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!

Introduction

bigstock-136761491-min

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).

It 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 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 convert to hypoxanthine, then to xanthine and xanthine converts to uric acid.

For the last two steps in conversion, we need the enzyme xanthine oxidase (uricase). Humans have less amount of the enzyme uricase (R). The ability to further metabolize uric acid is lost due to two mutations that silence the gene coding for the enzyme uricase (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. Too high or too low levels are not good (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.

High Levels of Uric Acid Can Lead to Gout 

bigstock-120575024-min

Gout is inflammatory arthritis associated with hyperuricemia. It is a different form of other form 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).

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

Chronic hyperuricemia in patients with gout causes 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 also associated with very high blood uric acid levels (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). 

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 might 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).  

Hypothyroidism Can Increase 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, and thus, 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

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 serum 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 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).

Fructose 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 decrease uric acid secretion (R).

Alcohol

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

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 and the degree of association varies with gender and BMI levels (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.

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).

Liver Diseases

Optic Neuritis

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).

Low dietary Zinc intake causes lower uric acid levels. This effect is more common in women taking oral contraceptives (R).

Patients with high copper/Fe levels experience hypouricemia (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

bigstock-135876392-min

Blood test

Most common test that is used to monitor people with gout, check kidney function, disorder or stones if you are under chemotherapy or radiation treatment.

Urine test

24hours urine is collected.

Treatment

Treatment With Agents that Reduce Uric Acid Level

Non-steroidal anti-inflammatory drugs

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

Xanthine oxidase inhibitors – allopurinol 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 – a selective xanthine oxidase/xanthine dehydrogenase inhibitor (R).

Weight loss – research suggests that losing weight may help reducing high levels.

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).

Water – keep yourself hydrated.

Vitamin C- Vitamin C can increase the excretion of uric acid in the urine, thereby lowering blood uric acid levels (R).

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

Treatment with Agents that Increase Uric Acid Levels

Inosine is the most powerful way to increase uric acid levels (R).

Zinc increases uric acid level if you are deficient.

Animal products increase levels in general.

Alcohol

Genetics of Uric Acid:

SNPs in the SLC2A9 Gene:

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

 

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 

SLC22A12

SLC22A11

SLC17A1

SLC17A3

UMOD

HPRT1

PRPS1

MTHFR

GCKR

Technical:

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).

Leave a Reply