Distinct Iron Deposition Profiles of Liver Zones in Various Models with Iron Homeostasis Disorders

Abstract

Determination of iron accumulation is crucial in diagnosing the occurrence and progression of many liver‐ and iron‐related diseases. Thus far, little is known about the profiles of iron deposition in different liver zones, particularly under conditions with disordered iron homeostasis. Here, uneven iron distribution in livers of patients with hereditary hemochromatosis (HH) is uncovered, showing the region with the highest iron concentration near the entrance site of the portal vein and hepatic artery in contrast to the sites with the lowest iron concentration close to the distal edge. Distinct iron distribution profiles are also found throughout liver zones in wild‐type mice and various mouse models with iron metabolism disorders, including hemochromatosis (Hfe−/−), iron deficiency, and inflammation. Of note, similar findings observed in HH patients are further demonstrated in Hfe−/− mice. Moreover, the zones with greater iron accumulation appear to be more sensitive to iron changes, e.g., there is iron increase upon iron overload and iron loss in response to iron deficiency. Mechanistic investigation manifests that these differential iron changes in liver zones are subjected to the regulation by the hepcidin–ferroportin axis. Additionally, the data corroborate the reliability of magnetic resonance imaging (MRI) in recognizing the differential iron deposition profiles among liver zones.

Liver Iron Retention Estimated from Utilization of Oral and Intravenous Radioiron in Various Anemias and Hemochromatosis in Humans

“…An older study reported already in 1982 a significantly lower 59 Fe-RBCIU in healthy aged subjects 14 days after an oral iron test dose, while RBCIU after an intravenous dose showed no difference [25]. In this small study RBCIU upon intravenous iron could not be measured in the same subjects as RBCIU upon oral iron administration.…”

“…Presented values are medians with interquartile ranges (IQR). Iron uptake, retention and transfer were calculated from the amount of 59 Fe and 51 Cr in the body 24 h after the oral iron test dose (uptake) and 14 days after the oral iron test dose (retention). Mucosal iron transfer is the fraction of iron retained after uptake.…”

“…The intravenous test dose of transferrin-bound 59 Fe-labeled iron could rapidly interact directly with iron in the peripheral venous system. In our studies oral iron was administered as 7 mg ferrous ammonium sulphate (1 mg 59 Fe(II)), which enters the portal vein via ferroportin.…”

“…In our studies oral iron was administered as 7 mg ferrous ammonium sulphate (1 mg 59 Fe(II)), which enters the portal vein via ferroportin. Part of this 59 Fe will bind to apotransferrin in plasma, similar to the injected 59 Fe, and will be cleared mainly by erythroblasts and other cells expressing transferrin receptors. The remaining 59 Fe will bind to other molecules with formation of NTBI and labile plasma iron (LPI), resulting in iron deposition in the liver.…”

“…We measured the amount of 59 Fe iron in peripheral blood samples 14 days after the iron test dose to determine the amount of iron utilized for RBC production. Mean percentages (± standard deviation) of RBC iron utilization (RBCIU) after an oral iron test dose were 37 ± 17% in untreated non-transfusion-dependent hereditary anemia, 53 ± 19% in treated non-transfusion-dependent hereditary anemia, 55 ± 20% in untreated hereditary hemochromatosis, 70 ± 22% in treated hereditary hemochromatosis, and 99 ± 22% in iron deficient patients.…”