Uric acid (UA) is a natural waste product generated from the breakdown of purines, organic compounds sourced from cell turnover and certain foods. Once produced, UA circulates in the bloodstream until the kidneys filter the majority of it out for excretion in the urine. A normal serum uric acid level varies by sex, typically falling between 1.5 to 6.0 milligrams per deciliter (mg/dL) for women and 2.5 to 7.0 mg/dL for men. Hypouricemia is the condition defined by an abnormally low level of uric acid in the blood, often considered a concentration less than 2 mg/dL. While less common than high uric acid levels (hyperuricemia), hypouricemia signals an underlying issue related to how the body produces or eliminates this substance.
Increased Excretion via the Kidneys
The most frequent cause of low uric acid levels is the excessive loss of the compound through the kidneys, known as enhanced renal clearance. The kidneys normally operate by filtering all the uric acid out of the blood and then reabsorbing approximately 90 percent of it back into the bloodstream. Hypouricemia occurs when this reabsorption process is defective, causing too much uric acid to be “flushed out” into the urine. This means the body is producing a normal amount of uric acid but is simply failing to conserve it effectively.
This enhanced loss can stem from two main categories: primary (genetic) and secondary (acquired) causes. Primary renal hypouricemia is a hereditary condition often involving mutations in specific transport proteins within the kidney tubules. The urate transporter 1 (URAT1) and the glucose transporter 9 (GLUT9) are responsible for reabsorbing uric acid from the filtered fluid back into the body. A defect in the function of these transporters prevents the normal reclamation of uric acid, leading to its persistent loss in the urine.
Secondary renal hypouricemia is a result of other systemic diseases that damage the kidney’s filtering and reabsorption machinery. Fanconi syndrome is a notable example, where the proximal tubules of the kidney fail to reabsorb various substances, including glucose, phosphate, amino acids, and uric acid. Other conditions, such as Wilson’s disease or certain malignancies, can also lead to acquired tubular defects and subsequent excessive uric acid excretion.
Impaired Production and Synthesis
A second major pathway leading to low uric acid levels involves a reduction in the body’s ability to manufacture the compound. Uric acid synthesis primarily occurs in the liver, where the breakdown of purines requires several specific enzymes. If the metabolic machinery is compromised or the necessary enzymes are missing, the production of uric acid decreases significantly. This cause is distinct from renal excretion issues, which involve normal production but abnormal loss.
The most well-defined cause in this category is hereditary xanthinuria, also known as Type I hypouricemia. This is a rare, inherited disorder caused by a deficiency in the enzyme xanthine oxidase (XO). Xanthine oxidase is responsible for the final steps in the purine breakdown process, converting the precursors hypoxanthine and xanthine into uric acid. Without this enzyme, uric acid levels drop sharply, sometimes below 1 mg/dL, while the precursors build up in the body instead.
Acquired conditions that impair liver function can also lead to decreased uric acid synthesis. Severe liver disease, such as advanced cirrhosis or hepatitis, compromises the liver’s metabolic capacity to process purines, resulting in diminished serum levels. Nutritional factors, such as severe malnutrition or a diet extremely low in purines, can also limit the raw materials available for uric acid synthesis.
Drug-Induced Hypouricemia
Numerous medications can cause a reduction in serum uric acid levels, often by mimicking the enhanced renal excretion seen in genetic conditions. The medications primarily work by acting as uricosuric agents, meaning they block the reabsorption of uric acid in the kidney tubules, thereby increasing its excretion.
Classical uricosuric drugs, such as Probenecid or Lesinurad, are often prescribed to treat hyperuricemia and gout by specifically targeting the URAT1 transporter. High doses of aspirin (over 3 grams per day) can also exhibit this uricosuric effect. Certain cardiovascular medications, like Losartan, are also known to lower uric acid levels because Losartan directly inhibits the URAT1 transporter.
A newer class of diabetes medications, the sodium-glucose cotransporter-2 (SGLT2) inhibitors, also consistently causes hypouricemia. These drugs, like empagliflozin, work primarily by blocking glucose reabsorption in the kidney. This action also promotes the renal excretion of uric acid, often by affecting other transporters like GLUT9. Some studies suggest SGLT2 inhibitors may also reduce purine synthesis in the liver, providing a dual mechanism for lowering uric acid levels.
Clinical Significance of Low Uric Acid
For many individuals, a low uric acid level is an incidental finding on a blood test and is entirely asymptomatic, requiring no specific treatment. However, the underlying cause of the hypouricemia can carry specific health implications that necessitate further investigation. The main concerns arise when the low serum level is caused by excessive renal excretion or a production defect, as both can lead to specific complications.
In cases of hereditary xanthinuria (XO deficiency), the buildup of uric acid precursors like xanthine can lead to the formation of xanthine kidney stones. Because xanthine is less soluble than uric acid, its high concentration in the urine can cause stone formation in approximately one-third of affected patients. For individuals with renal hypouricemia, a different risk exists related to kidney function under stress.
Hereditary renal hypouricemia has been linked to an increased risk of exercise-induced acute kidney injury (EIAKI). During intense physical activity, the body’s metabolism shifts, and the inability of the kidneys to properly manage the resulting purine load can lead to temporary kidney failure. When low uric acid is detected, a physician may order a fractional excretion test to measure the amount of uric acid leaving the body in the urine. This test helps determine if the cause is excessive loss or insufficient production, guiding necessary follow-up and management.