Rheumatology – Purine Biology and Metabolism
Uric acid
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 rising incidence linked to an ageing population, increasing obesity and the widespread use of hyperuricemic drugs.
Quick medical consultation recommended
An acute gout attack, characterized by sudden, severe joint pain accompanied by marked swelling, warmth, and redness of the affected joint, with or without fever, requires prompt medical consultation to confirm the diagnosis, rule out septic arthritis, and initiate effective anti-inflammatory treatment. Septic arthritis on top of microcrystalline arthropathy can threaten joint integrity without rapid antibiotic treatment.
Reference values for uricemia
Normal uricemia values vary by 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 reproductive age due to the uricosuric effect of estrogen |
| Pre-menopausal woman | 140 – 360 µmol/L | 2.4 - 6.0 mg/dL | Estrogens promote renal excretion of uric acid, lowering serum uric acid by 60 to 80 µmol/L compared to men |
| Postmenopausal woman | 200 – 420 µmol/L | 3.4 - 7.0 mg/dL | The drop in estrogen during menopause leads to an increase in uricemia, gradually reaching male levels. |
| Child (pre-puberty) | 120 – 300 µmol/L | 0.2 – 0.5 mg/dL | Low values related to higher relative renal clearance; uricemia progressively increases 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) | Less than 360 micromoles per liter | < 6.0 mg/dL | Recommended minimum target for gradual dissolution of existing urate deposits; target below 300 µmol/L (5.0 mg/dL) in tophaceous or severe forms |
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Hyperuricemia is biologically defined as a serum uric acid level above 420 µmol/L (7.0 mg/dL) in men and above 360 µmol/L (6.0 mg/dL) in women, regardless 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 drug-induced hypouricemic treatment but necessitates an evaluation of the underlying causes and appropriate lifestyle and dietary measures.
Purine Metabolism and Sources of Uric Acid
Uric acid production results from two main sources: the catabolism of endogenous purines from cellular renewal and the degradation of exogenous purines from diet. The ratio between these two sources partly determines uricemia levels and management strategies.
| Source | Mechanism | Contribution to hyperuricemia |
|---|---|---|
| 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. | Around 30 % of total production; adopting a low-purine diet can lower uricemia by 60 to 120 µmol/L on average |
| Dietary fructose | Fructose is metabolized in hepatocytes by fructokinase, consuming ATP and generating AMP which is degraded into uric acid via the usual purine pathway; this mechanism is independent of the purine content of the food. | Significantly contributes to hyperuricemia associated with high consumption of sugar-sweetened beverages with high-fructose corn syrup (sodas, processed juices) and alcohol (especially beer, which is rich in both purines and fermented fructose). |
Causes of hyperuricemia
Hyperuricemia results from either overproduction of uric acid, under-renal excretion, or a combination of both mechanisms, which is actually the most frequent situation in clinical practice. The distinction between these mechanisms guides the choice of hypouricemic treatment.
| Mechanism | Cause | Clinical details |
|---|---|---|
| Overproduction (approximately 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 | Blood disorders and accelerated cell proliferation | Leukemias, lymphomas, polycythemia vera, multiple myeloma, sickle cell disease, thalassemia, chronic hemolytic anemia; accelerated renewal of cellular nucleic acids |
| Overproduction | Tumor lysis syndrome | Massive release of intracellular purines during rapid destruction of tumor cells by chemotherapy; metabolic emergency that can lead to acute kidney injury due to urate precipitation in the tubules |
| Overproduction | Rare inherited enzyme deficiencies | Lesch-Nyhan Syndrome (complete HGPRT deficiency, X-linked): severe hyperuricemia, early gout, uric acid stones, severe neurological disorders, self-mutilation; partial HGPRT deficiency (Kelley-Seegmiller syndrome): hyperuricemia, nephropathy, juvenile gout without neurological involvement; PRPP synthetase overactivity |
| Overproduction | Extensive psoriasis, intense and prolonged physical exercise | Increased cell turnover in psoriasis; muscle catabolism and ATP degradation during intense and repeated physical exertion |
| Renal hyperexcretion (approximately 90 % of hyperuricemias) | Chronic renal failure | Reduced glomerular filtration and tubular secretion of urate; blood uric acid levels rise progressively with declining eGFR; the most common cause of severe hyperuricemia. |
| Renal hyposecretion | Hyperuricemic medications | Thiazide and loop diuretics (inhibition of tubular urate secretion); low-dose aspirin (inhibition of urate secretion at low concentrations); cyclosporine and tacrolimus (tubular nephrotoxicity); pyrazinamide and ethambutol (antituberculars); high-dose nicotinic acid (niacin); beta-blockers to a lesser extent |
| Renal hyposecretion | High blood pressure and metabolic syndrome | Reduction in renal plasma flow and tubular urate secretion; insulin resistance increasing tubular urate reabsorption via the URAT1 cotransporter; bidirectional association between hyperuricemia and arterial hypertension |
| Renal hyposecretion | Chronic alcohol consumption | Alcohol inhibits renal excretion of urate by competing with lactic acid (alcoholic lactic acidosis); beer combines renal inhibitory effect with a direct purine intake (guanosine); wine and spirits have a lesser hyperuricemic effect at equivalent consumption. |
| Renal hyposecretion | Hypothyroidism, hypoparathyroidism, lead poisoning (plumbism) | Reduced renal clearance of urate by various mechanisms; lead poisoning causes proximal tubulopathy with reduced urate secretion (saturnine gout, historically known as «gout of the aristocrats»). |
| Dehydration and prolonged fasting | Mixed causes | Dehydration reduces urine output and concentrates plasma urate; fasting generates ketone bodies that compete with urate for tubular secretion; a frequent trigger mechanism for acute gout attacks during hospitalizations or strict diets. |
Causes of hypouricemia
Hypouricemia, defined by a serum uric acid level below 120 µmol/L (2.0 mg/dL), is less common than hyperuricemia but is also a biological signal that warrants investigation. It can 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; collapsed or even undetectable uremia
- Treatment with allopurinol or febuxostat: xanthine oxidase inhibition reducing uric acid production; iatrogenic hypouricemia in therapeutic overdoses
- Fanconi syndrome and proximal tubulopathies: excessive renal loss of urate due to defective proximal tubular reabsorption; associated with normoglycemic glycosuria, aminoaciduria, and phosphaturia
- Severe liver diseases and end-stage hepatocellular insufficiency: reduction of hepatic uric acid synthesis by deficit of functional hepatocytes
- Severe malnutrition and very low protein intake: reduced 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 clearance of urates in the first trimester; uricemia physiologically decreases in early pregnancy then rises in the third trimester
Clinical manifestations of hyperuricemia
Hyperuricemia can remain asymptomatic for many years before manifesting 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 | Sudden onset of monoarticular arthritis, often nocturnal, with maximal pain from the outset, swelling, warmth, and redness of the joint; the first metatarsophalangeal joint (podagra) is affected in 50% to 70% % of initial attacks; the knee, ankle, tarsus, and wrist are also common; the attack lasts 7 to 14 days without treatment and resolves spontaneously | Phagocytosis of intra-articular monosodium urate crystals by synovial macrophages, triggering a massive inflammatory cascade via the NLRP3 inflammasome and IL-1 beta release |
| Intercritical drop | Asymptomatic period between attacks during which urate deposits continue to accumulate; without long-term treatment, attacks become progressively more frequent, longer, and affect more joints | Silent accumulation of urate crystals in cartilage, tendons, and periarticular tissues without an active inflammatory response |
| Chronic tophaceous gout | Visible and palpable deposits of urate (tophi) under the skin, classically on 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 | Radiotransparent kidney stones (not visible on a standard abdominal X-ray but visible on ultrasound and CT scan), which can cause recurrent renal colic | Uric acid precipitation in the urinary tract promoted by acidic urine (urinary pH below 5.5), hyperuricosuria, and low urine volume |
| Chronic urate nephropathy | Urate deposits in the interstitial renal parenchyma, associated with chronic inflammation and progressive fibrosis; contribution to chronic kidney disease, especially in severe, long-standing hyperuricemia. | Urate crystallization in the renal medullary interstitium, local granulomatous inflammatory reaction, and progressive tubular ischemia |
| Metabolic and cardiovascular associations | Hyperuricemia is frequently associated with metabolic syndrome, abdominal obesity, hypertension, insulin resistance, dyslipidemia, and chronic kidney disease; a complex bidirectional relationship, possibly causal for hypertension and nephropathy. | Uric acid inhibits the bioavailability of endothelial nitric oxide (NO), activates the renin-angiotensin system, and promotes systemic vascular inflammation. |
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During an acute gout attack, measured blood uric acid levels can be normal or even lowered due to the redistribution of plasma urates to tissue spaces as a result of the inflammatory reaction. Therefore, a normal uric acid level during an attack does not rule out a gout diagnosis and should not lead to the dismissal of this diagnosis. Blood uric acid levels are ideally measured when not experiencing a gout attack, at least three to four weeks after the complete resolution of inflammatory symptoms.
Diagnostic approach
The diagnosis of hyperuricemia is biological and only requires a fasting plasma uric acid level to be established. The diagnostic approach then aims to identify the dominant mechanism (overproduction or underexcretion), the underlying causes, and potentially affected target organs.
| Review | Indication | Clinical contribution |
|---|---|---|
| Fasting blood uric acid | Baseline assessment; to be performed at a distance from any recent inflammatory flare-up (at least 3-4 weeks), without recent dietary changes or introduction or discontinuation of uricosuric medications | Confirmation of hyperuricemia and quantification of the degree of elevation guiding therapeutic strategy |
| 24-hour uricuria | Useful for distinguishing renal overproduction and under-excretion; to be performed outside of hypouricemic treatment and under usual dietary conditions | Uricosuria greater than 700-800 mg/24h: overproduction of uric acid; normal or low uricosuria with hyperuricemia: predominant renal sub-excretion; guides the choice between allopurinol/febuxostat (all causes) and uricosurics (sub-excretion without lithiasis or renal insufficiency) |
| Serum creatinine and eGFR | Systematic approach for any confirmed hyperuricemia | Renal function assessment, a determining factor in the choice and dosage of hypo-uricemic treatment; renal insufficiency is both a cause and a consequence of hyperuricemia |
| Comprehensive metabolic panel | Fasting blood glucose, HbA1c, lipid panel, blood pressure, waist circumference | Systematic review of associated metabolic syndrome, common in primary gout; conditioning the overall management of cardiovascular risk |
| Synovial fluid analysis | In case of diagnostic doubt, particularly to distinguish a gout attack from septic arthritis or articular chondrocalcinosis (pseudogout) | Highlighting needle-shaped monosodium urate crystals with negative birefringence in polarized light, within or outside polynuclear cells; reference examination for definitive diagnosis |
| Joint ultrasound | First-line imaging for the detection of articular and periarticular urate deposits | Double contour sign (urate deposition on the surface of hyaline cartilage) and hyperechoic intra-articular tophi are highly suggestive of gout; superior sensitivity to standard radiography for early lesions |
| Low Dose CT | Dual-energy densitometry for characterizing the chemical nature of joint deposits | Detection and quantification of monosodium urate crystal deposits with high precision; useful in atypical or polyarticular forms, for monitoring the dissolution of tophi under treatment, and in complex diagnostic situations. |
| X-rays of affected joints | Useful in chronic forms for evaluating progressive osteoarticular lesions | Geodes from a punch-out of the articular interspaces, with a dense bony rim, pathognomonic of advanced tophaceous gout |
| Complete blood count and cell lysis panel | In case of suspected hematologic disease or accelerated cell lysis as a cause of overproduction | Orientation towards leukemia, lymphoma, polycythemia, or chronic hemolysis in case of associated abnormality |
| TSH | Screening for underlying hypothyroidism contributing to reduced renal excretion of urates | Partial normalization of uricemia under levothyroxine replacement therapy in cases of established hypothyroidism |
Therapeutic strategies
The management of symptomatic hyperuricemia is bimodal, distinguishing between the treatment of acute flares aimed at rapidly reducing inflammation, and long-term management aimed at durably lowering uricemia below the saturation threshold to prevent recurrences and dissolve existing deposits.
| Approach | Treatment | Indications and modalities |
|---|---|---|
| Acute crisis: non-steroidal anti-inflammatory drugs (NSAIDs) | Indomethacin, naproxen, ibuprofen at anti-inflammatory doses | First-line treatment for acute crisis in patients without contraindications; to be started as early as possible in the first hours of the crisis; to be continued until complete resolution of symptoms (7 to 14 days); contraindicated in case of significant renal insufficiency, active gastroduodenal ulcer, or anticoagulant therapy |
| Acute crisis: colchicine | Low-dose colchicine (0.5 mg two to three times a day) | Alternative to NSAIDs, particularly recommended in case of contraindication to NSAIDs or mild to moderate renal insufficiency; mechanism of action by inhibiting tubulin polymerization in polymorphonuclear leukocytes, reducing their migration and activation; particular attention to drug interactions (CYP3A4 and P-glycoprotein inhibitors) and dose-dependent gastrointestinal toxicity |
| Acute crisis: corticosteroids | Prednisone 30-40 mg/day orally or injectable methylprednisolone; intra-articular triamcinolone injection in case of accessible monoarthritis | Reserved for cases with contraindications to NSAIDs and colchicine (advanced renal insufficiency, serious drug interactions); efficacy equivalent to other treatments for flare-ups; to be avoided if septic arthritis cannot be ruled out |
| Background treatment: xanthine oxidase inhibitors | Allopurinol (100 to 900 mg/day depending on kidney function); febuxostat (80 to 120 mg/day) | Reference background treatment for gout; act by reducing uric acid production; initiate 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 crisis; 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 hyperexcretion, resistance or intolerance to xanthine oxidase inhibitors; contraindicated in cases of active uric lithiasis or significant renal insufficiency; require abundant hydration and urinary alkalization |
| Background treatment: biotherapies | Anakinra (IL-1 receptor antagonist); canakinumab (anti-IL-1beta antibody) | Reserved for gout attacks refractory to conventional treatments or in case of contraindication to all other treatments for the attack; canakinumab is indicated for recurrent attacks with contraindication to NSAIDs, colchicine, and corticosteroids; not available for the maintenance treatment of hyperuricemia |
| Hygiene and dietary measures | Reduction of purine-rich foods, elimination of sugary drinks containing fructose, reduction or cessation of alcohol (especially beer), abundant hydration (2 to 3 L/day), gradual weight loss | They allow for a reduction in uremia of 60 to 120 µmol/L on average; insufficient on their own to reach therapeutic targets in the majority of cases of established gout, but essential in addition to drug treatment to reduce doses and improve overall cardiovascular risk control |
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A common mistake is to start or change urate-lowering treatment during an acute gout attack. Any rapid change in uricemia, whether an increase or decrease, can trigger an attack by mobilizing urate crystals deposited in the joints. Maintenance treatment should be initiated well after the attack, accompanied by low-dose colchicine prophylaxis for at least six months to cover the period of urate deposit remodeling. The target uricemia should be reached gradually in monthly steps.
Consult at Clinique Omicron
Clinique Omicron has service points in Quebec offering medical consultations for the evaluation of hyperuricemia, management of acute gout attacks, and the initiation of disease-modifying treatments tailored to each clinical profile. The clinic's doctors and specialized nurse practitioners (SNPs) perform a complete assessment, including uricemia levels, evaluation of kidney function and associated metabolic profile, and ensure long-term therapeutic follow-up, including titration of hypouricemic treatments and adjustment of objectives according to recommended biological targets. To make an appointment at one of the 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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