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Training & Education - Pathophysiology

Iron Overload

Iron overload is the accumulation of excess iron in body tissues.

Iron overload usually occurs as a result of a genetic predisposition to absorb iron in excess of normal.

graphic of iron processing in bodyIron overload can also occur as a complication of:

  • Other hematologic disorders (e.g., inherited and acquired anemias).
  • Chronic transfusion therapy or repeated injections of iron dextram.
  • Chronic hepatitis.
  • Excessive iron ingestion.

Once iron is absorbed, there is no physiologic mechanism for excretion of excess iron from the body other than blood loss (i.e., pregnancy, menstruation or other bleeding). Iron is bound and transported in the body via transferrin and stored in ferritin molecules. All cells of the body contain ferritin.

When iron absorption exceeds the storage capacity of ferritin molecules, unbound iron may promote free-radical formation in cells, resulting in membrane lipid peroxidation and cellular injury.

Iron deposition occurs in many organs.


Hemochromatosis is a disease that occurs as a result of significant iron overload.

  • Hemochromatosis can have genetic and non-genetic causes.
  • Excess iron accumulates in organs (particularly the liver, pancreas, heart), joints, and the pituitary gland.
  • After several decades of increased iron absorption non-specific symptoms (i.e., fatigue, weakness, arthralgia) develop, followed by advanced conditions (i.e., arthritis, cirrhosis, liver cancer).

Hemochromatosis symptoms usually develop after decades of increased iron absorption.

  • Symptoms usually appear after 15–20 g of iron have accumulated in the body.
  • Men thus tend to become symptomatic in middle age (40s) and women who stop menstruating develop symptoms about 15 years later.

HFE Gene Mutations

The HFE gene codes for a transmembrane glycoprotein that modulates iron uptake. This protein is highly expressed in intestinal cells at the site of dietary iron absorption.

Mutations in the HFE gene compromise its function and can lead to iron overloading.

  • The precise mechanism by which the HFE protein is involved in normal iron metabolism is incompletely understood but is a topic of much research.
  • Recent studies suggest that loss of a functional HFE protein leads to increased iron uptake in the intestinal epithelial cell, which results in increased dietary iron absorption. (Britton RS, 2002; Fleming RE, 2002; Philpott CC, 2002; Townsend A, 2002).

Hereditary Hemochromatosis

Hereditary hemochromatosis is the genetic disease that results from significant iron overload.

  • The majority of hereditary hemochromatosis (also known as Type 1 Hemochromatosis) is associated with homozygous mutations in the HFE gene.
  • There are other heritable forms of hemochromatosis, some of which are caused by mutations in other known genes.

People with HFE mutations may have much greater iron stores because they absorb dietary iron at 2–3 times the normal rate absorbing a few extra milligrams of iron per day.

  • This leads to the accumulation of 0.5–1.0 g of iron per year.
  • Once absorbed, there is no physiologic mechanism for excretion of excess iron from the body other than blood loss (i.e., pregnancy, menstruation or other bleeding).
  • Over decades this leads to iron overloading with total body iron stores that may exceed 50 g.

HFE Mutations: Causing Iron Overload and Organ Damage

illustration of iron absorption

This online course focuses on adult onset HFE hereditary hemochromatosis.