Chem Path 1 - Gout Flashcards

1
Q

What are the three main purines?

A

Adenosine

Guanine

Inosine

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2
Q

List three roles of purines.

A

Genetic code

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

Energy transfer (e.g. ATP)

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3
Q

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

A

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

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4
Q

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

A

Uricase is inactive

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5
Q

Why are men more susceptible to gout than women?

A

They have higher average urate plasma concentrations

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6
Q

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

A

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)

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7
Q

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

A

pH

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8
Q

Describe how the kidneys handle urate

A

The proximal convoluted tubule reabsorbs and secretes urate

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9
Q

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

A

10%

This is fractional excretion of uric acid (FEUA)

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10
Q

What is inosinic acid (IMP)?

A

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

Also a product of de novo purine synthesis

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11
Q

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

A

De novo synthesis

Salvage pathway (PREDOMINANT)

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12
Q

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

A

Metabolically demanding and inefficient

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

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13
Q

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

A

PAT

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14
Q

Describe the inhibitory and stimulatory controls on this enzyme.

A

AMP and GMP negatively regulate the activity of PAT

PPRP positively regulates the activity of PAT

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15
Q

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

A

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

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16
Q

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

A

Lesch-Nyhan syndrome

17
Q

Describe the inheritance pattern of Lesch-Nyhan syndrome

A

X-linked recessive

18
Q

Outline the clinical features of Lesch-Nyhan syndrome.

A

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)

19
Q

Describe the biochemical basis of Lesch-Nyhan syndrome

A

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)

20
Q

What are the two mechanisms of hyperuricaemia? List some examples

A

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)

21
Q

What are the two types of gout?

A

Acute (podagra)

Chronic (tophaceous)

22
Q

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

A

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

23
Q

What is birefringence?

A

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

24
Q

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

A

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

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

25
Q

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

A

NSAIDs

Colchicine

Glucocorticoids

26
Q

Describe the mechanism of colchicine.

A

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)

27
Q

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

A

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)

28
Q

Which drug is contraindicated with allopurinol?

A

Azathioprine

29
Q

Describe the interaction between allopurinol and azathioprine.

A

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

30
Q

What underlying condition is pseudogout often associated with?

A

Osteoarthritis