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!
- High Levels of Uric Acid and Diseases Associated with it
- High Levels of Uric Acid Can Lead to Gout
- Hyperuricemia Increases the Risk of Kidney Stone Formation
- High Levels of Uric Acid are Associated with Hypertension and Chronic Kidney Diseases
- Hyperuricemia is Caused by Lesch-Nyhan Syndrome
- Hyperuricemia is Linked to Type 2 Diabetes
- High Uric Acid Levels May Lead to Metabolic Syndrome
- Hypothyroidism Can Raise Uric Acid Levels
- Tumor Lysis Syndrome Elevates Uric Acid Levels
- Chronic Lead Poisoning Can Lead to Hyperuricemia
- High Uric Acid Levels May Increase Bone Fracture Risk
- Uric Acid Levels are Elevated in Down Syndrome
- What Causes High Uric Acid Levels?
- Low Levels of Uric Acid and Diseases Associated with it
- What Causes Low Uric Acid Levels?
- Treatment With Agents that Reduce Uric Acid Level
- Treatment with Agents that Increase Uric Acid Levels
- Genetics of Uric Acid:
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.
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
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
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
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 (R, R) 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 (R, R2).
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).
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?
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).
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
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 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).
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).
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).
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).
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.
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).
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).
Vitamin D insufficiency is significantly correlated with hyperuricemia in post-menopausal women (R).
A ketogenic diet reduces the ability of the kidney to excrete uric acid because of competition for transport between uric acid and ketones (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?
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).
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).
Several malignant diseases including Hodgkin’s disease, sarcoma, glioblastoma and a variety of carcinomas have been associated with hypouricemia (R).
By following a low purine diet, uric acid levels are lowered by only 15% at most (R).
In a case study of molybdenum deficiency, blood hypouricemia was present (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).
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).
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.
24 hours urine is collected.
Treatment With Agents that Reduce Uric Acid Level
1) Non-Steroidal Anti-inflammatory Drugs
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).
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
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).
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).
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
Treatment with Agents that Increase Uric Acid Levels
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).
The SLC2A9 gene encodes the glucose transporter 9 protein (GLUT4). It transports urate and fructose (R).
- 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).
- RS734553 – The “T” allele is associated with a higher risk of gout (R).
- RS737267 – The GG genotype is associated with 1.25 times higher risk of gout (R).
- RS7442295 – The more common “A” allele is associated with higher blood urate levels and hyperuricemia (R).
This gene encodes a multifunctional transporter that belongs to the ATP-binding cassette family and controls the export of various compounds using ATP (R).
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).
The gene encodes a protein that is involved in the transport and excretion of organic anions (R).
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).
The gene encodes a voltage-driven transporter that transports intracellular urate and organic anions from the blood into kidney tubule cells (R).
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).
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).
- 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).