Gout: global epidemiology, risk factors, comorbidities and complications: a narrative review

Abstract

Background

Gout is one of the oldest known diseases and the most common form of inflammatory arthritis. The established risk factors for gout include hyperuricemia, chronic renal disease, genetic, alcohol consumption, dietary factors, diuretic use, hypertension, obesity, and metabolic syndrome. Patients with gout have an increased risk of all-cause mortality, particularly from cardiovascular disease, cancer, and infectious diseases. Gout is also associated with several complications, such as nephrolithiasis. This literature review describes the global epidemiology and trends associated with gout, before providing an overview of its risk factors and complications.

Methods

This research used the narrative review method. Thorough searches were performed in PubMed and Google scholar, up to June 15, 2024, for articles that evaluated the risk factors, comorbidities or complications associated with gout. Moreover, we also included studies that reported the epidemiological characteristics or burden of gout at the global, regional, or national level.

Results

Gout is more prevalent in developed countries, than in developing countries, although its prevalence is increasing globally. In addition, gout is much more prevalent among males than among females. Hyperuricemia has the largest role in the development of gout, although many risk factors contribute to the increasing prevalence of gout, including genes, several medications, and diet. Gout is associated with several comorbidities and complications, which need to be taken into consideration when managing gout. In recent years, gout has been found to be associated with several new comorbidities.

Conclusions

Our findings provide a comprehensive and informative overview that can be useful for the prevention, diagnosis, and management of gout.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12891-024-08180-9.

Introduction

Gout is an inflammatory joint disease and the most common form of inflammatory arthritis. The prevalence and incidence of gout are increasing in certain populations, due to changes in diet, lifestyle and several environmental factors [1, 2]. This disease is mediated by the supersaturation and crystallization of uric acid, also known as monosodium urate (MSU) crystals. Uric acid is produced through the degradation of purines, and is derived from cell turnover, dietary intake and de novo synthesis. The deposition of MSU occurs within joints and periarticular structures, especially in the first metatarsophalangeal (MTP) joint [3]. If hyperuricemia remains untreated for several years, chronic tophaceous gout develops. Tophaceous deposits, which are chronic mass-like nodules, can form soft tissue MSU deposits anywhere in the musculoskeletal system [4]. Tophi are typically located in the ears, joints, tendons, finger pads, and olecranon bursae [5]. The elevation of serum uric acid (SUA) levels is an essential risk factor for the deposit of MSU crystals, and consequently the development of gout. The balance between its dietary intake, synthesis, and excretion determines the level of urate in the body. Therefore, hyperuricemia can be as a result of both the overproduction of urate and its under-excretion [6].

Gout clinically presents as a self-limiting disease and is a result of an inflammatory response to the MSU crystals deposited in the tissues of the host [7, 8]. Aside from some rare monogenetic syndromes, gout is usually a multifaceted disorder that is precipitated by multiple risk factors that are linked directly or indirectly to either chronic hyperuricemia or local tissue characteristics that mediate the crystallization of MSU [9]. The established risk factors for this joint disease include hyperuricemia, genetic and dietary factors, hypertension, chronic renal disease, obesity, alcohol consumption, diuretic use and metabolic syndrome. Although osteoarthritis predisposes individuals to the deposit of crystals in the joints, it has not yet been established as one of the main risk factors [2, 8]. Several studies have discussed its association with an impaired quality of life [10–12]. As the previous studies have suggested, gout is an independent risk factor for all-cause mortality and especially cardiovascular mortality and morbidity. In addition, this disease has been found to be associated with cardiovascular risk factors, including hypertension and hypercholesterolemia [2]. Patients with gout have an increased risk of all-cause disease mortality, especially from cancer, infectious diseases and cardiovascular diseases [13]. Gout has also been found to be associated with several complications, such as chronic kidney disease (CKD) and nephrolithiasis [14]. Previous research has also found visual and retinal complications in those with severe and uncontrolled gout [15]. In this review, we discuss the global epidemiology, trends, risk factors, and complications associated with gout.

Methods

This is a narrative review and not a systematic review. A comprehensive literature search was undertaken using PubMed and Google scholar up to June 15, 2024. A wide range of keywords were used, including the following: (“Gout” OR “Hyperuricemia” OR “gouty arthritis”) AND (“epidemiology” OR “global burden of disease” OR “risk factor” OR “genetics” OR “sociodemographic characteristics” OR “dietary pattern” OR “habits” OR “comorbidities” OR “obesity” OR “diabetes” OR “hypertension” OR “metabolic syndrome” OR “cardiovascular disease” OR “renal disorders” OR “medications” OR “major organ transplants” OR "complications”). No search filters on date or publication type were implemented. This review included only articles that evaluated the risk factors, comorbidities, or complications of gout. Moreover, those studies that reported the epidemiological characteristics or burden of gout at the global, regional, or national levels were also included.

A brief history of gout

Gout, one of the oldest joint diseases known to humans, dates back to ancient civilizations. The term "gout" derives from the Latin word "gutta," reflecting the medieval belief that an excess of bodily humors led to joint inflammation and pain [16–18]. Ancient physicians like Hippocrates and Galen distinguished gout from other joint diseases, noting its association with affluent lifestyles characterized by rich diets and excessive alcohol consumption [19–23].

Throughout history, gout was often dubbed the "disease of kings" due to its prevalence among the wealthy elite, whose diets were abundant in meat and wine [24, 25]. Over time, the understanding of gout expanded with scientific advancements. Anthony van Leeuwenhoek, a pioneer of microscopy, first described uric acid crystals from gouty tophi, laying the foundation for further research [24].

Global epidemiology

Prevalence and its trends

The prevalence of gout varies substantially across the world. Although there is still a lack of comprehensive and reliable data for many countries, in 2017 gout was most prevalent in the Pacific countries [9]. Gout is particularly prevalent among several ethnic groups, such as the New Zealand Maori and Taiwanese Aboriginals, with an estimated prevalence of 10% [26]. According to Safiri et al., in 2017 the highest prevalence of gout was in Australia and its burden was increasing. In contrast, data from the 2019 global burden of disease (GBD) study showed that the United States had the highest point prevalence in the world (Fig. 1A) [27–30]. Information from the past two decades suggests that gout is more prevalent in the developed countries, but its prevalence is increasing in both developed and developing countries [31–33]. Table 1 shows the highest prevalence of gout to be in high-income North America (age-standardized point prevalence of 1722.4 [95% uncertainty interval (UI) 1471.5, 1999.1]) and Australasia (age-standardized point prevalence of 1422.0 [95% UI 1138.7, 1776.6]), while the lowest age-standardized point prevalence were seen in Central Latin America (183.8 [95% UI 145.3, 229.1]) and the Caribbean (247.1 [196.6, 305.3]) regions. In 2019, there were 53.9 million (95% UI 43.4, 66.3) prevalent cases of gout globally (Table 1). The global age-standardized point prevalence of gout was 652.2 per 100,000 (95% UI 528.6, 798.6) in 2019, which was 22.4% higher than in 1990 (Table 1). Gout prevalence steadily increases with age [30]. In 2019, the global prevalence of gout was significantly higher among males than in females and peaked in the 60–64 and 65–69 age groups for males and females, respectively (Fig. 2A). In 2019, the highest age-standardized point prevalence of gout were found in the United States (1752 cases [95% UI 1507.1, 2016.7]), New Zealand (1481.8 cases [95% UI 1244.4, 1750.4]), and Canada (1475.6 cases [95% UI 1160.8, 1857.5]). The nations with the largest increases in the age-standardized point prevalence of gout, from 1990 to 2019, were the United States (85.8% [95% UI 67.3%, 109.3%]), Australia (44.7% [95% UI 31.9%, 58.1%]), and Ecuador (30.8% [95% UI 20.6%, 41.1%]) [27]. In contrast, the lowest age-standardized point prevalence were found in Guatemala (158.6 [95% UI 125.1, 199.7]), El Salvador (167.7 [95% UI 132.7, 206.7]), and Colombia (168.3 [95% UI 132.4, 210.4]) (Table S1) [27].

Fig. 1.

Age-standardised point prevalence (A), incidence rate (B), and years lived with disability (YLDs) rate (C) of gout per 100,000 population in 2019, by country. (Generated from data available from http://ghdx.healthdata.org/gbd-results-tool)

Table 1.

Prevalent cases, incident cases and years lived with disability (YLDs) due to gout in 2019, and the percentage change in the age- standardised rates (ASRs) per 100,000, by GBD region, from 1990 to 2019 (Generated from data available from http://ghdx.healthdata.org/gbd-results-toolExternalRef>)

	Prevalence (95% UI)			Incidence (95% UI)			YLD (95% UI)
	No (95% UI)	ASRs per 100,000 (95% UI)	Percentage change in ASRs between 1990 and 2019	No (95% UI)	ASRs per 100,000 (95% UI)	Percentage change in ASRs between 1990 and 2019	No (95% UI)	ASRs per 100,000 (95% UI)	Percentage change in ASRs between 1990 and 2019
Global	53,871,846AQ (43,383,205, 66,342,327)	652.2 (528.6, 798.6)	22.4 (20.4, 24.9)	9,222,887 (7,419,132, 11,521,165)	111.3 (90, 139.2)	18 (16.5, 19.6)	1,673,973 (1,068,061, 2,393,469)	20.2 (12.9, 28.9)	22.2 (19.9, 25)
High-income Asia Pacific	2,615,785 (2,075,003, 3,304,051)	715.2 (568.6, 894.5)	10.2 (8.3, 12.2)	402,478 (321,235, 508,454)	119.1 (94.6, 149.6)	6.8 (5.2, 8.8)	81,033 (50,842, 117,445)	22.6 (14.2, 32.5)	10.8 (6.8, 15.1)
High-income North America	9,535,679 (8,117,193, 11,162,464)	1722.4 (1471.5, 1999.1)	79.1 (63.1, 99.3)	1,111,379 (916,930, 1,344,332)	214.2 (178.4, 256.6)	56.6 (44.5, 69.5)	285,584 (187,217, 395,015)	52.3 (34.4, 72.3)	77.9 (61.8, 98.3)
Western Europe	4,739,827 (3,714,280, 5,955,737)	606.5 (476.1, 764.1)	13.7 (11.2, 16)	612,861 (484,247, 773,724)	85.9 (68.4, 107.9)	7.3 (5.5, 9.4)	145,463 (92,307, 212,131)	18.9 (11.9, 27.5)	13.7 (9.4, 18)
Australasia	648,673 (518,803, 815,672)	1422 (1138.7, 1776.6)	37.6 (27.5, 46.8)	79,343 (63,678, 99,429)	186.6 (150.7, 233.2)	24.8 (17.1, 32.9)	19,660 (12,558, 28,111)	43.5 (28, 62.2)	37.5 (24.8, 49.6)
Andean Latin America	171,267 (137,241, 211,208)	292.1 (233.5, 359)	26 (21.1, 30.8)	33,280 (26,525, 41,171)	56.1 (44.8, 69.4)	23.9 (19.3, 28.4)	5467 (3384, 7886)	9.3 (5.8, 13.5)	25.6 (14.2, 39.1)
Tropical Latin America	633,426 (500,451, 782,069)	256 (202.7, 316.3)	21.5 (19.4, 23.6)	124,283 (99,346, 154,241)	50.3 (40.4, 62.5)	21.1 (19, 23.1)	20,017 (12,717, 28,847)	8.1 (5.1, 11.5)	21.8 (15.9, 28.2)
Central Latin America	454,341 (358,188, 565,604)	183.8 (145.3, 229.1)	14.5 (12.8, 16.3)	88,882 (70,005, 111,009)	35.7 (28.4, 44.6)	14.8 (13.1, 16.3)	14,594 (9226, 20,928)	5.9 (3.7, 8.5)	14.5 (9.1, 20.2)
Southern Latin America	734,806 (585,231, 916,520)	914 (724.7, 1135.3)	22.9 (17.4, 28.6)	105,043 (83,795, 131,907)	133.5 (106.7, 166.5)	16.2 (10.9, 21.2)	22,861 (14,244, 32,994)	28.5 (17.9, 41.2)	22.5 (13.3, 32.9)
Caribbean	126,664 (100,885, 156,323)	247.1 (196.6, 305.3)	17.7 (14.9, 20.6)	24,646 (19,827, 30,452)	48.3 (38.9, 59.4)	16.8 (14.4, 19.5)	4008 (2509, 5761)	7.8 (4.9, 11.3)	16.6 (8.3, 26.2)
Central Europe	618,750 (487,236, 785,555)	324.8 (259.2, 405.1)	13.4 (11.6, 15.3)	118,649 (94,774, 151,088)	64.4 (51.3, 81.1)	12.6 (11.1, 14.3)	19,058 (12,005, 27,777)	10.1 (6.4, 14.7)	13.9 (9, 18.7)
Eastern Europe	1,364,391 (1,080,184, 1,718,203)	423.7 (338.5, 531.2)	14.4 (12.5, 16.1)	263,543 (208,957, 336,557)	83.8 (67.1, 105.7)	13.4 (11.7, 15.1)	42,049 (26,393, 61,311)	13.1 (8.3, 19.1)	15 (10.9, 19.5)
Central Asia	334,316 (262,097, 415,617)	413.8 (329.2, 516.8)	12.9 (10.2, 15.7)	66,579 (52,455, 83,485)	79.9 (63.7, 100.1)	11.6 (9, 14.5)	10,642 (6722, 15,592)	13 (8.2, 18.9)	12.8 (5.4, 20.1)
North Africa and Middle East	2,455,601 (1,940,521, 3,045,022)	509.1 (406, 633.9)	12 (10.1, 13.9)	490,264 (389,868, 606,813)	97.7 (78.5, 123.2)	11.1 (9.2, 12.9)	77,514 (48,808, 111,730)	15.8 (10, 22.7)	11.7 (7.1, 16.4)
South Asia	5,815,980 (4,622,692, 7,305,040)	393.3 (315.2, 494)	6.3 (5, 7.5)	1,183,316 (944,272, 1,491,889)	77.9 (62.5, 98.2)	6 (4.9, 7.2)	180,046 (113,781, 261,292)	12 (7.6, 17.4)	6.8 (3.8, 9.9)
Southeast Asia	4,249,653 (3,363,354, 5,302,526)	646.3 (512.9, 802.9)	17.1 (14.5, 19.5)	831,398 (659,789, 1,041,228)	124 (99.6, 155.8)	15.9 (13.6, 18.1)	133,986 (84,560, 193,324)	20.2 (12.7, 29.1)	17.5 (13.4, 21.8)
East Asia	16,799,835 (13,315,688, 21,111,760)	807.4 (646.5, 998.2)	28.2 (25.2, 31.3)	3,153,169 (2,509,140, 4,008,346)	153.2 (123.1, 191.5)	25.5 (23.1, 27.7)	530,705 (327,808, 765,618)	25.5 (16, 36.6)	28.1 (24.2, 32.3)
Oceania	60,011 (47,069, 74,967)	732 (577.9, 918.1)	8.2 (3.8, 12.5)	12,144 (9536, 15,158)	139.4 (111.9, 173.7)	7.4 (3.1, 11.9)	1885 (1170, 2709)	22.5 (14.2, 32.4)	7.5 (−1.2, 16.2)
Western Sub-Saharan Africa	974,271 (773,039, 1,214,595)	447.6 (358.3, 558.3)	−2 (−3.2, −0.8)	202,296 (160,151, 251,196)	87.3 (69.9, 109.9)	−2.5 (−3.7, −1.3)	30,986 (19,519, 44,580)	14 (8.8, 20.2)	−1.6 (−4.1, 1)
Eastern Sub-Saharan Africa	905,265 (714,028, 1,123,373)	484 (384.5, 605)	6.1 (4.4, 7.7)	189,344 (150,163, 236,087)	94.5 (75.8, 119.8)	5.7 (4.4, 7.3)	28,605 (18,088, 41,433)	15 (9.5, 21.9)	6.6 (3.1, 10.4)
Central Sub-Saharan Africa	283,785 (221,836, 353,381)	460.2 (364.8, 573.3)	1.5 (−2.6, 5.8)	59,651 (47,074, 74,580)	90.1 (71.5, 114.5)	2.2 (−1.8, 6.2)	8962 (5634, 12,947)	14.2 (8.9, 20.7)	2.3 (−6.3, 11.9)
Southern Sub-Saharan Africa	349,520 (276,726, 437,086)	574 (453.2, 715.4)	6.3 (4, 8.4)	70,339 (56,010, 88,719)	111.3 (88.8, 141.1)	6.1 (3.9, 8.2)	10,849 (6755, 15,566)	17.6 (11.1, 25.5)	5.6 (1.1, 10.2)

Fig. 2.

Global number of prevalent cases and point prevalence (A), incident cases and incidence rate (B) and years lived with disability (YLDs) and YLD rate (C) of gout per 100,000 population, by age and sex in 2019; Dotted and dashed lines indicate 95% upper and lower uncertainty intervals, respectively. (Generated from data available from http://ghdx.healthdata.org/gbd-results-tool)

Incidence and trends

There is an approximately three fold higher incidence of gout in men than in women [9]. Furthermore, in 2019 the incident cases of gout increased with age until reaching a peak in the 50–69 age range in men and the 65–69 age range for women (Fig. 2B). In 2019, there were 9.2 million incident cases per year (95% UI 7.4, 11.5 million) and an annual age-standardized incidence rate of 111.3 (95% UI 90.0, 139.2) per 100,000 population, which had increased by 18.0% (95% UI 16.5%, 19.6%) since 1990 (Table 1). Almost all of the countries and territories included in this study had increases over the period 1990 to 2019, with the largest increases being found in high-income North America (56.6% [95% UI 44.5%, 69.5%]), Australasia (24.8% [95% UI 17.1%, 32.9%]), and Andean Latin America (23.9% [95% UI 19.3%, 28.4%]). The only region which had a decrease in the incidence of gout was Western Sub-Saharan Africa, which decreased by 2.5% (95% UI −3.7%, −1.3%) between 1990 and 2019 (Table 1). Countries with the greatest age-standardized incidence rates were the United States (216.9 [95% UI 181.5, 259.9]) and New Zealand (207.9 [95% UI 170.1, 252.3]), while the lowest rates were found in Guatemala (31.6 [95% UI 25.2, 39.5]) and Honduras (32.4 [95% UI 25.8, 40.2]) (Fig. 1B and Table S2). Those nations with the largest percentage change in age-standardized were the United States (61.0% [95% UI 47.6%, 76.0%]) and Australia (30.3% [95% UI 20.3%, 40.6%]), while Nigeria (−10.0% [95% UI −11.5%, −8.3%]) and Zimbabwe (−1.9% [95% UI −7.3%, 3.2%]) had decreases in their age-standardized incidence (Table S2) [27].

Burden of disease

In 2019, the number of years lived with disability (YLDs) peaked in the 60–64 age range in men and the 65–69 age range in women. The YLD rates followed a linear pattern with increasing age for both males and females (Fig. 2C). In addition, in 2019 the global number of YLDs increased from 691 thousand (95% UI 437 to 994 thousand) in 1990 to 1.6 million (95% UI 1 to 2.3 million) in 2019 (Tables 1). The age-standardized YLD rate was 20.2 (95% UI 12.9, 28.9) cases per 100,000 in 2019, which was 22.2% higher (95% UI 19.9%, 25.0%) than in 1990 (Table 1). The United States (53.0 [95% UI 35.0, 73.6]) and Canada (46.1 [95% UI 28.9, 66.1]) had the largest age-standardized YLD rates, while Guatemala (5.1 [95% UI 3.2, 7.4]), and Honduras (5.2 [95% UI 3.2, 7.6]) had the smallest (Fig. 1C and Table S3). The YLD percentage changes were highest in the United States (84.5% [95% UI 65.9%, 107.8%]) and Australia (44.5% [95% UI 28.8%, 61.8%]), while the largest reductions were found in Nigeria (−9.4% [95% UI −12%, −6.7%]) and Zimbabwe (−3.0% [95% UI −14.4%, 10.7%]) (Table S3) [27].

Generally, a positive correlation was found between the YLD rates of gout and the sociodemographic index (SDI), from 1990 to 2019, at both the global and regional levels. In contrast, at the national level this linear association became almost horizontal, indicating a weak positive association (Fig. 3 and Figure S1). In a report from the GBD 2019 study, the age-standardized YLD rate change from 1990 to 2019 was found to be considerably larger in the Middle East and North Africa (MENA), than it was globally [34]. Furthermore, in 2019 Qatar had the largest age-standardized YLD rates in MENA [34].

Fig. 3.

Age-standardised years lived with disability (YLDs) and the rate of gout for the 21 GBD regions, by SDI in 2019; Expected values based on the Socio-demographic Index and disease rates in all locations are shown as the black line. Each point shows the observed age-standardised YLD rate for each country in 2019. (Generated from data available from http://ghdx.healthdata.org/gbd-results-tool)

Future predictions

A recent update on the worldwide epidemiology of gout suggests that its mortality rate, associated with its comorbidities, may be 55% higher by 2060. Moreover, this finding indicates that the burden of gout is unlikely to be reversed in the near future. The study also predicts that the mortality rate associated with gout comorbidities will drop to 0.66 million deaths (0.08 per million inhabitants; − 2%) in 2030, rise to 0.90 million deaths (0.09 per million inhabitants; + 32%) in 2045, and then increase to 1.06 million deaths (0.10 per million inhabitants; + 55%) in 2060. The biggest increase in mortality rate associated with gout comorbidities by 2060 is anticipated to occur in the upper-middle-income countries (+ 69%) [35].

Economic burden

The overall annual healthcare cost of gout is estimated to be billions of dollars. For instance, in the United States from 2002 to 2008, there were 50.1 million gout-related ambulatory visits (an average of 7.2 million visits per year) reported, with an annual healthcare cost of approximately 1 billion dollars [36, 37]. A recent study has shown that the economic burden of gout, particularly among individuals with chronic kidney disease, is expected to rise from $38.9 billion in 2023 to $47.3 billion in 2035 [38].

Taking into account the ambulatory visits, overnight inpatients, outpatient physician visits, home care, emergency department visits, hospitalizations, reimbursed or nonsteroidal anti-inflammatory drug prescriptions, and same-day surgeries, this 5-year all-cause medical expenditure survey found that the gout-specific direct costs were much higher for gout patients than for patients without gout [36, 39–42]. The largest cost differences between patients with gout and those without gout, were found to be imposed during the first year following a gout diagnosis [39]. Furthermore, employees with gout had higher medical claims (excluding prescriptions) and prescription costs than those without gout. However, their annual salaries and tenure were higher at the index date, and they were more likely to work full time, but had taken more sick-leave [36]. The loss of social activity, lower productivity and higher work absences are among the most important indirect costs of gout. Gout patients have been shown to have a higher average number of work days lost, than those without gout, and thus gout imposes a substantial indirect economic burden [40]. Furthermore, gout patients with higher SUA levels have been found to adhere less strictly to treatment and to have higher rates of all-cause and gout-specific direct and indirect costs, in comparison to those without gout [43]. Moreover, these costs have been found to be more substantial among the elderly and treatment-refractory patients. In contrast, younger patients (mean age of 46–50 years) usually have a lower number of gout attacks per year, and the annual direct costs are considerably lower than those from the elderly population [44, 45].

Previous research has shown that employees with gout experience higher sick leave, increased presenteeism, elevated workers’ compensation expenses, and greater short-term disability costs [36, 40]. In addition, these employees are less likely to maintain positions requiring significant physical activity or to hold part-time status [36]. These problems are larger for patients with uncontrolled gout, in comparison to those with controlled gout or patients without gout [40]. Patients with uncontrolled gout have also been found to place a significantly higher burden on healthcare systems and incur higher economic costs and resource use, when compared to those with controlled gout or matched (equally sick) patients without gout [39, 40].

Gout patients with a SUA of more than 9 mg/dL or patients experiencing three or more annual flares have been found to have a higher prevalence of renal impairment [44, 46], hypertension [43, 44, 46, 47], ischemic heart disease [47], dyslipidemia [47], and chronic kidney disease [47], when compared to patients with lower SUAs. In addition, cases with higher SUA levels generally experience three or more gout flares per year and impose a significantly higher economic burden [46]. Moreover, there is a positive correlation between the presence of tophi, lower adherence to treatments, and the total direct all-cause healthcare costs attributable to gout [36, 44]. Consequently, the economic burden of gout varies according to SUA levels and the comorbidity burden is larger among gout patients with progressive disease characteristics (i.e., tophaceous gout, greater attack frequency, and higher SUA levels) [43, 44, 48, 49].

In summary, gout is a burdensome (but a clinically manageable) disease, but the development of more potent treatments for hyperuricemia, the effective management of SUA levels and gout flares can lower the economic burden imposed by this disease [36, 40].

Risk factors

Hyperuricemia

Hyperuricemia, which is defined as a serum urate concentration higher than or equal to 6.8 mg/dL (0.408 mmol/L), is a biochemical abnormality underlying the development of gout [50–53]. This definition aligns with the general target for urate-lowering drugs (ULDs). However, some guidelines, such as those from the European League Against Rheumatism (EULAR) and the National Institute for Health and Care Excellence (NICE), recommend a lower target for patients with tophi and other severe conditions [54, 55]. The actual probability of gout occurrence in the joint depends not only on the tissue content of urate, but also on the potential of hydrogen (pH) and the temperature of the joint fluid, as well as its macromolecular structure and the concentration of sodium ions and proteins [52, 56].

Hyperuricemia typically arises from either excessive production or insufficient excretion of urate [53]. Currently, nearly a quarter of men and a tenth of women suffer from asymptomatic or symptomatic hyperuricemia called gout [57]. The chances of developing gout is strongly related to the degree of hyperuricemia [53, 58]. However, hyperuricemia alone is not a sufficient cause of gout. This is evidenced by several studies, including the 2007–2008 National Health and Nutrition Examination Survey (NHANES) in the United States, which found that while 21% of the population had hyperuricemia, only 3.9% actually developed gout [59].

The prevalence of gout in hyperuricemic individuals has been found to be higher among men. Exposure to different risk factors in middle age, such as menopause in women and higher alcohol consumption in men, can contribute to these sex differences [60]. The risk factors for gout among the general population, or people with hyperuricemia, have been shown to be serum uric acid concentration, central obesity, and alcohol consumption [60]. Zitt et al. [61] showed that SUA levels are higher in men than in women, and that this difference is influenced by sex hormones. It has also been shown that the level of uric acid increases in women after menopause [62]. In addition, the consumption of vegetables, soy products, lean meat, fruit, coffee, soy milk, mushrooms, carrots, and eggs have been found to have a negative relationship with hyperuricemia, while the consumption of soft drinks, bamboo shoots, and organ meat had a positive relationship [63].

Although asymptomatic hyperuricemia often remains without progression for years [51], studies using ultrasound have shown there to be MSU deposition in a large proportion of asymptomatic hyperuricemic patients, which ultimately lead to persistent attacks, chronic pain, and joint damage [51]. The factors that control the amount, location and degree of persistent deposition in gout patients are not well defined [58]. Chronic gout is the natural evolution of untreated hyperuricemia in patients with gout attacks, accompanied by painless intercritical periods [58].

Genetics

Our knowledge about the genetic basis of gout has greatly improved over the last decade. A number of studies about the genetic basis of gout and genome-wide association studies (GWAS) have focused on the renal excretion of uric acid, confirming the importance of renal uric acid excretion in the control of SUA levels and the risk of gout. Moreover, there are genes that can increase the risk of gout via the hepatic urate production rate, MSU formation, and inflammatory responses to MSU [64]. Several studies have found elevated tubular reabsorption of uric acid in patients with gout [65, 66], due to genetic variations in the urate transporters, which cause increases in the reabsorption levels [67]. Studies on twins have found the heritability of this variation in the normal renal urate clearance and serum urate concentrations to be nearly 70% [68]. Moreover, GWAS have confirmed that more than 200 genetic loci are associated with hyperuricemia [69, 70], including PDZK1, GCKR, LRRC16A, SLC16A9, SLC22A11, ABCG2, SLC2A9, SLC17A1, and SLC17A3, in addition to the intensively-studied SLC22A12 which encodes URAT1 [71]. However, the most significant genetic associations are with SLC2A9 (GLUT9) and SLC22A12 (URAT1), along with several other genes, including numerous transporter genes [72]. Recent research has also discovered a link between reduced mitochondrial genetic copy numbers and gout [73].

SLC2A9/ GLUT-9

The SLC2A9 gene encodes GLUT-9. GWASs strongly suggest that the genetic variants of SLC2A9 are associated with SUA levels [60, 74–77]. Several of these studies have reported that variations in SLC2A9 contributes 3.4–8.8% of the variance in serum urate in women and 0.5–2.0% of the variance in men [60, 74–78].

SLC22A12 (URAT1)

The SLC22A12 gene encodes URAT1, a necessary urate transporter in the proximal tubules that is involved in the apical absorption of urate [79]. Several studies have found a relationship between SLC22A12 variants, serum uric acid concentrations, and gout [57, 60, 80–83].

ABCG2

GWASs have confirmed that polymorphisms in the ABCG2 gene are associated with SUA levels. ABCG2 is expressed in the brush border membrane of the proximal renal tubules, which has an important role in the apical secretion of urate [77, 78, 84–87]. ABCG2 encodes ABCG2, a multifunctional transporter that belongs to the ATP-binding cassette family [88]. Previous research has found that a nonsynonymous form of ABCG2, Gln141Lys (Q141K), explains about 0.5% of the variance in serum urate levels in Europeans [89].

NPT1 and other candidates

A meta-analysis of GWASs, which included 28,141 individuals, uncovered several other genes that are involved in the disease [71]. The renal urate transporters (SLC22A11/OAT4, SLC17A1/NPT1), a monocarboxylic acid transporter (SLC16A9/MCT9) that is correlated with serum urate in the kidney, and PDZK1, which encodes the PDZ domain-containing 1 protein and is associated with OAT4, URAT1, and NPT1, play significant roles in urate handling [90]. Other studies have also confirmed the associations SUA has with PDZK1, GCKR, SLC16A9, and OAT4 [91]. The role of NPT1 in the pathophysiology of gout has also been previously highlighted [81–83, 92].

Sociodemographic characteristics

Several demographic factors (e.g., age, sex, and ethnicity) contribute to the development of gout. A number of epidemiological studies have found that the prevalence of gout increases with advancing age [26, 93–96] and that the average onset of gout is around 60 years old. In contrast, some studies from China have reported a peak in the incidence of gout at between 30 to 39 years of age, as well as an increase in the incidence of juvenile gout [97]. Chen and Shen [60] found that patients with juvenile gout in a Chinese region had a family history of gout and were notably overweight. In a large primary care population in the United Kingdom, the mean age of first diagnosis in men and women were 60.1 and 67.7 years, respectively. In addition, approximately 40% of all incidence of gout were among those under 60 years old [98].

The prevalence of gout has been found to be higher in men [26]. In the NHANES study, which was conducted in the United States between 2007–2008, the male to female ratio was 3:1 [59]. Prior to the menopause, gout has a much lower prevalence in women than among men. The menopause results in a sharp reduction in estrogen levels, which leads to urate loss in the urine and therefore increases the risk of gout [99, 100]. Although the incidence of gout significantly increases in women after the menopause, compared to pre-menopausal women, the prevalence does not increase to the same level as it is in men. Therefore, overall women have a lower prevalence of gout than men do, at all ages [29]. The risk of gout in men increases gradually with age, but for women it increases sharply after menopause [100].

Ethnicity-related variances in diet, comorbidity patterns and genetics can increase susceptibility to gout [26]. Ethnicity greatly affects the prevalence of gout, with higher prevalence rates of the disease being found in the New Zealand Māori, Pacific Islanders and Taiwanese populations [101]. In another study, blacks and the Hmong Chinese in the United States, along with New Zealand Māori, were all found to have a higher prevalence of gout [102]. In addition, the NHANES found that the prevalence of gout was 4.0% among whites and 5.0% among blacks living in the United States [59]. In another study, among the Hmong Chinese living in the state of Minnesota, the prevalence of gout was found to be nearly twice that of the general US population [103]. More specifically, Hmong men were found to have a much higher prevalence than non-Hmong men, but Hmong females had a similar prevalence to non-Hmong females [103].

A number of other socioeconomic factors have been found to be associated with gout. Several European studies have found that rural populations have a lower risk of gout than those living in urban areas [104–106]. A high level of education has also been related to a lower risk of gout [107].

Habits and diet

Several studies have reported diet to be a risk factor for gout, due to the potential contribution to high levels of urate in the body fluids [8, 108]. Patients are routinely advised to refrain from eating purine-rich foods, since quantitative data shows there is a relationship between the intake of these substances and urate levels [109, 110]. Consuming foods that contain more than 200 mg per 100 gr of purines, such as sea foods, poses a high risk of developing gout [111]. Studies have shown that the consumption of meat and seafood increases SUA levels, while total protein consumption was not related to the development of gout [8, 112]. Peanuts, cold cereal, cheese, skim milk, non-citrus fruits, margarine, eggs, and brown bread reduce SUA levels [67]. There is also evidence that vegetables with high purine do not increase the likelihood of developing gout [113], while soy legume products increase the risk [62, 114].

Previous research has shown that alcoholic drinks, such as beer, increase uric acid production [115]. Therefore, drinking alcohol could be considered a risk factor for developing gout [116]. In contrast, drinking one or more glass of milk per day reduces the amount of urate in the body, so skim milk and low-calorie yogurt can reduce the risk of gout [8, 112, 117, 118]. In addition, long-term coffee and black tea consumption is related to a lower risk of gout [119]. Taking vitamin C has been shown to decrease SUA, but long-term use and high doses increase kidney stones, due to excessive excretion of uric acid [112, 120]. Vitamin C also lowers the incidence of gout by decreasing the NF-κB/NLRP3-related inflammatory response to MSU deposition, and also increases the glomerular uric acid filtration rate [121].

Medications

There are a number of medications, such as diuretics, which can induce gout or increase gout flares by elevating SUA, via mechanisms that include reducing the renal excretion of uric acid and influencing the renal urate transporters [7]. Loop, thiazide and thiazide-like diuretics are the most commonly used, and they increase the risk of gout flares among people with preexisting gout [8, 122–127]. In addition, the combination of a loop and a thiazide diuretic can raise the risk of developing gout by as much as five times. However, the elevated risk of gout is much more obvious in men than among women. Furthermore, the risk increases with both the duration and dosage of the diuretic therapy, providing evidence of a dose-dependent effect [128].

Several antihypertensive drugs, such as β-blockers, angiotensin-converting enzyme inhibitors and non-losartan angiotensin II antagonists are related to the incidence of gout [127, 129, 130]. Metabolic disturbance and hyperuricemia can also be caused by antiretroviral agents, such as ritonavir [131]. Moreover, some immunosuppression drugs, for instance cyclosporine and tacrolimus, increase the risk of gout by reducing renal urate excretion [132]. Similarly, low-dose aspirin, pyrazinamide and niacin reduce renal urate excretion and increase retention of uric acid, by acting on renal urate transporters [123, 124, 133–137]. In addition, ethambutol and nicotinic acid may cause hyperuricemia and gout [123]. However, there is some inconsistency in the research findings for some of the above-mentioned drugs. For example, research in the United States found that using low-dose aspirin resulted in a two-fold increase in the risk of recurrent gout attacks. In contrast, the Health Improvement Network study from the United Kingdom found that aspirin did not increase the risk of gout [98, 135].

Major organ transplantation

Patients with a history of kidney transplantation are at risk of hyperuricemia and new-onset gout, which has been found in 2–13% of recipients. In these types of patients, gout occurs earlier, more severely and poses greater challenges to pharmacologic management [56, 138–140]. Hyperuricemia and gout are common problems among transplant recipients, especially kidney transplant recipients, with delayed graft functioning, lower glomerular filtration rate, and post-transplant renal insufficiency being common markers in these patients [56, 141, 142]. In addition, kidney transplant recipients with gout are more likely to have severe uncontrolled gout, compared to gout patients without a history of kidney transplantation [139]. Hyperuricemia is common after liver transplantation, but only a small number of gout cases have been reported following a liver transplant. Kidney-pancreas transplant recipients, in whom diabetes might be “cured”, have a significantly lower risk of new-onset gout. However, prospective cohort studies are needed to confirm this finding [143].

Calcineurin inhibitors, especially cyclosporine, and diuretics have been found to be associated with a higher risk of hyperuricemia and new-onset gout in populations with a history of kidney, heart or heart/lung transplantations [56, 143–150]. These medical procedures may also raise serum urate levels [56, 132, 139, 151, 152]. Cyclosporine is more important than any other type of medicine, and its anti-uricosuric effect appears to be as a result of a reduction in the filtered load [146]. In addition, cyclosporine can inhibit probenecid-stimulated tubular secretion [144]. Furthermore, nephrotoxicity is the most common serious adverse effect of cyclosporine, which occurs in up to 80% of patients [132, 142, 151, 153–155]. Moreover, gout occurs in 23% of patients who are treated solely with azathioprine and prednisone [98, 156]. The infrequent reporting of gout following liver transplantation, compared to cardiac or renal transplantation, can be attributed to the lower doses of cyclosporine used and the limited number of patients on long-term azathioprine and diuretics [132, 150, 157, 158]. In contrast, in kidney transplant recipients who use corticosteroids, taxotere-adriamycin-cyclophosphamide, sirolimus or allopurinol, there does not appear to be an increased risk of renal dysfunctions, but this treatment may slow gout flares [98, 159, 160]. Gout prevalence is approximately eight times higher among males of the same age in the general population, and it is found in 10% of men following transplantation [150].

Comorbidities

Obesity

Obesity is a significant factor in the increase of gout. Several studies have found that people with a BMI ≥ 30 kg/m2 are more prone to developing gout [26, 161–163]. In addition, weight loss and bariatric surgery appear to reduce the risk of gout [26, 164].

Diabetes

Patients with gout have a high risk of developing Type 2 diabetes mellitus, with a prevalence of over 25% [165]. A study in the United States showed that 26% of patients with gout developed diabetes, and among patients with higher SUA levels, the prevalence was 33% [59]. Patients with gout experience a low-grade inflammation, which has been hypothesized to potentially contribute to the development of diabetes, suggesting a plausible mechanism for its higher prevalence [135]. It is important to note that this remains a hypothesis, and further research is needed to substantiate this association. In addition, a cross-sectional study showed that people with Type 2 diabetes have a higher prevalence of gout compared to those without Type 2 diabetes [166]. Patients with gout and those with Type 2 diabetes mellitus share several genetic risk factors and comorbidities that leads to their mutually high prevalence, but the duration of gout is not associated with a higher prevalence of diabetes [167].

Cardiovascular disorders

There is evidence to suggest that nitric oxide and the renin–angiotensin–aldosterone system are the mediating factors in the relationship between gout and high blood pressure [168–170]. Through the production of nitric acid, uric acid destroys the functioning of the capillary lining cells [171, 172] and increases the thickness of the vessels’ muscle wall [173], or it may directly cause activation of the renin–angiotensin–aldosterone system [168, 174]. Nearly three-fourths of patients with gout have high blood pressure, which can cause cardiovascular disease [26, 117]. Gout increases the risk of heart failure [175], atrial fibrillation [176], aortic stenosis [177], ischemic stroke and peripheral vascular disease [178], venous thromboembolism, deep vein thrombosis, pulmonary embolism [179], and coronary heart disease [119, 128, 180, 181]. In addition, MSU crystals can cause aortic and thoracic artery calcification [182]. Moreover, it seems that the inflammation caused by urate crystals plays an important role in cardiovascular disease [183].

Metabolic syndrome

Studies have found that the prevalence of metabolic syndrome among patients with gout ranges from 37 and 51% [184]. In addition, a population-based study in Korea found that 50.8% of gout patients subsequently developed metabolic syndrome [185]. Furthermore, the prevalence of gout rises in parallel with components of metabolic syndrome, such as hyperlipidemia, hypertension, and obesity [112, 185–188]. Increased SUA levels, as the largest risk factor for gout, have a linear relationship with the increasing incidence of metabolic syndrome [82, 159, 185, 189–192]. The prevalence of gout in patients with SUA levels < 6 mg/dl has been found to be 18.9%, while in patients with SUA levels > 10 mg/dl the prevalence was reported to be 70.7% [187]. In another study, they found that patients with SUA levels > 9 mg/dl had a five times higher risk of developing metabolic syndrome than patients with SUA levels < 7 mg/dl [159]. Furthermore, hyperuricemia was found to be directly correlated with the development of metabolic syndrome, as well as its severity [187, 191]. In addition, a recent meta-analysis found that a 1 mg/dl increase in SUA level elevated the incidence of gout by about 5% in men and 9% in women [187]. Moreover, an elevated SUA level was a predictive factor for metabolic syndrome in men, but not in women, and SUA levels were correlated with gout, including in children [187]. Therefore, measuring the serum uric acid level is important for both gout and metabolic syndrome [192]. Metabolic syndrome and obesity should be effectively managed in patients with gout [82, 185, 188].

Other conditions

A number of other gout comorbidities have been reported, including macular degeneration, osteoarthritis, macular dysfunction, hypothyroidism, cancers, erectile dysfunction, psoriasis, neurodegenerative diseases, obstructive sleep apnea, giant cell arteritis, gastrointestinal disorders, lung diseases, depression, and fractures [107, 193–197]. Gout and hyperuricemia increase the risk of stage 3–5 CKD [14, 159, 198]. Gout can also increase the risk of interstitial nephritis and kidney stones [199], which can be as a result of MSU deposition [107, 200].

Gout has been found to be associated with higher cancer incidence in both men and women [62, 193]. A meta-analysis reported that gout was associated with a higher incidence of cancers, including respiratory, digestive, and urinary cancers [195]. Furthermore, a population-based study indicated that middle-aged patients with gout had a higher incidence of head and neck, stomach, and hematologic or lymphoid cancers [201]. In women, digestive and urinary cancers are the most common [195]. Gout patients have several risk factors for cancers, such as smoking, obesity, and alcohol consumption [201].

A correlation has also been found between gout and psoriasis, which results from the increased SUA levels in psoriasis sufferers [194]. Patients with gout, including men and women, have a higher prevalence of psoriasis, especially among those aged 41–50 years old [194, 202, 203]. In addition, hyperuricemia can be an independent risk factor for the development of erectile dysfunction [204]. Patients with gout have a strong risk of erectile dysfunction, which should be considered when managing these patients [205]. Furthermore, available evidence indicates there is a correlation between sexual dysfunction and gout in both men and women [206].

Complications of gout

Kidney stones

Kidney stones are a common complication of gout, predominantly composed of uric acid or a combination of minerals [207]. Clinical studies have found that approximately one-third of gout patients have kidney stones, often bilaterally, with increased severity correlating with higher SUA levels and decreased renal function [207]. While the relationship between gout and kidney stones is well-established, certain aspects, such as the prevalence of both symptomatic and asymptomatic stones in gout patients, remain unclear [207].

Several pathophysiological mechanisms influence nephrolithiasis in gout patients. Gout is associated with increased uric acid levels in the blood, which can lead to the deposition of uric acid crystals in the joints during flares [208, 209]. These crystals can also precipitate in the kidneys, potentially forming uric acid stones. The acidic environment in the urine, often observed in gout patients due to increased uric acid excretion, further promotes the formation of uric acid stones [210]. Factors such as dietary purine intake and metabolic conditions can exacerbate this risk by influencing urine pH and uric acid levels [209]. The inflammatory response triggered by MSU crystals in gout, mediated by macrophages and neutrophils through NLRP3 inflammasome activation, may also contribute to nephrolithiasis [177].

The coexistence of gout and kidney stones highlights the need for comprehensive management strategies addressing both conditions [207].

Retinal complications

The ophthalmic manifestations of gout are rare but vary widely. The most common ocular symptom in gout patients is red eye, which may be partially due to hyperemic conjunctival and episcleral vessels [211]. Gout-related tophi, or MSU deposits, have been reported in various ocular structures, including the corneal epithelium, stroma, and Bowman’s layer [212–214], conjunctiva, sclera, lens, orbital fossa, retina, tarsal plates of the lids, iris and anterior chamber [15, 57, 212, 215–219]. Additionally, tophi have been observed in the eyelids [220], medial [52, 221] and lateral canthus [52, 220–224], and the limbal area near the episcleral vessels [216]. Affected individuals in these studies presented with burning ocular pain, progressive red eye, impaired vision and gradual enlargement of the mass, without any bleeding, inflammation, discomfort or any visual complaints [219]. These tophi can be seen as chalky white masses, yellow subcutaneous masses, or white subcutaneous masses resembling an epidermal inclusion cyst, or skin colored, resembling basal cell carcinoma [52, 222, 224]. Furthermore, in patients with gout, there have been reports of chronic conjunctivitis, subconjunctival transparent vesicles (which were four times more common in gout patients than in controls) [177, 212], subconjunctival hemorrhage, scleral vascular tortuosity [212], hyperemia secondary to acute conjunctival inflammation and anterior uveitis [57, 211, 213, 215, 219, 225], episcleritis, scleritis, rarely iritis [216], hemorrhagic retinitis, phlebo-sclerosis [226], age-related macular degeneration [227], and both bulbar and palpebral conjunctival injection [216].

Hyperuricemia may be the underlying cause in approximately 11% of patients presenting with episcleritis [216]. Moreover, several studies have independently reported a significant association between gout and dry eyes [216, 228–230]. However, a 10-year follow-up study, which measured the incidence of dry eyes, revealed no significant association between the two conditions [228]. Other ocular findings that have been associated with gout include raised intraocular pressure (with open-angle glaucoma or without glaucomatous nerve damage or visual field defects), blurred disc margins, possibly posterior uveitis, and asteroid hyalosis [177, 211, 216, 219, 231]. In addition, an association between allopurinol and exudative lesions in the macula has also been described in a case report [232].

Other complications

Gout has previously described as a nonthreatening condition that is associated with recurrent arthritis. However, chronic gout does not usually manifest itself as a benign condition, as initially believed, gout is a systemic disease that affects multiple organ systems [233]. The first case of urate crystal deposition in the spine was reported in 1950 [234]. Spinal gout detection is limited, due to radio-dense urate crystals on radiographs, as well as nonspecific magnetic resonance imaging and CT findings [233, 235]. Nonetheless, there have been over one hundred reported cases of MSU deposits within the cervical, thoracic and lumbar spine [236, 237]. In addition, several studies have claimed that lower pH levels and temperature, along with underlying degenerative conditions, can lead to spinal MSU deposition [235]. Spinal gout generally manifests itself with back pain. Spinal tophi can also cause neurologic impairment by compressing the nerve roots or the spinal cord. These complications can be manifested via radiculopathy symptoms, myelopathy, as well as bowel and bladder dysfunction [236, 237]. Several case report studies have reported urate deposition in the gastrointestinal system. In these cases, tophi have been reported in the liver, pancreas, small intestine and colon, with several being initially misdiagnosed as some type of malignancy [238–242]. Dermal tophi, due to intradermal MSU deposits, present as subcutaneous nodules or indurated plaques have also been reported, causing ulcers and preceding possible articular symptoms [243]. Several studies have also reported MSU deposition within the larynx, middle ear, surface of the Eustachian tube and nose, with the clinical manifestations including conductive hearing loss, otorrhea, hoarseness, odynophagia, dysphagia, and stridor [244, 245]. Tophi deposition has also been reported in the prostate glands, causing chronic prostatitis symptoms or mimicking prostate cancer. In addition, mammary and pulmonary tophi have been reported as non-specific masses in the mammary glands, lung nodules and endobronchial masses [246, 247].

Limitations

The current research is a narrative study and therefore the results may not be generalizable. Furthermore, our purpose was to gather evidence to identify gaps for future research. Although we tried to review all the related studies, there is a possibility that some studies were missed.

Conclusions

Gout is the most common form of inflammatory arthritis and there is substantial variance in its prevalence around the world. This review presented the global epidemiology, recent trends, and future predictions about gout. Hyperuricemia has the largest role in the development of gout, and there are many risk factors, including genes, certain medications, and diet that affects the serum uric acid level. Gout is associated with several comorbidities and complications that should be taken into consideration in the management of gout. In recent years, new comorbidities with gout have been found, and this review emphasizes the need for more studies to clarify several complex associations. Despite advancements in understanding the pathophysiology and risk factors associated with gout, it remains a poorly managed condition worldwide. Many patients fail to achieve optimal control of uric acid levels, resulting in recurrent flare-ups and chronic complications. This review highlights the gaps in gout management, underscores the need for improved clinical practices, and advocates for further research to address these challenges. By synthesizing current knowledge and identifying areas requiring attention, this review aims to contribute to better healthcare strategies and outcomes for individuals suffering from gout.

Abbreviations

MSU

Monosodium urate

MTP

Metatarsophalangeal

SUA

Serum uric acid

CKD

Chronic kidney disease

UI

Uncertainty interval

YLD

Year lived with disability

SDI

Sociodemographic index

MENA

Middle East and North Africa

GBD

Global burden of disease

NSAID

Nonsteroidal anti-inflammatory drug

ULD

Urate-lowering drug

pH

Potential of hydrogen

NHANES

National Health and Nutrition Examination Survey

GWAS

Genome-wide association studies

BMI

Body mass index

CT

Computed tomography

OR

Odds ratio

Authors' contributions

SS, SAN, AF and AAK designed the study. KMA, MZ, FS, AF, AM, MZo, AS, SJA, SEM, SAN, RM, JGS, NK and MJMS drafted the initial manuscript. All authors reviewed the drafted manuscript for critical content. All authors approved the final version of the manuscript.

Funding

The Shahid Beheshti University of Medical Sciences, Tehran, Iran (Grant No. 28705) supported the present report.

Data availability

The data used for these analyses are all publicly available at http://ghdx.healthdata.org/gbd-results-tool.

Declarations

Ethics approval and consent to participate

The present report was approved by the Ethics Committee at the Shahid Beheshti University of Medical Sciences (IR.SBMU.RETECH.REC.1401.216).

Consent for publication

Not required.

Competing interests

The authors declare no competing interests.