uric acid metabolism

Question 1

roles of purines

Answer 1

• In genetic code - A and G
• Second messengers in form of cAMP and cGMP
• energy transfer - Form of ATP and GTP - high energy intracellular stores

Question 2

pathway of purine catabolism

Answer 2

Question 3

what breaks down purines

Answer 3

xanthine oxidase

Question 4

difference in catabolism of purines in animals and humans and what this means

Answer 4

In animals Allantoin - highly soluble and freely excreted in urine
humans - don’t have working uricase
* so have to excrete urate
* this is more insoluble - circulates in blood stream at conc close to limit of solubility.
* ie close to precipitating out
* -> crystals ie gout

Question 5

why do women have less gout

Answer 5

they have a lower urate conc

Question 6

what does urate solubility depend on

Answer 6

temperature - colder = fall in solubility (hence gout in feet - where colder)
pH - more acidic = less soluble

Question 7

describe how urate is handled in kidney

Answer 7

1. Filtered at glomerulus - appear in prox convulated tubule fluid
2. reabsorbed and re-excreted - uric acid maybe an important anti-oxidant - This is speculation
3. At urine - only 10% of uric acid that was in filtrate is in urine - rest has been reabsorbed

Question 8

what are the different ways to metabolise purine

Answer 8

de novo or salvage mechanism

de novo is metabolically hard, it is inefficient - only used when mandated by high demand for purines

salvage = energy efficient - main pathway

De novo is more than salvage in bone marrow - so much cell division that salvage pathway is inadequate to provide supply

Question 9

which cells do purine metabolism

Answer 9

all - all have nucleus

Question 10

what is the rate limiting step in purine metabolism

Answer 10

catalysed by PAT
PAT is under feedback inhibition control
GMP and AMP feedback and negatively regulate PAT
Also subject to feed forward effect - the more PPRP -> activate PAT

green = de novo blue = salvage

Question 11

role of HPRT in purine metabolism

Answer 11

same as HGPRT

Scoop up partially metabolised purine and bringing them back
Main enzyme of the salvage pathway

Question 12

what is the other name for HGPRT deficiency

Answer 12

complete deficiency = lesch Nyhan syndrome

Question 13

features of lesch Nyhan syndrome (HGPRT def)

Answer 13

• X linked
• normal at birth
• developmental delay at 6mo
• hyperuricaemia = gout
• choreiform movement at 1yr (problem with basal ganglia function)
• spaciticity
• mental retardation (UMN lesion)
• self mutilation (bite lips/digits) - aged 1-16yrs

Question 14

pathophysiology of lesch nyhan syndrome

Answer 14

HPRT missing
* = no guanine recycled to GMP and no hypoxanthine recycled to inosinic acid
* This removes the feedback inhibition to PAT
* = de nevo pathway in overdrive
* = making IMP = accumulation - so shunt down catabolic pathway
* = urate levels build up

With no salvage pathway activity - PPRP also builds up -> positive feedback for PAT

With both = de novo pathway in overdrive

Question 15

presentation of partial HGPRT deficiency

Answer 15

lesser sx of Lesch Nyhan

Question 16

causes of decreased urate excretion

Answer 16

• CRF = CKD ie kidney failure - cant excrete uric acid
• Lead poisoning -> hyperuricaemia - reduced excretion
• Thiazide diuretics - rx for HTN - cause hyponatraemia, hypercalacaemia, hyperglycaemia, hyperuricaemia

Question 17

what is gout and who does it effect

Answer 17

Crystal arthropathy - monosodium urate crystals
acute = poagra
chronic = tophaceous
* don’t get acute arthropathy
* get deposition of uric acid in soft tissues - can be next to joints.
* Tophi - eg in ear lobes

If get multiple episodes of podagra - can end up having tophaceous gout.
more men
postpubertal men and postmenopausal women

Question 18

when would men get gout before puberty

Answer 18

lesch neyhan syndrome
rare esenteric familial juvenille hyperuricaemic nephropathy

Question 19

why does gout happen

Answer 19

When limit of solubility drops below circ conc
-> precipitation
Inflammatory stimuli -> intense inflammatory reacting in the synovium of the joint

Question 20

presentation of gout

Answer 20

pain
red, hot, swollen
skin tense because of underlying inflammation
1st MTP

Question 21

XR of gout

Answer 21

Radiograph of effect of tophi - soft tissue opacity
End of blue arrow - periosteal erosion, reaction to tophus

Question 22

aspiration of gout

Answer 22

needle shaped crystals of monosodium urate

Question 23

mx of gout

Answer 23

in acute gout - reduce inflammation:
* NSAIDS
* colchicine
* glucocorticoids
* dont try to reduce urate conc - will cause more crystals

Question 24

when can you not use NSAIDs

Answer 24

asthma
peptic ulcer
Toxic to kidney - so avoid if CKD

Question 25

mechanism of colchicine

Answer 25

inhibit microtubule assemby - important for mitosis. Reduce motility of neutrophils - cant get into the joint and react to uric acid crystals.

Question 26

how do you manage hyperuricaemia in non acute gout

Answer 26

drink plenty of water reverse things -> high urate **reduce synth with allopurinol** increase renal excretion with probenecid - uricosuric

Question 27

SE of allopurinol

Answer 27

**interact with azathioprine** - making **more toxic on bone marrow** 1. azathioprine metabolised -> **mercaptopurine** 2. -> thioinosinate 3. thioinosinate interferes with purine metabiolism and cell division 4. allopurinal makes mercapotopurine last longer because **mercapotopurine is metabolised by xanthine oxidase** * so **allopurinol -> inhibition of azithioprine break down -> toxic levels** -> neutropenia

Question 28

dx of gout

Answer 28

tap effusion view under polarised light red filter Urate crystals are **negatively birefringent** ie appear blue when perpendicular to red compensatory

Question 29

what is pseudogout and who does it effect

Answer 29

happens in OA effects knees pyrophosphate crystals self limiting in 1-3wks

Question 30

disorders of urate metabolism

Answer 30