The hyperferritinemic syndrome: macrophage activation syndrome, Still's disease, septic shock and catastrophic antiphospholipid syndrome

Abstract

Background: Over the last few years, accumulating data have implicated a role for ferritin as a signaling molecule and direct mediator of the immune system. Hyperferritinemia is associated with a multitude of clinical conditions and with worse prognosis in critically ill patients.

Discussion: There are four uncommon medical conditions characterized by high levels of ferritin, namely the macrophage activation syndrome (MAS), adult onset Still's disease (AOSD), catastrophic antiphospholipid syndrome (cAPS) and septic shock, that share a similar clinical and laboratory features, and also respond to similar treatments, suggesting a common pathogenic mechanism. Ferritin is known to be a pro-inflammatory mediator inducing expression of pro-inflammatory molecules, yet it has opposing actions as a pro-inflammatory and as an immunosuppressant. We propose that the exceptionally high ferritin levels observed in these uncommon clinical conditions are not just the product of the inflammation but rather may contribute to the development of a cytokine storm.

Summary: Here we review and compare four clinical conditions and the role of ferritin as an immunomodulator. We would like to propose including these four conditions under a common syndrome entity termed "Hyperferritinemic Syndrome".

Figure 1

Ferritin structure and function. Ferritin is a major intracellular iron storage protein in all organisms, and its structural properties are largely conserved through species. Apoferritin refers to the iron-free form of the protein; the iron-containing form is termed holoferritin or simply ferritin. Each apoferritin shell comprises 24 subunits of two kinds: a H-subunit and a L-subunit. Depending on the tissue type and physiologic status of the cell, the ratio of H- to L-subunits in ferritin can vary widely. Ferritin H- and L-subunits are mapped on chromosomes 11q23 and 19q13.3, respectively, and both have multiple pseudogenes [1]. H-ferritin plays a major role in the rapid detoxification of iron, while the L-subunit is involved in nucleation, mineralization and long-term storage of iron [10].

Figure 2

Control of ferritin expression. The expression of ferritin is regulated at both the transcriptional and post-transcriptional levels by iron, cytokine release, chemokine production, lipopolysaccharide, prostaglandins, hormones, growth factors, second messengers, hyperoxia and hypoxia, and oxidative stress [5]. Cytokines may also affect ferritin translation indirectly through their ability to induce nitric oxide synthase and, hence, increase nitric oxide (NO) (Figure 2) [11,12]. NO, in turn, causes inhibition of ferritin translation. Complex feedback mechanisms between ferritin and cytokines in the control of pro-inflammatory and anti-inflammatory mediators: cytokines can induce ferritin expression; otherwise, ferritin can induce the expression of pro- and anti-inflammatory cytokines.