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A 42-year-old male presents to the emergency room confused and combative with alcohol on his breath. He has a history of chronic alcoholism, alcoholic liver disease, and dementia. He had been "dry" for almost a year before resuming drinking a month ago. On examination he has normal vital signs, a sallow complexion, and multiple bruises over both shins and forearms. Liver and spleen are both palpable. Neurological examination is notable for stocking glove anesthesia and poor position sense. Routine labs are ordered:

CBC: Hematocrit/hemoglobin - 29%/9 g/dL

MCV - 107 fL MCH - 34 pg MCHC - 32 g/dL

RDW-CV - 15%

RDW-SD - 55 fL

Reticulocyte count/index -1.5%/<1

White cell count - 5,300/μL

Platelet count - 65,000/μL


Mixed population of normocytic and macrocytic red cells with moderate aniso- and poikilocytosis, polychromasia, and the occasional target cell.

A bone marrow aspirate is also obtained and on preliminary reading shows a relatively hypercellular marrow with a ratio of erythroid to granulocytic precursors (E/G ratio) of 1:1, megaloblastic maturation of both the erythroid and granulocyte progenitors, and normal megakaryocyte numbers.

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  • How should this anemia be described?

  • What is the differential diagnosis?

  • What additional tests are in order?


Folic acid and vitamin B12 deficiency are primary causes of macrocytic anemia in adults. Both vitamins are essential for normal DNA synthesis, and high turnover tissues such as marrow are especially sensitive to any deficiency state. With either deficiency, the marrow becomes megaloblastic; marrow precursors appear much larger than normal and are unable to complete cell division. This results in ineffective erythropoiesis, release of macrocytic red blood cells into circulation, and worsening anemia. The severity of the anemia and the degree of macrocytosis depend on the severity and duration of the deficient state.


The prevalence of folic acid deficiency depends on the frequency of diseases associated with a decreased dietary intake of folic acid, malabsorption, or an increased metabolic requirement. Alcoholism is a common cause of folic acid deficiency in Western societies because of the poor dietary habits of the alcoholic and alcohol's interference with folate metabolism. In developing countries, tropical and nontropical sprue are more common etiologies. Vitamin B12 deficiency can result from a dietary deficiency, an autoimmune process directed at intrinsic factor (IF), or any one of a number of gastrointestinal disorders that lead to vitamin B12 malabsorption.




Major metabolic pathways of folic acid and vitamin B12 are illustrated in Figure 8-1. These 2 vitamins are closely linked in the support of DNA synthesis. Within the cell, vitamin B12 is present in 2 forms. As deoxyadenosyl B12, it supports conversion of l-methylmalonyl-CoA to succinyl-CoA. It also accepts a methyl group from methyltetrahydrofolate to support synthesis of methionine. The transfer of a methyl group from methyltetrahydrofolate provides the ...

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