Biomarkers of Inflammation: Uric Acid

Optimal Takeaways

Uric acid is a byproduct of purine metabolism but also an important antioxidant. However, serum levels above optimal are associated with an increased risk of gout, heart disease, stroke, cognitive dysfunction, and kidney stones. Elevated levels can occur with excess intake or production of purines and decreased excretion via the kidney or GI tract. Levels can also increase with stress, alcoholism, cancer, or ketoacidosis.

Standard Range:

Male: 3.45 - 8.00 mg/dL (205.21 - 475.84 umol/L)        

Female: 2.50 - 7.00 mg/dL (148.70 - 416.36 umol/L)

The ODX Range:    

Male: 3.50 - 5.40 mg/dL (208.18 – 321.19 umol/L)  

Female: 3.00 – 4.70 mg/dL (178.44 - 279.57 umol/L)

Low uric acid is associated with Wilson’s disease, Fanconi syndrome, and liver atrophy. Drugs that decrease uric acid include high-dose aspirin, allopurinol, azathioprine, clofibrate, corticosteroids, estrogen, glucose infusion, guaifenesin, mannitol, probenecid, and warfarin (Pagana 2021).

High uric acid is associated with gout (inflammatory arthritis), increased purine ingestion, acidosis, multiple myeloma, metastatic cancer, chemotherapy, enzyme deficiency, alcoholism, hyperlipoproteinemia, diabetes, hemolysis, kidney failure, kidney stones, ketoacidosis, dehydration due to diuretics, hypothyroidism, rhabdomyolysis (e.g., myocardial infarction, injury, burns, excess exercise), stress, and lead poisoning. Drugs can also increase uric acid, including low-dose aspirin, alcohol, ascorbic acid, caffeine, cisplatin, diazoxide, diuretics, epinephrine, ethambutol, levodopa, methyldopa, nicotinic acid, phenothiazines, and theophylline (Pagana 2021).

Elevated uric acid is also associated with heart failure, upregulated xanthine oxidase activity (Tamariz 2011), hypertension, coronary artery disease, cognitive dysfunction, insulin resistance, metabolic syndrome, and increased consumption of high-fructose beverages (Desideri 2014). Elevated uric acid may be idiopathic, e.g., from an unknown cause.

Overview

Uric acid is primarily a nitrogen-based byproduct of purine catabolism; It is excreted via the kidney or intestine to avoid toxic build-up and crystallization with subsequent deposition in the joints and soft tissues. Elevated uric acid and joint crystallization is a hallmark sign of the inflammatory condition gout (Pagana 2021). In the body, purines are found in DNA, RNA, ATP, ADP, AMP, NADP, NADPH, and coenzyme Q10 (Keenan 2017). In food, they are found primarily in red meat, seafood, beer, alcohol, and high-fructose corn syrup (Ruoff 2016).

Uric acid is a metabolically active compound as well as a metabolic waste product. It is an important antioxidant that accounts for up to 50% of the total antioxidant capacity of plasma. It has an antioxidant capacity comparable to that of ascorbic acid. Uric acid protects against lipid and protein peroxidation, LDL oxidation, and superoxide dismutase degradation. It also protects tetrahydrobiopterin, a cofactor for nitric oxide synthase. However, depending on the biochemical milieu of the body and saturate threshold, it can act as a pro-oxidant and can also inhibit insulin, contributing to insulin resistance. Researchers note that mean uric acid levels in the United States have almost doubled from 3.4 mg/dL (190 umol/L) in the 1920s to 6.25 mg/dL (372 umol/L) in the 1970s, an increase attributed to increased consumption of high-purine foods, alcohol, and high-fructose soft drinks. Deposits of monosodium urate crystals can occur with a serum uric acid above 6.8 mg/dL (405 umol/L). Although this deposition may be asymptomatic, it can contribute to detrimental skeletal changes (Desideri 2014).

A higher uric acid is associated with cardiovascular risk factors, including diabetes, metabolic syndrome, and hypertension. Reducing uric acid to a level below 5 mg/dL (297 umol/L) was associated with normalizing blood pressure in adolescents with newly diagnosed essential hypertension. Research suggests that for each 0.5 mg/dL (30 umol/L) reduction in serum uric acid facilitated by losartan (which increases renal uric acid excretion), CVD risk decreased by 5.3%. Cognitive dysfunction and cerebral ischemia may also be associated with a higher versus a lower serum uric acid. A level of 5.75 mg/dL (342 umol/L) was associated with a significantly increased risk of dementia compared to 5.13 mg/dL (305 umol/L). An increased uric acid may also help predict stroke probability, with a 22% increased risk of stroke associated with each 1.5 mg/dL (89 umol/L) increase in uric acid (Desideri 2014).

In the Uric Acid Right for Heart Health (URRAH) retrospective observational study of 23,467 subjects, a uric acid above 5.7 mg/dL (339 umol/L) in general and above 5.26 mg/dL (313 umol/L) in women, specifically, may be associated with risk of fatal MI (Casiglia 2020). Data from the study also suggested that uric acid cut-offs of 5.4 mg/dL (321 umol/L) in men and 4.7 mg/dL (280 umol/L) in women and above were associated with an increased risk of all-cause mortality (Virdis 2020).

References

Casiglia, Edoardo et al. “Serum uric acid and fatal myocardial infarction: detection of prognostic cut-off values: The URRAH (Uric Acid Right for Heart Health) study.” Journal of hypertension vol. 38,3 (2020): 412-419. doi:10.1097/HJH.0000000000002287

Desideri, G et al. “Is it time to revise the normal range of serum uric acid levels?.” European review for medical and pharmacological sciences vol. 18,9 (2014): 1295-306.

Keenan, Robert T., Svetlana Krasnokutsky, and Michael H. Pillinger. "Etiology and pathogenesis of hyperuricemia and gout." Kelley and Firestein's Textbook of Rheumatology. Elsevier, 2017. 1597-1619.

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Ruoff, Gary, and N Lawrence Edwards. “Overview of Serum Uric Acid Treatment Targets in Gout: Why Less Than 6 mg/dL?.” Postgraduate medicine vol. 128,7 (2016): 706-15. doi:10.1080/00325481.2016.1221732

Tamariz, Leonardo et al. “Uric acid as a predictor of all-cause mortality in heart failure: a meta-analysis.” Congestive heart failure (Greenwich, Conn.) vol. 17,1 (2011): 25-30. doi:10.1111/j.1751-7133.2011.00200.x

Virdis, Agostino et al. “Identification of the Uric Acid Thresholds Predicting an Increased Total and Cardiovascular Mortality Over 20 Years.” Hypertension (Dallas, Tex. : 1979) vol. 75,2 (2020): 302-308. doi:10.1161/HYPERTENSIONAHA.119.13643