26/03/2026
Facts about Uric acid (UA).
Should asymptomatic hyperurecemia be treated with UA lowering drugs?
Basic physiology:
Physiological functioning of our body depends on several essential organic molecules in the body, such as DNA, RNA, ATP, GTP, NAD, and NADPH (please see chapter no: 4 for their introduction). These molecules are built from smaller building blocks known as nucleotides, which include Adenine, Guanine, Thymine, Cytosine, and Uracil. Among these, Adenine and Guanine belong to a group of compounds called purines. When purines, both endogenous or those consumed in diet, are broken down in the liver as part of normal cellular catabolism, a waste product is produced that is known as Uric acid (UA). At this point it very important to note that ~70% of UA is generated from the breakdown of endogenous purines while ~30% comes from purines in the diet, especially foods like organ meats (liver, kidneys, brain), red meat, seafood, peas, and lentils.
Causes of hyperuricemia
Uric acid is basically a waste product, ~70% of which is excreted by the kidneys, while ~30% is excreted by the liver through the bile. The uric acid level in the blood depends on a delicate balance between its rate of production and its rate of excretion. When this balance is disturbed, it leads to a rise in serum UA levels that is known as hyperuricemia (> 6.9 mg/dL). Contrary to the belief that hyperuricemia is the result of too much consumption of purine-rich foods, usually it is due to reduced excretion rather than increased production or consumption. Besides, the use of certain medications can also lead to a rise in serum UA levels. Among the common drugs that may lead to hyperuricemia, we include diuretics (e.g. Thiazides, Furosemide), Pyrazinamide, low-dose Aspirin, Levodopa, and Cyclosporine. Therefore, while elucidating the cause of hyperuricemia, the importance of drug history cannot be overemphasized.
Normal Range and risk of gout: Normal serum uric acid levels range between 4.5–6.8 mg/dL. A level of 6.9 mg/dL or above is classified as hyperuricemia, and a persistent rise in blood UA level may increase the risk of conditions like gout and uric acid nephropathy (UAN). It’s important to clarify that hyperuricemia alone does not equals gout. In individuals with UA levels between 6.9 and 8.9 mg/dL, the annual risk of developing gout is only 0.5%. Gout typically develops only when uric acid crystals deposit in joints, which occurs over time, not in all individuals. Clinical features, such as acute, localized joint pain, swelling, redness, and tenderness, especially in the (relatively colder) big toe or lower limb joints are essential for a diagnosis of gout.
Lifestyle and uric acid
Over the past 3-4 decades, a noticeable global trend of rising blood UA level has been observed. For instance, in the United States, it’s estimated that about 20% of the population has higher-than-normal UA levels. And it is worth noticing that this rise in UA has occurred alongside a parallel and alarming shift in global lifestyle and dietary habits, characterized by increased consumption of processed foods, sedentary behavior, and overnutrition. These changes have led to a sharp rise in obesity, metabolic syndrome, type 2 diabetes, hypertension, and other non-communicable diseases.
Important distinction: Association vs. Causation
In recent years, uric acid has become a popular “villain” in health discussions. Many people, even healthcare professionals, mistakenly attribute generalized body aches, heel pain, muscle soreness, or back pain to elevated uric acid levels, assuming that raised UA level is the cause of nearly all joint and muscular ailments. Let me state it explicitly, that this is a misconception. Before we delve deeper, it’s essential to understand a key scientific concept, the difference between “association” and “causation”. While elevated UA is clearly associated with many chronic conditions like obesity, insulin resistance, and high blood pressure, this doesn’t necessarily mean that UA causes them. Instead, UA may act as a biomarker, a signal that the body’s metabolism is off balance, just like those diseases are. In other words, the same lifestyle factors that increase the risk for metabolic syndrome and diabetes, such as poor dietary habits, lack of physical activity, and stress, also tend to raise uric acid levels. Therefore, high UA is more of a companion indicator (a bystander) than a root cause in many of these disorders. The good news is that by adopting healthier lifestyle, such as eating a balanced, moderate diet, engaging in regular physical activity, and avoiding excessive fructose and alcohol, it is often possible to lower both uric acid levels and the risk of chronic diseases at the same time.
Does treating asymptomatic hyperuricemia lower CV mortality?
The hypothesis that lowering uric acid might reduce CV risk stems from two facts; viz, experimental mechanistic indication that UA can reduce nitric oxide, increase (intracellular) oxidative stress, activate RAAS and promote endothelial dysfunction and strong observation that hyperuricemia is associated with hypertension, ASCVD, hear failure, chronic kidney disease. However, several outcome trials have shown that lowering uric acid does not reduce CV events, rather some agents (like Febuxostat) may increase CV mortality; therefore most professional societies, including European Society of Cardiology (ESC), American Heart Association (AHA), and American College of Rheumatology (ACR) do not recommend uric acid-lowering treatment solely for cardiovascular risk reduction, unless there are other valid indications like gout or uric acid nephropathy. Uric acid is a metabolic risk marker, not a validated cardiovascular treatment target. Lowering it treats gout, not atherosclerosis.
Misuse of uric acid testing
In recent years, the inappropriate testing and irrational and unnecessary management of uric acid levels has become increasingly common in clinical practice. A troublesome pattern has emerged: patients presenting with vague musculoskeletal complaints, such as heel pain, backache, or generalized body aches (often associated with obesity, poor posture, or sedentary lifestyle), are routinely subjected to serum uric acid testing, often without any supporting clinical signs of gout or any co-morbidity like DM, HTN or evidence of ASCVD. What follows is even more concerning: patients with mild to moderate hyperuricemia, without any symptoms of gout or kidney involvement, are prescribed uric acid-lowering medications such as Allopurinol or Febuxostat, without proper evaluation or justification. This practice Is clinically unjustified and ethically unacceptable. Prescribing medications solely based on laboratory values, without clinical correlation, is a form of professional negligence and may constitute medical malpractice. Every medication, including UA lowering therapies, carries potential adverse effects: Allopurinol may cause hypersensitivity reactions, liver dysfunction, and bone marrow suppression in rare cases. Febuxostat has been linked to cardiovascular risks in certain populations and is not without concerns. Initiating these therapies in the absence of clear clinical indications exposes patients to harm without benefit, while ignoring the root causes, such as obesity, poor diet, and sedentary lifestyle, which are often the real culprits behind generalized musculoskeletal pain.
Summary and ethical clinical approach
Do not treat numbers and lab results; treat patients. Never start urate-lowering drugs without clear clinical indications, such as recurrent gout attacks, tophaceous gout, uric acid nephropathy, uric acid kidney stones. Always consider reversible causes of mild hyperuricemia, like obesity, diet, alcohol, medications, and correct them first. Over-reliance on laboratory testing, in absence of thoughtful clinical evaluation, leads to misdiagnosis, polypharmacy, patient anxiety, and even harm.
To conclude, it is important to reiterate that hyperuricemia, aside from the two well-established conditions, gout and kidney disease, does not cause other disorders such as generalized body aches, lower back pain, or heel pain, which are often mistakenly attributed to elevated uric acid levels. Therefore, uric acid-lowering medications should only be prescribed when there is a clear clinical indication, such as gout or uric acid-related kidney disease. In individuals with asymptomatic hyperuricemia, medication is not needed. Instead, they should be strongly advised to:
Adopt a healthier lifestyle
Exercise regularly
Maintain a healthy weight
Moderate their diet, and avoid overeating purine-rich foods
Avoid fructose-sweetened drinks and fruit juices
Avoid alcohol
These measures not only help normalize uric acid levels naturally, but also reduce the risk of cardiovascular disorders associated with poor metabolic health.
Uric Acid: a major Extracellular Antioxidant
It would be quite a news for the readers that uric acid is not merely a metabolic waste product, but it also serves as a powerful natural antioxidant in the human body. In fact, uric acid is the most abundant extracellular antioxidant present in human plasma, contributing to over 50% of the total antioxidant capacity of the blood. Its antioxidant role is especially significant in neutralizing reactive and harmful compounds such as; Peroxynitrite (ONOO−), Peroxides and Hypochlorous acid (HOCl)
These reactive species are known to cause oxidative damage to cells and tissues, and uric acid helps in countering their toxic effects. Interestingly, the antioxidant function of UA is particularly valuable for individuals living at high altitudes, where chronic low oxygen levels (hypoxia) can lead to increased oxidative stress. In such environments, uric acid may offer protective benefits by reducing oxidative injury.
An abstract from my book on "Medical Nutritional Therapy in 21st Century".
Professor Dr Intekhab Alam
