Uric acid
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [21]
Overview
Uric acid (or urate) is an organic compound of carbon, nitrogen, oxygen and hydrogen with the formula C5H4N4O3.
Metabolic processes
Xanthine oxidase oxidizes oxypurines such as xanthine and hypoxanthine to uric acid. In humans and higher primates, uric acid is the final oxidation product of purine catabolism. In most other mammals, the enzyme uricase further oxidizes uric acid to allantoin.[1] The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid.[2] This may be because in higher primates uric acid (urate) partially replaces ascorbic acid.[3] Both urate and ascorbate are strong reducing agents (electron donors) and potent antioxidants. In humans, about half the antioxidant capacity of plasma comes from uric acid.
Uric acid is also the end product of nitrogen catabolism in birds and reptiles. In such species, it is excreted in feces as a dry mass. While this compound is produced through a complex and energetically costly metabolic pathway (in comparison to other nitrogenated wastes such as urea or ammonia), its elimination minimizes water loss. It is therefore commonly found in the excretions of animals—such as the kangaroo rat—that live in very dry environments. The Dalmatian dog has a defect in uric acid uptake by liver, resulting in decreased conversion to allantoin, so this breed excretes uric acid, and not allantoin, in the urine.
Medical issues
Humans produce large quantities of uric acid. In human blood, uric acid concentrations between 3.6 mg/dL (~214µmol/L) and 8.3 mg/dL (~494µmol/L) (1mg/dL=59.48 µmol/L)[4] are considered normal by the American Medical Association, although significantly lower levels are common in vegetarians due to a decreased intake of purine-rich meat.[5]
High uric acid
Gout
Excess serum accumulation of uric acid can lead to a type of arthritis known as gout.[6]
Elevated (serum uric acid) level (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 x-ray. Their presence must be diagnosed by ultrasound for this reason. 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[7] (no abstract available; levels reported at[8]).
Lesch-Nyhan syndrome
Lesch-Nyhan syndrome is also associated with very high serum uric acid levels.[9]
Spasticity, involuntary movement and cognitive retardation as well as manifestations of gout are seen in cases of this syndrome.[10]
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. High uric acid can cause kidney stones, gouts in joints, and disable the body to produce purines, which build up the genetic "blueprint". [11]
Cohort studies have proposed a relationship between hyperuricemia and cardiovascular disease, including the Kuopio Ischaemic Heart Disease Risk Factor Study of Finnish males[12] and the U.S. National Health and Nutrition Examination Survey (NHANES)[12].
On the other hand, the Framingham cohort study finds that the association between hyperuricemia nd cardiovascular disease is due to confounding[13].
- Does treatment help
A randomized controlled trial found that although febuxostat lowers uric acid levels more than does allopurinol, febuxostat increased cardiac mortality[14].
The above CARES trial by White has been included in a systematic review[15].
A more recent trial is the FAST trial[16].
A more recent systematic review finds no association[17].
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 [18]. 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 [19].
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 [20].
Low uric acid
Multiple sclerosis
Lower serum values of uric acid have been associated with Multiple Sclerosis.[21] 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.[22] (1mg/dL=59.48 µmol/L)[23]
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.[24]
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.[25]
Oxidative stress
Uric acid may be a marker of oxidative stress,[26] and may have a potential therapeutic role as an antioxidant (PMID 16375736). On the other hand, like other strong reducing substances such as ascorbate, uric acid can also act as a prooxidant,[27] 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.[28]
For example, some researchers propose that hyperuricemia-induced oxidative stress is a cause of Metabolic syndrome.[29][30] On the other hand, plasma uric acid levels correlate with longevity in primates and other mammals.[31] 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 food products, especially internal organs.[32]
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.
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.[33]
Moderate intake of purine-containing food is not associated with an increased risk of gout.[34]
Serum uric acid can be elevated due to high fructose intake [35], reduced excretion by the kidneys, and or high intake of dietary purine.
Fructose can be found in processed foods and soda beverages - in some countries, in the form of high fructose corn syrup.
Causes of low uric acid
Aside from avoidance of purine foods, both accumulated copper and low vitamin B2 can exacerbate low uric acid levels, which in turn is hypothesized to lead to myelin degeneration seen in multiple sclerosis.[36]
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.
See also
References
- ↑ Purines And Pyrimidines
- ↑ Ascorbic Acid and Uric Acid, Similar Functions ?
- ↑ Ascorbic Acid and Uric Acid, Similar Functions ?
- ↑ [1]SI Units for Clinical Data
- ↑ [2]The effect of a vegetarian and different omnivorous diets on urinary risk factors for uric acid stone formation
- ↑ [3]Hyperuricemia and gout: diagnosis and therapy
- ↑ [4]Biochemistry of uric acid and its relation to gout
- ↑ [5]Uric Acid, Serum
- ↑ [6]An amperometric uric acid biosensor based on modified Ir-C electrode
- ↑ [7]Lesch-Nyhan Disease
- ↑ [8]Role of uric acid in hypertension, renal disease, and metabolic syndrome
- ↑ 12.0 12.1 Niskanen LK, Laaksonen DE, Nyyssönen K, Alfthan G, Lakka HM, Lakka TA; et al. (2004). "Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study". Arch Intern Med. 164 (14): 1546–51. doi:10.1001/archinte.164.14.1546. PMID 15277287.
- ↑ Culleton BF, Larson MG, Kannel WB, Levy D (1999). "Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study". Ann Intern Med. 131 (1): 7–13. doi:10.7326/0003-4819-131-1-199907060-00003. PMID 10391820.
- ↑ White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A; et al. (2018). "Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout". N Engl J Med. 378 (13): 1200–1210. doi:10.1056/NEJMoa1710895. PMID 29527974.
- ↑ Brucato A, Cianci F, Carnovale C (2020). "Management of hyperuricemia in asymptomatic patients: A critical appraisal". Eur J Intern Med. 74: 8–17. doi:10.1016/j.ejim.2020.01.001. PMID 31952982.
- ↑ Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, Webster J; et al. (2020). "Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial". Lancet. 396 (10264): 1745–1757. doi:10.1016/S0140-6736(20)32234-0. PMID 33181081 Check
|pmid=value (help). - ↑ Li X, Meng X, Timofeeva M, Tzoulaki I, Tsilidis KK, Ioannidis JP; et al. (2017). "Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies". BMJ. 357: j2376. doi:10.1136/bmj.j2376. PMC 5461476. PMID 28592419.
- ↑ Cappuccio FP; et al. (1993). "Uric acid metabolism and tubular sodium handling. Results from a population-based study". Jama. 270 (3): 354-359.
- ↑ Dehghan A.; et al. (2007). "High serum uric acid as a novel risk factor for type 2 diabetes mellitus". Diabetes Care.
- ↑ Nakagawa T, Hu H, Zharikov S; et al. (2006). "A causal role for uric acid in fructose-induced metabolic syndrome". Am J Physiol Renal Physiol. 290 (3): F625-631.
- ↑ Blackwell Synergy - Eur J Neurol, Volume 9 Issue 3 Page 221-226, May 2002 (Article Abstract)
- ↑ Blackwell Synergy - Eur J Neurol, Volume 9 Issue 3 Page 221-226, May 2002 (Article Abstract)
- ↑ [9]SI Units for Clinical Data
- ↑ [10]Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiplesclerosis
- ↑ [11]Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis
- ↑ Towards the physiological function of uric acid. [Free Radic Biol Med. 1993] - PubMed Result
- ↑ Electron Transfer Factors in Psychosis and Dyskinesia
- ↑ [12]Free Radicals and Human Disease
- ↑ [13] A Causal Role for Uric acid in Fructose-induced Metabolic Syndrome
- ↑ [14]Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: The urate redox shuttle
- ↑ [15] Urate and ascorbate: their possible roles as antioxidants in determining longevity of mammalian species
- ↑ [16]Gout Causes: List of Diet/Food Sources High or Low in Purine Content
- ↑ [17] Gout Diet / Low Purine Diet - Limit High Purine foods
- ↑ [18]Purine-Rich Foods, Dairy and Protein Intake, and the Risk of Gout in Men
- ↑ [19]A causal role for uric acid in fructose-induced metabolic syndrome
- ↑ [20] The possible role of gradual accumulation of copper, cadmium, lead and iron and gradual depletion of zinc, magnesium, selenium, vitamins B2, B6, D, and E and essential fatty acids in multiple sclerosis
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