The appearance of sideroblasts in hypoplastic anemia
(HAl and acute myelocytic leukemia (AML), together with their sideroblastograms, was studied. Hematological studies on cases with type III sideroblast dominance by sideroblastograms produced the following results. Type III sideroblast dominant HA was observed in three of 63 cases. Two of the above three cases had what we call &#34;atypical
factor&#34;, while the remaining one became AML in its clinical course and could be considered to be leukemia in a hypoplastic preleukemic stage. Type III sideroblast dominant AML was noted in five of 32 cases. Three of these five cases are compatible with low percentage leukemia, and one of the above three cases showed ringed sideroblasts
exhibiting erythroleukemia in the terminal stage. In HA and
AML, type III sideroblast dominant cases have to be examined in relation to atypical HA and atypical leukemia. Changes of iron meta. bolism in erythroblasts with preleukemic stage will be attributable to disturbance of erythropoiesis such as erythroid hyperplasia in bone
marrow and also, in part, to disturbance of hemoglobin synthesis.</p

Kimura, Ikuro

Sugiyama, Motoharu

Takahashi, lsao

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 28, Issue 3 1974 Article 4JUNE 1974Clinical studies on iron metabolism oferythroblasts in preleukemic stageIkuro Kimura∗ lsao Takahashi†Motoharu Sugiyama‡∗Okayama University,†Okayama University,‡Okayama University,Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Clinical studies on iron metabolism oferythroblasts in preleukemic stage∗Ikuro Kimura, lsao Takahashi, and Motoharu SugiyamaAbstractThe appearance of sideroblasts in hypoplastic anemia (HAl and acute myelocytic leukemia(AML), together with their sideroblastograms, was studied. Hematological studies on cases withtype III sideroblast dominance by sideroblastograms produced the following results. Type IIIsideroblast dominant HA was observed in three of 63 cases. Two of the above three cases hadwhat we call “atypical factor”, while the remaining one became AML in its clinical course andcould be considered to be leukemia in a hypoplastic preleukemic stage. Type III sideroblast dom-inant AML was noted in five of 32 cases. Three of these five cases are compatible with lowpercentage leukemia, and one of the above three cases showed ringed sideroblasts exhibiting ery-throleukemia in the terminal stage. In HA and AML, type III sideroblast dominant cases have tobe examined in relation to atypical HA and atypical leukemia. Changes of iron meta. bolism inerythroblasts with preleukemic stage will be attributable to disturbance of erythropoiesis such aserythroid hyperplasia in bone marrow and also, in part, to disturbance of hemoglobin synthesis.∗PMID: 4280229 [PubMed - indexed for MEDLINE] Copyright c©OKAYAMA UNIVERSITYMEDICAL SCHOOLActa Med. Okayama 28, 173-180 (1974)CLINICAL STUDIES ON IRON METABOLISM OFERYTHROBLASTS IN PRELEUKEMIC STAGEIkuro KIMURA, lsao TAKAHASHI and Motoharu SUGIYAMADepartmet of Internal Medicine, Okayama University Medical School,Okayama, Japan (Director: Prof. K. Hiraki)Received for publication, August 6, 1973Abstract: The appearance of sideroblasts in hypoplastic anemia(HAl and acute myelocytic leukemia (AML), together with their sidero-blastograms, was studied. Hematological studies on cases with typeIII sideroblast dominance by sideroblastograms produced the followingresults. Type III sideroblast dominant HA was observed in three of63 cases. Two of the above three cases had what we call "atypicalfactor", while the remaining one became AML in its clinical courseand could be considered to be leukemia in a hypoplastic preleukemicstage. Type III sideroblast dominant AML was noted in five of 32cases. Three of these five cases are compatible with low percentageleukemia, and one of the above three cases showed ringed sidero-blasts exhibiting erythroleukemia in the terminal stage. In HA andAML, type III sideroblast dominant cases have to be examined inrelation to atypical HA and atypical leukemia. Changes of iron meta.bolism in erythroblasts with preleukemic stage will be attributable todisturbance of erythropoiesis such as erythroid hyperplasia in bonemarrow and also, in part, to disturbance of hemoglobin synthesis.Close clinical examination of cases with apparent hypoplastic anemia(HA) has often proved to be paroxysmal nocturnal hemoglobinuria (PNH) (l)or, in the clinical course, to be leukemia. We have already reported severalcases each of the above types (2). On the other hand, in our daily clinicalpractice it is sometimes found (3), though rarely, that in the category of leuke-mia, there are cases wherein differential diagnosis is required between atypicalleukemia, hypoplastic leukemia and low percentage leukemia with the bonemarrow showing remarkable hypoplasia and with the blast count so low assimilar to that observed in HA.The clinical picture of HA is characterized by peripheral pancytopenia andhematopoietic disturbance in bone marrow. Its diagnosis seems to be rathereasy based on hematological findings, tissue culture on the bone marrow, thesideroblastogram, and serum Fe and Cu levels. As mentioned, however, HAoccasionally turns out to be PNH or leukemia. Thus, the possibility cannotbe ruled out that one often includes some other diseases in so-called HA.1731Kimura et al.: Clinical studies on iron metabolism of erythroblasts inProduced by The Berkeley Electronic Press, 1974174 1. KIMURA, I. TAKAHASHI and M. SUGIYAMAFrom hematological findings, we have already instituted atypical HA.lf HA should include other diseases, it is necessary to watch for atypical HAand to study it not only in terms of peripheral bood, myelograms and serumFe and Cu levels but also from various other aspects, so as to identify moreatypical factors than those currently known.From the above point of view, we have studied the incidence of siderobastsand the sideroblastogram in HA, and have also carried out similar studies onacute myelocytic leukemia (AML).MATERIALS AND METHODS1) Subjects:Involved in our present studies were 63 cases of idiopathic HA and 32 casesof AML who were admitted to our department during the period from 1952 to1972 and were examined for sideroblasts. None of these cases had been treatedpreviously. The cases whose clinical picture and examinations indicated evi-dent complication by infections or hepato-renal damage were excluded fromthe studies. Thirty-eight normal subjects were employed as a control group.2) Methods:The method employed for sideroblasts was almost the same as that de-scribed by KAPLAN (4). The classification of sideroblasts and the preparation ofthe sideroblastogram were made according to our methods (5) (Fig. 1). Ourstudies emphasized the appearance of sideroblasts and the sideroblastogram inthe subjects; in particular, the cases dominated by the type III sideroblastwere statistically extracted and their hematological features were examined.No. of granules 0 1"'2 3 ""5 6'" incomplete completeRinged RingedType 0 IT ill ( TV) (V)Fig. 1. Classification of sideroblast (KIMURA 1955)RESULTS1) Sideroblast appearance in H A and AML :The appea.rance of sideroblasts in HA and AML is presented in the figure;30.6±8.2% in the control group, 85.3±ll.O% in HA, and 67.8±24. 7%in AML, indicating a high incidence in HA and AML. Especially in HAstatistics showed a low variance, which appeared to be characteristic. The2Acta Medica Okayama, Vol. 28 [1974], Iss. 3, Art. 4http://escholarship.lib.okayama-u.ac.jp/amo/vol28/iss3/4Siderob1ast in Preleukemic Stage 175appearance of sideroblasts in monocytic leukemia (MoL) was 70. 0 ± 24. 1%(Fig. 2).0--------50--------100 %CONTROLAML- ul"'[!}-:30.6:t8.2- C:-~· .: ~I:.:G7.Bt 24.7Mo L . ~ .. •• ••••_ •• ,JI70.0 t24.1HYPOPLA.ANEMIA ...""'t!~IHB~85.3 t 11.0Fig. 2. Incidences of siderob1ast2) Examinations of the sideroblatogram in H A and AML :The pattern of appearance in normal subjects was found to be, as pre-sented in the figure, type 0: 69.4±8.2%, type I: 26.4±7. 7%, type II:4. 9±2. 8%, type III: 0.8% or less; with statistically significant differences% %100 100o.<; 0 IT III TypeFig. 3. Sideroblastogram in control,type 0; 69. 4±8. 2%, type I; 26. 4± 7.7%,type I; 4.9±2.8%, type m ~0.8%o IT III TypeFig.4. Sideroblastogram in hypoplasticanemia, type 0; 14. 7± 11.0%, type I ;22.5±7.3%, type!; 45.0±9. 7%, type m17.7±10.9%3Kimura et al.: Clinical studies on iron metabolism of erythroblasts inProduced by The Berkeley Electronic Press, 1974176 1. KIMURA, 1. TAKAHASHI and M. SUGIYAMAbetween the types, the sideroblastogram showed a decreasing pattern from typeo to type III, as a characteristic finding (Fig. 3).For HA, as shown in the figure, the results were type 0: 14.7 ± 11.0%,type I: 22. 5± 7.3%, type II: 45. 0±9. 7%, and type III: 17. 7± 10.9%,confirming a characteristic pattern of type II sideroblast dominance reportedpreviously (5). The incidence of type II siderobalst dominant cases was veryhigh, being 54 (86.6%) of 63 cases (Fig. 4).On the other hand, the sideroblastogram in AML was not statisticallysignificant; type 0: 32.2±24.7%, type I: 21.6±8.3%, type II: 31.1 ± 16.8%,and type III: 20. O± 17. 6%. Type III sideroblast dominance was noted in5 (15.6%) of 32 cases (Fig. 5). In one (Case 5) of five cases, ringed sidero-blasts were present up to 8%.%100Case 1-Case 4.. Case 2.50 .c- Case 5Case :3.-....7.., :. I~0 D ill TypeFig. 5. Siderob1astogram in AML, type 0; 32. 2±24. 7%,type I ; 21. 6±8. 3%, type I; 31.1 ± 16. 8%, type BI 20. O± 17. 6%3) Hematological findings in type I I I sideroblast dominant H A:The hematological findings in three cases exhibiting type III sideroblastdominance are summarized in the Table. At the time of admission, one caseshowed reticulocytosis and two cases erythroid hyperplasia in bone marrow.On admission, Case 3 was complicated by an atypical factor, i. e. a shift tothe left in the granulocytic series and became AML (Table 1).4Acta Medica Okayama, Vol. 28 [1974], Iss. 3, Art. 4http://escholarship.lib.okayama-u.ac.jp/amo/vol28/iss3/4Sideroblast in Preleukemic StageTABLE 1 HEMATOLOGICAL FINDINGS OF TYPE III SIDEROBLAST DOMINANT**CASES IN HYPOPLASTIC ANEMIA177No of Peripheral Blood Bone Marrow My-Bl. Type IIICase Age Sex WBC RBC Thr. Retic. NCC Ery·Bl. Siderobl.(x103 ) (x104 ) (x 104 ) (%0) (x 104 ) (%) (%) (%)1. 60 F 5.4 266 10.6 ? ? 20.4 0.8 36.02. 12 M 3.1 251 1.5 24.0 23. 7 52.8 0.4 52.03.* 55 M 1.5 198 3.8 9.0 11. 0 31.8 1.4 40.0* Left shift of granulocyte series( +), terminated in AML.* 3 of 63 cases, 4.1%4) Hematoogical findings of type III sideroblast dominant AML:Hematological findings in five cases of AML exhibiting type III sidero-blast dominance in the sideroblastogram are presented in the Table. Lowlevels of blasts in the peripheral blood and bone marrow, :i. e., identicalfindings to those in low percentage leukemia, were observed in three cases.The Case 5 was, on admission, considered to belong to the preleukemic stageexhibiting incompletely ringed sideroblasts, and within a few months provedto be low percentage leukemia. About six months later, this case showederythroid hyperplasia, atypical erythroblasts, PAS-positivity and hiatus ery-throleukemia (Table 2).TABLE 2 HEMATOLOGICAL FINDINGS OF TYPE III SIDEROBLAST DOMINANT***CASES IN ACUTE MYELOCYTIC LEUKEMIANo of Peripheral Blood Bone MarrowCase Age Sex WBC Blast(x 103 ) (%) NCC(x104) Blast(%) Erythr. (%) Type III Siderobl. (%)1* 67 M 4.3 13 ? 14.8 49.6 712 57 M 10. 7 6 30.3 6.4 25.6 623 30 M 88.0 64.0 15.4 68.2 1.6 484 39 M 18.3 32.0 67.5 36.2 2.0 705* ** 34 M 2.8 0 8.6 5.8 29.4 51,* Megaloblastoid cell( +)** Ringed sideroblast(+ ), terminated in erythroleukemia*** 5 of 32 cases, 15.6%tOo % Ringed r. Ringel:! % Ringed::;":: l ='~: l :~' 'g"L LA 1)\<.o 0 1 n m w V- 0 I n m 'R V 0 I n m 11 VLow percentage leukemia - ErythroleukemiaFig. 6. Changes in the sideroblastogram of Case 55Kimura et al.: Clinical studies on iron metabolism of erythroblasts inProduced by The Berkeley Electronic Press, 1974178 1. KIMURA, 1. TAKAHASHI and M. SUGIYAMADISCUSSIONSideroblast is defined as an erythroblast containing stainable iron granules.These granules are known to be non-hemin iron along the iron metabolism oferythroblasts (4). The iron absorbed from the intestinal mucosa is directlyused for hematopoiesis and, at the same time, it is stored in the organs asferritin and hemosiderin, which, when needed, are mobilized to erythroblastsin bone marrow for heme synthesis. In iron metabolism, the erythroblastsplay an important role in the course of change from non-hemin iron to heminiron. Sideroblasts may be considered important for investigating the actualstate of iron metabolism. Thus far, numerous reports have been published onsideroblasts; systematic studies on sideroblasts in blood diseases have alreadybeen reported by the authors (5).Numerous reports have been published on PNH, leukemia with a hypo-plastic preleukemic stage, hypoplastic leukemia and low percentage leukemia,which should be differentiated from HA; and differentiation of HA, its ana-logous diseases and leukemia are clinically interesting problems (6). In ourstudies of leukemia with a hypoplastic preleukemic stage, we have alreadyinstituted as atypical HA group. Among cases of atypical HA, those thatshowed the presence of atypical factors, i. e. erythroblasts in the peripheralblood, erythroid hyperplasia in bone marrow, mild increase of blasts in bonemarrow or a shift to the left of the granulocytes, were classified as leukemiain a hypoplastic preleukemic stage. If HA should include not only leukemiabut also other diseases, this atypical HA group should draw attention (2).We have re-examined the sideroblasts in HA and AML, and studied thequestion as to whether or not type III sideroblast dominant cases on the sidero-blastogram can be clinically regarded as atypical cases. The incidence ofsiderobalsts in HA and AML was 85. 3± 11. 0% and 67. 8±24. 7%, respec-tively, while it was 30.6 ± 8. 2% in the control group. Sideroblasts are foundduring the dynamic course of hemoglobin synthesis from non-hemin iron (7),and the appearance of sideroblasts is influenced by serum iron, i. e., by thesupply of iron from the serum and by hematopoietic function. In HA and AMLwhereby erythropoietic function is low, the high appearance of sideroblasts canbe easily explained. In AML, the appea~ance of sideroblasts is higher thanin the control group, but is less uniform and shows a greater statistical variancethan in HA. This is believed to occur since the erythropoietic damage inin AML is mainly due to displacement of granulocytes by tumorous prolifera-tion, the incidence of granulocyte is not uniform, and latent hemorrhage andinfection are more frequent.Our study on sideroblastograms has confirmed that type II sideroblast6Acta Medica Okayama, Vol. 28 [1974], Iss. 3, Art. 4http://escholarship.lib.okayama-u.ac.jp/amo/vol28/iss3/4Sideroblast in Preleukemic Stage 179dominance in HA is a characteristic pattern (5). On the other hand, theincidence of type III sideroblast dominant cases was very low, being onlythree (4. 1%) of 63 cases. The question is as to whether or not such cases canbe regarded as atypical. Examination of the blood picture on admissionshowed, as already mentioned, the presence of reticulocytosis, erythroid hy-perplasia in bone marrow and a shift to the left in the granulocytic series,indicating hematologically atypical factors. Especially noteworthy is that oneof three cases became AML during its clinical course; retrospectively, thiscase was leukemia with a hypoplastic preleukemic stage. From this finding,cases among HA with type III sideroblast dominance on the sideroblastogramwill require clinical follow-up and pathologic analysis as cases of atypicalHA. Examining 53 cases exhibiting a preleukemic state, we reported thatmany of these c~ses showed erythrobalstic damage as seen in HA (frequentincidence of erythroid hyperplasia in bone marrow), pernicious anemia andsideroblastic anemia (3). Subsequently, we have watched erythroblastic kine-tics carefully prior to definite diagnosis of leukemia. The fact that perniciousanemia and sideroblastic anemia are representative diseases with type IIIsideroblast dominance and one of three cases with type III sideroblast domi-nance became AML seems to have important implications for the preleukemicstate.On the other hand, in AML no such characteristic pattern is observed asin HA nor any significant difference in the incidence of different types ofsideroblast. Thus, it may be difficult to pick up atypical cases in AML onthe basis of sideroblastograms. We, however, want to draw attention to thefact that three of five cases with type III sideroblast dominant cases turnedout to be of low percentage leukemia, and that one of these three cases was, inthe early stage, considered to belong to the preleukemic stage exhibiting in-completely ringed sideroblasts and, in the terminal stage, showed erythro-leukemia. As pointed out, leukemia with a hypoplastic preleukemic stage isa pathologic state that is potentially leukemic and is essentially different fromHA; from a hematological viewpoint we have also pointed out the relationshipbetween leukemia with a hypoplastic prelekemic stage and atypical types ofleukemia (hypoplastic leukemia and low percentage leukemia). An increase intype III sideroblasts may be significant with regard to the erythroblastic seriesin both diseases, i. e. leukemia and HA; this demands many more cases to bestudied. Changes in the sideroblastogram of Case 5 (low percentage leukemiafollowed by erythroleukemia) are presented in Fig. 6. Ringed sideroblasts,unlike non-ringed, are believed to be due to disturbed ALA and heme synthe-tases (9), and are characterisric for sideroblastic anemia. Ringed sideroblasts,however, have been also observed in erythremia and erythroleukemia indicating7Kimura et al.: Clinical studies on iron metabolism of erythroblasts inProduced by The Berkeley Electronic Press, 1974180 1. KIMURA, I. TAKAHASHI and M. SUGIYAMArelationship between the tumorous proliferation of erythroblasts and disturbedheme synthesis (10). Such cases are extremely rare, and many provide usefulinformations for the study on the relationship between sideroblastic anemia, DiGuglielmo syndrome and leukemia.Acknowledgement: The authors express their thanks to Prof. Kiyoshi HIRAKI for advice inthe present studies and for a criticial review on this paper.REFERENCES1. TAKAHASHI, R. et al: On the relationship of paroxysmal nocturnal hemoglobinuria andhypoplastic anemia. The Jap. J. of Clinical Hematology 9, 695-704, 1968 (in japanese)2. TAKAHASHI, I. et al: Clinical investigation on leukemia with hypoplastic preleukemicstage. ibid 12, 61-67, 1971 (in japanese)3. KITAJIMA, Y. et al: Atypical leukemia. Jap. J. of Clinical Medicine 30, 105-111, 1972 (injapanese)4. KAPLAN, E. et al: Sideroblasts, A study of stainable nonhemoglobin iron in marrownormoblasts. Blood 9, 203-213, 19545. KIMURA, 1.: Studies on sideroblasts. Vol. 1, Blood diseases and sideroblasts. Journal ofMed. Association of Okayama 69, 1173-1198, 1957 (in japanese)6. TAKAHASHI, 1. et al: Preleukemic states. Medical Juurnal of Kawasaki Hospital 2, 45-66, 1969(in japanese)7. HIRAKI, K. and KIMURA, I.: Physical significance of the development of sideroblasts andsiderocytes and its clinical application. Jap. }. of Clinical Medicine 19, 287-294, 1961 (injapanese)8. TAKAHASHI, I. et al: Clinical studies on leukemia with hypoplastic preleukemic stagein Japan. Acta Hematologica }aponica (in press) (in japanese)9. BROWN, W. D.: Abnormal (ringed) sideroblasts in various hematologic and non-hemato-logic disorders. Blood 18, 662-671, 196110. NAKAYAMA, S. et al: A case of acute leukemia, associated with sideroblastic bone marrowand termed in erythroleukemic picture. The lap. }. of Clinical Hematology 13, 50-57, 1973(in japanese)8Acta Medica Okayama, Vol. 28 [1974], Iss. 3, Art. 4http://escholarship.lib.okayama-u.ac.jp/amo/vol28/iss3/4

Clinical studies on iron metabolism of erythroblasts in preleukemic stage

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