Dr Marita du Plessis Department of Chemical Pathology January 2002

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).

(see Marshall, p 254-257) 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



However. HGPRT = hypoxanthine-guanine phosphoribosyl transferase. Xanthine is metabolised to uric acid by the enzyme xanthine oxidase. . but AMP/adenosine have to be converted to IMP/inosine first. also responsible for conversion of hypoxanthine to xanthine. adenosine and guanosine) (NUCLEOSIDES: purine base + sugar). Nucleotide degradation involves the formation of the respective nucleosides (inosine. which can be converted to AMP (adenosine monophosphate) and GMP (guanosine monophosphate) (NUCLEOTIDES: purine base + sugar + PO4). excretion of uric acid results in net energy loss. salvage pathways exist to convert purines back to their parent nucleotides and are therefore energy saving – accomplished by the following enzymes: .2 Figure 3: Diagram of the pathways of purine nucleotide metabolism and uric acid synthesis in humans. Because de novo synthesis is an energy requiring process.For guanine and hypoxanthine: HGPRT (hypoxanthine-guanine phosphoribosyl transferase). adenine and guanine) (PURINE BASES). these are subsequently metabolised to the respective purine bases (hypoxanthine. .For adenine: APRT (adenine phosphoribosyl transferase). Hypoxanthine and guanine can be metabolised directly to xanthine. - - De novo synthesis leads to the formation of IMP (inosine monophosphate). APRT = adenine phosphoribosyl transferase.

Presentation usually occurs in males over 30 years of age and females after the menopause.Hyperuricaemia is usually present for many years before the onset of symptoms. .Urolithiasis (kidney stones): .Gout can be precipitated by a sudden change (either increase or decrease) in urate concentration.Between attacks the patient is usually asymptomatic except for hyperuricaemia.This follows recurrent attacks and is characterised by the development of tophi (swellings containing uric acid crystals) in the periarticular tissue. - - - - . . decreased HDL cholesterol.Acute renal failure due to obstructive uropathy (urate crystals) may occur during cytotoxic treatment of malignancy (allopurinol cover should be used).4. knee. Diagnosis: The laboratory evaluation of hyperuricaemia is discussed below. decrease in alcohol consumption). . small dense LDL).NB: Only 1 in 20 subjects with hyperuricaemia will eventually develop clinical gout. impaired glucose tolerance. Acute gouty arthritis: . males affected more than females (8-10:1). wrist. .Renal failure: . Prevalence: 3/1000. and has also been described in gouty subjects after severe exercise. .Other joints that may be involved are the ankle. prothrombotic state. bursae and tendons. .3.3 GOUT: Gout is a group of metabolic diseases associated with hyperuricaemia and deposition of crystals of monosodium urate in tissues. characteristic dyslipidaemia (increased triglycerides. whilst others have recurrent attacks at shorter intervals. .Dysmetabolic syndrome (Insulin resistance syndrome)(syndrome X): Obesity. Definitive diagnosis: Examination of synovial fluid under polarizing light microscope for monosodium urate crystals (needle shaped and strongly negatively birefringent). .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.10% of gouty patients develop urate stones and 10% of all renal calculi are due to urate. Intercritical gout: .Classical presentation is acute inflammation of the metatarsophalangeal joint of the big toe (70%).Progressive chronic renal insufficiency is an important cause of morbidity and mortality in untreated chronic tophaceous gout. hypertension. Associated conditions: . elbow.Hyperuricaemia is not synonymous with gout (1 in 20 develop gout) . .Other sites include the helix of the ear. and the first attack is usually monoarticular (affects only 1 joint). Diagnosis is therefore usually made on clinical grounds. Chronic tophaceous gout: . although hyperuricaemia will be demonstrated at some stage. There are 4 stages in the development of the disorder: . It is important to recognise that: . .1.Alcoholism . Asymptomatic hyperuricaemia: .2. and small joints of hands and feet.Some patients may have only 1 attack. Complications of hyperuricaemia: .

Allopurinol: . spasticity. - INBORN ERRORS OF PURINE METABOLISM: A. 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). Glucose 6-phosphatase deficiency (Glycogen storage disease type I/ Von Gierke’s disease): (see figure 4) Deficiency of glucose 6-phosphatase (final enzyme in glycogenolysis pathway) results in accumulation of glycogen. inhibit the enzyme xanthine oxidase. Anti-inflammatory agents: . choreoathetosis and self-mutilation. mental deficiency. . resulting in further overload of the non-functioning salvage pathway and increased uric acid production. Increased metabolism of glucose 6-phosphate through glycolysis results in lactic acidosis. and hypoglycemia. . and its major metabolite. which is subsequently degraded to uric acid resulting in hyperuricaemia. B. It is characterised by hyperuricaemia. Hyperuricaemia is aggravated by increased lactic acid which inhibits renal excretion of uric acid. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency (LeschNyhan syndrome): The Lesch-Nyhan syndrome is an X-linked recessive disorder.Initial treatment with allopurinol should be covered with an anti-inflammatory agent.These drugs (eg Probenecid) increase the urinary excretion of urate by inhibiting tubular reabsorption. and overproduction results in hypertriglyceridaemia. .4 Therapeutic agents used in gout and hyperuricaemia: Three groups of drugs are available: 1.Allopurinol (structural analogue of hypoxanthine). due to severe deficiency of HGPRT. 2. Uricosuric agents: .They have no effect on plasma urate levels. Increased metabolism of glucose 6-phosphate through pentose phosphate pathway increases formation of ribose 5-phosphate and NADPH. oxypurinol. producing a decrease in the plasma and urinary concentrations of urate (hypoxanthine does not accumulate if the salvage pathway is intact).These agents (eg colchicine and indomethacin) are used symptomatically to relieve the pain of acute gouty arthritis. 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. Ribose 5-phosphate is a substrate for increased de novo purine nucleotide synthesis. NADPH is a coenzyme in triglyceride synthesis. 3.

Phosphoribosylpyrophosphate (PRPP) synthetase variant (with increased activity) An X-linked disorder resulting in purine overproduction and gout. This increased activity seems to be due to resistance to negative feedback inhibition by purine nucleotides. due to excessive activity of PRPP synthetase (first enzyme in de novo synthesis pathway) (see figure 5).5 Figure 4: Carbohydrate metabolism Glycogen Glycogenolysis Glucose 6-phosphatase Pentose phosphate pathway Glucose 6-phosphate Glycolysis Ribose 5phosphate NADPH Pyruvate Lactate Glucose Purine synthesis + degradation TGS synthesis Uric acid C. Gouty arthritis and urate lithiasis associated with hyperuricaemia occurs in childhood or early adult life. Figure 5: De novo synthesis of purine nucleotides: .

Age: Higher in older age groups.70.6 LABORATORY INVESTIGATION: Useful estimations in the evaluation of hyperuricaemia and gout are plasma urate.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).47 mmol/l. Plasma urate: Plasma urate is influenced by a wide variety of factors which should be taken into account when interpreting results: . .10 mmol/l higher in males (? Increased renal clearance in females. . (see case studies) C. Urinary urate:creatinine ratio: 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. .Adult males: 0. D. .70.36 mmol/l .Associated lactic acidosis decreases renal excretion.High meat (purine) intake . Urinary urate: Hyperuricaemia may be due to overproduction or decreased renal excretion or both. . thus a urate in excess of 0.Fasting (ketones inhibit renal urate excretion and there is increased purine degradation).0 mmol/day (normal diet) / < 3.Sex: 0.6 mmol/l suggests that renal failure is not the only cause of the high urate. Plasma creatinine: Hyperuricaemia may cause renal failure and renal failure will result in hyperuricaemia.Exercise: Increase (lactate effect).21-0.Urate nephropathy: urinary urate:creatinine ratio (mmol/l:mmol/l) > 0. alcohol free diet for 5-7 days’ duration).As renal failure progresses the plasma urate rises to a level of around 0. The rate of renal urate excretion provides a rough index of the production rate. . . Normal excretion rate: < 6.Levels initially fall by up to 25% in the first trimester. . In renal insufficiency: .31-0. Values in excess of the above are presumptive evidence of urate overproduction. . but then rise to values 20% higher than in the non-pregnant state. plasma creatinine (renal function) and urinary urate.Alcohol ingestion : . . B.Alcohol increases ATP turnover.Acute renal failure due to other causes: ratio < 0.Body mass: Elevated in obesity (? Reflection of dietary habits).Pregnancy: .Race: Markedly raised in Maoris.Commonly used reference values: . ? increased body mass in males).6 mmol/l and then plateaus. A.Purines in beer yeast.5 mmol/day (low purine. . provided renal function is normal. . .05-0.Adult females: 0.Diet: Increased values in: . .

Lymphoma. CASE STUDIES: Case 1: A man aged 50 years with an acutely swollen and painful right knee.Alcohol (increased ATP turnover) .Tissue hypoxia . eg diuretics.Excessive dietary purine intake Reduced excretion: .Glucose-6-phosphatase deficiency (Von Gierke’s disease) .Increased nucleic acid turnover: .Idiopathic .Decreased secretion (competition with urate for tubular secretion): .Idiopathic C.31-0. Physiological/environmental factors See above B.Disordered ATP metabolism: .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? .Increased reabsorption: .Cytotoxic therapy of malignancies . Primary hyperuricaemia Overproduction: . leukemia . Secondary hyperuricaemia Overproduction: . diabetes.47) 120 umol/l (60-120) Urine Urate (purine free diet) 10.Lactic acidosis – alcohol.Drugs – low dose salicylate .HGPRT deficiency (Lesch-Nyhan syndrome) Reduced excretion: .Ketoacidosis – alcohol.Decreased glomerular filtration: . Plasma Urate Creat 0.71 mmol/l (0.5 mmol/day (< 3. On careful history taking and thorough physical examination no secondary causes were found. eg polycythemia vera .Myeloproliferative disease. exercise . starvation .7 CAUSES OF HYPERURICAEMIA: A.Hypovolemia.Multiple myeloma .Renal failure .Psoriasis .

2. 4th edition. Oxford: Blackwell Scientific Publications.90 10 1. White GH.18 mmol/l 110 umol/l mmol/day (0.47) mmol/l (60-120) ml/min (> 120) mmol/day (< 6. .92 90 10. Plasma Urate Creat Urine Creat Clearance Urate (normal diet) 0.5 26/4 0. Date Plasma Urate Creat Urine Urate (normal diet) 23/4 0.2 mmol/l (0. Edinburgh: Mosby. Marshall WJ.8 Case 2: Acute myeloid leukemia in a 26-year-old woman.78 0. 2000: 254-260. A guide to diagnostic clinical chemistry. 1994: 416-425.31-0. 3 rd edition.21-0.36) (60-120) (<6. Clinical Chemistry. Walmsley RN.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: 1.0) 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.

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