WBR0161

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pharmacology
Sub Category	SubCategory::Hematology, SubCategory::Oncology
Prompt	[[Prompt::A 75-year-old man presents to his physician for excessive pruritus that is exacerbated by taking showers. On physical exam, the spleen is palpable 9 cm below the costal margin. Laboratory testing is notable for a hematocrit of 70%. Further testing confirms the diagnosis with the presence of a JAK2 mutation. Therapy consisting of regular phlebotomy and an agent that inhibits ribonucleotide reductase is initiated. For which of the following conditions may this drug also be used?]]
Answer A	AnswerA::Inflammatory arthritis due to deposition of monosodium urate
Answer A Explanation	[[AnswerAExp::Acute gout is an inflammatory arthritis due to deposition of monosodium urate. Gout is generally treated with NSAIDs and colchicine. However, many patients with polycythemia vera (PV) develop gout due to the rapid turnover of erythrocytes observed in PV that results in uric acid release, hyperuricemia, and gouty attacks.]]
Answer B	AnswerB::Skin cancer that demonstrates an appearance of palisading nuclei on biopsy
Answer B Explanation	AnswerBExp::Basal cell carcinoma is a skin cancer that demonstrates an appearance of palisading nuclei on biopsy. Basal cell carcinoma may be a rare consequence of hydroxyurea therapy. However, hydroxyurea is not indicated for basal cell carcinoma.
Answer C	AnswerC::Aggressive neuroendocrine lung tumor that demonstrates small dark blue cells on biopsy
Answer C Explanation	AnswerCExp::Small cell lung carcinoma is an aggressive neuroendocrine lung tumor that demonstrates small dark blue cells on biopsy. Hydroxyurea is not indicated for small cell lung carcinoma.
Answer D	AnswerD::Autoimmune inflammatory disease characterized by presence of anti-IgG antibodies
Answer D Explanation	AnswerDExp::Rheumatoid arthritis is an autoimmune inflammatory disease characterized by presence of anti-IgG antibodies. Hydroxyurea is not indicated for rheumatoid arthritis.
Answer E	AnswerE::Inherited disorder characterized by substitution of glutamic acid with valine
Answer E Explanation	[[AnswerEExp::Hydroxyurea is indicated for sickle cell disease because it increases the synthesis of fetal hemoglobin (HbF). Sickle cell disease is causede by a point mutation in the beta-globin chain, whereby glutamic acid is substituted for valine at position 6.]]
Right Answer	RightAnswer::E
Explanation	[[Explanation::The patient in this vignette is suffering from polycythemia vera and is being treated with hydroxyurea. Polycythemia vera (PV) is a myeloproliferative blood disorder in which the bone marrow produces red blood cells excessively. PV is caused by mutations in the JAK2 gene, which renders erythroid precursors hypersensitive to erythropoietin (EPO). PV is more common in the elderly and may be symptomatic or asymptomatic. Common signs and symptoms include pruritus and severe burning pain in the hands or feet that is usually accompanied by a reddish or bluish discoloration of the skin. Pruritis is often exacerbated by exposure to warm water, such as when taking a shower or bath. On physical examination, splenomegaly is common due to erythrocyte trapping. The rapid turnover of erythrocytes in PV can lead to release of uric acid and gout in 20% of patients. Treatment for PV includes regular aggressive phlebotomy to decrease blood count and the concentration of RBCs. Phlebotomy may be supplemented with pharmacologic therapy using pipobroman, hydroxyurea, busulfan, and ruxolitinib. Hydroxyurea inhibits ribonucleotide reductase and essentially starves erythrocyte precursors of necessary deoxynucleotides for DNA synthesis. Hydoxyurea is also indicated for sickle cell disease. Sickle cell disease is caused by a point mutation in the beta-globin chain of the hemoglobin tetramer, whereby glutamic acid is substituted for valine at position 6. Through unknown mechanisms, hydroxyurea administration increases the synthesis of fetal hemoglobin (HbF) in patients with sickle cell disease, which may replace the mutant beta-globin in sickle cell patients and thereby decrease sickling of RBCs. Notably, the efficacy and safety of hydroxyurea has also been variably studied for other disorders (eg. thalassemia intermedia, thalassemia major, and paroxysmal nocturnal hemoglobinuria, essential thrombocythemia, solid tumors, leukemia, and psoriasis). Educational Objective: Hydroxyurea is a ribonucleotide reductase inhibitor indicated for polycythemia vera and sickle cell disease. Sickle cell disease is caused by a point mutation in the beta-globin chain of the hemoglobin tetramer, whereby glutamic acid is substituted for valine at position 6. References: First Aid 2014 page 405]]
Approved	Approved::Yes
Keyword	WBRKeyword::Cancer, WBRKeyword::Hydroxyurea, WBRKeyword::Chemotherapy, WBRKeyword::Phlebotomy, WBRKeyword::JAK2, WBRKeyword::JAK-2, WBRKeyword::Polycythemia, WBRKeyword::Polycythemia vera, WBRKeyword::Itching. Pruritis, WBRKeyword::Hemoglobinopathy, WBRKeyword::Point, WBRKeyword::Mutation, WBRKeyword::Point mutation, WBRKeyword::Glutamic acid, WBRKeyword::Valine, WBRKeyword::Sickle cell disease, WBRKeyword::Sickle cell anemia, WBRKeyword::Ribonucleotide reductase, WBRKeyword::Ribonucleotide reductase inhibitor
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