Clinical evaluation of hyperferritinemia with or without iron overload

: Serum ferritin is a good biomarker; when it is low, it suggests iron deficiency, but in the case of hyperferritinemia it is not necessarily an index of iron overload. As a non-iron overload condition, physicians encounter mildly increased serum ferritin commonly associated with viral or bacterial infectious diseases, and autoinflammatory diseases like systemic juvenile idiopathic arthritis (sJIA) or adult-onset Still's disease (AOSD). When these diseases develop into severe forms like hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS), serum ferritin levels rise steeply to a marked increase. HLH develops as various hereditary forms or a secondary form while MAS is secondary. Precise diagnosis of hereditary HLH requires genetic study. On the other hand, hyperferritinemia is an index of iron overload in hemochromatosis and other iron-overloading anemias. The correct diagnosis of hemochromatosis (types 1–4) and various iron-overloading anemias could be made by genetic study. Metabolic hyperferritinemia is a mixed type with or without iron overload, which is mostly noted in middle-aged men, associated with non-alcoholic fatty liver disease (NAFLD) or dysmetabolic iron overload syndrome (DIOS). Rare hereditary hyperferritinemia without iron overload, currently described in 3 types, needs to be kept in mind for differential diagnosis. One representative type is Hereditary Hyperferritinemia-Cataract Syndrome (HHCS). Precise cause(s) of hyperferritinemia, if unexplained, require thorough examinations with the use of genetic study which may lead to the discovery of rare disease(s). In this review, the major causes of hyperferritinemia, the elevated ranges of serum ferritin, the glycosylation status of serum ferritin in each category, and the gene panel useful for differential diagnosis are discussed. This review is hoped to be useful for differentiating hyperferritinemia in daily clinical practice.