81-Year-Old Man With Insomnia and Pruritus.

An 81-year-old man presented to the clinic for an annual general medical examination with insomnia and pruritus. His insomnia was associated with nocturnal leg restlessness, foot cramping, and pruritus of his feet. His cramping was not associated with activity and occurred mostly at night. He reported no fevers, weight loss, night sweats, numbness, skin lesions, or purulence. His medical history included obstructive sleep apnea (OSA) treated with continuous positive airway pressure therapy, hypertension, hyperlipidemia, gastroesophageal reflux disease, bilateral chronic onychomycosis of the toenails (recently completed treatment), and bilateral carpal tunnel syndrome. He had no history of tobacco use, congestive heart failure, or venous thromboembolism. He had not completed routine colon cancer screening. Current medications included atorvastatin, lisinopril, omeprazole, ranitidine, and zolpidem. He had no family history of cardiac, hematologic, pulmonary, or oncological disease. On physical examination, the patient was afebrile (temperature, 36.9°C), his pulse rate was 80 beats/min, and his blood pressure was 121/72 mm Hg. He appeared well nourished and was resting comfortably. His lungs were clear to auscultation bilaterally. Skin and lower extremity examination revealed bilateral lower extremity edema, erythema, and scaly skin without purulent drainage. Abdominal, musculoskeletal, and rectal examination findings were within normal limits.1.Based on the available clinical data, which one of the following would be the best initial testing for this patient?a.Basic metabolic panelb.Ankle-brachial index testc.Bilateral foot radiographyd.Ferritin measuremente.Dermatology consultation A basic metabolic panel would be reasonable in a patient with insomnia, pruritus, or restless legs syndrome if there was suspicion that a comorbidity, such as renal failure or uremia, was contributing to the clinical presentation. Our patient had no history of renal disease and had no other signs or symptoms consistent with uremia (bleeding, confusion, nausea, friction rub). An ankle-brachial index test would be an appropriate initial test in patients suspected to have peripheral artery disease.1Gerhard-Herman M.D. Gornik H.L. Barrett C. et al.2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Circulation. 2017;135(12):e791-e792].Circulation. 2017; 135: e726-e779Crossref PubMed Scopus (370) Google Scholar Patients typically present with intermittent claudication in the lower extremities, and pain is brought on by exertion and relieved with rest. Erythema of the lower extremity can occur; however, it typically happens when the extremity is dependent.1Gerhard-Herman M.D. Gornik H.L. Barrett C. et al.2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Circulation. 2017;135(12):e791-e792].Circulation. 2017; 135: e726-e779Crossref PubMed Scopus (370) Google Scholar Our patient’s foot cramping is not consistent with peripheral artery disease. Bilateral foot radiography would be reasonable if the discomfort in the lower extremities was thought to be due to trauma or fracture. Because this patient had no history of trauma or point tenderness on examination, radiographic evaluation would not be helpful. The most likely explanation for our patient’s symptoms is restless legs syndrome causing impairment in his sleep cycle and insomnia. Most cases of restless legs syndrome are idiopathic, but certain conditions such as iron deficiency (ferritin level <50 μg/L) are associated with restless legs syndrome.2Çurgunlu A. Döventaş A. Karadeniz D. et al.Prevalence and characteristics of restless legs syndrome (RLS) in the elderly and the relation of serum ferritin levels with disease severity: hospital-based study from Istanbul, Turkey.Arch Gerontol Geriatr. 2012; 55: 73-76Crossref PubMed Scopus (26) Google Scholar In our patient presenting with restless legs syndrome, the best next step is obtaining a serum ferritin measurement to determine if iron deficiency is contributing to his symptoms.3Tefferi A. Hanson C.A. Inwards D.J. How to interpret and pursue an abnormal complete blood cell count in adults.Mayo Clin Proc. 2005; 80: 923-936Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Along with the ferritin measurement, a complete blood cell count (CBC) should be obtained to determine if anemia is present. At this point, the most likely cause of this patient’s lower extremity edema, scaling, and pruritus is dry skin and stasis dermatitis.4Sundaresan S. Migden M.R. Silapunt S. Stasis dermatitis: pathophysiology, evaluation, and management.Am J Clin Dermatol. 2017; 18: 383-390Crossref PubMed Scopus (34) Google Scholar Initial evaluation and treatment of stasis dermatitis involves local skin care, moisturizing lotions, and measures to reduce lower extremity edema.4Sundaresan S. Migden M.R. Silapunt S. Stasis dermatitis: pathophysiology, evaluation, and management.Am J Clin Dermatol. 2017; 18: 383-390Crossref PubMed Scopus (34) Google Scholar Dermatology consultation is typically not required initially. Our patient underwent initial laboratory testing, which revealed the following (reference ranges provided parenthetically): hemoglobin, 17.0 g/dL (13.2 to 16.6 g/dL); mean corpuscular volume, 75.8 fL (78.2 to 97.9 fL); erythrocyte count, 7.81 × 1012/L (4.35 to 5.65 × 1012/L); leukocyte count, 8.6 × 109/L (3.4 to 9.6 × 109/L); platelet count, 440 × 109/L (135 to 317 × 109/L); and ferritin, 10 μg/L (24 to 336 μg/L). A peripheral blood smear revealed microcytosis.2.Which one of the following is the most appropriate next step in this patient’s evaluation?a.Iron supplementationb.Copper measurementc.Colonoscopyd.Transferrin saturation measuremente.Bone marrow biopsy Iron supplementation would be indicated in the presence of anemia; however, our patient had iron deficiency without anemia. It is unusual for an elderly man with severe iron deficiency to have a hemoglobin level near the upper limit of the normal laboratory range and an elevated erythrocyte count. Therefore, additional investigation before initiation of iron treatment is warranted.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar Measurement of the copper level would be appropriate in patients who have evidence of malnutrition or malabsorption, which is not the case in our patient.6Myint Z.W. Oo T.H. Thein K.Z. Tun A.M. Saeed H. Copper deficiency anemia: review article.Ann Hematol. 2018; 97: 1527-1534Crossref PubMed Scopus (62) Google Scholar Especially with our patient’s lack of colon cancer screening, colonoscopy is necessary to rule out underlying colon cancer as a cause of iron deficiency.7García García de Paredes A. Teruel Sánchez-Vegazo C. Hernanz Ruiz N. et al.Do patients with iron deficiency without anemia benefit from an endoscopic examination?.J Dig Dis. 2017; 18: 416-424Crossref PubMed Scopus (5) Google Scholar Ferritin is the most sensitive and specific indicator of iron deficiency, and a low level is diagnostic.3Tefferi A. Hanson C.A. Inwards D.J. How to interpret and pursue an abnormal complete blood cell count in adults.Mayo Clin Proc. 2005; 80: 923-936Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Therefore, transferrin saturation would not provide any additional information.3Tefferi A. Hanson C.A. Inwards D.J. How to interpret and pursue an abnormal complete blood cell count in adults.Mayo Clin Proc. 2005; 80: 923-936Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Bone marrow biopsy is usually unnecessary for the diagnosis of iron deficiency.3Tefferi A. Hanson C.A. Inwards D.J. How to interpret and pursue an abnormal complete blood cell count in adults.Mayo Clin Proc. 2005; 80: 923-936Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Colonoscopy was obtained, and a 3-mm sessile polyp was removed. No source of iron deficiency was found. When the patient returned to the clinic for a follow-up appointment, he continued to have symptomatic pruritus. He reported bilateral foot pain, described as a severe, burning sensation, and had overlying erythema of the distal phalanges. Physical examination revealed slight bilateral erythema of the distal first phalange without underlying abscess or purulent drainage. He had normal vibratory and light touch sensation to the lower extremity. His mucous membranes were moist, and he was euvolemic on examination. A repeated CBC revealed the following: hemoglobin, 16.9 g/dL; hematocrit, 57.2%; erythrocytes, 7.93 × 1012/L; leukocytes, 9.2 × 109/L; platelets, 383 ×109/L; and ferritin, 7 μg/L. The rest of the cardiopulmonary examination findings were normal.3.In view of the current findings, which one of the following should be performed next?a.Oral iron replacementb.Upper endoscopyc.Erythropoietin (EPO) measurementd.Electromyographye.JAK2 mutation genetic analysis Our patient had a persistently elevated erythrocyte count despite iron deficiency, with hemoglobin near the upper end of the normal laboratory range. Erythrocytosis is defined as increased red blood cell mass with an elevation in hemoglobin or hematocrit of more than 2 SD when adjusted for age, race, and sex.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar In the appropriate clinical context, the possibility of erythrocytosis can be considered with either a hemoglobin or hematocrit level of 16.5 g/dL or greater or 49% or greater, respectively, for men and 16 g/dL or greater or 48% or greater, respectively, for women.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar Starting iron therapy in the setting of erythrocytosis is inappropriate before additional evaluation. Upper endoscopy could be considered if the patient had iron deficiency anemia and no abnormalities on colonoscopy to evaluate for possible underlying malignancy or other bleeding sources.7García García de Paredes A. Teruel Sánchez-Vegazo C. Hernanz Ruiz N. et al.Do patients with iron deficiency without anemia benefit from an endoscopic examination?.J Dig Dis. 2017; 18: 416-424Crossref PubMed Scopus (5) Google Scholar Work-up for common causes of iron deficiency should also be considered. However, iron deficiency with erythrocytosis is complex and the mechanism of action is poorly understood, although different theories have been postulated.9Ginzburg Y.Z. Feola M. Zimran E. Varkonyi J. Ganz T. Hoffman R. Dysregulated iron metabolism in polycythemia vera: etiology and consequences.Leukemia. 2018; 32: 2105-2116Crossref PubMed Scopus (28) Google Scholar Our patient’s presentation of elevated hematocrit level and erythrocyte count in the setting of iron deficiency is most consistent with a true erythrocytosis masked by iron deficiency; thus, EPO measurement would be most helpful at this time.3Tefferi A. Hanson C.A. Inwards D.J. How to interpret and pursue an abnormal complete blood cell count in adults.Mayo Clin Proc. 2005; 80: 923-936Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar,5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar Relative erythrocytosis is unlikely in our patient because he was not hypovolemic on examination and was not taking a diuretic (which causes a relative increase in hemoglobin through decreased plasma volume).3Tefferi A. Hanson C.A. Inwards D.J. How to interpret and pursue an abnormal complete blood cell count in adults.Mayo Clin Proc. 2005; 80: 923-936Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar,5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Electromyography would be appropriate for evaluation of peripheral neuropathy. However, our patient’s symptoms of pruritus and bilateral foot burning with erythema (ie, erythromelalgia) were likely symptoms from erythrocytosis.12Grunwald M.R. Burke J.M. Kuter D.J. et al.Symptom burden and blood counts in patients with polycythemia vera in the United States: an analysis from the REVEAL study.Clin Lymphoma Myeloma Leuk. 2019; 19: 579-584.e1Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,13Hou J.L. Onajin O. Gangat N. Davis M.D. Wolanskyj A.P. Erythromelalgia in patients with essential thrombocythemia and polycythemia vera.Leuk Lymphoma. 2017; 58: 715-717Crossref PubMed Scopus (4) Google Scholar JAK2 mutation genetic analysis is a reasonable test and should be obtained if the EPO level is low normal or subnormal or if there is a high clinical suspicion of a primary myeloproliferative neoplasm.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar Laboratory testing revealed an EPO level of 1.1 mIU/mL (2.6 to 18.5 mIU/mL).4.Which one of the following is the most likely underlying cause of the patient’s clinical findings?a.OSAb.Renal cell carcinomac.Essential thrombocythemia (ET)d.Congestive heart failuree.Polycythemia vera (PV) Obstructive sleep apnea is a possible cause of erythrocytosis. It causes secondary erythrocytosis due to tissue hypoxia from apneic events overnight causing EPO levels to rise and increasing red blood cell mass.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar,13Hou J.L. Onajin O. Gangat N. Davis M.D. Wolanskyj A.P. Erythromelalgia in patients with essential thrombocythemia and polycythemia vera.Leuk Lymphoma. 2017; 58: 715-717Crossref PubMed Scopus (4) Google Scholar Our patient’s low EPO level and adherence to continuous positive airway pressure therapy was not consistent with secondary erythrocytosis due to OSA. Renal cell carcinoma is another possible cause of secondary erythrocytosis.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar The increased production of EPO in renal cell carcinoma occurs due to mutations in the von Hippel-Lindau tumor suppressor gene.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Our patient’s low EPO level was not consistent with polycythemia due to renal cell carcinoma. Major criteria for ET include the following: (1) platelet count of 450 × 109/L or greater, (2) bone marrow with megakaryocyte lineage proliferation, (3) no World Health Organization (WHO) criteria for other myeloid neoplasms, and (4) demonstration of a JAK2, CALR, or MPL mutation. Minor criteria include (1) identification of clonal marker and (2) no identifiable cause of thrombocytosis (eg, infection, inflammation, iron deficiency anemia).8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar Definitive diagnosis of ET requires 4 major criteria or the first 3 major criteria plus the minor criteria, and our patient did not meet the 2016 revised WHO criteria.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar Congestive heart failure causes erythrocytosis from tissue hypoxia similar to OSA.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar However, congestive heart failure is a clinical diagnosis based on history and physical examination findings including paroxysmal nocturnal dyspnea, orthopnea, circulatory fluid overload, and diuretic response. Our patient had no clinical signs of congestive heart failure. Polycythemia vera is one of 3 classic Philadelphia chromosome–negative myeloproliferative neoplasms, also including ET and primary myelofibrosis.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar Polycythemia vera is characterized by JAK2 mutation, which occurs in 99% of patients.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar Among patients with PV, 96% and 3% have mutations in JAK2V617F exon 14 and exon 12, respectively.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar Although patients may be asymptomatic, our patient presented with classic symptoms of PV including erythromelalgia and pruritus.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,12Grunwald M.R. Burke J.M. Kuter D.J. et al.Symptom burden and blood counts in patients with polycythemia vera in the United States: an analysis from the REVEAL study.Clin Lymphoma Myeloma Leuk. 2019; 19: 579-584.e1Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar The 2016 revised WHO major criteria for diagnosis of PV include the following: (1) increased red blood cell mass (hemoglobin, >16.5 g/dL and >16 g/dL; hematocrit, 49% and 48% for males and females, respectively), (2) bone marrow with trilineage proliferation and pleomorphic mature megakaryocytes, and (3) presence of JAK2 mutation or JAK2 exon 12/14 mutation.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar Minor criteria include subnormal EPO levels.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar Definitive diagnosis of PV is fulfilled with 3 major criteria or the first 2 major criteria plus 1 minor criterion.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar The 2016 revised WHO criteria lowered the hemoglobin and hematocrit levels to increase sensitivity of diagnosing patients with PV, and especially those who have masked PV, such as our patient.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar Although our patient does not meet a definitive diagnosis of PV at this point, he warrants further investigation with JAK2V617F mutation blood testing given his low EPO level and unlikely alternative causes of erythrocytosis.3Tefferi A. Hanson C.A. Inwards D.J. How to interpret and pursue an abnormal complete blood cell count in adults.Mayo Clin Proc. 2005; 80: 923-936Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar,5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar Results of JAK2V617F mutation analysis were positive. Bone marrow biopsy was obtained, which confirmed PV (fulfilled 3 major and 1 minor WHO criteria).5.Which one of the following is the best next step in management of the patient’s condition?a.Oral iron replacementb.Phlebotomyc.Ruxolitinibd.Hydroxyureae.Aspirin Treatment of PV is based on individualized risk stratification based on age and history of thrombosis.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar Iron supplementation should not be given in PV because it can worsen erythrocytosis and hyperviscosity. Serial phlebotomy is the first step in management of patients with PV to reduce the risk of thrombosis or hyperviscosity syndrome.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar More advanced therapies for PV, such as pegylated interferon alfa, busulfan, and ruxolitinib, could be considered but are typically used in patients with hydroxyurea intolerance.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar Our patient’s condition was considered high-risk PV because of his age (older than 60 years), and therefore, he was a candidate for cytoreductive therapy with hydroxyurea.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,12Grunwald M.R. Burke J.M. Kuter D.J. et al.Symptom burden and blood counts in patients with polycythemia vera in the United States: an analysis from the REVEAL study.Clin Lymphoma Myeloma Leuk. 2019; 19: 579-584.e1Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Additionally, all patients with PV should be treated with aspirin for thromboprophylaxis regardless of risk stratification if von Willebrand disease is excluded.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar However, the best first step in management of patients with PV is serial phlebotomy with a strict hematocrit goal of less than 45%. Our patient was referred to a hematologist and achieved his hematocrit goal of less than 45% with repeated phlebotomy. Aspirin and hydroxyurea were also initiated. His erythromelalgia symptoms improved with phlebotomy after his goal hematocrit level was achieved. His pruritus improved but persisted with adequate PV treatment. His insomnia improved with restless legs syndrome treatment, although he continues to be iron deficient due to ongoing phlebotomy. He has no evidence of thrombosis, hyperviscosity symptoms, or fibrotic or leukemic transformation. Erythrocytosis, regardless of the etiology, is associated with thrombosis and is an independent risk factor for increased cardiac morbidity and mortality.11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Therefore, clinicians must have a thorough approach to diagnosis of the underlying cause. The first step is to rule out a relative erythrocytosis by assessing volume status and medication and substance use history.3Tefferi A. Hanson C.A. Inwards D.J. How to interpret and pursue an abnormal complete blood cell count in adults.Mayo Clin Proc. 2005; 80: 923-936Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar After determining true erythrocytosis with repeated CBC (at least 1-week testing interval), the next step is to measure the EPO level and consider JAK2V617F mutation analysis.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Additional testing is also dependent on whether the erythrocytosis is lifelong vs newly acquired.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar In patients with iron deficiency, PV may be masked with a normal hemoglobin or hematocrit level. Patient symptomology and a substantially elevated erythrocyte count should prompt clinicians to consider PV testing. Common causes of secondary erythrocytosis include hypoxia (smoking, lung or cardiac disease, sleep apnea), drugs (diuretics, corticosteroids, EPO), and polycythemia vera.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Other acquired causes of secondary erythrocytosis that are extrinsic to red blood cells include carbon monoxide poisoning, high altitude, renal hypoxia (renal artery stenosis, end-stage renal disease, post–renal transplant status, polycystic kidney disease), and pathologic EPO production (hepatocellular carcinoma, renal cell carcinoma, pheochromocytoma, parathyroid carcinoma, meningioma).5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Congenital causes include altered affinity to oxyhemoglobin or oxygen sensing pathways (von Hippel-Lindau gene mutations).5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Polycythemia vera is a chronic myeloid neoplasm and cause of true, clonal erythrocytosis with hematopoietic stem cell clonal myeloproliferation. The thresholds for erythrocytosis were lowered in the 2016 revised WHO criteria, which allowed for earlier detection of PV.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar While the incidence of PV is 44 to 57 per 100,000, the incidence of secondary erythrocytosis is more difficult to define given the variety of causes.5Patnaik M.M. Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired.Leukemia. 2009; 23: 834-844Crossref PubMed Scopus (69) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,11Lee G. Arcasoy M.O. The clinical and laboratory evaluation of the patient with erythrocytosis.Eur J Intern Med. 2015; 26: 297-302Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Patients may be asymptomatic, with CBC abnormalities as the only evidence of PV. Assessing for hyperviscosity or thrombosis is essential. Typical clinical signs and symptoms include pruritus (especially after hot baths), plethora (ruddy facial complexion), chest and abdominal pain, fatigue, myalgia, weakness, splenomegaly, thrombosis, bleeding, and microcirculatory symptoms (headaches, light-headedness, atypical chest pain, paresthesia, and visual disturbances).8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar,10Keohane C. McMullin M.F. Harrison C. The diagnosis and management of erythrocytosis.BMJ. 2013; 347: f6667Crossref PubMed Scopus (43) Google Scholar,12Grunwald M.R. Burke J.M. Kuter D.J. et al.Symptom burden and blood counts in patients with polycythemia vera in the United States: an analysis from the REVEAL study.Clin Lymphoma Myeloma Leuk. 2019; 19: 579-584.e1Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Pruritus in PV may not improve with treating to goal blood count levels (erythrocytes, leukocytes, platelets), but results from a recent study suggest that severe pruritus may correlate to more uncontrolled blood counts.12Grunwald M.R. Burke J.M. Kuter D.J. et al.Symptom burden and blood counts in patients with polycythemia vera in the United States: an analysis from the REVEAL study.Clin Lymphoma Myeloma Leuk. 2019; 19: 579-584.e1Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar A rare, but classic, symptom of myeloproliferative neoplasms is erythromelalgia, which consists of erythema, elevated temperature, and burning of the hands or feet.13Hou J.L. Onajin O. Gangat N. Davis M.D. Wolanskyj A.P. Erythromelalgia in patients with essential thrombocythemia and polycythemia vera.Leuk Lymphoma. 2017; 58: 715-717Crossref PubMed Scopus (4) Google Scholar Most patients have resolution or improvement of erythromelalgia with PV treatment.13Hou J.L. Onajin O. Gangat N. Davis M.D. Wolanskyj A.P. Erythromelalgia in patients with essential thrombocythemia and polycythemia vera.Leuk Lymphoma. 2017; 58: 715-717Crossref PubMed Scopus (4) Google Scholar Therefore, clinicians should monitor both symptoms and blood counts. Polycythemia vera is associated with an increased risk of thrombosis and microvascular disease in addition to other cardiovascular risk factors, and therefore, patients should undergo phlebotomy until a goal hematocrit level of less than 45% is achieved.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar In addition, patients should be started on low-dose aspirin therapy.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar Patients are then classified as having low-risk (≤60 years of age and no history of thrombosis) or high-risk (>60 years of age or a history of thrombosis) disease.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar Arterial and venous thrombosis risk factors in PV include prior thrombosis and hypertension.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar In high-risk patients, hydroxyurea should also be initiated to reduce early thrombosis risk.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar Risk factor modification is essential in PV management to reduce symptoms and thrombosis risk. Data from a single tertiary care center indicate a median survival of 14 years for patients older than 60 years and 24 years for patients younger than 60 years.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar Risk factors for increased mortality and leukemic transformation include advanced age, leukocytosis, and abnormal karyotype.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar The main causes of death in PV are thrombotic or hemorrhagic complications, myelofibrosis, and acute myeloid leukemia.14Vannucchi A.M. Guglielmelli P. Tefferi A. Polycythemia vera and essential thrombocythemia: algorithmic approach.Curr Opin Hematol. 2018; 25: 112-119Crossref PubMed Scopus (4) Google Scholar The estimated rate of leukemic transformation for patients with PV is less than 10% at 20 years.8Tefferi A. Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management.Am J Hematol. 2019; 94: 133-143Crossref PubMed Scopus (84) Google Scholar In conclusion, an algorithmic approach to erythrocytosis, along with a comprehensive history and physical examination, is crucial for appropriate diagnosis and management. Our patient presented with insomnia due to restless legs syndrome from iron deficiency, which masked his underlying PV that was contributing to his pruritus. A careful review of the CBC before starting iron therapy is important to prevent morbidity associated with correction of iron deficiency in masked PV.