Gout and Hyperuricemia
Uric Acid Metabolism
Uric acid is the final product of purine metabolism in humans. Purines are components of nucleosides, the building blocks of DNA and RNA. Purine nucleosides (adenosine and guanine) are used in the creation of other metabolically important factors as well, such as adenosine triphosphate (ATP; the energy-carrying molecule), S-adenosyl methionine (SAMe; the methyl donor), and nicotine adenine dinucleotide (NADH; an important cofactor in energy production and antioxidation). Given the importance of purine-containing molecules for survival, vertebrates, including humans, have developed robust systems for synthesizing sufficient purine nucleosides for their metabolism using readily available materials (such as glucose, glycine, and glutamine), as well as recycling purine nucleosides from throughout the body or from the diet.
In mammals, excess purine nucleosides are removed from the body by breakdown in the liver and excretion from the kidneys. For most mammals, the purines are first converted into the intermediate uric acid, which is then metabolized by the enzyme uricase into the compound allantoin. Allantoin is a very soluble compound that can easily travel through the bloodstream, become filtered by the kidneys, and be excreted from the body. In contrast to other mammals, humans and other primates lack a functional uricase enzyme, and can only break purines down into uric acid.
The levels of uric acid in the blood depend on two factors. The first is the rate of uric acid synthesis in the liver. Since uric acid results from purine degradation, its levels are influenced by both the amount of purines synthesized in the body, as well as the amounts of purines absorbed from the diet.3 The second determinant of blood uric acid levels is the rate of uric acid excretion from the kidneys. Excretion has the greatest effect on blood uric acid levels, with about 90% of hyperuricemia cases attributed to impaired renal excretion.4 Impaired excretion is most often due to abnormalities in the kidney urate transporter (called URAT1) or organic ion transporter (OAT), both of which control the movement of uric acid out of proximal kidney tubules and into urine.5
One of the most intriguing aspects of uric acid is that although it appears to be a "waste product" of purine metabolism, only about 10% of the uric acid that enters a normal human kidney is excreted from the body.3 In other words, rather than eliminating uric acid, a healthy kidney returns up to 90% of it to the bloodstream. The reason for this is likely due to the role or uric acid as one of the most important antioxidants in body fluids, responsible for the neutralization of over 50% of the free radicals in the blood stream.6
The ability of humans and primates to preserve blood levels of uric acid (due to slow kidney filtration and lack of a uricase enzyme) was probably advantageous to our evolution, by increasing antioxidant capacity of the blood.7
Humans and primates are one of the few mammals that cannot produce their own vitamin C, and may have evolved the ability to preserve uric acid to compensate for this.8 For example, blood uric acid levels in humans are normally about six times that of vitamin C, and about 10 times the levels in other mammals.9 Like vitamin C, uric acid has a principle role in protecting high-oxygen tissues (like the brain) from damage, and low blood uric acid levels have been associated with the progression or increased risk of several neurological disorders, including amyotrophic lateral sclerosis,10 multiple sclerosis,11 and Huntington's,12 Parkinson's,13 and Alzheimer's diseases.14