Is hepcidin (hepcidin) elevated in patients with iron deficiency anemia?

Hepcidin Levels in Iron Deficiency Anemia

Hepcidin levels are decreased, not elevated, in patients with iron deficiency anemia (IDA). This reduction in hepcidin is a physiological response to increase iron availability during states of iron deficiency.

Hepcidin Regulation in Iron Deficiency

Hepcidin is the master regulator of iron homeostasis in the body, primarily synthesized by hepatocytes. Its main function is to control iron flow into the bloodstream by:

• Binding to ferroportin (the cellular iron export protein) on enterocytes and macrophages
• Causing internalization and degradation of ferroportin
• Limiting intestinal iron absorption and iron release from storage sites

In iron deficiency anemia, several mechanisms lead to hepcidin suppression:

1. Low iron stores: Decreased iron levels directly signal the liver to reduce hepcidin production 1
2. Increased erythropoietic drive: The body's attempt to increase red blood cell production suppresses hepcidin 1
3. Hypoxia: Tissue hypoxia resulting from anemia activates the HIF system, which inhibits hepcidin 1

Laboratory Evidence

Multiple studies confirm that hepcidin levels are reduced in IDA:

• Screening hepcidin levels were significantly lower in patients with IDA who responded to oral iron therapy (11.3 ng/mL) compared to non-responders (38.4 ng/mL) 2
• In heart failure patients, those with iron deficiency had hepcidin levels in the lowest tertile (<31.7 ng/mL), strongly associated with iron deficiency (OR 16.5,95% CI 2.2-121.2) 3
• A recent study found that suppressed hepcidin levels (≤0.5 nM) were indicative of classical IDA 4

Contrasting with Other Anemias

It's important to distinguish IDA from other types of anemia where hepcidin may be elevated:

• Anemia of chronic disease (ACD): Inflammation increases hepcidin via IL-6 and other cytokines, leading to functional iron deficiency despite adequate iron stores 1
• Iron-refractory iron deficiency anemia (IRIDA): A genetic disorder with unregulated hepcidin synthesis causing iron-restricted erythropoiesis 1
• Mixed anemia (ACD+IDA): Hepcidin levels are higher than in pure IDA but lower than in isolated ACD 5

Clinical Implications

The hepcidin level has important diagnostic and therapeutic implications:

• Low hepcidin in IDA indicates that oral iron supplementation may be effective 2
• High hepcidin despite iron deficiency suggests poor response to oral iron, making IV iron a better option 2
• Hepcidin measurement can help differentiate between classical IDA and IRIDA or ACD 4

Diagnostic Algorithm

When evaluating a patient with suspected iron deficiency anemia:

1. Check complete blood count, serum iron, transferrin saturation, and ferritin
2. If available, measure hepcidin levels
   • Low hepcidin (<20 ng/mL) suggests classical IDA
   • High hepcidin despite low iron parameters suggests ACD or IRIDA
3. Consider transferrin/log ferritin ratio as a surrogate for hepcidin status if direct measurement is unavailable 4
4. In unclear cases, an oral iron absorption test may help differentiate between classical IDA and disorders of iron absorption 4

Understanding hepcidin's role in iron metabolism helps explain why some iron-deficient patients respond poorly to oral iron therapy and may require intravenous iron supplementation instead.