WBR0488

Author	[[PageAuthor::Rim Halaby, M.D. [1] (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pathophysiology
Sub Category	SubCategory::Hematology
Prompt	[[Prompt::A 62-year-old man presents to the physician's office with worsening pruritus for the past 3 months. He reports that his pruritus becomes much worse following a hot shower. On review of systems, the patient also complains of recurrent headaches for the past few weeks. His temperature is 37.1 °C (98.8 °F), blood pressure is 165/92 mmHg, and heart rate is 88/min. Physical examination is remarkable for facial plethora, engorged conjunctival veins, and splenomegaly palpated 3 cm below costal margin. Further investigation reveals hemoglobin of 18.8 g/dL and undetectable serum erythropoietin levels. The physician suspects a genetic disorder and confirms the diagnosis with genetic testing. Which of the following receptor types is most likely involved in this patient's condition?]]
Answer A	AnswerA::Intrinsic tyrosine kinase
Answer A Explanation	AnswerAExp::Insulin and growth factors, such as IGF-1, FGF, and PDGF, have receptors with an intrinsic tyrosine kinase activity.
Answer B	AnswerB::Receptor-associated tyrosine kinase
Answer B Explanation	[[AnswerBExp::Polycythemia vera may be caused by a mutation in JAK2. JAK/STAT pathway includes a receptor-associated tyrosine kinase.]]
Answer C	AnswerC::G-protein coupled receptor
Answer C Explanation	AnswerCExp::Alpha and beta adrenergic receptors are 2 examples of G-protein coupled receptors.
Answer D	AnswerD::Intracellular steroid receptor
Answer D Explanation	AnswerDExp::Receptors for vitamin D, thyroid hormones (T3 and T4), cortisol, aldosterone, and sex hormones (estrogen, progesterone, and testosterone) are intracellular steroid receptors.
Answer E	AnswerE::Inositol triphosphate receptor
Answer E Explanation	AnswerEExp::Receptors for oxytocin, TRH, Histamine-1 (H1), arginine vasopressor receptor-1 (V1), angiotensin II, and gastrin are inositol triphosphate (IP3) receptors.
Right Answer	RightAnswer::B
Explanation	[[Explanation::Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by excessive erythroid cell production. The massive increase in red blood cells leads to a higher blood viscosity that accounts for the symptoms and complications of the disease. The majority of patients with PV (95%) have a mutation of JAK2, a receptor-associated tyrosine kinase. In general, tyrosine kinases (TK) use ATP to catalyze the phosphorylation of tyrosine residues in substrates. They may be either non-receptor TK or receptor TK. Non-receptor TK: They are also called receptor-associated tyrosine kinases. They lack an intrinsic kinase activity. Instead, these receptors recruit intracellular protein kinases to the plasma membrane Receptor TK: They contain an intrinsic kinase activity that is a component of the receptor protein. JAK2 is a receptor-associated tyrosine kinase. JAK2 mutation in PV results in hypersensitivity to erythropoietin (EPO) signals with constitutive activation of EPO signaling, even in the absence of EPO (EPO-independent erythroid proliferation). Although some patients are asymptomatic and are diagnosed incidentally, symptoms include pruritus that is worsened following bathing, weight loss, erythromelalgia (burning pain in the distal extremities), GI distress, chest pain, epistaxis, headaches, weakness, and dizziness. Physical examination of patients with PV may demonstrate high blood pressure due to increased blood viscosity associated with the disease, facial plethora, splenomegaly, and engorged veins. The disease course may also be complicated by gouty arthritis, thrombotic events, and digital ischemia. Since polycythemia may be secondary to other systemic etiologies, physicians should always rule out other causes of polycythemia, such as diseases that are associated with chronic hypoxia (COPD, congestive heart failure, sleep apnea, and pulmonary hypertension) and paraneoplastic syndromes or EPO-secreting tumors (renal cell carcinoma or hepatocellular carcinoma, or adrenal tumors). PV should be suspected when patients have elevated Hb levels (Hb>18 g/dL for men and Hb>16 g/dL for women) and undetectable serum erythropoietin levels among patients with consistent signs, symptoms, or complications. Management consists of periodic phlebotomies to decrease blood viscosity (target Hct < 45% for men and Hct < 42% for women) and to prevent complications. The use of pharmacologic therapy (chlorambucil, busulfan, pipobroman) has been investigated, but the majority of these drugs were associated with significant risk. Currently, hydroxyurea is utilized as an effective pharmacologic therapy that is associated with a reduction in thrombotic events among patients with PV. Educational Objective: Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by excessive erythroid cell production. The majority of patients with PV (95%) have a mutation of JAK2, a non-receptor tyrosine kinase. This mutation results in hypersensitivity to erythropoietin (EPO) signals with constitutive activation of EPO signaling, even in the absence of EPO (EPO-independent erythroid proliferation). References: James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144-8. Stuart BJ, Viera AJ. Polycythemia vera. Am Fam Physician. 2004; 69(9):2139-2144. Levitzki A, Gazit A. Tyrosine kinase inhibition: an approach to drug development. Science. 1995; 267(5205):1782-8. First Aid 2014 page 397]]
Approved	Approved::Yes
Keyword	WBRKeyword::Polycythemia vera, WBRKeyword::JAK2, WBRKeyword::JAK/STAT, WBRKeyword::Pathway, WBRKeyword::Receptor, WBRKeyword::Tyrosine kinase, WBRKeyword::Facial plethora, WBRKeyword::Pruritus
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