Uric Acid and Gout Flashcards
Recap basic structure of nucleotides
- Phosphate
- Pentose sugar (ribose or deoxyribose)
- Purine/ pyrimidine base
2+3 = nucleoside
Nucleobases:
- adenine, guanine (purine)
- cytosine, thymine/ uracil (pyrimidine)
Purine Metabolism: degradation, synthesis and negative feedback
Ribose 5-P –> PRPP by PRPP synthetase
PRPP activates PRPP-AT and de novo synthesis of IMP
IMP converted to GMP or AMP
GMP (nucleotide) -> guanosine (nucleoside) -> guanine (base)
IMP -> inosine -> hypoxanthine
AMP -> adenosine -> adenine or inosine
Hypoxanthine -> Xanthine by xanthine oxidase
Guanine -> Xanthine by guanase
Xanthine -> URIC ACID by xanthine oxidase
Synthesis --------------- Salvage pathway: - HGPRT (hypoxanthine guanine phosphoribosyl-transferase) converts hypoxanthine and guanine back to IMP and GMP - APRT converts adenine to AMP
Negative feedback: AMP, IMP, GMP inhibits PRPP synthetase and PRPP-AT
Urate: excreted form, balance of production and excretion, pathological effects, RR for plasma uric acid
End product of nuclease purine metabolism
Excreted as sodium urate monohydrate in alkaline conditions (low solubility, 0.57 mmol/L)
- low pH decreases solubility – increased association of uric acid
Balance:
- production: 5-6 mmol generated per day (3-4 mmol endogenous tissue breakdown/ *de novo synthesis, 1-2 mmol *dietary)
- excretion: *renal, uricolysis in GI
Pathology:
- uric acid crystals as endogenous DAMPs (damage associated molecular pattern molecules) –> innate immunity mediated inflammation with leukocytes and cytokines e.g. IL-1, IL-18
- gout
- renal failure
- kidney stones
Hyperuricaemia:
Normal = <0.52 mmol/L (male), <0.36 mmol/L (female)
Causes of hyperuricaemia: overproduction (20%)
- Increase in purine synthesis
- primary e.g. increased PRPP synthetase activity in de novo synthesis
- glycogen storage disease type I (increased ribose 5-P due to accumulation of G6P)
- HGPRT deficiency in salvage pathway (Lesch-Nyhan syndrome) - Excessive intake of purine
- food with cell nuclei e..g. meats, seafood, mushrooms, beans, peas, lentils, spinach - Alcohol
- ethanol oxidation produces ATP which is converted to AMP
- alcohol conversion to lactic acid which competes with uric acid for clearance from kidneys - Increased tissue nucleic acids
- increased cell turnover e.g. leukaemia, myeloproliferative diseases, psoriasis
- increased tissue breakdown e.g. chemotherapy, trauma, starvation
Causes of hyperuricaemia: under-excretion (80%)
Normally renal route (75%), GI (25%)
Reduced renal excretion:
- hypovolaemia/ dehydration (AKI)
- diuretics (decrease water content; compete for excretion), LOW DOSE salicylate (damage tubules)
- renal vasoconstrictors
- lactic or ketoacidaemia (acidic env increases uric acid crystallisation and acid competes for secretion at distal tubules) – e.g. alcohol, DM, starvation
- anti-TB drugs e.g. pyrazinamide, ethambutol
- chronic lead poisoning
- inherited defects
Intestinal excretion:
- degraded by bacterial uricases into ammonia and CO2
- compensatory increase if there is reduced renal excretion
Differentiation of over-production and under-excretion
Purine free diet x3 days (negate dietary 1-2 mmol of purine)
Collect 24 hr urine
==> high urate excretion >3.6 mmol/day = overproducers (because only 3-4 mmol endogenously normally)
Clinical manifestations of hyperuricaemia
Gouty arthritis, renal failure, renal stones
Gout: definition, manifestation, causes, risk factors, diagnosis
Precipitation and deposition of uric acid crystals in joints stimulating intense acute inflammatory reaction
Most commonly starting at 1st metatarsophalangeal joint (peripheral colder = lower solubility of uric acid)
- red, hot, swelling, very painful
Causes:
- can be primary (absence of acquired or monogenetic conditions) or secondary (due to increased urate production or decreased excretion)
- mostly under excretion and partial deficiency of HGPRT
Risk factors:
- male, higher social class, >45 yrs old
- metabolic syndrome - obesity, hyperTG, HT
- excessive food and alcohol intake
in children: metabolic disorders of purine, malignancies, renal failure
Diagnosis:
- absolute criterion = negatively birefringent needle shaped crystals from joint fluid (but not usually done due to invasiveness)
or
- 6 of 12 criteria: >1 attack, maximal inflammation in 1 day, mono arthritis, redness, big toe painful/ swollen, unilateral, suspected tophus, hyperuricaemia, joint fluid culture neg for org, Xray evidence of asymmetric swelling or subcortical cysts
- joint aspirate urate levels is useless (qualitative result is enough since actual levels have no correlation with severity)
Asymptomatic hyperuricaemia and normouricaemic gout
Hyperuricaemia DOES NOT MEAN GOUT
- only 5% of hyperuricaemic patients will eventually develop gout
Note (vice versa)
- 30% patients have normal urate levels during acute gouty arthritis as conc fluctuates depending on diet and excretion
Treatment of Gouty Arthritis
Anti-inflammatory drugs
- colchicine (suppress neutrophil migration)
- NSAIDs
==> painkillers, doesn’t change urate metabolism, use in ACUTE situations
(consider IL-1 antagonist if ineffective)
Xanthine oxidase inhibitor: Allopurinol
- effective in over-producers
- used together with chemotherapy for tumours
==> structural isomer of hypoxanthine preventing hypoxanthine and xanthine oxidation
Uricase/ Urate oxidase: Rasburicase
- also used in patients receiving chemotherapy with hyperUr
==> catalyses oxidation uric acid to more soluble allantoin
Uricosuric agents: probenecid, sulphinpyrazone
- effective in under-excretors
- inhibit renal tubular reabsorption to increase renal clearance
Others: diet, weight control, avoid alcohol
Allopurinol and Uricosuric agents should be avoided within first few weeks of attack because acute changes (increase or decrease) in serum urate can precipitate attacks of gout
Renal failure cause, interpretation of results, outcomes
HyperUr and Renal failure are cause and effect of each other
- uric acid crystal in collecting ducts causes obstruction and acute renal failure
HyperUr unlikely to cause renal failure if urate plasma levels <0.6 mmol/L
HyperUr of >0.7 mmol/L is unlikely due to renal failure alone (normally = have overproduction)
Outcomes:
- acute uric acid nephropathy
- nephrolithiasis (renal stones)
Urate stone: threshold of uric acid levels for formation, treatment
Urine uric acid levels >6 mmol/day
- 10% hyperUr patients
- 10% of all stones
- renal colic
Increased incidence of Ca oxalate stone and melamine stone
Tx:
- fluids
- alkalinisation of urine (K-Na-H citrate/ NaHCO3)
- diet
- allopurinol
Ix of hyperUr
FHx of gout
Clinical Hx and PE for physiological factors e.g. diet, pregnancy and pathological factors e.g. drugs, renal diseases
Laboratory:
- 24 urine for urate
- RFT
- LFT (alcohol)
- Protein electrophoresis (myeloma)
- Blood gases, anion gap (acidosis)
- Glucose, Lipids
- Lead
- CBC: haemoatological malignancies
Inborn errors of purine metabolism
Lesch-Nyhan Syndrome
- deficiency of HGPRT (decreased salvage pathway) –> overproduction of purine, uric acid and PRPP
- X-linked recessive
- mental retardation, self-mutilation
- Tx: allopurinol
Glucose-6-Phosphatase deficiency (storage disease type I)
- AR
- accumulation of G6P increasing production of ribose 5-P for purine metab
- progressive mental retardation, hepatomegaly, persistent hypoglycaemia
Aberrations in other enzymes
- APRT deficiency
- Xanthine oxidase deficiency (hypoUr)
Hypouricaemia
Very rare
Inherited e.g. defects of xanthine oxidase/ PRPP synthetase/ nucleoside phosphorylase
Systemic disease:
- Fanconi syndrome (defective proximal tubular reabsorption)
- AR defect of xanthine oxidase (XANTHINE STONE and xanthinuria)
- ECF volume expansion e.g. SIADH, pregnancy
Drugs
- prolonged treatment by allopurinol and uricase
- probenecid
