Inappropriate expression of hepcidin by liver congestion contributes to anemia and relative iron deficiency.

Suzuki T, et al.

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address:



BACKGROUND: Anemia and relative iron deficiency (RID) are prevalent in patients with heart failure (HF). The etiology of anemia and RID in HF patients is unclear. Hepcidin expression may be closely related to anemia and RID in HF patients. Although hepcidin is produced mainly by the liver, and the most frequent histologic appearance of liver in HF patients is congestion, the influence of liver congestion (LC) on hepcidin production has not yet been investigated. We investigated whether hepcidin contributed to anemia and RID in rats with LC.

METHODS AND RESULTS: LC was induced in rats by ligating the inferior vena cava and compared with bleeding anemia (BA) model induced by phlebotomy and hemolytic anemia (HA) model induced by injection of phenylhydrazine. BA and HA strongly suppressed expression of hepcidin in liver and so did not cause decrease in serum iron and transferrin saturation. However, hepcidin expression did not decrease in LC rats, which resulted in anemia and lower transferrin saturation. In addition, many cells with hemosiderin deposits were observed in the liver and spleen and not in the bone marrow, and this appeared to be related to suppression of hepcidin expression. Iron accumulated in hepatocytes, and bone morphogenetic protein 6, which induces hepcidin, increased. Inflammation was observed in the congestive liver, and there was an increase in interleukin-6, which also induced hepcidin and was induced by free heme and hemoglobin via Toll-like receptor 4.

CONCLUSIONS: We conclude that LC contributes to RID and anemia, and it does so via inappropriate expression of hepcidin. Copyright © 2014 Elsevier Inc. All rights reserved.

KEYWORDS: Heart failure; Toll-like receptor 4; bone morphogenetic protein; cytokine

PMID: 24440572



The study by Suzuki et al. suggested that liver congestion caused inappropriate increased expression of hepcidin, which is mainly produced by the liver and a key regulator of mammalian iron metabolism, and contributed to anemia and relative iron deficiency. Most common cause of liver congestion in clinical patients is caused by right heart failure. Heart failure is sometimes complicated by anemia and relative iron deficiency. Because anemia in heart failure patients is an independent prognostic factor for mortality, it is important to treat anemia in heart failure patients. Clinicians tend to consider gastrointestinal bleeding and hemolysis as common causes of anemia and iron deficiency in right heart failure patients. However, hepcidin levels should be considered in such patients. Anemia by bleeding and hemolysis markedly reduce the expression of hepcidin. On the other hand, Suzuki et al. demonstrated that anemia and relative iron deficiency in rats with liver congestion only slightly reduced the expression of hepcidin. Suzuki et al. postulated two mechanisms of upregulation of hepcidin in liver congestion (i) BMP-6 pathway (ii) IL-6 pathway. Accumulation and destruction of red blood cells in liver seem to increase concentration of intracellular iron in hepatocytes. Increased intracellular iron induces expression of BMP-6 and resulting in increased expression of hepcidin. On the other hand, destruction of red blood cells may produce free hemoglobin and heme as danger signals that can induce proinflammatory cytokines such as IL-1 and IL-6 in Kupffer cells and hepatic stellate cells via Toll-like receptor 4 and resulting in increased expression of hepcidin. Liver congestion is suggested to be an important factor contributing to anemia and relative iron deficiency in heart failure via inappropriate increased hepcidin expression.