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Mayo Clin Proc. 2010 April; 85(4): 392–395.
PMCID: PMC2848427

38-Year-Old Woman With Increasing Fatigue and Dyspnea

A 38-year-old woman presented to the emergency department because of increasing fatigue and shortness of breath, worsening during the past 2 months. At the time of presentation, even minimal exertion caused her to become short of breath. She denied chest pain, cough, expectoration, orthopnea, paroxysmal nocturnal dyspnea, recent fevers, or chills. Her medical history was remarkable for a Roux-en-Y gastric bypass procedure 16 years earlier for morbid obesity. Her weight before surgery was approximately 100 kg (220 pounds), but she had lost considerable weight after surgery, with her recent weight being stable at around 57 kg (125 pounds). She had a history of frequent upper respiratory tract infections, urinary tract infections, and yeast infections since her obesity surgery.

Physical examination revealed a pale woman who appeared malnourished and in mild distress. She was afebrile. The patient's vital signs were as follows: pulse rate, 110 beats/min; respiration rate, 16 breaths/min; and blood pressure, 110/70 mm Hg. Her pulse oximetry revealed normal oxygen saturation while breathing room air. A grade 2/6 systolic ejection murmur was heard over the left sternal border. Her chest was clear to auscultation bilaterally. Examination or her ear, nose, and throat was remarkable for cheilitis and glossitis.

A complete blood cell count yielded the following results (reference ranges shown parenthetically): hemoglobin, 6.1 g/dL (12.0-15.5 g/dL); hematocrit, 18.1% (34.9%-44.5%); mean corpuscular volume, 104 fL (81.6-98.3 fL); white blood cell count, 1.1 × 109/L (3.5-10.5 × 109/L); and platelet count, 254 × 109/L (150-450 × 109/L). She had a blood urea nitrogen level of 17 mg/dL (6-21 mg/dL), a creatinine level of 0.7 mg/dL (0.6-0.9 mg/dL), and a reticulocyte count of 2.11% (0.60%-1.83%). A differential white blood cell count revealed 66% lymphocytes (16%-52%), 19% monocytes (1%-11%), and 11% neutrophils (42%-75%). A peripheral smear revealed mostly macrocytes, few hypochromic microcytes, and dacrocytes, with no schistocytes or spherocytes.

  1. Which one of the following is the most likely cause of this patient's anemia?
    1. Iron deficiency
    2. Autoimmune hemolytic anemia
    3. Hypothyroidism
    4. Hemolytic uremic syndrome
    5. Vitamin B12 or folate deficiency
    This patient's history of gastric bypass surgery is a major risk factor for developing iron deficiency anemia.1 However, laboratory studies of iron deficiency usually show a microcytosis, whereas macrocytes predominated on our patient's peripheral smear, making iron deficiency an unlikely explanation for her anemia. Autoimmune hemolytic anemia is due to the development of IgG or IgM antibodies that react with protein antigens on the red blood cell surface.2 The peripheral smear in autoimmune hemolytic anemia shows characteristic spherocytes, which were absent in our patient. Macrocytic anemia can occur in the setting of hypothyroidism. However, our patient had no clinical features suggestive of severe hypothyroidism, such as weight gain, constipation, cold intolerance, dry skin, or myxedema. Hemolytic uremic syndrome is a microangiopathic hemolytic anemia with decreased renal function and thrombocytopenia, most commonly associated with Shiga toxin–producing Escherichia coli (particularly type O157:H7). It is also associated with use of medications, especially certain chemotherapeutic agents, over-the-counter quinine preparations, and clopidogrel.3 Our patient had a normal platelet count and renal function, with none of the described risk factors, making the diagnosis of hemolytic uremic syndrome unlikely. Vitamin B12 and folate deficiencies often coexist, and it is difficult to distinguish between them on a clinical basis. Their deficiencies lead to megaloblastic anemia, which at this point is the most likely diagnosis for this patient.1
    The patient was admitted for blood transfusions and further work-up. A review of systems revealed that she had begun to become “clumsy” during the past 2 years. Her legs fell asleep easily, she felt unbalanced, and she could not walk in the dark or on uneven ground. She also had shooting pains in both lower extremities and tingling and numbness in both upper and lower extremities.
    The patient had loss of sensation to light touch in both her legs and lack of proprioception up to her ankles. She had hyperesthesia on the plantar surface of both feet. Her reflexes were brisk, and plantar reflexes were flexor. Gait appeared unsteady, and tandem gait was difficult. Romberg sign was present. She performed the finger-to-nose test slowly and deliberately, with some past pointing. Heel to shin motion was difficult to accomplish.
  2. Which one of the following is the most likely cause of the patient's neurologic symptoms?
    1. Vitamin B12 deficiency
    2. Folate deficiency
    3. Multiple sclerosis (MS)
    4. Cerebellar ataxia
    5. Bilateral vestibular dysfunction
    Vitamin B12 deficiency presents neurologically as subacute combined degeneration of the dorsal and lateral spinal columns due to a defect in myelin formation. The neuropathy is symmetrical and usually affects the legs more than the arms. It begins with paresthesias and a sensory ataxia because of loss of vibration and position sense. This can progress to severe weakness. Notably, our patient also had a macrocytic anemia, which supports B12 deficiency as the unifying diagnosis.4 Folate deficiency is a potential cause of her hematologic manifestations but does not explain these neurologic symptoms.
    Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system, affecting primarily young white women, like our patient. It is characterized pathologically by multifocal areas of demyelination. Common symptoms of MS include tingling numbness, loss of sensation to light touch, and gait imbalance (present in this patient). However, she did not have the relapsing-remitting course, visual disturbances, bladder or bowel involvement, or painful phenomena that are characteristic of MS. Additionally, MS does not cause the blood dyscrasias found in our patient.5
    Cerebellar ataxia is characterized by dysmetria, which manifests as overshooting in point-to-point movements. This patient had difficulty with the finger-to-nose test as well as the heel-to-shin maneuver. In addition, her gait was unsteady. However, the typical gait in cerebellar ataxia is wide-based with a reduced step length, described in the literature as “drunken” or “stumbling.” Patients with cerebellar dysfunction usually have scanning speech.6 Our patient did not have clinical features consistent with this syndrome. Bilateral vestibular dysfunction is a rare cause of ataxia and leads to a significantly impaired gait when vision and proprioceptive cues are reduced. This manifests as difficulty when walking in the dark or on uneven ground. Patients with bilateral vestibular damage often have a positive Romberg sign. They also usually have oscillopsia and/or vertigo, neither of which was present in our patient.7
    Review of the patient's medical records revealed that her anemia was long-standing. She confirmed that she had no history of chemotherapy, radiation therapy, or unusual exposure to chemicals. Notably, she had been receiving oral iron replacement therapy as an outpatient for several months. She had also been receiving B12 supplements intramuscularly once weekly since her neurologic symptoms began, but her symptoms had continued to progress. Her serum iron, transferrin, ferritin, B12, and folate levels were all normal. Her thyroid-stimulating hormone levels were normal. Haptoglobin, lactate dehydrogenase, urine hemosiderin, and bilirubin levels were checked for evidence of hemolysis and were also normal. Findings on the direct and indirect Coombs tests for the presence of antibody-related disease were negative. Tests for Fanconi anemia and paroxysmal nocturnal hemoglobinuria were both negative. Viral serologies, including human immunodeficiency virus, Epstein-Barr virus, cytomegalovirus, parvovirus, and hepatitis virus screens, were obtained and were all negative.
    Because the patient was leukopenic with a lymphocytic predominance, peripheral blood flow cytometry with immunophenotyping was performed to look for malignancy. This revealed no monotypic B-cell population or increase in blasts. A Wright-Giemsa–stained slide made from peripheral blood showed no morphologic features of acute leukemia or lymphoma. Findings on computed tomography of her chest, abdomen, and pelvis were negative for lymphadenopathy.
    Ultimately, a bone marrow biopsy was performed to determine a definitive etiology of her anemia and leukopenia. The bone marrow biopsy showed a normocellular bone marrow with trilineage hematopoiesis. The erythroid precursors were vacuolated, and 10% ringed sideroblasts were present. No definitive morphologic features of a myelodysplastic syndrome (MDS) or a lymphoproliferative disorder were present. A mild increase in the cytotoxic T-cell population was noted. Her marrow iron storage was normal.
  3. Which one of the following is the most likely cause of this patient's bone marrow abnormality?
    1. Medications
    2. Ethanol toxicity
    3. MDS
    4. X-linked sideroblastic anemia with ataxia
    5. Metal abnormalities
    The drugs principally associated with sideroblastic anemia are isoniazid and chloramphenicol. Sideroblastic anemia has also been reported with antibiotics such as fusidic acid, linezolid, and tetracycline; hormones such as progesterone replacement; copper-chelating agents such as penicillamine; and chemotherapeutic agents. Discontinuing the medication usually reverses the sideroblastic changes. Our patient had not been taking any of these medications. Sideroblastic anemia may be seen in up to 25% of alcoholics with anemia. Alcohol affects erythroid heme biosynthesis, but our patient did not have a history of alcohol abuse. Ringed sideroblasts may be one of the manifestations of the anemia of MDS. In patients with MDS, the bone marrow is usually hypercellular, and dysplasia in one or more cell lines is usually seen. Abnormal findings on cytogenetic analysis and flow cytometry also assist in making the diagnosis of MDS8; findings on both these tests were normal in this patient. X-linked sideroblastic anemia with ataxia is a rare cause of hereditary sideroblastic anemia. It is characterized by a relatively mild anemia, increased free erythrocyte protoporphyrin, and nonprogressive spinocerebellar ataxia. The severity of our patient's anemia, the nature of her neurologic deficits, and the rarity of the disease make this diagnosis unlikely.
    Lead poisoning causes sideroblastic anemia by inhibiting several key enzymes involved in heme synthesis. Adult lead toxicity is usually the result of work exposure in manufacturing batteries, pigments, ammunitions, paint, car radiators, cable wires, cosmetics, and ceramic ware with lead glazes. Our patient had no history of any of these exposures.
    Copper deficiency has been known to cause anemia and neutropenia with vacuolated precursors and ringed sideroblasts in the bone marrow. Neurologic deficits due to copper deficiency are increasingly being recognized in the literature. A Mayo Clinic series of 25 patients presenting with copper deficiency myelopathy reported gastric bypass surgery as the likely cause of the deficiency in 10 of the 25 patients studied.9 Zinc is relatively nontoxic but in very high doses can cause gastrointestinal symptoms. High zinc levels may induce copper deficiency and thereby cause clinical consequences.9
    Because all testing had been unrevealing up to this point, it was decided to screen this patient for heavy metal toxicity. Her serum copper levels were found to be severely low, and her serum zinc levels were abnormally high. She received copper infusions of 4 mg/d in dextrose intravenously for 2 days with subsequent improvement in her anemia and leukopenia. She was then prescribed 2 doses of multivitamins and oral copper supplements to ensure she would receive 6 mg/d of oral copper.
    Review of this patient's medical history revealed that she had experienced 2 episodes of nephrolithiasis subsequent to her gastric bypass surgery. She had experienced urosepsis after the last episode and had to be hospitalized in the intensive care setting for several days. Each episode had been followed by surgical removal of stones.
  4. Which one of the following types of renal stones is most likely to form after gastric bypass surgery?
    1. Calcium phosphate
    2. Calcium oxalate
    3. Struvite
    4. Cysteine
    5. Urate
    Calcium phosphate (hydroxyapatite) stones are commonly associated with type 1 renal tubular acidosis or primary hyperparathyroidism. Calcium oxalate stones are the most common type of stone formed in all patients with nephrolithiasis. Hyperoxaluria is a known risk factor for calcium oxalate stones. Dietary calcium decreases oxalate absorption in the gut by the formation of insoluble calcium oxalate salts in the intestinal lumen. In patients who have undergone gastric bypass surgery, there is an increase in oxalate absorption and subsequent excretion because of the binding of free calcium to fatty acids in the intestinal lumen. The incidence of nephrolithiasis after gastric bypass surgeries may be high as 6%.10
    Magnesium ammonium phosphate and calcium carbonate apatite are the principal constituents of struvite stones. Struvite stone formation can occur only when ammonia production is increased and the urine pH is elevated. This occurs with upper urinary tract infections with urease-producing organisms such as Proteus species. Cystinuria is a rare, autosomal-recessive disease that results in kidney stones. Patients with cystinuria usually develop their first renal stone as children. Elevations in plasma urate levels (>6.8 mg/dL) proportionally increase the risk of developing nephrolithiasis. Nephrolithiasis with urate stones is most commonly seen in patients with gout.
    The patient's anemia began to resolve, and she was ready to be discharged from the hospital. She was given instruction to continue taking oral copper and a multivitamin supplement as an outpatient.
  5. Which one of the following nutritional supplements is not recommended for patients after gastric bypass procedures?
    Vitamin B12
    Ferrous fumarate
    Calcium carbonate
    Vitamin B12 deficiency is a well-known complication after gastric bypass surgery, occurring in as many as one-third of patients 1 year after surgery. The amount of gastric acid produced after surgery may be inadequate to cleave B12 from meat protein, meat intake is reduced after surgery because it is poorly tolerated, and there may also be decreased availability of intrinsic factor required for the absorption of vitamin B12. Consensus has not been reached on the dose and route of administration, but an oral dose of 500 μg/d or a monthly injection of 1000 μg of vitamin B12 is generally considered adequate to maintain serum levels on a long-term basis.11
    Iron deficiency and consequently microcytic anemia are common in patients after bariatric surgery. In addition to a multivitamin with iron, patients should receive supplements of oral ferrous fumarate if they are able to tolerate them. Parenteral iron may need to be administered to replenish or maintain iron stores.12 Thiamine deficiency leading to Wernicke encephalopathy (ophthalmoplegia, ataxia, and encephalopathy) may occur if patients develop persistent vomiting after surgery. Patients who do not experience excessive vomiting usually need only thiamine in their multivitamin supplement. Symptoms of Wernicke encephalopathy resolve rapidly with intravenous or intramuscular administration of thiamine.
    Obese individuals are likely to develop problems with bone mineral density after bariatric surgery, especially with malabsorptive procedures. Relative hypochlorhydria is common after gastric bypass surgery. Because calcium carbonate is more dependent on gastric acid secretion than calcium citrate, 1.5 g/d of calcium citrate (not calcium carbonate) is the preferred supplement.13
    Folate is not stored in the body in significant levels because it is a water-soluble vitamin. Folate deficiency is associated with macrocytic anemia, leukopenia, thrombocytopenia, glossitis, and elevated homocysteine levels. Folate supplements in multivitamin preparations of 400 μg/d are considered adequate after bariatric surgery.11
    The patient was instructed to take 6 mg/d of oral copper supplement in addition to her multivitamin. Follow-up blood testing 2 months later showed that her anemia and leukopenia had resolved (hemoglobin, 13.1 g/dL; white blood cell count, 6.0 × 109/L, with 72% neutrophils). Her paresthesias persisted but had not progressed.


Bariatric surgical procedures cause weight loss through restrictive or malabsorptive processes or a combination of the two. Although low macronutrient and micronutrient levels are common after bariatric surgery, consensus has not been reached regarding supplementation. These patients require close follow-up with attention to individual signs and symptoms to avoid serious morbidity from nutrient deficiencies.14

Once a rare entity, acquired copper deficiency is becoming more recognized with the increase in gastric bypass procedures. Exogenous zinc ingestion, malnutrition, parenteral alimentation, and malabsorption are also recognized risk factors for copper deficiency. Copper deficiency has multiple clinical consequences because copper is an essential metal for the development and function of the bone marrow as well as the nervous system. Microcytic hypochromic anemia is most commonly seen with hypocupremia, but sideroblastic and macrocytic anemias have also been reported. Copper supplementation promptly resolves the anemia and neutropenia.9

Hypocupremia can present with many neurologic manifestations, including sensory ataxia, proprioceptive deficits, and paresthesias. The sensory ataxia is secondary to dorsal column dysfunction and often leads to gait difficulties. Clinical and neuroimaging findings closely resemble those for subacute combined degeneration seen in patients with vitamin B12 deficiency. Copper supplementation may prevent further neurologic deterioration in these patients, but it may not reverse them.9,15

Copper deficiency should be considered in patients who have undergone gastric bypass surgery and who develop unexplained anemia and neurologic symptoms. Copper deficiency can mimic vitamin B12 deficiency. However, in copper deficiency, symptoms continue to progress despite adequate vitmain B12 supplementation and normal vitamin B12 levels. Treatment of copper deficiency quickly reverses the hematologic symptoms and may prevent further neurologic disease progression.


See end of article for correct answers to questions.

Correct answers: 1. e, 2. a, 3. e, 4. b, 5. d


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