URIC ACID

Dr Marita du Plessis
Department of Chemical Pathology
January 2002
INTRODUCTION:
- Uric acid is the end product of purine metabolism.
- Hyperuricaemia is associated with a tendency to form crystals of monosodium urate
causing
- Clinical gout !due to the deposition of monosodium urate crystals in the cartilage"
syno#ium and syno#ial fluid of $oints%"
- &enal calculi
- 'ophi !accretions of sodium urate in soft tissues%
- (cute urate nephropathy !due to sudden increases in urate production leading to
widespread crystallisation in the renal tubules%.
URIC ACID METABOLISM:
!see Marshall" p 2)*+2),%
- -ources of purines in humans !see figure .%
- Diet
- Degradation of endogenous nucleotides
- De novo synthesis !energy re/uiring process%.
- Purines are degraded to uric acid.
- Urate is e0creted #ia 2 routes
- .12 Secretion into the gut" and subse/uent degradation by bacterial uricase to C32
and 4H2.
- 212 Renal excretion !see figure 2%
- Urate is filtered at the glomeruli.
- Pro0imal tubular reabsorption of 556 of filtered load.
- More distal part of pro0imal tubules secretion !also some reabsorption" but less
than secretion%.
- 4et e0cretion of .06 of filtered load.
- 7ody urate pool !and plasma concentration% depends on the relati#e rates of urate
formation and urate e0cretion.
- Figure 1: Sources and excretion o urate Figure !: Urate excretion in t"e #idne$
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Figure %: Diagra& o t"e 'at"(a$s o 'urine nuc)eotide &eta*o)is& and uric acid
s$nt"esis in "u&ans+
(P&' 8 adenine phosphoribosyl transferase9
H:P&' 8 hypo0anthine+guanine phosphoribosyl transferase.
- De novo synthesis leads to the formation of ;MP !inosine monophosphate%" which can be
con#erted to (MP !adenosine monophosphate% and :MP !guanosine monophosphate%
!NUCLEOTIDES: purine base + sugar + O!"#
- 4ucleotide degradation in#ol#es the formation of the respecti#e nucleosides !inosine"
adenosine and guanosine% !NUCLEOSIDES: purine base + sugar"" these are
subse/uently metabolised to the respecti#e purine bases !hypo0anthine" adenine and
guanine% !URINE $%SES"#
- Hypo0anthine and guanine can be metabolised directly to 0anthine" but (MP1adenosine
ha#e to be con#erted to ;MP1inosine first.
- <anthine is metabolised to uric acid by the en=yme 0anthine o0idase" also responsible for
con#ersion of hypo0anthine to 0anthine.
- 7ecause &e novo synthesis is an energy re/uiring process" e0cretion of uric acid results
in net energy loss. Howe#er" sal#age pathways e0ist to con#ert purines bac> to their
parent nucleotides and are therefore energy sa#ing ? accomplished by the following
en=ymes
- @or guanine and hypo0anthine H:P&' !hypo0anthine+guanine phosphoribosyl
transferase%.
- @or adenine (P&' !adenine phosphoribosyl transferase%.
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,OUT:
- :out is a group of metabolic diseases associated with hyperuricaemia and deposition of
crystals of monosodium urate in tissues.
- Pre#alence 21.000" males affected more than females !A+.0.%.
- Presentation usually occurs in males o#er 20 years of age and females after the
menopause.
- 'here are - stages in the de#elopment of the disorder
- .. (symptomatic hyperuricaemia
- Hyperuricaemia is usually present for many years before the onset of symptoms.
- 47 3nly . in 20 sub$ects with hyperuricaemia will e#entually de#elop clinical
gout.
- 2. (cute gouty arthritis
- Classical presentation is acute inflammation of the metatarsophalangeal $oint of
the big toe !,06%" and the first attac> is usually monoarticular !affects only .
$oint%.
- 3ther $oints that may be in#ol#ed are the an>le" >nee" wrist" elbow" and small
$oints of hands and feet.
- 2. ;ntercritical gout
- -ome patients may ha#e only . attac>" whilst others ha#e recurrent attac>s at
shorter inter#als.
- 7etween attac>s the patient is usually asymptomatic e0cept for hyperuricaemia.
- *. Chronic tophaceous gout
- 'his follows recurrent attac>s and is characterised by the de#elopment of tophi
!swellings containing uric acid crystals% in the periarticular tissue.
- 3ther sites include the heli0 of the ear" bursae and tendons.
- Co&')ications o "$'eruricae&ia:
- Urolithiasis !>idney stones%
- .06 of gouty patients de#elop urate stones and .06 of all renal calculi are due to
urate.
- &enal failure
- (cute renal failure due to obstructi#e uropathy !urate crystals% may occur during
cytoto0ic treatment of malignancy !allopurinol co#er should be used%" and has
also been described in gouty sub$ects after se#ere e0ercise.
- Progressi#e chronic renal insufficiency is an important cause of morbidity and
mortality in untreated chronic tophaceous gout.
- Associated conditions:
- (lcoholism
- Dysmetabolic syndrome !;nsulin resistance syndrome%!syndrome <% 3besity"
characteristic dyslipidaemia !increased triglycerides" decreased HDB cholesterol"
small dense BDB%" hypertension" impaired glucose tolerance" prothrombotic state.
- Diagnosis:
- 'he laboratory e#aluation of hyperuricaemia is discussed below. ;t is important to
recognise that
- Hyperuricaemia is not synonymous with gout !. in 20 de#elop gout%
- :out can be precipitated by a sudden change !either increase or decrease% in urate
concentration.
- (n acute gout attac> may be associated with a normal plasma urate le#el !due to a
fall in urate le#el as seen with a change in diet" decrease in alcohol consumption%"
although hyperuricaemia will be demonstrated at some stage.
- Diagnosis is therefore usually made on clinical grounds.
- Definiti#e diagnosis C0amination of syno#ial fluid under polari=ing light microscope for
monosodium urate crystals !needle shaped and strongly negati#ely birefringent%.
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- T"era'eutic agents used in gout and "$'eruricae&ia:
- 'hree groups of drugs are a#ailable
- .. (llopurinol
- (llopurinol !structural analogue of hypo0anthine%" and its ma$or metabolite"
o0ypurinol" inhibit the en=yme 0anthine o0idase" producing a decrease in the
plasma and urinary concentrations of urate !hypo0anthine does not accumulate if
the sal#age pathway is intact%.
- ;nitial treatment with allopurinol should be co#ered with an anti+inflammatory
agent" because an acute attac> of gout can be precipitated when the initial dose
is gi#en !sudden decrease in urate can cause mobilisation from body pools%.
- 2. Uricosuric agents
- 'hese drugs !eg Probenecid% increase the urinary e0cretion of urate by inhibiting
tubular reabsorption.
- 2. (nti+inflammatory agents
- 'hese agents !eg colchicine and indomethacin% are used symptomatically to
relie#e the pain of acute gouty arthritis.
- 'hey ha#e no effect on plasma urate le#els.
INBORN ERRORS OF .URINE METABOLISM:
A+ /$'oxant"ine0guanine '"os'"ori*os$) transerase 1/,.RT2 deicienc$ 1Lesc"0
N$"an s$ndro&e2:
- 'he Besch+4yhan syndrome is an <+lin>ed recessi#e disorder" due to se#ere deficiency of
H:P&'.
- ;t is characterised by hyperuricaemia" mental deficiency" spasticity" choreoathetosis and
self+mutilation.
- Hyperuricaemia is due to decreased acti#ity of the sal#age pathway causing decreased
purine reutili=ation and increased uric acid synthesis. &elati#ely low le#els of nucleotides
result in decreased inhibition of &e novo synthesis" resulting in further o#erload of the
non+functioning sal#age pathway and increased uric acid production.
7. ,)ucose 30'"os'"atase deicienc$ 1,)$cogen storage disease t$'e I4 5on ,ier#e6s
disease2: !see figure *%
- Deficiency of glucose D+phosphatase !final en=yme in glycogenolysis pathway% results in
accumulation of glycogen" and hypoglycemia.
- ;ncreased metabolism of glucose D+phosphate through glycolysis results in lactic acidosis.
- ;ncreased metabolism of glucose D+phosphate through pentose phosphate pathway
increases formation of ribose )+phosphate and 4(DPH.
- &ibose )+phosphate is a substrate for increased &e novo purine nucleotide synthesis"
which is subse/uently degraded to uric acid resulting in hyperuricaemia.
- 4(DPH is a coen=yme in triglyceride synthesis" and o#erproduction results in
hypertriglyceridaemia.
- Hyperuricaemia is aggra#ated by increased lactic acid which inhibits renal e0cretion of
uric acid.
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Figure -: Car*o"$drate &eta*o)is&
C+ ."os'"ori*os$)'$ro'"os'"ate 1.R..2 s$nt"etase 7ariant 1(it" increased acti7it$2
- (n <+lin>ed disorder resulting in purine o#erproduction and gout" due to e0cessi#e acti#ity
of P&PP synthetase !first en=yme in de no#o synthesis pathway% !see figure )%.
- 'his increased acti#ity seems to be due to resistance to negati#e feedbac> inhibition by
purine nucleotides.
- :outy arthritis and urate lithiasis associated with hyperuricaemia occurs in childhood or
early adult life.
Figure 8: De no7o s$nt"esis o 'urine nuc)eotides:
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:lycogen
:lucose D+phosphate :lucose
:lucose D+phosphatase
Pentose phosphate pathway
&ibose )+
phosphate
4(DPH
Pyru#ate Bactate
:lycolysis
:lycogenolysis
Purine
synthesis E
degradation
Uric acid
':-
synthesis
LABORATOR9 IN5ESTI,ATION:
Useful estimations in the e#aluation of hyperuricaemia and gout are plasma urate" plasma
creatinine !renal function% and urinary urate.
A+ .)as&a urate:
Plasma urate is influenced by a wide #ariety of factors which should be ta>en into account
when interpreting results
- &ace Mar>edly raised in Maoris.
- -e0 0.0)+0..0 mmol1l higher in males !F ;ncreased renal clearance in females" F
increased body mass in males%.
- (ge Higher in older age groups.
- 7ody mass Cle#ated in obesity !F &eflection of dietary habits%.
- Diet ;ncreased #alues in
- High meat !purine% inta>e
- (lcohol ingestion
- (ssociated lactic acidosis decreases renal e0cretion.
- (lcohol increases ('P turno#er.
- Purines in beer yeast.
- @asting !>etones inhibit renal urate e0cretion and there is increased purine
degradation%.
- C0ercise ;ncrease !lactate effect%.
- Pregnancy
- Be#els initially fall by up to 2)6 in the first trimester" but then rise to #alues 206
higher than in the non+pregnant state.
- Commonly used reference #alues
- (dult females 0.2.+0.2D mmol1l
- (dult males 0.2.+0.*, mmol1l.
B+ Urinar$ urate:
- Hyperuricaemia may be due to o#erproduction or decreased renal e0cretion or both.
- 'he rate of renal urate e0cretion pro#ides a rough inde0 of the production rate" pro#ided
renal function is normal.
- 4ormal e0cretion rate G D.0 mmol1day !normal diet% 1 G 2.) mmol1day !low purine" alcohol
free diet for )+, daysH duration%.
- Ialues in e0cess of the abo#e are presumpti#e e#idence of urate o#erproduction. !see
case studies%
C+ .)as&a creatinine:
- Hyperuricaemia may cause renal failure and renal failure will result in hyperuricaemia.
- ;n renal insufficiency
- 'he plasma urate usually does not begin to rise until the :@& !glomerular filtration
rate% falls to below 20 ml1min !e/ui#alent to a plasma creatinine of 200+*00 umol1l%.
- (s renal failure progresses the plasma urate rises to a le#el of around 0.D mmol1l and
then plateaus9 thus a urate in e0cess of 0.D mmol1l suggests that renal failure is not
the only cause of the high urate.
D+ Urinar$ urate:creatinine ratio:
- 'he urinary uratecreatinine ratio may be used to differentiate acute renal failure
precipitated by hyperuricaemia !urate nephropathy% from renal failure due to other
causes.
- Urate nephropathy urinary uratecreatinine ratio !mmol1lmmol1l% J 0.,0.
- (cute renal failure due to other causes ratio G 0.,0.
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CAUSES OF /9.ERURICAEMIA:
A+ ."$sio)ogica)4en7iron&enta) actors
-ee abo#e
B+ .ri&ar$ "$'eruricae&ia
O7er'roduction:
- ;diopathic
- :lucose+D+phosphatase deficiency !Ion :ier>eHs disease%
- H:P&' deficiency !Besch+4yhan syndrome%
Reduced excretion:
- ;diopathic
C+ Secondar$ "$'eruricae&ia
O7er'roduction:
- ;ncreased nucleic acid turno#er
- Myeloproliferati#e disease" eg polycythemia #era
- Bymphoma" leu>emia
- Multiple myeloma
- Cytoto0ic therapy of malignancies
- Psoriasis
- Disordered ('P metabolism
- (lcohol !increased ('P turno#er%
- 'issue hypo0ia
- C0cessi#e dietary purine inta>e
Reduced excretion:
- Decreased glomerular filtration
- &enal failure
- Decreased secretion !competition with urate for tubular secretion%
- Bactic acidosis ? alcohol" e0ercise
- Ketoacidosis ? alcohol" diabetes" star#ation
- Drugs ? low dose salicylate
- ;ncreased reabsorption
- Hypo#olemia" eg diuretics.
CASE STUDIES:
Case .
( man aged )0 years with an acutely swollen and painful right >nee. 3n careful history ta>ing
and thorough physical e0amination no secondary causes were found.
las'a
Urate 0.,. mmol1l !0.2.+0.*,%
Creat .20 umol1l !D0+.20%
Urine
Urate !purine free diet% .0.) mmol1day !G 2.)%
Luestions
a% Mhat is your diagnosis based on clinical information and laboratory in#estigationsF
b% ;s the patient an No#erproducerO or NundersecretorOF
c% Mhat is the treatment of choice in this patientF
d% Mhat further in#estigation would you li>e to perform to confirm the diagnosisF
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Case 2
(cute myeloid leu>emia in a 2D+year+old woman.
Date 221* 2D1*
las'a
Urate 0.52 0..A mmol1l !0.2.+0.2D%
Creat 50 ..0 umol1l !D0+.20%
Urine
Urate !normal diet% .0.) + mmol1day !GD.0%
(llopurinol was begun on 221*.
Luestions
a% Mhat is your diagnosis based on clinical information and laboratory in#estigationsF
b% ;s the patient an No#erproducerO or NundersecretorOF

Case 2
Chronic renal failure in a 25+year+old man.
las'a
Urate 0.,A mmol1l !0.2.+0.*,%
Creat 0.50 mmol1l !D0+.20%
Urine
Creat Clearance .0 ml1min !J .20%
Urate !normal diet% ..2 mmol1day !G D.0%
Luestions
a% Mhat is your diagnosis based on clinical information and laboratory in#estigationsF
b% ;s the patient an No#erproducerO or NundersecretorOF
c% ;s the plasma urate le#el appropriate for the degree of renal failureF
REFERENCES:
.. Malmsley &4" Mhite :H. ( guide to diagnostic clinical chemistry. 2
rd
edition. 30ford
7lac>well -cientific Publications" .55* *.D+*2).
2. Marshall MJ. Clinical Chemistry. *
th
edition. Cdinburgh Mosby" 2000 2)*+2D0.
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