Hospital Medicine

B12 deficiency

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B12 deficiency

I. What every physician needs to know.

Vitamin B12, also known as cobalamin, is a water-soluble vitamin essential to cell production, deoxyribonucleic acid (DNA) synthesis and neurologic function. It is required as a co-enzyme for the metabolism of amino acids methionine, threonine, and valine as well as the formation of tetrahydrofolate which is necessary for DNA synthesis. Common signs and symptoms of vitamin B12 deficiency include neurologic dysfunction such as gait instability, paresthesias, mental status changes, skin changes, diarrhea, pallor, weakness, depression, and fatigue.

Common lab findings include macrocytic, megaloblastic anemia, neutropenia, thrombocytopenia (in more severe cases), and low reticulocyte count, all in the setting of low or low-normal serum vitamin B12 levels and elevated methylmalonic acid (MMA) and homocysteine levels.

Vitamin B12 is obtained exclusively from dietary intake of animal products and absorption is dependent upon an acidic gastric environment, sufficient ileum surface area, a normally functioning pancreas, and intrinsic factor (IF). Vitamin B12 deficiency is most often a result of reduced absorption, not intake, of dietary vitamin B12. This is usually secondary to gastric disease such as atrophic gastritis or pernicious anemia, but can be due to a host of less common absorptive abnormalities.

Dietary deficiency is isolated to strict vegans or malnutrition. Because of extensive hepatic storage of vitamin B12, true deficiency usually takes years to develop.

II. Diagnostic Confirmation: Are you sure your patient has B12 deficiency?

Classic vitamin B12 deficiency consists of megaloblastic, macrocytic anemia with or without neuropsychiatric manifestations. However, patients often do not present with these classic symptoms, but instead present with a variety of more non-specific complaints associated with vitamin B12 deficiency.

Owing to the broad differential diagnoses of the many clinical manifestations of vitamin B12 deficiency, diagnostic confirmation of true vitamin B12 deficiency is based upon the laboratory assessment of serum vitamin B12 levels as well as serum metabolite levels when necessary. Once diagnosis of vitamin B12 deficiency is confirmed, further serologic testing can be used as needed to further clarify the etiology of deficiency.

A. History Part I: Pattern Recognition:

Clinical manifestations of vitamin B12 deficiency can be broken down into neuropsychiatric, hematologic, gastrointestinal (GI), and cutaneous categories. It is a slow process, which takes years to develop and occurs in 4 stages. Stage 1 is decreased levels of vitamin B12 in the blood. Stage 2 is low concentration of vitamin B12 in the cell and metabolic abnormalities. Stage 3 is increased levels of homocysteine and MMA and decreased DNA synthesis resulting in neuropsychiatric symptoms. Stage 4 is macrocytic anemia.

Neuropsychiatric manifestations are mostly due to posterior and lateral column demyelination and include symmetric peripheral neuropathy (legs greater than arms), weakness, gait instability, irritability, depression, and generalized cognitive impairment.

Hematologic manifestations include macrocytic, megaloblastic anemia, which can cause pallor, tachycardia, weakness, fatigue, and palpitations. Bleeding diathesis (thrombocytopenia) and opportunistic infections (neutropenia) can be present in more severe cases.

GI manifestations include glossitis, jaundice and occasionally diarrhea. Cutaneous manifestations include hyperpigmentation and vitiligo.

B. History Part 2: Prevalence:

According to National Health and Nutrition Examination Survey (NHANES) data, 3.2% of United States (US) adults over the age of 50 are vitamin B12 deficient. Closer to 20% of elderly patients have marginal vitamin B12 status. High-risk populations include patients with decreased ileal absorption, decreased IF, inadequate intake, and those taking certain medications known to contribute to vitamin B12 deficiency. Prevalence of B12 deficiency, specifically pernicious anemia, is higher in Latin America than it is in the rest of the world. The majority of patients with clinical vitamin B12 deficiency have IF-related malabsorption.

Examples of decreased ileal absorption include patients with Crohn's disease, ileal resection, bacterial overgrowth, pancreatic insufficiency, and rarely Diphyllobothrium latum infection. Decreased IF can be found in patients with atrophic gastritis, pernicious anemia, and postgastrectomy patients. In a recent meta-analysis, Roux-en-Y gastric bypass surgery doubled the risk of vitamin B12 deficiency from 2.3% at baseline to 6.5% at 12 months’ post-procedure.

Inadequate intake of vitamin B12 is seen in alcoholics, strict vegans and elderly patients in general. Medications known to contribute include proton pump inhibitors, histamine H2 receptor antagonists, metformin and illicit nitrous oxide use. Genetic causes include transcobalamin II deficiency. Helicobacter pylori infection is the leading cause of peptic ulcer disease and superficial atrophic gastritis, which in turn leads to B12 deficiency. As of May 2014, B12 deficiency is included in the consensus statement on H. pylori infection as an extra gastric manifestation.

C. History Part 3: Competing diagnoses that can mimic B12 deficiency.

Patients with folate deficiency can present with anemia and macrocytosis. However, isolated folate deficiency usually does not produce neurologic deficits and is usually associated with normal serum methylmalonic acid (MMA), in contrast to vitamin B12 deficiency where serum MMA is usually elevated.

Other causes of macrocytosis include myelodysplasia or other primary bone marrow disorders (especially with concomitant thrombocytopenia and neutropenia), medications (especially methotrexate, azathioprine, 6-mercaptopurine, and certain high active anti-retroviral therapy (HAART) medications), liver disease, alcohol abuse, reticulocytosis, and hypothyroidism.

Low serum vitamin B12 levels as well as elevated serum MMA help differentiate true vitamin B12 deficiency from these other causes of macrocytosis. Hypersegmented neutrophils can also be seen in renal failure and iron deficiency.

The differential for the neuropsychiatric manifestations of vitamin B12 deficiency is broad, owing to the multitude of etiologies related to non-specific findings such as mental status changes, weakness and fatigue. Lab findings consistent with B12 deficiency should prompt initiation of B12 replacement therapy and re-assessment of symptoms to dictate further work-up.

More specific neurologic findings such as gait ataxia, loss of vibration and position sense and paresthesias, in the absence of serologic evidence of vitamin B12 deficiency, is not consistent with vitamin B12 deficiency and should prompt further work-up for alternative diagnoses including primary central nervous system (CNS) disorders and metabolic disturbances.

D. Physical Examination Findings.

Findings related to anemia include tachycardia and pallor. Neurologic findings include paresthesias, gait abnormalities, decreased vibration sensation, and position sense related to dorsal column involvement, absence of ankle reflexes and extensor plantar responses. Vitiligo and thyroid tenderness related to thyroiditis can be found in patients with pernicious anemia. Mental status assessment and depression screening should be performed on selected patients with neuropsychiatric manifestations.

E. What diagnostic tests should be performed?

Serologic analysis is the mainstay of the diagnosis of vitamin B12 deficiency.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Measurement of serum vitamin B12 levels with or without serum MMA levels can confirm the diagnosis. Serum levels less than 200 pg/ml on two separate occasions or serum levels less than 200 pg/ml with hematological anomalies related to vitamin B12 deficiency are diagnostic of vitamin B12 deficiency. When serum vitamin B12 levels are low to normal (between 200-350pg/mL), an elevated serum MMA level (more than 0.4 micromol/L) is indicative of vitamin B12 deficiency. A vitamin B12 level of more than 350pg/mL indicates that true deficiency is unlikely.

Serum homocysteine levels are elevated in both vitamin B12 and folate deficiencies and while indicative of a nutritional deficiency, are not generally considered useful for diagnosing isolated vitamin B12 deficiency. Serum homocysteine levels can be falsely elevated in levodopa therapy and both homocysteine and MMA can be falsely elevated in renal insufficiency.

A peripheral blood smear can aid in diagnosis if macrocytosis and/or hypersegmented neutrophils are present, even in the absence of anemia. If severe pancytopenia is present, a bone marrow biopsy should be considered to rule out a primary bone marrow process, with results interpreted by a hematopathologist.

Once vitamin B12 deficiency has been confirmed, IF antibody serum tests can help differentiate between pernicious anemia and other etiologies of vitamin B12 deficiencies. A positive IF antibody suggests underlying clinical disease and potentially changes duration of replacement B12 therapy and therefore should always be checked in confirmed cases of vitamin B12 deficiency.

IF antibodies have sensitivity of approximately 60-70% and specificity of more than 95% in patients with pernicious anemia. Parietal cell antibodies are less sensitive and specific and are therefore used less frequently. IF antibody tests have largely taken the place of the Schilling test, which was historically used to diagnose pernicious anemia but is now considered more cumbersome.

Elevated serum gastrin is highly sensitive (more than 90%) for pernicious anemia and can be combined with the highly specific IF antibody test to increase the likelihood of correct diagnosis.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging studies are necessary for diagnosis. However, even in patients with confirmed vitamin B12 deficiency, consider CNS imaging in patients with neuropsychiatric deficits not explained by vitamin B12 deficiency to rule out concomitant CNS pathology.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Serum homocysteine levels are elevated in both vitamin B12 and folate deficiencies. Therefore, while elevated homocysteine levels are indicative of underlying nutritional deficiencies, it is not specific for vitamin B12 deficiency and therefore is less useful than MMA for diagnosing isolated vitamin B12 deficiency.

III. Default Management.

Vitamin B12 supplementation should be initiated upon diagnosis, with the remainder of management based upon specific hematologic and/or neuropsychiatric abnormalities. If medications are thought to contribute to the deficiency, they should be discontinued as allowed.

A. Immediate management.

Vitamin B12 supplementation should begin upon admission. Traditionally a non-per os (non-PO) route has been used, consisting of 1000mcg subcutaneous/intramuscular (SC/IM) daily for 1 week, followed by weekly for 1 month, followed by monthly administration indefinitely.

More recent evidence has indicated that per os (PO) routes of administration are acceptable, usually consisting of 1000mcg PO daily indefinitely. Sublingual and nasal routes of administration are available; these are more expensive and less extensively studied. Folic acid replacement is usually initiated at the same time as B12 deficiency. Folic acid, without B12, can worsen neurological symptoms of B12 deficiency so should never be started on its own without having ruled out B12 deficiency. Evidence points away from routine screening of folic acid levels as they do not appear to guide therapy in hospitalized patients. However, caution is advised against empiric folic acid therapy using large doses due to the link with certain malignancies.

Since anemia associated with vitamin B12 deficiency occurs over the course of months and therefore allows time for compensation in oxygen delivery, transfusion of packed red blood cells should be based upon clinical criteria and not absolute hemoglobin value alone.

B. Physical Examination Tips to Guide Management.

Tachycardia attributed to anemia should be monitored for resolution.

Neurologic manifestations can take months to improve and therefore neurologic exam should not be used to guide inpatient management.

This is with the notable exception that patients with undiagnosed vitamin B12 deficiency masked by folate deficiency can experience a worsening of neurologic symptoms after initiation of folate supplementation in the absence of vitamin B12 supplementation. Formal cognitive testing should be considered in patients with significant neuropsychiatric manifestations.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Documentation of normalization of initially elevated serum iron, lactate dehydrogenase (LDH) and indirect bilirubin are consistent with an appropriate hematologic response to vitamin B12 supplementation in patients with anemia. Reticulocyte count should begin to increase 3-4 days after initiation of B12 supplementation and should peak at around 7 days. MMA should return to normal limits within 7 days of initiation of treatment.

None of these test results should alter the dose of vitamin B12 replacement, but lack of expected resolution of lab abnormalities should trigger a search for an alternate diagnosis.

D. Long-term management.

Vitamin B12 supplementation should be continued indefinitely unless a reversible cause of vitamin B12 deficiency is identified (i.e. medications, infection, reversible malabsorption, diet, etc.). A diet rich in meat, milk, cheese and eggs is also recommended.

E. Common Pitfalls and Side-Effects of Management

Always check for vitamin B12 deficiency prior to initiating replacement therapy for confirmed folate deficiency. Failure to diagnose concomitant vitamin B12 deficiency prior to initiation of folic acid can cause worsening of neurologic symptoms secondary to vitamin B12 deficiency.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

In cases involving severe anemia and/or thrombocytopenia requiring transfusion of blood products, careful monitoring of volume status is required.

D. Coronary Artery Disease or Peripheral Vascular Disease

Consider a lower transfusion threshold for those patients with severe anemia and active coronary artery disease.

E. Diabetes or other Endocrine issues

Metformin should be discontinued if possible as it is associated with vitamin B12 deficiency. If metformin cannot be discontinued, calcium supplementation should be initiated as this can decrease metformin's inhibition of vitamin B12 absorption in the GI tract.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

Proton pump inhibitors (PPIs) should be discontinued if possible as they are associated with decreased GI absorption of dietary vitamin B12.

J. Hematologic or Coagulation Issues

Transfusion as per routine guidelines for severe anemia and thrombocytopenia.

K. Dementia or Psychiatric Illness/Treatment

Consider IM supplementation of vitamin B12 for greater medication compliance.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

None

B. Anticipated Length of Stay.

Variable, dependent upon severity of hematologic and neuropsychiatric manifestations.

C. When is the Patient Ready for Discharge.

For patients with severe cytopenias, stabilization of blood counts within non-transfusion range as well as documented hematologic and metabolic response to supplementation should be confirmed prior to discharge.

Neurologic symptoms can take months to improve, as the rate of improvement is inversely correlated to the extent and duration of the deficiency. Therefore this should not hold up discharge once appropriate placement has been obtained based upon functional assessment of neuropsychiatric status.

D. Arranging for Clinic Follow-up

Clinic follow-up should be focused on assessment of correction of hematologic abnormalities and any associated electrolyte abnormalities, replacement therapy adherence and adequacy of interventions addressing neuropsychiatric functional limitations.

1. When should clinic follow up be arranged and with whom.

For those patients with significant anemia, follow-up with primary care should occur within 7-10 days to ensure normalization of serum MMA, improvement in hematocrit and increase in reticulocytosis. Lack of these findings within 7-10 days should prompt further work-up for alternative diagnoses.

Primary care follow-up should also include routine colorectal malignancy screening, as limited evidence indicates an association between pernicious anemia and gastric and colorectal malignancies. Hematocrit can take up to 8 weeks to completely normalize and neurologic symptoms can take months to improve and therefore these should not dictate time to first follow-up appointment.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

For patients presenting with anemia, thrombocytopenia or neutropenia, consider a repeat complete blood count (CBC), reticulocyte count and MMA 7-10 days after hospital discharge.

E. Placement Considerations.

Consider physical therapy, occupational therapy, social work, and/or psychiatry assessment for any patient presenting with neuropsychiatric manifestations, especially those demonstrating gait instability or cognitive dysfunction.

F. Prognosis and Patient Counseling.

Neuropsychiatric symptoms can take weeks to months to improve, and sometimes do not completely normalize. Residual disability occurs in about 6% of patients with neurologic dysfunction and is more likely to persist if still present after 6 months to 1 year.

Hematologic abnormalities isolated to vitamin B12 deficiency should correct back to normal within approximately 8 weeks. Vegans again have to be extensively counseled on the importance of full compliance with replacement therapy and/or fortified foods. No conclusive evidence exists linking vitamin B12 deficiency directly to dementia or cardiovascular disease.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

No Joint Commission measures exist for vitamin B12 deficiency admissions.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Consider fall precautions for patients exhibiting gait instability.

If dietary vitamin B12 is utilized for treatment, patients should be encouraged to eat foods fortified with vitamin B12, as the crystalline formulations of fortified vitamin B12 are better absorbed than natural vitamin B12. Vegetarians in particular should be educated on the importance of fortified foods.

VII. What's the evidence?

Pruthi, RK, Tefferi, A. "Pernicious anemia revisited". Mayo Clin Proc. vol. 69. 1994. pp. 144-50.

Kuzminski, AM, Del Giacco, EJ, Allen, RH, Stabler, SP, Lindenbaum, J. "Effective treatment of cobalamin deficiency with oral cobalamin". Blood. vol. 92. 1998. pp. 1191-8.

Kaptan, K, Beyan, C, Ural, AU. "Helicobacter pylori--is it a novel causative agent in Vitamin B12 deficiency". Arch Intern Med. vol. 160. 2000. pp. 1349-53.

de Jager, J, Kooy, A, Lehert, P. "Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial". BMJ. vol. 340. pp. c2181-2010.

Carmel, R, Green, R, Rosenblatt, DS, Watkins, D. "Update on cobalamin, folate, and homocysteine". Hematology Am Soc Hematol Educ Program. 2003. pp. 62-81.

Carmel, R. "How I treat cobalamin (vitamin B12) deficiency". Blood. vol. 112. 2008. pp. 2214-21.

Allen, LH. "How common is vitamin B-12 deficiency". Am J Clin Nutr. vol. 89. 2009. pp. 693S-6S.

Bolaman, Z, Kadikoylu, G, Yukselen, V, Yavasoglu, I, Barutca, S, Senturk, T. "Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study". Clin Ther. vol. 25. 2003. pp. 3124-34.

Butler, CC, Vidal-Alaball, J, Cannings-John, R. "Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials". Fam Pract. vol. 23. 2006. pp. 279-85.

Campuzano-Maya, G. "Hematologic manifestations of Helicobacter pylori infection". World J Gastroenterol. vol. 20. Sep 28. pp. 12818-38.

Araújo, DA, Noronha, MB, Cunha, NA, Abrunhosa, SF. "Low serum levels of vitamin B12 in older adults with normal nutritional status by mini nutritional assessment". Eur J Clin Nutr. 2016 Mar 23.

Weng, TC, Chang, CH, Dong, YH, Chang, YC, Chuang, LM. "Anaemia and related nutrient deficiencies after Roux-en-Y gastric bypass surgery: a systematic review and meta-analysis". BMJ Open. vol. 5. 2015 Jul 16. pp. e006964.

Brito, A, Mujica-Coopman, MF, López de Romaña, D, Cori, H, Allen, LH. "Folate and Vitamin B12 Status in Latin America and the Caribbean: An Update". Food Nutr Bull. vol. 36. 2015 Jun. pp. S109-18.

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