METABOLISM OF IRON STORES

Abstract

Remarkable progress was recently achieved in the studies on molecular regulators of iron metabolism. Among the main regulators, storage iron, iron absorption, erythropoiesis and hepcidin interact in keeping iron homeostasis. Diseases with gene-mutations resulting in iron overload, iron deficiency, and local iron deposition have been introduced in relation to the regulators of storage iron metabolism. On the other hand, the research on storage iron metabolism has not advanced since the pioneering research by Shoden in 1953. However, we recently developed a new method for determining ferritin iron and hemosiderin iron by computer-assisted serum ferritin kinetics. Serum ferritin increase or decrease curves were measured in patients with normal storage iron levels (chronic hepatitis C and iron deficiency anemia treated by intravenous iron injection), and iron overload (hereditary hemochromatosis and transfusion dependent anemia). We thereby confirmed the existence of two iron pathways where iron flows followed the numbered order (1) labile iron, (2) ferritin and (3) hemosiderin in iron deposition and mobilization among many previously proposed but mostly unproven routes. We also demonstrated the increasing and decreasing phases of ferritin iron and hemosiderin iron in iron deposition and mobilization. The author first demonstrated here the change in proportion between pre-existing ferritin iron and new ferritin iron synthesized by removing iron from hemosiderin in the course of iron removal. In addition, the author disclosed the cause of underestimation of storage iron turnover rate which had been reported by previous investigators in estimating storage iron turnover rate of normal subjects.

Keywords: ferritin and hemosiderin; iron deficiency and overload; serum ferritin kinetics; storage iron turnover.

Fig. 1

Correlation between serum ferritin and the amount of storage iron. Fig. 1a: The ratio of serum ferritin to iron stores was lower below 1 g than above 1 g as observed in 9 cases with chronic hepatitis (round dot) and 1 case with treated iron deficiency anemia (square dot). ⁴⁾ Fig. 1b: The serum ferritin increase rate declined gradually along with the progress of iron addition by transfusion in a case with transfusion-dependent anemia before the treatment by deferasirox. The combination of Fig. 1a with Fig. 1b will be a top-heavy sigmoid correlation curve covering storage iron levels from low normal to iron overload.

Fig. 2

Interactions among the major factors regulating iron homeostasis. These factors; iron absorption, erythropoiesis, storage iron and hepcidin, are regulated by erythropoietin, transferrin saturation, interleukins, divalent metal transporter 1, iron regulatory proteins, iron responsive element, hemojuvelin, hypoxia-inducible factor¹¹⁰⁾, growth differentiation factor 15⁹¹⁾ and others.

Fig. 3

Iron pathways of ferritin and hemosiderin in iron deposition and mobilization.⁴⁾ The numbers in quotation indicate the order of tracing in the same lap route. Abbreviation: C.M., cell membrane.

Fig. 4

Fig. 4a: Increasing phases of serum ferritin in patient with transfusion-dependent anemia.²¹⁾ Declination of serum ferritin increase in iron addition reflects the transformation of ferritin into hemosiderin. Fig. 4b: Increasing phases of ferritin iron (solid curve) and hemosiderin iron (dotted curve) along with the linear increase of total iron stores in transfusion-dependent anemia.²¹⁾ The crossing point of increasing curves of ferritin iron and hemosiderin iron appears at a certain storage iron level in iron addition, when the amount of initial hemosiderin iron exceeds that of initial ferritin iron. The shifting of the crossing point toward a higher storage iron level in iron addition implies the increase of iron storing capacity of ferritin. Fig. 4b was made from the data of Fig. 4a.

Fig. 5

Decreasing phases of ferritin iron (solid curve) and hemosiderin iron (dotted curve) along with the linear decrease of total iron stores. Fig. 5a shows a case of hereditary hemochromatosis. Fig. 5b shows a case of treated iron deficiency anemia with constant blood loss.²¹⁾ The crossing point of decreasing curves of ferritin iron and hemosiderin iron does not appear in cases with the initial hemosiderin iron larger than the initial ferritin iron.

Fig. 6

Fig. 6a, 6b and 6c are made from the data of the same patient with hereditary hemochromatosis. Fig. 6a: Proportion of pre-existing ferritin iron and hemosiderin iron to total iron stores in the course of iron removal. Fig. 6b: Proportion of pre-existing (old) ferritin iron and new ferritin iron synthesized by taking iron from hemosiderin in the course of iron removal. Since, iron stores are composed of the sum of ferritin iron and hemosiderin iron, the only iron source available for the ferritin synthesis (recovery) is hemosiderin iron in iron removal under dietary iron-restriction. Fig. 6c: Proportion of old and new ferritin iron remaining in the course of iron removal. The area enclosed by points A, B, D and C indicates the total amount of ferritin iron, which is composed of old ferritin iron (square area ACDE) and new ferritin iron (quasi-triangular red area ABE). The area ABC is shifted to the equivalent area ACD to show the decreasing phase of total ferritin iron. Diagonal line CD indicates the amount of ferritin iron removed. Proportions of old and new ferritin iron in the area ACD are zoned green and red, respectively. The proportions of new ferritin iron (areas ABE) and old ferritin iron (area ACDE) are reflected by those in color zones, although old and new ferritin iron cannot be separated due to mixing.

Fig. 7

Iron turnover rates in the model of a typical normal male. The subject is under the conditions; red cell iron: 2400 mg (15 g/dl hemoglobin, and 4800 ml blood volume), total body iron: 3600 mg, red cell radioiron utilization (RCU): 80% and PIT: 30 mg/day (cf. Table 2 and Table 3). Abbreviations / Color / Arc angles (° = degree): PIT, plasma iron turnover rate / pink / 360°; Red cell iron turnover rate (not abbreviated) / blue / 288°; Red cell iron renewal rate (not abbreviated) / green / 240°; Parenchymal tissue iron turnover rate (not abbreviated) / purple / 120°; Tissue-fixed, parenchymal tissue iron turnover rate due to tissue-fixed radioiron / purple / 72°; Reflux, parenchymal tissue iron turnover rate due to refluxed and red cell-fixed radioiron / purple / 48°; SIT, storage iron turnover rate / red / 84°; SITf, storage iron turnover rate due to storage-fixed radioiron / red / 50.4°; SITr, storage iron turnover rate due to refluxed and red cell-fixed radioiron / red / 33.6°.