Chemical Pathology: Uric Acid Metabolism Flashcards
Give the 3 main forms of purines
Adenylic acid, Inosinic acid, Guanylic acid
Briefly outline purine catabolism
Inosinic acid > Hypo-xanthine >* Xanthine >* Urate (Excreted by kidneys). *By Xanthine Oxidase
Outline the pathophysiology of Gout
- Excess plasma urate causes precipitation in the extremities (Hyperuricaemia).
- Crystals form in the joints causing intense pain and inflammation (Crystal arthropathy)
- 1st metatarsal phalangeal joint most commonly affected.
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-Excess plasma monosodium urate causes precipitation in the extremities (Hyperuricaemia). -Crystals form in the joints causing intense pain and inflammation (Crystal arthropathy) -1st metatarsal phalangeal joint most commonly affected (big toe joint).
Outline the renal excretion of urate
-It is reabsorbed then secreted (believed to be due to antioxidant effect) -Fractional excretion of uric acid (FEUA) ~10%
Summarise the synthesis of purines
- 2 main pathways:
- De novo pathway:
- Purine formed from scratch.
- Main enzyme: PAT (Phosphoribosyl Pyrophosphate AmidoTransferase)
-Salvage pathway:
- Recycling from hypoxanthine and guanine.
- Main enzyme: HPRT (Hypoxanthine Guanine Phosphoribosyl transferase/ aka HGPRT)
In what tissue does the de novo pathway of purine synthesis predominate?
-The bone marrow: High cell turnover
What is the rate limiting step in de novo purine synthesis?
- PPRP to Inosinic acid,
- By enzyme PAT
(Phosphoribosyl Pyrophosphate AmidoTransferase)
What are the main features of Lesh Nyhan Syndrome?
- X-linked, absolute HPRT deficiency
- Developmental delays at 6-12 months.
- Hyperuricaemia
- Choreiform movements (repetitive, jerky, involuntary movement).
- Self-mutilation
Outline the pathophysiology of Lesh Nyhan Syndrome
- ↓ HPRT > ↓ Guanylic acid and ↓ Inosinic acid > reduced -ve feedback of de novo synthesis pathway
- ↓ HPRT > ↑PPRP > +ve feedback of de novo pathway
- These two effects lead to increased serum urate (Hyperuricaemia)
What is the main function of the PAT enzyme?
-Converts PPRP (phosphoribosyl pyrophosphate) to Inosinic acid precursor
What is the main function of HPRT?
- Converts guanine to guanylic acid
- Converts hypoxanthine to inosinic acid.
Give 3 causes of Hyperuricaemia due to increased urate production
- Primary causes:
- Lesh-Nyhan syndrome,
- Partial HPRT deficiency
- Secondary causes:
- Myoproliferative disorders
- lymphoproliferative disorders
- ie anything that causes increased cell turnover.
Give 3 causes of hypouricaemia due to decreased urate excretion
-Primary: FJHN (Familial Juvenile Hypouricaemic Nephropathy) -Secondary: CKD, Barter’s syndrome, Lead poisoning, thiazide diuretic use
Outline the clinical features of Gout
-Acute gout features: -Rapid build up of pain in the joints -Red, hot, swollen joints (Most likely 1st metatarsal phalangeal joint/ big toe joint).
Describe the management of acute gout
-Main principle: reduce inflammation -NSAIDS -Colchicine (Inhibits polymeristation of tubulin and therefore reduces neutrophil motility, therefore reducing inflammation) -Glucocorticoids (Massively powerful anti-inflammatory) -Do not try to modify plasma urate concentration.
