A 54-Year-Old Man with Pancytopenia

Clinical Review & Education

JAMA Clinical Challenge A 54-Year-Old Man With Pancytopenia

Kapil Saxena, MD; Khoan Vu, MD; Heather E. Nye, MD, PhD

A B

Figure. Histopathologic examination of bone marrow aspirate from patient (A, Wright-Giemsa, original magnification ×1000; B, Prussian blue iron, original magnification ×1000).

A 54-year-old man presented for evaluation of new-onset pancytopenia. He had a distant history of viral myocarditis and was taking lisinopril, carvedilol, furosemide, aspirin, and a WHAT WOULD YOU DO NEXT? multivitamin. No new medications had been started in the past year. Twelve years prior, he underwent uncomplicated Roux-en-Ygastric bypass (RYGB) surgery.Review of systems was A. Check serum trace element levels, notable for fatigue and negative for fever, night sweats, weight loss, dyspnea, or abnormal including iron, copper, and zinc bleeding. Examination revealed temperature of 36.7°C; heart rate, 91/min; blood pressure, 120/70 mm Hg; and body mass index, 20.1 (calculated as weight in kilograms divided by B. Obtain periodic outpatient height in meters squared). He was well-appearing with conjunctival pallor but no pete- complete blood cell counts and chiae, no hepatosplenomegaly, and a normal neurologic examination. treat with supportive transfusions Laboratory evaluation showed a white blood cell count of 1.7 × 103/μL with an abso- as clinically indicated lute neutrophil count of 0.17 × 103/μL; hemoglobin level, 7 g/dL with mean corpuscular volume of 103 fL (reticulocyte index, 0.94); and platelet count, 116 × 103/μL. Results of a complete blood cell count from 8 months prior were normal. Results of serum protein C. Perform endoscopy of upper electrophoresis were normal, as were levels of lactate dehydrogenase, ferritin, folate, and lower gastrointestinal tract

vitamin B12, and thyroid-stimulating hormone. A computed tomography (CT) scan of the abdomen showed no lymphadenopathy,masses, or hepatosplenomegaly.Peripheral blood D. Start erythropoiesis smear showed occasional pseudo Pelger-Huet cells and rare teardrop cells. Histopatho- stimulating agent logic examination of bone marrow aspirate revealed a normocellular marrow and dyseryth- ropoiesis with vacuolized and dysplastic erythroid precursors (Figure, panel A), left- shifted granulocytic maturation with vacuolized granulocytic precursors, ring sideroblasts (Figure, panel B), and no increase in blasts. Cytogenetic studies from the bone marrow did not reveal any abnormalities.

Diagnosis cies including copper deficiency. As part of the workup for pancyto- Pancytopenia secondary to copper deficiency penia or suspected myelodysplastic syndrome (MDS), potentially reversible causes of bone marrow failure such as nutritional deficien- What to Do Next cies must be ruled out. Workup for nutritional deficiency should be A.Check serum trace element levels, including iron, copper, and zinc performed before serologic and endoscopic evaluation for celiac The key to the correct diagnosis in this case is the patient’s his- disease. In this patient, iron and zinc levels were normal; however, tory of gastric bypass surgery,a risk factor for micronutrient deficien- serum copper level was less than 5 μg/dL (reference range, 70-175).

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In asymptomatic cases of pancytopenia due to copper deficiency, per deficiency include normocytic or macrocytic anemia and a trial of copper repletion should precede treatment with blood trans- neutropenia.7 Copper is a cofactor in multiple ferroxidases, sev- fusions or erythropoiesis-stimulating agent. eral of which are involved in hematopoiesis via iron storage, oxi- dation, and transport.2,7 Thus, many of the hematologic conse- Discussion quences of copper deficiency are linked to iron homeostasis. Copper deficiency rarely develops in patients without a history of Bone marrow histopathology can show ringed sideroblasts, hypo- malabsorption, as the average intake of 1 to 1.6 mg/d typically ex- cellular marrow, and vacuolized erythroid and granulocytic ceeds the estimated requirement of 0.9 mg/d.1,2 However, RYGB sur- precursors.7 Such dysplastic changes may be interpreted as mani- gery and other bariatric procedures including partial gastrectomy festations of MDS; however, the diagnosis of MDS requires persis- are underrecognized causes of copper deficiency. These proce- tent cytopenias in addition to at least 1 of 3 histopathologic crite- dures bypass portions of the stomach and proximal small intestine, ria from bone marrow aspirate, biopsy, or both: (1) dysplasia in at the major sites of copper absorption in the gut. The incidence of cop- least 10% of cells from erythroid, granulocytic, or megakaryocytic per deficiency after RYGB varies and is estimated to range from 4% lineages; (2) 5% to 19% blast cells; or (3) MDS-specific cytoge- to 19% in the first 2 to 5 years after the procedure. However, case netic abnormalities such as 5q deletion and monosomy 7.8 Diag- reports have described symptomatic copper deficiency occurring nosis of MDS also requires exclusion of other potential etiologies more than 10 years after RYGB.2,3 In addition to copper, deficien- of marrow dysplasia, including HIV infection, acquired sideroblas-

cies in levels of iron, zinc, vitamin B12, vitamin D, and thiamine have tic anemia, and deficiencies in vitamin B12 or copper. This is par- been reported after RYGB.4 ticularly important in patients predisposed to micronutrient mal- Other conditions associated with copper deficiency include ce- absorption. After RYGB, patients generally undergo scheduled liac disease and excessive zinc ingestion. Copper absorption in monitoring of micronutrients such as copper. If a copper defi- celiac disease is directly impaired via malabsorption due to ciency develops, then supplementation is typically initiated with small intestinal inflammation. In cases of excess zinc ingestion, cop- oral or intravenous elemental copper.4 Although neurologic defi- per absorption is indirectly impaired due to an increase in entero- cits frequently do not respond to copper supplementation, hema- cyte metallothionein levels leading to increased fecal excretion of tologic changes are generally fully reversible.2 copper.5,6 Copper deficiency has also been reported after prolonged enteral and parenteral nutrition administration when cop- Patient Outcome per is not supplemented.7 Supplementation was initiated with oral copper gluconate (4 mg Patients with prolonged copper deficiency can develop both 3 times daily). Within 2 months, serum copper level normalized and neurologic and hematologic abnormalities. Neurologic manifesta- blood counts improved (hemoglobin, 13.2 g/dL; white blood cell tions of copper deficiency include myeloneuropathic changes count, 8.5 × 103/μL; absolute neutrophil count, 5.6 × 103/mL; and that present as an unsteady gait, distal muscle weakness, or sen- platelet count, 202 × 103/mL). The copper gluconate dosage was sory deficits in the extremities.2,3 Notably, this patient did not subsequently reduced and maintained at 2 mg daily without recur- have any neurologic findings. Hematologic manifestations of cop- rence of cytopenias.

ARTICLE INFORMATION Submissions: We encourage authors to submit trace minerals. Nutr Clin Pract. 2017;32(4):471-480. Author Affiliations: University of California, papers for consideration as a JAMA Clinical doi:10.1177/0884533617712226 San Francisco (Saxena, Vu, Nye); San Francisco VA Challenge. Please contact Dr McDermott at 5. Halfdanarson TR, Kumar N, Hogan WJ, Health Care System, San Francisco, California (Nye). [email protected]. Murray JA. Copper deficiency in celiac disease. J Clin Gastroenterol. 2009;43(2):162-164. doi:10. Corresponding Author: Heather E. Nye, MD, PhD, REFERENCES 4150 Clement St, San Francisco, CA 94121 1097/MCG.0b013e3181354294 ([email protected]). 1. Collins JF, Klevay LM. Copper. Adv Nutr. 2011;2 6. Willis MS, Monaghan SA, Miller ML, et al. (6):520-522. doi:10.3945/an.111.001222 Section Editor: Mary McGrae McDermott, MD, Zinc-induced copper deficiency: a report of three Senior Editor. 2. Gletsu-Miller N, Broderius M, Frediani JK, et al. cases initially recognized on bone marrow Incidence and prevalence of copper deficiency examination. Am J Clin Pathol. 2005;123(1):125-131. Published Online: February 11, 2019. following Roux-en-Y gastric bypass surgery. Int J doi:10.1309/V6GVYW2QTYD5C5PJ doi:10.1001/jama.2018.21899 Obes (Lond). 2012;36(3):328-335. doi:10.1038/ijo. 7. Halfdanarson TR, Kumar N, Li CY, Phyliky RL, Conflict of Interest Disclosures: None reported. 2011.159 Hogan WJ. Hematological manifestations of copper Additional Contributions: We sincerely thank 3. Griffith DP, Liff DA, Ziegler TR, Esper GJ, deficiency: a retrospective review. Eur J Haematol. Chuanyi Mark Lu, MD (University of California, Winton EF. Acquired copper deficiency: a potentially 2008;80(6):523-531. doi:10.1111/j.1600-0609.2008. San Francisco/San Francisco VA Health Care serious and preventable complication following 01050.x System, Department of Laboratory Medicine), for gastric bypass surgery. Obesity (Silver Spring). 2009; 8. Arber DA, Orazi A, Hasserjian R, et al. his expertise in analyzing hematologic specimens 17(4):827-831. doi:10.1038/oby.2008.614 The 2016 revision to the World Health Organization and preparing images. We thank the patient for 4. Patel JJ, Mundi MS, Hurt RT, Wolfe B, classification of myeloid neoplasms and acute providing permission to share his information. Martindale RG. Micronutrient deficiencies after leukemia. Blood. 2016;127(20):2391-2405. doi:10. bariatric surgery: an emphasis on vitamins and 1182/blood-2016-03-643544

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