Learning Objective

By the end of this article, you should be able to describe the key processes of iron metabolism—including absorption, transport, storage, recycling, and regulation—explain how the body balances iron to prevent deficiency or toxicity, and recognize the clinical consequences of disrupted iron homeostasis, including iron deficiency and hereditary hemochromatosis.

Overview

Iron is an essential trace element vital for numerous biological functions, including oxygen transport (as a component of hemoglobin), DNA synthesis, and the activity of various enzymes. However, free iron is highly reactive and can catalyze the formation of harmful free radicals, making tight regulation of iron homeostasis critical.

Iron Absorption

Iron absorption primarily occurs in the duodenum and upper jejunum through specialized transport mechanisms:

Non-heme iron (Fe²⁺): Uptake is facilitated by Divalent Metal Transporter 1 (DMT1) on the apical surface of enterocytes.
Heme iron (from animal sources): More efficiently absorbed via heme-specific transporters.
Ferric iron (Fe³⁺): Must first be reduced to ferrous iron (Fe²⁺) by duodenal cytochrome B reductase (DcytB) before DMT1-mediated absorption.

Once inside the enterocyte, iron has two fates:

Storage: Bound to ferritin for temporary intracellular sequestration.
Export to circulation: Through ferroportin, then bound to transferrin in the plasma for delivery to the bone marrow for erythropoiesis or to other tissues.

Key Insight: Only about 10% of dietary iron is absorbed daily, making regulation of absorption critical to meet physiological needs.

Iron Recycling

The majority of iron required for erythropoiesis is recycled from senescent red blood cells via the reticuloendothelial system (RES):

Macrophages in the spleen and liver phagocytose old erythrocytes.
Iron is released from heme and returned to the plasma bound to transferrin, maintaining the active iron pool.

Daily dietary intake alone is insufficient to meet total iron requirements, making recycling the main source of usable iron.

Iron Storage

Iron is stored safely in cells as:

Ferritin: Soluble and readily mobilized.
Haemosiderin: Insoluble, accumulates with chronic iron excess.

Highest concentrations are found in the liver, spleen, and bone marrow.

Regulation of Iron Homeostasis

Hepcidin, a peptide produced by the liver, is the master regulator of iron metabolism:

Mechanism: Binds to ferroportin → induces degradation → prevents iron export from enterocytes and macrophages.
Additional regulation: Inhibits DMT1 transcription, reducing intestinal iron absorption.

Excretion: The human body lacks a dedicated excretory system for iron. Daily losses occur passively via:

Shedding of skin and gastrointestinal mucosa (~1–2 mg/day).
Menstrual blood loss in women.

Balance is maintained primarily by adjusting absorption according to physiological demand.

Clinical Relevance

Iron Deficiency

A sign, not a diagnosis—underlying causes must be investigated.
Causes:
- Insufficient intake or absorption (e.g., malnutrition, celiac disease).
- Increased demand (pregnancy, growth).
- Chronic blood loss (GI bleeding, menorrhagia).
Symptoms: Fatigue, pallor, microcytic anemia.
Diagnosis: Low ferritin, low transferrin saturation, microcytic hypochromic RBCs.

Hereditary Hemochromatosis (HHC)

Autosomal recessive disorder caused by mutations in the HFE gene (chromosome 6).

Pathophysiology: Excessive intestinal iron absorption, progressive tissue iron deposition.
Target organs: Liver (cirrhosis), pancreas (diabetes), heart (cardiomyopathy), joints (arthritis), adrenal glands (insufficiency).
Complications: Organ failure if untreated.
Treatment: Therapeutic phlebotomy to remove excess iron.

Key Insight: Because the body cannot actively excrete iron, disorders of absorption can rapidly lead to toxicity and organ damage.