Pernicious anemia: presentations mimicking acute leukemia.Abstract: Vitamin [B.sub.12] deficiency can cause profound alterations in the bone marrow. These alterations can mimic the more serious diagnosis of acute leukemia. The two patients described in this report were originally suspected of having acute leukemia or myelodysplasia on the basis of the bone marrow smear, and induction chemotherapy was considered. However, after further studies, they were both found to have vitamin [B.sub.12] deficiency, and parenteral vitamin [B.sub.12] administration resulted in normalization of the bone marrow.
Vitamin [B.sub.12] deficiency can produce severe alterations in bone marrow morphology and function with associated megaloblastic anemia. It can also cause a serious constellation of symptoms that can affect all the organ systems in the body resulting in neurologic, mucosal, gastrointestinal, and constitutional changes. The most common cause of vitamin [B.sub.12] deficiency, pernicious anemia, is caused by autoantibodies produced against intrinsic factor, a protein produced in the stomach necessary for absorption of vitamin [B.sub.12] in the small intestine. A typical hematologic hematological, hematologic
pertaining to or emanating from blood cells.
total and differential white cell counts, hematocrit estimation, erythrocyte count. presentation of pernicious anemia includes an increased mean cell volume (MCV MCV mean corpuscular volume.
mean corpuscular volume
Mean corpuscular volume (MCV)
A measure of the average volume of a red blood cell. ), hypersegmented neutrophils, hemolysis hemolysis (hĭmŏl`ĭsĭs), destruction of red blood cells in the bloodstream. Although new red blood cells, or erythrocytes, are continuously created and old ones destroyed, an excessive rate of destruction sometimes occurs. with reticulocytosis, and sometimes leukopenia leukopenia /leu·ko·pe·nia/ (-pe´ne-ah) reduction of the number of leukocytes in the blood below about 5000 per cubic mm.leukope´nic
basophilic leukopenia basophilopenia. and thrombocytopenia. These changes rapidly resolve soon after parenteral administration of vitamin [B.sub.12]. In severe disease, the initial look of the bone marrow can reveal hypercellular blastic changes resembling acute leukemia. We present two cases of pernicious anemia in which a preliminary diagnosis of acute leukemia was made.
A 65-year-old man with a significant history of chronic alcoholism presented in July 2002 with generalized declining health over the previous month. He had been feeling poorly, with loss of appetite loss of appetite Medtalk Anorexia, see there , increased fatigue, shortness of breath Shortness of Breath Definition
Shortness of breath, or dyspnea, is a feeling of difficult or labored breathing that is out of proportion to the patient's level of physical activity. with exertion, and onset of visual hallucinations. He usually drinks 12 to 24 cans of beer a day, but had discontinued drinking 1 month previously because he felt so poorly. He stated that he generally was in good health and does not actively seek health care, nor does he have a primary care physician. He had occasionally been managed through the Veteran's Administration system to get diuretics for mild hypertension. His physical examination revealed poor dentition dentition, kind, number, and arrangement of the teeth of humans and other animals. During the course of evolution, teeth were derived from bony body scales similar to the placoid scales on the skin of modern sharks. , bilateral shoddy axillary lymphadenopathy, and mild right upper quadrant right upper quadrant Physical exam The abdominal region that contains the liver, duodenum and head of pancreas tenderness with a slightly enlarged liver. He was found to be in atrial fibrillation and a peripheral smear showed significant pancytopenia pancytopenia /pan·cy·to·pe·nia/ (-sit-ah-pe´ne-ah) abnormal depression of all the cellular elements of the blood.
n. with megaloblastic megaloblastic
pertaining to or emanating from a megaloblast. changes. There were no hypersegmented neutrophils seen. His complete blood count showed a hemoglobin of 6.7 g/dl, an MCV of 118 fl, a platelet count of 96,000 cells/[micro]l, a markedly decreased white count of 2,800 cells/[mm.sup.2], and a normal differential. He also had a lactate dehydrogenase (LDH LDH -lactate dehydrogenase.
lactic acid dehydrogenase; see lactate dehydrogenase. ) of 1,345 U/L, a reticulocyte count of 8.68%, and a urobilinogen of 2.0 EU/dl, all consistent with hemolysis. The bone marrow demonstrated a predominance of large blasts that appeared to be highly suggestive of M1 acute myelogenous leukemia acute myelogenous leukemia
n. Abbr. AML
Myelogenous leukemia characterized by rapid abnormal increase in the number of myeloblasts and progression of symptoms. (AML AML - A Manufacturing Language ), with a cellularity of 85% (Fig. 1). However, special stains later revealed atypical blasts negative for myeloperoxidase and positive for hemoglobin, consistent with erythroblastic erythroblastic
of, or relating to erythroblasts.
a bone marrow unit consisting of a central macrophage and surrounding erythroblasts and in which differentiation of erythroblasts takes place. origin. Subsequent flow cytometry and cytogenetic studies showed no apparent abnormalities. The vitamin [B.sub.12] level was then found to be low and a therapeutic trial of vitamin [B.sub.12] was begun. The patient later was found to be positive for intrinsic factor antibody, and a diagnosis of pernicious anemia was made. His blood counts completely normalized within 3 weeks and his constellation of symptoms was ameliorated.
A 51-year-old man presented in November 2001 with pancytopenia and marked anemia found on routine CBC (1) (Cell Broadcast Center) See cell broadcast.
(2) (Cipher Block Chaining) In cryptography, a mode of operation that combines the ciphertext of one block with the plaintext of the next block. by his primary care physician. He complained of shortness of breath, progressive fatigue, and episodes of dark urine after heavy work during the day. His physical examination was unremarkable. He reported a long history of exposure to methyl ethyl ketones at work without proper safety precautions. He had a brother who died as a result of acute leukemia in his late 30s. His peripheral blood revealed left-shifted and hypersegmented neutrophils, neutropenia, and mildly reduced platelets. However, the erythroid erythroid /er·y·throid/ (er´i-throid)
1. of a red color; reddish.
2. pertaining to the cells of the erythrocytic series.
1. series showed no morphologic abnormalities and an MCV of 94.6 fl. His bone marrow was hypercellular and appeared to show increased numbers of myeloblasts with morphologic features most suggestive of early myelodysplastic syndrome (MDS MDS,
n See temporomandibular pain-dysfunction syndrome.
MDS 1 Maternal deprivation syndrome, see there 2 Myelodysplastic syndrome, see there ) or incipient AML (Fig. 2). There was a delay in erythroid maturation, with a megaloblastoid nuclear chromatic pattern in basophilic basophilic /ba·so·phil·ic/ (-fil´ik)
1. pertaining to basophils.
2. staining readily with basic dyes.
staining readily with basic dyes. normoblasts. A manual bone marrow count showed 18% blasts. His chemistry studies showed an elevated bilirubin and an LDH of over 6,000 U/L, suggesting a hemolytic he·mo·lyt·ic
Destructive to red blood cells; hematolytic.
Referring to the destruction of the cell membranes of red blood cells, resulting in the release of hemoglobin from the damaged cell. process. A preliminary diagnosis of MDS with transformation into acute leukemia was made. However, further cytogenetic analysis and flow cytometry failed to show a definitive malignant process. The patient was subsequently found to have low serum vitamin [B.sub.12], and a therapeutic trial of vitamin [B.sub.12] was begun. The patient later was found to be positive for intrinsic factor antibody, and a diagnosis of pernicious anemia was made. His blood counts entirely normalized after vitamin [B.sub.12] administration.
Vitamin [B.sub.12] is a necessary cofactor cofactor
An atom, organic molecule, or molecular group that is necessary for the catalytic activity (see catalysis) of many enzymes. A cofactor may be tightly bound to the protein portion of an enzyme and thus be an integral part of its functional structure, or it may required for DNA synthesis. A deficiency will result in defective nuclear maturation because of inadequate DNA but not RNA or protein, thus giving the characteristic appearance of asynchronism asynchronism /asyn·chro·nism/ (a-sing´krah-nizm) asynchrony.
occurrence at different times; disturbance of coordination. between the cytoplasmic maturation and nuclear maturation. The ineffective hematopoiesis Hematopoiesis
The process by which the cellular elements of the blood are formed. The three main types of cells are the red cells (erythrocytes), which serve to carry oxygen, the white cells (leukocytes), which function in the prevention of and recovery from results in megaloblastoid changes of the erythroid precursors in the bone marrow. Many of these developing red blood cells Red blood cells
Cells that carry hemoglobin (the molecule that transports oxygen) and help remove wastes from tissues throughout the body.
Mentioned in: Bone Marrow Transplantation
red blood cells are destroyed in the bone marrow before they are released into the circulation. This results in the increased indirect bilirubin and LDH. Vitamin [B.sub.12] deficiency can produce a variety of other effects on the body as well, such as in the alimentary tract and central nervous system. The fact that these symptoms may range from minimal to profound can sometimes make this simple and reversible diagnosis not quite so obvious. Because vitamin [B.sub.12] is stored in the liver for several years, it may take 3 to 6 years to deplete. Therefore, the anemia may be severe when discovered, although there is a concurrent lack of symptoms. Pernicious anemia, the most common cause of vitamin [B.sub.12] deficiency, is predominately a disease of the elderly, with the average patient presenting near 60 years of age. Coexisting morbidity can further cloud the diagnosis. In the case of the alcoholic patient we presented, the macrocytosis macrocytosis /mac·ro·cy·to·sis/ (-si-to´sis) macrocythemia.
n. pl. mac·ro·cy·to·ses
The presence of unusually large numbers of macrocytes in the blood. , increased LDH, and urobilinogen could be because of the alcohol or the vitamin [B.sub.12] deficiency. This fact, in conjunction with the unusually marked blastic changes and atypical morphology of the bone marrow, made the preliminary diagnosis of acute leukemia a viable option. The conflict arises from the fact that these patients are at risk of erroneously receiving potentially fatal induction chemotherapy for acute leukemia, when all they require is a vitamin [B.sub.12] injection. Dokal et al (1) previously acknowledged this possibility as well.
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
There have been several cases reported of concurrent pernicious anemia and myelodysplastic syndrome or acute myelogenous leukemia. Drabick et al (2) reported a case in which vitamin [B.sub.12] replacement therapy resulted in the resolution of neurologic findings and macrocytosis; however, the anemia and monocytosis mon·o·cy·to·sis
An abnormal increase in the number of monocytes in the blood, occurring in infectious mononucleosis and certain bacterial infections such as tuberculosis. Also called monocytic leukocytosis. persisted. Cytogenetics continued to reveal a clonality and the MDS eventually converted to AML. They also pointed out that reversible cytogenetic abnormalities have been observed with megaloblastic anemia, even including karyotypes typically associated with MDS or AML. Vogelsang et al (3) reported another case in which 57-year-old women developed acute leukemia with coexisting pernicious anemia. There was a decline in circulating blasts after vitamin [B.sub.12] replacement; however, the blast cells persisted in the bone marrow.
Ahman el al (4) went a step further with this issue, suggesting that excessive replacement of vitamin [B.sub.12] may in some cases even accelerate underlying hematologic malignancies. This is based on the observation that patients with vitamin [B.sub.12] deficiencies have an increased incidence of hematologic malignancies. They demonstrated in vitro that adding vitamin [B.sub.12] could stimulate blast colony formation.
These cases demonstrate that on some occasions, it may be difficult to distinguish pernicious anemia from other hematologic abnormalities. Because of the variability of the effects of vitamin [B.sub.12] deficiency on hematopoiesis, a preliminary look at the bone marrow may masquerade as an acute leukemia to the unsuspecting eye. Generally, immunohistochemistry, flow cytometry, and cytogenetics can be used to distinguish ineffective hematopoiesis caused by a monoclonality rather than a deficiency of vitamin [B.sub.12]. However, as we have presented, this may not always separate the diseases, and clinicians should be aware of this issue.
I enjoy convalescence. It is the part that makes the illness worthwhile. --George Bernard Shaw
Accepted January 13, 2003.
Copyright [c] 2004 by The Southern Medical Association
1. Dokal IS, Cox TM, Galton DA. Vitamin [B.sub.12] and folate deficiency presenting as leukaemia. BMJ 1990;300:1263-1264.
2. Drabick JJ, Davis BJ, Byrd JC. Concurrent pernicious anemia and myelodysplastic syndrome. Ann Hematol 2001;80:243-245.
3. Vogelsang GB, Spivak JL. Unusual case of acute leukemia: Coexisting acute leukemia and pernicious anemia. Am J Med 1984;76:1144-1150.
4. Ahmann FR, Durie BG. Acute myelogenous leukaemia modulated by [B.sub.12] deficiency: A case with bone marrow blast cell assay corroboration. Br J Haematol 1984;58:91-94.
RELATED ARTICLE: Key Points
* The clinical features of vitamin [B.sub.12] deficiency are protean.
* Vitamin [B.sub.12] deficiency can cause profound hematologic changes well beyond megaloblastic anemia.
* The clinical and hematologic manifestations of vitamin [B.sub.12] deficiency can be readily ameliorated with parenteral vitamin [B.sub.12] injections.
Cristi Aitelli, BS, Lori Wasson, DO, and Ray Page, DO, PHD
From Texas Cancer Care, Fort Worth, TX.
Reprint requests to Ray Page, DO, PhD, Texas Cancer Care, 750 8th Avenue, Suite 200, Fort Worth, TX 76104. Email: firstname.lastname@example.org