VITAMIN B₁₂ DEFICIENCY

Justin D. Chaltry, DO • Katie L. Westerfield, DO

 BASICS

•  Vitamin deficiency related to inadequate intake or absorption of cobalamin (vitamin B₁₂)

•  Cobalamin is critical for CNS myelination and normal functioning.

•  Deficiency can cause a multitude of symptoms and disorders including megaloblastic anemia, bone marrow dysfunction, and diverse and potentially irreversible neuropsychiatric changes.

•  Neuropsychiatric disorders are due to demyelination of cervical, thoracic dorsal, and lateral spinal cords; demyelination of white matter; and demyelination of cranial and peripheral nerves (1)[C].

•  Low vitamin B₁₂ level can lead to elevated methylmalonic acid (MMA) and homocysteine levels.

•  Elevated MMA causes abnormality in fatty acid synthesis affecting neuronal membrane.

•  Elevated homocysteine is neurotoxic through overstimulation of the N-methyl-D-aspartate (NMDA) receptor and toxic to vasculature through activation of coagulation system and effects on endothelium.

DESCRIPTION

Normal B₁₂ absorption

•  B₁₂ present in animal-source foods (meat, fish, eggs, milk) and foods fortified with B₁₂

•  Dietary vitamin B₁₂ (cobalamin) bound to food is cleaved by acids in stomach and bound to haptocorrin (commonly known as R-factor).

•  Duodenal proteases cleave B₁₂ from haptocorrin.

•  In duodenum, B₁₂ uptake depends on binding to intrinsic factor (IF) secreted by gastric parietal cells.

•  B₁₂-IF complex is absorbed by terminal ileum into portal circulation.

•  Body’s B₁₂ stored in liver = 50–90%

–  B₁₂ secreted into bile from liver recycled via enterohepatic circulation

–  Delay 5 to 10 years from onset of B₁₂ deficiency to clinical symptoms due to hepatic stores and enterohepatic circulation

•  Typical Western diet: 5 to 30 μg/day; however, only 1 to 5 μg/day is effectively absorbed.

–  Recommend 2.4 μg/day for adults and 2.6 μg/day during pregnancy and 2.8 μg/day during lactation (most prenatal vitamins contain B₁₂).

EPIDEMIOLOGY

Prevalence

•  Endemic area: Northern Europe, including Scandinavia; more common in those of African ancestry

•  Increasing recognition in breastfed-only infant populations with vitamin B12–deficient mothers

•  Prevalence 5–20% in developed countries

–  12% in elderly living in community

–  30–40% in elderly in institutions, sick, or malnourished

–  5% patients in tertiary reference hospitals

•  Prevalence by age group

–  20 to 39 years old: prevalence 3%

–  40 to 59 years old: prevalence 4%

–  >70 years old: prevalence 6%

ETIOLOGY AND PATHOPHYSIOLOGY

•  Decreased oral intake

–  Vegetarians and vegans: B₁₂ is found in animal-source foods; however, strict vegetarians uncommonly develop deficiency because only 1 mg/day is needed, with adequate amounts present in legumes.

•  Decreased intrinsic factor (IF)

–  Pernicious anemia (PA): can be associated with autoantibodies directed against gastric parietal cells and/or IF

–  Chronic atrophic gastritis: autoimmune attack on gastric parietal cells causing autoimmune gastritis and leading to decreased IF production

–  Gastrectomy: Removal of entire or part of stomach decreases amount of parietal cells.

•  Decreased ileal absorption

–  Crohn disease: Terminal ileal inflammation decreases body’s ability to absorb B₁₂.

–  Chronic alcoholism: decreases body’s ability to absorb B₁₂

–  Ileal resection

–  Pancreatic insufficiency: Pancreatic proteases are required to cleave the vitamin B₁₂–haptocorrin bond to allow vitamin B₁₂ to bind to intrinsic factor.

–  Helicobacter pylori infection: impairs release of B₁₂ from bound proteins.

•  Medications: proton pump inhibitors (PPIs), H₂ antagonists, and antacids decrease gastric acidity, inhibiting B₁₂ release from dietary protein; metformin

–  Metformin usage

  Chronic metformin usage leads to Vitamin B₁₂ deficiency. Caused by calcium-dependent membrane inhibition, interfering with vitamin B₁₂–intrinsic factor absorption. Years on metformin is the only predictive factor for B₁₂ deficiency.

•  Hereditary (rare)

–  Imerslund-Grasbeck disease (juvenile megaloblastic anemia)

–  Congenital deficiency of transcobalamin

–  Severe methylene tetrahydrofolate reductase deficiency

–  Abnormalities of methionine synthesis

•  Causes:

–  Food-cobalamin malabsorption syndrome

  As many as 60–70% of cases

  Primary cause in elderly

  Pathophysiology: inability to release cobalamin from food or binding protein, especially if in the setting of hypochlorhydria

  Seen in atrophic gastritis, long-term ingestion of antacids and biguanides, possible relationship to H. pylori infection

–  PA

  15–30% of all cases; most frequent cause of severe disease. Neurologic disorders are common presenting complaints.

  Common in elderly, as high as 20%, with mild atrophic gastritis, hypochlorhydria, and impaired release of dietary vitamin B₁₂

  Autoimmune disease with destruction of gastric fundal mucosa cells via a cell-mediated process

  Anti-gastric parietal cell antibodies: sensitivity >90%, specificity 50%; use for screening test

  Anti-intrinsic factor antibodies: sensitivity 50%

  Associated with other autoimmune diseases

–  Insufficient dietary intake: 2% of cases; vegans or long-standing vegetarians

–  Infants born to vitamin B₁₂–deficient mothers may have deficiency or develop it if breastfed exclusively.

–  Intestinal causes:

  1% of cases; prevalence depends on risk factors, such as surgical conditions

  Gastrectomy: due to decreased production of intrinsic factor

  Gastric bypass: appears 1 to 9 years after surgery, prevalence 12–33%

  Ileal resection or disease

  Fish tapeworm

  Severe pancreatic insufficiency

–  Undetermined etiology

  1/10 of cases

Genetics

Imerslund-Grasbeck disease (juvenile megaloblastic anemia) caused by mutations in the amnionless (AMN) or cubilin (CUBN) genes with autosomal recessive pattern of inheritance; inadequate ileal uptake of B₁₂-IF complex and B₁₂ renal protein reabsorption

GENERAL PREVENTION

Risk factors: vegan diet, age >65 years, female, chronic atrophic gastritis, Crohn disease or other ileal disorders, chronic medication use including PPI, metformin, H₂ antagonists

 DIAGNOSIS

Symptoms and physical exam findings:

•  Asymptomatic patients may be diagnosed by the incidental finding of anemia or an elevated mean corpuscular volume (MCV) during routine testing or evaluation of unassociated disorders.

•  Hematologic

–  Frequent: macrocytosis, neutrophil hypersegmentation, spinal cord medullar megaloblastosis (blue spinal cord)

–  Rare: isolated thrombocytopenia and neutropenia, pancytopenia

–  Very rare: hemolytic anemia, thrombotic microangiopathy with schistocytes

•  Neuropsychiatric

–  Frequent: sensory polyneuritis, paresthesias, positive Babinski sign, weakness, gait unsteadiness, loss of proprioception (impaired vibratory sensation, positive Romberg, ataxia, hyperreflexia)

–  Classic but uncommon: subacute combined degeneration of spinal cord associated with PA; myelin degeneration in the lateral and posterior columns; ataxia, proprioception and vibration loss, bowel and bladder incontinence, orthostatic hypotension, decreased memory, mania, delirium, psychosis, depression

•  Digestive

–  Classic: Hunter glossitis, jaundice, and high lactate dehydrogenase and bilirubin

–  Possible: abdominal pain, dyspepsia, nausea, vomiting, diarrhea

–  Rare: mucocutaneous ulcers

•  Other

–  Frequent: pallor, edema, jaundice

–  Under investigation: chronic vaginal and urinary infections, atrophy of vaginal mucosa, hypofertility, venous thromboembolism, angina, miscarriages

–  Commonly insidious and nonspecific; thus, delay in diagnosis is common

HISTORY

•  Underlying disease associated with vitamin B₁₂ deficiency

•  Fatigue, anorexia

•  Depression

•  Falls (due to diminished proprioception)

•  Loss of sensation in “stocking-glove” distribution

•  Glossitis/loss of sense of taste and other subtle, nonspecific neurologic symptoms

DIAGNOSTIC TESTS & INTERPRETATION

•  Measurement of vitamin B₁₂, CBC (MCV)

•  Measurement of B₁₂ may be low or low normal depending on institution’s cutoff value.

–  65–95% sensitivity levels <200 pg/mL

–  May need additional tests such as MMA and homocysteine if vitamin B₁₂ level is low normal (<350 pg/mL) and no evidence of anemia depending on clinical suspicion

•  If high suspicion on normal B₁₂ with high/normal MCV, consider testing MMA and homocysteine levels.

•  MCV often increased

•  Measurement of MMA

–  More sensitive and specific than homocysteine

–  Levels increased in renal failure and volume depletion

•  Measurement of homocysteine

–  Levels increased in folate deficiency, renal failure, and homocystinuria

•  MMA and homocysteine levels only reliable in an untreated patient, as levels fall with supplementation

•  Other tests: folate and other markers of anemia (iron studies)

•  MCV may be normal, decreased, or increased if vitamin B₁₂ deficiency coexists with other forms of anemia, such as iron deficiency or hemolysis. Thus, RBCs may be normochromic, normocytic, or hypochromic microcytic.

ALERT

•  Low levels of vitamin B₁₂ are seen in folate deficiency, HIV, and multiple myeloma.

•  Elevated levels of vitamin B₁₂ are seen in renal disease, occult malignancy, and alcoholic liver disease and as a result of technical error.

•  Macrocytosis may be due to folate deficiency, reticulocytosis, medications, bone marrow dysplasia, and hypothyroidism or be masked by concomitant microcytic anemia.

•  Serum homocysteine and MMA

–  Elevated in B₁₂ deficiency secondary to decreased metabolism

–  If both are normal, B₁₂ deficiency is effectively ruled out.

–  If MMA is normal and homocysteine is increased, think folate deficiency.

•  PA

–  Check antibody to intrinsic factor; positive test is confirmatory for PA, but sensitivity is only 50–70%.

–  Antiparietal cell antibody positivity indicates PA.

–  For patients who are antibody positive, consider screening for autoimmune thyroid disease.

Pregnancy Considerations

•  Because B₁₂ crosses the placenta, pregnant women with low levels of B₁₂ are at higher risk of having children with neural tube defects, congenital heart defects, developmental delay, and failure to thrive.

•  Exclusively breastfed infants of mothers who are B₁₂ deficient are at risk of developing B₁₂ deficiency. Infants breastfed from B₁₂-deficient mothers might not show signs or symptoms until 4 to 6 months of age, which may include developmental regression, feeding difficulties, lethargy, or hypotonia.

Diagnostic Procedures/Other

•  Bone marrow exam is usually unnecessary in the evaluation of B₁₂ deficiency because of the inability to differentiate from folate deficiency.

•  Spinal cord imaging is not standard; MRI in selected cases, especially with severe myelopathy

 TREATMENT

MEDICATION

•  Parenteral cyanocobalamin replacement recommended in patients with severe neurologic symptoms: IM cyanocobalamin (2)[C]

–  1,000 μg/day for 7 days, then

–  1,000 μg weekly for 4 weeks, then

–  1,000 μg monthly for life

•  High-dose, daily oral cyanocobalamin at doses of 1,000 to 2,000 μg are as effective as monthly intramuscular injection and is the preferred route of initial therapy in most circumstances because it is cost-effective and convenient (3)[A]. Requires greater patient compliance. Transnasal and buccal preparations of cyanocobalamin are also available; however, further study is needed.

ALERT

Folic acid without vitamin B₁₂ in patients with PA is contraindicated; it will not correct neurologic abnormalities.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

•  Consider blood transfusion for severe anemia.

•  Draw blood for hematologic parameters before transfusing.

 ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

•  Hematologic

–  Reticulocytosis in 1 week

–  Rise in hemoglobin beginning at 10 days; usually will return to normal in 6 to 8 weeks

–  Monitor potassium in profoundly anemic patients (hypokalemia due to potassium use).

–  Serum MMA decreases with replacement therapy.

•  Neurologic: can note improvement within 3 months of treatment; however, maximum improvement noticed at 6 to 12 months. Some symptoms may be irreversible.

DIET

Meat, animal protein, and legumes unless contraindicated

REFERENCES

1.  Lachner C, Steinle NI, Regenold WT. The neuropsychiatry of vitamin B₁₂ deficiency in elderly patients. J Neuropsychiatry Clin Neurosci. 2012;24(1):5–15.

2.  Stabler SP. Clinical practice. Vitamin B₁₂ deficiency. N Engl J Med. 2013;368(2):149–160.

3.  Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B₁₂ versus intramuscular vitamin B₁₂ for vitamin B₁₂ deficiency. Cochrane Database Syst Rev. 2005;(3):CD004655.

ADDITIONAL READING

•  Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr. 2009;89(2):693S–696S.

•  Aroda VR, Edelstein SL. Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study. J Clin Endocrinol Metab. 2016;101(4):1754–1761.

•  Bizzaro N, Antico A. Diagnosis and classification of pernicious anemia. Autoimmun Rev. 2014;13(4–5):565–568.

•  Fernández-Bañares F, Monzón H, Forné M. A short review of malabsorption and anemia. World J Gastroenterol. 2009;15(37):4644–4652.

•  Langan RC, Zawistoski KJ. Update on vitamin B₁₂ deficiency. Am Fam Physician. 2011;83(12):1425–1430.

•  Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B₁₂ (Cbl) deficiency. Diabetes Res Clin Pract. 2012;97(3):359–367.

•  Oberley MJ, Yang DT. Laboratory testing for cobalamin deficiency in megaloblastic anemia. Am J Hematol. 2013;88(6):522–526.

 CODES

ICD10

•  E53.8 Deficiency of other specified B group vitamins

•  D51.0 Vitamin B12 defic anemia due to intrinsic factor deficiency

•  D51.3 Other dietary vitamin B12 deficiency anemia

CLINICAL PEARLS

•  Consider screening for B₁₂ deficiency in high-risk patients including the elderly and monitoring B₁₂ levels annually if on metformin or on chronic PPIs.

•  Correcting folate deficiency without treating with cyanocobalamin in megaloblastic anemia may correct hematologic but not neurologic disorders.

•  Vitamin B₁₂ deficiency can coexist with other causes of anemia, including iron deficiency or hemolysis; thus, MCV can be normal, decreased, or increased.

•  For patients with PA, cyanocobalamin replacement must be lifelong.

•  Patients with PA are at increased risk for other autoimmune conditions as well as gastric malignancy.