1. Gout is a species-wide inborn error of purine metabolism D. Branch Moody, M.D. Professor of Medicine Immunology Laboratory, Smith Building 514 617-525-1037 bmoody@rics.bwh.harvard.edu Slide credits: Douglas Levinson PhD Robert Terkeltaub MD ACR Slide Collection

5. Serum urate levelAnnual incident of acute gouty arthritis <7 mg/dl0.1 percent 7- 8.9 mg/dl0.5 percent >9 mg/dl5.0 percent EW Campion et al, Am J Med 82, p. 421-6 (1987). Steady state serum urate levels correlate with gout risk Important caveats in clinical interpretation Most patients with hyperuricemia do not get crystals Serum urate levels can fall by ~2 mg/dl during attack

6. Chronic Tophaceous Gout

7. What is the white material? A crystals B cells C cottage cheese D toothpaste

8. Chronic Tophaceous Gout solubility in tissues ~ 6.8 mg/dl -

9. Acute Gouty Arthritis with “ Podagra ”

11. Why does sodium urate, but not protein, DNA or lipids light up on plane polarization light microscopy? A larger mass of sodium urate B crystalline nature of sodium urate C UV absorption by urate D Acid-base effects of sodium urate

13. extracellular intracellular

14. allantoin H20 + O2 amidophosphoribosyltransferase What genetic deficiencies involving enzymes in purine pathways predispose to gout? What dietary factors contribute to gout? What enzymes could be targeted for Gene therapy or conventional therapy of gout? What is the role of kidney disease in affecting gout risk? Why do diuretics cause gout?

15. allantoin H20 + O2 amidophosphoribosyltransferase ATP 1.failure to excrete

16. allantoin H20 + O2 amidophosphoribosyltransferase ATP 2.failure to metabolize 1.failure to excrete

17. allantoin H20 + O2 amidophosphoribosyltransferase ATP 2.failure to metabolize 1.failure to excrete 3.Increased de novo synthesis

18. allantoin H20 + O2 amidophosphoribosyltransferase ATP 2.failure to metabolize 1.failure to excrete 3.Increased de novo synthesis 4. increased dietary intake of nucleotide precursors

19. allantoin H20 + O2 amidophosphoribosyltransferase ATP 2.failure to metabolize 1.failure to excrete 3.Increased de novo synthesis 4. increased dietary intake of nucleotide precursors 5. decreased or absent salvage

20.  high purine diets (brain, intestine, and many other foods)  lymphoproliferative and myeloproliferative diseases  myelodysplasias  chronic inflammatory diseases like psoriasis  rhabdomyolysis  tumor lysis syndrome  hypoxanthine phosphoribosyltransferase (Lesch-Nyhan Syndrome)  phosphoribosylpyrophosphate (PPRP) synthetase Gout risk factors can be understood as clinical variables that increase urate levels

21. Renal handling of uric acid explains clinical causes of gout the mechanism of actions of anti-gout drugs Renal insufficiency Probenecid (anion transporter inhibitor) Loop diuretics (HCTZ, furosemide) Organic acids  -hydroxybutyrate Lactate Salicylates

22.  Drugs  loop diuretics (furosemide, thiazides)  salicylic acid (low dose ie 80 mg per day)  cyclosporine  Renal tubular disease  lead poisoining ( “ saturnine gout ” )  polycystic kidney disease  Renal insufficiency  hypertension  vascular disease  Renal acidosis  lactic acidosis  renal acidosis “ Underexcretion ”

24. Why does more than 90 percent gout occur in men? A Males have higher levels of urate in the blood B Males have altered pH in the tissues C Males have higher IL-1 precursors D Males have NALP-3 pathways that are more easily triggered