B12 Active Holotranscobalamin

To B12 or not to B12…

Dr. Dicken Weatherby & Beth Ellen DiLuglio, MS, RDN, LDN

Vitamin B12 is an essential micronutrient required for DNA synthesis, amino acid metabolism, nerve cell integrity, neurotransmitter synthesis, folate metabolism, and homocysteine processing. Its deficiency or insufficiency can have wide-reaching neurological and hematological consequences. These can include damage to the myelin sheath; tingling of hands and feet; difficulty with walking; disorientation; mood changes; dementia; memory loss; gastrointestinal symptoms; and megaloblastic and pernicious anemia.[1] [2] [3] Individuals with early stages of B12 deficiency may be asymptomatic.

B12 is found in abundance in animal-based foods but has a complex absorption pathway. Certain groups are at significant risk of deficiency including vegetarians; the elderly; pregnant and breast-feeding women; and individuals with HIV or kidney, gastrointestinal, or autoimmune disorders.[4]

Serum measurement of vitamin B12 alone may not reflect insufficiency as it is a relatively insensitive and unspecific marker that may not change until late in a deficiency. Other markers such as methylmalonic acid and homocysteine may be measured to help assess B12 status. Methylmalonic acid will be produced and increase once B12 stores are depleted, even if serum B12 is normal. Elevated homocysteine may indicate deficiency though it is not specific to B12.

Instead, holotranscobalamin (holoTC), a critical binding protein, serves as the best biomarker for identifying early phases of vitamin B12 deficiency. Reduced levels of holoTC signal B12 insufficiency or functional deficiency even if total serum B12 is within normal range. Approximately 10-30% of circulating B12 is carried on holoTC and is readily available to cells and tissues. The remaining 70-90% is bound to haptocorrin and is not available for delivery. Early identification of B12 insufficiency is vital as even mild deficiency can cause neurocognitive consequences.[5]

Holotranscobalamin may also be called holoTC, holo TCII, transcobalamin II-bound, or active B12. Although it is the preferred biomarker for identifying early B12 insufficiency, evaluation of an individual’s risk factors and clinical presentation are important as well.

Causes and Symptoms of B12 deficiency

[6] [7] [8] [9] [10]

Causes

• Alcohol abuse
• Gastrointestinal disorders including resection, bariatric surgery, inflammation, celiac disease, tropical sprue, Crohn’s disease, achlorhydria, atrophic gastritis, malabsorption due to lack of intrinsic factor
• Genetic disorders such as Transcobalamin deficiency, Imerslund Grasbeck syndrome
• Inadequate intake due to anorexia nervosa, strict vegetarian or vegan diet
• Infection with H. pylori, Giardia lamblia, fish tapeworm
• Medication use including proton pump inhibitors, histamine blockers, metformin, and nitrous oxide

Symptoms and clinical manifestations

• Anemia (macrocytic, megaloblastic, pernicious)
• Appetite loss
• Areflexia
• Cognitive impairment
• Constipation
• Dementia
• Demyelination
• Depression
• Gait abnormalities
• Gastric inflammation
• Glossitis
• Fatigue
• Infertility
• Inflammation
• Irritability
• Jaundice
• Loss of proprioception and vibratory sensation
• Mood changes
• Neurological impairment
• Olfactory impairment
• Palpitations
• Pancytopenia
• Peripheral neuropathy
• Psychosis
• Skin pallor or hyperpigmentation
• Thromocytopenia
• Thrombocytosis
• Vitiligo

Vitamin B12 insufficiency should be resolved as early as possible to avoid neurological, psychological, and hematological manifestations. If supplementation is indicated, intramuscular, sublingual, and oral options are available. Certain conditions such as pernicious anemia and ileal resection may require intramuscular or sublingual administration to bypass intestinal absorption complications.

REFERENCES

[1] Devalia, Vinod et al. “Guidelines for the diagnosis and treatment of cobalamin and folate disorders.” British journal of haematology vol. 166,4 (2014): 496-513. [R]

[2] Langan, Robert C, and Andrew J Goodbred. “Vitamin B12 Deficiency: Recognition and Management.” American family physician vol. 96,6 (2017): 384-389. [R]

[3] Linus Pauling Institute Vitamin B12. [R]

[4] Herrmann, Wolfgang, and Rima Obeid. “Causes and early diagnosis of vitamin B12 deficiency.” Deutsches Arzteblatt international vol. 105,40 (2008): 680-5. [R]

[5] Green, Ralph. “Vitamin B12 deficiency from the perspective of a practicing hematologist.” Blood vol. 129,19 (2017): 2603-2611. doi:10.1182/blood-2016-10-569186 [R]

[6] Devalia, Vinod et al. “Guidelines for the diagnosis and treatment of cobalamin and folate disorders.” British journal of haematology vol. 166,4 (2014): 496-513. [R]

[7] Langan, Robert C, and Andrew J Goodbred. “Vitamin B12 Deficiency: Recognition and Management.” American family physician vol. 96,6 (2017): 384-389. [R]

[8] Linus Pauling Institute Vitamin B12. [R]

[9] Del Bo', Cristian et al. “Effect of two different sublingual dosages of vitamin B12 on cobalamin nutritional status in vegans and vegetarians with a marginal deficiency: A randomized controlled trial.” Clinical nutrition (Edinburgh, Scotland) vol. 38,2 (2019): 575-583. [R]

[10] Sugihara, Takaaki et al. “Falsely Elevated Serum Vitamin B12 Levels Were Associated with the Severity and Prognosis of Chronic Viral Liver Disease.” Yonago acta medica vol. 60,1 31-39. 9 Mar. 2017 [R]