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Occam's Razor for Severe B12 Deficiency

Published:February 06, 2022DOI:https://doi.org/10.1016/j.amjmed.2022.01.039

      Presentation

      A 23-year-old female patient with no past medical history presented to our hospital with chief concern of constipation, decreased food intake, and nausea and vomiting daily for the past 2 months. She reports coming to the hospital because her mother noticed an increase in pallor. One week prior, she presented to affiliated urgent care who recommended docusate and the BRAT diet (Bananas, Rice, Applesauce, Toast), which provided mild constipation relief; however, she had since been averaging 1 bowel movement per week. She had not experienced shortness of breath at rest, chest pain, fevers, chills, dysuria, hematuria, melena, hematochezia, or hematemesis. Her menstrual cycle had been regular without recent change. She had not traveled out of the country since 2018 and did not endorse any recent outdoor activities such as hiking. There was no history of tobacco use and no current use of alcohol or illicit drugs.

      Assessment

      Initial examination revealed normal vital signs with a temperature of 99.0°F, blood pressure of 98/60 mmHg, pulse rate of 89 beats/min, respiratory rate of 16 breaths/min, and a body mass index of 34.03 kg/m2. Physical examination findings were significant for bilateral conjunctival and sublingual pallor. Cardiovascular, neurologic, and abdominal examinations were unremarkable. Review of systems was positive for mild lightheadedness without syncope, fatigue including shortness of breath with exertion, and an unintentional 9.07 kg (20 pounds) of weight loss over the past 2 months.
      The initial blood draw was reported to be abnormally “thin like water.” Complete blood count (CBC) was significant for hemoglobin of 2.8 g/dL, mean corpuscular volume of 107.7 fL, reticulocyte count of 1.7%, and platelet count of 43,000 platelets/µL. Blood smear showed polychromasia along with microcytes and macrocytes, ovalocytes, schistocytes, teardrop cells, anisocytosis, nucleated red blood cells, and large platelets but without any organisms (Figure 1). The hepatic panel was significant for mildly elevated total and direct bilirubin to 1.9 mg/dL and 0.5 mg/dL, respectively. Prothrombin time was 17.2 seconds and international normalized ratio was 1.4. A basic metabolic panel was entirely within normal limits. Therefore, the patient was admitted for anemia workup and to initiate blood transfusion.
      With Hematology service consultation, further laboratory testing was significant for serum haptoglobin <10 mg/dL (below assay), lactate dehydrogenase >2500 U/L (above assay), ferritin 484 ug/L, iron saturation 64%, total iron-binding capacity 184 µg/dL, vitamin B12 <150 pg/mL (below assay), folate 17 µg/L, and methylmalonic acid elevated to 15.68 nmol/L (limit of normal ≤ 0.40 nmol/L). Infectious workup for Babesia species, Ehrlichia species, Anaplasma phagocytophilum, Borrelia burgdorferi, parvovirus B19, Epstein-Barr virus, cytomegalovirus, and malaria was negative, as was testing for ADAMTS13, Glucose 6 phosphate dehydrogenase, and direct Coombs. Additional testing revealed an immunoassay positive for intrinsic factor antibodies, though negative for parietal cell antibodies. Hemoglobin electrophoresis study was normal.
      Given the presence of intrinsic factor antibodies, further workup for pernicious anemia was pursued. Esophagogastroduodenoscopy showed a normal-appearing esophagus, stomach, and duodenum (Figure 2). Although the esophageal and duodenal biopsies were normal histologically, the gastric body biopsy specimen showed features of autoimmune atrophic gastritis characterized by chronic active gastritis with pseudopyloric gland and intestinal metaplasia along with lack of oxyntic glands (Figure 3, Figure 4). These changes were accompanied by linear and micronodular enterochromaffin-like cell hyperplasia. The antral biopsy showed mild chronic inactive gastritis without intestinal metaplasia. No Helicobacter pylori was identified in any of the gastric specimens.
      Figure 2
      Figure 2Gross anatomy, esophagogastroduodenoscopy.
      Figure 3
      Figure 3Gastric body biopsy showing chronic atrophic gastritis characterized by expansion of the lamina propria by lymphocytes and plasma cells. There is complete absence of oxyntic glands. Instead, there is evidence of pseudopyloric metaplasia (red arrow) and intestinal metaplasia (black arrow) (hematoxylin and eosin stain, 200x magnification).
      Figure 4
      Figure 4Gastrin immunohistochemical is negative for G cells confirming that the biopsy originates from the body. G cells are usually located only in the gastric antrum. Chromogranin immunohistochemical stain highlights linear (black arrow) and micronodular (red arrows) enterochromaffin-like cell hyperplasia (brown staining cells), which is a feature of autoimmune atrophic gastritis.

      Diagnosis

      This patient presented at a relatively young age and with minimal healthcare encounters, which caused our team to adopt a broad differential diagnosis. The most profound abnormality on presentation was profound anemia with concurrent vitamin B12 deficiency, for which there is wide-ranging etiology (Table). Serum vitamin B12 is an adequate precursive test, yet a more specific marker, methylmalonic acid, should be used to distinguish from folate deficiency.
      TableVitamin B12 Deficiency Differential
      Vitamin B12 Deficiency Differential Diagnosis
      GastrointestinalAchlorhydria
      Alcoholic fatty liver
      Alcoholic hepatitis
      Atrophic gastritis
      Hyperbilirubinemia
      Cirrhosis
      Gastric cancer
      EndocrineHyperthyroidism and thyrotoxicosis
      Hypothyroidism
      Zollinger-Ellison syndrome
      HematologicBone marrow failure
      Immune thrombocytopenia
      Macrocytosis
      Hemolytic anemia
      Megaloblastic anemia
      Myeloproliferative disease
      MalnutritionTropical sprue and celiac disease
      Malabsorption
      Iron deficiency anemia
      Folate deficiency
      Because pernicious anemia is the leading cause of severe vitamin B12 deficiency worldwide, it should be considered in those presenting with hematopoietic deficiencies.
      • Oh R
      • Brown DL.
      Vitamin B12 deficiency.
      Although typical of pernicious anemia, her presenting symptoms were predominantly gastrointestinal and non-specific. Identifying pernicious anemia as the etiology is aided by evidence of atrophic body gastritis, which is often associated with achlorhydria and subsequent iron deficiency anemia; these findings are more prevalent in women and can precede vitamin B12-associated anemias by 20 years.
      • Toh BH.
      Pathophysiology and laboratory diagnosis of pernicious anemia.
      Additional confirmatory testing includes the presence of autoantibodies against intrinsic factor and/or parietal cells, which have a specificity of 100% and 90.3%, respectively.
      • Lahner E
      • Annibale B.
      Pernicious anemia: new insights from a gastroenterological point of view.
      Previous studies suggest that African-American women are more likely to present with pernicious anemia at a younger age and with autoantibodies.
      • Carmel R
      • Johnson CS
      Racial patterns in pernicious anemia. Early age at onset and increased frequency of intrinsic-factor antibody in black women.
      Although vitamin B12 deficiency is typically associated with megaloblastic anemia, hematologic findings can vary and also include mixed anemia and cytopenia.
      • Andrès E
      • Affenberger S
      • Zimmer J
      • et al.
      Current hematological findings in cobalamin deficiency. A study of 201 consecutive patients with documented cobalamin deficiency.
      Deficiencies can also manifest as thrombocytopenia, leukopenia, or pancytopenia, and can be conflated with an acute leukemic process; thus, diagnostic stewardship should be expressed when considering further advanced invasive testing such as bone marrow biopsy, which can lead to misdiagnosis and iatrogenic harm.
      • Randhawa J
      • Ondrejka SL
      • Setrakian S
      • Taylor H.
      What should I know before ordering a bone marrow aspiration/biopsy in patients with vitamin B12 deficiency?.
      Our patient endorsed significant unintentional weight loss; however, preserved white blood cell count within normal limits and absence of blasts on smear was reassuring against an acute hematologic malignancy. Therefore, given the lack of credible signs, symptoms, or laboratory findings, our team reserved bone marrow biopsy as a consideration only after other diagnostic options were exhausted.

      Management

      We performed daily CBC tests to monitor hematologic status and response to treatment. Hemoglobin was maintained above 7.0 g/dL and platelets above 50,000 platelets/µL, ultimately requiring transfusions of 4 packed red blood cells and 2 units of platelets. Intramuscular vitamin B12 1000 mcg daily injections were initiated on hospital day 2, with corrected reticulocyte counts of 3.0% and 6.3% (limits of normal = 0.7-2.5%) 3 and 4 days after initiating treatment, respectively.
      The patient had a primary care visit 5 days after discharge to establish care and continue weekly vitamin B12 injections. A repeat CBC test showed continued improvement of hematopoietic cell lines at that visit, with persistent elevation of reticulocyte count and return of platelets to normal range. After completing weekly intramuscular injections for 1 month, and subsequent monthly injections for 3 months, the patient was found to be vitamin B12 replete determined by serum levels within normal limits 21 days following last intramuscular injection. Eighteen weeks after her initial presentation, final laboratory testing reflected complete correction of all cell lines: hemoglobin was 14.0 mg/dL, platelet of 361,000 cells/µL, and vitamin B12 at 458 pg/mL (limits of normal = 232-1245 pg/mL). Following repletion, our patient was transitioned to high-dose oral vitamin B12 at 1000 mcg daily, which is equally effective as intramuscular injections in patients with pernicious anemia.
      • Chan CQ
      • Low LL
      • Lee KH.
      Oral vitamin B12 replacement for the treatment of pernicious anemia.
      At that time, her condition was well-managed and could be followed yearly with her primary care physician. Given the association of pernicious anemia with gastric neuroendocrine tumors and adenocarcinomas, she was recommended to repeat esophagogastroduodenoscopy in 3 years; however, no guideline has been established.
      • Lahner E
      • Annibale B.
      Pernicious anemia: new insights from a gastroenterological point of view.
      ,
      • Lahner E
      • Esposito G
      • Annibale B.
      Pernicious anemia: time to justify endoscopic monitoring?.

      References

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        What should I know before ordering a bone marrow aspiration/biopsy in patients with vitamin B12 deficiency?.
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        Oral vitamin B12 replacement for the treatment of pernicious anemia.
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        • Esposito G
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        Pernicious anemia: time to justify endoscopic monitoring?.
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