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Kat's Pathology > Uric Acid Metabolism > Flashcards

Uric Acid Metabolism Flashcards

1
Q

What are purines?

A

They are ubiquitous molecules.

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2
Q

What 3 molecules are purines?

A

Adenosine. Guanosine. Inosine.

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3
Q

What are the three biological roles of purine?

A

They form part of the genetic code (A and G). They act as second messengers for hormone action (e.g. cAMP). They are involved in energy transfer (e.g. ATP).

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4
Q

What process underlies gout.

A

Purine catabolism.

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5
Q

What are the steps of purine catabolism?

A

purines –> hypo-xanthine hypo-xanthine –> xanthene (xanthine oxidase) xanthene –> urate (Xanthine oxidase) Urate –> allantoin (urlease not present in humans)

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6
Q

What percentage of men are affected by gout?

A

3%

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7
Q

What is the main pathology of gout?

A

Build up of urate, which is insoluble.

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8
Q

What is the end product of purine metabolism in humans?

A

Urate.

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9
Q

Why is gout so common?

A

Urate circulates in the blood stream at concentrations close to its limit of solubility.

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10
Q

What is the plasma concentration of monosodium urate in men?

A

0.12-0.42mmol/L

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11
Q

What is the plasma concentration of monosodium urate in women?

A

0.12-0.36mmol/L

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12
Q

What effect does temperature have on urate?

A

More soluble at higher temperatures.

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13
Q

What affects the solubility of urate? (2)

A

Temperature. pH.

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14
Q

What effect will an acidic pH have on urate solubility?

A

Solubility falls with increasing acidity.

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15
Q

What is the most commonly affected joint in gout?

A

First metatarsophalangeal joint of the foot.

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16
Q

What organ is responsible for the excretion of urate?

A

Tubules of the kidneys.

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17
Q

What happens to urate as it travels along the kidney tubule?

A

It is freely filtered at the glomerulus. It is both reabsorbed and secreted as it travels along the proximal convoluted tubule.

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18
Q

Approximately what percentage of urate is reabsorbed by the kidney?

A

90%

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19
Q

What do we call the percentage of urate that has been excreted into the collecting duct of the kidney?

A

Fractional Excretion of Uric Acid (FEUA).

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20
Q

What are the two metabolic pathways used to create purines in the body. (2)

A

De Novo creation. Salvage Pathway.

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21
Q

What is the preferred route of purine metabolism in the body?

A

Salvage pathway.

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22
Q

What organ uses the de novo pathway for purine synthesis?

A

Bone marrow.

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23
Q

What is the rate limiting step of purine synthesis?

A

PAT. This enzyme is under feedback inhibition control from AMP and GMP. (the more AMP and GMP, the less active PAT becomes) This enzyme is also subject to feedforward control from PPRP (the more PPRP, the more active PAT becomes)

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24
Q

What enzyme brings partially catabolised purines back up the pathway for synthesis.

A

HPRT (also called HGPRT)

25
Q

What is the primary pathology in Lesch Nyhan Syndrome?

A

Complete HGPRT deficiency. Almost completely removes the negative feedback mechanism on PAT. This sends the de novo purine metabolic pathway into overdrive, over-producing purines, which are catabolised and accumulate as urate at the end of the pathway (in the blood). With no activation of the salvage pathway, PPRP also builds up, driving PAT even more.

26
Q

What is the incidence of Leisch Nyhan Syndrome?

A

1/40,000 live births.

27
Q

What is the inheritance of Leishc Nyhan Syndrome?

A

X-linked.

28
Q

What are the main clinical features of Leisch Nyhan Syndrome? (6)

A

Normal at birth. Developmental delay apparent by 6 months old. Hyperuricaemia (very rare in children). Choreiform movements by 1 year (basal ganglia dysfunction). Spasticity, mental retardation. Self-mutilation apparent in 85% by aged 1-16 (lip biting and finger-biting).

29
Q

What are the two main mechanisms of hyperuricaemia.

A

Increased urate production. Decreased urate excretion.

30
Q

What are the two main mechanisms of hypouricaemia.

A

Decreased urate production. Increased urate excretion.

31
Q

What are some primary causes of increased urate production? (5)

A

Lesch Nyham Syndrome. Partial HRPT deficiency. Glycogen Storage Disorders. Fructose Intolerance. PRPP Synthetase over Activity.

32
Q

What are some secondary causes of increased urate production? (6)

A

Myeloproliferative disorders. Lymphoproliferative disorders. Carcinomatosis. Chronic Haemolytic anaemia. Gaucher’s disease. Severe psoriasis.

33
Q

What is a primary cause of decreased urate excretion?

A

FJHN.

34
Q

What are some secondary causes of decreased urate excretion? (6)

A

CKD. Bartter’s Syndrome. Down’s Syndrome. Saturnine Gout (Pb). Diuretics. Aspirin.

35
Q

What are some causes of decrease urate production? (3)

A

Xanthine oxidase deficiency. Severe hepatic disease. Appopurinol.

36
Q

What are some causes of increased urate excretion? (4)

A

Idiopathic hypouricaemia. Fanconi Syndrome. Uricosuric drugs. URATI inactivation.

37
Q

What is gout.

A

Accumulation of monosodium urate crystals in tissues and joints.

38
Q

What is the prevalence of gout. (2)

A

Men: 0.5-3% Women: 0.1-0.6%

39
Q

What two age groups are most often affected by gout.

A

Post-pubertal males. Post-menopausal females.

40
Q

What are the main clinical features of gout? (2)

A

Rapid build up of pain. Affected joint is red, hot and swollen.

41
Q

What word do patients often use to describe the pain caused by gout?

A

Exquisite.

42
Q

In what percentage of cases is the 1st MTP joint affected in gout?

A

Involved in over 90% of cases.

43
Q

How often is the 1st MTP joint affected first in gout?

A

50%

44
Q

What is the diagnostic test for gout?

A

Polarised light microscopy.

45
Q

What steps are involved in the diagnosis of gout? (3)

A

Tap effusion of affected joint. View under polarised light using a red filter.

46
Q

What filter must be used when undergoing microscopy for gout?

A

Red filter in a polarised light microscope.

47
Q

What are you looking for microscopically to diagnose gout?

A

Negatively birefringent urate crystals.

48
Q

What do urate crystals look like under polarised light microscopy?

A

Blue and perpendicular. Negatively birefringent.

49
Q

What are the two main steps in managing gout? (2)

A

Reducing inflammation during an acute attack.

Managing hyperuricaemia.

50
Q

How do you manage an acute attack of gout? (3)

A

NSAIDs.

Colchicine.

Glucocorticoids.

51
Q

What is the mechanism of action of colchecine.

A

Inhibits polymerisation of tubulin. Tubulin is involved in cell division.

Given short term, it reduces the motility of neutrophils, so prevents the inflammatory reaction to the urate crystals in the joint.

52
Q

What must never be done during an acute attack of gout.

A

Never attempt to modify plasma urate concentraion.

53
Q

How do you manage hyperuricaemia (gout) long-term? (4)

A

Drink plenty of water.

Reverse factors that increase urate (e.g. beer, offle)

Reduce synthesis with allopurinol.

Increase renal excretion with probenecid.

54
Q

What is the main drug-drug interaction that must be considered with allopurinol.

A

Interacts with azathioprine, increasing bone marrow toxicity.

Azathioprine is a pro-drug, which is metabolised to mercaptopurine and then to thionosinate which intereferes with purine metabolism.

Mercaptopurine is metabolised by xanthine oxidase.

Allopurinol makes the levels of mercaptopurine last linger, increasing the levels of urate in the system.

55
Q

What is pseudogout.

A

Caused by an accumulation of pyrophospate crystals in the tissues and joints.

56
Q

What other condition is pseudogout associated with.

A

osteoarthritis.

57
Q

How long does a pseudogout attack last?

A

1-3 weeks (self-limiting)

58
Q

How do pyrophosphate (pseudogout) crystals differ to urate (gout) cystals under polarised light?

A

Positively birefringent and blue when parallel to the filter.

Kat's Pathology (105 decks)

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