Chem Path: Uric acid metabolism and gout Flashcards
What are the 3 purines in our body?
Adenosine, Guanosine and Inosine
What are 3 functions of purines?
Genetic code A & G
Second messengers for hormone action cAMP
Energy transfer - ATP
How are purines catabolised?
Purines are converted to hypo xanthines.
Hypo xanthines are converted to xanthines by xanthine oxidase
Xanthines are converted to urate by the same enzyme
What happens to urate
They are insoluble so they just circulate, almost always on the brink of conversion to uric acid crystals
Which joint is most often first affected in gout?
first metatarso phalangeal joint
What does Fractional Excretion of Uric Acid (FEUA) mean
Urate is freely excreted in the renal tubules. But by the end of PCT 90% of it has been reabsorbed
What are the 2 ways purines are metabolised?
De novo - Synthesised from scratch
Salvage pathway - They are recycled and this is energy efficient
Which purine synthesis pathway is preferred by the body cells?
Most of them prefer salvage pathway, EXCEPT the bone marrow, which has such a high cell turnover rate that it prefers the de novo pathway
What is the rate limiting step in the de novo pathway
PAT enzyme
It converts PPRP to GMP and AMP
GMP and AMP exert a negative feedback effect on PAT while PPRP exerts a positive feedback effect on PAT
What is a crucial enzyme in the salvage pathway?
HPRT/HGPRT
What is Lesch Nyhan syndrome
X linked disease
Complete deficiency of HGPRT/HPRT
How does Lesch Nyhan syndrome present?
Normal at birth Developmental delay shows at 6 months Choreiform movements Spasticity and UMN problems Mental retardation Self mutilation Hyperuricaemia
Why does Lesch Nyhan syndrome cause problems?
Since there is a deficiency of HPRT, PPRP accumulates, exerting more positive feedback on the salvage pathway and since there is no production on AMP and GMP, there is no negative feedback on the pathway to stop it. So the de novo pathway takes over, producing more urate.
Summarise the causes of hyperuracaemia?
Increased urate production:
- Primary
- Lesch Nyhan
- Secondary
- Myeloproliferative diseases
- Lymphoproliferative diseases
- Severe psoriasis
- Gaucher’s
- Chronic haemolytic anaemia
Decreased urate excretion:
- Primary
- FJHN
- Secondary
- CKD
- Lead poisoning
- Down’s
- Aspirin
- Diuretics
What is gout
Accumulation of monosodium urate crystals - Crystal arthropathy
What are the 2 types of gout
Acute - Podagra
Chronic - Tophaceous
How does acute gout present?
Rapid build up of pain
Red, hot and swollen joint
1st MTP
Periosteal erosion
Which parts do chronic gout affect
Peri-articular areas
Ear lobes
What is pseudo gout
Accumulation of calcium pyrophosphate crystals
How to differentiate gout from pseudo gout
Tap the effusion
View under polarised light using a red filter
Monosodium urate - Negatively birefringence - Blue perpendicular to the axis - Needle
Calcium pyrophosphate - Positive birefringence - Blue within the axis - Rhomboid
What are the 2 aims of managing gout
Reduce inflammation
Manage hyperuricaemia
How is inflammation reduced?
NSAIDs 1st line - Diclofenac
Colchicine - Inhibits tubulin formation and stops neutrophils from causing inflammation
Glucocorticoids - Inject or give prednisalone tablets
When would you not give NSAIDS
If patient has CKD
What can colchicine cause in the long term
Marrow toxicity
How to manage hyperuracaemia
Allopurinol
Drink water
Avoid things that increase urate (eg Port wine)
Increase renal excretion with probenecid (uricosuric)
How does allopurinol work?
Inhibits xanthine oxidase
What are the side effects of allopurinol
Interacts with azathioprine, making it very toxic for the bone marrow by accumulating mercaptopurine. Patient will become neutropaenic
What is azathioprine used for?
Immunosuppressant for IBD
