2. Hyperferritinemic Syndromes
The hyperferritinemic syndromes pathogenesis is extremely complex and variable. Genetic mutations, infections, underlying diseases, and immunosuppression can play a distinct role in these conditions, leading to the unique epilogue that is hyperferritinemia (> 500 µg/L) and hyperinflammation (28, 29). According to Schulter et al. (29), despite the numerous protagonists that can play a role in the development of hyperferritinemic syndrome, they might converge in at least two mechanisms that provoke hyperferritinemia: over activation of T lymphocytes and over-activity of IFN-γ (29). Nevertheless, recent evidences described the direct role of the H-chain of ferritin in activating macrophages to increase the secretion of inflammatory cytokines (30).
Several diseases that may present both hyperinflammation and hyperferritinemia have been grouped under this common umbrella named hyperferritinemic syndrome (Table 1). These include MAS, a secondary form of HLH (also called hemophagocytic syndrome), AOSD, cAPS and septic shock (31, 32). Although these conditions are characterized by different pathogenesis and clinical presentation, it is likely that pathogenically elevated levels of ferritin sustain the inflammatory process (31).
Nonetheless, hyperferritinemia is not specific of the abovementioned hyperferritinemic syndromes. Indeed, levels up to 2000 µg/L of ferritin can be found in other conditions such as liver damage and infections, even if the first is one of the possible clinical manifestations of HLH while the second is the most common trigger of secondary HLH (33).