Pathophysiology of uric acid and how its disregulation can lead to hyperuricemia and different gout diseases

  • Uric acid is a waste product that is produced as the final product of purine metabolism & is excreted via the urine (2/3) & GI (1/3)
    • Hyperuricemia occurs when there’s an imbalance between the production & excretion
    • Overproduction of uric acid may be a result of:
      • a large destruction of tissue nucleic acids (as a result of a myeloproliferative or lymphoproliferative disorder)
      • Deficiency in Phosphoribosyl pyrophosphate (PRPP) synthetasewhich  regulates purine metabolism
      • Deficiency in hypoxanthine-guanine phosphoribosyl transferase (HGPRT) resulting in increased uric acid production from guanine & hypoxanthine metabolism
    • Underexcretion of uric acid can result from:
      • Increased reabsorption of uric acid (primarily in the proximal tubules)–when there is Na reabsorption, there tends to be uric acid reabsorption  (ex. Dehydration)
      • Drugs can also cause it’s accumulation (FYI–diuretics, alcohol, etc)
  • Gout is caused by hyperuricemia & may result in arthritis (as a result of the buildup of urate crystals)
  • No genetic marker for gout but it’s thought that genetics & environmental factors may play a role
  • Acute gouty arthritis:  formation of urate crystals (tophi) which usually occurs when water is evacuate from the joint space faster than the urate is   (ex. Edema, trauma, drugs, EtOH, stress, etc)
    • These urate crystals get phagocytized by neutrophils leading to cell lysis and the release of inflammatory mediators

Clinical manifestations of gout / hyperuricemia

  • Hyperuricemia:  asymptomatic but when the urate concentration > 7.0 mg/dL there is an increased risk of gout
  • Acute gouty arthritis:  first attack is generally characterized by explosive, sudden, rapid surge of pain (intense inflammation; aka podagra) most commonly in the big toe
    • Areas most affected by acute gouty arthritis:  inside of feet, ankles, heels, knees, wrists, fingers, elbows
  • Chronic gouty arthritis:  most often occurs with time either in untreated acute attacks or severe acute attacks
    • Characteristics:  increased frequency of attacks, inflammation last longer, involves multiple joints, tophi become more noticeable on examination  (deformation occurs over time)
  • Uric acid nephroliathisis (kidney stones)
    • Dependent on the saturation of uric acid  (depends on the pH of the urine)
      • The more acidic the environment, the less excretion, the more urate crystals/kidney stones
    • Can lead to kidney failure

Treatment goals in managing gout

  • Acute gouty arthritis:  treat acute gout attacks, prevent future exacerbations, reduce serum uric acid levels (after 1st attack), prevent monosodium urate disposition
  • Chronic goat:
    • Goal:  prophylactic, preventative care
    • Begin treatment after the 1st attack of severe acute gout or after the first occurrence of kidney stones

Pharmacologic agents for different types of gout

  • Acute gouty arthritis:
    • NSAIDs are the mainstay of therapy for acute gout
      • All NSAIDs are equally effective & may take up to a week for complete resolution but should be continued for 24 hours after resolution
      • Precautions:  peptic ulcers/bleed, CHF, uncontrolled HTN, severe renal failure, coronary artery disease, CV risk, anticoags
      • SE:  hypersensitivity, GI, kidney, CNS, metabolic acidosis & respiratory alkalosis
    • Indomethacin (Indocin—NSAID) is FDA approved for the management of acute gouty arthritis & is the historical NSAID of choice
      • It’s as effective as colchicine
      • Preferable safety profile
    • Sulindac (max: 400 mg/day),   Naproxen (Naprosyn max:  1500 mg/day),  & Naproxen Sodium (Anaprox max:  1250 mg/day) are all also approved for acute gouty arthritis
    • Celebrex isn’t FDA approved for acute gouty arthritis (risk of CV issues) but it has been used in some patients unable to tolerate regular NSAIDs
    • Colchicine is indicated in patients who are contraindicated or have failed NSAIDs
      • Interferes with the inflammation process (decreases deposition of urate crystals into tissues) & decreases the amount of lactic acid release from leukocytes
      • Colcrys is use for both treatment & prophylaxis
        • Treatment:  1.2 mg once then 0.6 mg in one hour
        • Prophylaxis:  0.6 mg QD to BID
      • Avoid use in patients renal or hepatic dysfunction or those that are on P-gp or strong CYP3A4 inhibitors
      • Precautions:  GI tract disorders, hepatic, CV or renal disorders (drug is non-dialyzable)
      • SE:  bone marrow toxicity (suppression), neutropenia, renal dysfunction, hepatic dysfunction, tissue necrosis
    • Corticosteroids are the last resort in the management of acute gouty arthritis (only use if colchicine or NSAIDs are ineffective/CI)
      • Triamcinolone is admin’d via a shot into the joint.
      • Other FDA approved corticosteroids for gout:  cortisone, methylprednisolone, dexamethasone, prednisone
  • Chronic gouty arthritis:
    • Choice of treatment agent depends on kidney/liver function, serum uric acid level, amount of excretion in the last 24 hours
    • Xanthine oxidase inhibitors:  inhibit the conversion to uric acid  (inhibit production)
      • Allopurinol (zyloprim):  dose needs to be adjusted for renal function
        • 1st line therapy for chronic gout
        • Max dose:  800 mg/day
      • Febuxostat (uloric):  no dose adjustment is needed for renal or hepatic impairment
        • Max:  80 mg/day
      • SE:  hypersensitivity, leukopenia, GI toxicity, increased frequency & length of attacks, symptoms of CVA  & MIs, transaminase elevations
    • Uricosuric agents:  inhibit the tubular reabsorption or uric acid (increase excretion)
      • Probenecid (Benemid)
        • Max dose:  2 grams/day
      • SE:  GI irritation, hypersensitivity, skin rash, exacerbate acute gout attacks, kidney stones, interacts with ASA & NSAID excretion
        • Give these with at least 2 L of water per day to avoid kidney stones
      • Start low & go slow with these agents
    • Pegloticase (Krystexxa):  recombinant uricase (urate oxidase) drug that catalyzes the oxidation of uric acid to allantoin
      • Indicated for chronic gout refractory to conventional therapies
      • Risk of anaphylax/infusion reactions is if this drug is administered IV too quickly
      • Contraindicated in patients with a G-6-PD deficiency (risk of hemolysis)
      • May exacerbate CHF
  • Nephroliathisis (kidney stones)
    • Hydration:  should have urine volume of 2-3 L/day
    • Avoid purine rich food (protein)
    • Alkalinize the urine (take potassium citrate or potassium carbonate every day)
    • Avoid sodium to risk of hypercalcemia
    • Older ppl w/ disease states are more at risk
    • Allopurinol prevents the recurrece of gout related kidney stones  (mainstay of choice for recurrent gout-related kidney stones)
    • Acetazolamide (diamox–carbonic anhydrase inibitor) causes a rapid & effective urinary alkalinization

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