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

2. 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

3. 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

4. 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

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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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%

20. 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:

21. 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

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

23. 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

24. 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

25. 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

26. 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

27. 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

28. Gout - Treatment
Acute attack
NSAIDS
Colchicine
Glucocorticoids

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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]

35. 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

36. 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:

37. 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

38. 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

39. References http://www.gouteducation.org/gout/history.aspx
RL Wortman. Disorders of Purine and Pyrimidine Metabolism: Harrison’s Principles of Internal Medicine 17th ed, McGraw Hill p
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:
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:
P Monach, MA Becker. Pathophysiology of gouty arthritis: UpToDate 18.1
HR Schumacher, LX Chen. Gout and Other Crystal Associated Arthropathies: Harrison’s Principles of Internal Medicine 17th ed, McGraw Hill P
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: