Hyperuricaemis And Purine Turnover Flashcards
Biological roles or ubiquitous purines
Genetic codes Energy metabolism Enzyme co factors Extracellular message Intracellular message
Ubiquitous purines
Nucleobases-> adenine, guanine
Nucleosides-> Nucleobase and ribose/deoxyribose -> ‘osides’
Nucleotides-> nucleoside and phosphate-> AMP,ADP,ATP,cAMP etc
Nuclei acids-> nucleotide polymers-> RNA and DNA
Sources of purines
Endogenous synthesis-> energetically expensive-> tissues with high cellular turnover
Dietary intake-> very limited
Purine salvage/recycling-> main source
Purine biosynthesis
Precursors-> amino acids
Produces nucleotides
Majority in liver, also brain
Ribose 5-phosphate-> ATP/PRPP synthase-> PRPP
PRPP+glut amine-> phosphoribosylamine first committed step
Phosphoribosylamine is converted to inosine monophosphate->
Adenosine/guanine mono-phosphate-> phosphorylated with 5NT-> adenosine/guanosine
Adenosine -> phosphorylated with PNP-> adenine
Or with ADA-> inosine
Guanosine-> phosphorylated with 5HT-> guanine
Inosine-> PNP-> hydroxyxanthine
Hydroxyxanthine/guanine-> XO-> xanthine1-> XO-> uric acid
Purine salvage
Using hypoxanthine phosphoribosyltransferase HPRT
Recovers nucleotides from nucleobases
eg adenine to adenosine monophosphate
Hypoxanthine-> inosine monophosphate and phosphorinosyl pyrophosphat
Guanine-> guanine 5 monophosphate and pyro phosphate
In between stages require PRPP
Key enzymes
5NT-> 5’nucleotidase-> hydrolysed nucleotides to nucleosides
ADA-> adenosine deaminase-> produces inosine from adenosine
PNP-> purine nucleoside phosphorylase-> hydrolysed nucleosides into nucleobases
XO-> xanthine oxidase-> produces uric acid from purines
HPRT
Uric acid
End product of purine catabolism via XO
>70% excreted by kidney, remainder metabolised by commensal bacteria in the GI tract
Non primates have uricase-> uric acid to allantoin
Water soluble anti oxidant-> preferential binding of hydroxyl and hypochlorus acid radicals
Net production is by coronary vasculature and lungs
Body levels effected by-> diet, age, sex
Plasma urate levels
Adult male-> 281+-41mmol/l
Adult female-> 222+- 42
Children-> 1 dayr up to 310
-> 7 days up to 140
Urinary urate levels
Adult males <1.5
Causes of hyperuricaemia
Excessive production -> idiopathic gout, myeloproliferative disease, malignancy, tumour lysis, alcohol, genetic defects
Excessive intake
Defective excretion-> idiopathic gout, renal failure, drugs, organic acids, low urine volume, genetic defects
Pathophysiology of gout
Precipitation of crystals of mono sodium urate mono hydrate
Joints-> acute arthritis
Subcutaneously-> tophi-> bulges under skin
Don’t know the cause
Local inflammation-> cytokines and lysosomal enzymes
Male to female 7:1
3 per 100 75% male over 65
The higher your uric acid levels the higher the prevelance of gout
Clinical features of gout
Age of onset-> 45-50 most common More common in males Joints most commonly effected-> 1st metatarsal, ankle, knee Acute attack-> pre existing crystals Age of onset-> slow crystal growth?
Symptoms
Exquisite pain and tenderness Sudden onset, often at night Redness, desquamation Naturally resolves in 1-3 weeks Isolated attack in 5-10% Unpredictable time between attacks Many progress to chronic tophaceous gout
Treatment of gout
Most people with hyperuricaemia remain asymptomatic Conservative treatment-> weight reduction, low purine diet, alcohol reduction Consider drug treatment if: Serum urate >700mmol/l >2 attacks per year Radiological evidence of joint damage Tophi are present Renal dysfunction
Anti hyperuricaemia drugs
Xanthine oxidase inhibitors -> allopurinol, febuxostat
-> may precipitate an acute attack-> give anti inflams to cover this
Uricosuric drugs-> probeneciol, contraindicated in impaired renal function
Anti- inflams-> idomethacin, colchicine
