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. 2024 Apr 10;13(8):2176. doi: 10.3390/jcm13082176

Table 1.

Expert consensus was reached after 2 survey cycles on all of the following topics related to the diagnosis of vitamin B12 deficiency and its causes.

Questions n (Panelists) 1 Mean (95% CI) 2
Identification of vitamin B12 deficiency: Challenges, barriers and obstacles
1. The delay in diagnosing B12 deficiency in a significant number of patients may be due to the following factors:

  • Complexity and variability of signs and symptoms of the deficiency that extend across several medical specialization (hematologic, neuropsychiatric, gastroenterological and other manifestations).

 42 0.95 (0.84–0.99)

  • Doctors may not have sufficient awareness of risk factors for B12 deficiency.

 42 0.93 (0.81–0.99)

  • Not paying sufficient attention to patients’ complaints which are often vague.

 41 0.85 (0.71–0.94)

  • High costs and limited availability of advanced laboratory B12 markers such as plasma methylmalonic acid, total homocysteine and holotranscobalamin.

 41 0.68 (0.52–0.82)
2. The following initiatives can reduce the burden of unidentified B12 deficiency:

  • Increase awareness of doctors and medical personnel toward signs and symptoms of B12 deficiency, diagnostic measures and people at risk.

 42 100%

  • People at risk of B12 deficiency due to their lifestyle, background diseases, or family history of B12 deficiency should regularly receive understandable information from their doctors explaining causes and consequences of B12 deficiency and possible prophylactic measures.

 41 0.83 (0.68–0.93)
3. Signs and symptoms of B12 deficiency may affect multiple organ systems at variable frequency. The crude order of affected systems (highest to lowest prevalence) is shown in Figure S3. 41 0.71 (0.54–0.84)
4. The most difficult symptoms to link to clinically manifested B12 deficiency are (as ordered from most to least difficult) as shown in Figure 1. 40 0.80 (0.64–0.91)
5. Clinically manifested B12 deficiency is commonly first identified in primary medical care. Some patients may require referral to a specialist. Referral of patients to gastroenterologists is least frequent compared to referral to neurologists/psychiatrists and hematologists 38 0.71 (0.54–0.85)
6. Concordance with the diagnostic pathway shown in Figure 2. 42 0.76 (0.61–0.88)
Biomarkers and their utility in clinical practice
7. Considering the cost‒benefit and the added value of advanced laboratory tests beyond plasma B12 concentrations and blood cell count:

  • Measurement of a metabolic marker such as plasma methylmalonic acid (or total homocysteine if methylmalonic acid is not available) is useful in guiding the diagnosis of B12 deficiency.

 41 0.88 (0.74–0.96)

  • If available, plasma methylmalonic acid concentration is a useful marker for monitoring the effectiveness of B12 treatment in general.

 41 0.76 (0.60–0.88)

  • If available, plasma methylmalonic acid concentration is useful in monitoring the success of oral B12 treatment in particular when it is questionable whether the B12 dose is appropriate or people can absorb B12.

 39 0.69 (0.52–0.83)

  • Plasma methylmalonic acid concentration (or at least total homocysteine) should be made available for all people suspected of having B12 deficiency.

 41 0.83 (0.68–0.93)

  • Although the metabolic markers (plasma methylmalonic acid and total homocysteine) have some limitations, they can be very helpful when the clinical picture is uncertain.

 41 0.88 (0.74–0.96)
8. Because chronic use of metformin in patients with diabetes is associated with lower plasma concentrations of B12 and linked to the frequency and severity of neuropathy, measurement of B12 status once per year in this group of patients can help detecting a deficiency prior to clinical manifestation. 40 0.83 (0.67–0.93)
9. If plasma B12 concentrations far above the reference range are encountered in a person without specific medical conditions:

  • Inquire if the person is using any supplemental B12 source (food supplements or OTC).

 41 0.98 (0.87–0.999)

  • If the person is not using a B12-supplement, repeat plasma B12 test after few months.

 40 0.70 (0.53–0.83)

  • Rule out disturbed blood count, liver and renal function markers that may explain high plasma B12 levels due to liver or kidney diseases or undiagnosed malignancies.

 39 0.85 (0.69–0.94)
Identifying the cause of vitamin B12 deficiency
10. A holistic approach is deemed necessary for diagnosing B12 deficiency and identifying the cause(s). This includes:

  • In elderly people food-cobalamin malabsorption may cause B12 deficiency even if the intake of B12 from foods is adequate and in the absence of gastrointestinal disorders.

 42 0.93 (0.81–0.99)

  • To clarify the cause of B12 deficiency, ask the person about:
  • ○

    practicing a vegan diet, a vegetarian diet, or avoiding animal source foods.

 42 0.93 (0.81–0.99)
  • ○

    gastrointestinal problems or previous gastric or intestinal diseases or surgeries.

 42 0.95 (0.84–0.99)
  • ○

    regular use of medications (e.g., gastric acid blockers, metformin, L-DOPA).

 42 0.98 (0.87–0.999)
  • ○

    recreational use of laughing gas.

 40 0.70 (0.53–0.83)
11. The following conditions may provide clues for B12 deficiency being due to B12 malabsorption:

  • Autoimmune diseases in the person’s medical history (e.g., thyroid dysfunction, T1DM, celiac disease, or rheumatoid arthritis).

 39 0.87 (0.73–0.96)

  • Gastric surgery in the person’s medical history (due to cancer or for weight loss).

 42 0.98 (0.87–0.999)

  • Family history of pernicious anemia.

 42 100%

  • Chronic gastrointestinal conditions.

 41 0.93 (0.80–0.98)

  • Positive serum antibody results against parietal cells or intrinsic factor.

 42 0.88 (0.74–0.96)
12. In context of the B12 diagnostic work-up, folate and iron status should also be assessed. 42 0.95 (0.84–0.99)

1 Total number of the panelists who answered each of the questions. 2 Mean percentage and the 95% confidence intervals of the panelists who considered themselves qualified to answer the question and chose “agree” or “strongly agree” to the answer. We considered that a consensus was reached when the lower bound of the 95% confidence interval was 50% or higher. T1DM, type 1 diabetes mellitus.