Sideroblastic anemia

The WHO International Working Group on Morphology of MDS (IWGM-MDS) defined three types of sideroblasts:^[citation needed]

1. Type 1 sideroblasts: fewer than 5 siderotic granules in the cytoplasm
2. Type 2 sideroblasts: 5 or more siderotic granules, but not in a perinuclear distribution
3. Type 3 or ring sideroblasts: 5 or more granules in a perinuclear position, surrounding the nucleus or encompassing at least one third of the nuclear circumference.

Type 1 and type 2 are found in non-sideroblastic anemias. Type 3 is found only in sideroblastic anemia.^{[citation needed]}

Symptoms and signs

Symptoms of sideroblastic anemia include skin paleness, fatigue, dizziness, and enlarged spleen and liver. Heart disease, liver damage, and kidney failure can result from iron buildup in these organs.^[5]

Symptoms of sideroblastic anemia usually resemble the common symptoms of anemia. In addition to the symptoms listed above, patients with sideroblastic anemia may experience shortness of breath, heart palpitations, and headache. Some patients may have bronze-colored skin due to an overload of iron. Patients with syndromic hereditary sideroblastic anemia may experience diabetes mellitus and deafness.^[6]

Causes

Causes of sideroblastic anemia can be categorized into three groups: congenital sideroblastic anemia, acquired clonal sideroblastic anemia, and acquired reversible sideroblastic anemia. All cases involve dysfunctional

• Congenital sideroblastic anemia
  • X-linked sideroblastic anemia: This is the most common congenital cause of sideroblastic anemia and involves a defect in ALAS2,^[7] which is involved in the first step of heme synthesis. Although X-linked, approximately one third of patients are women due to skewed X-inactivation (lyonizations).
  • Autosomal recessive sideroblastic anemia involves mutations in the
    SLC25A38 gene. The function of this protein is not fully understood, but it is involved in mitochondrial transport of glycine. Glycine is a substrate for ALAS2
    and necessary for heme synthesis. The autosomal recessive form is typically severe in presentation.
  • Genetic syndromes: Rarely, sideroblastic anemia may be part of a congenital syndrome and present with associated findings, such as
    pancreatic insufficiency
    .
• Acquired clonal sideroblastic anemia
  • Clonal sideroblastic anemias fall under the broader category of
    thrombocytosis
    (RARS-T), and refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS). These anemias are associated with increased risk for leukemic evolution.
• Acquired reversible sideroblastic anemia
  • Causes include excessive alcohol use (the most common cause of sideroblastic anemia),
    pyridoxine deficiency (vitamin B₆ is the cofactor in the first step of heme synthesis^[8]), lead poisoning^[9] and copper deficiency.^[10] Excess zinc^[11] can indirectly cause sideroblastic anemia by decreasing absorption and increasing excretion of copper. Antimicrobials that may lead to sideroblastic anemia include isoniazid (which interferes with pyridoxine metabolism), chloramphenicol (which, by inhibiting the synthesis of mitochondrial membrane protein, impairs mitochondrial respiration^[10]), cycloserine, and linezolid.^[12]

Ringed sideroblasts are seen in the bone marrow.

On the peripheral blood smear can be found erythrocytes with basophilic stippling (cytoplasmic granules of RNA precipitates) and Pappenheimer bodies (cytoplasmic granules of iron).^[13]

The anemia is moderate to severe and dimorphic. Microscopic viewing of the red blood cells will reveal marked

• Hereditary or congenital sideroblastic anemia may be X-linked[14] or autosomal.

GLRX5 has also been implicated.^[15]

• Acquired, or secondary, sideroblastic anemia develops after birth and is divided according to its cause.

Laboratory findings

• Serum Iron: high
• increased ferritin levels
• decreased total iron-binding capacity
• high transferrin saturation
• Hematocrit of about 20-30%
• The mean corpuscular volume or MCV is usually normal or low for congenital causes of sideroblastic anemia but normal or high for acquired forms.
• With lead poisoning, see coarse basophilic stippling of red blood cells on peripheral blood smear
• Specific test: Prussian blue stain of RBC in marrow shows ringed sideroblasts. Prussian blue staining involves a non-enzymatic reaction of ferrous iron with ferrocyanide forming ferric-ferrocyanide, which is blue in color. A counterstain may be used to provide better visualization.

Treatment

Occasionally, the anemia is so severe that support with transfusion is required. These patients usually do not respond to erythropoietin therapy.^[16] Some cases have been reported that the anemia is reversed or heme level is improved through use of moderate to high doses of pyridoxine (vitamin B₆). 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 B₆ is sufficient to correct the anemia. Deferoxamine, a chelating agent, is used to treat iron overload from transfusions. Therapeutic phlebotomy can be used to manage iron overload.^[17]

Prognosis

Sideroblastic anemias are often described as responsive or non-responsive in terms of increased hemoglobin levels to pharmacological doses of vitamin B₆.^{[citation needed]}

1- Congenital: 80% are responsive, though the anemia does not completely resolve.

2- Acquired clonal: 40% are responsive, but the response may be minimal.

3- Acquired reversible: 60% are responsive, but course depends on treatment of the underlying cause.

Severe refractory sideroblastic anemias requiring regular transfusions and/or that undergo leukemic transformation (5–10%) significantly reduce life expectancy.

See also

• Anemia
• Siderosis
• List of hematologic conditions
• Hematopoietic stem cell transplantation

References