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Biomedical subjects

G M Brittenham

Publications and source records attributed to G M Brittenham.

At least 55 records · Page 3Linked to original sources
PubMed1996

Primary iron overload in African Americans.

PURPOSE: To report African Americans with primary iron overload diagnosed during life and to study iron stores in African Americans undergoing autopsy. PATIENTS AND METHODS: We summarized information for 4 African-American patients diagnosed during life with iron overload not explainable by alcohol, blood transfusions, or ineffective erythropoiesis. We reviewed liver specimens and hospital records of 326 unselected adult African Americans who were autopsied, assessing Prussian blue-stained sections for hepatocellular iron and measuring iron quantitatively in specimens that stained positively. We calculated the hepatic iron index (the hepatic iron concentration in mumol/g dry weight divided by the age in years). In autopsy subjects we corrected the index to account for iron administered by blood transfusion (the adjusted hepatic iron index). The hepatic iron index is useful for distinguishing primary iron overload from the moderate siderosis that may accompany alcoholic liver disease. The normal index is < or = 1.0. An index > or = 1.7 cannot be explained by alcohol effects and an index > or = 1.9 indicates the magnitude of iron-loading found in Caucasian homozygous HLA-linked hemochromatosis. RESULTS: The 4 living patients, all males and 27 to 50 years of age, had elevated body iron burdens and one or more of the following: hepatomegaly, cirrhosis, cardiomyopathy, diabetes mellitus, and impotence. Hepatic iron indices were 2.3, 11.5, and 20.2 in the 3 whose liver iron concentrations were measured. Among the autopsy subjects, 4 (1.2%), 2 men and 2 women aged 50 to 63 years, had adjusted hepatic iron indices > or = 1.9 (range 1.9 to 5.6). CONCLUSIONS: Primary iron overload occurs in African Americans. Further studies are needed to define prevalence, pathophysiology and clinical consequences. Clinicians should look for this condition.

Adult↗
PubMed1995

Prevalence of heterozygotes for hemochromatosis in the white population of the United States.

In previous studies, the prevalence of HLA-linked hemochromatosis, thought to be the most common genetic illness in whites, has been estimated by identifying homozygotes in the population. Because not all homozygotes express the disease phenotypically, the accuracy of these estimates is uncertain. We analyzed the distribution of transferrin saturation values in the second National Health and Nutrition Examination Survey to estimate the prevalence of hemochromatosis heterozygotes in the US population. After removing values for possible homozygotes, two populations were present (P < .01 for each gender). When weighted to reflect the US adult white male population as a whole, a proportion of 850 per 1,000 (95% confidence interval, 0.81 to 0.89) were included in a population with a lower mean saturation of 29.7% (29.1% to 30.3%), whereas 150 per 1,000 (0.11 to 0.19) comprised a population with a higher mean saturation of 47.0% (45.1% to 49.0%). Similar results were found for the female population. The gene frequencies were estimated to be 0.081 from the male population and 0.070 from the female population corresponding to prevalences of homozygotes of 6.6 and 4.8 per 1,000, respectively. Our results confirm that the gene for hemochromatosis is common.

Adolescent↗
PubMed1995

Transferrin saturation and recovery from coma in cerebral malaria.

To determine if the elevated transferrin saturations found in some patients with severe malaria are associated with an adverse outcome in cerebral malaria, we retrospectively measured baseline saturations in stored serum samples from 81 Zambian children with strictly defined cerebral malaria. The children had been treated with quinine, sulfadox-ine-pyrimethamine, and intravenous infusions of either placebo (n = 39) or the iron chelator, desferrioxamine B (n = 42), in a previously reported trial (Gordeuk et al, N Engl J Med 327:1473, 1992). More than one-third of children in both the placebo- and iron chelator-treated groups had transferrin saturations exceeding 43%, which is 3 standard deviations above the expected mean for age. Among children receiving quinine and placebo, those with elevated transferrin saturations had a delayed estimated median time to recover full consciousness (68.2 hours) compared with those with saturations < or = 43% (25.4 hours; P = .006). The addition of iron chelation to quinine therapy in children with high saturations appeared to hasten recovery (P = .046). We conclude that increased transferrin saturations may be associated with delayed recovery from coma during standard therapy for cerebral malaria and that serum iron and total iron binding capacity should be measured in future studies.

Chelation Therapy↗
PubMed1995

Iron-chelation therapy with oral deferiprone in patients with thalassemia major.

BACKGROUND: To determine whether the orally active iron chelator deferiprone (1,2-dimethyl-3-hydroxy-pyridin-4-one) is efficacious in the treatment of iron overload in patients with thalassemia major, we conducted a prospective trial of deferiprone in 21 patients unable or unwilling to use standard chelation therapy with parenteral deferoxamine. METHODS: Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens or magnetic-susceptibility measurements. Detailed clinical and laboratory studies were used to monitor safety and compliance. RESULTS: The patients received deferiprone therapy for a mean (+/-SE) of 3.1 +/- 0.3 years. Ten patients in whom previous chelation therapy with deferoxamine had been ineffective had initial hepatic iron concentrations of at least 80 mumol per gram of liver, wet weight -- values associated with complications of iron overload. Hepatic iron concentrations decreased in all 10 patients, from 125.3 +/- 11.5 to 60.3 +/- 9.6 mumol per gram (P < 0.005), with values that were less than 80 mumol per gram in 8 of the 10 patients (P < 0.005). In all 11 patients in whom deferoxamine therapy had previously been effective, deferiprone maintained hepatic iron concentrations below 80 mumol of iron per gram. CONCLUSIONS: Oral deferiprone induces sustained decreases in body iron to concentrations compatible with the avoidance of complications from iron overload. The risk of agranulocytosis associated with deferiprone may restrict its administration to patients who are unable or unwilling to use deferoxamine.

Administration, Oral↗
PubMed1995

Experimental liver cirrhosis induced by alcohol and iron.

To determine if alcoholic liver fibrogenesis is exacerbated by dietary iron supplementation, carbonyl iron (0.25% wt/vol) was intragastrically infused with or without ethanol to rats for 16 wk. Carbonyl iron had no effect on blood alcohol concentration, hepatic biochemical measurements, or liver histology in control animals. In both ethanol-fed and control rats, the supplementation produced a two- to threefold increase in the mean hepatic non-heme iron concentration but it remained within or near the range found in normal human subjects. As previously shown, the concentrations of liver malondialdehyde (MDA), liver 4-hydroxynonenal (4HNE), and serum aminotransferases (ALT, AST) were significantly elevated by ethanol infusion alone. The addition of iron supplementation to ethanol resulted in a further twofold increment in mean MDA, 4HNE, ALT, and AST. On histological examination, focal fibrosis was found < 30% of the rats fed ethanol alone. In animals given both ethanol and iron, fibrosis was present in all, with a diffuse central-central bridging pattern in 60%, and two animals (17%) developed micronodular cirrhosis. The iron-potentiated alcoholic liver fibrogenesis was closely associated with intense and diffuse immunostaining for MDA and 4HNE adduct epitopes in the livers. Furthermore, in these animals, accentuated increases in procollagen alpha 1(I) and TGF beta 1 mRNA levels were found in both liver tissues and freshly isolated hepatic stellate cells, perisinusoidal cells believed to be a major source of extracellular matrices in liver fibrosis. The dietary iron supplementation to intragastric ethanol infusion exacerbates hepatocyte damage, promotes liver fibrogenesis, and produces evident cirrhosis in some animals. These results provide evidence for a critical role of iron and iron-catalyzed oxidant stress in progression of alcoholic liver disease.

Animals↗
PubMed1994

Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major.

BACKGROUND: To determine whether deferoxamine prevents the complications of transfusional iron overload in thalassemia major, we evaluated 59 patients (30 were female and 29 male; age range, 7 to 31 years) periodically for 4 to 10 years or until death. METHODS: At each follow-up visit, we performed a detailed clinical and laboratory evaluation and measured hepatic iron stores with a noninvasive magnetic device. RESULTS: The body iron burden as assessed by magnetic measurement of hepatic iron stores was closely correlated (R = 0.89, P < 0.001) with the ratio of cumulative transfusional iron load to cumulative deferoxamine use (expressed in millimoles of iron per kilogram of body weight, in relation to grams of deferoxamine per kilogram, transformed into the natural logarithm). Each increase of one unit in the natural logarithm of the ratio (transfusional iron load to deferoxamine use) was associated with an increased risk of impaired glucose tolerance (relative risk, 19.3; 95 percent confidence interval, 4.8 to 77.4), diabetes mellitus (relative risk, 9.2; 95 percent confidence interval, 1.8 to 47.7), cardiac disease (relative risk, 9.9; 95 percent confidence interval, 1.9 to 51.2), and death (relative risk, 12.6; 95 percent confidence interval, 2.4 to 65.4). All nine deaths during the study occurred among the 23 patients who had begun chelation therapy later and used less deferoxamine in relation to their transfusional iron load (P < 0.001). CONCLUSIONS: The early use of deferoxamine in an amount proportional to the transfusional iron load reduces the body iron burden and helps protect against diabetes mellitus, cardiac disease, and early death in patients with thalassemia major.

Adolescent↗
PubMed1994

New advances in iron metabolism, iron deficiency, and iron overload.

Rapid advances were made in understanding the molecular and cellular bases of iron metabolism and its disorders. Molecular mechanisms for the cellular uptake, storage, and utilization of iron were clarified in investigations of the structure and functions of transferrin, transferrin receptor, ferritin, erythroid delta-aminolevulinic acid synthase, and the RNA-binding protein termed the iron responsive-element binding protein. Evidence was obtained that a nuclear DNA-binding protein, NF-E2, may be involved in the regulation of both hemoglobin synthesis in erythroid cells and of iron absorption in the intestine. Clinically, progress was made in improving the diagnosis and management of both iron deficiency and iron overload, with studies of the usefulness of serum transferrin receptor measurements, of a new therapeutic preparation of iron using a "gastric delivery system," and of the development of new orally active iron-chelating agents.

Anemia, Iron-Deficiency↗
PubMed1993

Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major.

To examine the relationship between hepatic iron stores and plasma ferritin concentration in individuals treated with red cell transfusion and iron chelation therapy, 37 patients with sickle cell anemia and 74 patients with thalassemia major were studied. In each patient, hepatic iron stores were measured by an independently validated noninvasive magnetic method, and plasma ferritin was determined by immunoassay. The correlation between hepatic iron and plasma ferritin was significant both in patients with sickle cell anemia (R = 0.75, P < 0.0001) and in those with thalassemia major (R = 0.76, P < 0.0001). Regression analysis showed no significant difference between the two groups in the linear relationships between hepatic iron stores and plasma ferritin. Considering all 111 transfused patients as a group, the coefficient of correlation between hepatic iron stores and plasma ferritin was highly significant (R = 0.76, P < 0.0001). Regression analysis found that variation in body iron stores, as assessed by magnetic determinations of hepatic iron, accounted for only approximately 57% of the variation in plasma ferritin, suggesting that the remainder was the result of other factors, such as hemolysis, ineffective erythropoiesis, ascorbate deficiency, inflammation, and liver disease. The 95% prediction intervals for hepatic iron concentration, given the plasma ferritin, were so broad as to make a single determination of plasma ferritin an unreliable predictor of body iron stores. Variability resulting from factors other than iron status limits the clinical usefulness of the plasma ferritin concentration as a predictor of body iron stores.

Adolescent↗
PubMed1993

Pyridoxine responsive hereditary sideroblastic erythropoiesis and iron overload: two microcytic subpopulations in the affected male, one normocytic and one microcytic subpopulation in the obligate female carrier.

Mild hepatic iron overload has been demonstrated by magnetic susceptibility measurements in a 22-year-old man with hereditary sideroblastic erythropoiesis despite hemoglobin levels in the normal range and a normal erythropoietin level. His grandfather's sideroblastic anemia has been found to be responsive to pyridoxine; his mother's hemoglobin has persisted in the normal range but red cell volume distribution analysis demonstrated two subpopulations; 30% with estimated geometric mean of 68 fl and 70% an estimated mean of 93 fl. Red cell distribution analysis of the grandson demonstrated two microcytic subpopulations; 46% with an estimated geometric mean of 45 fl and 54% an estimated mean of 70 fl. A therapeutic regimen is outlined to reduce to normal his iron stores and to prevent the future development of excessive iron overload.

Adolescent↗
PubMed1993

Iron chelation as a chemotherapeutic strategy for falciparum malaria.

To examine the effect of iron chelation against human malaria, 37 Zambians with asymptomatic Plasmodium falciparum infections were randomly assigned to 72-hr infusions of desferrioxamine B or placebo. Mean concentrations of ring forms decreased significantly with desferrioxamine B (P < 0.001) but not with a placebo. Over seven days of observation, mean parasite concentrations remained at the initial levels in six individuals originally given placebo, but decreased promptly with administration of desferrioxamine B (P = 0.001). Mean parasitemia was significantly lower for up to four weeks in 16 subjects treated with desferrioxamine B when compared with the eight who had received placebo only (P = 0.027). We conclude that iron chelation has antiplasmodial activity and may offer a new therapeutic strategy for falciparum malaria.

Adult↗
PubMed1992

Bleomycin-reactive iron in patients with acute non-lymphocytic leukemia.

Bleomycin-reactive iron was detected in the sera of six out of nine adults undergoing intensive chemotherapy for acute non-lymphocytic leukemia. In these individuals the corresponding transferrin saturation ranged from 96% to 113% and the serum ferritin from 775 to 9975 micrograms/l. Nontransferrin-bound iron has been postulated to be a factor in organ toxicity in iron overload conditions such as beta thalassemia and hereditary hemochromatosis by facilitating the production of tissue-damaging free radicals. We propose that bleomycin-reactive iron should be considered as a possible factor in organ dysfunction seen with intensive cancer chemotherapy.

Adult↗
PubMed1992

Decreased concentrations of tumor necrosis factor-alpha in supernatants of monocytes from homozygotes for hereditary hemochromatosis.

To determine whether release of tumor necrosis factor-alpha (TNF-alpha), a cytokine that affects iron homeostasis, may be selectively altered in hereditary hemochromatosis, we measured concentrations of TNF-alpha and interleukin-1 beta (IL-1 beta) in supernatants of cultured peripheral blood monocytes from 11 homozygotes for hereditary hemochromatosis, 11 healthy individuals, and five patients with iron-loading anemia. The gene for hereditary hemochromatosis is tightly linked to the HLA locus on chromosome 6, but its exact site and product are not known. The gene for TNF-alpha also is located within the HLA region. Monocytes were incubated from 4 to 36 hours in medium alone or with added lipopolysaccharide. Mean concentrations of immunoreactive TNF-alpha in supernatants were significantly lower for subjects with hereditary hemochromatosis as compared to healthy controls (P less than .037) and patients with iron-loading anemia (P less than .005); differences between homozygotes for hemochromatosis and healthy controls were up to 4.5-fold at 4 hours (P = .008), 1.9-fold at 12 hours (P = .036), and 7.0-fold at 36 hours (P = .001). Importantly, concentrations of IL-1 beta in supernatants were not significantly different among the three groups. We conclude that release of TNF-alpha by monocytes may be selectively impaired in hereditary hemochromatosis. Deficient activity of TNF-alpha may contribute to the disordered iron metabolism of this disease.

Adult↗
PubMed1992

Iron chelation with desferrioxamine B in adults with asymptomatic Plasmodium falciparum parasitemia.

To determine if iron chelation therapy has activity against human malaria, we administered desferrioxamine B in amounts of 100 mg/kg per day by continuous 72-hour subcutaneous infusions to 28 volunteers with asymptomatic Plasmodium falciparum infection in a randomized, double-blind, placebo-controlled crossover trial. Peripheral blood concentrations of P falciparum ring forms were determined at 12-hour intervals in all subjects and serum concentrations of desferrioxamine B + ferrioxamine (the iron complex of desferrioxamine B) were measured in 26 subjects. Geometric mean concentrations of asexual intraerythrocytic parasites decreased with both chelator and placebo treatment, but the decrement with desferrioxamine B was significantly greater than that with placebo (P less than .006) during both the initial and crossover periods. Compared with placebo, desferrioxamine B treatment was associated with an almost 10-fold enhancement of the rate of parasite clearance during both phases of the trial (P less than .007). Mean +/- SEM steady state concentrations of desferrioxamine B + ferrioxamine were 6.90 +/- 0.60 mumol/L at 36 hours and 7.72 +/- 0.68 mumol/L at 72 hours; in vitro, the ID50 has been reported to be approximately 4 to 20 mumol/L. No drug toxicity was detected. Parasitemia recurred in 19 of 24 participants followed-up over 1 to 6 months. We conclude that desferrioxamine B enhances the clearance of P falciparum parasitemia and that iron chelation may provide a new strategy to be developed for the treatment of malaria.

Adolescent↗
PubMed1991

Bioavailability of carbonyl iron: a randomized, double-blind study.

49 female blood donors with iron-deficiency anemia were treated with equal doses of iron either as carbonyl iron or ferrous sulfate in a randomized, double-blind fashion. The prevalence of side-effects was similar in the two groups. Mean values for hemoglobin concentration, mean corpuscular volume, corrected reticulocyte count, platelet count, serum iron, total iron-binding capacity, transferrin saturation or erythrocyte protoporphyrin did not differ significantly between the two groups throughout the study. After 16 weeks of therapy, the mean increase in hemoglobin iron was similar in both groups (p = 0.2). Estimates of net changes in total body iron suggested that the overall bioavailability of carbonyl iron was high, about 70% that of ferrous sulfate.

Adult↗
PubMed1991

Stage-specific ultrastructural effects of desferrioxamine on Plasmodium falciparum in vitro.

Desferrioxamine (DFO) is an iron chelator that inhibits the in vitro and in vivo growth of rodent and human malarial parasites. Previous studies with this chelator have suggested that it might interfere with the intraerythrocytic growth of Plasmodium sp. by withholding iron from any of several essential iron-dependent parasite enzymes, including those involved in CO2 fixation, mitochondrial electron transport, pyrimidine synthesis, and the reduction of ribonucleotides for DNA synthesis. We studied the ultrastructural effects of DFO on synchronized cultures of P. falciparum to identify the specific site of action of this compound. Synchronized cultures of early rings or schizonts were exposed to 100 microM DFO for up to 48 hr, and fixed and processed at regular intervals for electron microscopy. Untreated cultures and cultures exposed to DFO saturated with Fe3+ were processed at the same time. When DFO was added to synchronized cultures containing early rings, parasites developed normally until the late trophozoite stage, when all growth ceased. Ultrastructural lesions included the breakdown of the nuclear envelope into small membranous fragments and progressive vacuolization of the nucleoplasm. Other organelles, including food vacuoles and mitochondria, were not affected. The addition of DFO to synchronized cultures of schizonts had similar effects on nuclei of early schizonts, but little or no effect on mature schizonts and segmenters. Erythrocyte invasion by merozoites proceeded in the presence of the chelator. These findings support the hypothesis that DFO acts specifically during the late trophozoite/early schizont stage of parasite maturation by preventing nuclear division, an effect consistent with inhibition of the iron-dependent enzyme ribonucleotide reductase.

Animals↗