Hereditary hemochromatosis exemplifies inappropriate regulation of the iron absorptive setpoint in the crypt.

Individuals with hereditary hemochromatosis (HH) have decreased levels of functional HFE. This contributes to a higher labile iron pool in the precursor cells of an individual with hereditary hemochromatosis than an individual with functional HFE (wild type). When the precursor cell of a hereditary hemochromatotic individual differentiates, the labile iron pool will initially be high. We speculate that this increase in the labile iron pool up-regulates machinery responsible for basolateral iron transfer such as Ferroportin1/Ireg1/MTP1 (F/I/M). The increased amount of basolateral iron efflux will lead to a depletion of the labile iron pool, which will increase levels of the apical iron transporter, DMT1. If Ferroportin1/Ireg1/MTP1 is a very stable protein, or its activity exceeds that of DMT1 in the individual with hereditary hemochromatosis, the iron efflux activity of that enterocyte will overcome the uptake activity of DMT1, keeping intracellular iron levels low. This model explains why individuals with hereditary hemochromatosis have higher levels of DMT1 and low ferritin levels in their duodenum and can be tested further by determining the activity of Ferroportin1/Ireg1/MTP1 in hereditary hemochromatotic individuals and controls as well as in HFE-deficient mice.