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

Why are humans susceptible to gout?

Answer 2

Purines –> hypo-xanthine –> xanthine –> uric acid
Xanthine oxidase is involved in the production of both xanthine and uratet

humans are susceptible to gout because they don’t have the enzyme that. breaks down uric acid into soluble products (as is the case in animals)

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!

**most of it is actually reabsorbed into the bloodstream - urate is meant to be a beneficial antioxidant**

Question 4

Name one disorder of inborn error of purine
metabolism

Answer 4

Lesch Nyhan Syndrome

*deficiency of HPRT enzyme (which is important in synthesising purines via salvage pathway*

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, 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?

how doesit happen?

Answer 9

Monosodium urate

happens when the crystals are no longer soluble so they precipitate out of solution

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) – this inhibits neutrophil action
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. - stop thiazide diuretics
3. Allopurinol - xanthine oxidase inhibitor
4. Probenecid - increases uric acid excretion via the urine

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 and view under a microscope using POLARISED LIGHT with a red filter

**analyse birefringence - ability of crystal to rotate the axis of polarised light

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)
Pseudogout crystals - positively birefringent (red) - this is parallel to the compensator

Question 20

Which other condition predisposes to pseudogout?

Answer 20

Osteoarthritis

Question 21

How long does pseudogout last?

Answer 21

1-3 weeks

**it is self limiting unlike gout which needs to be treated

Question 22

What are the 3 main purines?

Answer 22

guanosine

adenosine

inosine

Question 23

Why is chance of gout lower in women than men?

Answer 23

Women have lower monosodium urate in the plasma

Question 24

What factors influence the solubility of gout and how does that explain where you get gout

Answer 24

1. Temperature - solubility is less at lower temperatures hence gout in peripheries
2. acidosis - acidosis decreases solubility as well

Question 26

What are the two main pathways of purine synthesis?

Answer 26

1. de novo pathway
   - energy inefficient
   - mostly used by bone marrow where high demand for purines
   - main enzyme= PAT
2. salvage pathway
   - partially cataobolised purines are essentially recycled
   - way more energy efficinet
   - every cell is able to utilise this pathway
   - main enzyme = HPRT

Question 27

What are some triggers of gout?

Answer 27

ASPIRIN triggers gout

alcohol

chemo

dehydration

thiazides

AACDD

aspirin alcohol chemo diuretics dehydration

Question 28

Characeristics of crystals in gout

Answer 28

yellow

needle shaped

negatively birefringent

Question 29

What type of crystals do you have in psueodgout?

Answer 29

calcium pyrophosphate crystals

these are parallel and positively birefringent