Anemia and impaired stress-induced erythropoiesis in aceruloplasminemic mice

Ceruloplasmin (Cp) is an abundant, copper-containing plasma protein with an important role in iron homeostasis. Patients with hereditary Cp deficiency have iron deposits in liver and other organs, consistent with impaired iron flux. The mild anemia reported in some patients suggests a possible role for Cp in iron delivery to red cell precursors during erythropoiesis. To investigate this function of Cp, we determined the hematologic parameters in Cp-deficient mice under normal conditions and after erythropoiesis-inducing stress. Cp(-/-) mice have below normal hematocrit, red cell hemoglobin and volume, and serum iron. Red cell number and turnover and reticulocyte counts were identical in Cp(-/-) and Cp(+/+) mice. Thus, Cp(-/-) have mild microcytic, hypochromic anemia consistent with normal red cell formation but defective iron availability. Cp(-/-) and Cp(+/+) mice subjected to phenylhydrazine-induced hemolytic anemia exhibited identical decreases in hematologic parameters, but Cp(-/-) mice showed diminished recovery after removal of the stress. Administration of purified human Cp or iron-saturated transferrin to Cp(-/-) mice partially restored hemoglobin formation in reticulocytes. The mild anemia in Cp(-/-) mice and the diminished response to stress may reflect inefficient recycling of iron between the reticuloendothelial and erythropoietic systems. Our findings suggest a role for Cp in erythropoiesis by providing sufficient iron to the erythroid tissue and that the requirement for Cp is raised after erythropoietic stress.     

Congenital dyserythropoietic anemia type II: epidemiology,clinical appearance,and prognosis based on long-term observation

Congenital dyserythropoietic anemia type II (CDA II) is the most frequent type of congenital dyserythropoietic anemia. More than 200 cases have been described, but with the exception of a report by the International CDA II Registry, these reports include only small numbers of cases and no data on the lifetime evolution of the disease. Since 1967, we were able to follow 48 cases of CDA II from 43 families for up to 35 years. All patients exhibit chronic anemia of variable severity requiring regular red cell transfusions only in a minority of children; 60% developed gallstones before the age of 30 years, and 16 patients had cholecystectomy between 8 and 34 years of age. Iron overload was a frequent complication. In 16 cases, iron depletion started between 7 and 36 years. Three patients died from secondary hemochromatosis. Splenectomy, performed in 22 cases, led to moderate increases in hemoglobin values and eliminated the need for transfusions but did not prevent further iron loading. The current recommendation is to consider splenectomy if the anemia compromises patients' performance, and to manage iron overload according to the guidelines derived from patients with thalassemia.     

Erythroid progenitors in anemic Belgrade laboratory (b/b) rats

The anemia of Belgrade b/b rats has been shown to be due to intracellular iron deficiency. The aim of this study of erythropoiesis at the progenitor cell level in these rats was to determine if a defect is present in the early phase of red cell production. Both erythroid colony-forming unit (CFU-E)- and erythroid burst-forming unit (BFU-E)-derived colonies were found to be few in untreated b/b rats and made up of a small number of poorly hemoglobinized erythroblasts of different size and irregular cell shape. Following treatment with iron, the anemia of the rats improved, and the number of CFU-E-derived colonies and the number of cells per colony increased, but the peculiar erythroblast morphology persisted. The high serum level of biologically active erythropoietin (Ep) in b/b rats rules out inadequate Ep production as a cause of their anemia. The results presented indicate, in addition to the earlier described defective transmembrane iron transport, a defect in erythroid progenitor cells. The effect of iron treatment in these rats detected in vitro on erythroid progenitors confirms the importance of iron for cellular proliferation.     

Diagnosing anemia in inflammatory bowel disease: Beyond the established markers

The main types of anemia in inflammatory bowel disease (IBD) are iron deficiency anemia (IDA) and anemia of inflammatory etiology, or anemia of chronic disease (ACD). In the management of IBD patients with anemia it is essential for the physician to diagnose the type of anemia in order to decide in an evidence-based manner for the appropriate treatment. However, the assessment of iron status in IBD in many cases is rather difficult due to coexistent inflammation. For this assessment several indices and markers have been suggested. Ferritin, seems to play a central role in the definition and diagnosis of anemia in IBD and transferrin, transferrin saturation (Tsat), and soluble transferrin receptors are also valuable markers. All these biochemical markers have several limitations because they are not consistently reliable indices, since they are influenced by factors other than changes in iron balance. In this review, in addition to them, we discuss the newer alternative markers for iron status that may be useful when serum ferritin and Tsat are not sufficient. The iron metabolism regulators, hepcidin and prohepcidin, are still under investigation in IBD. Erythrocytes parameters like the red cell distribution width (RDW) and the percentage of hypochromic red cells as well as reticulocyte parameters such as hemoglobin concentration of reticulocytes, red blood cell size factor and reticulocyte distribution width could be useful markers for the evaluation of anemia in IBD.     

The anemia of the Di Guglielmo syndrome

The physiopathology of the anemia of the Di Guglielmo syndrome (erythremic myelosis) was studied in 11 patients with the acute and chronic varieties of the disease. Ferrokinetic studies were performed in three additionalpatients.

1. The anemia was normochromic and macrocytic; in contrast to the meancorpuscular volume, which was elevated, the mean corpuscular hemoglobinwas often normal. In several patients the mean corpuscular hemoglobin concentration was slightly lower than normal, suggesting slight hypochromia.

2. Reticulocytes were often increased but bore no relationship to the degree of the anemia nor to the shortening of the red cell life span. The reticulocyte count is an unreliable index of blood production in this disease.

3. The degree of erythroblastemia was highly variable. No direct correlation existed between the degree of erythroblastemia and the acuteness of thedisease, nor was there any relationship between the degree of erythroblastemiaand either the degree of anemia or the degree of erythrocytic destruction.

4. The bone marrow showed striking erythroblastic hyperplasia. This wasusually of the megaloblastic type. Primitive erythroblasts (erythrogones) wereconspicuous. The erythroblastic hyperplasia was out of proportion to the relatively minor reticulocytosis or the relatively slight diminution in red cellsurvival.

5. The nucleated red cells of the marrow showed variable numbers ofmegaloblasts and megaloblastoid forms, suggesting the presence of a vitaminB₁₂ deficiency (pernicious anemia). However, the vitamin B₁₂ concentrationof the serum was elevated, and there was no response to the administrationof vitamin B₁₂ or folic acid.

6. Varying numbers of erythroblasts in the bone marrow and in the peripheral blood showed periodic acid-Schiff (PAS)-positive granules in the cytoplasm. No chemical abnormalities of hemoglobin could be detected either bythe method of paper electrophoresis or by the alkali denaturation test.

7. Diminished red cell survival was present in most cases, but it was of arelatively slight degree. It was due to an "intracorpuscular" defect of the redcells.

8. The often great increase in fecal urobilinogen output as compared witha relatively minor rate of red cell destruction suggests "heme pigment diversion" or increased destruction of precursor red cells, as in pernicious anemia,where the same phenomenon has been observed.

9. The great increase in the number of erythroid cells in the bone marrowand the increased rate of iron turnover as compared with the relatively minorincrease in red cell destruction and iron utilization point to an "ineffective"type of erythropoiesis. The high degree of "ineffective erythropoiesis" seenin this disease may be characteristic of the neoplastic proliferation of the redcell series.

10. In conclusion, the anemia of the Di Guglielmo syndrome is due to acombined disturbance: (1) an "ineffective" type of erythropoiesis of markeddegree, perhaps due to an acquired (neoplastic) defect in the uptake or utilization of B₁₂ by the erythroblasts and (2) increased hemolysis resulting fromthe increased destruction of defective red cells.

Submitted on June 11, 1958 Accepted on August 13, 1958     

Abnormal megakaryocytopoiesis in the Belgrade laboratory rat

The Belgrade laboratory rat (b/b rat) has hereditary, hypochromic, microcytic anemia with a variety of red cell abnormalities. Although this anemic syndrome has been recently ascribed to the defective delivery of iron to the developing red cell, the basic hematopoietic defect is still unknown. In this article we present evidence that the b/b rat has an additional hematologic defect. We have found that the megakaryocyte number in the marrow of the b/b rat is decreased to one half that of the normal rat, but the maturation rate of recognizable megakaryocytes is accelerated and the size is increased. The platelet count is moderately reduced. These findings indicate that megakaryocytopoiesis in the anemic b/b rat is abnormal and suggest that the genetic defect may involve the progenitors of the megakaryocyte cell lineage. Alternatively, the megakaryocytic abnormalities may be secondary to the severe anemia.     

Excess Hemolysis in Subjects with Severe Iron Deficiency Anemia Associated and Nonassociated with Hookworm Infection

An excess hemolysis was found in subjects with iron deficiency anemia associated with hookworm infection. Red cell survival, measured with Cr⁵¹ andDFP³² in the subjects before deworming, showed a marked disproportionbetween the decrease of the survival and the amount of daily intestinal bloodloss in most cases. Excess of hemolysis was still present after more than 90 percent of the parasites were removed. Red cell survival became normal aftercorrection of anemia through iron treatment. Excess of hemolysis was alsopresent in noninfected subjects with iron deficiency anemia due to othercauses.

The reduction in the survival of the erythrocytes from infected subjectstransfused into normal recipients shows that the hemolytic process is due toan intrinsic defect of the red cells. The low values of hemoglobinemia andthe presence of haptoglobins in the plasma indicate that hemoglobin has notbeen liberated in excess intravascularly. Finally, the fact that the red cellsfrom an infected patient taken after deworming survived normally in splenectomized recipients indicates that the spleen is probably the principal siteof the red cell destruction. The clinical and autopsy findings suggest thatsplenic function is not pathologically increased, but rather that this organ isacting physiologically at a more rapid rate, "culling" the abnormal circulatingred cells and thus leading to a decrease in red cell survival.

The studies presented here also indicate that the hookworm infection perse does not induce hemolysis.

Submitted on January 13, 1964 Accepted on April 24, 1964     

Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload

Divalent metal transporter 1 (DMT1) is a transmembrane protein crucial for duodenal iron absorption and erythroid iron transport. DMT1 function has been elucidated largely in studies of the mk mouse and the Belgrade rat, which have an identical single nucleotide mutation of this gene that affects protein processing, stability, and function. These animals exhibit hypochromic microcytic anemia due to impaired intestinal iron absorption, and defective iron utilization in red cell precursors. We report here the first human mutation of DMT1 identified in a female with severe hypochromic microcytic anemia and iron overload. This homozygous mutation in the ultimate nucleotide of exon 12 codes for a conservative E399D amino acid substitution; however, its pre-dominant effect is preferential skipping of exon 12 during processing of pre-messenger RNA (mRNA). The lack of full-length mRNA would predict deficient iron absorption in the intestine and deficient iron utilization in erythroid precursors; however, unlike the animal models of DMT1 mutation, the patient is iron overloaded. This does not appear to be due to up-regulation of total DMT1 mRNA. DMT1 protein is easily detectable by immunoblotting in the patient's duodenum, but it is unclear whether the protein is properly processed or targeted.     

The Anaemia of Chronic Disorders: Studies of Iron Reutilization in the Anaemia of Experimental Malignancy and Chronic Inflammation

The purpose of this study was to evaluate the contribution of defective reutilization of iron in the pathogenesis of the anaemia of chronic disease (ACD). Normal rats with or without splenectomy and rats with Walker 256 carcinosarcoma with or without splenectomy were studied. The reutilization of ⁵⁹Fe labelled heat-damaged red cells (⁵⁹Fe DRBC), the sequestration of ⁵⁹Fe DRBC in major organs, red cell mass, ⁵¹Cr red cell survival, serum iron, plasma erythropoietin and routine haematological parameters were measured.
Three weeks after tumour implantation in rats a moderate degree of anaemia was noted. The maximum ⁵⁹Fe reutilization in the tumour group and tumour with splenectomy group (63 ± 6% and 56 ± 9%, respectively) was not significantly different than observed in the normal group (64 ± 6%) or normal with splenectomy group (53 ± 7%). Excessive iron sequestration in liver and spleen was not observed in animals with cancer. Red cell survival in the tumour group was slightly decreased as compared to normal. Plasma erythropoietin levels were appropriately increased for the degree of anaemia in rats with cancer. This type of experiment was repeated in a second group of anaemic animals with turpentine induced abscesses. Reutilization of ⁵⁹Fe DRBC in rats with inflammation was normal.
These results indicate that adult rats with anaemia of malignancy or chronic inflammation do not have a decreased reutilization of red cell iron. Thus RE blockade of iron is not a major factor in anaemia of chronic disease in this experimental model. Furthermore, these experiments confirm the importance of decreased red cell production in the anaemia of malignancy.     

A Local Equation for Differential Diagnosis of β-Thalassemia Trait and Iron Deficiency Anemia by Logistic Regression Analysis in Southeast Iran

The most common differential diagnosis of β-thalassemia (β-thal) trait is iron deficiency anemia. Several red blood cell equations were introduced during different studies for differential diagnosis between β-thal trait and iron deficiency anemia. Due to genetic variations in different regions, these equations cannot be useful in all population. The aim of this study was to determine a native equation with high accuracy for differential diagnosis of β-thal trait and iron deficiency anemia for the Sistan and Baluchestan population by logistic regression analysis. We selected 77 iron deficiency anemia and 100 β-thal trait cases. We used binary logistic regression analysis and determined best equations for probability prediction of β-thal trait against iron deficiency anemia in our population. We compared diagnostic values and receiver operative characteristic (ROC) curve related to this equation and another 10 published equations in discriminating β-thal trait and iron deficiency anemia. The binary logistic regression analysis determined the best equation for best probability prediction of β-thal trait against iron deficiency anemia with area under curve (AUC) 0.998. Based on ROC curves and AUC, Green & King, England & Frazer, and then Sirdah indices, respectively, had the most accuracy after our equation. We suggest that to get the best equation and cut-off in each region, one needs to evaluate specific information of each region, specifically in areas where populations are homogeneous, to provide a specific formula for differentiating between β-thal trait and iron deficiency anemia.     

Hookworm Anemia: Iron Metabolism and Erythrokinetics

Iron metabolism, balance of red cell production and destruction and ironabsorption from hemoglobin were determined in 11 patients with heavy hookworm infection and severe anemia.

The plasma iron, total iron binding capacity, bone marrow hemosiderinand plasma Fe⁵⁹ clearance are in agreement with the idea that the anemia associated with hookworm infection is of the iron deficiency type.

The rate of red cell production measured by the E/M ratio, absolute reticulocyte count and plasma iron turnover showed an increase to about twicenormal, while the rate of destruction estimated by the T erythrocytesurvival showed a destruction about 5 times normal. This unbalance betweenproduction and destruction could explain the severity of the anemia.

The increase of fecal urobilinogen output to twice normal was interpretedas due to the metabolism of the hemoglobin lost into the intestine rather than toan increase of hemolysis.

The estimation of fecal blood loss in the patients whose red cells weretagged with Cr⁵¹ and Fe⁵⁹, showed that the radioactivity counted with Fe⁵⁹was only about 63 per cent of the radioactivity counted with Cr⁵¹. This difference was interpreted as due to iron absorption from the hemoglobin lostinto the intestine.

The mean daily fecal excretion of iron reaches 4.7 mg. Since the ironmetabolism in these patients is in equilibrium, we have concluded that theiron loss is replaced by the iron from food; this is in addition to the 3 mg.hemoglobin iron which is reabsorbed from the blood lost into the gut.

Submitted on January 9, 1961 Accepted on April 2, 1961     

Studies on abnormal hemoglobins. V. The distribution of type S,sickle cell,hemoglobin and type F,alkali resistant,hemoglobin within the red cell population in sickle cell anemia

1. By transfusing sickle cell anemia erythrocytes with a relatively high concentration of F hemoglobin into normal recipients, it was demonstrated that thedisappearance rates of the transfused cells and of their alkali resistant pigmentconsistently showed great discrepancies. These observations suggest an unequaldistribution of the F pigment within the erythrocyte population. A nonuniformdistribution of F hemoglobin could also be detected in vitro by exposing sicklecell anemia bloods to mechanical trauma for a longer period of time. The cellsmost resistant to trauma contained a higher percentage of F hemoglobin thanthe original blood specimen.

2. The red cell population of patients with sickle cell anemia seems to be composed of three main fractions: (1) cells containing S hemoglobin and no or littleF hemoglobin, (2) cells containing both pigments and (3) cells containing Fpigment with no or little S hemoglobin.

3. The erythrocytes carrying mostly S hemoglobin have the shortest life span,whereas the red cells containing mostly F hemoglobin have the longest survivaltime.

4. The significance of these findings in regard to clinical and genetic aspectsof sickle cell anemia is discussed. No direct correlation is demonstrable in anindividual patient between the absolute amounts of either type S or type Fhemoglobin and the severity of the anemia. The latter depends on the variablesize of the portion of red cells containing mostly S hemoglobin, and also on theability of the marrow to replace this particular fraction.

Submitted on August 5, 1952 Accepted on September 10, 1952     

Evaluation of Applying a Combination of Red Cell Indexes and Formulas to Differentiate β-Thalassemia Trait from Iron Deficiency Anemia in the Thai Population

Red cell indexes and formulas have been established as simple, fast, and inexpensive tools to differentiate β-thalassemia (β-thal) trait from iron deficiency anemia. However, none of them showed 100.0% sensitivity and specificity. Moreover, one index may show greater sensitivity and specificity in one population but is ineffective in another population. This study evaluated the diagnostic reliability of a combination of two red cell indexes [red blood cell (RBC) and red blood cell distribution width (RDW)] and nine formulas called ‘11T score’ for differentiation of β-thal trait and iron deficiency anemia in the Thai population. A total of 103 cases, 67 β-thal trait and 36 iron deficiency anemia, Thai subjects with microcytic hypochromic anemia [mean corpuscular volume (MCV) <80.0?fL and mean corpuscular hemoglobin (Hb) (MCH) <27.0?pg] were involved in this retrospective study. The results showed that the 11T score with a cutoff value of 7 was able to discriminate between β-thal trait and iron deficiency anemia with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and efficiency (EFF) higher than 70.0%. It also had 85.4% of correctly identified cases and the highest value of Youden’s Index (YI) (73.8%) when compared to the 11T score with other cutoff values (5, 6, 8 and 9) and other indexes. Thus, the 11T score with the cutoff value of 7 could be used to differentiate β-thal trait from iron deficiency anemia in the Thai population.     

Iron Metabolism and “Sports Anemia”

Abstract Several reports have suggested that iron deficiency might explain “sports anemia” especially in long distance runners. The present study was made to further study the iron metabolism in runners as the proposed cause of “sports anemia” is abstruse considering the good iron nutrition in these athletes. Based on a screening of 43 elite male runners, using bone marrow hemosiderin, serum ferritin and transferrin saturation, two groups of subjects were selected for a very extensive study on iron metabolism. In group 1 (n=5) iron depletion was suggested in at least one of the screening studies. In group 2 (n=7) at least one test strongly indicated good iron repletion. This experimental design was chosen to obtain two groups with similar body composition and exercise load but different iron metabolism. The studies comprised determinations of red cell and plasma volumes, plasma iron turnover and red cell incorporation of radioiron, red cell indices, plasma iron and transferrin, red cell protoporphyrin, serum ferritin, serum haptoglobin, urinary iron losses, iron absorption, bone marrow hemosiderin, dietary intake of energy and nutrients and a Desferal test. Pooling the results together it was obvious that none of the subjects were truly iron-deficient. A few occasional findings suggesting low iron stores cannot be satisfactorily explained and indicate that further studies are needed     

Autoimmune gastritis in type 1 diabetes: a clinically oriented review

CONTEXT: Autoimmune gastritis and pernicious anemia are common autoimmune disorders, being present in up to 2% of the general population. In patients with type 1 diabetes or autoimmune thyroid disease, the prevalence is 3- to 5-fold increased. This review addresses the epidemiology, pathogenesis, diagnosis, clinical consequences, and management of autoimmune gastritis in type 1 diabetic patients. SYNTHESIS: Autoimmune gastritis is characterized by: 1) atrophy of the corpus and fundus; 2) autoantibodies to the parietal cell and to intrinsic factor; 3) achlorhydria; 4) iron deficiency anemia; 5) hypergastrinemia; 6) pernicious anemia may result from vitamin B12 deficiency; and 7) in up to 10% of patients, autoimmune gastritis may predispose to gastric carcinoid tumors or adenocarcinomas. This provides a strong rationale for screening, early diagnosis, and treatment. The management of patients with autoimmune gastritis implies yearly determination of gastrin, iron, vitamin B12 levels, and a complete blood count. Iron or vitamin B12 should be supplemented in patients with iron deficiency or pernicious anemia. Whether regular gastroscopic surveillance, including biopsies, is needed in patients with autoimmune gastritis/pernicious anemia is controversial. The gastric carcinoids that occur in these patients generally do not pose a great threat to life, whereas the danger of developing carcinoma is controversial. Nevertheless, awaiting a consensus statement, we suggest performing gastroscopy and biopsy at least once in patients with autoantibodies to the parietal cell, iron-, or vitamin B12-deficiency anemia, or high gastrin levels. CONCLUSION: The high prevalence of autoimmune gastritis in type 1 diabetic patients and its possible adverse impact on the health of the patient provide a strong rationale for screening, early diagnosis, periodic surveillance by gastroscopy, and treatment.     

Erythropoiesis during recovery from macrocytic anemia: macrocytes, normocytes, and microcytes

In seven patients with marked megaloblastic anemia (MCV greater than 110 fl), red cell size distribution curves (erythrograms) demonstrated the size of red cells produced after therapy. In six, the new red cells were normocytic throughout recovery. In the seventh patient, folate repletion along produced a new population of microcytes, due to unsuspected iron deficiency; after iron repletion normocytes were produced. Three patients with autoimmune hemolytic anemia had macrocytosis (MCV greater than 110 fl) without folate or vitamin B12 deficiency. During recovery with predisone therapy, instead of a discrete new normocytic population appearing, the entire population progressively returned to normal size. Normal rather than "stress" reticulocytes, and remodeled stress reticulocytes remaining, may explain this different pattern of recovery. Two patients initially had minor subpopulations of smaller red cells that disappeared soon after therapy. These probably reflected the dyserythropoiesis of severe megaloblastic anemia.     

Anemia and iron status of Malay women attending an antenatal clinic in Kubang Kerian, Kelantan, Malaysia

The purpose of this study was to detect the frequency of iron deficiency anemia in women attending their first antenatal clinic at a Maternal and Child Health Clinic in Kubang Kerian, a district of Kelantan that is located on the East coast of Malaysia. A cross-sectional study was done over a two-month period and fifty-two Malay women were enrolled in this study. Red blood cell indices and serum ferritin were used as a screening tool for anemia and iron status. Eighteen patients (34.6%) were anemic. The majority were classified as having mild anemia (90%). Four of them had hypochromic microcytic anemia. Of 52 women, 7 had iron deficient erythropoiesis and 11 (61.1%) had iron deficient anemia. The prevalence of iron deficiency anemia in pregnant women was 21.2%, which is similar to other developing countries. The serum ferritin level was significantly associated with the hemoglobin level (p=0.003). Other red blood cell indices were not useful in predicting iron deficient erythropoiesis. It is important to detect iron deficient erythropoiesis during the first antenatal check-up, as it is an early manifestation of iron deficiency anemia. In conclusion, screening for iron deficient is recommended during first antenatal visit because iron deficiency anemia is still the leading cause of nutritional deficiency in pregnant women. This will initiate an early therapeutic intervention so as to reduce public health problem.     

Erythrokinetics: quantitative measurements of red cell production and destruction in normal subjects and patients with anemia

Red cell turnover of 19 normal subjects and 25 anemic patients was measuredwith the following technique: erythroid-myeloid ratio of the marrow, reticulocytecounts, plasma iron turnover, red cell utilization of radioiron, and urobilinogendeterminations. Measurements of blood production and destruction were so expressed as to allow comparison between normal and anemic individuals of different size and different red cell mass. The usefulness and disadvantages of eachprocedure in the study of anemia are discussed.

From studies of various types of anemia, it has become apparent that erythropoiesis must be defined in terms of total quantity of red cells produced and interms of the portion of red cells produced in the marrow which are delivered tothe circulating blood (effective versus ineffective erythropoiesis). A quantitativedefect alone exists when a normal ratio is maintained between effective andtotal erythropoiesis. Here, there are changes of similar magnitude of all erythrokinetic indices, although reticulocyte and urobilinogen values are occasionallydisproportionately high. The normal marrow appears to be able to increase itseffective red cell production to three times normal in acute anemia and six timesnormal in chronic anemia. In many disease states this maximal quantitativeresponse is impaired.

Dyspoiesis of the marrow is characterized by a dissociation of erythrokineticindices. Values which reflect total erythropoiesis (i.e., plasma iron turnover,fecal urobilinogen and erythroid-myeloid ratio of the marrow) are considerablygreater than the reticulocyte level and red cell utilization of radioiron whichrepresent effective erythropoiesis. Such defects may result in the pattern of ahemolytic process or aregenerative anemia, depending on their severity.

Submitted on October 26, 1955 Accepted on December 7, 1955     

Treatment of primary defective iron-reutilization syndrome: revisited

 We encountered two patients who presented with hypochromic–microcytic anemia and were refractory to iron therapy. The symptoms were suggestive of anemia of chronic disease (ACD); however, there was no evidence of any such disease, either inflammatory or malignant. These patients were reminiscent of patients originally described as having primary defective iron reutilization. The hematologic picture consisted of hypochromic–microcytic anemia, low serum iron, low to normal iron binding capacity, high serum ferritin, and increased bone marrow iron in the absence of ringed sideroblasts. These patients had symptomatic anemia and received danazol (200 mg orally) three times per day to which they responded very well with an increase of approximately 3 g in the hemoglobin concentration over 1 year and amelioration of their symptoms. Danazol was well tolerated and did not cause any virilizing side effects. Doses were lowered in maintenance after 1 year to 200 mg once per week, and responses were sustained up to 36 months of follow-up duration. In the differential diagnosis of hypochromic–microcytic anemia, especially in postmenopausal women, one has to consider this type of treatable anemia when more common types such as iron deficiency, chronic inflammation, malignancy, sideroblastic anemia, or thalassemia have been ruled out. Received: 16 June 1999 / Accepted: 1 February 2000     

Hypothyroidism in adults with sickle cell anemia.

Persons with sickle cell anemia have several indications for transfusion of red blood cells. One of the complications of transfusion of red blood cells is iron overload. Iron overload has been associated with multiple endocrine abnormalities. We report herein three cases of hypothyroidism in adult individuals with sickle cell disease. All three patients were over the age of 45 years at the time of the diagnosis and had received multiple units of transfused red blood cells and had serum ferritin levels of greater than 6,000 ng/mL. All patients were diagnosed during times when they were critically ill. Replacement therapy was instituted in all cases; however, all three patients died shortly after the diagnosis of hypothyroidism was made. Congestive heart failure appeared to be a primary cause of death in all three patients. In the one patient in whom a postmortem examination was done, there was evident extensive fibrosis of the thyroid gland as well as extensive deposition of iron in the cells lining the thyroid follicles. We believe that this represents the first report of clinical hypothyroidism in patients with sickle cell anemia who have received multiple transfusions. Awareness of this condition is especially important given that congestive heart failure is common in sickle cell disease.