Physiology, Hepcidin

Article Author:
Kevin Chambers
Article Editor:
Sandeep Sharma
3/16/2019 2:27:20 PM
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Physiology, Hepcidin


Hepcidin is a peptide hormone produced in the liver that plays a crucial role in iron homeostasis. Iron is an essential part of oxygen transport within the body and is present in hemoglobin, myoglobin, and the electron transport chain. Serum iron levels must be tightly regulated to ensure an adequate supply is available for hemoglobin synthesis during erythropoiesis, without allowing iron overload to occur in the body. Hepcidin decreases the level of iron by reducing dietary absorption and inhibiting iron release from cellular storage. Hepcidin production increases when iron levels rise above the normal range of 65 to 175 mcg/dL in males and 50 to 170 mcg/dL in females.

Hepcidin is an acute-phase reactant, one of many molecules whose plasma concentration changes in response to inflammation. During states of acute or chronic inflammation, levels of hepcidin and other acute-phase reactants increase, leading to a decrease in serum iron levels as hepcidin levels rise. Increased hepcidin correlates with the pathophysiology of anemia of chronic disease; the increase in inflammation causes a decrease in serum iron levels because the increase in hepcidin reduces iron transport out of cells. Conversely, a deficiency in hepcidin production can result in iron overload as seen in hereditary hemochromatosis.[1][2]


Hepatocytes are primarily responsible for the synthesis of hepcidin. Hepcidin is produced initially as a preprohormone of eighty-four amino acids before being enzymatically cleaved into a prohormone and then cleaved again into hepcidin, a peptide hormone 25 amino acids in length. Many factors influence hepcidin gene expression. Up-regulation occurs during inflammatory states and is primarily mediated by IL-6, a pro-inflammatory cytokine released from a variety of cell types. Transferrin, an iron binding transport molecule in the blood, can also up-regulate hepcidin production, signaling that iron storage in the serum is adequate and that the release of iron from intracellular storage is not currently needed. Erythroferrone, produced by erythroblasts during erythropoiesis, down regulates hepcidin gene expression. Another down-regulator of hepcidin gene expression is hypoxia. Both erythroferrone and hypoxia signal a demand for iron to construct new hemoglobin molecules.[3][4][2]

Organ Systems Involved

Iron plays a central role in the maturation and proper functioning of erythrocytes and is therefore essential to hematologic function. Hepcidin acts as a key regulator in serum iron levels by modulating the release of iron from intracellular storage sites. When hepcidin levels are elevated, iron remains in its intracellular storage form, bound to the molecule ferritin. Hepcidin forms a connection between the immune system and the hematologic system. The theory is that during inflammatory states caused by infection hepcidin levels increase, so that serum iron levels decrease. The decreased serum iron levels prevent the invading pathogen from using the host’s iron stores for its own growth. Therefore, hepcidin is an essential mediator for immune defenses as well as hematologic functioning.[5]


Once released into circulation from hepatocytes, hepcidin regulates plasma iron levels through interactions with ferroportin, an iron export transmembrane protein. Specifically, hepcidin binds to ferroportin signaling a cascade of intracellular messengers that target the hepcidin-ferroportin complex for lysosomal degradation. The cell types most affected by this interaction are duodenal enterocytes and reticuloendothelial macrophages. Duodenal enterocytes absorb dietary iron, and reticuloendothelial macrophages release iron recovered from degraded erythrocytes in the bone marrow, liver, and spleen. The degradation of ferroportin blocks iron from entering circulation and instead remains in its intracellular storage form.[6][7]

Related Testing

Serum iron studies are used to evaluate the status of iron homeostasis in the body. This panel of blood tests typically includes serum iron, transferrin or total iron binding capacity (TIBC), ferritin, and the percentage of transferrin saturation. A level of urinary excreted hepcidin can also be measured. A complete blood count (CBC) may be used to evaluate signs of anemia.

  • Serum Iron: circulating iron with a normal range of 65 to 175 mcg/dL in males and 50 to 170 mcg/dL in females
  • Ferritin: predominantly an intracellular iron storage molecule, serum ferritin directly correlates to total body iron stores - the normal range is 20 to 250 mcg/L in males and 10 to 120 mcg/L in females
  • Transferrin or total iron binding capacity: a measure of transferrin molecules available to bind iron - TIBC is an indirect measurement
  • Transferrin saturation: a calculated measurement that reflects the amount of bound serum iron using the equation: serum iron divided by TIBC


Hereditary Hemochromatosis:

An autosomal recessive defect in the HFE gene, resulting in decreased hepcidin production. HFE mutations are more prevalent in individuals of European descent. Decreased hepcidin results in abnormal iron sensing. Continued iron absorption despite adequate serum levels can lead to iron overload when total body iron exceeds 20g. Symptoms of hemochromatosis are secondary to iron deposition in bodily tissue and typically present in the 4th and 5th decade of life for men and women respectively. The classic triad includes skin hyperpigmentation, liver cirrhosis, and diabetes mellitus. Additional findings include dilated cardiomyopathy, hypogonadism, arthropathy, and hypothyroidism. Hemochromatosis patients also have increased infection risk now that serum iron levels cannot decrease during inflammatory states. Diagnosis is based on iron panel results showing an increased serum iron level with increased ferritin and transferrin saturation levels. Treatment involves the use of phlebotomy or an iron chelating agent like deferoxamine to remove iron from the circulation.[8][9]

Anemia of chronic disease:

This condition is the second most common cause of anemia after iron deficiency anemia. Associated with a variety of disease states including infection, neoplasm, chronic kidney disease, and autoimmune conditions like systemic lupus erythematosus. Hepcidin gets upregulated by IL-6 and other proinflammatory cytokines and leads to degradation of ferroportin. Serum iron levels decline in an attempt to deprive rapidly dividing cells and invading microbes from nutrients. Anemia of chronic disease typically begins as a mild to moderate normocytic normochromic anemia denoted by a hemoglobin concentration of 8 to 9.5 g/dL. The anemia can progress to microcytic and hypochromic if the inflammatory conditions remain. Presenting symptoms are often nonspecific signs of anemia including fever, pallor, and fatigue. An iron panel would show a decrease in serum iron level despite an increase in ferritin because of intracellular iron sequestration. Treatment with iron supplementation is often not beneficial as the issue lies with iron availability and not an iron deficiency. It is crucial to treat the underlying condition to prevent further inflammation.[10]

Clinical Significance

Hepcidin plays a role in innate immunity through its interactions with IL-6 and other pro-inflammatory cytokines. The ability to sequester iron within cells to prevent its availability for pathogenic or neoplastic growth appears to be largely dependent on hepcidin stimulation by IL-6. This innate defense may help protect against many pathogens including streptococcal and malarial species. [11]

Several hepcidin agonists are currently in development and may become a viable treatment for hereditary hemochromatosis. Currently, phlebotomy is the mainstay of treatment for iron overload states, but a hepcidin agonist could help alleviate the symptoms from the deficient natural hepcidin. [12]

Hepcidin plays a central role in iron transport and utilization and is, therefore, an important marker of iron bioavailability.


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