USMLE® Step 1 style questions USMLE
A 15-year-old man comes to his pediatrician after several months of weakness. Laboratory workup reveals a hematocrit of 20%, a decreased mean corpuscular volume, and an increased RDW (red blood cell distribution width). There is no history of metal poisoning or substance abuse. The patient denies taking any medications. A bone marrow aspirate revealed erythroid hyperplasia. Which of the following cofactors could cause similar laboratory findings if it was deficient?
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.
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.
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.
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.
- "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
- "X-Linked, Pyridoxine-Responsive Sideroblastic Anemia" New England Journal of Medicine (1994)
- "Robbins Basic Pathology" Elsevier (2017)
- "Sideroblastic anemias." Wintrobe's Clinical Hematology. 10th ed. (1999)
- "Sideroblastic Anemias" (2020)