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]

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

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]

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.