Kresser Institute

Tools, Training & Community for Functional Health Professionals

Functional Blood Chemistry Manual

Serum B12

Marker Name: Serum B12


Laboratory reference range: 211–946 pg/mL

Functional reference range: 450–2000 pg/mL


Vitamin B12 (cobalamin) is one of the water-soluble B vitamins.1 Vitamin B12 is essential for DNA synthesis, as it is required for synthesis of the purine and pyrimidine nucleotide bases.2 Vitamin B12 is particularly important for the formation of morphologically normal and functional red blood cells, and it plays an important role in nervous system development and neurological function.3

Vitamin B12 is a cofactor for the enzymes methionine synthase and L-methylmalonyl-CoA mutase.4 Methionine synthase transfers a methyl group from

methyltetrahydrofolate to homocysteine, which forms the amino acid methionine and tetrahydrofolate (THF). L-methylmalonyl-CoA mutase, on the other hand, produces succinyl-CoA from L-methylmalonyl-CoA. Succinyl-CoA is a key intermediate in the citric acid cycle.

Vitamin B12 is not a single molecule, but rather several related cobalt-containing molecules (corrinoids) that have vitamin B12 activity in the body.3 The principal forms of vitamin B12 active in the human body are methylcobalamin and 5-deoxyadenosylcobalamin.3

Since humans cannot synthesize vitamin B12, it must be obtained from dietary sources or supplementation. Orally consumed vitamin B12 requires acid-pepsin and pancreatic proteases to free cobalamin from proteins and ligands, respectively.5 Simultaneously, ingested vitamin B12 must be protected from acid and enzymatic degradation. Intrinsic factor, a substance secreted by parietal cells in the stomach, provides this protection for vitamin B12.5 Intrinsic factor binds to vitamin B12 and essentially shuttles it to the terminal ileum, where it is absorbed into the portal circulation and carried to the liver.3 Intrinsic factor is essential for vitamin B12 absorption in the terminal ileum.6

Most vitamin B12 is transported in the blood bound to plasma binding proteins, specifically, transcobalamins. Approximately 80 percent of circulating vitamin B12 is bound to transcobalamin I, though transcobalamin II is the principal plasma binding protein responsible for delivering B12 to tissues.7

Half of circulating vitamin B12 is taken up by the liver, and the other half is transported to tissues. The portion of B12 taken up by the liver enters the biliary system, and vitamin B12 is continually secreted in the bile. Intrinsic factor may bind to secreted B12 in the bile for reuptake in the terminal ileum, thereby preserving total body vitamin B12 levels.3,7 Vitamin B12 not reabsorbed by the intestine is passed in the feces.

Laboratories currently measure total cobalamin blood assays of vitamin B12; however, many groups have argued that holotranscobalamin, or “active B12,” more accurately reflects the level of bioavailable vitamin B12 in the blood.8-10  Holotranscobalamin is the portion of circulating vitamin B12 that is bound to transcobalamin proteins. While holotranscobalamin carries only 6 to 20 percent of total plasma B12,10 it delivers the majority of usable B12 to tissues, which is why holotranscobalamin is also known as “active B12.” Although holotranscobalamin is a better indicator of early vitamin B12 deficiency than total serum B12 levels, few clinical laboratories routinely measure holotranscobalamin.9

Hypercobalaminemia is an abnormally high serum vitamin B12 level. Since vitamin B12 is a water-soluble vitamin, it has been long assumed that an elevated B12 level is both uncommon and of little clinical importance.11 Within the last decade, however, new research has revealed that hypercobalaminemia is more common than previously realized and may have deleterious effects for patients.11-13 Interestingly, elevated vitamin B12 levels may indicate functional vitamin B12 deficiency.11 Excessive intake of vitamin B12 is likely the most common cause of hypercobalaminemia. This is most often caused by excess oral supplementation or excessive parenteral administration of vitamin B12.11 Various solid and blood cancers can cause abnormally high levels of circulating vitamin B12. Some solid tumors can cause hypercobalaminemia, especially cancers of the gastrointestinal organs. Inflammatory conditions, liver disease, and kidney disease may also cause abnormally elevated vitamin B12 levels in the blood.11

An abnormally low serum vitamin B12 level is hypocobalaminemia. Insufficient consumption of vitamin B12 in the diet, gastric diseases, and malabsorption are the main causes of hypocobalaminemia.2,5 Pernicious anemia is a major cause of vitamin B12 deficiency among white and black adults, but it is much less frequently seen in Hispanics or Asians.14 Pernicious anemia results from a defect in the activity of intrinsic factor, which is thought to be caused by autoimmunity against intrinsic factor or gastric parietal cells.15 Other reasons for malabsorption of vitamin B12 and subsequent hypocobalaminemia include reduced gastric acid secretion, failure of the exocrine pancreas, chronic alcoholism, H. pylori infection, the effect of certain drugs, and gastrointestinal surgeries (e.g., gastric bypass).5,16

Serum vitamin B12 is virtually always measured with folate. Investigations of vitamin B12 deficiency may include holotranscobalamin, homocysteine, and/or methylmalonic acid assays.17,18


High in:3,11

  • Excessive intake (especially parenteral)
  • Paradoxical functional vitamin B12 deficiency
  • Inflammatory disease (e.g., lupus, rheumatoid arthritis)
  • Renal failure
  • Liver disease (e.g., acute hepatitis, liver cirrhosis, alcoholic liver disease)
  • Blood disorder
    • Chronic myeloid leukemia
    • Polycythemia vera
    • Primary myelofibrosis
    • Acute leukemia
    • Primary hypereosinophilic syndrome
  • Solid neoplasm
    • Hepatocellular carcinoma
    • Breast cancer
    • Colon cancer
    • Gastric cancer
    • Pancreatic cancer

Low in:5,19

  • Insufficient dietary intake
  • Gastrointestinal conditions
    • Pernicious anemia
    • Gastrectomy/bariatric surgery
    • Gastritis
    • Crohn’s disease
    • Malabsorption (e.g., tropical sprue)
    • Small bowel disease
    • Ileal resection
    • Pancreatic insufficiency
    • Pancreatitis
    • Tapeworm infestation
  • Inherited transcobalamin II deficiency
  • Drugs
    • Metformin
    • Proton pump inhibitors (e.g., omeprazole)
    • Histamine receptor antagonists


High in:

  • B12 supplementation
  • Impaired B12 metabolism

Low in:

  • Functional B12 metabolism
  • GI conditions impairing B12 absorption


Kresser Institute Icon ADAPT Health Coach Training Program Icon ADAPT Practitioner Training Program Icon ADAPT Courses Icon