Uric acid

Uric acid

Overview
Uric acid is a heterocyclic compound
Heterocyclic compound
A heterocyclic compound is a cyclic compound which has atoms of at least two different elements as members of its ring. The counterparts of heterocyclic compounds are homocyclic compounds, the rings of which are made of a single element....

 of carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

, nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

, oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

, and hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

 with the formula
Chemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....

 C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....

 nucleotides. High blood concentrations of uric acid can lead to a type of arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

 known as gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...

. The chemical is associated with other medical conditions like ammonium acid urate kidney stones.

Uric acid is a diprotic acid with pKa1=5.4 and pKa2=10.3.
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Encyclopedia
Uric acid is a heterocyclic compound
Heterocyclic compound
A heterocyclic compound is a cyclic compound which has atoms of at least two different elements as members of its ring. The counterparts of heterocyclic compounds are homocyclic compounds, the rings of which are made of a single element....

 of carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

, nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

, oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

, and hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

 with the formula
Chemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....

 C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....

 nucleotides. High blood concentrations of uric acid can lead to a type of arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

 known as gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...

. The chemical is associated with other medical conditions like ammonium acid urate kidney stones.

Chemistry


Uric acid is a diprotic acid with pKa1=5.4 and pKa2=10.3. Thus in strong alkali at high pH, it forms the dually charged full urate ion, but at biological pH or in the presence of carbonic acid or carbonate ions, it forms the singly charged hydrogen or acid urate ion as its pKa2 is greater than the pKa1 of carbonic acid. As its second ionization is so weak, the full urate salts tend to hydrolyze back to hydrogen urate salts and free base at pH values around neutral. It is aromatic because of the purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....

 functional group.

As a bicyclic, heterocyclic purine derivative, uric acid does not protonate like carboxylic acids. X-Ray diffraction studies on the hydrogen urate ion in crystals of ammomium hydrogen urate, formed in vivo as gouty deposits, reveal the keto-oxygen in the 2 position of a tautomer
Tautomer
Tautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond...

 of the purine structure exists as a hydroxyl group and the two flanking nitrogen atoms at the 1 and 3 positions share the ionic charge in the six membered pi-resonance-stabilized ring.

Thus, whereas most organic acids are deprotonated by the ionization of a polar hydrogen-to-oxygen bond, usually accompanied by some form of resonance stabilization (resulting in a carboxylate ion), uric acid is deprotonated at a nitrogen atom and uses a tautomeric keto/hydroxy group as an electron-withdrawing group to increase the pK1 value. The five membered ring also possesses a keto group (in the 8 position), flanked by two secondary amino groups (in the 7 and 9 positions), and deprotonation of one of these at high pH could explain the pK2 and behavior as a diprotic acid. Similar tautomeric rearrangement and pi-resonance stabilization would then give the ion some degree of stability.
(On the structure shown at the upper right, the NH at the upper right on the six membered ring is "1", counting clockwise around the six membered ring to "6" for the keto carbon at the top of the six membered ring. The upper most NH on the five membered ring is "7", counting counter clockwise around this ring to the lower NH, which is "9".)

Uric acid was first isolated from kidney stones in 1776 by Scheele. As far as laboratory synthesis is concerned, in 1882, Horbaczewski claimed to have prepared uric acid by melting urea hydrogen peroxide with glycine, trichlorolactic acid, and its amide. Soon after, repetition by Eduard Hoffmann shows that this preparation with glycine gives no trace of uric acid, but trichlorolactimide produces some uric acid. Thus, Hoffmann was the first to synthesize uric acid.

Solubility of uric acid and its salts


Generally, the water solubilitity of uric acid and its alkali metal and alkaline earth salts is rather low. All these salts exhibit greater solubility in hot water than cold, allowing for easy recrystallization. This low solubility is significant for the etiology of gout. The solubility of the acid and its salts in ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...

 is very low or negligible. In ethanol water mixtures, the solubilities are somewhere between the end values for pure ethanol and pure water.
Compound Cold Water Boiling Water
Uric Acid 15000 2000
NH4HUrate - 1600
LiHUrate 370 39
NaHUrate 1175 124
KHUrate 790 75
Mg(HUrate)2 3750 160
Ca(HUrate)2 603 276
Na2Urate 77 -
K2Urate 44 35
CaUrate 1500 1440
SrUrate 4300 1790
BaUrate 7900 2700


The figures given indicate what mass of water is required to dissolve a unit mass of compound indicated, the lower the number, the more soluble the substance in the said solvent.

Biology


The enzyme xanthine oxidase
Xanthine oxidase
Xanthine oxidase Xanthine oxidase Xanthine oxidase (XO (sometimes 'XAO'), a form of xanthine oxidoreductase that generates reactive oxygen species. Is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid...

 makes uric acid from xanthine
Xanthine
Xanthine , is a purine base found in most human body tissues and fluids and in other organisms. A number of stimulants are derived from xanthine, including caffeine and theobromine....

 and hypoxanthine
Hypoxanthine
Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids where it is present in the anticodon of tRNA in the form of its nucleoside inosine. It has a tautomer known as 6-Hydroxypurine. Hypoxanthine is a necessary additive in certain cell,...

, which in turn are produced from purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....

s. Xanthine oxidase is a large enzyme whose active site consists of the metal, molybdenum, binded to sulfur and oxygen. Within cells, xanthine oxidase can exist as xanthine dehydrogenase and xanthine oxireductase, which has also been purified from bovine milk and spleen extracts. Uric acid is released in hypoxic conditions.

In humans and higher primates, uric acid is the final oxidation (breakdown) product of purine metabolism
Purine metabolism
-Biosynthesis:Purines are biologically synthesized as nucleotides and in particular as ribotides, i.e. bases attached to ribose 5-phosphate. A key regulatory step is the production of 5-phospho-α-D-ribosyl 1-pyrophosphate by PRPP synthetase, which is activated by inorganic phosphate and...

 and is excreted in urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

. In most other mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...

s, the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 uricase further oxidizes uric acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...

 to allantoin
Allantoin
Allantoin is a chemical compound with formula C4H6N4O3. It is also called 5-ureidohydantoin or glyoxyldiureide. It is a diureide of glyoxylic acid....

. The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...

, leading to the suggestion that urate may partially substitute for ascorbate in such species. Both uric acid and ascorbic acid are strong reducing agent
Reducing agent
A reducing agent is the element or compound in a reduction-oxidation reaction that donates an electron to another species; however, since the reducer loses an electron we say it is "oxidized"...

s (electron donor
Electron donor
An electron donor is a chemical entity that donates electrons to another compound. It is a reducing agent that, by virtue of its donating electrons, is itself oxidized in the process....

s) and potent antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

s. In humans, over half the antioxidant capacity of blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 comes from uric acid.
The Dalmatian dog has a genetic defect in uric acid uptake by the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 and kidneys, resulting in decreased conversion to allantoin
Allantoin
Allantoin is a chemical compound with formula C4H6N4O3. It is also called 5-ureidohydantoin or glyoxyldiureide. It is a diureide of glyoxylic acid....

, so this breed excretes uric acid, and not allantoin, in the urine.

In bird
Bird
Birds are feathered, winged, bipedal, endothermic , egg-laying, vertebrate animals. Around 10,000 living species and 188 families makes them the most speciose class of tetrapod vertebrates. They inhabit ecosystems across the globe, from the Arctic to the Antarctic. Extant birds range in size from...

s and reptile
Reptile
Reptiles are members of a class of air-breathing, ectothermic vertebrates which are characterized by laying shelled eggs , and having skin covered in scales and/or scutes. They are tetrapods, either having four limbs or being descended from four-limbed ancestors...

s, and in some desert dwelling mammals (e.g., the kangaroo rat
Kangaroo rat
Kangaroo rats, genus Dipodomys, are small rodents native to North America. The common name derives from their bipedal form: as they hop in a manner similar to the much larger kangaroo, although they are not related...

), uric acid also is the end product of purine metabolism, but it is excreted in feces
Feces
Feces, faeces, or fæces is a waste product from an animal's digestive tract expelled through the anus or cloaca during defecation.-Etymology:...

 as a dry mass. This involves a complex metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...

 that is energetically costly in comparison to processing of other nitrogenous wastes such as urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....

 (from urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...

) or ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...

, but has the advantage of reducing water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...

 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
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...

.

Genetics


A proportion of people have mutations in the proteins responsible for the excretion of uric acid by the kidneys. Nine genes have so far been identified:
SLC2A9
SLC2A9
Solute carrier family 2, facilitated glucose transporter member 9 is a protein that in humans is encoded by the SLC2A9 gene.SLC2A9 has also recently been found to transport uric acid, and genetic variants of the transporter have been linked to increased risk of development of both hyperuricemia and...

; ABCG2
ABCG2
ATP-binding cassette sub-family G member 2 is a protein that in humans is encoded by the ABCG2 gene. ABCG2 has also been designated as CDw338 . - External links :...

; SLC17A1
SLC17A1
Sodium-dependent phosphate transport protein 1 is a protein that in humans is encoded by the SLC17A1 gene.-Further reading:...

; SLC22A11
SLC22A11
Solute carrier family 22 member 11 is a protein that in humans is encoded by the SLC22A11 gene.-Further reading:...

; SLC22A12
SLC22A12
Solute carrier family 22 , member 12, also known as SLC22A12 and URAT1, is a protein which in humans is encoded by the SLC22A12 gene.-Function:...

;
SLC16A9
SLC16A9
The solute carrier family 16, member 9 also known as the monocarboxylate transporter 9 is a protein that in humans is encoded by the SLC16A9 gene.- Clinical relevance :...

; GCKR; LRRC16A; and PDZK1
PDZK1
Na/H exchange regulatory cofactor NHE-RF3 is a protein that in humans is encoded by the PDZK1 gene.-Interactions:PDZK1 has been shown to interact with AKAP10, FARP2, Sodium-hydrogen antiporter 3 regulator 1, SLC22A12, SLK, SLC22A4, CLCN3, PDZK1IP1, Cystic fibrosis transmembrane conductance...

. SLC2A9 is known to transport both uric acid and fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...

.

Medicine


In human blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

, the reference range of uric acid is between 3.6 mg/dL (~214 µmol/L) and 8.3 mg/dL (~494 µmol/L) (1 mg/dL=59.48 µmol/L). This range is considered normal by the American Medical Association Manual of Style
AMA Manual of Style
AMA Manual of Style: A Guide for Authors and Editors is a style guide by the editors of JAMA and the Archives Journals, most recently published by Oxford University Press. It specifies the writing and citation styles for use in scholarly publications in medicine internationally, including JAMA...

. Uric acid concentrations in blood plasma above and below the normal range are known, respectively, as hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...

 and hypouricemia
Hypouricemia
Hypouricemia is a level of uric acid in blood serum that is below normal. In humans, the normal range of this blood component has a lower threshold set variously in the range of 2 mg/dL to 4 mg/dL, while the upper threshold is 530 micromol/L for women and 619 micromol/L for men...

. Similarly, uric acid concentrations in urine above and below normal are known as hyperuricosuria
Hyperuricosuria
Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia...

 and hypouricosuria. Such abnormal concentrations of uric acid are not medical conditions, but are associated with a variety of medical conditions.

Causes of high uric acid

  • In many instances, people have elevated uric acid levels for hereditary reasons.

  • Diet may be a factor. High intake of dietary purine as well as fructose (and table sugar which is roughly 50% fructose) can cause increased levels of uric acid.

  • Serum uric acid can be elevated due to reduced excretion by the kidney
    Kidney
    The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

    s.

  • Fasting or rapid weight loss can temporarily elevate uric acid levels.

  • Iron (Fe) activates xanthine oxidase (XO) and copper (Cu) deactivates it, so as men accumulate Fe with age (ferritin
    Ferritin
    Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...

     levels rise above 45 ng/dl) and Cu levels decline as testosterone levels drop with age (testosterone increases Cu half life), eventually the high Fe/Cu results in more active XO and higher urate levels. Excess Fe can be eliminated through phlebotomy (blood donation) and low Cu can be corrected through daily intake of 2 mg Cu per day, reducing urate levels.

Gout


Excess serum accumulation of uric acid can lead to a type of arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

 known as gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...

. This painful condition is the result of needle-like crystals of uric acid precipitating in joints and capillaries. Kidney stones can also form through the formation and deposition of sodium urate microcrystals.

It has also been found that men who drank two or more sugar-sweetened beverages a day have an 85% higher chance of developing gout than those who drank such beverages infrequently.

Gout can occur where serum uric acid levels are as low as 6 mg/dL (~357 µmol/L), but an individual can have serum values as high as 9.6 mg/dL (~565 µmol/L) and not have gout.

One treatment for gout, in the 19th century, had been administration of lithium
Lithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...

 salts; lithium urate is more soluble. Today, inflammation during attacks is more commonly treated with NSAIDs, and urate levels are managed with allopurinol
Allopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...

. Allopurinol, developed over 30 years ago by Elion et al., weakly inhibits xanthine oxidase. It is an analog of hypoxanthine that is hydroxylated by xanthine oxireductase at the 2-position to give oxipurinol. Oxipurinol has been supposed to bind tightly to the reduced molybdenum ion in the enzyme and thus inhibits uric acid synthesis.

Lesch-Nyhan syndrome


Lesch-Nyhan syndrome
Lesch-Nyhan syndrome
Lesch–Nyhan syndrome , also known as Nyhan's syndrome, Kelley-Seegmiller syndrome and Juvenile gout, is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase , produced by mutations in the HPRT gene located on X chromosome. LNS affects about...

, 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
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...

. 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. The same may account for the putative role of uric acid in the etiology of stroke.

Type 2 Diabetes


The association of high serum uric acid with insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

 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, a prospective follow-up study showed high serum uric acid is associated with higher risk of type 2 diabetes, independent of obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...

, dyslipidemia
Dyslipidemia
Dyslipidemia or dyslipidaemia is an abnormal amount of lipids in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. The prolonged elevation of insulin levels can lead to dyslipidemia...

, and hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

.

Metabolic syndrome


Hyperuricemia is associated with components of metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

. A study has suggested fructose-induced hyperuricemia may play a pathogenic role in the metabolic syndrome. This is consistent with the increased consumption in recent decades of fructose-containing beverages (such as fruit juices and soft drinks sweetened with sugar
Sucrose
Sucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...

 and high-fructose corn syrup) and the epidemic of diabetes and obesity.

Uric acid stone formation


Saturation levels of uric acid in blood may result in one form of kidney stone
Kidney stone
A kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...

s when the urate crystallizes in the kidney. These uric acid stones are radiolucent
Radiodensity
Radiodensity refers to the relative inability of electromagnetic radiation, particularly X-rays, to pass through a particular material. Radiolucency indicates greater transparency or "transradiancy" to X-ray photons...

 and so do not appear on an abdominal plain X-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...

. 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.

Uric acid stones
Kidney stone
A kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...

, which form in the absence of secondary causes such as chronic diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, vigorous exercise, dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...

, 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 promoter and inhibitor factors may be affected. This explains the high prevalence of uric stones and unusually acidic urine seen in patients with type 2 diabetes. Uric acid crystals can also promote the formation of calcium oxalate
Calcium oxalate
Calcium oxalate is a chemical compound that forms needle-shaped crystals, known in plants as raphides. A major constituent of human kidney stones, the chemical is also found in beerstone, a scale that forms on containers used in breweries...

 stones, acting as "seed crystals" (heterogeneous nucleation
Nucleation
Nucleation is the extremely localized budding of a distinct thermodynamic phase. Some examples of phases that may form by way of nucleation in liquids are gaseous bubbles, crystals or glassy regions. Creation of liquid droplets in saturated vapor is also characterized by nucleation...

).

Causes of low uric acid


Low uric acid (hypouricemia
Hypouricemia
Hypouricemia is a level of uric acid in blood serum that is below normal. In humans, the normal range of this blood component has a lower threshold set variously in the range of 2 mg/dL to 4 mg/dL, while the upper threshold is 530 micromol/L for women and 619 micromol/L for men...

) can have numerous causes.

Low dietary zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

 intakes cause lower uric acid levels. This effect can be even more pronounced in women taking oral contraceptive medication.

Xanthine oxidase is an Fe-Mo enzyme, so people with Fe deficiency (the most common cause of anemia in young women) or Mo deficiency can experience hypouricemia.

Xanthine oxidase loses its function and gains ascorbase function when some of the Fe atoms in XO are replaced with Cu atoms. Accordingly, people with high Cu/Fe can experience hypouricemia and vitamin C deficiency, resulting in oxidative damage. Since estrogen increases the half life of Cu, women with very high estrogen levels and intense blood loss during menstruation are likely to have a high Cu/Fe and present with hypouricemia.

Sevelamer
Sevelamer
Sevelamer is a phosphate binding drug used to prevent hyperphosphatemia in patients with chronic renal failure. When taken with meals, it binds to dietary phosphate and prevents its absorption...

, a drug indicated for prevention of hyperphosphataemia in patients with chronic renal failure
Chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...

, can significantly reduce serum uric acid.

Multiple sclerosis


Lower serum values of uric acid have been associated with multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...

 (MS). MS patients have been found to have serum levels ~194 µmol/L, with patients in relapse averaging ~160 µmol/L and patients in remission averaging ~230 µmol/L. Serum uric acid in healthy controls was ~290 µmol/L. Conversion factor: 1 mg/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 elevation of serum uric acid values in multiple sclerosis patients, by oral supplementation with inosine
Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond....

, resulted in lower relapse rates, and no adverse effects.

Normalizing low uric acid


Correcting low or deficient zinc levels can help elevate serum uric acid. Inosine
Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond....

 can be used to elevate uric acid levels.
Zn inhibits Cu absorption, helping to reduce the high Cu/Fe in some people with hypouricemia. Fe supplements can ensure adequate Fe reserves (ferritin above 25 ng/dl), also correcting the high Cu/Fe.

Oxidative stress


Uric acid may be a marker of oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

, and may have a potential therapeutic role as an antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

. 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
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

 and atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

 are a protective response or a primary cause.

For example, some researchers propose hyperuricemia-induced oxidative stress is a cause of metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

. 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

  • In humans, purines are excreted as uric acid. Purines are found in high amounts in animal food products, such as liver and sardines. 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 and Fe sources include: sweetbread
    Sweetbread
    Sweetbreads or ris are culinary names for the thymus or the pancreas especially of the calf and lamb...

    s, anchovies, sardine
    Sardine
    Sardines, or pilchards, are several types of small, oily fish related to herrings, family Clupeidae. Sardines are named after the Mediterranean island of Sardinia, around which they were once abundant....

    s, liver, beef kidneys, brains, meat extract
    Meat extract
    Meat extract is highly concentrated meat stock, usually made from beef. It is used to add meat flavor in cooking, and to make broth for drinking....

    s (e.g., Oxo, Bovril), herring, mackerel
    Mackerel
    Mackerel is a common name applied to a number of different species of fish, mostly, but not exclusively, from the family Scombridae. They may be found in all tropical and temperate seas. Most live offshore in the oceanic environment but a few, like the Spanish mackerel , enter bays and can be...

    , scallop
    Scallop
    A scallop is a marine bivalve mollusk of the family Pectinidae. Scallops are a cosmopolitan family, found in all of the world's oceans. Many scallops are highly prized as a food source...

    s, game meats, and gravy.

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

Further reading

  • Nakamura, T. (April 2008). [Historical review of gout and hyperuricemia investigations]. Nippon Rinsho 66 (4): 624-635. .

External links