Iron absorption and cellular transport: the mobilferrin/paraferritin paradigm.

Dietary inorganic iron is mostly ferric iron. This is solubilized at the acid pH level of the stomach where it chelates mucins and certain dietary constituents to keep them soluble and available for absorption in the more alkaline duodenum. Mucosal uptake of iron is facilitated by a beta 3 integrin and a 56 kDa protein known as mobilferrin. In the cytosol of the absorptive cell, iron is associated with a 520-kDa complex known as paraferritin which contains integrin, mobilferrin, and flavin monooxygenase. This complex serves as a ferrireductase to reduce iron to the ferrous state so that it is available for formation of end products such as heme proteins. The large complex has other constituents, such as beta 2 microglobulin, whose functions remain to be delineated. We postulate that the basolateral membranes of absorptive cells possess both holo-transferrin and apotransferrin receptors that regulate the ingress and egress of cellular iron, respectively. Unlike absorptive cells, nonintestinal cells appear to possess three pathways for uptake of inorganic iron: (1) the classical transferrin-transferrin receptor pathway, (2) the transferrin-associated transferrin receptor independent pathway (TRIP), and (3) the transferrin-independent mobilferrin-integrin pathway (MIP) observed in intestinal absorptive cells. The TRIP is used when transferrin receptors become saturated at physiological concentrations of iron and transferrin. The MIP may only be used efficiently for mucosal uptake of iron and iron-overloaded individuals with fully saturated transferrin. Alternatively, it may facilitate iron uptake from the TRIP after degradation of transferrin near the surface of the cell. However, both transferrin-associated pathways donate iron to a common intracellular iron pathway for ferri-reduction and probably other functions.

The alternate iron transport pathway: mobilferrin and integrin in reticulocytes.

Iron transport in reticulocytes is known to occur via the well-described transferrin-receptor-endosome pathway. An alternative pathway for iron transport independent of transferrin has been postulated in reticulocytes and other cells. Transport of iron into reticulocytes from ferric citrate solutions was shown to be saturable and independent of transferrin. During transport of iron from ferric citrate, both cell surface integrins, and a soluble protein, mobilferrin, were labelled. This demonstrated that the reticulocyte transferrin independent pathway for iron transport involved integrins and mobilferrin similar to intestinal absorptive cells. This pathway would be expected to transport iron into cells under conditions of iron overload and was capable of providing iron for haemoglobin synthesis. Mobilferrin was also radiolabelled when radioiron labelled transferrin was incubated with reticulocytes and this occurred with a different time course than was observed following reticulocyte exposure to radiolabelled ferric citrate. This suggested that mobilferrin may serve as an intermediary in both pathways.

Rapid progression of acquired amegakaryocytic thrombocytopenia to aplastic anemia.

Acquired amegakaryocytic thrombocytopenia is a rare disorder characterized by severe thrombocytopenia and selective, marked decrease or absence of megakaryocytes. Although immunosuppressive therapy (prednisone and/or antithymocyte globulin) has been shown to induce remissions in a subset of patients, most patients do not respond, and progression to aplastic anemia occurs in some cases. We report a case of acquired amegakaryocytic thrombocytopenia which, despite aggressive immunosuppressive treatment, rapidly progressed to aplastic anemia. Clinical, laboratory, and immunologic features of our patient's case are described and compared to those of the previously reported six cases that progressed from amegakaryocytic thrombocytopenia to aplastic anemia.