Chemical Patholgy 1 - 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

Answer 4

Lesch Nyhan Syndrome

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 dinovosynthesis of purines, plasma urate increases a LOT

Question 8

What are the symptoms of Lesch-Nyhan syndrome?

Answer 8

Choreform movements (rythmic almost dancelike spasms/movements), spasticity and UMN signs with mental retardation
Self-mutilation in 85% :-( They bite their lips and digits with a great deal of force

HPRT mutation, leading to no salvage pathway, reduced negative inhibition on PAT and thus hyperurea

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
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

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 crystals = negatively birefringent (BLUE - this is perpendicular to compensator, orange colour will be parallel)
Pseudogout crystals - positively birefringent (red)

Question 20

Which other condition predisposes to pseudogout?

Answer 20

Osteoarthritis

Question 21

How long does pseudogout last?

Answer 21

1-3 weeks