The Effect of Dietary Factors on Hemochromatosis Disease Expression in C282Y Homozygotes.

Abstract Background. Hereditary hemochromatosis (HHC) is a common inherited disorder and the vast majority of cases are associated with HFE gene mutations; about 80% are homozygous for the C282Y HFE mutation. Although homozygosity for C282Y is relatively common among individuals of northern European descent, the penetrance, as measured by clinically relevant iron overload, is low. Both environmental and genetic factors have been implicated in modulating disease expression. Most clinicians and patients attribute at least some of the observed variation to differences in dietary patterns. Methods: 28 C282Y homozygous subjects who had completed de-ironing therapy at our center, and were on stable maintenance phlebotomy treatments, participated in a previously validated dietary survey. We examined the influence of dietary iron, heme iron, fiber, ascorbic acid and alcohol intake on disease expression as measured by liver iron, phlebotomy-mobilized iron and maintenance phlebotomy requirement. Results. We developed a maintenance iron score (Maint Fe) which was the iron in milligrams removed per month by phlebotomy treatments in order to maintain serum ferritin in the 25–75 μG/L range. Maint Fe ranged from 36.8–203 mg/month in our patients (87.8 ± 37.7). Liver iron ranged from 30.5 to 505.4 micromoles per gram dry weight (192.7 ± 123). Phlebotomy-mobilized iron ranged from 2.35–18.03 G (6.43 ± 4.08). The Spearman’s Rank Correlation was used to compare dietary parameters with each of the above measures of disease expression. No significant correlation was found. Conclusions. Disease expression varied considerably in our C282Y homozygous subjects as measured by liver iron, phlebotomy-mobilized iron and Maint Fe. The observed variation is not explained by variations in dietary iron, fiber, ascorbic acid or ethanol intake. Our data suggests that other unknown environmental variables or alternatively, modifier genes, may play a role in modulating disease expression in these patients. Contrary to popular belief, dietary variation does not appear to play a major role.

Download Full-text

Haptoglobin modifies the hemochromatosis phenotype in mice

Blood ◽

10.1182/blood-2004-07-2814 ◽

2005 ◽

Vol 105 (8) ◽

pp. 3353-3355 ◽

Cited By ~ 29

Author(s):

Emanuela Tolosano ◽

Sharmila Fagoonee ◽

Cinzia Garuti ◽

Linda Valli ◽

Nancy C. Andrews ◽

...

Keyword(s):

Genetic Disorder ◽

Hereditary Hemochromatosis ◽

Reticuloendothelial System ◽

Heme Iron ◽

Hfe Gene ◽

Plasma Hemoglobin ◽

Sufficient Cause ◽

Common Genetic Disorder ◽

Free Plasma

Abstract Classic hereditary hemochromatosis (HH) is a common genetic disorder of iron metabolism caused by a mutation in the HFE gene. Whereas the prevalence of the mutation is very high, the clinical penetrance of the disease is low, suggesting that the HFE mutation is a necessary but not sufficient cause of clinical HH. Several candidate modifier genes have been proposed in mice and humans, including haptoglobin. Haptoglobin is the plasma protein with the highest binding affinity for hemoglobin. It delivers free plasma hemoglobin to the reticuloendothelial system, thus reducing loss of hemoglobin through the glomeruli and allowing heme-iron recycling. To gain insight into the role of haptoglobin as a modifier gene in HH, we used Hfe and haptoglobin double-null mice. Here, we show that Hfe and haptoglobin compound mutant mice accumulate significantly less hepatic iron than Hfe-null mice, thus demonstrating that haptoglobin-mediated heme-iron recovery may contribute significantly to iron loading in HH. (Blood. 2005;105:3353-3355)

Download Full-text

Duodenal nonheme iron content correlates with iron stores in mice, but the relationship is altered by Hfe gene knock-out

Blood ◽

10.1182/blood-2002-10-3112 ◽

2003 ◽

Vol 101 (8) ◽

pp. 3316-3318 ◽

Cited By ~ 8

Author(s):

Robert J. Simpson ◽

Edward S. Debnam ◽

Abas H. Laftah ◽

Nita Solanky ◽

Nick Beaumont ◽

...

Keyword(s):

Iron Content ◽

Iron Absorption ◽

Hereditary Hemochromatosis ◽

Iron Concentration ◽

Nonheme Iron ◽

Hfe Gene ◽

Liver Iron ◽

Knock Out ◽

Iron Stores ◽

Knock Out Mice

Abstract Hereditary hemochromatosis is a common iron-loading disorder found in populations of European descent. It has been proposed that mutations causing loss of function of HFE gene result in reduced iron incorporation into immature duodenal crypt cells. These cells then overexpress genes for iron absorption, leading to inappropriate cellular iron balance, a persistent iron deficiency of the duodenal mucosa, and increased iron absorption. The objective was to measure duodenal iron content in Hfe knock-out mice to test whether the mutation causes a persistent decrease in enterocyte iron concentration. In both normal and Hfe knock-out mice, duodenal nonheme iron content was found to correlate with liver iron stores (P < .001, r = 0.643 and 0.551, respectively), and this effect did not depend on dietary iron levels. However, duodenal iron content was reduced in Hfe knock-out mice for any given content of liver iron stores (P < .001).

Download Full-text

Discrepancy between Serum Ferritin and Liver Iron Concentration in a Patient with Hereditary Hemochromatosis – The Value of T2* MRI

Case Reports in Oncology ◽

10.1159/000507756 ◽

2020 ◽

Vol 13 (2) ◽

pp. 712-715

Author(s):

Mustafa A. Al-Tikrity ◽

Mohamed A. Yassin

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Ferritin Level ◽

Hereditary Hemochromatosis ◽

Iron Concentration ◽

Hfe Gene ◽

Liver Iron Concentration ◽

C282y Mutation ◽

Liver Iron ◽

T2 Mri

Primary hemochromatosis is an inherited disorder, and the homeostatic iron regulator (HFE) gene C282Y mutation is a common cause of hemochromatosis in Europe. We are reporting a case of a 56-year-old female known to have hemochromatosis with the HFE gene C282Y mutation with a serum ferritin level of 482 μg/L who underwent heart and liver T2* MRI which showed no evidence of iron overload – neither in the heart nor in the liver. This indicates that there is a discrepancy between serum ferritin and liver iron concentration by MRI and the superiority of T2* MRI in diagnosis and follow-up of iron overload in patients with hereditary hemochromatosis.

Download Full-text

Oral Administration of Ginger-Derived Lipid Nanoparticles and Dmt1 siRNA Potentiates the Effect of Dietary Iron Restriction and Mitigates Pre-Existing Iron Overload in Hamp KO Mice

Nutrients ◽

10.3390/nu13051686 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1686

Author(s):

Xiaoyu Wang ◽

Mingzhen Zhang ◽

Regina R. Woloshun ◽

Yang Yu ◽

Jennifer K. Lee ◽

...

Keyword(s):

Iron Overload ◽

Iron Absorption ◽

Hereditary Hemochromatosis ◽

Heme Iron ◽

Dietary Iron ◽

Iron Loading ◽

Body Iron ◽

Iron Restriction ◽

Sirna Treatment ◽

Non Heme Iron

Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40–50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.

Download Full-text

Hfe Acts in Hepatocytes To Prevent Hemochromatosis.

Blood ◽

10.1182/blood.v110.11.703.703 ◽

2007 ◽

Vol 110 (11) ◽

pp. 703-703

Author(s):

Martina U. Muckenthaler ◽

Maja Vujic-Spasic ◽

Judit Kiss ◽

Thomas Herrmann ◽

Bruno Galy ◽

...

Keyword(s):

Iron Overload ◽

Hereditary Hemochromatosis ◽

Hfe Gene ◽

Hepatic Iron ◽

Type I ◽

Cell Type ◽

Severe Liver ◽

Liver Iron ◽

Hepcidin Expression ◽

Hepatic Iron Overload

Abstract Hereditary hemochromatosis (HH) is a prevalent, potentially fatal disorder hallmarked by intestinal iron hyperabsorption, hyperferremia and hepatic iron overload. In both humans and mice, type I HH is associated with mutations in the ubiquitously expressed HFE/Hfe gene. To understand the molecular mechanism(s) underlying HH and to identify the cell type in which Hfe acts to prevent HH we generated mice with tissue-specific Hfe ablations. We demonstrate that hepatocyte-specific Hfe deficiency fully recapitulates the phenotype observed in Hfe−/− mice with severe liver iron accumulation, reduced splenic iron content, increased Tf saturation, hyperferremia and reduced hepcidin expression. These findings unambiguously and directly show that Hfe acts in hepatocytes to prevent hemochromatosis.

Download Full-text

Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading

Blood ◽

10.1182/blood-2005-02-0629 ◽

2005 ◽

Vol 106 (6) ◽

pp. 2189-2195 ◽

Cited By ~ 52

Author(s):

Hortence Makui ◽

Ricardo J. Soares ◽

Wenlei Jiang ◽

Marco Constante ◽

Manuela M. Santos

Keyword(s):

Bone Marrow ◽

Iron Absorption ◽

Hereditary Hemochromatosis ◽

Peptide Hormone ◽

Hfe Gene ◽

Mrna Levels ◽

Iron Loading ◽

Liver Iron ◽

Hepcidin Expression ◽

Hepcidin Mrna

Abstract Hereditary hemochromatosis (HH), an iron overload disease associated with mutations in the HFE gene, is characterized by increased intestinal iron absorption and consequent deposition of excess iron, primarily in the liver. Patients with HH and Hfe-deficient (Hfe-/-) mice manifest inappropriate expression of the iron absorption regulator hepcidin, a peptide hormone produced by the liver in response to iron loading. In this study, we investigated the contribution of Hfe expression in macrophages to the regulation of liver hepcidin levels and iron loading. We used bone marrow transplantation to generate wild-type (wt) and Hfe-/- mice chimeric for macrophage Hfe gene expression. Reconstitution of Hfe-deficient mice with wt bone marrow resulted in augmented capacity of the spleen to store iron and in significantly decreased liver iron loading, accompanied by a significant increase of hepatic hepcidin mRNA levels. Conversely, wt mice reconstituted with Hfe-deficient bone marrow had a diminished capacity to store iron in the spleen but no significant alterations of liver iron stores or hepcidin mRNA levels. Our results suggest that macrophage Hfe participates in the regulation of splenic and liver iron concentrations and liver hepcidin expression. (Blood. 2005;106:2189-2195)

Download Full-text

Hepcidin, a candidate modifier of the hemochromatosis phenotype in mice

Blood ◽

10.1182/blood-2003-09-3358 ◽

2004 ◽

Vol 103 (7) ◽

pp. 2841-2843 ◽

Cited By ~ 32

Author(s):

Gaël Nicolas ◽

Nancy C. Andrews ◽

Axel Kahn ◽

Sophie Vaulont

Keyword(s):

Iron Overload ◽

Iron Metabolism ◽

Genetic Modifier ◽

Hereditary Hemochromatosis ◽

Iron Accumulation ◽

Hfe Gene ◽

Type I ◽

Regulatory Peptide ◽

Liver Iron ◽

Very High

Abstract Hereditary hemochromatosis (HH) type I is a disorder of iron metabolism caused by a mutation in the HFE gene. Whereas the prevalence of the mutation is very high, its penetrance seems very low. The goal of our study was to determine whether hepcidin, a recently identified iron-regulatory peptide, could be a genetic modifier contributing to the HH phenotype. In mice, deficiency of either HFE (Hfe-/-) or hepcidin (Usf2-/-) is associated with the same pattern of iron overload observed in patients with HH. We intercrossed Hfe-/- and Usf2+/- mice and asked whether hepcidin deficiency increased the iron burden in Hfe-/- mice. Our results showed that, indeed, liver iron accumulation was greater in the Hfe-/-Usf2+/- mice than in mice lacking Hfe alone. This result, in agreement with recent findings in humans, provides a genetic explanation for some variability of the HH phenotype. (Blood. 2004;103: 2841-2843)

Download Full-text

Iron and Liver Diseases

Canadian Journal of Gastroenterology ◽

10.1155/2000/954802 ◽

2000 ◽

Vol 14 (suppl d) ◽

pp. 89D-92D ◽

Cited By ~ 11

Author(s):

Silvia Fargion ◽

Michela Mattioli ◽

Anna Ludovica Fracanzani ◽

Gemino Fiorelli

Keyword(s):

Liver Diseases ◽

Hereditary Hemochromatosis ◽

Hfe Gene ◽

Chronic Liver Diseases ◽

Liver Iron ◽

Excess Iron ◽

Cancer Occurrence ◽

History Of ◽

Genetic Hemochromatosis ◽

Severe Fibrosis

A mild to moderate iron excess is found in patients with liver diseases apparently unrelated to genetic hemochromatosis. Iron appears to affect the natural history of hepatitis C virus-related chronic liver diseases, alcoholic liver disease and nonalcoholic steatohepatitis by leading to a more severe fibrosis and thus aiding the evolution to cirrhosis.Ahigher frequency of mutations of the HFE gene, the gene responsible for hereditary hemochromatosis, is found in patients with liver diseases and increased liver iron than in normal patients. Patients with excess iron are potentially at a higher risk of developing hepatocellular carcinoma. Iron depletion therapy could interfere with fibrosis development and possibly reduce the risk of liver cancer occurrence.

Download Full-text