Hyperuricemia and Related Diseases Registrar: JLeR Malherbe Consultant: J Van Rensburg

Historical perspective 4000 BC Mummies with gout 400BC  Hippocrates  beyond power of medicine 190AD  Galen  imbalance in four humors 6th Century  Alexander of Tralles  hermodactyl 1679 Antonij van Leeuwenhoek  ID crystals in gouty tophy

Historical perspective 1683  Thomas Sydenham  Classic essay 1776  Charl Scheele Discovers UA 1797  Willian Hyde Wollaston identifies UA in tophi 1798  Antoine Fourcroy coins term “uric acid” 1848 Aflred Garrod 1st test for UA 1859 Garrod determines gout caused by overproduction or underexcretion of UA

Historical perspective 1899  Emil Fischer  molecular structure of UA 1913  Otto Folin, Willey Dennis  1st test sensitive to detect UA in normal blood 1937  Mortensen shows UA lower in females 1951  Probenicid 1963  Allopurinol is approved

Uric Acid Metabolism Final breakdown product of purine metabolism All Tissues Liver and Small Intestine Other Mammals Xanthine Oxidase Uricase Allantoin

UA Properties Weak acid pKA 5.75 Uric Acid  Urate- + H+ At normal body pH of 7.4 shifted far to right 98% circulates as monosodium urate

Uric Acid Pool Base, Sugar (Ribose or Deoxyribose) and Phosphate DNA and RNA Nucleotides Base and Sugar (Ribose or Deoxyribose) Nucleosides Bases Urate Urine Intestine Tophi Salvage Pathways Diet De novo biosynthesis Nucleic Acids Adenine and Guanine (Purines). The pyrimidines cytosine and thymine not degraded to urate Urate Production varies with diet purine content and rates of purine synthesis, degradation and salvage Normal urate pool 1200mg in male. Females half Steady state  60% daily turnover with balanced production and elimination Elimination 2/3 Kidney 1/3 Gut <2% Tissue uricolysis by non- specific catalases and peroxidases

Gut Elimination Passive process Urate moves down concentration gradient Degraded by intestinal bacteria Very little uric acid in stool Gut elimination increased in renal failure

Kidney Elimination Traditional four compartment model Glomerular filtration Very little protein binding Almost all filtered Tubular reabsorption Most of filtered  Early proximal tubule Secretion 50% secreted back into tubule by S2 segment of proximal tubule Postsecretory reabsorption Large fraction reabsorbed in S3 segment of proximal tubule Net effect: 7 – 12% of filtered load exreted Steps actually in parallel  Organic ion transporters

Urate transporter 1 is most well typed Chromosome 11 Exchanges urate for other organic anions Drug/Metabolites Uricosuric from tubular lumen Uricoretentive from intracellular space Uricosuric Uricoretentive Estrogens Fenofibrate Glucocorticosteroids Losartan Salicylates (High dose >2g/d) Probenicid Ascorbic acid Calcitonin Phenylbutazone Expired Tetracycline Lactate Ketones (acetoacetate and Hydroxybutyrate) Alcohol Salicylates (Low dose <2g/d) Diuretics (volume depletion) Ethambutol Pyrazinamide Nicotinic Acid Cyclosporine

Urate reabsorption indirectly linked to Sodium reabsorption Na+-anion cotransporters Na+ into tubular cell with organic anions such as Lactate Organic anion then exchanged for urate by URAT1 Diuretics and dehydration

URAT1 cannot explain renal urate handling alone Various other OAT Glut9 on chromosome 4 Human uric acid transporter (hUAT) Monocarboxylix acid trasporter 9 (MCT9) hUAT and GLUT9 also involved in export of urate from tubular cell to interstitium and circulation Probenicid action on URAT1 and GLUT9

Hyperuricemia Not normal bell curve distribution Hyperuricemia difficult to define statistically >416µmol/L  Supersaturation  Appropriate cut-off for crystal deposition diseases Non-crystal deposition associations such as CV risk at lower levels Overproduction, underexcretion or combination

Increased Urate Production 10 – 15% of patients Purine content of diet 60µmol/L Liver, anchovies, kidneys Increased purine degradation  rapid cell tunover, proliferation, cell death Leukemic blast crises, hemolysis, rhabdomyolisis, chemotherapy, myeloproliferative diseases Intense exercise  ATP degradation in skeletal muscle Alcohol  Increased hepatic ATP breakdown Rare Enzyme abnormalities

Decreased Uric Acid Excretion 85% - 95% “Underexcretors” actually have daily UA excretion within the normal range Reduced efficiency of clearance New steady state with high p[UA] and normal UA excretion Renal failure Reduced GFR Compensated by increased GIT clearance and reduced activity of xanthine oxidase Poor correlation between UA levels and creatinine

Decreased Uric Acid Excretion Various organic substances cause hyperuricemia due to increased reabsorption Lactate Lactic acidosis and alcohol Ketones acetoacetate, hydroxybutyrate  DKA Low dose salicylate Drugs Diuretics  via dehydration and subsequent sodium reabsorption Ethambutol, Pyrazinamide, Nicotinic acid, Cyclosporine

Asymptomatic Hyperuricemia Persistant hyperuricemia without crystal deposition 5% general population, 25% hospitalized UA level rise Puberty in men Post menopause in women (less if HRT) 2/3 will remain asymptomatic through life Risk of crystal deposition linked to level In Study of 2046 initially healthy men followed for 15 years Annual gout incidence1 4.9% if >535µmol/L (levels found in <20% of hyperuricemic pt’s) 0.5% if >416 to 535µmol/L 0.1% if <416µmol/L 1. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study: Am J Med 1987 Mar;82(3):421-6

Asymptomatic Hyperuricemia - Workup Exclude secondary treatable causes (table p5) Exclude drugs  Substitute if possible If no clear cause 24hour uric acid excretion (normal diet, no alcohol, no drugs) >800mg/day (4.8mmol/day) Overproduction  Repeat 24hr exretion after 5 day isocaloric reduced purine diet >670mg/day (4.0mmol/day) pt has primary idiopathic hyperuricemia, inherited enzyme defect or disordered ATP metabolism if other secondary causes excluded If excretion normalize dietary purine excess is confirmed Normal excretion  signifies reduced renal clearance Fractional excretion of uric < 6%

Gout MSU crystals in joints and soft tissues 1.3 – 13.2% of general population Males 30 to 45 Females 55 to 70 Hyperuricemia = risk ≠ disease Obesity, trauma, surgery, starvation, dietary overindulgence, alcohol, drugs Choi et al1 47150 men followed 12 years Increased incidence of gout with meat and seafood (RR 1.41 and 1.51) Each additional daily serving of meat 21% risk increase. 7% for seafood Purine rich vegetables did not increase risk Dairy protein protective (RR 0.52) Two decades asymptomatic hyperuricemia 1. HK Choi, PK Atkinson. Purine-Rich Foods, Dairy and Protein Intake, and the Risk of Gout in Men: N Engl J Med 2004;350:1093-103

Gout - Pathogenesis Supersaturation not enough for crystal formation  Gout sufferers has tendency to form crystals Temperature Nucleation  IgG IgG coat  Initiate and sustain inflammation Macrophages/Monocytes phagocytose crystals  TLR-2 and 4 important  Release cytokines (IL-1, IL-6, IL-8, TNF)  attract Neutrophils  Also phagocytose crystals  respiratory burst  inflammation and damage

Gout - Pathogenesis Spontaneous resolution Feedback mechanism  inactivation of inflammatory mediators, apoptosis of inflammatory cells Upregulation anti-inflammatory cytokines e.g TGFβ Apolipoprotein B

Tophi MSU deposits joints, skin, kidneys, heart valves, larynx Mass of crystals Surrounding chronic granulomatous inflammation Longstanding uncontrolled gout Pt’s with acute gout and no macrotophi have microtophi in synovium

Gout – Clinical Picture Early attack usually monoarticular  later can be polyarticular 1st MTP, knees, tarsal joints, ankles Hands in elderly and advanced disease Typical early attack  overnight, dramatic joint pain and swelling. Warm, red, tender (mimics cellulitis) Resolve 3-10 days  varying periods interattack symptoms free periods Triggers  diet, alcohol, trauma, MI, initiating hypouricemic drugs

Gout – Clinical Picture Chronic nonsymmetric synovitis in some after many attacks  Can confuse with RA Occasionally present only with chronic gouty arthritis Rarely with periarticular tophi and no synovitis Differences between RA and Chronic gout RA Chronic gout Symmetrical polyarthritis No crystals on joint aspirate No Tophi Serology usually positive Female predominance Marginal erosions on x-rays No history of dietary triggers No history of typical acute gout attacks Asymmetrical polyarthritis Crystals present Tophi Negative (Note 10-20% of normal elderly have low positive RF) Male predominance (in younger patients) Periarticular “rat eaten” erosions History of dietary triggers History of typical acute gout attacks

Gout - Diagnosis Ideally confirm with joint aspirate Gram stain and culture Leuc 2000 to 60000/µL  Cloudy Elongated needle like crystals intra and extracellularly p[UA] can be normal or low during attack Some cytokines uricosuric

Gout - Diagnosis X-rays Normal early in disease Advanced disease Cystic changes, well-defined erosion with sclerotic margins and overhanging edges  periarticular “rat eaten” appearance Joint space relatively spared

Gout - Treatment Acute attack NSAIDS Colchicine Glucocorticoids

Gout - Treatment Reducing uric acid pool Goals Diet, limit alcohol, lose weight, increase fluids, avoid diuretics Urate lowering drugs if 2nd attack or [UA] > 535µmol/L Probenicid if underexcretor with normal kidney function. Fluid intake 1.5l/day Allopurinol Goals [UA] < 300µmol/L Prevention of attacks Resolution of Tophi Prophylaxis against flares Colchicine 0.5mg  until flare free 6/12 or tophi gone

Uric Acid Nephrolithiasis Most commonly in gout sufferers, but also pt’s with no arthritis. 20% have normal UA 80% of stones in gout sufferers are pure uric acid. Rest calcium oxalate or calcium phosphate  nidus of uric acid Correlation with UA excretion  50% if >1000mg/day. Uricosuric Rx can precipitate/Chronic Rx not Urinary pH critical Warm climates Chronic diarrhea Diabetes mellitus, metabolic syndrome, obesity

Uric Acid Nephrolithiasis Diagnosis Clinical and non-contrast CT scan Treatment Fluids  u-output 2L/day Alkalinization Potassium bicarbonate/citrate Avoid sodium bicarbonate/citrate  Secondary calciuria  Calcium stones Allopurinol if above fails or UA excretion >1000mg/day

Acute Uric Acid Nephropathy Precipitation of UA crystals in tubules and collecting ducts Obstruct urine flow  ARF Sudden severe increase in UA levels Dehydration and urinary acidosis Prevention  aggressive IV hydration, allopurinol or raburicase. Sodium bicarbonate only if metabolic acidosis Treatment  rehydration, loop diuretics  diuresis. Dialyse if no diuresis

Chronic Urate Nephropathy Urate crystals in medullary interstitium  chronic inflammation  fibrosis and CRF In setting of Chronic tophaceous gout uncommon where effective Rx common practice Causative association between hyperuricemia and chronic renal disease in general more controversial Hyperuricemia out of proportion to renal insufficiency

Uric Acid and Cardiovascular Risk Association between hyperuricemia and hypertension, diabetes, kidney disease and cardiovascular disease High normal values (310 to 330µmol/L) ?Causative Some say it’s not independent of traditional risk factors Others argue that a factor doesn’t need to be independent to be causative Sharp rise in HPT, obesity, DM, kidney disease over past 100 years associated with rise in [UA]

Hypertension Only cardiovascular disease where hyperuricemia consistantly showen as independent risk factor Precede onset of HPT by 5 years More common in primary HPT Lowering [UA] in adolescents with primary HPT effectively lowers BP In animal studies not same effect in long standing HPT Thus role in pathogenesis of early hypertension

Hypertension UA causes endothelial dysfunction by reducing nitric oxide levels and activation of RAAS and renal vasoconstriction Over time renal microvascular disease develops  net effect is salt sensitive hypertension  would not respond to lowering uric acid levels Watanabe et al.1 Uricase mutation during Miocene in early hominoids and great apes  survival benefit  very low salt in diet  hyperuricemia induces salt sensitivity  improved BP homeostasis 1. S Watanabe, DH Kang. Uric Acid, Hominoid Evolution, and the Pathogenesis of Salt-Sensitivity Hypertension 2002;40:355-360

Metabolic syndrome and Diabetes Historically hyperuricemia in metabolic syndrome attributed to hyperinsulinemia Hyperuricemia often precedes hyperinsulinemia, obesity and diabetes In animal models lowering [UA] prevents/reverse features of metabolic syndrome Glucose uptake in skeletal muscle depends in part on normal endothelial function  Uric acid induces endothelial dysfunction in rats Uric acid induces inflammatory changes in adipocytes  been linked to metabolic syndrome in obese mice

Conclusion Link between hyperuricemia and cardiovascular disease is clear but causative role needs to be clarified Better understanding of biologic effects of uric acid is needed It remains possible that UA may have a variety of as yet undefined actions of cardiovascular disease Currently there is not sufficient data to recomment the treatment of asymptomatic hyperuricemia to reduce cardiovascular risk Clearly a need for RCT

References http://www.gouteducation.org/gout/history.aspx http://en.wikipedia.org/wiki/Colchicine RL Wortman. Disorders of Purine and Pyrimidine Metabolism: Harrison’s Principles of Internal Medicine 17th ed, McGraw Hill 2008. p2444-2449 RL Wortman. Gout and Hyperuricemia: Kelley’s Textbook of Rheumatology 8th ed. Elsevier. Online edition S Watanabe, DH Kang. Uric Acid, Hominoid Evolution, and the Pathogenesis of Salt-Sensitivity Hypertension 2002;40:355-360 MA Becker. Uric Acid Balance: UpToDate 18.1 BD Rose. Diuretic-induced Hyperuricemia and Gout: UpToDate 18.1 MA Becker. Asymptomatic Hyperuricemia: UpToDate 18.1 Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study: Am J Med 1987 Mar;82(3):421-6 MA Becker. Clinical manifestations and diagnosis of gout: UpToDate 18.1 HK Choi, PK Atkinson. Purine-Rich Foods, Dairy and Protein Intake, and the Risk of Gout in Men: N Engl J Med 2004;350:1093-103 P Monach, MA Becker. Pathophysiology of gouty arthritis: UpToDate 18.1 http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970695-7 HR Schumacher, LX Chen. Gout and Other Crystal Associated Arthropathies: Harrison’s Principles of Internal Medicine 17th ed, McGraw Hill 2008. P2165-2169 BD Rose, MA Becker. Uric acid renal disease: UpToDate 18.1 BD Rose, MA Becker. Uric acid nephrolithiasis: UpToDate 18.1 DI Feig, D Kang, RJ Johnson. Uric acid and Cardiovascular Risk: N Engl J Med 2008;359:1811-21