Help with hepcidin

Over the past several years, the mechanisms involved in iron overload have been carefully examined and the genetic basis for most of these disorders is now understood.  Several review articles on these disorders have been published; the most recent with excellent diagrams is in last week’s NEJM (NEJM 2012; 366: 348-59 & NEJM 2012; 366: 376-77). Although the process is quite complicated, the most important aspect regarding iron homeostasis is a feedback loop involving hepcidin-ferroportin.  Hepcidin functions as a ‘hypoferremia hormone.’  It down regulates ferroportin release of iron into the circulation.  Hepcidin is also an acute-phase protein and inflammation affects its function.

Hepcidin levels fluctuate in response to the body’s iron needs: more hepcidin causes less iron absorption & less hepcidin causes more iron absorption.

  • Iron balance disorders can usually be attributed to altered hepcidin production.
  • Anemia of chronic disease, though multifactorial, is mostly due to increased hepcidin production in response to inflammation.
  • Hemochromatosis results from genetic mutations causing lack of normal hepcidin production.  The severity of these disorders correlates with hepcidin levels.
  • Hepcidin agonists could be used to treat hemochromatosis and other iron overload conditions (eg. thalassemia with transfusion therapy).  For hemochromatosis, phlebotomy will be less expensive.
  • Hepcidin antagonists could treat anemia of chronic disease

Additional references:

  • -Hepatology 2011; 54: 328.  Review.  Guidelines.
  • -Hepatology 2010; 52: 925.  HFE homozygotes, n=31,192 w low risk of clinical symptoms if ferritin <1000.
  • -Gastroenterology 2010; 139: 393. Review –pathogenesis/dx/Rx
  • -Hepatology 2009; 50: 94.  C282Y/H63D compound heterozygotes (n=180) are at low risk for hemochromatosis-related morbidity compared with control group.
  • -Hepatology 2008; 48: 991.  Review.
  • -Hepatology 2007; 46: 960, 1071.  Review of clinical phenotypes.  Of C282Y homozygotes, only 1-2% develop HCC, 6% cirrhosis, 25% liver fibrosis, 38% Fe overload, 61-75% develop raised serum iron indices.
  • -Hepatology 2007; 46: 1291. Review of hemochromatosis
  • -Hepatology 2007; 45: 253. Review of iron metabolism
  • -NEJM 2004; 350: 2383. Review.  Several genetic mutations associated with clinical phenotype.  type 1: Classic HFE, types 2A & 2B: (Juvenile type)  HJV & HAMP (gene products hemojuvelin & hepcidin), type 3:TFR2 (transferrin receptor 2), and type 4:SLC40A1
  • -NEJM 2005; 352: 1011. Algorithm.  If transferrin saturation <16%, check ferritin.  If ferritin less than 30, Fe-deficiency; if >100, anemia of chronic disease.  If 30-100, check soluble transferrin receptor (level of sTranReceptor/log ferritin less than 1 is c/w anemia of chronic disease whereas when this ratio is greater than 2, c/w combined Fe-def anemia and anemia of chronic disease).  Hepcidin is produced by hepatocytes and regulates iron homeostasis.  Hepcidin interacts with ferroportin, an iron export protein on enterocytes (& other cells), & facilitates internalization and degradation of ferroportin.  It may lead to decreased dietary iron absorption and to retention of iron body stores.  Hepcidin expression can be up-regulated by high iron levels or during acute phase inflammatory responses (thus can contribute to anemia of chronic disease).  Hereditary hemochromatosis associated with low hepcidin levels in the face of increased iron body stores.  Several genes can affect hepcidin loss of function, including HFE, hemojuvelin (HJV), and transferrin receptor 2 (TFR2).
  • -Gastroenterology 1996; 110: 1107.  Sentinel article discussing long-term survival in hemochromatosis and role of iron.
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7 thoughts on “Help with hepcidin

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