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Biomedical subjects

G M Brittenham

Publications and source records attributed to G M Brittenham.

At least 91 records · Page 5Linked to original sources
PubMed1986

Hepatic microsomal function in rats with chronic dietary iron overload.

We determined whether alterations in hepatic microsomal function occur in association with iron-induced lipid peroxidation in vivo in rats with chronic dietary iron overload. In rats fed a 2.0% carbonyl iron diet for a period of 20 wk, there was no significant microsomal conjugated diene formation (evidence of microsomal lipid peroxidation) or difference in cytochrome P450 concentration found at mean (+/- SEM) hepatic iron concentrations of 1210 +/- 92 micrograms/g liver (wet wt) or 2730 +/- 100 micrograms/g. At a hepatic iron concentration of 4090 +/- 245 micrograms/g, however, there was significant conjugated diene formation (p less than 0.001) and a 56% decrease in the cytochrome P450 concentration (p less than 0.001). In rats fed a 2.5% carbonyl iron diet for 10 wk, achieving a liver iron concentration of 4820 +/- 420 micrograms/g, there was significant microsomal conjugated diene formation (p less than 0.001), a 35% reduction in cytochrome P450 (p less than 0.005), and a 16% reduction in aminopyrine demethylase activity (p less than 0.025), but only an 8% reduction in glucose-6-phosphatase activity (p = not significant). Finally, in rats fed a 3.0% iron-supplemented diet for 7 wk, achieving a liver iron concentration of 2730 +/- 205 micrograms/g, there was a 23% reduction in cytochrome P450 (p less than 0.025), a 28% reduction in cytochrome b5 (p less than 0.001), and a 47% increase in heme oxygenase activity (p less than 0.025) (heme oxygenase activity measured in this group only). We conclude that oral iron loading can produce microsomal lipid peroxidation in vivo that is associated with selective decreases in microsomal hemoprotein concentrations and cytochrome P450-dependent enzymes.

Aminopyrine N-Demethylase↗
PubMed1986

Iron therapy for hepatic dysfunction in erythropoietic protoporphyria.

Erythropoietic protoporphyria, caused by an inherited deficiency of ferrochelatase, results in increased free protoporphyrin concentrations in erythrocytes and plasma. Cutaneous photosensitivity is the primary clinical manifestation, but in some patients, protoporphyrin accumulation in the liver may lead to fatal hepatic failure. No treatment exists for this lethal complication. We report the case of a patient with erythropoietic protoporphyria and abnormal results of liver function tests in whom oral iron therapy led to a substantial decrease in free erythrocyte and stool protoporphyrin levels with return of liver function to normal. Iron therapy should be considered for preventing potentially fatal hepatic failure in patients with erythropoietic protoporphyria.

Administration, Oral↗
PubMed1986

Hyperferremia in immunosuppressed patients with acute nonlymphocytic leukemia and the risk of infection.

Hypothesizing that any effect of an increased serum iron and transferrin saturation on the risk of bacterial infection would be particularly important in immunosuppressed patients, we reexamined the effect of hyperferremia on bacterial growth in vitro and studied the pattern and prevalence of hyperferremia in patients receiving treatment for acute nonlymphocytic leukemia (ANLL). Growth of inocula of Escherichia coli and Staphylococcus aureus was significantly greater (1.3- to 5.8-fold) in fresh or heat-inactivated sera obtained from 10 healthy volunteers 3 hours after oral ingestion of ferrous sulfate (mean +/- SEM transferrin saturation 95% +/- 3%) than before (transferrin saturation 34% +/- 10%). Similarly, in heat-inactivated serum samples obtained from six patients with various malignancies, growth of E. coli was significantly greater (2.3- to 5.5-fold) with the elevated transferrin saturation (97% +/- 3%) present 1 to 7 days after receiving chemotherapy than with the normal transferrin saturation (33% +/- 9%) present before. In a prospective evaluation of serial serum iron studies in 12 patients receiving treatment for ANLL, five patients had normal serum iron concentrations initially, but in each patient the transferrin saturation was elevated after receiving chemotherapy, usually to greater than 90% for greater than 15 days in conjunction with prolonged, profound granulocytopenia and fever.

Acute Disease↗
PubMed1986

Analysis of the volume of red blood cells: application of the expectation-maximization algorithm to grouped data from the doubly-truncated lognormal distribution.

In accordance with general principles recommended by the International Committee for Standardization in Haematology (1982, Journal of Clinical Pathology 35, 1320-1322), we have developed statistical methods for the analysis of red cell volume distributions. To select an appropriate reference distribution for goodness-of-fit testing, we derived a mathematical model of erythropoiesis that predicted a lognormal form for the distribution of erythrocyte volumes. Model predictions were then tested using samples obtained from 50 healthy individuals. Each grouped red cell volume distribution was doubly-truncated to eliminate artifactual frequency counts. Distribution parameter estimates were computed using the expectation-maximization algorithm, a missing information technique. Results of the one-sample chi-square goodness-of-fit test showed a fairly even distribution of P-values over the interval. Examples of the application of these statistical procedures to distributions from patients with anemia are given. Our results suggest that, for the analysis of red blood cell volumes, (i) parameter estimation should be made with the expectation-maximization method, and (ii) the truncated lognormal distribution should be used as a reference distribution for goodness-of-fit testing. This method could be applied to any set of grouped doubly-truncated data which, after transformation, follows the normal model.

Anemia, Hypochromic↗
PubMed1986

Absorption of carbonyl iron.

The mechanism of carbonyl iron absorption has been studied in rats. Solubilization by gastric acid was a prerequisite for subsequent absorption. The slow rate of solubilization resulted in a more prolonged absorption, responsible for the low toxicity of carbonyl iron. Large doses of carbonyl iron were held for several days by the gastric mucosa of iron-deficient animals. Once it had been solubilized, the subsequent pathway of absorption by the intestinal mucosa and the amount absorbed was similar to that of ferrous ammonium sulfate.

Animals↗
PubMed1986

Carbonyl iron therapy for iron deficiency anemia.

To determine if elemental carbonyl iron powder is safe and effective therapy for iron deficiency anemia, 20 nonanemic and 32 anemic volunteers were studied. Single doses of 1,000 to 10,000 mg of carbonyl iron (15 to 150 times the 65 mg of iron in the usual dose of ferrous sulfate) were tolerated by nonanemic volunteers with no evidence of toxicity and only minor gastrointestinal side effects. Anemic volunteers (menstruating women who had previously donated blood) were treated with several regimens providing 1,000 to 3,000 mg of carbonyl iron daily in one to three doses for 8 to 28 days. After 12 weeks anemia was corrected in 29 of 32 patients, and serum ferritin was greater than 12 micrograms/L in 14. Hemoglobin regeneration proceeded at a rate similar to that described for therapy with oral iron salts and parenteral iron dextran. There was no evidence of hematologic, hepatic, or renal toxicity, but mild gastrointestinal side effects occurred in a majority of anemic volunteers. Carbonyl iron is an effective, inexpensive treatment for iron deficiency anemia, is accompanied by tolerable side effects and may have an advantage over therapy with iron salts by substantially reducing or eliminating the risk of iron poisoning in children.

Adult↗
PubMed1986

Oxygen saturation with sleep in patients with sickle cell disease.

Ear oximetry was used to monitor arterial oxygenation in seven patients who had a history of frequent admissions for sickle cell crisis and were taking narcotic analgesics. Five full-night studies and seven daytime "nap" studies were performed in which sleep state was monitored by electroencephalography, and respiratory rate and tidal volume were monitored by inductance plethysmography. For all patients the mean (+/- SEM) of the median oxygenation values was 93.3% +/- 0.4% during wakefulness and 91.4% +/- 0.8% during sleep. During wakefulness the lowest saturation was 90% +/- 0.5%; during sleep there was a fall in the lowest oxygen saturation to 86.5% +/- 0.9%. In all patients a fall in oxygen saturation was associated with a decrease in respiratory depth without a change in respiratory frequency. The results indicate that in sickle cell disease oxygen saturation is lower during sleep than during wakefulness and that hypoxemia can be attributed to a fall in tidal volume.

Adult↗
PubMed1985

Fetal lead exposure: antenatal factors.

It was hypothesized that maternal blood lead level at delivery and cord blood lead level of the neonate would be affected by maternal use of alcohol, history of alcohol abuse, and smoking. The possibility that iron status, as reflected in maternal serum ferritin, would be related to lead level was also explored. The maternal history of alcohol abuse was unrelated to lead level in 208 samples of maternal blood and 178 samples of cord blood. However, alcohol use during pregnancy was related in a dose-response fashion to maternal and to cord blood lead level. This effect was significant with and without control of maternal smoking. The effect of maternal smoking and serum thiocyanate on maternal and cord blood lead level were also highly significant with and without control of the maternal drinking variable. Serum ferritin was marginally related to lead level for white women and for black infants, but tests of the dichotomized maternal ferritin variable did not yield a significant linkage with maternal or cord blood lead level. The results further support recommendations that women abstain from alcohol consumption and cigarette smoking in pregnancy.

Adult↗
PubMed1985

Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes.

We examined the extent to which the intracellular polymerization of sickle hemoglobin (HbS) can account for the severity of anemia and of vaso-occlusive manifestations in the various sickling syndromes. Polymer formation in sickle cell disease depends principally on the intraerythrocytic hemoglobin composition and concentration. In our studies, the polymer fraction in sickle red cells was determined from reported mean values for hemoglobin composition and mean corpuscular hemoglobin concentration (MCHC) in 12 groups of patients with sickle hemoglobinopathies (homozygotes for HbS, with and without coexistent alpha-thalassemia or various forms of the hereditary persistence of fetal hemoglobin [HPFH], beta+-, beta 0-, and delta beta-thalassemia, and heterozygotes for HbS with HbA). The calculated HbS polymer fractions at full deoxygenation and at physiologic oxygen saturation values were closely correlated with mean blood hemoglobin concentrations. In addition, polymer fraction correlated with the ranking of the sickling syndromes by vaso-occlusive severity. We find that polymer fraction accounts for about 80% of the variability in hemolytic and clinical severity. The method of analysis presented here provides a quantitative and systematic means of assessing the role of polymer formation in the pathophysiologic manifestations of the sickling syndromes. Our results support the hypothesis that the intracellular polymerization of HbS is the primary determinant of the severity of both anemia and clinical symptomatology in the sickle hemoglobinopathies.

Anemia, Sickle Cell↗
PubMed1983

Hepatic lipid peroxidation in vivo in rats with chronic iron overload.

Peroxidative decomposition of cellular membrane lipids is a postulated mechanism of hepatocellular injury in parenchymal iron overload. In the present study, we looked for direct evidence of lipid peroxidation in vivo (as measured by lipid-conjugated diene formation in hepatic organelle membranes) from rats with experimental chronic iron overload. Both parenteral ferric nitrilotriacetate (FeNTA) administration and dietary supplementation with carbonyl iron were used to produce chronic iron overload. Biochemical and histologic evaluation of liver tissue confirmed moderate increases in hepatic storage iron. FeNTA administration produced excessive iron deposition throughout the hepatic lobule in both hepatocytes and Kupffer cells, whereas dietary carbonyl iron supplementation produced greater hepatic iron overload in a periportal distribution with iron deposition predominantly in hepatocytes. Evidence for mitochondrial lipid peroxidation in vivo was demonstrated at all three mean hepatic iron concentrations studied (1,197, 3,231, and 4,216 micrograms Fe/g) in both models of experimental chronic iron overload. In contrast, increased conjugated diene formation was detected in microsomal lipids only at the higher liver iron concentration (4,161 micrograms Fe/g) achieved by dietary carbonyl iron supplementation. When iron as either FeNTA or ferritin was added in vitro to normal liver homogenates before lipid extraction, no conjugated diene formation was observed. We conclude that the presence of conjugated dienes in the subcellular fractions of rat liver provide direct evidence of iron-induced hepatic mitochondrial and microsomal lipid peroxidation in vivo in two models of experimental chronic iron overload.

Animals↗
PubMed1982

Magnetic-susceptibility measurement of human iron stores.

We made direct noninvasive magnetic measurements of hepatic iron stores with a specially designed superconducting quantum-interference-device (SQUID) susceptometer in 20 normal subjects and in 110 patients with liver disease, iron deficiency, hereditary hemochromatosis, or transfusional iron overload. Magnetic in vivo measurements of liver non-heme iron were closely correlated with chemical in vitro measurements in liver-biopsy specimens (r = 0.98, P less than 10(-5) up to 115 mumol per gram of liver tissue (wet weight) or more. Magnetically determined storage-iron concentrations were below 6.0 mumol per gram in iron-deficient patients and normal men and premenopausal women, but they were raised (9.7 to 31.4 mumol) in 12 of 67 patients with liver disease and were greatly increased (22.9 to 117.7 mumol) in patients with untreated hereditary hemochromatosis or transfusional iron overload. Magnetic measurements of iron stores provide a new quantitative technique for early detection of hereditary hemochromatosis and for rapid evaluation of treatment regimens for transfusional iron overload.

Female↗
PubMed1982

The effects of short-term oral iron therapy on developmental deficits in iron-deficient anemic infants.

To assess the effects of iron therapy on developmental test scores in infants with iron deficiency anemia, 68 Guatemalan babies 6 to 24 months of age, with and without mild iron deficiency anemia, were tested with the Bayley Scales of Infant Development before and after one week of oral iron treatment. The two major findings of the study were developmental deficits in the anemic group prior to treatment, and lack of rapid improvement with short-term oral iron therapy. The mean pretreatment Mental Development Index of the anemic group was significantly lower than that of nonanemic infants. The anemic group's pretreatment Psychomotor Development Index was also lower than that of the nonanemic control group. In a double-blind randomized study, six to eight days of oral iron therapy did not reverse these deficits. Consequently, the deficits of the anemic group cannot be unequivocably attributed to iron lack. However, no significant differences were found between anemic and nonanemic groups in birth histories, socioeconomic level, or general nutritional status which might otherwise explain the lower developmental test scores of the anemic babies.

Anemia, Hypochromic↗