gout

see also:

• colchicine
• non-steroidal anti-inflammatory drugs (NSAIDs)
• uricosuric agents
• hyperuricaemia
• allopurinol
• urolithiasis / renal stones / renal calculi

• Described by Hippocrates
• Podagra was the foot goddess, a bad tempered virgin, who attacked victims after they overindulged.
• Autumn crocus used to Rx arthritis in 6th Century
• For many centuries, thought to be confined to men who had indulged in dietary or sexual excess.
• Benjamin Franklin's advice:
  • “Be temperate in wine, eating, girls & sloth or the gout will seize you & plague you both”
• Sydenham wrote the classic description of the disease in 1684.
• colchicine isolated 1820
• Probenecid developed to inhibit penicillin excretion in 1951

• up to 21% of the general population and 25% of hospitalized patients are estimated to have asymptomatic hyperuricemia
  • uric acid levels can be elevated 10 to 15 years before clinical manifestations of gout
  • hyperuricaemiais asymptomatic in 90% to 95% of people
  • hyperuricemia is particularly high in Pacific islanders
• gout occurs in men 4x the rate for women
• uric acid stones comprise 5% to 10% of all urinary stones and are most likely to form if acidic urine, hypovolaemia, and hyperuricosuria
• hyperuricaemia may also cause hypertension via activation of the renin-angiotensin system, oxidative stress, endothelial inflammation, endothelin-1 activation, and nitrous oxide reduction¹⁾

• gout is deposition of uric acid crystals from a supersaturated extracellular fluid
  • an acute attack only happens when a sudden trigger (perhaps changes in the levels of metabolites, such as uric acid, hypoxanthine, adenosine, creatinine, and DL-2-aminoadipic acid) pushes an already overloaded, borderline system past the tipping point
  • risk is increased with elevated serum uric acid levels however more than half of patients with acute gout have normal serum uric acid levels ²⁾
    • only 20% of people with hyperuricaemia develop gout but the higher the level the greater the risk
    • risk of gout attacks correlates with serum uric acid levels although “healthy levels” of less than 0.42mM is not as important as whether the concentration places the patient at risk of crystal formation.
    • serum uric acid levels are dependent upon:
      • renal excretion (90% of causes of high serum uric acid levels)
        • genetic factors:
          • specific genes (such as ABCG2, SLC2A9, and SLC22A12) alter renal uric acid transport and excretes urate
        • alcohol competes with uric acid for renal excretion
        • oestrogen increases uric acid excretion
        • general renal function
          • decreased renal excretion with:
            • dehydration, alcohol
            • AKI, chronic renal failure, acidosis
            • sarcoidosis, hyperparathyroidism, hypothyroidism, Down's syndrome, Bartter syndrome
            • lead, beryllium, ?metal fume fever
            • medications
              • thiazides and proximal loop diuretics - net increase in relative risk of gout by diuretics is almost 80%
              • nephrotoxins
      • over-production of uric acid by the body
        • high cell turnover
          • myeloproliferative or lymphoproliferative diseases, polycythaemia rubra vera, pagets, psoriasis
        • high cell breakdown
          • Acute tumour lysis syndrome, haemolysis, rhabdomyolysis, extreme exercise, chemotherapy
      • high levels of dietary purines
        • account for 10-20% of total body uric acid but binges can be the tipping point factor
      • high levels of dietary fructose
        • hepatic metabolism of fructose through the aldolase reductase pathway produces uric acid
    • pre-existing uric acid crystal deposition becomes a nidus for further deposition

• gout is deposition of uric acid crystals from a supersaturated extracellular fluid.
• the crystals are ingested by PMNLs resulting in inflammatory reaction
• calcium channel blockers and Losartan appear to mildly reduce incidence of gout while other antihypertensives especially diuretics may increase the risk³⁾
• metabolism and immune systems developed hand-in-hand from an evolutionary and survival perspective as resisting starvation and mounting an immune response to pathogens was paramount, nutrients use the pathogen-sensing systems to trigger inflammatory responses. Most humans do not have to face food scarcity, thus, once beneficial, uric acid metabolism triggers the accumulation of fats and inflammation even without infection, a biological process driving renal impairment. A metabolomic analysis in 2023 found a characteristic metabolite profile for gout, in which 10 of 46 metabolites showed marked differences, and nearly all were related to metabolic inflammation: ⁴⁾
  • DL-2-aminoadipic acid, an intermediate lysine metabolism metabolite, plays a key role in glucose and lipid metabolism, thus, its elevated concentrations promote fat consumption. However, that damages renal function in gout patients by enhancing their metabolism
  • hypoxanthine could cause inflammation in the kidneys
  • adenosine, a purine metabolite, bound different purinergic receptors to regulate interleukin-1beta (IL-1β) secretion and played an anti-inflammatory role in gout development and remission
  • kynurenic acid (KYNA), a byproduct of the tryptophan metabolism, regulates immune system cells and several immune-mediated diseases - chronic stress or mild inflammation could promote KYNA production and immunomodulatory actions
  • they suggest changes in the levels of metabolites, such as UA, hypoxanthine, adenosine, creatinine, and DL-2-aminoadipic acid, form the basis of gout development and confirmed the significance of metabolic inflammation in gout pathogenesis. The authors found that the signaling pathways used by metabolic and traditional inflammation were relatively consistent and originated from the energy metabolism pathways finding related biomarkers in the evolutionary journey, which could help detect or prevent gout attacks

• in average adults on normal diets, ~90% is produced by the body and 10-20% is derived from dietary purines via xanthine oxidase metabolism
  • the endogenous production rate of uric acid averages about 300 to 600 mg per day (~300–400 mg from de novo purine synthesis and cell turnover)
• normally 88-93% of all renal filtered uric acid is reabsorbed back into the bloodstream
  • hyper-excretion of uric acid from the kidneys risks urate stones
• on a normal diet the 24hr urine output of uric acid in adults is 400 to 800 mg
• normal serum concentrations generally range from 3.4 to 7.2 mg/dL (0.20–0.43 mmol/L) in men and 2.4 to 6.0 mg/dL (0.14–0.36 mmol/L) in pre-menopausal women
• monosodium urate crystal deposition occurs if extracellular fluid concentrations exceed the physiologic saturation threshold is 6.0 to 7.0 mg/dL at 37°C, above which solutions risk supersaturation
• uric acid poorly crosses cell membranes hence volume of distribution (Vd) = 0.2-0.3L/lean body weight in kg = 14-21L for an average 70kg adult
• GIT bioavailability of purines is ~60%
• every 1mg of base purines yields roughly 1.2mg of uric acid
• a 300g steak plus a beer gives ~450mg purines of which ~270mg is absorbed and metabolized which gives about 324mg uric acid
• assuming 324mg uric acid is absorbed, the expected rise in serum levels would be = 324mg / 17L = 19mg/L = 1.9mg/dL
• a renal clearance of 12mL/min for uric acid with serum levels of 10mg/dL would give a uric acid excretion rate of 72mg/hr
  • assuming the kidneys need to excrete the endogenous production rate of uric acid of ~20mg/hr, this means the kidneys can excrete 52mg/hr of the dietary uric acid
  • and thus take the kidneys over 6 hours to reduce serum uric acid levels back to normal after this spike (even longer if impaired renal function, concomitant alcohol or a larger intake)

• genetic factors:
  • a genomic study published in 2024 found 377 loci and 410 genetically independent signals linked to gout and in addition, 65 loci with signals in urate but who had not reported gout ⁵⁾
  • “healthy lifestyle” may reduce risk of gout by 1/3rd ⁶⁾
• obesity or weight gain in young adulthood
• high food intake of purines
• high dietary intake of fructose
• hypertension
• diabetes
• alcohol consumption
  • high purine levels if beer
  • ethanol competes with uric acid for renal excretion
• proximal loop diuretics
• thiazide diuretics
• beta adrenergic blockers
• lead exposure
• GTN infusions (? due to alcohol in mixture)
• post-menopausal women (oestrogens increase renal excretion of uric acid)
• renal insufficiency
• polycythaemia rubra vera

• these are completely metabolized by xanthine oxidase in the gut or in the liver to harmful uric acid and high levels may result in gout
• they only account for 10-20% of total body uric acid so other factors are required to be also present to cause gout - a binge may precipitate an attack but eliminating these from diet may not reduce attacks - moderation is the key
• very high purine foods include:
  • offal (liver, kidneys, sweetbreads, heart, and brains)
  • certain seafoods - anchovies, sardines, herring, mackerel, mussels, scallops, and gamey fish like trout
  • game meats - venison, pheasant, wild boar, and rabbit
  • yeast extracts and yeast-based drinks - Vegemite (23-90mg per 5g serve), Marmite, and brewer's yeast (500ml beer: lager 20-50mg, ale 30-90mg, stout/craft 75-140mg)
    • dried yeast has exceptionally high concentrations of hypoxanthine (often exceeding 440 µg/g) alongside adenine and guanine
• high purine foods include:
  • other meats and seafood eg. 300g steak = 330-400mg purines; 150g roast chicken= 165-210g; 150g barramundi = 135-165mg; 150g salmon = 150-195mg; for gout patients 100g serves of salmon or barramundi are recommended once or twice a week - minimise red meats and poultry;
  • certain vegetables - asparagus, spinach, mushrooms, green peas, and cauliflower
  • legumes - lentils, chickpeas, beans, and soybeans
• NB. plant based purines excluding yeast are generally low in the troublesome hypoxanthine and the dietary fiber and slowed digestion with microbial action results in a much lower and slower absorption of uric acid and very little absorption of hypoxanthine (which otherwise will be converted to uric acid by xanthine oxidase in the liver) hence these are unlikely to cause gout

• stress of illness or surgery
• alcohol or dietary excess
• organ transplant patients taking cyclosporine
• diuretics

• occurs most commonly in middle-aged men & postmenopausal women
• increased serum uric acid levels are usually present for 20yrs before the 1st attack however, over 50% have normal serum uric acid levels at the time of an acute attack
• gouty attacks most often affect the 1st MTP jt (up to 75%), the tarsal joints, ankle & knee
• 40% have polyarticular involvement
• rarely, it may involve the spine and tophi may mimic an epidural abscess (half are lumbar, quarter each in Tx and Cx spine) and ~20% have fevers, and may cause radicular pain or acute spinal cord compression⁷⁾
• pain is excruciating at the onset & some cannot tolerate even the weight of a sheet on the joint
• fever may be present but serum uric acid level may be normal during acute attack
• without Rx, self-limiting lasting several days to weeks & followed by an intercritical period of wks-yrs.
• subsequent attacks get closer together, involve more jts & last longer

• an uncommon severe acute presentation of gout involving at least 5 joints and usually bilateral
• usually presents with very high C reactive protein (CRP) > 80
• may develop acute kidney injury (AKI) / acute renal failure (ARF)
• responds poorly to non-steroidal anti-inflammatory drugs (NSAIDs)
• use corticosteroids or colchicine
• may need inpatient management due to severe pain or renal issues
• https://www.jscimedcentral.com/Arthritis/arthritis-2-1024.pdf

• urolithiasis / renal stones / renal calculi
• tophi (foreign body granulomas with the crystal as the nidus)
  • form in the musculotendinous unit:
    • olecranon bursa, Achilles tendon, ulnar surface of forearm, hands, feet, toes, finger, helix of ear
• nephropathy
• bone erosions with overhanging margins
• patients with persistent urate levels > 360 micromol/L (6 mg/dL) have higher risks of heart attacks and stroke suggesting that the dose of allourinol should be considered for aiming for this response level target ⁸⁾

• is it possible that joint is infected or is joint easy to aspirate? if so, aspirate joint looking for urate crystals (must be done within 24hrs of aspirate to avoid degradation)
• otherwise treat as gout:
  • early Rx within hours is probably more important than which anti-inflammatory:
    • corticosteroids such as prednisolone 50mg/d for 5 days is as efficacious as non-steroidal anti-inflammatory drugs (NSAIDs) and has less adverse effects (ICEM2004)
    • non-steroidal anti-inflammatory drugs (NSAIDs) for 1wk after symptoms have settled if no C/I such as PU, renal/cardiac/liver failure; post-op. state, anticoagulant Rx or poorly controlled HT
    • if C/I to NSAIDS then consider either:
      • corticosteroids 
        • eg. oral prednisone 10mg bd for 3-5 days then taper
        • if cannot tolerate oral, a single IM steroid dose can be used
        • intra-articular methylprednisolone if no sepsis on aspirate eg. 40mg for knee joint 
        • low dose colchicine 0.5mg bd if healthy adult over 50kg to prevent short term recurrence
          • avoid colchicine in the elderly, weight < 50kg or severe liver or renal impairment.
    • if C/I to NSAIDs and steroids and no C/I to colchicine then:
      • colchicine if no severe liver or renal impairment:
        • low dose Rx regime: 1 mg orally initially, then 500 micrograms 1 hour later, as a single one-day course (total dose is 1.5 mg) (as per eTG 2024), OR,
        • prolonged low dose regime: 500 micrograms orally, 8- to 12-hourly until symptoms abate [maximum of 6 mg over 4 days];
        • total dose of colchicine given in an acute attack should not exceed 6 mg over 4 days
        • reduce dosage in renal impairment and avoid in severe renal impairment
    • avoid changing anti-gout Rx as any sudden change in uric acid levels (esp. a fall) will exacerbate the attack.
    • assess & Mx associated disorders of obesity, excess alcohol intake, hypertension, hyperlipidaemia & renal insufficiency.

• Rx if either frequent attacks, tophi, joint destruction, or renal stones:
  • take baseline U&E, uric acid level
  • reduce alcohol consumption to reduce risk of acute attacks as there is dose-related risk:
    • 1.36 (95% CI: 1.00 to 1.88) times higher for >1-2 alcoholic beverages/day
    • 1.51 (95% CI: 1.09 to 2.09) times higher for >2-4 alcoholic beverages/day⁹⁾
  • commence Rx to reduce uric acid levels:
    • historically, the choice of drug is allopurinol starting at 200mg/day and increasing to 600mg/day
    • assuming there is no evidence of acute gout but be aware of risks of allopurinol Rx:
      • precipitation of acute gout attack
      • rarely, a potentially fatal syndrome 1-6wks after starting Rx of:
        • exfoliative rash
        • fever
        • hepatitis
        • renal failure
        • NB. this syndrome is more likely if pre-existing renal insufficiency or concomitant diuretics
    • in 2015, a new Rx, febuxostat was introduced and trials suggest it may be more effective than allopurinol but does risk cessation due to causing abnormal LFTs, and commencement needs to be covered with NSAIDs or colchicine for 6 months as flare ups at commencement are more likely.
      • for patients with tophi, start at 40mg/d, if urate levels > 0.36mM after 2-4wks Rx, then increase to 80mg/d
    • may also consider probenecid
  • plus non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine 0.5mg bd for 6-12mths if frequent attacks
    • BUT note that NSAIDs may have very limited efficacy for prevention of attacks and has higher risk of cardiovascular issues
• Risk of no Rx:
  • further exacerbation of gouty nephropathy
  • renal stones
  • gouty arthritic attacks
  • further tophi
  • joint destruction