GDF15 Is Not The Sole Negative Regulator Of Hepcidin In Hereditary Xerocytosis

Hereditary xerocytosis (HX) is a rare form of hemolytic anemia with autosomal dominant inheritance in which iron loading is a prominent feature. The mutated gene causing HX has been identified as FAM38A, which codes for the PIEZO1 protein, a mechanosensitive ion channel [1].The phenotype and genotype of HX has been characterized in a large Canadian family with members spanning three generations and seven decades[2]. Affected family members demonstrate fully-compensated hemolytic anemia (average reticulocyte count 9.9%, hemoglobin 135g/L) and their red cells exhibit decreased levels of osmotic fragility. Despite elevated reticulocyte counts and elevated unconjugated bilirubin levels, serum lactate dehydrogenase levels are normal, suggesting that little if any of the erythropoiesis is ‘ineffective’. Affected family members accumulate iron with age, with average ferritin levels for adults of 478 μg/L. The mechanism behind the iron loading in HX is not known. It is now recognized that in these forms of anemia, hepcidin levels are inappropriately low for the degree of iron store, implying the presence of a mediator produced by the hematopoietic progenitors that acts on the liver to suppress hepcidin production. One pathway that appears important in regulating hepcidin synthesis is the bone morphogenetic protein (BMP)-SMAD signaling cascade. The importance of BMP6 is evident from studies using gene knockout mice. Likewise, liver-targeted knockdown of SMAD4 impairs production of hepcidin and resulted in iron overload in the mice [3]. BMP6 may act in an autocrine fashion, and its secretion by hepatocytes is upregulated in the presence of elevated iron levels.

Another proposed pathway for hepcidin regulation – speculated to be involved in the erythropoietic regulation of iron – involves another cytokine also from the TGF-β superfamily. Growth differentiation factor 15 (GDF15) is expressed in high levels in placenta tissue and in smaller quantities in the liver, lungs and kidneys. It is also secreted by erythroblasts, at least in culture. Plasma levels of GDF15 are greatly increased in thalassemia and correlate with markers of erythroid mass such as the soluble transferrin receptor. Serum from thalassemic patients suppresses hepcidin mRNA expression by cultured hepatocytes, an effect partially recapitulated by recombinant GDF15, suggesting that the cytokine requires a co-factor for full hepcidin inhibition [4].

We evaluated the level of hepcidin, EPOand ferritin along with GDF15 in 29 affected individuals from a single kindred with HX, and a similar number of age matched unaffected family members to explore the putative erythropoietic regulator of iron absorption in a homogeneous genetic context. We find that ferritin level positively predicts hepcidin level (p<.001) and age negatively predicts hepcidin level. After adjustment for age and ferritin, GDF15 does negatively predict hepcidin level(p=.046 in the final fully-adjusted model). However, in a regression model adjusting for ferritin, age and GDF15, xerocytosis still predicts hepcidin level, with lower hepcidin among the affected family members (p<.001).

These results suggest that GDF15 may be one mediator of hepcidin suppression and iron loading in hereditary xerocytosis. However, its effect is insufficient to explain the full iron-loading propensity.’

1. Zarychanski, R., et al., Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis. Blood, 2012. 120(9): p. 1908-15.

2. Houston, B.L., et al., Refinement of the hereditary xerocytosis locus on chromosome 16q in a large Canadian kindred. Blood Cells Mol Dis, 2011. 47(4): p. 226-31.

3. Corradini, E., et al., Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology, 2011. 54(1): p. 273-84.

4. Tanno, T., et al., High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med, 2007. 13(9): p. 1096-101.