Iron loading in HFE p.C282Y homozygotes found by population screening: relationships to HLA-type and T-lymphocyte subsets.

Iron loading in p.C282Y homozygous HFE hemochromatosis subjects is highly variable, and it is unclear what factors cause this variability. Finding such factors could aid in predicting which patients are at highest risk and require closest follow-up. The degree of iron loading has previously been associated with certain HLA-types and with abnormally low CD8 + cell counts in peripheral blood. In 183 Norwegian, p.C282Y homozygotes (104 men, 79 women) originally found through population screening we determined HLA type and measured total T-lymphocytes, CD4 + and CD8 + cells, and compared this with data on iron loading. In p.C282Y homozygous men, but not in homozygous women, we found that the presence of two HLA-A*03 alleles increased the iron load on average by approximately 2-fold compared to p.C282Y homozygous men carrying zero or one A*03 allele. On the other hand, the presence of two HLA-A*01 alleles, in male subjects, apparently reduced the iron loading. In p.C282Y homozygous individuals, the iron loading was increased if the CD8 + cell number was below the 25 percentile or if the CD4 + cell number was above the 75 percentile. This effect appeared to be additive to the effect of the number of HLA-A*03 alleles. Our data indicate that homozygosity for the HLA-A*03 allele significantly increases the risk of excessive iron loading in Norwegian p.C282Y homozygous male patients. In addition, low CD8 + cell number or high CD4 + cell number further increases the risk of excessive iron loading.

Lower hemoglobin with lower ferritin - results from the HUNT 2 Study.

AIM: We wanted to study the association between blood hemoglobin concentration (b-hemoglobin) and serum ferritin concentration (s-ferritin) in a healthy female population, and compare the findings to those in a previous study of ambulant female patients. METHODS: We compared median b-hemoglobin and the fraction with anemia in groups of women with s-ferritin from less than 10 µg/L to 100 µg/L. These women, aged 20-55 years, were part of a health screening survey (HUNT 2) where they reported to have 'good' or 'very good' general health and were found to have normal s-creatinine. The s-ferritin values were adjusted to the level of the previous study. The 10, 50 and 90 percentiles of b-hemoglobin were modelled as functions of s-ferritin using quantile regression. RESULTS: Among 2122 healthy females the entire b-hemoglobin distribution was shifted downwards in women with s-ferritin less than 20 µg/L. Accordingly, the median b-hemoglobin was statistically significantly lower. In women with s-ferritin less than 20 µg/L the fraction with anemia was 0.15. CONCLUSIONS: Lower s-ferritin is associated with lower b-hemoglobin in many more subjects than those labelled anemic.

Unbound iron binding capacity (UIBC) as a test for empty iron stores--results from the HUNT Study.

BACKGROUND: When s-iron and s-transferrin are used to diagnose empty iron stores, the measurements are usually combined in the calculation of s-transferrin saturation. This may not be the best way to utilize the information in s-iron and s-transferrin, as s-transferrin alone has a better diagnostic accuracy than s-transferrin saturation. We suggest that unbound iron binding capacity (UIBC), which is s-total iron binding capacity (2 times s-transferrin) minus s-iron could be used for diagnosing empty iron stores. METHODS: To test this hypothesis, we used ROC curve analysis to compare the diagnostic accuracy of s-iron, s-transferrin, s-transferrin saturation and s-UIBC in diagnosing empty iron stores in 3029 women of childbearing age. Empty iron stores were defined as s-ferritin less than 10 µg/L or less than 15 µg/L. RESULTS: At both definitions of empty iron stores s-UIBC had a better diagnostic accuracy than the other tests, with area under the ROC curve of 0.80-0.87. This was also the trend in a subpopulation of 172 anemic women, where the area under the ROC curve of s-UIBC was 0.92. CONCLUSION: When diagnosing empty iron stores calculation of s-UIBC is a better way to utilize the information in s-iron and s-transferrin than is calculation of s-transferrin saturation.

Low iron stores are related to higher blood concentrations of manganese, cobalt and cadmium in non-smoking, Norwegian women in the HUNT 2 study.

Low iron (Fe) stores may influence absorption or transport of divalent metals in blood. To obtain more knowledge about such associations, the divalent metal ions cadmium (Cd), manganese (Mn), cobalt (Co), copper (Cu), zinc (Zn) and lead (Pb) and parameters of Fe metabolism (serum ferritin, haemoglobin (Hb) and transferrin) were investigated in 448 healthy, menstruating non-smoking women, age 20-55 years (mean 38 years), participating in the Norwegian HUNT 2 study. The study population was stratified for serum ferritin: 257 were iron-depleted (serum ferritin < 12 microg/L) and 84 had iron deficiency anaemia (serum ferritin < 12 microg/L and Hb < 120 g/L). The low ferritin group had increased blood concentrations of Mn, Co and Cd but normal concentrations of Cu, Zn and Pb. In multiple regression models, ferritin emerged as the main determinant of Mn, Co and Cd (p < 0.001), while no significant associations with Cu, Zn and Pb were found. Adjusted r(2) for the models were 0.28, 0.48 and 0.34, respectively. Strong positive associations between blood concentrations of Mn, Co and Cd were observed, also when controlled for their common association with ferritin. Apart from these associations, the models showed no significant interactions between the six divalent metals studied. Very mild anaemia (110 < or = Hb < 120 g/L) did not seem to have any effect independent of low ferritin. Approximately 26% of the women with iron deficiency anaemia had high concentrations of all of Mn, Co and Cd as opposed to 2.3% of iron-replete subjects. The results confirm that low serum ferritin may have an impact on body kinetics of certain divalent metal ions, but not all. Only a fraction of women with low iron status exhibited an increased blood concentration of divalent metals, providing indication of complexities in the body's handling of these metals.

[Regulation of the iron metabolism]. / Regulering av jernbalansen.

BACKGROUND: The regulation of iron absorption has previously been considered <>. Recent research has given us interesting information on the regulation of the iron metabolism and pathological iron overload; the present article aims at providing an overview of these topics. MATERIALS AND METHODS: The article is based on a review of literature retrieved from PubMed. RESULTS: The peptide hepcidin binds to ferroportin on membranes of enterocytes, macrophages and hepatocytes. The complex is internalised and degraded and this results in decreased export of iron to the circulation, and thus a lower level of plasma iron. Hepcidin production is up-regulated in iron overload and down-regulated with iron deficiency. The liver proteins human haemochromatosis protein (HFE), transferrin receptor 2 (TfR2), haemojuvelin (HJV) and bone morphogenetic protein (BNP) are necessary regulators for activation of the hepcidin synthesis. Lack of or mutations in the genes for these proteins, e.g. the HFE mutation C282Y in primary haemochromatosis, reduces the synthesis of hepcidin. Iron regulatory proteins (IRP) may bind to iron responsive elements (IRE) of ferritin-mRNA and transferritin-mRNA and regulate the protein synthesis. INTERPRETATION: Regulation of uptake, utilization, release and storage of iron occurs at the gene level. Hepcidin is currently considered to be the <> of the iron balance. Intracellular iron balance is maintained by iron regulating proteins. Synthesis of ferritin increases with high iron levels, while synthesis of TfR1 is reduced. The opposite occurs with a low iron level.

[Hemochromatosis--from an underdiagnosed curiosity to a common disease]. / Hemokromatose --fra underdiagnostisert kuriositet til folkesykdom.

BACKGROUND: Hemochromatosis is a common disease with a good prognosis, when diagnosed early and treated appropriately. The aim of this overview is to give updated information on hemochromatosis with special focus on biochemical features, diagnosis and treatment. MATERIAL AND METHODS: This article is based on our own experience and a review of available literature in various databases such as PubMed and Medline. RESULTS: Hereditary hemochromatosis is an autosomal recessive disease characterized by iron overload due to increased intestinal iron uptake over many years. Hemochromatosis is often discovered through coincidental detection of high levels of transferrin and/or ferritin. The early symptoms are asthenia and joint pain. About 85 % of patients with hereditary hemochromatosis are homozygote for the C282Y mutation in the HFE: gene, but the majority of homozygotes remain asymptomatic. With ferritin levels > 500 microg/, both hereditary hemochromatosis and iron overload (of unknown cause) are treated with blood-letting. INTERPRETATION: The pathogenesis is not fully elucidated but recent reports indicate that the protein hepcidin (produced in the liver) plays a key role in the development of hemochromatosis. Iron overload may also be secondary to other diseases such as thalassemia and other conditions requiring multiple long-term blood transfusions. The goal is to maintain ferritin values at approximately 20 - 50 microg/L.

Predictors of serum ferritin and serum soluble transferrin receptor in newborns and their associations with iron status during the first 2 y of life.

BACKGROUND: Adequate iron status at birth may prevent iron deficiency in early childhood. OBJECTIVES: We aimed to identify predictors of serum ferritin (SF) and serum soluble transferrin receptor (sTfR) in healthy newborns and to relate these iron indexes to iron status in the first 2 y of life. DESIGN: Using bivariate correlations and linear regression, we related various factors in pregnancy to SF (n=363) and sTfR (n=350) in healthy, term infants. Measurements of cord SF and sTfR were compared with those of SF and sTfR at 6, 12, and 24 mo. All 4 measurements were available for 191 and 169 infants for SF and sTfR, respectively. RESULTS: Geometric mean (and 95% CI) cord SF and sTfR measurements were 159 (148, 171) microg/L and 7.3 (7.0, 7.6) mg/L, respectively. Cord SF correlated with sTfR (rho=-0.21, P<0.001). In regression analysis, cord SF correlated with smoking and the use of iron supplements during pregnancy (partial r=-0.12 and 0.16; P<0.05 for both). Cord sTfR was associated with first trimester BMI, gestational age, and male sex (partial r=0.30, 0.24, and 0.19, respectively; P<0.01 for all). Cord SF correlated with SF at 6, 12, and 24 mo (rho=0.45, 0.31, and 0.16 respectively; P<0.05 for all). At age 6 mo, 16 of 17 infants with SF <15 mug/L were boys. CONCLUSIONS: Cessation of smoking and adequate iron prophylaxis during pregnancy may improve iron status in infancy. Cord SF is a predictor of iron status in the first 2 y of life. Boys are at particular risk of low iron status in early infancy.

Selective iron supplementation based on serum ferritin values early in pregnancy: are the Norwegian recommendations satisfactory?

BACKGROUND: The aims of the present study were to evaluate the recommendations by comparing compliance and adequacy of iron status at 6 weeks postpartum between one group given advice only and one group given advice plus iron supplement. In the latter group the efficacies of two iron preparations of different strengths and types were compared. METHODS: Ninety-three women had been given advice only (Group I) and were enrolled in the project at 6 weeks postpartum. Two hundred and thirty-three women enrolled at their second antenatal visit and were given advice plus iron supplement; those with s-ferritin <60 microg/L were randomized to a daily dose of 1) 60 mg Fe2+ (Ferromax) or 2) 3.6 mg heme iron plus 24 mg Fe2+ (Hemofer), and started taking the supplement at once if s-ferritin <20 microg/L or at 20 weeks if 20-60 microg/L. In addition to hemoglobin as routine, s-ferritin was measured in all the women at 6 weeks postpartum. RESULTS: At 6 weeks postpartum median s-ferritin was 28 and 34 microg/L in Groups I and II, respectively, and a significantly higher mean s-ferritin (46.5 vs. 37.3 microg/L; p < 0.05) was found in women taking the highest dose. There were no correlations between s-ferritin in early pregnancy and at 6 weeks postpartum. Peripartum blood loss was the main indicator for iron status at 6 weeks postpartum. CONCLUSION: Iron supplementation based on iron status early in pregnancy, with 60 mg ferrous iron or 27 mg iron containing heme, resulted in adequate iron stores at 6 weeks postpartum among 75% or 70% of the women, respectively. However, 6 weeks were not sufficient to rebuild iron stores in women with large peripartum blood loss.