Sideroblastic anemia: What is it? Causes, Symptoms and Treatment

Mitochondria are the source of oxidative phosphorylation that provides most of the ATP used by eukaryotic cells.

Sideroblastic anemias are a heterogeneous group of disorders with two common characteristics: ring sideroblasts in the bone marrow (abnormal normoblasts with excessive iron accumulation in the mitochondria) and alteration of heme biosynthesis (Bottomley, 1982; May et al., 1994 ).

The etiology, epidemiology, pathophysiology, and treatment of these conditions differ significantly. The mitochondria are the nexus of sideroblastic anemia, however. Altered mitochondrial metabolism is at the center of all sideroblastic anemias in which a cause has been determined.

The mature erythrocyte is the only mammalian cell that lacks mitochondria and is dependent on glycolysis as an energy source. Most cells contain between 100 and 300 mitochondria (Jaussi, 1995).

Mitochondria are semi-autonomous organelles that probably started as independent prokaryotes that invaded eukaryotic cells more than a billion years ago.

A symbiotic relationship eventually developed between these prokaryotic cells and their eukaryotic hosts. The ancient prokaryotes lost the capacity for independent existence but became indispensable for eukaryotic cells. Mitochondria retain vestiges of their previous independent life.

Most importantly, mitochondria have small DNA genomes (approximately 16 kb) and replicate independently within their host cells. Mitochondrial DNA retains many characteristics of prokaryotic genomes, including a circular structure lacking introns.

 

The mitochondrial genome encodes a small number of proteins and several transfer RNA molecules.

The DNA mitochondrial lacks chromatin organelles have limited capacity for DNA repair.

These characteristics mean that mutations in the mitochondrial genome that produce sideroblastic anemia will probably not be corrected. Mitochondria replicate independently of the nuclear genome.

When the cells undergo mitosis, the mitochondria are distributed stochastically to the daughter cells. Therefore, acquired mitochondrial defects pass unequally to daughter cells. This property is essential for some inherited mitochondrial disorders that produce sideroblastic anemia.

This characteristic also raises an enigma regarding the acquired sideroblastic anemias. Some cases of sideroblastic anemia associated with myelodysplasia have acquired mutations that affect the function of some cytochromes. The modification presumably began as an alteration in a single mitochondrion.

The puzzling question is how mitochondria with altered enzyme function predominate in cells.

Each mitochondrion has several genomes (that is, several circular DNA molecules), and each cell has several hundred mitochondria. Logically, the defective mitochondria should be at a survival disadvantage.

Acquired sideroblastic anemias remind us that much remains to be learned about the physiology of these fascinating organelles.

In 1945, Thomas Cooley described the first cases of sideroblastic anemia linked to the X chromosome in two brothers of a large family. The inheritance of the disease was documented over six generations.

Although rare, the disorder is, however, the most common hereditary sideroblastic anemia. The most frequent of the two known genetic defects involve the ALAS-2 gene—the second consists of abnormalities in the Xq13 region of the X chromosome.

Although a genetic mutation specific to the latter has not been identified, several laboratories have shown a link to the phosphoglycerate kinase (PGK) gene, close to the Menkes syndrome gene (an innate abnormality of copper transport).

Copper is essential for the absorption of cellular iron from transferrin. In addition, Cooper is a cofactor of several enzymes in the mitochondrial electron transport chain. Abnormalities in the Xq13 chromosomal region could subtly alter the cellular metabolism of copper.

Sideroblastic anemias, in this case, would be a secondary phenomenon in a condition whose primary alteration involves copper metabolism.

Misal mutations of the ALAS-2 gene produce most cases of linked sideroblastic anemia. Years after their initial evaluation, the researchers located several members of the pedigree described initially by Cooley and analyzed their DNA using current molecular biology techniques.

These adults now had nonsense mutations involving the ALAS-2 gene. Rarely has someone correctly described two significant disorders that withstood the rigors of later scientific inquiry through more powerful analytical tools.

Sideroblastic anemia can be caused by hereditary factors acquired as part of an underlying condition or exposure to drugs or toxins, or the cause may be unknown (idiopathic).

Causes of Sideroblastic Anemia

Hereditary causes of sideroblastic anemia include:

  • Mutations in the genes ALAS2, ABCB7, SCL19A2, GLRX5, and PSU.
  • Pearson syndrome.
  • Wolfram syndrome or DIDMOAD.
  • Mitochondrial SLC25A38.
  • Protoporfiria eritropoyética.

Acquired causes of sideroblastic anemia include:

  • Myelodysplastic syndrome
  • SF3B1 – mutations of the 1B subunit of the splicing factor 3B.
  • Nutritional deficiencies (copper, vitamin B6).
  • Lead poisoning
  • Zinc overdose
  • Alcohol.
  • Drugs (antituberculous agents, antibiotics, progesterone, chelators, busulfan).
  • Hypothermia.

Symptoms

Signs and symptoms of sideroblastic anemia may include:

  • Weakness.
  • Accelerated heartbeat or accelerated heartbeat (palpitations).
  • Difficulty breathing.
  • Headaches.
  • Irritability and pain in the chest and fatigue.

Physical findings may include pale skin, a lemon-yellow tint on the skin, and a brownish discoloration caused by bleeding under the skin.

Enlargement of the spleen ( splenomegaly ) and liver (hepatomegaly) can also occur. Rarely, in severe cases, acute leukemia may develop.

Treatment of Sideroblastic Anemia

The first step in treating sideroblastic anemia is to rule out reversible causes, including the toxicity of alcohol or other drugs and exposure to toxins.

The treatment of sideroblastic anemia is mainly supportive, primarily consisting of blood transfusions to maintain an acceptable hemoglobin level.

A trial of pyridoxine in pharmacological doses (500 mg per day) is a reasonable intervention since it has few drawbacks and is a massive benefit in cases where it works. A complete response to pyridoxine generally occurs in cases that result from ethanol abuse or pyridoxine antagonists.

The interruption of the offending agent accelerates the recovery. Some patients with X-linked hereditary sideroblastic anemia also respond to pyridoxine. The improvement with pyridoxine is rare for sideroblastic anemias of other etiologies.

After obtaining the initial parameters (red blood cell indices, iron studies), the initial dose of pyridoxine should be from 100 to 200 mg orally with a gradual escalation at a daily dose of 500 mg.

In the case of pyridoxine works, folic acid supplementation compensates for the possible increase in erythropoiesis.

Reticulocytosis occurs within two weeks in response cases, followed by a progressive increase in hemoglobin level during the following months. The maintenance dose of pyridoxine is the one that maintains a stable hemoglobin level. The microcytosis often persists but has no clinical significance.

Except in cases induced by toxins, treatment with pyridoxine is generally undefined. Patient compliance or side effects of medications can limit the treatment regimen.

Fortunately, side effects are rare, with less than 500 mg daily doses. Some patients with doses higher than 1000 mg daily have developed a reversible peripheral neuropathy. In receptive patients, anemia recurs with the interruption of pyridoxine.

Many patients with sideroblastic anemia require chronic transfusion to maintain acceptable hemoglobin levels.

Instead of an absolute level of hemoglobin or hematocrit, the patient’s symptoms should guide the transfusion. This will limit the adverse consequences of transfusion, including the transmission of infections, alloimmunization, and secondary hemochromatosis.

Some authorities recommend an annual control of ferritin level and transferrin saturation even in patients without a significant transfusion history. Chelation with iron with desferrioxamine is the standard treatment for transfusion hemochromatosis.

Occasionally, patients with moderate anemia (e.g., hemoglobin = 10 g / dl) who are not transfusion-dependent will tolerate small-volume phlebotomies to eliminate iron.

In some cases, anemia improves with the elimination of excess iron (Hines, 1976, French et al., 1976). This could reflect a reduction in mitochondrial injury by reactive oxygen-mediated oxygen species. This is pure speculation, however, and the scenario is unusual.

Anecdotal reports and small case series describe allogeneic bone marrow transplantation or stem cells for sideroblastic anemia. The obvious advantage is the possibility of cure, as has occurred in patients with β-thalassemia.