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URIC ACID
Dr Marita du Plessis
Department of Chemical Pathology
January 2002
INTRODUCTION:
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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,
synovium and synovial fluid of joints),
- Renal calculi
- Tophi (accretions of sodium urate in soft tissues)
- Acute urate nephropathy (due to sudden increases in urate production leading to
widespread crystallisation in the renal tubules).
URIC ACID METABOLISM:
(see Marshall, p 254-257)
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Sources of purines in humans (see figure 1):
- Diet
- Degradation of endogenous nucleotides
- De novo synthesis (energy requiring process).
Purines are degraded to uric acid.
Urate is excreted via 2 routes:
- 1/3: Secretion into the gut, and subsequent degradation by bacterial uricase to CO2
and NH3.
- 2/3: Renal excretion (see figure 2):
- Urate is filtered at the glomeruli.
- Proximal tubular reabsorption of 99% of filtered load.
- More distal part of proximal tubules: secretion (also some reabsorption, but less
than secretion).
- Net excretion of 10% of filtered load.
Body urate pool (and plasma concentration) depends on the relative rates of urate
formation and urate excretion.
Figure 1: Sources and excretion of urate
Figure 2: Urate excretion in the kidney
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Figure 3: Diagram of the pathways of purine nucleotide metabolism and uric acid
synthesis in humans.
APRT = adenine phosphoribosyl transferase;
HGPRT = hypoxanthine-guanine phosphoribosyl transferase.
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-
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De novo synthesis leads to the formation of IMP (inosine monophosphate), which can be
converted to AMP (adenosine monophosphate) and GMP (guanosine monophosphate)
(NUCLEOTIDES: purine base + sugar + PO4).
Nucleotide degradation involves the formation of the respective nucleosides (inosine,
adenosine and guanosine) (NUCLEOSIDES: purine base + sugar), these are
subsequently metabolised to the respective purine bases (hypoxanthine, adenine and
guanine) (PURINE BASES).
Hypoxanthine and guanine can be metabolised directly to xanthine, but AMP/adenosine
have to be converted to IMP/inosine first.
Xanthine is metabolised to uric acid by the enzyme xanthine oxidase, also responsible for
conversion of hypoxanthine to xanthine.
Because de novo synthesis is an energy requiring process, excretion of uric acid results
in net energy loss. However, salvage pathways exist to convert purines back to their
parent nucleotides and are therefore energy saving – accomplished by the following
enzymes:
- For guanine and hypoxanthine: HGPRT (hypoxanthine-guanine phosphoribosyl
transferase).
- For adenine: APRT (adenine phosphoribosyl transferase).
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GOUT:
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Gout is a group of metabolic diseases associated with hyperuricaemia and deposition of
crystals of monosodium urate in tissues.
Prevalence: 3/1000, males affected more than females (8-10:1).
Presentation usually occurs in males over 30 years of age and females after the
menopause.
There are 4 stages in the development of the disorder:
- 1. Asymptomatic hyperuricaemia:
- Hyperuricaemia is usually present for many years before the onset of symptoms.
- NB: Only 1 in 20 subjects with hyperuricaemia will eventually develop clinical
gout.
- 2. Acute gouty arthritis:
- Classical presentation is acute inflammation of the metatarsophalangeal joint of
the big toe (70%), and the first attack is usually monoarticular (affects only 1
joint).
- Other joints that may be involved are the ankle, knee, wrist, elbow, and small
joints of hands and feet.
- 3. Intercritical gout:
- Some patients may have only 1 attack, whilst others have recurrent attacks at
shorter intervals.
- Between attacks the patient is usually asymptomatic except for hyperuricaemia.
- 4. Chronic tophaceous gout:
- This follows recurrent attacks and is characterised by the development of tophi
(swellings containing uric acid crystals) in the periarticular tissue.
- Other sites include the helix of the ear, bursae and tendons.
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Complications of hyperuricaemia:
- Urolithiasis (kidney stones):
- 10% of gouty patients develop urate stones and 10% of all renal calculi are due to
urate.
- Renal failure:
- Acute renal failure due to obstructive uropathy (urate crystals) may occur during
cytotoxic treatment of malignancy (allopurinol cover should be used), and has
also been described in gouty subjects after severe exercise.
- Progressive chronic renal insufficiency is an important cause of morbidity and
mortality in untreated chronic tophaceous gout.
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Associated conditions:
- Alcoholism
- Dysmetabolic syndrome (Insulin resistance syndrome)(syndrome X): Obesity,
characteristic dyslipidaemia (increased triglycerides, decreased HDL cholesterol,
small dense LDL), hypertension, impaired glucose tolerance, prothrombotic state.
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Diagnosis:
The laboratory evaluation of hyperuricaemia is discussed below. It is important to
recognise that:
- Hyperuricaemia is not synonymous with gout (1 in 20 develop gout)
- Gout can be precipitated by a sudden change (either increase or decrease) in urate
concentration.
- An acute gout attack may be associated with a normal plasma urate level (due to a
fall in urate level 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.
Definitive diagnosis: Examination of synovial fluid under polarizing light microscope for
monosodium urate crystals (needle shaped and strongly negatively birefringent).
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Therapeutic agents used in gout and hyperuricaemia:
Three groups of drugs are available:
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1. Allopurinol:
- Allopurinol (structural analogue of hypoxanthine), and its major metabolite,
oxypurinol, inhibit the enzyme xanthine oxidase, producing a decrease in the
plasma and urinary concentrations of urate (hypoxanthine does not accumulate if
the salvage pathway is intact).
- Initial treatment with allopurinol should be covered with an anti-inflammatory
agent, because an acute attack of gout can be precipitated when the initial dose
is given (sudden decrease in urate can cause mobilisation from body pools).
2. Uricosuric agents:
- These drugs (eg Probenecid) increase the urinary excretion of urate by inhibiting
tubular reabsorption.
3. Anti-inflammatory agents:
- These agents (eg colchicine and indomethacin) are used symptomatically to
relieve the pain of acute gouty arthritis.
- They have no effect on plasma urate levels.
INBORN ERRORS OF PURINE METABOLISM:
A. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency (LeschNyhan syndrome):
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The Lesch-Nyhan syndrome is an X-linked recessive disorder, due to severe deficiency of
HGPRT.
It is characterised by hyperuricaemia, mental deficiency, spasticity, choreoathetosis and
self-mutilation.
Hyperuricaemia is due to decreased activity of the salvage pathway causing decreased
purine reutilization and increased uric acid synthesis. Relatively low levels of nucleotides
result in decreased inhibition of de novo synthesis, resulting in further overload of the
non-functioning salvage pathway and increased uric acid production.
B. Glucose 6-phosphatase deficiency (Glycogen storage disease type I/ Von Gierke’s
disease): (see figure 4)
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Deficiency of glucose 6-phosphatase (final enzyme in glycogenolysis pathway) results in
accumulation of glycogen, and hypoglycemia.
Increased metabolism of glucose 6-phosphate through glycolysis results in lactic acidosis.
Increased metabolism of glucose 6-phosphate through pentose phosphate pathway
increases formation of ribose 5-phosphate and NADPH.
Ribose 5-phosphate is a substrate for increased de novo purine nucleotide synthesis,
which is subsequently degraded to uric acid resulting in hyperuricaemia.
NADPH is a coenzyme in triglyceride synthesis, and overproduction results in
hypertriglyceridaemia.
Hyperuricaemia is aggravated by increased lactic acid which inhibits renal excretion of
uric acid.
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Figure 4: Carbohydrate metabolism
Glycogen
Glycogenolysis
Glucose 6-phosphatase
Pentose phosphate pathway
Glucose 6-phosphate
Glucose
Glycolysis
Ribose 5phosphate
NADPH
Purine
synthesis +
degradation
TGS
synthesis
Pyruvate
Lactate
Uric acid
C. Phosphoribosylpyrophosphate (PRPP) synthetase variant (with increased activity)
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An X-linked disorder resulting in purine overproduction and gout, due to excessive activity
of PRPP synthetase (first enzyme in de novo synthesis pathway) (see figure 5).
This increased activity seems to be due to resistance to negative feedback inhibition by
purine nucleotides.
Gouty arthritis and urate lithiasis associated with hyperuricaemia occurs in childhood or
early adult life.
Figure 5: De novo synthesis of purine nucleotides:
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LABORATORY INVESTIGATION:
Useful estimations in the evaluation of hyperuricaemia and gout are plasma urate, plasma
creatinine (renal function) and urinary urate.
A. Plasma urate:
Plasma urate is influenced by a wide variety of factors which should be taken into account
when interpreting results:
- Race: Markedly raised in Maoris.
- Sex: 0.05-0.10 mmol/l higher in males (? Increased renal clearance in females, ?
increased body mass in males).
- Age: Higher in older age groups.
- Body mass: Elevated in obesity (? Reflection of dietary habits).
- Diet: Increased values in:
- High meat (purine) intake
- Alcohol ingestion :
- Associated lactic acidosis decreases renal excretion.
- Alcohol increases ATP turnover.
- Purines in beer yeast.
- Fasting (ketones inhibit renal urate excretion and there is increased purine
degradation).
- Exercise: Increase (lactate effect).
- Pregnancy:
- Levels initially fall by up to 25% in the first trimester, but then rise to values 20%
higher than in the non-pregnant state.
- Commonly used reference values:
- Adult females: 0.21-0.36 mmol/l
- Adult males: 0.31-0.47 mmol/l.
B. Urinary urate:
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Hyperuricaemia may be due to overproduction or decreased renal excretion or both.
The rate of renal urate excretion provides a rough index of the production rate, provided
renal function is normal.
Normal excretion rate: < 6.0 mmol/day (normal diet) / < 3.5 mmol/day (low purine, alcohol
free diet for 5-7 days’ duration).
Values in excess of the above are presumptive evidence of urate overproduction. (see
case studies)
C. Plasma creatinine:
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Hyperuricaemia may cause renal failure and renal failure will result in hyperuricaemia.
In renal insufficiency:
- The plasma urate usually does not begin to rise until the GFR (glomerular filtration
rate) falls to below 20 ml/min (equivalent to a plasma creatinine of 300-400 umol/l).
- As renal failure progresses the plasma urate rises to a level of around 0.6 mmol/l and
then plateaus; thus a urate in excess of 0.6 mmol/l suggests that renal failure is not
the only cause of the high urate.
D. Urinary urate:creatinine ratio:
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The urinary urate:creatinine ratio may be used to differentiate acute renal failure
precipitated by hyperuricaemia (urate nephropathy) from renal failure due to other
causes.
- Urate nephropathy: urinary urate:creatinine ratio (mmol/l:mmol/l) > 0.70.
- Acute renal failure due to other causes: ratio < 0.70.
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CAUSES OF HYPERURICAEMIA:
A. Physiological/environmental factors
See above
B. Primary hyperuricaemia
Overproduction:
- Idiopathic
- Glucose-6-phosphatase deficiency (Von Gierke’s disease)
- HGPRT deficiency (Lesch-Nyhan syndrome)
Reduced excretion:
- Idiopathic
C. Secondary hyperuricaemia
Overproduction:
- Increased nucleic acid turnover:
- Myeloproliferative disease, eg polycythemia vera
- Lymphoma, leukemia
- Multiple myeloma
- Cytotoxic therapy of malignancies
- Psoriasis
- Disordered ATP metabolism:
- Alcohol (increased ATP turnover)
- Tissue hypoxia
- Excessive dietary purine intake
Reduced excretion:
- Decreased glomerular filtration:
- Renal failure
- Decreased secretion (competition with urate for tubular secretion):
- Lactic acidosis – alcohol, exercise
- Ketoacidosis – alcohol, diabetes, starvation
- Drugs – low dose salicylate
- Increased reabsorption:
- Hypovolemia, eg diuretics.
CASE STUDIES:
Case 1:
A man aged 50 years with an acutely swollen and painful right knee. On careful history taking
and thorough physical examination no secondary causes were found.
Plasma
Urate
Creat
0.71 mmol/l (0.31-0.47)
120 umol/l (60-120)
Urine
Urate (purine free diet) 10.5 mmol/day (< 3.5)
Questions:
a) What is your diagnosis based on clinical information and laboratory investigations?
b) Is the patient an “overproducer” or “undersecretor”?
c) What is the treatment of choice in this patient?
d) What further investigation would you like to perform to confirm the diagnosis?
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Case 2:
Acute myeloid leukemia in a 26-year-old woman.
Date
23/4
Plasma
Urate
Creat
0.92
90
Urine
Urate (normal diet)
10.5
26/4
0.18 mmol/l
110 umol/l
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mmol/day
(0.21-0.36)
(60-120)
(<6.0)
Allopurinol was begun on 23/4.
Questions:
a) What is your diagnosis based on clinical information and laboratory investigations?
b) Is the patient an “overproducer” or “undersecretor”?
Case 3:
Chronic renal failure in a 39-year-old man.
Plasma
Urate
Creat
0.78
0.90
mmol/l (0.31-0.47)
mmol/l (60-120)
Urine
Creat Clearance
Urate (normal diet)
10
1.2
ml/min (> 120)
mmol/day (< 6.0)
Questions:
a) What is your diagnosis based on clinical information and laboratory investigations?
b) Is the patient an “overproducer” or “undersecretor”?
c) Is the plasma urate level appropriate for the degree of renal failure?
REFERENCES:
1. Walmsley RN, White GH. A guide to diagnostic clinical chemistry. 3rd edition. Oxford:
Blackwell Scientific Publications, 1994: 416-425.
2. Marshall WJ. Clinical Chemistry. 4th edition. Edinburgh: Mosby, 2000: 254-260.