Which characteristics place the patient at high risk for developing acute gout?

Curr Opin Rheumatol. Author manuscript; available in PMC 2014 Jul 21.

Published in final edited form as:

PMCID: PMC4104583

NIHMSID: NIHMS601629

Abstract

Purpose

Our objective was to perform a systematic review of risk factors and prevention of gout. We searched Medline for fully published reports in English using keywords including but not limited to “gout”, “epidemiology”, “primary prevention”, “secondary prevention”, “risk factors’. Data from relevant articles meeting inclusion criteria was extracted using standardized forms.

Main Findings

Of the 751 titles and abstracts, 53 studies met the criteria and were included in the review. Several risk factors were studied. Alcohol consumption increased the risk of incident gout, especially beer and hard liquor. Several dietary factors increased the risk of incident gout, including meat intake, seafood intake, sugar sweetened soft drinks, and consumption of foods high in fructose. Diary intake, folate intake and coffee consumption were each associated with a lower risk of incident gout and in some cases a lower rate of gout flares. Thiazide and loop diuretics were associated with higher risk of incident gout and higher rate of gout flares. Hypertension, renal insufficiency, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, diabetes, obesity and early menopause were each associated with a higher risk of incident gout and/or gout flares.

Summary

Several dietary risk factors for incident gout and gout flares are modifiable. Prevention and optimal management of comorbidities is likely to decreased risk of gout. Research in preventive strategies for the treatment of gout is needed.

Keywords: Gout, risk factors, systematic review, gouty arthritis, alcohol, medications, chronic diseases, diet

Gout is an inflammatory arthritis that presents either as recurrent acutely painful arthritis of few joints, or as chronic inflammatory polyarthritis affecting both upper and lower extremity small and large joints, in a pattern similar to rheumatoid arthritis. Gout has a significant impact on a patient’s health related quality of life as well as his or her productivity and ability to function (1–2). It is estimated that approximately 5 million Americans have gout [1]. A recent cross-sectional study conducted in a managed care population using data from 1990–1999 found a 60% increase in prevalent gout or hyperuricemia over 10-years (3). Another population-based study in Olmsted County, Minnesota examined the development of incident gout, defined using the American College of Rheumatology preliminary criteria (4). The etio-pathogenesis of gout is well-understood with development of hyperuricemia as one of the key intermediary steps. However, it is well-known that hyperuricemia is far more common than gout implying that additional factors increase the risk of gout. A large majority of people with hyperuricemia do not have gout; however the risk of gout increases dramatically with increasing serum urate level.

Prevention of acute and chronic gout has the likelihood of decreasing not only the suffering associated with gout, but also reducing associated health care costs. This systematic review seeks to review published literature regarding risk factors for gout and primary and secondary prevention of this debilitating disease.

Methods

Search Criteria for the Systematic Review

An expert Cochrane librarian (L.F.) searched the OVID MEDLINE from 1950 to June Week 5 2010 using keywords including but not limited to “gout”, “epidemiology”, “primary prevention”, “secondary prevention”, “risk factors’(Appendix 1).

Study Selection and Data Abstraction

All titles and abstracts were screened for inclusion by two review authors independently (SR, JK), trained by the senior author (JAS) in performing systematic reviews. Any disagreements were resolved by referral to the senior coauthor (JAS). Data were abstracted by one coauthor (SR) from the included studies and checked for accuracy by another abstractor (AD). We utilized a standardized abstraction form. Studies were broadly divided into those providing information on risk factors for gout, prevention of gout, or both. Standardized data abstraction was done including the type of study (case control, cohort, randomized), incident or prevalent gout, number of patients involved in the study, risk factors assessed, and primary versus secondary prevention. We abstracted the odds ratios, relative risk or hazard ratios with 95% confidence intervals (95% CI).

Results

The search identified 751 articles related to prevention and/or risk factors for gout. With title and abstract review, 65 unique articles qualified for full text review. After full text review, 53 studies were included (5–57) (Figure 1). We excluded 12 studies because they did not provide data on risk factors/prevention, were reviews or abstracts (58–69). Of these included studies, 1 was related to prevention, 48 were related to risk factors, and 4 to both risk factors and prevention. In this study, we summarize all the available data in the tables and highlight key studies and findings in the narrative.

Flow chart of included studies

Risk Factors for Gout

Current published evidence shows that there are numerous risk factors that contribute to the onset or progression of gout. All relevant information associated with gout and their risk factors have been summarized in the table below (Tables 1–4). Risk factors were grouped into categories relating to alcohol use, diet, medications, and the presence of chronic disease. Several studies specified whether they examined each risk factor for the risk of incident or prevalent gout, although some studies did not specify this. The majority presented the risk of gout flares in either patient with known gout (termed prevalent gout in these studies and in this review) or gout flares in those without previous known gout (incident gout).

Table 1

Demographic characteristics of patients in studies included in the systematic review

Table 4

Medications as a Risk Factor for gout

Alcohol consumption and the risk of gout

We identified 15 articles that included alcohol as a risk factor for incident and/or prevalent gout (Table 2) (11)(13)(14)(17)(26)(30)(40)(41)(43)(44)(50)(53)(54)(57); 2 studies did not provide risk ratios or p-values (50)(44). Almost all studies reported that alcohol intake increased the risk of developing incident or prevalent gout. For instance, in the Framingham cohort of 2,476 women and 1,951 men, alcohol use was associated with the 3-fold higher risk of incident gout among women and 2-fold higher risk in men, compared to those with no alcohol intake or ≤1 ounce/week (11) (Table 2).

Table 2

Alcohol consumption as a risk factor for gout

Five articles focused on alcohol consumption measured as grams per day or drinks per day (11)(13)(17)(57)(43). Choi et al. analyzed the prospective data, derived from the Health Professionals follow-up study over 12 years investigating the relationship between various risk factors (diet, alcohol, soft drinks, coffee etc.) and the risk of incident gout in 47,150 males with no history of gout at baseline (17). During the 12 year period, 730 confirmed new cases of gout were identified, that met the American College of Rheumatology Preliminary criteria for acute gouty arthritis (4). In this study, Choi and colleagues (2004) showed that increasing alcohol intake is associated with higher risk of incident gout (17), similar to findings from other studies (40)(41)(43)(57). The consumption of hard liquor, or having the equivalent of one shot per day, was also significantly associated with the risk of incident gout. Consumption of beer, but not wine, was significantly associated with incident gout (17). Thus, the risk of developing gout varies greatly and is dependent on the type and amount of the alcoholic beverage that is consumed (Table 2). As stated above, beer bestows a larger risk of incident gout as compared to wine or spirits. Alcohol was also a risk factor for prevalent gout in several studies, although the majority of these studies did not specify the association by the amount of alcohol (14)(26)(30)(53)(57). Chen et al. found that alcohol intake was associated with a higher risk of gout flares per year, after controlling for age, gender, and time elapsed since onset of gout (14). Chou et al. indicated that significantly increased alcoholism was found in gouty patients when compared with non-gouty patients (26) . Fam et al. confirmed that alcoholism was indeed, a risk factor for the development of gouty arthritis (30). Tikly et al. stated that gout patients were 3.5 times more likely to consume alcohol when compared to those individuals that do not have gout (53). Lastly, Zhang et al. discovered that, when compared with no alcohol consumption, odds ratios were 1.1, 0.9, 2.0, and 2.5 for 1, 2, 3, to 4, 5 to 6, and 7 or more drinks consumed over a 2-day period, respectively (57).

Diet, Beverages and the risk of gout

Evidence suggests that diet is a risk factor for incident or prevalent gout (Table 3). We found several articles assessing diet as a risk factor for gout (21)(13)(20)(50)(25)(43)(54)(23)(18)(24)(25). Two articles described the relationship of soft drink or consumption and gout or hyperuricemia (21)(25). Using a validated food frequency questionnaire, Choi et al. reported that consumption of 2 or more sugar sweetened soft drinks a day was strongly associated with an increased risk of gout in men (RR=1.85, 95% CI: 1.08–3.16) (21). Moreover, it was also found that those fruits which are high in fructose, as well as fruit juices are also a contributing factor to an increased risk of gout in men (21). Consumption of diet soft drinks does not seem to be associated with an increased risk of gout (21). Sugar-sweetened soft drinks in increasing amounts are associated with higher odds of hyperuricemia (25).

Table 3

Diet as a Risk Factor for gout

A few studies reported on the relationship between dairy, meat, seafood, fruit, and purine rich vegetable intake and risk of gout (18)(21)(54) . In their analyses of Health professional follow-up study, Choi et al. found that increasing daily servings of meat and seafood were associated with significantly increased risk of incident gout, while dairy products were protective (18). Most recently, Dalbeth et al. found that all types of milk increase the fractional excretion of uric acid in humans (70) and both lipid and protein fractions of dairy products modulate the inflammatory response to monosodium urate crystals in animal models (71). These mechanisms may explain the lowering of risk of incident gout as noted by Choi and others.

Moderate intake of vegetables that are rich in purine or protein was not associated with increased risk of incident gout. In one study, greater intake of fruits was associated with significantly lower risk of incident gout (54), while in another study consumption of an apple or orange a day or more was associated with higher risk of incident gout with relative risk of 1.64 [95% CI: 1.05–2.56], compared to those with <1 apple or orange /day (21).

Two studies investigated coffee consumption and the risk of gout (20)(24) using the data from the National Health and Nutrition Examination Survey (20) and the data from the Health Professionals follow-up study (24). Increasing coffee intake, but not tea intake, was associated with significantly lower risk of incident gout in men (24).

One study indicated that intake of folate was associated with lower risk of incident gout (43), while higher intake of total Vitamin C was associated with lower risk of incident gout in two studies (23)(43).Higher dietary fiber intake had a non-significant association with lower risk of incident gout (p=0.09) in one study (43). The chewing of Betel quid, which is the leaf of a vine valued for its medicinal and mild stimulant properties, was associated with a 2-fold increase in the risk of developing gout among the Taiwanese aborigine population (13).

Medications and the risk of gout

Our search resulted in 13 articles that examined the relationship between medications and risk of gout (11)(14)(36)(37)(16)(40)(51)(52)(28)(32)(49)(38)(5) (Table 4). Most articles focused on the use of diuretics, including thiazide and loop diuretics. Studies reported increased risk of both incident gout and gout flares in patients with prevalent gout receiving loop or thiazide diuretics. In one study, cyclosporine was compared to tacrolimus and found to be associated with higher risk of incident gout than tacrolimus in transplant patients (5). Use of colchicine and urate-lowering therapy were each associated with reduction in the risk of gout flares in subjects with prevalent gout (38)(49).

Although, not included in our search of the literature, investigating the relationship between low and high dose aspirin and the maintenance of uric acid levels is critical. Evidence suggests that high doses of aspirin are uricosuric, while low dosages cause uric acid retention (72). It is thought that this withholding of uric acid may lead to hyperuricemia, which is a causal agent in the development of gout. One particular study found that mini-dose aspirin, even at a dosage of 75mg a day, caused significant changes in renal function and uric acid handling in a group of elderly patients (73). Therefore, the administering of low dose aspirin may also be a risk factor for gout.

Chronic Diseases and the risk of gout

Current evidence indicates that the presence of chronic disease is a common risk factor for gout. Our search found 34 articles that assessed chronic disease as a risk factor for gout (Table 5). Many of the included articles explored multiple studies and were either cohort (5)(8)(10)(11)(12)(14)(15)(17)(18)(19)(21)(22)(23)(24)(28)(32)(35)(42)(47)(54) or case-control studies (37)(43)(45)(53) . Study populations in the cohort studies varied from 57 individuals in one study (42) to 51,297 in another (19). For case control studies, sample sizes ranged from 70 in Janssens et al.(37) to 380 in Padang et al. (45). Study findings have indicated that heart disease, diabetes, hypertension, hyperuricemia, obesity, renal disease including renal insufficiency, elevated triglyceride and cholesterol levels, menopause, undergoing surgery, and elevated creatinine levels were all associated with the risk of gout (Table 5).

Table 5

Chronic Disease as a Risk Factor for gout

Hyperuricemia is perhaps the most common and well-studied risk factor for developing gout; it is also one of the causal pathways of gout, so some may argue that it is the common channel to gout and, therefore, not a risk factor. Hypertension was consistently associated with higher risk of incident gout and more flares in those with prevalent gout (Table 5). Higher body mass index was a risk factor for gout and overweight and obese patients were at significantly higher risk of incident gout. Diabetics were at higher risk of incident gout and of gout flares in patients with prevalent gout, with 4 studies providing evidence. Renal insufficiency, but neprolithiasis, was not associated with higher risk of gout flares. Both hypertriglyceridemia and hypercholesterolemia were associated with significantly increased risk of gout flares in patients with prevalent gout.

Gout is extremely uncommon in premenopausal women, but postmenopausal women are at risk. In a study conducted by Hak et al., 2010 studied physician-diagnosed incident gout among 92,535 women prospectively followed in the Nurse’s Health Study (34). The study examined the relationship between menopause, postmenopausal hormone use and risk of gout. Study findings indicated that menopause, especially at an earlier age, increased the risk of gout in women, whereas post menopausal hormone therapy modestly reduced risk of gout (RR=0.82, 95% CI: .70-.96). Friedman et al (2007) conducted a retrospective multi-institutional review of 411 consecutive laparoscopic gastric bypass patients and identified those that had experienced incident postoperative gouty attacks after undergoing bariatric surgery (31). Study findings illustrate that 33.3% of patients with a previous history of gout in this study population developed an acute gout attack postoperatively (31).

In summary, the current evidence suggests that there are several risk factors for incident gout and gout flares in patients with gout. Most of the associations have been examined in at least one or more well-designed study, although further study in different populations can verify these associations. Several comorbidity risk factors are usually coexisting in patients, most common example being hypertension, renal insufficiency, heart disease and diabetes. It is difficult to tease the individual effects of these illnesses and it is conceivable that several of these risk factors mediate their effects through common pathways of inflammation and/or renal mechanisms of urate excretion.

Primary and Secondary Prevention of Gout

We did not find any articles that focused on primary prevention, and four articles were focused on secondary prevention (42)(38)(40)(47).

One article that focused on secondary prevention focused on hyperuricemia and the maintenance of serum urate levels. Li-Yu et al, (2001) conducted a prospective study, at the Philadelphia VA medical center, to determine if lowering of serum urate levels to 6 mg/dl or if a longer duration of lowered serum urate levels will result in depletion of urate crystals and prevent further attacks of gout (42). Study findings indicated that keeping serum urate levels at ≤ 6mg/dl, led to the prevention of future acute gouty flares.

Another article described the clinical characteristics and risk factors associated with gout during the post-surgical period. Kang et al. (2008) conducted a case control study which showed that the site of a recurrent gout flare had a preference for the previously affected site (38). A history of cancer surgery, elevated serum urate levels of ≥ 9 mg/dl, and failure to administer colchicine prophylaxis were all found to be significant risk factors for postsurgical gout. Therefore, an adequate control of pre-surgical serum urate levels and/or the administration of a colchicine prophylactic may prevent postsurgical acute gout.

Lin et al. (2000) conducted a prospective study to examine the association of serum uric acid and other risk factors related to the development of gout flares (40). Findings illustrated that excessive alcohol consumption, especially if sporadic, was the most important risk factor for the development of gout even when serum uric acid concentrations were below 8mg/dl. This study suggested that maintenance of serum urate levels below 8mg/dl was key to secondary prevention of gout flares.

Lastly, Roubenoff et al. studied the incidence and risk factors for gout in white men (47). Study findings indicate that obesity, excessive weight gain and hypertension are significant risk factors for the development of gout. Consequently, prevention of obesity and hypertension may decrease the incidence of gout.

Limitations

Our search was limited to articles since 1950, and we were unable to capture epidemiological and clinical studies examining risk factors for gout prior to 1950. The epidemiology of gout may be changing with the obesity epidemic and therefore the estimates presented here from the literature review may not be precise and applicable in the future. For most studies, ACR classification criteria were used, but others used alternate definitions for gout; this could have lead to misclassification bias in the included studies. No validated definition of gout flare was used in previous studies. Gout flare definitions were not provided in most studies and defined ambiguously in others, which may have lead to misclassification bias. There is an ongoing initiative for the development of validated gout flare definition, which may help to avoid this limitation in future.

Conclusions

We performed a systematic review of the literature to summarize published data on the risk factors and prevention of gout. Several comorbidities, diet, medications and alcohol intake increase the risk for incident gout and/or gout flares in patients with known gout. Studies focused on primary and secondary prevention of gout were scarce. Primary and secondary prevention studies are needed to identify whether prevention of gout is achievable. Risk factors should be often taken into consideration in the medical management of patients with gout, since several risk factors (alcohol, obesity, thiazide diuretics etc.) are potentially modifiable, of which at least some are amenable to behavioral and other interventions.

​

Take Home Messages

1. Alcohol consumption increased the risk of incident gout, especially higher intake of beer and hard liquor.

2. Several dietary factors including higher intake of meat intake, seafood intake, sugar sweetened soft drinks, and foods high in fructose increased the risk of incident gout.

3. Dairy intake, folate intake and coffee consumption were each associated with lower risk of incident gout and in some cases lower rate of gout flares.

4. Among medications, consistent evidence exists for thiazide and loop diuretics to be associated with higher risk of incident gout and higher rate of gout flares.

5. Hypertension, renal insufficiency, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, diabetes, obesity and early menopause were each associated with higher risk of incident gout and/or gout flares.

Supplementary Material

Appendix

Acknowledgements

We thank Louise Falzon, of the Cochrane Library, for performing and updating the search for this systematic review and April DeMedicis, of the Birmingham VA Medical Center, for reviewing titles and abstracts prior to conducting the full text review as well as assisting with the data abstraction process.

Grant support: This material is the result of work supported with the resources and the use of facilities at the Birmingham VA Medical Center, Alabama, USA.

Footnotes

Financial Conflict: There are no financial conflicts related to this work. J.A.S. has received speaker honoraria from Abbott; research and travel grants from Allergan, Takeda, Savient, Wyeth and Amgen; and consultant fees from Savient, URL pharmaceuticals and Novartis.

The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

This study did not require Institutional Review Board since it did not include human subject research.

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