hematology


Iron, Vitamin B12 and folate metabolism.

 

                   IRON

•Iron is an essential mineral and normally, it is present in ferrous (Fe²֗ )form.

 

•It is in unstable or loose form. In some abnormal conditions, the iron is converted into ferric (Fe³֗) state, which is a stable form.

 

•The iron is attached to ‘N’ of each pyrrole ring and ‘N’ of globin molecule.

 

 

•It has vital roles in oxidative metabolism, cellular growth and proliferation,

and oxygen transport and storage. Iron must be bound to protein compounds to fulfill these functions.

 

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                  IRON METABOLISM

•Iron in inorganic compounds or in an ionized form is potentially dangerous.

 

•If the amount of iron exceeds the body’s capacity for transport and storage in the protein-bound form, iron toxicity can develop, causing damage to cells and a potentially lethal condition.

 

•Conversely, if too little iron is available, the synthesis of physiologically active iron compounds is limited, and critical metabolic processes are inhibited

 


                  IRON METABOLISM

•Iron cannot freely diffuse across membranes but requires special transport involving a variety of proteins.

 

•Enterocytes (absorptive cells at the luminal [apical] surface of the duodenum), hepatocytes, and macrophages can import and export iron.

 

•On the other hand, erythrocyte precursors use most, if not all, of the imported iron and do not export it.

 

•Important advances in our understanding of iron metabolism are the result of the discovery of genes and proteins that participate in regulating iron homeostasis

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                 IRON CON’T

•Distribution of Iron-

Iron containing compounds in the body are of two types:

 

•Functional compounds that serve in metabolic functions (haemoglobin, myoglobin) or enzymatic functions (cytochromes, cytochrome oxygenase, catalase, peroxidase)

 

•Compounds that serve as transport proteins (transferrin, transferrin receptor) or storage depots for iron (ferritin and haemosiderin)

 

•Iron is found primarily in erythroblasts, erythrocytes, macrophages, hepatocytes, and enterocytes.

                         IRON CON’T

•Haemoglobin constitutes the major fraction of body iron (functional iron) with a concentration of about 1 mg iron/mL erythrocytes.

 

•Iron in haemoglobin remains in the erythrocyte until the cell is removed from the circulation

                       IRON CON’T

•Most iron enter erythroid cells, through mitochondria for haemoglobin synthesis and iron-sulfur (Fe-S) cluster (iron containing functional group) assembly.

 

•Mitochondrial ferritin serves as an iron storage molecule and is highly expressed in tissue with numerous mitochondria.

 

•Frataxin is the protein in the mitochondrial matrix that is thought to play a role in mitochondrial iron expo

ABSORPTION OF IRON

•Iron is absorbed mainly from the small intestine, It is absorbed through the intestinal cells (enterocytes) by pinocytosis and transported into the blood, Bile is essential for the absorption of iron.

 

•Iron is present mostly in ferric (Fe³֗ )form. It is converted into ferrous form (Fe²֗ ) which is absorbed into the blood.

•Hydrochloric acid from gastric juice makes the ferrous iron soluble so that it could be converted into ferric iron by the enzyme ferric reductase from enterocytes.

•From enterocytes, ferric iron is transported into blood by a protein called ferroportin. In the blood, ferric iron is converted into ferrous iron and transported.

NORMAL VALUE OF IRON IN THE BODY

•Total quantity of iron in the body is about 4 g. Approximate

•Distribution of iron in the body is as follows:

•In the haemoglobin : 65% to 68%

•In the muscle as myoglobin : 4%

•As intracellular oxidative heme compound : 1%

TRANSPORT OF IRON

 

•Immediately after absorption into blood, iron combines with a β-globulin called apotransferrin (secreted by liver through bile) resulting in the formation of transferrin.

 

•And iron is transported in blood in the form of transferrin.

 

•Iron combines loosely with globin and can be released easily at any region of the body

STORAGE OF IRON

•Iron is stored in large quantities in reticuloendothelial cells and liver hepatocytes.

 

•In other cells also it is stored in small quantities.

 

•In the cytoplasm of the cell, iron is stored as ferritin in large amount.

 

•Small quantity of iron is also stored as haemosiderin.

Iron is an essential trace element critical for oxygen transport (as part of hemoglobin), cellular respiration (cytochromes and iron-sulfur clusters), DNA synthesis, and many enzymatic reactions. The human body contains 3–5 grams of iron in adults, with about two-thirds in hemoglobin within red blood cells (RBCs), and the rest distributed in storage sites, myoglobin, and enzymes. Iron balance is tightly regulated because there is no active excretion pathway—losses occur only through minor bleeding, desquamation of skin/gut cells, or menstruation (typically 1–1.5 mg/day in adults). Homeostasis relies on controlling absorption, transport, storage, and recycling.10

Iron Absorption

Absorption occurs mainly in the duodenum and upper jejunum (about 1–2 mg/day in steady state, matching daily losses). Dietary iron exists in two forms:

  • Heme iron (from animal sources like meat): More bioavailable; absorbed directly via heme transporters (e.g., HCP1) and broken down inside enterocytes by heme oxygenase to release Fe²⁺.

  • Non-heme iron (from plants, supplements; majority of dietary iron): Less bioavailable. Ferric iron (Fe³⁺) is first reduced to ferrous iron (Fe²⁺) by duodenal cytochrome b (Dcytb) on the apical membrane. Fe²⁺ then enters enterocytes via divalent metal transporter 1 (DMT1).13

Inside the enterocyte:

  • Iron can be stored temporarily as ferritin.

  • Or exported across the basolateral membrane via ferroportin (the sole known cellular iron exporter). Hephaestin (a ferroxidase) oxidizes Fe²⁺ to Fe³⁺ for loading onto plasma transferrin.

Regulation: The liver-derived hormone hepcidin is the master regulator. High iron stores or inflammation increase hepcidin, which binds ferroportin, causing its internalization and degradation (or functional inactivation). This traps iron inside enterocytes as ferritin, which is lost when enterocytes are sloughed off (every few days). Low hepcidin (e.g., during iron deficiency or increased erythropoiesis) allows more export. Hepcidin can also indirectly reduce DMT1 levels.1

Absorption increases with iron deficiency, hypoxia, or high erythropoietic demand, and decreases with iron overload or inflammation.

Iron Transport

Once exported, Fe³⁺ binds to transferrin (a plasma glycoprotein that carries two iron atoms safely, preventing free iron toxicity and oxidative damage). Transferrin-bound iron circulates and delivers iron to tissues via transferrin receptor 1 (TfR1) on cell surfaces (especially high on erythroid precursors in bone marrow).

  • Iron-loaded transferrin binds TfR1 → endocytosis → acidification of endosome releases Fe³⁺ (reduced to Fe²⁺) → transported out via DMT1 into cytosol.

  • Apo-transferrin (iron-free) recycles back to plasma.

Plasma iron turnover is rapid: the small circulating pool (~3 mg) turns over several times daily to meet demand.4

Iron Storage

Excess iron is stored primarily in the liver (hepatocytes) and reticuloendothelial system (macrophages in spleen, liver Kupffer cells, bone marrow). Total storage iron is ~1 gram in adults.

  • Ferritin: Soluble protein complex (H and L subunits) that oxidizes Fe²⁺ to Fe³⁺ and stores up to ~4500 iron atoms in a safe, bioavailable form. Serum ferritin reflects body iron stores.

  • Hemosiderin: Insoluble, aggregated/degraded ferritin found in lysosomes; less readily mobilizable, accumulates in iron overload.

Storage protects against iron toxicity (free iron generates reactive oxygen species via Fenton reaction) while allowing mobilization when needed. Macrophages also store recycled iron from RBC breakdown.16

Daily Iron Cycle (Recycling and Homeostasis)

The body recycles iron efficiently, with minimal net loss. Daily requirement for erythropoiesis (RBC production) is ~20–25 mg of iron, but only 1–2 mg comes from diet. The rest (~20–25 mg) is recycled:

  1. Senescent RBCs (lifespan ~120 days) are phagocytosed by macrophages in spleen, liver, and bone marrow (erythrophagocytosis).

  2. Hemoglobin is degraded; heme oxygenase releases iron from heme.

  3. Macrophages export recycled iron via ferroportin (oxidized and bound to transferrin).

  4. Transferrin delivers iron mainly to bone marrow erythroid precursors for new hemoglobin synthesis.

  5. New RBCs enter circulation → cycle repeats.

Key regulator: Hepcidin-ferroportin axis

  • Hepcidin (produced by hepatocytes) decreases when iron is needed (e.g., iron deficiency, anemia, hypoxia) → more iron release from stores and absorption.

  • Hepcidin increases with high iron stores, inflammation (via IL-6), or infection → blocks ferroportin → reduces circulating iron (protective against pathogens that need iron).

  • Erythropoiesis suppresses hepcidin via erythroferrone (ERFE) from erythroblasts, prioritizing iron for RBC production.30

This creates a closed daily loop: recycling > absorption > utilization in erythropoiesis >> storage as buffer.

Disruptions lead to disorders:

  • Iron deficiency anemia (low absorption/recycling).

  • Iron overload (hemochromatosis: low hepcidin → excessive absorption).

  • Anemia of inflammation (high hepcidin → iron sequestration in macrophages).

In summary, iron metabolism is a highly conserved, hepcidin-orchestrated system emphasizing recycling over new absorption, with storage as a dynamic reserve. Factors like diet, inflammation, and erythropoietic demand fine-tune the balance. Consult a healthcare professional for personal concerns related to iron levels or tests (e.g., serum ferritin, transferrin saturation).