HYPERURICEMIA IN OBESITY, HEART DISEASE & MORE + 6 TIPS FOR LOWER URIC ACID

More than just a feature of gout, hyperuricemia is now recognized as a common symptom associated with many states of disease.

This article highlights the importance of uric acid in the context of heart disease, obesity, metabolic syndrome, diabetes and more. Symptoms, potential causes and risk factors for hyperuricemia are discussed below, as well as 6 tips for maintaining balanced uric acid levels.

What is Hyperuricemia?

Hyperuricemia is a condition characterized by elevated serum uric acid levels (also known as urate).^[1] Uric acid is a waste product of purine metabolism. Purines are protein peptides found in DNA and RNA.

Uric acid may either enhance or inhibit inflammation, giving the substance an ambiguous reputation in the context of health and disease. It would appear that a lower amount is required for optimal health, and that too little or too much is associated with disease.

Prevalence

Uric acid levels naturally fluctuate depending on one’s metabolism, electrolyte balance, diet, lifestyle and physical activity levels. It is estimated that up to 21% of healthy people have hyperuricemia at any given time. The prevalence may rise up to 25% in hospitalized patients. Men more commonly acquire hyperuricemia than women.

Types of Hyperuricemia

The condition can be acute or chronic, presenting as a stand-alone disease or as secondary to another ailment.

1. Primary

Hyperuricemia may occur as a primary condition or as secondary to various states of disease. As a primary condition, prolonged hyperuricemia tends to result in gout and/or kidney disease.

2. Secondary

Secondary hyperuricemia occurs in a fraction of those with diabetes, obesity, metabolic syndrome, hypertension, cardiovascular diseases, and digestive disorders such as Crohn’s Disease. Asthma and other allergic diseases may also present with secondary hyperuricemia. 

As reduced liver function is often seen in those with hyperuricemia, it may express in a subset of patients with liver disease. Excessive cell turnover promotes secondary hyperuricemia, as seen in muscle wasting, chronic infection and hemolytic anemia.

Detection

Hyperuricemia is diagnosable using multiple blood tests and assessing uric acid levels through time. Clinicians use a standard measurement of 6.8mg/dL to assess the upper limit in a healthy person, with men typically having higher levels than women on average. Levels over 7mg/dL are considered too high for men and constitute hyperuricemia^[2], while for women, the limit is generally greater than 6mg/dL.

The condition may present as asymptomatic and treatment is often delayed until symptoms become apparent.

Symptoms

Hyperuricemia tends to perpetuate bodily inflammation, allowing for it to contribute towards many states of disease. On the other hand, uric acid has been studied for both its pro- and anti-inflammatory properties, some of which may be beneficial under certain conditions. Therefore the symptoms and their severity may differ among those with hyperuricemia.

Chronic hyperuricemia can affect multiple systems of the body, giving rise to one or more of the following symptoms:

• Excitotoxicity

In the case of gout, hyperuricemia may be accompanied by an increase in neuronal excitotoxicity as it is associated with glutamate excess^[3]. Glutamate, in excess, promotes the destruction of neurons, suggesting that neurodegenerative diseases may promote and/or be exacerbated by hyperuricemia.

• Arterial Fibrillation and Vascular Dysfunction

Hyperuricemia is associated with persistent arterial fibrillation as well as an increased risk of arterial fibrillation just after cardiovascular surgery. Intracellular uric acid concentrations are thought to be the main culprit, suggesting a dysregulation of uric acid transporters may be involved.^[4]

Chronic high serum uric acid can additionally induce abhorrent vascular growth, damage and dysfunction. Not surprisingly, it is a major risk factor for several cardiovascular diseases, including atherosclerosis and coronary artery disease.^[5]

• Elevated Fat Deposition

High serum urate levels may oxidize lipid membranes, resulting in excessive serum fat levels. This, in turn, encourages fat deposition into adipocytes (fat cells)^[6] as well as the liver. In females, hyperuricemia was associated with having high triglyceride levels; while in men, it was more frequently correlated with waist circumference.^[7]

• Liver Damage

Hyperuricemia tends to be coupled with increased liver fat deposition, liver damage and metabolic impairments^[8]. It is seen in patients with advanced non-alcoholic fatty liver disease^{[9] [10]}, after prolonged liver damage. This suggests that hyperuricemia promotes liver damage in the long run, perpetuating excessive uric acid levels.

• Kidney Damage

Prolonged hyperuricemia may result in hyperuricosuria, the chronic formation of kidney or bladder stones. Uric acid is a primary component of kidney and bladder stones^{[11] [12]}. Both types cause abdominal pain, promote urinary tract infections, increase kidney and/or bladder damage and eventually induce kidney failure. ^[13]

Hyperuricosuria is indicative of low urinary pH, decreased urea formation and less urine production. Uric acid dissolves at a pH of 6 or higher and tends to precipitate at a pH of 5.5 or lower. Urine can be tested to detect whether a patient is suffering from uric acid stone formation.

Hyperuricemia additionally contributes to kidney damage and disease by promoting vascular instability, hypertension and chronic inflammation.^[14] Animal studies highlight that hyperuricemia may result in kidney fibrosis and enlargement.^[15]

• Urate Crystal Deposition

Aside from increasing the risk of kidney stones, hyperuricemia may cause urate crystals to precipitate in joints, resulting in gout or contributing to the severity of arthritic diseases. When deposited in joints, urate crystals collect, promoting swelling and chronic low-grade inflammation in the affected areas.

• Enhances Inflammation

Uric acid in the right amounts may serve to counter inflammation. Yet, in the presence of inflammation, the opposite effect is observed. In general, high levels of uric acid result in excessive low-grade inflammation and contribute to the pathology of a number of inflammatory diseases, particularly gout and kidney disease. ^[16] As an inducer of the allergic response, hyperuricemia can make one more sensitive to allergens and can exacerbate allergic diseases, such as asthma.^[17]

It has a more potent antioxidant capacity than vitamin C when neutralizing peroxynitrite; however other antioxidant functions have yet to be proven. It may exert antimicrobial effects and help to promote a healthy gut microbiome at the right concentrations. Other studies suggest healthy levels of uric acid are required for optimal tissue healing, while elevated amounts may promote tissue damage.

• May Promote Pain

Elevated uric acid levels have been shown to increase COX-2 expression^[18] and, therefore, may induce or increase pain and stiffness^[19].

Potential Protective Effects of Uric Acid

Having elevated uric acid levels might just protect one from developing some autoimmune and neurodegenerative disorders. In multiple sclerosis (MS), peroxynitrite is known to increase demyelination. Uric acid neutralizes peroxynitrite and is commonly seen to be low in MS patients. ^[20]

Low uric acid levels are also associated with Pemphigus Vulgaris and Lichen Planus (rare autoimmune diseases), Parkinson’s disease, Alzheimer’s disease, and Hungtington’s disease, suggesting a protective benefit of uric acid.^[21]

Causes of Hyperuricemia

There are two common events that can precipitate hyperuricemia. The first is overproduction of urate and the second is reduced excretion of uric acid.

Either of these may be caused by a number of factors, some of which are discussed below.

Overproduction of Urate

Urate is the transportable form of uric acid, which is mainly excreted via the kidneys and intestines. Two-thirds of the body’s urate supply is excreted via the kidneys, while the remaining third is expelled via the intestines. 90% of kidney urate is reabsorbed.

• Excess Purines

Uric acid is formed from the conversion of purines. Pyrimidines and purines form the basic protein building blocks of the strands that make up DNA and RNA. Purines consist of adenine and guanine and pyrimidines consist of cytosine, thymine and uracil.^[22]

Excessive purine levels promote hyperuricemia. As DNA and RNA are a part of several cellular components, a high degree of cell damage and turnover increases purine metabolism. Elevated purine turnover is seen during infection, after injury, post intensive exercise, in chronic illness and as a result of prolonged, persistent inflammation. Reduced kidney filtration can also promote excessive urate reabsorption, resulting in hyperuricemia.

Additionally, consuming a high-purine diet for a prolonged period of time may also cause hyperuricemia as a result of excess purine intake. Purines are typically found in high-protein foods but may also be found in large quantities in beer and other fermented products. Studies reveal that foods high in hypoxanthine are known to increase uric acid levels, while foods high in guanine don’t appear to affect serum uric acid levels.^[23]

• Impaired Purine Metabolism

Most purines are metabolized in the liver, and to a lesser degree, in the intestines. Inside the cell, purines are transformed into first inosines, which are then transformed into hypoxanthines and xanthines.^[24] Through a series of chemical transformations, xanthine oxidase breaks xanthine down into urate (uric acid).

Impaired purine metabolism may contribute to hyperuricemia through the buildup of waste products. By-products of purine metabolism are toxic^[25] and increase the risk of hyperuricemia due to promoting inflammation and cellular damage^[26]. Common impairments in purine metabolism include elevated phosphoribosylpyrophosphate synthetase activity or decreases in hypoxanthine phosphoribosyltransferase (an enzyme that limits and regulates purine metabolism).

Xanthinuria is an uncommon purine metabolism condition where genes coding for xanthine oxidase are ineffective (type 1) or where the enzyme is unable to assemble, usually due to an inability to utilize sulfur (type 2). This leads to low xanthine oxidase levels, a buildup of xanthines, hyperuricemia and gout.^[27] Those with liver disease and cardiovascular problems are at an increased risk for this form of hyperuricemia.

Reduced Excretion of Uric Acid

Below are some key factors known to reduce uric acid elimination and promote hyperuricemia.

• Insulin Resistance

Elevated blood glucose levels and insulin resistance result in reduced excretion of uric acid and hyperuricemia.^[28] Glucose transporter protein 9 may be implicated as it transports both glucose and uric acid; however, more research is required before a conclusion can be made^{[29] [30]}. Factors that promote insulin resistance include a high sugar diet, chronic stress, neurotransmitter imbalances, and metabolic disorders including diabetes.

Metabolic acidosis is common in advanced diabetes as a result of perpetual insulin resistance. Bodily acidity can decrease ammonia levels and urea production, leading to reduced uric acid excretion and contributing to chronic hyperuricemia.

• Dehydration

Dehydration promotes reduced excretion of uric acid and increased serum levels^[31]. Profuse sweating^[32], diarrhea and vomiting can all promote hyperuricemia in this regard.

• High Serum Sodium

Sodium excretion promotes uric acid excretion, suggesting that increased serum sodium may promote higher uric acid levels. Potassium can increase sodium excretion and may therefore enhance uric acid excretion.

• Creatine and Kidney Disease

Creatinine is excreted alongside urate^[33] and is used as a marker for kidney disease and hyperuricemia. Elevated creatinine levels promote an increase in uric acid levels^[34] and are further associated with over-activation of the HPA axis. Over time, excess creatine by-products can lead to kidney damage, reducing the excretion of uric acid.

• Glutamate Excess

Glutamate excess may promote hyperuricemia. Increased levels reduce ammonia metabolism and increase purine metabolism, resulting in less urea formation, increased uric acid levels and decreased uric acid excretion. This tends to occur during glutamic dehydrogenase deficiency and is common in gout.^[35]

Risks for Hyperuricemia

The following factors can increase the risk of developing hyperuricemia:

• Male sex. Having an increased metabolism and cell turnover increases the risk for hyperuricemia in males. Males also tend to like eating a purine-rich diet and are at a higher risk for gout than females. Females excrete more uric acid than males on average and tend to have lower systemic uric acid levels. Just before and during menstruation, uric acid levels may slightly increase in women due to increased tissue breakdown and lower hormone production.^[36]
• Aging. The risk of hyperuricemia increases with aging, with greater risk seen in those with comorbidities^[37]. In healthy elderly individuals, aging only promotes a mildly reduced excretion of uric acid^[38].
• Disease. Metabolic Syndrome, male-phenotype obesity^[39], hypertension, diabetes, cardiovascular disease, stress disorders, hemolytic anemia, chronic infection, altitude sickness^[40], cancer, preeclampsia^[41], PCOS and hormonal imbalances place one at a higher risk for hyperuricemia.
• Allergens. Upon exposure to allergens, uric acid levels become elevated. Uric acid is one of several compounds involved in initiating an allergic (type 2) immune response.^[42]
• High Purine Diet. A diet high in purines can increase intake as well as promote increased production of purines in the liver. Purine-rich foods include beer and animal products, particularly organ meats, poultry, fish and red meat. Mushrooms, broccoli, spinach, Brussel sprouts, blue cheese and other cheeses are considered medium purine foods.^[43] All umami foods have a high level of purines in them, and purines are speculated to be responsible for umami taste^[44]. Aside from beer and cheese, other fermented foods are umami foods that may be purine-heavy.
• Intensive Exercise. Exercise can increase uric acid levels while decreasing excretion. ^[45] The more intensive the exercise, the greater the increase in uric acid levels. This is due to the way in which exercise releases inflammation and promotes cell turnover. Moderate regular exercise lowers inflammation and is conducive to regulating metabolism.
• Fructose. While increased sugar consumption, in general, is a risk for hyperuricemia, fructose poses a greater risk than other types of sugar. When taken up during digestion, fructose is metabolized to fructose 1-phosphate, depleting cellular phosphate and ATP stores. The reduction in ATP results in uric acid formation through intermediate by-products. Depending on the amount of fructose consumed, uric acid levels may transiently rise as much as 1-2mg/dL. Not surprisingly, fructose may exacerbate disease states associated with hyperuricemia.^[46]
• Drug-Induced Toxicity. Many pharmaceutical drugs interfere with liver and uric acid metabolism. Some of them may even contribute towards causing gout as a result. Some drugs used to treat hyperuricemia may also promote kidney damage due to increased uric acid excretion. High dosages of some pharmaceuticals are hypouricemic (inhibit uric acid production), while lower doses promote hyperuricemia.^[47] Loop diuretics^[48] and excess vitamin B3 intake are known to induce secondary hyperuricemia ^{[49] [50]}.

6 Tips for Decreasing the Risk of Hyperuricemia

The following tips may help to maintain healthy uric acid levels and reduce the risk of acquiring hyperuricemia:

1. Keep Sodium Balanced

Moderate to high sodium intake reduces serum uric acid levels in normotensive people.^[51] Over time, high sodium intake increases the risk of hypertension and has been found to increase uric acid production.^[52]

Consuming adequate potassium helps to regulate blood sodium. Potassium should be consumed in slightly higher amounts than sodium to maintain optimal cardiovascular and kidney health^{[53] [54]},  as well as to lower the risk of hyperuricemia^[55].

Decreasing salt and increasing the consumption of fresh fruit and vegetables is conducive to a healthy potassium-to-sodium ratio. Potatoes and other root vegetables, green leafy vegetables, nuts, and dairy products are high in potassium.^[56] Meat contains decent amounts of potassium yet is high in purines and therefore promotes hyperuricemia.

2. Try Not to Exercise in Extreme Heat

Intensive exercise, heat stress^[57] and prolonged or profuse sweating reduce uric acid excretion and promote hyperuricemia. This is related to the increase in urea excretion via sweat, which subsequently decreases uric acid excretion.^[58]

To avoid an excessive rise in uric acid levels, it’s important to keep well hydrated during exercise and not to break too much of a sweat. Exercising more frequently at a moderate intensity is healthier in this respect than exercising intensively less often. If you live in a warm climate, it’s advisable not to exercise during the warmest parts of the day.

On this point, saunas that increase sweating can also promote hyperuricemia. If one enjoys taking a sauna, moderation and rehydration are important for regulating serum uric acid.

3. Restrict Coffee Intake

Moderate amounts of good-quality coffee are associated with a decreased risk of gout and possibly hyperuricemia ^[59]. One study reveals that women require more cups per day (4-6 cups) for lowering serum uric acid than men (1-3 cups) ^[60]. However, as coffee is a mild diuretic and drinking too much of it on a daily basis may promote hyperuricemia. Restricting coffee intake to less than 3 cups a day is likely to be sufficient for both genders, as women already have reduced serum uric acid levels.

4. Up Your Vitamin C Intake with Cherries

Cherries are known for helping those with gout to reduce symptom severity and have uric acid-lowering properties.^[61] 100% tart cherry juice has been shown to lower uric acid levels in both overweight and obese adults by as much as 19.2%.^[62] Other studies highlight how consuming cherries can reduce uric acid levels in healthy women^[63] and hyperuricemic rats^[64].

Aside from some of the beneficial components of cherries, the vitamin C content is believed to be responsible for lowering serum uric acid^[65]. Vitamin C has been shown to mitigate fructose-induced and altitude-induced hyperuricemia^[66]. Total vitamin C levels and dietary vitamin C intake are associated with a reduced incidence of hyperuricemia in the general American population.^[67]

5. Avoid Excessive Sugar Consumption

Sugar, particularly fructose, temporarily increases uric acid levels and is related to a rise in insulin and blood glucose. Consuming high amounts of sugar relative to other dietary nutrients on a continuous basis tends to promote metabolic syndrome, diabetes, cardiovascular disease, obesity, and hyperuricemia.^[68]

While whole fruits are high in fructose, they have plenty of other components, like vitamin C, that offset the negative effects. Furthermore, the amounts in individual fruits are too small to provoke a serious reaction. Fruit juice and extracts of fructose, such as high-fructose corn syrup, are concentrated enough to drastically elevate uric acid post consumption^[69]. Many mass produced products use a combination of fructose with other forms of sugar as a sweetening agent. ^[70]

Extra sugar is also often incorporated into refined savory foods, such as in condiments, deep fried foods, and pickled produce. These products can substantially increase the risk of hyperuricemia due to their high sodium content.

Those at increased risk should avoid frequently consuming these high-sugar products.

6. Moderate Intake of Purine-Rich Foods

While there are many benefits to consuming many purine-rich foods, they may increase uric acid production and worsen the prognosis of gout and other diseases characterized by hyperuricemia. Therefore the below foods ought to be moderated by those at a high risk.

It’s worth mentioning that those wishing to improve their health should not avoid purine-rich foods on principle. The total amount of purines in a meal can be moderated by adding more foods that are low in purines, as opposed to cutting out all high-purine foods. Consuming a balanced diet that is low in refined foods and high in whole foods is a better point of focus than avoiding dietary purines.

High purine foods include^[71]:

• Yeast
• Beer
• Chlorella
• Spirulina
• Oriental powdered soups 
• Rice bran
• Buckwheat
• Adzuki beans
• Royal jelly
• Red miso
• Natto
• Soy and tofu
• Dried seaweed including nori, wakame, and hijiki
• All meat products including poultry, red meat, fish and shellfish
• The upper parts of shoots/sprouts, including bamboo, broccoli, white radish and asparagus
• Broccoli
• Brussel sprouts
• Peas
• Green pepper
• Parsley
• Spinach, especially young leaves
• Dried mushrooms, particularly shiitake, maitake, jew’s-ear, and hiratake
• Cheese, such as blue cheese and Roquefort

Many purine-rich foods have an umami flavor and umami foods have been associated with elevating serum uric acid levels. High umami foods include many of the above foods as well as parmesan, tomatoes, red bell peppers, pickles and many fermented foods.^[72]

When to See a Doctor

Often asymptomatic, hyperuricemia usually presents alongside other conditions, which are typically first to be diagnosed. It’s important to see a doctor when dealing with unmanageable weight gain, erratic dips in energy levels or mood (these often arise together), increased tension, pain or stiffness in the joints or lower back (kidney pain), heart palpitations and in the event of urinary issues (including blood in the urine and decreased urination frequency).

Conclusion

Hyperuricemia represents an important symptom that has the potential to contribute to many states of disease by promoting chronic low-grade inflammation. Men with heart disease, metabolic syndrome, diabetes, or obesity are in the highest risk category. Refined diets high in salt, sugar and purines are known to increase the risk; while balanced wholefood diets high in antioxidant nutrients (like vitamin C) may prove beneficial. Careful attention ought to be paid to intensive exercise, dehydration, transitioning to high altitudes, and infection, which all elevate uric acid levels.

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