Chem Path 1 - Gout

Question 1

What are the three main purines?

Answer 1

Adenosine

Guanine

Inosine

Question 2

List three roles of purines.

Answer 2

Genetic code

Second messengers for hormone action (e.g. cAMP)

Energy transfer (e.g. ATP)

Question 3

Describe the pathway of purine catabolism (include the enzymes and substrate names).

Answer 3

Purines to Hypoxanthine to Xanthine to Urate to Allantoin

Conversion from hypoxanthine to urate is performed by xanthine oxidase

Conversion of urate to allantoin is performed by uricase

Question 4

What feature of the human purine catabolism pathway means that they are susceptible to a build-up of uric acid?

Answer 4

Uricase is inactive

Question 5

Why are men more susceptible to gout than women?

Answer 5

They have higher average urate plasma concentrations

Question 6

Which joint is most commonly affected by gout and why might this be?

Answer 6

1st metatarsophalangeal joint – found at the periphery of the body so is likely to be cooler (lower temperatures reduce the concentration at which urate precipitates out of solution)

Question 7

What factor, other than temperature, affects the solubility of uric acid?

Answer 7

pH

Question 8

Describe how the kidneys handle urate

Answer 8

The proximal convoluted tubule reabsorbs and secretes urate

Question 9

Roughly what proportion of filtered urate will be found in the urine? What term is used to describe this?

Answer 9

10%

This is fractional excretion of uric acid (FEUA)

Question 10

What is inosinic acid (IMP)?

Answer 10

An intermediate metabolite of AMP (adenylic acid) and GMP (guanylic acid)

Also a product of de novo purine synthesis

Question 11

What are the two methods of purine synthesis? Which is predominant in most tissues?

Answer 11

De novo synthesis

Salvage pathway (PREDOMINANT)

Question 12

Describe de novo purine synthesis. In which tissue is this dominant?

Answer 12

Metabolically demanding and inefficient

Only occurs when there is a high demand for purines (e.g. bone marrow)

Question 13

What is the rate limiting step in the de novo purine synthesis pathway?

Answer 13

PAT

Question 14

Describe the inhibitory and stimulatory controls on this enzyme.

Answer 14

AMP and GMP negatively regulate the activity of PAT

PPRP positively regulates the activity of PAT

Question 15

What is the main enzyme of the salvage pathway? Describe its role.

Answer 15

HPRT (aka HGPRT)

It mops up partially catabolised purines and brings them back up the metabolic pathway to produce IMP and GMP

NOTE: hypoxanthine to IMP; guanine to GMP

Question 16

What inborn error of purine metabolism is characterised by HPRT deficiency?

Answer 16

Lesch-Nyhan syndrome

Question 17

Describe the inheritance pattern of Lesch-Nyhan syndrome

Answer 17

X-linked recessive

Question 18

Outline the clinical features of Lesch-Nyhan syndrome.

Answer 18

Normal at birth

Developmental delay at 6 months

Hyperuricaemia

Choreiform movements at 1 year

Spasticity and mental retardation

Self-mutilation present in 85% (e.g. biting lips very hard)

Question 19

Describe the biochemical basis of Lesch-Nyhan syndrome

Answer 19

It is caused by absolute deficiency of HPRT

This reduces the production of AMP and GMP by the salvage pathway

This reduces the inhibitory effect of AMP and GMP on PAT, thereby increasing the activity of the de novo pathway

This leads to the production of vast amounts of IMP, which will be shunted down the catabolic pathway to produce urate (which accumulates)

Less conversion of guanine to GMP leads to a build-up of PPRP (which stimulates PAT)

Question 20

What are the two mechanisms of hyperuricaemia? List some examples

Answer 20

Increased urate production (e.g. rapid cells turnover in myeloproliferative diseases and psoriasis)

Decreased urate excretion (e.g. saturnine gout (caused by lead poisoning) and diuretic use)

Question 21

What are the two types of gout?

Answer 21

Acute (podagra)

Chronic (tophaceous)

Question 22

How can gout be diagnosed if there is still doubt after history, examination and measurement of uric acid levels?

Answer 22

The effusion can be tapped and viewed under polarised light using a red compensator

Question 23

What is birefringence?

Answer 23

The ability of a crystal to rotate the axis of the polarised light

NEGATIVE – appear blue at 90 degrees to the axis of the red compensator

POSITIVE – appear blue in the axis of the red compensator

Question 24

Describe how the birefringence/crystals differ between gout and pseudogout.

Answer 24

Gout – monosodium urate crystals – needle-shaped and negatively birefringent

Pseudogout – calcium pyrophosphate crystals – rhomboid-shaped and positively birefringent

Question 25

List three drug classes that are used in the acute management of gout

Answer 25

NSAIDs Colchicine Glucocorticoids

Question 26

Describe the mechanism of colchicine.

Answer 26

Inhibits the manufacture of tubulin Short-term administration of colchicine inhibits microtubule formation enough to reduce the motility of neutrophils (thereby reducing their ability to migrate to the site of inflammation)

Question 27

Describe the management of gout after the acute phase is over.

Answer 27

Encourage fluid intake Reverse factors that may increase the concentration of uric acid (e.g. stopping diuretics) Allopurinol – reduces synthesis of urate by inhibiting xanthine oxidase Probenecid – increases renal excretion of urate (increases FEUA)

Question 28

Which drug is contraindicated with allopurinol?

Answer 28

Azathioprine

Question 29

Describe the interaction between allopurinol and azathioprine.

Answer 29

Azathioprine is a pro-drug that is metabolised to mercaptopurine and thioinosate Mercaptopurine (being a purine) is metabolised by the xanthine oxidase pathway Inhibiting xanthine oxidase with allopurinol leads to a build-up of mercaptopurine resulting in bone marrow toxicity

Question 30

What underlying condition is pseudogout often associated with?

Answer 30

Osteoarthritis