Ferritin is an iron storage protein with a wide distribution in animal cells. It consists of outer protein shell (apoferritin) and inner iron cores. Recent advance of radioimmunoassay enabled us to detect a trace amount of ferritin in serum. To evaluate the clinical and pathophysiological significance of serum ferritin, it would be worthy to have a basic knowledge about the charateristics of ferritin molecules. In this paper, we performed analysis of human, rat, and horse ferritins electrophoretically and immunologically and the results were obtained as follows:
1) All tissue ferritins showed multiple forms designated as isoferritin, when analyzed by isoelectric focusing. In human and rat, the heart ferritins were more acidic than the liver or spleen ferritins and vise versa in horse.
2) By subunit analysis using SDS/polyacrylamide gel electrophoresis, all ferritin molecules were fashioned from a set of subunits, H and L and the hetergeneous profiles on IEF were reflecting the different proportion of these subunits. Therefore it was suggested that ferritin is a hybrid molecule composed of two dissimilar subunits.
3) Isoferritiins from different tissues varies qualitatively and quantitavely in their immunological reactivities and these differences pararelled the proportion of H and L subunits.
4) The long term iron administration to rats showed a shift of liver isoferritin profile to more basic pI range, which supports the similar obseration of phenotypic shift of ferritins in haemochromatosis tissues.
5) Two types of subunits of ferritin molecules were demonstrated in a cell free synthesizing system of wheat germ lysate programmed by rat liver mRNA, indicating that these two subunits are indeed primary gene product.

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Although some biochemical and metabolic properties of the isoferritin in erythroid cells designated “erythroblast or red cell ferritin” were previously reported, clinical or pathophysiologic significance of red cell ferritin quantitation remains to be clarified. However, the recent development of a sensitive immunoradiometric assay method for ferritin has made it possible to quantitate ferritin in blood cells as well as serum. This report describes the results of red cell ferritin measurements in normals and hematologic disorders by the two site radioimmunoassay method and of some analysis undertaken to reveal factors regulating red cell ferritin concentration. The results obtained revealed two important points indicating clinical and pathophysiologic significance of red cell ferritin measurement. The first one demonstrated is that red cell ferritin constitutes a functional metabolic pool which shows variable sensitive changes dependent on some intrinsic and extrinsic factors. The second point disclosed is that red cell ferritin concentrations in hematologic disorders show characteristic changes among disorders which were found to be regulated by three main factors, iron store, reticulocyte percentage and disturbance of hemoglobin synthesis or ineffective erythropoiesis. Significant correlation between serum iron values and red cell ferritin concentrations was observed in most hematological disorders except ones with ineffective erythropoiesis or disturbed hemoglobin synthesis. This fact revealed that the level of transferrin-bound iron is a direct extrinsic factor determining red cell ferritin levels. It was also found that red cell ferritin concentrations show remarkable changes during the treatment of hematologic disorders such as iron deficiency anemia, pernicious anemia and polycythemia vera. The density gradient centrifugation analysis demonstrated that red cell ferritin posses a higher molecular density than serum ferritin which is similar to that of liver ferritin. These results presented in this paper disclosed not only the clinical significance of red cell ferritinmeasurements but also some physiologic or pathophysiologic nature of red cell ferritin in humans.

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Serum ferritin concentration as a measurement of storage iron was evaluated by the two site immunoradiometric assay technique. Normal value of serum ferritin in male and female was 144±75 and 40±22 ng/ml respectively. In the patients with iron deficiency anemia, serum ferritin value was less than normal (6.8±5.1 ng/ml, the same in male and female), and turned to normal after iron supplement therapy. Serum ferritin concentration in the population was measured near Fukushima city. The results showed 25% of pre-latent iron deficiency (low ferritin value with normal serum iron, TIBC and hematocrit) in adult female. In the iron overload states, there was good relationship between serum ferritin and storage iron. There were also good correlations between serum ferritin, total liver iron, hemosiderin and ferritin content in the experimental iron-overloaded rats. In conclusions, it was discussed serum ferritin concentration was good indicator of storage iron measurement.

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Clinical implications of serum ferritin levels were studied in patients with hepatobiliary diseases. Hyperferritinemia was found in patients with acute hepatitis, chronic active hepatitis, cirrhosis, primary liver cancer, cholangioma and haemochromatosis. There was a good correlation between serum ferritin and glutamic oxaloacetic transaminase (GOT) in patients with hepatitis (r=0.52). There was no correlation between serum ferritin and iron in hepatobiliary diseases, but a significant correlation was observed between serum ferritin and transferrin saturation in patients with cirrhosis (r=0.66). Serum ferritin level showed no dependency on the results of ICG test in patients with liver diseases. A high acidic ferritin level was demonstrated in 65% of patients with primary liver cancer. In the case of acute hepatitis, alteration in serum ferritin was accompanied by proportional change in serum GOT. In the case of choledocholithiasis, decrease of serum ferritin was accompanied by decrease of serum alkaline phosphatase and GOT following papillotomy. Serum ferritin in hepatic vein tended to be lower than that in the portal vein in cirrhosis and chronic active hepatitis. It was suggested that the elevation of serum ferritin in hepatobiliary diseases was due to release of ferritin from damaged liver cells, disturbance of biliary passages and increased production of ferritin by tumor cells. These results indicate that serum ferritin is just as useful as the conventional liver function tests in monitoring the progress of the disease during treatment in patients with hepatobiliary diseases.

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Serum ferritin was examined by 2-site immunoradiometric assay in various hematological disorders which showed impaired erythropoiesis and received blood transfusion (BTF). Aplastic anemia (AA) and polycythemia vera which showed pancytopenia in the course of treatment revealed high serum ferritin concentration because of depressed erythropoiesis. Pernicious anemia (PA) and sideroblastic anemia (SA) also revealed high serum ferritin concentration because of ineffective erythropoiesis.
Also, it was clear that there was a close correlation between serum ferritin concentration in various hematological disorders (hemolytic anemia, AA. SA and various types of leukemia) and voluminous BTF.
It may be suggested that, in addition to impaired erythropoiesis and voluminous BTF, serum ferritin could be related to many other factors, e.g. bleeding, production by tumorcell, hepatocellular injury, infection etc., in complication with hematological diseases.

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Serum ferritin were measured by SPAC FERRITIN KIT (immunoradiometrical assay) on 20 cases with various type of hemolytic anemia, 6 PS, 2 PNH and 12 Coombs positive. And the results are as in followed:
Serum ferritin level is elevated in generally with relatively moderate degree (420.0±410.2 ng/ml, normal level are 79.0±30.4 and 26.7±9.9 female) among various blood diseases associated with hyperferritinemia. But in there, big differences were seen between case by case and these individual difference looks like most important problems to be disolved.
The statistical data induced from references between serum ferrin and RBC, Hb, Rc, Serum iron, Iron saturation rate of transferrin, PID, PIT, RCIUR, Red cell ferritin and also therapeutic course suggests that elevated serum ferritin level in hemolytic anemia are very concerned to next two main fundamental mechanism, (1)…the total iron stores of individual patient and (2)…the red cell ferritin destroyed continously.

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Serum ferritin and ferritin concentrations within circulating leukocytes were determined by radioimmunoassay in various kinds of leukemia.
(1) Serum ferritin concentrations are high in acute leukemia, especially in acute myelogeneous leukemia, acute monocytic leukemia and erythroleukemia.
(2) In acute non-lymphocytic leukemia, circulating leukemic cells contain higher concentrations of ferritin than normal leukocytes. Serum ferritin levels are directly proportional to the ferritin concentrations within circulating leukocytes (r=0.707, p<0.02).
(3) Liver injury, blood transfusion or infection is an increasing factor of serum ferritin concentrations in acute non-lymphocytic leukemia.
(4) Serum ferritin concentrations are well correlated with serum lactic dehydrogenase levels and are high in acute monocytic leukemia both at presentation and during remission.
(5) In acute non-lymphocytic leukemia, serum ferritin concentrations increase in proportion to blast cell counts of the bone marrow cells (r=0.85, p<0.01).
Based on these observations, high concentrations of serum ferritin may be due to increased ferritin production by leukemic cells and augmented release from it in acute non-lymphocytic leukemia.

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The clinical significance of serum ferritin was studied for its possible use in serodiagnosis of malignancies.
Using immunoradiometric assay, a high incidence of elevated serum ferritin levels were found in patients with pancreatic carcinoma (75%), hepatoma (73%), lung cancer (59%), and acute myelogenous leukemia (95.5%). When blined serum samples (143) from NIH were tested, the sensitivity was somewhat decreased (40∼45%) but the specificity was reasonably high (85%). This sensitivity and specificity was almost the same as that of CEA.
The combination assay of ferritin and CEA for lung cancer and that of ferritin and ribonuclease for pancreatic carcinoma seemes to be promising to increase the sensitivity. In most cases of lung cancer and pancreatic carcinoma, serum ferritin assay was useful in monitoring the operative treatment of tumor. No apparent correlation was observed in serum ferritin levels and the staging of lung cancer, whereas in pancreatic carcinoma, mean serum ferritin concentration increases as the stage advanced.
The heart ferritin assay (acidic isoferritin assy) was also evaluated for the diagnosis of some malignancies. The sensitivity was increased by this assay in most of pancreatic carcinoma and some of hepatoma. Elevated levels were also observed in acute myocardial infarction.

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Two cases of leukemia associated with DIC and hypocomplementemia were described. A 42-year-old woman with blastic transformation of chronic myelocytic leukemia was transferred to our hospital for further intensive chemotherapy. Despite of the vigorous chemotherapy, there was no hematological recovery and occasional mild hematemesis was noticed. Serum complement components (C1q, C 3, C 4, C 5, C 3 anaphylatoxin and factor B) declined insidiously with concomitant decrease in plasma protease inhibitors such as anti-thrombin III (ATIII), α₂^- macroglobulin (α₂ M) and inter-α-trypsin inhibitor (IαI). Blood coagulation study also showed abnormal findings corresponding to the changes in complement components and protease inhibitors. On the 112th hospital day she suddenly became oliguric and in shock state and on the 120th hospital day expired.
A 71-year-old man with acute monocytic leukemia was admitted because of pallor, purpura and general malaise. Under the diagnosis of acute DIC he received heparin therapy from the 2nd hospital day. He abruptly died of splenic rupture on the 6th hospital day, though his serum complement components and plasma protease inhibitors increased to nearly normal value transiently.
In both cases, in vivo activation of complement could not be detected by immunoelectrophoretic tecnique. However, it is strongly suggested that complement activation may play a relatively important role in DIC, and thus serial examinations of complement may give a prognostic clue.

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Sixty-three patients with hematological malignancy who were admitted into the Department of Internal Medicine, Hirosaki University Hospital, from 1978 to 1979, were investigated. In the siwty-four courses of the concurrent infections gammaglobulin was administered intravenously, courses (59%) the treatment was effective. Gammaglobulin was rather ineffective in sepsis and perianal abscess which were complications of severe underlying diseases. Gammaglobulin was effective in the treatment of the febrile episodes of probable infection without positive blood culture. It was not so effective in eight out of nine elderly patients with pneumonia, which suggested their resistance to infection was low. During the therapeutic course in the hematological malignancies neutropenia was often induced, where gammaglobulin was effective in 57% of severe neutropenia below 100/μl. Lymphocyte count, serum immunoglobulin level and tuberculin reaction were examined, but there was no significant correlation between these data and efficiency of gammaglobulin. Gammaglobulin was more effective when administered within three days from the onset of the febrile episodes. In some cases where there was high risk of infection, preventive administration was given but further investigation is needed to eveluate the effects. No serious side effects of the gammaglobulin preparation were observed.

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While the antimicrobial capacity of the neutrophils has been extensively examined, the eosinophil has recently been received attention as an effective phagocyte, especially in patients with congenital neutropcnia.
We examined bactericidal properties and chemotaxis of eosinophils and compared with those of neutrophils. Eosinophils were obtained from a patient with hypereosinophilic syndrome and neutrophils were obtained from healthy adults.
The response of eosinophils in the chemotaxis to Staphylococcus aureus culture filtrates under agarose plate method was low compared with that of neutrophils. At bacteria/phagocytes ratio of 1:3∼4, eosinophils killed Staphylococcus aureus and Streptococcus faecalis as effectively as neutrophils, but at bacteria/phagocytes ratio of 1:2, eosinophils were observed to be less active in killing bacteria than neutrophils. Eosinophils showed a greater capacity in reducing NBT dye under resting conditions than neutrophils.
These findings suggested that eosinophil failed to protect the host from bacterial infection when neutrophil reserves were diminished.

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A 64-year-old female was admitted to our hospital in March, 1976, for evaluation of severe anemia and leukopenia. Hematological data on admission were as follows: RBC 2.07×10¹²/l, Hb 6.6 g/dl, Ht 19.5%, MCV 94 fl, MCH 31.9 pg, MCHC 34.0 g/dl, reticulocyte 3.2%, WBC 2.2×10⁹/l without abnormal cells, and platelets 200×10⁹/l. Serial bone marrow examinations showed erythroid hyperplasia associated with slight increase of plasma cells, a few of which were polynuclear. The karyotype of bone marrow cells was normal. Haptoglobin levels were always remarkably low, but hemolysis test on the peripheral red blood cells were within normal limits. An immunological study revealed high level of IgA (λ). Treatment with prednisolone and vitamin B₆ was disappointing for anemia and leukopenia. She gradually became pancytopenic and died of pulmonary infection in June, 1977. During her hospitalization there were no biochemical and hematological evidences indicative of sideroblastic anemia, multiple myeloma, or leukemia. The autopsy revealed hyperplastic marrow in sternal and femoral bones with slight extramedullary hematopoiesis in the spleen.
In this case a definite diagnosis was not made and the hematological improvement was not obtained. Though her hematological conditions were compatible with atypical aplastic anemia (Hasegawa), a diagnosis of refractory anemia with excess of blasts (Sultan) seems to be more suitable.
Pancytepenia with hyperplastic bone marrow and immunological abnormality in relation to hematopoietic dysplasia were discussed.

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A 27-year-old pregnant woman was admitted because of ankle edema and bleeding tendency of sudden onset at 27 weeks of gestation. On physical examination, her blood pressure was 168/108 mmHg and many purpuras were noted on her extensor side of extremities. Proteinuria (4.5 g/day) and microscopic hematuria were present. Red blood cell count was 250×10⁴/mm³, platelet count 1.7×10⁴/mm³, Hb 7.5 g/dl, Ht 25% and reticulocyte 4.5%. Serum Fe was 85 μg/dl. Direct and indirect Coombs' test were negative. Many fragmented red blood cells were noted on peripheral blood smear. With the presumptive diagnosis of microangiopathic hemolytic anemia associated with pre-eclampsia, she was treated by daily infusion of 10,000 U of heparin and 48,000 U of urokinase. Four hundred of fresh blood was transfused. Overt bleeding tendency, platelet count, severity of anemia and proteinuria responded only partially. After she had her pregnancy terminated by Caeasarian section at 29 weeks of gestation, she recovered completely. Renal biopsy performed five months after clinical recovery showed mild endocapillary proliferation with remarkable fibrin deposits along the capillary wall of glomeruli.
The authors suggest that the present case was pre-eclampsia with intravascular coagulation following microangiopathic hemolytic anemia. The fact that the heparin and urokinase appeared to improve the proteinuria and bleeding tendency in this patient suggests the usefulness of these drugs on such a condition.

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Two cases of T cell type tumor were reported. Case 1: A 54-year-old male was admitted to Nihon University Hospital because of general lymphadenopathy. From the histological examination of the left supraclavicular lymph node biopsy specimen, a diagnosis of malignant lymphoma (large lymphoid type) was made. The roentgenogram demonstrated a solid tumor with ulcer creator im the stomach. The diagnosis of malignant lymphoma was established by gastroscopic biopsies and cytologic study. In the examination of surface markers, E rosette forming cells were 26% in peripheral blood and 42% in lymph node cells, EAC rosette forming cells were 42% in peripheral blood and 58% in lymph node cells. These results suggested that tumor cells were of T cell origin with C₃ receptor. Case 2: A 72-year-old male was admitted to the hospital because of general lymphadenopathy and leukocytosis. On admission, tumor cells reached 69.5% of the leukocytes in the peripheral blood and 30.8% of the nucleated cells in the bone marrow. In the examination of suface markers, E rosette forming cells were 38% in peripheral blood and 59% in lymph node cells, EAC rosette forming cells were 8% in peripheral blood and 40.5% in lymph node cells. By acid phosphotase staining, a coarse granule was observed in the cytoplasm. Skin involvement was present. He was an inhabitant of Nagasaki district. These findings were considered to be similar in many respects to “adult T cell leukemia” described by Takatsuki et al.

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A 54 year-old man was admitted to the Toho university hospital because of general malaise in May 1976. On admission he had anemia, slight icterus and hepatosplenomegaly. Laboratory findings revealed severe anemia, thrombocytosis and reticulocytosis.
The leukocyte count was 10,000/mm³ with 12% myeloblasts, 0.5% promyelocytes, 2.0% myelocytes, 0.5% metamyelocytes, 6.0% band forms, 38.0% segmented neutrophils, 2.5% eosinophils, 15.5% basophils, 1.0% monocytes and 22.0% lymphocytes. Circulating nucleated red cells were also seen.
A bone marrow aspiration showed normocellularity but it revealed outstanding erythroid hyperplasia with atypical and megaloblastoid forms.
He was treated with prednisolone but on February 8 1977, hemoglobinemia occurred in him. A sugar water test, Ham test and Crosby test were all positive. In April 1977, he died of lung tuberculosis after 7 months from admission.
For this case, PNH occured during the course of erythroleukemia. This complication is rare but according to Dameshek, PNH is supposed to be a variant form of myeloproliferative disorders.
This was an interesting case in point of pathogenetic relationship between PNH and erythroleukemia.

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A 10-year-old girl with erythrocytosis is reported. She had occasional mild headache and nausea from three years old. Erythrocytosis was noticed at the age of ten when she first visited the outpatient clinic of the Pediatric Department of Hirosaki University because of upper respiratory infection. The routine laboratory studies showed red blood cell count of 755×10⁴/mm³, hemoglobin of 22.1 g/dl, and hematocrit of 70%. Erythropoietin activity in the plasma was found to be an upper limits of the normal control. But it rose twice at 24 hours after phlebotomy. Subsequent investigations failed to support the diagnosis such as polycythemia vera, secondary polycythemia due to hypoxia, ectopic erythropoietin production and abnormal hemoglobin. Although there was no evidence of erythrocytosis in the family, the findings in this patient appear to be those of a condition which has been called benign familial erythrocytosis. She has been followed for more than 6 years, but no complications has developed and is living in a healthy normal life.

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Two cases of purpura hyperglobulinemica were observed. The first case, 30-year-old female, presented purpura on the both lower extremities and diffuse swelling of the left parotid gland with normal salivary excretion. The second case, 27-year-old female, presented purpura on both legs after longtime standing. Both cases showed accelerated erythrocyte sedimentation rate, polyclonal hypergammaglobulinemia (31.4% and 36.4%), positive RA test and positive anti-platelet antibody by indirect Coombs' consumption test.
Besides, the second case revealed positive anti-nuclear factor (speckled pattern) and decrease of values of C₄ and C₃C, however, since renal biopsy disclosed no deposit of immunoglobulin nor complement, the diagnosis as SLE was excluded. Administration of prednisolone brought good clinical effects and reappearance of purpura was hardly seen even after provocation in both cases.
It would be suggested that purpura hyperglobulinemica is a prodromal or partial symptom of collagen disease, therefore, the careful follow-up study should be needed.

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The patient, 15-year-old boy, was reffered for evaluation of nasal and subcutaneous bleeding in August 1976. Idiopathic thrombocytopenic purpura (I.T.P) was diagnosed by thrombocytopenia, increased immature megakaryocytes in bone marrow and positive antiplatelet antibody. Prednisolone was administered without remarkable benefit.
About 2 years later, he gradually became pancytopenic with slightly increased myeloblasts in bone marrow, but immature cells were not detected in peripheral blood. Late in Octover 1978, acute myelomonocytic leukemia was diagnosed by hematological findings such as remarkably increased leukemic cells with abnormal chromosomal pattern in peripheral blood and bone marrow. Spleen and liver enlarged rapidly without administration of antileukemic agents. Late in February 1979, he died of fungal infection.
Autopsy findings showed bone marrow fibrosis, extramedullary hematopoiesis and leukemic infiltration in spleen and liver. This case was thought that his I.T.P like symptoms at clinical onset might be those of preleukemic stage and myelofibrosis progressed secondarily due to changes of hematopoietic microenvironment in its stage.

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A 28-year-old, married woman admitted because of severe anemia. She had passed dark urine twice since about a year. Sugar-water test and Ham's test were positive, and a diagnosed of paroxysmal nocturnal hemoglobinuria (PNH) was made and she was 16-weeks pregnant.
Washed red cells transfusions were repeated to keep Hb concentration of 7 g/dl or more. Outcome was successful gestation and labor, although edema was observed in the last trimester.
Pregnancy in the patients with PNH is rare and some accidents may occur during the period of pregnancy as well as in the puerperium. The decision to continue the pregnancy or not in such patients must be done carefully according to the severity of the disease in each case.

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A case of acute myelogenous leukemia, 27-year-old woman with increased activity of terminal deoxynucleotidyl transferase (TdT) in blast cells, is reported. Hematological examinations on admission revealed that WBC count of peripheral blood was 26,600/mm³ with 88.5% myeloblasts, and nucleated cell count of bone marrow was 355,000/mm³ with 77.2% myeloblasts. The blasts had a myeloid appearance with Auer rods on light microscopy, and were positive for peroxidase, and negative for PAS. TdT activity was 15.8 U/10⁹ cells, which was definitely high, compared with other 4 cases of AML (<0.1 U/10⁹ cells). Chemotherapy including vincristine and prednisolone was given, but it was not effective, and she died 9 months after admission. The significance of TdT activity in various types of leukemia is discussed.

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A pleomorphic adult Tγ-cell leukemia which showed many interesting manifestations including cellular morphological changes and immunological abnormalities was reported.
The patient was a 66-year-old man having lymphadenopathy, hepatosplenomegaly, pleural effusion and skin eruption. Leukemic cells in the peripheral blood possessed convoluted and lobulated nuclei, and in the pleural effusion had been transformed into blastoid cells, some of which simulated Hodgkin's cells or Reed-Sternberg's giant cells. These cells formed spontaneous rosettes with sheep erythrocytes and possessed IgG Fc receptor, but never had immunophagocytic function. Serum immunoglobulin levels were all depressed and unresponsiveness in several skin tests suggested decreased cell-mediated immunity as well. According to these results, leukemic cells were considered Tγ-cells with suppressor activity. The histological appearance of lymphnode specimen was highly pleomorphic, similar to that of reticulum cell sarcoma. The histological examination of the skin lesion revealed mild infiltration of leukemic cells into the upper dermis and formation of Pautrier's microabscess in the epidermis.
The patient was treated with prednisolone, cyclophosphamide and 6-MP, but finally died of pulmonary candidiasis on the 62nd hospital day.

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