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Seasonal iron overload in Svalbard reindeer liver.

Changes in liver iron concentration in relation to seasonal body weight variations and food iron intake have been investigated in 77 Svalbard reindeer by chemical and histological methods. During the winter season the body weight decreased about 43% in females and 39% in males. Liver weight was reduced about 65% in both sexes. The liver iron concentration showed little or no difference between the sexes and was 29 +/- 13 mg iron/100 g wet weight in the autumn. The concentration increased in late winter to 291 +/- 52 mg iron/100 g in animals eating iron-rich forage plants, and to 165 +/- 92 mg iron/100 g in animals eating forage plants with a normal iron content. Starving animals with a very high iron concentration of the rumen content usually had massive siderosis in both parenchymal and nonparenchymal cells of the liver. In contrast, siderosis was restricted to nonparenchymal cells in starving animals with normal rumen iron concentration. Transferrin saturation was significantly higher in animals eating iron-rich forage plants than in those eating forage plants with a normal content. Therefore it is proposed that seasonal liver siderosis is a result of a) translocation of iron from catabolized blood and lean tissue that is recovered in nonparenchymal cells and b) high uptake of food iron with deposition in the parenchymal cells.

Animals↗

Iron overload before cecal ligation and puncture increases mortality.

Iron metabolism is dysregulated in critically ill patients. A mouse model of dysregulated iron metabolism was used to examine the consequence of iron loading upon sepsis. Mice deleted in the hfe gene (hfe-/-) abnormally accumulate iron in tissue; defects in the human hfe gene are clinically expressed as hemochromatosis. Hfe-/- mice and wild-type counterparts were randomized to receive either high- or low-iron diets for 2 weeks. After iron loading, mice were subjected to cecal ligation and puncture (CLP), a clinically relevant animal model of intra-abdominal sepsis. A preliminary (but underpowered) study suggested that iron-loaded hfe-/- mice had increased mortality as compared with hfe-/- mice fed a low-iron diet. There was no difference between wild-type and hfe-/- mice fed a low-iron diet or between wild-type mice fed hihg- and low-iron diets. A subsequent, appropriately powered study showed that iron-loaded hfe-/- mice had significantly higher mortality from intra-abdominal sepsis than hfe-/- mice fed a low-iron diet. Iron loading was confirmed through chemical assay of iron concentration in hepatic tissue. Animals with dysregulated iron handling, loaded with iron and subjected to CLP, had double the mortality of animals with normal iron levels. Critical care patients often have altered iron metabolism. In clinical practice, critically ill patients may receive iron through direct administration and the transfusion of blood products. Iron therapy may adversely affect the clinical outcome from sepsis.

Administration, Oral↗

Prevalence of iron overload in central Sweden.

An increase in the iron content of food may be harmful to people with genetic hemochromatosis. We studied the prevalence of this disorder in Sweden, which is the country with the world's highest iron fortification of food. Serum ferritin and transferrin (TIBC) saturation levels were used as initial screening methods. Three (0.5%) of 623 males aged 30-39 years were found to have genetic hemochromatosis. Family studies revealed 10 additional homozygotic family members. A prevalence of 0.5% of homozygotes (q2) implies a gene frequency (q) of 6.9% or a heterozygote frequency (2 x Q) of 13.8%. The high gene frequency may be explained by a possible genetic advantage of heterozygotes in the past. We conclude that idiopathic hemochromatosis is not as rare as previously thought. Affected persons should be detected and treated before irreversible organ damage occurs. This study demonstrates that serum ferritin levels together with TIBC saturation levels are adequate methods for screening populations.

Adult↗

Transferrin receptor expression in normal and iron overloaded liver.

Hepatocytes take up transferrin-bound iron by two mechanisms. One pathway consists in the binding of transferrin to high affinity receptor sites. This process results in receptor-mediated endocytosis and is highly efficient and saturable. The other mechanism involves low affinity, non-specific and non-saturable internalization of transferrin-bound iron, probably through pinocytosis, adsorptive endocytosis or low affinity binding sites. At low transferrin saturation, the first mechanism is quantitatively most important, at high transferrin saturation the latter mechanism becomes more significant. A mechanism whereby transferrin-bound iron is not endocytosed but reduced at and translocated through the plasma membrane has also been invoked and challenges the concept of (receptor-mediated) endocytosis of transferrin. However, this hypothesis remains to be confirmed.

Animals↗

Molecular structure and biological and pharmacological properties of 3-hydroxy-2-methyl-1-(beta-D-ribofuranosyl or pyranosyl)-4-pyridinone: potential iron overload drugs for oral administration.

Replacing alkyl groups by sugar moieties at N-1 position of 3-hydroxy-2-methyl-4-pyridinone did not affect the geometry of the iron chelating sites but increased the hydrophilic nature. The formation of a polymer cluster through the intermolecular hydrogen bonds was also revealed by X-ray crystal structure analysis for the first time in all known 3-hydroxy-4-pyridinone crystal structures. Iron removal from ferritin by the title compounds was more efficient than with DFO.

Administration, Oral↗

The use of skin Fe levels as a surrogate marker for organ Fe levels, to monitor treatment in cases of iron overload.

A system based on the detection of K-shell x-ray fluorescence (XRF) has been used to investigate whether a correlation exists between the concentration of iron in the skin and the concentration of iron in the liver, as the degree of iron loading increases. The motivation behind this work is to develop a non-invasive method of determining the extent of the body's iron stores via measurements on the skin, in order to monitor the efficacy of chelation therapy administered to patients with beta-thalassaemia. Sprague-Dawley rats were iron loaded via injections of iron dextran and subsequently treated with the iron chelator CP94. The non-haem iron concentrations of the liver, heart and spleen were determined using bathophenanthroline sulphonate as the chromogen reagent. Samples of abdominal skin were taken and the iron concentrations determined using XRF. A strong correlation between the skin iron concentration and the liver iron concentration has been demonstrated (R2 = 0.86). Similar correlations exist for the heart and the spleen. These results show that this method holds great potential as a tool in the diagnosis and treatment of hereditary haemochromatosis and beta-thalassaemia.

Animals↗

Respiratory function in patients with thalassaemia major: relation with iron overload.

AIMS: (1) To determine the pattern of respiratory impairment in children with thalassaemia major (TM); (2) to assess the relation between the degree of respiratory impairment and total body iron content. METHODS: Twenty nine TM patients were recruited. All underwent physical examination, standardised pulmonary function tests (spirometry, lung volume, and single breath diffusion capacity for carbon monoxide), and magnetic resonance imaging measurements of the liver. Serum ferritin was measured. The signal intensity ratio of liver to that of paraspinal muscle (T1 weighted sequence) and serum ferritin were used as surrogate index of body iron content. RESULTS: Sixteen boys and 13 girls (median age 14.2 years) were studied. None had clinical evidence of congestive heart failure. Sixteen had normal lung function. Impairment of diffusion capacity (median DL(co) 83.5% predicted) was the most common abnormality, being observed in 34% of patients. Pure restrictive and obstructive ventilatory impairment was found in one and two patients respectively. Five patients had a combination of ventilation and diffusion defects. There was no correlation between the degree of impairment of each respiratory abnormality and body iron content. CONCLUSION: Diffusion impairment was the commonest abnormality found in our cohort of paediatric TM patients. Our data did not support the notion that respiratory function impairment was correlated with body iron content.

Adolescent↗