Hyperuricemia is increasing globally and affecting millions of Americans, as documented by NIH. Why does the body create excessive uric acid, and how can we lower its impact to prevent associated disorders based on scientific reviews?

This story does not include health advice. It is for information, inspiration, and awareness purposes.

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Understanding the adverse effects of waste products, which we call cellular debris, on the brain has been a strong research interest for me. Cellular debris mainly comprises damaged organelles, misfolded proteins, and some degraded neurotransmitters.

However, during my research into metabolism in the 1990s, I also encountered waste products the cells, tissues, and organs create due to the metabolic processes. In the early 2000s, several studies indicated that elevated uric acid was a predictor of cardiovascular mortality.

For example, I came across an eye-opening investigation paper published in JAMA in 2004 titled Uric Acid Level as a Risk Factor for Cardiovascular and All-Cause Mortality in Middle-aged Men. These researchers concluded that serum uric acid levels are a strong predictor of cardiovascular disease mortality in healthy middle-aged men, independent of variables commonly associated with gout or metabolic syndrome.

This JAMA paper concerned me as, during my previous reviews, I learned that uric acid serves as an antioxidant and even has neuroprotective effects in right amounts, so I wondered how it might be a cause of cardiovascular disease and other conditions mentioned in the growing literature.

Numerous studies demonstrated that uric acid may exert neuroprotective actions in Alzheimer’s disease and Parkinson’s dementia, and hypouricemia (low uric acid levels) represents a risk factor for a quicker disease progression and a possible marker of malnutrition.

However, high blood uric acid (hyperuricemia) may negatively influence the disease course in vascular dementia. So, both very low and very high uric acid levels might be problematic in theory.

In another story, I will cover hypouricemia, a condition characterized by abnormally low uric acid levels in the blood. It relates to malnutrition or starvation due to eating disorders, genetic factors, Fanconi syndrome, kidney disorders, or liver disease.

In this story, I aim to introduce the adverse effects of hyperuricemia, which is linked to obesity, type II diabetes, erectile dysfunction, heart disease, and dementia, in the growing literature.

I wrote about addressing erectile dysfunction in an article on NewsBreak titled: If Viagra or Cialis Don't Work, Here's Another Option to Solve Erection Problems for Older Men.,

First, I’d like to briefly describe uric acid and its role in the body and then provide some perspectives from the literature on how its excessive amount relates to some serious health issues and what we can do about lowering it.

What is uric acid?

In simple terms, uric acid is a waste product formed when the body breaks down purines, which are found in certain foods and are produced naturally in the body during cell and DNA breakdown.

This NIH book chapter defines uric acid as the ultimate catabolite of purine metabolism in humans and higher primates. It is a weak organic acid that, under physiologic conditions, exists mainly as a monosodium salt. Epidemiologic studies in the United States have generally accepted 7.0 mg/dl as the upper limit in adult men and 6.0 mg/dl in women.

The book informs that uric acid levels are influenced by age and sex. For example, before puberty, the average blood uric acid for males and females is 3.6 mg/dl. Following puberty, values rise to adult levels, with women typically 1 mg/dl less than men. Other factors, like exercise, diet, drugs, and state of hydration, may result in fluctuations in uric acid levels.

Uric acid dissolves in the blood and is excreted through urine. However, if the body produces too much uric acid or the kidneys cannot remove enough, levels can rise, leading to hyperuricemia. While uric acid is not inherently harmful, high uric acid levels can form urate crystals, causing inflammation and gout.

Spiked rods of monosodium urate crystals photographed under polarized light from a synovial fluid sample. Formation of en: monosodium urate crystals in the joints are associated with gout.

For example, this paper in Nature informs that uric acid comes to clinical attention when it nucleates to form monosodium urate crystals in joints or other tissues, thereby causing the inflammatory disease of gout.

Some studies also link uric acid to high blood pressure. This book chapter informs that small clinical trials have shown that urate-lowering drugs may decrease the development of hypertension in adolescents. However, these drugs can have serious adverse effects, so this is not recommended as a treatment.

Recent studies link elevated uric acid to cardiometabolic and neurological issues, mentioning insulin resistance, type 2 diabetes, hypertension, heart disease, and cognitive decline. The exact mechanisms are still under study, but oxidative stress, inflammation, and endothelial dysfunction are thought to be involved.

What is hyperuricemia, and why does it matter?

According to this NIH book chapter, hyperuricemia is a common disorder that affects patients of all ages and genders. It is associated with uric acid and calcium nephrolithiasis. The most common manifestation is gout, which can be very painful and is amenable to treatment.

The book informs that hyperuricemia affects about 38 million Americans, over 11% of the population, and the incidence is increasing worldwide. Most patients with hyperuricemia are asymptomatic, and the diagnosis requires a high degree of suspicion as serum uric acid levels are no longer routinely measured on serum blood panels.

This 2021 paper explains that xanthine oxidase inhibitors are the safest and most effective drugs for managing chronic hyperuricemia, while pharmacogenetics strongly modulates the efficacy of uricosuric agents.

The paper states that emergent drugs like lesinurad and peglotidase are more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials, so further well-designed clinical research is needed to deepen their efficacy and safety profile.

Hyperuricemia matters due to its association with various health conditions. Primarily, it can lead to the formation of urate crystals, causing painful conditions like gout and kidney stones.

Beyond acute symptoms, hyperuricemia has been linked to metabolic disorders. Additionally, recent studies suggest a potential connection between high uric acid levels and cognitive decline, dementia, and other neurological conditions.

While the exact mechanisms are still being understood, addressing hyperuricemia is crucial not only for managing acute symptoms but also for mitigating long-term health risks.

Dr. Casey Means interviewed Dr. David Perlmutter about the discovery that the elevation of uric acid in the body is a causative mechanism in the development of metabolic diseases and one of the critical links between obesity, diabetes, heart disease, neurologic diseases like dementia, ADHD, fatty liver disease, and erectile dysfunction.

Insights from Growing Literature

A 2018 paper in the Journal of Rheumatology published a 20-year population study on the growing incidence of gout globally. The same year, a public health review reported that in the 2007–2008 NHANES, over 43 million Americans had sex-specific hyperuricemia.

The review highlighted that the prevalence of gout and hyperuricemia in the US appears to be on the rise, with incidence cases of gout more than doubling between 1969 and 1996 and then doubling again between 1990 and 2010.

When I reviewed the literature on uric acid, I noticed a strong correlation between obesity and hyperuricemia. Some preliminary studies suggested that obesity was one of the causes of hyperuricemia.

A 2019 epidemiological study of 8331 people informed that nearly half were obese, about 14% had high uric acid levels, and 8% were both obese and had high uric acid. The group with both obesity and high uric acid had the highest rate of hypertension (high blood pressure).

As documented in a 2023 NIH book chapter, the proposed mechanisms were visceral adipose tissue providing free fatty acids to the liver, inducing uric acid production, and dysregulation of adipocytes causing decreased uric acid and sodium excretion by the kidneys.

Examining these mechanisms led the researchers to find links between excessive uric acid in the body and multiple health conditions like weight gain, diabetes, heart disease, erectile dysfunction, and neurological disorders like dementia.

This 2022 study, published in Frontiers, covered 12,876 patients and examined the relationship between blood uric acid levels and metabolic phenotypes in overweight and obese individuals. It found that hyperuricemia was positively associated with metabolically healthy overweight and obese people.

This 2019 paper in the Journal of Endocrinology documented the significant association of uric acid with obesity, metabolic syndrome, nonalcoholic fatty liver disease, and type II diabetes. The mechanisms are considered to be inflammation, oxidative stress, and vascular endothelial injury, exacerbating the progression of these diseases.

This study in Hypertension tracked blood urate levels over time among CARDIA participants. Over a 10.6-year follow-up, the high-increasing group faced nearly three times the risk of cardiovascular disease compared to the low-stable group. Their findings suggest that monitoring urate trajectories may offer insights into heart disease risk in middle age, with blood pressure as a potential mediator.

In a 2013 study published in the Journal of Sexual Medicine involving 312 adult males, researchers found a correlation between uric acid levels and endothelial dysfunction, oxidative stress, and cardiovascular disease.

Their study led to the hypothesis that higher serum uric acid levels might be a predictor for erectile dysfunction, especially in patients at risk for coronary artery disease. Subjects with elevated uric acid levels who presented with chest pain of presumed cardiac origin were more likely to experience erectile dysfunction.

A 2023 paper in Medicine mentioned that insulin resistance reduces renal excretion of uric acid on the proximal tubular of the kidney, leading to hyperuricemia. In rats, insulin administration decreased urinary urate excretion, with concurrent increased expression of a major urate reabsorption transporter and decreased expression of a major urate secretory transporter.

This 2021 meta-analysis in Frontiers Aging and Neuroscience examined the link between uric acid levels and dementia risk. Analyzing data from 23 studies with over 5,000 participants, they found that low uric acid levels were associated with Alzheimer’s and Parkinson’s dementia but not vascular dementia.

Surprisingly, very high uric acid levels were also linked to dementia. Factors like age and smoking didn’t affect this relationship, but education did. The review suggests that low uric acid levels may increase the risk of Alzheimer’s and Parkinson’s dementia, but more research is needed to understand this connection better. To me, this is puzzling, and we need clinical studies to understand the link.

There are mixed findings about the neurological effects of uric acid. For example, this 2022 review paper in Frontier mentioned that increasing evidence supports the hypothesis that hyperuricemia may be beneficial for cognitive functioning because of its antioxidant effects but may also be a potential risk factor for cognitive dysfunction, partly because of increased inflammatory activity.

Another review paper in Frontiers in 2023 highlighted that when considering both risk and neurological diseases, it is important to consider uric acid's conflicting dual nature as both a vascular risk factor and a neuroprotective factor. This dual nature of uric acid is important because it may help elucidate its biological role in various neurological diseases and provide new insights into the etiology and treatment of these diseases.

How can we prevent hyperuricemia?

Based on my literature reviews and insight from the ideas of clinicians who deal with it, I want to summarize the critical points for lowering excessive uric acid formation and preventing hyperuricemia.

The most common prevention method is to limit the intake of foods high in purines, such as too much red meat, high-fructose foods, especially sugary drinks, and some high glycemic index fruits. So, keeping track of purine-rich food intake might be helpful.

Alcohol, especially beer and spirits, can increase uric acid levels. Therefore, limiting them can be helpful. As alcohol also causes dehydration, we need to drink more water to flush out uric acid from the body.

Rapid weight loss can increase uric acid levels, so we must aim for gradual and sustainable weight loss. However, maintaining a healthy weight can reduce the risk of hyperuricemia.

As insulin resistance can reduce the excretion of uric acid from the kidney, making the body insulin-sensitive can lower the risk of hyperuricemia.

Apart from benefits for insulin sensitivity, regular physical activity can have a positive additional impact on uric acid levels. For example, exercise can improve circulation and metabolism, which may aid in the excretion of uric acid. Besides, exercise can contribute to weight management, and maintaining a healthy weight is essential for managing uric acid levels.

Chronic stress can lead to unhealthy habits like poor diet and reduced physical activity, raising uric acid levels. The stress hormone cortisol can affect metabolism and kidney function. Therefore, managing stress through relaxation techniques, exercise, and healthy coping mechanisms can indirectly support optimal uric acid levels.

How do we get tested?

As documented in MedlinePlus, doctors can order uric acid to check and measure the uric acid level in blood or urine (urinalysis). The test, also known as serum urate or UA helps diagnose gout and monitor uric acid levels during cancer treatments, as high purine release can cause problems. A urine test may also detect kidney stone risk in those with gout or symptoms of kidney stones.

Conclusions and Takeaways

I know elevated uric acid was associated with gout symptoms, as some relatives suffered from this painful condition. Intriguingly, hyperuricemia, the elevation of uric acid levels in the blood, has emerged as a significant player in metabolic disorders, including obesity, diabetes, heart disease, and even cognitive decline.

Although traditionally seen as a benign waste product, uric acid has taken on a multifaceted role, with both protective and detrimental effects on health. While early research suggested its neuroprotective benefits, recent studies implicate it in the pathogenesis of some diseases.

My deep dive into the literature reveals a complex relationship between uric acid and metabolic health. From the alarming rise in gout cases to the intriguing connections between uric acid levels and obesity, the evidence points to a profound impact on our health.

Mechanistically, food, alcohol, visceral adipose tissue, and dysregulated adipocytes appear to fuel uric acid production, setting the stage for metabolic disturbances. Yet, the story doesn’t end there. Links between uric acid and neurological conditions add another layer of complexity, with conflicting evidence suggesting both protective and harmful effects.

So, what can we do to address this growing health concern?

The answer is multifaceted, mainly around a proactive risk management approach. Moderating purine-rich foods, limiting alcohol intake, staying hydrated, maintaining a healthy weight through gradual weight loss strategies, making the body insulin sensitive, regular physical activity and stress management are proactive steps to manage uric acid levels.

The increasing incidence of hyperuricemia globally and in the US can be attributed to several factors. One significant factor seems to be the changing dietary patterns and lifestyles, characterized by high consumption of purine-rich foods, processed foods, and sugary beverages. These dietary choices might contribute to elevated uric acid levels in the blood.

Additionally, sedentary lifestyles and rising rates of obesity are associated with higher uric acid levels. Genetic predisposition also plays a role, as some people may have a higher likelihood of developing hyperuricemia due to their genetic makeup.

Furthermore, improved awareness and screening for hyperuricemia may also contribute to the observed increase in diagnosed cases, as more people are being tested for uric acid levels, leading to higher reported incidence rates.

So far, our knowledge is limited, mainly theoretical, and somewhat conflicting. However, as the research landscape continues to evolve with specific clinical studies investigating each connection identified in growing literature, understanding the nuanced role of uric acid in health and disease will be possible to unlock new avenues for prevention and treatment.

Thank you for reading my perspectives. I wish you a healthy and happy life.

If you found this story helpful, you may also check out my other articles on NewsBreak. As a postdoctoral researcher and executive consultant, I write about important life lessons based on my decades of research and experience in cognitive, metabolic, and mental health.