Ferritin in decompensated cirrhosis: Iron or inflammation?

Abstract

Serum ferritin predicts early mortality in patients with decompensated cirrhosisJournal of HepatologyVol. 61Issue 1PreviewSerum ferritin is a known marker of hepatic necro-inflammation and has been studied to predict 1 year mortality and post-transplant survival in decompensated cirrhotics. However, there are no studies evaluating ferritin as a predictor of early mortality. We investigated whether serum ferritin levels could predict 15 day and 30 day mortality in patients with decompensated cirrhosis. Full-Text PDF Reply to: “Ferritin in decompensated cirrhosis: Iron or inflammation?”Journal of HepatologyVol. 62Issue 2PreviewWe would like to thank Ryan et al. for taking keen interest in our recently published manuscript wherein we show that serum ferritin is a predictor of early mortality in patients with decompensated cirrhosis (DC) [1]. We completely agree with their comments that serum ferritin in patients with DC is a marker of both inflammation and iron overload. Ferritin is an established marker of secondary iron overload in these patients. We in our study, therefore excluded patients with secondary iron overload to demonstrate the role of ferritin primarily as a marker of systemic inflammation and macrophage activation in the absence of iron overload. Full-Text PDF Open Access In a recent article, Maiwall and colleagues describe serum ferritin as a predictor of mortality in patients with decompensated cirrhosis. The authors conclude that the association between elevated serum ferritin and mortality may have therapeutic implications [[1]Maiwall R. Kumar S. Chaudhary A.K. Maras J. Wani Z. Kumar C. et al.Serum ferritin predicts early mortality in patients with decompensated cirrhosis.J Hepatol. 2014; 61: 43-50Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar].Elevated serum ferritin is commonly seen in many causes of chronic liver disease and is thought to relate to hepatic iron overload or inflammation, or a combination of both. Indeed, in the absence of systemic inflammation, serum ferritin is an excellent marker of body iron stores, such as is seen in hereditary haemochromatosis, a frequent cause of hepatic iron excess [[2]Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment.Gastroenterology. 2010; 139 (408 e391–e392.): 393-408Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar]. Alcoholic and non-alcoholic fatty liver disease and chronic viral hepatitis are associated with hepatic inflammation and mild to moderate hepatic iron accumulation, making serum ferritin less interpretable. Distinguishing the cause of hyperferritinaemia is an often encountered clinical issue.Although it has been widely accepted that damaged hepatocytes are the main source of circulating ferritin, Cohen et al. recently revealed that a major contribution occurs from macrophages [[3]Cohen L.A. Gutierrez L. Weiss A. Leichtmann-Bardoogo Y. Zhang D.L. Crooks D.R. et al.Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway.Blood. 2010; 116: 1574-1584Crossref PubMed Scopus (296) Google Scholar]. In the context of decompensated cirrhosis and acute-on-chronic liver failure, where the importance of macrophage activation is well recognized [[4]Waidmann O. Brunner F. Herrmann E. Zeuzem S. Piiper A. Kronenberger B. Macrophage activation is a prognostic parameter for variceal bleeding and overall survival in patients with liver cirrhosis.J Hepatol. 2013; 58: 956-961Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar], this finding is of relevance. The addition of C-reactive protein (CRP) measurement in this study would help to clarify the driver of hyperferritinaemia, indeed CRP has been shown to predict short-term survival in patients with cirrhosis and acute-on-chronic liver failure [5Cervoni J.P. Thevenot T. Weil D. Muel E. Barbot O. Sheppard F. et al.C-reactive protein predicts short-term mortality in patients with cirrhosis.J Hepatol. 2012; 56: 1299-1304Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 6Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437 e1421–e1429): 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1689) Google Scholar].As hepatic synthetic dysfunction progresses in end stage liver disease, reduced production of hepcidin, the liver-derived iron regulatory hormone may occur [7Detivaud L. Nemeth E. Boudjema K. Turlin B. Troadec M.B. Leroyer P. et al.Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function.Blood. 2005; 106: 746-748Crossref PubMed Scopus (178) Google Scholar, 8Tan T.C. Crawford D.H. Franklin M.E. Jaskowski L.A. Macdonald G.A. Jonsson J.R. et al.The serum hepcidin: ferritin ratio is a potential biomarker for cirrhosis.Liver Int. 2012; 32: 1391-1399Crossref PubMed Scopus (43) Google Scholar]. Hepcidin may be further suppressed by oxidative stress, which is prevalent in decompensated cirrhosis [9Trinder D. Ayonrinde O.T. Olynyk J.K. HCV, iron, and oxidative stress: the new choreography of hepcidin.Gastroenterology. 2008; 134: 348-351Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 10Oettl K. Birner-Gruenberger R. Spindelboeck W. Stueger H.P. Dorn L. Stadlbauer V. et al.Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.J Hepatol. 2013; 59: 978-983Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. Deficient hepcidin production leads to elevated iron absorption, hyperferritinaemia and hepatic iron deposition, which would exacerbate the original insult. No comment is made on the potential value of serum hepcidin measurements in these patients. Furthermore, the authors do not provide transferrin saturation levels, which, if raised, would indicate iron overload as a contributing factor.In summary, while Maiwall and colleagues provide an interesting addition to the predictors of outcome in patients with decompensated cirrhosis, further information would be of value in order to guide therapeutic strategies and future research in this area.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. In a recent article, Maiwall and colleagues describe serum ferritin as a predictor of mortality in patients with decompensated cirrhosis. The authors conclude that the association between elevated serum ferritin and mortality may have therapeutic implications [[1]Maiwall R. Kumar S. Chaudhary A.K. Maras J. Wani Z. Kumar C. et al.Serum ferritin predicts early mortality in patients with decompensated cirrhosis.J Hepatol. 2014; 61: 43-50Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar]. Elevated serum ferritin is commonly seen in many causes of chronic liver disease and is thought to relate to hepatic iron overload or inflammation, or a combination of both. Indeed, in the absence of systemic inflammation, serum ferritin is an excellent marker of body iron stores, such as is seen in hereditary haemochromatosis, a frequent cause of hepatic iron excess [[2]Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment.Gastroenterology. 2010; 139 (408 e391–e392.): 393-408Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar]. Alcoholic and non-alcoholic fatty liver disease and chronic viral hepatitis are associated with hepatic inflammation and mild to moderate hepatic iron accumulation, making serum ferritin less interpretable. Distinguishing the cause of hyperferritinaemia is an often encountered clinical issue. Although it has been widely accepted that damaged hepatocytes are the main source of circulating ferritin, Cohen et al. recently revealed that a major contribution occurs from macrophages [[3]Cohen L.A. Gutierrez L. Weiss A. Leichtmann-Bardoogo Y. Zhang D.L. Crooks D.R. et al.Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway.Blood. 2010; 116: 1574-1584Crossref PubMed Scopus (296) Google Scholar]. In the context of decompensated cirrhosis and acute-on-chronic liver failure, where the importance of macrophage activation is well recognized [[4]Waidmann O. Brunner F. Herrmann E. Zeuzem S. Piiper A. Kronenberger B. Macrophage activation is a prognostic parameter for variceal bleeding and overall survival in patients with liver cirrhosis.J Hepatol. 2013; 58: 956-961Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar], this finding is of relevance. The addition of C-reactive protein (CRP) measurement in this study would help to clarify the driver of hyperferritinaemia, indeed CRP has been shown to predict short-term survival in patients with cirrhosis and acute-on-chronic liver failure [5Cervoni J.P. Thevenot T. Weil D. Muel E. Barbot O. Sheppard F. et al.C-reactive protein predicts short-term mortality in patients with cirrhosis.J Hepatol. 2012; 56: 1299-1304Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 6Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437 e1421–e1429): 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1689) Google Scholar]. As hepatic synthetic dysfunction progresses in end stage liver disease, reduced production of hepcidin, the liver-derived iron regulatory hormone may occur [7Detivaud L. Nemeth E. Boudjema K. Turlin B. Troadec M.B. Leroyer P. et al.Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function.Blood. 2005; 106: 746-748Crossref PubMed Scopus (178) Google Scholar, 8Tan T.C. Crawford D.H. Franklin M.E. Jaskowski L.A. Macdonald G.A. Jonsson J.R. et al.The serum hepcidin: ferritin ratio is a potential biomarker for cirrhosis.Liver Int. 2012; 32: 1391-1399Crossref PubMed Scopus (43) Google Scholar]. Hepcidin may be further suppressed by oxidative stress, which is prevalent in decompensated cirrhosis [9Trinder D. Ayonrinde O.T. Olynyk J.K. HCV, iron, and oxidative stress: the new choreography of hepcidin.Gastroenterology. 2008; 134: 348-351Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 10Oettl K. Birner-Gruenberger R. Spindelboeck W. Stueger H.P. Dorn L. Stadlbauer V. et al.Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.J Hepatol. 2013; 59: 978-983Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. Deficient hepcidin production leads to elevated iron absorption, hyperferritinaemia and hepatic iron deposition, which would exacerbate the original insult. No comment is made on the potential value of serum hepcidin measurements in these patients. Furthermore, the authors do not provide transferrin saturation levels, which, if raised, would indicate iron overload as a contributing factor. In summary, while Maiwall and colleagues provide an interesting addition to the predictors of outcome in patients with decompensated cirrhosis, further information would be of value in order to guide therapeutic strategies and future research in this area. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.