Biomarkers

Target: Uric acid

Uric acid is a heterocyclic purine derivative that is the final oxidation product of purine metabolism. It is a weak acid distributed throughout the extracellular fluid as sodium urate. Uric acid is produced by the enzyme xanthine oxidase, which oxidizes oxypurines such as xanthine into uric acid. In most mammals, except humans and higher primates, the enzyme uricase further oxidizes uric acid to allantoin. Interestingly, during the Miocene epoch (~15-20 million years ago), two distinct mutations in the primate genome occurred that led to a nonfunctioning uricase gene. Consequently, humans, apes, and certain New World monkeys have much higher uric acid levels (>120 μM) compared with other mammals (<<120 uM). The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid vitamin C. This may be because in higher primates uric acid partially replaces ascorbic acid. Like ascorbic acid, uric acid is an antioxidant. In fact, in primates, uric acid is the major antioxidant in serum and is thought to be a major factor in lengthening life-span and decreasing age-specific cancer rates in humans and other primates (PMID: 6947260 ). Uric acid is also the end product of nitrogen metabolism in birds and reptiles. In these animal species, it is excreted in feces as a dry mass. In humans and other mammals, the amount of urate in the blood depends on the dietary intake of purines, the level of endogenous urate biosynthesis, and the rate of urate excretion. Several kidney urate transporters are involved in the regulation of plasma urate levels. These include the urate transporter 1 (URAT1), which controls the reabsorption of urate as well as a number of organic ion transporters (OAT), such as OAT1 and OAT3, and the ATP-dependent urate export transporter MRP4. URAT1 is believed to be most critical in the regulation of plasma urate levels. (PMID: 17890445 ) High levels of plasma uric acid lead to a condition called hyperuricemia while low levels are associated with a condition called hypouricemia. Hyperuricemia has been defined as a uric acid concentration greater than 380 μM, while hypouricemia is generally defined as a urate concentration of less than 120 μM. Hyperuricemia can arise from a number of factors, including both acute and chronic causes. Acute causes of hyperuricemia include the intake of large amounts of alcohol, tumor lysis syndrome and a diet that is rich in purines or proteins. Chronic hyperuricemia can arise from a reduction in the kidney’s glomerular filtration rate, a decrease in the excretion of urate or an increase in overall tubular absorption in the kidneys. Hyperuricemia has been linked to a number of diseases and conditions, including gout, hypertension, cardiovascular disease, myocardial infarction, stroke, and renal disease. Uric acid has been identified as a uremic toxin according to the European Uremic Toxin Working Group (PMID: 22626821 ). Uremic toxins are compounds that are normally secreted by the kidney that interact negatively with normal biological functions. Many of the causes of hyperuricemia are correctable either with lifestyle changes or drugs. Lifestyle changes include reducing weight and reducing the consumption of protein, purines, and alcohol. There are two kinds of drugs that can be used to treat chronic hyperuricemia. Xanthine oxidase inhibitors, such as allopurinol, inhibit the production of urate by blocking urate synthesis. Alternately, uricosuric drugs, such as probenecid, sulfinpyrazone, and benzbromarone, are used to reduce the serum urate concentration through the inhibition of the URAT1 transporter. (PMID: 17890445 ). Uric acid (especially crystalline uric acid) is also thought to be an essential initiator and amplifier of allergic inflammation for asthma and peanut allergies (PMID: 21474346). Uric acid is also associated with Canavan Disease where adults (>18 years old) with the disease have elevated levels of uric acid in the urine at a concentration of 1554.14 +/- 748.85 μmol/mmol creatinine (PMID: 16139832) compared to normal adults at a concentration of 209.55 +/- 104.52 μmol/mmol creatinine (PMID: 16139832). A similar trend is observed in all age groups (PMID: 16139832). Uric acid is also identified as a biomarker in individuals with xanthinuria type 1. Adults (>18 years old) with xanthinuria type 1 have shown significantly reduced levels of uric acid in the blood at a concentration <10 μM (PMID: 23249873) compared to normal adults at a concentration of 200-420 μM (PMID: 23249873). Uric acid has also been associated with molybdenum cofactor deficiency, a rare condition characterised by brain dysfunction (encephalopathy) that worsens over time. In children (1-13 years old) with molybdenum cofactor deficiency, uric acid is found to be significantly reduced in the urine at a concentration of 5 μmol/mmol creatinine (PMID: 8051926) compared to normal children at a concentration of 2210.4 (218.8-4202.0) (GeneReviews).