Registrar: JLeR Malherbe Consultant: J Van Rensburg
Slide 2
Historical perspective 4000 BC Mummies with gout 400BC
Hippocrates beyond power of medicine 190AD Galen imbalance in four
humors 6 th Century Alexander of Tralles hermodactyl 1679 Antonij
van Leeuwenhoek ID crystals in gouty tophy
Slide 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 1 st test for UA 1859 Garrod determines gout caused by
overproduction or underexcretion of UA
Slide 4
Historical perspective 1899 Emil Fischer molecular structure of
UA 1913 Otto Folin, Willey Dennis 1 st test sensitive to detect UA
in normal blood 1937 Mortensen shows UA lower in females 1951
Probenicid 1963 Allopurinol is approved
Slide 5
Slide 6
Uric Acid Metabolism Final breakdown product of purine
metabolism All Tissues Liver and Small Intestine Xanthine Oxidase
Uricase Allantoin Other Mammals
Slide 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
Slide 8
Uric Acid Pool 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 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 biosynthesisNucleic Acids
Adenine and Guanine (Purines). The pyrimidines cytosine and thymine
not degraded to urate Elimination 2/3 Kidney 1/3 Gut
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
UricosuricUricoretentive 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
Slide 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
Slide 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
Slide 14
Hyperuricemia Not normal bell curve distribution Hyperuricemia
difficult to define statistically >416mol/L Supersaturation
Appropriate cut-off for crystal deposition diseases Non-crystal
deposition associations such as CV risk at lower levels
Overproduction, underexcretion or combination
Slide 15
Increased Urate Production 10 15% of patients Purine content of
diet 60mol/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
Slide 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
Slide 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
Slide 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 incidence 1 4.9% if >535mol/L (levels found in
416 to 535mol/L 0.1% if
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 o >670mg/day
(4.0mmol/day) pt has primary idiopathic hyperuricemia, inherited
enzyme defect or disordered ATP metabolism if other secondary
causes excluded o If excretion normalize dietary purine excess is
confirmed Normal excretion signifies reduced renal clearance
Fractional excretion of uric < 6%
Slide 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 al 1 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) 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 Two decades asymptomatic
hyperuricemia
Slide 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
Slide 22
Gout - Pathogenesis Spontaneous resolution Feedback mechanism
inactivation of inflammatory mediators, apoptosis of inflammatory
cells Upregulation anti-inflammatory cytokines e.g TGF
Apolipoprotein B
Slide 23
Tophi MSU deposits joints, skin, kidneys, heart valves, larynx
Mass of crystals Surrounding chronic granulomatous inflammation
Longstanding uncontrolled gout Pts with acute gout and no
macrotophi have microtophi in synovium
Slide 24
Gout Clinical Picture Early attack usually monoarticular later
can be polyarticular 1 st 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
Slide 25
Gout Clinical Picture Chronic nonsymmetric synovitis in some
after many attacks Can confuse with RA Differences between RA and
Chronic gout RAChronic 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 Occasionally present
only with chronic gouty arthritis Rarely with periarticular tophi
and no synovitis
Slide 26
Gout - Diagnosis Ideally confirm with joint aspirate Gram stain
and culture Leuc 2000 to 60000/L Cloudy Elongated needle like
crystals intra and extracellularly p[UA] can be normal or low
during attack Some cytokines uricosuric
Slide 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
Gout - Treatment Reducing uric acid pool Diet, limit alcohol,
lose weight, increase fluids, avoid diuretics Urate lowering drugs
if 2 nd attack or [UA] > 535mol/L Probenicid if underexcretor
with normal kidney function. Fluid intake 1.5l/day Allopurinol
Goals [UA] < 300mol/L Prevention of attacks Resolution of Tophi
Prophylaxis against flares Colchicine 0.5mg until flare free 6/12
or tophi gone
Slide 30
Uric Acid Nephrolithiasis Most commonly in gout sufferers, but
also pts 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
Slide 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
Slide 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
Slide 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
Slide 34
Uric Acid and Cardiovascular Risk Association between
hyperuricemia and hypertension, diabetes, kidney disease and
cardiovascular disease High normal values (310 to 330mol/L)
?Causative Some say its not independent of traditional risk factors
Others argue that a factor doesnt need to be independent to be
causative Sharp rise in HPT, obesity, DM, kidney disease over past
100 years associated with rise in [UA]
Slide 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
Slide 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;40:355-360
Slide 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
Slide 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
Slide 39
References http://www.gouteducation.org/gout/history.aspx
http://en.wikipedia.org/wiki/Colchicine RL Wortman. Disorders of
Purine and Pyrimidine Metabolism: Harrisons Principles of Internal
Medicine 17 th ed, McGraw Hill 2008. p2444-2449 RL Wortman. Gout
and Hyperuricemia: Kelleys Textbook of Rheumatology 8 th 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: Harrisons Principles of Internal Medicine 17 th 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