PBL: Gout

  • By: Terri
  • Date: November 5, 2010
  • Time to read: 5 min.


  • 43 y/o lady
  • Outpatient department
  • pain, swelling and limitation of movement in her right knee
  • awakened from sleep at night due to severe pain
    • paroxysmal nocturnal
  • Aggravating factor
    • high protein meal – red meat, liver, kidney
    • Extending to her ankle and foot

  • Pic: swelling of right foot
  • In the past weeks
    • frequency and severity of painful episodes increased
    • involving whole foot and akle
  • referred to rheumatologist
  • Urinalysis
    • uric acid increased
    • presence of mono-sodium urate crystals
    • serum uric acid level increased

  • Radiograph (metatarsal & phalanges)
    • loss of continuity of bone
      • destruction
    • soft tissue shadowing around 1st metatarsal & phalanges
    • hyperdense part at medial 1st metatarsal
      • cortical thickening


  • Trauma
  • Arthrritis
  • Rheumatism
  • Nephropathy (uric acid increase)
  • Gout

Final diagnosis

  • Gout


Extra learning issues:

1) Gout

Definition: Disorder of uric acid metabolism that can lead to deposition of monosodium urate (MSU) crystals in soft tissue

Clinical features

  • Recurrent episodes of debilitating joint inflammation
    • untreated –> joint destruction, renal damage
  • Early gout – 1-2 joints involved
    • smaller, lower extremity joints
      • Podagra (1st metatarsophalangeal joint) initial joint manifestation in 50% of acses
    • Erythema, swollen
  • Becomes more polyarticular with time
    • more frequent, lasts longer, less intense
    • change to upper extremity joints later on
  • Can cause inflammation in other synovial based structures
    • bursae, tendon
  • Urate crystals in soft tissues – lumps/nodules
    • classically along helix of ear
    • fingers, toes, olecronon bursae
  • Nodules may mimic rheumatoid nodule
    • should suspect gout if rheumatoid factor is –ve & if there is drainage from nodule


  • MSU crystals are normally coated with serum proteins (apolipoprotein E or B)
    • which inhibits binding of MSU crystals to cell receptors
  • Gout happens when
    • there is release of uncoated crystals (due to dissolution) because of changing of serum urate levels
    • precipitation of crystals in a supersaturated microenvironment
      • release of urate due to cellular damage
  • These naked crystals then interact with intracellular & surface receptors of local dendritic cells & macrophages
    • activate innate immune system

Eventhough urate crystals is a prerequisite for gouty attack (deposited in the soft tissues & synovial tissues), but there might not be joint inflammation as there usually is. Because, these urate crystals can also be gound in the synovial fluid, which is not sufficient to cause flares of gouty arthritis.

However, these features can subside in an acute gout attack when the damaged neutrophils are cleared, the urate crystals are recoated and due to the production of anti-inflammatory cytokines.

Risk factors:

  • family history
  • women
    • age at onset due to oestrogen depletion (uricosuric effect)
  • cyclosporin A
    • cause accelerated form of gout (esp if receiving diuretics)
  • diuretics
  • dietary (increased levels of serum acid)
    • beer/liquor
    • food with high purine content (liver)
  • trauma, haemorrhage, dehydration
  • use of medications that elevate levels of uric acid
  • also from decreased levels of serum uric acid
    • allopurinol, uricosurics
  • renal stones
  • renal disease
    • hypertension
    • diabetes
  • lead intoxication
    • damage the renal tubules
  • medication of peptic ulcer disease, renal disease

Lab studies

    • Synovial fluid aspiration
      • identify crystals
        • needle shaped
        • differentiate from pseudogout
          • no pointed ends
          • birefringent –ve
      • diagnostic!
    • Serum uric acid
      • not diagnostic
      • may be normal at the time of attack
    • Uric acid (24 hour urine sample)
      • more than 800mg of uric acid in 24 hours on a regular diet
        • require allopurinol
      • more than 1100 mg in 24 hours
        • close renal function monitoring because of risk of stones & urate nephropathy
    • Blood chemistry
    • CBC count
      • WBC elevated
    • Lipids
      • hypertriglyceridemic & LDL
    • Urinalysis
      • risk of stones – history of hematuria
    • Imaging studies
      • Radiography
        • soft tissue swelling
        • not diagnostic
        • crystal tophi calcify – hyperdense!
        • erosions
    • Histologic
      • MSU dissolves in formalin
      • Alcohol fixed tissue is best for identification of urate crystals


  • Treat acute attact
  • Provide prophylaxis to prevent acute flares
  • Lowering excess stores of urate
  • Diet
  • Surgical care
  • Increase activity
  • Medication
    • NSAIDS/painkillers (acute)
    • Corticosteroids
      • contraindicated with NSAIDs
    • Contraceptives
      • increase oestrogen
    • Colchicine
      • nausea & vomiting
    • Probenecid, allopurinol
    • Uricase
    • Uricosuric agents
    • Xanthine oxidase inhibitors
    • ACe, fenofibrate
      • for heart patients

2) Purine metabolism

  • Read from semester 1 physiology – Genetics

Denovo biosynthesis of nucleotides

  • pentose required by nucleotides are synthesized by the pentose phosphate pathway

Synthesis of purine bases

  • atoms in the purine ring are contributed by
    • amino acid
      • glutamine
      • glycine
      • aspartate
    • carbon dioxide
    • formyl-tetrahydrofolate (formyl-THF)

Synthesis of pyrimidine bases

  • Atoms in the pyrimidine ring are contributed by:
    • Amino acid
      • glutamine
      • aspartate
    • carbon dioxide

Salvage pathways

  • This pathway allows undegraded purine & pyrimidine from diet/from normal turnover of cellular nucleic acid, to be salvaged and reutilized by the body to form nucleotides.
    • results in energy saving for cells
  • A critical step in the salvage pathway of purines is catalysed by the enzyme Hypoxanthine Guanine Phosphoribosyltransferase (HGPRT)

Catabolism of nucleotides

  • Degradation of nucleotides involves sequential removal of phosphate groups and pentose sugar
  • Finally, excess purines and pyrimidines that cannot be utilized through salvage pathways are degraded

Degradation of purines

*refer diagram in foundation 1 notes

  • Degradation of guanine produces xanthine
  • Degradation of adenine produces hypoxanthine
    • which is oxidised to xanthine by xanthine oxidase
  • Xanthine is oxidised to uric acid by xanthine oxidase
    • uric acid is secreted in the urine

Disorders of purine nucleotide metabolism

  • Gout
    • caused by
      • increased conversion of purine bases to uric acid
      • decreased excretion of uric acid by kidney
    • uric acid which is very insoluble, accumulates. Resulting in the precipitation of sodium urate in the joints
    • Treatment
      • allopurinol (chemically modified form of xanthine)
        • which inhibits xanthine oxidase and prevents hypoxanthine and xanthine from being converted to uric acid
        • binds to xanthine oxidase
  • Lesch Nyhan syndrome
    • caused by deficiency of the enzyme HGPRT
    • Purine bases cannot be salvaged
      • instead purines are degraded, forming excessive amount of uric acid
    • Associated with gout, increased sodium urate, mental retardation and self-mutilation

3) Allopurinol

Drug used primarily to treat hyperuricemia  and it’s complication (gout)

Mechanism of action

Allopurinol is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an enzyme inhibitor, inhibiting xanthine oxidase.Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine resulting in the production of uric acid, the product of human purine metabolism. In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine, which are converted to closely related purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides causes feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol therefore decreases both uric acid formation and purine synthesis.


Allopurinol is rapidly metabolized by its target, xanthine oxidase, to its active metabolite oxypurinol, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxypurinol within two hours of oral administration, whereas oxypurinol is slowly excreted by the kidneys over 18-30 hours. For this reason, oxypurinol is believed to be responsible for the majority of allopurinol’s effect.

4) Differentiate the different types of arthritis

  • Rheumatoid arthritis
    • asymmetrical
  • Osteoarthritis
    • no acute attacks, progressive (swelling)
  1. One aspect of gout which is overlooked in this lecture is that most gout flares are initiated during sleep. The sleep connection has been known at least since Dr. Thomas Sydenham wrote about it in 1683. It is a very important clue to the pathogenesis of gout.
    Most gout flares are a direct result of sleep apnea, and overcoming the sleep apnea can cure the gout. The hypoxemia of sleep apnea has three effects which lead to an overnight gout flare in short order. Effect #1 is cellular catabolism in which ATP degradation is accelerated, culminating irreversibly in the cellular generation of excess uric acid fed into the blood, faster than any food would cause. Effect #2 is hypercapnia and acidosis, so that the blood can hold less uric acid in solution. Effect #3 is a long term acceleration of the deterioration of the kidneys’ glomerular filtration rate so that removal of uric acid from the blood is slowed. Thus, with sleep apnea there is an abrupt increase in the influx of uric acid in the blood, slowed efflux, and reduced storage capacity — perfect storm conditions for monosodium urate precipitation. Furthermore, after awakening and normal breathing is restored, the first two effects dissipate so that a blood test taken during waking hours misses their peaks.
    Gout experts should feel embarrassed for having missed this connection for so long, especially since gout has been reported to have so many of the same comorbidities already known to be consequences of long-term untreated sleep apnea (eg., cardiovascular diseases, diabetes, kidney disease.) One of the first steps for treating gout should be screening and diagnosis for sleep apnea, followed by treatment of the sleep apnea where indicated. I know from my own experience and the experiences of others that overcoming sleep apnea can prevent additional inflammatory gout flares immediately. More importantly, gout is an early warning of sleep apnea, which when heeded can lead to the early treatment of sleep apnea, thereby greatly reducing the risk for the development of sleep apnea’s life-threatening consequences.

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