Gout and Hyperuricemia

• Gout


  Hyperuricemia, recurrent attacks of acute arthritis with monosodium urate (MSU) crystals in synovial fluid leukocytes, deposits of MSU crystals in tissues in and around joints (tophi), interstitial renal disease, and uric acid nephrolithiasis
• Hyperuricemia


  Serum uric acid level that is elevated more than two standard deviations above the population mean
• Types of hyperuricemia and gout

  • Primary
  • Secondary
• Primary hyperuricemia and gout


  Apparently result from an innate defect in purine metabolism or uric acid excretion
• Causes of primary hyperuricemia and gout


  • Uric acid overproduction
  • Impaired renal clearance of uric acid
  • Combination of overproduction and impaired clearance
• Overproducers


  Synthesize abnormally large amounts of uric acid and excrete excessive amounts
• Underexcretors


  Generally produce normal or nearly normal amounts of uric acid but excrete < 600 mg daily on a purine-restricted diet
• Causes of secondary hyperuricemia and gout

  • Hematological causes (lymphoproliferative disorders, myeloproliferative disorders, certain hemolytic anemias and hemoglobinopathies)
  • Chronic renal failure
  • Drug-induced (aspirin, other salicylates, cytotoxic drugs, diuretics, ethambutol, nicotinic acid, cyclosporine, ethanol)
  • Miscellaneous disorders (diabetic ketoacidosis, psoriasis, chronic lead poisoning)
• Asymptomatic hyperuricemia


  Elevated serum uric acid level but no signs or symptoms of urate deposition disease
• Hyperuricemia in and of itself is not believed to be a disease. There also has to be evidence of deposition of urate in the joints, soft tissues, or kidney to routinely warrant drug therapy intervention.
• Serum urate levels of up to 13 mg/dL in men and 10 mg/L in women have not been shown to cause deterioration in renal function.
• Urate lowering drug treatment for most asymptomatic patients is not required, general interventions such as encouraging maintenance of good urine output (to prevent uric acid stone formation), avoidance of high purine meats and fish, and regular medical exams to get serum urate levels and to check for clinical evidence of gout related signs.
• Uric acid formation


  1. Purines originate from dietary purine, conversion of tissue nucleic acid to purine nucleotides, and de novo synthesis of purine bases

  2. Overproduction of uric acid may result from abnormalities in enzyme systems that regulate purine metabolism

  3. Uric acid may be overproduced because of increased breakdown of tissue nucleic acids

  4. Dietary purines are insignificant in generation of hyperuricemia without some derangement in purine metabolism or elimination

  5. Two thirds of uric acid produced daily is excreted in urine, the remainder is eliminated through gastrointestinal tract

  6. Drugs that decrease renal uric acid clearance include diuretics, nicotinic acid, salicylates, ethanol, pyrazinamide, levodopa, ethambutol, cyclosporine, and cytotoxic drugs

  
• Pathophysiology of gout

  1. Deposition of urate crystals in synovial fluid results in inflammation, vasodilation, increased vascular permeability, complement activation, and chemotactic activity for polymorphonuclear leukocytes

  2. Phagocytosis of urate crystals by leukocytes results in rapid lysis of cells and discharge of proteolytic enzymes into cytoplasm

  3. Uric acid nephrolithiasis occurs in 10% to 25% of patients with gout

  4. In acute uric acid nephropathy, acute renal failure occurs because of blockage of urine flow from massive precipitation of uric acid crystals

  5. Chronic urate nephropathy is caused by long-term deposition of urate crystals in the renal parenchyma

  6. Tophi (urate deposits) are uncommon and are a late complication of hyperuricemia
• Acute gout attacks


  • Rapid onset of excruciating pain, swelling, and inflammation
  • Typically monoarticular, most often affecting the first metatarsophalangeal joint
  • Attacks commonly begin at night
  • Affected joints are erythematous, warm, and swollen
  • Fever and leukocytosis are common
  • Untreated attacks last from 3 to 14 days before spontaneous recovery
• Acute attacks may occur without provocation or be precipitated by stress, trauma, alcohol ingestion, infection, surgery, rapid lowering of serum uric acid by uric acid–lowering agents, and ingestion of drugs known to elevate serum uric acid concentrations.
• Corticosteroids


  Corticosteroid efficacy is equivalent to NSAIDs; they can be used systemically or by intra-articular (IA) injection. Systemic therapy is necessary if an attack is polyarticular.
• Prednisone or prednisolone oral dosing strategies

  1. 0.5 mg/kg daily for 5 to 10 days followed by abrupt discontinuation

  2. 0.5 mg/kg daily for 2 to 5 days followed by tapering for 7 to 10 days
• Methylprednisolone dose pack

  1. day regimen starting with 24 mg on day 1 and decreasing by 4 mg each day
• Triamcinolone acetonide

  20–40 mg given by IA injection may be used if gout is limited to one or two joints
• Methylprednisolone (a long-acting corticosteroid)


  1. Given by a single intramuscular (IM) injection followed by oral corticosteroid therapy

  2. IM corticosteroid monotherapy may be considered in patients with multiple affected joints who cannot take oral therapy
• Short-term corticosteroid use

  • Generally well tolerated
  • Use with caution in patients with diabetes, GI problems, bleeding disorders, cardiovascular disease, and psychiatric disorders
  • Avoid long-term use because of risk for osteoporosis, hypothalamic–pituitary–adrenal axis suppression, cataracts, and muscle deconditioning
• Adrenocorticotropic hormone (ACTH) gel

  40 to 80 USP units may be given IM every 6 to 8 hours for 2 or 3 days and then discontinued
• Adrenocorticotropic hormone (ACTH) gel

  • Limit use for patients with contraindications to first-line therapies (eg, heart failure, chronic renal failure, history of GI bleeding) or patients unable to take oral medications
• Colchicine


  Highly effective in relieving acute gout attacks; when it is started within the first 24 hours of onset, about two thirds of patients respond within hours
• Use colchicine only within 36 hours of attack onset because the likelihood of success decreases substantially if treatment is delayed
• Colchicine

  • Causes dose-dependent GI adverse effects (nausea, vomiting, and diarrhea)
  • Non-GI effects include neutropenia and axonal neuromyopathy, which may be worsened in patients taking other myopathic drugs (eg, statins) or in renal insufficiency
  • Do not use concurrently with P-glycoprotein or strong CYP450 3A4 inhibitors (eg, clarithromycin) because reduced biliary excretion may lead to increased plasma colchicine levels and toxicity
  • Use with caution in renal or hepatic insufficiency
• Colcrys

  • FDA-approved colchicine product available in 0.6 mg oral tablets
  • Recommended dose is 1.2 mg (two tablets) initially, followed by 0.6 mg (one tablet) 1 hour later
  • ACR gout treatment guidelines suggest that colchicine 0.6 mg once or twice daily can be started 12 hours after the initial 1.2 mg dose and continued until the attack resolves
• Patient education should address the recurrent nature of gout and the objective of each lifestyle/dietary modification and medication
• Promote weight loss

  Through caloric restriction and exercise in all patients to enhance renal urate excretion
• Alcohol restriction is important because consumption correlates with gout attacks
• ACR guidelines recommend

  • Limiting alcohol use in all gout patients
  • Avoidance of any alcohol during periods of frequent gout attacks and in patients with advanced gout under poor control
• Dietary recommendations

  • Limiting consumption of high-fructose corn syrup and purine-rich foods (organ meats and some seafood)
  • Encouraging consumption of vegetables and low-fat dairy products
• Evaluate the medication list


  For potentially unnecessary drugs that may elevate uric acid levels
• Gout is not necessarily a contraindication to use of thiazide diuretics in hypertensive patients
• Low-dose aspirin for cardiovascular prevention should be continued in patients with gout because aspirin has a negligible effect on elevating serum uric acid
• Prophylactic pharmacotherapy


  Recommended if patients have two or more attacks per year, even if serum uric acid is normal or only minimally elevated
• Other indications for prophylactic pharmacotherapy

  • Presence of tophi
  • Chronic kidney disease
  • History of urolithiasis
• Urate-lowering therapy can be started during an acute attack if anti-inflammatory prophylaxis has been initiated
• Goal of urate-lowering therapy

  Achieve and maintain serum uric acid less than 6 mg/dL (357 μmol/L), and preferably less than 5 mg/dL (297 μmol/L) if signs and symptoms of gout persist