Mechanistic and regulatory aspects of intestinal iron absorption

Abstract

Iron is an essential trace mineral that plays a number of important physiological roles in humans, including oxygen transport, energy metabolism, and neurotransmitter synthesis. Iron absorption by the proximal small bowel is a critical checkpoint in the maintenance of whole-body iron levels since, unlike most other essential nutrients, no regulated excretory systems exist for iron in humans. Maintaining proper iron levels is critical to avoid the adverse physiological consequences of either low or high tissue iron concentrations, as commonly occurs in iron-deficiency anemia and hereditary hemochromatosis, respectively. Exquisite regulatory mechanisms have thus evolved to modulate how much iron is acquired from the diet. Systemic sensing of iron levels is accomplished by a network of molecules that regulate transcription of the HAMP gene in hepatocytes, thus modulating levels of the serum-borne, iron-regulatory hormone hepcidin. Hepcidin decreases intestinal iron absorption by binding to the iron exporter ferroportin 1 on the basolateral surface of duodenal enterocytes, causing its internalization and degradation. Mucosal regulation of iron transport also occurs during low-iron states, via transcriptional (by hypoxia-inducible factor 2α) and posttranscriptional (by the iron-sensing iron-regulatory protein/iron-responsive element system) mechanisms. Recent studies demonstrated that these regulatory loops function in tandem to control expression or activity of key modulators of iron homeostasis. In health, body iron levels are maintained at appropriate levels; however, in several inherited disorders and in other pathophysiological states, iron sensing is perturbed and intestinal iron absorption is dysregulated. The iron-related phenotypes of these diseases exemplify the necessity of precisely regulating iron absorption to meet body demands.

Modern iron replacement therapy: clinical and pathophysiological insights

“…Many preparations are over the counter and often aggressively advertised as "ideal", or the "most natural" way to reintegrate ID. Pharmacological iron is absorbed through the same pathway of non-heme dietary iron found in plant foods, which is exceedingly less efficient than absorption of heme-iron found in meat [47,48]. Non-heme dietary iron is largely ferric, and, as such, highly insoluble.…”

“…like during acute inflammation) to be substantially suppressed it needs to be reduced by a brush-border ferrireductase (duodenal cytochrome b or DCYTB), allowing the resulting divalent iron to enter the luminal surface of enterocytes through a specialized transporter (Divalent Metal Transporter 1, or DMT1). By contrast, the absorption of heme-iron is less well understood [48], and attempts to produce heme-iron polypeptides has resulted in greater costs and insufficient clinical evaluation [49]. Thus, for the moment divalent iron salts appear the most appropriate form of oral iron replacement therapy, the most used being ferrous gluconate, ferrous fumarate, and ferrous sulfate (FS) ( Table 2).…”

Influence of Pharmacists’ Intervention on Drug-Related Problems Related to Change in Hemoglobin Levels of Hemodialysis Patients at Adjidarmo Hospital, Lebak, Banten

“…Monitoring of patients' Hb levels is recommended. The studies have noted that iron absorption can reduce by 60% when it is given with calcium carbonate [9]. Further, patients were given natrium bicarbonate tablets (3×1 or 3×2) immediately after a meal.…”

Mice are poor heme absorbers and do not require intestinal Hmox1 for dietary heme iron assimilation

“…4 Ingested Fe(III) is reduced to Fe(II) in the intestinal lumen and then internalized by enterocytes via the apical transporter DMT1. The basolateral transporter ferroportin mediates Fe(II) efflux to the bloodstream.…”

“…Since iron absorption is enhanced by erythropoietic drive, 4 we examined heme bioavailability under anemia. Wild-type mice were subjected to a 4-week dietary iron restriction during their rapid growth period, immediately after weaning.…”