Low Serum Hepcidin in Patients with Autoimmune Liver Diseases

Lyberopoulou, Aggeliki; Chachami, Georgia; Gatselis, Nikolaos; Kyratzopoulou, Eleni; Saitis, Asterios; Gabeta, Stella; Eliades, Petros; Paraskeva, Efrosyni; Zachou, Kalliopi; Koukoulis, George Κ.; Mamalaki, Avgi; Dalekos, George Ν.; Simos, George

doi:10.1371/journal.pone.0135486

Cited by 26 publications

(28 citation statements)

References 62 publications

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“…Hyperferritinemia has been the principal manifestation of a disturbed iron homeostasis in chronic liver disease, but other findings have included inappropriate serum hepcidin levels, increased serum iron concentrations, stainable iron in hepatic tissue, normal or moderately increased transferrin saturations, and mutations of the HFE gene . The similarity of the findings across a broad spectrum of different chronic liver diseases and resolution of the abnormalities during treatment suggest that the disturbances are consequences of liver injury .…”

Section: Resultsmentioning

confidence: 99%

“…The laboratory indices of liver inflammation (ALT, aspartate aminotransferase [AST], alkaline phosphatase, and CRP) do not correlate with the circulating hepcidin level, and the homeostatic relationship between the serum hepcidin concentration and the standard iron parameters is not restored until induction of biochemical remission . Furthermore, the hepcidin mRNA level in liver tissue has correlated positively with the serum ferritin level but not with the serum hepcidin level, and the serum hepcidin concentration has remained low in some patients during a 2‐year period of treatment …”

Section: Resultsmentioning

confidence: 99%

“…The unexplained inappropriately low serum hepcidin level in autoimmune hepatitis could reflect the severity of liver injury and impairment of the hepatic production of hepcidin . Persistence of a low hepcidin concentration despite protracted therapy in some patients with autoimmune hepatitis suggests that the loss of hepcidin production by the liver is irreversible or that other factors suppressing hepcidin production are persistent . Furthermore, the observation that the hepatic content of mRNA for hepcidin does not correlate with the serum hepcidin level suggests that translation of the mRNA for hepcidin is impaired or that the delivery of hepcidin to the circulation is compromised by post‐transcriptional processes .…”

Section: Resultsmentioning

confidence: 99%

“…Serum ferritin levels are increased in cohorts with non‐alcoholic fatty liver disease (NAFLD), chronic alcoholic liver disease (ALD), chronic hepatitis B, chronic hepatitis C, alpha‐1 anti‐trypsin deficiency, and autoimmune hepatitis . Stainable iron has been present in 32% of cirrhotic livers of various causes, and serum hepcidin levels that regulate the duodenal absorption and tissue storage of iron have been low in autoimmune hepatitis, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), alcohol‐related cirrhosis, chronic hepatitis B‐related cirrhosis, and alpha‐1 anti‐trypsin deficiency . In contrast, circulating hepcidin concentrations have been increased in NAFLD …”

Section: Introductionmentioning

confidence: 99%

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Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

Czaja

2019

Aliment Pharmacol Ther

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Background: Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome. Aims:To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management Methods: English abstracts were identified in PubMed by multiple search terms.Full length articles were selected for review, and secondary and tertiary bibliographies were developed.Results: Hyperferritinemia is present in 4%-65% of patients with non-alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%-52%. Heterozygosity for the C282Y mutation is present in 17%-48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non-alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists. Conclusions:Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co-morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

Czaja

2019

Aliment Pharmacol Ther

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“…Decreased hepcidin synthesis leads to impairment of the pathogenesis of alcoholic cirrhosis and autoimmune hepatitis, with increased production of hydrogen peroxide in which alcohol functions as negative regulator of hepcidin [119,120,121,122,123]. …”

Section: Hepcidinmentioning

confidence: 99%

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

et al. 2017

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Iron is an essential metal for cell survival that is regulated by the peptide hormone hepcidin. However, its influence on certain diseases is directly related to iron metabolism or secondary to underlying diseases. Genetic alterations influence the serum hepcidin concentration, which can lead to an iron overload in tissues, as observed in haemochromatosis, in which serum hepcidin or defective hepcidin synthesis is observed. Another genetic imbalance of iron is iron-refractory anaemia, in which serum concentrations of hepcidin are increased, precluding the flow and efflux of extra- and intracellular iron. During the pathogenesis of certain diseases, the resulting oxidative stress, as well as the increase in inflammatory cytokines, influences the transcription of the HAMP gene to generate a secondary anaemia due to the increase in the serum concentration of hepcidin. To date, there is no available drug to inhibit or enhance hepcidin transcription, mostly due to the cytotoxicity described in the in vitro models. The proposed therapeutic targets are still in the early stages of clinical trials. Some candidates are promising, such as heparin derivatives and minihepcidins. This review describes the main pathways of systemic and genetic regulation of hepcidin, as well as its influence on the disorders related to iron metabolism.

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The Hepatitis C virus NS5A and core proteins exert antagonistic effects on HAMP gene expression: the hidden interplay with the MTF‐1/MRE pathway

et al. 2020

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Hepcidin, a 25-amino acid peptide encoded by the HAMP gene and produced mainly by hepatocytes and macrophages, is a mediator of innate immunity and the central iron-regulatory hormone. Circulating hepcidin controls iron efflux by inducing degradation of the cellular iron exporter ferroportin. HCV infection is associated with hepatic iron overload and elevated serum iron, which correlate with poor antiviral responses. The HCV non-structural NS5A protein is known to function in multiple aspects of the HCV life cycle, probably exerting its activity in concert with cellular factor(s). In this study, we attempted to delineate the effect of HCV NS5A on HAMP gene expression. We observed that transient transfection of hepatoma cell lines with HCV NS5A resulted in downregulation of HAMP promoter activity. A similar effect was evident after transduction of Huh7 cells with a recombinant baculovirus vector expressing NS5A protein. We proceeded to construct an NS5A-expressing stable cell line, which also exhibited down-regulation of HAMP gene promoter activity and significant reduction of HAMP mRNA and hepcidin protein levels. Concurrent expression of HCV core protein, a well characterized hepcidin inducer, revealed antagonism between those two proteins for hepcidin regulation. In attempting to identify the pathways involved in NS5Adriven reduction of hepcidin levels, we ruled out any NS5A-induced alterations in the expression of the well-known hepcidin inducers SMAD4 and STAT3. Further analysis linked the abundance of intracellular zinc ions and the deregulation of the MTF-1/MRE/hepcidin axis with the observed phenomenon. This effect could be associated with distinct phases in HCV life cycle.

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Low Serum Hepcidin in Patients with Autoimmune Liver Diseases

Cited by 26 publications

References 62 publications

Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

The Hepatitis C virus NS5A and core proteins exert antagonistic effects on HAMP gene expression: the hidden interplay with the MTF‐1/MRE pathway

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