Subclinical vitamin B12 deficiency

South Asians (persons originating from the Subcontinent of India including India, Bangladesh, Pakistan, and Sri Lanka) have long been identified as an at-risk ethnic group for vitamin B12 deficiency.

• For people from India, this has largely been explained by their lifelong and multigenerational lactovegetarian dietary practices, which result in prolonged inadequate dietary intake of vitamin B12
  • in addition, intake of animal products is still frequently low in non-vegetarians

Vitamin B12 deficiency can have neurologic and hematologic sequelae and can lead to hyperhomocysteinemia.

• Symptoms of B12 deficiency include fatigue, weakness, anorexia, paresthesias, numbness, and dizziness.
• Initial presentation is often vague.

Main causes of B12 deficiency include lack of intrinsic factor and other intestinal factors (eg, malabsorption), rare genetic disorders, and inadequate intake.

• Absorption problems (due to lack of intrinsic or intestinal factors) are thought to be the most common cause of B12 deficiency.
• Inadequate intake of B12 through diet is believed to be a rare cause of B12 deficiency, although people who follow a vegan diet are considered at elevated risk.

Dietary vitamin B12 deficiency
Some evidence suggests South Asians, lactovegetarians, and in particular South Asians who are lactovegetarians are at greater risk of B12 deficiency (1,2):

• One study found that about 38% of people in western India followed a lactovegetarian diet and that 47% of the study population (60% of vegetarian and 39% of nonvegetarian people) were B12 deficient (1).
• Another study supports the recognition of Asian Indians as an at-risk group for low vitamin B12 status, with low serum vitamin B12 concentrations being seen particularly in the vegetarians of this group.
  • nearly one-fourth of the vegetarians in this study had vitamin B12 concentrations below the recommended cutoff values for deficiency (<150 pmol/L) and 35% had a marginal vitamin B12 status (150-221 pmol/L) (2).
• Another study found that South Asian men in the United Kingdom had lower mean B12 levels than European controls (270 pmol/L vs 357 pmol/L) (1).
• In Asia, Indians had lower B12 levels than Chinese or Malays (2).

Management (3,4,5):

• screen for causes of vitamin B12 deficiency other than dietary (3,5)
  • pernicious anaemia screen
    • anti-intrinsic factor (anti-IF) antibodies - highly specific (95-100%) for pernicious anaemia (PA) but not very sensitive (only positive in 50-60% of patients with PA)
    • anti-gastric parietal cell (anti-GPC) antibodies - reasonably sensitive (80-90%) for PA but not as specific as anti-IF antibodies
  • thyroid function tests and anti-thyroid antibodies, liver function tests, GGT
  • test for coeliac disease
  • tests for generalised malabsorption - calcium and vitamin D, folate, ferritin
  • Schilling test generally only indicated if levels of B12 less than 100 ng/L (5)
    
• treatment of clinical vitamin B12 deficiency has traditionally been accomplished by intramuscular injection vitamin B12
  • a Cochrane review, patients who received high dosages of oral vitamin B12 for 90 to 120 days had an improvement in serum vitamin B12 similar to patients who received intramuscular injections of vitamin B12 (3,4)
    
• in asymptomatic patients with low-normal levels of vitamin B12, elevated levels of the precursor compounds homocysteine and methylmalonic acid may prompt a decision to supplement patients with vitamin B12 (3)
  
• there are no clinical guidelines for the treatment of subclinical vitamin B12 deficiency (asymptomatic patients with decreased levels of vitamin B12 and elevated levels of homocysteine and/or methylmalonic acid) (3)
  • physicians may opt to treat these patients and monitor for improvement of metabolic markers, particularly in populations at high risk of clinical vitamin B12 deficiency, or observe these patients and periodically reassess their levels of vitamin B12, homocysteine, and/or methylmalonic acid
  • a suggested algorithm for management is (5)
    • management of patients with apparently asymptomatic vitamin B12 deficiency is a source of considerable debate. These patients usually have a serum vitamin B12 >150ng/l
      • it is worth confirming the 'deficiency' by repeating the serum vitamin B12 level
      • if the level is still low, a significant proportion of these patients will go on to develop symptomatic vitamin B12 deficiency in the future
        • if the serum B12 is < 150 ng/l
          • consider treating with vit B12 50-100mcg PO daily and recheck serum vit B12 and FBC after 2 months
• OR
• monitor serum vit B12 level every 6 months for 1 yr then annually for 2-5 yrs
  
• if serum B12 is > 150 ng/L
  • recheck serum vit B12 level after 2 months. If still low, monitor serum B12 level every 6 months for 1 yr then annually for 2-5 yrs - however if < 150ng/L then manage as stated above
    
• rationale for treating patients with apparently asymptomatic but significantly reduced levels (<150ng/l) of serum vitamin B12 is that some of these patients show biochemical evidence of subclinical vitamin B12 deficiency e.g. increased levels of plasma homocysteine and methylmalonic acid and some will develop symptomatic problems if left untreated.
• patients treated with oral repletion therapy need to have their initial response to treatment monitored with vitamin B12 levels after 2-3 months followed by 6-12 monthly tests to ensure an ongoing response

Notes:

• measurements of serum vitamin B12 may not reliably detect deficiency, and measurement of serum homocysteine and/or methylmalonic acid should be used to confirm deficiency in asymptomatic high-risk patients with low normal levels of vitamin B12 (3)
• folic acid deficiency can cause falsely low serum vitamin B12 levels
• methylmalonic acid levels can be elevated in patients with renal disease (the result of decreased urinary excretion); thus, elevated levels must be interpreted with caution

Reference:

• (1) Gupta AK, Damji A, Uppaluri A.Vitamin B12 deficiency. Prevalence among South Asians at a Toronto clinic. Can Fam Physician. 2004 May;50:743-7.
• (2) Gammon CS et al. Vegetarianism, vitamin B12 status, and insulin resistance in a group of predominantly overweight/obese South Asian women. Nutrition. 2012 Jan;28(1):20-4. Epub 2011 Aug 11.
• (3) Langan RC, Goodbred AJ. Vitamin B12 Deficiency: Recognition and Management. Am Fam Physician. 2017 Sep 15;96(6):384-389. PMID: 28925645.
• (4) Wang H, Li L, Qin LL, Song Y, Vidal-Alaball J, Liu TH. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2018 Mar 15;3(3):CD004655. doi: 10.1002/14651858.CD004655.pub3.
• (5) Royal United Hospital Bath NHS Trust. Guidelines for the Investigation & Management of vitamin B12 deficiency (accessed 13/05/2022).