GOUT

I. Pathophysiology and epidemiology

  1. A multi-organ disease resulting from inflammation and tissue damage triggered by precipitation of monosodium urate monohydrate (MUS) crystals
  2. Uric acid metabolism
    1. Produced by action of xanthine oxidase on the purines hypoxanthine and xanthine (mostly from breakdown of senescent cells; also some from diet).
    2. Filtered at the glomerulus (filtration inhibited by diuretics)
    3. Secreted by the tubules (secretion inhibited by pyrazinamide, low-dose ASA, and alcohol)
    4. Also reabsorbed by the tubules (reabsorption inhibited by uricosuric drugs--probenecid, sulfinpyrazone, benzbromarone, ASA at doses > 2g/d).
    5. About 33% of uric acid elimination is by bacterial degradation in the gut
  1. Chronic hyperuriciemia is necessary but not sufficient for the development of gout. Note that serum uric acid levels can be temporarily lowered during a gout attack.  Nml uric acid levels close to limits of urate solubility.
  1. Usually idiopathic (> 99%) but can be secondary to:
  1. Increased urate production due to
  1. Rare inherited metabolic disorders causing increased uric acid production (PP-ribose-P synthetase over-activity; hypoxanthine-guanine phosphoribosyltransferase deficiency; G5PD deficiency)
  2. Chronic hemolysis
  3. Increased WBC turnover, e.g. leukemia
  4. High dietary purine content (meats esp. organ meats; meat extracts & gravies; seafood; yeast; beer; legumes; oatmeal; spinach; asparagus; cauliflower; mushrooms)
  1. Impaired renal urate secretion
  1. Chronic renal insufficiency of any cause
  2. Meds which inhibit urate secretion or enhance reabsorption
  1. Diuretics (thiazide and loop)
  2. Cyclosporine in organ transplant pt's
  3. Lead
  4. Low-dose ASA
  5. Pyrazinamide
  6. Ethambutol
  7. Niacin
  8. Alcohol
  1. More common in men than women [7-9:1]; very rare before puberty; peak incidence around age 45 for men; for women; more common after menopause
  2. Obesity is a risk factor; unclear why
  3. Hypertension appears to be a risk factor, though this may be be confounded by diuretic use.

II. Clinical features

  1. Gouty arthritis--an acute, inflammatory arthritis caused by intra-articular precipitation of MUS
  1. Predominantly PMN-mediated
  2. Usually monoarticular; 50% involve the big toe MTP joint ("podagra")
  3. Usually exquisitely tender
  4. Can be accompanied by fever and elevation of WBC and ESR
  5. Can last anywhere from hours to weeks without tx
  6. Can be precipitated by exercise, trauma, physiologic stress e.g. surgery, alcohol, "dietary overindulgence," starvation, or start of uric acid-lowering meds
  7. In recovery phase, desquamation of overlying skin may occur
  1. Extra-articular manifestations
  1. Deposition of monosodium urate monohydrate crystals in extra-articular locations ("tophi")
  1. In cartilage (including ear), tendon sheaths, bursae, subcutaneous tissues, bone, renal interstitium, and rarely, cardiac valves or conduction system
  2. Usually not ass'd with inflammation
  3. Can cause stiffness and aching due to mechanical impingement on surrounding tissue and even, in rare cases, extensive joint destruction
  1. Can get inflammatory tenosynovitis, bursitis, or cellulitis.
  2. Gouty nephropathy
  1. Deposits of monosodium urate monohydrate in renal interstitium with attendant monuclear and giant cel reaction
  2. Renal failure due to gout is generally mild and slowly progressive
  3. Can rarely get acute oliguric renal failure from bilateral tubular obstruction by uric acid crystals--typically in leukemia or lyphoma (esp. during chemotherapy--tumor lysis syndrome) or in setting of severe volume depletion and acidosis
  1. Uric acid urolithiasis is seen in 10-25% of pts with gout ; also inc risk calcium oxalate stones [inc risk w/ persistently acidic urine]

III. Diagnosis

  1. Gold standard for diagnosis is observation of negatively birefringent, needle-shaped crystals on polarized light microscopy in synovial fluid. [84%sens, 100% spec]
  2. WBC count in synovial fluid is usually 5-50k/mm3 in acute gout
  3. Differential diagnosis for acute gouty arthritis
  1. Pseudogout
  2. Acute rheumatic fever
  3. Rheumatoid arthritis
  4. Traumatic arthritis
  5. Osteoarthritis
  6. Septic arthritis--Consider w/u with synovial fluid culture in acute gout, esp. first episode, to r/o alternate diagnosis of septic arthritis
  7. Cellulitis
  8. Bursitis
  9. Thrombophlebitis
  10. Acute sarcoidosis
  11. Psoriatic arthritis.
  12. Reiter's syndrome

Dx Criteria: 1.rapid dev severe jt pain 2.MSU crystals on aspiration 3.clinical recurrent gout w/ hyperuricemia 4.all pt's w/ inflamed jt's need aspiration  5.MSU testing can be done between flares, urate crystals persist in 70% pts 6.always ck gram stain and cx w/ syn fluid, gout can exist w/ sepstic arthritis  7.many people w/ hi urate do not develop gout  8.if <25 yo w/ fhx gout ck 24h uric acid/cr ratio 9.radiographs useful but cannot r/o gout 10.rf male, htn CAD, CRF, obesity, etoh, diuretics

IV. Tx- Asx hyperuricemia not indication for tx.  ?indep risk factor for vascular disease

  1. Tx of acute gouty arthritis
    1. Rest the affected joint
    2. Ice significantly reduces pain (J. Rheum. 29:331, 2002--JW)
    3. NSAIDs (don't use salicylates because decrease tubular secretion of uric acid) until attack subsides
    4. Colchicine PO
      1. Reduces PMN phagocytosis of urate crystals
      2. 0.6-1.2mg then 0.6mg Q1-2h until attack subsides or side f/x develop (us. 18-24h) [max 3 pills]
      3. Reduce dose in pts with renal or hepatic disease
      4. Side f/x include nausea, abdominal cramping, and diarrhea; may also cause alopecia, hepatotoxicity, reversible myopathy, and bone-marrow suppression in high doses
      5. Monitor CBC in pts on long-term colchicine therapy
    5. Colchicine IV--much higher risk of bone marrow suppression, nephrotoxicity, and hepatotoxicity--2mg then 1mg Q6h; max dose 4mg; reduce dose by 50% in elderly or pts with hepatic or renal disease
    6. Systemic Corticosteroids if other meds are contraindicated (prednisone 40-60mg/d  for 3d then dec by 10-15mg/d q3d until d/c'd, or intra-articular steroids)
    7. Don't start hypouricemic therapy during acute attack--doesn't help and may induce a recurrent attack by mobilizing uric acid from the tissues. However, if pt is on hypouricemic tx, don't d/c during acute attacks.
    8. Corticotropin:25 USP units for small joint  40USP units for large joint
  1. Preventive tx
    1. May result in diminution of tophi as well as prevention of acute attacks
    2. Hypouricemic agents
  1. Criteria for use
  1. Frequent or severe attacks
  2. Severe hyperuricemia
  3. Tophi
  4. Radiographic evidence of urate deposits
  5. Urolithiasis
  6. Urate overexcretion
  1. Try to maintain serum uric acid at < 6mg/dl [dec frequency gout attcks w/ urate levels <6mg/dl  Arthr and Rheum, Vol51, N3, pp321-325].
  2. The optimal duration of hypouricemic tx is unknown; may experts recommend lifelong tx
  3. Hypouricemic tx may precipitate acute gout (unclear why)--to prevent this, start Colchicine 1-2wks before and continue for several months after initiation of hypouricemic tx [.6mg po bid crcl >50; .6mg po qd crcl 35-49; .6mg po qd q 2-3d crcl 10-34; avoid if crcl <10 or in hemodialysis pt, pt's w/ liver dz; reduce maint to 50%nml if >70yo.  Avoid w/ statins, macrolides, cyclosporine sec dec colchicine elim.
  4. Specific agents--Pts with elevated urinary uric acid excretion are at increased risk for urolithiasis and should be tx'd with allopurinol rather than uricosuric agents; this would be the only reason to check urinary uric acid excretion (normal = 330-600mg/d; don't check during an acute attack b/c won't be accurate).  No clear evidence that tailoring tx based on 24h urinary urate beneficial.  75%pt's have dec urate excretion.
  1. Allopurinol
    1. Reduces serum uric acid levels by inhibiting xanthine oxidase
    2. Dosing: 300mg QD, may increase to up to 900mg if needed; 100-200mg/d in pts with renal insufficiency [200mg crcl 60-90, 100mg crcl 30-60, 50-100mg crcl <30].
    3. May cause gastric irritation, diarrhea, skin rash, and rarely, hypersensitivity syndrome (more likely in pts with renal insufficiency) with acute interstitial nephritis, hepatitis, fever, vasculitis, and severe skin injury
    4. In a case-control study of 3,677 pts and 21,868 control, allopurinol use > 3y ass'd with RR for cataracts of 1.53 (sig.) (Arch. Ophth. 116:1652, 1998--JW)
  2. Uricosuric agents
  1. Ineffective--and more dangerous re: risk of uric acid urolithiasis--if CrCl < 30ml/min
  2. Before starting tx, check to make sure 24h urine uric acid secretion is not high, b/c if it is, tx'ing with a uricosuric agent may raise the risk of uric acid stones as well as uric acid deposition in renal tubules.  Flase positives possible if not on strict low purine diet.  Not accurate if crcl<60
  3. Consider co-treating with urine alkalinizing agents (e.g. acetazolamide 250mg HS)
  4. Probenecid 500-1000mg BID--effectiveness reduced by salicylates
  5. Sulfinpyrazone 100mg TID-QID--may cause HA, GI upset, rash; effectiveness reduced by salicylates
  6. Losartan- ARB, effect appears to plateau at 50mg dose
  1. Encourage high fluid intake
  2. Diet changes: purine restricted diets unpalatable to many, only mod effective in dec urate levels.  A small non-random study showed dec insulin sens and urate levels w/ caloric rest/low cho diet
  3. Treat HTN if present
  4. Avoid excessive alcohol intake
  5. Colchicine 0.6-1.2mg/d can be used as preventive monotherapy
  6. Ditto for low-dose NSAIDs
  7. Weight loss

(Sources: Cecil Textbook of Medicine 20th ed.; NEJM 334:445, 1996, NEJM 349;17, 1647-55)