A case of asymptomatic pancytopenia with clinical features of hemolysis as a presentation of pernicious anemia


A case of asymptomatic pancytopenia with clinical features of hemolysis as a presentation of pernicious anemia

Venkateswara K. Kollipara, MD*, Patrick L. Brine, MD, David Gemmel, PhD and Sisham Ingnam, MD

Mercy Health St Elizabeth Health Center, Youngstown, OH, USA


Pernicious anemia is an autoimmune disease with a variety of clinical presentations. We describe a case of pernicious anemia presenting with pancytopenia with hemolytic features. Further workup revealed very low vitamin B12 levels and elevated methylmalonic acid. It is important for a general internist to identify pernicious anemia as one of the cause of pancytopenia and hemolytic anemia to avoid extensive workup. Pernicious anemia can present strictly with hematological abnormalities without neurological problems or vice versa as in our case.

Keywords: pernicious anemia; hemolytic anemia; pancytopenia; intramedullary hemolysis; anti-intrinsic factor antibody

Citation: Journal of Community Hospital Internal Medicine Perspectives 2016, 6: 32493 - http://dx.doi.org/10.3402/jchimp.v6.32493

Copyright: © 2016 Venkateswara K. Kollipara et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 3 June 2016; Revised: 21 June 2016; Accepted: 1 August 2016; Published: 7 September 2016

Competing interests and funding: The authors have not received any funding or benefits from industry or elsewhere to conduct this study.

*Correspondence to: Venkateswara K. Kollipara, Mercy Health St Elizabeth Health Center, Youngstown, OH, USA, Email: kumarkollipara.0308@gmail.com


A 42-year-old Latin American woman with significant past medical history of asthma, unknown cause of anemia since childhood, diabetes, and hyperlipidemia was admitted for worsening cough and shortness of breath for 3 days. Her symptoms are associated with rhinorrhea, dry cough, sore throat, and chest congestion. Review of systems was otherwise unremarkable. Her presenting vital signs revealed a temperature 97.9 F, blood pressure 132/72 mmHg, heart rate 120/min, and oxygen saturation 98% on room air. Physical examination was notable for conjunctival pallor and mild upper lobe wheezing with the rest of the examinations otherwise unremarkable. She was subsequently admitted for a suspected acute asthma exacerbation. Incidentally, her laboratory values revealed a hemoglobin (Hgb) level of 6.8, white blood cell count (WBC) of 1.3, and platelet count of 112. Therefore, a new diagnosis of pancytopenia was established with further workup to follow exhibiting an elevated lactate dehydrogenase (LDH) (1,155 U/L), low haptoglobin (<10 mg/dL), and normal bilirubin levels. Peripheral smear revealed normocytic, normochromic anemia with ovalocytes and an admixture of ‘teardrop-shaped’ red blood cells (Fig. 1). There was a concern for underlying myelodysplastic syndrome because of pancytopenia and teardrop cells on the peripheral smear. Therefore, for further evaluation a bone marrow biopsy was performed, which showed hypercellular (for age) bone marrow with significant erythroid hyperplasia and megaloblastic changes (Fig. 2). Autoimmune workup was negative for anti-nuclear antibodies (ANA), DS-DNA, anti-neutrophilic antibodies (C-ANCA), rheumatoid factor (RF), anti-scleroderma antibody (SLC) 70, anticentromere, antiribonuclear protein (RNP), hypersensitivity panel, HIV, and hepatitis panel. She also was found to have normal folic acid and iron studies. However, her vitamin B12 was markedly decreased (59). Patient had been taking iron supplementation for her undiagnosed anemia since childhood. Further workup for vitamin B12 deficiency showed elevated methylmalonic acid (18.96) and homocysteine (83.6), as well as positive anti-parietal cell and intrinsic factor antibodies. She was started on vitamin B12 shots every day for 7 days and then once a month. Follow-up after 4 months showed normal WBC, Hgb, and platelet levels (Table 1).

Fig 1

Fig. 1.   Peripheral smear normocytic, normochromic anemia with ovalocytes and an admixture of “teardrop-shaped” red blood cells.

Fig 2

Fig. 2.   Bone marrow biopsy revealing hyper cellular (for age) bone marrow with significant erythroid hyperplasia and megaloblastic changes.

Table 1.  Cell lineages at presentation and after treatment with vitamin B12
  Day 1 Day 2 1 week 4 months Reference range
WBC 1.3 1.5 2.7 5.9 4.5–11.5 E9/L
Hemoglobin 6.8 7.1 6.9 12.8 11.5–15.5 g/dl
Platelets 112 108 101 248 130–450 E9/L
Vitamin B12 N/A 59 >2,000 >2,000 211–946 pg/ml
Folic acid N/A >20 N/A >20 7.3–26.1 ng/ml
Iron/TIBC 74/321 N/A N/A N/A 37–145 mcg/ml
250–450 mcg/dl


Pernicious anemia is an autoimmune disease that causes a variety of clinical features as described in Table 2. The incidence of disease peaks at the age of 60 with known associations with other autoimmune diseases such as vitiligo, Hashimoto’s thyroiditis, hypoparathyroidism, and Addison’s disease. It can also be associated with hypogammaglobinemia, premature graying or blue eyes, and blood group A. It is characterized by antibodies to intrinsic factor and/or parietal cells, which causes vitamin B12 deficiency due to failure of B12 absorption. Anti-parietal cell antibodies (PCA) are present in 90% of pernicious anemia patients, but lack specificity to the disease where 16% of healthy patients can have these antibodies, particularly women older than 60. Anti-intrinsic factor is less sensitive but more specific at >90%. Autoantibodies cause destruction of parietal cells and gastric atrophy, decrease in hydrochloric acid and serum pepsinogen, and increase in serum gastrin levels. Among previous postulated theories regarding the mechanism for pernicious anemia, chronic Helicobacter pylori infection can potentially lead to gastric inflammation, gastric atrophy, and intestinal metaplasia. These changes can predispose to gastric carcinoid and adenocarcinoma (1, 2). Therefore, continuous surveillance every 3 years in patients with pernicious anemia and Helicobacter pylori infection with endoscopy is strongly recommended (3). Other causes of vitamin B12 deficiency apart from pernicious anemia are listed in Table 3.

Table 2.  Clinical features of vitamin B12 deficiency
Brain and spinal cord Megaloblastic madness – depression, mania, irritability, paranoia, delusions, dementia Myelopathy, subacute combined degeneration of spinal cord, optic atrophy, loss of taste, glossitis
Autonomic nervous system dysfunction Postural hypotension, incontinence, impotence
Peripheral nervous system Sensory loss, hyporeflexia, paresthesias
Peripheral smear Macrocytic red cells, hypersegmented neutrophils, leukopenia, thrombocytopenia, elevated LDH, indirect bilirubin, decreased haptoglobin, elevated MMA and homocysteine
Bone marrow Hypercellular, increased erythroid precursors, dyssynchrony between maturation of cytoplasm and nuclei

Table 3.  Causes of vitamin B12 deficiency
Food Decreased consumption – vegan diet, food cobalamin malabsorption (more common in elderly)
Stomach Pernicious anemia, partial or total gastrectomy, gastric bypass, atrophic gastritis, Helicobacter pylori infection, Zollinger–Ellison syndrome
Intestine Chronic pancreatitis, bacterial overgrowth, fish tapeworm infestation, celiac disease, tropical sprue, Imerslund–Grasbeck disease, intestinal stagnant loop syndrome, ileal resection (>1.2 m), HIV
Drugs Proton pump inhibitors, H2 blockers, nitric oxide anesthesia

Common findings on peripheral smear are megaloblastic anemia with hypersegmented neutrophils. Vitamin B12 is essential for DNA synthesis and cell division of hematopoietic cells. Vitamin B12 deficiency leads to disassociation between the maturation of cytoplasm and that of nuclei exhibiting macrocytosis, immature nuclei, and hypersegmentation in neutrophils (4). Therefore, intramedullary cell death due to arrest of various precursor cells in hypercellular bone marrow causes release of LDH and low haptoglobin levels resulting in a presentation of similar to microangiopathic hemolytic anemia (5). Patients who present with normal vitamin B12 levels, but show clinical signs and symptoms of pernicious anemia, should have functional assays like methylmalanoic acid (MMA) and homocysteine levels checked (2). It is noted that competitive binding assays are susceptible to interference due to anti-IF antibodies resulting in false normal vitamin B12 levels (2). MMA is mildly elevated in 30% of healthy patients, 15% of elderly and in renal failure patients. Sometimes, iron deficiency anemia can be accompanied with vitamin B12 deficiency, which makes mean corpustular volume (MCV) appear normal. Leukopenia, thrombocytopenia, and pancytopenia can occur in extreme deficiency cases, such as in our case. It is very important to rule out vitamin B12 deficiency before treating folate deficiency as neuropathy can worsen with improving anemia. High-dose oral vitamin B12 supplementation of 1,000 to 2,000 µg/d is usually as effective as parenteral administration. If patients present with severe anemia and neurological complications, six shots without interval periods can be administered for 1 week. Treatment should be followed with 1,000 µg monthly IM injections or every 3 months based on severity. Folate levels in pernicious anemia will be normal or increased as conversion of methyl tetrahydrofolate (MTHF) to tetrahydrofolate (THF) is blocked because of lack of vitamin B12. However, during supplementation of vitamin B12, folate should also be supplemented in cases of severe anemia or pancytopenia due to increased folate utilization for cell production.


Vitamin B12 deficiency can be caused by a number of various etiologies. Thorough evaluation and detection of underlying etiology is essential for long-term treatment. B12 deficiency can have a multitude of presentations including strictly hematological abnormalities without neurological problems or vice versa, as in our case. It is recommended to have one-time endoscopy with biopsy in every pernicious anemia patient as it has been postulated to be associated with gastric cancer and carcinoid with subsequent 3-year surveillance. Both pernicious anemia and autoimmune thyroid disease can cause hyper-homocysteinemia, a strong independent risk factor for CVD (6). As in our case, vitamin B12 should be in differential diagnosis in any patient who presents with pancytopenia.


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About The Authors

Venkateswara K. Kollipara
St Elizabeth Health Center, Youngstown, Ohio
United States

Internal medicine resident

Patrick L. Brine
St Elizabeth Health Center, Youngstown, Ohio
United States

Internal Medicine faculty

David Gemmel
St Elizabeth Health Center, Youngstown, Ohio
United States

Director Medical Education and Research

Sisham Ingnam
St Elizabeth Health Center, Youngstown, Ohio
United States

Internal medicie resident

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