Hepcidin resistance in dysmetabolic iron overload

Rametta, Raffaela; Dongiovanni, Paola; Pelusi, Serena; Francione, Paolo; Iuculano, F.; Borroni, V.; Fatta, E.; Castagna, Annalisa; Girelli, Domenico; Valenti, Luca

doi:10.1111/liv.13124

Cited by 41 publications

(13 citation statements)

References 46 publications

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“…Also, bone morphogenic protein-binding endothelial regulator [ 34 ] and hepatocyte nuclear factor-4alpha [ 35 ] have been reported to influence iron absorption, and in mice, a high fat diet by itself could increase iron absorption [ 36 ]. An impairment in the ability of hepcidin to inhibit iron absorption was demonstrated in DIOS, suggesting hepcidin resistance in this condition [ 37 ]. Nevertheless, it is unknown if the iron loading seen in up to one-third of patients with NAFLD is a consequence of the altered lipid metabolism, or an altered expression of iron-regulatory genes, or a combination of both.…”

Section: Discussionmentioning

confidence: 99%

Hepcidin levels correlate to liver iron content, but not steatohepatitis, in non-alcoholic fatty liver disease

et al. 2018

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BackgroundOne-third of patients with non-alcoholic fatty liver disease (NAFLD) develop dysmetabolic iron overload syndrome (DIOS), the pathogenesis of which is unknown. Altered production of the iron-regulatory peptide hepcidin has been reported in NAFLD, but it is unclear if this is related to iron accumulation, lipid status or steatohepatitis.MethodsEighty-four patients with liver disease, 54 of which had iron overload, underwent liver biopsy (n = 66) and/or magnetic resonance imaging (n = 35) for liver iron content determination. Thirty-eight of the patients had NAFLD, 29 had chronic liver disease other than NAFLD, and 17 had untreated genetic hemochromatosis. Serum hepcidin was measured with ELISA in all patients and in 34 controls. Hepcidin antimicrobial peptide (HAMP) mRNA in liver tissue was determined with real-time-quantitative PCR in 36 patients.ResultsSerum hepcidin was increased similarly in NAFLD with DIOS as in the other chronic liver diseases with iron overload, except for genetic hemochromatosis. HAMP mRNA in liver tissue, and serum hepcidin, both correlated to liver iron content in NAFLD patients (r2 = 0.45, p < 0.05 and r2 = 0.27, p < 0.05 respectively) but not to body mass index, NAFLD activity score or serum lipids. There was a good correlation between HAMP mRNA in liver tissue and serum hepcidin (r2 = 0.39, p < 0.01).ConclusionsIn NAFLD with or without dysmetabolic iron overload, serum hepcidin and HAMP mRNA in liver correlate to body iron content but not to the degree of steatohepatitis or lipid status. Thus, the dysmetabolic iron overload syndrome seen in NAFLD is not caused by an altered hepcidin synthesis.

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Section: Discussionmentioning

confidence: 99%

Hepcidin levels correlate to liver iron content, but not steatohepatitis, in non-alcoholic fatty liver disease

et al. 2018

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“…Iron-load is present in 1/3 of the patients with NAFLD and is a risk factor for progressive liver damage, especially when NAFLD is part of DIOS. In DIOS there is an adequate increase in hepcidin levels in response to iron-load, but the increase in hepcidin levels cannot control the rise in transferrin saturation (TS), suggesting a hepcidin-resistant state (Rametta et al 2016 ). It remains to be seen how could these changes affect iron-load in the liver and the tendency towards liver fibrosis.…”

Section: Mechanisms Of Low Hepcidin In Liver Diseasementioning

confidence: 99%

Low hepcidin in liver fibrosis and cirrhosis; a tale of progressive disorder and a case for a new biochemical marker

Vela

2018

Mol Med

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Liver fibrosis is a precursor of liver cirrhosis, which is associated with increased mortality. Though liver biopsy remains the gold standard for the diagnosis of fibrosis, noninvasive biochemical methods are cost-effective, practical and are not linked with major risks of complications. In this respect, serum hepcidin, has emerged as a new marker of fibrosis and cirrhosis. In this review the discussion uncovers molecular links between hepcidin disturbance and liver fibrosis/cirrhosis. The discussion also expands on clinical studies that suggest that hepcidin can potentially be used as a biochemical parameter of fibrosis/cirrhosis and target of therapeutic strategies to treat liver diseases. The debatable issues such as the complicated nature of hepcidin disturbance in non-alcoholic liver disease, serum levels of hepcidin in acute hepatitis C virus infection, cause of hepcidin disturbance in autoimmune hepatitis and hepatic insulin resistance are discussed, with potential solutions unveiled in order to be studied by future research.

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“…Indeed, DIOS and NAFLD disorders show elevated hepcidin levels related to hyperferritinemia. To confirm this hypothesis, we have recently demonstrated that iron challenge in iron-depleted DIOS patients did not restrain iron absorption despite adequate hepcidin production, suggesting that hepcidin resistance (i.e., the impaired hepcidin activity) and not the deficit of hormone production is involved in DIOS pathogenesis [81].…”

Section: Insulin Resistance and Iron Homeostasismentioning

confidence: 95%

From Environment to Genome and Back: A Lesson from HFE Mutations

Rametta

Meroni

Dongiovanni

2020

IJMS

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The environment and the human genome are closely entangled and many genetic variations that occur in human populations are the result of adaptive selection to ancestral environmental (mainly dietary) conditions. However, the selected mutations may become maladaptive when environmental conditions change, thus becoming candidates for diseases. Hereditary hemochromatosis (HH) is a potentially lethal disease leading to iron accumulation mostly due to mutations in the HFE gene. Indeed, homozygosity for the C282Y HFE mutation is associated with the primary iron overload phenotype. However, both penetrance of the C282Y variant and the clinical manifestation of the disease are extremely variable, suggesting that other genetic, epigenetic and environmental factors play a role in the development of HH, as well as, and in its progression to end-stage liver diseases. Alcohol consumption and dietary habits may impact on the phenotypic expression of HFE-related hemochromatosis. Indeed, dietary components and bioactive molecules can affect iron status both directly by modulating its absorption during digestion and indirectly by the epigenetic modification of genes involved in its uptake, storage and recycling. Thus, the premise of this review is to discuss how environmental pressures led to the selection of HFE mutations and whether nutritional and lifestyle interventions may exert beneficial effects on HH outcomes and comorbidities.

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Hepcidin resistance in dysmetabolic iron overload

Cited by 41 publications

References 46 publications

Hepcidin levels correlate to liver iron content, but not steatohepatitis, in non-alcoholic fatty liver disease

Hepcidin levels correlate to liver iron content, but not steatohepatitis, in non-alcoholic fatty liver disease

Low hepcidin in liver fibrosis and cirrhosis; a tale of progressive disorder and a case for a new biochemical marker

From Environment to Genome and Back: A Lesson from HFE Mutations

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