Introduction

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 reduction 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]

Cellular Level

Hepatocytes are primarily responsible for the synthesis of hepcidin. Hepcidin is produced initially as a preprohormone with eighty-four amino acids. It is then cleaved into a prohormone, which gets cleaved again, forming hepcidin. The final hepcidin protein has 25 amino acids. 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 is a hormone produced by erythroblasts during erythropoiesis. It down-regulates the hepcidin gene expression. Hepcidin gene is also downregulated during hypoxic conditions. 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. It is essential to hematologic function. Hepcidin acts as a critical regulator for serum iron levels by modulating the release of iron from intracellular storage sites. When hepcidin levels become 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, 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 growth. Therefore, hepcidin is an essential mediator for immune defenses as well as hematologic functioning.[5]

Function

Once released into circulation from hepatocytes, hepcidin regulates plasma iron levels through interactions with ferroportin-1. Ferroportin is an iron export transmembrane protein present in the macrophages and the enterocytes. When hepcidin binds to ferroportin, it causes the cell to 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 store iron recovered from degraded erythrocytes in the bone marrow, liver, and spleen. The degradation of ferroportin blocks iron absorption from enterocytes and iron mobilization from the macrophages.[6][7]

Related Testing

Serum iron studies are useful 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

Pathophysiology

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 increased iron uptake from diet and increased iron mobilization from macrophages. Continued iron absorption despite adequate serum levels can lead to iron overload (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. The diagnostic basis is iron panel results showing an increased serum iron level with increased ferritin (> 200 mcg/L) and transferrin saturation levels (> 45%). Treatment involves lifestyle modifications, therapeutic phlebotomy, and medications. Dietary changes include a diet low in iron, restriction of vitamin C supplements and alcohol, and consuming tea because tannates reduce iron absorption by binding to it. About 1 to 2 therapeutic phlebotomy sessions per week initially to bring ferritin and hemoglobin to the target level and then every 2 to 4 months. The iron-chelating agents like deferoxamine to remove iron from the circulation.[8][9]

Anemia of Chronic Disease

Anemia of chronic disease is the second most common cause of anemia after iron deficiency anemia. It is associated with a variety of disease states, including infection, neoplasm, chronic kidney disease, and autoimmune conditions like systemic lupus erythematosus. Hepcidin is an acute-phase protein, and upregulation is by interleukin-6 (IL-6) and other proinflammatory cytokines. As a result, hepcidin causes enterocytes and macrophages to degrade ferroportin, reducing absorption and promoting storage, respectively. 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 rather than 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.