A 40-year-old woman comes to the office with a 3-month history of progressively limited physical activity due to fatigue. The patient says, "I could barely walk from my car to the office." Medical history is significant for a positive tuberculin skin test 7 months ago with a normal chest radiograph. She has been compliant with the prescribed treatment despite its bitter taste. Physical examination shows a tired-appearing woman with conjunctival and palmar pallor. Complete blood count is as follows: A bone marrow aspirate representative of this patient's disease process is shown below (Prussian blue stain). Decreased activity of which of the following enzymes most likely explains the anemia found in this patient?

Question

A 40-year-old woman comes to the office with a 3-month history of progressively limited physical activity due to fatigue.  The patient says, "I could barely walk from my car to the office."  Medical history is significant for a positive tuberculin skin test 7 months ago with a normal chest radiograph.  She has been compliant with the prescribed treatment despite its bitter taste.  Physical examination shows a tired-appearing woman with conjunctival and palmar pallor.  Complete blood count is as follows:  A bone marrow aspirate representative of this patient's disease process is shown below (Prussian blue stain).  Decreased activity of which of the following enzymes most likely explains the anemia found in this patient?

Quizplus · Accepted Answer

11ec160b_36ea_edad_9249_bde88f988d51_MD0001_00 This patient with latent tuberculosis has laboratory values and bone marrow aspirate findings consistent with sideroblastic anemia due to isoniazid use. Sideroblastic anemia is caused by impaired heme production within red blood cells. When iron is transported to developing erythrocytes that cannot form heme, iron granules accumulate in mitochondria circumferentially around the nucleus, forming ring sideroblasts that can be seen on Prussian blue-stained bone marrow aspirate. Etiologies include X-linked sideroblastic anemia (due to an δ-aminolevulinic acid synthase mutation), myelodysplastic syndrome, alcohol use disorder, copper deficiency, and certain medications (eg, isoniazid, chloramphenicol, linezolid). Isoniazid directly inhibits the enzyme pyridoxine phosphokinase, which normally converts pyridoxine (vitamin B₆) to its active form, pyridoxal 5' phosphate. Pyridoxine is a cofactor for δ-aminolevulinic acid (ALA) synthase, the enzyme that catalyzes the rate-limiting step in heme synthesis. Inhibition of this enzyme impairs heme production and erythroid development to produce a microcytic anemia. Pyridoxine deficiency can also lead to seborrheic dermatitis, glossitis, and peripheral neuropathy. Therefore, pyridoxine is typically prescribed with isoniazid. (Choice A) δ-aminolevulinic acid dehydratase is another enzyme involved in heme synthesis. Lead poisoning can cause anemia by directly inhibiting this enzyme. However, pyridoxine is not a cofactor for this step; therefore, isoniazid would not affect its activity. (Choice C) Cystathionine synthase catalyzes the formation of cystathionine from homocysteine. Deficiency results in homocystinuria, an autosomal recessive disorder characterized by a marfanoid body habitus and hypercoagulability. Although cystathionine synthase is a pyridoxine-dependent enzyme, impairment does not result in sideroblastic anemia. (Choice D) Glucose-6-phosphate dehydrogenase (G6PD) deficiency results in increased red blood cell susceptibility to oxidative stress (eg, infection, medication, fava beans), which triggers hemolysis. This results in a normocytic, normochromic, hemolytic anemia without ring sideroblasts. (Choice E) Pyruvate kinase deficiency, an autosomal recessive disorder, results in a normocytic, normochromic, hemolytic anemia without ring sideroblasts. Educational objective: Isoniazid inhibits pyridoxine phosphokinase, leading to impaired activation of pyridoxine (vitamin B₆). Pyridoxine is a cofactor for δ-aminolevulinic acid synthase, the enzyme that catalyzes the rate-limiting step of heme synthesis. Inhibition of this step can result in sideroblastic anemia. __________ References: Severe isoniazid related sideroblastic anemia. (http://www.ncbi.nlm.nih.gov/pubmed/22184524)

A 40-Year-Old Woman Comes to the Office with a 3-Month