Functional vitamin B12 deficiency in alcoholics: An intriguing finding in a retrospective study of megaloblastic anemic patients

Abstract

Background

Measurement of serum cobalamin levels is the standard investigation for assessing Vitamin B12 deficiency. However some patients with clinical evidence of cobalamin deficiency may have serum levels within the normal range. Since falsely increased values of cobalamin can be caused by alcoholic liver disease, we evaluated the impact of this disease on the diagnosis of cobalamin and folic acid deficiency.

Methods

We reviewed data of 101 adult patients with megaloblastic anemia assessed by measuring in parallel serum cobalamin, serum folate and red blood cell folate levels. Further tests were performed in order to find the cause of megaloblastosis. All patients were treated with cobalamin and/or folic acid therapy.

Results

Vitamin B12, folate and both deficiency were found in 86, 5 and 6 cases respectively. Normal cobalamin serum levels, normal serum and erythrocyte folate levels were found only in 3 patients, all alcohol-dependent, while in another alcoholic borderline vitamin B12 serum levels were found. All the four patients responded to cobalamin treatment.

Conclusion

Some alcohol-dependent patients with megaloblastic anemia may respond to vitamin B12 treatment despite normal cobalamin serum levels; therefore in alcoholics caution is urged in the interpretation of these vitamin assays, because of possible functional vitamin B12 deficiency.

Introduction

Megaloblastic anemia results from vitamin B12 (cobalamin) and folate deficiency or from the intake of some drugs. In adults cobalamin (Cbl) deficiency is generally caused by malabsorption, in most cases resulting from pernicious anemia (PA); on the contrary folate deficiency is often caused by insufficient intake [1]. Typical clinic manifestations of this vitamin deficiency are megaloblastic anemia with variable degrees of pancytopenia, glossitis, malabsorption, and neurological signs and symptoms. In some patients with Cbl and folate deficiency the classic hematologic, neurologic or biochemical abnormalities are lacking [2]. Measurement of total serum Cbl is the standard screening test for assessing vitamin B12 deficiency, but a diagnostic “gold standard” for this purpose is still lacking, especially in cases with borderline values. Serum folate levels decrease within a few days of low folate diet, therefore the determination of red blood cell (RBC) folate levels has been advocated as a better measure of folate tissue stores. These assays also lack specificity and sensitivity. In anemic megaloblastic patients the evaluation of all these parameters is recommended [3]. A vitamin B12 deficiency increases the concentration of total plasma homocysteine (tHcy) and methylmalonic acid (MMA), while folate deficiency only increases the concentration of tHcy. Many authors recognize tHcy and MMA as the most sensitive and early indicators of vitamin B12 and folate status [4]; the combined determination of the two metabolites has a sensitivity of 99.8% [5]. In these studies the two metabolic markers are more specific than serum Cbl levels; however this opinion is not unanimous [6], [7]. Vitamin B12 in serum is bound to proteins called transcobalamin (TC): most cobalamin is carried on TC I, also called haptocorrin (HC), 20–30% is carried on TC II. The TC II–cobalamin complex is called holotranscobalamin (HoloTC), that is the metabolically active fraction. Recently immunoassay methods for measuring HoloTC have been introduced [8]. HoloTC, or “active” B12, contain the biologically available Cbl; several studies have shown that HoloTC is the earliest and most specific marker of vitamin B12 deficiency [9], [10]. Further studies are needed to establish the role of this metabolite in diagnosing Cbl deficiency. Falsely increased Cbl values are caused by liver diseases [11]; particularly elevated serum vitamin B12 levels were found in alcoholics with liver disease [12]. In order to evaluate the impact of these diseases on the diagnosis of Cbl and folic acid deficiencies, we have reviewed data of a sample of 126 patients with megaloblastic anemia admitted in our medical unit in the past years.