Reply to: “Hepatic hepcidin expression is decreased in cirrhosis and HCC”
Authors: Mariia Lunova, Christian Trautwein, Pavel Strnad, Pierre Nahon
Journal: Journal of Hepatology (2014)

Hepcidin knockout mice fed with iron-rich diet develop chronic liver injury and liver fibrosis due to lysosomal iron overloadJournal of HepatologyVol. 61Issue 3PreviewHepcidin is the central regulator of iron homeostasis and altered hepcidin signalling results in both hereditary and acquired iron overload. While the association between iron overload and development of end-stage liver disease is well established, the underlying mechanisms are largely unknown. To improve that, we analysed hepcidin knockout (KO) mice as a model of iron overload-associated liver disease. Full-Text PDF Hepatic hepcidin expression is decreased in cirrhosis and HCCJournal of HepatologyVol. 62Issue 4PreviewRecent evidence published in this Journal showed the protective role of the iron homeostasis regulator hepcidin (Hamp) in iron overload-related liver diseases [1]. The study by Lunova et al. elegantly demonstrated that the knockdown of hepcidin promotes hepatic inflammation and fibrogenesis after feeding mice an iron-rich diet [1]. Full-Text PDF Open Access We read with interest the letter by Kessler et al. [[1]Kessler Sonja M. Barghash Ahmad Laggai Stephan Helms Volkhard Kiemer Alexandra K. Hepatic hepcidin expression is decreased in cirrhosis and HCC.J Hepatol. 2015; 62: 977-979Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar] that demonstrated decreased hepcidin levels in various stress situations as well as in hepatocellular carcinoma. Lowered hepcidin levels seen in diethylnitrosamine-treated mice nicely complement earlier data on mice subjected to thioacetamide-induced liver fibrosis or administered Lieber-DeCarli diet (an experimental model of alcoholic liver disease), and suggest that diminished hepcidin levels represent a common reaction to various liver stresses [1Kessler Sonja M. Barghash Ahmad Laggai Stephan Helms Volkhard Kiemer Alexandra K. Hepatic hepcidin expression is decreased in cirrhosis and HCC.J Hepatol. 2015; 62: 977-979Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 2Harrison-Findik D.D. Schafer D. Klein E. Timchenko N.A. Kulaksiz H. Clemens D. et al.Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression.J Biol Chem. 2006; 281: 22974-22982Crossref PubMed Scopus (260) Google Scholar, 3Mueller K. Sunami Y. Stuetzle M. Guldiken N. Kucukoglu O. Mueller S. et al.CHOP-mediated hepcidin suppression modulates hepatic iron load.J Pathol. 2013; 231: 532-542Crossref PubMed Scopus (17) Google Scholar]. Similarly, observations predominantly made in hepatitis B-infected patients extend previous findings, obtained in subjects with chronic liver disease due to hepatitis C infection or excessive alcohol intake, which all display reduced liver hepcidin levels [1Kessler Sonja M. Barghash Ahmad Laggai Stephan Helms Volkhard Kiemer Alexandra K. Hepatic hepcidin expression is decreased in cirrhosis and HCC.J Hepatol. 2015; 62: 977-979Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 4Meynard D. Babitt J.L. Lin H.Y. The liver: conductor of systemic iron balance.Blood. 2014; 123: 168-176Crossref PubMed Scopus (129) Google Scholar]. Most importantly, in an elegant molecular analysis, Kessler et al. also showed that hepatocellular carcinomas exhibit diminished hepcidin expression, that was previously reported only in smaller studies. Since hepcidin represents the central negative regulator of iron metabolism [[4]Meynard D. Babitt J.L. Lin H.Y. The liver: conductor of systemic iron balance.Blood. 2014; 123: 168-176Crossref PubMed Scopus (129) Google Scholar], these data reinforce the hypothesis that chronic liver disorders may promote development of acquired iron overload again triggering the progression of liver fibrosis and/or development of hepatocellular carcinoma. As an underlying mechanism, iron overload has multiple deleterious downstream effects, such as formation of reactive oxygen species, mitochondrial or lysosomal injury [5Ramm G.A. Ruddell R.G. Iron homeostasis, hepatocellular injury, and fibrogenesis in hemochromatosis: the role of inflammation in a noninflammatory liver disease.Semin Liver Dis. 2010; 30: 271-287Crossref PubMed Scopus (55) Google Scholar, 6Lunova M. Goehring C. Kuscuoglu D. Mueller K. Chen Y. Walther P. et al.Hepcidin knockout mice fed with iron-rich diet develop chronic liver injury and liver fibrosis due to lysosomal iron overload.J Hepatol. 2014; 61: 633-641Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. However, while several reports demonstrated an association between increased hepatic iron load and progression of liver fibrosis and/or HCC development [[7]Valenti L. Fracanzani A.L. Bugianesi E. Dongiovanni P. Galmozzi E. Vanni E. et al.HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease.Gastroenterology. 2010; 138: 905-912Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar], no such studies are available for hepcidin. This is rather surprising given the availability of multiple assays that can conveniently assess hepcidin serum levels. However, the extent to which these assessments can accurately reflect liver hepcidin expression or iron content in complex clinical settings, comprising multiple confounding factors, remains to be clarified. Nevertheless and without any doubt, such studies are of obvious medical and biological interest, although their interpretation will likely be complicated. In that respect, the regulation of hepcidin production is complex and is affected, not only by iron metabolism, but also by various hepatic factors; by inflammation, erythropoietic drive, hypoxia etc. [[4]Meynard D. Babitt J.L. Lin H.Y. The liver: conductor of systemic iron balance.Blood. 2014; 123: 168-176Crossref PubMed Scopus (129) Google Scholar]. Moreover, hepcidin has a short half-life and displays a circadian rhythm [[8]Ganz T. Iron homeostasis: fitting the puzzle pieces together.Cell Metab. 2008; 7: 288-290Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. Even more challenging will be to dissect whether the altered hepcidin levels represent a cause or consequence of liver disease/fibrosis progression. Finally, the deleterious effects of iron metabolism in liver carcinogenesis are further modulated by complex genetic factors at both the constitutional and functional levels; indeed, multiple genetic traits seem to impact hepatic iron content in patients with chronic liver disease [[9]Nahon P. Sutton A. Rufat P. Charnaux N. Mansouri A. Moreau R. et al.A variant in myeloperoxidase promoter hastens the emergence of hepatocellular carcinoma in patients with HCV-related cirrhosis.J Hepatol. 2012; 56: 426-432Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar]. While in-depth transcriptomic analyses reveal that expression of the HAMP gene could participate in a refinement of molecular classification of HCCs [[10]Boyault S. Rickman D.S. de Reyniès A. Balabaud C. Rebouissou S. Jeannot E. et al.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.Hepatology. 2007; 45: 42-52Crossref PubMed Scopus (920) Google Scholar]. In conclusion, although the road ahead will likely be bumpy, it will be challenging to uncover the complex interaction between liver disease and iron metabolism. These interactions are now more important than ever given the rapid emergence of hepcidin-targeted therapeutic strategies that could be further modulated by host- and/or tumour-related genetic factors in the setting of personalized medicine. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.