ChemPath 1S: Uric Acid Metabolism Flashcards

1
Q

Name the purines

A
  • Adenosine
  • Guanosine
  • Inosine
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2
Q

What do the purines act as?

A
  • Genetic code markers (A & G)
  • 2nd messengers for hormones (e.g. cAMP)
  • Energy transfer (e.g. ATP)
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3
Q

What are the steps in purine catabolism i.e. breakdown and which enzymes are involved in each step?

A

Purines

→ hypo-xanthine (Xanthine Oxidase / XO)

→ Xanthine (XO)

→ Urate (Uricase)

Allantoin

N.B uricase is not present in humans, hence urate circulates in bloodstream

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4
Q

What are the features of allantoin?

A
  • highly soluble
  • freely excreted in urine

N.B. enzyme catabolising urate into allantoin (uricase) is not present in humans, hence allantoin is not present in human bloodstream or urine

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5
Q

What are the Monosodium Urate (MSU) plasma concentrations in men and women?

A
  • Men = 0.12 - 0.42mmol/L
  • Women = 0.12 - 0.36mmol/L

lower concentrations in women!

As temperature goes up, solubility (and thus, concentration) goes up

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6
Q

What proportion of urate is excreted by the kidneys? What happens to the rest?

A
  • Fractional Excretion of Uric Acid (FEUA) ~10% from kidneys
  • (90% of urate is reabsorbed)
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7
Q

What are the 2 ways of synthesising purines?

A
  • de novo synthesis
  • salvage pathway
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8
Q

Summarise the de novo synthesis of purines

A

green box = de novo synthesis of purines

N.B. guanylic acid = GMP, adenylic acid = AMP

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9
Q

Summarise the salvage pathway of purine synthesis

A

blue box curvy upward arrows = salvage pathway of purines

i.e. recycling purines using breakdown products

N.B. guanylic acid = GMP, adenylic acid = AMP

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10
Q

Summarise the features of the de novo synthesis of purines

A
  • inefficient
  • only done when high demand
  • PAT enzyme is rate-limiting step
  • Only dominant in the bone marrow, salvage pathway dominates in every other cell in the body
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11
Q

Summarise the features of the salvage pathway synthesis of purines

A
  • highly efficient
  • predominant pathway for purine synthesis
  • H(G)PRT is the main enzyme involved in this
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12
Q

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

A

PAT is the rate limiting enzyme

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13
Q

Summarise the components of the salvage pathway in purine synthesis

A

N.B. guanylic acid = GMP, adenylic acid = AMP, inosinic acid = IMP

These are all converted to guanine, adenosine and insosine respectively

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14
Q

What is Lesch Nyhan syndrome?

A

COMPLETE HGPRT Deficiency

N.B. HGPRT = Hypoxanthine-Guanine Phosphoibosyltransferase

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15
Q

What is the pattern of inheritance of Lesch Nyhan syndrome?

A

X linked recessive (predominantly affects males)

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16
Q

What are the signs and symptoms of Lesch Nyhan syndrome?

A

NORMAL AT BIRTH!

Symptoms:

  • Developmental delay (6months)
  • Choreiform movements (1yr)
  • Spasticity, mental retardation
  • Self-mutilation (lips and finger biting) (85%)(1-16yr)
  • symptoms of gout

Signs:

  • hyperuricaemia
17
Q

What is the aetiology of Lesch Nyhan syndrome?

A

Complete HPRT deficinecy

  • HPRT is usually used to recycle hypoxanthine and guanine back into DNA synthesis
  • Hence, lack of this enzyme → less production of IMP and GMP from hypoxanthine and guanine respectively
  • → lack of IMP and GMP causes less feedback inhibition of PAT enzyme in de novo synthesis of purines pathway (dotted lines)
  • → cells produce IMP along de novo pathway uncontrolled (producing IMP/inosinic acid just under green box)
  • → IMP is shunted down the catabolic pathway (blue box)
  • → uncontrolled breakdown of IMP into uric acid/urate
  • PPRP also builds up (next to HPRT upwards arrow blue box) → driving further positive feedback of PAT
18
Q

What are the causes of hyperuricaemia?

A
19
Q

What is the cause of gout?

A

brought about by build-up of MSU crystals

20
Q

What are the 2 presentations of gout?

A
  • Acute (Podagra)
  • Chronic (Tophaceous)
21
Q

What is the epidemiology of gout?

A
  • Male (0.5-3% prevalence) post-pubertal
  • Female (0.1-0.6% prevalence) post-menopausal
22
Q

Summarise the presentation of acute gout?

A
  • Rapid build-up of pain → red, hot and swollen joint
  • 1st MTP joint is the first affected in 50% (Podagra) → MTP joint affected in 90% of all cases
23
Q

What is the acute Mx of gout?

A

Aim of ACUTE Mx = reducing inflammation [do NOT attempt to reduce plasma urate concentration]

  • NSAIDs (do not give if CKD is the cause of gout)
  • Glucocorticoids
  • Colchicine (inhibit microtubule assembly in neutrophils by inhibiting tuberculin)
    • Inhibits mitosis and so reduces cell turnover
    • Reduces neutrophil motility so less invasion and reaction with uric acid
24
Q

What is the non-acute/interval Mx of gout?

A

Aim = Manage hyperuricaemia – NON-ACUTE / INTERVAL

  • Hydrate
  • Allopurinol
    • (reduce synthesis; ok in CKD)
  • Probenecid
    • (increase urate excretion; only give if GFR >50)
25
Q

Describe the Allopurinol-Azathioprine interaction

A
  • Azathioprine → mercatopurine → thioinosinate
    • This interferes with purine metabolism
    • Allopurinol makes mercatopurine last longer
  • NEVER give someone allopurinol if they’re on azathioprine or vice versa
26
Q

How is gout diagnosed?

A

Tap effusion → view under polarised light with red filter

27
Q

What is seen in gout in tap effusion?

A
  • MSU crystals (monosodium urate monohydrate)
  • Needle-shaped,
  • Negatively birefringent
28
Q

What is seen in psuedogout in tap effusion?

A
  • Pyrophosphate crystals,
  • Rhombus-shaped,
  • Positively birefringent

Occurs in those with osteoarthritis

29
Q

Tap effusion, what is the diagnosis?

A
  1. crystals are needle shaped, so already know that it’s gout
  2. Negative birefringence seen
  • black and yellow arrows are direction of axis of the red compensator
  • crystals appear yellow in same direction of arrow & blue perpendicular to arrow
30
Q

Tap effusion, what is the diagnosis?

A
  1. crystals are rhombus shaped, so we already know that it is pseudogout
  2. POSITIVE birefringence seen
  • black and yellow arrows are direction of axis of the red compensator
  • crystals appear blue in same direction of arrow & yellow perpendicular to arrow