Iron plays a central role in oxygen transport and cellular function, but the body has a limited capacity to excrete excess amounts. Iron deposition, known medically as hemosiderosis, occurs when total body iron stores become elevated, leading to accumulation primarily within organs. Since the liver is the main organ responsible for iron storage and regulation, it is the primary site for this excess deposition. This accumulation, known as iron overload, can cause severe and life-threatening damage, including organ failure, if left unchecked.
Understanding How Iron Overload Happens
Iron overload is classified as primary (genetic) or secondary (acquired). Primary overload is most commonly Hereditary Hemochromatosis (HH), a genetic disorder linked to mutations in the HFE gene that regulates iron absorption.
The HFE gene mutation leads to low levels of hepcidin, a hormone produced by the liver that regulates iron. When hepcidin is low, the body signals the intestines to absorb excessive dietary iron. This hyperabsorption causes iron to accumulate gradually in various organs, especially the liver.
Secondary iron overload results from external factors or diseases that impair iron handling. A frequent cause is chronic blood transfusions, often required for patients with iron-loading anemias like thalassemia or sickle cell disease. Repeated transfusions introduce significant iron, quickly overwhelming the body’s storage capacity.
Other chronic liver diseases also contribute to iron deposition by interfering with regulation. Conditions like alcoholic liver disease, chronic hepatitis C infection, and non-alcoholic fatty liver disease (NAFLD) are associated with higher liver iron levels. This accumulation is connected to the chronic inflammation and reduced hepcidin production seen in these diseases, contributing to progressive liver injury.
How Excessive Iron Damages the Liver
Excess iron damages the liver through its chemical reactivity within hepatocytes. Iron not safely sequestered in storage proteins like ferritin becomes “free,” promoting the generation of free radicals. This process, called oxidative stress, is initiated through the Fenton reaction, where excess iron catalyzes the formation of these reactive oxygen species.
These free radicals damage cellular components, including lipids, proteins, and DNA. This injury leads to hepatocyte death, triggering a chronic inflammatory response. The body attempts to repair this damage by laying down scar tissue, a process known as fibrosis.
As iron deposition progresses, fibrosis advances into cirrhosis, which is irreversible, widespread scarring that distorts the liver’s architecture. Cirrhosis severely impairs the liver’s ability to perform functions like detoxification and protein synthesis. Chronic iron overload also increases the risk of developing hepatocellular carcinoma (HCC), the most common form of liver cancer.
Testing and Identifying Iron Overload
Identifying iron overload begins with routine blood tests. Serum ferritin is a primary indicator, reflecting total stored iron, and high levels suggest overload. However, ferritin is also an acute phase reactant, meaning inflammation or chronic liver disease can elevate its levels.
Another measure is transferrin saturation, which indicates the percentage of the protein transferrin that is currently bound to iron. A high saturation suggests that circulating iron is exceeding the body’s capacity to bind it safely, a finding often present early in hereditary hemochromatosis. If these initial blood markers are persistently elevated, non-invasive imaging is often used to confirm and quantify the iron accumulation.
Magnetic Resonance Imaging (MRI) is a standard method for directly measuring hepatic iron concentration. This technique allows clinicians to assess iron deposition without requiring an invasive biopsy. If hereditary hemochromatosis is suspected, genetic testing can be performed to look for common HFE gene mutations.
Strategies for Managing Iron Deposition
The primary goal of managing iron deposition is to remove excess iron before it causes permanent organ damage. For hereditary hemochromatosis, the first-line treatment is therapeutic phlebotomy. This involves regularly removing a measured volume of blood, forcing the body to mobilize stored iron to replenish lost red blood cells.
Phlebotomy frequency is determined by ferritin levels, aiming to deplete iron stores until a target range is reached. Once stores are reduced, a less frequent maintenance schedule prevents re-accumulation. This treatment can halt the progression of liver damage if initiated before advanced scarring develops.
For patients who cannot tolerate phlebotomy or those with secondary iron overload due to chronic anemia and frequent transfusions, chelation therapy is required. This involves administering iron-chelating drugs designed to bind tightly to excess iron in the bloodstream and tissues. Once bound by the chelator, the iron-drug complex is made water-soluble and safely excreted, typically through urine or feces. Chelation therapy prevents iron-induced complications in organs like the heart and liver. Patients are also advised to avoid unnecessary iron and vitamin C supplements, which enhance iron absorption, and to limit alcohol intake, as it worsens liver damage.