ChemPath: Hyperuricaemia and Gout Flashcards
(36 cards)
What are purines and name the 3 purines?
Ubiquitous Biomolecules
Adenosine, Guanosine and Inosine
What are the 3 important biological roles purines?
Genetic code A & G
Second messengers for hormone action in the form of cAMP and cGMP
Energy transfer/stores as ATP and GTP
What is the prevalence of gout?
3% of males have gout sometime in life. Lower prevalence in females due to lower plasma concs of urate.
Describe purine catabolism.
Humans don’t have uricase
What is the difference between human and cow purine metabolism?
Cows (and other animals) have enzyme Uricase which converts urate to allantoin which is highly soluble and freely excreted in the urine.
Homosapiens have an inactive mutation of uricase.
Urate is relatively insoluble.
Urate is relatively _______ . It circulates in blood streams at a concentration close to its ______ of _______ . It is constantly on the brink of ________ out and forming ______ ______ _________ which are the aetiology of gout.
Urate is relatively insoluble. It circulates in blood streams at a concentration close to it limit of solubility. It is constantly on the brink of precipitating out and form uric acid crystals which are the aetiology of gout.
What are the normal plasma concentrations of monosodium urate?
Men 0.12 - 0.42 mmol/l
Women 0.12 - 0.36 mmol/l
What does solubility of urate depend on?
Temperature and pH.
Solubility at 37oC = 0.40 mmol/l At 30oC = 0.27 mmol/l
Lower pH –> solubility decreases
Cooler temperatures –> solubility decreases
This may be why the first MTP joint is the first to be affected - cooler temperature on the extremities
What is FEUA, and what is the FEUA of uric acid?
Fractional Excretion of Uric Acid is about 10%.
Meaning 10% excreted from kidneys, 90% is reabsorbed
Compare and contrast the 2 main methods of purine synthesis
De novo synthesis - this is metabolically hard work, insufficient in terms of energy use. Only dominates in bone marow
Salvage pathway - highly energy efficient. Recycles purines. Vast majority of purine synthesis via salvage pathway. This pathway dominates
Which tissue does the de novo purine pathway dominate?
Bone marrow
What is the rate-limiting step in de novo purine synthesis? What are the positive and negative feedback mechanisms of this rate-limiting step?
The reaction catalysed by PAT enzyme is the rate-limiting step.
The outputs of the enzyme PAT are AMP and GMP which exert a negative feedback on PAT.
If PRPP levels increase this provides positive feedback on PAT.
What is the main enzyme in the purine salvage pathway & what does it do?
HGPRT or HPRT
Used to recycle hypoxanthine and guanine by bringing them back to the metabolic pathway of IMP and GMP
What is Lesch-Nyhan syndrome? What does it result in?
Complete HGPRT deficiency. It is an X-linked disease.
No HGPRT means you cannot do the salvage pathway of purine metabolism.
Results in INCREASED URATE PRODUCTION
What are the characteristics of Lesch-Nyhan syndrome?
- Normal at birth
- Developmental delay apparent at 6-12 months
- Hyperuricaemia
- Choreiform movements (1 year)
- Spasticity, mental retardation
- Self mutilation (85%) aged 1-16
Describe the pathology of Lesch-Nyhan syndrome.
HGPRT is missing so no guanine or hypoxanthine can be recycled back to GMP and IMP respectively.
Lack of negative feedback from GMP and IMP on PAT means the de novo pathway goes into overdrive → lots of IMP → catabolised into lots of urate
PRRP also builds up which has a positive feedback effect on PAT
How many causes of hyperuricaemia be divided?
- Increased urate production
- Decreased urate excretion
Each of these can be divided into primary and secondary causes. Secondary increased urate causes are due to conditions where there is so much cell division/turnover that you overload the body’s ability to excrete urate.
What are some causes of decreased urate excretion?
Chronic renal failure
Barrter’s syndrome
Down’s syndrome
Thiazide diuretics.
In purine metabolism:
- The salvage pathway predominates over de-novo synthesis in most tissues
- Xanthine oxidase oxidises xanthine to uric acid
- HPRT is deficient in Lesch-Nyhan disease
- PAT (PRPP Amino Transferase) is the rate limiting enzyme
- PAT is under –ve feedback control from AMP and GMP
- All of the above
- All of the above
What crystals are found in Gout?
Monosodium urate crystals
What are other names of acute and chronic gout?
Acute = Podagra
Chronic = Tophaceous
What is the prevalence of gout in males and females?
Males 0.5 - 3%
Females 0.1 - 0.6%
Most common in post pubertal males and post menopausal females
Describe the pathology of gout.
When the limit of solubility drops below the prevailing concentration, precipitation occurs forming needle-shaped crystals which are powerful inflammatory stimuli for neutrophils and macrophages. These set up an intense immune reaction in the synovial of the joint.
In chronic gout (tophaceous) you get cumulative deposition of uric acid in ______ ______. These can be _________ (next to joints such as in the fingers). Classically tophi deposits are found in the ___ ______. It looks like hard cheese.
In chronic gout (tophaceous) you get cumulative deposition of uric acid in soft tissue. These can be periarticular (next to joints such as in the fingers). Classically tophi deposits are found in the ear lobe. It looks like hard cheese.
