Uric Acid

Uric acid is the end product of purine metabolism in humans, who lack uricase. About two thirds is made endogenously and one third comes from diet. About 70% is excreted by the kidney (filtered, then reabsorbed and secreted in the proximal tubule through URAT1, GLUT9 and ABCG2) and the rest through the gut. It is measured by the uricase peroxidase method in serum. Monosodium urate crystallises when the serum concentration exceeds the solubility limit of about 400 micromol/L (6.8 mg/dL) at 37 °C, which is the basis of gout and uric acid stones.

Hyperuricaemia is common (about 10 to 20% of adults in many populations) and most affected people never develop gout. The risk of gout rises steeply with concentration. The test is used to support the diagnosis of gout, to set and monitor urate lowering treatment, and to assess tumour lysis risk. It is not diagnostic of gout on its own.

Indications. Suspected gout and monitoring of urate lowering therapy, recurrent uric acid or calcium oxalate stones, chronic kidney disease, tumour lysis risk or established tumour lysis, haematological malignancy before chemotherapy, hypertension in pregnancy, unexplained polyarthritis, and before rasburicase.

Specimen. Serum or heparin plasma. Fasting is preferred, and alcohol and a high purine meal are avoided for 24 hours. Where rasburicase has been given, the sample must go on ice and be analysed within 4 hours, because the enzyme continues to destroy uric acid in the tube and gives falsely low results.

Reference ranges. Men 200 to 430 micromol/L (3.4 to 7.2 mg/dL), women 140 to 360 micromol/L (2.4 to 6.0 mg/dL). Premenopausal women have lower values because oestrogen promotes urinary excretion, and values converge after the menopause. Conversion: mg/dL multiplied by 59.5 gives micromol/L.

Hyperuricaemia. Defined as over 420 micromol/L (7.0 mg/dL) in men and over 360 micromol/L (6.0 mg/dL) in women in many laboratories, with the saturation limit of about 400 micromol/L (6.8 mg/dL) the relevant physical threshold.

Treatment targets in gout. Under 360 micromol/L (6.0 mg/dL) for most patients, and under 300 micromol/L (5.0 mg/dL) in severe, tophaceous or frequently recurrent gout, until crystals dissolve. Levels are checked every 2 to 5 weeks while the dose is titrated, then every 6 to 12 months.

Diagnosis of gout. Identification of needle shaped, negatively birefringent monosodium urate crystals in synovial fluid or tophus aspirate under polarised light is diagnostic. Serum urate may be normal or low during an acute attack in a substantial minority of patients, because inflammation increases renal excretion, so a normal level does not exclude gout. The level is best measured at least 2 weeks after the flare has settled.

Tumour lysis syndrome (laboratory criteria). Two or more of uric acid 476 micromol/L (8 mg/dL) or more (or a rise of 25%), potassium 6.0 mmol/L or more, phosphate 1.45 mmol/L or more, and corrected calcium 1.75 mmol/L or less, within 3 days before to 7 days after starting treatment. Clinical tumour lysis adds creatinine rise, arrhythmia or seizures.

Acute urate nephropathy. A urinary uric acid to creatinine ratio over 1.0 (mg to mg) in acute kidney injury suggests uric acid precipitation, and a ratio under 1.0 suggests other causes.

Pre-eclampsia. Uric acid rises with the disease and correlates with maternal and foetal risk, but it lacks the accuracy to diagnose or exclude it, and it is used only as a supporting measure.

Raised (overproduction). High purine diet (red meat, offal, seafood), fructose and sugar sweetened drinks, alcohol (especially beer), obesity, myeloproliferative neoplasms, leukaemia and lymphoma, tumour lysis, haemolysis, psoriasis, rhabdomyolysis, strenuous exercise, and inherited disorders (Lesch-Nyhan syndrome, partial HPRT deficiency, glycogen storage disease type I, PRPP synthetase overactivity).

Raised (reduced excretion). Chronic kidney disease, dehydration, lactic acidosis and ketoacidosis, hypothyroidism, hyperparathyroidism, sarcoidosis, pre-eclampsia, lead nephropathy, Down syndrome, inherited variants of SLC2A9, ABCG2 and SLC22A12, and drugs: thiazides, loop diuretics, low dose aspirin, ciclosporin, tacrolimus, pyrazinamide, ethambutol, nicotinic acid, levodopa and cytotoxic drugs.

Lowered. Allopurinol, febuxostat, probenecid, benzbromarone, rasburicase, SGLT2 inhibitors, losartan, fenofibrate, high dose vitamin C and contrast agents, pregnancy (first and second trimesters), SIADH, Fanconi syndrome and other tubular disorders, Wilson disease, xanthine oxidase deficiency, severe liver disease, and malnutrition.

Gout risk. Annual incidence of gout rises from under 1% at urate under 360 micromol/L to about 5% at levels over 540 micromol/L (9 mg/dL). Asymptomatic hyperuricaemia is not usually treated, except in tumour lysis risk and recurrent urate stones.

Critical findings needing immediate action.

• Uric acid over 476 micromol/L with rising creatinine, potassium or phosphate in a patient with haematological malignancy starting treatment, or established tumour lysis.
• Uric acid with oliguria and a high urinary uric acid to creatinine ratio.
• Rasburicase is contraindicated in G6PD deficiency, so a deficiency screen is advised before it is given where risk exists.
• A hot, swollen joint with fever needs urgent joint aspiration, since septic arthritis can coexist with gout, and a high serum urate does not exclude infection.

Interferences and pitfalls.

• The acute attack dip makes a single level during a flare unreliable.
• Peroxidase based assays are lowered by high dose ascorbic acid and some contrast agents, and raised or lowered by haemolysis, severe lipaemia and hyperbilirubinaemia depending on the method.
• Rasburicase degrades uric acid in vitro unless the sample is cooled and analysed promptly.
• Diurnal variation, diet, alcohol, exercise and fasting alter the result, and levels vary by about 10 to 15% in the same person.
• Serum urate does not measure total body urate load and tophus burden.
• Concurrent drug therapy needs review, since many drugs raise or lower urate.
• Normal urate with strong clinical suspicion of gout is investigated by joint aspiration.

Special groups.

• Children: values are lower (about 140 to 340 micromol/L) and rise at puberty, especially in boys. A high value in a child suggests an inherited purine disorder, renal disease or tumour lysis.
• Pregnancy: levels fall early in pregnancy and rise in the third trimester, and a sharp rise suggests pre-eclampsia.
• Older adults: reduced renal clearance and diuretic use are the main drivers, and gout is often atypical, affecting the hands and tophi.
• Chronic kidney disease: dose of allopurinol and febuxostat is adjusted to eGFR, with the target kept.
• Ancestry: levels and gout risk are higher in some Pacific, Maori and East Asian populations, and HLA-B*5801 carriage increases the risk of severe allopurinol hypersensitivity in people of Han Chinese, Thai and Korean ancestry, so testing is considered before starting.
• Regions with high alcohol and sugar sweetened drink intake carry a higher burden.

Follow up tests. Synovial fluid analysis with crystal examination, joint imaging (ultrasound double contour sign, dual energy CT), urea and electrolytes with eGFR, 24-hour urine uric acid and urine pH, urine uric acid to creatinine ratio, lipid profile and HbA1c, liver function tests, thyroid function tests, full blood count, HLA-B*5801 genotyping where indicated, G6PD assay before rasburicase, stone analysis, renal tract imaging.