Hepcidin resistance in dysmetabolic iron overload

Rametta, R.; Pelusi, S.; Dongiovanni, P.; Iuculano, F.; Fracanzani, A.L.; Fargion, S.; Valenti, L.

doi:10.1016/j.dld.2015.01.038

Cited by 15 publications

(23 citation statements)

References 43 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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%

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

Czaja

2019

Aliment Pharmacol Ther

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

Czaja

2019

Aliment Pharmacol Ther

View full text Add to dashboard Cite

show abstract

“…This effect should limit systemic iron levels. Instead, a failure of hepcidin action (‘hepcidin resistance') may prevail, leading to increased liver iron, with augmented iron absorption reported in NASH patients, despite elevated hepcidin levels …”

Section: Discussionmentioning

confidence: 99%

“…27 This effect should limit systemic iron levels. Instead, a failure of hepcidin action ('hepcidin resistance') may prevail, 28 leading to increased liver iron, with augmented iron absorption reported in NASH patients, despite elevated hepcidin levels. 29 In the discovery cohort, hepatic iron levels were determined by MR, an excellent indicator of liver iron concentration, even in the presence of steatosis.…”

Section: Discussionmentioning

confidence: 99%

Hepatic iron is the major determinant of serum ferritin in NAFLD patients

Ryan

Armitage

Cobbold

et al. 2017

Liver International

View full text Add to dashboard Cite

Background and Aims Elevated serum ferritin is common in NAFLD, and is associated with more advanced disease and increased mortality. Hyperferritinaemia in NAFLD is often attributed to inflammation, while in other conditions ferritin closely reflects body iron stores. The aim of this study was to clarify the underlying cause of hyperferritinaemia in NAFLD. Methods Ferritin levels were examined with markers of iron status, inflammation and liver injury across the clinical spectrum of NAFLD using blood, tissue and magnetic resonance (MR) imaging. A separate larger group of NAFLD patients with hepatic iron staining and quantification were used for validation. Results Serum ferritin correlated closely with the iron regulatory hormone hepcidin, and liver iron levels determined by MR. Furthermore, ferritin levels reflected lower serum adiponectin, a marker of insulin resistance, and liver fat, but not cytokine or CRP levels. Ferritin levels differed according to fibrosis stage, increasing from early to moderate disease, and declining in cirrhosis. A similar pattern was found in the validation cohort of NAFLD patients, where ferritin levels were highest in those with macrophage iron deposition. Multivariate analysis revealed liver iron and hepcidin levels as the major determinants of serum ferritin. Conclusions While hyperferritinaemia is associated with markers of liver injury and insulin resistance, serum hepcidin and hepatic iron are the strongest predictors of ferritin levels. These findings highlight the role of disordered iron homeostasis in the pathogenesis of NAFLD, suggesting that therapies aimed at correcting iron metabolism may be beneficial.

show abstract

“…19 Ten out of 64 had p.C282Y HFE +/+ HH, while the remaining 54 were subjects with normal TS% and wild type for p.C282Y HFE; five of them carried the p.L390M variant of NMBR. 19 Ten out of 64 had p.C282Y HFE +/+ HH, while the remaining 54 were subjects with normal TS% and wild type for p.C282Y HFE; five of them carried the p.L390M variant of NMBR.…”

Section: Oral Iron Tolerance Test Cohortmentioning

confidence: 99%

“…We considered 64 subjects, whose iron homeostasis was studied by oral iron tolerance test (OITT) with serum hepcidin measurement at baseline and at 4, 8, and 24 hours after the administration of 105 mg of ferrous sulfate. 19 Ten out of 64 had p.C282Y HFE +/+ HH, while the remaining 54 were subjects with normal TS% and wild type for p.C282Y HFE; five of them carried the p.L390M variant of NMBR. Table 1 shows demographic and clinical features of the OITT cohort.…”

Section: Oral Iron Tolerance Test Cohortmentioning

confidence: 99%

Impact of natural neuromedin‐B receptor variants on iron metabolism

et al. 2019

View full text Add to dashboard Cite

Iron overload heritability remains partly unexplained. By performing whole exome sequencing in three patients with a clinical phenotype of hemochromatosis not accounted by known genetic risk factors, we identified in all patients rare variants predicted to alter activity of Neuromedin-B receptor (NMBR). Coding NMBR mutations were enriched in 129 patients with hereditary hemochromatosis or iron overload phenotype, as compared to ethnically matched controls, including 100 local healthy blood donors and 1000Genomes project participants (15.5% vs 5%, P = .0038 at burden test), and were associated with higher transferrin saturation in regular blood donors (P = .04). Consistently, in 191 patients with nonalcoholic fatty liver, the most common low-frequency p.L390 M variant was independently associated with higher ferritin (P = .03). In 58 individuals, who underwent oral iron challenge, carriage of the p.L390 M variant was associated with higher transferrin saturation and lower hepcidin release. Furthermore, the circulating concentration of the natural NMBR ligand, Neuromedin-B, was reduced in response to iron challenge.It was also decreased in individuals carrying the p.L390 M variant and with hemochromatosis in parallel with increased transferrin saturation. In mice, Nmbr was induced by chronic dietary iron overload in the liver, gut, pancreas, spleen, and skeletal muscle, while Nmb was downregulated in gut, pancreas and spleen. Finally, Nmb amplified holo-transferrin dependent induction of hepcidin in primary mouse hepatocytes, which was associated with Jak2 induction and abolished by the NMBR antagonist PD168368. In conclusion, NMBR natural variants were enriched in patients with iron overload, and associated with facilitated iron absorption, possibly related to a defect of iron-induced hepcidin release.

show abstract

Hepcidin resistance in dysmetabolic iron overload

Cited by 15 publications

References 43 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

Hepatic iron is the major determinant of serum ferritin in NAFLD patients

Impact of natural neuromedin‐B receptor variants on iron metabolism

Contact Info

Product

Resources

About