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The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia of varying severity and the presence of ring sideroblasts in the bone marrow.

The International Working Group on Morphology of Myelodysplastic Syndrome IWGM-MDS recommended that ring sideroblasts be defined as erythroblasts in which there are a minimum of five siderotic granules covering at least one third of the circumference of the nucleus. These latter are normal erythroblasts that, after Prussian blue staining, show a few blue granules scattered in the cytoplasm, representing endosomes filled with excess iron not utilized for heme synthesis siderosomes.

While the iron of ferritin sideroblasts is stored in cytosolic ferritin, whose subunits are encoded by the FTH1 and FTL genes, the iron of ring sideroblasts is stored in mitochondrial ferritin, encoded by the FTMT gene.

The sideroblastic anemias include both hereditary and acquired conditions, and the main disorders are reported in Table 1. Representative peripheral blood and bone marrow smears from a patient with X-linked sideroblastic anemia XLSA and a patient with refractory anemia with ring sideroblasts RARS are shown in Figures 1 and 2respectively.

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Indeed in some developing countries where health care and facilities are limited there may be little alternative. Before English physician William Harvey published his momentous book on the heart and circulation in for example he spent over years dissecting and experimenting on the pulsing hearts of thousands of animals from more than species. If there is low or intermediate probability clinical suspicion determines the next step.

Representative peripheral blood and bone marrow smears from a patient with X-linked sideroblastic anemia. A Peripheral blood smear showing many hypochromic and microcytic cells. B Bone marrow smear showing erythroid hyper plasia: C Bone marrow smear showing erythroblasts with defective hemoglobinization left and erythroblasts containing multiple Pappenheimer bodies right.

D Bone marrow smear. The management of XLSA involves not only treatment of anemia, but also prevention and treatment of iron overload, family studies to identify additional at-risk individuals, and genetic counseling. Patients affected with other inherited forms of sideroblastic anemia are not responsive to pyridoxine, and the molecular basis of these autosomal recessive disorders has been clarified only recently. The phenotype of this patient resembled that of the shiraz zebrafish, a mutant resulting from a large deletion encompassing the GLRX5 gene.

GLRX5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. Two years ago, Guernsey et al. The data available were inconsistent with an X-linked recessive inheritance, while the families derived from a local subpopulation isolate, consistent with a possible genetic founder effect.

A single nucleotide polymorphism-based genome-wide scan performed in individuals belonging to these families led to the identification of SLC25A38 as the mutant gene responsible for this type of autosomal recessive pyridoxine-refractory sideroblastic anemia.

SLC25A38 encodes the erythroid specific mitochondrial carrier protein, which is important for the biosynthesis of heme in eukaryotes.

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Representative peripheral blood and bone marrow smears from a patient with refractory anemia with ring sideroblasts. Peripheral blood smear showing dimorphic red cells with a population of macrocytes and a population of hypochromic microcytes. B Bone marrow smear showing a marked erythroid hyperplasia with megaloblastoid features. The rare granulocytic cells look normal.

Upper right, a late erythroblast with defective hemoglobinization; lower right, an early erythroblast with vacuolated cytoplasm and a late erythroblast with Pappenheimer bodies. Mitochondrial ferritin is detected in granules surrounding the nucleus. Immunoalkaline phosphatase reaction, MGG x Following the identification of mutant SLC25A38 as a novel cause of inherited sideroblastic anemia, Bergmann et al.

In this issue of the journal, Kannengiesser et al.

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Eleven patients of several different ancestral origins carried SLC25A38 mutations: All patients required blood transfusions that inevitably became regular within the first few years of life. Two patients underwent allogeneic stem cell transplantation with complete correction of anemia.

Since the clinical course of congenital sideroblastic anemia associated with SLC25A38 mutations is very similar to that of thalassemia major, conservative therapy includes regular red cell transfusion and iron chelation.

However, as in thalassemia major, allogeneic stem cell transplantation represents the only curative therapy at present, and should, therefore, be considered for young patients with this congenital sideroblastic anemia. What are the implications of recent advances in our understanding of the molecular basis of congenital sideroblastic anemia for the acquired forms, i.

However, a few studies of X-chromosome inactivation patterns performed in female patients have suggested that RARS derives from the clonal proliferation of a multipotent hematopoietic stem cell with the potential for myeloid and lymphoid differentiation.

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  • The sideroblastic anemias include both hereditary and acquired conditions, and the main disorders are reported in Table 1. Representative peripheral blood and bone marrow smears from a patient with X-linked sideroblastic anemia (XLSA) and a patient with refractory anemia with ring sideroblasts (RARS) are shown in.
  • 18 Nov In some instances, both the synthesis of heme and the incorporation of iron can be altered, and the result is a porphyria with sideroblasts (eg, erythropoietic protoporphyria). Sideroblastic anemia is primarily a laboratory diagnosis, made on the basis of bone-marrow examination with Prussian blue stain.
  • 18 Nov Workup may include a complete blood count (CBC), peripheral smear, iron studies (eg, ferritin and total iron-binding capacity [TIBC]), bone marrow aspiration and biopsy, and other studies as appropriate. Next: Complete Blood Cell Count and Peripheral Smear.
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Unfortunately none of the candidate genes, i. Thus, the available evidence suggests that the clonal hematopoiesis of RARS and RARS-T is associated with abnormal expression of several genes of heme synthesis and mitochondrial iron processing. Identifying the somatic mutation s that can be responsible for these abnormalities represents the current challenge in this field. The two most common forms of congenital sideroblastic anemia, i. Overall, XLSA is a benign disorder that generally responds to pyridoxine with substantial amelioration of anemia; prevention and treatment of iron overload is also important and can be generally achieved through phlebotomy.

By contrast, the congenital autosomal recessive congenital sideroblastic anemia due to SLC25A38 mutations is a severe disease, not responsive to pyridoxine and with a clinical course very similar to that of thalassemia major: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

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Ring sideroblasts and sideroblastic anemias. Mario CazzolaRosangela Invernizzi. Haematologica June Classification of sideroblastic anemias The sideroblastic anemias include both hereditary and acquired conditions, and the main disorders are reported in Table 1.

View inline View popup Download powerpoint. Classification of congenital and acquired sideroblastic anemias. Refractory anemia with ring sideroblasts What are the implications of recent advances in our understanding of the molecular basis of congenital sideroblastic anemia for the acquired forms, i. Conclusions The two most common forms of congenital sideroblastic anemia, i.

Missense mutations in the erythroid delta-aminolevulinate synthase ALAS2 gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest 96 4: J Clin Invest 5: Nat Genet 41 6: Pediatr Blood Cancer 54 2: IARCLyonpp 88 — J Clin Oncol 23 Br J Haematol 6: Vol 96 Issue 6.

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Lab Values In Anemia - Iron Deficiency, Chronic Disease, Hemochromatosis & Pregnancy

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Alert me when this article is cited Alert me if a correction is posted. Jump To Article Ring sideroblasts Classification of sideroblastic anemias X-linked versus autosomal recessive congenital sideroblastic anemias Refractory anemia with ring sideroblasts Conclusions Footnotes References. How we diagnose neutropenia in the adult and elderly patient. Age and aging in blood disorders: Show more Editorials and Perspectives.

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  1. The X-linked hereditary sideroblastic anemias result from mutations in the gene encoding ALA-S. Isoniazide, a drug used to treat Mycobacterium tuberculosis .. The blood smear sometimes reveals basophilic stippling, hypochromia and microcytosis, although normocytosis and macrocytosis are possible, particularly in.:
    Sideroblastic anemia or sideroachrestic anemia is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells ( erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need in order to transport oxygen. Sideroblastic anemia occurs due to defects in heme synthesis pathway. In addition, defects in iron sulfur pathways or other important pathways in the mitochondria of erythroblasts, which indirectly impair heme production, are responsible for pathogenesis of sideroblastic anemia. A result of these abnormalities is decreased. 21 Jun The sideroblastic anemias comprise a wide spectrum of relatively uncommon heritable and acquired erythropoietic disorders that are due to various abnormalities in heme synthesis and mitochondrial function ().In many of these disorders, the severity o.
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Most automated instruments cannot make this distinction. Hence, a blood smear is still advised for validation. A blood smear is particularly important in the diagnosis of acute hemolysis induced by oxidant damage. These irregularly contracted cells share with spherocytes the lack of central pallor but differ in that they have an irregular outline. Oxidant-induced hemolysis is most often seen in glucosephosphate dehydrogenase G6PD deficiency but can also occur with other defects in the pentose shunt or in glutathione synthesis and when oxidant exposure overwhelms normal protective mechanisms.

Oxidant damage may be exogenous, as in exposure to oxidant chemicals or drugs most often dapsone , or endogenous, as in Wilson's disease. G6PD deficiency affects millions of persons worldwide. A blood smear is important for the diagnosis of this condition, for two reasons.

First, it is available far more rapidly than are the results of a G6PD assay and, when considered together with the patient's ethnic origin and clinical history, permits a provisional diagnosis. First, men of African or African-American ancestry who are hemizygous for the A— alloenzyme which is present at normal levels in reticulocytes can have normal G6PD levels because the reticulocyte count is high after hemolysis.

Second, female carriers — for example, those who are hemizygous for the common Mediterranean variant of G6PD — can have a normal assay result after an acute hemolytic episode because the abnormal cells have lysed preferentially, leaving mainly the cells expressing the normal allele in the circulation. In both of these circumstances, the observation of a typical blood smear in an appropriate clinical setting is an indication to repeat the assay once the acute hemolytic episode is over. Other features may aid in the differential diagnosis of hemolytic anemia.

For example, the presence of red-cell agglutinates usually indicates the presence of a cold agglutinin, and erythrophagocytosis is often a feature of paroxysmal cold hemoglobinuria Figure 2D.

The blood smear is of great importance in the differential diagnosis of macrocytic anemias. For patients in whom there is a deficiency of vitamin B 12 or folic acid, the blood smear shows not only macrocytes but also oval macrocytes and hypersegmented neutrophils Figure 3A and the slide show.

When the anemia is more severe, there may be marked poikilocytosis, with teardrop poikilocytes and red-cell fragments. Although these deficiency states are now usually recognized on the basis of assays of vitamin B 12 and folic acid, the blood smear remains important for two reasons. First, it permits a speedy provisional diagnosis, and initiation of appropriate treatment in severely anemic patients while assay results are pending.

Second, occasionally there are patients with a clinically significant vitamin B 12 deficiency despite a normal assay result. This discrepancy occurs because much of the vitamin B 12 that is measured in the assay is bound to haptocorrin, whereas the functional vitamin B 12 , which is bound to transcobalamin, contributes much less to the assay of total B Similarly, acute folic acid deficiency sometimes develops in patients even though the total red-cell folate level remains normal.

The observation of a blood smear that is typical of megaloblastic anemia despite normal assays is an indication that further investigation and a trial of treatment are needed.

Liver disease and excess ethanol consumption are common causes of macrocytosis, with the blood smear usually showing round rather than oval macrocytes and lacking hypersegmented neutrophils; target cells and stomatocytes may also be present. In elderly patients, the myelodysplastic syndromes are an important cause of macrocytosis. Blood-smear features that may point to the diagnosis include hypogranular or hypolobulated neutrophils Figure 3B , blast cells Figure 3B , giant or hypogranular platelets, Pappenheimer bodies Figure 3C , and the presence of a minor population of hypochromic microcytic cells, leading to a dimorphic smear Figure 3C.

Macrocytic anemia resulting from congenital dyserythropoietic anemia also yields a characteristic blood smear, with striking poikilocytosis Figure 3D.

When macrocytosis is the result of hemolysis or recent blood loss, the blood smear shows polychromasia, which results from an increased reticulocyte count. The blood smear is generally less important in the differential diagnosis of the microcytic than the macrocytic anemias. Red-cell indices and serum ferritin levels, sometimes supplemented by markers of inflammation, that are interpreted in the context of clinical features, permit the diagnosis of the majority of cases.

However, it is important to note that the presence of Pappenheimer bodies and red-cell dimorphism in the sideroblastic anemias and of basophilic stippling in cases of lead poisoning Figure 4A and the slide show and in some types of thalassemia is diagnostically significant.

A blood smear is useful in the diagnosis and differential diagnosis of sickle cell disease, particularly if there is an urgent need for diagnosis and if the results of hemoglobin electrophoresis or high-performance liquid chromatography are not instantly available. Patients with sickle cell anemia in which there is homozygosity for hemoglobin S have anemia, but those with compound heterozygosity for hemoglobin S and hemoglobin C may have a normal hemoglobin level, and the condition thus may be confused with sickle cell trait if a blood smear is not examined.

Consideration of the blood-smear features, of the hemoglobin level, and of the results of a sickle cell solubility test usually permits an accurate diagnosis 4,5 Figure 4B and Figure 4C. The blood smear of a compound heterozygote usually shows target cells, irregularly contracted cells, and boat-shaped cells but few classic sickle cells; typical hemoglobin SC poikilocytes formed only when hemoglobin S and hemoglobin C are both present are often seen.

Sometimes the blood smear of a compound heterozygote shows only target cells and irregularly contracted cells and cannot be distinguished from the smear in hemoglobin C homozygosity; a positive sickle cell solubility test permits these conditions to be distinguished in an emergency situation e. A blood smear is also important in the diagnosis of an unstable hemoglobin, with irregularly contracted cells and macrocytosis being characteristic of this condition Figure 4D ; sometimes there is coexisting thrombocytopenia.

A blood smear should always be examined for patients with thrombocytopenia, both to confirm the thrombocytopenia and to look for the underlying cause. Falsely low platelet counts may be the result of small clots, platelet clumping Figure 5A and the slide show , platelet satellitism Figure 5B , or abnormally large platelets.

Fibrin strands Figure 5C indicate that thrombocytopenia is likely to be factitious. Underlying causes that may be revealed by the blood smear include the May—Hegglin anomaly Figure 5D , microangiopathic thrombopathies, and leukemias and lymphomas.

High platelet counts should be confirmed microscopically with a blood smear; falsely high counts may be the result of other particles red-cell fragments, fragments of leukemic cells, or fungi being counted as platelets. A sudden, unexpected improvement in the platelet count also should be confirmed by blood-smear examination, since such an improvement may be factitious 7 Figure 5E.

Blood smears must always be examined when there is unexplained leukocytosis, lymphocytosis, or monocytosis or when the flagging system of an automated instrument suggests the presence of blast cells.

Depending on the instrument and the practice of the local laboratory, a flag for atypical or variant lymphocytes may also be an indication for examination of a blood smear, since this flag is sometimes indicative of the presence of blast cells. Low rather than high counts likewise are an indication for a smear, since they may be indicative of aplastic anemia, acute leukemia, hairy-cell leukemia, or infiltration of nonhematopoietic malignant cells into the bone marrow.

The role of the blood smear in the diagnosis of leukemia and lymphoma is to suggest a likely diagnosis or range of diagnoses, to indicate which additional tests should be performed, and to provide a morphologic context without which immunophenotyping and other sophisticated investigations cannot be interpreted.

For two conditions, Burkitt's lymphoma Figure 6A and the slide show and acute promyelocytic leukemia Figure 6B , a blood smear is of particular importance because it facilitates rapid diagnosis and specific treatment. Members of the laboratory staff should always initiate a blood smear if an automated instrument produces a highly improbable result. Such results may be factitious, resulting from the accidental freezing or heating of the blood, from hyperlipidemia, or from the presence of cold agglutinins, a cryoglobulin Figure 6C , bacteria, or fungi.

This is an important step that is impaired in some types of both congenital and acquired forms. Iron sulfur clusters are protein complexes that are involved in electron transfer of important mitochondrial and cytosolic pathways. Mutation or inactivation of these proteins can lead to abnormal iron metabolism and accumulation.

One mechanism could be through influence on iron regulatory proteins IRPs. There are other mitochondrial pathways which are disrupted in some forms of sideroblastic anemia, such as production of certain proteins essential for mitochondrial function. It is less clear how they eventually produce imbalance in iron metabolism and cause anemia.

Increased iron accumulation in mitochondria from abnormal iron metabolism causes formation of reactive oxygen species, and damages forming erythrocytes, usually in later stages of maturation. Thus, even though the bone marrow is hyperplastic and forming effective red cells, many of them are destroyed within the marrow. In addition to this, impaired hemoglobin production, causes reduced number of mature erythrocytes.

Resulting anemia is usually microcytic and hypochromic with some exceptions that will be discussed. The degree of ineffective erythropoiesis usually corresponds to anemia severity. Despite the abnormalities in iron utilization in sideroblastic anemia, iron transport to erythroblasts continues since the body senses anemia. Intestinal iron absorption increases which eventually causes both iron accumulation in mitochondria of erythroblasts and possible systemic iron accumulation.

It is interesting to note that systemic iron overload occurs only in some forms of sideroblastic anemia, usually when the defects in iron metabolisms involve earlier stages of erythroid pathways. The reasons for this are not entirely clear. It is then transported to cytoplasm, and then to mitochondria of erythroblast. Most of the iron is used for hemoglobin production.

Anemia is usually microcytic and hypochromic due to abnormal hemoglobin production, but sometimes can be dimorphic with normocytic or macrocytic cells, depending on the cause.

Typical symptoms of anemia, if severe enough, such as fatigue, light-headedness, pallor, decreased cardiac endurance. Sideroblastic anemia is divided into 2 groups: X-linked sideroblastic anemia - due to mutation in ALAS 2 enzyme. It is the most common congenital cause. Mostly affects males, but can also affect women when skewed inactivation of X chromosome occurs with aging.

Women usually manifest the anemia later in life. Anemia is variable in severity and more commonly remains stable. SCL25A38 defects - this is a gene for mitochondrial transporter, likely involved in bringing glycine into mitochondria, which is required for ALA production. This type is inherited in an autosomal recessive pattern and is usually a more severe anemia requiring chronic transfusion support.

Glutaredoxin deficiency - protein involved in iron sulfur biogenesis, which potentially reduces ALAS 2 translation through iron regulatory protein 1 IPR1. X-linked sideroblastic anemia with non-progressive cerebellar ataxia - defect in ABCB 7 protein involved in iron sulfur machinery. With the defect, iron remains trapped in mitochondria.

Anemia is usually mild and no iron overload is observed. Pearson marrow pancreas syndrome - severe anemia, neutropenia, thrombocytopenia, exocrine pancreatic insufficiency, lactic acidosis, hepatic and renal problems and failure to thrive as a child.

The defects are usually in the structure of mitochondria DNA deletions thus impairing synthesis of proteins crucial to mitochondrial function of the red cells. Starts in childhood with exercise intolerance, and then progresses to anemia, lactic acidosis and worsening myopathy in adolescence. Starts between infant to adolescent age and manifests with anemia, diabetes and sensorineural deafness. Alcohol use inhibits heme synthesis in several ways and may cause dietary deficiency in pyridoxine.

If sideroblastic anemia is noted in alcoholics, it usually indicates a more severe case of anemia. Interestingly alcohol effects red blood cell production more than white cells. Chloramphenicol inhibits mitochondrial membrane protein synthesis. Ring sideroblasts usually appear in most patients taking the drug, especially in longer courses and with higher doses.

Anemia is moderate to severe. Isoniazid INH reacts with pyridoxine, thus inhibiting the first step of heme synthesis. Also may inhibit ALAS 2 activity. It usually develops months after starting the therapy and usually manifests as typical, moderate to severe sideroblastic anemia. Lead toxicity - rare and questionable cause, and most often just leads to microcytic anemia with basophilic stippling.

Pyridoxine deficiency can be due to malnutrition which is quite rare or from discontinuation of multivitamin which contained it. Typically, peripheral neuropathy and dermatitis are more pronounced than anemia. Copper deficiency - copper has complex role in iron metabolism. It participates in intestinal iron absorption and mobilization from the liver.

It is also a part of cytochrome oxidase, an enzyme involved in iron reduction. The deficiency usually occurs in patients who have decreased absorption of copper. Examples include gastric surgery, prolonged parenteral nutrition or enteral feedings without inclusion of copper in the feeds.

Decreased intestinal absorption such as celiac disease or other malabsorptive syndromes may also be the cause. Lastly, copper chelation has been reported to cause anemia which tends to be severe with hemoglobin levels as low as 5 with normal to slightly-increased mean corpuscular volume MCV. Iron overload is usually not observed. In addition to sideroblastic changes, patients may develop neutropenia and neurologic abnormalities.

The next big group in terms of prevalence after reversible. Refers to myelodysplastic syndrome MDS related or clonal sideroblastic anemia here the abnormal cells grow in clones. The defects are thought to be in heme synthesis pathways, although no clear mutations have been identified.

ABCB7 transporter levels were found to be reduced, and so this protein might be involved in pathogenesis. Unlike in congenital forms of sideroblastic anemia, erythroblasts are effected at all stages of maturation, beginning from stem cells. It usually occurs in the middle age to older population and is often discovered by laboratory abnormalities or symptoms consistent with anemia. Patients may become transfusion dependent and develop iron overload. Refractory anemia with ring sideroblasts RARS - occurs as sole anemia.

Often very similar phenotypically to X-linked sideroblastic anemia. Usually runs a benign course and has very low chance of transformation to leukemia. This also has a higher incidence of acute leukemia conversions.

RARS-T - a variant of anemia with thrombocytosis, frequently associated with JAK2 mutation, has the best prognosis of all 3 categories. Any anemia can be considered in the differential diagnosis of sideroblastic anemia. The most important types of anemia to consider are the other causes of microcytic anemia, such as thalassemia, iron deficiency or lead poisoning.

In addition, different anemias can coexist, for example, a patient with sideroblastic anemia can also be iron deficient. Some types of sideroblastic anemias can have normocytic or macrocytic cells, and therefore, the differential diagnosis should include any cause of anemia that fits the clinical presentation of a patient. Many different anemias may show similar exam and laboratory findings.

Sideroblastic anemia can be guessed based on history, clinical and laboratory presentation, however bone marrow examination is the only study that can accurately distinguish sideroblastic anemia from other types. Findings related to cardiac damage in case of iron accumulation, such as arrhythmias, or heart failure, which usually occur late in disease course - rare.

The degree of microcytosis and hypochromia parallel the severity of anemia. Red cell distribution width RDW is increased as there are variable sizes of cells. Often at times you may see dimorphic cells, different in sizes - micro and macrocytic or normocytic especially in females with X-linked sideroblastic anemia, MDS and alcohol use. Complete blood count with differential will show variable severity of anemia, with usually normal leukocytes and platelets. However the latter 2 cell lines may be abnormal if hypersplenism is present, in some subtypes of MDS, drug or alcohol toxicity.

Mitochondrial ferritin is detected in granules surrounding the nucleus. Immunoalkaline phosphatase reaction, MGG x Following the identification of mutant SLC25A38 as a novel cause of inherited sideroblastic anemia, Bergmann et al. In this issue of the journal, Kannengiesser et al. Eleven patients of several different ancestral origins carried SLC25A38 mutations: All patients required blood transfusions that inevitably became regular within the first few years of life.

Two patients underwent allogeneic stem cell transplantation with complete correction of anemia. Since the clinical course of congenital sideroblastic anemia associated with SLC25A38 mutations is very similar to that of thalassemia major, conservative therapy includes regular red cell transfusion and iron chelation.

However, as in thalassemia major, allogeneic stem cell transplantation represents the only curative therapy at present, and should, therefore, be considered for young patients with this congenital sideroblastic anemia. What are the implications of recent advances in our understanding of the molecular basis of congenital sideroblastic anemia for the acquired forms, i. However, a few studies of X-chromosome inactivation patterns performed in female patients have suggested that RARS derives from the clonal proliferation of a multipotent hematopoietic stem cell with the potential for myeloid and lymphoid differentiation.

Unfortunately none of the candidate genes, i. Thus, the available evidence suggests that the clonal hematopoiesis of RARS and RARS-T is associated with abnormal expression of several genes of heme synthesis and mitochondrial iron processing.

Identifying the somatic mutation s that can be responsible for these abnormalities represents the current challenge in this field. The two most common forms of congenital sideroblastic anemia, i.

Overall, XLSA is a benign disorder that generally responds to pyridoxine with substantial amelioration of anemia; prevention and treatment of iron overload is also important and can be generally achieved through phlebotomy. By contrast, the congenital autosomal recessive congenital sideroblastic anemia due to SLC25A38 mutations is a severe disease, not responsive to pyridoxine and with a clinical course very similar to that of thalassemia major: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail.

We do not capture any email address. Skip to main content. Ring sideroblasts and sideroblastic anemias. Mario Cazzola , Rosangela Invernizzi. Haematologica June Classification of sideroblastic anemias The sideroblastic anemias include both hereditary and acquired conditions, and the main disorders are reported in Table 1.

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The defect results in impaired oxidative phosphorylation, which explains the muscle and nerve manifestations, and sideroblastic anemia due to dysfunctional mitochondria, the center of heme synthesis. An autosomal dominantly inherited form also exists but is extremely rare. Pearson marrow-pancreas syndrome , described in , [ 12 ] is a juvenile multisystem disorder caused by deletions in mitochondrial DNA mtDNA and manifested as severe, refractory sideroblastic anemia, neutropenia , vacuolated cells in bone-marrow precursors, exocrine pancreas insufficiency, malabsorption, and growth failure.

DIDMOAD diabetes insipidus, diabetes mellitus, optic atrophy, and deafness syndrome is associated with sideroblastic anemia that is responsive to vitamin B-1 thiamine. Acquired sideroblastic anemias can be classified into clonal myelodysplastic syndrome and nonclonal metabolic types. Of the numerous classes of myelodysplastic syndrome in the World Health Organization classification updated in , 2 represent sideroblastic anemias refractory anemia with ring sideroblasts [RARS] and refractory cytopenia with multilineage dysplasia [RCMD].

Refractory anemia with ring sideroblasts with thrombocytosis variant RARS-T; JAK2 vf mutation predominant , which has both sideroblastic anemia and thrombocytosis, is an additional consideration as a distinct entity. Recently, a new mutation, SF3B1 ,in the spliceosome apparatus, which catalysis mRNA splicing, was noted to have a predominant presence among patients with ring sideroblasts. Interestingly, the more numerous the sideroblasts, the lower the risk of progression.

Copper deficiency, which can occur as a part of malabsorption, [ 21 ] nephrotic syndrome loss of ceruloplasmin , [ 22 ] gastric surgery, [ 23 ] or as a consequence of excessive zinc intake supplements , [ 24 ] can masquerade as myelodysplastic syndrome with sideroblastic anemia and leukopenia. Low serum copper and ceruloplasmin are typical.

Copper replacement reverses the hematologic abnormalities. Excessive alcohol consumption can cause several forms of anemia through nutritional deficiencies eg, of iron or folate , hemolysis, splenic sequestration due to liver cirrhosis, direct bone marrow toxicity to erythroid precursors, [ 29 ] inhibition of pyridoxine, [ 30 ] lead contamination of wine, [ 31 ] and inhibition of ferrochelatase enzyme during heme formation.

Drugs reported to cause sideroblastic anemia include diverse classes, such as antibiotics eg, chloramphenicol, [ 33 ] fusidic acid, [ 34 ] linezolid, [ 35 ] tetracycline, [ 36 ] isoniazid [ 37 ] , hormones eg, progesterone [ 38 ] , pain medicines eg, phenacetin [ 39 ] , copper chelating agents eg, penicillamine [ 40 ] and trientine [ 41 ] , and chemotherapy agents eg, busulfan, melphalan.

Hypothermia has been reported to cause sideroblastic anemia with a marked reduction in normoblastic erythropoiesis and thrombocytopenia with normal megakaryocytes. The changes reverse in most cases with the normalization of temperature. Although usually manifested in childhood, congenital X-linked sideroblastic anemia due to ALAS mutation can remain undiagnosed and then present late in the fourth to eighth decades of life.

X-linked recessive types of sideroblastic anemia occur more commonly in males. A female would have to inherit 1 abnormal chromosome from each parent to acquire the disease. Progesterone and pregnancy have been reported to induce relapse of sideroblastic anemia. The prognosis of sideroblastic anemia is highly variable.

Reversible causes such as alcohol and drugs do not appear to carry long-term sequelae. On the other hand, patients with transfusion dependence, those with conditions unresponsive to pyridoxine and other therapies, and those with MDS that develops into acute leukemia have a less bright prognosis.

In congenital sideroblastic anemias, mitochondrial abnormalities may produce neuromuscular dysfunction. In acquired sideroblastic anemias, mortality and morbidity is obviously variable as some of the causes are reversible. Major causes of death in cases of sideroblastic anemia are secondary hemochromatosis from transfusions and leukemia. The patients who die of acute leukemia tend to have a more severe anemia, a lower reticulocyte count, an increased transfusion requirement, and thrombocytopenia.

Thrombocytosis appears to be a relatively good prognostic sign. Genetic counseling and an antenatal diagnosis of sideroblastic anemia have in recent years become of practical relevance to families with known cases of congenital sideroblastic anemia.

Careful documentation of the clinical outcome of these cases and of other family members is invaluable. X-linked, pyridoxine-responsive sideroblastic anemia.

N Engl J Med. Erythropoietic protoporphyria without cutaneous photosensitivity and with ringed sideroblasts in an atomic bomb survivor. Accumulation of iron in erythroblasts of patients with erythropoietic protoporphyria. Eur J Clin Invest. Clinical and genetic characteristics of congenital sideroblastic anemia: Enzymatic defect in "X-linked" sideroblastic anemia: Harigae H, Furuyama K.

Identification of a human mitochondrial ABC transporter, the functional orthologue of yeast Atm1p. Cloning and chromosomal mapping of a novel ABC transporter gene hABC7 , a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia. Hereditary sideroblastic anaemia and ataxia: Mitochondrial myopathy, sideroblastic anemia, and lactic acidosis: A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction.

Sideroblastic anaemia and primary adrenal insufficiency due to a mitochondrial respiratory chain disorder in the absence of mtDNA deletion. Patnaik MM, Tefferi A. Refractory anemia with ring sideroblasts and RARS with thrombocytosis. SF3B1 and the riddle of the ring sideroblast.

Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms. Ringed sideroblasts in primary myelodysplasia. Leukemic propensity and prognostic factors. Anemia in congenital nephrotic syndrome: Copper deficiency after gastric surgery: Am J Med Sci.

Am J Clin Pathol. Copper deficiency masquerading as myelodysplastic syndrome. Conversion of amino acids to specialized products. JB Lippincott Co; These latter are normal erythroblasts that, after Prussian blue staining, show a few blue granules scattered in the cytoplasm, representing endosomes filled with excess iron not utilized for heme synthesis siderosomes. While the iron of ferritin sideroblasts is stored in cytosolic ferritin, whose subunits are encoded by the FTH1 and FTL genes, the iron of ring sideroblasts is stored in mitochondrial ferritin, encoded by the FTMT gene.

The sideroblastic anemias include both hereditary and acquired conditions, and the main disorders are reported in Table 1. Representative peripheral blood and bone marrow smears from a patient with X-linked sideroblastic anemia XLSA and a patient with refractory anemia with ring sideroblasts RARS are shown in Figures 1 and 2 , respectively.

Representative peripheral blood and bone marrow smears from a patient with X-linked sideroblastic anemia. A Peripheral blood smear showing many hypochromic and microcytic cells.

B Bone marrow smear showing erythroid hyper plasia: C Bone marrow smear showing erythroblasts with defective hemoglobinization left and erythroblasts containing multiple Pappenheimer bodies right. D Bone marrow smear.

The management of XLSA involves not only treatment of anemia, but also prevention and treatment of iron overload, family studies to identify additional at-risk individuals, and genetic counseling.

Patients affected with other inherited forms of sideroblastic anemia are not responsive to pyridoxine, and the molecular basis of these autosomal recessive disorders has been clarified only recently.

The phenotype of this patient resembled that of the shiraz zebrafish, a mutant resulting from a large deletion encompassing the GLRX5 gene. GLRX5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts.

Two years ago, Guernsey et al. The data available were inconsistent with an X-linked recessive inheritance, while the families derived from a local subpopulation isolate, consistent with a possible genetic founder effect. A single nucleotide polymorphism-based genome-wide scan performed in individuals belonging to these families led to the identification of SLC25A38 as the mutant gene responsible for this type of autosomal recessive pyridoxine-refractory sideroblastic anemia.

SLC25A38 encodes the erythroid specific mitochondrial carrier protein, which is important for the biosynthesis of heme in eukaryotes. Representative peripheral blood and bone marrow smears from a patient with refractory anemia with ring sideroblasts.

Peripheral blood smear showing dimorphic red cells with a population of macrocytes and a population of hypochromic microcytes. B Bone marrow smear showing a marked erythroid hyperplasia with megaloblastoid features. The rare granulocytic cells look normal. Upper right, a late erythroblast with defective hemoglobinization; lower right, an early erythroblast with vacuolated cytoplasm and a late erythroblast with Pappenheimer bodies. Mitochondrial ferritin is detected in granules surrounding the nucleus.

Immunoalkaline phosphatase reaction, MGG x First, men of African or African-American ancestry who are hemizygous for the A— alloenzyme which is present at normal levels in reticulocytes can have normal G6PD levels because the reticulocyte count is high after hemolysis. Second, female carriers — for example, those who are hemizygous for the common Mediterranean variant of G6PD — can have a normal assay result after an acute hemolytic episode because the abnormal cells have lysed preferentially, leaving mainly the cells expressing the normal allele in the circulation.

In both of these circumstances, the observation of a typical blood smear in an appropriate clinical setting is an indication to repeat the assay once the acute hemolytic episode is over. Other features may aid in the differential diagnosis of hemolytic anemia. For example, the presence of red-cell agglutinates usually indicates the presence of a cold agglutinin, and erythrophagocytosis is often a feature of paroxysmal cold hemoglobinuria Figure 2D.

The blood smear is of great importance in the differential diagnosis of macrocytic anemias. For patients in whom there is a deficiency of vitamin B 12 or folic acid, the blood smear shows not only macrocytes but also oval macrocytes and hypersegmented neutrophils Figure 3A and the slide show. When the anemia is more severe, there may be marked poikilocytosis, with teardrop poikilocytes and red-cell fragments. Although these deficiency states are now usually recognized on the basis of assays of vitamin B 12 and folic acid, the blood smear remains important for two reasons.

First, it permits a speedy provisional diagnosis, and initiation of appropriate treatment in severely anemic patients while assay results are pending. Second, occasionally there are patients with a clinically significant vitamin B 12 deficiency despite a normal assay result. This discrepancy occurs because much of the vitamin B 12 that is measured in the assay is bound to haptocorrin, whereas the functional vitamin B 12 , which is bound to transcobalamin, contributes much less to the assay of total B Similarly, acute folic acid deficiency sometimes develops in patients even though the total red-cell folate level remains normal.

The observation of a blood smear that is typical of megaloblastic anemia despite normal assays is an indication that further investigation and a trial of treatment are needed. Liver disease and excess ethanol consumption are common causes of macrocytosis, with the blood smear usually showing round rather than oval macrocytes and lacking hypersegmented neutrophils; target cells and stomatocytes may also be present. In elderly patients, the myelodysplastic syndromes are an important cause of macrocytosis.

Blood-smear features that may point to the diagnosis include hypogranular or hypolobulated neutrophils Figure 3B , blast cells Figure 3B , giant or hypogranular platelets, Pappenheimer bodies Figure 3C , and the presence of a minor population of hypochromic microcytic cells, leading to a dimorphic smear Figure 3C.

Macrocytic anemia resulting from congenital dyserythropoietic anemia also yields a characteristic blood smear, with striking poikilocytosis Figure 3D.

When macrocytosis is the result of hemolysis or recent blood loss, the blood smear shows polychromasia, which results from an increased reticulocyte count. The blood smear is generally less important in the differential diagnosis of the microcytic than the macrocytic anemias. Red-cell indices and serum ferritin levels, sometimes supplemented by markers of inflammation, that are interpreted in the context of clinical features, permit the diagnosis of the majority of cases.

However, it is important to note that the presence of Pappenheimer bodies and red-cell dimorphism in the sideroblastic anemias and of basophilic stippling in cases of lead poisoning Figure 4A and the slide show and in some types of thalassemia is diagnostically significant. A blood smear is useful in the diagnosis and differential diagnosis of sickle cell disease, particularly if there is an urgent need for diagnosis and if the results of hemoglobin electrophoresis or high-performance liquid chromatography are not instantly available.

Patients with sickle cell anemia in which there is homozygosity for hemoglobin S have anemia, but those with compound heterozygosity for hemoglobin S and hemoglobin C may have a normal hemoglobin level, and the condition thus may be confused with sickle cell trait if a blood smear is not examined.

Consideration of the blood-smear features, of the hemoglobin level, and of the results of a sickle cell solubility test usually permits an accurate diagnosis 4,5 Figure 4B and Figure 4C. The blood smear of a compound heterozygote usually shows target cells, irregularly contracted cells, and boat-shaped cells but few classic sickle cells; typical hemoglobin SC poikilocytes formed only when hemoglobin S and hemoglobin C are both present are often seen.

Sometimes the blood smear of a compound heterozygote shows only target cells and irregularly contracted cells and cannot be distinguished from the smear in hemoglobin C homozygosity; a positive sickle cell solubility test permits these conditions to be distinguished in an emergency situation e. A blood smear is also important in the diagnosis of an unstable hemoglobin, with irregularly contracted cells and macrocytosis being characteristic of this condition Figure 4D ; sometimes there is coexisting thrombocytopenia.

A blood smear should always be examined for patients with thrombocytopenia, both to confirm the thrombocytopenia and to look for the underlying cause. Falsely low platelet counts may be the result of small clots, platelet clumping Figure 5A and the slide show , platelet satellitism Figure 5B , or abnormally large platelets.

Fibrin strands Figure 5C indicate that thrombocytopenia is likely to be factitious. Underlying causes that may be revealed by the blood smear include the May—Hegglin anomaly Figure 5D , microangiopathic thrombopathies, and leukemias and lymphomas. High platelet counts should be confirmed microscopically with a blood smear; falsely high counts may be the result of other particles red-cell fragments, fragments of leukemic cells, or fungi being counted as platelets.

A sudden, unexpected improvement in the platelet count also should be confirmed by blood-smear examination, since such an improvement may be factitious 7 Figure 5E. Blood smears must always be examined when there is unexplained leukocytosis, lymphocytosis, or monocytosis or when the flagging system of an automated instrument suggests the presence of blast cells.

Depending on the instrument and the practice of the local laboratory, a flag for atypical or variant lymphocytes may also be an indication for examination of a blood smear, since this flag is sometimes indicative of the presence of blast cells. Low rather than high counts likewise are an indication for a smear, since they may be indicative of aplastic anemia, acute leukemia, hairy-cell leukemia, or infiltration of nonhematopoietic malignant cells into the bone marrow.

The role of the blood smear in the diagnosis of leukemia and lymphoma is to suggest a likely diagnosis or range of diagnoses, to indicate which additional tests should be performed, and to provide a morphologic context without which immunophenotyping and other sophisticated investigations cannot be interpreted. For two conditions, Burkitt's lymphoma Figure 6A and the slide show and acute promyelocytic leukemia Figure 6B , a blood smear is of particular importance because it facilitates rapid diagnosis and specific treatment.

Members of the laboratory staff should always initiate a blood smear if an automated instrument produces a highly improbable result. Such results may be factitious, resulting from the accidental freezing or heating of the blood, from hyperlipidemia, or from the presence of cold agglutinins, a cryoglobulin Figure 6C , bacteria, or fungi. Factitious results also may stem from unusual characteristics of the blood cells or the plasma, such as a pseudo-neutropenia caused by a myeloperoxidase deficiency that occurs when the automated instrument employs a peroxidase reaction for the identification of neutrophils, eosinophils, and monocytes.

Falsely low counts also may result from neutrophil or platelet clumping or from platelet satellitism. Occasionally, a blood smear leads to a fortuitous diagnosis that can be very important to the patient Table 2.

As an example, the detection of features of unexpected hyposplenism Figure 6D may suggest a congenital absence of the spleen, splenic atrophy, deposition of amyloid in the spleen, infiltration of neoplastic cells e. Conversely, the failure to observe expected hyposplenism in a blood smear from a patient who has undergone splenectomy for the treatment of autoimmune thrombocytopenic purpura may indicate that there is functioning residual splenic tissue, either from splenosis or from accessory spleens, that may be responsible for a relapse of the disease.

Sometimes the blood smear provides the primary or the only evidence of a specific diagnosis, such as myelodysplastic syndrome, leukemia, lymphoma, or hemolytic anemia.

It is important that, if possible, such blood smears be stored over the long term, just as a tissue that provides a histologic diagnosis is stored over the long term. In practice, such storage is easily achieved if a patient has also had a bone marrow aspirate since a blood smear should always be stored with an aspirate , but it is harder to achieve if the blood smear alone has provided the diagnosis.

Individual laboratories should have a mechanism to make possible the retention of such smears or an image derived from them.

biggest hurdle

Representative peripheral blood and bone marrow smears from a patient with X-linked sideroblastic anemia XLSA and a patient with refractory anemia with ring sideroblasts RARS are shown in Figures 1 and 2 , respectively. Representative peripheral blood and bone marrow smears from a patient with X-linked sideroblastic anemia. A Peripheral blood smear showing many hypochromic and microcytic cells.

B Bone marrow smear showing erythroid hyper plasia: C Bone marrow smear showing erythroblasts with defective hemoglobinization left and erythroblasts containing multiple Pappenheimer bodies right.

D Bone marrow smear. The management of XLSA involves not only treatment of anemia, but also prevention and treatment of iron overload, family studies to identify additional at-risk individuals, and genetic counseling.

Patients affected with other inherited forms of sideroblastic anemia are not responsive to pyridoxine, and the molecular basis of these autosomal recessive disorders has been clarified only recently. The phenotype of this patient resembled that of the shiraz zebrafish, a mutant resulting from a large deletion encompassing the GLRX5 gene. GLRX5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts.

Two years ago, Guernsey et al. The data available were inconsistent with an X-linked recessive inheritance, while the families derived from a local subpopulation isolate, consistent with a possible genetic founder effect.

A single nucleotide polymorphism-based genome-wide scan performed in individuals belonging to these families led to the identification of SLC25A38 as the mutant gene responsible for this type of autosomal recessive pyridoxine-refractory sideroblastic anemia. SLC25A38 encodes the erythroid specific mitochondrial carrier protein, which is important for the biosynthesis of heme in eukaryotes.

Representative peripheral blood and bone marrow smears from a patient with refractory anemia with ring sideroblasts. Peripheral blood smear showing dimorphic red cells with a population of macrocytes and a population of hypochromic microcytes. B Bone marrow smear showing a marked erythroid hyperplasia with megaloblastoid features. The rare granulocytic cells look normal.

Upper right, a late erythroblast with defective hemoglobinization; lower right, an early erythroblast with vacuolated cytoplasm and a late erythroblast with Pappenheimer bodies. Mitochondrial ferritin is detected in granules surrounding the nucleus. Immunoalkaline phosphatase reaction, MGG x Following the identification of mutant SLC25A38 as a novel cause of inherited sideroblastic anemia, Bergmann et al.

In this issue of the journal, Kannengiesser et al. Eleven patients of several different ancestral origins carried SLC25A38 mutations: All patients required blood transfusions that inevitably became regular within the first few years of life.

Two patients underwent allogeneic stem cell transplantation with complete correction of anemia. Since the clinical course of congenital sideroblastic anemia associated with SLC25A38 mutations is very similar to that of thalassemia major, conservative therapy includes regular red cell transfusion and iron chelation.

However, as in thalassemia major, allogeneic stem cell transplantation represents the only curative therapy at present, and should, therefore, be considered for young patients with this congenital sideroblastic anemia. What are the implications of recent advances in our understanding of the molecular basis of congenital sideroblastic anemia for the acquired forms, i.

However, a few studies of X-chromosome inactivation patterns performed in female patients have suggested that RARS derives from the clonal proliferation of a multipotent hematopoietic stem cell with the potential for myeloid and lymphoid differentiation. Unfortunately none of the candidate genes, i. Thus, the available evidence suggests that the clonal hematopoiesis of RARS and RARS-T is associated with abnormal expression of several genes of heme synthesis and mitochondrial iron processing.

Identifying the somatic mutation s that can be responsible for these abnormalities represents the current challenge in this field. The two most common forms of congenital sideroblastic anemia, i. Overall, XLSA is a benign disorder that generally responds to pyridoxine with substantial amelioration of anemia; prevention and treatment of iron overload is also important and can be generally achieved through phlebotomy. By contrast, the congenital autosomal recessive congenital sideroblastic anemia due to SLC25A38 mutations is a severe disease, not responsive to pyridoxine and with a clinical course very similar to that of thalassemia major: A physician-initiated request for a blood smear is usually a response to perceived clinical features or to an abnormality shown in a previous complete blood count.

Less often, it is a response to clinical details given with the request for a complete blood count when the physician has not specifically requested examination of a smear. For example, a laboratory might have a policy of always examining a blood smear if the clinical details indicate lymphadenopathy or splenomegaly. The International Society for Laboratory Hematology has published consensus criteria available at www.

The indications for smear review differ according to the age and sex of the patient, whether the request is an initial or a subsequent one, and whether there has been a clinically significant change from a previous validated result referred to as a failed delta check. All laboratories should have a protocol for the examination of a laboratory-initiated blood smear, which can reasonably be based on the criteria of the International Society for Laboratory Hematology.

Regulatory groups should permit the examination of a blood smear when such protocols indicate that it is necessary. There are numerous valid reasons for a clinician to request a blood smear Table 1 , and these differ somewhat from the reasons why laboratory workers initiate a blood-smear examination. Sometimes it is possible for a definitive diagnosis to be made from a blood smear. More often, the smear is an important tool in the provision of a differential diagnosis and the indication of further necessary tests.

The blood smear can have an important part in the speedy diagnosis of certain specific infections. Otherwise, its major roles are in the differential diagnosis of anemia and thrombocytopenia and in the identification and characterization of leukemia and lymphoma. In patients with anemia, physician-initiated examinations of blood smears are usually performed in response to clinical features or to a previously abnormal complete blood count.

The presence of unexplained jaundice, particularly if unconjugated hyperbilirubinemia is also present, is an additional reason for a blood-smear examination.

Laboratory-initiated examinations of blood smears for patients with anemia are usually the result of a laboratory policy according to which a blood smear is ordered whenever the hemoglobin concentration is unexpectedly low. This policy should be encouraged, since the consideration of the blood smear and the red-cell indices is a logical first step in the investigation of any unexplained anemia.

Modern automated instruments impart valuable information about the nature of anemia. They provide not only a red-cell count, mean cell volume, mean cell hemoglobin a measure of the average amount of hemoglobin in an individual red cell , and the mean cell hemoglobin concentration a measure of the average concentration of hemoglobin in a cell but also newer variables that give information that previously could be derived only from a blood smear.

These variables usually include the red-cell—distribution width, which correlates on a blood smear with anisocytosis, and they may also include the hemoglobin-distribution width and the percentages of hypochromic and hyperchromic cells, which correlate with anisochromasia, hypochromia, and hyperchromia.

A variety of histograms and scatterplots give a visual representation of red-cell characteristics. It may be possible to detect increased numbers of hyperchromic cells spherocytes or irregularly contracted cells , small hyperchromic cells microspherocytes , hypochromic microcytic cells, large normochromic cells normally hemoglobinized macrocytes , and hypochromic macrocytes either reticulocytes or dysplastic red cells. Despite this wealth of information, there are still morphologic abnormalities that are critical in the differential diagnosis of anemia and that can be determined only from a blood smear.

Particularly important is the detection of variations in cell shape and of red-cell inclusions, such as Howell—Jolly bodies nuclear fragments , Pappenheimer bodies hemosiderin-containing granules , and basophilic stippling or punctate basophilia altered ribosomes. In the hemolytic anemias, red-cell shape is of considerable diagnostic importance. Some types of hemolytic anemia yield such a distinctive blood smear that the smear is often sufficient for diagnosis.

This is true of hereditary elliptocytosis which is only infrequently associated with anemia Figure 1A a slide show is available with the full text of this article at www. The presence of spherocytes is not diagnostically specific, since this may result from hereditary spherocytosis, autoimmune hemolytic anemia, or alloimmune hemolytic anemia e. Nevertheless, consideration of the clinical features, together with the results of a direct antiglobulin test, in patients with spherocytes will generally indicate the correct diagnosis.

The detection of a microangiopathic hemolytic anemia Figure 1D is of considerable clinical significance, since this type of anemia may indicate pregnancy-associated hypertension, disseminated cancer, chronic disseminated intravascular coagulation, the hemolytic—uremic syndrome, or thrombotic thrombocytopenic purpura; the latter two conditions both require urgent diagnosis so that appropriate management can be initiated.

In microangiopathic hemolytic anemia, examination of the blood smear is also important to validate the platelet count, since red-cell fragments and platelets may be of similar size.

Most automated instruments cannot make this distinction. Hence, a blood smear is still advised for validation. A blood smear is particularly important in the diagnosis of acute hemolysis induced by oxidant damage. These irregularly contracted cells share with spherocytes the lack of central pallor but differ in that they have an irregular outline.

Oxidant-induced hemolysis is most often seen in glucosephosphate dehydrogenase G6PD deficiency but can also occur with other defects in the pentose shunt or in glutathione synthesis and when oxidant exposure overwhelms normal protective mechanisms. Oxidant damage may be exogenous, as in exposure to oxidant chemicals or drugs most often dapsone , or endogenous, as in Wilson's disease.

G6PD deficiency affects millions of persons worldwide. A blood smear is important for the diagnosis of this condition, for two reasons. First, it is available far more rapidly than are the results of a G6PD assay and, when considered together with the patient's ethnic origin and clinical history, permits a provisional diagnosis.

First, men of African or African-American ancestry who are hemizygous for the A— alloenzyme which is present at normal levels in reticulocytes can have normal G6PD levels because the reticulocyte count is high after hemolysis. Second, female carriers — for example, those who are hemizygous for the common Mediterranean variant of G6PD — can have a normal assay result after an acute hemolytic episode because the abnormal cells have lysed preferentially, leaving mainly the cells expressing the normal allele in the circulation.

In both of these circumstances, the observation of a typical blood smear in an appropriate clinical setting is an indication to repeat the assay once the acute hemolytic episode is over. Other features may aid in the differential diagnosis of hemolytic anemia. For example, the presence of red-cell agglutinates usually indicates the presence of a cold agglutinin, and erythrophagocytosis is often a feature of paroxysmal cold hemoglobinuria Figure 2D.

The blood smear is of great importance in the differential diagnosis of macrocytic anemias. For patients in whom there is a deficiency of vitamin B 12 or folic acid, the blood smear shows not only macrocytes but also oval macrocytes and hypersegmented neutrophils Figure 3A and the slide show. When the anemia is more severe, there may be marked poikilocytosis, with teardrop poikilocytes and red-cell fragments. Although these deficiency states are now usually recognized on the basis of assays of vitamin B 12 and folic acid, the blood smear remains important for two reasons.

First, it permits a speedy provisional diagnosis, and initiation of appropriate treatment in severely anemic patients while assay results are pending.

Second, occasionally there are patients with a clinically significant vitamin B 12 deficiency despite a normal assay result. This discrepancy occurs because much of the vitamin B 12 that is measured in the assay is bound to haptocorrin, whereas the functional vitamin B 12 , which is bound to transcobalamin, contributes much less to the assay of total B Similarly, acute folic acid deficiency sometimes develops in patients even though the total red-cell folate level remains normal.

The observation of a blood smear that is typical of megaloblastic anemia despite normal assays is an indication that further investigation and a trial of treatment are needed.

Liver disease and excess ethanol consumption are common causes of macrocytosis, with the blood smear usually showing round rather than oval macrocytes and lacking hypersegmented neutrophils; target cells and stomatocytes may also be present. In elderly patients, the myelodysplastic syndromes are an important cause of macrocytosis. Blood-smear features that may point to the diagnosis include hypogranular or hypolobulated neutrophils Figure 3B , blast cells Figure 3B , giant or hypogranular platelets, Pappenheimer bodies Figure 3C , and the presence of a minor population of hypochromic microcytic cells, leading to a dimorphic smear Figure 3C.

Macrocytic anemia resulting from congenital dyserythropoietic anemia also yields a characteristic blood smear, with striking poikilocytosis Figure 3D. When macrocytosis is the result of hemolysis or recent blood loss, the blood smear shows polychromasia, which results from an increased reticulocyte count. The blood smear is generally less important in the differential diagnosis of the microcytic than the macrocytic anemias.

Red-cell indices and serum ferritin levels, sometimes supplemented by markers of inflammation, that are interpreted in the context of clinical features, permit the diagnosis of the majority of cases. However, it is important to note that the presence of Pappenheimer bodies and red-cell dimorphism in the sideroblastic anemias and of basophilic stippling in cases of lead poisoning Figure 4A and the slide show and in some types of thalassemia is diagnostically significant.

A blood smear is useful in the diagnosis and differential diagnosis of sickle cell disease, particularly if there is an urgent need for diagnosis and if the results of hemoglobin electrophoresis or high-performance liquid chromatography are not instantly available. Patients with sickle cell anemia in which there is homozygosity for hemoglobin S have anemia, but those with compound heterozygosity for hemoglobin S and hemoglobin C may have a normal hemoglobin level, and the condition thus may be confused with sickle cell trait if a blood smear is not examined.

Consideration of the blood-smear features, of the hemoglobin level, and of the results of a sickle cell solubility test usually permits an accurate diagnosis 4,5 Figure 4B and Figure 4C. The blood smear of a compound heterozygote usually shows target cells, irregularly contracted cells, and boat-shaped cells but few classic sickle cells; typical hemoglobin SC poikilocytes formed only when hemoglobin S and hemoglobin C are both present are often seen.

Sometimes the blood smear of a compound heterozygote shows only target cells and irregularly contracted cells and cannot be distinguished from the smear in hemoglobin C homozygosity; a positive sickle cell solubility test permits these conditions to be distinguished in an emergency situation e. A blood smear is also important in the diagnosis of an unstable hemoglobin, with irregularly contracted cells and macrocytosis being characteristic of this condition Figure 4D ; sometimes there is coexisting thrombocytopenia.

A blood smear should always be examined for patients with thrombocytopenia, both to confirm the thrombocytopenia and to look for the underlying cause. Falsely low platelet counts may be the result of small clots, platelet clumping Figure 5A and the slide show , platelet satellitism Figure 5B , or abnormally large platelets. Fibrin strands Figure 5C indicate that thrombocytopenia is likely to be factitious. Underlying causes that may be revealed by the blood smear include the May—Hegglin anomaly Figure 5D , microangiopathic thrombopathies, and leukemias and lymphomas.

High platelet counts should be confirmed microscopically with a blood smear; falsely high counts may be the result of other particles red-cell fragments, fragments of leukemic cells, or fungi being counted as platelets.

A sudden, unexpected improvement in the platelet count also should be confirmed by blood-smear examination, since such an improvement may be factitious 7 Figure 5E. Blood smears must always be examined when there is unexplained leukocytosis, lymphocytosis, or monocytosis or when the flagging system of an automated instrument suggests the presence of blast cells.

Depending on the instrument and the practice of the local laboratory, a flag for atypical or variant lymphocytes may also be an indication for examination of a blood smear, since this flag is sometimes indicative of the presence of blast cells. Low rather than high counts likewise are an indication for a smear, since they may be indicative of aplastic anemia, acute leukemia, hairy-cell leukemia, or infiltration of nonhematopoietic malignant cells into the bone marrow.

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Sideroblastic anemia due to linezolid in a patient with a left ventricular assist device. J Heart Lung Transplant. Reversible sideroblastic anemia associated with the tetracycline analogue COL Acquired sideroblastic anaemia following progesterone therapy. Sideroblastic anemia in chronic phenacetin misuse. Acquired sideroblastic anaemia associated with penicillamine therapy for rheumatoid arthritis. Acquired sideroblastic anaemia induced by a copper-chelating agent. Sideroblastic anemia following treatment of chronic myeloid leukemia with busulfan.

Two types of acquired idiopathic sideroblastic anaemia AISA: Recurrent thrombocytopenia, erythroid hypoplasia and sideroblastic anaemia associated with hypothermia. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia.

Iron-sulfur cluster biogenesis and human disease. SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value.

Frequent pathway mutations of splicing machinery in myelodysplasia. Genet Test Mol Biomarkers. Bone marrow biopsy findings in childhood anemia: Arch Pathol Lab Med.

Prevalence and distribution of ringed sideroblasts in primary myelodysplastic syndromes. The bone marrow aspirate of healthy subjects. Onset of X-linked sideroblastic anemia in the fourth decade. Late-onset X-linked sideroblastic anemia following hemodialysis. Primary acquired sideroblastic anemia and myelodysplastic syndrome from a geriatric point of view. Recurrent acquired sideroblastic anemia in a twin pregnancy.

J Matern Fetal Med. Current Medical Diagnosis and Treatment. Heterogeneity of acquired idiopathic sideroblastic anaemia AISA. Idiopathic refractory sideroblastic anemia: Natural history of idiopathic refractory sideroblastic anemia.

May A, Fitzsimons E. Kumar A, Jazieh AR. Case report of sideroblastic anemia caused by ingestion of coins. Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase ALAS2 gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.

Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia. A novel form of hereditary sideroblastic anaemia with macrocytosis. Dorland's Illustrated Medical Dictionary. Basophilic stippling - lead poisoning.

American Society of Hematology image bank. Severe iron deficiency causing loss of ring sideroblasts. Determination of vitamin B6 vitamers and pyridoxic acid in plasma: NCCN clinical practice guidelines in oncology. Koc S, Harris JW. Primary acquired sideroblastic anaemia: Hosp Pract Off Ed.

Zoller WG, Hehlmann R. Sideroachrestic anemia with iron loading: French TJ, Jacobs P. Sideroblastic anaemia associated with iron overload treated by repeated phlebotomy. S Afr Med J. Haem arginate treatment for hereditary sideroblastic anaemia.

Hypochromic red blood cells in low-risk myelodysplastic syndromes: Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. Efficacy of single-agent lenalidomide in patients with JAK2 VF mutated refractory anemia with ring sideroblasts and thrombocytosis. Danazol therapy in acquired idiopathic sideroblastic anemia. Acute sideroblastic anemia in active systemic lupus erythematosus.

Antibody-mediated acquired sideroblastic anemia: Treatment of sideroblastic anemia with chloroquine. This leads to granular deposition of iron in the mitochondria that form a ring around the nucleus of the developing red blood cell. Congenital forms often present with normocytic or microcytic anemia while acquired forms of sideroblastic anemia are often normocytic or macrocytic.

The anemia is moderate to severe and dimorphic. Microscopic viewing of the red blood cells will reveal marked unequal cell size and abnormal cell shape. Basophilic stippling is marked and target cells are common.

Pappenheimer bodies are present in the red blood cells. The mean cell volume is commonly decreased i. The RDW is increased with the red blood cell histogram shifted to the left. Leukocytes and platelets are normal. Bone marrow shows erythroid hyperplasia with a maturation arrest. Serum iron , percentage saturation and ferritin are increased. The total iron-binding capacity of the cells is normal to decreased.

Stainable marrow hemosiderin is increased. Occasionally, the anemia is so severe that support with transfusion is required. These patients usually do not respond to erythropoietin therapy.

In severe cases of SBA, bone marrow transplant is also an option with limited information about the success rate. Some cases are listed on MedLine and various other medical sites.

In the case of isoniazid -induced sideroblastic anemia, the addition of B 6 is sufficient to correct the anemia. Desferrioxamine , a chelating agent , is used to treat iron overload from transfusions.

Therapeutic phlebotomy can be used to manage iron overload. Sideroblastic anemias are often described as responsive or non-responsive in terms of increased hemoglobin levels to pharmacological doses of vitamin B 6. It is the most common congenital cause. Mostly affects males, but can also affect women when skewed inactivation of X chromosome occurs with aging. Women usually manifest the anemia later in life. Anemia is variable in severity and more commonly remains stable.

SCL25A38 defects - this is a gene for mitochondrial transporter, likely involved in bringing glycine into mitochondria, which is required for ALA production. This type is inherited in an autosomal recessive pattern and is usually a more severe anemia requiring chronic transfusion support. Glutaredoxin deficiency - protein involved in iron sulfur biogenesis, which potentially reduces ALAS 2 translation through iron regulatory protein 1 IPR1.

X-linked sideroblastic anemia with non-progressive cerebellar ataxia - defect in ABCB 7 protein involved in iron sulfur machinery. With the defect, iron remains trapped in mitochondria. Anemia is usually mild and no iron overload is observed. Pearson marrow pancreas syndrome - severe anemia, neutropenia, thrombocytopenia, exocrine pancreatic insufficiency, lactic acidosis, hepatic and renal problems and failure to thrive as a child.

The defects are usually in the structure of mitochondria DNA deletions thus impairing synthesis of proteins crucial to mitochondrial function of the red cells. Starts in childhood with exercise intolerance, and then progresses to anemia, lactic acidosis and worsening myopathy in adolescence.

Starts between infant to adolescent age and manifests with anemia, diabetes and sensorineural deafness. Alcohol use inhibits heme synthesis in several ways and may cause dietary deficiency in pyridoxine. If sideroblastic anemia is noted in alcoholics, it usually indicates a more severe case of anemia. Interestingly alcohol effects red blood cell production more than white cells. Chloramphenicol inhibits mitochondrial membrane protein synthesis.

Ring sideroblasts usually appear in most patients taking the drug, especially in longer courses and with higher doses. Anemia is moderate to severe. Isoniazid INH reacts with pyridoxine, thus inhibiting the first step of heme synthesis. Also may inhibit ALAS 2 activity. It usually develops months after starting the therapy and usually manifests as typical, moderate to severe sideroblastic anemia.

Lead toxicity - rare and questionable cause, and most often just leads to microcytic anemia with basophilic stippling. Pyridoxine deficiency can be due to malnutrition which is quite rare or from discontinuation of multivitamin which contained it. Typically, peripheral neuropathy and dermatitis are more pronounced than anemia. Copper deficiency - copper has complex role in iron metabolism.

It participates in intestinal iron absorption and mobilization from the liver. It is also a part of cytochrome oxidase, an enzyme involved in iron reduction. The deficiency usually occurs in patients who have decreased absorption of copper. Examples include gastric surgery, prolonged parenteral nutrition or enteral feedings without inclusion of copper in the feeds. Decreased intestinal absorption such as celiac disease or other malabsorptive syndromes may also be the cause.

Lastly, copper chelation has been reported to cause anemia which tends to be severe with hemoglobin levels as low as 5 with normal to slightly-increased mean corpuscular volume MCV.

Iron overload is usually not observed. In addition to sideroblastic changes, patients may develop neutropenia and neurologic abnormalities. The next big group in terms of prevalence after reversible.

Refers to myelodysplastic syndrome MDS related or clonal sideroblastic anemia here the abnormal cells grow in clones. The defects are thought to be in heme synthesis pathways, although no clear mutations have been identified.

ABCB7 transporter levels were found to be reduced, and so this protein might be involved in pathogenesis. Unlike in congenital forms of sideroblastic anemia, erythroblasts are effected at all stages of maturation, beginning from stem cells.

It usually occurs in the middle age to older population and is often discovered by laboratory abnormalities or symptoms consistent with anemia. Patients may become transfusion dependent and develop iron overload.

Refractory anemia with ring sideroblasts RARS - occurs as sole anemia. Often very similar phenotypically to X-linked sideroblastic anemia. Usually runs a benign course and has very low chance of transformation to leukemia. This also has a higher incidence of acute leukemia conversions.

RARS-T - a variant of anemia with thrombocytosis, frequently associated with JAK2 mutation, has the best prognosis of all 3 categories. Any anemia can be considered in the differential diagnosis of sideroblastic anemia. The most important types of anemia to consider are the other causes of microcytic anemia, such as thalassemia, iron deficiency or lead poisoning. In addition, different anemias can coexist, for example, a patient with sideroblastic anemia can also be iron deficient.

Some types of sideroblastic anemias can have normocytic or macrocytic cells, and therefore, the differential diagnosis should include any cause of anemia that fits the clinical presentation of a patient.

Many different anemias may show similar exam and laboratory findings. Sideroblastic anemia can be guessed based on history, clinical and laboratory presentation, however bone marrow examination is the only study that can accurately distinguish sideroblastic anemia from other types.

Findings related to cardiac damage in case of iron accumulation, such as arrhythmias, or heart failure, which usually occur late in disease course - rare. The degree of microcytosis and hypochromia parallel the severity of anemia. Red cell distribution width RDW is increased as there are variable sizes of cells.

Often at times you may see dimorphic cells, different in sizes - micro and macrocytic or normocytic especially in females with X-linked sideroblastic anemia, MDS and alcohol use. Complete blood count with differential will show variable severity of anemia, with usually normal leukocytes and platelets. However the latter 2 cell lines may be abnormal if hypersplenism is present, in some subtypes of MDS, drug or alcohol toxicity.

The smear shows many microcytic and hypochromic cells. Some dysmorphic cells can also be seen. Occasionally Pappenheimer bodies, which are iron inclusions, can be seen as well see Figure 1 , Figure 2. Iron studies usually show elevated iron, transferrin saturation and ferritin levels with low transferrin levels.

However, iron deficiency may coexist, especially in young menstruating women. At this point, would need to confirm the suspected diagnosis with bone marrow biopsy, which is the only way to accurately diagnose the disease. Bone marrow examination - shows crowded hyperplastic marrow with ineffective erythrocytes and ring sideroblasts, that are mostly seen in the later non-dividing stages of erythroblasts differentiation except MDS where they are seen in all stages.

Bone marrow biopsy will also help in diagnosis of MDS, if sideroblastic anemia is related to it see Figure 3 , Figure 4 , Figure 5. As a note - often it is possible to see blue iron granules scattered around the cytoplasm on bone marrow examination. This is a normal finding and represents endosomes filled with ferritin loaded with unutilized iron. Ring sideroblasts, on the other hand, are never a normal finding.

The iron in them is stored in mitochondrial ferritin. Once the diagnosis of sideroblastic anemia is made, will need to perform other tests to find the etiology: May check red blood cell protoporphyrin levels. They will be normal or low in X-linked sideroblastic anemia and SLC25A38 deficiency as the defect is in early step of heme pathway, thus not forming enough porphyrins.

They will be high in X-linked sideroblastic anemia with ataxia since the defect is not in heme synthesis pathway. It is also elevated in acquired forms related to MDS.

If diagnosis of MDS type sideroblastic anemia is suspected, bone marrow performed would aid in the diagnosis. With any of the causes found, may need to perform tests to look for complications of the disease: Liver biopsy may be considered if iron overload is suspected.

It may show iron deposition or evidence of cirrhosis.

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Patient with X-linked sideroblastic anemia. (A) Peripheral blood smear with many Peripheral blood smear shows dimorphic red cells How should the results be. Sideroblastic anemia or sideroachrestic anemia is a form of anemia in which the bone see coarse basophilic stippling of red blood cells on peripheral blood smear;. Nov 18,  · Sideroblastic Anemias Workup. Complete Blood Cell Count and Peripheral Smear. two patients with acquired idiopathic sideroblastic anemia. Blood.