Iron Disorders

Hepcidin Excess

Anemia of Inflammation (also referred to as anemia of chronic disease)

Hepcidin is increased in many patients with chronic inflammation, infections, rheumatologic disorders and inflammatory bowel diseases. Inflammatory stimulation of hepcidin production through interleukin-6 (IL-6) and other pathways is well documented and would be expected to produce a clinical picture of anemia of inflammation.

Anemia of Chronic Kidney Disease

Hepcidin is elevated in patients with chronic kidney disease. These patients commonly suffer from iron-restrictive disorder. Recent studies indicate that CKD patients have high circulating hepcidin levels, likely due to decreased clearance of hepcidin and its induction by inflammation related to the underlying disease or hemodialysis.

Anemia of Cancer

Anemia of some cancers, including Hodgkin’s disease and multiple myeloma, is associated with increased hepcidin production and resembles anemia of inflammation.

IRIDA

Hepcidin excess is associated with familial iron-refractory iron deficiency anemia (IRIDA), caused by the mutation in a negative hepcidin regulator, matriptase-2 (also called TMPRSS6). Despite severe iron deficiency, patients with IRIDA show high-normal or even increased serum hepcidin and are resistant to oral iron therapy. They are partially responsive to parenteral iron therapy.

 

Hepcidin Deficiency

Hereditary Hemochromatosis

Hepcidin deficiency is the cause of most forms of genetic iron overload disorder, known as hereditary hemochromatosis. In this disease, hepcidin is decreased either as a result of mutations in the hepcidin gene itself or in the proteins that regulate hepcidin synthesis. The degree of hepcidin deficiency correlates with the severity of iron overload. Hereditary hemochromatosis patients are currently treated by bleeding. The treatment is effective, but it is inconvenient and may be difficult for patients with poor venous access or coexisting medical conditions. Furthermore, once iron-depleted, patients with hereditary hemochromatosis experience a dramatic decrease in hepcidin and this further accelerates iron absorption and the need for further phlebotomy.

Iron-Loading Anemias

Hepcidin deficiency also contributes to iron-loading anemias, such as  β-thalassemia. This disorder is characterized by ineffective erythropoiesis, during which the defective β-globin is produced, causing excess ∝-globin to precipitate. Thalassemia patients are currently treated by iron chelation, which can have significant side effects. In β-thalassemia patients treated with regular transfusions, iron overload is primarily the consequence of the treatment, and hepcidin levels are normal or even increased, although still deficient considering the iron overload.

Serum hepcidin in various disease processes 1

Disease Pathophysiology Serum hepcidin
Iron deficiency Blood loss, malnutrition Low/undetectable
Iron-refractory iron deficiency anemia Genetic overproduction of hepcidin High normal to high
Anemia of hepatic adenomas Autonomous hepcidin production by tumor High? (only tumor mRNA measured)
Hereditary hemochromatosis Genetic hepcidin deficiency, varying severity Undetectable, low, or low for iron load
Secondary iron overload Transfusions, iron therapy High
β-thalassemia intermedia (rare transfusions) Ineffective erythropoiesis, high erythropoietic drive Low
β-thalassemia major (regular transfusions) Ineffective erythropoiesis, moderated erythropoietic drive, secondary iron overload Low or low for iron load
Hepatitis C, alcoholic liver disease Suppression of hepcidin by alcohol, virus or growth factors Low
Infections, rheumatologic diseases, inflammatory bowel disease, cancer Inflammation High
Chronic kidney diseases Decreased clearance of hepcidin, variable inflammation High

(1) T Ganz and E Nemeth. Hepcidin and Disorders of Iron Metabolism. 2011. Ann Rev Med 62: 347-360.