Uric Acid as a Marker for Cardiac Risk

Uric Acid as a Marker for Cardiac Risk

Once considered a “waste product” and only discussed in terms of gout or kidney stones, uric acid is proving to be a powerful indicator to assess your risk factors for metabolic syndrome, hypertension, obesity and other imbalances in metabolism and cardiac health. Sometimes, uric acid levels rise even before symptoms develop, suggesting that it could become an important screening tool in medicine. 

In today’s article, we will discuss these details and answer these questions: 

  • What is uric acid? 
  • What is the role of uric acid in metabolic and cardiac risk? 
  • What causes uric acid to be elevated?
  • How can I decrease and manage uric acid levels, naturally and safely? 

Let’s get started!

What Is Uric acid?

Uric acid, or urate, is the end product of compounds metabolized through the purine pathway. These include fructose (a type of sugar found in fruit) and nucleotides (part of the building blocks of DNA and RNA). When these are metabolized, mainly in the liver, uric acid is released, and concentrations can be measured in the blood. Then, uric acid undergoes excretion by the kidneys, as do other compounds like creatinine.

Uric acid can be an antioxidant or pro-oxidant, contributing to oxidative stress, depending upon its microenvironment in the body. (Source 1)

Interestingly, most animals make an enzyme called uricase, that breaks down uric acid, keeping serum uric acid levels low. Humans have lost the ability to make their own uricase and have higher uric acid levels in the blood compared to other mammals, typically over 3 mg/dl. (Source 2)

This may have been a beneficial adaptation earlier in human evolution, allowing us to store more body fat. However, it may not be so beneficial in modern times, as we will discuss.

Health Risks of Elevated Uric Acid

Elevated serum uric acid, or hyperuricemia, is associated with a range of metabolic and cardiovascular diseases. These include:

  • Metabolic syndrome
  • Insulin resistance
  • Hypertension (high blood pressure)
  • Obesity
  • Type 2 diabetes (diabetes mellitus)
  • Chronic kidney disease (renal disease)
  • Dyslipidemia
  • Non-alcoholic fatty liver disease 
  • Obstructive sleep apnea
  • Coronary heart disease/coronary artery disease/ischemic heart disease
  • Cardiovascular events, including stroke and heart attack (myocardial infarction)
  • Atherosclerosis 
  • Vascular dementia 
  • Osteoarthritis (Source 1, 2, 3, 4)

In addition, hyperuricemia is associated with cardiovascular mortality and all-cause mortality. (Source 1, 4)

Metabolic Syndrome

Metabolic syndrome is the collection of several known cardiovascular risk factors associated with insulin resistance. For diagnosis, three of the five characteristics need to be met:

  1. Central obesity – as measured by a waist circumference greater than 40 inches for men and 35 inches for women. 
  1. Hyperglycemia – or high blood sugar as measured by fasting blood glucose at or above 100mg/dl.
  1. Dyslipidemia – an imbalance of lipids as measured by elevated serum triglycerides at or above 150mg/dl. 
  1. Dyslipidemia – as measured by high density lipoprotein cholesterol (HDL cholesterol) lower than 40 mg/dl for men or 50 mg/dl for women. 
  1. Hypertension – as measured by blood pressure greater than 130 mmHg systolic (the pressure when your heart pushes blood out) or 85 mmHg diastolic (the pressure when your heart rests between beats). (Source 5)

Mechanistically, the metabolism of purines stimulates fat storage and insulin resistance. (Source 2)

Over time, metabolic syndrome progresses to type 2 diabetes, which increases risk for heart disease and heart failure. The cardiometabolic factors are all connected.

Essential Hypertension

Elevated uric acid concentration is an independent predictor for the development of high blood pressure. In addition, lowering uric acid has also been shown to lower blood pressure in hypertensive patients. (Source 2)

When uric acids are elevated over time, uric acid creates both inflammation in the kidney and changes to the microvascular system in the kidney. While the uric acid initiates hypertension, it’s the damage to the kidney that perpetuates it, making one more sensitive to salt and damaging renal function. (Source 2)

Several mechanisms are at play here. Elevated uric acid:

  • Inhibits endothelial function (the cells that line blood vessels),
  • Increases inflammation,
  • Increases oxidative stress,
  • Increases vascular smooth muscle cell proliferation,
  • And increases the renin- angiotensin system (hormones involved in maintaining blood pressure). (Source 2)

The result is hypertension. So, while medication like diuretics or nutrition interventions like a low sodium diet helps manage the symptom, they don’t address the root cause. 

Pre-diabetes and Type 2 Diabetes

High uric acid is not a consequence of insulin resistance but a driver. In fact, uric acid levels are an independent risk factor for insulin resistance, which leads to pre-diabetes, diabetes and associated complications, including heart disease. Epidemiological studies suggest high serum uric acid levels predict insulin resistance and diabetes, even before diagnosis is made. In addition, allopurinol, a uric acid-lowering medication, may improve insulin resistance. (Source 2)

In insulin resistance, blood sugar levels are high. Insulin, the hormone required to move glucose from the bloodstream and into cells where it can enter the citric acid cycle and create energy, becomes required in greater amounts to address the blood sugar levels. Eventually, the cells are overwhelmed and insulin signaling becomes impaired. 

Mechanistically, too much uric acid plays a causal role in insulin resistance because it:
  • Decreases nitric oxide (that dilates blood vessels), 
  • Increases gluconeogenesis (the production of blood glucose from other molecules), 
  • Decreases adiponectin (a hormone involved in blood glucose regulation),
  • Increases oxidative stress,
  • And decreases insulin secretion. (Source 2, 6)

Obesity

With obesity, we are talking about not simply body mass index, but the accumulation of visceral, midsection fat which is associated with insulin resistance. Like the other condition, epidemiology shows elevated uric acid in the blood predicts the incidence of obesity and the development of fatty liver disease. 

(Source 2)

This is because uric acid directs fat storage to adipose tissue (fat tissue) as well as the liver. Underlying factors include:
  • Decreased fatty acid oxidation (the decreased use and efficiency of making energy out of fat), 
  • Increased production of fat,
  • Increased triglycerides, 
  • And oxidative stress. (Source 2)

Cardiovascular Disease

The association between heart health and uric acid has been known for decades in cardiology, but the role of uric acid doesn’t seem to directly cause or contribute to heart disease, like the other conditions above. Instead, uric acid contributes to hypertension, insulin resistance, obesity and kidney disease. These are all risk factors for heart disease. (Source 2)

In addition, uric acid promotes inflammation, oxidative stress and endothelial dysfunction, which may influence atherosclerosis and the development of coronary heart disease. (Source 2)

On the other hand, lowering uric acid improves markers of heart health and metabolic syndrome as well as decreases cardiovascular events (heart attack and stroke), especially in those without renal disease. (Source 2)

As you can see, the metabolic conditions we’ve discussed today are modern chronic disease related to lifestyle factors, including diet. 

What Causes High Uric Acid?

Uric acid plays an important role in determining metabolic health. Because of this, it may not be surprising to learn that the main factor contributing to hyperuricemia is diet, specifically a highly processed standard American or Western diet. This type of diet already puts someone in a high-risk category for chronic disease. 

Certain foods are higher in purines than others, and lowering purines in the diet is the main nutrition intervention in those with gout, a type of arthritis where uric acid crystals form in the big toe and other joints. These foods include: 

  • Alcohol, especially beer
  • Meat
  • Fish
  • Poultry
  • Organ meat
  • Shellfish
  • Some beans and nuts
Eliminating these foods does not always decrease uric acid levels, especially if whole protein-rich foods are replaced with processed options, especially those that include sugar. High fructose foods are abundant in the USA and may be the single most problematic category of food when it comes to uric acid. 

Sucrose is a naturally occurring sugar found in fruit and some other plant foods, that contains one molecule of glucose and one molecule of fructose. Adding sugar to food increases its fructose content. Fructose is also concentrated in sweeteners like agave syrup and high fructose corn syrup. Soda, juice and other sweetened beverages deliver extremely high amounts of fructose rapidly into the body and result in high uric acid levels. 

Now, let’s talk about how to reduce uric acid levels, naturally and safely to decrease health risk and mortality. 

Action Steps to Maintain Healthy Uric Acid Levels

There is an association of serum uric acid levels and diet, which in turn either directly or indirectly contribute to cardiometabolic disease. To manage this, we can start with diet and add in other supportive measures. Here’s how:
  1. Have uric acid levels checked. This isn’t always a standard test for the general population, but perhaps it should be given the fact that uric acid levels may predict the development of hypertension, obesity and metabolic syndrome. Increased uric acid levels mean increased risk. Levels above 6 mg/dL for women and 7 mg/dL for men are considered high and prognostic.
  1. Decrease dietary fructose. If uric acid levels are high, or are trending up, this may be a sign that you are consuming more fructose in the diet than the body can handle. Check labels for added sugars, ditch soda and other sugary beverages and prioritize whole, nutrient-dense food. Decreasing or eliminating alcohol, especially beer and sugary mixers, is supportive as well. 
  1. Use supplements. Certain supplements are helpful for decreasing uric acid levels in the body. Here are some to consider:
      • Quercetin – Quercetin is a flavonoid plant compound naturally found in foods like onions, apples and tea. It can also be used in supplemental form. Previous studies suggest it may work to block xanthine oxidase, one of the key enzymes in uric acid production. Therefore, quercetin is considered a uric acid inhibitor
        In a 4-week randomized controlled trial, 500mg of quercetin taken daily was shown to decrease plasma uric acid levels from baseline in healthy participants, along with decreasing both blood pressure and blood glucose levels. (Source 7)
      • Tart cherry juice. Although we just discussed not drinking juice because of the high fructose content, tart cherry juice, used therapeutically might be the exception. In a randomized controlled crossover study of overweight or obese people (with body max index over 25), when participants were given tart cherry juice their serum uric acid levels decreased by 19 percent at follow-up compared to the placebo beverage. In addition, c-reactive protein, a marker of inflammation, decreased by over 6 percent. (Source 4)
      • Vitamin C. Vitamin C is an essential vitamin, and like we discussed with uricase, humans can’t make their own as many other mammals can. We must obtain vitamin C from the diet or through supplementation. Vitamin C plays many important roles in the body from antioxidant protection to immune support to building collagen. A lesser-known role of vitamin C is as an inhibitor of uric acid synthesis. (Source 3)
In a meta-analysis and systematic review of randomized controlled trials, vitamin C supplementation showed a significant decrease in uric acid levels. The average vitamin C dose was around 500mg, taken for 30 days. (Source 3)We recommend CoreMed Science’s Liposomal Vitamin C for superior absorption and bioavailability of this key nutrient. Unlike other vitamin C supplements that may cause side effects at high dosages or are derived from GMO corn, liposomal vitamin C is well tolerated and of the highest quality and purity.

When you go to the doctor, they might look at blood pressure or other biomarkers of heart and metabolic health. Uric acid is a lab to add to the list, because it may increase risk of cardiovascular disease and all-cause mortality. If uric acid levels are high, in addition to diet lifestyle changes to support overall health, certain supplements, including Liposomal Vitamin C are incredibly helpful. 


References: 

      1. So, A., & Thorens, B. (2010). Uric acid transport and disease. The Journal of clinical investigation120(6), 1791–1799. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877959/ 
      2. Kanbay, M., Jensen, T., Solak, Y., Le, M., Roncal-Jimenez, C., Rivard, C., Lanaspa, M. A., Nakagawa, T., & Johnson, R. J. (2016). Uric acid in metabolic syndrome: From an innocent bystander to a central player. European journal of internal medicine29, 3–8. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826346/ 
      3. Juraschek, S. P., Miller, E. R., 3rd, & Gelber, A. C. (2011). Effect of oral vitamin C supplementation on serum uric acid: a meta-analysis of randomized controlled trials. Arthritis care & research63(9), 1295–1306. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169708/ 
      4. Martin, K. R., & Coles, K. M. (2019). Consumption of 100% Tart Cherry Juice Reduces Serum Urate in Overweight and Obese Adults. Current developments in nutrition3(5), nzz011. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483050/ 
      5. Huang P. L. (2009). A comprehensive definition for metabolic syndrome. Disease models & mechanisms2(5-6), 231–237. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675814/ 
      6. Wu, G., & Meininger, C. J. (2009). Nitric oxide and vascular insulin resistance. BioFactors (Oxford, England)35(1), 21–27. Abstract: https://pubmed.ncbi.nlm.nih.gov/19319842/ 
      7. Shi, Y., & Williamson, G. (2016). Quercetin lowers plasma uric acid in pre-hyperuricaemic males: a randomised, double-blinded, placebo-controlled, cross-over trial. The British journal of nutrition115(5), 800–806. Abstract: https://doi.org/10.1017/S0007114515005310
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