Sideroblastic anemia

Definitions & Key takeaways

Sideroblastic anemia occurs when the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes). It is due to either a congenital abnormality or an acquired cause such as vitamin B6 deficiency, excessive alcohol use, or lead poisoning which leads to an inability to incorporate iron to form heme.

The lack of functional heme results in anemia and fatigue. Also, the overload of iron that is unable to be incorporated into RBCs can damage other organs. Diagnosis of sideroblastic anemia involves a medical history and physical examination, along with tests like full blood count and peripheral blood smear. Treatment involves the removal of toxins and the administration of vitamin B6, thiamine, and folic acid.

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Introduction0:00–0:30

With sideroblastic anemia, sidero- means iron and -blastic meaning immature and anemia refers to a condition where there’s a decrease in the number of healthy red blood cells, or RBCs in the body.
So sideroblastic anemia is a type of blood disorder where there’s a buildup of iron in the RBC’s in the body causing them to be immature and dysfunctional.
This buildup occurs because these RBC’s are unable to incorporate iron into hemoglobin which is necessary for RBC’s to transport oxygen.
In order to better understand sideroblastic anemia, we need to first take a look at hemoglobin, the main protein within RBC’s that’s responsible for carrying oxygen.

Physiology0:30–2:30

Now hemoglobin is made up of hemes and globins. There are 4 globin subunits, typically two alpha and two beta, and each one has its own heme group.
This heme is a large molecule that’s made up of four pyrrole subunits that forms a ring, and this structure is called a porphyrin.
In the middle, there is an ionically bond iron 2+ and the iron is what binds to and carries the oxygen molecule. So each hemoglobin can carry four oxygen molecules when it’s fully saturated.
The process of heme synthesis occurs both within the mitochondria and the cytosol of a cell and requires multiple enzymes to catalyze the numerous steps.
It begins in the mitochondria where succinyl CoA binds to glycine via delta-ALA synthase which uses vitamin B6 as a cofactor to produce delta-aminolevulinic acid, or ALA.
Then, in the cytosol, delta-aminolevulinic acid is converted to porphobilinogen, or PBG, via delta-ALA dehydratase. From there, four molecules of porphobilinogen condense together to form hydroxymethylbilane with the help of porphobilinogen deaminase.
Note that porphobilinogen deaminase is sometimes called uroporphyrinogen I synthase or hydroxymethylbilane synthase, or HMBS for short.
Afterwards, hydroxymethylbilane is converted to uroporphyrinogen III and catalyzed to coproporphyrinogen III via uroporphyrinogen III cosynthase and uroporphyrinogen decarboxylase, respectively.
Next, coproporphyrinogen III is brought back into the mitochondria and converted into protoporphyrinogen IX by coproporphyrinogen oxidase.
Protoporphyrinogen IX is converted to protoporphyrin IX by protoporphyrinogen oxidase. Lastly, an iron molecule is added to protoporphyrin IX via the enzyme ferrochelatase, and 10 tongue twisters later, voila!
We got ourselves a completed heme!Now, with sideroblastic anemia, there is defective protoporphyrin synthesis which results in impaired incorporation of iron to form heme.

Congenital Causes2:30–3:06

Sideroblastic anemia can be congenital or acquired. The most common congenital cause is an X-linked form which means it occurs on the X chromosome and affects mainly boys since boys only have one copy of the X chromosome.
This X-link form is caused by mutations in the ALAS2 gene. The ALAS2 gene is involved in coding for delta-ALA synthase.
Without delta-ala-synthase, there is a buildup of iron and not enough normal heme production.The acquired causes of sideroblastic anemia include excessive alcohol use, pyridoxine or vitamin B6 deficiency and lead poisoning.

Acquired Causes3:06–4:43

Excessive alcohol consumption can lead to mitochondrial damage and nutritional deficiencies like vitamin B6, iron and folate which affects the mitochondria’s ability to form heme.
Vitamin B6 deficiencies can also commonly occur as a result of isoniazid treatment for tuberculosis as isoniazid attaches and inactivates vitamin B6.
Lead poisoning has also been shown to like denature delta-aminolevulinate dehydratase and ferrochelatase, which are important for heme synthesis.
Additionally lead poisoning can also denature ribonuclease an enzyme which degrades ribosomes. Without it, this leads to a buildup of ribosomes in the RBC and can cause a characteristic studded appearance on histology called basophilic stippling.
Basophilic stippling is indicative of ineffective hematopoiesis and can be seen in other types of anemias. These causes of sideroblastic anemia stops the iron from being incorporated to form heme which allows the iron to accumulate in the mitochondria resulting in Pappenheimer bodies seem on blood film.
In the bone marrow, immature RBCs mitochondria surround the nucleus and get ladden with excess iron deposits which produces ringed sideroblasts on histology, hence the name of the disease.
These sideroblasts have ineffective erythropoiesis which means they don’t develop normally to become a mature RBC and end up dying in the bone marrow with a few escaping into the peripheral blood.
A diagnosis of sideroblastic anemia can be reached with a combination of both clinical judgement and laboratory findings.

Diagnosis4:43–5:44

Clinically, patients with sideroblastic anemia present very similarly to patients with hemochromatosis as both these diseases involve a buildup of excess iron within the body.
The excess iron damages multiple organs which can cause fatigue, heart disease, liver damage, enlarged spleen, kidney failure and diarrhea.Investigations should include a complete blood count, peripheral blood smear and iron studies.
On the full blood count, the mean corpuscular volume which reflects the size of the RBC is usually normal or low for the congenital causes.
For acquired forms, the mean corpuscular volume is normal or high. While on the peripheral blood smear we would expect to see erythrocytes with basophilic stippling and Pappenheimer bodies which are purple staining granules of iron found inside RBC’s.
Iron studies will show a high serum iron, increased ferritin levels and decreased total iron-binding capacity. Treatment of sideroblastic anemia involves removal of toxins if there are any and administering pyridoxine, thiamine and folic acid.

Treatment5:44–6:05

Therapeutic phlebotomy or bloodletting can be used to manage iron overload as well as deferoxamine, an iron chelating agent.
In severe cases a bone marrow or liver transplant may be needed. ##SummaryAll right, as a quick recap, sideroblastic anemia occurs when there is either a congenital abnormality or an acquired cause such as vitamin B6 deficiency, excessive alcohol use or lead poisoning which leads to an inability to incorporate iron to form heme.

Summary6:05–6:36

The overload of iron that is unable to be incorporated into RBC’s can damage other organs. The lack of functional heme results in anaemia and fatigue.
For diagnosis, a full blood count and peripheral blood smear should be performed. Treatment involves removal of toxins and administration of pyridoxine, thiamine and folic acid.
diagnosis A full blood count in peripheral blood smear should be performed Treatment involves removal of toxins and administration