Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Search in posts
Search in pages
Filter by Categories
Case Report
Case Series
Editorial
Letter to the Editor
Media and News
Notice of Retraction
Original Article
Review Article
Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Search in posts
Search in pages
Filter by Categories
Case Report
Case Series
Editorial
Letter to the Editor
Media and News
Notice of Retraction
Original Article
Review Article
Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Search in posts
Search in pages
Filter by Categories
Case Report
Case Series
Editorial
Letter to the Editor
Media and News
Notice of Retraction
Original Article
Review Article
View/Download PDF

Translate this page into:

Review Article
4 (
1
); 4-10
doi:
10.25259/MEDINDIA_7_2025

Pre-hyperuricemia: The silent precursor to metabolic disorders

Department of Medicine, Farukh Hussain Medical College, Agra, Uttar Pradesh, India
Department of Pulmonary Medicine, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India
Author image

*Corresponding author: Rahul Garg, Department of Medicine, Farukh Hussain Medical College, Agra, Uttar Pradesh, India. gargrahul27@gmail.com

Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Garg R, Prakash P. Pre-hyperuricemia: The silent precursor to metabolic disorders. Med India. 2025;4:4-10. doi: 10.25259/MEDINDIA_7_2025

Abstract

The global prevalence of hyperuricemia has been rapidly increasing over the past two decades, primarily due to changes in dietary habits and lifestyle. Recent research has unveiled a strong association between hyperuricemia and various non-communicable diseases, suggesting that uric acid-induced systemic inflammation and endothelial dysfunction may begin even before reaching the current diagnostic threshold for hyperuricemia. This review introduces the concept of “pre-hyperuricemia,” defined as a high normal serum uric acid level, and explores its potential role as an early indicator and risk factor for metabolic disorders. We have discussed the molecular mechanisms underlying uric acid-induced inflammation, the epidemiology of hyperuricemia, and its associations with various extra-articular diseases. Furthermore, we have emphasized the importance of early detection and management of pre-hyperuricemia through lifestyle modifications to prevent the development and progression of uric acid-related diseases.

Keywords

Extra-articular diseases
Hyperuricemia
Non communicable diseases
Pre-hyperuricemia
Serum uric acid

INTRODUCTION

Uric acid, the end product of purine metabolism in humans, has long been associated with gout and kidney stones. However, recent epidemiological studies have revealed a more complex role of uric acid in human health, particularly its involvement in various metabolic disorders.[1,2] The prevalence of hyperuricemia has increased dramatically worldwide, with some populations reporting rates as high as 85%.[3]

Conventionally, hyperuricemia has been defined as a serum uric acid (SUA) level exceeding 7 mg/dL in men and 6 mg/dL in women.[1] However, emerging evidence suggests that uric acid-induced systemic inflammation and endothelial dysfunction may begin at levels below these thresholds.[4-6] This review introduces the concept of “pre-hyperuricemia,” defined as a high normal SUA level between 6 and 7 mg/dL in men and 5 and 6 mg/dL in women, and explores its potential significance in the early detection and prevention of metabolic disorders [Figure 1].

Classification framework for uric acid disorders showing progression from normal to pre-hyperuricemia to hyperuricemia.
Figure 1:
Classification framework for uric acid disorders showing progression from normal to pre-hyperuricemia to hyperuricemia.

The global population is living amid a metabolic explosion, with hyperuricemia becoming the second most common metabolic disorder after diabetes mellitus.[1] Importantly, the concept of hyperuricemia has evolved from being merely a crystallization disease causing gout to a significant metabolic disorder with wide-ranging systemic effects. This paradigm shift necessitates a reevaluation of how we define, detect, and manage elevated uric acid levels.

The introduction of pre-hyperuricemia as a clinical entity aligns with other established “pre-” conditions, such as prediabetes and prehypertension, emphasizing the importance of early detection and intervention in preventing the development and progression of more severe metabolic disorders. Just as prediabetes allows for early intervention to prevent the development of type 2 diabetes, recognizing prehyperuricemia could provide a critical window for preventing hyperuricemia and its associated complications.

HISTORICAL PERSPECTIVE

The relationship between uric acid and human health has been recognized for centuries, with gout being one of the oldest known diseases. However, the understanding of uric acid’s role in metabolism has evolved significantly over time. Humans lost the ability to degrade uric acid due to a mutation in the uricase enzyme approximately 15 million years ago.[7] This evolutionary change has led to higher baseline SUA levels in humans compared to other mammals.

In the early 20th century, SUA levels in the general population were relatively low, with mean values below 3.5 mg/dL. However, a dramatic increase occurred between the 1950s and 1980s, with mean SUA levels rising from 5.0 to over 6.0 mg/dL.[1] This trend has continued into the 21st century, paralleling the rise in metabolic disorders and noncommunicable diseases (NCDs) [Figure 2].

Historical trend showing mean serum uric acid levels. Serum uric acid levels rose from 4.2 mg/dL in 1950 to 6.4 mg/dL in 2020, now exceeding hyperuricemia thresholds for men (6.4 mg/dL) and women (6.0 mg/dL). SUA: Serum uric acid.
Figure 2:
Historical trend showing mean serum uric acid levels. Serum uric acid levels rose from 4.2 mg/dL in 1950 to 6.4 mg/dL in 2020, now exceeding hyperuricemia thresholds for men (6.4 mg/dL) and women (6.0 mg/dL). SUA: Serum uric acid.

EPIDEMIOLOGY OF HYPERURICEMIA AND PRE-HYPERURICEMIA

The prevalence of hyperuricemia has increased significantly in recent decades, becoming the second most common metabolic disorder after diabetes mellitus.[1] In some populations, the prevalence has reached as high as 85%.[3] Recent estimates suggest that approximately 170 million people in China and 32.5 million in the United States were affected by hyperuricemia in 2019.[1,3,8]

The increase in hyperuricemia prevalence is largely attributed to changing dietary patterns, including higher consumption of high-purine foods, red meat, alcohol, and high fructose-containing products. As the lifestyle of the present generation has changed dramatically, hyperuricemia has become the fourth highest NCD after hypertension, diabetes mellitus, and dyslipidemia.[1]

While the epidemiology of pre-hyperuricemia has not been extensively studied, a substantial proportion of the population likely falls within this category. Given the linear relationship between SUA levels and the risk of metabolic syndrome, even at levels below the current hyperuricemia threshold, the prevalence of pre-hyperuricemia may be considerable.[9]

MOLECULAR MECHANISMS OF URIC ACID-INDUCED INFLAMMATION

Uric acid exhibits a paradoxical nature, acting as both an antioxidant and pro-oxidant depending on its concentration and cellular location.[10] At physiological levels (below 4.7 mg/dL), uric acid functions as an antioxidant in the extracellular environment. However, at higher concentrations or within cells, it can induce oxidative stress and inflammation.[4-6]

The pro-inflammatory effects of uric acid are mediated through several mechanisms [Figure 3]:

Molecular mechanisms of uric acid-induced inflammation.
Figure 3:
Molecular mechanisms of uric acid-induced inflammation.

  1. Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase: When uric acid enters vascular cells and adipocytes, it activates the NADPH oxidase system, leading to increased production of reactive oxygen species.[11]

  2. Mitochondrial oxidative stress: Elevated uric acid levels can stimulate mitochondrial dysfunction, further contributing to oxidative stress.[11]

  3. Inflammatory cytokine production: High uric acid levels are associated with increased production of inflammatory markers such as C-reactive protein, interleukin (IL)-6, IL-1 receptor antagonist, IL-18, and tumor necrosis factor-α.[12]

  4. Endothelial dysfunction: Uric acid can impair endothelial function by reducing nitric oxide production and increasing the expression of adhesion molecules.[6]

  5. Insulin resistance: Elevated uric acid levels can interfere with insulin signaling, contributing to the development of insulin resistance.[13]

Importantly, these molecular changes may begin to occur even at SUA levels considered to be within the high normal range, supporting the concept of pre-hyperuricemia as a potential risk factor for metabolic disorders.

THE “CHICKEN OR THE EGG” QUESTION

An important question in the uric acid debate is whether hyperuricemia precedes insulin resistance and hypertension or vice versa. Recent research by Jesse Dawson and colleagues suggests that the relationship between uric acid and insulin resistance is unidirectional, with hyperuricemia occurring first, followed by insulin resistance and hypertension [Figure 4].[13] This finding underscores the potential importance of targeting uric acid levels as a primary intervention point in the prevention of metabolic disorders.

Chicken-egg relationship between pre-hyperuricemia and metabolic disorders. NCDs: Non-communicable diseases.
Figure 4:
Chicken-egg relationship between pre-hyperuricemia and metabolic disorders. NCDs: Non-communicable diseases.

Importantly, these molecular changes may begin to occur even at SUA levels considered to be within the high normal range, supporting the concept of pre-hyperuricemia as a potential risk factor for metabolic disorders. The evidence suggests that reducing SUA levels can improve markers of systemic inflammation, potentially preventing or mitigating the development of NCDs and their complications.

PRE-HYPERURICEMIA AND ASSOCIATED EXTRA-ARTICULAR DISEASES

Various extra-articular diseases associated with pre-hyperuricemia have been summarized in Table 1, and important ones have been shown in Figure 5.

Table 1: Extra-articular diseases associated with pre-hyperuricemia.
Cardiovascular
• Hypertension
• Atherosclerosis
• Coronary artery disease
• Atrial fibrillation
• Heart failure
• Sudden cardiac death
Respiratory
• COPD
• Pulmonary hypertension
• Obstructive sleep apnea
Reproductive
• PCOS
• Infertility
• Erectile dysfunction
Metabolic syndrome
Dyslipidemia Obstetrical
• Eclampsia
• Pre-eclampsia
• Gestational diabetes mellitus
Endocrinological
• Diabetes mellitus
• Hypothyroidism
• Hyperthyroidism
Renal
• Chronic kidney disease
Dermatological
• Psoriasis
• Chronic dermatitis
• Androgenic alopecia
Hepatological
• Non-alcoholic fatty liver disease
• Cirrhosis
Ocular
• Retinopathy
• Uveitis
• Glaucoma
• Cataract
Neurological
• Vascular Stroke
• Dementia
Oral
• Periodontitis
• Recurrent aphthous ulcers

COPD: Chronic obstructive pulmonary disease, PCOS: Polycystic ovarian syndrome.

Extra-articular manifestations of pre-hyperuricemia. CAD: Coronary artery disease, NAFLD: Nonalcoholic fatty liver disease, PCOS: Polycystic ovarian syndrome, COPD: Chronic obstructive pulmonary disease.
Figure 5:
Extra-articular manifestations of pre-hyperuricemia. CAD: Coronary artery disease, NAFLD: Nonalcoholic fatty liver disease, PCOS: Polycystic ovarian syndrome, COPD: Chronic obstructive pulmonary disease.

Cardiovascular diseases

Pre-hyperuricemia has been associated with various cardiovascular conditions:

  1. Hypertension: SUA is a biomarker for hypertension, with each 1 mg/dL increase in SUA resulting in a 13% higher risk of incident hypertension [Figure 6].[14] Even at the pre-hypertensive stage, elevated SUA levels are associated with a higher risk of progression to hypertension.[15] SUA has emerged as one of the strongest and independent risk factors for pre-hypertension, which later progresses to hypertension.

    Bar chart demonstrating increased disease risk per 1 mg/dL rise in serum uric acid. CAD: Coronary artery disease, NAFLD: Non-alcoholic fatty liver disease, NCD: Non-communicable diseases.
    Figure 6:
    Bar chart demonstrating increased disease risk per 1 mg/dL rise in serum uric acid. CAD: Coronary artery disease, NAFLD: Non-alcoholic fatty liver disease, NCD: Non-communicable diseases.

  2. Atherosclerosis: High normal SUA levels are associated with subclinical atherosclerosis and increased arterial stiffness.[16]

  3. Coronary artery disease (CAD): Each 1 mg/dL increase in SUA is associated with a 15% higher risk of CAD mortality [Figure 6].[17]

  4. Atrial fibrillation: SUA levels are independently associated with the risk of atrial fibrillation, both chronic and paroxysmal.[18]

  5. Heart failure: The risk of heart failure increases by 20% for every 1 mg/dL increase in SUA [Figure 6].[19]

Metabolic syndrome

Pre-hyperuricemia is strongly associated with metabolic syndrome. The Third National Health and Nutrition Examination Survey reported a linear increase in the prevalence of metabolic syndrome with rising SUA levels, even below 6 mg/dL.[9] Some researchers have suggested including hyperuricemia as a criterion for metabolic syndrome diagnosis.

Diabetes mellitus

SUA is an independent risk factor for type 2 diabetes mellitus (T2DM). The risk of developing T2DM increases by 15–20% for every 1 mg/dL increase in SUA [Figure 6].[20] Notably, even high normal SUA levels (5–6 mg/dL in women and 6–6.8 mg/dL in men) are associated with an increased risk of diabetes.[21]

Kidney disease

Pre-hyperuricemia is associated with a higher risk of chronic kidney disease (CKD) and a more rapid decline in renal function. In patients with T2DM, renal dysfunction may begin at SUA levels as low as 6.3 mg/dL.[22] Lowering SUA levels has been shown to slow the progression of renal disease, even in patients with moderate CKD.[23]

Non-alcoholic fatty liver disease (NAFLD)

NAFLD is strongly associated with elevated SUA levels, with each 1 mg/dL increment in SUA leading to a 21% increase in NAFLD risk [Figure 6].[24]

Neurological diseases

  1. Stroke: Higher uric acid levels are associated with increased stroke rate and mortality.[25]

  2. Dementia: SUA levels are high in vascular or mixed dementia.[26] However, SUA levels should not be reduced below 2.5 mg/dL because it has a neuroprotective role in Alzheimer’s disease and Parkinson’s disease because of its antioxidant nature.

Other associated conditions

Pre-hyperuricemia has been linked to various other conditions, including:

  • Chronic obstructive pulmonary disease[27]

  • Psoriasis, chronic dermatitis, and androgenic alopecia[28]

  • Polycystic ovarian syndrome

  • Gestational diabetes mellitus

  • Erectile dysfunction[29]

  • Ocular abnormalities such as retinopathy, dry eye syndrome, uveitis, glaucoma, and cataract[30]

  • Periodontitis and recurrent aphthous ulcer

MANAGEMENT OF PREHYPERURICEMIA

Given the potential risks associated with pre-hyperuricemia, early detection and management are crucial. However, the current evidence does not support pharmacological intervention at this stage. The primary approach to managing pre-hyperuricemia is through lifestyle modifications:

  1. Dietary changes: Recommend a low purine diet, limit red meat consumption, reduce alcohol intake, and avoid high fructose-containing foods

  2. Increase water intake: Adequate hydration can help promote uric acid excretion

  3. Regular exercise: Physical activity can help improve insulin sensitivity and reduce inflammation

  4. Weight management: Maintaining a healthy body weight can help reduce SUA levels

  5. Dairy consumption: Encourage low-fat milk products, which have been associated with lower SUA levels.

These lifestyle interventions have been shown to reduce SUA levels by approximately 1 mg/dL,[1] which may be sufficient to mitigate the risks associated with pre-hyperuricemia.

For patients with comorbidities, consider medications that have uric acid-lowering effects as secondary benefits, such as losartan for hypertension, fenofibrate for dyslipidemia, or sodium-glucose transport protein 2 inhibitors for diabetes.

CONCLUSION

Pre hyperuricemia represents a new frontier in our understanding of metabolic disorders. By recognizing the potential risks associated with high normal SUA levels, we can intervene earlier to prevent the development and progression of various NCDs. The concept of pre-hyperuricemia aligns with other “pre-” conditions, such as pre-diabetes and prehypertension, emphasizing the importance of early detection and intervention.

Author contributions:

RG is responsible for concept, organization, execution and manuscript writing. PP provided review and critique.

Ethical approval:

Institutional Review Board approval is not required.

Declaration of patient consent:

Patient’s consent is not required as there are no patients in this study.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Financial support and sponsorship: Nil.

References

  1. , , , . Prehyperuricemia: New milestone in metabolic disorders. Int J Res Rev. 2022;9:1-10.
    [CrossRef] [Google Scholar]
  2. , , . Hyperuricemia In: StatPearls. Treasure Island, FL: StatPearls Publishing; . Available from: https://www.ncbi.nlm.nih.gov/books/NBK459218 [Last accessed 2025 March 1]
    [Google Scholar]
  3. , . Global prevalence of hyperuricemia: A systematic review of population-based epidemiological studies. Arthritis Rheumatol. 2015;67(Suppl 10) Available from: https://acrabstracts.org/abstract/global-prevalence-of-hyperuricemiaa-systematic-review-of-population-based-epidemiological-studies/ [Last accessed 2025 March 1]
    [Google Scholar]
  4. , . The biomarkers discovery of hyperuricemia and gout: proteomics and metabolomics. PeerJ. 2023;11:e14554.
    [CrossRef] [PubMed] [Google Scholar]
  5. , , , , , , et al. Soluble uric acid increases NALP3 inflammasome and interleukin-1beta expression in human primary renal proximal tubule epithelial cells through the Toll-like receptor 4-mediated pathway. Int J Mol Med. 2015;35:1347-54.
    [CrossRef] [PubMed] [Google Scholar]
  6. , , , , . Uric acid enhances PKC-dependent eNOS phosphorylation and mediates cellular ER stress: A mechanism for uric acid-induced endothelial dysfunction. Int J Mol Med. 2016;37:989-97.
    [CrossRef] [PubMed] [Google Scholar]
  7. , , , . Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992;34:78-84.
    [CrossRef] [PubMed] [Google Scholar]
  8. , , . Gout and hyperuricaemia in the USA: prevalence and trends. Rheumatology (Oxford). 2019;58:2177-80.
    [CrossRef] [PubMed] [Google Scholar]
  9. , . Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med. 2007;120:442-7.
    [CrossRef] [PubMed] [Google Scholar]
  10. , . Uric acid puzzle: Dual role as anti-oxidant and pro-oxidant. Electrolyte Blood Press. 2014;12:1-6.
    [CrossRef] [PubMed] [Google Scholar]
  11. , , , . Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol. 2007;293:C584-96.
    [CrossRef] [PubMed] [Google Scholar]
  12. , , , , , , et al. Uric acid and inflammatory markers. Eur Heart J. 2006;27:1174-81.
    [CrossRef] [PubMed] [Google Scholar]
  13. , . Chicken or the egg? Hyperuricemia, insulin resistance, and hypertension. Hypertension. 2017;70:698-9.
    [CrossRef] [PubMed] [Google Scholar]
  14. , , , . Hyperuricemia and incident hypertension: A systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2011;63:102-10.
    [CrossRef] [PubMed] [Google Scholar]
  15. , , , , , , et al. Uric acid is a strong risk marker for developing hypertension from prehypertension: A 5-year Japanese cohort study. Hypertension. 2018;71:78-86.
    [CrossRef] [PubMed] [Google Scholar]
  16. , , , , , , et al. Longitudinal association between serum uric acid and arterial stiffness: Results from the Baltimore longitudinal study of aging. Hypertension. 2017;69:228-35.
    [CrossRef] [PubMed] [Google Scholar]
  17. , , , , , , et al. Hyperuricemia and the risk for coronary heart disease morbidity and mortality: a systematic review and dose-response meta-analysis. Sci Rep. 2016;6:19520.
    [CrossRef] [PubMed] [Google Scholar]
  18. , , , . The key role of uric acid in oxidative stress, inflammation, fibrosis, apoptosis, and immunity in the pathogenesis of atrial fibrillation. Front Cardiovasc Med. 2021;8:641136.
    [CrossRef] [PubMed] [Google Scholar]
  19. , , , , , , et al. Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail. 2014;16:15-24.
    [CrossRef] [PubMed] [Google Scholar]
  20. , , , , . Serum uric acid levels and the risk of type 2 diabetes: A prospective study. Am J Med. 2010;123:957-61.
    [CrossRef] [PubMed] [Google Scholar]
  21. , , , , , , et al. High normal uric acid levels are associated with an increased risk of diabetes in lean, normoglycemic healthy women. J Clin Endocrinol Metab. 2016;101:3772-8.
    [CrossRef] [PubMed] [Google Scholar]
  22. , , , , , , et al. Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type 2 diabetes. J Diabetes Investig. 2014;6:98-104.
    [CrossRef] [PubMed] [Google Scholar]
  23. , , , , , , et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5:1388-93.
    [CrossRef] [PubMed] [Google Scholar]
  24. , , , , , , et al. Serum uric acid levels and risk of metabolic syndrome: A dose-response meta-analysis of prospective studies. J Clin Endocrinol Metab. 2015;100:4198-207.
    [CrossRef] [PubMed] [Google Scholar]
  25. , , , . Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke. 1998;29:635-9.
    [CrossRef] [PubMed] [Google Scholar]
  26. , , , , , . Uric acid and incident dementia over 12 years of follow-up: a population-based cohort study. Ann Rheum Dis. 2018;77:328-35.
    [CrossRef] [Google Scholar]
  27. , , , , , , et al. Serum uric acid as a predictor of mortality and future exacerbations of COPD. Eur Respir J. 2014;43:43-53.
    [CrossRef] [PubMed] [Google Scholar]
  28. , , , , . Hyperuricemia is associated with androgenetic alopecia in men: A cross-sectional case-control study. J Cosmet Dermatol. 2020;19:3122-6.
    [CrossRef] [PubMed] [Google Scholar]
  29. , , , . Serum uric acid as a risk predictor for erectile dysfunction. J Sex Med. 2014;11:1118-24.
    [CrossRef] [PubMed] [Google Scholar]
  30. , . Beyond joints: a review of ocular abnormalities in gout and hyperuricemia. Curr Rheumatol Rep. 2016;18:37.
    [CrossRef] [PubMed] [Google Scholar]
Show Sections