Different Forms of Sideroblastic Anemia

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This entry is adapted from the peer-reviewed paper 10.3390/diagnostics12071752

Ring sideroblasts are commonly seen in myelodysplastic neoplasms and are a key condition for identifying distinct entities of myelodysplastic neoplasms according to the WHO classification. However, the presence of ring sideroblasts is not exclusive to myelodysplastic neoplasms. Ring sideroblasts are as well either encountered in non-clonal secondary acquired disorders, such as exposure to toxic substances, drug/medicine, copper deficiency, zinc overload, lead poison, or hereditary sideroblastic anemias related to X-linked, autosomal, or mitochondrial mutations.

sideroblastic anemia ring sideroblasts Perls’ stain iron overload

1. Introduction

Perls’ stain is a cytochemical reaction performed on bone marrow (BM) smears ^[1]. It remains the gold standard method for the detection of iron overload, and its main purpose is to detect the presence of ring sideroblasts (RS). RS are pathological erythroblasts with an excess of iron-loaded mitochondria. They have a minimum of five blue granules covering at least one-third of the nuclear circumference ^[2]. Ring sideroblasts should not be confused with ferritin sideroblasts. After Perls’ stain, ferritin sideroblasts, corresponding to normal erythroblasts, show few blue granules scattered in the cytoplasm, which represent endosomes filled with excess iron not used for heme synthesis. While the iron in ferritin sideroblasts is stored in cytosolic ferritin, the iron in ring sideroblasts is stored in mitochondrial ferritin ^[3].

Heme, which is composed of iron and protoporphyrin, is an essential component of hemoglobin. The control of heme biosynthesis in the erythrocyte depends on the availability of intracellular iron. Inefficient heme biosynthesis results in an imbalance between the amount of iron overloaded in the erythroblasts and the amount of iron released into the circulation ^[4]^[5]. The defective use of iron at normal or high plasma concentrations leads to its accumulation in erythroblasts. Hemoglobin synthesis is then impaired, resulting in the development of anemia ^[6]. The detection of RS is required in myelodysplastic neoplasms (MDSs) or myelodysplastic/myeloproliferative neoplasms (MDS/MPNs), allowing a more accurate classification of these acquired clonal conditions according to WHO recommendations ^[7]^[8]^[9]^[10].

2. Diagnosis

Sideroblastic anemia is a heterogeneous group of rare BM disorders that can be inherited or acquired, isolated, or as part of a syndrome. They can occur in both adults and children. Common causes of sideroblastic anemia are alterations in heme biosynthesis, disturbance of the stability or biogenesis/repair of the iron-sulfur (Fe-S) cluster, and dysfunction of the mitochondrial respiratory chain ^[11]^[12]^[13].

The incidence of acquired sideroblastic anemias far exceeds that of the inherited varieties. Except for MDSs, which are the main clonal acquired form of sideroblastic anemias, the other acquired forms are reversible and are also the consequence of toxic exposure or nutritional factor deficiencies. Congenital sideroblastic anemias are due to X-linked or autosomal dominant or recessive mutations, which induce abnormal iron deposition in the mitochondria of erythroblasts. Two forms of congenital sideroblastic anemia exist: syndromic and non-syndromic.

3. Congenital Sideroblastic Anemias

Congenital sideroblastic anemias are a rare condition and constitute a heterogeneous group of disorders. The genetic inheritance is transmitted in three modes: X-linked, autosomal recessive, and maternal from mitochondrial DNA mutations or large deletions. This type of anemia is more frequent in children. Congenital sideroblastic anemias are isolated or syndromic, associated with various extra-hematological affectations (developmental, neurological, diabetes, myopathy, etc.) or malformative syndromes.

3.1. Non-Syndromic Forms

The non-syndromic forms of congenital sideroblastic anemias are related to abnormalities in the genes for heme metabolism (ALAS2: XLSA form, SLC25A38: SLC25A38 deficiency form) and, more rarely, to mutations in the Fe-S cluster biogenesis protein (GLRX5: GLRX5 deficiency form; HSPA9: HSPA9 deficiency form; HSCB: HSCB deficiency form) ^[14]^[15]^[16]. Hepatic iron overload is the major feature of non-syndromic forms.

The anemia is microcytic hypochromic and is accompanied by an increased red cell distribution width and hemochromatosis. In BM, erythroblasts are dysplastic and vacuolized with areas of empty cytoplasm due to a lack of hemoglobinization. All the mutations that cause congenital sideroblastic anemias have not yet been identified.

The most frequent non-syndromic congenital sideroblastic anemia is caused by mutations in the ALA synthase gene (ALAS2). It is transmitted in an X-linked recessive mode. This gene is expressed exclusively in erythroblasts and codes for the first enzyme of heme synthesis, delta-aminolevulinic acid synthase. This mutation has an impact on the affinity of the enzyme for its cofactor pyridoxal-5 phosphate. The degree of anemia and the age of diagnosis (infancy to adulthood) is very variable. Approximately two-thirds of patients are sensitive to pyridoxine therapy. The risk of iron overload, even in the absence of blood transfusions, is almost constant and represents a serious complication that must be treated. Several cases of heterozygous women with ALAS2 mutations and an unusual phenotype of macrocytic anemia have been described. This particular type of ALAS2 mutation induces prenatal male lethality.

The second most common non-syndromic congenital sideroblastic anemia is due to mutations in the SLC25A38 gene ^[17]. It is transmitted in an autosomal recessive mode. This gene is expressed mainly in erythroblasts and codes for transporter proteins present in the inner membrane of mitochondria. SLC25A38 codes for the mitochondrial glycine transporter, which is essential for the synthesis of ALA synthase. The phenotype associated with SLC25A38 mutations is very similar to that of ALAS2 mutations, including iron overload. The diagnosis is made at birth or in early childhood as severe anemia. Patients are not sensitive to pyridoxine therapy and are transfusion-dependent.

GLRX5, HSPA9, and HSCB mutations are very rare. These genes encode a mitochondrial protein involved in Fe-S clusters biogenesis. The Fe-S cluster has an essential role in the maintenance of iron homeostasis and regulation of ALAS2 biogenesis. Mutation of the GLRX5 gene leads to the abnormality of Fe-S cluster biosynthesis, the mutation of the ABCB7 gene leads to impaired Fe-S cluster transportation, and the mutation of the HSPA9 gene leads to the defection of the Fe-S cluster. Fe-S cluster production and transport is essential for the assembly of hemoglobin and leads to cytosolic iron depletion in erythroblasts. The deficiency of GLRX5 generates mild to severe anemia with iron overload in the liver, enlargement of the spleen and liver, and type 2 diabetes. The diagnosis is made during adulthood. Patients are not responsive to pyridoxine therapy ^[3]. HSPA9 and HSCB deficiencies are both diagnosed in childhood. Anemia is mild to severe for HSPA9 deficiency and moderate for HSCB deficiency. A clinical symptom is retinitis pigmentosa for HSPA9 deficiency, whereas no abnormality is associated with HSCB deficiency.

RS has been documented in very few patients, usually children, with erythropoietic protoporphyria, which is a disorder characterized by a marked deficiency of FECH. This enzyme is required for the catalysis of iron incorporation in protoporphyrin IX. EPP is characterized by cutaneous manifestations of acute painful photosensitivity with erythema and edema. Mild anemia is observed in most patients, and occasionally, erythropoietic porphyria results in sideroblastic anemia.

Special attention should be paid to patients with beta-thalassemia major, who also present with microcytic anemia, a hemolytic component, and the presence of a variable proportion of RS. On bone marrow smears, the presence of acidophilic erythroblasts with an area of hemoglobin condensation and precipitates of unpaired globin chains that appear as large dark granules is identified ^[18]. This appearance allows differential diagnosis with congenital sideroblastic anemias due to abnormalities in heme synthesis.

3.2. Syndromic Forms

Syndromic hereditary sideroblastic anemias are diverse, very uncommon, and are all autosomal recessive disorders ^[19]. The anemia is typically either normocytic or macrocytic.

They are due to mitochondrial dysfunction such as deletions in mitochondrial DNA (Pearson marrow-pancreas syndrome (PMPS) ^[20]) or mutations in nuclear genes coding for mitochondrial proteins (TRNT1: SFID form; LARS2: LARS2 deficiency form; YARS2: MLASA2 form; PUS1: MLASA1 form), or mutations in mitochondrial respiratory chain proteins (MT-ATP6, SLC19A2, NDUFB11) and mutations in the Fe-S cluster biogenesis protein (ABCB7: XLSA/A form) ^[15]^[17]. Mutations lead to mitochondrial respiratory chain biosynthesis impairment and affect iron metabolism. In many of these forms, there are signs of mitochondrial cytopathy with high blood lactate to pyruvate ratio.

In Pearson syndrome, the percentage of RS in the BM is variable and is sometimes low or absent ^[21]. Vacuolation of marrow erythroid and myeloid precursors and the presence of erythroblasts with laminated cytoplasm is a diagnostic clue. This syndrome presents macrocytic anemia with neutropenia, thrombocytopenia, and growth retardation due to exocrine pancreatic insufficiency. The initial presentation occurs in the neonatal period, and patients succumb before three-years-old.

Sideroblastic anemia with B cell Immunodeficiency, periodic Fevers, and Developmental delay (SFID syndrome) is characterized by markedly microcytic anemia ^[22]. As mentioned earlier, this syndrome is due to mutation of the TRNT1 gene, which encodes an enzyme that is involved in the maturation of mitochondrial and nuclear transfer RNAs ^[23]. This disorder onsets in the neonatal period, and patients succumb in their first decade of life.

PUS1, LARS2, and YARS2 mutations are rare and associated with impaired mitochondrial protein synthesis as a result of disrupted post-transcriptional modification of mitochondrial and cytosolic tRNA. PUS1 and YARS2 disorders usually onset in childhood. Anemia is normocytic, mild to severe. Clinical symptoms include myopathy, and lactic acidosis, and although few patients survive to adulthood, the majority die in childhood. LARS2 disorder onsets in infancy and shows a marked phenotypic severe: some patients have a severe multi-systemic disorder since infancy, including lactic acidosis, hydrops, cardiomyopathy, and respiratory insufficiency that causes early death, while others present in the second or third decade of life a mild muscle weakness. Anemia is severe and macrocytic.

Mutations in the specific mitochondrial respiratory complex are rare. The NDUFB11 gene encodes supernumerary subunits of respiratory chain complex (complex I), and the MT-ATP6 gene encodes subunits of adenosine triphosphate synthase (complex V). NDUFB11 disorder onsets in early childhood. Anemia is moderate and normocytic and associated with lactic acidosis and mild myopathy. MT-ATP6 disorder is highly variable, owing to varying degrees of heteroplasmy in the bone marrow and other tissues. It onsets in infancy to early childhood and induces moderate to severe lactic acidosis, myopathy, and neurological abnormalities.

XLSA with ataxia form is characterized by mild to moderate microcytic anemia accompanied by neurologic deficits of delayed motor and cognitive development, incoordination early in life, and cerebellar hypoplasia. ABCB7 encodes an adenosine triphosphate-binding cassette transporter which is responsible for the exportation of Fe-S cluster from the mitochondria to the cytosol. This disorder starts in childhood and usually causes mild to moderate microcytic anemia, spinocerebellar ataxia and hypoplasia, and delayed motor development.

There are additional metabolic diseases that combine macrocytic anemia with variable counts of RS. These include, in particular, congenital defects in folate and cobalamin metabolism and thiamine-sensitive megaloblastic anemia (TRMA form: mutations in the thiamine high-affinity transporter Slc19A2) ^[24]. TRMA form is a rare autosomal recessive disorder defined by the occurrence of megaloblastic anemia, variable neutropenia, variable thrombocytopenia, diabetes mellitus, and sensorineural hearing loss between infancy and adolescence. Mutations in the SLC19A2 gene lead to a decrease in the cell membrane transporter of thiamine, Slc19A2. Thiamine deficiency causes impaired production of succinyl-coenzyme A, a substrate of ALAS2, needed for heme biosynthesis. The block of heme biosynthesis is suspected to be involved in the cause of ineffective erythropoiesis and thus the presence of RS in the BM.

4. Secondary Acquired Sideroblastic Anemias

Acquired metabolic sideroblastic anemias are non-clonal and reversible forms. They may be distinguished from acquired clonal forms representing a group of acquired clonal myeloid neoplasia (myelodysplastic neoplasms) characterized by ineffective hematopoiesis. Sideroblastic anemia occurs in a number of different situations, and a specialist in laboratory medicine should therefore study all possible etiologies to rule out secondary causes ^[25]. Indeed, some of their characteristics may overlap with those of congenital or acquired clonal forms. Agents known in the literature to produce metabolic sideroblastic anemia are listed below: exposure to toxic substances (alcohol use ^[26], heavy metal intoxication (lead ^[27], arsenic, mercury), benzene exposure, drugs (anti-tuberculosis: isoniazid, pyrazinamide ^[28], cycloserine), antibiotics (chloramphenicol, D-penicillamine, linezolid ^[29]^[30]^[31], lincomycin, cefadroxil, fusidic acid ^[32], tetracyclines), cancer chemotherapy (chlorambucil, busulfan, melphalan, lenalidomide ^[33]), malnutrition/deficiency in nutrition or other metabolic disorders (vitamin B1, B6, B9, B12 deficiencies, copper deficiency ^[34]^[35], prolonged parenteral nutrition, gastric surgery, and zinc overdose ^[28]). The action of these agents is to inhibit steps in the heme biosynthetic pathway. Thus, for example, alcohol use and isoniazid interfere with pyridoxine metabolism and leads to the impairment function of the enzyme ALAS2. Lead poisoning inhibits various enzymes (FECH among others) involved in heme biosynthesis. Both chloramphenicol and linezolid inhibit mitochondrial synthesis protein by a dose-dependent action. Copper deficiency reduces the activity of mitochondrial superoxide dismutase and leads to mitochondrial iron accumulation. Zinc overdose, which is often associated with copper deficiency, increases its incorporation into protoporphyrin to the detriment of iron and induces metallothionein, which prevents intestinal absorption of copper.

Hypothermia has also been reported to cause sideroblastic anemia. Marked reduction in erythropoiesis and peripheral thrombocytopenia are described. Hypothermia is thought to interfere with mitochondrial metabolism and oxidative phosphorylation. The changes usually reverse with the normalization of temperature.

In all these situations, deficient reticulocyte production, intramedullary death of red blood cells, and BM erythroid hyperplasia with dysplasia occur. Anemia and morphological abnormalities disappear when drugs are discontinued, toxins avoided, and minerals or vitamins supplemented.

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