Uric acid

Uric acid is the final product of the metabolic breakdown of purine nucleotides. The presence of an excess amount of uric acid in the body may lead to various diseases. Read this article to know about the medical conditions associated with either high or low levels of uric acid and methods to increase or decrease it!

Contents

Introduction

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Uric acid is an end-product of purine degradation in humans. Purines are generated as a final product in the digestion of certain proteins in the diet, but some are synthesized in the body (R).

Uric acid has antioxidant properties but can be pro-oxidant depending on its chemical environment (R).

In normal conditions, uric acid is eliminated via urine (R). Abnormal blood levels (too high or too low) have been linked to a variety of diseases including kidney stones, gout,  high blood pressure, kidney disease, obesity, diabetes, and cognitive dysfunction (R).

Production in the Body

Uric acid is the last step in the breakdown pathway of purines. Purines are converted to hypoxanthine, then to xanthine and finally, to uric acid.

For the last two steps in conversion, we need the enzyme xanthine oxidase (uricase). Humans have less uricase (R). The ability to further metabolize uric acid is lost due to two mutations that silence the gene encoding the enzyme uricase (R).

Consequently, humans have higher urate levels (around 240–360 μM) compared to other mammals (around 30–50 μM in mice) (R).

Disposition of the Body

Uric acid is removed from kidney and gut routes. It is almost completely filtered by the glomerulus. 98 – 100% is then reabsorbed in the proximal tubule and 50% is secreted by the distal tubule (R).

About 70% is removed from the urine and 30% is removed from the gut route (R).

Normal Range of Uric Acid in the Body

Humans have a higher uric acid level because they lack a functional uricase gene. Levels start to rise after puberty. Men have slightly higher levels than women until the female menopause (R).

Normal blood level for women: 2.6 – 5.7 mg/dl, and for men: 3.5 – 7 mg/dl.

These levels depend on the balance between purine production and the ingestion of dietary purines, as well as the elimination of urates by the kidney and intestine. Abnormal levels (too high or too low) are detrimental and can lead to a variety of health conditions (R).

High Levels of Uric Acid and Diseases Associated with it

An excess of uric acid in the body is known as hyperuricemia. High levels of uric acid in the blood usually forms urates and acid urates in the blood. Acid urates are any salt of uric acid such as sodium urate.

Urates are found in urine, blood and in tissue. Urate deposits can lead to oxidative stress (R), inflammation and endothelial dysfunction (R).

Most people with hyperuricemia are asymptomatic and don’t need any clinical treatment. However, hyperuricemia can lead to several diseases including gout, heart disease, stroke, and kidney disease (R).

High Levels of Uric Acid Can Lead to Gout 

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Gout is inflammatory arthritis associated with hyperuricemia. It is a different form of arthritis because it occurs when there are high levels of uric acid in the circulating blood.  That can cause urate crystals to settle in the tissues of the joints.

The symptoms appear suddenly, overnight. It comes with agonizing pain, swelling, and redness of the joint. The attack may be precipitated by too much food, alcohol, by starting a diuretic or by dehydration.

Symptoms go away after 10-15 days and can keep recurring. Eventually, stone-like deposits known as tophi may build up in joints, ligaments, and tendons and therefore can lead to joint deformation (R).

Hyperuricemia Increases the Risk of Kidney Stone Formation

If your urine contains more calcium, oxalate and uric acid you are more likely to develop kidney stones (R).

The most common risk factor for uric acid stones is decreased urinary pH (<5.5). Because uric acid stones precipitate in acidic environments, patients should increase their alkaline load by eating more fruits and vegetables (R).

High Levels of Uric Acid are Associated with Hypertension and Chronic Kidney Diseases

High levels of uric acid in the blood are associated with hypertension (HTN) and chronic kidney disease (CKD) (R, R2).

It is proposed that hyperuricemia can directly cause hypertension. This is supported by animal studies showing that induced hyperuricemia and resultant hypertension was reversible with hypouricemic drugs including febuxostat and allopurinol (R).

Hypertension and chronic kidney disease are associated with higher risk of cardiovascular events (RR) like hardening of the arteries, heart failure, stroke, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease and others (R).

Potential mechanisms linking blood uric acid to heart disease include its detrimental effects on blood vessel function, oxidative metabolism,  and platelet adhesiveness, as well as increased red blood cell aggregation (R, R2, R3).

Chronic hyperuricemia in patients with gout increases uric acid crystal build-up in kidney tissues, resulting in tissue injury and inflammation (R).

Hyperuricemia is Caused by Lesch-Nyhan Syndrome

Lesch-Nyhan syndrome, an extremely rare genetic disorder, is associated with very high blood uric acid levels (R).

In Lesch–Nyhan syndrome,  hypoxanthine-guanine phosphoribosyltransferase (HPRT), an enzyme involved in the recycling of purine nucleotides, is mutated. This leads to increased uric acid production because purine nucleotides cannot be reused, so they are therefore degraded (R).

Muscle tightness, involuntary movement, self-injury, cognitive retardation and gout formation are exhibited in cases of this syndrome (R).

Hyperuricemia is Linked to Type 2 Diabetes

High blood uric acid is associated with higher risk of type 2 diabetes, independent of obesity, high cholesterol, and blood pressure (R). 

It is thought that hyperuricemia raises the risk for diabetes by increasing oxidative stress and inflammation (by increasing tumor necrosis factor-α), both of which are related to the development of diabetes (R).

High Uric Acid Levels May Lead to Metabolic Syndrome

Blood uric acid is significantly associated with metabolic syndrome and its components, particularly blood triglycerides and waist circumference (R).

One study found that fructose-induced hyperuricemia may play a role in the development of metabolic syndrome. This is consistent with the increased consumption of fructose-containing beverages in the recent decades and the epidemic of diabetes and obesity (RR2).  

The rise in uric acid after fructose intake can induce insulin resistance (by lowering nitric oxide), a key factor involved in metabolic syndrome (R).

Hypothyroidism Can Raise Uric Acid Levels

There is a high prevalence of hyperuricemia and gout in patients with hypothyroidism (R).

Thyroid hormones (T4 and T3) stimulate metabolic processes so their deficiency can affect purine metabolism, resulting in increases in uric acid levels and hyperuricemia (R).

Also, hypothyroidism can lead to a reduction in renal plasma flow and glomerular filtration rate, which raises uric acid levels in the blood (R).

Tumor Lysis Syndrome Elevates Uric Acid Levels

Tumor lysis syndrome (TLS) is characterized by a group of metabolic abnormalities that occur during cancer treatment, where large amounts of tumor cells are killed at the same time by the treatment, resulting in the release of their contents into the bloodstream. High concentrations of uric acid are generated by tumor lysis (rupture), due to the large quantities of nucleic acids released from massive cell death and nuclear breakdown (R).

Chronic Lead Poisoning Can Lead to Hyperuricemia

Lead exposure is associated with impaired kidney function and increased blood uric acid levels (R).

High levels of lead damage the kidneys, causing inflammation and inhibiting urate excretion, resulting in urate build-up and eventually, saturnine gout (i.e., lead gout) (R).

High Uric Acid Levels May Increase Bone Fracture Risk

Increased blood urate levels are associated with an increased risk of hip fractures in men (R).

High uric acid levels can induce inflammation in the bone, impair nitric oxide availability, and suppress vitamin D activation, all of which increase bone fragility and fracture risk (R,R2,R3).

Uric Acid Levels are Elevated in Down Syndrome

Patients with down syndrome consistently report higher blood uric acid levels (R).

What Causes High Uric Acid Levels?

Kidney Problems

Higher levels of uric acid can occur when your kidneys don’t eliminate it efficiently due to kidney dysfunction and/or influence by certain metabolites and medications (R).

Food Consumption

Studies have shown that each additional intake of meat portion per day increases the risk of gout by 21% (R).

In a crossover study design, the effect of ingesting some purine-rich foods like beef liver, haddock fillets and soybean was investigated. Results showed that the ingestion of all the test meals caused an increase in blood uric acid levels (R).

High Dietary Intake of Fructose

High dietary intake of fructose in foods and drinks increase the production of inosine and purines. Also, fructose competes with uric acid for secretion in the kidney (R).

Fructose rapidly raises uric acid levels as a consequence of its activation of fructokinase with ATP consumption, intracellular phosphate depletion, and stimulation of AMP deaminase,  which leads to the increased production of inosines (R).

It also stimulates uric acid synthesis from amino acid precursors, such as glycine (R).

Diuretics

Diuretics are one of the most important causes of secondary hyperuricemia. Drugs increase blood uric acid levels by an increase of uric acid reabsorption and/or a decrease of uric acid secretion (R).

Alcohol

According to a population-based cohort study, alcohol-related diseases were significantly associated with gout risk. Also, severe alcohol-dependent patients were associated with an increased risk of gout (R).

Ethanol (i.e., alcohol) stimulates uric acid production by increasing the production of lactic acid, which reduces the excretion of uric acid in the kidneys (R).

It also accelerates the degradation of purine nucleotides, thereby increasing the production of uric acid (R,R2).

Obesity

According to a population-based epidemiological study, Obesity resulted in an increased risk of developing hyperuricemia. If you are overweight your body produces more uric acid. As a result, the kidney has a more difficult time eliminating uric acid (R).

Blood uric acid levels positively correlate with leptin levels. Since obese individuals have higher leptin levels (due to leptin resistance), leptin may be linked to the development of hyperuricemia in obesity (R).

Genetics

According to one study, the gene UCP2 influenced blood urate concentration and the risk of hyperuricemia. The degree of association varies with gender and BMI levels (R).

Mutations in the secretory urate transporter genes, ABCG2, SLC17A1 or SLC17A3, can cause hyperuricemia (R).

Psoriasis

Blood uric acid levels were significantly higher in patients with psoriasis compared with controls (R). But these levels did not modulate the inflammation seen in these patients.

Male Gender

Men have higher blood uric acid levels than women and are more at risk for developing gout (R).

Estrogen is required for the normal renal secretion of urates. During the post-menopausal period, women have the same content of uric acid as men of similar age, suggesting that low estrogen may have a role in hyperuricemia development (R).

Older Age

Blood uric acid content increases with age (R).

Also, the prevalence of gout increases approximately four-fold to 4.1% by the age of 75 years (R).

Nutrient Deficiencies

Vitamin D insufficiency is significantly correlated with hyperuricemia in post-menopausal women (R).

Diet

A ketogenic diet reduces the ability of the kidney to excrete uric acid because of competition for transport between uric acid and ketones (R).

Others

Niacin, hypothyroidism (R), renal insufficiency, immune-suppressing drugs, tumor lysis syndrome (R).

Low Levels of Uric Acid and Diseases Associated with it

Hypouricemia occurs when you have a low level of uric acid in your blood (2mg/dl or less) (R).

It is not considered to be a medical condition, but a useful medical sign.

Uric Acid is Lower in Multiple Sclerosis, Parkinson’s Disease, and Motor Neuron Disease

Individuals with Multiple Sclerosis, Parkinson’s disease, and motor neuron disease have significantly lower blood uric acid levels than healthy controls; and low uric acid levels correlate with symptom severity and disease remission (R).

It has been proposed that higher blood uric acid levels may be neuroprotective. In a large population-based cohort study, a negative relationship was observed between gout and Parkinson’s disease in patients aged 65 and above. A similar trend has been shown between uric levels and Huntington’s disease, suggesting that uric acid may play a role in preventing neurodegeneration (R,R2).

Uric Acid is Reduced in Optic Neuritis

Uric acid levels are lower in patients with optic neuritis, an inflammatory demyelinating disease of the optic nerve that is often the first symptom of Multiple Sclerosis (R).

Wilson’s Disease Can Lead to Low Uric Acid Levels

Wilson’s disease, a disease in which copper accumulates in tissues of vital organs like the brain and liver, can lead to decreased blood uric acid levels because of associated renal tubular dysfunction (i.e., Fanconi syndrome), which increases urinary uric acid excretion (R).

What Causes Low Uric Acid Levels?

Medication/Treatments

Hypouricemia can be found in 1% of hospitalized patients. In most cases, the cause is related to drugs like salicylates, allopurinol, x-ray contrast agents and glyceryl guaiacholate (R).

Also, drugs like losartan  (an angiotensin II receptor antagonist drug), fenofibrate (drug of the fibrate class, mainly used to reduce cholesterol levels) and some non-steroidal anti-inflammatory drugs (NSAIDs) reduce the serum uric acid (SUA) levels (R).

Forced diuresis used mainly in the treatment of suicide-attempt patients renal colic may result in hypouricemia (R).

Genetics

The human urate transporter 1 (URAT 1) and human glucose transporter-like protein 9 (GLUT 9) are two kidney urate transporters.

A genetic mutation in these two transporters is responsible for idiopathic hypouricemia (R).

The gene SLC2A9 encodes a protein that helps transport uric acid in the kidney. Variants of this gene are known to have significant associations with blood uric acid (R).  

Nervous System Disorders

Lower blood values have been associated with several nervous system disorders such as multiple sclerosis (MS)(R), Alzheimer’s disease (AD) (R), Huntington’s disease (HD), Parkinson’s disease (PD) (R).

Malignant Diseases

Several malignant diseases including Hodgkin’s disease, sarcoma, glioblastoma and a variety of carcinomas have been associated with hypouricemia (R).

Diet

By following a low purine diet, uric acid levels are lowered by only 15% at most (R).

Mineral intake/deficiency

In a case study of molybdenum deficiency, blood hypouricemia was present (R).

Inadequate dietary Zinc intake can lead to lower uric acid levels. This effect is more common in women taking oral contraceptives (R).

Patients with high copper/Fe levels experience hypouricemia (R).

Magnesium intake is inversely correlated with hyperuricemia in males. This is possibly due to magnesium’s laxative effect, which may play a potential role in increasing the excretion of uric acid (R).

Hormones

Estrogen suppresses proximal tubule epithelial cell OAT (organic anion transporter) expression which explains the lower serum urate levels in postmenopausal women as opposed to men (R).

Investigations

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Blood test

A uric acid blood test is the most common test used to monitor people with gout, check kidney function, and kidney disorders or stones if you are under chemotherapy or radiation treatment.

Urine test

24 hours urine is collected.

Treatment

Treatment With Agents that Reduce Uric Acid Level

1) Non-Steroidal Anti-inflammatory Drugs

Most non-steroidal anti-inflammatory drugs increase urinary uric acid excretion and are recommended for the treatment of gout (R, R2).

2) Uricosuric Drugs

These drugs increase the secretion of uric acid in urine – probenecid or sulfinpyrazone (R).

3) Xanthine Oxidase Inhibitors

Allopurinol is recommended because it prevents gout but it also can be given to you when you have a certain form of leukemia or lymphoma, to prevent a complication of chemotherapy or tumor lysis syndrome.

Also, due to its adverse effect, allopurinol is currently not indicated in asymptomatic hyperuricemia and its related cardiovascular disease or in the diseases other than gout (R).

4) Febuxostat

Febuxostat is a selective xanthine oxidase/xanthine dehydrogenase inhibitor (R).

It has several advantages over allopurinol including tolerability in allopurinol-hypersensitive patients, better retention of efficacy in kidney failure, and more rapid dissolution of tophi (R).

Febuxostat works fairly rapidly and treatment usually starts with doses of  40 mg/day. If blood uric acid is not less than 6.0 mg/dL by 2 weeks, the dose can be increased to 80 mg/day. The average reduction in blood uric acid level is 40% and 56% at 40 mg/day and 80 mg/day respectively and is similar in those with and without kidney failure, in contrast to allopurinol (R).

5) Weight loss 

Research suggests that losing weight may help reduce high uric acid levels (R).

6) Purine – Restricted Diet

You should avoid alcohol, red meat, seafood, sugary beverages. Avoid/ limit refined carbs. The foods lowest in purine content include eggs, fruit, cheese, nuts and vegetables other than legumes (R).

7) Water

Keep yourself hydrated as dehydration can lead to elevated uric acid levels (R).

8) Vitamin C 

Vitamin C can increase the excretion of uric acid in the urine and thereby lower blood uric acid levels (R).

9) Caffeine

Caffeine is a methylxanthine and a competitive inhibitor of xanthine oxidase (R). 

10) Dairy Products

Milk proteins (i.e., casein and lactalbumin) have a uricosuric effect and promote the excretion of uric acid in the urine (R).

11) Cherry Juice

Eating cherries can lower blood uric acid levels by increasing glomerular filtration rate and decreasing tubular reabsorption. Cherries are also natural xanthine oxidase inhibitors (R,R2).

Treatment with Agents that Increase Uric Acid Levels

1) Inosine

Inosine, a uric acid precursor,  is the most effective way to increase uric acid levels (R, R2).

2) Zinc

Zinc normalizes uric acid levels if you are deficient (R).

3) Animal Products

Animal products increase levels in general (R).

4) Alcohol Consumption

Alcoholic drinks increase uric acid levels (R).

5) Intense Exercise

Uric acid levels rise after strenuous exercise, potentially a result of purine nucleotide degradation and fast-twitch fiber utilization during conditions of high energy usage (R).

Genetics of Uric Acid:

SLC2A9 Gene-The Urate transporter:

The SLC2A9 gene encodes the glucose transporter 9 protein (GLUT4). It transports urate and fructose  (R).

  1. RS10017674 
  2. RS10018204 
  3. RS1014290 – The “G” allele is associated with a lower age at onset of Parkinson’s disease (R).Individuals with the TT genotype had higher blood uric acid levels after increasing their consumption of soft drinks (R).

    The GG genotype is associated with significantly higher serum uric acid levels when compared with the TT/TG genotypes (R).

  4. RS1079128 
  5. RS10805346
  6. RS11722228
  7. RS12498150 
  8. RS12498742 
  9. RS12498956 
  10. RS13103879 
  11. RS13129697 
  12. RS13131257 
  13. RS13328050 
  14. RS16868246 
  15. RS16890979 
  16. RS17185835 
  17. RS17185870 
  18. RS1850744 
  19. RS2018643 
  20. RS3733585 
  21. RS3733591 
  22. RS3775948 
  23. RS4311316 
  24. RS4312757 
  25. RS4314284 
  26. RS4339211 
  27. RS4455410 
  28. RS4473653 
  29. RS4475146 
  30. RS4481233 
  31. RS4519796 
  32. RS4580649 
  33. RS4621431 
  34. RS6449157 
  35. RS6449159 
  36. RS6449171 
  37. RS6449172 
  38. RS6449174 
  39. RS6449176 
  40. RS6449178 
  41. RS6449201 
  42. RS6449213 
  43. RS6814664 
  44. RS6815001 
  45. RS6823361 
  46. RS6832439 
  47. RS6834893 
  48. RS6836706 
  49. RS6838021 
  50. RS6839490 
  51. RS6843873 
  52. RS6844316 
  53. RS6849729 
  54. RS6852441 
  55. RS6855911 
  56. RS733175 
  57. RS734553 – The “T” allele is associated with a higher risk of gout (R).
  58. RS737267  – The GG genotype is associated with 1.25 times higher risk of gout (R).
  59. RS7376948 
  60. RS7378305 
  61. RS7378340 
  62. RS7435196 
  63. RS7442295  – The more common “A” allele is associated with higher blood urate levels and hyperuricemia (R).
  64. RS7658170 
  65. RS7671266 
  66. RS7672947 
  67. RS7676733 
  68. RS7677710 
  69. RS7680126 
  70. RS7686538 
  71. RS938554 
  72. RS9993410 
  73. RS9994266 

SNPs in the ABCG2 Gene:

This gene encodes a multifunctional transporter that belongs to the ATP-binding cassette family and controls the export of various compounds using ATP (R).

  1. RS13120400 
  2. RS1481012 
  3. RS17731538 
  4. RS2199936 
  5. RS2231137 
  6. RS2231142 
  7. RS2622604 
  8. RS2728124 
  9. RS2728125 
  10. RS3114018 
  11. RS4148152 
  12. RS4148155 
  13. RS72552713 

SNP’s in the SLC22A12 Gene:

This gene encodes a protein that is a member of the organic anion transporter (OAT) family, and it transports urate. Found in the epithelial cells of the proximal tubule of the kidney, this protein helps control the amount of urate present in the blood (R).

  1. RS10897518 
  2. RS12800450 
  3. RS505802 
  4. RS524023 

SNPs in the SLC22A11 Gene:

The gene encodes a protein that is involved in the transport and excretion of organic anions (R).

  1. RS17300741 
  2. RS2078267 
  3. RS505802 
  4. RS524023 
  5. RS7124676 

SNPs in the SLC17A1 Gene:

This gene encodes a protein that helps transport glucose and other sugars, bile salts and organic acids, metal ions and amine compounds. It is associated with a higher risk of gout and hyperuricemia (R).

  1. RS1165151 
  2. RS1165152 
  3. RS1165196
  4. RS1165209
  5. RS1183201 
  6. RS1185567 
  7. RS1408272
  8. RS17270561 
  9. RS17342717 
  10. RS2762353

SNPs in the SLC17A3 Gene: 

The gene encodes a voltage-driven transporter that transports intracellular urate and organic anions from the blood into kidney tubule cells (R).

  1. RS1165205 
  2. RS13198474 
  3. RS1408272 
  4. RS548987 
  5. RS6910741 

SNPS in the UMOD Gene:

This gene encodes uromodulin, a protein that is highly abundant in urine under physiological conditions. Defects in this gene are associated with various kidney diseases including glomerulocystic kidney disease with hyperuricemia (R).

  1. RS11859916 
  2. RS12444268 
  3. RS12917707 
  4. RS13333226 
  5. RS4293393 

SNPs in the HPRT1 Gene:

This gene encodes hypoxanthine phosphoribosyltransferase 1, an enzyme that allows cells to recycle purines. Mutations in this gene can result in gout or Lesch-Nyhan syndrome (R).

SNPs in the PRPS1 Gene:

The PRPS1 gene encodes an enzyme called phosphoribosyl pyrophosphate synthetase 1, or PRPP synthetase 1. This enzyme helps produce phosphoribosyl pyrophosphate (PRPP), which is involved in making purine and pyrimidine nucleotides (R).

Technical:

  • Uric acid scavenges reactive oxygen species and chelates transition metals (R,R2).
  • When fructose enters the liver cell, it is metabolized by a specific enzyme, fructokinase C. This enzyme lacks a negative feedback system to prevent excessive phosphorylation, so phosphate and ATP levels in cells are rapidly depleted.  Low intracellular phosphate levels stimulate AMP deaminase, which leads to the increased production of inosines (R).

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