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Pathophysiology
Iron Overload
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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.
Iron 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.
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 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
HFE gene mutations can lead to excessive iron absorption. The liver
and heart are especially vulnerable. |
This online course focuses on adult onset HFE hereditary hemochromatosis.
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