Urate Metabolism and Hyperuricaemia

Question 1

Describe the basic catabolism of purines (iosinic acid)

Answer 1

Iosinic Acid

Hypo-Xanthine

Xanthine (xanthine oxidase)

Urate (xanthine oxidase)

• Allantoin (uricase)
• This step does not exist in humans

Question 2

Describe the solubility of urate, and the concentrations at which it circulates the blood.

Answer 2

Urate is less soluble than allantoin, and travels at the following concentrations:

• Men: 0.12 - 0.40 mmol/L
• Women: 0.12 - 0.36 mmol/L

Urate is more soluble at higher temperatures.

Question 3

Describe the renal handling of urate

Answer 3

Urate is freely filtered at the glomerulus and is then both reabsorbed and excreted throughout the nephron.

By the time urine is excreted, 10% of the filtered urate is excreted (Fractional Excretion of Uric Acid)

Question 4

Describe, in simple terms, the different aspects of the purine metabolism pathway

Answer 4

There are two pathways:

De Novo Pathway

• Requires a lot of energy
• Is limited by the PAT enzyme
• Has feedback inhibition by AMP and GMP
• Has feedback activation by PRPP

Salvage Pathway

• Requires far less energy
• Predominates as the pathway of choice in most cells
• Powered by the HPRT/HGPRT enzyme

Question 5

Describe an inborn error of purine metabolism, and its clinical features.

Answer 5

Complete HGPRT deficiency - Lesch-Nyhan Syndrome

• X-linked disease
• 1:40,000 live births

Clinical features:

• Normal at birth
• Developmental delay at 6 months
• Hyperuricaemic
• Choreiform movements at 1 year
• Spasticity and mental retardation
• Self-mutilation (85%) between 1-6 years

Question 6

How does an HPRT/HGPRT deficiency affect urate?

Answer 6

This inhibits the salvage pathway, which reduced the feedback inhibition of the De Novo pathway (with no AMP or GMP, PAT is not inhibited)

Question 7

Describe how causes of hyperuricaemia can be classified

Answer 7

Increased production:

Primary
- HPRT/HGPRT deficiency

Secondary (increased cell turnover)

• Myeloproliferative disorders
• Lymphoproliferative disorders
• Carcinoma
• Psoriasis

Decreased Excretion

Primary
- Familial juvenile hyperuricaemic nephropathy (FJHN)

Secondary

• Down’s Syndrome
• Bartter’s Syndrome
• CKD
• Lead poisoning
• Thiazide diuretics and Aspirin

Question 8

What is gout? What is the epidemiology surrounding it

Answer 8

A crystal arthropathy, caused by deposition of monosodium urate crystals in joints. It can be acute (podagra) or chronic (tophaceous).

It affects men at a rate of 0.5-3% and women at a rate of 0.1-0.6%

Question 9

Describe the clinical features of gout

Answer 9

Acute:

• Rapid pain
• Usually the first metatarso-phalyngeal joint
• Swollen, red joint

Chronic:
- Deposition at interphalangeal joints or at ear lobe

Question 10

Describe the management of gout

Answer 10

Acute:

• NSAIDs
• Colchicine
• Glucocorticoids
• DO NOT ATTEMPT TO MODIFY URATE

Chronic:

• Drink plenty of water
• Reverse factors increasing urate (e.g. diuretics)
• Allopurinol
• Uricosurics (e.g. probenecid)
• DO NOT PRESCRIBE ALLOPURINOL WITH AZATHIOPRINE

Question 11

How is gout diagnosed?

Answer 11

Usually a clinical history and examination. But, if in doubt:

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

Look for BIREFRINGENCE

Positive birefringence will look BLUE, parallel to the polarised light.
Negative birefringence will look YELLOW parallel to polarised light.

Gout (monosodium urate crystals) are negatively birefringent.

Question 12

What is pseudogout?

Answer 12

This is caused by pyrophosphate crystals.

It is associated with osteoarthritis and is usually self-limiting within 1-3 weeks.

Pyrophosphate crystals are positively birefringent.