is a pre-med Neuroscience student at the University of Texas at Austin.

Mahi Raju

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, B

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.”

 What did this experiment establish? The importance of vital amines, or as we know them, 

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.

 Examples of water-soluble and fat-soluble vitamins can be found in 

 (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.

 Individuals who have low levels of vitamin B

, due to either increased demand or poor absorption, are labeled vitamin B

 deficiency can lead to the formation of abnormal hematopoietic precursor cells such as megaloblastic RBCs, as seen in 

 deficiency is not only problematic for hematopoiesis; it also has severe neuropsychiatric consequences, including cognitive impairment, depression, 

, peripheral sensory deficits, and weakness. Lhermitte sign (

 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 B

 deficiency may lead to demyelination of the peripheral nervous system and central nervous system.

 MMA accumulates in cells due to lack of vitamin B

 as a cofactor in the conversion of MMA to succinyl Co-A in cell metabolism.

There are several potential causes of vitamin B

 deficiency. Autoimmune pernicious anemia is the most common cause of vitamin B

 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 B

 in the terminal ileum. The depletion or lack of IF in pernicious anemia causes cobalamin deficiency.

 Other causes such as poor absorption related to pancreatic insufficiency, gastrectomy, intestinal surgeries, and inflammatory bowel disorders can also contribute to poor vitamin B

 absorption. Intestinal infections competing for vitamin B

 absorption such as small intestinal bacterial overgrowth or a parasitic infection should also be considered. 

 affecting absorption and transport of vitamin B

, such as transcobalamin deficiency, are currently being studied. Several medications can also lead to vitamin B

 deficiency via impaired absorption, metabolism, and utilization; these are listed in 

 Pure nutritional deficiency is usually only seen in strict vegans and is extremely rare.

Who Is at Highest Risk for This Disorder?

Some people are at more of an increased risk of vitamin B

 deficiency than others. Older adults are at increased risk of vitamin B

 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.

 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 B

 treatment has proven beneficial to some alcohol-dependent patients with megaloblastic anemia.

 Older adults, individuals taking the medications listed in 

 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.

In 2008, the World Health Organization recommended vitamin B

 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 B

 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 B

 deficiency. If an asymptomatic high-risk patient presents with low to normal serum vitamin B

 levels, obtain serum homocysteine and MMA levels as a confirmatory test.

 If pernicious anemia is suspected, confirm the diagnosis by obtaining anti-IF antibody levels and serum gastrin/pepsinogen levels.

Those aged 50 years or older and strict vegetarians may benefit from vitamin B

 supplements or food fortified with vitamin B

, as the crystalline formulation is better absorbed than natural dietary cobalamin. Following gastric bypass surgery, patients should supplement with vitamin B

In the United States, older adults have the highest prevalence of vitamin B

 deficiency. In the United States and the United Kingdom, the prevalence of vitamin B

 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%.

Patients exhibiting macrocytic anemia on initial complete blood count and peripheral blood smear should be evaluated for both folate and vitamin B

 deficiency, as these 2 conditions often present simultaneously. This can be done by assessing serum folate and B

 deficiency is usually made when serum levels are less than 111 pmol/L (150 pg/mL).

 Measurement of serum homocysteine and MMA can also aid in differentiating between folate and vitamin B

 deficiency, both homocysteine and MMA levels can be elevated.

 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.

 are both effective treatments for vitamin B

 is a key nutrient that is essential for our hematologic and neuropsychiatric functioning. With the prevalence of vitamin B

 deficiency reaching 20% in certain populations, it is crucial to recognize patients who are at risk and/or require treatment. Vitamin B

 replacement is relatively inexpensive and can be lifesaving when administered via the appropriate route and at the appropriate dosage.

 is an associate clinical professor in the Department of Psychiatry at the University of North Texas Health Science Center in Fort Worth, Texas.

is a research coordinator in the Department of Behavioral Health Research at John Peter Smith Health Network in Fort Worth, TX. 

is a resident physician in the Department of Psychiatry at John Peter Smith Hospital. 

 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.

1. Piro A, Tagarelli G, Lagonia P, et al. 

Casimir Funk: his discovery of the vitamins and their deficiency disorders.

3. National Center for Biotechnology Information. PubChem Compound Summary for CID 46853873, Cobalamin. Accessed August 26, 2021. 

https://pubchem.ncbi.nlm.nih.gov/compound/Cobalamin

5. Leishear K, Boudreau RM, Studenski SA, et al. 

 and sensory and motor peripheral nerve function in older adults.

6. Rodriguez NM, Shackelford K. Pernicious anemia. In: 

7. Busti AJ. Medications known to decrease vitamin B

 levels. Evidence-Based Medicine Consult. October 2015. Accessed August 26, 2021. 

https://www.ebmconsult.com/articles/vitamin-b12-medication-interactions-lower-levels

Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies

9. US Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference. Accessed August 26, 2021. 

https://www.ars.usda.gov/ARSUserFiles/80400535/DATA/sr21/sr21_doc.pdf

10. Andrès E, Loukili NH, Noel E, et al. 

 (cobalamin) deficiency in elderly patients. 

11. Fragasso A, Mannarella C, Ciancio A, Sacco A. 

 deficiency in alcoholics: an intriguing finding in a retrospective study of megaloblastic anemic patients

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