Chemical Patholgy - Uric acid metabolism

Question 1

Recall 3 roles of purines

Answer 1

1. Base in DNA
2. 2nd messengers for cAMP
3. Form part of ATP

Question 2

Recall the pathway of purine catabolism

Answer 2

Purines –> hypo-xanthine –> xanthine –> uric acid

Xanthine oxidase is involved in the production of both xanthine and urate

Question 3

Recall the renal handling of urate

Answer 3

Urate is fairly insoluble
It is freely-filtered at the Bowman’s capsule
Bizzarely: it is both reabsorbed and re-excreted in the proximal convoluted tubule!

Question 4

Name one disorder of inborn error of purine
metabolism. Outline the mechanism

Answer 4

Lesch Nyhan Syndrome = complete HPGRT deficiency causing increased urate production as PAT not inhibited

No HPRT so no conversion of guanine back to GMP and less hypoxanthine back to IMP

Less IMP and GMP LACK of inhibition on PAT and so de novo synthesis goes into overdrive

Cells start to uncontrollably make IMP and this abundance of IMP à abundance of urate

PPRP also starts to build up à driving further positive feedback of PAT

Question 5

What is the inheritance pattern of Lesch Nyhan syndrome

Answer 5

X-linked

Question 6

How does Lesch-Nyhan syndrome first present?

Answer 6

With developmental delay at 6-12 months

Question 7

What is the mutation that causes Lesch-Nyhan syndrome?

Answer 7

HPRT - an enzyme that is key in purine recycling
Since there is no feedback inhibition on denovosynthesis of purines, plasma urate increases a LOT

Question 8

What are 5 symptoms of Lesch-Nyhan syndrome?

Answer 8

Choreform movements, spasticity and UMN signs with mental retardation
Self-mutilation in 85% They bite their lips and digits with a great deal of force

Question 9

What type of crystals cause gout?

Answer 9

Monosodium urate

Question 10

What are the 2 clinical forms of gout?

Answer 10

Acute - “podagra”
Chronic - “tophaceous”

Question 11

How should acute gout be treated?

Answer 11

Key thing is to reduce inflammation
1. NSAIDs (not if CKD is cause!)
1b. Colchicine (this is 2nd line, if NSAIDs contra-indicated)
1c. Glucocorticoids (if all else fails!!)
Nb: if you try to correct urate in the acute phase, you can actually make it worse!!

Question 12

How should chronic gout be treated?

Answer 12

Need to manage the hyperuricaemia

1. Hydration (water!)
2. Reverse the factors driving urate up
3. Allopurinol
4. Probenecid (increase curate excretion, ok if GFR over 50)

Question 13

What prescription drug can drive urate up?

Answer 13

Thiazide diuretics

Question 14

What is the mechanism of action of allopurinol?

Answer 14

Inhibits xanthine oxidase

Question 15

What is the mechanism of action of probenecid?

Answer 15

Increases renal excretion of urate

Question 16

Recall one very important drug interaction to avoid when prescribing gout drugs

Answer 16

Allopurinol and azothioprine
The intermediary of azothioprine = mercaptopurine - which needs xanthine oxidase to be catabolised

Question 17

Recall the diagnostic approach for gout

Answer 17

1. History and examination should be sufficient
2. If not clear: TAP effusion

Question 18

How can gout crystrals be visualised?

Answer 18

View effusion material under polarised light - use RED filter

Question 19

How can gout and pseudogout crystals be differenitated under the microscope?

Answer 19

Gout MSU crystals = negatively birefringent (BLUE, orientated left to right), needle shaped
Pseudogout calcium pyrophosphate crystals - positively birefringent, rhombus shaped, right to left

Question 20

Which other condition predisposes to pseudogout?

Answer 20

Osteoarthritis

Question 21

How long does pseudogout last?

Answer 21

1-3 weeks

Question 22

2 pathways of purine synthesis

Answer 22

de novo = inefficient, done when high demanded, PAT is rate limiting step. PAT = Phosphoribosyl pyrophosphate amidotransferase
salvage = highly efficient, therefore predominant pathway

Question 23

what drug should you never give someone if on allopurinol & vice versa

Answer 23

AZATHIOPRINE

Question 24

distinguish between colour of gout and pseudogout crystals under polarised light

Answer 24

 NEGATIVELY birefringent crystals will appear BLUE at 90 degrees (peperndicular) to the axis of the red compensator
 POSITIVELY birefringent crystals will appear BLUE in the axis of the red compensator

Question 25

primary vs secondary gout

Answer 25

primary = inherited (X-linked) gene. Is either due to excess de novo purine synthesis, or reduced renal excretion of uric acid. 
secondary = increased lysis of cells – e.g. in chemotherapy treatment OR decreased uric acid excretion which is usually idiopathic or due to thiazides, or CKD

Question 26

what joint typically affected in gout

Answer 26

Typically it presents in the 1st MTP (metatarsal – phalangeal joint) of the foot, but can affect any joint, and rarely, multiple joints can be affected simultaneously.

Question 27

what is the normal function of the HPGRT enzyme

Answer 27

HPRT is usually used to recycle hypoxanthine and guanine back into DNA synthesis