INTRODUCTION

In humans, uric acid (UA) is an end product of purine metabolism. The prevalence of hyperuricemia (HU) has been alarmingly increasing worldwide during the last two decades. Recent epidemiological studies have clearly shown that HU has a strong relation with noncommunicable diseases (NCDs) and many other conditions, especially type 2 diabetes mellitus (T2DM). The pathophysiology involved in HU includes oxidative stress, endothelial dysfunction, and end-organ damage as in T2DM. Various studies have shown that the underlying molecular changes induced by HU start even before the present cutoff value of 7 mg/dL. Studies have shown that a reduction in serum uric acid (SUA) can prevent the development of many NCDs and their complications. Hence, it is advisable to screen HU early and prevent metabolic issues. The concept of prehyperuricemia (pre-HU) may need to be introduced as a new term for this intermediate metabolic condition. Managing pre-HU with nonpharmacologic measures like lifestyle modification can prevent the development of NCDs and improve the quality of life.

DEFINITION OF HYPERURICEMIA

Hyperuricemia is defined as a SUA level of >7 mg/dL in men and 6 mg/dL in women on a “physiochemical” basis. The incidence of gout in the HU population is 7–9% only. Rest we named comfortably as asymptomatic HU. Asymptomatic HU is more dangerous as it leads to endothelial dysfunction, oxidative stress, insulin resistance, macrovascular, and microvascular complications silently—a classical iceberg phenomenon. Thus, high UA imposes detrimental effects on almost all systems. The threshold of UA level increased total mortality at 4.7 mg/dL and cardiovascular mortality at 5.6 mg/dL risk, which was significantly lower than the clinical diagnostic value of 7 mg/dL. Hence on a “metabolic” basis, it is advisable to lower the cutoff value below 7 mg/dL in men and below 6 mg/dL in women or give more importance to SUA at a high normal value, as HU is now concerned with the metabolic disorder than a crystallization disease.

DEFINITION OF PREHYPERURICEMIA

Prehyperuricemia may be defined as a metabolic condition where SUA value is at a high normal level between 6–7 mg/dL in men and 5–6 mg/dL in women. This value is presently considered normal or high normal. At this level or even below this, UA-induced systemic inflammation develops.

EPIDEMIOLOGY

Over 15 million years ago, by mutation, humans lost their ability to degrade UA by uricase enzyme. Gout is one of the oldest diseases and was first described around 1200 AD. Although UA was identified two centuries ago, we still do not fully understand its pathophysiology. In the present generation, the mean SUA level is slowly increasing from 4.5 to 6 mg/dL. Presently, HU is the second most common metabolic disorder after T2DM. Since, the lifestyle of the current generation has significantly changed due to the consumption of high-purine diets, red meat, alcohol, and high fructose-containing foods; HU has become the fourth most common NCD after hypertension (HTN), T2DM, and dyslipidemia. The prevalence of HU has increased manyfold in the last two decades globally.

URIC ACID-INDUCED MOLECULAR MECHANISM

In humans, UA is the most abundant and powerful antioxidant. However, at higher concentrations, UA expresses a prooxidant effect also. This paradox could be an antioxidant effect in the extracellular environment or a prooxidant at the intracellular level. UA acts as an antioxidant up to 4.7 mg/dL level only. When UA enters the cells, at a higher serum value, mediated by specific transporters, it induces an oxidative cascade. HU is connected with the development of NCDs by regulating molecular signals, such as oxidative stress, insulin resistance, endothelial dysfunction, and even before pre-HU. Researchers have linked HU and pre-HU with systemic inflammation. The relationship between HU and insulin resistance is unidirectional and HU comes first and later these two lead to T2DM and HTN. The mean value of UA is slowly increasing in the entire world population, and by the time it crosses a high normal value, adverse molecular and inflammatory mechanisms might have started, which in turn leads to NCDs and end-organ damages. SUA reduction improves the markers of systemic inflammation, NCDs, and their complications (Flowchart 1).

FLOWCHART 1: Impact of hyperuricemia in human.

(AFib: atrial fibrillation; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; DM: diabetes mellitus; GDM: gestational diabetes mellitus; HF: heart failure; HTN: hypertension; MetS: metabolic syndrome; NAFLD: nonalcoholic fatty liver disease; OSAS: obstructive sleep apnea syndrome; PCOS: polycystic ovarian syndrome; SCD: sudden cardiac death)

HYPERURICEMIA-ASSOCIATED EXTRA-ARTICULAR DISEASES

    Uric Acid and Cardiovascular Disease

Uric acid is a marker for HTN, coronary artery disease (CAD), atrial fibrillation (AFib), and heart failure (HF). Nearly 47% of hypertensive patients are hyperuricemic. Increasing SUA levels by 1 mg/dL results in a 13% hike in incident HTN. SUA is strongly and independently associated even with nocturnal nondipping of HTN. Recently, reports coming with urate-lowering therapy (ULT) results in the reduction of blood pressure in adolescents. HU causes atherosclerosis in macrovascular beds and microvessels of major organs. Young adults with HU develop coronary artery calcification which leads to premature CAD. The overall risk of CAD mortality increases by 15% for an increase of 1 mg/dL of SUA. SUA increases aortic pressure, aortic stiffness, arterial stiffness, pulse wave velocity, and accelerates vascular aging. The risk of HF increases by 20% for every 1 mg/dL increase of SUA. HU is associated with AFib and expresses resistance to treatment.

    Uric Acid and Metabolic Syndrome

A quarter of the adult population in the entire world suffers from metabolic syndrome (MetS). Up to 60% of MetS are hyperuricemic. Presently, HU is a marker for early diagnosis and prevention of MetS. Maintaining SUA at a lower level may avoid the burden of MetS.

    Diabetes Mellitus

A population-based study reported UA as a solid and independent risk factor for T2DM. The risk of developing T2DM increases by 15–20% for every 1 mg/dL increase of SUA. HU leads to insulin resistance and hyperinsulinemia. Today there is mounting evidence available to suggest that HU is equivalent to T2DM, from the standpoints of etiology, pathophysiology, complications, and therapeutics.

    Uric Acid and Cholesterol

Serum total cholesterol, low-density lipoprotein (LDL) cholesterol, and especially triglyceride are directly associated with SUA levels, but high-density lipoprotein (HDL) cholesterol is inversely related.

    Uric Acid and Kidney

Serum uric acid is a marker of chronic kidney disease (CKD), especially with diabetes mellitus. Accumulating evidence shows that a high SUA level is associated with a decline in estimated glomerular filtration rate (eGFR) and worsening renal function. High SUA is associated with a reduction in the number of nephrons, renal tubular atrophy, and hence low GFR. ULT decreases inflammation and slows down renal disease progression even in patients with moderate CKD. Renal dysfunction in T2DM starts even at SUA level 6.3 mg/dL (high normal value) and carries a poor prognosis.

    Uric Acid and Liver

The relationship between SUA and nonalcoholic fatty liver disease (NAFLD) was first described in a small Italian study in 2002. Every 1 mg/dL SUA level increment led to a 21% increase in the NAFLD risk. UA lowering may be one of the aims in the management of NAFLD.

    Uric Acid and Brain

The pro-oxidant neurotoxic effect of UA may negatively affect acute stroke. A higher SUA level shows an increased stroke rate and mortality. UA is high in vascular or mixed dementia. Meanwhile, UA as an antioxidant has a neuroprotective role in Alzheimer’s disease and Parkinson’s disease. Hence, UA should not be reduced to hypouricemia level (SUA below 2.5 mg/dL). However, recent studies do not support this.

    Other Uric Acid-associated Disorders

Serum uric acid level is higher in women with polycystic ovarian syndrome. In 1917, Slemons and Bogert first noticed that UA was elevated in pre-eclampsia/eclampsia, and a high level of SUA is now recognized as a stable biomarker in these conditions. An increased level of SUA in pregnancy may also lead to the development of gestational diabetes mellitus (GDM) by 4%. Ample evidence is available now, that HU may be a marker for the increased risk of erectile dysfunction (ED) and infertility in men. Each 1 mg/dL increment in SUA level is associated with a twofold increased risk of ED. SUA may be high in chronic obstructive pulmonary disease (COPD) and the higher the value higher the mortality. In acute respiratory distress syndrome, the SUA level is on the higher side, and it has a prognostic role. In hyperthyroidism, HU is due to higher basal metabolic rate (BMR) and elevated urate production. However, in hypothyroidism, HU is due to decreased renal blood circulation. High levels of SUA were detected in patients with chronic dermatitis and psoriasis. Younger males with high SUA levels are associated with androgenic alopecia. Ocular abnormalities like retinopathy, dry eye syndrome, red eye, uveitis, glaucoma, and cataracts are associated with high UA. High salivary UA is associated with periodontitis and recurrent aphthous ulcers.

LIFE SPAN

According to a recent study by researchers at the University of Limerick’s School of Medicine, HU can reduce lifespan by up to 11 years for men and 6 years for women.

DISCUSSION

In this obesity-prone era, NCDs have become the leading cause of morbidity and mortality. There is an exponential increase in the prevalence of HU in the entire world. Recent works of literature quoted that HU is linked not only to cardio-reno-metabolic disorders but many more to add to this list. HU is not synonymous with gout. The association between NCDs and HU has become more pronounced in recent years and goes hand in hand. Today HU is more of a metabolic disorder than a crystallization disease. UA has recently regained clinical interest and popularity based on emerging data suggesting the causative role of HU in NCDs and many other conditions. It is time to change the term asymptomatic HU; it is a killer disease now. The detrimental effect of HU starts even earlier than the HU cutoff value of 7 mg/dL. The incompletely explained and invisible relationship between UA and diabetes has gradually become a hot topic for researchers. In gout and even patients with tophi, UA may be normal. All HU is not symptomatic, and all gout patients are not hyperuricemic. However, there can be systemic inflammation in both these groups of people. HU is not gout equivalent or vice versa and is a metabolic disorder. Gout is one of the few clinical manifestations of HU, which is painful, whereas other significant groups are painless and comfortably categorized as asymptomatic HU. This asymptomatic HU is a causal factor for many NCDs. Researchers now recommend that HU be included in the MetS criteria.

A few diabetes patients may be asymptomatic; most hypertensive and dyslipidemia patients are asymptomatic. These patients are not referred to as asymptomatic diabetes, asymptomatic HTN, or asymptomatic dyslipidemia but are treated based on target values. Even painless acute myocardial infarction may come across. Pain should not be the criteria for the diagnosis and treatment of metabolic disorders. Pre-HU, like prediabetes and pre-HTN, needs to be screened, diagnosed early, and managed to prevent the progression of many NCDs and their complications. Like prediabetes, pre-HU is also reversible with lifestyle modifications. HU and diabetes mellitus are siblings now; manage them with the same weapon. In the current century, HU is the diabetes equivalent. It should not be ignored that during the long journey of pre-HU to overt HU, the whole endothelium is exposed to inflammatory changes that may lead to the development of many NCDs and organ injuries. A preventative approach is always preferable to a therapeutic approach and hence pre-HU deserves more attention to control the metabolic explosion.

MANAGEMENT OF PREHYPERURICEMIA

Pharmacological: The available UA-lowering drugs have more adverse effects and drug interactions. The present evidence does not satisfy to recommendation of pharmacological therapy in pre-HU. Treat other comorbidities with drugs that reduce UA, like losartan, fenofibrate, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors.

Nonpharmacological: By following a healthy lifestyle, pre-HU and many metabolic disorders can be prevented. In pre-HU, lifestyle modification is cost-effective and straightforward. According to various studies, lifestyle measures alone reduce SUA by 1 mg/dL. Recommend a low purine diet, and limit red meat, alcohol, and high fructose-containing food. Encourage low-fat milk products, adequate water intake, regular exercise, and maintaining ideal body weight. Maintain the SUA level at a safer level of <6 mg/dL in men and <5 mg/dL in women to prevent the development of systemic inflammation.

CONCLUSION

Noncommunicable diseases are alarmingly increasing. The association between HU and NCDs is becoming clearer and stronger. The molecular mechanism involved is UA-induced systemic inflammation and endothelial dysfunction. This starts even before the present cutoff value of HU. UA could emerge as one of the most important risk factors ever identified for many NCDs in the near future. For more acceptance, early diagnosis, treatment, and preventing the development of many UA-related diseases and their complications, the high normal value of SUA may be termed “prehyperuricemia”. Lifestyle modification is the best measure that we can adopt at this stage to maintain the SUA level at a safer level to prevent many cardio-reno-metabolic diseases. The authors conclude this article with some exaggeration that if we can control SUA at the level below pre-HU, we can “eradicate” this oldest disease gout, and prevent the development of HU-related diseases.

SUGGESTED READINGS

1.   Subbu GR, Anita N, Hari K, Martin M. Prehyperuricemia: new milestone in metabolic disorders. Int J Res Rev. 2022;9(6):1-10.

2.   Kundu AK. Gout in Indian Scenario. In: Muruganathan A (Ed). Medicine Update. New Delhi: Jaypee Brothers Medical Publishers; 2013. pp. 445-58.

3.   Yu W, Cheng JD. Uric Acid and Cardiovascular Disease: An Update From Molecular Mechanism to Clinical Perspective. Front Pharmacol. 2020;11:582680.

4.   Dawson J, Wyss A. Chicken or the Egg? Hyperuricemia, Insulin Resistance, and Hypertension. Hypertension. 2017;70(4):698-9.

5.   Cannon PJ, Stason WB, Demartini FE, Sommers SC, Laragh JH. Hyperuricemia in primary and renal hypertension. N Engl J Med. 1966;275(9):457-64.

6.   Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2011;63(1):102-10.

7.   Huang H, Huang B, Li Y, Huang Y, Li J, Yao H, et al. Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail. 2014;16(1):15-24.

8.   Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincón A, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5(8):1388-93.

9.   Browne LD, Jaouimaa FZ, Walsh C, Perez-Ruiz F, Richette P, Burke K, et al. Serum uric acid and mortality thresholds among men and women in the Irish health system: A cohort study. Eur J Intern Med. 2021;84:46-55.

10. Subbu GR. Gout/Hyperuricemia—The Significance of Non-Pharmacological Management in the 21st Century. Int J Sci Res. 2022;11(3):9-10.