This study is, to our knowledge, the first to identify anemia as a risk factor for gout over nine years of follow-up in a large population-based study of middle-aged adults. Even after adjustment for kidney function, comorbid conditions, and education and baseline smoking status, anemia remained an independent predictor of incident gout. Unlike traditional risk factors, anemia was associated with gout, even after adjustment for urate levels, suggesting an independent pathway. No differences in the association between anemia and gout were observed by race, or baseline kidney function. However, there is slight evidence of a difference in the association between anemia and gout between men and women, with a stronger association observed for women.
Although, at this time there is no clear biological link between anemia and gout, there are potential explanations for this observed association. Anemia is an independent risk factor for the development of adverse cardiovascular outcomes, both short-term [27
] and long-term [10
]. Previous studies have identified anemia as a risk factor for CVD and independent of chronic kidney disease (CKD). For example, anemia was associated with an adjusted HR of 1.41 (95% CI: 1.01, 1.95) for incident CVD [10
], and in a population of patients with normal kidney function, anemia was associated with first cardiovascular-specific hospitalizations (HR = 2.49, 95% CI: 1.99, 3.12) [33
], supporting the role of anemia as an independent risk factor above and beyond the effects of kidney function [14
]. Renal tubular dysfunction can occur in the absence of renal insufficiency (as measured by the creatinine clearance), so alterations in renal urate excretion could occur if the anemia was related to lead poisoning, chronic aspirin use, sickle cell and early CKD (particularly polycystic kidney disease).
Additionally, anemia increases cardiovascular mortality in specific disease states, such as CKD, both in dialysis patients [34
] and intermediate CKD stages [11
]; as well as CHF [34
], diabetes [36
] and myelodysplastic syndrome [37
]. There has been tremendous interest in anemia as a risk factor for CVD because it is potentially modifiable with iron therapy or erythropoietin [38
Oxidative stress is increased in anemia [17
], perhaps particularly in iron-deficiency anemia [39
] where iron-deficiency affects catalase activity. The increased oxidative stress could have long-term consequences. One such consequence is induction of hyperuricemia due to increased xanthine oxidase activity, increased cell death/turnover, alteration of cellular macromolecules making them more amenable to urate crystallization (a mechanism akin to the role of oxidized lipoproteins contributing to atherosclerotic plaques) or impairment in renal urate excretion (increased lactate production, increased urate reabsorption because of hypoxic signal to kidney) [17
Serum urate levels are thought to be positively correlated with iron levels [40
]. Previous evidence supports a role for iron deficiency in the pathogenesis of gout; when iron is added to media containing urate crystals there is a stimulated oxidative stress with subsequent complement and neutrophil activation. Conversely, the removal of iron inhibits these responses and maintenance of near iron deficiency diminished gouty attacks in patients with gout [43
]. However, these results are not in conflict with the reported findings. Anemia may be associated with other chronic disease not captured in ARIC or low B12 folate levels. Furthermore, patients with anemia may also be taking iron supplements, which increase iron levels and thus leads to increased serum urate level and gout risk.
Both gout and anemia are associated with CKD [44
] and anemia may be a marker for the duration and severity of kidney disease. Thus, anemia could be a proxy for CKD and the association of anemia and incident gout could have been confounded by CKD. However, we found that anemia remained statistically associated with the development of gout after adjustment for kidney function and in participants without renal impairment. Therefore, anemia may be a marker of gout independent of kidney function, as has been demonstrated with CVD [14
Anemia could also be a marker of chronic conditions and not an independent risk factor for gout. Previous studies have identified anemia as predictor of mortality and morbidity [11
]. In our study, a baseline history of chronic conditions was not associated with anemia although in the same cohort, anemia was associated with incident CVD [10
]. Additionally, the presence of chronic diseases did not explain the association of anemia and gout. However, another feature of chronic diseases, such as inflammation, may be the link between anemia and gout. Inflammation occurs in patients with anemia [46
] and urate crystals trigger inflammation during a gout attack [48
]. Additionally, inflammation has been found to occur more often in older anemic patients than younger patients [47
], which may explain why this association was first observed in a middle-aged adult population. Although, our results were similar when fibrinogen, an acute phase reactant, was included in the multivariate model, we cannot rule out the possibility that inflammation or another factor confounds the association of anemia and gout.
Additionally, different female-specific health factors may be driving the association of anemia and incident gout. Anemia was much more common in women and traditional gout risk factors, such as BMI, alcohol intake and diuretic use, are stronger predictors of gout in men compared to women [3
]. Our results provide slight evidence that the association between anemia and gout may exist for women but not men. African-American women typically have a higher prevalence of iron-deficiency anemia due to the bleeding associated with fibroids [26
]. Fibroids are also associated with increased BMI and hypertension, factors which may affect the development of gout, and this may be one explanation for the observed results [26
]. However, in the models restricted to women, when we adjusted for history of surgical menopause, the best proxy available in these data, anemia remained associated with the development of gout.
Finally, anemia may be a cause of gout. Although it is unclear whether the observed association of anemia and gout is causal, anemia is thought to be more than just a bystander on the biological pathway between anemia and chronic conditions [16
]. We did not identify possible biological explanations of the observed association of anemia and gout; although, it is possible that anemia causes gout. However, this study was not designed to establish causality.
Strengths and limitations
To our knowledge, this is the first study to identify anemia as a risk factor for incident gout. This is one of the largest biracial studies of gout, which included both men and women with gout. Anemia was established prior to the onset of gout, thus supporting temporality. Additionally, we were able to control for kidney function at baseline and other important risk factors for both gout and anemia. For example, we adjusted for race, hypertension and kidney function, which are known common risk factors for gout and anemia [5
]. Finally, our measure of socioeconomic status and education did not alter our results. Additionally, ARIC is one of the few studies that has measures of serum urate and collected data on incident gout during follow-up. This allowed us to test whether the association of anemia and gout remained after adjustment for serum urate levels.
As with any epidemiology study there are limitations to our study. The main limitation of our study was that gout was self-reported by participants at visit 4 and incidence of gout was based on reported age at onset. However, our previous work has suggested that self-reported gout and age of onset is both sensitive and reliable [21
]. Participants had to survive until visit 4 and be healthy enough to attend the clinical visit to be included in this study. This may induce bias if those who attended visit 4 were different from the study population with respect to the association between anemia and gout. However, if anemia is non-differentially related to mortality, then this would bias our results towards the null, suggesting that our results are an underestimate of the true association. The etiology of participants' anemia could not be determined in this study and we were unable to establish whether participants had a hemoglobinopathy. Additionally, it is not known whether participants were taking iron supplements. Finally, the hemoglobin cutpoints for anemia were relatively high as severe anemia, hemoglobin <11 g/dL, was rare in this population as it would be in the general population. However, previous studies of anemia have used hemoglobin levels and not established the etiology [10
]. We cannot be assured that we have eliminated residual confounding, although we have adjusted for the main confounders as was previously noted.