A Deeper Dive Into B12 - Part 2

Welcome to part 2 of the ODX B12 Deficiency Series. In this post, the ODX Research Team reviews how we become vitamin B12 deficiency and what happens when get there.

The road to B12 deficiency and what happens when we get there…

Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

The ODX B12 Series

1. Vitamin B12 Part 1 - Biochemistry and Physiology
2. Vitamin B12 Part 2 - The Road to B12 Deficiency
3. Vitamin B12 Part 3 - Biomarkers & Assessing B12 Deficiency
4. Vitamin B12 Part 4 - How to Correct B12 Deficiency

Elderly status, strict vegetarianism, and lack of intrinsic factor have been traditionally recognized as the main causes of B12 deficiency.[1]

However, additional causes have been recognized including poor appetite and insufficient intake, restricted intake of animal-based products, impaired absorption, drug-induced depletion, and genetic variations that affect uptake and distribution.[2]

In general, bioavailability of B12 will depend on gastrointestinal competence, age, and single nucleotide polymorphisms (SNPs). SNPs can have effect the absorption, transport, uptake, and intracellular metabolism of B12. Those with genetic SNPs in the metabolic pathways that process B12 may be unable to metabolize cyanocobalamin.[3]

Causes of B12 deficiency[4] [5] [6] [7] [8] [9] [10] [11]

• Alcohol abuse
• Gastrointestinal disorders including ileal resection, gastrectomy, bariatric surgery, gastric bypass, inflammation, celiac disease, tropical sprue, Crohn’s disease, bacterial overgrowth, hypochlorhydria, atrophic gastritis, malabsorption due to lack of intrinsic factor
• Inadequate intake due to poor-quality diet, anorexia nervosa, strict vegetarian or vegan diet
• Impaired absorption
  • Gastric phase impairment
    • Decreased production of intrinsic factor
    • Insufficient gastric acid to cleave B12 from food
  • Intestinal phase impairment
    • Surgical resection of terminal ileum where B12 is absorbed
    • Inflammation of terminal ileum
  • Elderly status
• Genetic disorders such as Transcobalamin deficiency, Imerslund Grasbeck syndrome, SNPs
• Infection with H. pylori, Giardia lamblia, fish tapeworm, HIV
• Drug-induced nutrient depletions
  • Medication use including antibiotics, proton pump inhibitors, histamine blockers, metformin, and nitrous oxide (causes irreversible oxidation of methylcobalamin)

According to RDA guidelines, up to 30% of adults over the age of 50 often have malabsorption, reducing absorption of B12 to ~1% of what is ingested. In such cases, an individual would have to ingest 240 ug of B12 to absorb 2.4 ug. Specific conditions that impair B12 absorption include inflammatory bowel disease (Crohn’s and ulcerative colitis), celiac disease, gastric inflammation (including that caused by H. pylori), and autoimmune atrophic gastritis.[12] Autoimmune pernicious anemia is thought to be relatively rare.[13]

Some B12 can be absorbed through mucous membranes (e.g. mouth, nose), providing an alternative route for supplementation in those with gastrointestinal compromise.[14] Sublingual B12 has become a commonly used supplement form.

Vegetarians and B12   

Even moderate restriction of animal-based foods may negatively affect B12 status. Omnivores tend to have better B12 status than those who avoid meat, fish, and poultry but consume eggs and dairy. Vegetarians who avoid meat, fish, poultry, and eggs had worse status than those who completely avoid all animal-based foods such as vegans, who had the worst B12 status.[15]

B12 deficiency diseases

Vitamin B12 deficiency can be debilitating and even life threatening as it can cause demyelination of nerve cells and bone marrow failure as well as anemia.[16]

As both RBC and white blood cell precursors are dependent on folate and B12, pancytopenia and disturbances in both cellular and humoral immunity may occur. [17]

Although the liver can store a substantial amount of B12, the prevalence of B12 deficiency may be surprising.[18]

USA and UK                             6% under age 60           20% over age 60

Latin America                            40% overall

Kenyan school children              70%

East Indian pre-school               80%

East Indian adults                      70%

Neuropathy and megaloblastic anemia are the readily recognized consequences of B12 deficiency, though insufficiency may be manifest in a wider variety of symptoms.[19]

Megaloblastic anemia is characterized by hypersegmented neutrophils (1% with six lobes or 5% with five lobes) and large immature red blood cells. An elevated mean corpuscular volume (MCV) is common though not in all cases of deficiency. Red cell distribution width (RDW) may be elevated due to presence of larger cells.

Bone marrow changes seen with B12 deficiency may be mistaken for signs of acute leukemia. Neurological effects of B12 deficiency occur due to demyelination of the spinal cord, cranial and peripheral nerves, and white matter in the brain.[20]

Neurological deficits due to B12 insufficiency are often present without the occurrence of megaloblastic anemia, so a comprehensive assessment is needed.

Folate may correct megaloblastic anemia while “masking” a B12 deficiency. In such cases, progressive damage to the nervous system can occur if B12 is not provided concurrently. Note that most fortified foods contain folic acid (synthetic folate) but not B12.[21] Breakfast cereals may be an exception and provide B12 as well as folic acid.[22] The issue of providing biologically active 5-methyltetrahydrofolate versus synthetic folic acid will need to be covered another day!

Insufficiency of B12 contributes to or causes a variety of symptoms and clinical manifestations: [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]

• Abnormal erythropoiesis
• Anemia (macrocytic, megaloblastic, pernicious, unexplained)
• Anorexia, appetite loss
• Areflexia
• Ataxia, gait abnormalities
• Balance problems
• Cardiovascular symptoms
• Cognitive impairment
• Confusion
• Constipation
• Decreased haptoglobin
• Dementia
• Demyelination
• Depression
• Diarrhea
• Elevated lactate dehydrogenase
• Elevated reticulocyte count
• Failure to thrive, feeding difficulty in infants
• Fatigue
• Gastrointestinal symptoms (nonspecific)
• Glossitis, soreness of mouth and tongue
• Hyper-homocysteinemia
• Hypoesthesia or paresthesias
• Hypotonia, hypokinesia
• Infertility
• Inflammation
• Irritability
• Jaundice
• Lethargy
• Leukopenia
• Loss of proprioception and vibratory sensation
• Loss of taste
• Macular degeneration
• Megaloblastic anemia
• Memory impairment
• Methylmalonic acid build up
• Mood changes
• Neural tube defects
• Neurological impairment
• Numbness, tingling in hands and feet
• Olfactory impairment
• Orthostatic hypotension
• Palpitations
• Pancytopenia
• Peripheral neuropathy
• Postural hypotension
• Psychosis
• Skin pallor or hyperpigmentation
• Stomatitis
• Stroke
• Thrombocytopenia
• Thrombocytosis
• Transient ischemic attacks
• Vitiligo
• Weakness
• Weight loss
• Whole-brain atrophy

A postmortem study of brain levels of Vitamin B12 revealed that levels of both MeCbl and AdCbl were three times lower in autistic individuals and in schizophrenic subjects. The lower MeCbl in autistics correlated with decreased activity of methionine synthase and increased levels of homocysteine. Interestingly, in controls, fetal brain samples had remarkably high levels of cyanocobalamin, prompting questions about cyanocobalamin processing.[34]

Stages of B12 insufficiency[ 35]

• Events in the blood:
  • Increase in plasma MMA concentration and urinary MMA excretion
  • Decrease in serum holoTC and serum B12
  • Increase in plasma tHcy concentration
  • Reduction in RBC B12
  • Hypersegmentation of nuclei in neutrophils
• Megaloblastic anemia—abnormally large RBCs with large nuclei; increased mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC)
• Megaloblastic changes in bone marrow.
• Infertility and recurrent fetal loss.
• Weakness and fatigue.
• Demyelination of neurons.
• Reduced conductivity of peripheral and central neurons.
• Peripheral neuropathy, abnormal gait, and position sense.
• Subacute combined degeneration (myelopathy).
• Brain atrophy.
• Dementia, depression, memory loss, and psychosis.

Insufficiency of vitamin B12, whether due to inadequate intake, impaired absorption, or genetic factors, can have incapacitating consequences.

B12 status should be assessed and addressed in individuals displaying related symptoms or biochemical clues that indicate the possibility that B12 insufficiency may be present.

Next Up: Vitamin B12 Part 3 - Biomarkers & Assessing B12 Deficiency

References

[1] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

[2] Smith, A David et al. “Vitamin B12.” Advances in food and nutrition research vol. 83 (2018): 215-279.

[3] Paul, Cristiana, and David M Brady. “Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.” Integrative medicine (Encinitas, Calif.) vol. 16,1 (2017): 42-49.

[4] 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.

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

[6] Linus Pauling Institute Vitamin B12. https://lpi.oregonstate.edu/mic/vitamins/vitamin-B12

[7] 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. 

[8] 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 

[9] Gökışık, Melih Tansel, and Seyit Uyar. “The role of Helicobacter pylori in vitamin-B12 deficiency due to metformin use.” Helicobacter, e12718. 19 Jun. 2020.

[10] NIH ODS. Vitamin B12 Fact Sheet for Consumers. Retrieved October 22, 2020 from https://ods.od.nih.gov/pdf/factsheets/VitaminB12-Consumer.pdf

[11] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

[12] Paul, Cristiana, and David M Brady. “Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.” Integrative medicine (Encinitas, Calif.) vol. 16,1 (2017): 42-49. 

[13] Sukumar, Nithya, and Ponnusamy Saravanan. “Investigating vitamin B12 deficiency.” BMJ (Clinical research ed.) vol. 365 l1865. 10 May. 2019.

[14] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

[15] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

[16] Stabler, Sally P. “Clinical practice. Vitamin B12 deficiency.” The New England journal of medicine vol. 368,2 (2013): 149-60. 

[17] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

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

[19] Watanabe, Fumio. “Vitamin B12 sources and bioavailability.” Experimental biology and medicine (Maywood, N.J.) vol. 232,10 (2007): 1266-74. 

[20] Stabler, Sally P, and Robert H Allen. “Vitamin B12 deficiency as a worldwide problem.” Annual review of nutrition vol. 24 (2004): 299-326. 

[21] NIH ODS. Vitamin B12 Fact Sheet for Consumers. Retrieved October 22, 2020 from https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/#en13

[22] NIH. ODS. Vitamin B12 Fact Sheet for Health Professionals. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/#en13

[23] Smith, A David et al. “Vitamin B12.” Advances in food and nutrition research vol. 83 (2018): 215-279. 

[24] 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. 

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

[26] Linus Pauling Institute Vitamin B12.

[27] 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.

[28] 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

[29] NIH ODS. Vitamin B12 Fact Sheet for Consumers. Retrieved October 22, 2020 from https://ods.od.nih.gov/pdf/factsheets/VitaminB12-Consumer.pdf

[30] Stabler, Sally P. “Clinical practice. Vitamin B12 deficiency.” The New England journal of medicine vol. 368,2 (2013): 149-60. 

[31] Thakkar, K, and G Billa. “Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion.” European journal of clinical nutrition vol. 69,1 (2015): 1-2. 

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

[33] Hannibal, Luciana et al. “Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency.” Frontiers in molecular biosciences vol. 3 27. 27 Jun. 2016, 

[34] Zhang, Yiting et al. “Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia.” PloS one vol. 11,1 e0146797. 22 Jan. 2016, 

[35] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S.