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Review Question - QID 108271

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QID 108271 (Type "108271" in App Search)
A 75-year-old woman with a history of Hashimoto's disease on thyroid replacement and hypertension presents to your outpatient clinic for fatigue that has progressively worsened over the last year. She has also experienced a fall a few days prior to presentation due to "not knowing where I was stepping when the lights are off." She reports that her husband has noticed she has become more forgetful lately, such as not remember she is expecting visitors or turning the stove off after she finished cooking. She denies fevers, chills, weight loss, and night sweats. She has no chest pain, shortness of breath, constipation, diarrhea, dysuria, heat or cold intolerance. Her temperature is 99.5 deg F (37.5 deg C), blood pressure is 103/72 mmHg, pulse is 76/min, respirations are 12/min. On physical examination, she has a slightly large tongue. She has decreased vibration and proprioception sense in her bilateral lower extremities. She also has a positive Romberg test. Her lab results demonstrate a normal TSH. A peripheral blood smear shows the following: (Figure A). Which of the following lab results would be most consistent with the patient’s clinical presentation?
  • A

High methylmalonic acid, high homocysteine

66%

111/169

Low methylmalonic acid, low homocysteine

4%

7/169

High methylmalonic acid, low homocysteine

14%

23/169

Low methylmalonic acid, high homocysteine

10%

17/169

Normal methylmalonic acid, normal homocysteine

3%

5/169

  • A

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The clinical presentation is most consistent with vitamin B12 deficiency, which would cause elevated levels of both methylmalonic acid and homocysteine.

The patient presents with classical signs and symptoms of vitamin B12 deficiency. These include fatigue likely from macrocytic anemia, large swollen tongue, memory loss, and decreased vibration and proprioception sensation. The patient’s peripheral smear also demonstrates a hypersegmented neutrophil (Figure A). Finally, the patient has a history of autoimmune disease and likely developed vitamin B12 deficiency from pernicious anemia. In vitamin B12 deficiency, it is expected that methylmalonic acid and homocysteine will be elevated since B12 is an important cofactor for their metabolism.

Oh et al. examine how pernicious anemia is a classical malabsorption syndrome that can lead to vitamin B12 deficiency. It occurs when there are autoantibodies against parietal cells that produce intrinsic factor, which is important for B12 absorption. B12 is a cofactor for the conversion of methylmalonic acid to succinyl-CoA and homocysteine to methionine. Thus, a deficiency in vitamin B12 would lead to elevated methylmalonic acid and homocysteine (Illustration A).

Hernandez et al. describe how vitamin B12 is important in DNA synthesis in all hematopoietic lineages. A deficiency in DNA synthesis in erythropoiesis prohibits proper maturation of erythroid precursors causing the cells to have high MCV and undergo apoptosis. Similarly, impaired DNA synthesis leads to hypersegmented neutrophils (greater than 6 lobes).

Figure A shows a hypersegmented neutrophil which occurs as a result of improper DNA synthesis secondary to deficiency in B12. Illustration A shows the pathways that B12 is involved in for the conversation of methylmalonic acid to succinyl-CoA and homocysteine to methionine.

Incorrect Answers:
Answers 2-5: Vitamin B12 is an important cofactor for the conversion of methylmalonic acid to succinyl-CoA and homocysteine to methionine. Low B12 would lead to increased substrate. Therefore, it is expected that mathylmalonic acid and homocysteine levels are elevated.

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