ChemPath: Hyperuricaemia and Gout Flashcards
What are purines?
Ubiquitous Biomolecules:
Adenosine, Guanosine and Inosine
What are the 3 important biological roles purines?
- Genetic code A & G
- Second messengers for hormone action in the form of cAMP and cGMP
- Energy transfer/stores as ATP and GTP
What is the prevalence of gout?
3% of males have gout sometime in life. Lower prevalence in females.
Describe purine catabolism.
Purine is down into urate
Urate is relatively ____ . It circulates in blood streams at a concentration close to its ______ of ______ . It is constantly on the brink of ________ out and forming ____ _________ which are the aetiology of gout.
Urate is relatively insoluble. It circulates in blood streams at a concentration close to its limit of solubility. It is constantly on the brink of precipitating out and form uric acid crystals which are the aetiology of gout.
What are the normal plasma concentrations of monosodium urate?
Men 0.12 - 0.42 mmol/l
Women 0.12 - 0.36 mmol/l
What does solubility of urate depend on?
Temperature and pH.
Solubility at 37C = 0.40 mmol/l
At 30C = 0.27 mmol/l
Lower pH - solubility decreases
Cooler temperatures - solubility decreases
This may be why the first MTP joint is the first to be affected - cooler temperature on the extremities
Describe renal urate handling.
Uric acid is reabsorbed and re-excreted at the PCT → 90% gets reabsorbed
What is the FEUA?
Fractional Excretion of Uric Acid - approximately 10%.
90% is reabsorbed which keeps the uric acid levels in circulation high and close to its limit of solubility
What are the two main ways of purine synthesis?
- De novo synthesis - this is metabolically hard work, insufficient in terms of energy use
- Salvage pathway - highly energy efficient. Recycles purines. Vast majority of purine synthesis via salvage pathway.
Which tissue does the de novo purine pathway dominate?
Bone marrow
What is the rate-limiting step in de novo purine synthesis? What are the positive and negative feedback mechanisms of this rate-limiting step?
The reaction catalysed by PPAT enzyme is the rate-limiting step.
The outputs of the enzyme PPAT are AMP and GMP which exert a negative feedback on PPAT.
If PRPP levels increase this provides positive feedback on PPAT.
What is the main enzyme in the purine salvage pathway?
HGPRT (hypoxanthine-guanine-phosphoribosyltransferase)
What does HGPRT do?
Salvages partially-catabolised purines and converts them back into subtrates for purine synthesis
What is Lesch-Nyhan syndrome? What is its pattern of inheritance?
- Complete HGPRT deficiency
- It is an X-linked disease
- No HGPRT means you cannot do the salvage pathway of purine metabolism.
What are the clinical features of Lesch-Nyhan syndrome?
- Normal at birth
- Developmental delay apparent at 6-12 months
- Hyperuricaemia
- Choreiform movements (1 year)
- Spasticity, mental retardation
- Self mutilation (85%) aged 1-16
How many causes of hyperuricaemia be divided?
- Increased urate production
- Decreased urate excretion
Each of these can be divided into primary and secondary causes
What are some causes of decreased urate excretion?
- FJHN
- Chronic renal failure
- Bartters syndrome
- Saturnine gout (lead poisoning)
- Thiazides.
What crystals are found in Gout?
Monosodium urate crystals
What are other names of acute and chronic gout?
Acute = podagra
Chronic = tophaceous
What is the prevalence of gout in males and females?
Males 0.5 - 3%
Females 0.1 - 0.6%
Most common in post pubertal males and post menopausal females
Describe the pathophysiology of gout.
When the limit of solubility drops below the prevailing concentration, precipitation occurs forming needle-shaped crystals which are powerful inflammatory stimuli for neutrophils and macrophages. These set up an intense immune reaction in the synovial of the joint.
In chronic gout (tophaceous) you get cumulative deposition of uric acid in ______ ______. These can be _________ (next to joints such as in the fingers). Classically tophi deposits are found in the ___ ______. It looks like hard cheese.
In chronic gout (tophaceous) you get cumulative deposition of uric acid in soft tissue. These can be periarticular (next to joints such as in the fingers). Classically tophi deposits are found in the ear lobe. It looks like hard cheese.
What are the clinical features of acute gout?
- Rapid build up of ‘exquiste’ pain
- Affected joint red, hot and swollen
- 1st MTP joint first site in 50%
- This joint is involved in 90% overall
What are the 2 treatment pathways in gout?
- Reducing inflammation in acute attack
- Reducing blood urate levels
What should you NOT do in management of acute gout?
Do not try to lower plasma urate levels in acute gout attacks. Paradoxically, acutely changing plasma urate levels can lead to further precipitation of crystals.
What is the management of acute gout?
Main aim is to reduce inflammation.
- NSAIDS (diclofenac)
- Colchicine - inhibits polymerisation of tubulin. This inhibits microtubule assembly. Microtubules are needed for mitosis and motility of neutrophils. Decreased microtubule assembly means fewer neutrophils moving int the joint and reacting with crystals to set off and inflammatory reaction.
- Glucocorticoids - can massively decrease inflammation and may be injected into the joint or given systemically as prednisolone tables.
Once an acute attack is over, hyperuricaemia may be managed. How is hyperuricaemia managed?
Management of chronic gout:
- Drink a lot of water
- Reverse factors putting up urate e.g. stop diuretics
- Reduce synthesis with allopurinol (xanthine oxidase inhibitor)
- Increase renal excretion with uricosurics - probenecid
What is important contra-indication for allopurinol?
- Interacts with azathioprine, making it more toxic on bone marrow.
- Azathioprine is metabolised to mercaptopurine and then to thioinosinate which interferes with purine metabolism
- Allopurinol makes the mercaptopurine last longer
How is gout diagnosed?
- Tap effusion of joint
- View effusion under polarised light
- Use a red filter
What do you expect to see under polarised light microscopy with monosodium urate monohydrate crystals?
Urate crystals are negatively birefringent needle-shaped crystals. Negatively birefringent waves show up as blue perpendicular to the compensator filter axis and yellow parallel to the filter axis.
What do you expect to see under polarised light microscopy with pyrophosphate crystals?
Pyrophosphate crystals are positively birefringent rhomboid shaped crystals. They are blue parallel to the axis of the compensator filter and yellow perpendicular to the filter axis.
In what sort of patients does pseudogout occur in?
Patients with osteoarthritis. It is self limiting 1 - 3 weeks.
What sort of crystals are found in pseudogout?
Pyrophosphate
What joints are affected in pseudogout?
Joints all around the body. Typically it affects the knee.
