Hyperferritinemia increases the risk of hyperuricemia in HFE-hereditary hemochromatosis

Flais, Jérémy; Bardou-Jacquet, Édouard; Deugnier, Yves; Coiffier, Guillaume; Perdriger, Aleth; Chalès, Gérard; Ropert, Martine; Loréal, Olivier; Guggenbuhl, Pascal

doi:10.1016/j.jbspin.2016.05.020

Cited by 15 publications

(11 citation statements)

References 40 publications

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“…development of gout, suggesting the potential involvement of Mo in this disease (31,41,42), xanthine oxidase being the Mo-dependent enzyme involved in uric acid production. Moreover, it is noteworthy that, during HFE-hereditary hemochromatosis, hyperferritinemia level, which reflects iron stores, was recently found to be associated with the risk of hyperuricemia (43). Lastly, it has been suggested that Mo accumulation is correlated with C-parathormone and calcium levels and could contribute to dialysis-related arthritis (44).…”

Section: Discussionmentioning

confidence: 99%

Spleen iron, molybdenum, and manganese concentrations are coregulated in hepcidin‐deficient and secondary iron overload models in mice

et al. 2019

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Iron excess increases the hepatic expression of hepcidin, the systemic iron metabolism regulator that favors iron sequestration in the spleen. Genetic iron overload related to hepcidin insufficiency decreases the spleen iron concentration and increases hepatic iron concentration, whereas during secondary iron overload, the hepcidin expression increases together with spleen iron concentration in addition to hepatic iron concentrations increase. Links between iron metabolism and other metals being suggested, our aim was to investigate, during iron overload, the relationships between the hepatic hepcidin expression level and the hepatic and splenic concentrations of iron, manganese, copper, zinc, and molybdenum, determined using inductively coupled plasma mass spectrometry. Hepcidin‐deficient mice, secondary iron overload mice models, and their respective controls were studied. Spleen molybdenum and manganese concentrations paralleled the modulation of both spleen iron concentrations, increasing in secondary iron overload and decreasing in hepcidin deficiency related iron overload, as well as hepatic hepcidin mRNA expression. Our data suggest that iron, manganese, and molybdenum metabolisms could share mechanisms controlling their distribution that are associated to hepcidin modulation. In diseases with abnormal hepcidin levels, including chronic inflammation, special attention should be paid to those metals that can participate with the phenotype.—Cavey, T., Latour, C., Island, M.‐L., Leroyer, P., Guggenbuhl, P., Coppin, H., Roth, M.‐P., Bendavid, C., Brissot, P., Ropert, M., Loréal, O. Spleen iron, molybdenum, and manganese concentrations are coregulated in hepcidin‐deficient and secondary iron overload models in mice. FASEB J. 33, 11072–11081 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Spleen iron, molybdenum, and manganese concentrations are coregulated in hepcidin‐deficient and secondary iron overload models in mice

et al. 2019

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“…To the best of our knowledge, studies by Flais et al [45] is the only report in published literature that addressed hyperuricemia in HH. These investigators found that in a large cohort of patients who harbored C282Y mutation in HFE, hyperferritinemia (an evidence for iron overload) was associated with hyperuricemia occurrence.…”

Section: Discussionmentioning

confidence: 98%

Hereditary hemochromatosis disrupts uric acid homeostasis and causes hyperuricemia via altered expression/activity of xanthine oxidase and ABCG2

Ristić

Sivaprakasam

Narayanan

et al. 2020

Biochemical Journal

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Hereditary hemochromatosis (HH) is mostly caused by mutations in the iron-regulatory gene HFE. The disease is associated with iron overload, resulting in liver cirrhosis/cancer, cardiomegaly, kidney dysfunction, diabetes, and arthritis. Fe2+-induced oxidative damage is suspected in the etiology of these symptoms. Here we examined, using Hfe−/− mice, whether disruption of uric acid (UA) homeostasis plays any role in HH-associated arthritis. We detected elevated levels of UA in serum and intestine in Hfe−/− mice compared with controls. Though the expression of xanthine oxidase, which generates UA, was not different in liver and intestine between wild type and Hfe−/− mice, the enzymatic activity was higher in Hfe−/− mice. We then examined various transporters involved in UA absorption/excretion. Glut9 expression did not change; however, there was an increase in Mrp4 and a decrease in Abcg2 in Hfe−/− mice. As ABCG2 mediates intestinal excretion of UA and mutations in ABCG2 cause hyperuricemia, we examined the potential connection between iron and ABCG2. We found p53-responsive elements in hABCG2 promoter and confirmed with chromatin immunoprecipitation that p53 binds to this promoter. p53 protein was reduced in Hfe−/− mouse intestine. p53 is a heme-binding protein and p53-heme complex is subjected to proteasomal degradation. We conclude that iron/heme overload in HH increases xanthine oxidase activity and also promotes p53 degradation resulting in decreased ABCG2 expression. As a result, systemic UA production is increased and intestinal excretion of UA via ABCG2 is decreased, causing serum and tissue accumulation of UA, a potential factor in the etiology of HH-associated arthritis.

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“…Increasing evidence shows that body iron metabolism plays an important role in the development of HU [ 2 , 15 , 16 , 17 , 18 ]. Serum ferritin (SF) is the most widely used biomarker in clinical and epidemiological studies to evaluate body iron stores, despite being affected by inflammation status.…”

Section: Introductionmentioning

confidence: 99%

“…Serum ferritin (SF) is the most widely used biomarker in clinical and epidemiological studies to evaluate body iron stores, despite being affected by inflammation status. Several studies [ 2 , 15 , 16 , 17 ] have assessed the relationship between SF and the risk of HU, but few studies have adjusted for some important lifestyle factors, such as cigarette smoking, physical activity, and dietary factors, which are associated with the risk of HU [ 11 , 12 , 19 , 20 , 21 ]. As such, it is still not clear whether the relationship between SF and the risk of HU is independent of these risk factors.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies showed that the concentrations of SF increase rapidly on exposure to trauma or infection [ 22 ], and remain high during the chronic phases of inflammatory process [ 23 ], so it is necessary to exclude those participants with acute inflammation, and adjust for the confounders of chronic inflammation. However, only a few studies had adjusted for the parameters of inflammation status, such as C-reactive protein (CRP) [ 15 ] or white blood cell count (WBC) [ 17 ]. Furthermore, the associations between other important proteins involved in iron metabolism, in addition to SF, such as transferrin and soluble transferrin receptors (sTfR), and SUA, have not been widely investigated.…”

Section: Introductionmentioning

confidence: 99%

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Markers of Iron Status Are Associated with Risk of Hyperuricemia among Chinese Adults: Nationwide Population-Based Study

et al. 2018

Nutrients

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Background: Elevated serum uric acid (SUA) involved in iron metabolism, has been increasingly recognized as a risk factor for gout and cardiovascular diseases. The objective of this study was to examine the associations between markers of iron status with risk of hyperuricemia (HU) in Chinese adult population. Methods: Data were extracted from the 2009 wave of the China Health and Nutrition Survey, consisting of 7946 apparently healthy adults. Serum ferritin (SF), transferrin, soluble transferrin receptors (sTfR), hemoglobin (Hb), high-sensitivity C-reactive protein (hs-CRP), and SUA were measured. Diet was assessed with three consecutive 24 h recalls. Demographic characteristics, smoking status, alcohol consumption, and physical activities were investigated using a structured questionnaire. Multilevel mixed-effects models were constructed to estimate the associations of SF, transferrin, sTfR, and Hb with SUA and the risk of HU. Results: The crude prevalence of HU was 16.1%. SF, transferrin, and Hb levels were positively associated with SUA and the risk of HU after adjustment for cluster effects and potential confounders (all p-trend < 0.05). Compared with participants in the lowest quartile of SF, those in the highest quartile had significantly higher SUA concentrations (β = 0.899 mg/dL, 95% confidence interval (CI): 0.788, 1.010; p < 0.001) and higher risk of HU (odds ratio (OR) = 3.086, 95% CI: 2.450, 3.888; p < 0.001). Participants with the highest quartile of transferrin had significantly higher SUA concentrations (β = 0.488 mg/dL, 95% CI: 0.389, 0.587; p < 0.001) and higher risk of HU (OR: 1.900; 95% CI: 1.579, 2.286; p < 0.001) when compared with those with the lowest quartile. In male participants, those in the highest quartile of Hb had significantly higher risk of HU when compared to the reference group (OR: 1.401, 95% CI: 1.104, 1.777; p < 0.01); however, this association was not found in female participants (OR: 1.093; 95% CI: 0.821, 1.455; p = 0.544). Conclusion: SF, transferrin, and Hb levels were positively associated with the risk of HU, and additional studies are needed to confirm the findings, as well as to elucidate their underlying mechanisms.

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Hyperferritinemia increases the risk of hyperuricemia in HFE-hereditary hemochromatosis

Cited by 15 publications

References 40 publications

Spleen iron, molybdenum, and manganese concentrations are coregulated in hepcidin‐deficient and secondary iron overload models in mice

Spleen iron, molybdenum, and manganese concentrations are coregulated in hepcidin‐deficient and secondary iron overload models in mice

Hereditary hemochromatosis disrupts uric acid homeostasis and causes hyperuricemia via altered expression/activity of xanthine oxidase and ABCG2

Markers of Iron Status Are Associated with Risk of Hyperuricemia among Chinese Adults: Nationwide Population-Based Study

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