2.06 Uric Acid Metabolism And Gout

Front 1

What is gout?

Back 1

A crystal arthropathy due to elevated serum uric acid levels.

Front 2

What is uric acid derived from?

Back 2

Breakdown of purine nucleosides (A,G and hypoxanthine) and nucleotides (ATP, ADP, GTP).
Found within us and sourced from diet in meats and beer.

Front 3

What processes can increase uric acid levels?

Back 3

Increase in purines (high dietary intake of purines, tumour lysis syndrome) acceleration of purine breakdown (via xantine oxidase), active de novo synthesis pathway (extra PRPP increasing purine and it breakdown, as in Lesch Nyhan Syndrome), slow/inactive purine nucleotide synthesis salvage pathway (no HGRP for this pathway in Lesch Nyhan Syndrome).

Front 4

How do you treat acute gout attacks?

Back 4

Suppress inflammation with NSAIDs, Cochicine (inhibits phagocytosis) and COX-2 selective inhibitors (celecoxib).

Lowering hyperuricaemia will not help acute gout, and may make it worse.

Front 5

How do you treat gout when the patient is not in an acute attack?

Back 5

Prevent attacks and/or treat the tophi.

This is done by:
- reducing hyperuricemia through inhibitng xanthine oxidase (xanthine/hypoxanthine->uric acid enzyme, drug e.g. hypoxanthine analogue allopurinol which is converted to aloxanthine and the xanthine oxidase blocker febuxostat)
- promoting uric acid excretion (renal reabsorption drug e.g. uricosurics like benzbromarone, probenicid)
- using uricase to convert uric acid into the soluble allantoin to deplete uric acid and dissolve tophi (expensive).

Front 6

What are the possible benefits of having high uric acid levels, as a species?

Back 6

Uric acid scavenges ROS, promotes salt retention in low salt conditions.

Front 7

Describe the De Novo Synthesis Pathway in purine metabolism.

Back 7

Uses ribose (with amino acids and folate, enhanced by PRPP) to create nucleotides (with DNA and RNA), which go on to become purine bases and then uric acid.

An increase in this pathway may lead to hyperurcaemia downstream.

Front 8

Describe the Salvage Pathway in purine metabolism.

Back 8

Uses purine bases to reform nucleotides (using PRPP and the enzyme HGPRT) instead of synthesising uric acid.

An increase in this pathway will see uric acid levels decrease in the blood.

Front 9

How does Lesch Nyhan Syndrome effect uric acid synthesis?

Back 9

An x-linked condition where there is no functional HGPRT. This prevents the salvage pathway from converting purines and PRPP into nucleotides, and results in an increase in xanthine and subsequent uric acid.

The result is increased PRPP whish is positive feedback to increase De Novo Synthesis Pathway, with no salvaging hyperuricaemia develops, and gout, and serious CNS effects of mental and growth retardation and spasticity (less neurotransmitters made from the salvage pathway).

Front 10

How does ethanol effect uric acid production?

Back 10

Beer is high in purines and can contribute to hyperuricaemia.

Ethanol is broken down into acetaldehyde and acetate, and eventually Acetyl CoA, or it eventually can become AMP, a nucleotide which can be broken down into uric acid, leading to possible hyperuricaemia.

Front 11

What are the side effects of using benzbromarone or probenecid?

Back 11

These drugs enhance renal excretion of uric acid and as such increase its concentration within the tubules, promoting the formation of uric acid stones.

Front 12

What are the most and least effective gout treatments for reducing tophi?

Back 12

Allopurinol is the least effective, as it acts on xanthine not uric acid.?

Uricase acts directly on the monosodium urate crystals in the tophi, converting them into the water soluble allontoin.

Front 13

What is tumour lysis syndrome?

Back 13

It is a common side effect of using chemotherapy in treating tumours. It results from the breakdown of huge numbers of mitotically active cells, leading to an increase in intracellular contents throughout the body.