Clinical Relevance of Hyperuricemia Dr Ahmad ALEnizi MD, Rheumatologist FRCPC, RACR, MACP

Outline Purine metabolism Definition of Hyperuricemia (HU) Epidemiology Clinical relevance of hyperuricemia Asymptomatic Hyperuricemia Crystal-Deposition related Non-Crystal deposition associations

Purine Metabolism Purine Hypoxanthine Xanthine Uric acid Xanthine Oxidase Xanthine Xanthine Oxidase XO XO Uric acid

Definition No universally accepted definition Statistical definition : UA values exceeding 2SD of normal population Physiochemical definition: based upon solubility UA in body fluids > 7 mg/dl ( 416 micmol/L) Zhang WAnn Rheum Dis 2006; 65:1312. Khanna D, Arthritis Care Res (Hoboken) 2012; 64:1431. Neogi T. Clinical practice. Gout. N Engl J Med 2011; 364:443. Terkeltaub R. Nat Rev Rheumatol 2010; 6:30. Yamanaka H, Nucleo Nucl Nucl Acids 2011; 30:1018. Richette P,. Ann Rheum Dis 2017; 76:29.

Definition Definition of Hyperuericemia in non-crystal deposition conditions is problematic: high prevalence of UA above Saturation level but within 2 SD Association of UA level with CVD detected at subsaturating levels Lin KCJ Rheumatol 2000; 27:1045. Sánchez-Lozada LG, Semin Nephrol 2005; 25:19. Neogi T. Philadelphia 2012. p.226

Definition Clinically relevant definition ( Experts suggested): UA > 6 mg/dl ( 360 mmol/L) integrate : Threshold for lifelong risks of complications Widely recommended goal level for successful treatment Zhang WAnn Rheum Dis 2006; 65:1312. Khanna DArthritis Care Res (Hoboken) 2012; 64:1431 Yamanaka H .nucl Nucl Nuc Acids 2011; 30:1018. Perez-Ruiz F, Ann Rheum Dis 1998; 57:545. Shoji A. Arthritis Rheum 2004; 51:321. Richette P,. Ann Rheum Dis 2017; 76:29.

Definition Goal in Gout Management UA < 6 mg/dl ( 360 mmol/L) as a target level is CONTRAVERSIAL Goal in Gout Management

Classification of persistent Hyperuricemia Primary : in absence of coexisting diseases/drugs Secondary : Excessive production Diminished renal clearance

Epidemiology Very common 20-25% of adult men Less frequent in women renal urate clearance enhanced by estrogenic compounds above 50 years of age = males hormone replacement decrease UA at menopause Lin KC et al. J Rheumatol 2000; 27:1045. Zhu Y. Arthritis Rheum 2011; 63:3136.

Potential Clinical consequences Asymptomatic Hyperuricemia Crystal deposition related: Gout & tophaceous gout Acute or chronic hyperuricemic nephropathy Uric acid nephrolithiasis Asymptomatic MSU crystal deposition. Other associations: Hypertension Chronic kidney disease Cardiovascular disease Insulin resistence syndrome

Crystal deposition related disorders: Seen in < 25% of cases of HU. i.e Most cases are asymptomatic HU. Degree of HU is proportional to the risk of deposition related diseases. Awareness of gout/crystal deposition diagnosis and management Campion EW, Am J Med 1987; 82:421. Langford HG.Arch Intern Med 1987; 147:645. Hall AP. Am J Med 1967; 42:27.

Stages of Gout Stage 1 Stage 2 Stage 3 Stage 4 Asymptomatic Hyperuricemia Acute attack - Gout Flares Inter-critical Period Chronic Gout Stage 1 Stage 2 Stage 3 Stage 4

Gout Study of 2046 males for 15 Y, serial UA level Annual Incidence of gout based on UA level: UA > 9 mg/dl ( 530 mmol/L) : 4.9% UA 7-8.9 mg/dl ( 416-529 mmol/L): 0.5% UA < 7 mg/dl ( 416 mmol/L) : 0.1% The Accumulative risk after 5 years: 22% i.e 78% remains asymptomatic hyperuricemia Campion EW, Am J Med 1987; 82:421.

Tophaceous Gout Associated with HU and antecedent gouty arthritis. More frequently in older patients with asymptomatic Hyperuricemia ( being treated with NSAIDs and/or steroids for other reasons).

Risk factors for developing Gout in asymptomatic Hyperuricemia Alcohol Meat /seafood Diuretics Beta-blockers ACE inhibitors Non-Losartan ARB inhibtors Hypertension Obesity Choi HK, Lancet 2004; 363:1277. Choi HKN Engl J Med 2004; 350:1093. Choi HK, BMJ 2012; 344:d8190. Lin KC, J Rheumatol 2000; 27:1501. Choi HKArch Intern Med 2005; 165:742.

Asymptomatic MSU crystal deposition Detected by: Sonography, Arthroscopy, Dual energy CT. Lack of evidence to address: Prediction of clinical gout. Prediction of HU associated comorbid diseases. De Miguel E, Ann Rheum Dis 2012; 71:157. Pineda CArthritis Res Ther 2011; 13:R4. Chowalloor PV.Ann Rheum Dis 2013; 72:638. Ottaviani S. Clin Exp Rheumatol 2011; 29:816. Puig JG,Nucleosides Nucleotides Nucleic Acids 2008; 27:592. Ottaviani S,Clin Exp Rheumatol 2012; 30:499. Baker JF, Arthritis Rheum 2010; 62:895. Ogdie A, Ann Rheum Dis 2015; 74:1868.

Chronic Renal failure Association with HU Causal role of HU not established yet. HU in CKD due to reduced UA excretion unaccompanied with hyperuricosuria. Acute UA nephropathy overproduction leads to enhanced UA exertion. Uncertainty : extent of Hyperuricemia contribution to chronic renal impairment. Liang MH. Ann Intern Med 1978; 88:666. Bose BNephrol Dial Transplant 2014; 29:406.

Urate nephropathy : A form of CKD UA deposits in renal interstitium inflammatory reaction tubulointerstitial injury renal tophi

Urate nephropathy : A form of CKD Study: Hyperuricemia of clinical importance to CKD: 13 mg/dl ( 773 mmol/L) in males 10 mg/dl ( 595 mmol/L) in females Fessel WJ. Am J Med 1979; 67:74. 1979; 67:74.

Urate nephropathy : A form of CKD Elevation of UA out of proportion of the degree of renal insufficiency : > 9 mg/dl ( 535 mmol/L) creatinine level < 132 mmol/L. > 10 mg/dl ( 595 mmol/L) Crt level 132-176 mmol/L. > 12 mg/dl ( 714 mmol/L) Crt level > 176 mmol/L. Murray T, Ann Intern Med 1975; 82:453.

Nephrolithiasis Increased urinary UA is a risk factor ( not ca.oxalate) 50% if daily urinary UA > 1100 mg Uncommon Yü T. Ann Intern Med 1967; 67:1133.

Non-Crystal deposition disorder HTN, CKD, CVD, Insulin resistance. HU has not been well established as causal factor. Evidence supports protective role in degenerative/inflammatory neurogenic disorders ( antioxidant). Lu N,Ann Rheum Dis 2016; 75:547.

Cardiovascular disease HU has increased incidence of CHD and mortality Proposed mechanism: development of HTN oxidative stress Unclear yet if HU has causal effect just a marker of other risk factors Fang J, JAMA 2000; 283:2404. Niskanen LK, Arch Intern Med 2004; 164:1546. Choi HK, Circulation 2007; 116:894. Kuo CFRheumatology (Oxford) 2013; 52:127. Kivity S. Am J Cardiol 2013; 111:1146.

Cardiovascular disease Study: 112 patients with heart failure for 4 years survival rate: UA > 9.5 mg/dl ( 565 mmol/L): 19% UA < 9.5 mg/dl: 79% ? low cardiac output & diuretic therapy: both reduce UA excretion Danesh J. N Engl J Med 2004; 350:1387.

GFR The primary objective of this study was to analyze the effect of allopurinol in patients with moderate CKD in reduction of inflammatory markers and renal disease progression. Allopurinol improves GFR with stage 3 or worse chronic kidney disease patients more than control GFR = Glomerular filtration Rate

P=0.039 CV Risk Allopurinol control One of the secondary end-points was looking at cardiovascular risk and hospitalization. They had a 71% reduction in cardiovascular events and a 62% reduction in hospitalization.

Cardiovascular disease EXACT-HF Trial: Effect of allopurinol in symptomatic HF and UA > 9.5 mg/dl 253 patients Followed for 24 weeks no effect on several markers : survival, HF, QoL, LVEF, PGA conclusion: UA is a marker of worse outcomes Lowering UA not clinically effective Michel M et al. Circulation 2015

Conclusions Hyperuricemia is extremely common lab finding that may or may not have clinical relevance. UA level 6 mg/dl (360mmol/L) most accepted upper limit of normal, but remains controversial. Vast majority of individuals with asymptomatic HU remains silent. UA crystal deposition is the only well established clinical implication of HU. Despite of high associations, HU still needs further studies to establish its causal effect in non-crystal deposition conditions Awareness of the clinical relevance of HU is important among physicians, given its high prevalence and variable outcomes.

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