Background

• Vitamin B12 (cobalamin) is synthesised by microorganisms and found in animal products (meat, organ meat, fish, seafood, dairy and eggs). Some packaged cereals and soy milk are also fortified with B12 
• B12 is important in haematopoiesis and the central nervous system and is an enzyme cofactor
• Recommended daily requirements range from 0.4 mcg (infants) to 2.4 mcg (>14 years age)
• Most diets containing animal products contain a much higher intake than this. B12 is safe in doses up to 1000 times the RDI. See B12 content of common foods.

Causes of low vitamin B12

• Exclusively breastfed infants of mothers with B12 deficiency may develop deficiency and typically present from 4-6 months of age
• Malabsorption - causes include: ileal resection, inflammatory bowel disease, medication (e.g. proton pump inhibitors), parasites (including Giardia intestinalis), bacterial overgrowth, tropical sprue, possibly H. pylori
• Vegan/vegetarian diet - due to low intake
• Pernicious anaemia - autoimmune atrophic gastritis causes loss of intrinsic factor (IF)
• Rare metabolic disorders - including transcobalamin II (TCII) deficiency, cobalamin C/D defects

Causes by age

• Birth - 6 months - severe maternal deficiency, consider metabolic causes, especially if severe metabolic disturbance (acidosis/vomiting) and neurological features
• 6 months - mid-childhood - dietary deficiency, maternal deficiency (causing deficiency in breast fed infants), malabsorption 
• Mid-childhood onwards - juvenile pernicious anaemia, gastritis, malabsorption, medication

In refugee populations the most common cause is low intake - typically a diet low in animal products, due to chronic food insecurity in the country of origin.

Prevalence

• A 2013 study of 916 refugees presenting to Australian health centres for screening found:  
  • The prevalence of low B12 was 17% overall, including 12% of children aged under 14 yrs (low B12 defined as total serum B12 <150 pmol/L) 
  • Only 4.6% of those with low B12 had macrocytosis, and none of the cohort had folate deficiency
  • The highest prevalence of B12 deficiency was in people from Bhutan, Iran, Iraq and Afghanistan (up to 20-30%) 
  • Lower prevalence was found in refugees from Africa (4-11%) and Burma (2%)
• There are no data for the Australian population overall
• Globally very high prevalence of B12 deficiency is reported in Kenyan schools (including Sudanese refugees: up to 40%) and pregnant women in Nepal (including Bhutanese refugees: up to 50%). 

Assessment

B12 deficiency can cause life threatening disease due to megaloblastic anaemia with cytopaenias or neurological abnormalities (regression/seizures). Findings in children include delay or regression of developmental milestones, feeding difficulties, hypotonia, lethargy or hyperirritability, microcephaly and coma. Other patients may be asymptomatic or diagnosed incidentally. There are associations with decreased cognitive function, mental health and long-term cardiovascular outcomes.

History

• Dietary intake current and previous. Consumption of animal products more often than weekly should be protective – consider malabsorption in children with clinical symptoms and apparent adequate intake. Check maternal dietary history in breast fed infants
• Symptoms of anaemia or other cytopaenias
• Developmental and neurological symptoms - regression, seizures, floppy/hypotonia, dystonia/involuntary movements
• Underlying disorders causing malabsorption, including bowel surgery/short bowel syndrome, symptoms of malabsorption (diarrhoea, failure to thrive).

Examination

• Pallor, Jaundice, bruising
• Neurological – reduced tone in infants, defects in vibration sense, proprioception, cutaneous sensation, ataxia, weakness, abnormal reflexes, choreo-athetoid movements, gait abnormalities
• Microcephaly
• Skin pigmentation changes and oedema in infants.

Screening

• Routine measurement of B12 is not recommended for all refugees 
• Consider B12 screening in people from Afghanistan (see below), Bhutan, Iran, and Iraq, especially where there is a history of poor food access. Screening is generally not required for asymptomatic individuals with an adequate dietary intake, or those who have been in Australia for >6 months and consume animal products
• Complete screening in exclusively breastfed babies where there has been poor maternal food access or where deficiency is suspected clinically or based on initial blood test results
• An FBE (and ferritin) is part of initial refugee health screening, although this is not adequate screening for B12 deficiency.

Where B12 deficiency is suspected:

• Active B12 (holotranscobalamin) is more sensitive and the appropriate initial investigation (used at RCH) 
  • Measurement of total serum B12 (Note: this test is not available at RCH) 
    • Not sensitive or specific for clinical deficiency 
    • Total serum B12 <150 pmol/L is usually consistent with significant clinical deficiency , however results at the lower end of the normal range may in fact be deficient (false negative)
• Full blood examination and film - macrocytic red cells, hypersegmented neutrophils. Note: Macrocytosis can be masked by concomitant iron deficiency and thalassemia, and is not a useful screening test. Leukopaenia/thrombocytopenia/pancytopaenia are all possible associations.

If B12 deficiency is confirmed:

• Urinary methylmalonic acid (MMA) and serum homocysteine are useful to confirm tissue deficiency. One or both are elevated in almost all patients with clinical deficiency, but decrease immediately after treatment. Homocysteine may also be elevated in folate deficiency
• Haemolysis screen - Increased LDH (often very high), bilirubin and AST, decreased haptoglobin
• Iron studies and red cell folate for coexisting deficiency
• Bone marrow aspirate is not usually necessary
• If history does not suggestive dietary deficiency, consider other causes and investigate as appropriate.

Special note: B12 screening and preventive treatment in Afghan cohorts

We have seen widespread B12 deficiency in refugee children from Afghanistan in 2021-22. 

• We suggest FBE, ferritin, B12 and folate screening for all new arrivals from Afghanistan. 
• In infants, and anyone with poor nutrition, disability or neurological symptoms (all ages) - prioritise early screening, and also check serum homocysteine, and urine methylmalonic acid (Note - these tests may not be possible, and also may be billed outside the hospital setting).
• Where screening will be delayed, commence 3m oral B12 supplements (100 mcg oral daily, all ages), or give 1000 mcg IMI if possible.
  • When screening is later completed: if B12 levels are replete - stop supplements and repeat levels in 3-6 months, if levels remain low, complete serum homocysteine & urine methylmalonic acid, and seek specialist advice.
• Provide appropriate dietary advice.
• In breastfeeding infants with low B12 - seek specialist advice, and ensure their mothers also have screening for B12 and treatment if deficiency identified. 

Management

Seek specialist advice for patients with symptomatic B12 deficiency. At RCH management is usually in consultation with the Haematology and/or the Metabolic units. 

For infants and those with neurological involvement, standard replacement is intramuscular B12 (hydroxocobalamin (preferred), cyanocobalamin). Although oral doses (cyanocobalamin) are poorly absorbed (0.5-4% absorbed), high doses can be effective for lower-risk cases - i.e. older children/adults without evidence of tissue deficiency (i.e. no clinical features and normal homocysteine/MMA).

Regimens vary:

• Infants with clinical deficiency (macrocytic anaemia or neurological involvement) - one approach would be:
  
  • 250-1000 mcg intramuscular B12, on alternate days for 1-2 weeks, then 250 mcg weekly 
  • Short term parenteral therapy is often sufficient, especially if maternal deficiency is proven 
  • Switch to oral supplements once child is well, no diarrhoea, feeding improved, and maternal stores are replaced 
  • If diagnosis is unclear, where a metabolic cause is possible, or there are ongoing symptoms, seek ongoing specialist advice 
• Older children with mild disease - an alternative would be: 
  • 1000 mcg oral daily 
• Subclinical, dietary deficiency 
  • 50-200 mcg oral daily (generally as 100 mcg tablets, which can be crushed; also available as sublingual sprays/tablets - note: there is limited evidence to inform dosing for sublingual/spray replacement, but small studies suggest therapy is effective if the dose is sufficient)
  • Increase dietary intake
• Supplement (not deficient, no dietary intake)
  • 50-100 mcg daily or alternate daily.

Follow-up

• In infants and children with severe deficiency, repeat homocysteine and MMA levels 1-2 weeks after commencement of treatment (levels should normalise quickly). Once established on oral therapy, repeat B12 levels after 3 months, then regularly until several months after completing treatment 
• Patients with deficiency due to metabolic causes require individual and specialised management
• In patients with subclinical deficiency: repeat B12 levels at 3 months, treat for 3-6 months total.

Rapid clinical improvement is usually seen with replacement, but neurological impairment may persist if there has been prolonged deficiency. Long term developmental follow-up may be required if presentation included neurological features (seizures and neurocognitive deficits are common). 

_{Immigrant health resources Author: Daniel Engelman. Initial - November 2013, reviewed and updated Sophie Oldfield, Georgie Paxton and Rija Khanal, April 2022. Contact: georgia.paxton@rch.org.au}