A mechanistic theory explaining hyperferritinaemia in haemophagocytic lymphohistiocytosis.

Intracellular ferritin is known to store iron, an essential element in an array of physiological processes. But what purpose does serum ferritin serve, what controls ultra-high hyperferritinaemia (ferritin levels above 4000 ng/ml), and finally why is it raised in inflammatory diseases, the most impressive being haemophagocytic lymphohistiocytosis? This paper proposes a hypothesis and model to explain the above questions. Serum ferritin has some unfamiliar physiological properties. It dampens severe inflammation by inhibiting lymphocyte activity, hinders bacterial growth by acting as an iron chelator and slows malignant growth by having an antiangiogenic effect. Therefore, serum ferritin is effective at modulating many conditions and could be a desired physiological process in malignancy or infection. The proposed theory is that phagocytic cells fuse with pathological native cells in much the same way as macrophages do when forming multinucleated giant cells. The pathological cells can be "infected" by intracellular pathogens or the malignant phenotype. These fusion cells result in a massive upregulation of exclusive features of macrophage activity such as phagocytosis, iron metabolism and ferritin release. Dysfunctional mitochondria are critical to this process, Pathological cells that contain dysfunctional mitochondria "infect" phagocytic mitochondrial following cellular fusion, resulting in ferritin release. The key evidence suporting this idea: macrophages are the source of ferritin secretion; they have intimate contact with known triggers of HLH, allowing for fusion hybrids, and they commonly fuse with cells. It is also argued that exclusively intracellular pathologies trigger HLH, which is a requirement for this model. HLH has features of a mitochondriopathy and finally it is debated that all the defective genes known to trigger familial-HLH can increase the likelihood of macrophage fusion. If this hypothesis is correct, the implications might discover novel diagnostic tools to detect HLH and point to avenues of targeted therapy. This is a bold theory with interesting perspectives on cell biology and clinical medicine. The paper discusses the evidence and challenges of this proposed mechanism in describing hyperferritinaemia and its relation to HLH.