Unexplained isolated hyperferritinemia without iron overload

Abstract

Although hyperferritinemia may be reflective of elevated total body iron stores, there are conditions in which ferritin levels are disproportionately elevated relative to iron status. Autosomal dominant forms of hyperferritinemia due to mutations in the L2ferritin IRE or in A helix of L2ferritin gene have been described, however cases of isolated hyperferritinemia still remain unsolved. We describe 12 Italian subjects with unexplained isolated hyperferritinemia (UIH). Four probands have affected siblings, but no affected parents or offspring. Sequencing analyses did not identify casual mutations in ferritin gene or IRE regions. These patients had normal levels of intracellular ferritin protein and mRNA in peripheral blood cells excluding pathological ferritin production at transcriptional and post-transcriptional level. In contrast with individuals with benign hyperferritinemia caused by mutations affecting the ferritin A helix, low rather than high glycosylation of serum ferritin was observed in our UIH subjects compared with controls. These findings suggest that subjects with UIH have a previously undescribed form of hyperferritinemia possibly attributable to increased cellular ferritin secretion and/or decreased serum ferritin clearance. The cause remains to be defined and we can only speculate the existence of mutations in gene/s not directly implicated in iron metabolism that could affect ferritin turnover including ferritin secretion.

Acute and Chronic Iron Overloading Differentially Modulates the Expression of Cellular Iron-homeostatic Molecules in Normal Rat Kidney

“…13,50 In addition, the levels of serum ferritin, which is mainly composed of L-chains, increase markedly in response to iron overloading. [51][52][53] Cohen et al have reported that renal PT and macrophages are the main sources of circulatory ferritin, 9 and marked increases in both serum ferritin and the renal expression of the L-chain were also observed in mice following the deletion of the H-chain gene in the PT. 54 AKI similarly resulted in a significant decrease in the H-chain of hepcidin knockout mice.…”

“…We, therefore, speculate that acute iron overloading may either induce disassembly of both ferritin chains, and/or paradoxically upregulate the L-and inhibit the H-chain expressions in renal tubular cells followed by the release of L-chain into systemic circulation, thus, resulting in the observed inverse relationship between serum and renal tissue ferritin. 9,13,51,52 In contrast, chronic iron overload may offer the necessary time for renal cells to compensate for the excessive intracellular accumulations of reabsorbed iron together with the release of the L-chain into circulation by increasing the production of both ferritin chains. 42,55 Hepcidin is the main iron regulatory hormone through its receptor, FPN, and both molecules are expressed by renal tubular cells.…”

“…13,50 In addition, the levels of serum ferritin, which is mainly composed of L-chains, increase markedly in response to iron overloading. 51–53…”

Inherited iron overload disorders

“…Mutations in the IRE region of the 5'UTR L-ferritin mRNA that disrupt the irondependent post-transcriptional regulation of L-ferritin (hereditary-hyperferritinemia-cataract syndrome) and mutations in the first exon of L-ferritin gene that alter ferritin glycosylation and secretion in the blood (5,6). Recently, patients with unexplained hyperferritinemia not associated with iron overload and cataract and possibly inherited as a recessive trait, have been described, suggesting the existence of mutations in gene/s not directly implicated in iron metabolism that could affect ferritin secretion and turnover (167). Last, hyperferritinemia is a common manifestation of Gaucher's disease and can be the revealing cause of the disease in some patients (168).…”

L-Ferritin: One Gene, Five Diseases; from Hereditary Hyperferritinemia to Hypoferritinemia—Report of New Cases

“…There are three known mutations in the N-terminal region of the FTL gene that cause benign hyperferritinemia [15]. Despite serum ferritin hyperglycosylation, no other harmful effects have been detected in patients with this disorder [16].…”