How can hepcidin levels be increased?

Methods to Increase Hepcidin Levels

Iron reduction therapy is the most effective approach to increase hepcidin levels in patients with iron overload disorders, as it directly addresses the underlying pathophysiology and improves clinical outcomes. 1

Understanding Hepcidin's Role in Iron Metabolism

Hepcidin is a 25-amino acid peptide hormone primarily produced by the liver that serves as the master regulator of systemic iron homeostasis. It functions by:

• Binding to ferroportin (the only cellular iron exporter)
• Causing internalization and degradation of ferroportin
• Blocking iron export from enterocytes, macrophages, and hepatocytes
• Decreasing systemic iron availability when levels are elevated 1

Low hepcidin levels are observed in hereditary hemochromatosis and non-hemochromatosis iron overload diseases, making hepcidin regulation a key therapeutic target 1.

Therapeutic Approaches to Increase Hepcidin Levels

1. Iron Reduction Therapy

Iron reduction is the most established method to increase hepcidin levels:

• Phlebotomy: Regular blood removal decreases iron stores and stimulates hepcidin production
• Chelation therapy: Iron chelators like deferoxamine, deferiprone, and deferasirox can reduce iron stores
• Caution: Monitor for anemia during phlebotomy, especially in patients with ferroportin disease (LOF mutations) 1

2. Hepcidin Inducers

Several compounds can stimulate hepcidin production:

• BMP pathway activators: Enhance the BMP/SMAD signaling pathway that regulates hepcidin expression
• Inflammation modulators: IL-6 stimulates hepcidin via the STAT3 pathway, though this approach must be carefully managed 1, 2

3. Hepcidin Supplements

Direct supplementation with synthetic hepcidin or hepcidin analogs:

• Minihepcidins (synthetic hepcidin peptides)
• Hepcidin mimetics that bind ferroportin 3

4. Calcium Channel Blockers

Calcium channel blockers (CCBs) may indirectly increase hepcidin levels:

• Verapamil and amlodipine have shown promise in mouse models of iron overload cardiomyopathy
• CCBs inhibit L-type calcium channels (LTCC), which are involved in iron uptake
• This reduces myocardial iron accumulation and may affect hepcidin regulation 1

5. Gene Therapy Approaches

Emerging but still experimental:

• Targeting overexpression of hepcidin gene (HAMP)
• Inhibition of DMT-1 expression
• Modulation of ferroportin expression
• Expression of wild-type HFE gene using duodenal stem cells 1

Clinical Considerations and Pitfalls

Monitoring Parameters

When attempting to increase hepcidin levels, monitor:

• Serum hepcidin levels (using mass spectrometry techniques)
• Ferritin and transferrin saturation (TSAT)
• Hemoglobin levels to avoid anemia
• Liver and cardiac iron content (by MRI when appropriate) 1

Potential Complications

• Anemia risk: Excessive hepcidin can lead to iron-restricted erythropoiesis
• Infection risk: Iron is essential for immune function; rapid changes may affect immunity
• Cardiac function: Monitor for cardiac complications in patients with existing iron overload cardiomyopathy 1

Special Populations

• Patients with renal disease: Hepcidin levels are already elevated in chronic kidney disease; additional increases may worsen anemia 1
• Patients with inflammatory conditions: Already have elevated hepcidin; additional increases may exacerbate anemia of inflammation 2, 4

Algorithm for Increasing Hepcidin Levels

1. Assess baseline iron status:

   • Measure serum ferritin, TSAT, hemoglobin, and hepcidin levels
   • Evaluate for underlying conditions (hemochromatosis, thalassemia, etc.)

2. For patients with iron overload:

   • Begin with iron reduction therapy (phlebotomy or chelation)
   • Target ferritin <1000 ng/mL initially
   • Monitor hepcidin response

3. For patients with normal iron stores but low hepcidin:

   • Consider hepcidin inducers or supplements
   • Monitor for development of anemia

4. For patients with cardiac iron overload:

   • Consider adding calcium channel blockers to the regimen
   • Monitor cardiac function closely

5. For all patients:

   • Regular monitoring of iron parameters every 3-6 months
   • Adjust therapy based on hepcidin levels and clinical response

Remember that hepcidin regulation is complex and influenced by multiple factors including iron status, inflammation, erythropoiesis, and hypoxia. A targeted approach based on the underlying pathophysiology will yield the best results.