GOUT, GOUT, GOUT its everywhere Part 1

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GOUT, GOUT, GOUT -its everywhere!Part 1

• Dr. Laurence Rubin
• Dr. Rachel Shupak
• Dr. Louise Perlin
• Division of Rheumatology
• St. Michaels Hospital
• Grand Rounds
• July 12, 2006

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Objectives

• To review the pathogenesis
• To delineate the diagnosis and indications for
  treatment
• To discuss the best management and options for
  the future

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Why gout?

• Humans are the only mammals in whom gout develops
  spontaneously
• WHY?
• lack uricase (oxidative degeneration of UA to
  allantoin)
• extensive reabsorption of filtered urate
• UA ANTIOXIDANT?

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Disease burden

• 2 in Males gt 30 yrs, females gt 50 yrs
• Prevalence increasing
• 9 in men, 6 in women gt 80 yrs
• Incidence of primary gout has doubled over the
  past 20 yrs

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WHY so much?

• Adiposity and Insulin resistance
• Insulin enhanced urate reabsorption
• Increased adenosine levels
• Hypertension
• independent of drugs
• Renal urate excretion lower in patients with EHTN
• Marker of renal insufficiency and nephrosclerosis

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The relationship between serum uric acid levels
and the incidence of gout
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Serum Uric Acid and the risk for Gout

• UA exists as urate at physiologic pH
• Solubility in joints is influenced by
• Temperature
• pH
• Concentration of cations
• Articular hydration
• Nucleating agents e.g., PGs, collagen, CS (DJD)

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Overview of the pathogenesis of gout
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80
Choi, H. K. et. al. Ann Intern Med
2005143499-516
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Dietary influences on the risk for gout and their
implications within the Harvard Healthy Eating
Pyramid
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Urate production pathways implicated in the
pathogenesis of gout
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Urate transport mechanisms in human proximal
tubule
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URAT-1- the mediator of renal urate transport

• Enhanced reabsorption is the most common
  mechanism for hyperuricemia
• Antiuricosuric effects
• Future target for treatment
• Binary effects that are dose dependent (eg ASA)
• cis inhibition at high dose
• trans stimualtion at low dose

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Pathogenesis of joint injury

• Acute
• Chronic

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Mechanisms of monosodium urate crystal formation
and induction of crystal-induced inflammation
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Putative mechanisms for chronic monosodium
urate-induced inflammation and cartilage and bone
destruction