Rheumatology - Purine biology and metabolism
Acide urique | Clinique Omicron Québec
Uric acid is the end product of purine catabolism in humans, resulting from the oxidation of hypoxanthine and xanthine by hepatic and intestinal xanthine oxidase. Unlike most mammals, which have an enzyme called uricase to break down uric acid into the much more soluble allantoin, the human species has lost this functional gene during evolution, which explains why blood uric acid concentrations are so much higher than in other vertebrates. Physiologically, uric acid is present in the blood as monosodium urate at normal plasma pH, and is one of the body's main antioxidants, helping to neutralize free radicals and protect cells against oxidative stress. Around two-thirds of uric acid is eliminated via the kidneys, by glomerular filtration followed by predominant tubular reabsorption, and one-third via the digestive tract. When uric acid production exceeds elimination capacity, or when renal excretion is insufficient, uricemia rises above the plasma saturation threshold for monosodium urate, set at around 360 to 420 micromoles per liter, depending on physicochemical conditions. Above this threshold, monosodium urate crystals can be deposited in joints, bursae, tendons, periarticular soft tissues and renal parenchyma, giving rise to the characteristic clinical manifestations of gout and uratic nephropathy. Gout is the world's most common microcrystalline arthropathy, affecting around 3 to 4 % of the Canadian adult population, with a clear male predominance and a growing incidence linked to an ageing population, increasing obesity and the widespread use of hyperuricemic drugs.
Prompt medical consultation recommended
An acute gout attack manifested by sudden onset of intense joint pain, accompanied by marked swelling, heat and redness of the affected joint, with or without fever, requires prompt medical consultation to confirm the diagnosis, exclude septic arthritis and institute effective anti-inflammatory treatment. Septic arthritis in microcrystalline arthropathy can threaten joint integrity in the absence of prompt antibiotic treatment.
Uricemia reference values
Normal uricemia values vary according to sex, age and the laboratory performing the assay. Results can be expressed in micromoles per liter (µmol/L) or milligrams per deciliter (mg/dL), with a conversion factor of 59.5 between the two units.
| Population | Normal values (µmol/L) | Normal values (mg/dL) | Comments |
|---|---|---|---|
| Adult male | 200 - 420 µmol/L | 3.4 - 7.0 mg/dL | Higher values than in women of childbearing age, due to the uricosuric effect of estrogen |
| Women before menopause | 140 - 360 µmol/L | 2.4 - 6.0 mg/dL | Estrogens promote renal excretion of uric acid, lowering uricemia by 60 to 80 µmol/L compared to men |
| Women after menopause | 200 - 420 µmol/L | 3.4 - 7.0 mg/dL | The fall in estrogen during the menopause leads to an increase in uricemia, which gradually returns to male values. |
| Children (before puberty) | 120 - 300 µmol/L | 2.0 - 5.0 mg/dL | Low values associated with higher relative renal clearance; uricemia increases progressively from puberty, especially in boys |
| Plasma saturation threshold | 360 - 420 µmol/L | 6.0 - 7.0 mg/dL | Above this threshold, the risk of monosodium urate crystallization in tissues increases significantly, depending on local temperature and pH |
| Therapeutic target (treated gout) | < 360 µmol/L | < 6.0 mg/dL | Minimum target recommended for progressive dissolution of existing urate deposits; target less than 300 µmol/L (5.0 mg/dL) in tophaceous or severe forms |
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Hyperuricemia is defined biologically as uricemia above 420 µmol/L (7.0 mg/dL) in men and above 360 µmol/L (6.0 mg/dL) in women, irrespective of the presence or absence of symptoms. It is essential to remember that asymptomatic hyperuricemia, without documented urate deposits or clinical manifestations of gout, does not systematically require hypo-uricemic drug treatment, but does call for evaluation of the underlying causes and appropriate hygienic and dietary measures.
Purine metabolism and sources of uric acid
Uric acid production results from two main sources: catabolism of endogenous purines produced by cell renewal, and degradation of exogenous purines supplied by the diet. The relationship between these two sources partly determines uricemia levels and management strategies.
| Source | Mechanism | Contribution to uricemia |
|---|---|---|
| Endogenous purines (cellular catabolism) | Degradation of nucleic acids (DNA and RNA) released during physiological cell renewal, apoptosis, accelerated cell destruction (hemolysis, tumor cytolysis); purines adenine and guanine are converted into hypoxanthine, then xanthine, then uric acid by xanthine oxidase | Approx. 70 % of total uric acid production; particularly high in cases of rapid cell proliferation, tumor lysis, hemopathies or extensive psoriasis |
| Exogenous purines (food) | Intestinal degradation of dietary purines contained in red meats, offal, game, seafood, shellfish, sardines, anchovies and certain legumes; digestive absorption of purine bases and hepatic conversion to uric acid. | Approximately 30 % of total production; adoption of a low-purine diet can lower uricemia by an average of 60 to 120 µmol/L |
| Dietary fructose | Fructose is metabolized in hepatocytes by fructokinase, consuming ATP and generating AMP, which is degraded to uric acid via the usual purine pathway; a mechanism independent of the purine content of the food. | Contributes significantly to hyperuricemia associated with high consumption of fructose-sweetened corn syrup beverages (sodas, industrial juices) and alcohol (especially beer, rich in both purines and fermented fructose) |
Causes of hyperuricemia
Hyperuricemia results either from uric acid overproduction or renal underexcretion, or from a combination of the two, which is in fact the most frequent situation in clinical practice. The distinction between these mechanisms guides the choice of hypo-uricemic treatment.
| Mechanism | Cause | Clinical details |
|---|---|---|
| Overproduction (about 10 % of hyperuricemias) | A diet rich in purines and fructose | Red meats, offal, seafood, beer, soft drinks; moderate contribution but easily corrected by dietary measures |
| Overproduction | Hemopathies and accelerated cell proliferation | Leukemias, lymphomas, polyglobulia Vaquez, multiple myeloma, sickle cell anemia, thalassemias, chronic hemolytic anemia; accelerated renewal of cellular nucleic acids |
| Overproduction | Tumor lysis syndrome | Massive release of intracellular purines during rapid destruction of tumor cells under chemotherapy; metabolic emergency that can lead to acute renal failure through urate precipitation in the tubules |
| Overproduction | Rare hereditary enzyme deficiencies | Lesch-Nyhan syndrome (complete X-linked HGPRT deficiency): severe hyperuricemia, early-onset gout, uric lithiasis, severe neurological disorders, self-mutilation; partial HGPRT deficiency (Kelley-Seegmiller syndrome): hyperuricemia, nephropathy, juvenile gout without neurological involvement; overactivity of PRPP synthetase. |
| Overproduction | Extensive psoriasis, intense and prolonged physical exercise | Increased cell turnover in psoriasis; muscle catabolism and ATP degradation during intense, repeated physical effort |
| Renal under-excretion (approx. 90 % of hyperuricemias) | Chronic renal failure | Reduction in glomerular filtration and tubular urate secretion; uricemia rises progressively as eGFR falls; most frequent cause of severe hyperuricemia |
| Renal under-excretion | Hyperuricemic drugs | Thiazide and loop diuretics (inhibition of urate secretion); low-dose aspirin (inhibition of urate secretion at low concentration); cyclosporine and tacrolimus (tubular nephrotoxicity); pyrazinamide and ethambutol (antituberculosis drugs); nicotinic acid (niacin) in high doses; beta-blockers to a lesser degree |
| Renal under-excretion | Hypertension and metabolic syndrome | Reduced renal plasma flow and tubular urate secretion; insulin resistance increases tubular urate reabsorption via the URAT1 cotransporter; bidirectional association between hyperuricemia and hypertension |
| Renal under-excretion | Chronic alcohol consumption | Alcohol inhibits renal urate excretion through competition with lactic acid (alcoholic lactic acidosis); beer combines the renal inhibitory effect with a direct supply of purines (guanosine); wine and spirits have a lesser hyperuricemic effect with equivalent consumption. |
| Renal under-excretion | Hypothyroidism, hypoparathyroidism, lead poisoning | Reduced renal urate clearance through various mechanisms; lead poisoning leads to proximal tubulopathy with reduced urate secretion (saturnine gout, historically known as «aristocrats» gout"). |
| Dehydration and prolonged fasting | Mixed causes | Dehydration reduces diuresis and concentrates plasma urate; fasting generates ketone bodies that compete with urate for tubular secretion; frequent trigger mechanism for acute gout attacks during hospitalization or strict diets |
Causes of hypouricemia
Hypouricemia, defined as uricemia below 120 µmol/L (2.0 mg/dL), is less frequent than hyperuricemia, but is also a biological signal worthy of investigation. It may result from reduced uric acid production or increased renal excretion.
- Xanthine oxidase deficiency (hereditary xanthinuria types I and II): accumulation of xanthine and hypoxanthine, xanthine renal lithiasis, crystalline myopathy; uricemia collapsed or undetectable
- Treatment with allopurinol or febuxostat: inhibition of xanthine oxidase reducing uric acid production; iatrogenic hypouricemia in therapeutic overdoses
- Fanconi syndrome and proximal tubulopathies: excessive renal urate loss due to proximal tubular reabsorption failure; associated with normoglycemic glycosuria, aminoaciduria and phosphaturia
- Severe liver disease and end-stage hepatocellular failure: reduced hepatic uric acid synthesis due to deficiency of functional hepatocytes
- Severe malnutrition and very low protein intake: reduction in purine substrate available for uric acid synthesis
- Uricosuric drugs: probenecid, benzbromarone, losartan (partial uricosuric effect), fenofibrate, high-dose vitamin C
- Pregnancy: hemodilution and increased renal urate clearance in the first trimester; uricemia falls physiologically in early pregnancy, then rises again in the third trimester
Clinical manifestations of hyperuricemia
Hyperuricemia may remain asymptomatic for many years before manifesting itself clinically. When it persistently exceeds the plasma saturation threshold, the crystallization of monosodium urate in tissues generates a spectrum of progressive clinical manifestations.
| Event | Clinical description | Mechanism |
|---|---|---|
| Acute gout attack | Monoarticular arthritis of abrupt onset, often nocturnal, with initial maximal pain, swelling, heat and erythema of the joint; the first metatarsophalangeal joint (podgre) is affected in 50 to 70 % of the first attacks; knee, ankle, tarsus and wrist are also frequent; the attack lasts 7 to 14 days without treatment and regresses spontaneously | Precipitation of intra-articular monosodium urate crystals phagocytosed by synovial macrophages, triggering a massive inflammatory cascade via the NLRP3 inflammasome and IL-1beta release |
| Intercritical drop | Asymptomatic period between attacks during which urate deposits continue to accumulate; without background treatment, attacks become progressively more frequent, longer and affect more joints. | Silent accumulation of urate crystals in cartilage, tendons and periarticular tissues without active inflammatory response |
| Chronic tophaceous gout | Visible, palpable urate deposits (tophi) under the skin, classically in the ears (helix), elbows (olecranon), fingers, toes and Achilles tendons; chronic arthropathy with progressive bone and cartilage destruction; late stage after years of untreated hyperuricemia | Massive accumulation of urate crystals forming whitish concretions surrounded by a chronic giant cell inflammatory reaction |
| Renal uric lithiasis | Radio-transparent kidney stones (not visible on the standard unprepared abdomen, but visible on ultrasound and CT scan), which can cause recurrent renal colic. | Precipitation of uric acid in the urinary tract favored by acidic urine (urinary pH below 5.5), hyperuricuria and low urine volume |
| Chronic uratic nephropathy | Urate deposits in interstitial renal parenchyma, associated with chronic inflammation and progressive fibrosis; contribution to chronic renal failure, especially in long-standing severe hyperuricemia | Urate crystallization in renal medullary interstitium, local granulomatous inflammatory reaction and progressive tubular ischemia |
| Metabolic and cardiovascular associations | Hyperuricemia is frequently associated with metabolic syndrome, abdominal obesity, arterial hypertension, insulin resistance, dyslipidemia and chronic renal failure; complex bidirectional relationship, possibly causal for hypertension and nephropathy | Uric acid inhibits endothelial nitric oxide (NO) bioavailability, activates the renin-angiotensin system and promotes systemic vascular inflammation |
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During an acute gout attack, the uricemia measured may be normal or even lower, due to the redistribution of plasma urates to the tissue spaces as a result of the inflammatory reaction. A normal uricemia result during an attack therefore does not exclude the diagnosis of gout, nor should it be ruled out. Ideally, uricemia should be measured at a distance from an attack, at least three to four weeks after the complete resolution of inflammatory symptoms.
Diagnostic approach
The diagnosis of hyperuricemia is a biological one, requiring only a fasting plasma assay to be established. The diagnostic approach then aims to identify the dominant mechanism (overproduction or underexcretion), the underlying causes and the target organs potentially affected.
| Review | Indication | Clinical contribution |
|---|---|---|
| Fasting uraemia | Basic examination; to be carried out at a distance from any recent inflammatory crisis (at least 3-4 weeks), with no recent dietary changes and no introduction or discontinuation of uricosuric drugs. | Confirmation of hyperuricemia and quantification of the degree of elevation to guide treatment strategy |
| 24-hour uricuria | Useful for distinguishing between renal overproduction and underexcretion; to be carried out in the absence of hypo-uricemic treatment and on the usual diet. | Uricuria greater than 700-800 mg/24h: overproduction of uric acid; normal or low uricuria with hyperuricemia: predominant renal underexcretion; guides choice between allopurinol/febuxostat (all causes) and uricosurics (underexcretion without lithiasis or renal insufficiency) |
| Creatinine and eGFR | Systematic for any confirmed hyperuricemia | Assessment of renal function, a determining factor in the choice and dosage of hyperuricemia-lowering therapy; renal insufficiency is both cause and consequence of hyperuricemia |
| Complete metabolic workup | Fasting blood glucose, HbA1c, lipid profile, blood pressure, waist circumference | Systematic search for associated metabolic syndrome, common in primary gout; conditions overall management of cardiovascular risk |
| Synovial fluid analysis | In case of diagnostic doubt, particularly to distinguish a gout attack from septic arthritis or chondrocalcinosis of the joints (pseudogout) | Detection of needle-shaped monosodium urate crystals, with negative birefringence in polarized light, inside or outside polynuclear cells; reference examination for diagnosis of certainty. |
| Joint ultrasound | First-line imaging for the detection of articular and periarticular urate deposits | Double contour sign (urate deposits on the surface of hyaline cartilage) and hyperechoic intra-articular tophi are highly suggestive of gout; greater sensitivity than standard radiography for early lesions |
| Low-dose CT scanner (DECT) | Dual-energy computed tomography to characterize the chemical nature of joint deposits | Highly accurate detection and quantification of monosodium urate deposits; useful in atypical or polyarticular forms, for monitoring tophi melting under treatment and in complex diagnostic situations |
| X-rays of affected joints | Useful in chronic forms to assess progressive osteoarticular lesions | Die-cut geodes at a distance from the joint spaces, with dense bone edging, pathognomonic of advanced tophaceous gout |
| Blood count and cytolysis test | In cases of suspected haemopathy or accelerated cell lysis as a cause of overproduction | Referral to leukemia, lymphoma, polycythemia or chronic hemolysis in case of associated abnormalities |
| TSH | Screening for underlying hypothyroidism contributing to reduced renal urate excretion | Partial normalization of uricemia under levothyroxine replacement therapy in proven hypothyroidism |
Therapeutic strategies
The management of symptomatic hyperuricemia is bimodal, distinguishing between treatment of the acute crisis to rapidly reduce inflammation, and background treatment aimed at permanently lowering uricemia below the saturation threshold to prevent recurrences and dissolve existing deposits.
| Approach | Treatment | Indications and procedures |
|---|---|---|
| Acute crisis: non-steroidal anti-inflammatory drugs (NSAIDs) | Indomethacin, naproxen, ibuprofen in anti-inflammatory doses | First-line treatment of acute attacks in patients with no contraindications; to be started as early as possible in the first few hours of the attack; to be continued until complete resolution of symptoms (7 to 14 days); contraindicated in cases of significant renal impairment, active peptic ulcer or anticoagulant therapy. |
| Acute crisis: colchicine | Low-dose colchicine (0.5 mg twice or three times a day) | Alternative to NSAIDs, particularly recommended in cases of contraindication to NSAIDs or mild to moderate renal impairment; mechanism of action: inhibition of tubulin polymerization in polymorphonuclear cells, reducing their migration and activation; special attention to drug interactions (CYP3A4 and P-glycoprotein inhibitors) and dose-dependent gastrointestinal toxicity |
| Acute crisis: corticosteroids | Prednisone 30-40 mg/day per os or methylprednisolone injection; intra-articular injection of triamcinolone in case of accessible mono-arthritis. | Reserved for cases with contraindications to NSAIDs and colchicine (advanced renal failure, serious drug interactions); equivalent efficacy to other crisis treatments; avoid if septic arthritis cannot be ruled out. |
| Background treatment: xanthine oxidase inhibitors | Allopurinol (100 to 900 mg/day depending on renal function); febuxostat (80 to 120 mg/day) | Reference background treatment for gout; acts by reducing uric acid production; to be initiated at a distance from an acute attack (at least 2 to 4 weeks after resolution), under prophylactic anti-inflammatory cover (colchicine 0.5 mg/day for 3 to 6 months) to avoid triggering a mobilization attack; gradual titration of allopurinol with adaptation to renal function; febuxostat is more potent and does not require renal adaptation up to an eGFR of 30 mL/min. |
| Background treatment: uricosurics | Probenecid, benzbromarone (availability varies by country); losartan and fenofibrate as accessory uricosurics | Increase renal urate excretion by inhibiting tubular reabsorption transporters (URAT1, GLUT9); indicated in cases of predominant renal underexcretion, resistance or intolerance to xanthine oxidase inhibitors; contraindicated in cases of active uric lithiasis or significant renal impairment; require abundant hydration and urinary alkalinization |
| Background treatment: biotherapies | Anakinra (IL-1 receptor antagonist); canakinumab (anti-IL-1beta antibody) | Reserved for gout attacks that are refractory to conventional treatments or when all other treatments for the attack are contraindicated; canakinumab is indicated for recurrent attacks when NSAIDs, colchicine and corticoids are contraindicated; not available for the background treatment of hyperuricemia. |
| Hygienic and dietary measures | Reduction of purine-rich foods, elimination of fructose-sweetened beverages, reduction or cessation of alcohol (especially beer), abundant hydration (2 to 3 L/day), gradual weight loss. | Reduce uricemia by 60 to 120 µmol/L on average; insufficient alone to reach therapeutic targets in the majority of cases of established gout, but essential as a complement to drug treatment to reduce doses and improve overall control of cardiovascular risk. |
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A common mistake is to introduce or modify hypo-uricemic therapy during an acute gout attack. Any rapid rise or fall in uricemia can trigger an attack by mobilizing urate crystals deposited in the joints. Background treatment should be initiated at a distance from the attack, accompanied by prophylaxis with low-dose colchicine for at least six months to cover the period of remodelling of urate deposits. Target uricemia should be achieved progressively in monthly increments.
Consult at Clinique Omicron
Clinique Omicron has points of service in Quebec offering medical consultations for the evaluation of hyperuricemia, the management of acute gout attacks and the initiation of disease-modifying treatments adapted to each clinical profile. The clinic's physicians and specialized nurse practitioners (SPNs) carry out a complete workup, including uricemia measurement, assessment of renal function and associated metabolic workup, and provide long-term therapeutic follow-up, including titration of hyperuricemia-lowering treatments and adjustment of objectives in line with recommended biological targets. To book an appointment at one of our Quebec locations, visit cliniqueomicron.ca or contact the clinic directly.
The content of this page is provided for informational purposes only and is not intended to replace the advice of a qualified healthcare professional. Consult a physician for any symptoms, questions or decisions you may have regarding your health.
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