ChemPath: Hyperuricaemia and Gout

Question 1

What are purines?

Answer 1

Ubiquitous Biomolecules:

Adenosine, Guanosine and Inosine

Question 2

What are the 3 important biological roles purines?

Answer 2

• Genetic code A & G
• Second messengers for hormone action in the form of cAMP and cGMP
• Energy transfer/stores as ATP and GTP

Question 3

What is the prevalence of gout?

Answer 3

3% of males have gout sometime in life. Lower prevalence in females.

Question 4

Describe purine catabolism.

Answer 4

Purine is down into urate

Question 5

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.

Answer 5

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.

Question 6

What are the normal plasma concentrations of monosodium urate?

Answer 6

Men 0.12 - 0.42 mmol/l

Women 0.12 - 0.36 mmol/l

Question 7

What does solubility of urate depend on?

Answer 7

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

Question 8

Describe renal urate handling.

Answer 8

Uric acid is reabsorbed and re-excreted at the PCT → 90% gets reabsorbed

Question 9

What is the FEUA?

Answer 9

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

Question 10

What are the two main ways of purine synthesis?

Answer 10

• 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.

Question 11

Which tissue does the de novo purine pathway dominate?

Answer 11

Bone marrow

Question 12

What is the rate-limiting step in de novo purine synthesis? What are the positive and negative feedback mechanisms of this rate-limiting step?

Answer 12

The reaction catalysed by PAT enzyme is the rate-limiting step.

The outputs of the enzyme PAT are AMP and GMP which exert a negative feedback on PAT.

If PRPP levels increase this provides positive feedback on PAT.

Question 13

What is the main enzyme in the purine salvage pathway?

Answer 13

HGPRT (hypoxanthine-guanine-phosphoribosyltransferase)

Question 14

What does HGPRT do?

Answer 14

Salvages partially-catabolised purines and converts them back into subtrates for purine synthesis

Question 15

What is Lesch-Nyhan syndrome? What is its pattern of inheritance?

Answer 15

• Complete HGPRT deficiency
• It is an X-linked disease
• No HGPRT means you cannot do the salvage pathway of purine metabolism.

Question 16

What are the clinical features of Lesch-Nyhan syndrome?

Answer 16

• Normal at birth
• Developmental delay apparent at 6-12 months
• Hyperuricaemia
• Choreiform movements (1 year)
• Spasticity, mental retardation
• Self mutilation (85%) aged 1-16

Question 17

How many causes of hyperuricaemia be divided?

Answer 17

1. Increased urate production
2. Decreased urate excretion

Each of these can be divided into primary and secondary causes

Question 18

What are some causes of decreased urate excretion?

Answer 18

• FJHN
• Chronic renal failure
• Bartters syndrome
• Saturnine gout (lead poisoning)
• Thiazides.

Question 19

What crystals are found in Gout?

Answer 19

Monosodium urate crystals

Question 20

What are other names of acute and chronic gout?

Answer 20

Acute = podagra

Chronic = tophaceous

Question 21

What is the prevalence of gout in males and females?

Answer 21

Males 0.5 - 3%

Females 0.1 - 0.6%

Most common in post pubertal males and post menopausal females

Question 22

Describe the pathophysiology of gout.

Answer 22

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.

Question 23

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.

Answer 23

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.

Question 24

What are the clinical features of acute gout?

Answer 24

• 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

Question 25

What are the 2 treatment pathways in gout?

Answer 25

• Reducing inflammation in acute attack
• Reducing blood urate levels

Question 26

What should you NOT do in management of acute gout?

Answer 26

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.

Question 27

What is the management of acute gout?

Answer 27

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.

Question 28

Once an acute attack is over, hyperuricaemia may be managed. How is hyperuricaemia managed?

Answer 28

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

Question 29

What is important contra-indication for allopurinol?

Answer 29

• 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

Question 30

How is gout diagnosed?

Answer 30

• Tap effusion of joint
• View effusion under polarised light
• Use a red filter

Question 31

What do you expect to see under polarised light microscopy with monosodium urate monohydrate crystals?

Answer 31

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.

Question 32

What do you expect to see under polarised light microscopy with pyrophosphate crystals?

Answer 32

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.

Question 33

In what sort of patients does pseudogout occur in?

Answer 33

Patients with osteoarthritis. It is self limiting 1 - 3 weeks.

Question 34

What sort of crystals are found in pseudogout?

Answer 34

Pyrophosphate

Question 35

What joints are affected in pseudogout?

Answer 35

Joints all around the body. Typically it affects the knee.