Use of isotopes in the diagnosis of hematopoietic disorders
2007; Elsevier BV; Volume: 35; Issue: 4 Linguagem: Inglês
10.1016/j.exphem.2007.01.027
ISSN1873-2399
Autores Tópico(s)Hematological disorders and diagnostics
ResumoIsotopes of iron have been paramount in clinical tracer studies of hematopoiesis. Kinetics of disappearance from plasma, appearance in circulating erythrocytes, and localization in general areas of bone marrow, spleen, and liver were early revealed by gamma-/beta-emitting Fe-59 with note of characteristic differences of kind and degree of dysfunction among various anemias. Findings have helped in management (e.g., decisions about splenectomy). Positron/gamma-emitting Fe-52 (better for imaging) has provided more detail on marrow expansion and erythropoietic relocation. Other gamma-emitting tracers of hematopoiesis have been In-111 (linked to transferrin) and technetium 99m (Tc-99m) colloids (localizing to reticuloendothelial cells, which have close association with blood cell progenitors), but Fe-52 has proved to be more accurate for recognition of erythropoiesis. Occasional diverse heterotopic sites of hematopoiesis beyond spleen and liver in states of bone marrow disease have posed diagnostic challenges and also raised questions about migration and/or activation of stem cells. Studies of granulopoiesis utilize Tc-99m–labeled leukocytes or Tc99m-labeled antibodies to circulating and progenitor white cells. Iron-deficiency anemias due to malnutrition, malabsorption, blood loss, or special need are explored by dual study (oral vs intravenous) with radioactive (Fe-59, Fe-55) or stable (Fe-54, Fe-57) iron isotopes, which can guide dietary supplementation. Tests for B-12 deficiency in pernicious anemia or malabsorption with radioisotopes of cobalt (Co-57, Co-58) have been upgraded in sensitivity and scope. Rates of oxidation to expired carbon dioxide from particular carbon (radioactive C-14 or stable C-13)−labeled compounds can test B-12 or folic acid deficiencies or gastric infestation as causes of megaloblastic anemias. Isotopes of iron have been paramount in clinical tracer studies of hematopoiesis. Kinetics of disappearance from plasma, appearance in circulating erythrocytes, and localization in general areas of bone marrow, spleen, and liver were early revealed by gamma-/beta-emitting Fe-59 with note of characteristic differences of kind and degree of dysfunction among various anemias. Findings have helped in management (e.g., decisions about splenectomy). Positron/gamma-emitting Fe-52 (better for imaging) has provided more detail on marrow expansion and erythropoietic relocation. Other gamma-emitting tracers of hematopoiesis have been In-111 (linked to transferrin) and technetium 99m (Tc-99m) colloids (localizing to reticuloendothelial cells, which have close association with blood cell progenitors), but Fe-52 has proved to be more accurate for recognition of erythropoiesis. Occasional diverse heterotopic sites of hematopoiesis beyond spleen and liver in states of bone marrow disease have posed diagnostic challenges and also raised questions about migration and/or activation of stem cells. Studies of granulopoiesis utilize Tc-99m–labeled leukocytes or Tc99m-labeled antibodies to circulating and progenitor white cells. Iron-deficiency anemias due to malnutrition, malabsorption, blood loss, or special need are explored by dual study (oral vs intravenous) with radioactive (Fe-59, Fe-55) or stable (Fe-54, Fe-57) iron isotopes, which can guide dietary supplementation. Tests for B-12 deficiency in pernicious anemia or malabsorption with radioisotopes of cobalt (Co-57, Co-58) have been upgraded in sensitivity and scope. Rates of oxidation to expired carbon dioxide from particular carbon (radioactive C-14 or stable C-13)−labeled compounds can test B-12 or folic acid deficiencies or gastric infestation as causes of megaloblastic anemias. Research and clinical application of radioactive or stable isotopes to characterize abnormal hematopoiesis have changed with the advances in instrumentation and techniques during the past 50 to 60 years. Autoradiography, mainly with tritiated (H-3) thymidine, was used early to study kinds and rates of generation from undifferentiated stem cells in bone marrow to produce mature, circulating erythrocytes, granulocytes, lymphocytes, megakaryocytes, etc. [1Kniseley R.M. Kurst D.R. Nelp W.B. Berlin N.I. The blood.in: Wagner Jr., H.N. Principles of Nuclear Medicine. 1st ed. W.B. Saunders Co., Philadelphia1968: 404-471Google Scholar]. For different reasons (including radiation dose), little direct clinical application has followed this seminal research. Also in the mid-20th century, study of the kinetics and localization of red cell production and turnover was started, principally with radioisotopes of iron (Fe-59, Fe-55), as was study of iron absorption by means of in vitro analyses of blood samples and by external area or whole body counting. Imaging (with positron-emitting Fe-52) was then only in initial experimental form. Because of the close biological association of the reticuloendothelial system (RES) with blood cell formation, various radioisotopic colloids were used early to study sites of hematopoiesis [1Kniseley R.M. Kurst D.R. Nelp W.B. Berlin N.I. The blood.in: Wagner Jr., H.N. Principles of Nuclear Medicine. 1st ed. W.B. Saunders Co., Philadelphia1968: 404-471Google Scholar]. White cells, labeled in early times with In-111, were used to detect inflammation [2Forstrom L. Indium-labeled leukocyte imaging in the diagnosis of infection and inflammatory disease.in: Henkin R.E. Boles M.A. Dillehay G.L. Nuclear Medicine. Vol. II, 1st ed. Mosby-Yearbook, Inc., St. Louis1996: 1619-1635Google Scholar] and to do some preliminary bone marrow imaging [3Price D.C. McIntyre P.A. The hematopoietic system.in: Harbert J. Da Rocha A.F.G. Textbook of Nuclear Medicine. Vol. II. Clinical Applications. 2nd ed. Lea & Febiger, Philadelphia1984: 535-605Google Scholar, 4Kim C.K. Reske S.N. Alavi A. Bone marrow scintigraphy.in: Henkin R.E. Boles M.A. Dillehay G.L. Nuclear Medicine. Vol. II, 1st ed. Mosby-Yearbook, Inc., St. Louis1996: 123-1249Google Scholar], while some limited studies of normal kinetics of granulopoiesis were performed with the somewhat indiscriminate labeling agent, DFP-32 [3Price D.C. McIntyre P.A. The hematopoietic system.in: Harbert J. Da Rocha A.F.G. Textbook of Nuclear Medicine. Vol. II. Clinical Applications. 2nd ed. Lea & Febiger, Philadelphia1984: 535-605Google Scholar]. The importance of availability of cobalamin (vitamin B-12) for supporting synthesis of purines and pyrimidines (especially in bone marrow) led to early use of radioisotopes of cobalt and carbon to evaluate absorption of B-12. This review will describe how newer techniques and wider clinical applications of isotopes to problems of hematopoiesis, especially erythropoiesis, have benefited the field of hematology, while raising additional questions.Studies of erythropoiesis with radioisotopes of iron, indium, and technetiumThe radioisotope, Fe-59, a beta-/gamma-emitter with relatively high gamma energies (1.0 and 1.3 MEV) and long physical half-life (45 days) is well-suited for kinetics and area localization of iron in the body after intravenous injection. The rate of iron disappearance from the plasma; the percent of injected Fe-59 accumulating in red cells over a period of 14 days; and, by external counting over sacrum, liver, and spleen, the relative amounts of Fe-59 at these locations at different times were early evaluated [3Price D.C. McIntyre P.A. The hematopoietic system.in: Harbert J. Da Rocha A.F.G. Textbook of Nuclear Medicine. Vol. II. Clinical Applications. 2nd ed. Lea & Febiger, Philadelphia1984: 535-605Google Scholar]. In cases of ineffective erythropoiesis due to such conditions as thalassemia, pernicious anemia, G6PD deficiency, iron deficiency, or severe autoimmune states there were changes in kinetics indicating fast uptake but long residence time in bone marrow and much lowered incorporation into red cells. In myelofibrosis with extramedullary hematopoiesis (EMH), there was observed a reversal of relative activities in different organs with spleen and (to a lesser extent) liver appearing to carry out essentially all red cell production. In severe hemolysis, there was evidence of splenic sequestration, indicated by gradually rising spleen activity over 14 days. The latter pattern indicates a preponderance of destruction over production and is a finding taken to favor splenectomy.At a relatively early time, Fe-52, a positron emitter, with consequent dual photons at 511 KEV, plus a fair abundance of gamma-emission at 170 KEV and a half-life of about 8 hours, was used to image the central skeleton of one normal person and seven subjects with moderate or severe anemia from various causes [5Ferrant A. Rodhain J. Cordier A. Symann M. Michaux J.L. Sokal G. Selective hypoplasia of pelvic bone marrow.Scand J Haematol. 1980; 25: 10-18Google Scholar]. As seen in Figure 1, there was notable lack of Fe-52 in the pelvic bones in abnormal subjects, which correlated with hypoplastic or aplastic cellularity of bone marrow by iliac crest biopsy. Yet compensatory bone marrow expansion and possibly EMH in liver and/or spleen in some subjects (Fig. 1) could explain the finding of only marginally low blood hemoglobin in four of the seven patients. This study exemplifies the role of total body imaging with appropriate radioisotopes for global evaluation of hematopoiesis.The occasional occurrence of EMH at sites even beyond the liver and spleen can present interesting diagnostic challenges. In a case of hereditary spherocytosis being considered for splenectomy, there was observed by computed tomography (CT) scan a mediastinal, paraspinal mass (Fig. 2A) [6Petit J.J. Estany C. Mediastinal extramedullary erythropoiesis in hereditary spherocytosis.Clin Lab Haematol. 1987; 9: 327-332Crossref PubMed Scopus (12) Google Scholar]. Scanning of this patient with another gamma-emitting tracer of red blood cell formation, In-111−transferrin (energies: 174,247 KEV; half-life: 2.8 days) suggested that the mass was a site of erythropoiesis (Fig. 2B). Aspiration of the mass (at the time of splenectomy) and appropriate staining further testified to the erythropoietic activity. In a case of thalassemia intermedia [7Vardareli E. Entok E. Ak I. Bayhan H. An unusual localization of extramedullary hematopoiesis.Clin Nucl Med. 1996; 21: 256-257Crossref PubMed Scopus (3) Google Scholar], bone marrow scintigraphy with sulfur colloid−labeled with technetium 99m (Tc-99m-SC) (gamma-energy: 141 KEV; half-life: 6 hours) showed incidental observation of a large, round, mid-pelvic collection. A distended bladder filled with freed technetium was ruled out by post-void films. In this case, In-111 (given simply as the chloride salt, which can attach to circulating transferrin) showed a positive image suggesting erythropoiesis, which was, again, confirmed by CT scan and guided-needle biopsy. In a case of long-standing agnogenic myeloid metaplasia, there was a puzzling development of progressive dementia and gait abnormalities [8Cornfield D.B. Shipkin P. Alavi A. Becker J. Peyster R. Intracranial myeloid metaplasia: diagnosis by CT and Fe-52 scans and treatment by cranial irradiation.Am J Hematol. 1983; 15: 273-278Crossref PubMed Scopus (6) Google Scholar]. CT scan of the head (Fig. 3A) showed left-sided paracranial masses, which were compressing the lateral ventricles. Tc-99m-SC in this patient concentrated at the site of the masses, and a further study of the positron emissions from Fe-52 (Fig. 3B) verified the occurrence of erythropoiesis. A course of cranial irradiation resulted in regression of the masses with clearing of the patient's dementia and much improved gait. It has been observed that some patients with various anemias or other bone marrow disorders show disparity between uptake of Fe-52 or Fe-59 and uptake of radiocolloids or In-111−Cl [9Van Dyke D. Shkurkin C. Price D. Yano Y. Anger H.O. Differences in distribution of erythropoietic and reticuloendothelial marrow in hematologic disease.Blood. 1967; 30: 364-374PubMed Google Scholar, 10Adams B.K. Jacobs P. Byrne M.J. Bird A.R. Boniaczszuk J. Fe-52 imaging of intrathoracic extramedullary hematopoiesis in a patient with beta-thalassemia.Clin Nucl Med. 1995; 20: 619-622Crossref PubMed Scopus (7) Google Scholar, 11Aburano T. Yokoyama K. Shuke N. et al.Tc-99m HMPAO-labeled leukocytes for hematopoietic marrow imaging. Comparison with In-111 chloride.Clin Nucl Med. 1992; 17: 938-944Crossref PubMed Scopus (6) Google Scholar]. It has become recognized that In-111−labeled compounds will in part or in whole be taken up by the RES rather than red blood cell progenitor cells, particularly when circulating transferrin is relatively saturated with iron. A comparison has been made between relative bone marrow uptakes of Tc-99m-SC and In-111−transferrin among a group of patients with preleukemia [12Chomienne C. Najean Y. Vigneron N. Dresch C. Rain J.D. An analysis of prognostic factors in preleukemia: interest of bone marrow scintigraphy.Am J Hematol. 1984; 16: 235-242Crossref PubMed Scopus (1) Google Scholar]. Results (Fig. 4) were separated into different categories: A) low but about parallel uptake of both tracers, B) high and about parallel uptake of both tracers, and C) mostly high uptake of the colloid but relatively lower uptake of In-111−transferrin. Findings were later correlated to outcome of leukemia (almost all in group B, who also tended to show high In-111 in spleen) and others (group C) who instead developed, and mostly died from, pancytopenia. The authors suggested that tracer findings could be used to help decide to use chemotherapy in group B, but not in groups A or C.Figure 2In a patient with hereditary spherocytosis mid-thoracic, axial computed tomography scan (A) shows right paraspinal mass of unknown origin. Subsequent focal concentration of In-111−transferrin in site of mass (B) indicates erythropoietic activity [6Petit J.J. Estany C. Mediastinal extramedullary erythropoiesis in hereditary spherocytosis.Clin Lab Haematol. 1987; 9: 327-332Crossref PubMed Scopus (12) Google Scholar].View Large Image Figure ViewerDownload (PPT)Figure 3In a patient with agnogenic myeloid metaplasia and abnormal neurological signs axial computed tomography scan of the head (A) showed bilateral (mostly left-sided) subcranial masses. Corresponding view of concentration of Fe-52 in same sites (B) indicates extramedullary erythropoiesis [8Cornfield D.B. Shipkin P. Alavi A. Becker J. Peyster R. Intracranial myeloid metaplasia: diagnosis by CT and Fe-52 scans and treatment by cranial irradiation.Am J Hematol. 1983; 15: 273-278Crossref PubMed Scopus (6) Google Scholar].View Large Image Figure ViewerDownload (PPT)Figure 4Relative uptake of technetium 99m (Tc-99m)-sulfur colloid and In-111−transferrin into summed areas (6) of bone by scintigraphy of patients with preleukemia portrayed with designation of subsequent (3-year) outcomes: (Δ) death due to overt leukemia (9 of 10 in group B); (□) death due to pancytopenia (11 of 15 in Group C); (○) living; (+) splenic In-111 uptake; (no distinction of death cause in group A) [12Chomienne C. Najean Y. Vigneron N. Dresch C. Rain J.D. An analysis of prognostic factors in preleukemia: interest of bone marrow scintigraphy.Am J Hematol. 1984; 16: 235-242Crossref PubMed Scopus (1) Google Scholar].View Large Image Figure ViewerDownload (PPT)It is known that circulating stem cells (presumably pluripotential) are more numerous in the circulating blood of subjects with homeostatic perturbations due to disease or injury of bone marrow. Colonization of liver, spleen, lymph nodes, or receptive, "expandable" bone marrow may represent a form of migration or metastasis of normal or abnormal stem cells to organs that retain an intrinsic potential (e.g., RES cells) to support hematopoiesis. From a certain standpoint, this leakage of stem cells represents a benign, physiological sort of metastasis that attempts to maintain, and sometimes achieves, homeostasis of blood cell production [13Fliedner T.M. Graessle D. Paulsen C. Reimers K. Structure and function of bone marrow hemopoiesis: mechanisms of response to ionizing radiation exposure.Cancer Biother Radiopharm. 2002; 17: 405-426Crossref PubMed Scopus (143) Google Scholar]. Questions remain, however, as to whether or not (and if so, how and why) pluripotential cells (or just multipotential for certain cell lines [14Gao J. Dennis J.E. Muzik R.F. Lundburg M. Caplan A.I. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion.Cells Tissues Organs. 2001; 169: 12-20Crossref PubMed Scopus (785) Google Scholar]) take up residence in heterotopic sites other than those known to particularly harbor RES cells. It is supposed that both short-range signals (e.g., interleukins) from the microenvironment and long-range signals from circulating poietins encourage stem cell anchoring and erythroid colony-forming units [15Erslev A.J. Lichtman M.A. Structure and function of the marrow.in: Williams W.J. Beutler E. Erslev A.J. Lichtman M.A. Hematology. 4th ed. McGraw-Hill, Inc., New York1990: 37-47Google Scholar]. More knowledge about the natural phenomenon of EMH, not only in spleen and liver but in aberrant sites as well, might provide clues about the general handling of stem cell applications (e.g., stem cell implants or control of stem cell multiplication in cancers) [14Gao J. Dennis J.E. Muzik R.F. Lundburg M. Caplan A.I. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion.Cells Tissues Organs. 2001; 169: 12-20Crossref PubMed Scopus (785) Google Scholar].Studies of granulopoiesis with radioactive technetiumThere is some activity in exploring with tracers the sites of granulopoiesis, and in comparison with erythropoiesis, in conditions where there is EMH due to various bone marrow disorders. One study [11Aburano T. Yokoyama K. Shuke N. et al.Tc-99m HMPAO-labeled leukocytes for hematopoietic marrow imaging. Comparison with In-111 chloride.Clin Nucl Med. 1992; 17: 938-944Crossref PubMed Scopus (6) Google Scholar] compared in 11 patients with diverse disorders (myelofibrosis, myelodysplastic syndromes, pernicious anemia, etc.) the distribution of In-111−Cl with that of Tc-99m−hexamethylpropyleneamine oxime (HMPAO)-labeled leukocytes. Ten of 11 subjects showed good concordance at sites of intra- and extramedullary hematopoiesis. In just one subject (Fig. 5), who had myelofibrosis, there was discordance (high uptake of In-111−Cl and low uptake of Tc-99m−HMPAO–white blood cells), but this correlated with bone marrow biopsy that confirmed granuloid hypoplasia and erythroid hyperplasia. The findings could be explained by the known fact that granulocytes (like erythrocytes) are degraded by the RES, but there is also the possibility of some kind of affinity between mature leukocytes and their progenitors. Another study [16Jamar F. Field C. Leners N. Ferrant A. Scintigraphic evaluation of the haemopoietic bone marrow using a Tc-99m-anti-granulocyte antibody: a validation study with Fe-52.Br J Haematol. 1995; 90: 22-30Crossref PubMed Scopus (11) Google Scholar] compared, in patients with various hematopoietic disorders, the percentages of total body uptake into different organs of Fe-52 and of a Tc-99m−labeled monoclonal antibody to a granulocyte surface protein. There was fairly good concordance of the distributions of the two tracers into bone marrow, liver, and spleen. This tracer is said to be attracted to granulocyte progenitors to a much greater extent than to circulating mature granulocytes.Figure 5Whole body distribution of technetium 99m-hexamethylpropyleneamine oxime-labeled leukocytes (A) and In-111−chloride (B) in a patient with myelofibrosis showing discordance of uptake of the two tracers into bone marrow consistent with granuloid hypo- and erythroid hyperplasia by marrow biopsy [11Aburano T. Yokoyama K. Shuke N. et al.Tc-99m HMPAO-labeled leukocytes for hematopoietic marrow imaging. Comparison with In-111 chloride.Clin Nucl Med. 1992; 17: 938-944Crossref PubMed Scopus (6) Google Scholar].View Large Image Figure ViewerDownload (PPT)Studies of intestinal absorption of cobalamin (vitamin B-12) with isotopes of cobalt and carbon and of iron with isotopes of ironA long-time test with radioisotopes of cobalt, either or both (dual study) Co-57 and/or Co-58, called the Schilling test, was intended to detect malabsorption of vitamin B-12 due to lack of "intrinsic factor" (IF) as a cause of pernicious anemia and possibly other megaloblastic anemias [3Price D.C. McIntyre P.A. The hematopoietic system.in: Harbert J. Da Rocha A.F.G. Textbook of Nuclear Medicine. Vol. II. Clinical Applications. 2nd ed. Lea & Febiger, Philadelphia1984: 535-605Google Scholar, 17Zuckier L.S. Chervu L.R. Schilling evaluation of pernicious anemia: current status.J Nucl Med. 1984; 25: 1032-1039PubMed Google Scholar]. In this test (if dual), one cobalt isotope is attached to B-12 bound to IF and the other isotope attached to free B-12. Combined intramuscular injection of a load of B-12 allows urinary excretion of the isotopes to represent intestinal absorption. If the ratio of bound B-12 (B) to free B-12 (F) in urine is >1.7, the explanation is said to be lack of IF [17Zuckier L.S. Chervu L.R. Schilling evaluation of pernicious anemia: current status.J Nucl Med. 1984; 25: 1032-1039PubMed Google Scholar]. Normal subjects show B/F ratio <1.3 with high excretion of both isotopes. Low B/F ratio with low extraction suggests malabsorption in general. The original Schilling test is too simplistic and not physiological, because B-12 (cobalamin), when naturally consumed, is bound to protein. A more sensitive test can be obtained by combining the labeled B-12 to chicken protein before oral administration [18Dawson D.W. Sawers A.H. Sharma R.K. Malabsorption of protein bound vitamin B-12.Br Med J. 1984; 288: 675-678Crossref PubMed Scopus (58) Google Scholar, 19Shreeve W.W. In vitro indicators of metabolism of natural compounds.in: Feinendegen L.E. Shreeve W.W. Eckelman W.C. Bahk Y.-W. Wagner Jr., H.N. Molecular Nuclear Medicine: The Challenge of Genomics and Proteomics to Clinical Practice. 1st ed. Springer, Berlin, Heidelberg, New York2003: 327-354Crossref Google Scholar]. Further knowledge of particular components of cleavage of binding to ingested protein, transfer to particular intestinal proteins and eventual absorption of B-12 presently allows for more specific diagnoses [19Shreeve W.W. In vitro indicators of metabolism of natural compounds.in: Feinendegen L.E. Shreeve W.W. Eckelman W.C. Bahk Y.-W. Wagner Jr., H.N. Molecular Nuclear Medicine: The Challenge of Genomics and Proteomics to Clinical Practice. 1st ed. Springer, Berlin, Heidelberg, New York2003: 327-354Crossref Google Scholar].Another kind of isotopic test for B-12 deficiency in megaloblastic anemias involves measurement of carbon (long-lived, beta-emitting C-14 or stable C-13)−labeled carbon dioxide in the breath after giving labeled propionate intravenously [20Fish M.B. Pollycove M. Wallerstein R.O. In vivo oxidative metabolism of propionic acid in human vitamin B-12 deficiency.J Lab Clin Med. 1968; 72: 767-777PubMed Google Scholar, 21Shreeve W.W. Labeled carbon breath analysis.in: Harbert J. Da Rocha A.F.G. Textbook of Nuclear Medicine. Vol. I: Basic Science. 2nd ed. Lea & Febiger, Philadelphia1984: 351-362Google Scholar]. Metabolism of propionate requires B-12, which is involved in formation and transfer of one-carbon units. So also does the formation of nucleic acid bases (purines and pyrimidines) involve one-carbon units, which accounts for the role of B-12 in cell division and multiplication. There is a decidedly slower formation of carbon dioxide from C-14−propionate when there is B-12 deficiency than in cases of normal or folic acid deficiency. Results of breath analysis do not always correlate with the serum B-12 level or even the degree of anemia, and may give a better idea of the intracellular activity of B-12 [20Fish M.B. Pollycove M. Wallerstein R.O. In vivo oxidative metabolism of propionic acid in human vitamin B-12 deficiency.J Lab Clin Med. 1968; 72: 767-777PubMed Google Scholar]. There can be a similar breath test for folic acid deficiency (also causing megaloblastic anemia), when the administered labeled precursor is either histidine or serine [3Price D.C. McIntyre P.A. The hematopoietic system.in: Harbert J. Da Rocha A.F.G. Textbook of Nuclear Medicine. Vol. II. Clinical Applications. 2nd ed. Lea & Febiger, Philadelphia1984: 535-605Google Scholar, 22Fish M.B. Pollycove M. Feichtmeir T.V. Differentiation between vitamin B-12-deficient and folic acid-deficient megaloblastic anemias with C-14-histidine.Blood. 1963; 21: 447-461PubMed Google Scholar], the metabolism of which also involves transfer of one-carbon units, though differently than B-12. Another application of the breath carbon dioxide technique has been oral administration of carbon (C-13)−labeled urea to demonstrate gastric mucosal infection with Helicobacter pylori, a bacterium that contains urease (unlike the stomach) and that sequesters iron, causing anemia [23Konno M. Muraoka S. Takahashi M. Imai T. Iron-deficiency anemia associated with Helicobacter pylori gastritis.J Pediatr Gastroenterol Nutr. 2000; 31: 52-56Crossref PubMed Scopus (95) Google Scholar, 24Kato S. Nikayama K. Minouri T. et al.Comparison between the C-13-urea breath test and stool antigen test for the diagnosis of childhood Helicobacter pylori infection.J Gastroenterol. 2004; 39: 1045-1050Crossref PubMed Scopus (38) Google Scholar]. Technical advances in the measurement of C-14 (as well as C-13) [19Shreeve W.W. In vitro indicators of metabolism of natural compounds.in: Feinendegen L.E. Shreeve W.W. Eckelman W.C. Bahk Y.-W. Wagner Jr., H.N. Molecular Nuclear Medicine: The Challenge of Genomics and Proteomics to Clinical Practice. 1st ed. Springer, Berlin, Heidelberg, New York2003: 327-354Crossref Google Scholar, 21Shreeve W.W. Labeled carbon breath analysis.in: Harbert J. Da Rocha A.F.G. Textbook of Nuclear Medicine. Vol. I: Basic Science. 2nd ed. Lea & Febiger, Philadelphia1984: 351-362Google Scholar] justify renewed use of these kinds of tests.Due mainly to the widespread occurrence of malnutrition in impoverished countries, the worldwide incidence of iron-deficiency anemia might now be close to 1 billion people [25Walczyk T. The potential of inorganic mass spectrometry in mineral and trace element nutrition research.Fresenius J Anal Chem. 2001; 370: 444-453Crossref PubMed Scopus (33) Google Scholar]. Other causes are malabsorption, chronic blood loss, or excessive need. Children and pregnant women are at particular risk. The percentage of ingested iron, which is absorbed, can be measured by whole body counting of administered Fe-59 at 1 hour and at 14 days postabsorption [26Barrett J.F.R. Whittaker P.G. Fenwick J.D. Williams J.G. Lind T. Comparison of stable isotopes and radioisotopes in the measurement of iron absorption in healthy women.Clin Sci. 1994; 87: 91-95PubMed Google Scholar]. Another way is to give two iron isotopes simultaneously, one orally and one intravenously, and compare the two in serum samples. This has been done with radioisotopes [Fe-59 and Fe-55 (beta energy: 6 KEV; half-life: 2.7 years)] [27Viteri F.E. Warren R. Considerations on the use of radioisotopes in human nutrition research.Food Nutr Bull. 2002; 23: 7-16PubMed Google Scholar] or with stable isotopes (Fe-54 and Fe-57) [26Barrett J.F.R. Whittaker P.G. Fenwick J.D. Williams J.G. Lind T. Comparison of stable isotopes and radioisotopes in the measurement of iron absorption in healthy women.Clin Sci. 1994; 87: 91-95PubMed Google Scholar]; the latter can be applied widely under field conditions with later analysis in central locations [25Walczyk T. The potential of inorganic mass spectrometry in mineral and trace element nutrition research.Fresenius J Anal Chem. 2001; 370: 444-453Crossref PubMed Scopus (33) Google Scholar]. Areas under the curves of radioactivity or stable isotope enrichment, for both oral and intravenous isotopes, up to 10 hours are graphed and measured by the trapezoidal method [26Barrett J.F.R. Whittaker P.G. Fenwick J.D. Williams J.G. Lind T. Comparison of stable isotopes and radioisotopes in the measurement of iron absorption in healthy women.Clin Sci. 1994; 87: 91-95PubMed Google Scholar]. Directly measured values need correction for the much greater (e.g., 10- to 20-fold) amount of oral than of intravenous isotope given. Recent studies of this type have been done to assess optimal nutritional supplement of iron (amount or chemical form) and effects of co-nutrients (e.g., ascorbic acid or zinc). Research and clinical application of radioactive or stable isotopes to characterize abnormal hematopoiesis have changed with the advances in instrumentation and techniques during the past 50 to 60 years. Autoradiography, mainly with tritiated (H-3) thymidine, was used early to study kinds and rates of generation from undifferentiated stem cells in bone marrow to produce mature, circulating erythrocytes, granulocytes, lymphocytes, megakaryocytes, etc. [1Kniseley R.M. Kurst D.R. Nelp W.B. Berlin N.I. The blood.in: Wagner Jr., H.N. Principles of Nuclear Medicine. 1st ed. W.B. Saunders Co., Philadelphia1968: 404-471Google Scholar]. For different reasons (including radiation dose), little direct clinical application has followed this seminal research. Also in the mid
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