Approaches to vitamin B12 deficiency
Early treatment may prevent devastating complications
T. S. Dharmarajan, MD; Edward P. Norkus, PhD

VOL 110 / NO 1 / JULY 2001 / POSTGRADUATE MEDICINE

http://www.postgradmed.com/issues/20...harmarajan.htm

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CME learning objectives

To understand the complex process of absorption of vitamin B12 and how a defect in any step can lead to deficiency
To learn that patients with vitamin B12 deficiency may be asymptomatic or may present with a wide spectrum of hematologic or neuropsychiatric manifestations
To become familiar with correction of vitamin B12 deficiency and how to maintain adequate body stores for life

The authors disclose no financial interest in this article.



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Preview: Vitamin B12 deficiency is a common problem that affects the general population and the elderly in particular. Persons with the deficiency may be asymptomatic or may have hematologic or neuropsychiatric signs and symptoms. If the disorder is untreated, complications may cause significant morbidity. In this article, Drs Dharmarajan and Norkus discuss approaches to screening and diagnosis as well as the nontoxic, low-cost treatments now available.
Dharmarajan TS. Approaches to Vitamin B12 deficiency: early treatment may prevent devastating complications. Postgrad Med 2001;110(1):99-105



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Vitamin B12, also known as cobalamin, was first isolated in 1948 and immediately shown to be effective in the treatment of pernicious anemia (1). Recently, interest in the vitamin has been renewed because of the recognition that cobalamin deficiency occurs in 3% to 40% of the general population (2-7). Our own studies of community, hospital, and nursing home subjects (3,7) found the prevalence to be 15% to 25%. The most recent Food Guide Pyramid for persons over age 70 features a flag to emphasize the importance of adequate daily B12 intake (8).

Sources and chemistry
As a required nutrient, vitamin B12 is obtained primarily from animal proteins (ie, red meat, poultry, fish, eggs, and dairy); plants and vegetables lack the vitamin unless they have been contaminated by soil microorganisms (9). Thus, ovolactovegetarians and lactovegetarians obtain adequate cobalamin, but vegans risk deficiency (9). There are two commercial forms of B12: cyanocobalamin crystalline, which is available in the United States, and hydroxocobalamin crystalline, available in Europe. Enzymatic removal of the cyano group from cyanocobalamin is required to create the active molecule (1,10).

Absorption, storage, and elimination
Absorption of vitamin B12 from foods is complex; a defect in any step can lead to deficiency. In the stomach, gastric acid and pepsin release cobalamin from animal proteins, and it binds preferentially to salivary R protein. In the upper small intestine, pancreatic enzymes and an alkaline pH digest the R protein-cobalamin complex. B12 then binds to intrinsic factor (IF) to form an IF-cobalamin complex. Endogenous B12, excreted in bile, also binds to IF. The IF-cobalamin complex attaches to membrane receptors in the ileum and is absorbed through endocytosis. Absorption of vitamin B12 by this process is limited (<3 micrograms per meal). About 1% of the B12 dose is absorbed by passive diffusion even in the absence of IF (1,11).

The liver contains most of the body's cobalamin (about 1.5 mg), followed by the kidneys, heart, spleen, and brain. Normal body stores of vitamin B12 range from 2 to 10 mg; daily losses are 2 to 5 micrograms. Over 75% of the cobalamin excreted in bile is reabsorbed. Urinary excretion of cobalamin usually is low (10). Because of this efficient enterohepatic circulation, vitamin B12 deficiency typically takes many years to develop. The latest Recommended Dietary Allowance (RDA) for vitamin B12 is 2.4 micrograms/day for persons aged 14 to 70 years; the average diet in the United States contains about 5 micrograms daily (6).

Function
Two cobalamin-dependent enzymatic reactions occur in humans. The first reaction converts methylmalonyl-coenzyme A (CoA) to succinyl-CoA using cobalamin as a cofactor. Vitamin B12 deficiency leads to an increase in serum methylmalonyl-CoA and its metabolic product, methylmalonic acid (MMA). The second reaction uses cobalamin as a cofactor in the synthesis of methionine from homocysteine. Deficiency in B12 leads to an accumulation of homocysteine. Thus, both MMA and homocysteine levels increase in vitamin B12 deficiency. Homocysteine levels also increase in folic acid deficiency (12), vitamin B6 deficiency, renal failure, and hypothyroidism as well as in aging persons and persons with a genetic defect involving cystathionine beta-synthase (13,14). Thus, an elevated MMA level is viewed as a more specific marker for vitamin B12 deficiency except in chronic renal failure, in which MMA increases independently of B12 levels.

Conditions that affect absorption
Table 1 summarizes several conditions and mechanisms that affect absorption of vitamin B12 from the intestine (4,12). Pernicious anemia, once believed to be the most common cause of vitamin B12 deficiency (15), may account for only a small percentage of cases (4). Deficiency most often results from food-cobalamin malabsorption due to gastric dysfunction that may be exacerbated by the use of acid-lowering agents (eg, proton pump inhibitors, histamine2 receptor antagonists) (16,17).Certain other drugs (eg, cholestyramine [LoCHOLEST, Prevalite, Questran], p-aminosalicylate, metformin hydrochloride [Glucophage], colchicine) cause malabsorption through effects on the ileal mucosa or membrane receptors or by other means (10).

Table 1. Partial list of states that impair absorption of dietary vitamin B12
State Cause
Lack of B12 in food Veganism
Failure to digest food protein Decreased gastric acid
Absence of intrinsic factor Pernicious anemia, gastrectomy
Failure to digest R protein Pancreatic diseases
Inadequate absorption Ileal resection, Crohn's disease
Altered intestinal utilization Bacterial growth, fish tapeworm
Other malabsorption syndromes HIV infection, multiple sclerosis
Congenital disease Transcobalamin deficiency
Mucosal or receptor defects Certain drugs

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Manifestations
Vitamin B12 deficiency may take decades to develop, and affected patients may be asymptomatic or may present with a wide spectrum of hematologic and neuropsychiatric manifestations. Herbert (1) outlined four stages in the development of vitamin B12 deficiency. Stages 1 and 2 represent conditions in which the biochemical depletion of vitamin B12 occurs prior to any obvious clinical damage; serum B12 levels may still be normal. Stages 3 and 4 represent conditions of true deficiency with obvious metabolic components, clinical components, or both; serum B12 levels are low, and serum MMA and homocysteine levels are high. Any hematologic and neurologic features tend to occur in the late stages (1).

Hematologic and neuropsychiatric manifestations can occur simultaneously, in sequence, or independently (tables 2 and 3). They may resemble typical complaints of aging, such as fatigue, weakness, loss of memory, and depression. When these symptoms occur in the elderly, vitamin B12 deficiency should be ruled out. Complications typically develop over time and can be severe or even life-threatening. However, a rapid-onset, postoperative myeloneuropathy due to nitrous oxide anesthesia that inactivates marginal B12 stores has been described (18). Shooting pains in the extremities (Lhermitte's sign) indicate spinal cord involvement, root involvement, or both, but are not specific for vitamin B12 deficiency. The presence of ataxia, altered tendon reflexes, Romberg's sign, and extensor plantar reflexes suggests subacute combined degeneration (ie, involvement of posterior or lateral columns of the spinal cord, or both). Neurologic features may improve rapidly with therapy, and damaged axons may regenerate (10,19). The window of opportunity to initiate treatment to reverse or minimize complications is narrow. Vitamin B12 deficiency should be considered in the initial workup of patients with dementia and psychiatric disorders (20,21).

Table 2. Neuropsychiatric features of vitamin B12 deficiency
Autonomic
Impotence, urinary or fecal incontinence

Cerebral
Dementia, depression, memory loss, psychosis, cerebrovascular disease (through high serum homocysteine levels)

Myelopathic
Subacute combined degeneration, ataxia, spasticity, and abnormal gait

Myeloneuropathic
Combined myelopathy and neuropathy

Neuropathic
Peripheral sensory and motor neuropathy (paresthesias, numbness, weakness), mononeuropathy (optic or olfactory atrophy), Lhermitte's sign


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Table 3. Hematologic features of vitamin B12 deficiency
Source Features
Blood Anemia, leukopenia, thrombocytopenia
Smear Hypersegmentation of polymorphs, macro-ovalocytosis
Serum Elevated lactic dehydrogenase levels, elevated indirect bilirubin levels
Bone marrow Megaloblastic changes, increased iron stores

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Unexplained anemia with or without macrocytosis may be the presenting feature. Both anemia and macrocytosis occur in later stages of deficiency but may be absent in pernicious anemia. Classic vitamin B12 deficiency is characterized by macro-ovalocytosis (mean cell volume >100 fL) in a peripheral smear with hypersegmented polymorphonuclear leukocytes (at least one neutrophil with six or more lobes or 5% neutrophils with five lobes) (12,22). Other features include leukopenia and thrombocytopenia; increased lactic dehydrogenase and bilirubin levels suggest ineffective erythropoiesis. Bone marrow examination shows megaloblastic changes (15).

Vitamin B12 deficiency may potentiate mental illness and further damage neurons and myelin sheaths. Some patients with Alzheimer's disease and low vitamin B12 levels seem to improve with cobalamin replacement (2). Similarly, vitamin B12 deficiency may aggravate multiple sclerosis (2). These associations require further evaluation. An elevated homocysteine level is considered an independent risk factor for cardiovascular and cerebrovascular disease. Vitamin B12 deficiency is one known, treatable cause of elevated homocysteine levels (2,12,14).

Screening and diagnosis
Diagnostic tests may be divided into those that screen for vitamin B12 deficiency and those that determine the causes of deficiency. Physician preference, cost, and the healthcare environment influence test selection (4,12). Here, we summarize our approach (23) to screening for and treatment of vitamin B12 deficiency, as well as approaches of others (4,12,14,24).

The true challenge is to identify vitamin B12 deficiency in a preclinical stage, when treatment can avert complications. This is particularly relevant in view of the 1998 decision by the US Food and Drug Administration (FDA) to fortify cereals with folic acid, which may accelerate the development of neuropsychiatric complications in persons with vitamin B12 deficiency. Approaches to diagnosis and treatment include the following: doing nothing until symptoms are recognized, continuing with the traditional approach of selective screening and treatment, treating all patients with low serum vitamin B12 levels, treating all patients regardless of these levels, and considering fortification of foods with vitamin B12 (4,6,12,23).

The goal of our approach to screening for vitamin B12 status is early diagnosis to prevent complications of the deficiency (table 4). In patients prone to deficiency, screening should be considered at the first opportunity. In all others, screening may begin at age 50 (or earlier if deficiency is suspected on clinical grounds). If serum vitamin B12 levels are above 400 pg/mL, screening at 5-year intervals through age 65 is recommended, after which screening should be performed annually.