Vitamin B12 Deficiency in Alcoholics

Abstract

Vitamin B12 (also referred as cobalamin) has a crucial biological role, because its intracellular availability is necessary for DNA synthesis. Cobalamin (Cbl) and folic acid are closely related; both are involved in a common metabolic pathway. The clinical pictures of these vitamin deficiencies are overlapping. Cobalamin deficiency is a significant public health issue, because it is estimated to affect 10–15 % of people over the age of 60 [1] and is generally caused by malabsorption, in most cases resulting from pernicious anemia (PA). On the contrary, folate deficiency is often caused by insufficient intake [2]. 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 [3]. The early diagnosis of vitamin B12 and folate deficiency is critical since neurologic disease of Cbl deficiency may be irreversible if treatment, safe and inexpensive, is delayed [4]. 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. There are major limitations with this approach, and the type of assay used may be relevant. Sensitivity is about 97 %, and specificity is limited. In a study, specificity is 90 % in patients with Cbl levels below 100 pg/ml but only 60 % with Cbl levels <200 pg/ml [3]. Falsely increased values are caused by myeloproliferative disorders, liver diseases, intestinal bacterial overgrowth, congenital transcobalamin (TC) II deficiency, nitrous oxide, and seldom by circulating antibody to TC II, high serum vitamin B12 binding protein, and analytical problems [5–9]. Falsely low values can be seen with folate deficiency, pregnancy, myeloma, AIDS, and TC I deficiency. 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. Serum folate levels increase in patients with Cbl deficiency and with hemolysis; falsely low RBC folate levels also occur in vitamin B12 deficiency. In anemic megaloblastic patients, evaluation of all these parameters is recommended. 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; the two metabolite determinations combined have a sensitivity of 99.8 % [10, 11]. In these studies, the two metabolic markers are more specific than are serum Cbl levels; this opinion is not unanimous [12, 13]. Increased MMA and tHcy together can be found with primary metabolic defects, renal insufficiency, and hypovolemia, while tHcy alone can increase in alcohol abuse and vitamin B6 deficiency [14]. Furthermore, in the ambulatory care setting, not only Cbl but also MMA and tHcy levels fluctuate with time and neither predict nor preclude the presence of Cbl-responsive hematologic or neurologic disorders [15]. 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. The HoloTC RIA is the first available method for measurement of HoloTC [16]; recently, an automated assay for measuring HoloTC on the Abbott AxSYM analyzer has been introduced [17]. HoloTC, or “active” B12, contains the biologically available Cbl; several studies have shown that HoloTC is the earliest and most specific marker of vitamin B12 deficiency [18, 19], but further studies are needed to establish the role of this metabolite. Alcohol has a variety of pathologic effects on erythropoiesis: induces macrocytosis, sideroblastic anemia, hemolytic anemia, and megaloblastic anemia that result from nutritional deficiency and/or a direct toxic effect on erythroid precursor [20] and may particularly disturb folate metabolism [21, 22]; this vitamin deficiency may be ascribed to dietary inadequacy, intestinal malabsorption, decreased hepatic uptake and retention, and increased urinary excretion. In a previous study, low serum folate levels were found in more than two-thirds of alcohol abusers [23]. Vitamin B12 metabolism in alcoholics was investigated in the past years [24], and it is thought that Cbl deficiency is not common in these patients. In many reports, serum Cbl levels were found higher in alcoholics than in the control group but generally remain in the reference range [22, 25]. Falsely increased Cbl values are caused by liver diseases [5]; particularly elevated serum vitamin B12 levels were found in alcoholics with liver disease [26], also associated with a lowered liver tissue Cbl concentration [27]. Measurements of serum B12 levels also include metabolically inactive Cbl analogs (HC); therefore, Cbl depletion in tissue may be masked by normal to high serum vitamin B12 levels [28]. Elevated Cbl levels are also found in acute hepatitis; the hepatocellular necrosis may cause the release of stored Cbl following tissue depletion. Alcoholic liver disease leads to elevated Cbl levels in serum despite lowered liver tissue total vitamin B12 concentration accompanied by a lowering of HoloTC distribution. Possible explanations for this phenomenon may be the failure of the damaged liver to take up Cbl from the serum and/or a defective storage that causes vitamin B12 to leak out of the liver into circulation, where it predominantly binds to HC; on the other hand, a diminished concentration of TC II and a reduced clearance of HC may be the result of an impaired synthesizing liver capability [27–29]. Moreover, a specific role for alcohol abuse may be assumed in inducing a hematologic significant “functional” Cbl deficiency, as nitrous oxide exposure (which oxidizes cob(I)alamin inactivating methionine synthase) does. In the same way, for patients with Cbl-responsive neurologic disorders despite normal serum Cbl levels, Solomon considered a pathophysiologic role for oxidant stress (as alcohol abuse) leading to “functional” Cbl deficiency [30]. A significant positive correlation between serum Cbl and hepatocellular enzymes GGT, AST, and ALT was found [25, 29, 31]. With increasing hepatocellular damage, serum Cbl also tends to be higher and reflects the degree of liver injury by alcohol; increased serum vitamin B12 titers correlate with disease severity, and declining levels were found during remission of the disease [32, 33].

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