Cobalamin Deficiency Presenting as Dementia and Severe Pancytopenia in an Elderly Patient With a Known History of Macrocytic Anemia: A Cautionary Tale
Cobalamin (vitamin B12, cyanocobalamin) deficiency is both relatively common, affecting up to 15% of elderly patients in the original Framingham study population,1 and easily treatable. However, if it is not properly identified and treated, cobalamin deficiency can result in significant morbidity, including debilitating neuropsychiatric symptoms and life-threatening hematological derangements. These hematological abnormalities range from isolated macrocytosis without anemia to severe macrocytic anemia with leukopenia and thrombocytopenia.2 Cobalamin is crucial in the conversion of homocysteine to methionine.3 This conversion is required for the synthesis of thymidine, and the deficiency of thymidine impairs DNA synthesis by causing misincorporation of uracil.3 Neuropsychiatric manifestations of cobalamin deficiency range from mild peripheral neuropathy to degeneration of the posterior columns and pyramidal tracts of the spinal cord, psychosis, and dementia.2 The pathogenesis of these neuropsychiatric symptoms is not clear; however, there is evidence of dysregulation of growth factors and cytokines in persons with cobalamin deficiency.3
Dietary cobalamin is obtained from foods of animal origin, including meat, fish, and dairy products. To maintain steady-state levels, daily dietary absorption of cobalamin must equal daily losses in the urine and feces, typically 1 μg to 3 μg per day. The Recommended Dietary Allowance for adults is 2 μg to 4 μg per day. The typical Western diet contains 5 μg to 30 μg of cobalamin per day; thus, deficiency rarely results from inadequate dietary intake, particularly among patients who do not follow strict vegan diets.4 Rather, deficiencies of cobalamin most commonly reflect abnormalities of the gastrointestinal (GI) tract. There are two pathways for cobalamin absorption in the GI tract. The passive diffusion through the buccal, duodenal, and ileal mucosa is responsible for the absorption of approximately 1% to 5% of an ingested cobalamin load, while the active transport through the ileal mucosa is responsible for the remainder.2,3 A prerequisite for active absorption of cobalamin in the ileum is the binding of cobalamin to intrinsic factor, a protein secreted by gastric parietal cells. Both absorption pathways rely on the gastric acidity, which aids in the dissociation of cobalamin from binding proteins in the ingested food.2
Because humans are capable of storing 2 mg to 3 mg of cobalamin, symptoms of cobalamin deficiency often are not unmasked until up to 3 years after GI absorption has been disrupted,2 as this is the length of time it will take for the body to use up its stores if no additional cobalamin is absorbed. The most common causes of cobalamin malabsorption include pernicious anemia and an entity known as food-cobalamin malabsorption (FCM). In pernicious anemia, autoantibodies cause destruction of gastric parietal cells that produce the intrinsic factor, thereby impairing the absorption of cobalamin. In contrast, FCM is characterized by an inability to properly liberate cobalamin from other proteins in ingested food.4 This is thought to be due in most cases to defects in gastric acidification, as seen in atrophic gastritis.5 Research suggests that FCM, rather than pernicious anemia, likely represents the most common cause of cobalamin deficiency.4 Less common causes of cobalamin deficiency include celiac disease, tropical sprue, infection with Diphyllobothrium latum (also known as the fish tapeworm), and absent or defective function of the ileum (the site of absorption of the intrinsic factor-cobalamin complex), such as occurs in patients with Crohn’s disease after an ileal resection.2
Cobalamin deficiency can be diagnosed based on direct measurements of serum cobalamin, or by the characteristic elevations in plasma homocysteine and methylmalonic acid levels often seen in patients with cobalamin deficiency.3 Although pernicious anemia and FCM are treated similarly, FCM can be differentiated from pernicious anemia clinically by the presence of antiparietal cell antibodies and by the results of the Schilling test. In the Schilling test, a radiolabeled form of cobalamin is given orally with or without exogenous intrinsic factor, and the proportion of cobalamin excreted in the urine is measured. In a patient with pernicious anemia, free oral cobalamin is absorbed only when given with exogenous intrinsic factor. In contrast, there is no defect in the absorption of free cobalamin in a patient with FCM.4
We present the case of an elderly patient with a rare and exceptionally severe presentation of cobalamin deficiency: dementia and severe pancytopenia. The most striking aspect of this case is that the patient had a known history of cobalamin deficiency requiring parenteral supplementation; however, neither parenteral nor treatment dose of cobalamin had been given for 5 years prior to his current presentation, even while he had continued to receive regular medical care for other problems. Thus, these severe sequelae of cobalamin deficiency were easily preventable with proper recognition of the patient’s medical history. Following the case presentation, we review the recent literature regarding the manifestations of cobalamin deficiency and treatment strategies.
A 74-year-old white man presented to the emergency department with a 3-month history of deteriorating cognitive function, and increasing fatigue and extreme dyspnea on exertion over the past 2 weeks. He reported progressive problems with memory, such as often forgetting where he was going while walking around his home, and also reported numbness and tingling in his bilateral hands and feet in a glove and stocking distribution. These neurological symptoms and memory problems had begun abruptly 3 months prior to his current presentation, and had progressed rapidly. His self-reported medical history was significant for hypertension, chronic hepatitis B, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma, which was in remission status after Helicobacter pylori eradication therapy 11 years earlier. The patient’s medications included amlodipine, entecavir, and an oral B complex vitamin supplement containing 1 μg of cyanocobalamin. His physical examination was notable only for disorientation, conjunctival pallor, and sensory loss in his bilateral feet and hands. The results of the Romberg test were normal. Laboratory studies revealed severe pancytopenia with a hemoglobin of 5.7 g/dL, hematocrit of 17.5%, white blood cell count of 2100/μL with an absolute neutrophil count (ANC) of 500/μL, and platelet count of 57x103/μL. Red blood cell analysis revealed macrocytosis (mean corpuscular volume, 117.3 μm3), and a peripheral smear showed hypersegmented neutrophils. The patient’s cobalamin level was low at 104 pg/mL (normal >160 pg/mL), while his folate level was normal.
A review of the patient’s electronic medical records revealed that he had presented to the emergency department 11 years earlier with similar reports of deteriorating memory and numbness in his hands and feet. At that time, he was found to have a mild macrocytic anemia (hemoglobin, 12.9 g/dL; hematocrit, 37.4%; mean corpuscular volume, 132.2 fL) without leukopenia or thrombocytopenia, and he was found to be severely deficient in cobalamin with a level of less than 68 pg/mL. He was started on intramuscular (IM) cobalamin injections with complete resolution of his neurological symptoms and his hematological parameters. At the same time (ie, 11 years prior to his current presentation), the patient also reported abdominal pain, nausea and vomiting, early satiety, and a 20-pound weight loss over the preceding month. An endoscopy with biopsy revealed aggregates of well-differentiated CD20-positive B cells, Paneth cell metaplasia, and intestinal metaplasia, and a diagnosis of MALT lymphoma was made. Biopsy specimens tested positive for H. pylori, and the patient was treated with bismuth subsalicylate, tetracycline, and metronidazole for H. pylori eradication. He continued to undergo surveillance endoscopy every 2 years since the H. pylori eradication therapy, which revealed continued remission of the MALT lymphoma, but ongoing chronic atrophic gastritis. The patient was continued on monthly IM cobalamin injections until 5 years prior to his current presentation, when these injections were discontinued for unclear reasons following a brief hospitalization for abdominal aortic aneurysm repair. The patient continued to receive regular medical care subsequently, including screening complete blood counts (CBCs). His hematologic parameters remained normal until 11 months prior to his current presentation, when a routine CBC revealed a mild macrocytosis (mean corpuscular volume, 102 fL) without anemia. His cobalamin level was checked 6 months later (5 months prior to his current presentation), presumably due to continued macrocytosis without anemia, and was found to be mildly reduced at 133 pg/mL. He was started on an oral B vitamin supplement containing 1µg of cyanocobalamin per day. Shortly thereafter, he started developing the aforementioned neurological symptoms and memory problems, which prompted his current presentation in the emergency department.
Due to his severe pancytopenia, the patient was admitted to respiratory isolation and was transfused with 2 units of packed red blood cells, with an appropriate response of his hemoglobin level from 5.7 g/dL to 8.6 g/dL. His fatigue and dyspnea had significantly improved by the following day. Given the severity of his hematological derangements, bone marrow biopsy was performed to rule out myelodysplastic syndrome or a myelophthisic process. The results of the bone marrow biopsy revealed cobalamin deficiency. The patient was restarted on IM cobalamin supplementation with cyanocobalamin 1 mg IM daily for 1 week, then weekly for 1 month, with a transition to oral cyanocobalamin supplementation indefinitely thereafter. Eleven days after his initial presentation, a repeat CBC revealed that the patient remained anemic with a hemoglobin of 7.9 g/dL and hematocrit of 23.7%; however, his white blood cell count (5500/µL), ANC (3200/µL), and platelet count (402x103/µL) had all returned to normal levels. After another 10 days, his hemoglobin and hematocrit had improved to 12.4 g/dL and 37.8%, respectively, while his white blood cell count, ANC, and platelet count had remained stable. As of the time of this writing, it is unknown whether the patient’s neurological symptoms and memory problems have improved.
Severe pancytopenia is an uncommon sequela of cobalamin deficiency. In a case series published in 2006, macrocytosis (mean corpuscular volume >100 fL) was found in 54% of patients with cobalamin deficiency, anemia (hemoglobin <12 g/dL) in 37%, leukopenia (white blood cell count <4000/µL) in 13.9%, and thrombocytopenia (platelets <150x103/µL) in 9.9%.6 Only 2.5% of patients had severe anemia (defined as hemoglobin <6.0 g/dL), and only 5% of patients had symptomatic pancytopenia.6 Hypersegmented neutrophils were identified in only 32% of patients with cobalamin deficiency6; thus, even in the absence of this classic finding, one must have a high suspicion for cobalamin deficiency in the context of macrocytic anemia.
Equally as uncommon as severe pancytopenia in patients with cobalamin deficiency is cognitive impairment. In the largest case series reporting neuropsychiatric findings in patients with cobalamin deficiency, only approximately 3% of 369 patients with identified cobalamin deficiency reported impairments in cognition, manifested most commonly by memory loss and deficits in attention.7 Underscoring the rarity of cobalamin deficiency as a cause for dementia in the general population, several clinical trials have failed to show any benefit in cognitive function with cobalamin supplementation in the general elderly population.8,9 But while cognitive impairment is a rare sequela of cobalamin deficiency, symptoms such as numbness, weakness, and paresthesia attributable to peripheral neuropathy and/or myelopathy are common, occurring in approximately 40% of patients with cobalamin deficiency in the aforementioned case series.7 Interestingly, in another cohort of patients, there was an inverse correlation between the severity of anemia and the severity of neurological symptoms. In fact, among the group of patients with the most severe neuropsychiatric manifestations—those with cognitive symptoms in addition to the more commonly encountered neuropathy and/or myelopathy—72% had no detectable abnormality in their hemoglobin or mean corpuscular volume.10 Overall, nearly 30% of patients in this study who had neurological findings had no hematological abnormalities whatsoever.10 These data underscore the necessity for clinicians to suspect cobalamin deficiency in patients with the appropriate neuropsychiatric manifestations even in the absence of hematological abnormalities. Collectively, these data indicate the exceeding rarity of the combination of severe pancytopenia with cognitive impairment as a presentation of cobalamin deficiency.
Perhaps more striking than the severity of the case patient’s condition is the fact that the patient had a known history of cobalamin deficiency previously requiring parenteral supplementation. As described earlier, the patient had been maintained on monthly IM cobalamin injections for 6 years, but these were discontinued 5 years prior to his current presentation for reasons that were not discernible from the patient’s electronic medical records. In this patient, the time elapsed between the discontinuation of cobalamin supplementation and the unmasking of symptoms is somewhat longer than the 3 years predicted by average total body cobalamin stores,3 possibly indicating that the patient’s absorption of dietary cobalamin was partially—rather than completely—impaired. When questioned about his medical history, the patient reported his history of MALT lymphoma, but failed to report his history of cobalamin deficiency. Clearly, it will come as no surprise to most clinicians that patients are not always completely accurate historians; however, it is striking that in the 5 years since the discontinuation of the cobalamin supplementation, clinicians’ notes in his electronic medical records consistently failed to list his history of cobalamin deficiency. During this time, the patient continued to receive regular medical care for multiple medical problems, including hepatitis B and surveillance of MALT lymphoma. Particularly given the evidence of ongoing gastritis in his surveillance endoscopies, and the connection between atrophic gastritis and cobalamin deficiency, the index of suspicion for the need for continued cobalamin supplementation would have been high. While it is unclear how the patient’s history of cobalamin deficiency was initially omitted from his medical record from the last 5 years, it is tempting to speculate that this omission was then propagated due to the tendency of clinicians to obtain information such as a patient’s medical history by looking at more recent notes rather than earlier notes. Unfortunately for the patient, a brief study of earlier notes from his electronic medical records by any of the clinicians who had seen him in the intervening 5 years likely would have prevented him from developing the severe and indeed life-threatening sequela of cobalamin deficiency with which he presented.
This case also highlights a number of issues regarding the treatment of cobalamin deficiency. Although the condition has traditionally been treated with parenteral supplementation, oral supplementation strategies have received much recent attention. Several small clinical trials comparing oral and parenteral cobalamin repletion in patients with cobalamin deficiency have demonstrated the efficacy of the oral approach11-14; however, these data require replication in larger patient populations. Oral supplementation is based on the idea that approximately 1% to 5% of an ingested cobalamin load is absorbed passively.3 Thus, even in patients with complete absence of intrinsic factor, sufficient cobalamin can be absorbed if the oral load is large enough. For this reason, the oral dose used in these trials is typically around 1 mg per day, far exceeding the recommended daily intake of 2.5 µg. Clearly, oral supplementation is preferable to parenteral, as it would spare the patient the pain of the injection and the need for a nurse to administer it. These data justify the case patient’s physicians’ decision to transition him to oral cobalamin supplementation after first repleting him parenterally. While an oral B vitamin supplement containing 1 µg of cyanocobalamin per day (which was started 5 months prior to the case patient’s current presentation) may have benefited a patient with a pure dietary deficiency, a patient with defective GI absorption of cobalamin would require a dose 1000 times higher. Had the case patient been started on the proper oral dose, the severe symptoms that he went on to develop may have been prevented.
Cobalamin (vitamin B12) deficiency is both common and relatively benign if properly identified and treated. However, as reported in the case patient, severe sequelae can develop if the deficiency is not recognized.
The authors report no relevant financial relationships.
Mr. Dodson is a medical student, David Geffen School of Medicine, University of California, Los Angeles, and Dr. Li is Professor of Clinical Medicine, David Geffen School of Medicine, University of California, Los Angeles, and VA Greater Los Angeles Healthcare System.
1. Lindenbaum J, Rosenberg IH, Wilson PW, et al. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. 1994;60(1):2-11.
2. Hoffbrand AV. Megaloblastic anemias. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: The McGraw-Hill Companies, Inc.; 2008:643-665.
3. Solomon LR. Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment. Blood Rev. 2007;21(3):113-130.
4. Carmel R. Cobalamin, the stomach, and aging. Am J Clin Nutr. 1997;66(4):750-759.
5. Andrès E, Dali-Youcef N, Vogel T, et al. Oral cobalamin (vitamin B) treatment. An update. Int J Lab Hematol. 2009;31(1):1-8.
6. Andrès E, Affenberger S, Zimmer J, et al. Current hematological findings in cobalamin deficiency. A study of 201 consecutive patients with documented cobalamin deficiency. Clin Lab Haematol. 2006;28(1):50-56.
7. Healton EB, Savage DG, Brust JC, et al. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore) 1991;70(4):229-245.
8. McMahon JA, Green TJ, Skeaff CM, et al. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006;354(26):2764-2772.
9. Aisen PS, Schneider LS, Sano M, et al; Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300(15):1774-1783.
10. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1988;318(26):1720-1728.
11. Kuzminski AM, Del Giacco EJ, Allen RH, et al. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92(4):1191-1198.
12. 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(12):3124-3134.
13. Andrès E, Loukill NH, Noel E, et al. Effects of oral crystalline cyanocobalamin 1000 μg/d in the treatment of pernicious anemia: an open-label, prospective study in ten patients. Current Therapeutic Research. 2005;66(1):13-22.
14. Andres E, Affenberger S, Vinzio S, et al. Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment. Am J Med. 2005;118(10):1154-1159.