Sideroblastic anemia overview

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Differentiating Sideroblastic Anemia from other Diseases

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nazia Fuad M.D.

Overview

Sideroblastic anemia is diverse type of anemia with both congenital and acquired underlying causative factors. The resulting anemia varies in severity. Ring sideroblasts in the bone marrow are the pathognomic feature of both congenital and acquired sideroblastic anemias. Ringed sideroblasts are the erythroblasts in bone marrow with iron loaded mitochondria and are visualized with prussian blue staining. The underlying cause for these iron deposits is defect in incorporation of iron in to heme resulting in accumulation of iron in mitochondria. The main acquired factors in etiology of sideroblastic anemia are alcohol and drugs, which responds well to removing the underlying agent and pyridoxine therapy. The common forms of congenital sideroblastic anemias are X-linked sideroblastic anemia due to an ALAS2 mutation and the autosomal recessive pattern with mutations in SLC25A38 genes. Overall, XLSA is a benign disorder and mostly responds to pyridoxine. The congenital autosomal recessive sideroblastic anemia due to SLC25A38 mutations is considered to be more severe. It does not respond to pyridoxine. The patients are usually of young age and stem cell transplantation is the only treatment of these patients.

Ring sideroblasts

Ring sideroblasts are erythroblasts with iron-loaded mitochondria visualized by Prussian blue staining (Perls’ reaction) as a perinuclear ring of blue granules

Historical Perspective

X-linked sideroblastic anemia was first described by Cooley (1945), a Detroit pediatrician-hematologist. He considered possible X-linkage in a family in which 19 males in 5 generations were affected, with transmission through unaffected females. In 1946 Rundles and Falls reported 2 families. Slightly enlarged spleens and minor red cell abnormalities without anemia were observed in female carriers. Pyridoxine responsiveness was observed in at least 2 affected members of Rundles and Falls' family In 1961 Byrd and Cooper named the disorder as hereditary iron-loading anemia. In 1983 Peto et al concentrated on iron overload in mild sideroblastic anemia after the death from cardiac siderosis of a middle-aged woman with a very mild form of familial sideroblastic anemia. Cotter et al. (1995) described a previously healthy 81-year-old woman with microcytic sideroblastic anemia. The diagnosis of the X-linked congenital sideroblastic anemia resulted in successful treatment with pyridoxine. She was diagnosed to be heterozygous for a point mutation of the ALAS2 gene. Aivado et al. (2006) reported a family in which a mother and her 2 daughters had sideroblastic anemia that was unresponsive to pyridoxine. It was confirmed by genetic analysis. The disorder was variable in severity and X-chromosome inactivation studies were done. In 1971 Hines found decreased levels of pyridoxal phosphokinase in red cells and livers of patients with pyridoxine-dependent refractory sideroblastic anemia. In 1973A oki et al found deficiency of delta-aminolevulinic acid synthetase in the red cells of patients with sideroblastic anemia. In 2001 Levi et al discovered that iron accumulates in the mitochondria.

Classification

sideroblastic anemia may be classified according to its etiology into two groups, congenital and acquired. Congenital catagory include X-linked, autosomal and mitochondrial DNA defects. Acquired sideroblastic anemias is divided in to 2 catogries, acquired reversible and acquired clonal. Sideroblastic anemias secondry to alcohol ingestion,drugs like isoniazid and chloramphenicol, comes under the catagory of acquired reversible sideroblastic anemia. Copper and vitamin B6 deficiency also causes acquired reversible sideroblastic anemias. Acquired clonal sideroblastic anemias include refractory anaemia with ring sideroblasts (RARS) refractory anaemia with multilineage dysplasia and ring sideroblasts (RCMD) and refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T). sideroblastic anemia can be divided according to MCV mean corpuscular volume in to two catogries, MCV decreased and MCV normal or increased. X linked sideroblastic anemia in males, X linked sideroblastic anemia with ataxia, and autosomal recessive congenital sideroblastic anemia (ARCSA) present with low MCV. Isoniazid also causes low MCV. Alcoholism, copper defeciency, X linked sideroblastic anemia in females and pearson marrow-pancreas syndrome will show either high or normal MCV

Pathophysiology

It is understood that sideroblastic anemia is the result of defects in the steps of heme biosynthesis that occur within the mitochondrion. Sideroblasts are the pathognomic feature of sideroblastic anemia. There is deffect in incorporation of iron in to heme. As a result the iron accumulates in mitochondria of red cell precursors. Ring sideroblasts are erythroblasts that have iron-loaded mitochondria. The iron granules are arranged around the nucleus in a ring form. They can be seen with prussian blue staining as blue granules around the nucleus.The pathophysiology of sideroblastic anemia depends on the underlying cause. Impaired hemoglobin production, results in reduced number of mature erythrocytes. Resulting anemia is usually microcytic and hypochromic. The iron overload in sideroblastic anemia is due to abnormalities in iron utilization. There is increased iron transport to erythroblasts. Since the body sense anemia intestinal iron absorption increases. There is increased iron content in mitochondria of erythroblasts and systemic iron accumulation. 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 development of congenital sideroblastic anemia is the result of multiple genetic mutations in several genes involved in heme synthesis resulting in autosomal recessive congenital sideroblastic anemia. Out of many genes SLC25A38 mutations is the most common.

Causes

There are no life-threatening causes of sideroblastic anemia, however complications resulting from untreated sideroblastic anemia are common. Common causes of sideroblastic anemia include, alcoholism, chloramphenicol, isoniazid, copper deficiency (nutritional, zinc-induced, copper chelation), vit B-6 deficiency, X-linked sideroblastic anemia. Less common causes of sideroblastic anemia include those associated with myelodysplastic syndrome, autosomal recessive disorders, X-linked sideroblastic anemia, defect in ALAS2 autosomal recessive sideroblastic anemia with mutations in the SLC25A38 gene and genetic syndromes.

Differentiating Sideroblastic anemia overview from Other Diseases

Epidemiology and Demographics

Patients of all age groups may develop sideroblastic anemia. The incidence of acquired sideroblastic anemia increases with age; the median age at diagnosis is 74 years. Chronic sideroblastic anemia is usually first diagnosed among middle and older age group. There is no racial predilection to sideroblastic anemia. Males are more commonly affected than females in X-linked recessive types of sideroblastic anemia.

Risk Factors

Common risk factors in the development of sideroblastic anemia are male gender (X-linked SA) family history of hreditary SA. chronic alcohol abuse.Less common risk factors in the development of sideroblastic anemia are drugs, isoniazid, pyrazinamide, chloramphenicol, cycloserine, and azathioprine, copper deficiency and pyridoxine deficiency. Hypothermia causes sideroblastic anemia by affecting mitochondrial functions.

Screening

According to The National Center for Biotechnology Information NCBI, screening for sideroblastic anemia by using one of the tests, mitochondrial focused nuclear gene panel, congenital sideroblastic anemia panel and PUS1 gene sequencing is available for, molecular confirmation of genetic sideroblastic anemia, testing of patients with positive family history of sideroblastic anemia and prenatal diagnosis for gene mutation in at-risk pregnancies.

Natural History, Complications, and Prognosis

Natural History

Majority of patients of sideroblastic anemia at the time of diagnosis shows erythroid abnormalities and ineffective erythropoiesis. Granulocytic and megakaryocytic cell lines involvement is also common. In the initial stages bone marrow reveal erythroid expansion with ineffective erythropoiesis. Progression to bone marrow failure occurs in the course of the disease. The next phase in natural history of sideroblastic anemia is iron overload and evolution to nonlymphocytic leukemia. The most common causes of death are related to complications of iron overload and evolution into acute nonlymphocytic leukemia ANLL.

Complications

Common complications of sideroblastic anemia include secondry hemochromatosis, thrombocytopenia, growth retardation, blindness, deafness, Ineffective erythropoiesis. myocardial siderosis, liver cirrhosis and malabsorption.

Prognosis

Depending on the type of sideroblastic anemia the prognosis may vary. However, the prognosis is generally regarded as good. Sideroblastic anemia secondry to drugs or alcohol as underlying cause is associated with the most favorable prognosis. (5-10%) of Severe refractory sideroblastic anemias associated with MDS undergo leukemic transformation. and acute myeloid leukemia markedly reduce life expectancy. Patients who do not need blood transfusions are likely to be long-term survivors. The transfusion dependent are at risk of death from the complications of secondary hemochromatosis.

Diagnosis

Diagnostic Criteria

Sideroblastic anemia may be diagnosed at any time if one or more of the following criteria are met, microcytic hypochromic anemia and ring sideroblasts.

History and Symptoms

The hallmark of sideroblastic is fatigue, decreased tolerence to physical activity and dizziness. A positive history of toxin or drug exposure, family history of unexplained anemia, and alcoholism is suggestive of sideroblastic anemia. The most common symptoms of sideroblastic anemia include malaise, irritibility, fatigue, dyspnea on exertion, and palpiataion. Less common symptoms are diarrhea, polyuria, deafness, blindness, and abdominal pain.

Physical Examination

Patients usually presents with signs of anemia with pale skin, dyspnea, tachycardia. Growth retardation is seen in children. Other signs include hypothermia, lead line on teeth margins, photosensitivity, petechiae, optic atrophy, ataxia, incoordination. Hepatosplenomegaly is common patients with iron overload.

Laboratory Findings

Laboratory findings consistent with the diagnosis of sideroblastic anemia include decreased MCV, low reticulocyte count, increased ferritin levels, decreased total iron binding capacity. Hematocrit falls to 20-30%. Serum iron levels are high so as transferrin saturation. In sideroblastic anemia associated with lead toxicity, basophilic stippling of red blood cells on peripheral smear is common. Prussian Blue stain of RBC in marrow, shows ringed sideroblasts. sideroblastic anemia that is associated with myelodysplastic syndrome (MDS), may show leukopenia, and thrombocytopenia,

Imaging Findings

No imaging studies are usually done for sideroblastic anemia.

Other Diagnostic Studies

Genetic testing is done to diagnose the type of mutations and diagnose the disease in high risk patients with positive family history of sideroblastic anemia.

Treatment

Medical Therapy

The medical therapy for sideroblastic anemia include pyridoxine, thiamine and follic acid. For iron overload iron chelators are used. In severe cases, bone marrow transplant is also an option with limited information about the success rate.

Surgery

there is no surgical treatment for sideroblastic anemia.

Prevention

Effective measures for the prevention of acquired sideroblastic anemia include refraining from alcohol, avoiding excessive intake of zinc, nutritional supplements, pyridoxine prophylaxis in patients recieving isoniazid.

References


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