CHEMPATH: Uric acid metabolism Flashcards
Name the three purines involved in uric acid metabolism. What is their role?
Purines = Adenosine, Guanosine & Inosine
- Genetic code A and G
- 2nd messengers for hormone e.g. cAMP
- Energy transfer (e.g. ATP)
How are inosinic acids/purines converted to urate? (What is the evolutionary basis around this?)
- Purines –>
- hypo-xanthine – Xanthine Oxidase (XO)–>
- Xanthine –(XO)–>
- Urate –(Uricase)–>
- Allantoin
Evolution: uricase has been knocked out in humans and some other mammals so instead of allantoin, we have to excrete urate which is relatively insoluble and it circulates in bloodstream at close to its limit of solubility (at brink of precipitating out and causing gout).
What are the normal MSU concentrations in males and females? What factors affect MSU levels?
MSU - monosodium urate
- Men = 0.12-0.42mmol/L
- Women = 0.12-0.36mmol/L *
Factors:
- As temperature falls, MSU solubility falls (so peripheries most affected)
- Also depends on pH: at more acidic conditions solubility of MSU falls
What is the FEUA of uric acid? Where is it most reabsorbed?
Fractional Excretion of Uric Acid (FEUA)*
~10% from kidneys (90% of urate is reabsorbed) - mostly in PCT
* this is the net result of filtration, reabsorption and excretion. High absorption suggests it may have important antioxidant functions.
What are the two methods of purine production? Compare their efficiency and enzymes involved.
- De novo synthesis – inefficient and only done when high demand (_PAT_ is rate-limiting step). Only dominant in the bone marrow; everywhere else, the salvage synthesis dominates
- Salvage synthesis – highly efficient and the predominant pathway (_HPRT_ is an important enzyme for recycling hypoxanthine and guanine to start of pathway)
What exerts negative feedback on PAT in the de novo pathway?
ANP and GNP
What does the direction of the arrows indicate?
- Any arrows going towards the central intermediary, INP/ANP/GNP, indicate purine synthesis.
- Any arrows going down from ANP, INP and GNP show purine breakdown.
What is the function of HPRT(aka HGPRT)?
Main enzyme of the salvage pathway
HPRT (a.k.a. HGPRT) = hypoxanthine guanine phosphoribosyl transferase
Its function is to collect partially catabolised purine and bring them back to the start of the pathway
Defects or deficiency can cause primary hyperuricaemia due to increased production of urate.
What is the function of PAT?
Rate limiting step in the de novo pathway of purine sythesis
PAT = phosphoribosyl pyrophosphate synthetase
Under negative feedback from ANP and GNP (coming from INP) which are the ultimate outputs.
Under positive feedback from PPRP; the more is available the higher the activity of PAT
List some examples of conditions causing disorders of urate homeostasis.
Hypouricaemic conditions have very little clinical impact.
Hyperuricaemic conditions predispose to gout so are more important:
Myeoproliferative disorders etc, have high cell turnover and breakdown so a lot of purine catabolism is occurring so urate builds up
FJHN (familial juvenile hyperuricaemic nephropathy) is caused by a mutation in a gene
Batter’s is a tubular disorder, Saturnine gout is lead poisoning, diuretis cause hyperuricaemia as well as hyperglycaemia, hypercalcaemia and hyponatreaemia.
What are the signs and symptoms of Lesch Nyhan syndrome and when do they occur?
Signs/symptoms within a few months:
- Normal at birth
- Developmental delay (6/12)
- Hyperuricaemia (and develop gout)
- Choreiform movements (1yr)
- Spasticity (UMN), mental retardation
- Self-mutilation (85%) (1-16yr)
How common is Lesch Nyhan syndrome? What is the epidemiology and pathophysiology?
1 in 40,000 affected so RARE
X-linked (male-dominant) –
Complete* deficiency of active HPGRT so salvage pathway not active
Signs/symptoms within a few months but asymptomatic at birth
*NB also possible to have partial deficiency but this would not be called Lesch Nyhan syndrome.
Why can you get hyperuricaemia in Down’s syndrome?
Caused by reduced excretion of uric acid
Why may a HPGRT deficiency cause an increase in PAT activity?
Because PPRP is at the same level as HGPRT in the pathway so if this is not available then PPRP is not being used up. PPRP therefore instead causes positive feedback to be exerted on PAT
All of the above
What is the cause of gout? What are the two types?
Excess monosodium urate crystals
- Podagra = acute - usually affects feet
- Tophaceous = chronic - there is constant deposition of uric acid crystals in soft tissues e.g. para-articular or earlobes.
How common is gout in males/females? What other prediposing factors exist?
- Male (0.5-3% prevalence) and only after puberty
- Female (0.1-0.6% prevalence) and commonly post-menopausal
What are the features of acute gout? What joint is most affected?
- Rapid build-up of pain
- Red, hot and swollen joint
- MOST AFFECTED: 1st MTP joint is the first affected in 50% (Podagra) (MTP joint affected in 90% of all cases)
What is the basic of management of acute and non-acute/interval hyperuricaemia?
Acute = ONLY therapy to reduce inflammation
Chronic = manage high uric acid levels and prevent further episodes
What is the medical management of acute gout? What is the MOA of each?
-
NSAIDs
- Do not give if CKD is the cause of gout
-
Glucocorticoids
- Injection or oral
-
Colchicine
- Inhibit microtubule assembly in neutrophils by inhibiting tuberculin
- Reduces neutrophil motility so less invasion and reaction with uric acid
- Inhibits mitosis and so reduces cell turnover
What is the mangement of chronic gout?
- Hydrate
-
Reduce predisposing factors
- e.g. reduce alcohol especially beer and port which is high in dietary purines
-
Allopurinol
- Reduce synthesis by inhibiting XO reduing uric acid production; ok in CKD
-
Probenecid
- Increase tubular excretion of urate/increase FEUA; only give if GFR >50
What is the MOA of
- Colchicine
- Allopurinol
- Probenecid
Colchicine - reduced neutrophil motility to site of gout so reducing inflammation (via microtubule assembly inhibition)
Allopurinol - xanthine oxidase inhibitor
Probenecid - increases tubular excretion of urate/increases FEUA
What caution must be taken when prescribing allopurinol?
NEVER give someone azathioprine if they are on allopurinol (and vice-versa)
- Azathioprine (AZA) often used in IBD etc, dampens down cell turnover in BM to immunosuppress
- BUT allopurinol when given alongside AZA can cause bone marrow shut down and neutropenia because…
- AZA is a prodrug which –> mercaptopurine** –> thioinosinate (active form which intervenes with purine synthesis etc)
- Mercaptopurine is a purine + if you are giving allopurinol (a XO inhibitor) it will keep building up
- So mercaptopurine will reach toxic levels quickly
- So you will be making a therapeutic dose into toxic dose
2 and 5
What is the primary way of diagnosing gout?
Usually take a history, examination and measure uric acid levels, which should be enough for diagnosis but if not…
Tap effusion of affected area + view under
(1)polarised light with
(2) red filter
What is seen in gout vs pseudogout when investigation sample from tap effusion under polarised light and with a red filter
SHAPE:
- MSU = needle-shaped
- Pyrophosphate = rhomboid shaped
BIREFRINGENCE:
- MSU = needle + negative
- Pyrophosphate = positive + pyrophosphate
Summarise the principles of birefringence.
- NEGATIVELY birefringent crystals will appear BLUE and at 90 degrees to the axis of the red compensator
- POSITIVELY birefringent crystals will appear BLUE in the axis of the red compensator
Summary:
- Look at the direction of the axis of the filter
- Negatively birefringent crystals will be blue perpendicular to this
Why is this negatively birefringent?
Because blue at 90degrees to the axis and pale yellow parallel to the axis.
Why is this positively birefringent?
Because it is blue parallel to the angle of the axis of the red compensator
The cells are neutrophils and so you can see that the blue crystal inside this.
The crystal is needle shaped and so you know its urate.
It is also blue at 90 degrees to the compensator angle therefore negatively birefringent.
Here the shape is not a needle and it is positively birefringent (because blue parallel to the direction of the compensator
