Approach

Patients with severe haematological or neurological symptoms of vitamin B12 deficiency require immediate treatment with an intensive regimen of cyanocobalamin or hydroxocobalamin over 1 month, followed by ongoing maintenance doses.

Patients with mild to moderate symptoms of vitamin B12 deficiency should be started and continue on maintenance-level doses of cyanocobalamin or hydroxocobalamin.

Asymptomatic patients with a high risk of vitamin B12 deficiency (e.g., vegans and strict vegetarians, older patients, those with chronic gastrointestinal [GI] illnesses) require maintenance-level doses of cyanocobalamin or hydroxocobalamin (because haematological and neurological complications of vitamin B12 deficiency may be irreversible once they develop).[79][80]​ 

If the cause of the vitamin B12 deficiency is not yet established, or if vitamin B12 deficiency is clinically suspected despite normal or high serum vitamin B12 levels, treatment should be commenced while awaiting results of further investigations (e.g., anti-intrinsic factor antibody testing).

Vitamin B12 therapy options

Options available include parenteral (intramuscular or subcutaneous), oral, sublingual, or intranasal cyanocobalamin.

Parenteral cyanocobalamin or hydroxocobalamin

By far the most reliable and most familiar treatment for vitamin B12 deficiency, particularly for patients with severe anaemia and/or neurological disease (sub-acute combined spinal degeneration, dementia, or cognitive impairment).[49]

In Europe, parenteral hydroxocobalamin is more commonly used than parenteral cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.

Self-administration of vitamin B12 by intramuscular injection may be appropriate in some patients, and can lead to improved patient satisfaction and health outcomes.[80]

Oral cyanocobalamin

Patients may prefer oral cyanocobalamin administration to intramuscular administration.[99] High-dose oral cyanocobalamin can be adequately absorbed, even in patients with pernicious anaemia or significant terminal ileum resection.[100][101][102]​​​​ Absorption can be maximised by administering on an empty stomach.

Findings from one Cochrane review suggest that oral cyanocobalamin is at least as effective as intramuscular cyanocobalamin in patients with vitamin B12 deficiency.[103]

Sublingual and intranasal cyanocobalamin

Intranasal cyanocobalamin may be considered in patients who have undergone bariatric surgery, or to limit the number of painful intramuscular injections in older people.[94][104]​ ​

Sublingual and intranasal cyanocobalamin are generally not used in the treatment of vitamin B12 deficiency due to limited evidence and limited knowledge regarding optimal dosing.[105][106][107]​​

Patients presenting with severe symptoms

Patients presenting with severe haematological (pancytopenia and marked symptomatic anaemia) or neurological (sub-acute combined spinal degeneration, dementia, or cognitive impairment) symptoms of vitamin B12 deficiency require hospital admission and acute and urgent treatment.[108]

Patients with symptomatic anaemia and pancytopenia require hospital admission and haematological consultant referral, and, rarely, may require red blood cell (RBC) transfusion. If there are signs of congestive cardiac failure, cardiac monitoring is advised and packed RBCs should be given together with low-dose diuretic therapy. An acute regimen of parenteral cyanocobalamin is given until significant reticulocytosis is seen in the bone marrow.[109] Folic acid supplementation may help reverse the haematological abnormalities.

Replacement therapy may potentially improve cognition outcomes in patients with noted cognitive impairment and vitamin B12 deficiency.[110]​ 

Patients with severe neurological symptoms may require neurological and psychogeriatric referral and evaluation while commencing the acute parenteral treatment regimen. Unfortunately, neurological disease associated with vitamin B12 deficiency may be irreversible, despite adequate therapy.[79][80]

Ongoing maintenance treatment is with once-daily oral cyanocobalamin, or once-monthly parenteral cyanocobalamin.

Patients with mild to moderate symptoms

Acute and maintenance treatment of patients with mild to moderate symptoms of vitamin B12 deficiency (e.g., mild anaemia, dysaesthesia/paraesthesias, polyneuropathy, depression) is with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin, depending on clinician preference.

Patients treated with oral cyanocobalamin should respond within 8 weeks. If serum vitamin B12 does not rise significantly after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.

Asymptomatic or borderline deficiency in high-risk patients

High-risk patients (e.g., older patients, and those with restrictive diets or chronic GI illness) should be monitored for vitamin B12 deficiency. Treatment with oral or parenteral cyanocobalamin should be considered, even if they are asymptomatic. This is because the haematological and neurological complications of vitamin B12 deficiency may be irreversible once they develop. In the UK, guidelines recommend considering an empirical trial of treatment with low-dose cyanocobalamin for 1 month in patients with serum cobalamin levels of borderline (subclinical) deficiency on two occasions.[1]

Older patients (>65 years)

Dietary advice should be given on the importance of eating animal-derived foods (such as meat, fish, eggs, and milk), and taking vitamin B12-containing supplements. Older people who have a poor diet should be counselled that lifelong monitoring and supplements may be required.

Vegan or strict vegetarian diet

Should be counselled to supplement their diet with appropriate vitamin B12-fortified foods and supplements containing vitamin B12 in order to meet the recommended dietary allowance of 2.4 micrograms/day.[72][111]

Chronic GI illness

Patients with a chronic GI illness at high risk of vitamin B12 deficiency (e.g., extensive ileal disease, ileal surgery) should be monitored annually for vitamin B12 deficiency.[112][113]

Patients with a chronic GI illness that can cause malabsorption or inadequate absorption (e.g., pernicious anaemia, Crohn's disease with more than 20 cm of terminal ileum resected, coeliac disease), or who have undergone gastric surgery or terminal ileectomy, may be treated with parenteral or oral cyanocobalamin.[1][114]​ Guidelines recommend parenteral administration, based on expert opinion.[114]

Bariatric surgery

Patients who have had bariatric surgery may not be able to adequately maintain serum vitamin B12 levels with vitamin B12-containing supplements.​[115] US guidance recommends oral, parenteral, or intranasal cyanocobalamin to prevent deficiency.[94]​ European guidance recommends vitamin B12 supplementation in addition to multivitamins.[116]

An oral multivitamin supplement optimised for bariatric surgery has shown potential benefit in reducing vitamin deficiencies following Roux-en-Y gastric bypass surgery, but the evidence is limited.[117]

Pregnancy and breastfeeding

Up to 20% to 30% of pregnant women may be at risk for vitamin B12 deficiency.[11]​ Deficiency found in pregnancy should be treated, even if the woman is asymptomatic, because deficiency may be associated with adverse risk for preterm delivery and lower birth weight.[11][29]​​[71]​​ Treatment of pregnant women is generally the same as for non-pregnant patients.

Evidence is unclear as to whether vitamin B12 supplementation affects pregnancy outcomes, or maternal and child health outcomes.[118]​ Studies included in the Cochrane review were not designed to evaluate the effects of maternal vitamin B12 supplementation on specific pregnancy outcomes; they may not have been sufficiently powered to evaluate these outcomes.

Pregnant and breastfeeding women who have a strict vegetarian or vegan diet should be counselled about adequate intake of vitamin B12 and supplementation.[29]​ Breastfeeding women who adhere to a vegan diet will only provide adequate vitamin B12 for their infant if the mother satisfies vitamin B12 requirements through supplementation.[119]

Monitoring response to treatment

Brisk bone marrow reticulocytosis occurs within 1-2 weeks of initiating treatment in patients with severe anaemia due to vitamin B12 deficiency.

Other markers of deficiency, including methylmalonic acid, homocysteine, and mean corpuscular volume, should normalise in 8 weeks with adequate treatment. Serum vitamin B12 (serum cobalamin) levels should return to normal before starting maintenance therapy.

Maintenance therapy

Most patients with vitamin B12 deficiency require lifelong maintenance therapy with once-daily oral cyanocobalamin, or once-monthly parenteral cyanocobalamin.

Oral cyanocobalamin is generally well tolerated for maintenance. Parenteral cyanocobalamin is often reserved for those who cannot take daily pills or have documented failure to oral therapy. Parenteral cyanocobalamin may also be considered when there are concerns about adherence to oral vitamin B12 replacement therapy.[120]

Some clinicians may attempt to lower the effective dose of maintenance oral cyanocobalamin. Periodic monitoring after replacement may be able to identify patients who may maintain serum levels with oral doses <1000 micrograms/day.[121] However, absorption may be variable, and some patients may experience less than maximal clinical and laboratory response with oral cyanocobalamin doses <1000 micrograms/day.[122][123][124]

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