A WHO reference reagent for the Serum Transferrin Receptor (sTfR): international collaborative study to evaluate a recombinant soluble transferrin receptor preparation.

Background: The usefulness of serum transferrin receptor (sTfR) as a marker of iron deficiency is limited by lack of standardization of commercial immunoassays for sTfR. An international collaborative study was performed to evaluate a lyophilized preparation of recombinant soluble transferrin receptor (rsTfR) for its suitability to serve as a World Health Organization (WHO) Reference Reagent to standardize immunoassays for sTfR.

Methods: The concentration of pure rsTfR was determined from the A(280 nm) using the adjusted theoretical extinction coefficient and molecular weight calculated from its sequence, before dilution and lyophilization in a sTfR-depleted serum matrix.

Hereditary hemochromatosis gene (HFE) variants are associated with birth weight and childhood leukemia risk.

Background: Our original studies reported an association between the iron-metabolism gene HFE and risk of childhood acute lymphoblastic leukemia (ALL), and a birth weight association in ALL. Through its effect on cell proliferation, iron is involved in both fetal development and cancer. We hypothesize that HFE links higher infant birth weight with leukemia risk and that maternal HFE genotype modifies this association.

Automated immunoassay methods for ferritin: recovery studies to assess traceability to an international standard.

Background: Ferritin standardisation is problematical due to the heterogeneity of ferritin isoforms and the antibodies used in its immunoassay, and the lack of a reference measurement procedure. We investigated the performance of the 1st (liver), 2nd (spleen) and 3rd (recombinant) International Standards (ISs) for ferritin in major assays.

Methods: The ferritin in a serum pool 'spiked' with either the 2nd or 3rd IS for ferritin was measured by 52 laboratories using five automated methods and the recovery of the target values calculated.

Erythropoiesis and iron metabolism in dominant erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) results from deficiency of ferrochelatase (FECH). Accumulation of protoporphyrin IX causes life-long acute photosensitivity. Microcytic anemia occurs in 20% to 60% of patients.

Haptoglobin: a review of the major allele frequencies worldwide and their association with diseases.

Haptoglobin (Hp) is a plasma alpha(2)-glycoprotein which binds free haemoglobin, thus preventing oxidative damage. The complex is rapidly removed from the circulation by a specific receptor (CD163) found on macrophages. Three major subtypes, Hp1-1, Hp2-1 and Hp2-2 are the product of two closely related genes HP(1) and HP(2).

Heteroduplex analysis for the three common HFE variants: methodology, reliability and analysis of over 5000 requests for testing.

Objective: To describe the analysis of over 5300 patient samples for the HFE genotype.

Methods: Blood samples received from hospitals in England, Wales and Ireland were analysed with a single, multiplex PCR using heteroduplex generators for the C282Y, H63D and S65C variants of the HFE gene. PCR products labelled with fluorescent dyes were analysed by capillary electrophoresis.

Risk of iron overload in carriers of genetic mutations associated with hereditary haemochromatosis: UK Food Standards Agency workshop.

The UK Food Standards Agency convened a group of expert scientists to review current research investigating diet and carriers of genetic mutations associated with hereditary haemochromatosis. The workshop concluded that individuals who are heterozygous for the C282Y mutation of the HFE gene do not appear to respond abnormally to dietary Fe and therefore do not need to change their diet to prevent accumulation of body Fe.

The limited value of methylmalonic acid, homocysteine and holotranscobalamin in the diagnosis of early B12 deficiency.

Treatment of B12 deficiency is important to prevent progressive neurological and/or hematologic disease but requires a secure diagnosis. The aim of this study was to evaluate second line tests of B12 status as prognostic indicators of a hematologic response to vitamin B12 therapy. Forty-nine patients referred with low, serum vitamin B12 concentrations were treated with intramuscular B12 and re-assessed after 3 months.

Diet and genetic factors associated with iron status in middle-aged women.

Background: Gene mutations associated with iron overload have been identified. How food and nutrient intakes affect iron status in persons who may be at risk of iron overload because their genetic status is unknown.

Objective: The objective was to determine the relation between food and nutrient intakes, HFE genotype, and iron status.

HFE gene mutations in susceptibility to childhood leukemia: HuGE review.

The hereditary hemochromatosis (HHC) gene, HFE on chromosome 6p21.3, encodes a protein involved in iron homeostasis. HFE mutations have low penetrance with a mild effect on serum iron levels.

Changes in erythropoiesis in hereditary hemochromatosis are not mediated by HFE expression in nucleated red cells.

Background And Objectives: The HFE protein interacts with the transferrin receptor (TfR) to regulate cellular iron uptake. Nucleated erythroid cells have the highest number of TfR and the greatest iron uptake. The aim of this study was to investigate whether erythroid iron uptake is directly affected by HFE mutations.

Inherited iron loading: genetic testing in diagnosis and management.

Elucidation of the molecular pathways of iron transport through cells and its control is leading to an understanding of genetic iron loading conditions. The general phenotype of haemochromatosis is iron accumulation in liver parenchymal cells, a raised serum transferrin saturation and ferritin concentration. Four types have been identified: type 1 is the common form and is an autosomal recessive disorder of low penetrance strongly associated with mutations in the HFE gene on chromosome 6(p21.

The origin and spread of the HFE-C282Y haemochromatosis mutation.

The mutation responsible for most cases of genetic haemochromatosis in Europe (HFE C282Y) appears to have been originated as a unique event on a chromosome carrying HLA-A3 and -B7. It is often described as a "Celtic mutation"--originating in a Celtic population in central Europe and spreading west and north by population movement. It has also been suggested that Viking migrations were largely responsible for the distribution of this mutation.

Screening for hereditary haemochromatosis within families and beyond.

Screening programmes for haemochromatosis that include follow-up identification of relatives are claimed to be cost effective. We assessed uptake of screening by first-degree relatives of two groups of index cases: people homozygous for the C282Y mutation ascertained by genetic screening of blood donors; and patients presenting clinically with haemochro matosis. Only 40 (24%) of 165 relatives of blood donors had been tested.

Haptoglobin type neither influences iron accumulation in normal subjects nor predicts clinical presentation in HFE C282Y haemochromatosis: phenotype and genotype analysis.

In the UK, 90% of patients with hereditary haemochromatosis (HH) are homozygous for HFE C282Y, as are one in 150 people in the general population. However, only a minority of these will develop clinical haemochromatosis. Iron loss modifies iron accumulation but so may other genetic factors.

Hereditary haemochromatosis: only 1% of adult HFEC282Y homozygotes in South Wales have a clinical diagnosis of iron overload.

In northern Europe, about 90% of patients with hereditary haemochromatosis (HH) are homozygous for a single mutation (C282Y) of the HFEgene and approximately 1 in 150 people in the general population carries this genotype. However, the clinical significance of HFE mutations remains uncertain, as is the proportion of people homozygous for C282Y who will develop clinical symptoms leading to a diagnosis of HH. A systematic review of patients with HH over a 2-year period within a defined UK region has revealed that only 1.

HFE Mutations as risk factors in disease.

Iron deficiency is the most common disorder of iron metabolism worldwide, but there is concern that iron accumulation resulting from enhanced iron absorption may also be a cause of morbidity. In patients with genetic haemochromatosis the clinical manifestations of iron overload are well-known. In northern Europe 90% of such patients are homozygous for the C282Y mutation of the HFE gene and this genotype is found in 1 in 200 of the population.

Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3).

We describe a family with autosomal dominant inheritance of increased body iron stores characterized by raised serum ferritin concentration and normal transferrin saturation. Liver biopsy showed iron deposition in Kupffer cells without fibrosis. The clinical features of HFE-related hemochromatosis were absent, as were the Cys282Tyr and His63Asp mutations.

Serum transferrin receptor assays and their application.

Most cells acquire iron from plasma transferrin and it is the transferrin receptor that is responsible for the internalization of transferrin-bound iron and its subsequent intracellular release. Plasma concentrations of the receptor reflect cellular receptor numbers and may be determined by enzyme immunoassay on automated analysers. Although determination of receptor concentrations may provide little additional value to existing measures of iron status, particular circumstances may dictate the use of these assays.

Hemochromatosis gene in leukemia and lymphoma.

The gene causing hereditary hemochromatosis (HH), HFE is an HLA class I-like gene with no known immunological function but indirectly related to the immune functions because of its role in iron transport. It is located 6.5 Mb telomeric to HLA-A.