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44-Year-Old Man With Shortness of Breath, Fatigue, and Paresthesia

      A 44-year-old man presented to the Primary Care Internal Medicine clinic with a 1-month history of shortness of breath, fatigue, and paresthesia. He reported increasing shortness of breath while stocking shelves at work and recently stopped recreational jogging because of this symptom. He also described a new, painless numbness and tingling in his fingertips bilaterally.
      The patient denied any history of chest pain, syncope, palpitations, muscle weakness, incontinence, weight changes, or recent illness. He was taking no prescription or over-the-counter medications or food supplements. He had no other relevant medical or surgical history. He had never used tobacco or illicit drugs and consumed an average of 1 alcoholic beverage per month. He had no siblings. Family history was remarkable for coronary artery disease in his father and osteoarthritis in his mother.
      Physical examination revealed a blood pressure of 101/58 mm Hg, with a regular pulse of 86 beats/min. The patient was afebrile, alert, and well nourished. Head and neck evaluation demonstrated a supple neck without tenderness to palpation or carotid bruits. Scleras were normal. Neck range of motion and strength were normal. Findings on thyroid and lymph node examinations were unremarkable. Cardiac examination revealed normal first and second heart sounds without murmurs, gallops, or rubs. Lung sounds were clear. The patient's skin was pale. Abdominal examination revealed no tenderness, masses, or hepatosplenomegaly. Cranial nerve examination revealed no abnormalities in cranial nerves II through XII. Sensation was intact throughout, except for reduced pinpoint discrimination of the bilateral finger tips. The Phalen maneuver and Tinel sign were negative. The extremities, including the thenar musculature, were of normal tone, bulk, and strength, with symmetric and normal reflexes throughout. The lower extremities had mild varicosities but were not edematous. Babinski testing was normal. Gait testing was normal except for mild unsteadiness during the tandem walk.
      • 1.
        On the basis of this patient's history and findings on physical examination, which one of the following diagnoses is most likely?
        • a.
          Carpal tunnel syndrome
        • b.
          Cervical disc impingement
        • c.
          Anemia
        • d.
          Angina
        • e.
          Multiple sclerosis
      This patient has a combination of shortness of breath, fatigue, and new-onset paresthesia. His shortness of breath, fatigue, and paresthesia can be related to a wide spectrum of cardiovascular, pulmonary, hematologic, or metabolic diseases.
      Carpal tunnel syndrome may cause the paresthesia but in the median nerve distribution. Advanced cases may demonstrate a positive Phalen maneuver, Tinel sign, and thenar muscle atrophy. Our patient does not have any of these signs. This diagnosis would not explain his shortness of breath. His bilateral symptoms are possible but do not classically occur in median nerve entrapment.
      Cervical disc impingement may cause symmetric paresthesias. However, the patient had unremarkable findings on neurologic examination except for sensation, no recent history of trauma or osteoarthritis, and no other pertinent history or examination findings indicating impingement. This diagnosis would not explain the patient's shortness of breath or fatigue.
      Anemia is consistent with the patient's shortness of breath and fatigue, and certain types of anemia can be associated with paresthesia. Therefore, anemia is the most likely diagnosis on the given differential diagnosis. Shortness of breath can occur with angina. However, this patient does not have any chest pain or relevant personal or family cardiac history. Angina would also not explain his paresthesia.
      Multiple sclerosis can present with fatigue, and a variety of neurologic symptoms including paresthesia may be associated. It occurs more often in women, with a typical age of onset of 20 to 40 years. Episodes can last for days, weeks, or months. Although multiple sclerosis is a reasonable consideration, the patient's dyspnea, pallor on examination, and lack of other neurologic findings suggest that anemia is more likely.
      The patient's complete blood cell count (CBC) was remarkable for the following (reference ranges provided parenthetically): white blood cell count, 2.3 × 109/L (3.5-10.5 × 109/L); hemoglobin level, 5.1 g/dL (13.5-17.5 g/dL); mean corpuscular volume, 119 fL (81.2-95.1 fL); and platelets, 77 × 109/L (150-450 × 109/L). His electrolyte panel yielded the following unremarkable findings: sodium, 141 mEq/L (135-145 mEq/L); potassium, 4.3 mmol/L (3.6-4.8 mmol/L); creatinine, 0.9 mg/dL (0.9-1.4 mg/dL); and glucose, 92 mg/dL (70-100 mg/dL). His thyroid panel was normal. The patient's levels of C-reactive protein and creatine kinase as well as his sedimentation rate were all within normal limits. Electrocardiography revealed normal sinus rhythm.
      • 2.
        Which one of the following tests would be most helpful in establishing a diagnosis?
        • a.
          Bone marrow biopsy
        • b.
          Folate assay
        • c.
          Vitamin B12 assay
        • d.
          Methylmalonic acid (MMA) assay
        • e.
          Homocysteine assay
      Our patient was diagnosed as having macrocytic anemia on the basis of his low hemoglobin level and elevated mean corpuscular volume. The differential diagnosis of macrocytosis is broad and outlined in the Table. It includes myelodysplastic syndromes, drugs (including chemotherapeutic agents) that affect or block DNA metabolism, and folate and vitamin B12 deficiencies, all of which may be characterized by oval macrocytes on the peripheral smear. The differential diagnosis also includes alcohol abuse, hypothyroidism, and liver disease, which can be associated with round macrocytes. The peripheral smear in macrocytosis may also demonstrate the regenerative macrocytosis seen with reticulocytosis.
      • Pruthi RK
      • Tefferi A
      Pernicious anemia revisited.
      TABLEDifferential Diagnosis of Macrocytosis
      • DNA metabolism abnormalities
        • Vitamin B12 deficiency
        • Folate deficiency
        • Drugs (including chemotherapeutic agents) that affect or block DNA metabolism (eg, methotrexate, azathioprine, hydroxyurea)
      • Lipid abnormalities
        • Hypothyroidism
        • Liver disease
      • Bone marrow disorders
        • Myelodysplastic syndromes
        • Large granular lymphocytic leukemia
      • Other
        • Alcoholism
        • Multiple myeloma
        • Reticulocytosis
        • Fanconi anemia
      Anemias due to vitamin B12 or folate deficiency, chemotherapeutic agents, or myelodysplasia are commonly the result of impaired DNA synthesis and are typically characterized by large immature red blood cells and hypersegmented neutrophils.
      • Marks PW
      • Zukerberg LR
      Case 30-2004: a 37-year old woman with paresthesias of the arms and legs.
      • Bain BJ
      Diagnosis from the blood smear.
      Although a bone marrow biopsy may reveal a primary bone marrow disorder, less invasive measures should be considered first.
      Folate and vitamin B12 deficiency both can lead to macrocytic anemia. Because of the corresponding paresthesias known to occur with vitamin B12 deficiency and not with folate deficiency, checking a vitamin B12 level is most useful during this point of the evaluation.
      The MMA and homocysteine levels are used to confirm the diagnosis of vitamin B12 deficiency, especially in the setting of concurrent folate deficiency. In vitamin B12 deficiency, the MMA and homocysteine levels are both elevated. Only the homocysteine level is elevated in folate deficiency. Before testing these levels, however, it will be most useful to check the vitamin B12 level in this patient.
      Our patient's blood tests revealed a markedly low vitamin B12 level of less than 70 ng/L (180-914 ng/L). His diagnosis was confirmed with an elevated MMA level of 46 μmol/L (≤0.40 μmol/L). His folate level was normal. A peripheral blood smear showed oval macrocytes, marked anisocytosis, marked polychromasia, slight poikilocytosis, and occasional dacrocyte tailed blood cells. Intrinsic factor antibodies were positive, and a polyspecific direct antiglobulin test yielded negative results.
      • 3.
        On the basis of these test results, which one of the following is the most likely etiology of the patient's anemia?
        • a.
          Malabsorption
        • b.
          Pernicious anemia
        • c.
          Achlorhydria
        • d.
          Dietary insufficiency
        • e.
          Diphyllobothrium latum
      When vitamin B12 is ingested, it initially binds to protein carriers. The acidic environment in the stomach then causes it to dissociate from the protein carriers. Intrinsic factor is manufactured by the parietal and zymogenic cells in the gastric fundus and body and binds to the free vitamin B12 in the duodenum. This complex travels through the intestines and is absorbed by receptors in the terminal ileum. Dysfunction during any part of this process can lead to total body vitamin B12 deficiency.
      Malabsorption of vitamin B12 can occur specifically in patients who have lost their ileal receptors, such as those with inflammatory bowel disease or those whose terminal ileum has been surgically removed. Our patient does not have this history.
      Pernicious anemia results when the autoimmune destruction of the gastric parietal and zymogenic cells inhibits intrinsic factor production. Intrinsic factor antibodies may also be present and bind to existing intrinsic factor. Our patient's undetectable vitamin B12 levels, elevated MMA level, and positive intrinsic factor antibodies make pernicious anemia the most likely diagnosis.
      Achlorhydria, or lack of acid in the stomach, can also lead to vitamin B12 deficiency. If the environment in the stomach is not acidic, the vitamin B12 and protein carrier complex does not dissociate, and intrinsic factor is unable to bind to vitamin B12. Such is the case in patients taking medications that inhibit acid production (eg, proton pump inhibitors). Achlorhydria can also be secondary to aging, and vitamin B12 deficiency is seen frequently in elderly patients. This etiology was unlikely in our patient who was not elderly and was not taking medications that inhibited acid production.
      Dietary insufficiency is rare but can occur. D latum (fish tapeworm) and other biological competition (eg, bacterial overgrowth syndromes) can lead to vitamin B12 deficiencies.
      • Marks PW
      • Zukerberg LR
      Case 30-2004: a 37-year old woman with paresthesias of the arms and legs.
      Humans are the definitive hosts for D latum and can be infected by consuming undercooked fish, including walleye and pike.
      • Maniu CV
      • Acostamadiedo JM
      • Alvarez S
      73 year old man with hepatomegaly and weight loss.
      Nothing in this patient's history suggests any of these processes.
      The patient was informed of his diagnosis. In discussing the diagnosis with his family, the patient learned that his father required vitamin B12 supplementation to compensate for a vitamin B12 deficiency.
      • 4.
        Which one of the following would be the best treatment for this patient's condition?
        • a.
          Packed red blood cell (PRBC) transfusion
        • b.
          Intramuscular vitamin B12 and PRBC transfusion
        • c.
          Intravenous vitamin B12 and PRBC transfusion
        • d.
          Omeprazole, amoxicillin, clarithromycin, and PRBC transfusion
        • e.
          Omeprazole, amoxicillin, clarithromycin, vitamin B12, and PRBC transfusion
      Given the patient's symptoms of dyspnea and low hemoglobin level, it is appropriate to treat with PRBCs. It is also important to initiate vitamin B12 therapy to treat his deficiency and neurologic symptoms. Vitamin B12 is available in oral, intramuscular, and intranasal forms. Vitamin B12 is also compatible in intravenous solutions of normal saline but is not easily administered. Treatment with both PRBCs and intramuscular vitamin B12 is preferred. Adding the omeprazole, amoxicillin, and clarithromycin treatment would be appropriate if the patient were positive for Helicobacter pylori. H pylori may lead to vitamin B12 deficiency by causing atrophic gastritis.
      • Kaptan K
      • Beyan C
      • Ural AU
      • et al.
      Helicobacter pylori—is it a novel causative agent in Vitamin B12 deficiency?.
      However, no information on H pylori status was available for this patient, and he had known intrinsic factor antibodies that explained his anemia.
      This patient was treated with a transfusion of PRBCs. He also received 1000 μg of vitamin B12 intramuscularly daily for 1 week, then weekly for 1 month, and then monthly indefinitely.
      • 5.
        Which one of the following is the most appropriate study to order during follow-up testing?
        • a.
          Hemoglobin assay
        • b.
          Hemoglobin and potassium assay
        • c.
          CBC
        • d.
          CBC and potassium assay
        • e.
          CBC and potassium and creatinine assays
      Follow-up should include a hemoglobin assay to determine the patient's response to treatment. His bone marrow may respond to the high loads of vitamin B12 with a sudden increase in erythropoiesis. Therefore, a CBC is necessary in addition to a hemoglobin assay, especially to monitor platelets. Aspirin can be administered if the platelet levels increase above normal limits.
      The potassium level should be monitored because potassium is consumed during erythropoiesis, and its rapid consumption could lead to life-threatening hypokalemia. A creatinine assay is not indicated. Therefore, the most appropriate follow-up studies are a CBC and a potassium assay.
      Follow-up CBC was unremarkable, with all values within normal limits. The patient tested negative for the H pylori antibody. He had hypergastrinemia (gastrin level, 1102 pg/mL [<100 pg/mL]), and benign findings on esophagogastroduodenoscopy. After initiation of treatment, the patient's symptoms of fatigue, shortness of breath, and paresthesia entirely resolved. He will require lifelong vitamin B12 supplementation.

      DISCUSSION

      Patients with vitamin B12 deficiency often first present to the primary care physician. Because these patients are at risk of long-term neurologic deficits, it is critical that physicians be able to diagnose a vitamin B12 deficiency. Promptly diagnosing and treating a vitamin B12 deficiency may even reverse ongoing neurologic changes.
      Folic acid deficiency may lead to a megaloblastic anemia similar to that caused by a lack of vitamin B12. Replacement of folic acid alone may correct the anemia but can mask a concurrent vitamin B12 deficiency. Folic acid supplementation will not prevent the progression of neurologic symptoms.
      • Malouf R
      • Grimley Evans J
      Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people.
      Of note, patients with vitamin B12 deficiency may present with neurologic symptoms without a corresponding anemia. Our patient had a pancytopenia, which can be seen in advanced cases of pernicious anemia. However, the severity of leukopenia and thrombocytopenia can vary among patients.
      • Pruthi RK
      • Tefferi A
      Pernicious anemia revisited.
      The vitamin B12 level may be falsely normal in patients with liver disease, myeloproliferative diseases, and long-term nitrous oxide exposure or abuse. If vitamin B12 levels are normal but the diagnosis is strongly suspected, the MMA and homocysteine levels should be checked to confirm the diagnosis.
      Hypergastrinemia in patients with pernicious anemia can lead to enterochromaffin cell hyperplasia and gastric carcinoid tumors. As many as 1% to 7% of patients with pernicious anemia develop gastric carcinoid tumors that may be identified via esophagogastroduodenoscopy.
      • Jordan PH
      • Barroso A
      • Sweeney J
      Gastric carcinoids in patients with hypergastrinemia.
      Patients with pernicious anemia are also estimated to have a 3- to 5-fold higher risk of developing gastric adenocarcinoma compared with the general population. Colorectal cancers may also be more frequent.
      • Pruthi RK
      • Tefferi A
      Pernicious anemia revisited.
      However, no formal recommendations are available regarding the frequency of monitoring.
      Fortunately, our patient's paresthesias resolved with adequate vitamin B12 supplementation. Nonetheless, approximately 50% of patients have residual neurologic disease despite treatment.
      • Marks PW
      • Zukerberg LR
      Case 30-2004: a 37-year old woman with paresthesias of the arms and legs.
      In pernicious anemia patients with neurologic symptoms, the use of intramuscular vs oral vitamin B12 remains a subject of debate. Studies suggest that vitamin B12 is equally effective when taken orally (in a high dose daily) as when administered via the intramuscular route,
      • Butler CC
      • Vidal-Alaball J
      • Cannings-John R
      • et al.
      Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systemic review of randomized controlled trials.
      • Bolaman Z
      • Kadikoylu G
      • Yukselen V
      • et al.
      Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study.
      because passive diffusion of vitamin B12 accounts for 1% to 2% of total absorption and is unaffected in patients with pernicious anemia. However, these studies are limited, and further research is indicated.
      In summary, early recognition and treatment of vitamin B12 deficiency can resolve anemia and prevent and potentially reverse any neurologic sequelae.

      REFERENCES

        • Pruthi RK
        • Tefferi A
        Pernicious anemia revisited.
        Mayo Clin Proc. 1994; 69: 144-150
        • Marks PW
        • Zukerberg LR
        Case 30-2004: a 37-year old woman with paresthesias of the arms and legs.
        N Engl J Med. 2004; 351: 1333-1341
        • Bain BJ
        Diagnosis from the blood smear.
        N Engl J Med. 2005; 353: 498-507
        • Maniu CV
        • Acostamadiedo JM
        • Alvarez S
        73 year old man with hepatomegaly and weight loss.
        Mayo Clin Proc. 1998; 73: 899-902
        • Kaptan K
        • Beyan C
        • Ural AU
        • et al.
        Helicobacter pylori—is it a novel causative agent in Vitamin B12 deficiency?.
        Arch Intern Med. 2000; 160: 1349-1353
        • Malouf R
        • Grimley Evans J
        Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people.
        Cochrane Database Syst Rev. 2008; (CD004514.)
        • Jordan PH
        • Barroso A
        • Sweeney J
        Gastric carcinoids in patients with hypergastrinemia.
        J Am Coll Surg. 2004; 199: 552-555
        • Butler CC
        • Vidal-Alaball J
        • Cannings-John R
        • et al.
        Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systemic review of randomized controlled trials.
        Fam Pract. 2006; 23: 279-285
        • Bolaman Z
        • Kadikoylu G
        • Yukselen V
        • et al.
        Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study.
        Clin Ther. 2003; 25: 3124-3134