Vitamin B-12 Therapy

Number: 0536

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses vitamin B-12 therapy.

1. Medical Necessity

   Aetna considers the following interventions medically necessary:

   1. Intramuscular or subcutaneous vitamin B-12 injections

      Intramuscular or subcutaneous vitamin B-12 injections only for members with current or previously documented B-12 deficiency and any of the following diagnoses and conditions:

      1. Anemia

         1. Fish tapeworm anemia; or
         2. Macrocytic anemia; or
         3. Megaloblastic anemia; or
         4. Pernicious anemia (Addisonian anemia, Biermer’s anemia); or

      2. Gastrointestinal Disorders

         1. Conditions associated with decreased production of intrinsic factor; or
         2. Malabsorption syndromes (e.g. sprue, idiopathic steatorrhea, and other malabsorption syndromes); or
         3. Surgical or mechanical disorders (e.g., gastrectomy (subtotal or total), blind loop syndrome, intestinal anastomosis, intestinal strictures, and resection of the small intestine)Footnote1*; or

      3. Neuropathy

         1. Acute phase or acute exacerbation of a neuropathy due to malnutrition or alcohol use disorderFootnote1*; or
         2. Neuropathies associated with pernicious anemia (Addisonian anemia, Biermer’s anemia); or
         3. Posterolateral sclerosis; or
      4. Dementia Secondary - dementia secondary to vitamin B-12 deficiency; or
      5. Homocystinuria; or
      6. Methotrexate or Pralatrexate - members receiving methotrexate or pralatrexate (Folotyn)Footnote1*; or
      7. Pemetrexed (Alimta) - members receiving pemetrexed (Alimta)Footnote1*; or
      8. Metformin - members with vitamin B-12 deficiency due to use of metformin that is not corrected by oral vitamin B-12; or
      9. Methylmalonic aciduria; or
      10. Tobacco Amblyopia - retrobulbar neuritis associated with heavy smoking, also known as tobacco amblyopia.

      Physician administration of intramuscular or subcutaneous vitamin B-12 injections is considered medically necessary for the diagnoses and conditions listed above. 

      Intramuscular or subcutaneous administration of vitamin B-12 injections for more than 2 to 3 months is subject to review to ascertain if deficiency/abnormalities have improved and to decide whether continued treatment is medically necessary. 

      Footnote1*Documentation of B-12 deficiency is not required in these circumstances. 

   2. Homocysteine

      Measurement of serum homocysteine in persons with borderline vitamin B-12 deficiency, where the results will impact the member's management. 

2. Experimental, Investigational, or Unproven

   Aetna considers the following interventions experimental, investigational, or unproven because the effectiveness of these approaches has not been established:

   1. Vitamin B-12 injections

      Vitamin B-12 injections for all other indications not listed as medically necessary above, including use for the treatment of the following because there is insufficient evidence in the peer-reviewed literature to support the use of B-12 injections for these indications:

      1. Age-related cataract
      2. Amyotrophic lateral sclerosis
      3. Autism
      4. Chronic fatigue syndrome (myalgic encephalomyelitis)
      5. Delayed sleep-wake phase disorder
      6. Non-24-hour sleep-wake rhythm disorder
      7. Depression
      8. Diabetic peripheral neuropathy
      9. Elevated homocysteine in persons not diagnosed with homocysteinuria
      10. Fibromyalgia
      11. Hidradenitis suppurativa
      12. Impaired cognitive function (except for dementia secondary to vitamin B-12 deficiency)
      13. Individuals with MTHFR mutation
      14. Peripheral entrapment neuropathies (e.g., carpal tunnel syndrome)
      15. Post-herpetic neuralgia
      16. Tinnitus
      17. Vasodilatory shock (septic shock)
      18. For the prevention of osteoporotic fracture
      19. For prophylaxis of headache disorders including migraines
      20. For the reduction of cardiovascular risks
      21. For the prevention of stroke
      22. As adjunctive therapy for weight loss.

   2. Holotranscobalamin

      Measurements of holotranscobalamin (a biologically active vitamin B-12 fraction) for the diagnosis of vitamin B-12 deficiency because its clinical value has not been established.

3. Policy Limitations and Exclusions

   Note: Most Aetna plans exclude coverage of nutritional supplements. Under these plans, Aetna does not cover charges for oral vitamins that can be purchased without a prescription, or for oral vitamins that are prescribed solely as a dietary supplement even if a physician’s prescription is needed for purchase. Please check benefit plan descriptions.

4. Related Policies

   • CPB 0348 - Recurrent Pregnancy Loss
   • CPB 0381 - Cardiac Disease Risk Tests
   • CPB 0562 - Biochemical Markers of Bone Remodeling
   • CPB 0763 - Homocysteine Testing

Background

Vitamin B-12 belongs to the family of cobalamins.  It is available in all animal-derived foods, and is absorbed at a rate of 5 mcg per day.  After being ingested, vitamin B-12 becomes bound to intrinsic factor, a protein secreted by gastric parietal cells.  The vitamin B-12/intrinsic factor complex is absorbed in the terminal ileum by cells with specific receptors for the complex.  The absorbed complex is then transported via plasma and stored in the liver.  Since the liver stores 2,000 to 5,000 mcg vitamin B-12 (adequate for up to 5 years), dietary deficiency of cobalamin (Cbl) is rare.  In most cases, vitamin B-12 deficiency is due to an inability of the intestine to absorb the vitamin, which may result from an autoimmune disease that reduces the production or blocks the action of intrinsic factor, or from other diseases that result in intestinal malabsorption.  The most frequent underlying cause of vitamin B-12 deficiency is pernicious anemia, which is associated with decreased production of intrinsic factor.  Abdominal surgery may cause Cbl deficiency in several ways: gastrectomy eliminates the site of intrinsic factor production; blind loop syndrome results in competition for vitamin B-12 by bacterial overgrowth in the lumen of the small intestine; and surgical resection of the ileum eliminates the site of vitamin B-12 absorption.  Rare causes of vitamin Cbl deficiency include pancreatic insufficiency; fish tapeworm infection, in which the parasite uses luminal vitamin B-12; and severe Crohn’s disease, resulting in reduced ileal absorption of vitamin B-12.

Cobalamin deficiency is more common in the elderly primarily because of the increasing prevalence with age of Cbl malabsorption due to autoimmune atrophic gastritis.

Most patients with overt Cbl deficiency report serum vitamin B-12 levels of less than 100 pg/ml.  The hallmark of vitamin B-12 deficiency is megaloblastic anemia.  Vitamin B-12 deficiency also leads to neurological deficits including paresthesias, sensory loss, ataxia, disequilibrium, diminished or hyperactive reflexes, and spasticity.  In more advanced cases, cerebral function may also be affected resulting in disturbances of mood, psychoses, and dementia.

In a systematic review of randomized trials on vitamin B-6, B-12, and folic acid supplementation and cognitive function, Balk and colleagues (2007) stated that despite their important role in cognitive function, the value of B vitamin supplementation is unknown.  A total of 14  trials met selection criteria; most were of low quality and limited applicability.  Approximately 50 different cognitive function tests were assessed.  Three trials of vitamin B-6 and 6 of vitamin B-12 found no effect overall in a variety of doses, routes of administration, and populations.  One of 3 trials of folic acid found a benefit in cognitive function in people with cognitive impairment and low baseline serum folate levels.  Six trials of combinations of the B vitamins all concluded that the interventions had no effect on cognitive function.  Among 3 trials, those in the placebo arm had greater improvements in a small number of cognitive tests than participants receiving either folic acid or combination B-vitamin supplements.  The evidence was limited by a sparsity of studies, small sample size, heterogeneity in outcomes, and a lack of studies that evaluated symptoms or clinical outcomes.  The authors concluded that there is insufficient evidence of an effect of vitamin B-6, B-12, or folic acid supplementation, alone or in combination, on cognitive function testing in people with either normal or impaired cognitive function.  This is in agreement with Clarke et al (2007) who stated that randomized trials are needed to ascertain the relevance of vitamin B-12 supplementation for the prevention of dementia.

In a randomized, double-blind, placebo-controlled trial, Albert et al (2008) examined if a combination of folic acid, vitamin B-6, and vitamin B-12 lowers risk of cardiovascular disease (CVD) among high-risk women with and without CVD.  A total of 5,442 women aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, were enrolled in this study.  Subjects received a combination pill containing 2.5 mg folic acid, 50 mg vitamin B-6, and 1 mg vitamin B-12 or a matching placebo, and were treated for 7.3 years.  Main outcome measures were a composite outcome of myocardial infarction, stroke, coronary re-vascularization, or CVD mortality.  Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group).  Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person-years versus 219.2/10,000 person-years for the active versus placebo group; relative risk [RR], 1.03; 95 % confidence interval [CI]: 0.90 to 1.19; p = 0.65), as well as for the secondary outcomes including myocardial infarction (34.5/10,000 person-years versus 39.5/10,000 person-years; RR, 0.87; 95 % CI: 0.63 to 1.22; p = 0.42), stroke (41.9/10,000 person-years versus 36.8/10,000 person-years; RR, 1.14; 95 % CI: 0.82 to 1.57; p = 0.44), and CVD mortality (50.3/10,000 person-years versus 49.6/10,000 person-years; RR, 1.01; 95 % CI: 0.76 to 1.35; p = 0.93).  In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5 % (95 % CI: 12.5% to 24.1%; p < 0.001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 micromol/L (95 % CI: 1.54  to 2.96 micromol/L).  The authors concluded that after 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B-6, and vitamin B-12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering.

Vitamin B-12 therapy can be administered orally or by injection.  Vitamin B12 tablets of up to 5,000 mcg may be obtained over the counter without a prescription. 

In a review on vitamin B-12 deficiency, Oh and Brown (2003) noted that, because most clinicians are generally unaware that oral vitamin B-12 therapy is effective, the traditional treatment for B-12 deficiency has been intramuscular injections.  The authors cited evidence that demonstrates, however, that oral vitamin B-12 has been shown to have an efficacy equal to that of injections in the treatment of pernicious anemia and other B-12 deficiency states (Elia, 1998; Lederle, 1998; Kuzminski et al, 1998; Lederle, 1991).   The authors explained that, although the majority of dietary vitamin B-12 is absorbed in the terminal ileum through a complex with intrinsic factor, there is mounting evidence that approximately 1 % of a large dose of oral vitamin B-12 is absorbed by simple diffusion which is independent of intrinsic factor or even an intact terminal ileum.

Kuzminzki et al (1998) reported on the outcome of 33 patients with vitamin B-12 deficiency who were randomized to receive oral or parenteral vitamin B-12 therapy.  Patients in the parenteral therapy group received 1,000 mcg of vitamin B-12 intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90, while those in the oral treatment group received 2,000 mcg daily for 120 days.  At the end of 120 days, patients who received oral therapy had significantly higher serum vitamin B-12 levels and lower methylmalonic acid levels than those in the parenteral therapy group.

Adachi et al (2000) reported the results of a study that showed that even in patients who had undergone gastrectomy, vitamin B-12 deficiency could be easily reversed with oral supplementation.

Oh and Brown (2003) explained that intramuscular injections have several drawbacks. Injections are painful, medical personnel giving the injections are placed at risk of needlestick injuries, and administration of intramuscular injections often adds to the cost of therapy.

Lane and Rojas-Fernandez (2002) reported on a meta-analysis of studies of oral versus parenteral therapy for vitamin B-12 deficiency.  The investigators concluded that daily oral vitamin B-12 at doses of 1,000 to 2,000 mcg can be used for treatment in most cobalamin-deficient patients who can tolerate oral supplementation. The investigators noted, however, that there are inadequate data at the present time to support the use of oral vitamin B-12 replacement in patients with severe neurologic involvement.  The investigators explained that oral cyanocobalamin replacement may not be adequate for a patient presenting with severe neurologic manifestations that could have devastating consequences if the most rapid-acting therapy is not used immediately. Therefore, parenteral cobalamin is preferable in neurologically symptomatic patients until resolution of symptoms and hematologic indices.

Although the daily requirement of vitamin B-12 is approximately 2 mcg, the initial oral replacement dosage consists of a single daily dose of 1,000 to 2,000 mcg (Lederle, 1991; Oh and Brown, 2003).  This high dose is required because of the variable absorption of oral vitamin B-12 in doses of 500 mcg or less.  This regimen has been shown to be safe, cost-effective, and well tolerated by patients.

Treatment schedules for intramuscular administration vary widely but usually consist of initial loading doses followed by monthly maintenance injections.  Little (1999) recommended an initial treatment of intramuscular injections of vitamin B-12 1,000 mcg daily for 5 days, followed by 1,000 mg weekly for 4 weeks, and a maintenance therapy of 1,000 mcg every 1 to 3 months.  Intramuscular injections of Cbl are well-tolerated. 

Hematological improvements should commence within 5 to 7 days, and the deficiency should resolve after 3 to 4 weeks of therapy.  However, 6 months or longer of Cbl treatment may be needed before appearance of signs of improvement in neurological manifestations of vitamin B-12 deficiency.  Total or partial resolution of neurological deficits has been reported in as many as 80 % of patients (Healton et al, 1991).  Neurological improvement is less likely to occur in patients with severe or longstanding deficiency, and in patients with less severe accompanying anemia.

Guidelines from the British Columbia Medical Association (2003) state that "[o]ral doses of vitamin B12 are as effective as parenteral administration in treating deficiency in most cases."  The guidelines include the following recommendation: “Oral replacement of vitamin B12 is the treatment of choice in most cases, including pernicious anemia.  Patients with significant neurological deficits, however, should receive initial intramuscular injections of 1,000 micrograms vitamin B12, followed by oral doses of 1,000-2,000 micrograms/day.  The duration of therapy depends on the cause of deficiency.  In pernicious anemia treatment is life-long.  Early treatment of vitamin B12 deficiency is particularly important because neurologic symptoms may be irreversible.”

1. it measures total, not metabolically active cobalamin;
2. the levels of cobalamin do not correlate well with clinical symptoms; elderly patients may have normal cobalamin levels with clinically significant cobalamin deficiency, while women taking oral contraceptives may have decreased blood cobalamin levels due to a decrease in transcobalamin, a carrier protein, but no clinical symptoms of deficiency;
3. there is a large ‘gray zone’ between the normal and abnormal levels;
4. the reference intervals may vary between laboratories.

The guidelines state that the conventional cut-off for serum cobalamin deficiency varies from 150-220 pmol/L. Using a more common cut-off of 220 pmol/L, the guidelines recommend the following interpretation:

The British Columbia Guidelines and Protocols Advisory Committee (2012) states that oral crystalline cyanocobalamin (commonly available form) is the treatment of choice. Dosing for pernicious anemia or food-bound cobalamin malabsorption is 1000 mcg/day. In most other cases a dose of 250 mcg/day may be used. The guidelines state that oral administration of cobalamin is as effective as parenteral. Advantages of oral supplementation mentioned in the guidelines are comfort, ease of administration, and cost. The guidelines state that prophylactic cobalamin supplementation is recommended for strict vegans and patients with food bound cobalamin malabsorption, and for pernicious anemia. The usefulness of prophylactic administration of cobalamin in elderly is unknown. The guidelines state that parenteral administration should be reserved for those with significant neurological symptoms. It includes 1-5 intramuscular or subcutaneous injections of 1000 mcg crystalline cyanocobalamin daily, followed by oral doses of 1000-2000 mcg/day. The guidelines recommend retesting serum cobalamin levels after 4-6 months to ensure they are in the normal range.

In general, the medically necessary initial parenteral dose for medically necessary diagnoses (other than pemetrexed administration, see below) consists of 1,000 mcg vitamin B-12 daily for 5 days, then 1,000 mg weekly for 4 weeks.  For maintenance therapy, 1,000 mcg every 1 to 3 months is usually medically necessary.  Requests for vitamin B-12 injections more frequently than the schedule stated above is subject to medical review.

Pemetrexed disodium (Alimta) was approved by the Food and Drug Administration (FDA) on February 5, 2004.  It is the first drug approved for mesothelioma.  The recommended dose of Alimta is 500 mg/m2 administered as an intravenous infusion over 10 mins on day 1 of each 21-day cycle.  Patients must take daily doses of folic acid and vitamin B-12 to reduce the severity of side effects such as low white blood cell count, nausea, vomiting, fatigue, rash, and diarrhea.  Patients must receive 1 intra-muscular injection of 1,000 µg vitamin B-12 during the week preceding the first dose of Alimta and every 3 cycles thereafter.

Sanchez-Moreno et al (2009) noted that several studies have reported benefits on lowering the risk of stroke and improving the post-stroke-associated functional declines in patients who ate foods rich in micronutrients, including B vitamins and antioxidant vitamins E and C.  Folic acid, vitamin B-6 and vitamin B-12 are all co-factors in homocysteine metabolism.  Growing interest has been paid to hyper-homocysteinemia as a risk factor for cardiovascular disease.  Hyper-homocysteinemia has been linked to inadequate intake of vitamins, particularly to B-group vitamins and therefore may be amenable to nutritional intervention.  Hence, poor dietary intake of folate, vitamin B-6 and vitamin B-12 are associated with increased risk of stroke.  Elevated consumption of fruits and vegetables appears to protect against stroke.  Antioxidant nutrients have important roles in cell function and have been implicated in processes associated with ageing, including vascular, inflammatory and neurological damage.  Plasma vitamin E and C concentrations may serve as a biological marker of lifestyle or other factors associated with reduced stroke risk and may be useful in identifying those at high risk of stroke.  After reviewing the observational and intervention studies, there is an incomplete understanding of mechanisms and some conflicting findings; therefore the available evidence is insufficient to recommend the routine use of B vitamins, vitamin E and vitamin C for the prevention of stroke.  A better understanding of mechanisms, along with well-designed controlled clinical trials will allow further progress in this area.

Scott (2010) stated that "[v]itamin B12 has been touted as an energy enhancer and metabolism booster.  These claims are based on the fact that correcting vitamin B12 deficiency should improve the associated symptoms of fatigue and weakness; however, in the absence of a nutritional deficit, vitamin B12 supplementation does not affect physical performance.  No form of vitamin B12 (intra-muscular, oral, or other routes) has been credibly tested as an aid to weight loss.  A search of MEDLINE using the search terms "cyanocobalamin or vitamin B12" and "weight loss ordiet" yielded no clinical studies using vitamin B12 supplements.  Although no adverse effects have been associated with excess vitamin B12 intake from food and supplements in healthy people, weight loss programs that promote vitamin B12, particularly in injectable form, suggest treatment that is not based on sound evidence".

In a pilot study, Bertoglio and colleagues (2010) examined if methyl B-12 treatment improves behavioral measures in children with autism and whether improvement is associated with increased plasma concentrations of glutathione (GSH) and an increased redox ratio of reduced glutathione to oxidized glutathione (GSH/GSSG), both of which have been previously identified to be low in children with autism.  This was a 12-week, double-blind, placebo-controlled, cross-over clinical trial of injectable methyl B-12.  Following this 12-week study, subjects were given the option of entering a 6-month open-label trial of methyl B-12.  Subjects were 3 to 8 years old with autism.  All subjects received 6 weeks of placebo and 6 weeks of methyl B-12 at a dose of 64.5 mcg/kg every 3 days administered subcutaneously into the buttocks.  Blood for GSH analysis and behavioral assessments were obtained at baseline, week 6, and week 12.  A total of 30 subjects completed the 12-week, double-blind study, and 22 subjects completed the 6-month extension study.  No statistically significant mean differences in behavior tests or in glutathione status were identified between active and placebo groups.  Nine subjects (30 %) reported clinically significant improvement on the Clinical Global Impression Scale and at least 2 additional behavioral measures.  More notably, these responders exhibited significantly increased plasma concentrations of GSH and GSH/GSSG.  The authors concluded that comparison of the overall means between groups suggests that methyl B-12 is ineffective in treating behavioral symptoms of autism.  However, detailed data analysis suggests that methyl B-12 may alleviate symptoms of autism in a subgroup of children, possibly by reducing oxidative stress.  An increase in glutathione redox status (GSH/GSSG) may provide a biomarker for treatment response to methyl B-12.  They stated that additional research is needed to delineate a subgroup of potential responders and ascertain a biomarker for response to methyl B-12.

O'Leary et al (2012) noted that poor vitamin B-12 status may lead to the development of cognitive decline and dementia but there is a large variation in the quality, design of and results reported from these investigations.  These researchers performed a systematic review of the evidence for the association between vitamin B-12 status and cognitive decline in older adults.  A database search of the literature to 2011 was undertaken, using keywords related to vitamin B-12 and cognition.  All prospective cohort studies assessing the association of serum vitamin B-12 or biomarkers were included.  Quality assessment and extraction of the data were undertaken by 2 researchers.  The quality assessment tool assigns a positive, neutral or negative rating.  Of 3,772 published articles, 35 cohort studies (14,325 subjects) were identified and evaluated.  No association between serum vitamin B-12 concentrations and cognitive decline or dementia was found.  However, 4 studies that used newer biomarkers of vitamin B-12 status (methylmalonic acid and holoTC) showed associations between poor vitamin B-12 status and the increased risk of cognitive decline or dementia diagnosis.  In general, the studies were of reasonable quality (21 positive, 10 neutral and 4 negative quality) but of short duration and inadequate subject numbers to determine whether an effect exists.  The authors concluded that future studies should be of adequate duration (at least 6 years), recruit subjects from the 7th decade, choose markers of vitamin B-12 status with adequate specificity such as holoTC and/or methylmalonic acid and employ standardized neurocognitive assessment tools and not screening tests in order to ascertain any relationship between vitamin B-12 status and cognitive decline.

Doets et al (2013) stated that current recommendations on vitamin B-12 intake vary from 1.4 to 3.0 μg per day and are based on the amount needed for maintenance of hematologic status or on the amount needed to compensate obligatory losses.  In a systematic review, these investigators evaluated whether the relation between vitamin B-12 intake and cognitive function should be considered for under-pinning vitamin B-12 recommendations in the future.  The authors summarized dose-response evidence from randomized controlled trials (RCTs) and prospective cohort studies on the relation of vitamin B-12 intake and status with cognitive function in adults and elderly people.  Two RCTs and 6 cohort studies showed no association or inconsistent associations between vitamin B-12 intake and cognitive function.  Random-effects meta-analysis showed that serum/plasma vitamin B-12 (50 pmol/L) was not associated with risk of dementia (4 cohort studies), global cognition z scores (4 cohort studies), or memory z scores (4 cohort studies).  Although dose-response evidence on sensitive markers of vitamin B-12 status (methylmalonic acid and holotranscobalamin) was scarce, 4 of 5 cohort studies reported significant associations with risk of dementia, Alzheimer's disease, or global cognition.  The authors concluded that current evidence on the relation between vitamin B-12 intake or status and cognitive function is not sufficient for consideration in the development of vitamin B-12 recommendations.  They stated that further studies should consider the selection of sensitive markers of vitamin B-12 status.

Current biochemical markers of vitamin B-12 deficiency include methylmalonic acid (MMA), homocysteine (Hcy) and cobalamin.  Serum concentrations of MMA and Hcy are increased in B-12-deficient patients due to inhibition of methylmalonyl-CoA mutase and methionine synthase, respectively.  Some authorities have recommended measurement of Hcy and MMA in persons with borderline vitamin B-12 deficiency, although it is usually easier to treat such cases with oral vitamin B-12 (BCMA, 2003).

In an editorial that addressed whether clinicians should routinely measure Hcy levels and treat patients with mild hyperhomocysteinemia, Rosenberg and Mulrow (2006) stated that clinicians need not routinely measure Hcy levels nor routinely treat mild hyperhomocysteinemia with folic acid or vitamin B supplementation.

Although total serum cobalamin is used to diagnose B-12 deficiency, it may not reliably indicate vitamin B-12 status.  A normal serum cobalamin concentration does not reliably rule out a functional cobalamin deficiency.  Previous studies have reported problems of sensitivity and specificity with this test (Green, 1996; Stabler, 1998).  On the other hand, serum level of holotranscobalamin (holoTC), a metabolically active cobalamin bound to the transport protein transcobalamin, becomes reduced prior to the development of metabolic dysfunction.  To enhance the sensitivity and specificity in diagnosing vitamin B-12 deficiency, some investigators have advocated measuring holoTC.  This is performed by giving a small oral dose of vitamin B-12 and assessing the subsequent increase in the amount of holoTC in the serum.  However, there is currently no gold standard or true reference method to diagnose subtle vitamin B-12 deficiency, which makes evaluation of the clinical usefulness of holoTC and the estimation of sensitivity and specificity problematic. 

The causes of vitamin B-12 deficiency in the elderly are only partly understood.  van Asselt and colleagues (2003) examined the role of the cobalamin-binding proteins regarding B-12 deficiency in older people, and tested the hypothesis that low saturated transcobalamin concentration is an early marker of B-12 deficiency.  Saturated (holo) and unsaturated (apo) transcobalamin and haptocorrin concentrations were measured in healthy middle-aged volunteers, healthy older volunteers, cobalamin-deficient older volunteers and cobalamin-deficient older patients.  Holo and apo concentrations of transcobalamin and haptocorrin were similar in healthy middle-aged and older subjects.  HoloTC concentrations were significantly reduced in cobalamin-deficient subjects but did not differ between healthy volunteers and patients.  Furthermore, the relative amount of cobalamin on transcobalamin was similar in all four groups.  These researchers concluded that abnormalities of the cobalamin-binding proteins are not a cause of vitamin B12 deficiency in the elderly.  Plasma holoTC concentration did not differ between stages of vitamin B12 deficiency in the elderly.  As a result, plasma holoTC is not an early marker of vitamin B12 deficiency in the elderly and has no additional value in the diagnostic work-up of reduced plasma cobalamin concentrations in older people.

Nilsson et al (2004) examined if low holoTC concentrations are congruent with other biochemical signs of cobalamin deficiency in a group of psychogeriatric patients.  The findings in their study showed that holoTC is strongly related to serum cobalamin (0.68; p < 0.001 in both patients and controls).  Distribution of the different markers for cobalamin/folate status in the 33 patients with low levels of serum holoTC (below 40 pmol/L) showed that 17 patients had normal levels of the other markers for cobalamin status.  This may indicate poor specificity of low holoTC for cobalamin deficiency.  In 23 out of 176 patients with normal levels of holoTC, pathological levels of other markers for cobalamin deficiency was observed.  The use of holoTC did not provide significant additional information other than that given by serum cobalamin and thus can not be recommended in this clinical setting.

Loikas et al (2003) assessed a commercial holoTC radioimmunoassay, determined reference values, and evaluated holoTC concentrations in relation to other biochemical markers of vitamin B-12 deficiency.  The reference population consisted of 303 subjects 22 to 88 years of age, without disease or medication affecting cobalamin or Hcy metabolism.  In elderly individuals (65 years or older), normal B-12 status was further confirmed by total Hcy (less than 19 micro mol/L) and MMA (less than 0.28 umol/L) concentrations within established reference intervals.  HoloTC in B12 deficiency was studied in a population of 107 elderly individuals with normal renal function.  B-12 deficiency was graded as potential (total vitamin B12 of 150 pmol/L or less; or total Hcy of 19 umol/L or more), possible (total B-12 of 150 pmol/L or less; AND either total Hcy of 19 micro mol/L or more, or MMA of 0.45 umol/L or more), and probable (total Hcy of 19 umol/L or more, AND MMA of 0.45 umol/L or more).  These investigators concluded that the holoTC radioimmunoassay is precise and simple to perform.  Low holoTC is found in persons with biochemical signs of vitamin B-12 deficiency, but the sensitivity and specificity of low holoTC in diagnosis of vitamin B-12 deficiency need to be further evaluated.

In a prospective study, Serefhanoglu et al (2008) assessed circulating holoTC to estimate the diagnosis of vitamin B-12 deficiency in the first ischemic cerebrovascular attack.  These researchers also compared the efficacy of the measurement of plasma holoTC with the other standard biochemical and hematological markers used to reach the diagnosis of Cbl deficiency.  A total of 45 patients (age 71 years; range of 35 to 90; 16 men and 29 women) within the first ischemic cerebrovascular event were included in this study.  All the enrolled patients received 1-mg vitamin B-12 intramuscular injection once-daily for 10 days.  At the baseline and on the 10th day of treatment, plasma levels of holoTC and the proper biochemical and hematological markers in diagnosing Cbl deficiency were measured.  After admission, anemia and diminished serum vitamin B-12 levels were determined to be only 20 % (9/45) and 44 % (20/45), respectively; 78 % (35/45) of the patients had low serum holoTC (less than 37 pmol/L).  Serum Hcy was higher in patients (49 % of them) who had suffered a stroke.  Thrombocytopenia, hyper-segmentated neutrophils, and indirect hyper-bilirubinemia were observed in 20 % of the patients.  Leukopenia and macrocytosis were not evident in any of them.  In 18 of 27 patients (67 %) that had low holoTC levels after joining the study and who remained in the study until the end of Cbl treatment, serum holoTC levels returned to normal values.  Cobalamin deficiency should be considered in patients with CVD, even if anemia, elevated mean cell volume, depression of the serum Cbl, or other classic hematological and/or biochemical abnormalities are lacking.  The authors noted that measurement of serum holoTC looks promising as a 1st-line of tests for diagnosing early vitamin B-12 deficiency.

In summary, the usefulness of holoTC in diagnosing B-12 deficiency in various clinical settings has not been established.  Large-scale clinical studies are needed to determine the clinical value of holoTC.

Regland et al (2015) noted that patients with myalgic encephalomyelitis (ME, also called chronic fatigue syndrome) may respond most favorably to frequent vitamin B-12 injections, in vital combination with oral folic acid.  However, there is no established algorithm for individualized optimal dosages, and rate of improvement may differ considerably between responders.  These researchers evaluated clinical data from patients with ME, with or without fibromyalgia, who had been on B-12 injections at least once-weekly for 6months and up to several years.  A total of 38 patients were included in a cross-sectional survey.  Based on a validated observer's rating scale, they were divided into good (n = 15) and mild (n = 23) responders, and the 2 groups were compared from various clinical aspects.  Good responders had used significantly more frequent injections (p < 0.03) and higher doses of B-12 (p < 0.03) for a longer time (p < 0.0005), higher daily amounts of oral folic acid (p < 0.003) in good relation with the individual MTHFR genotype, more often thyroid hormones (p < 0.02), and no strong analgesics at all, while 70 % of mild responders (p < 0.0005) used analgesics such as opioids, duloxetine or pregabalin on a daily basis.  In addition to ME, the higher number of patients with fibromyalgia among mild responders was bordering on significance (p < 0.09).  Good responders rated themselves as "very much" or "much" improved, while mild responders rated "much" or "minimally" improved.  The authors concluded that dose-response relationship and long-lasting effects of B-12/folic acid support a true positive response in the studied group of patients with ME/fibromyalgia.  It's important to be alert on co-existing thyroid dysfunction, and the authors suspected a risk of counteracting interference between B-12/folic acid and certain opioid analgesics and other drugs that have to be demethylated as part of their metabolism.  These issues should be considered when controlled trials for ME and fibromyalgia are to be designed.  This was a small study (n = 38) and its findings were confounded by the combinational use of B-12 injection and oral folic acid.  These preliminary findings need to be validated by well-designed studies.

UpToDate reviews on “Initial treatment of fibromyalgia in adults” (Goldenberg, 2015a), “Treatment of fibromyalgia in adults not responsive to initial therapies” (Goldenberg, 2015b), “Fibromyalgia in children and adolescents: Treatment and prognosis” (Kimura and Walco, 2015) do not mention vitamin B-12 injection as a therapeutic option.

Furthermore, an UpToDate review on “Treatment of chronic fatigue syndrome (systemic exertion intolerance disease)” (Gluckman, 2015) states that “A number of medications and special diets have been evaluated in patients with CFS/SEID, but none has proved successful.  Among the modalities that have been tried are immune serum globulin, rituximab, acyclovir, galantamine, fluoxetine and other antidepressants, methylphenidate and modafinil (stimulants), glucocorticoids, amantadine, doxycycline, magnesium, evening primrose oil, vitamin B12, Ampligen, essential fatty acids, bovine or porcine liver extract, dialyzable leukocyte extract, cimetidine, ranitidine, interferons, exclusion diets, BioBran MGN-3 (a natural killer cell stimulant), and removal of dental fillings.  Only a few of these approaches have been tested in controlled trials.  A major problem with evaluating the effect of therapy in CFS/SEID is that the symptoms fluctuate over time, may remit spontaneously, and are subject to substantial response rates to placebo”.

Prevention of Osteoporotic Fracture

Ruan and colleagues (2015) stated that B vitamins (including folate, B-6, and B-12) supplementation can modify high plasma Hcy. However, the role of Hcy in the pathogenesis of osteoporotic fracture and bone turnover is still controversial.  In a meta-analysis, these investigators evaluated the impact of B vitamin supplementation on occurrence of any osteoporotic fracture and bone turnover by pooling the results of previous studies.  Relevant RCTs were searched in databases; data integration and analysis were done by using Review Manager 5.3 (the Cochrane Collaboration).  The RR and corresponding 95 % CI of fracture (intervention versus control) were estimated.  Changes in bone turnover indicators (continuous data), weighted mean difference (WMD), and corresponding 95 % CI were pooled for estimation.  Based on the results of 4 RCTs, this meta-analysis failed to identify a risk-reducing effect of daily supplementation of B vitamins on osteoporotic fracture in patients with vascular disease and with relatively normal plasma Hcy.  In addition, these researchers also did not find any positive effects of B vitamin supplementation on bone turnover.  The authors concluded that B vitamin supplementation might not be effective in preventing fracture and improving bone turnover.  However, the possible benefits in selective populations, such as populations with very high plasma Hcy and from regions without B vitamin fortification should be explored in the future.

Treatment of Delayed Sleep-Wake Phase Disorder and Non-24-Hour Sleep-Wake Rhythm Disorder

American Academy of Sleep Medicine’s updated clinical practice guideline on “Treatment of intrinsic circadian rhythm sleep-wake disorders” (Auger et al, 2015) provided the following recommendations:

• There is insufficient evidence to support the use of oral vitamin B12 (and no evidence to support alternate somatic interventions) among patients with delayed sleep-wake phase disorder (DSWPD) (versus no treatment). No recommendation.
• There is insufficient evidence to support the use of oral vitamin B12 (and no evidence to support alternate somatic interventions) among patients with non-24-hour sleep-wake rhythm disorder (N24SWD) (versus no treatment). No recommendation.

Treatment of Depression

In a systematic review, Almeida and associates (2015) examined if, compared with placebo, treatment with folate and/or vitamin B-12 reduces depression scale scores, increases remission, and prevents the onset of clinically significant symptoms of depression in people at risk. These investigators searched the PubMed, PsychInfo, Embase, and Cochrane databases from inception to June 6, 2014, using the following terms and strategy: (vitamin B12 or vitamin B9 or folate or folic acid or cobalamin or cyanocobalamin) and (depression or depressive disorder or depressive symptoms) and (randomized controlled trial or RCT).  The electronic search was supplemented by manual search.  Two independent reviewers assessed all papers retrieved for eligibility and bias, and extracted crude data.  Review Manager 5 was used to manage and analyze the data.  A total of 269 manuscripts were identified, of which 52 were RCTs and 11 fulfilled criteria for review.  These researchers found that the short-term use of vitamins (days to a few weeks) did not contribute to improve depressive symptoms in adults with major depression treated with anti-depressants (5 studies, standardized mean difference = -0.12, 95 % CI: -0.45 to 0.22), but more prolonged consumption (several weeks to years) may decrease the risk of relapse (1 study, OR = 0.33, 95 % CI: 0.12 to 0.94) and the onset of clinically significant symptoms in people at risk (2 studies, RR = 0.65, 95 % CI: 0.43 to 0.98).  The authors concluded that the number of available trials remained small and heterogeneity between studies high.  They stated that the results of these meta-analyses suggested that treatment with folate and vitamin B-12 did not decrease the severity of depressive symptoms over a short period of time, but may be helpful in the long-term management of special populations.

Age-Related Cataract

In a randomized, double-masked, placebo-controlled trial,, Christen and colleagues (2016) examined the incidence of cataract and cataract extraction in a trial of folic acid and vitamins B-6 and B-12.  A total of 5,442 female health professionals aged 40 years or older with pre-existing cardio-vascular disease (CVD) or 3 or more CVD risk factors were randomly assigned to receive a combination of folic acid (2.5 mg/day), vitamin B-6 (50 mg/day), and vitamin B-12 (1 mg/day), or placebo.  A total of 3,925 of these women did not have a diagnosis of cataract at baseline and were included in this analysis.  The primary end-point was age-related cataract, defined as an incident age-related lens opacity, responsible for a reduction in best-corrected visual acuity (BCVA) to 20/30 or worse, based on self-report confirmed by medical record review.  Extraction of incident age-related cataract was a secondary end-point of the trial.  During an average of 7.3 years of treatment and follow-up, 408 cataracts and 275 cataract extractions were documented.  There were 215 cataracts in the combination treatment group and 193 in the placebo group (hazard ratio [HR] 1.10, 95 % CI: 0.90 to 1.33; p = 0.36).  For the secondary end-point of cataract extraction, there were 155 in the combination treatment group and 120 in the placebo group (HR 1.28, 95 % CI: 1.01 to 1.63; p = 0.04).  The authors concluded that in this large-scale randomized trial of women at high risk of CVD, daily supplementation with a combination of folic acid, vitamin B-6, and vitamin B-12 had no significant effect on cataract, but may have increased the risk of cataract extraction.

Prevention of Cognitive Decline in Diabetic Individuals with Borderline Low Serum Vitamin B-12

Kwok and colleagues (2017) noted that older diabetic people are at risk of cognitive decline.  Vitamin B-12 deficiency in older people is associated with cognitive impairment and Alzheimer's disease.  Vitamin B-12 deficiency may therefore contribute to cognitive decline in older diabetic people.  These researchers performed a randomized placebo-controlled trial of vitamin B-12 supplementation to prevent cognitive decline in older diabetic people with mild vitamin B-12 deficiency.  A total of 271 diabetic non-demented out-patients aged 70 years or older with plasma vitamin B-12  of 150 to 300 pmol/L in out-patient clinics were randomly assigned to take either methylcobalamin 1,000 μg or 2 similar looking placebo tablets once-daily for 27 months.  All subjects were followed-up at 9 monthly intervals.  The primary end-point was cognitive decline as defined by an increase in clinical dementia rating scale (CDR) global score.  The secondary outcomes included Neuropsychological Test Battery (NTB) z-scores, serum MMA and Hcy.  The subjects in the trial groups were well-matched in clinical characteristics, except that active intervention group had more smokers; 46.5 % and 74.1 % had elevated serum MMA (greater than or equal to 0.21 μmol/L) and Hcy (greater than or equal to 13 μmol/L) respectively; 44 % of the subjects had CDR score of 0.5 suggesting questionable dementia.  At month 9 and 27, serum MMA and Hcy was significantly reduced in the active treatment group, when compared with placebo group (p < 0.0001, student t-test).  At month 27, there was no significant group difference in changes in CDR or NTB z-scores.  Exclusion of smokers did not alter the results; subgroup analysis of high MMSE and serum MMA showed similar results.  The authors concluded that vitamin B-12 supplementation did not prevent cognitive decline in older diabetic patients with borderline vitamin B-12 status.

Diabetic Peripheral Neuropathy

Jayabalan and Low (2016) stated that vitamin B-12 deficiency has been associated with significant neurological pathology, especially peripheral neuropathy.  These investigators examined the existing evidence on the effectiveness of vitamin B-12 supplementation for the treatment of diabetic peripheral neuropathy (DPN).  They performed a search of PubMed and the Cochrane Central Register of Controlled Trials for all relevant RCTs in December 2014.  Any type of therapy using vitamin B-12 or its co-enzyme forms was evaluated for safety and effectiveness in patients with DPN.  Changes in vibration perception thresholds, neuropathic symptoms and nerve conduction velocities, as well as the adverse effects of vitamin B-12 therapy, were assessed.  A total of 4 studies comprising 363 patients met the inclusion criteria.  The authors concluded that this review found no evidence that the use of oral vitamin B-12 supplements is associated with improvement in the clinical symptoms of DPN.  Furthermore, the majority of studies reported no improvement in the electrophysiological markers of nerve conduction.

Furthermore, and UpToDate review on “Treatment of diabetic neuropathy” (Feldman and McCulloch, 2017) does not mention vitamin B supplementation as a therapeutic option.

In a systematic review and meta-analysis, Sawangjit and colleagues (2020) examined the safety and effectiveness of mecobalamin on peripheral neuropathy.  Relevant electronic databases were systematically searched for RCTs examining the safety and effectiveness of mecobalamin on peripheral neuropathy, from inception through December 2019.  Study selection, data extraction, and quality assessment were conducted independently by 2 reviewers.  The clinical therapeutic efficacy, pain score, neuropathic symptom score, nerve conduction velocities (NCVs), and AEs of mecobalamin were evaluated and were pooled by using a random-effects model.  Heterogeneity was examined by I2 and Chi-squared tests.  A total of 15 studies with 1,707 peripheral neuropathy patients caused by DPN and herpetic neuropathy were included.  Based on Cochrane's risk of bias criteria, most of the included studies (11/15, 73 %) were rated high risk of bias, whereas 20 % and 7 % were rated some concerns and low risk of bias, respectively.  In terms of the proportion of patients achieving clinical therapeutic efficacy, mecobalamin alone (RR = 1.17; 95 % CI: 1.03 to 1.33) and mecobalamin in combination (RR = 1.32; 95 % CI: 1.21 to 1.45) are more effective than active control.  For NCV outcomes, only mecobalamin combination treatment was effective.  Neither mecobalamin alone nor mecobalamin in combination was effective on the pain score and neuropathic symptom outcomes.  No serious AEs associated with mecobalamin were reported during the treatment periods.  The authors concluded that these findings indicated that mecobalamin in combination may be effective in improving clinical therapeutic efficacy and NCV outcomes for patients with peripheral neuropathy; however, the evidence was unclear for mecobalamin alone.  These researchers stated that more high-quality studies are needed to confirm these findings.

Peripheral Entrapment Neuropathies

Negrao and Nunes (2016) noted that carpal tunnel syndrome is the most common type of peripheral entrapment neuropathy.  On behalf of the Portuguese Group for the Study of Peripheral Neuropathy, these researchers performed an exploratory, open-label, multi-center, observational study of 48 patients with peripheral entrapment neuropathy.  Patients received a daily capsule of uridine monophosphate, folic acid + vitamin B-12 for 2 months and were evaluated using the Pain DETECT questionnaire.  The global score for pain decreased from 17.3 ± 5.9 at baseline to 10.3 ± 6.1 at the final evaluation (p < 0.001).  Concomitant analgesic and anti-inflammatory treatment was stopped or the dose reduced in 77.4 % of patients.  The authors concluded that uridine monophosphate + folic acid + vitamin B-12 reduced total pain score, intensity and characterization of pain and associated symptoms.  They stated that these findings should be tested in a well-designed, adequately powered RCT.

Tinnitus

In a randomized, double-blind, pilot study, Singh and colleagues (2016) examined the role of vitamin B-12 in treatment of chronic tinnitus.  A total 40 patients were enrolled, of which 20 in Group A (cases) received intra-muscular (IM) therapy of 1 ml vitamin B-12 (2,500 mcg) weekly for a period of 6 weeks, and Group B (n = 20) patients received placebo IM isotonic saline (1 m).  The patients were subjected to vitamin B-12 assay and audiometry pre- and post-therapy.  Of the total patients of tinnitus, 17 were vitamin B-12 deficient that is 42.5 % showed deficiency when the normal levels were considered to be 250 pg/ml.  A paired t-test showed that in Group A, patients with vitamin B-12 deficiency showed significant improvement in mean tinnitus severity index score and visual analog scale (VAS) after vitamin B-12 therapy.  The authors concluded that the findings of this pilot study shed light on the relationship of deficient B-12 levels and tinnitus and its supplementation playing a therapeutic role in tinnitus; though more studies with larger groups are needed to corroborate and establish a direct relationship.

Post-Herpetic Neuralgia

Wang and colleagues (2018) stated that post-herpetic neuralgia (PHN) is the most distressful complication of herpes zoster; PHN results in an impaired quality of life (QOL) and higher healthcare utilization.  These researchers carried out a systematic review and a meta-analysis to examine the efficacy of vitamin B12 supplementation in PHN patients.  PubMed, Embase, Cochrane Library, CINAHL, and ClinicalTrials.gov registry were searched; RCTs evaluating the safety and efficacy of vitamin B12 in PHN patients were selected.  Eligible trials were abstracted and assessed for the risk of bias by 2 reviewers, and the results of pain indicators in the selected trials were analyzed.  A total of 4 trials including 383 subjects were published between 2013 and 2016.  Compared with the placebo group, the vitamin B12 group exhibited a significant decrease in the Numeric Rating Scale (NRS) score, with a MD of -4.01 (95 % CI: -4.70 to -3.33).  Vitamin B12 administration improved the QOL of PHN patients with moderate quality evidence and significantly decreased the number of patients using analgesics.  The authors concluded that vitamin B12 appeared to be an attractive complementary therapy for PHN patients.  Moreover, these researchers stated that further investigation is needed before conclusive recommendations could be made.

Furthermore, an UpToDate review on “Postherpetic neuralgia” (Bajwa and Ortega, 2019) does not mention vitamin B-12 injection as a therapeutic option.

Amyotrophic Lateral Sclerosis

In a phase-II/III RCT, Kaji and colleagues (2019) examined the safety and efficacy of IM ultrahigh-dose of methylcobalamin (a form of vitamin B-12) in patients with amyotrophic lateral sclerosis (ALS).  A total of 373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration  of less than or equal to 36 months) were randomly assigned to placebo, 25-mg or 50-mg of methylcobalamin groups.  The primary end-points were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182.  Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered less than or equal to 12 months after symptom onset).  No significant differences were detected in either primary end-point (minimal p = 0.087).  However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (less than or equal to 12 months' duration) showed longer time intervals to the primary event (p < 0.025) and less decreases in the ALSFRS-R score (p < 0.025) than the placebo group.  The incidence of treatment-related adverse events (AEs) was similar and low in all groups.  The authors concluded that although ultra-high-dose methylcobalamin did not demonstrate significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early.

The authors stated that this study had several drawbacks.  First, the strict criteria for study inclusion may have excluded some patients with ALS, which has heterogeneous pathogeneses. Second, although post-hoc analysis identified only 1 subgroup of patients, additional factors may influence the safety and efficacy profile of methylcobalamin.  Third, these researchers did not examine higher doses (greater than 50 mg) for dose finding, and it is possible that these mega-doses might have even better outcome.  These researchers stated that these potential factors may warrant future analyses in other study cohorts such as the Japanese Early-stage Trial of High Dose Methylcobalamin for ALS (JETALS).

Furthermore, UpToDate reviews on “Symptom-based management of amyotrophic lateral sclerosis” (Galvez-Jimenez, 2020) and “Disease-modifying treatment of amyotrophic lateral sclerosis” (Galvez-Jimenez et al, 2020) and do not mention vitamin B-12 injection as a management / therapeutic option.

Hidradenitis Suppurativa

Hendricks and colleagues (2021) noted that hidradenitis suppurativa (HS) is a chronic inflammatory skin condition presenting with painful nodules and sinus tracts primarily in intertriginous regions.  The persistent nature of HS and challenges in symptom management lead many patients to seek non-pharmacologic approaches due to the paucity and limited efficacy of conventional HS therapeutic options.  In a systematic review, these researchers examined the available evidence regarding non-pharmacologic modalities in the treatment of HS.  They discussed non-pharmacologic modalities with evidence of efficacy in HS treatment, including weight loss, vitamin B12, vitamin D and zinc supplementation, as well as dietary avoidance of brewer's yeast.  Limitations of the available data on non-pharmacologic therapies in HS included the predominance of pilot and single-armed studies, heterogeneity in study design, subject disease severity, concomitant treatment as well as co-morbid conditions.  The authors concluded that HS patients are becoming increasingly interested in the use of non-pharmacologic approaches to augment conventional treatments.  Strength of evidence for non-pharmacologic therapies in HS is limited by small study size and lack of RCTs.  These researches stated that future large-scale studies are needed to better establish efficacy and dosing regimens for the use of non-pharmacologic treatments in HS.

Furthermore, an UpToDate review on “Hidradenitis suppurativa: Management” (Ingram, 2021) does not mention vitamin B12 as a management / therapeutic option.

Prophylaxis of Headache Disorders Including Migraines

Liampas and colleagues (2020) noted that there is a possible relationship between migraine and hypercoagulability inducing factors, such as hyperhomocysteinemia.  In this context, homocysteine (Hcy)-lowering vitamins (B6-folate-B12) may prove beneficial in the management/prophylaxis of migraine.  These investigators carried out a systematic literature search to identify studies examining the supplementation of B6, folate and B12 (alone or as adjunctive therapies) to migraine patients, as well as patients suffering from other primary headache disorders.  Medline, Embase, CENTRAL, Google Scholar, trial registries and OpenGrey were searched.  A total of 12 relevant articles were retrieved.  The management of acute migraine attacks with Hcy-lowering vitamins has not provided promising results (1 RCT and 1 prospective uncontrolled trial).  On the contrary, significant benefits were registered for the use of B6 alone, in combination with folate and in combination with folate and B12 in the prophylaxis of migraine with aura (MA) in adults compared to placebo (5 RCTs, only 1 did not obtain significant results).  Folate supplementation alone was not more effective than placebo (1 RCT).  Limited data for the prophylaxis of migraine without aura (MO) in children (2 prospective uncontrolled trials) and adults (2 prospective uncontrolled trials involving both MA and MO subjects) impeded the extraction of safe conclusions.  An overall attractive safety profile was exhibited with gastro-intestinal (GI) AEs being the most common.  The authors concluded that a potential beneficial effect regarding the administration of B6, folate and/or B12 in the prophylaxis of MA in adults was indicated; however, additional high-quality RCTs are needed to examine MO in adults as well as MO and MA in children.

Individuals with MTHFR Mutation

Huemer et al (2017) noted that re-methylation defects are rare inherited disorders in which impaired re-methylation of Hcy to methionine results in accumulation of Hcy and perturbation of numerous methylation reactions.  These investigators summarized clinical and biochemical characteristics of these severe disorders and provided guidelines on diagnosis and management.  A panel of experts carried out review, evaluation and discussion of the medical literature (Medline, Cochrane databases) on these rare diseases following the GRADE approach.  The authors strongly recommended measuring plasma total Hcy in any patient presenting with the combination of neurological and/or visual and/or hematological symptoms, subacute spinal cord degeneration, atypical hemolytic uremic syndrome or unexplained vascular thrombosis.  They strongly recommended commencement of treatment with parenteral hydroxocobalamin without delay in any suspected re-methylation disorder; it significantly improved survival and incidence of severe complications (long-term IV application is impracticable; and the subcutaneous route appeared to be less effective than IM injections).  Moreover, these investigators strongly recommended betaine treatment in individuals with MTHFR deficiency; it improved the outcome and prevented disease when given early.

Furthermore, an UpToDate review on “Overview of homocysteine” (Rosenson et al, 2022) states that “The majority of hyperhomocysteinemia is caused by low levels of folate and vitamin B12 in patients with or without the thermolabile variant of methylene tetrahydrofolate reductase (MTHFR).  Correcting nutritional inadequacy of folic acid and vitamin B12 will lower homocysteine levels in most patients.  A diet rich in fruits, vegetables, and low-fat dairy products and low in saturated and total fat can also lower serum homocysteine when compared with a diet relatively low in fruits, vegetables and dairy products, with a fat content typical of United States consumption”.

Treatment of Vasodilatory Shock

Patel et al (2023) stated that elevated hydrogen sulfide (H2S) contributes to vasodilatation and hypotension in septic shock, and traditional therapies do not target this pathophysiologic mechanism.  High-dose IV hydroxocobalamin scavenges and prevents H2S formation, which may restore vascular tone and may accentuate recovery; however, no experimental human studies have examined the use of high-dose IV hydroxocobalamin in adults with septic shock.  In an allocation-concealed, double-blind, placebo-controlled, parallel-group, single-center, randomized controlled phase-II clinical trial, these researchers compared high-dose IV hydroxocobalamin with placebo in critically ill adults with septic shock.  Patients meeting Sepsis 3 criteria were randomized 1:1 to receive a single 5-g dose of high-dose IV hydroxocobalamin or equivalent volume 0.9 % saline solution as placebo.  The primary outcome was study feasibility (enrollment rate, clinical and laboratory compliance rate, and contamination rate).  Secondary outcomes included between-group differences in plasma H2S concentrations and vasopressor dose before and after infusion.  A total of 20 patients were enrolled over 19 months, establishing an enrollment rate of 1.05 patients per month.  Protocol adherence rates were 100 % with 0 contamination.  In the high-dose IV hydroxocobalamin group, compared to placebo, there was a greater reduction in vasopressor dose between randomization and post-infusion (-36 % versus 4 %, p < 0.001) and randomization and 3-hour post-infusion (-28 % versus 10 %, p = 0.019).  In the high-dose IV hydroxocobalamin group, the plasma H2S level was reduced over 45 mins by -0.80 ± 1.73 μM, as compared with -0.21 ± 0.64 μM in the placebo group (p = 0.3).  The authors concluded that this pilot trial established favorable feasibility metrics.  Consistent with the proposed mechanism of benefit, high-dose IV hydroxocobalamin compared with placebo was associated with reduced vasopressor dose and H2S levels at all time-points and without serious AEs.  These data provided the 1st proof of concept (POC) for feasibility of delivering high-dose IV hydroxocobalamin in septic shock.

The authors stated that this study had several drawbacks.  First, this trial entailed a small cohort from a single center, which limited the ability to detect differences in clinical outcomes and to conduct meaningful subgroup analyses to identify groups of patients with septic shock who may benefit from high-dose IV hydroxocobalamin.  Second, these investigators excluded 1,164 of 1,234 screened patients (receiving norepinephrine) and did not record the cause of shock for the excluded patients.  Third, despite taking measures to conceal the 2 interventions, patients receiving high-dose IV hydroxocobalamin could demonstrate chromaturia, which may be visible to patients and health-care providers.  However, all study team members were quarantined from the bedside to remain masked to the intervention, and vasopressors were titrated to a MAP of greater than 65 mm Hg.  Fourth, these researchers did not examine concomitant cardiac dysfunction, and it was unclear how high-dose IV hydroxocobalamin impacted the subset of patients with septic shock who exhibited cardiac dysfunction compared with those without cardiac dysfunction.  However, as in other micronutrient trials, the authors included patients in septic shock using current (Sepsis 3) criteria, and future trials could establish subgroups based on the presence or absence of cardiac dysfunction.  Fifth, patients receiving high-dose IV hydroxocobalamin received antibiotic 1 hour earlier than the placebo group.  Sixth, these investigators did not randomize patients to different high-dose IV hydroxocobalamin doses or infusion times.  High-dose IV hydroxocobalamin has a half-life of 26 to 31 hours and was dosed at a concentration 100-fold higher than accumulated H2S concentrations measured in plasma.  Lower doses may suffice, but require further study. 

Brokmeier et al (2023) noted that hydroxocobalamin inhibits nitric oxide-mediated vasodilation, and has been employed in settings of refractory shock.  However, its effectiveness and role in the treatment of hypotension remain unclear.  In a systematic review with meta-analysis, these investigators searched Ovid Medline, Embase, EBM Reviews, Scopus, and Web of Science Core Collection for clinical studies reporting on adults who received hydroxocobalamin for vasodilatory shock.  They carried out a meta-analysis with random-effects models comparing the hemodynamic effects of hydroxocobalamin to methylene blue.  The risk of bias in non-randomized studies of interventions tool was used to examine the risk of bias.  A total of 24 studies were identified and comprised mainly of case reports (n = 12), case series (n = 9), and 3 cohort studies.  Hydroxocobalamin was employed mainly for cardiac surgery vasoplegia, but also was reported in the settings of liver transplantation, septic shock, drug-induced hypotension, and non-cardiac post-operative vasoplegia.  In the pooled analysis, hydroxocobalamin was associated with a higher mean arterial pressure (MAP) at 1 hour than methylene blue (mean difference [MD] 7.80, 95 % CI: 2.63 to 12.98).  There were no significant differences in change in MAP (MD -4.57, 95 % CI: -16.05 to 6.91) or vasopressor dosage (MD -0.03, 95 % CI: -0.12 to 0.06) at 1 hour compared to baseline between hydroxocobalamin and methylene blue.  Mortality was also similar (odds ratio [OR] 0.92, 95 % CI: 0.42 to 2.03).  The authors concluded that the evidence supporting the use of hydroxocobalamin for shock was limited to anecdotal reports and a few cohort studies; hydroxocobalamin appeared to positively affect hemodynamics in shock, albeit similar to methylene blue.

In an editorial that accompanied the afore-mentioned study by Brokmeier et al (2023), Kumar et al (2023) stated that the findings of Brokmeier and colleagues were useful in guiding further investigations into hydroxocobalamin but, unfortunately, did not yet answer the lingering questions clinicians have had.  Ultimately, prospective, randomized-controlled, multi-center studies are needed to examine effectiveness, establish treatment protocols, and verify optimal dosing.

Wedemire et al (2024) stated that high-dose vitamin B12 is a potential treatment for patients with vasodilatory shock that is refractory to other therapies.  Vasodilatory shock is characterized by low blood pressure (BP) and low systemic vascular resistance.  Nitric oxide and hydrogen sulfide, 2 potential targets of high-dose vitamin B12 given as hydroxocobalamin, facilitate this syndrome.  In a narrative review, these investigators examined the relationship between high-dose vitamin B12 and hemodynamic outcomes in adults with vasodilatory shock and provided an update on the literature since a 2019 review on this topic.  They carried out a literature search of studies published in the past 5 years in the CINAHL, PubMed, Cochrane, and Embase databases in May 2023.  After evaluating for eligibility, 8 studies met inclusion criteria; 7 of the 8 studies reported decreased vasopressor requirements for part or all of the study samples after receiving a hydroxocobalamin infusion.  However, not all patients responded to hydroxocobalamin.  These findings were limited by patient selection and differences in the timing of vasopressor requirement and BP outcome assessments.  The current evidence is promising as to whether vitamin B12 , given as a hydroxocobalamin infusion, may improve hemodynamic outcomes in vasodilatory shock; however, the evidence was of low-quality.  The authors concluded that the use of hydroxocobalamin for the treatment of refractory, vasodilatory shock remains investigative.  They stated that larger RCTs are needed to examine the role of vitamin B12 in the treatment of refractory, vasodilatory shock, including in conjunction with other alternative therapies such as methylene blue and corticosteroids.

Appendix

Several commercial laboratories use different methods (chemiluminescence or radioassay) for measuring vitamin B12 (Schrier, 2011).  As a result, there are different normal ranges and no "gold standard".  In general, however, serum vitamin B12 levels can be interpreted, as follows:

• greater than 300 pg/ml (greater than 241 pmol/L): Normal result; vitamin B12 deficiency is unlikely (i.e., probability of 1 to 5 %).
• 200 to 300 pg/ml (148 to 241 pmol/L): Borderline result; vitamin B12 deficiency possible.
• less than 200 pg/ml (less than 148 pmol/L): Low; consistent with vitamin B12 deficiency (specificity of 95 to 100 %).

Note: The prescribing information of cyanocobalamin (vitamin B12) states that the drug is for intramuscular (IM) or subcutaneous (SC) use only.  The prescribing information also notes that administration of the drug via the intravenous (IV) route should be avoided since IV use of cyanocobalamin will result in almost all of the vitamin being lost in the urine. 

References