Hepcidin is a small peptide hormone, typically composed of 25 amino acids, that the body uses to manage iron levels. It is primarily produced by hepatocytes, the main cells of the liver. Hepcidin acts as the central regulator of iron metabolism, controlling how much of this metal enters the bloodstream for use by the rest of the body. It maintains a stable balance, preventing both iron deficiency and toxic iron overload.
Hepcidin’s Role as Iron Regulator
The body tightly controls iron flow through a single mechanism centered on the protein ferroportin. Ferroportin is the only known cellular channel responsible for exporting iron from cells into the blood plasma. This protein is found on the surface of specific cells, including those in the gut, liver, and macrophages, which are immune cells responsible for recycling iron from old red blood cells.
Hepcidin functions by acting directly on this iron exporter. When hepcidin levels rise in the blood, the hormone binds to ferroportin molecules on the cell surface. This binding action triggers the internalization of the ferroportin protein, effectively pulling it off the membrane and into the cell.
Once inside the cell, the hepcidin-ferroportin complex is directed to the lysosomes, where it is degraded. By causing the destruction of the iron export channel, hepcidin immediately shuts off the release of iron into the blood. This mechanism prevents iron from the diet, iron recycled by macrophages, and iron stored in the liver from reaching the rest of the body.
Action in the gut’s duodenal enterocytes halts the absorption of dietary iron, reducing the total iron entering the system. Simultaneously, by trapping iron within macrophages and liver cells, hepcidin ensures that iron is safely sequestered in storage.
Factors Influencing Hepcidin Production
The liver constantly adjusts hepcidin production in response to signals reflecting the body’s current need for iron. The most direct signal is the body’s iron status; when iron stores are high, the liver increases hepcidin synthesis via a signaling pathway involving Bone Morphogenetic Protein 6 (BMP6). This negative feedback loop limits further iron absorption and accumulation, protecting against toxicity.
Conversely, when the body experiences low iron levels or increased demand for red blood cell production, hepcidin synthesis is suppressed. A high rate of erythropoiesis (red blood cell production) leads to the release of factors that inhibit hepcidin production. This reduction in hepcidin allows ferroportin to remain active, maximizing iron release from storage and absorption from the diet to support hemoglobin synthesis.
A major non-iron signal influencing hepcidin is inflammation, often initiated by infection or chronic disease. Pro-inflammatory signaling molecules, most notably Interleukin-6 (IL-6), stimulate the liver to increase hepcidin production through the JAK/STAT signaling pathway. This inflammatory response is a component of the body’s innate immune defense, as the resulting iron restriction limits the amount of available iron that invading pathogens need to thrive.
Another regulating factor is hypoxia (low oxygen levels), which acts to suppress hepcidin. When oxygen is scarce, the body needs more red blood cells to carry oxygen, prompting a decrease in hepcidin. This suppression ensures that iron is available for the accelerated production of new oxygen-carrying cells.
Health Implications of Hepcidin Imbalance
Dysregulation of hepcidin levels is responsible for several iron-related disorders. Persistently high hepcidin levels lead to Anemia of Inflammation (AI), historically called Anemia of Chronic Disease (ACD). Ongoing inflammation causes the liver to overproduce hepcidin, locking iron inside macrophages and liver cells.
The resulting iron restriction prevents iron from reaching the bone marrow for red blood cell production, leading to a functional iron deficiency. Even with adequate total iron stores, the iron is inaccessible, resulting in iron-restricted erythropoiesis and anemia. Measuring serum hepcidin can be useful in distinguishing this condition, where hepcidin is high, from classic Iron Deficiency Anemia (IDA), where hepcidin is appropriately low.
Chronically low or absent hepcidin causes excessive iron release and absorption. Hereditary Hemochromatosis (HH) is a genetic disorder where mutations in the hepcidin gene or its regulatory pathways result in insufficient hepcidin production. Without the hepcidin brake, the body continuously absorbs and releases iron without restraint, leading to a buildup in organs.
Iron overload can cause severe damage to the liver, heart, and pancreas if left untreated. Conversely, in classic IDA caused by chronic blood loss or poor diet, hepcidin levels are suppressed and often undetectable. The low hepcidin is a proper biological response, as the body attempts to compensate for its iron deficit by maximizing the iron it can absorb.