Hepcidin is a hormone primarily produced by the liver, acting as a central regulator of iron in the body. Its discovery marked a significant advancement in understanding how the body maintains iron balance. This small peptide hormone plays a fundamental role in ensuring that iron levels are neither too high nor too low, which is a delicate balance given iron’s necessity for many bodily functions and its potential toxicity in excess.
The body lacks a specific mechanism for actively excreting iron, making regulation at the point of absorption and release particularly important. Hepcidin helps manage this by responding to the body’s iron needs and other signals like inflammation.
Hepcidin’s Master Role in Iron Regulation
Hepcidin functions as the body’s iron gatekeeper by directly controlling ferroportin, the only known protein responsible for exporting iron from cells. When hepcidin levels rise, it binds to ferroportin, causing the iron exporter to be internalized and degraded. This action effectively shuts down the pathways through which iron enters the bloodstream.
Hepcidin reduces the absorption of dietary iron from the gut by blocking ferroportin on intestinal cells. It also prevents iron release from macrophages, which are immune cells that recycle iron from old red blood cells. Furthermore, hepcidin inhibits the release of stored iron from liver cells.
By blocking iron export from these key cells, hepcidin ensures that iron is sequestered within them, decreasing the amount of iron circulating in the blood plasma. This tight control helps prevent iron overload, which can be damaging to tissues and organs. This process helps coordinate iron use and storage with iron acquisition, maintaining overall iron homeostasis.
When Hepcidin Levels Are Too Low
When hepcidin levels are insufficient, the body absorbs and retains too much iron, leading to hereditary hemochromatosis. This genetic disorder is often linked to mutations in the HFE gene, which affects hepcidin’s regulatory function. With low hepcidin, ferroportin remains active, allowing excessive iron to enter the bloodstream from the gut and to be released from storage cells.
Iron accumulates in various organs, including the liver, heart, pancreas, and joints. The symptoms of hereditary hemochromatosis typically appear in adulthood, often between the ages of 40 and 60 for men, and after menopause for women. Early signs can include fatigue, joint pain, and abdominal discomfort.
As iron continues to build up, more severe complications can develop, such as liver damage, which may progress to cirrhosis and an increased risk of liver cancer. Other issues include diabetes due to iron deposition in the pancreas, heart problems like arrhythmias or heart failure, and joint pain or arthritis. Some individuals may also notice skin discoloration, appearing bronze or gray, due to iron deposits.
When Hepcidin Levels Are Too High
Elevated hepcidin levels can also lead to “anemia of chronic disease” or “anemia of inflammation.” Chronic inflammation, often associated with long-term infections, autoimmune diseases, or cancers, causes the liver to produce an excess of hepcidin. This increased hepcidin traps iron within cells, even if the body has adequate overall iron stores.
The heightened hepcidin production inhibits iron absorption from the small intestine and restricts the release of recycled iron from macrophages. This action effectively limits the amount of iron available for red blood cell production in the bone marrow, leading to anemia despite sufficient iron reserves. The body’s attempt to withhold iron from invading pathogens during inflammation inadvertently reduces iron availability for red blood cell synthesis.
Symptoms of anemia of chronic disease are similar to other forms of anemia and can include fatigue, weakness, shortness of breath, and pale skin. The severity of the anemia is often mild to moderate, with hemoglobin levels typically ranging from 8 to 10 grams per deciliter. Managing this type of anemia often involves addressing the underlying inflammatory condition, as iron supplementation alone may not be effective due to the iron-trapping effect of high hepcidin.