Understanding What Is the Pathophysiology of Iron Deficiency Anaemia?

October 18, 2025 •

3 min read

Iron deficiency is the most common single-nutrient deficiency globally, affecting over 2 billion people worldwide. What is the pathophysiology of iron deficiency anaemia? It is a progressive process that begins with depleted iron stores and culminates in the production of small, pale red blood cells, impairing oxygen delivery to tissues.

Quick Summary

An in-depth look at how the body develops iron deficiency anaemia, detailing the stages of iron depletion, the hormonal regulatory mechanisms, and the subsequent impact on red blood cell production.

Key Points

Iron Depletion is the First Stage: The pathophysiology begins with the gradual exhaustion of the body's stored iron, mainly affecting serum ferritin levels without causing immediate anaemia.
Hepcidin Regulates Iron Availability: The hormone hepcidin controls iron absorption and release from storage, with its expression decreasing in iron deficiency and increasing in inflammation.
Functional Iron Deficiency Affects Erythropoiesis: As iron stores dwindle, a state of iron-deficient erythropoiesis occurs, leading to the production of smaller, paler red blood cells.
Microcytic, Hypochromic RBCs Define IDA: The final stage is characterized by the presence of small (microcytic) and pale (hypochromic) red blood cells, which results in reduced oxygen-carrying capacity.
Chronic Blood Loss is a Major Cause: In adults, persistent, low-grade bleeding from the gastrointestinal tract or heavy menstruation is a common trigger for the development of IDA.

Iron Metabolism: A Primer

To understand the pathophysiology of iron deficiency anaemia (IDA), it is essential to first grasp the body's normal iron metabolism. Iron is a vital mineral, playing a crucial role in haemoglobin synthesis, enzyme function, and cellular metabolism. The body maintains a delicate balance, recycling most of its iron and absorbing only a small amount from the diet to cover daily losses.

Absorption: Dietary iron is absorbed primarily in the duodenum. Heme iron is more easily absorbed than non-heme iron. Absorbed iron is either stored in enterocytes or transported into the bloodstream.
Regulation by Hepcidin: Hepcidin, produced in the liver, controls iron levels. High iron levels increase hepcidin, which blocks iron release into the blood. Low iron levels decrease hepcidin, promoting iron absorption and release.
Transport and Storage: Transferrin transports iron in the blood to where it's needed, such as the bone marrow for red blood cell production. Excess iron is stored as ferritin, mainly in the liver.

The Three Stages of Pathophysiology

IDA develops through three stages.

Stage 1: Iron Depletion

Initial iron deficiency depletes the body's iron stores, often due to blood loss, poor diet, or increased demand. Ferritin stores are used, leading to low serum ferritin, while haemoglobin remains normal.

Stage 2: Iron-Deficient Erythropoiesis

Severe iron depletion restricts iron supply to bone marrow. Transferrin levels rise (high TIBC) to increase transport, but iron is insufficient for normal haemoglobin synthesis. Red cells with reduced haemoglobin are produced, and RDW increases.

Stage 3: Iron Deficiency Anaemia (IDA)

With exhausted stores and limited iron, bone marrow produces small (microcytic) and pale (hypochromic) red blood cells. Haemoglobin and haematocrit drop, causing anaemia symptoms like fatigue and shortness of breath.

Role of Hepcidin and Inflammation

Inflammation can raise hepcidin levels, trapping iron in storage cells and causing functional iron deficiency, even if total stores are adequate. This differs from IDA.


Indicator	Iron Deficiency Anaemia (IDA)	Anemia of Chronic Disease (ACD)
Serum Iron	Low	Low
Serum Ferritin	Low to very low	Normal to high
Transferrin Saturation	Low	Low
Total Iron-Binding Capacity (TIBC)	High	Low to normal
Hepcidin Levels	Low (allows more absorption)	High (traps iron)
RBC Morphology	Microcytic, Hypochromic	Normocytic, Normochromic (early stage)
Underlying Cause	Lack of iron stores	Functional iron block due to inflammation

Etiological Factors Driving Pathophysiology

Causes of iron deficiency include:

Blood Loss: Chronic loss, such as heavy menstruation or GI bleeding from conditions like ulcers or polyps, is a major cause.
Increased Requirements: Growth periods (infancy, adolescence) and pregnancy increase iron needs.
Poor Dietary Intake: Insufficient consumption of iron-rich foods, especially heme iron, contributes, particularly in developing countries or with restrictive diets.
Impaired Absorption: Conditions like coeliac disease, H. pylori infection, or GI surgery can hinder iron absorption.
Iron-Refractory Iron Deficiency Anaemia (IRIDA): A rare genetic disorder causing high hepcidin, blocking iron use despite low stores.

Clinical Manifestations and Consequences

Reduced oxygen capacity leads to fatigue and shortness of breath. Other effects include:

Cardiovascular: Increased heart workload can cause rapid heartbeat and potentially heart failure.
Epithelial: Iron deficiency can affect skin, nails (brittle, spoon-shaped), tongue (glossitis), and mouth corners (angular cheilitis).
Neurological: Cognitive delays in children and symptoms like headaches and poor concentration in adults.
Pica: Craving for non-food items, such as ice.

Conclusion

The pathophysiology of iron deficiency anaemia involves the depletion of iron stores, impaired red blood cell production, and the resulting microcytic, hypochromic anaemia. Disruption of iron regulation, especially via hepcidin, is key. Understanding these stages and mechanisms helps in diagnosing IDA, distinguishing it from other anaemias, and implementing effective treatments. Identifying and treating the underlying cause, not just replacing iron, is vital for recovery and preventing recurrence. For further information, resources like the National Institutes of Health provide detailed guidance.

Frequently Asked Questions

In adults, the most common cause is chronic, low-grade blood loss, often from the gastrointestinal tract due to issues like ulcers or cancer, or from heavy menstrual bleeding in women.

Hepcidin is a hormone that blocks the release of iron into the bloodstream. While it is suppressed in classic iron deficiency, it can be inappropriately high in conditions like anaemia of chronic disease, trapping iron in storage and preventing its use for red blood cell production.

Microcytic refers to red blood cells that are smaller than normal, while hypochromic refers to them being paler in color. Both are key characteristics of iron deficiency anaemia, caused by a lack of iron for proper haemoglobin synthesis.

Yes, especially in high-demand situations like infancy, adolescence, or pregnancy, or in individuals following restrictive diets low in bioavailable iron (e.g., strict vegetarian/vegan diets).

Iron deficiency is the state of depleted iron stores, while iron deficiency anaemia is the more severe stage where haemoglobin levels have dropped due to the lack of iron. Symptoms of anaemia usually only appear in the latter stage.

It is crucial to identify and treat the root cause, such as internal bleeding or malabsorption, rather than just replenishing iron stores. Failing to address the underlying issue means the deficiency is likely to return.

Inflammation increases hepcidin levels, which traps iron within storage cells and reduces its availability for making red blood cells. This leads to a functional iron deficiency and anaemia, despite the body potentially having adequate iron stores.