About this Journal Submit a Manuscript Table of Contents
International Journal of Inflammation
Volume 2012 (2012), Article ID 298405, 7 pages
Review Article

Ferritin in Adult-Onset Still’s Disease: Just a Useful Innocent Bystander?

1Rheumatology Division, Lincoln Medical and Mental Health Center, New York, NY 10451, USA
2Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA

Received 26 October 2011; Accepted 16 January 2012

Academic Editor: Bruno Fautrel

Copyright © 2012 Bella Mehta and Petros Efthimiou. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Background. Adult-Onset Still’s Disease (AOSD) is an immune-mediated systemic disease with quotidian-spiking fever, rash, and inflammatory arthritis. Hyperferritinemia is a prominent feature, often used for screening. Methods. The key terms “ferritin” and “hyperferritinemia” were used to search PubMed and Medline and were cross-referenced with “Still’s Disease.” Results. Hyperferritinemia, although nonspecific, is particularly prevalent in AOSD. While most clinicians associate ferritin with iron metabolism, this is mostly true for the H isoform and not for the L isoform that tends to increase dramatically in hyperferritenemia. In these situations, hyperferritinemia is not associated with iron metabolism and may even mask an underlying iron deficiency. We review, in systematic fashion, the current basic science and clinical literature regarding the regulation of ferritin and its use in the diagnosis and management of AOSD. Conclusion. Serum hyperferritinemia in AOSD has been described for 2 decades, although its mechanism has not yet been completely elucidated. Regulation by proinflammatory cytokines such as interleukin (IL)-1b, IL-6, IL-18, MCSF, and INF-α provides a link to the disease pathogenesis and may explain rapid resolution of hyperferritinemia after targeted treatment and inhibition of key cytokines.

1. Introduction

Adult-Onset Still’s disease (AOSD) is a rare, immune-mediated, multisystem inflammatory disorder characterized by quotidian spiking fevers, evanescent rash, and arthritis. It is frequently underdiagnosed and one of the main reasons for hospital admissions due to pyrexia of unknown origin (PUO).

The disease characteristically affects young individuals, with three quarters of the patients reporting disease onset between 16 and 35 years of age [1, 2]. Other symptoms include myalgia, inflammatory myopathy, liver abnormalities, pseudoangiocholitis, pleuritis, pericarditis, splenomegaly, pericardial tamponade and myocarditis, pulmonary fibrosis, pleural effusions, adult respiratory distress syndrome, interstitial nephritis, subacute glomerulitis, renal amyloidosis, collapsing glomerulopathy, thrombotic thrombocytopenic purpura, pure red cell aplasia, cranial nerve palsies, seizures, aseptic meningoencephalitis, and Miller-Fisher syndrome.

This syndrome was formerly thought to occur solely in children as systemic-onset juvenile idiopathic arthritis (SoJIA), previously known as juvenile Still’s disease. Bywaters described in, 1971, a new disease entity that he named adult Still’s disease; it involved adult patients who did not meet the criteria for classic rheumatoid arthritis (RA) but displayed features similar to those described in pediatric Still’s disease [3].

Its etiology remains unknown. An infectious etiology has been postulated, although a definitive agent has never been identified and infectious agents are thought to be innate immunity triggers, leading to the clinical phenotype.

2. Methods

The key terms “ferritin” and “hyperferritinemia” were used to search Medline and Pubmed and cross-referenced with the key term “Still’s disease” and “Adult-Onset Still’s Disease” for all available full-text articles. Studies identified by the search strategies were assessed for relevance prior to inclusion in the paper. While the emphasis was on human studies, a few selected animal studies were included which provided important clues about the underlying pathophysiology.

3. Results

3.1. Regulation of Ferritin

A well-known feature of AOSD has increased levels of serum ferritin, usually five times, or more, above the upper limits of normal that at times may be extreme (>50,000 ug/dL). While by no means specific for the disease, serum hyperferritinemia is often used to aid the diagnosis of AOSD and serial serum levels are often used as a sort of biomarker to monitor response to treatment. Ferritin (apoferritin/iron-free ferritin) is a high-molecular-weight protein (450 to 600 kDa) composed of a nanocage of 24 assembled subunits. It can sequester up to 4500 iron atoms [24]. It is 8–12 nm in diameter which is as small as spherical viruses [25, 26]. It is found in many tissues and cell types. It is a necessary molecule for the cell’s respiratory function where iron storage could cause free radical injury. The best-known function of ferritin is storage of iron. Ferritin captures the intracellular labile iron pool and thus “buffers” its effect. It is also an acute phase reactant, involved in inflammatory processes, which includes oxidative-stress-induced cell processes. Complementary DNA (antioxidant responsive element/Maf recognition element) along with mRNA (iron responsive element) regulates rate of ferritin synthesis [5, 27]. The cytoplasmic ferritin content is regulated by the translation of ferritin mRNAs in response to an intracellular pool of “chelatable” and “labile” iron. Inflammation is associated with increased production of ferritin by the histiocytomacrophage system and/or increased release from damaged hepatocytes. However, the precise mechanism and the regulation of this phenomenon are poorly defined [28]. Ferritin levels are increased in a few autoimmune diseases like RA but they hardly ever go as high as in AOSD [5].

3.2. Heme Oxygenase-1 Enzyme and Ferritin Expression

There has been a close association between the heme oxygenase-1 (HO-1) enzyme and ferritin expression in AOSD. HO-1 is an enzyme that degrades heme when induced to CO, Fe2+, and biliverdin. It is expressed by macrophages and endothelial cells in response to stress. Studies have shown that HO-1 mRNA increases in AOSD and that it may correlate with AOSD disease activity [15, 33], making it a potentially useful biomarker.

3.3. Ferritin Isoforms

Isoelectric-focusing studies have identified several isoforms of ferritin. The acid form (H, heavy) is found chiefly in organs with low iron content, such as the heart and pancreas. In contrast, the base form (L, light) is found in organs (liver, spleen) and the histiocyte-macrophage system that has a significant iron storage capacity (Figure 1). The L-ferritin isoform is the one which is released in the circulation. The H-isoform has multiple catalytic sites and is faster than the L form. H-ferritin plays a major role rapid detoxification of iron and intracellular iron transport, whereas L-ferritin is involved in iron nucleation, mineralization, and long-term storage. The H : L ratio is normally constant in a cell, although it may change in hemochromatosis and other iron overload diseases [1012]. The H : L ferritin ratio has not yet been defined in AOSD. In situations of iron overload, it may be advantageous to the cell to synthesize L-ferritin, since these ferritins are not only able to store higher iron amounts but can also retain iron more firmly and turn over iron more slowly than their H-ferritin counterparts [11]. In diseases like hyperferritinemia cataract syndrome, mutations in L ferritin have been documented [50]. However, no such study in AOSD has been contacted yet. A new isoform of ferritin has recently been described in breast cancer patients, HIV patients, and in pregnancy [51]. This finding suggests that there may be other isoforms that have not been identified yet and could explain the hyperferritinemia phenomenon in AOSD.

Figure 1
3.4. Ferritin and Disease Pathogenesis

The pathogenesis behind increased ferritin levels is thought to be cytokine mediated. Cytokines regulate ferritin synthesis at transcriptional, posttranscriptional, and translational stages. Cytokines implicated are IL1α, IL1β, IL18, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), macrophage-colony stimulating factor (M-CSF), IL6, and IL-18 [28, 5255]. IL1α, IFN-γ, and TNF-α have shown to induce the expression of H-ferritin [54, 56, 57]. Translation of ferritin is induced by IL1β, IL-6, or TNF-α [58]. IL1β also affects ferritin regulation at a posttranscriptional stage [59]. The serum levels of Th1 cytokines and soluble IL-2 receptors are higher in AOSD than in other inflammatory joint diseases and have been correlated to the serum ferritin level [10].

A study by Choi et al. on cytokines in AOSD showed significantly high IL-18, IFN-γ, and IL-8 levels in the sera of AOSD patients than healthy controls. Also, soluble IL-2 receptors level was increased only in active stage of AOSD which would indicate that soluble IL-2 receptor may be used as a potential marker for monitoring the disease activity in AOSD [42].

Cytokines may also affect ferritin translation indirectly by their ability to induce nitric oxide synthase (iNOS) and hence increase NO. NO in turn induces ferritin expression [53, 60].

The cytokine-mediated regulation suggests that inflammation can affect ferritin regulation.

There is also data to suggest that thyroid hormones play a role in ferritin expression [53, 61].

Lipopolysaccharide (LPS; endotoxin), an outer membrane component of several Gram-negative bacteria, elicits a variety of reactions that involve ferritin [53].

In most studies, a threshold for serum ferritin levels of 1000 ng/mL, five times the upper limits of normal (40–200 ng/mL), has been used to suggest the presence of AOSD [28]. Very high levels ranging from 4000 ng/mL to 30,000 ng/mL are not uncommon, and even extreme levels as high as 250,000 ng/mL have been reported [2]. Ferritin levels in AOSD are usually higher than those found in patients with other autoimmune or inflammatory diseases [44]. It is not clear yet whether ferritin plays a role in the disease pathogenesis or it is just an acute phase reactant/silent bystander. In patients with chronic hepatitis C, ferritin and AST levels have been correlated, although increased ferritin does not seem to have a role in the extrahepatic manifestations of the disease. Also, in these patients, increased ferritin levels are not associated with the B-cell dysfunction represented by cryoglobulin and nonorgan-specific antibody production [18]. Additionally, there are several diseases associated with high ferritin levels that do not share any symptoms or signs of AOSD. The usefulness of serum ferritin is limited by the fact that elevated levels can also be seen in other diseases, such as infiltrative diseases (hemochromatosis, Gaucher’s disease), infections (sepsis, HIV), malignancies (leukemia, lymphomas), and in the macrophage activation syndrome [62]. Table 1 illustrates all the diseases where ferritin levels increase or decrease, whereas Table 3 provides a summary of the studies of autoimmune diseases where ferritin is increased. Furthermore, there are several well-documented reports of AOSD without increase in ferritin levels, hinting on possible different underlying mechanisms [37].

Table 1: Diseases in which ferritin levels increase or decrease.

Interestingly, serum ferritin levels often correlate with disease activity and can normalize when the disease goes into remission [47, 49, 63]. Ferritin is known to release free Fe2+ ions, which catalyze the reaction leading to the formation of free OH−1 radicals, although it can also chelate these free Fe2+ ions, thereby limiting the deleterious effects of oxidative stress [64, 65]. The unresolved question is whether ferritin acts as a buffer to minimize the pathogenic effects of free radicals or is it the one to cause the release of them.

3.5. Ferritin Glycosylation in AOSD

In healthy individuals, 50–80% of ferritin is glycosylated and the attachment of glucose molecules at the surface of the ferritin molecule may provide protection against proteolytic enzymes. There have been several studies which point to the fact that AOSD patients have low glycosylation levels (<20%) [37, 40]. Abnormally, low levels of ferritin glycosylation were shown to be a more specific, albeit less sensitive, diagnostic test for AOSD. Unfortunately, this test is not readily available in clinical practice, hence limiting its usefulness. Moreover, ferritin glucosylation remains low both during active state and in remission, unlike serum ferritin levels [40]. The pathogenic mechanisms underlying the decrease in glycosylation are poorly defined. A probably theory could be that, due to excess of ferritin, the glycosylation process could be saturated. In addition to saturation of glycosylation mechanisms, abnormalities that are more specific of AOSD have been suggested, particularly decreased clearance of nonglycosylated proteins by the histiocyte-macrophage system.

The defect in ferritin glycosylation, although more specific for the diagnosis of AOSD than serum ferritin, is by no means pathognomonic for the disease and has several limitations. Individual patients can have normal levels of glycosylation and low glycosylation levels can be seen in other inflammatory disorders and in a few patients with infectious diseases [37]. Glycosylated ferritin cannot be used to monitor disease activity or response to treatment, as it remains low for many months after the disease goes into remission [40]. Glycosylated ferritin (<20%) has a sensitivity of 78% and specificity of 64%. When glycosylated ferritin levels are combined with a fivefold serum rise in ferritin, the sensitivity fell to 43% and specificity rose to 93% [37]. Therefore, the combined use of both parameters has been suggested and included in the Fautrel et al. criteria.

3.6. Ferritin Association with Atherosclerosis

AOSD is one of the diseases under the banner of autoinflammatory diseases, a new disease category where atherosclerosis has been suggested as a possible member. Ferritin has also been implicated in the pathogenesis a number of diseases (Table 2). It has been described more clearly and significantly in atherosclerosis [17, 29, 6668]. Epidemiological studies have linked elevated serum ferritin levels with an increased risk for coronary artery disease (CAD) and myocardial infarction (MI) [63]. This finding led to the “iron hypothesis” which suggested a link between abnormal iron storage and atherosclerosis. Furthermore, the hemochromatosis gene (HFE), C282Y, has been associated with an increased risk of CAD and cardiovascular mortality [69, 70]. There is an ongoing debate whether ferritin acts as a prooxidant, releasing free iron that was previously bound to it, or antioxidant, sequestering excess unbound iron. Excessive iron in tissues can catalyze the formation of oxygen-free radicals that can lead to low-density lipoprotein (LDL) oxidation, a trigger for the development of atherosclerosis.

Table 2: Ferritin implicated in the pathogenesis of the following diseases.
Table 3: Hyperferritinemia in Adult-Onset Still’s Disease patient cohorts ( ).
3.7. Mutated Ferritin Theory

During infection or inflammation, iron is sequestered in the ferritin contained inside macrophages, and, as a result, serum iron decreases. This artificial “iron deficiency,” which in reality is scarcity in the midst of plenty, is thought to be protective for the host, depriving invading microorganisms from much needed iron [71]. Some research suggested that iron release is defective due to the hyperferritinemia in AOSD [72, 73]. Reports of iron supplementation successfully treating systemic-onset juvenile chronic arthritis [74] prompted the performance of iron studies on AOSD patients, showing iron deficiency, and suggested that low-dose intravenous iron supplementation could be effective in AOSD patients with anemia [48, 74, 75]. The investigators suggested that intravenous iron could by-pass macrophage trapping and become directly available for erythropoiesis. This strategy could prove to be effective in anemic AOSD patients who often have normal or increased iron stores. Despite the massive amounts of circulating ferritin, its saturation with iron molecules since AOSD is not associated with iron overload [40, 76, 77]. This has also been proven with the use of automated analyzers that measure the transferring receptors in the serum [78]. Moreover, since the serum-transferring receptor concentration is not altered in inflammatory states, it may be a more useful test than serum ferritin in assessing the iron stores in AOSD [79]. The defective release of iron from ferritin could be secondary to the presence of a mutant form of ferritin, which could also explain the defect in ferritin glucosylation seen in AOSD.

4. Conclusion

Very high and often extreme serum ferritin levels have been described in AOSD for more than 2 decades now. While widely thought to be an acute phase reactant, ferritin could be intimately involved in the disease pathogenesis as an oxygen radical donor or scavenger or via a yet to be defined mechanism, possibly including mutated ferritin. Further research is warranted to bridge the knowledge gap and identify the missing links.

Conflict of Interests

The authors have no conflict of interests.


  1. L. B. A. Van de Putte and J. M. G. W. Wouters, “Adult-onset Still's disease,” Bailliere's Clinical Rheumatology, vol. 5, no. 2, pp. 263–275, 1991. View at Scopus
  2. A. Ohta, M. Yamaguchi, H. Kaneoka, T. Nagayoshi, and M. Hiida, “Adult Still's disease: review of 228 cases from the literature,” Journal of Rheumatology, vol. 14, no. 6, pp. 1139–1146, 1987. View at Scopus
  3. E. G. Bywaters, “Still's disease in the adult,” Annals of the Rheumatic Diseases, vol. 30, no. 2, pp. 121–133, 1971. View at Scopus
  4. G. H. Guyatt, C. Patterson, M. Ali et al., “Diagnosis of iron-deficiency anemia in the elderly,” American Journal of Medicine, vol. 88, no. 3, pp. 205–209, 1990. View at Publisher · View at Google Scholar · View at Scopus
  5. G. Zandman-Goddard and Y. Shoenfeld, “Ferritin in autoimmune diseases,” Autoimmunity Reviews, vol. 6, no. 7, pp. 457–463, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. M. H. Kryger, K. Otake, and J. Foerster, “Low body stores of iron and restless legs syndrome: a correctable cause of insomnia in adolescents and teenagers,” Sleep Medicine, vol. 3, no. 2, pp. 127–132, 2002. View at Publisher · View at Google Scholar · View at Scopus
  7. S. Davì, A. Consolaro, D. Guseinova et al., “An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis,” Journal of Rheumatology, vol. 38, no. 4, pp. 764–768, 2011. View at Publisher · View at Google Scholar
  8. A. R. J. Curtis, C. Fey, C. M. Morris et al., “Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease,” Nature Genetics, vol. 28, no. 4, pp. 350–354, 2001. View at Publisher · View at Google Scholar · View at Scopus
  9. C. Sfagos, A. C. Makis, A. Chaidos et al., “Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients,” Multiple Sclerosis, vol. 11, no. 3, pp. 272–275, 2005. View at Publisher · View at Google Scholar · View at Scopus
  10. L. F. Dickey, S. Sreedharan, E. C. Theil, J. R. Didsbury, Y. H. Wang, and R. E. Kaufman, “Differences in the regulation of messenger RNA for housekeeping and specialized-cell ferritin. A comparison of three distinct ferritin complementary DNAs, the corresponding subunits, and identification of the first processed in amphibia,” Journal of Biological Chemistry, vol. 262, no. 16, pp. 7901–7907, 1987. View at Scopus
  11. K. White and H. N. Munro, “Induction of ferritin subunit synthesis by iron is regulated at both the transcriptional and translational levels,” Journal of Biological Chemistry, vol. 263, no. 18, pp. 8938–8942, 1988. View at Scopus
  12. B. A. Leggett, L. M. Fletcher, G. A. Ramm, L. W. Powell, and J. W. Halliday, “Differential regulation of ferritin H and L subunit mRNA during inflammation and long-term iron overload,” Journal of Gastroenterology and Hepatology, vol. 8, no. 1, pp. 21–27, 1993. View at Scopus
  13. M. Souroujon, A. Ashkenazi, and M. Lupo, “Serum ferritin levels in celiac disease,” American Journal of Clinical Pathology, vol. 77, no. 1, pp. 82–86, 1982. View at Scopus
  14. M. B. Zimmermann and J. Köhrle, “The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health,” Thyroid, vol. 12, no. 10, pp. 867–878, 2002. View at Scopus
  15. Y. Kirino, M. Takeno, M. Iwasaki et al., “Increased serum HO-1 in hemophagocytic syndrome and adult-onset Still's disease: use in the differential diagnosis of hyperferritinemia,” Arthritis Research &amp; Therapy, vol. 7, no. 3, pp. R616–R624, 2005. View at Scopus
  16. Y.-T. Tseng, W.-H. Sheng, B.-H. Lin et al., “Causes, clinical symptoms, and outcomes of infectious diseases associated with hemophagocytic lymphohistiocytosis in Taiwanese adults,” Journal of Microbiology, Immunology and Infection, vol. 44, no. 3, pp. 191–197, 2011. View at Publisher · View at Google Scholar
  17. A. Lecube, C. Hernández, J. Genescà et al., “Diabetes is the main factor accounting for the high ferritin levels detected in chronic hepatitis C virus infection,” Diabetes Care, vol. 27, no. 11, pp. 2669–2675, 2004. View at Publisher · View at Google Scholar · View at Scopus
  18. G. M. Sousa, R. C. Oliveira, M. M. Pereira, R. Paraná, M. L. B. Sousa-Atta, and A. M. Atta, “Autoimmunity in hepatitis C virus carriers: involvement of ferritin and prolactin,” Autoimmunity Reviews, vol. 10, no. 4, pp. 210–213, 2011. View at Publisher · View at Google Scholar · View at Scopus
  19. A. J. W. Branten, D. W. Swinkels, I. S. Klasen, and J. F. M. Wetzels, “Serum ferritin levels are increased in patients with glomerular diseases and proteinuria,” Nephrology Dialysis Transplantation, vol. 19, no. 11, pp. 2754–2760, 2004. View at Publisher · View at Google Scholar · View at Scopus
  20. C. Beaumont, P. Leneuve, I. Devaux et al., “Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract,” Nature Genetics, vol. 11, no. 4, pp. 444–446, 1995. View at Scopus
  21. A. Shander and K. Sazama, “Clinical consequences of iron overload from chronic red blood cell transfusions, its diagnosis, and its management by chelation therapy,” Transfusion, vol. 50, no. 5, pp. 1144–1155, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. L. Le Page, P. Leflon, M. Mahévas et al., “Aetiological spectrum of hyperferritinemia,” Revue de Medecine Interne, vol. 26, no. 5, pp. 368–373, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. P. Stein, H. Yu, D. Jain, and P. K. Mistry, “Hyperferritinemia and iron overload in type 1 Gaucher disease,” American Journal of Hematology, vol. 85, no. 7, pp. 472–476, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. P. M. Harrison and P. Arosio, “The ferritins: molecular properties, iron storage function and cellular regulation,” Biochimica et Biophysica Acta, vol. 1275, no. 3, pp. 161–203, 1996. View at Publisher · View at Google Scholar · View at Scopus
  25. N. D. Chasteen and P. M. Harrison, “Mineralization in ferritin: an efficient means of iron storage,” Journal of Structural Biology, vol. 126, no. 3, pp. 182–194, 1999. View at Publisher · View at Google Scholar · View at Scopus
  26. X. Liu and E. C. Theil, “Ferritins: dynamic management of biological iron and oxygen chemistry,” Accounts of Chemical Research, vol. 38, no. 3, pp. 167–175, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. K. J. Hintze and E. C. Theil, “Cellular regulation and molecular interactions of the ferritins,” Cellular and Molecular Life Sciences, vol. 63, no. 5, pp. 591–600, 2006. View at Publisher · View at Google Scholar · View at Scopus
  28. B. Fautrel, “Ferritin levels in adult Still's disease: any sugar?” Joint Bone Spine, vol. 69, no. 4, pp. 355–357, 2002. View at Publisher · View at Google Scholar · View at Scopus
  29. M. Haidari, E. Javadi, A. Sanati, M. Hajilooi, and J. Ghanbili, “Association of increased ferritin with premature coronary stenosis in men,” Clinical Chemistry, vol. 47, no. 9, pp. 1666–1672, 2001. View at Scopus
  30. W. Linert and G. N. L. Jameson, “Redox reactions of neurotransmitters possibly involved in the progression of Parkinson's Disease,” Journal of Inorganic Biochemistry, vol. 79, no. 1–4, pp. 319–326, 2000. View at Publisher · View at Google Scholar · View at Scopus
  31. T. Kondo, T. Shirasawa, Y. Itoyama, and H. Mori, “Embryonic genes expressed in Alzheimer's disease brains,” Neuroscience Letters, vol. 209, no. 3, pp. 157–160, 1996. View at Publisher · View at Google Scholar · View at Scopus
  32. T. P. Ryan, R. F. Krzesicki, D. P. Blakeman et al., “Pulmonary ferritin: differential effects of hyperoxic lung injury on subunit mRNA levels,” Free Radical Biology and Medicine, vol. 22, no. 5, pp. 901–908, 1997. View at Publisher · View at Google Scholar · View at Scopus
  33. T. Miyazaki, Y. Kirino, M. Takeno et al., “Serum HO-1 is useful to make differential diagnosis of secondary hemophagocytic syndrome from other similar hematological conditions,” International Journal of Hematology, vol. 91, no. 2, pp. 229–237, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. G. Zandman-Goddard and Y. Shoenfeld, “Hyperferritinemia in autoimmunity,” Israel Medical Association Journal, vol. 10, no. 1, pp. 83–84, 2008. View at Scopus
  35. R. da Costa, M. Szyper-Kravitz, Z. Szekanecz et al., “Ferritin and prolactin levels in multiple sclerosis,” Israel Medical Association Journal, vol. 13, no. 2, pp. 91–95, 2011.
  36. F. Lian, Y. Wang, X. Yang, H. Xu, and L. Liang, “Clinical features and hyperferritinemia diagnostic cutoff points for AOSD based on ROC curve: a Chinese experience,” Rheumatology International, pp. 1–4, 2010. View at Publisher · View at Google Scholar · View at Scopus
  37. B. Fautrel, G. Le Moël, B. Saint-Marcoux et al., “Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease,” Journal of Rheumatology, vol. 28, no. 2, pp. 322–329, 2001. View at Scopus
  38. M. Sobieska, K. Fassbender, A. Aeschlimann, P. Bourgeois, S. Mackiewicz, and W. Müller, “Still's disease in children and adults: a distinct pattern of acute- phase proteins,” Clinical Rheumatology, vol. 17, no. 3, pp. 258–260, 1998. View at Publisher · View at Google Scholar · View at Scopus
  39. D. Schiller, H. Mittermayer, and J. V. Hirschmann, “Hyperferritenemia as a marker of Still's disease,” Clinical Infectious Diseases, vol. 26, no. 2, pp. 534–535, 1998. View at Scopus
  40. S. Vignes, G. Le Moël, B. Fautrel, B. Wechsler, P. Godeau, and J. C. Piette, “Percentage of glycosylated serum ferritin remains low throughout the course of adult onset Still's disease,” Annals of the Rheumatic Diseases, vol. 59, no. 5, pp. 347–350, 2000. View at Publisher · View at Google Scholar · View at Scopus
  41. S. S. Uppal, M. Al-Mutairi, S. Hayat, M. Abraham, and A. Malaviya, “Ten years of clinical experience with adult onset Still's disease: is the outcome improving?” Clinical Rheumatology, vol. 26, no. 7, pp. 1055–1060, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. J. H. Choi, C. H. Suh, Y. M. Lee et al., “Serum cytokine profiles in patients with adult onset Still's disease,” Journal of Rheumatology, vol. 30, no. 11, pp. 2422–2427, 2003. View at Scopus
  43. J. B. Arlet, D. L. T. Huong, A. Marinho et al., “Reactive haemophagocytic syndrome in adult-onset Still's disease: a report of six patients and a review of the literature,” Annals of the Rheumatic Diseases, vol. 65, no. 12, pp. 1596–1601, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. M. Coffernils, A. Soupart, O. Pradier, W. Feremans, P. Neve, and G. Decaux, “Hyperferritinemia in adult onset Still's disease and the hemophagocytic syndrome,” Journal of Rheumatology, vol. 19, no. 9, pp. 1425–1427, 1992. View at Scopus
  45. T. Ota, S. Higashi, H. Suzuki, and S. Eto, “Increased serum ferritin levels in adult Still's disease,” The Lancet, vol. 1, no. 8532, pp. 562–563, 1987. View at Scopus
  46. G. Baxevanos, T. Tzimas, G. Pappas, and N. Akritidis, “A series of 22 patients with adult-onset Still's disease presenting with fever of unknown origin. A difficult diagnosis?” Clinical Rheumatology, vol. 31, no. 1, pp. 49–53, 2011. View at Publisher · View at Google Scholar
  47. N. Akritidis, Y. Giannakakis, and L. Sakkas, “Very high serum ferritin levels in adult-onset Still's disease,” British Journal of Rheumatology, vol. 36, no. 5, pp. 608–609, 1997. View at Scopus
  48. C. Montecucco, R. Caporali, and R. Invernizzi, “Iron status in Still's disease,” The Lancet, vol. 345, no. 8941, pp. 58–59, 1995. View at Scopus
  49. C. Van Reeth, G. Le Moel, Y. Lasne et al., “Serum ferritin and isoferritins are tools for diagnosis of active adult Still's disease,” Journal of Rheumatology, vol. 21, no. 5, pp. 890–895, 1994. View at Scopus
  50. E. Messa, R. M. Pellegrino, A. Palmieri et al., “Identification of a novel mutation in the L ferritin iron-responsive element causing hereditary hyperferritinemia-cataract syndrome,” Acta Haematologica, vol. 122, no. 4, pp. 223–225, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. G. Zandman-Goddard, M. Blank, P. Langevitz et al., “Anti-serum amyloid component P antibodies in patients with systemic lupus erythematosus correlate with disease activity,” Annals of the Rheumatic Diseases, vol. 64, no. 12, pp. 1698–1702, 2005. View at Publisher · View at Google Scholar · View at Scopus
  52. J. T. Rogers, K. R. Bridges, G. P. Durmowicz, J. Glass, P. E. Auron, and H. N. Munro, “Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1,” Journal of Biological Chemistry, vol. 265, no. 24, pp. 14572–14578, 1990. View at Scopus
  53. F. M. Torti and S. V. Torti, “Regulation of ferritin genes and protein,” Blood, vol. 99, no. 10, pp. 3505–3516, 2002. View at Publisher · View at Google Scholar · View at Scopus
  54. S. V. Torti, E. L. Kwak, S. C. Miller et al., “The molecular cloning and characterization of murine ferritin heavy chain, a tumor necrosis factor-inducible gene,” Journal of Biological Chemistry, vol. 263, no. 25, pp. 12638–12644, 1988. View at Scopus
  55. C. A. Dinarello, “Interleukin-1 and the pathogenesis of the acute-phase response,” New England Journal of Medicine, vol. 311, no. 22, pp. 1413–1418, 1984. View at Scopus
  56. I. M. Smirnov, K. Bailey, C. H. Flowers, N. W. Garrigues, and L. J. Wesselius, “Effects of TNF-α and IL-1β on iron metabolism by A549 cells and influence on cytotoxicity,” American Journal of Physiology, vol. 277, no. 2, pp. L257–L263, 1999. View at Scopus
  57. Y. Wei, S. C. Miller, Y. Tsuji, S. V. Torti, and F. M. Torti, “Interleukin 1 induces ferritin heavy chain in human muscle cells,” Biochemical and Biophysical Research Communications, vol. 169, no. 1, pp. 289–296, 1990. View at Publisher · View at Google Scholar · View at Scopus
  58. T. N. Tran, S. K. Eubanks, K. J. Schaffer, C. Y. J. Zhou, and M. C. Linder, “Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron,” Blood, vol. 90, no. 12, pp. 4979–4986, 1997. View at Scopus
  59. D. J. Piñero, J. Hu, B. M. Cook, R. C. Scaduto Jr., and J. R. Connor, “Interleukin-1β increases binding of the iron regulatory protein and the synthesis of ferritin by increasing the labile iron pool,” Biochimica et Biophysica Acta, vol. 1497, no. 3, pp. 279–288, 2000. View at Publisher · View at Google Scholar
  60. G. Weiss, B. Goossen, W. Doppler et al., “Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway,” EMBO Journal, vol. 12, no. 9, pp. 3651–3657, 1993. View at Scopus
  61. J. M. Ladero Quesada, M. Gómez Pérez, and M. Díaz-Rubio, “Hyperferritinemia in hyperthyroidism,” Anales de Medicina Interna, vol. 10, no. 12, p. 617, 1993.
  62. M. H. Lee and R. T. Means, “Extremely elevated serum ferritin levels in a university hospital: associated diseases and clinical significance,” American Journal of Medicine, vol. 98, no. 6, pp. 566–571, 1995. View at Publisher · View at Google Scholar · View at Scopus
  63. N. Akritidis, I. Giannakakis, and T. Giouglis, “Ferritin levels and response to treatment in patients with adult Still's disease,” Journal of Rheumatology, vol. 23, no. 1, pp. 201–202, 1996. View at Scopus
  64. G. Cairo, E. Castrusini, G. Minotti, and A. Bernelli-Zazzera, “Superoxide and hydrogen peroxide-dependent inhibition of iron regulatory protein activity: a protective stratagem against oxidative injury,” FASEB Journal, vol. 10, no. 11, pp. 1326–1335, 1996. View at Scopus
  65. J. Rogers, L. Lacroix, G. Durmowitz, K. Kasschau, J. Andriotakis, and K. R. Bridges, “The role of cytokines in the regulation of ferritin expression,” Advances in Experimental Medicine and Biology, vol. 356, pp. 127–132, 1994. View at Scopus
  66. J. T. Salonen, K. Nyyssonen, R. Salonen et al., “Body iron stores and the risk of coronary heart disease,” New England Journal of Medicine, vol. 331, no. 17, pp. 1159–1160, 1994. View at Publisher · View at Google Scholar · View at Scopus
  67. J. L. Sullivan, “Iron and the sex difference in heart disease risk,” The Lancet, vol. 1, no. 8233, pp. 1293–1294, 1981. View at Scopus
  68. R. M. Salonen, K. Nyyssönen, J. Kaikkonen et al., “Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the antioxidant supplementation in atherosclerosis prevention (ASAP) study,” Circulation, vol. 107, no. 7, pp. 947–953, 2003. View at Publisher · View at Google Scholar · View at Scopus
  69. S. A. You and Q. Wang, “Ferritin in atherosclerosis,” Clinica Chimica Acta, vol. 357, no. 1, pp. 1–16, 2005. View at Publisher · View at Google Scholar · View at Scopus
  70. M. L. Rasmussen, A. R. Folsom, D. J. Catellier, M. Y. Tsai, U. Garg, and J. H. Eckfeldt, “A prospective study of coronary heart disease and the hemochromatosis gene (HFE) C282Y mutation: the Atherosclerosis Risk in Communities (ARIC) study,” Atherosclerosis, vol. 154, no. 3, pp. 739–746, 2001. View at Publisher · View at Google Scholar · View at Scopus
  71. R. Invernizzi, M. Cazzola, P. De Fazio, V. Rosti, G. Ruggeri, and P. Arosio, “Immunocytochemical detection of ferritin in human bone marrow and peripheral blood cells using monoclonal antibodies specific for the H and L subunit,” British Journal of Haematology, vol. 76, no. 3, pp. 427–432, 1990. View at Scopus
  72. B. Kirel, S. Yetgin, U. Saatci, S. Ozen, A. Bakkaloglu, and N. Besbas, “Anaemia in juvenile chronic arthritis,” Clinical Rheumatology, vol. 15, no. 3, pp. 236–241, 1996. View at Publisher · View at Google Scholar · View at Scopus
  73. C. H. Hinze, N. Fall, S. Thornton et al., “Immature cell populations and an erythropoiesis gene-expression signature in systemic juvenile idiopathic arthritis: implications for pathogenesis,” Arthritis Research and Therapy, vol. 12, no. 3, article R123, 2010. View at Publisher · View at Google Scholar
  74. A. Martini, A. Ravelli, G. Di Fuccia, V. Rosti, M. Cazzola, and G. Barosi, “Intravenous iron therapy for severe anaemia in systemic-onset juvenile chronic arthritis,” The Lancet, vol. 344, no. 8929, pp. 1052–1054, 1994. View at Publisher · View at Google Scholar · View at Scopus
  75. S. Patel, S. Monemian, A. Khalid, and H. Dosik, “Iron deficiency anemia in adult onset still's disease with a serum ferritin of 26,387 μg/L,” Anemia, vol. 2011, Article ID 184748, 4 pages, 2011. View at Publisher · View at Google Scholar
  76. J. Ten Kate, J. P. H. Drenth, M. F. Kahn, and C. Van Deursen, “Iron saturation of serum ferritin in patients with adult onset still's disease,” Journal of Rheumatology, vol. 28, no. 10, pp. 2213–2215, 2001. View at Scopus
  77. M. Cazzola, L. Ponchio, F. De Benedetti et al., “Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis,” Blood, vol. 87, no. 11, pp. 4824–4830, 1996. View at Scopus
  78. K. Punnone, O. Kaipiainen-Seppänen, L. Riittinen, T. Tuomisto, T. Hongisto, and I. Penttila, “Evaluation of iron status in anemic patients with rheumatoid arthritis using an automated immunoturbidimetric assay for transferrin receptor,” Clinical Chemistry and Laboratory Medicine, vol. 38, no. 12, pp. 1297–1300, 2000. View at Publisher · View at Google Scholar · View at Scopus
  79. S. M. Kivivuori, P. Pelkonen, H. Ylijoki, P. Verronen, and M. A. Siimes, “Elevated serum transferrin receptor concentration in children with juvenile chronic arthritis as evidence of iron deficiency,” Rheumatology, vol. 39, no. 2, pp. 193–197, 2000. View at Scopus