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At least 991 records · Page 55Linked to original sources
PubMed1996

beta2 knockout mice develop parenchymal iron overload: A putative role for class I genes of the major histocompatibility complex in iron metabolism.

Hemochromatosis (HC) is an inherited disorder of iron absorption, mapping within the human major histocompatibility complex (MHC). We have identified a multigene system in the murine MHC that contains excellent candidates for the murine equivalent of the human HC locus and implicate nonclassical class I genes in the control of iron absorption. This gene system is characterized by multiple copies of two head-to-head genes encoded on opposite strands and driven by one common regulatory motif. This regulatory motif has a striking homology to the promoter region of the beta-globin gene, a gene obviously involved in iron metabolism and hence termed beta-globin analogous promoter (betaGAP). Upstream of the betaGAP sequence are nonclassical class I genes. At least one of these nonclassical class I genes, Q2, is expressed in the gastrointestinal tract, the primary site of iron absorption. Also expressed in the gastrointestinal tract and downstream of the betaGAP motif is a second set of putative genes, termed Hephaestus (HEPH). Based on these observations, we hypothesized that the genes that seem to be controlled by the betaGAP regulatory motifs would be responsible for the control of Fe absorption. As a test of this hypothesis, we predicted that mice which have altered expression of class I gene products, the beta2-microglobulin knockout mice, [beta2m(-/-)], would develop Fe overload. This prediction was confirmed, and these results indicate beta2m-associated proteins are involved in the control of intestinal Fe absorption.

Animals↗
PubMed2006

R2 relaxometry with MRI for the quantification of tissue iron overload in beta-thalassemic patients.

PURPOSE: To evaluate the usefulness of a time-efficient MRI method for the quantitative determination of tissue iron in the liver and heart of beta-thalassemic patients using spin-spin relaxation rate, R2, measurements. MATERIALS AND METHODS: Images were obtained at 1.5 T from aqueous Gd-DTPA solutions (0.106-8 mM) and from the liver and heart of 46 beta-thalassemic patients and 10 controls. The imaging sequence used was a respiratory-triggered 16-echo Carr-Purcell-Meiboom-Gill (CPMG) spin-echo (SE) pulse sequence (TR = 2000 msec, TE(min) = 5 msec, echo spacing (ES) = 5 msec, matrix = 192 x 256, slice thickness = 10 mm). Liver iron concentration (LIC) measurements were obtained for 22 patients through biopsy specimens excised from the relevant liver segment. Biopsy specimens were also evaluated regarding iron grade and fibrosis. Serum ferritin (SF) measurements were obtained in all patients. RESULTS: A statistically significant difference was found between patients and healthy controls in mean liver (P < 0.004) and myocardium (P < 0.004) R2 values. The R2 values correlated well with Gd DTPA concentration (r = 0.996, P < 0.0001) and LIC (r = 0.874, P < 0.0001). A less significant relationship (r = 0.791, P < 0.0001) was found between LIC measurements and SF levels. R2 measurements appear to be significantly affected (P = 0.04) by different degrees of hepatic fibrosis. The patients' liver R2 values did not correlate with myocardial R2 values (r = 0.038, P < 0.21). CONCLUSION: Tissue iron deposition in beta-thalassemic patients may be adequately quantified using R2 measurements obtained with a 16-echo MRI sequence with short ES (5 msec), even in patients with a relatively increased iron burden.

Adolescent↗
PubMed2001

Progression of iron overload in sickle cell disease.

The expanding indications for transfusions in patients with sickle cell disease raise the issues of appropriate measurement of body iron burden and optimal timing of iron chelation therapy. In this study, we obtained 42 biopsy specimens from 20 patients with sickle cell disease (mean age, 15.7 years) who received transfusions. In 12 patients whose mean age was 11.3 years at the time of liver biopsy, hepatic iron concentration was measured to provide information about the rate of iron accumulation in sickle cell disease, as well as to guide the initiation of chelating therapy. Mean hepatic iron concentration after an average of 15.4 transfusions administered over 21 months was 9.4 +/- 1.2 mg/g liver, dry weight, which did not correlate significantly with determinations of serum transferrin or ferritin levels. On Initial liver biopsy, hepatic portal fibrosis was noted in 4 of 12 patients. Twenty-nine biopsies in 16 patients were performed after variable periods of treatment with deferoxamine. These 16 patients had received a mean of 38.5 transfusions over 4 years. Hepatic iron was 14.1 +/- 1.9 mg/g of liver, dry weight, Indicating poor control of body iron in many patients. Cirrhosis was reported in one of 29 and portal fibrosis in 10 biopsy specimens. Hepatic iron concentration in patients in whom fibrosis was observed varied from 8.9 to 37.7 mg/g of liver, dry weight. These data show that after 1 to 2 years of conventional transfusions, variable tissue iron concentrations and tissue damage are observed in patients with sickle cell disease. In some patients, iron chelation therapy may not be appropriate after 1 year of transfusions; in others, therapy is clearly indicated by this time to prevent tissue injury. The data also suggest that patients with sickle cell disease develop increased portal fibrosis at the thresholds previously described in young patients with thalassemia (approximately 7 mg/g of liver, dry weight).

Adolescent↗