Each week, Osmosis shares a USMLE® Step 1-style practice question to test your knowledge of medical topics. Today’s case involves a 25-year-old woman with symptoms of fatigue and reduced exercise tolerance. Can you figure out the cause?
A 25-year-old woman presents to her outpatient provider for symptoms of fatigue and reduced exercise tolerance that started 2 weeks ago. Past medical history is notable for a seizure disorder that is currently managed with phenytoin. In addition, the patient had an episode of pyelonephritis several weeks ago that was successfully treated with trimethoprim-sulfamethoxazole. The patient has menstrual periods every 28 days, and denies dysmenorrhea and menorrhagia. Physical examination is notable for conjunctival pallor. Laboratory testing reveals a hemoglobin on 9.3 g/dL. A peripheral blood smear is performed and shows the following:
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Which of the following sets of red blood cell characteristics is most likely to be seen in this patient?
A. Impaired Process: Heme Synthesis, Red Blood Cell Maturity: Immature, Mean Corpuscular Volume: 75 mm3
B. Impaired Process: DNA Synthesis, Red Blood Cell Maturity: Mature, Mean Corpuscular Volume: 75 mm3
C. Impaired Process: Heme Synthesis, Red Blood Cell Maturity: Mature, Mean Corpuscular Volume: 105 mm3
D. Impaired Process: DNA Synthesis, Red Blood Cell Maturity: Immature, Mean Corpuscular Volume: 105 mm3
E. Impaired Process: DNA Synthesis, Red Blood Cell Maturity: Mature, Mean Corpuscular Volume: 105 mm3
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The correct answer to today’s USMLE® Step 1 Question is…
D. Impaired Process: DNA Synthesis, Red Blood Cell Maturity: Immature, Mean Corpuscular Volume: 105 mm3Before we get to the Main Explanation, let’s look at the incorrect answer explanations. Skip to the bottom if you want to see the correct answer right away!
Incorrect answer explanations
The incorrect answers to today’s USMLE® Step 1 Question are…
A. Impaired Process: Heme Synthesis, Red Blood Cell Maturity: Immature, Mean Corpuscular Volume: 75 mm3
Incorrect: Iron deficiency, lead poisoning, and thalassemias can impair heme synthesis and result in a microcytic anemia. Female patients are generally at higher risk of iron deficiency due to menstrual blood loss. However, this patient has no history of overly frequent or heavy menses. In contrast, the patient’s history of phenytoin and trimethoprim-sulfamethoxazole use puts her at risk of folate deficiency, which is a more likely cause of her anemia.
B. Impaired Process: DNA Synthesis, Red Blood Cell Maturity: Mature, Mean Corpuscular Volume: 75 mm3
Incorrect: In normal red blood cell (RBC) development, large red blood cell precursors (erythroblasts) undergo DNA replication and cellular division. This results in the creation of several smaller mature RBCs. Impaired DNA replication would prevent RBC maturation and cause immature and macrocytic (mean corpuscular volume > 100 mm3) RBCs to be observed on laboratory testing.
C. Impaired Process: Heme Synthesis, Red Blood Cell Maturity: Mature, Mean Corpuscular Volume: 105 mm3
Incorrect: Iron deficiency, lead poisoning, or thalassemia can result in impaired heme synthesis. DNA synthesis will be unaffected and hence the RBCs will be mature. However, the RBCs will most likely be microcytic. This is because the body attempts to preserve a normal RBC hemoglobin concentration. So when hemoglobin production is decreased, the body makes smaller RBCs to compensate.
E. Impaired Process: DNA Synthesis, Red Blood Cell Maturity: Mature, Mean Corpuscular Volume: 105 mm3
Incorrect: Causes of impaired DNA replication include vitamin B12 deficiency, folate deficiency, orotic aciduria, and Fanconi anemia. However, defects in DNA synthesis would hinder RBC maturation and cause immature RBCs to be found in the patient’s circulation.
Main Explanation
This patient is taking phenytoin and trimethoprim-sulfamethoxazole. Phenytoin impairs folate absorption. Trimethoprim-sulfamethoxazole prevents the conversion of folate into tetrahydrofolate, the active form used in DNA synthesis. As a result, this patient most likely has impaired DNA synthesis secondary to folate deficiency, which results in macrocytic megaloblastic anemia.
Macrocytic anemias (MCV > 100 mm3) can be classified based on the presence/absence of megaloblasts. Megaloblasts are large, immature red blood cells produced when the cytoplasm develops normally, but the DNA synthesis is impaired and cell division is delayed. Therefore, when there are defects in DNA synthesis or repair (e.g., folate deficiency, vitamin B12 deficiency, Fanconi anemia, orotic aciduria, etc.) there will be megaloblastic macrocytic anemia. Megaloblastic anemia can also affect white blood cell production, resulting in the release of immature neutrophils with hypersegmented nuclei into the bloodstream. The observation of these hypersegmented neutrophils on peripheral blood smear can help distinguish megaloblastic from non-megaloblastic anemias.
In contrast, non-megaloblastic macrocytic anemias arise from conditions that do not affect DNA synthesis. Causes of non-megaloblastic macrocytic anemia include Diamond-Blackfan Anemia, which results from a defect in protein synthesis, and chronic alcohol use, which has a toxic effect on the bone marrow.
Major Takeaway
Macrocytic anemias are characterized by the presence of RBCs with a mean corpuscular volume exceeding 100 mm3. They can be divided into megaloblastic anemia, where DNA synthesis is impaired, and non-megaloblastic anemia. Causes of megaloblastic macrocytic anemia include folate deficiency, vitamin B12 deficiency, orotic aciduria, and Fanconi anemia. Causes of non-megaloblastic macrocytic anemia include Diamond-Blackfan anemia and chronic alcohol use.
References
Agabegi, S.S., Agabegi, E.D. (2012) Step-Up to Medicine. Wolters Kluwer/Lippincott Williams & Wilkins. ISBN: 978-1609133603.
Aslinia, F., Mazza, J.J. (2006) Megaloblastic anemia and other causes of macrocytosis. Clinical Medicine & Research. 4(3), 236-241. Doi: 10.3121/cmr.4.3.236.
Moore, C.A., Adil, A. (2019) Macrocytic anemia. StatPearls [Internet]. Web Address: https://www.ncbi.nlm.nih.gov/books/NBK459295/?report=classic.
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