Iron deposition in the liver, also known as hepatic iron overload, occurs when the body accumulates an excessive amount of iron over time. The liver is the body’s primary storage site for iron, making it the first and most severely affected organ when iron levels become unregulated. This excessive accumulation can damage the liver tissue, potentially leading to fibrosis, cirrhosis, and liver failure if the underlying cause is not addressed.
The Mechanism of Iron Overload
The body maintains iron balance through iron homeostasis, which primarily regulates absorption since humans lack a mechanism for actively excreting excess iron. Iron is absorbed from the diet in the small intestine and is transported through the bloodstream, primarily bound to transferrin. The liver plays a central role by producing and responding to hepcidin, a peptide hormone that is the master regulator of iron.
Hepcidin controls the release of iron into the blood by binding to and degrading ferroportin, the cellular iron exporter found on intestinal cells, macrophages, and liver cells. When iron levels are high, hepcidin production increases, reducing iron absorption from the gut and trapping iron within storage cells. In healthy individuals, the liver stores iron safely inside ferritin, a protein shell.
When regulatory signals fail or the body is overwhelmed by iron, this protective system breaks down. Excess iron saturates transferrin and is deposited in liver cells. As iron stores exceed the capacity of ferritin, the iron aggregates into hemosiderin, a less soluble and more toxic form. This excess iron generates reactive oxygen species, leading to oxidative stress that directly damages liver tissue, causing inflammation and scarring.
Primary and Secondary Causes
Iron overload is categorized into primary (genetic) and secondary (acquired) causes. The most common primary cause is Hereditary Hemochromatosis (HH), a genetic disorder leading to excessive iron absorption from the diet. Most HH cases are linked to mutations in the HFE gene, which causes the liver to inappropriately sense low iron levels and suppress hepcidin production. This hepcidin deficiency allows the body to constantly absorb and retain too much iron, leading to progressive accumulation over decades.
Secondary iron overload is acquired and typically results from conditions that bypass the body’s natural regulatory mechanisms. The most frequent cause is repeated blood transfusions, often required for individuals with chronic anemias like thalassemia or sickle cell disease. Each unit of transfused red blood cells contributes a significant amount of iron that the body cannot excrete, leading to accumulation primarily in the liver and heart.
Chronic liver diseases can also contribute to secondary iron deposition, even without high dietary intake or multiple transfusions. Conditions such as non-alcoholic steatohepatitis (NASH), alcoholic liver disease, and chronic viral hepatitis impair the liver’s ability to regulate iron. In these cases, the disease process itself can interfere with hepcidin signaling, leading to increased iron absorption and storage.
Recognising the Signs and Diagnosis
Recognizing iron overload can be challenging because early signs are often vague and non-specific, resembling symptoms of many other common conditions. Patients may initially report chronic fatigue, generalized weakness, and persistent joint pain, particularly in the knuckles of the index and middle fingers. As iron deposits increase, localized symptoms may emerge, such as upper abdominal discomfort and an enlarged liver.
Late-stage symptoms reflect significant organ damage from iron toxicity, including the development of cirrhosis or heart rhythm abnormalities. Skin darkening, often described as a bronze or grayish tint, can occur due to iron deposits. These advanced signs often prompt diagnosis, but the goal is to identify the condition before irreversible damage occurs.
Diagnosis typically begins with blood tests to measure the body’s iron status. The two most informative tests are serum transferrin saturation (TSAT) and serum ferritin. TSAT measures the percentage of iron-carrying transferrin molecules bound to iron, while serum ferritin indicates the amount of iron stored. A TSAT value greater than 45% is considered elevated, suggesting too much circulating iron, and a high ferritin level suggests excessive iron storage. If these markers are high, genetic testing for the HFE gene mutation can confirm Hereditary Hemochromatosis. Advanced diagnostic tools include Magnetic Resonance Imaging (MRI), which non-invasively quantifies liver iron, and a liver biopsy, sometimes used to confirm the extent of deposition and determine if cirrhosis has developed.
Management and Treatment Approaches
The primary goal of treatment is to reduce the total body iron burden to prevent or reverse organ damage. For Hereditary Hemochromatosis, the standard treatment is therapeutic phlebotomy, which involves the regular removal of a unit of blood, similar to blood donation. This procedure stimulates the body to use stored iron to make new red blood cells, physically removing excess iron. Initially, phlebotomy may be performed weekly until iron levels normalize, followed by a maintenance phase every few months, depending on the patient’s iron accumulation rate.
When phlebotomy is not a suitable option, such as in cases of iron overload secondary to anemia or heart conditions, chelation therapy is utilized. This treatment involves administering medications, either orally or via injection, that bind to the excess iron. The medication-iron complex is then excreted by the body through the urine or stool, clearing the iron that cannot be removed by bloodletting.
Beyond medical procedures, certain lifestyle modifications are important for managing iron overload. Patients are advised to avoid iron supplements and multivitamins containing iron. They should also minimize the consumption of raw shellfish, which can carry bacteria that thrive in high-iron environments. Moderating alcohol intake is highly recommended, as excessive consumption can accelerate liver damage and progression to cirrhosis. Regular monitoring of serum ferritin and transferrin saturation is necessary to ensure iron levels remain within the safe range.