Effect of hydroxyurea on G gamma chain fetal hemoglobin synthesis by sickle-cell disease patients

Hydroxyurea is used for sickle-cell disease patients in order to increase fetal hemoglobin synthesis and consequently decrease the severity of pain episodes. Fetal hemoglobin, which is formed by gamma-globin chains A and G, is present in a constant composition throughout fetal development: about 75% of Ggamma and 25% of Agamma. In contrast, adult red cells contain about 40% of Ggamma and 60% of Agamma. In the present study, we analyzed the effect of hydroxyurea induction on the gamma chain composition of fetal hemoglobin in 31 sickle-cell disease patients treated with hydroxyurea. The control group was composed of 30 sickle-cell disease patients not treated with hydroxyurea in clinical steady state. The patients were older than 13 years and were not matched for age. All patients were seen at Hemocentro/UNICAMP and Boldrini Infantile Center, Campinas, SP, Brazil. The levels of total hemoglobin were significantly higher in patients treated with hydroxyurea (mean ± SD, 9.6 ± 2.16 g/dl) than in untreated patients (8.07 ± 0.91 g/dl). Fetal hemoglobin levels were also higher in treated patients (14.16 ± 8.31%) than in untreated patients (8.8 ± 4.09%), as was the Ggamma/Agamma ratio (1.45 ± 0.78 vs 0.98 ± 0.4, P < 0.005). The increase in the Ggamma/Agamma ratio in patients treated with hydroxyurea suggests the prevalence of a pattern of fetal hemoglobin synthesis, whereas patients not treated with hydroxyurea maintain the adult pattern of fetal hemoglobin synthesis. Because no correlation was observed between the Ggamma/Agamma ratio and total hemoglobin or fetal hemoglobin levels, the increase in Ggamma chain synthesis may not imply a higher production of hemoglobin.1289129

Evaluation Of Erythrocyte And Reticulocyte Parameters As Indicative Of Iron Deficiency In Patients With Anemia Of Chronic Disease

Objective: The aim of this study was to evaluate the effectiveness of mature red cell and reticulocyte parameters to identify three conditions: iron deficiency anemia, anemia of chronic disease, and anemia of chronic disease associated with absolute iron deficiency. Methods: Peripheral blood cells from 117 adult patients with anemia were classified according to iron status, inflammation, and hemoglobinopathies as: iron deficiency anemia (n = 42), anemia of chronic disease (n = 28), anemia of chronic disease associated with iron deficiency anemia (n = 22), and heterozygous β-thalassemia (n = 25). The percentage of microcytic erythrocytes, hypochromic erythrocytes, and the levels of hemoglobin in both reticulocytes and mature red cells were determined. Receiver operating characteristic analysis was used to evaluate the accuracy of the parameters in differentiating anemia. Results: There was no difference between the groups of iron deficiency and anemia of chronic disease associated with absolute iron deficiency for any of the parameters. The percentage of hypochromic erythrocytes was the best parameter to identify absolute iron deficiency in patients with anemia of chronic disease (area under curve = 0.785; 95% confidence interval: 0.661-0.909 with sensitivity of 72.7%, and specificity of 70.4%; cut-off value 1.8%). The formula microcytic erythrocyte count minus hypochromic erythrocyte count was very accurate to differentiate iron deficiency anemia from heterozygous β-thalassemia (area under curve = 0.977; 95% confidence interval: 0.950-1.005 with a sensitivity of 96.2%, and specificity of 92.7%; cut-off value 13.8). Conclusion: The erythrocyte and reticulocyte indices are moderately good to identify absolute iron deficiency in patients with anemia of chronic disease

Blood Cell Analysis: The Importance For Biopsy Interpretation [o Hemograma: Importância Para A Interpretação Da Biópsia]

Examination of blood cells is an essential part of the hematological investigation. The introduction of new physical principles for cell analysis incorporated into automated cell counters has provided new information about blood cells. Data related to both quantification and cell morphology features observed in peripheral blood examinations may be helpful during bone marrow analysis. In this brief review some of these new parameters are presented, such as the red blood cell distribution width (RDW) and indices related to volume, immaturity and hemoglobin content of reticulocytes. The interpretation of graphic displays (histograms of red cells, white cells and platelets) can provide further information that is not available from the assessment of numeric data. Other parameters and platelet indices, such as the mean platelet volume (MPV) and immature platelet fraction (IPF) are introduced, although they are still not standardized and must be used with caution. The quantification of various white blood cell populations present in peripheral blood and the advantages and limitations of automated counts are considered. Although the development of sophisticated automated blood cell analyzers has reduced the number of blood smear examinations, this type of procedure should be encouraged as the smear is an important tool in the diagnosis of several pathologic conditions.313178182(2008) Interpretação Clínica Do Hemograma, , Grotto HZW (ed), São Paulo: Editora AtheneuSandhaus, L.M., Meyer, P., How useful are CBC and reticulocyte reports to clinicians? (2002) Am J Clin Pathol, 118 (5), pp. 787-793Dixon, L.R., The complete blood count: Physiologic basis and clinical usage (1997) J Perinat Neonatal Nurs, 11 (3), pp. 1-18(2001) Practical Haematology, , Lewis SM, Bain BJ, Bates I (eds)., 9th ed. London: Churchill LivingstoneGreen, R., King, R., A new red cell discriminant incorporating volume dispersion for differentiating iron deficiency anemia from thalassemia minor (1989) Blood Cells, 15 (3), pp. 481-491Lima, C.S., Reis, A.R., Grotto, H.Z., Saad, S.T., Costa, F.F., Comparison of red cell distribution width and a red cell discriminant function incorporating volume dispersion for distinguishing iron deficiency from beta thalassemia trait in patients with microcytosis (1996) Sao Paulo Med J, 114 (5), pp. 1265-1269Noronha, J.F., Lorand-Metze, I.G., Grotto, H.Z., Hematopoietic progenitor cells (HPC) and immature reticulocytes evaluations in mobilization process: New parameters measured by conventional blood cell counter (2006) J Clin Lab Anal, 20 (4), pp. 149-153Cortellazzi, L.C., Teixeira, S.M., Borba, R., Gervásio, S., Cintra, C.S., Grotto, H.Z.W., Reticulocyte parameters in hemoglobinopathies and iron deficiency anemia (2003) Rev Bras Hematol Hemoter, 25 (2), pp. 97-102Lambert, J.-F., Beris, P., Pathophysiology and differential diagnosis of anemia (2006) Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis, pp. 73-101. , In: Beaumont C, Beris P, Beuzard Y, Brugnara C., Genoa, Italy: Forum Service Editore, cap 3Brugnara, C., Schiller, B., Moran, J., Reticulocyte hemoglobin equivalent (Ret He) and assessment of iron-deficient states (2006) Clin Lab Haematol, 28 (5), pp. 303-308Mast, A.E., Blinder, M.A., Dietzen, D.J., Reticulocyte hemoglobin content (2008) Am J Hematol, 83 (4), pp. 307-310Kim, J.M., Ihm, C.H., Kim, H.J., Evaluation of reticulocyte haemoglobin content as marker of iron deficiency and predictor of response to intravenous iron in haemodialysis patients (2008) Int J Lab Hematol, 30 (1), pp. 46-52Schaefer, M., Rowan, R.M., The clinical relevance of nucleated red blood celll counts (2000) Sysmex J Intern, 10, pp. 59-63Cornet, E., Perol, J.P., Troussard, X., Performance evaluation and relevance of the CellaVision DM96 system in routine analysis and in patients with malignant hematological diseases (2008) Int J Lab Hematol, 30 (6), pp. 536-542Felle, P., McMahon, C., Rooney, S., Donnelly, P., Ni Chonchubhair, F., Platelets in the paediatric population: The influence of age and the limitations of automation (2005) Clin Lab Haematol, 27 (4), pp. 250-257Abe, Y., Wada, H., Tomatsu, H., Sakaguchi, A., Nishioka, J., Yabu, Y., A simple technique to determine thrombopoiesis level using immature platelet fraction (IPF) (2006) Thromb Res, 118 (4), pp. 463-469Takami, A., Shibayama, M., Orito, M., Omote, M., Okumura, H., Yamashita, T., Immature platelet fraction for prediction of platelet engraftment after allogeneic stem cell transplantation (2007) Bone Marrow Transplant, 39 (8), pp. 501-507Threatte, G.A., Usefulness of the mean platelet volume (1993) Clin Lab Med, 13 (4), pp. 937-950Buttarello, M., Plebani, M., Automated blood cell counts: State of the art. State of the art (2008) Am J Clin Pathol, 130 (1), pp. 104-116Sugimori, N., Kondo, Y., Shibayama, M., Omote, M., Takami, A., Sugimori, C., Aberrant increase in the immature platelet fraction in patients with myelodysplastic syndrome: A marker of karyotypic abnormalities associated with poor prognosis (2009) Eur J Haematol, 82 (1), pp. 54-6

Anaemia Of Cancer: An Overview Of Mechanisms Involved In Its Pathogenesis

Anaemia is a common complication in cancer patients. The decrease in haemoglobin is associated with an impaired quality of life, poorer response to therapy and worse prognosis. Numerous factors are involved in the physiopathology of cancer-related anaemia. Some factors such as bleeding, bone marrow infiltration, the effects of chemoradiotherapy and associated nutritional deficiencies are related to the disease itself. In addition, the interaction of the immune system with iron metabolism and erythropoiesis has been shown to be an important factor in the development of anaemia in cancer patients and can be seen in the action of several cytokines on different iron-homeostasis and erythrocyte-cell-production pathways. Some inhibitory cytokines, such as tumour necrosis factor-α and interleukin-1, act on the suppression of erythroid precursor cells and erythropoietic production and response; others, such as interleukins 1 and 6 and hepcidin, impair iron metabolism, causing iron to be diverted from erythropoiesis and retained within the reticuloendothelial system. The main mechanisms involved in the development of cancer-related anaemia are discussed in this review. © 2007 Humana Press Inc.2511221Skillings, J.R., An epidemiological review of red cell transfusions in cancer chemotherapy (1999) Cancer Prev Control, 3, pp. 207-12Coiffier, B., Guastalla, J.P., Pujade-Lauraine, E., Bastif, P., Anemia Study Group. Predicting cancer-associated anaemia in patients receiving non-platinum chemotherapy: Results of a retrospective survey (2001) Eur J Cancer, 37, pp. 1617-23Ludwig, H., The European Cancer Anaemia Survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients (2004) Eur J Cancer, 40, pp. 2293-306Birgegard, G., Gascon, P., Ludwig, H., Evaluation of anemia in patients with multiple myeloma and lymphoma: Findings of the European Cancer Anaemia Survey (2006) Eur J Haemaol, 77, pp. 378-86. , 5Kosmidis, P., Krzakowski, M., Prospective data from the European Cancer Anaemia Survey (ECAS): Focus on patients with lung cancer (2003) Lung Cancer, 41, p. 265Schrijvers, D., European Cancer Anaemia Survey (ECAS): Prospective evaluation of anemia in patients (pts) with gastrointestinal (GI) or colorectal (CR) cancer (CA) (2002) Proc Euro School Oncol 2nd Colorectal Cancer Confer, 2, p. 71. , (abstract 18)Richardson, A., Fatigue in cancer patients: A review of the literature (1995) Eur J Cancer Care, 4, pp. 20-32. , 1Stone, P., Richards, M., Hardy, J., Fatigue in patients with cancer (1998) Eur J Cancer, 34, pp. 1670-6. , 11Cella, D., Factors influencing quality of life in cancer patients: Anemia and fatigue (1998) Semin Oncol, 25, pp. 43-6. , 3 Suppl 7Stone, P., Cancer-related fatigue: Inevitable, unimportant and untreatable? Results of a multi-centre patient survey. Cancer Fatigue Forum (2000) Ann Oncol, 11, pp. 971-5Curt, G.A., Impact of fatigue on quality of life in oncology patients (2000) Semin Hematol, 37, pp. 14-7. , 4 Suppl 6Harper, P., Littlewood, T., Anaemia of cancer: Impact on patient fatigue and long-term outcome (2005) Oncology, 69, pp. 2-7. , Suppl 2Dicato, M., Harper, P., The optimal hemoglobin level in the cancer patient (2002) Semin Oncol, 29, pp. 88-91. , 3 Suppl 8Ludwig, H., Strasser, K., Symptomatology of anemia (2001) Semin Oncol, 28, pp. 7-14. , 2 Suppl 8Caro, J.J., Salas, M., Ward, A., Goss, G., Anemia as an independent prognostic factor for survival in patients with cancer: A systemic, quantitative review (2001) Cancer, 91, pp. 2214-21Waters, J.S., O'Brien, M.E., Ashley, S., Management of anemia inpatients receiving chemotherapy (2002) J Clin Oncol, 20, pp. 601-3. , 2Obermair, A., Impact of hemoglobin levels before and during concurrent chemotherapy on the response to treatment in patients with cervical cancer: Preliminary results (2001) Cancer, 92, pp. 903-8Grogan, M., The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix (1999) Cancer, 86, pp. 1528-36. , 8Vaupel, P., Kelleher, D.K., Thews, O., Modulation of tumor oxygenation (1998) Int J Radiat Oncol Biol Phys, 42, pp. 843-8Vaupel, P., Kelleher, D.K., Höckel, M., Oxygenation status of malignant tumours: Pathogenesis of hypoxia and significance for tumor Therapy (2001) Semin Oncol, 28, pp. 29-35. , 2 Suppl 8Dunst, J., Hemoglobin level and anemia in radiation oncology: Prognostic impact and therapeutic implications (2000) Semin Oncol, 27, pp. 4-8. , 2 Suppl 4Teicher, B.A., Holden, S.A., Al Achi, A., Herman, T.S., Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma (1990) Cancer Res, 50, pp. 3339-44. , 11Green, S.L., Giaccia, A.J., Tumor hypoxia and the cell cycle: Implications for malignant progression and response to therapy (1998) Cancer J Sci Am, 4, pp. 218-23Harris, A.L., Hypoxia-a key regulatory factor in tumour growth (2002) Nat Rev Cancer, 2, pp. 38-47Graeber, T.G., Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours (1996) Nature, 379, pp. 88-91Littlewood, T.J., Impact of hemoglobin levels on treatment outcomes in patients with cancer (2001) Semin Oncol, 28, pp. 49-53. , 2 Suppl 8(1998) Common Toxicity Criteria, , NCI. Cancer therapy evaluation program, version 2.0. Published April 1998 by National Institute of Health, National Cancer Institute. Bethesda, MD [NLM 9810879]Montserrat, E., Bosch, F., Rozman, C., B-cell chronic lymphocytic leukaemia: Recent progress in biology, diagnosis, and therapy (1997) Ann Oncol, 8, pp. 93-101. , Suppl 1Mercadante, S., Gebbia, V., Marrazzo, A., Filosto, S., Anaemia in cancer: Pathophysiology and treatment (2000) Cancer Treat Rev, 26, pp. 303-11Groopman, J.E., Itri, L.M., Chemotherapy-induced anemia in adults: Incidence and treatment (1999) J Natl Cancer Inst, 91, pp. 1616-34Tas, F., Anemia in oncology practice: Relation to disease and their therapies (2002) Am J Clin Oncol, 25, pp. 371-9. , 4Okamoto, H., Chemotherapy-induced anemia in patients with primary lung cancer (1992) Ann Oncol, 3, pp. 819-24Tanvetyanon, T., Choudhury, A.M., Severity, risk factors, and physician practices in the management of anemia during concurrent chemoradiation for head and neck carcinoma (2006) Cancer, 106, pp. 1554-9. , 7Doll, D.C., Weiss, R.B., Hemolytic anemia associated with antineoplastic agents (1985) Cancer Treat Rep, 69, pp. 777-82. , 7-8Barrett-Lee, P.J., Bailey, N.P., O'Brien, M.E., Wager, E., Large-scale UK audit of blood transfusion requirements and anaemia in patients receiving cytotoxic chemotherapy (2000) Brit J Cancer, 82, pp. 93-7Faquin, W.C., Schneider, T.J., Goldberg, M.A., Effect of inflammatory cytokines on hypoxia-induced erythropoietin production (1992) Blood, 79, pp. 1987-94Nairz, M., Weiss, G., Molecular and clinical aspects of iron homeostasis: From anemia to hemochromatosis (2006) Wien Klin Wochenschr, 118, pp. 442-462. , 15-16Ponka, P., Beaumont, C., Richardson, D.R., Function and regulation of transferrin and ferritin (1998) Semin Hematol, 35, pp. 35-54Wardrop, S.L., Richardson, D.R., Interferon-gamma and lipopolysaccharide regulate the expression of Nramp2 and increase the uptake of iron from low relative molecular mass compleses by macrophages (2000) Eur J Biochem, 267, pp. 6586-93Aigner, E., Weiss, G., Regulation of iron transport by inflammatory cytokines in human monocytic cells (2001) 13th European Macrophage Conference, , Vienna. Aug 31th-Sept 1st, abstractByrd, T., Horwitz, M.A., Regulation of transferrin receptor expression and ferritin content in human mononuclear macrophages. Coordinate upregulation by iron transferrin and downregulation by interferon gamma (1993) J Clin Invest, 91, pp. 969-76Ludwiczek, S., Aigner, E., Theurl, I., Weiss, G., Cytokine-mediated regulation of iron transport in human monocytic cells (2003) Blood, 101, pp. 4148-54. , 10Rafferty, S.P., Domachowske, J.B., Malech, H.L., Inhibition of hemoglobin expression by heterologous production of nitric oxide synthase in the K562 erythroleukemic cell line (1996) Blood, 88, pp. 1070-8Furukawa, T., Kohno, H., Tokynaga, R., Taketani, S., Nitric oxide mediated inactivation of mammalian ferrochelatase in vivo and in vitro: Possible involvement of the iron-sulphur cluster of the enzyme (1995) Biochem J, 310, pp. 533-8MacIejewski, J.P., Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha (1995) J Clin Invest, 96, pp. 1085-92Ponka, P., Tissue specific regulation of iron metabolism and heme synthesis: Distinct control mechanism in erythroid cells (1997) Blood, 89, pp. 1-25Murr, C., Widner, B., Wirleitner, B., Fuchs, D., Neopterin as a marker for immune system activation (2002) Curr Drug Metab, 3, pp. 175-87. , 2Reibnegger, G.J., Bichler, A.H., Dapunt, O., Neopterin as a prognostic indicador in patients with carcinoma of the uterine cervix (1986) Cancer Res, 46, pp. 950-5Sheldon, J., Plasma neopterin as an adjunct to C-reactive protein in assessment of infection (1991) Clin Chem, 37, pp. 2038-42Fuchs, D., Association between immune activation, changes of iron metabolism and anaemia in patients with HIV infection (1993) Eur J Haematol, 50, pp. 90-4Grotto, H.Z.W., Costa, F.F., Carneiro, M.V., Galiza Neto, G.C., Serum neopterin in patients with Chagas disease (1994) Trans R Soc Trop Med Hyg, 88, p. 75. , 1Muller, T.F., Noninvasive monitoring using serum amyloid a and serum neopterin in cardiac transplantation (1998) Clin Chim Acta, 276, pp. 63-74Hamerlinck, F.F., Neopterin: A review (1999) Exp Dermatol, 8, pp. 167-76Weiss, G., Neopterin and prognosis in patients with adenocarcinoma of the colon (1993) Cancer Res, 53, pp. 260-65Reibnegger, G.J., Predictive value of interlukin-6 and neopterin in patients with multiple myeloma (1991) Cancer Res, 51, pp. 6250-3Birk, D., Gansauge, F., Gansauge, S., Schwarz, A., Berger, H.G., Levels of serum neopterin are increased in pancreatic cancer patients and correlate with the prognosis (1999) Eur J Med Res, 4, pp. 156-60Berdowska, A., Zwirska-Korczala, K., Neopterin measurement in clinical diagnosis (2001) J Clin Pharm Ther, 26, pp. 319-29Weiss, G., Neopterin modulates toxicity mediated by reactive oxygen and chloride species (1993) FEBS Lett, 321, pp. 89-92Barak, M., Gruener, N., Neopterin augmentation of tumor necrosis factor production (1991) Immunol Lett, 30, pp. 101-6Denz, H., Weight loss in patients with haematological neoplasia is associated with immune system stimulation (1993) Clin Invest, 71, pp. 37-41Denz, H., Association between the activation of macrophages, changes of iron metabolism and the degree of anaemia in patients with malignant disorders (1992) Eur J Haematol, 48, pp. 244-8Pagel, H., Fandrey, J., Schobersberger, W., Fuchs, D., Jelkmann, W., Effects of neopterin and 7, 8-dihydroneopterin on hypoxia-induced renal erythropoietin production (1999) Eur J Haematol, 62, pp. 341-5Johnson, C.S., Cook, C.A., Furmanski, P., In vivo suppression of erythropoiesis by tumour necrosis factor alfa (TNF-alfa): Reversal with exogenous erythropoietin (EPO) (1990) Exp Hematol, 18, pp. 109-13Ulich, T.R., Del Castilho, J., Yin, S., Tumor necrosis factor exerts dose-dependent effects on erythropoiesis and myrlopoiesis in vivo (1990) Exp Hematol, 18, pp. 311-5Moldawer, L.L., Marano, M.A., Wei, H., Cachectin/tumor necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo (1898) FASEB J, 3, pp. 1637-43. , 5Trey, J.E., Kushner, I., The acute phase response and the hematopoietic system: The role of cytokines (1995) Crit Rev Oncol Hematol, 21, pp. 1-18Weiss, G., Modification of iron regulation by the inflammatory response (2005) Best Pract Res Clin Haematol, 18, pp. 183-201Miller, L.L., Miller, S.C., Torti, S.V., Tsuji, Y., Torti, F.M., Iron-independent induction of ferritin H-chain by tumor necrosis factor (1991) Proc Natl Acad Sci USA, 88, pp. 4946-50. , 11Weiss, G., Pathogenesis and treatment of anaemia of chronic disease (2002) Blood Rev, 16, pp. 87-96Rogers, J.T., Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1 (1990) J Biol Chem, 265, pp. 14572-8. , 24Means Jr., R.T., Dessypris, E.N., Krantz, S.B., Inhibition of human erythroid colony-forming units by interleukin-1 is mediated by gamma interferon (1992) J Cell Physiol, 150, pp. 59-64Jelkmann, W., Pagel, H., Wolff, M., Fandrey, J., Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidney (1991) Life Sci, 50, pp. 301-8Salvarani, C., The role of interleukin 1, erythropoietin and red cell bound immunoglobulins in the anaemia of rheumatoid arthritis (1991) Clin Exp Rheumatol, 9, pp. 241-6. , 3Maury, C.P., Anaemia of chronic disease in AA amyloidosis is associated with allele 2 of the interleukin-1beta-511 promoter gene and raised levels of interlukin-1beta and interleukin-18 (2004) J Intern Med, 256, pp. 145-52. , 2Graziadei, I., Gaggl, S., Kaserbacher, R., Braunsteiner, H., Vogel, W., The acute-phase protein alpha 1-antitripsin inhibits growth and proliferation of human early erythroid progenitor cells (BFU-E) and of human erythroleukemic cells (K562) in vitro by interfering with transferrin iron uptake (1994) Blood, 83, pp. 260-8Peetre, C., Gullberg, U., Nilsson, E., Olsson, I., Effects of recombinant tumor necrosis factor on proliferation and differentiation of leukemic and normal hemopoietic cells in vitro. Relationship to cell surface receptors (1986) J Clin Invest, 78, pp. 1694-700Torti, F.M.S.V., Regulation of ferritin genes and protein (2002) Blood, 99, pp. 3505-16Graversen, J.H., Madsen, M., Moestrup, S.K., CD163: A signal receptor scavenging haptoglobin-hemoglobin complexes from plasma (2002) Int J Biochem Cell Biol, 34, pp. 309-14. , 4Weiss, G., Iron and anemia of chronic disease (1999) Kidney Int Suppl, 69, pp. 12-7Krause, A., LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity (2000) FEBS Lett, 480, pp. 147-50Park, C.H., Valore, E.V., Waring, A.J., Ganz, T., Hepcidin, a urinary antimicrobial peptide synthesized in the liver (2001) J Biol Chem, 276, pp. 7806-10Ganz, T., Hepcidin-a regulator of intestinal iron absorption and iron recycling by macrophages (2005) Best Pract Res Clin Haematol, 18, pp. 171-82Zasloff, M., Antibiotic peptides as mediators of innate immunity (1992) Curr Opin Immunol, 4, pp. 3-7Singh, P.K., Parsek, M.R., Greenberg, E.P., Welsh, M.J., A component of innate immunity prevents bacterial biofilm development (2002) Nature, 417, pp. 552-5. , 6888Pigeon, C., A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload (2001) J Biol Chem, 276, pp. 7811-9Nicolas, G., Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice (2001) Proc Natl Acad Sci USA, 98, pp. 8780-5. , 15Nemeth, E., Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization (2004) Science, 306, pp. 2090-3Donovan, A., Roy, C.N., Andrews, N.C., The ins and outs of iron homeostasis (2006) Physiology, 21, pp. 115-23Kemna, E., Pickkers, P., Nemeth, E., Van Der Hoeven, H., Swinkels, D., Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in human injected with LPS (2005) Blood, 106, pp. 1864-6. , 5Nieken, J., Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients (1995) Blood, 86, pp. 900-5Nemeth, E., Valore, E.V., Territo, M., Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein (2003) Blood, 101, pp. 2461-3Nemeth, E., IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004) J Clin Invest, 113, pp. 1271-6Cartwright, G.E., The anemia of chronic disorders (1966) Semin Hematol, 3, pp. 351-75Fuchs, D., Immune activation and the anemia associated with chronic inflammatory disorders (1991) Eur J Haematol, 46, pp. 65-70Spivak, J.L., Iron and the anemia of chronic disease (2002) Oncology, 16, pp. 25-33. , 9 Suppl 10Practice Guidelines in Oncology. Version 1.2007. Cancer- and Treatment-related Anemia, , http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf, Available at Accessed May 18, 2007Blumberg, N., Heal, J.M., Effects of transfusion on immune function. Cancer recurrence and infection (1994) Arch Pathol Lab Med, 118, pp. 371-9Cella, D., Quality of life and clinical decisions in chemotherapy-induced anemia (2006) Oncology, 20, pp. 25-8. , 8 Suppl 6Littewood, T.J., Effects of epoetin alfa on hematologic parameters and quality of life in patients receiving nonplatinum chemotherapy: Results of a randomized, double-blind, placebo-controlled clinical trial (2001) J Clin Oncol, 19, pp. 2865-74Hedenus, M., Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: A randomized, double-blind, placebo-controlled study (2003) Br J Haematol, 122, pp. 394-403Seidenfeld, J., Epoetin treatment of anemia associated with cancer therapy: A systematic review and meta-analysis of controlled clinical trials (2001) J Natl Cancer Inst, 93, pp. 1204-14Bohlius, J., Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients (2006) J Natl Cancer Inst, 98, pp. 708-14Henke, M., Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotheraphy: Randomized, double-bind, placebo-controlled trial (2003) Lancet, 362, pp. 1255-60Leyland-Jones, B., BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated unexpectedly (2003) Lancet Oncol, 4, pp. 459-60(2006) Interim Analysis of DAHANCA, 10. , http://www.dahanca.dk/get_media_file.php?mediaid=125, December 1. Avaiable at Accessed May 21, 2007Weiss, M.J., New insights into erythropoietin and epoetin alfa: Mechanisms of action, target tissues, and clinical applications (2003) Oncologist, 8, pp. 18-29. , Suppl 3Lappin, T.R., Maxwell, A.P., Johnston, P.G., Warning flags for erythropoiesis-stimulating agents and cancer-associated anemia (2007) Oncologist, 12, pp. 362-5Parganas, E., Jak2 is essential for signaling through a variety of cytokine receptors (1998) Cell, 93, pp. 385-95Yasuda, Y., Erythropoietin regulates tumor growth of human malignancies (2003) Carcinogenesis, 24, pp. 1021-9(2007) Information for Healthcare Professionais, , http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE2007HCP.htm, Erytropoiesis Stimulating Agents (ESA). FDA Alert, February 16, Avaiable at Accessed May 15, 2007Bokemeyer, C., EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 Update (2007) Eur J Cancer, 43 (2), pp. 258-27

Iron Metabolism: An Overview On The Main Mechanisms Involved In Its Homeostasis [metabolismo Do Ferro: Uma Revisão Sobre Os Principais Mecanismos Envolvidos Em Sua Homeostase]

The perfect synchronism of intestinal absorption, use and storage of iron is critical for maintaining a balance in the organism. Disorders in these processes may lead either to iron deficiency or to iron overload, both of which have important clinical and laboratorial consequences for the patient. This review describes aspects related to iron metabolism and the participation of several proteins and mediators in these mechanisms. Moreover, intracellular and systemic regulation is responsible for providing the optimal iron concentration for cellular metabolism and, in particular, for adequate hematopoiesis. The relationship between hepcidin and acute phase response is presented and how changesin hepcidin expression may be related to the physiopathogenesis of anemia of chronic disease.305390397Wijayanti, N., Katz, N., Immenschuh, Biology of heme in health and disease (2004) Curr Med Chem, 11 (8), pp. 981-986Hoffbrand AV, Pettit FE, Moss PAH. Essential Haematology. 5th ed. Oxford (UK): Blackwell Publishingc2006. Chapter 3, Hypochromic anaemias and iron overloadp. 28-43Fairbanks, V.G., Beutler, E., Iron metabolism (2001) Williams-Hematology, pp. 295-304. , Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, editors, 6th ed. New York: Mcgraw-Hill;Beaumont, C., Vailont, S., Iron homeostasis (2006) Disorders of iron homeostasis, erythrocytes, erythropoiesis. Genova, Italy: Forum Service Editore, pp. 393-406. , Beaumont C, Beris P, Beuzard Y, Brugnara C, editorsDonovan, A., Roy, C.N., Andrews, N.C., The ins and outs of iron homeostasis (2006) Physiology (Bethesda), 21, pp. 115-123Chung, J., Wessling-Resnick, M., Molecular mechanisms and regulation of iron transport (2003) Crit Rev Clin Lab Sci, 40 (2), pp. 151-182Andrews, N.C., A genetic view of iron homeostasis (2002) Semin Hematol, 39 (4), pp. 227-234Krishnamurthy, P., Xie, T., Schuetz, J.D., The role of transporters in cellular heme and porphyrin homeostasis (2007) Pharmacol Ther, 114 (3), pp. 345-358Pietrangelo, A., The ferroportin disease (2004) Blood Cells Mol Dis, 32 (1), pp. 131-138Oates, P.S., The role of hepcidin and ferroportin in iron absorption (2007) Histol Histopathol, 22 (7), pp. 791-804Nairz, M., Weiss, G., Molecular and clinical aspects of iron homeostasis: From anemia to hemochromatosis (2006) Wien Klin Wochenschr, 118 (15-16), pp. 442-462Frazer, D.M., Anderson, G.J., The orchestration of body iron intake: How and where do enterocytes receive their cues? (2003) Blood Cells Mol Dis, 30 (3), pp. 288-297Knutson, M., Wessling-Resnick, M., Iron metabolism in the reticuloendothelial system (2003) Crit Rev Biochem Mol Biol, 38 (1), pp. 61-88Ponka, P., Beaumont, C., Richardson, D.R., Function and regulation of transferrin and ferritin (1998) Semin Hematol, 35 (1), pp. 35-54Worwood, M., Serum transferrin receptor assays and their application (2002) Ann Clin Biochem, 39 (PART 3), pp. 221-230Baynes, R.D., Assessment of iron status (1996) Clin Biochem, 29 (3), pp. 209-215Ohgami, R.S., Campagna, D.R., Greer, E.L., Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells (2005) Nat Genet, 37 (11), pp. 1264-1269Beguin, Y., The soluble transferrin receptorbiological aspects and clinical usefulness as quantitative measure of erythropoiesis (1992) Haematologica, 77 (1), pp. 1-10Skikne, B.S., Flowers, C.H., Cook, J.D., Serum transferrin receptor: A quantitative measure of tissue iron deficiency (1990) Blood, 75 (9), pp. 1870-1876Kawabata, H., Yang, R., Hirama, T., Vuong, P.T., Kawano, S., Gombart, A.F., el al, Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family (1999) J Biol Chem, 274 (30), pp. 20826-20832. , Jul 23;Roetto, A., Daraio, F., Alberti, F., Porporato, P., Call, A., De Gobbi, M., Hemochromatosis due to mutations in transferrin receptor 2 (2002) Blood Cells Mol Dis, 29 (3), pp. 465-470Dunn, L.L., Rahmanto, Y.S., Richardson, D.R., Iron uptake and metabolism in the new millennium (2007) Trends Cell Biol, 17 (2), pp. 93-100Cooper, J.M., Schapira, A.H., Friedreich's ataxia: Coenzyme Q10 and vitamin E therapy (2007) Mitochondrion, 7 (SUPPL. 1), pp. S127-S135Alcindor, T., Bridges, K.R., Sideroblastic anaemias (2002) Br J Haematol, 116 (4), pp. 733-743Park, C.H., Valore, E.V., Waring, A.J., Ganz, T., Hepcidin, a urinary antimicrobial peptide synthesized in the liver (2001) J Biol Chem, 276 (11), pp. 7806-7810Krause, A., Neitz, S., Mägert, H.J., LEAP-I, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity (2000) FEBS Lett, 480 (2-3), pp. 147-150Nicolas, G., Bennoun, M., Porteu, A., Severe iron deficiency anemia in transgenic mice expressing liver hepcidin (2002) Proc Natl Acad Sci USA, 99 (7), pp. 4596-4601. , Apr 2;Ganz, T., Nemeth, E., Iron imports. IV. Hepcidin and regulation of body iron metabolism (2006) Am J Physiol Gastrointest Liver Physiol, 290 (2), pp. G199-G203Ganz, T., Hepcidin - a regulator of intestinal iron absorption and iron recycling by macrophages (2005) Best Pract Res Clin Haematol, 18 (2), pp. 171-182Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B.K., IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004) J Clin Invest, 113 (9), pp. 1271-1276Rivera, S., Liu, L., Nemeth, E., Gabayan, V., Sorensen, O.E., Ganz, T., Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia (2005) Blood, 105 (4), pp. 1797-1802Nemeth, E., Tuttle, M.S., Powelson, J., Vaughn, M.B., Donovan, A., Ward, D.M., Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization (2004) Science, 306 (5704), pp. 2090-2093De Domenico, I., Ward, D.M., Kaplan, J., Hepcidin regulation: Ironing out the details (2007) J Clin Invest, 117 (7), pp. 1755-1758Mena, N.P., Esparza, A., Tapia, V., Valdes, P., Nunez, M.T., Hepcidin inhibits apical iron uptake in intestinal cells (2007) Am J Physiol Gastrointest Liver Physiol. 2007, , DOI 10.1152/ajpgi.00122Wrighting, D.M., Andrews, N.C., Interleukin-6 induces hepcidin expression through STAT3 (2006) Blood, 108 (9), pp. 3204-3209Verga Falzacappa, M.V., Vujic Spasic, M., Kessler, R., Stolte, J., Hentze, M.W., STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation (2007) Blood, 109 (1), pp. 353-358Steele, T.M., Frazer, D.M., Anderson, G.J., Systemic regulation of intestinal iron absorption (2005) IUBMB Life, 57 (7), pp. 499-503Weiss, G., Modification of iron regulation by the inflammatory response (2005) Best Pract Res Clin Haematol, 18 (2), pp. 183-201Grotto, H.Z.W., Anaemia of cancer: An overview of mechanisms involved in its pathogenesis Med Oncol, 2007. , DOI 10.1007/S12032-007-9000-8Weiss, G., Pathogenesis and treatment of anaemia of chronic disease (2002) Blood Rev, 16 (2), pp. 87-9

Human Immunodeficiency Virus-related Anemia Of Chronic Disease: Relationship To Hematologic, Immune, And Iron Metabolism Parameters, And Lack Of Association With Serum Interferon-γ Levels

Anemia of chronic disease (ACD) is frequent in patients with human immunodeficiency virus (HIV) and its etiology is multifactorial. In a group of 111 patients with HIV, 19 were diagnosed with ACD. Parameters related to iron metabolism, such as serum iron (SI), serum ferritin (SF), and soluble transferrin receptor (sTfR) were correlated to levels of interferon-γ (IFN-γ) and results compared to a group of 42 nonanemic patients with HIV. Measurements of erythropoietin (EPO), CD4/CD8 T-cell ratio, and reticulocyte count (RTC) were determined to verify aspects related to severity of disease and bone marrow response. The results showed higher SF concentrations in ACD patients and normal or slightly increased sTfR measurements in both groups. There was no correlation between IFN-γ and SF and between IFN-γ and sTfR determinations. Lower CD4/CD8 values were obtained in ACD, and an inverse correlation was observed between IFN-γ and CD4/CD8 in groups with and without anemia. RTC counts and EPO concentrations were similar in both groups: Immature RTC were increased in patients with anemia, indicating an apparent attempt of marrow response to compensate the increased demand. Our data showed no correlation between IFN-γ levels and iron disturbances in ACD, but results reinforced the observation of enhanced immunologic system deterioration in patients with HIV and ACD.168361365Bain, B.J., Pathogenesis and pathophysiology of anemia in HIV infection (1999) Curr Opin Hematol, 6, p. 89Kreuzer, K.A., Rockstroh, J.K., Pathogenesis and pathophysiology of anemia in HIV infection (1997) Ann Hematol, 75, pp. 179-187Evans, R.H., Scadden, D.T., Haematological aspects of HIV infection (2000) Baillières Clin Haematol, 13, pp. 215-230Moses, A., Nelson, J., Bagby G.C., Jr., The influence of human immunodeficiency virus-1 on hematopoiesis (1998) Blood, 91, pp. 1479-1495Forsyth, B.W., Andiman, W.A., O'Connor, T., Development of a prognosis-based clinical staging system for infants infected with human immunodeficiency virus (1996) J Pediatr, 129, pp. 648-655Moore, R.D., Keruly, J.C., Chaisson, R.S., Anemia and survival in HIV infection (1998) J Acquir Immune Syndr Hum Retrovirol, 19, pp. 29-33Coyle, T.E., Hematologic complications of human immunodeficiency virus infection and the acquired immunodeficiency syndrome (1997) Med Clin North Am, 81, pp. 449-470Weiss, G., Iron and anemia of chronic disease (1999) Kidney Int, 55, pp. S12-S17Curran, J.W., HIV e a síndrome da imunodeficiência adquirida: Epidemiologia da infecção por HIV e AIDS/SIDA (1997) Cecil Tratado de Medicina Interna, 20th ed., pp. 2037-2042. , Bennett JC, and Plum F, eds, Rio de Janeiro: Guanabara KooganGupta, S., Imam, A., Licorish, K., Serum ferritin in acquired immune deficiency syndrome (1986) J Clin Lab Immunol, 20, pp. 11-13Brock, J.H., Iron homeostasis and macrophage function in inflammation (1997) Biometals, 10, p. 231Savarino, A., Pescarmona, G.P., Boelaert, J.R., Iron metabolism and HIV infection: Reciprocal interactions with potentially harmful consequences? (1999) Cell Biochem Funct, 17, pp. 279-287Means R.T., Jr., Advances in the anemia of chronic disease (1999) Int J Hematol, 70, pp. 7-12Weinberg, E.D., Weinberg, G.A., The role of iron infection (1995) Curr Opin Infect Dis, 8, pp. 164-169Aboulafia, D.M., Mitsuyasu, R.T., Hematologic abnormalities in AIDS (1991) Hematol Oncol Clin North Am, 5, pp. 195-214Spada, C., Treitinger, A., Hoshikawa-Fujimura, A.Y., HIV influence on hematopoiesis at the initial stage of infection (1998) Eur J Haematol, 61, pp. 255-260Sullivan, P.S., Hanson, D.L., Chu, S.Y., Jones, J.L., Ward, J.W., Epidemiology of anemia in human immunodeficiency virus (HIV)-infected persons: Results from the multistate adult and adolescent spectrum of HIV disease surveillance project (1998) Blood, 91, pp. 301-30