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

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

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

4. 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.

5. 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 p.226

6. 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.

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

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

11. 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.

12. 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

13. 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.

14. 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

15. 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 mg/dl ( 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.

16. 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).

17. 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.

18. 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.

19. 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.

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

21. 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: ; 67:74.

22. 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 mmol/L.
> 12 mg/dl ( 714 mmol/L) Crt level > 176 mmol/L.
Murray T, Ann Intern Med 1975; 82:453.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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

28. 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.

29. 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

30. 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.

31. Thank You