Iron Deposition in Liver: Causes and Clinical Impact

Iron is essential for many biological functions, but excessive accumulation in the liver can lead to serious health consequences. The liver plays a central role in iron metabolism, storing excess amounts when regulatory mechanisms fail. Over time, this buildup can cause cellular damage, fibrosis, and even organ failure if left untreated.

Iron Distribution In The Body

Iron is a fundamental element in human physiology, with its distribution tightly regulated to balance metabolic demands and prevent toxicity. The majority of iron is incorporated into hemoglobin within red blood cells, facilitating oxygen transport. Approximately 65–70% of total body iron is found in circulating erythrocytes, bound to heme groups that enable oxygen binding and release. This iron is continuously recycled by macrophages in the spleen and liver, which break down aging red blood cells and return iron to the bloodstream.

Beyond hemoglobin, iron is also a key component of myoglobin in muscle tissue, supporting oxygen storage and utilization. Additionally, iron serves as a cofactor for enzymes involved in DNA synthesis, mitochondrial respiration, and neurotransmitter production. These roles necessitate a steady supply of bioavailable iron, maintained through dietary absorption in the duodenum. Enterocytes regulate iron uptake via divalent metal transporter 1 (DMT1), transferring non-heme iron into the bloodstream. Once absorbed, iron binds to transferrin, a plasma protein that delivers it to tissues with high metabolic demand.

The liver is the primary storage site for excess iron, sequestering it in ferritin to prevent toxicity. When iron levels rise, ferritin synthesis increases to limit free iron, which can catalyze harmful oxidative reactions. If ferritin capacity is exceeded, excess iron is stored as hemosiderin, an insoluble aggregate that accumulates over time. The liver also produces hepcidin, a regulatory hormone that controls iron absorption and release by binding to ferroportin, the only known cellular iron exporter. Elevated hepcidin degrades ferroportin, reducing iron efflux from enterocytes and macrophages, while low hepcidin levels promote iron availability.

Factors Leading To Hepatic Iron Buildup

Iron accumulation in the liver arises from disruptions in regulatory mechanisms controlling absorption, storage, and mobilization. A primary driver is dysregulation of hepcidin, the hormone governing systemic iron homeostasis. Hepcidin levels fluctuate in response to iron availability, inflammation, and erythropoietic activity. When hepcidin production is abnormally low or its function impaired, ferroportin remains active, leading to excessive intestinal iron absorption and unregulated release from macrophages. This overwhelms the liver’s storage capacity, causing progressive iron deposition.

Genetic mutations affecting iron metabolism contribute significantly to hepatic iron overload. Variants in the HFE gene, particularly the C282Y homozygous mutation, are strongly associated with hereditary hemochromatosis, a condition marked by excessive intestinal iron absorption. Mutations in genes such as HJV (hemojuvelin), HAMP (hepcidin antimicrobial peptide), and TFR2 (transferrin receptor 2) can further disrupt hepcidin regulation, leading to severe forms of iron overload.

Excessive dietary iron intake or prolonged iron supplement use can also contribute to hepatic deposition, particularly in individuals with genetic predisposition. While enterocytes regulate absorption based on systemic needs, compromised hepcidin activity allows even moderate dietary increases to cause disproportionate accumulation. Diets rich in heme iron, such as those heavy in red meat or organ meats, may exacerbate this process, especially when combined with alcohol consumption, which enhances gut permeability and reduces hepcidin expression.

Repeated blood transfusions are another major source of hepatic iron overload, particularly in individuals with chronic anemia requiring lifelong transfusion therapy. Each unit of transfused blood contains approximately 200–250 mg of iron, and since the body lacks an efficient excretion mechanism, recurrent transfusions lead to cumulative deposition in the liver and other organs. Patients with conditions such as thalassemia major, sickle cell disease, and myelodysplastic syndromes are at high risk, as sustained iron loading accelerates liver dysfunction.

Liver diseases that impair iron storage and mobilization further contribute to abnormal retention. Chronic hepatitis C has been associated with mild to moderate hepatic iron accumulation, likely due to inflammatory processes altering hepcidin expression. Similarly, non-alcoholic fatty liver disease (NAFLD) has been linked to increased hepatic iron levels, with studies suggesting that iron overload exacerbates liver injury by promoting oxidative stress and fibrosis.

Types Of Genetic Iron Overload Syndromes

Genetic disorders affecting iron metabolism lead to excessive accumulation in the liver, often due to mutations disrupting hepcidin regulation or iron transport. These conditions vary in severity, age of onset, and inheritance patterns, with some leading to early and aggressive iron deposition while others result in a more gradual buildup.

Hemochromatosis

Hereditary hemochromatosis is the most common genetic cause of iron overload, primarily linked to mutations in the HFE gene. The C282Y homozygous mutation reduces hepcidin production, leading to excessive intestinal iron absorption and progressive hepatic deposition. This increases the risk of fibrosis, cirrhosis, and hepatocellular carcinoma. While symptoms often emerge in mid-adulthood, early detection through genetic testing and serum ferritin measurements can help prevent complications.

Other rarer forms of hemochromatosis involve mutations in genes such as HJV, HAMP, and TFR2, which typically cause more severe, early-onset disease. Juvenile hemochromatosis, caused by HJV or HAMP mutations, leads to aggressive iron accumulation in adolescence or early adulthood, often resulting in endocrine dysfunction and cardiomyopathy in addition to liver damage.

Ferroportin Disease

Ferroportin disease, also known as autosomal dominant hemochromatosis, arises from mutations in the SLC40A1 gene, which encodes ferroportin. Unlike classic hemochromatosis, where iron accumulates primarily in hepatocytes, ferroportin disease often leads to iron deposition in Kupffer cells, the liver’s resident macrophages. This distinct pattern of iron overload may not always be accompanied by elevated transferrin saturation, making diagnosis more challenging.

Since ferroportin disease follows an autosomal dominant inheritance pattern, affected individuals have a 50% chance of passing the mutation to their offspring, highlighting the importance of family screening.

Other Rare Conditions

Other rare genetic disorders can contribute to hepatic iron overload. Aceruloplasminemia, caused by mutations in the CP gene, leads to systemic iron accumulation due to the absence of ceruloplasmin, a ferroxidase enzyme required for iron export. This results in iron buildup in the liver, brain, and pancreas, leading to neurological symptoms and diabetes.

Congenital atransferrinemia, caused by mutations in the TF gene, impairs iron transport, leading to severe anemia and hepatic iron overload. Additionally, mutations in DMT1 (divalent metal transporter 1) can cause iron accumulation due to defective iron export from enterocytes and macrophages.

Secondary Overload From External Sources

Excess iron accumulation in the liver can also arise from external sources. Chronic blood transfusion therapy is a primary cause, particularly in individuals with conditions such as thalassemia major and sickle cell disease. Each transfusion introduces iron the body cannot excrete, leading to relentless accumulation. Patients undergoing long-term transfusion therapy often require iron chelation treatment to prevent toxicity.

Dietary intake plays a role, particularly in populations with high consumption of iron-rich foods or excessive supplementation. While the body regulates iron absorption, individuals consuming large amounts of heme iron—found in red meat and organ meats—may absorb more than necessary. Alcohol further exacerbates this by increasing gut permeability and reducing hepcidin expression.

Effects On Liver Tissues

Excess iron disrupts normal cellular function, triggering oxidative stress that damages hepatocytes. The Fenton reaction generates hydroxyl radicals, which attack lipids, proteins, and DNA, leading to apoptosis and necrosis. Over time, this oxidative burden triggers fibrosis and cirrhosis.

Hepatic stellate cells respond to injury by increasing extracellular matrix production, leading to excessive collagen deposition. If iron accumulation persists, fibrosis progresses to cirrhosis, impairing liver function and increasing the risk of hepatocellular carcinoma.

Clinical Indicators And Diagnostic Approaches

Hepatic iron overload is often detected through clinical suspicion, especially in individuals with unexplained liver dysfunction, diabetes, or fatigue. Laboratory assessments, including serum ferritin and transferrin saturation, serve as initial markers. A ferritin level exceeding 1,000 ng/mL, particularly with transferrin saturation above 45%, strongly suggests iron overload.

MRI-based techniques, such as T2-weighted imaging and R2 relaxometry, allow noninvasive quantification of hepatic iron concentration. Genetic testing confirms hereditary hemochromatosis, while broader panels may be required for rarer forms.

Other Organ Systems Affected By Excess Iron

Iron overload extends beyond the liver, affecting multiple organ systems. The pancreas is particularly vulnerable, as iron accumulation in beta cells impairs insulin secretion, contributing to diabetes. Cardiac involvement can lead to restrictive cardiomyopathy and arrhythmias, while endocrine dysfunction may result in hypogonadotropic hypogonadism and osteoporosis.