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 for hemoglobin synthesis during erythropoiesis, without allowing iron overload. Hepcidin decreases iron levels by reducing dietary iron 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 acute or chronic inflammation, hepcidin and other acute-phase reactants increase, leading to decreased serum iron levels. Increased hepcidin correlates with the pathophysiology of anemia of chronic disease; inflammation reduces serum iron levels by increasing hepcidin, which 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 initially produced as an 84-amino-acid preprohormone. It is then cleaved into a prohormone, which is further cleaved to form 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 downregulates the hepcidin gene expression. The Hepcidin gene is also downregulated during hypoxic conditions. Both erythroferrone and hypoxia signal a demand for iron to construct new hemoglobin molecules.[2][3][4]

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 increase, iron remains in its intracellular storage form, bound to the protein ferritin. Hepcidin links the immune and hematologic systems. The theory is that during inflammatory states, hepcidin levels increase, leading to decreased serum iron levels. 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 of immune defenses and hematologic function.[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 for evaluating iron homeostasis. This panel of blood tests typically includes serum iron, transferrin, total iron-binding capacity (TIBC), ferritin, and 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 the 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 decades 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 an increased risk of infection, as serum iron levels cannot decrease during inflammatory states. The diagnostic basis is iron panel results showing elevated serum iron, ferritin (>200 mcg/L), and transferrin saturation (>45%). Treatment involves lifestyle modifications, therapeutic phlebotomy, and medications. Dietary changes include a low-iron diet, restricting vitamin C supplements and alcohol, and consuming tea, as tannins 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, such as deferoxamine, are used 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, neoplasms, chronic kidney disease, and autoimmune conditions such as 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, thereby reducing iron absorption and promoting iron storage. Serum iron levels decline in an attempt to deprive rapidly dividing cells and invading microbes of nutrients. Anemia of chronic disease typically begins as a mild-to-moderate normocytic, normochromic anemia, with a hemoglobin concentration of 8 to 9.5 g/dL. Anemia can progress to microcytic and hypochromic if the inflammatory conditions persist. 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 symptoms associated with 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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References

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Disclosure: Kevin Chambers declares no relevant financial relationships with ineligible companies.

Disclosure: Muhammad Ashraf declares no relevant financial relationships with ineligible companies.

Disclosure: Sandeep Sharma declares no relevant financial relationships with ineligible companies.