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Case Study: 52 Year-Old Woman with Fatigue and Neuropathy

A 52-year-old woman who presents complaining of fatigue and shortness of breath on exertion is evaluated in hematology clinic. Her medical and surgical history includes type 2 diabetes mellitus complicated by diabetic neuropathy, hypertension, morbid obesity status post Roux-en-Y gastric bypass surgery five years ago, and obstructive sleep apnea. Initial laboratory evaluation reveals the following:

White blood cells 2.14 x 109/L (4-10 x 109/L)
Hemoglobin 9.7 g/dL (12-15 g/dL)
Hematocrit 27% (36%-47%)
Platelets 358 x 1097/L (150-400 x 109/L)
Mean corpuscular volume 106 fL (80-100 fL)
Mean corpuscular hemoglobin concentration 34.3 g/dL (33-36 g/dL)
Red blood cell distribution width (11.5%-14.5%)
Reticulocytes (0.5%-1.5%)
Ferritin (12-150 ng/mL)
B12 486 (130-700 ng/L)
Folate (2-20 ng/mL)


Review of prior laboratory data has shown a slow decline in her hemoglobin during the past two years; ferritin and B12 levels have been within the reference range multiple times in that interval. On review of systems, she reports worsening numbness and tingling in her arms and legs. She is particularly troubled by this because her diabetes has been under excellent control for the past year, and despite this, the neuropathy symptoms have continued to worsen. On physical examination, she has impaired vibratory sense in her legs and feet and a positive Romberg test. Her medications include chlorthalidone, metformin, and gabapentin.

Which of the following is the next best step in diagnosis

  1. Bone marrow biopsy and aspirate
  2. MRI of the spinal cord
  3. Homocysteine and methylmalonic acid levels
  4. Heavy metal toxicity screening
  5. Serum trace mineral evaluation


  1. Serum trace mineral evaluation


This patient presents with copper deficiency anemia, leukopenia, and myeloneuropathy. Copper is a coenzyme for numerous enzymes involved in hematopoiesis and the normal functioning of the nervous system. From a hematopoietic perspective, copper deficiency results in impaired stem cell differentiation and renewal and reduced heme synthesis, resulting in anemia (which may be macrocytic, normocytic, or microcytic) and neutropenia. Thrombocytopenia is unusual in copper deficiency. The most common causes of copper deficiency include gastric bypass surgery, excessive zinc ingestion (typically from use of zinc-rich denture creams), and malabsorptive enteropathies such as celiac disease and cystic fibrosis. In the case presented, the patient had a Roux-en-Y gastric bypass operation five years ago, which has reduced her ability to ingest and absorb copper. Evaluation of a copper level is an essential part of any anemia evaluation in a patient who has had a gastric bypass surgery, in addition to the more usual B12 assay and iron studies. In this case, the patient has had progressive neurologic symptoms in addition to anemia and leukopenia, which have been previously (and inappropriately) dismissed as diabetic neuropathy.

A bone marrow biopsy and aspirate, performed before a thorough laboratory evaluation including copper level, could lead a hematologist down a wrong—and potentially dangerous—road. Bone marrow biopsies in patients with copper deficiency may show changes that are indistinguishable from myelodysplasia, and indeed this diagnosis may be incorrectly given to these patients after a marrow evaluation. The clinical presentation of B12 deficiency overlaps considerably with copper deficiency and certain clinical situations could cause either, or both, deficiencies (including malabsorptive states and following gastric bypass). Because B12 deficiency is more common and more readily tested for, it is important to remember to also test for copper deficiency in a patient with a compatible history. In patients with borderline B12 levels (<400 ng/L), it is appropriate to check homocysteine and methylmalonic acid levels to ensure there is no occult deficiency state. We are told that this patient currently has a B12 level of 486 ng/L and has had normal B12 evaluations for the past two years, making serum trace mineral evaluation a better answer to the question.

While an MRI of the spinal cord would not be inappropriate given the patient’s neurologic symptoms, it would be unlikely to provide a unifying diagnosis to explain both of her hematologic and neurologic symptoms. Heavy metal toxicity, such as lead poisoning, can result in anemia and neurologic symptoms, though the anemia of lead poisoning is microcytic, and we are given no indications in the clinical history that the patient is at risk for lead exposure.

Case study submitted by Hanny Al-Samkari, MD, of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

  1. Prodan CI, Bottomley SS, Vincent AS, et al. Copper deficiency after gastric surgery: A reason for caution. Am J Med Sci 2009 337:256-258.
  2. Gregg XT, Reddy V, Prchal JT Copper deficiency masquerading as myelodysplastic syndrome. Blood. 2002 1493-1495.
  3. Kumar N, Gross JB Jr, Ahlskog JE Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology. 2004 63:33-39.