USMLE® Step 1 style questions USMLE
A 40-year-old man comes to the office because of fever, cough, and night sweats. The patient has felt fatigued over the past six-months and has experienced a 15 lb (6.8 kg) weight loss. Past medical history is significant for hypertension and hyperlipidemia. Temperature is 37.7°C (99.9°F), pulse is 78/min, respirations are 17/min, and blood pressure is 142/88 mmHg. A chest radiograph shows a cavitary lesion in the left upper lobe and an interferon-gamma release assay is positive. The patient is started on appropriate antimicrobial therapy. Three months later, he is seen in the office for follow-up. Laboratory testing reveals the following results:
|Laboratory Value||Result (U.S. Conventional Units)||Results (S.I. Units)|
|Hemoglobin||9.2 g/dL||5.71 mmol/L|
|Mean corpuscular volume||75 μm3||75 fL|
A peripheral blood smear shows Pappenheimer bodies. Bone marrow aspirate is subsequently obtained and demonstrates the following:
Image reproduced from Wikimedia Commons
Which of the following processes is most likely impaired in this patient?
Sideroblastic anemia exam links
Content Reviewers:Rishi Desai, MD, MPH, Viviana Popa, MD
Contributors:Tanner Marshall, MS, Evan Debevec-McKenney, Jung Hee Lee, MScBMC
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.
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.
The acquired causes of sideroblastic anemia include excessive alcohol use, pyridoxine or vitamin B6 deficiency and lead poisoning.
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.
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.
- "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)