Showing papers by "Gary M. Brittenham published in 2000"

Hepatic Iron Concentration and Total Body Iron Stores in Thalassemia Major

Abstract: Background and Methods We tested the usefulness of measuring the hepatic iron concentration to evaluate total body iron stores in patients who had been cured of thalassemia major by bone marrow transplantation and who were undergoing phlebotomy treatment to remove excess iron. Results We began treatment with phlebotomy a mean (±SD) of 4.3±2.7 years after transplantation in 48 patients without hepatic cirrhosis. In the group of 25 patients with liver-biopsy samples that were at least 1.0 mg in dry weight, there was a significant correlation between the decrease in the hepatic iron concentration and total body iron stores (r=0.98, P<0.001). Assuming that the hepatic iron concentration is reduced to zero with complete removal of body iron stores during phlebotomy, the amount of total body iron stores (in milligrams per kilogram of body weight) is equivalent to 10.6 times the hepatic iron concentration (in milligrams per gram of liver, dry weight). With the use of this equation, we could reliably estimate tot...

Genetic Disorders Affecting Proteins of Iron Metabolism: Clinical Implications

Abstract: Remarkable progress is being made in understanding the molecular basis of disorders of human iron metabolism. Recent work has uncovered unanticipated relationships with the immune and nervous systems, intricate interconnections with copper metabolism, and striking homologies between yeast and human genes involved in the transport of transition metals. This review examines the clinical consequences of new insights into the pathophysiology of genetic abnormalities affecting iron metabolism. The proteins recently found to be involved in the absorption, transport, utilization, and storage of iron are briefly described, and the clinical manifestations of genetic disorders that affect these proteins are discussed. This chapter considers the most common inherited disorder in individuals of European ancestry (hereditary hemochromatosis), a widespread disease in sub-Saharan populations for which the genetic basis is still uncertain (African dietary iron overload), and several less frequent or rare disorders (juvenile hemochromatosis, atransferrinemia, aceruloplasminemia, hyperferritinemia with autosomal dominant congenital cataract, Friedreich's ataxia, and X-linked sideroblastic anemia with ataxia).

Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism.

Abstract: This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage-transferrin, transferrin receptor, and ferritin-have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the "Stimulator of Fe Transport" (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice. In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.

Contrasting functions of IgG and IgE antimalarial antibodies in uncomplicated and severe Plasmodium falciparum malaria.

Abstract: Plasmodial infection results in a significant elevation of the blood concentrations of immunoglobulins including IgE. Two well-characterized groups of adult Thai patients with either uncomplicated or severe Plasmodium falciparum malaria were studied over a period of four weeks. The mean parasitemias were approximately three-fold higher in patients with severe malaria than in those with uncomplicated disease. The mean concentrations of both total IgG and IgG antiplasmodial antibodies tended to be highest in the group with uncomplicated disease while total IgE and IgE antibodies were higher in the group with severe disease. The IgE antibodies detected in approximately 65% of the patients were positively correlated to parasitemia. These results suggest that antiplasmodial IgG antibodies are involved in reducing the severity of P. falciparum malaria, while IgE antibodies may contribute to the pathogenesis of this infection.

Thrombopoietin in Plasmodium falciparum malaria

Abstract: Thrombopoietin (TPO) is the key growth factor for platelet production and is elevated in states of platelet depletion. As thrombocytopenia is a common finding in malaria, we analysed TPO regulation before, during and after antimalarial treatment. Before treatment, TPO serum levels were significantly higher in patients with severe malaria (n = 35) than in patients with uncomplicated malaria (n = 44; P = 0.024), normalizing within 14-21 d of therapy. The rapid normalization of TPO levels and increase in low peripheral platelet counts after treatment indicate that the biosynthesis of TPO and its regulation in malaria patients are normal.

Influence of Hemoglobin E Trait on the Antimalarial Effect of Artemisinin Derivatives

Abstract: To determine whether hemoglobin E trait influences the antimalarial effect of artemisinin derivatives, we retrospectively compared 32 case patients with hemoglobin E trait to 32 control patients who did not have hemoglobin E, beta-thalassemia, glucose-6-phosphate dehydrogenase deficiency, or alpha-thalassemia trait on the basis of a mean corpuscular volume > or =78 femtoliters. All patients were admitted to the Hospital for Tropical Diseases in Bangkok, Thailand, with acute falciparum malaria. Control patients were matched to case patients with hemoglobin E trait by treatment with artemisinin derivatives versus other antimalarial drugs, by ethnic group, and by parasite count. Among 38 patients treated with artemisinin derivatives, the presence of hemoglobin E trait was associated with significantly faster parasite clearance (2.9-fold; 95% confidence interval [CI], 1.4-6.3; P=.006). Among 26 patients treated only with other antimalarial drugs, hemoglobin E trait did not significantly enhance parasite clearance (hazards ratio, 1.1; 95% CI, 0.5-2.5; P=. 8). Hemoglobin E trait may potentiate the antimalarial effect of artemisinin derivatives.

Iron overload and iron-chelating therapy in hemoglobin E-beta thalassemia.

Abstract: Whereas hemoglobin (Hb) E-beta thalassemia is recognized as probably the most common serious hemoglobinopathy worldwide, its natural history remains poorly defined. The interaction of hemoglobin E and beta-thalassemia result in a wide spectrum of clinical disorders, some indistinguishable from thalassemia major and some milder and not transfusion-dependent. Partially as a result of this wide range of phenotypes, clear guidelines for approaches to transfusion and to iron-chelating therapy for patients with Hb E-beta thalassemia have not been developed. By contrast, data that have accumulated during the past 10 years in patients with beta-thalassemia permit a quantitative approach to the management of iron overload and provide guidelines for the control of body iron burden in individual patients treated with iron-chelating therapy. These guidelines may be applicable to patients with Hb E-beta thalassemia. Preliminary evidence from our studies of iron loading in affected patients with Hb E-beta thalassemia in Sri Lanka suggest that this disorder may be associated with variable, but accelerated, gastrointestinal iron absorption, and that the iron loading associated with chronic transfusions in patients with Hb E-beta thalassemia is similar to that observed in patients with beta-thalassemia. These data, in the only cohort of patients with Hb E-beta thalassemia to have undergone quantitative assessment of body iron burden, suggest that the principles that guide assessment of iron loading and initiation of chelating therapy in patients with beta-thalassemia may be generally applicable to those with Hb E-beta thalassemia. Further quantitative studies in both nontransfused and transfused patients will be necessary to permit firm conclusions.

Prognostic significance of skin and subcutaneous fat sequestration of parasites in severe falciparum malaria.

Abstract: Intradermal blood smear, histopathologic and immunohistologic studies were performed in severe malaria (n=10) and uncomplicated malaria (n=10) patients during positive parasitemia and within 6 hours after negative parasitemia by finger prick smears. Intradermal blood smears showed asexual forms and intraleukocytic pigments when finger prick blood smears showed negative results; however intradermal blood smear did not indicate disease severity within 6 hours after negative parasitemia by finger prick. Histopathologic findings showed 15 fold higher parasitized red blood cells sequestered in vessels of subcutaneous fatty tissue in severe malaria than in uncomplicated malaria (p<0.001) and may indicate disease severity. A panel of polyclonal antibodies against cytokines applied to skin biopsies clearly detected a higher titer against tumor necrosis factor-alpha (TNFalpha) and interleukin-10 (IL-10) in dermal vessels and stratum granulosum respectively, in severe malaria compared with uncomplicated malaria. Results of the study suggest that histopathology and immunohistology of skin and subcutaneous fatty tissue may indicate prognostic severity of malaria and may be associated with focal accumulation of cytokines.

Patient-specific analysis of sequential haematological data by multiple linear regression and mixture distribution modelling.

Abstract: Automated storage and analysis of the results of serial haematologic studies are now technically feasible with present-day laboratory instruments and devices for data storage and processing. In current practice, physicians mentally compare a laboratory result with previous values and use their clinical judgement to determine the significance of any change. To provide a statistical basis for this process, we describe a new approach for the detection of changes in patient-specific sequential measurements of standard haematologic laboratory tests. These methods include hierarchical multiple regression modelling, with a weighted minimum risk criteria for model selection, to choose models indicating changes in mean values over time. This study is the first to analyse sequential patient-specific distributions of laboratory measurements, utilizing mixture distribution modelling with systematic selection of starting values for the EM algorithm. To evaluate these statistical methods under controlled conditions, we studied 11 healthy human volunteers who were depleted of iron by serial phlebotomy to iron-deficiency anaemia, then treated with oral iron supplements to replete iron stores and correct the anaemia. Application of sequential patient-specific analyses of haemoglobin, haematocrit, and mean cell volume showed that significant departures from past values could be identified, in many cases, even when values were still within the population reference ranges. Additionally, for all subjects sequential alterations in red blood cell volume distributions during development of iron-deficiency anaemia could be characterized and quantified. These methods promise to provide more sensitive techniques for improved diagnostic evaluation of developing anaemia and serial monitoring of response to therapy.

Apparatus and method for determining magnetic susceptibility

Abstract: The invention relates to an apparatus and method for high-sensitivity non-destructive evaluation of the magnetic susceptibility. An apparatus for determining magnetic susceptibility in an object, the temperature being maintained at approximately 77K, the apparatus comprising a permanent magnet (12), a superconducting quantum interference device (14) constructed from material having a critical temperature above 77K, and a flexible superconducting flux transformer (16) that couples the susceptibility signal to the superconducting quantum interference device, the transformer comprising superconducting material disposed on a flexible metallic substrate.

Predicting mortality in patients with malarial acute renal failure

Abstract: SUMMARY: Acute Physiology and Chronic Health Evaluation (APACHE) III scores, calculated within the first 24 h of admission, were analysed in 108 patients with acute renal failure due to falciparum malaria who were admitted to Bangkok Hospital for Tropical Diseases, Thailand. Twelve (11.1%) patients died. The mean APACHE III score was 82.0 ± 25.5 (range, 45–171). There was a close relation between the APACHE III score and the hospital mortality rate. The non-survivors had significantly higher APACHE III scores than the survivors, 109.8 ± 36.7 and 75.7 ± 21.6, respectively (P 0.05), but the former had a 4.4-times higher risk of dying compared with those dialysed (95% CI 1.6–12.3; P = 0.019). Using the APACHE III score and its ability to predict death, we calculated its sensitivity, specificity and accuracy to be 0.92, 0.31 and 0.41, respectively, at a cut-off score of 67 points. The area under the receiver operating characteristic (ROC) curve was 0.75. The APACHE III scoring system correlated well with the outcome of critically ill malaria patients with acute renal failure, although it was not possible to identify individual survivors or non-survivors. APACHE III should not be used for individual prognosis or treatment decisions.

IRON METABOLISM: Clinical Implications

Abstract: Remarkable progress is being made in understanding the molecular basis of disorders of human iron metabolism. Recent work has uncovered unantici- pated relationships with the immune and nervous systems, intricate interconnections with copper metabolism, and striking homologies between yeast and human genes involved in the transport of transition metals. This review examines the clinical con- sequences of new insights into the pathophysiology of genetic abnormalities affecting iron metabolism. The proteins recently found to be involved in the absorption, trans- port, utilization, and storage of iron are briefly described, and the clinical manifes- tations of genetic disorders that affect these proteins are discussed. This chapter considers the most common inherited disorder in individuals of European ancestry (hereditary hemochromatosis), a widespread disease in sub-Saharan populations for which the genetic basis is still uncertain (African dietary iron overload), and several less frequent or rare disorders (juvenile hemochromatosis, atransferrinemia, acerulo- plasminemia, hyperferritinemia with autosomal dominant congenital cataract, Fried- reich's ataxia, and X-linked sideroblastic anemia with ataxia).