest pain (ie no false negatives)
troponins may be increased in myocarditis, stroke, pulmonary embolism, severe sepsis

Question 20

liver function tests

Answer 20

bilirubin - normal adult makes 450 micromol/day; serum conc up when biliary track blocked; usually <21micromol/L and when >50 get jaundice
aminotransferase activity is sensitive but non-specific indicator of acute hepatocyte damage (infection, toxicity/overdose, cardiac failure/shock) - AST/ALT
alkaline phosphatase activity up indicates cholestasis (>2x the normal upper limit of activity range), as well as indicating infiltrating lesions eg tumours, and in cirrhosis - note though that if cause such as above not indicated by other stuff too, alkaline phosphatase activity is found in other structures like the bone so cant just use this
gamma-GT activity raised with cholestasis, alcohol, phenytoin, and also parallel the changes in aminotransferases
hypoalbuminaemia suggests advanced chronic liver disease or notably severe acute liver disease
AFP conc increased in 80-90% hepatocellular carcinoma cases,
prothrombin has v short half life, so prothrombin time increase may be earliest indicator of reduced hepatic synthesis and is preferred to albumin usually

Question 21

glucose metabolism biochemistry

Answer 21

fasting sample is preferred, and if results from this (or random sample if needed) inconclusive can give oral glucose tolerance test
fasting (venous) blood glucose of >7mmol/L regarded as diagnostic of diabetes, fast overnight (at least 10 hours) - if between 6-6.9mmol/L then patient has impaired fasting glycaemia
random measurement (done in eg patient presenting with hyperglycaemic symptoms, and if >11mmol/L suggests but confirm with a fasting sample)
for the oral test, give glucose and measure plasma conc at start and 2hrs after; see if it increases to >11mmol/L from a raised baseline (though not usually done, only if discrepancy eg between random and fasted results)

Question 22

impaired glucose tolerance and impaired fasting glycaemia

Answer 22

IGT can only be diagnosed after oral glucose challenge
these peeps have elevated risk of getting diabetes
IFG diagnosed from single fasted sample, with risks etc less well defined

Question 23

glycated haemoglobin

Answer 23

reflects glycaemia over 2 months prior to measurement (t0.5 of Hg)
optimal unclear but around 50mmol glycated per mol total
spurious results in some hamoglobinopathies
diabetes may be revealed by glycosuria found in various health checks etc, but the false negative rate is high hence not used to make a diagnosis

Question 24

hypocalcaemia

Answer 24

healthy serum calcium is approx 2.4mmol/L, half bound to plasma proteins (less in acidosis and more in alkalosis)
if albumin falls, total serum Ca will also fall but will have normal unbound Ca levels as this is the regulated part, thus not hypocalcaemic
many labs thus reported a calcium figure adjusted for this, reporting what the total would be is normal albumin present
after the initial test for ca ask: renal disease? measure urea and creatinine, and if fine then measure Mg and phosphate - > low suggests vit D deficiency and high hypopara; vit D def even more likely if PTH levels appropriately elevated, other rare causes and pseudohypopara; if PTH is inappropriately low may be due to post-surgery, Mg deficiency, or else idiopathic
chronic renal failure affects synthesis of vit D metabolites giving hypocalcaemia quite commonly, and from that bone disease and hyperparathyroidism

Question 25

hypercalcaemia

Answer 25

if >2.8mmol/L, non-specific symptoms so may find in any ward
if >3.5 after adjusted for albumin then life threatening and treat immediately, if remains over 2.8 but <3.5 then measure PTH: if undetectable then why has Ca become high enough to suppress it? suggests malignancy or other cause of high Ca; if detectable/high then suggests primary hyperparathyroidism (often adenoma)

Question 26

phosphate

Answer 26

phosphate (mono and dihydrogen) usually maintained at 0.8-1.4mmol/L; usually reciprocal relationship with Ca so things which change it often also change phosphate but note: acidosis decreases metabolism, so utilisation of phosphate, thus its levels inc; also inc’d by tissue damage, tumour lysis, rhabdomyolysis etc as released from cells
low levels become severe around <0.3mmol/L and needs iv correction; modest impairment more common, alcoholics esp prone; may arise from hyperparathryoidism, treating diabetic ketoacidosis (insulin causes uptake into cells), alkalosis, refeeding syndrome, ingestion of non-absorbable antacids like aluminium hydroxide which prevent its absorption; and certain congenital defects and tumours

Question 27

magnesium

Answer 27

hypomagnesaemia usually due to deficiency (main source is chlorophyll ie green veg), resembles hypocalacaemia and may cause hypoparathyroidism; usually only dont get enough due to general nutritional insufficiency
may also get it though from diuretics, ciclosporin, cisplatin and some cytotoxic drugs, osmotic diuresis as in eg diabetes mellitus, or prolonged nasogastric suction
<0.7mmol/L in serum suggests patient is very deficient and would benefit from treatment; sometimes intracellular depletion occurs w/o serum depletion, and would need NMR spectroscopy, or muscle biopsies, or WBC sampling to diagnose
uncommon to see hypermagnesaemia but can get in renal failure

Question 28

testing in calcium and bone disorders

Answer 28

first for calcium, albumin, phosphate, alkaline phosphatase (marker for bone formation)
follow ups: PTH, Mg, urine Ca excretion, 25-hydroxycholecalciferol, urinary hydroxyproline (marker for bone resorption) excretion, osteocalcin