Exploring Vital Amines: The Who, What, When, Where, Why, and How of B12 Deficiency

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FROM THE ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY

This article is the second of a 3-part series that aims to highlight and review the prevalence, risk factors, clinical manifestations, diagnostic recommendations, proposed mechanisms of disease, and current treatment recommendations of folate, B₁₂, and thiamine deficiencies. The first article ran in the March 2021 issue.

Exploring Vitamins

As reviewed in the previous article, key nutrients—or what Casimir Funk, PhD, termed vital amines—are essential to maintaining good health. Deficiencies in these key nutrients lead to certain pathognomonic disease states, as Funk initially observed when he fed birds a diet of only polished rice and they developed a diffuse polyneuritis (beriberi). Afterwards, the same birds were fed a diet of brown rice, and their “nervous symptoms rapidly disappeared.”¹ What did this experiment establish? The importance of vital amines, or as we know them, vitamins.

Vitamins can be broadly delineated into 2 categories: water-soluble and fat-soluble. Water-soluble vitamins are absorbed rapidly via the gastrointestinal tract and distributed widely in various body tissues; however, as these vitamins are water-soluble, they are not efficiently stored in tissues. Therefore, these vitamins require regular consumption (either through diet or supplementation) to avoid deficiency states. Fat-soluble vitamins, on the other hand, are more easily stored, typically in adipose tissue, and require less frequent intake.² Examples of water-soluble and fat-soluble vitamins can be found in Table 1.²

Table 1. Water-Soluble vs Fat-Soluble Vitamins²

What is Vitamin B₁₂?

B₁₂ (cobalamin) is a water-soluble vitamin that is found in certain foods and is required for DNA synthesis and the formation of several hematologic elements, such as red blood cells (RBCs), white blood cells, and platelets.³ Individuals who have low levels of vitamin B₁₂, due to either increased demand or poor absorption, are labeled vitamin B₁₂ deficient. Vitamin B₁₂ deficiency can lead to the formation of abnormal hematopoietic precursor cells such as megaloblastic RBCs, as seen in Figure 1.

Figure 1. Vitamin B₁₂ Deficiency

Vitamin B₁₂ deficiency is not only problematic for hematopoiesis; it also has severe neuropsychiatric consequences, including cognitive impairment, depression, insomnia, psychosis, peripheral sensory deficits, and weakness. Lhermitte sign (Figure 2)⁴ can be tested by flexing the neck and assessing for shock-like sensations radiating to the feet. The mechanism is better understood for neuropathies (primarily dorsolateral myelopathy) associated with this deficiency as opposed to neuropsychiatric conditions. Most theories suggest that elevated methylmalonic acid (MMA) levels found in vitamin B₁₂ deficiency may lead to demyelination of the peripheral nervous system and central nervous system.⁵ MMA accumulates in cells due to lack of vitamin B₁₂ as a cofactor in the conversion of MMA to succinyl Co-A in cell metabolism.

Figure 2. Lhermitte’s Sign⁴

Why Does B₁₂ Deficiency Happen?

There are several potential causes of vitamin B₁₂ deficiency. Autoimmune pernicious anemia is the most common cause of vitamin B₁₂ deficiency. Intrinsic factor (IF) and gastric parietal cells are attacked by gastric autoantibodies. IF is a glycoprotein that binds cobalamin and aids in the absorption of vitamin B₁₂ in the terminal ileum. The depletion or lack of IF in pernicious anemia causes cobalamin deficiency.⁶ Other causes such as poor absorption related to pancreatic insufficiency, gastrectomy, intestinal surgeries, and inflammatory bowel disorders can also contribute to poor vitamin B₁₂ absorption. Intestinal infections competing for vitamin B₁₂ absorption such as small intestinal bacterial overgrowth or a parasitic infection should also be considered. Genetic disorders affecting absorption and transport of vitamin B₁₂, such as transcobalamin deficiency, are currently being studied. Several medications can also lead to vitamin B₁₂ deficiency via impaired absorption, metabolism, and utilization; these are listed in Table 2.^7,8 Pure nutritional deficiency is usually only seen in strict vegans and is extremely rare.⁹ Selected food sources of vitamin B₁₂ can be found in Table 3.⁹

Table 2. Medications That Cause Vitamin B₁₂ Deficiency^7,8

Who Is at Highest Risk for This Disorder?

Some people are at more of an increased risk of vitamin B₁₂ deficiency than others. Older adults are at increased risk of vitamin B₁₂ deficiency due to gastric malabsorption secondary to gastric atrophy, chronic H. pylori infection, increased probability of gastric surgery history, and chronic use of medications like metformin and proton pump inhibitors.¹⁰ In patients with alcoholic liver disease, cobalamin levels may remain falsely elevated or normal despite low concentrations of liver tissue cobalamin and its active metabolites. This leads to a functional cobalamin deficiency. Proposed mechanisms of action include impaired uptake of serum cobalamin by the damaged liver, impaired storage of cobalamin in the liver that causes it to leak out, and reduced hepatic ability to synthesize transcobalamin. Vitamin B₁₂ treatment has proven beneficial to some alcohol-dependent patients with megaloblastic anemia.¹¹ Older adults, individuals taking the medications listed in Table 2,^7,8 those with alcohol use disorders, pure vegans, and individuals with poor access to adequate nutrition (either through economic limitations or malabsorptive limitations) are at highest risk.

Table 3. Selected Food Sources of Vitamin B₁₂⁹

In 2008, the World Health Organization recommended vitamin B₁₂ fortification standards in order to prevent deficiency in high-risk populations. Since then, some nations have implemented these strategies and are working to improve dosing standards. The United States has yet to implement mandatory vitamin B₁₂ fortification, but certain foods, such as cereals, can be found to be fortified voluntarily.

When Should Screening and Prevention Be Done?

Screening and testing should occur in the following groups: those at high risk; individuals who have evidence of a macrocytosis or hyper-segmented neutrophils on peripheral blood smear; those with unexplained neurological conditions (eg, cognitive decline, weakness, ataxia, paresthesia); and those with unexplained psychosis and mood disturbances. Serum cobalamin levels are not always reliable in detecting vitamin B₁₂ deficiency. If an asymptomatic high-risk patient presents with low to normal serum vitamin B₁₂ levels, obtain serum homocysteine and MMA levels as a confirmatory test.¹² If pernicious anemia is suspected, confirm the diagnosis by obtaining anti-IF antibody levels and serum gastrin/pepsinogen levels.¹²

Those aged 50 years or older and strict vegetarians may benefit from vitamin B₁₂ supplements or food fortified with vitamin B₁₂, as the crystalline formulation is better absorbed than natural dietary cobalamin. Following gastric bypass surgery, patients should supplement with vitamin B₁₂, 1 mg daily.¹³

Where Is This Condition Most Prevalent?

In the United States, older adults have the highest prevalence of vitamin B₁₂ deficiency. In the United States and the United Kingdom, the prevalence of vitamin B₁₂ deficiency was found to be 6% in adults 60 years of age or younger. In adults 60 years of age or older, the prevalence increases to 20%.¹⁴

How Do You Diagnose and Treat B₁₂ Deficiency?

Patients exhibiting macrocytic anemia on initial complete blood count and peripheral blood smear should be evaluated for both folate and vitamin B₁₂ deficiency, as these 2 conditions often present simultaneously. This can be done by assessing serum folate and B₁₂ levels. The diagnosis of vitamin B₁₂ deficiency is usually made when serum levels are less than 111 pmol/L (150 pg/mL).¹⁵ Measurement of serum homocysteine and MMA can also aid in differentiating between folate and vitamin B₁₂ deficiencies. In vitamin B₁₂ deficiency, both homocysteine and MMA levels can be elevated.

Repletion with vitamin B₁₂ is the standard treatment. The cause of the deficiency will dictate how one administers the medication and how much to dose. Those with poor absorption, altered anatomy, and/or neurological/neuropsychiatric manifestations would likely benefit more from parenteral than from oral administration. Typical dosing for adults is 1000 mcg parenterally several times per week until the deficiency is corrected, then once per month.¹⁶ High-dose oral vitamin B₁₂ and intramuscular vitamin B₁₂ are both effective treatments for vitamin B₁₂ deficiency.¹²

Concluding Thoughts

Vitamin B₁₂ is a key nutrient that is essential for our hematologic and neuropsychiatric functioning. With the prevalence of vitamin B₁₂ deficiency reaching 20% in certain populations, it is crucial to recognize patients who are at risk and/or require treatment. Vitamin B₁₂ replacement is relatively inexpensive and can be lifesaving when administered via the appropriate route and at the appropriate dosage.

Dr DeMoss is an associate clinical professor in the Department of Psychiatry at the University of North Texas Health Science Center in Fort Worth, Texas. Dr Elbasheer is a research coordinator in the Department of Behavioral Health Research at John Peter Smith Health Network in Fort Worth, TX. Dr Kunnel is a resident physician in the Department of Psychiatry at John Peter Smith Hospital. Mahi Raju is a pre-med Neuroscience student at the University of Texas at Austin. Drs DeMoss, Elbasheer, Kunnel, and Mahi Raju report no conflicts of interest concerning the subject matter of this article.

References

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