Primary Hemochromatosis in Children: Report of Three Newly Diagnosed Cases and Review of the Pediatric Literature

PEDIATRICS ◽  
1992 ◽  
Vol 90 (1) ◽  
pp. 37-42
Author(s):  
Yigal Kaikov ◽  
Louis D. Wadsworth ◽  
Eric Hassall ◽  
James E. Dimmick ◽  
Paul C.J. Rogers
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Serum Iron ◽  
Hereditary Hemochromatosis ◽  
Elevated Serum ◽  
Significant Decline ◽  
Hepatic Iron ◽  
Unexpected Finding ◽  
Newly Diagnosed ◽  
Review Of The Literature

Hereditary hemochromatosis was diagnosed in three asymptomatic siblings following the unexpected finding of elevated serum iron concentrations. This diagnosis was confirmed by hepatic biopsy. Repeated phlebotomies resulted in a significant decline of serum iron and ferritin concentrations and a decrease of hepatic iron content. This report and a review of the literature indicate that the diagnosis of hereditary hemochromatosis must be considered more frequently in childhood. Organ dysfunction from iron overload may be minimized in children by the early commencement of regular phlebotomy.

scholarly journals Down-regulation of hepcidin in porphyria cutanea tarda

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4723-4728 ◽  
Author(s):  
Richard S. Ajioka ◽  
John D. Phillips ◽  
Robert B. Weiss ◽  
Diane M. Dunn ◽  
Maria W. Smit ◽  
...  
Keyword(s):  
Iron Overload ◽  
Porphyria Cutanea Tarda ◽  
Hereditary Hemochromatosis ◽  
Elevated Serum ◽  
The Other ◽  
Hepatic Iron ◽  
Iron Loading ◽  
Hepatic Expression ◽  
Hepatic Iron Overload ◽  
Genetic And Environmental Factors

Abstract Hepatic siderosis is common in patients with porphyria cutanea tarda (PCT). Mutations in the hereditary hemochromatosis (hh) gene (HFE) explain the siderosis in approximately 20% patients, suggesting that the remaining occurrences result from additional genetic and environmental factors. Two genes known to modify iron loading in hh are hepcidin (HAMP) and hemojuvelin (HJV). To determine if mutations in or expression of these genes influenced iron overload in PCT, we compared sequences of HAMP and HJV in 96 patients with PCT and 88 HFE C282Y homozygotes with marked hepatic iron overload. We also compared hepatic expression of these and other iron-related genes in a group of patients with PCT and hh. Two intronic polymorphisms in HJV were associated with elevated serum ferritin in HFE C282Y homozygotes. No exonic polymorphisms were identified. Sequencing of HAMP revealed exonic polymorphisms in 2 patients with PCT: heterozygosity for a G→A transition (G71D substitution) in one and heterozygosity for an A→G transition (K83R substitution) in the other. Hepatic HAMP expression in patients with PCT was significantly reduced, regardless of HFE genotype, when compared with patients with hh but without PCT with comparable iron overload. These data indicate that the hepatic siderosis associated with PCT likely results from dysregulated HAMP.

scholarly journals Clinical Manifestations of Hemochromatosis inHFEC282Y Homozygotes Identified by Screening

2008 ◽  
Vol 22 (11) ◽  
pp. 923-930 ◽  
Author(s):  
Gordon D McLaren ◽  
Christine E McLaren ◽  
Paul C Adams ◽  
James C Barton ◽  
David M Reboussin ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Elevated Serum ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Joint Stiffness ◽  
Chronic Fatigue ◽  
Newly Diagnosed ◽  
Wild Type ◽  
Control Subjects

BACKGROUND: Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences.OBJECTIVE: To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE)mutation (C282Y) identified by screening.METHODS: Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without theHFEC282Y or H63D alleles (ie, wild type/wild type; n=364).RESULTS: Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects.CONCLUSIONS: Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study.

Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 17-21 ◽  
Author(s):  
Emanuele Angelucci ◽  
Pietro Muretto ◽  
Antonio Nicolucci ◽  
Donatella Baronciani ◽  
Buket Erer ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Iron Overload ◽  
Iron Content ◽  
Hazard Rate ◽  
Iron Concentration ◽  
Dry Weight ◽  
Interquartile Range ◽  
Hepatic Iron ◽  
Fibrosis Progression

Abstract To identify the role of iron overload in the natural history of liver fibrosis, we reviewed serial hepatic biopsy specimens taken annually from patients cured of thalassemia major by bone marrow transplantation. The patients underwent transplantation between 1983 and 1989 and did not receive any chelation or antiviral therapy. Two hundred eleven patients (mean age, 8.7 ± 4 years) were evaluated for a median follow-up of 64 months (interquartile range, 43-98 months) by a median number of 5 (interquartile range, 3-6) biopsy samples per patient. Hepatic iron concentration was stratified by tertiles (lower, 0.5-5.6 mg/g; medium, 5.7-12.7 mg/g; upper, 12.8-40.6 mg/g dry weight). Forty-six (22%) patients showed signs of liver fibrosis progression; the median time to progression was 51 months (interquartile range, 36-83 months). In a multivariate Cox proportional hazard model, the risk for fibrosis progression correlated to medium hepatic iron content (hazard rate, 1.9; 95% confidence interval [CI], 0.74-5.0), high hepatic iron content (hazard rate, 8.7; 95% CI, 3.6-21.0) and hepatitis C virus (HCV) infection (hazard rate, 3.1; 95% CI, 1.5-6.5). A striking increase in the risk for progression was found in the presence of both risk factors. None of the HCV-negative patients with hepatic iron content lower than 16 mg/g dry weight showed fibrosis progression, whereas all the HCV-positive patients with hepatic iron concentration greater than 22 mg/g dry weight had fibrosis progression in a minimum follow-up of 4 years. Thus, iron overload and HCV infection are independent risk factors for liver fibrosis progression, and their concomitant presence results in a striking increase in risk.

Determinants for Iron Overload-Related Disease in Siblings of Probands with Clinically Detected HFE Hereditary Hemochromatosis: The Hemochromatosis Family Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1857-1857
Author(s):  
Esther M.G. Jacobs ◽  
Jan C.M. Hendriks ◽  
Herman G. Kreeftenberg ◽  
Richard A. de Vries ◽  
Joannes J.M. Marx ◽  
...  
Keyword(s):  
Iron Overload ◽  
Predictive Value ◽  
Serum Iron ◽  
Alcohol Intake ◽  
Hereditary Hemochromatosis ◽  
High Risk Group ◽  
Early Screening ◽  
Related Disease ◽  
Iron Parameters ◽  
And Gender

Abstract The clinical expression of HFE-associated hereditary hemochromatosis (HH) gen is highly variable and may be influenced by nongenetic factors and coinherited genetic modifiers, complicating early screening options to prevent iron-overload related disease. The aim of this study was to verify the existence of HH-related disease in C282Y homozygous siblings of C282Y homozygous probands with clinically detected HFE-related HH and to identify factors predictive for the iron-related disease within these siblings. To this end, C282Y homozygous (n=110, males n=53) and non-homozygous siblings (n=318, males n=145) of 224 probands were compared for levels of serum iron parameters, and self-reported environmental and lifestyle factors and previously diagnosed HH-related diseases. Compared to non-homozygous C282Y siblings, C282Y homozygous siblings more often mentioned to have been diagnosed with arthropathy (Odds Ratio [OR] 2.76, 95% Confidential Interval [CI] 1.71–4.46) and liver disease (OR 2.90, 95%CI 1.27– 6.62). Using multivariate logistic regression modelling, genotype (OR 2.29, 95%CI 1.04– 5.02), age (OR 1.07, 95% CI 1.04–1.09) and gender (OR 1.71, 95%CI 1.04–2.80) were found predictive for the development of iron-associated organ disease. With genotype in the model, there was neither an additive predictive value of the serum iron parameters, nor of body mass index (BMI) or alcohol intake. However, when the predictive value of the iron parameters was analyzed in siblings above 55 yrs, the input of the serum ferritin levels was also significant, with a less prominent influence of gender. In conclusion, our results show that the prevalence of hemochromatosis-attributed morbid conditions is increased in the C282Y homozygous siblings compared to their non-homozygous counterparts. Results furthermore suggest that age and gender, but not BMI and alcohol intake, add to the identification of C282Y homozygous siblings most at risk to develop hemochromatosis-associated disease. These findings will be instrumental in the definition of a high-risk group for iron overload-related disease among siblings of clinically detected C282Y homozygous probands and may contribute to the cost-effectiveness of family screening.

RNAi-Mediated Inhibition of Tmprss6 Elevates Hamp1 Expression and Reduces Serum Iron Levels in Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1045-1045 ◽  
Author(s):  
Ivanka Toudjarska ◽  
Zuhua Cai ◽  
Tim Racie ◽  
Stuart Milstein ◽  
Brian R Bettencourt ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Iron ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Elevated Serum ◽  
High Serum ◽  
Therapeutic Modality ◽  
Deficiency Anemia ◽  
Loss Of Function ◽  
Hepcidin Expression

Abstract Abstract 1045 The liver hormone Hepcidin (encoded by Hamp1) regulates serum iron levels by controlling the efflux of iron from intestinal enterocytes and macrophages. Maintaining sufficient iron levels to support erythropoiesis while preventing iron overload requires tight control of Hepcidin expression. Transcription of Hamp1 in hepatocytes is stimulated by high serum iron levels, via Transferrin Receptor signaling, as well as by activation of the BMP/SMAD pathway. The membrane serine protease Matriptase-2 (encoded by Tmprss6) inhibits BMP induced Hamp1 induction through the regulation of the BMP co-receptor, Hemojuvelin. In humans, loss of function mutations in TMPRSS6 lead to elevated Hepcidin levels resulting in iron-resistant iron-deficiency anemia (IRIDA). In diseases associated with iron overload, such as Thalassemia intermedia (TI) and Familial Hemochromatosis (FH), Hepcidin levels are low despite elevated serum iron concentrations. Studies in murine models of TI and FH have shown that elevating Hepcidin levels by genetic inactivation of Tmprss6 can prevent iron overload and correct aspects of the disease phenotype. Therefore, therapeutic strategies aimed at specifically inhibiting Tmprss6 expression could prove efficacious in these, and other, iron overloading diseases. Here we show that systemic administration of a potent lipid nanoparticle (LNP) formulated siRNA directed against Tmprss6 leads to durable inhibition of Tmprss6 mRNA in the mouse liver, with concomitant elevation of Hamp1 expression. This leads to significant decreases in serum iron concentration and Transferrin saturation, along with changes in hematologic parameters consistent with iron restriction. Further testing in mouse genetic models of TI and FH will support the rationale for developing LNP formulated Tmprss6 siRNA as a novel therapeutic modality. Disclosures: Toudjarska: Alnylam Pharmaceuticals, Inc.: Employment. Cai:Alnylam Pharmaceuticals, Inc.: Employment. Racie:Alnylam Pharmaceuticals, Inc.: Employment. Milstein:Alnylam Pharmaceuticals, Inc.: Employment. Bettencourt:Alnylam Pharmaceuticals, Inc.: Employment. Hettinger:Alnylam Pharmaceuticals, Inc.: Employment. Sah:Alnylam Pharmaceuticals, Inc.: Employment. Vaishnaw:Alnylam Pharmaceuticals, Inc.: Employment. Bumcrot:Alnylam Pharmaceuticals, Inc.: Employment.

scholarly journals Hepatic Iron Overload: Direct HLA-HMutation AnalysisvsQuantitative Iron Assays for the Diagnosis of Hereditary Hemochromatosis

1998 ◽  
Vol 109 (5) ◽  
pp. 577-584 ◽  
Author(s):  
Richard D. Press ◽  
Ken Flora ◽  
Cindy Gross ◽  
John M. Rabkin ◽  
Christopher L. Corless
Keyword(s):  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Hepatic Iron ◽  
Hepatic Iron Overload

HAMP and HVJ as Candidate Modifier Genes in Type1 Hereditary Hemochromatosis with High Iron Burden and in Porphyria Cutanea Tarda (PCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1544-1544
Author(s):  
Richard S. Ajioka ◽  
John D. Phillips ◽  
Robert B. Weiss ◽  
Diane M. Dunn ◽  
James P. Kushner
Keyword(s):  
Iron Overload ◽  
Splice Site ◽  
Hereditary Hemochromatosis ◽  
Modifier Genes ◽  
Hepatic Iron ◽  
Iron Loading ◽  
Wild Type ◽  
Hepatic Iron Overload ◽  
Number Of Patients

Abstract Homozygosity for the HFE C282Y mutation accounts for approximately 90 percent of HFE-associated (type 1) hereditary hemochromatosis. The clinical phenotype in C282Y homozygotes, however, ranges from simply an elevated percent saturation of transferrin to organ damage due to iron overload. Modifier genes have been proposed to explain this phenotypic variability. Hepatic siderosis is a nearly constant finding in patients with PCT. Approximately 20 percent of patients with PCT are homozygotes for the C282Y HFE mutation but the cause of hepatic iron loading in the remaining 80 percent is not known. Approximately one-third of patients with PCT are heterozygotes for mutations of the uroporphyrinogen decarboxylase (URO-D) gene (familial PCT) but pedigree studies indicate that clinical expression occurs only in those URO-D heterozygotes who develop hepatic siderosis. Most patients with PCT have no URO-D mutations (sporadic PCT) but virtually all sporadic cases have hepatic iron overload. Two genes known to affect iron homeostasis are hepcidin (HAMP) and hemojuvelin (HJV). Heterozygosity for HAMP and HJV mutations have been associated with marked iron overload in a small number of patients with type 1 hemochromatosis (Blood.2004; 103:2835–40; Blood Cells Mol Dis.2004; 33:338–43). We asked if mutations of HAMP or HJV could account for hepatic iron overload in highly penetrant C282Y homozygotes and in PCT patients with or without HFE mutations. We sequenced the HAMP and HJV genes in 96 hemochromatosis patients with grade 3–4 (scale 0–4) hepatic parenchymal cell stainable iron (HPCSI) and 96 PCT patients with variable degrees of hepatic siderosis. Ninety-four percent (90) of the hemochromatosis patients were C282Y homozygotes, 4.2 percent (4) were C282Y heterozygotes and 2.1 percent (2) were wild type 282 homozygotes. No exonic changes or splice site mutations were detected in either the HAMP or HJV genes. Eighty-three of the 96 PCT patients were genotyped at the HFE locus. Twenty-five percent (21) were C282Y homozygotes, 23 percent (19) were C282Y heterozygotes and 52 percent (43) were wild type 282 homozygotes. No exonic changes or splice site mutations were detected in the HJV gene of patients with PCT but two PCT patients were found to be heterozygotes for HAMP mutations. The first had the previously identified 212G→A transition leading to a G71D substitution. The second had a 248A→C transversion corresponding to K83R in the peptide. Both of these PCT patients were HFE 282 wild type homozygotes but both had grade 4 HPCSI. These data indicate that heterozygosity for mutations of HAMP or HJV rarely modifies the iron loading phenotype in either type 1 hemochromatosis or PCT. Other modifier loci must exist.

Mini-Hepcidins Prevent Iron Overload In A Mouse Model of Hereditary Hemochromatosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 689-689
Author(s):  
Elizabeta Nemeth ◽  
Emilio Ramos ◽  
Peter Ruchala ◽  
Gloria Preza ◽  
Tomas Ganz
Keyword(s):  
Iron Overload ◽  
Knockout Mice ◽  
Serum Iron ◽  
Conflicts Of Interest ◽  
Hereditary Hemochromatosis ◽  
Microcytic Anemia ◽  
Iron Loading ◽  
High Doses ◽  
Biophysical Interactions

Abstract Abstract 689 Mini-hepcidins are synthetic peptide analogues of the hepcidin N-terminus which is crucial for hepcidin interaction with ferroportin. Due to their small size and relative ease of synthesis, mini-hepcidins are better candidates than native hepcidin as therapeutics for the prevention and treatment of iron overload. In our previous studies, the first 9 amino acids of hepcidin (DTHFPICIF) were sufficient for in vitro activity (measured as ferroportin-GFP degradation). We modified the amino acid sequence of hepcidin-9 to improve resistance to proteolysis and to enhance the biophysical interactions with ferroportin. From >70 modified mini-hepcidins, we selected several that were more potent than native hepcidin in vitro, and tested them in mouse models. Bioactivity was assessed by measuring the hypoferremic effect of minihepcidins in C57BL/6 mice 4h after administration. Several minihepcidins administered by intraperitoneal or subcutaneous injection were more potent than the native hepcidin in reducing serum iron. Remarkably, retroinverted mini-hepcidins modified by palmitoylation or bile acid conjugation were active also by gavage. None of the tested mini-hepcidins altered endogenous hepcidin production. We also examined the ability of parenteral minihepcidins to prevent tissue iron loading in hepcidin knockout mice. Daily injections for 12 days completely prevented iron loading of the liver, decreased serum iron and increased splenic iron content. At high doses, minihepcidins were sufficiently potent that they caused iron-restricted microcytic anemia in hepcidin knockout mice. Minihepcidins may be useful for the treatment of human iron overload conditions caused by hepcidin deficiency. Disclosures: No relevant conflicts of interest to declare.

In Vivo Disruption Of The Hepcidin−Ferroportin Regulatory Circuitry Causes Fatal Systemic and Exocrine Pancreatic Iron Overload

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 175-175
Author(s):  
Sandro Altamura ◽  
Hermann Josef Gröne ◽  
Regina Kessler ◽  
Bruno Galy ◽  
Matthias W. Hentze ◽  
...  
Keyword(s):  
Iron Overload ◽  
Molecular Mechanisms ◽  
Histological Analysis ◽  
Conflicts Of Interest ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Iron Accumulation ◽  
Blue Staining ◽  
Hepatic Iron

Abstract Systemic iron levels are tightly controlled by the hepatic hormone hepcidin in response to iron availability, inflammation, hypoxia or the iron demand for erythropoiesis. Hepcidin binds to the iron export protein ferroportin (FPN1) to regulate iron release from exporting cells. A mutation of cysteine 326 (C326S) of FPN1 was reported in a patient with non−classical ferroportin disease (Sham et al, 2005) and shown to abrogate hepcidin binding in vitro (Fernandes et al, 2009). To study consequences of the disruption of the hepcidin−ferroportin interaction in vivo, we generated the first knock−in mouse model of C326S non−classical ferroportin disease. Mice with either heterozygous or homozygous C326S FPN alleles are viable and fertile. At 8−weeks of age both heterozygous and homozygous mice show profoundly increased transferrin saturation and serum ferritin levels as well as hepatic iron overload. Histological analysis by Perl’s Prussian blue staining revealed that hepatic iron accumulation is restricted to hepatocytes and that Kupffer cells are spared of iron. In addition, splenic macrophages and duodenal enterocytes are iron−depleted. Macroscopically, C326S homozygous mice show progressive, brown discoloration of the pancreas that correlates with profound iron deposition. Histological analysis reveals that iron localizes exclusively to the exocrine pancreas sparing the islets of Langerhans. Consistently, C326S homozygous mice do not show any signs of diabetes. Pancreatic iron accumulation is closely associated with increased reactive oxygen species (ROS), degeneration of exocrine pancreatic cells, increased plasma lipase and exocrine pancreatic failure. Starting at the age of 33 weeks, pancreatic failure is accompanied by progressive wasting and death. We believe that C326S FPN mice represent the first example of fatal iron overload in an animal model, opening avenues to investigate the underlying molecular mechanisms. Sham R, Phatak PD, West C, et al. Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features. Blood Cells Mol. Dis. 2005; 34:157−61. Fernandes A, Preza GC, Phung Y, et al. The molecular basis of hepcidin−resistant hereditary hemochromatosis. Blood. 2009;114:437−443. Disclosures: No relevant conflicts of interest to declare.

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