Uric acid

Uric acid (or urate) is an organic compound of carbon, nitrogen, oxygen and hydrogen with the formula C5H4N4O3.

Biology
Uric acid is produced by xanthine oxidase from xanthine and hypoxanthine, which in turn are produced from purine. Uric acid is more toxic to tissues than either xanthine or hypoxanthine.

In humans and higher primates, uric acid is the final oxidation (breakdown) product of purine metabolism and is excreted in urine. In most other mammals, the enzyme uricase further oxidizes uric acid to allantoin. The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid. Both uric acid and ascorbic acid are strong reducing agents (electron donors) and potent antioxidants. In humans, over half the antioxidant capacity of blood plasma comes from uric acid.

The Dalmatian dog has a genetic defect in uric acid uptake by the liver, resulting in decreased conversion to allantoin, so this breed excretes uric acid, and not allantoin, in the urine.

In birds and reptiles, and in some desert dwelling mammals (eg kangaroo rat), uric acid also is the end product of purine metabolism, but it is excreted in feces as a dry mass. This involves a complex metabolic pathway that is energetically costly in comparison to processing of other nitrogenous wastes such as urea or ammonia, but has the advantage of reducing water loss.

In humans, about 70% of daily uric acid disposal occurs via the kidneys, and in 5-25% of humans impaired renal (kidney) excretion leads to hyperuricemia.

Genetics
A proportion of people have mutations in the proteins responsible for the excretion of uric acid by the kidneys. Four genes have so far been identified: SLC22A12, SLC2A9, ABCG2 and SLC17A3). SLC2A9 is known to transport both uric acid and fructose.

Medicine
In human blood plasma, the reference range of uric acid is between 3.6 mg/dL (~214µmol/L) and 8.3 mg/dL (~494µmol/L) (1mg/dL=59.48 µmol/L). This range is considered normal by the American Medical Association. Uric acid concentrations in blood plasma above and below the normal range are known, respectively, as hyperuricemia and hypouricemia. Similarly, uric acid concentrations in urine above and below normal are known as hyperuricosuria and hypouricosuria. Such abnormal concentrations of uric acid are not medical conditions, but are associated with a variety of medical conditions.





Gout
Excess serum accumulation of uric acid can lead to a type of arthritis known as gout.

Elevated serum uric acid (hyperuricemia) can result from high intake of purine-rich foods, high fructose intake (regardless of fructose's low glycemic index (GI) value) and/or impaired excretion by the kidneys. Saturation levels of uric acid in blood may result in one form of kidney stones when the urate crystallizes in the kidney. These uric acid stones are radiolucent and so do not appear on an abdominal plain x-ray or CT scan. Their presence must be diagnosed by ultrasound for this reason. Very large stones may be detected on x-ray by their displacement of the surrounding kidney tissues. Some patients with gout eventually get uric kidney stones.

Gout can occur where serum uric acid levels are as low as 6 mg/dL (~357µmol/L), but an individual can have serum values as high as 9.5 mg/dL (~565µmol/L) and not have gout (no abstract available; levels reported at ).

Lesch-Nyhan syndrome
Lesch-Nyhan syndrome, an extremely rare inherited disorder, is also associated with very high serum uric acid levels.

Spasticity, involuntary movement and cognitive retardation as well as manifestations of gout are seen in cases of this syndrome.

Cardiovascular disease
Although uric acid can act as an antioxidant, excess serum accumulation is often associated with cardiovascular disease. It is not known whether this is causative (e.g., by acting as a prooxidant ) or a protective reaction taking advantage of urate's antioxidant properties.

Diabetes
The association of high serum uric acid with insulin resistance has been known since the early part of the 20th century, nevertheless, recognition of high serum uric acid as a risk factor for diabetes has been a matter of debate. In fact, hyperuricemia has always been presumed to be a consequence of insulin resistance rather than its precursor. However, it was shown in a prospective follow-up study that high serum uric acid is associated with higher risk of type 2 diabetes independent of obesity, dyslipidemia, and hypertension.

Metabolic syndrome
Hyperuricemia is associated with components of metabolic syndrome and it has been debated for a while to be a component of it. It has been shown in a recent study that fructose-induced hyperuricemia may play a pathogenic role in the metabolic syndrome. This agrees with the increased consumption of fructose-base drinks in recent decades and the epidemic of diabetes and obesity.

Uric acid stone formation
Uric acid stones, which form in the absence of secondary causes such as chronic diarrhea, vigorous exercise, dehydration, and animal protein loading, are felt to be secondary to obesity and insulin resistance seen in metabolic syndrome. Increased dietary acid leads to increased endogenous acid production in the liver and muscles which in turn leads to an increased acid load to the kidneys. This load is handled more poorly because of renal fat infiltration and insulin resistance which are felt to impair ammonia excretion (a buffer). The urine is therefore quite acidic and uric acid becomes insoluble, crystallizes and stones form. In addition, naturally present promotor and inhibitor factors may be affected. This explains the high prevalence of uric stones and unusually acid urine seen in patients with type 2 diabetes. Uric acid crystals can also promote the formation of calcium oxalate stones, acting as "seed crystals" (heterogenous nucleation).

Multiple sclerosis
Lower serum values of uric acid have been associated with Multiple Sclerosis. Multiple sclerosis (MS) patients have been found to have serum levels ~194µmol/L, with patients in relapse averaging ~160µmol/L and patients in remission averaging ~230µmol/L. Serum uric acid in healthy controls was ~290µmol/L. Conversion factor: 1mg/dL=59.48 µmol/L

A 1998 study completed a statistical analysis of 20 million patient records, comparing serum uric acid values in patients with gout and patients with multiple sclerosis. Almost no overlap between the groups was found.

Uric acid has been successfully used in the treatment and prevention of the animal (murine) model of MS. A 2006 study found that elevation of serum uric acid values in multiple sclerosis patients, by oral supplementation with inosine, resulted in lower relapse rates, and no adverse effects.

Oxidative stress
Uric acid may be a marker of oxidative stress, and may have a potential therapeutic role as an antioxidant. On the other hand, like other strong reducing substances such as ascorbate, uric acid can also act as a prooxidant, particularly at elevated levels. Thus, it is unclear whether elevated levels of uric acid in diseases associated with oxidative stress such as stroke and atherosclerosis are a protective response or a primary cause.

For example, some researchers propose that hyperuricemia-induced oxidative stress is a cause of metabolic syndrome. On the other hand, plasma uric acid levels correlate with longevity in primates and other mammals. This is presumably a function of urate's antioxidant properties.

Sources of uric acid

 * In many instances, people have elevated uric acid levels for hereditary reasons. Diet may also be a factor.


 * Purines are found in high amounts in animal internal organ food products, such as liver. A moderate amount of purine is also contained in beef, pork, poultry, fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran and wheat germ.


 * Examples of high purine sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g Oxo, Bovril), herring, mackerel, scallops, game meats, and gravy.


 * Moderate intake of purine-containing food is not associated with an increased risk of gout.


 * Serum uric acid can be elevated due to high fructose intake, reduced excretion by the kidneys, and or high intake of dietary purine.


 * Added fructose can be found in processed foods and soda beverages as sucrose, or in some countries, as high fructose corn syrup.

Causes of low uric acid
Low uric acid (hypouricemia) can have numerous causes.

Sevelamer, a drug indicated for prevention of hyperphosphataemia in patients with chronic renal failure, can significantly reduce serum uric acid.

Other uric acid facts
The high nitrogen content of uric acid makes guano a useful agricultural fertilizer.

The crystalline form of uric acid is used as a reflector in certain species of fireflies.

The uric acid in urine can also dry in a baby's diaper to form a pinkish powder that is harmless.

-

Papers

 * Google Scholar

Dissertations
Aagaard, N. K., Thogersen, T., Grofte, T., Greisen, J., & Vilstrup, H. (2004). Alcohol Acutely Down-Regulates Urea Synthesis in Normal Men: Alcoholism: Clinical and Experimental Research Vol 28(5) May 2004, 697-701.